article dict | reports listlengths 1 3.97k |
|---|---|
{
"abstract": "OBJECTIVE\nReport a case of concurrent unilateral optic neuritis and central retinal artery occlusion as the presenting signs of syphilis.\n\n\nMETHODS\nA case report of a 22-year-old man with progressive unilateral vision loss.\n\n\nRESULTS\nWith no known previous history of syphilis, genital lesions, or other extraocular manifestations, the patient presented with pain with eye movements and decreased color vision. His vision dramatically worsened after a course of oral steroids. Examination was remarkable for severe right optic disk edema with a macular cherry-red spot and mild posterior uveitis. Magnetic resonance imaging of the orbits with contrast revealed enhancement and enlargement of the distal right optic nerve. Fluorescein angiography demonstrated delayed filling of the right central retinal artery, suggestive of impending central retinal artery occlusion. Syphilis serologies were positive from the serum, and cerebrospinal fluid Venereal Disease Research Laboratory test was reactive, consistent with neurosyphilis. Oral steroids were discontinued and vision improved with 2 weeks of intravenous penicillin.\n\n\nCONCLUSIONS\nThis unusual case highlights one of the possible initial presentations of syphilis: unilateral optic neuritis and central retinal artery vasculitis with mild posterior uveitis. The worsening of vision after administration of oral steroids also highlights a potential complication of oral steroid use in the absence of a known etiology of vision loss. A thorough history and examination may be helpful in identifying risk factors for infectious causes, including syphilis, and should prompt additional evaluation.",
"affiliations": "Department of Neurology, Indiana University, Indianapolis, Indiana.;Department of Neurology, Indiana University, Indianapolis, Indiana.;Indiana University School of Medicine, Indianapolis, Indiana; and.;Departments of Neurosurgery, and.;Department of Neurology, Indiana University, Indianapolis, Indiana.",
"authors": "Khan|Murtaza S|MS|;Kuruppu|Dulanji K|DK|;Popli|Tanav A|TA|;Moorthy|Ramana S|RS|;Mackay|Devin D|DD|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1097/ICB.0000000000000614",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1935-1089",
"issue": "14(1)",
"journal": "Retinal cases & brief reports",
"keywords": null,
"medline_ta": "Retin Cases Brief Rep",
"mesh_terms": "D003937:Diagnosis, Differential; D038524:Diffusion Magnetic Resonance Imaging; D015818:Eye Infections, Bacterial; D005451:Fluorescein Angiography; D005654:Fundus Oculi; D006801:Humans; D008297:Male; D009900:Optic Nerve; D009902:Optic Neuritis; D012160:Retina; D031300:Retinal Vasculitis; D013587:Syphilis; D055815:Young Adult",
"nlm_unique_id": "101298744",
"other_id": null,
"pages": "35-38",
"pmc": null,
"pmid": "28816862",
"pubdate": "2020",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "UNILATERAL OPTIC NEURITIS AND CENTRAL RETINAL VASCULITIS DUE TO OCULAR SYPHILIS.",
"title_normalized": "unilateral optic neuritis and central retinal vasculitis due to ocular syphilis"
} | [
{
"companynumb": "US-TEVA-2020-US-1218212",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drugadditional": "1",
... |
{
"abstract": "Takayasu arteritis is a rare, chronic vasculitis of unknown etiology characterized by inflammation of the aorta and its main branches. Although Takayasu arteritis mostly affects women of childbearing age, there is a paucity in the literature on pregnancy associated with Takayasu arteritis. Pregnant patients are at increased risk of cardiovascular complications, including hypertension and congestive heart failure, which may jeopardize both maternal and fetal outcomes. Furthermore, optimal management has not yet been established for pregnant patients with Takayasu arteritis, posing a clinical challenge. We present a case of a young woman with Takayasu arteritis whose symptoms and disease activity improved during 2 pregnancies. Although her first pregnancy was complicated with preeclampsia, gestational diabetes, and preterm vaginal delivery, her second pregnancy was uneventful. This case provides a rare glimpse of Takayasu arteritis in pregnancy and highlights the challenges of medical management in gravid patients.",
"affiliations": "1 Minneapolis Heart Institute Research Foundation, Minneapolis, MN, USA.;1 Minneapolis Heart Institute Research Foundation, Minneapolis, MN, USA.;1 Minneapolis Heart Institute Research Foundation, Minneapolis, MN, USA.;2 Vascular Medicine, Minneapolis Heart Institute, Minneapolis, MN, USA.",
"authors": "Soo-Hoo|Sarah|S|;Seong|Jenny|J|;Porten|Brandon R|BR|;Skeik|Nedaa|N|",
"chemical_list": "D007166:Immunosuppressive Agents",
"country": "United States",
"delete": false,
"doi": "10.1177/1538574417698904",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1538-5744",
"issue": "51(4)",
"journal": "Vascular and endovascular surgery",
"keywords": "Takayasu arteritis; case study; pregnancy; vasculitis",
"medline_ta": "Vasc Endovascular Surg",
"mesh_terms": "D000328:Adult; D016640:Diabetes, Gestational; D018450:Disease Progression; D057915:Drug Substitution; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents; D018810:Magnetic Resonance Angiography; D011225:Pre-Eclampsia; D011247:Pregnancy; D011249:Pregnancy Complications, Cardiovascular; D047928:Premature Birth; D012074:Remission Induction; D013625:Takayasu Arteritis; D013997:Time Factors; D016896:Treatment Outcome",
"nlm_unique_id": "101136421",
"other_id": null,
"pages": "195-198",
"pmc": null,
"pmid": "28424040",
"pubdate": "2017-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Challenges of Takayasu Arteritis in Pregnancy: A Case Report.",
"title_normalized": "challenges of takayasu arteritis in pregnancy a case report"
} | [
{
"companynumb": "US-AMGEN-USASP2019079031",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "3",
"activesubstance": {
"activesubstancename": "ETANERCEPT"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nConflicting challenges abound in the management of the newborn with intractable epilepsy related to hemimegalencephaly. Early hemispherectomy to stop seizures and prevent deleterious consequences to future neurocognitive development must be weighed against the technical and anesthetic challenges of performing major hemispheric surgery in the neonate.\n\n\nMETHODS\nWe hereby present our experience with two neonates with hemimegalencephaly and intractable seizures who were managed using a strategy of initial minimally invasive embolization of the cerebral blood supply to the involved hemisphere.\n\n\nRESULTS\nImmediate significant seizure control was achieved after embolization of the cerebral blood supply to the involved hemisphere followed by delayed ipsilateral hemispheric resection at a later optimal age.\n\n\nCONCLUSIONS\nThe considerations and challenges encountered in the course of the management of these patients are discussed, and a literature review is presented.",
"affiliations": "Department of Neurosurgery, Children's National Health System, 111 Michigan Avenue NW, Washington, DC, USA. coluigbo@cnmc.org.;Department of Radiology, Children's National Health System, Washington, DC, USA.;Department of Neurology, Children's National Health System, Washington, DC, USA.;Department of Neurology, Children's National Health System, Washington, DC, USA.;Department of Neuropathology, Children's National Health System, Washington, DC, USA.;Department of Neurology, Children's National Health System, Washington, DC, USA.",
"authors": "Oluigbo|Chima|C|http://orcid.org/0000-0002-7851-3792;Pearl|Monica S|MS|;Tsuchida|Tammy N|TN|;Chang|Taeun|T|;Ho|Cheng-Ying|CY|;Gaillard|William D|WD|",
"chemical_list": null,
"country": "Germany",
"delete": false,
"doi": "10.1007/s00381-016-3289-6",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0256-7040",
"issue": "33(3)",
"journal": "Child's nervous system : ChNS : official journal of the International Society for Pediatric Neurosurgery",
"keywords": "Cerebral hemispheric infarction; Endovascular embolization; Epilepsy; Hemimegalencephaly; Neonates",
"medline_ta": "Childs Nerv Syst",
"mesh_terms": "D019468:Disease Management; D004569:Electroencephalography; D004827:Epilepsy; D005260:Female; D007839:Functional Laterality; D038421:Hemispherectomy; D006801:Humans; D007231:Infant, Newborn; D008279:Magnetic Resonance Imaging; D008297:Male",
"nlm_unique_id": "8503227",
"other_id": null,
"pages": "521-527",
"pmc": null,
"pmid": "27796549",
"pubdate": "2017-03",
"publication_types": "D016428:Journal Article",
"references": "20132288;16146448;11124637;16821075;8847583;14758940;27012547;26099232;7617183;4811318;23933627;7639130",
"title": "\"Endovascular embolic hemispherectomy\": a strategy for the initial management of catastrophic holohemispheric epilepsy in the neonate.",
"title_normalized": "endovascular embolic hemispherectomy a strategy for the initial management of catastrophic holohemispheric epilepsy in the neonate"
} | [
{
"companynumb": "US-UCBSA-2017019261",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FOSPHENYTOIN"
},
"drugadditional": "3",
"... |
{
"abstract": "BACKGROUND\nLinezolid is a synthetic antibiotic which is active against most Gram-positive bacteria, especially on Staphylococcus aureus. Its administration can be required when the infection is due to staphylococcus strains, which are resistant to vancomycin. Although mostly well tolerated, some mild to moderate side effects have been reported.\n\n\nMETHODS\nThis case report describes an infant with multiloculated hydrocephalus, staphylococcal meningitis and prolonged linezolid therapy, in which we observed the association between linezolid administration and a lengthened QTc interval at the electrocardiogram (ECG). To rule out toxic levels during the therapy, plasma and cerebro-spinal fluid concentrations of linezolid were measured and reported.\n\n\nCONCLUSIONS\nAlthough generally well tolerated in neonates and infants, linezolid prolonged administration seems be able to cause QTc interval prolongation. Therefore, its administration in such patients should be limited to cases of bacterial resistance to other antibiotics. In addition to well-known close monitoring of the platelet level, we suggest serial ECG controls before and during linezolid administration. In the case we report, linezolid plasma concentrations resulted within the therapeutic range during therapy, while cerebrospinal fluid (CSF) concentrations appeared lower than those considered effective.",
"affiliations": "Department of Neonatology, Neonatal Intensive Care Unit, Bambino Gesù Children's Hospital, IRCCS, Piazza S. Onofrio 4, 00165, Rome, Italy. cinzia.auriti@opbg.net.;Department of Neonatology, Neonatal Intensive Care Unit, Bambino Gesù Children's Hospital, IRCCS, Piazza S. Onofrio 4, 00165, Rome, Italy.;Department of Neonatology, Neonatal Intensive Care Unit, Bambino Gesù Children's Hospital, IRCCS, Piazza S. Onofrio 4, 00165, Rome, Italy.;Department of Pediatric Medicine, Laboratory of Metabolic Biochemistry Unit, Bambino Gesù Children's Hospital, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.;Department of Neurosciences, Neurosurgery Unit, Bambino Gesù Children's Hospital, Rome, Italy.;Department of Imaging, Bambino Gesù Childrens' Hospital, IRCCS, Rome, Italy.;Department of Pediatric Medicine, Laboratory of Metabolic Biochemistry Unit, Bambino Gesù Children's Hospital, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.",
"authors": "Auriti|Cinzia|C|http://orcid.org/0000-0001-9820-6557;Piersigilli|Fiammetta|F|;Bersani|Iliana|I|;Cairoli|Sara|S|;Amante|Paolina Giuseppina|PG|;Longo|Daniela|D|;Goffredo|Bianca Maria|BM|",
"chemical_list": "D000900:Anti-Bacterial Agents; D000069349:Linezolid",
"country": "England",
"delete": false,
"doi": "10.1186/s13052-020-00854-z",
"fulltext": "\n==== Front\nItal J Pediatr\nItal J Pediatr\nItalian Journal of Pediatrics\n1824-7288 BioMed Central London \n\n854\n10.1186/s13052-020-00854-z\nCase Report\nStaphylococcal meningitis therapy with linezolid in a young infant: efficacy, CSF levels and side effects\nhttp://orcid.org/0000-0001-9820-6557Auriti Cinzia cinzia.auriti@opbg.net 1 Piersigilli Fiammetta 1 Bersani Iliana 1 Cairoli Sara 2 Amante Paolina Giuseppina 3 Longo Daniela 4 Goffredo Bianca Maria 2 1 grid.414125.70000 0001 0727 6809Department of Neonatology, Neonatal Intensive Care Unit, Bambino Gesù Children’s Hospital, IRCCS, Piazza S. Onofrio 4, 00165 Rome, Italy \n2 grid.414125.70000 0001 0727 6809Department of Pediatric Medicine, Laboratory of Metabolic Biochemistry Unit, Bambino Gesù Children’s Hospital, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy \n3 grid.414125.70000 0001 0727 6809Department of Neurosciences, Neurosurgery Unit, Bambino Gesù Children’s Hospital, Rome, Italy \n4 grid.414603.4Department of Imaging, Bambino Gesù Childrens’ Hospital, IRCCS, Rome, Italy \n29 6 2020 \n29 6 2020 \n2020 \n46 9014 3 2020 22 6 2020 © The Author(s) 2020Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.Background\nLinezolid is a synthetic antibiotic which is active against most Gram-positive bacteria, especially on Staphylococcus aureus. Its administration can be required when the infection is due to staphylococcus strains, which are resistant to vancomycin. Although mostly well tolerated, some mild to moderate side effects have been reported.\n\nCase presentation\nThis case report describes an infant with multiloculated hydrocephalus, staphylococcal meningitis and prolonged linezolid therapy, in which we observed the association between linezolid administration and a lengthened QTc interval at the electrocardiogram (ECG). To rule out toxic levels during the therapy, plasma and cerebro-spinal fluid concentrations of linezolid were measured and reported.\n\nConclusions\nAlthough generally well tolerated in neonates and infants, linezolid prolonged administration seems be able to cause QTc interval prolongation. Therefore, its administration in such patients should be limited to cases of bacterial resistance to other antibiotics. In addition to well-known close monitoring of the platelet level, we suggest serial ECG controls before and during linezolid administration. In the case we report, linezolid plasma concentrations resulted within the therapeutic range during therapy, while cerebrospinal fluid (CSF) concentrations appeared lower than those considered effective.\n\nKeywords\nLinezolidStaphylococcal meningitisQTc intervalNeonateSide effectissue-copyright-statement© The Author(s) 2020\n==== Body\nBackground\nLinezolid belongs to a new generation group of synthetic antibiotics, the oxazolidinones, which is active against gram-positive microorganisms, including methicillin-resistant staphylococci, staphylococci with low susceptibility to vancomycin, some gram-negative anaerobic species, and some mycobacterial species (Mycobacterium tuberculosis and Mycobacterium avium complex). Linezolid binds to the 23S site of the 50S ribosomal sub-unit, blocks the formation of the 70S ribosomal complex thereby inhibiting protein synthesis. Cross-resistance with other antibiotics seems to be only exceptional. Linezolid has excellent tissue penetration and oral and intravenous administration provide almost equivalent drug availability.\n\nLinezolid administration is currently used in adults when the infection is due to staphylococcus strains resistant to vancomycin, as the drug has been approved by the Food and Drug Administration since 2002. Contrarywise, the clinical experience with linezolid in the pediatric population is still limited [1–4]. There are age-related characteristics in the pharmacokinetic parameters of linezolid. Its half-life in adults and older children is about 4–6 h, suggesting that it can be administered twice a day. Children younger than 12 years have a smaller Area Under the Curve (AUC), a faster clearance and a shorter elimination half-life than adults. Neonates have clearance values that increase markedly during the first week of life, to values 2- to 3-fold in excess of those observed in older children and adults [5–7]. Therefore, a shorter dosing interval is required for neonates to achieve a linezolid exposure similar to that observed in adults receiving 600 mg twice daily and to reach a rate of pathogen eradication similar to that of vancomycin. It has been therefore proposed that children younger than 12 years should receive linezolid 10 mg/kg or more every 8 h [6, 7] only to treat infections due to bacteria resistant to other, best studied drugs.\n\nAlthough mostly well tolerated, some mild to moderate side effects have however been reported.\n\nIn infants and children adverse events, including abnormal kidney function and oral/skin candidiasis, were less frequent with linezolid administration than with vancomycin, although reversible thrombocytopenia after 2 weeks of therapy occurred more frequently with linezolid than the other antibiotic [8].\n\nIn adults it has been suggested that bradycardia could represent a further side effect of linezolid, but this has not been confirmed by numerically adequate studies [9].\n\nThis case report describes an infant with staphylococcal meningitis and multi-loculated hydrocephalus, requiring a prolonged linezolid therapy, in which we observed the association between linezolid administration and a lengthened QTc interval at the 12 lead ECG.\n\nPlasma and cerebrospinal fluid levels of linezolid were monitored, to rule out toxic levels of the drug.\n\nCase presentation\nA 1.600 g male neonate was delivered by urgent cesarean section at 30 weeks’ gestation. On the third day of life (DOL) he developed a bilateral, grade II-III intraventricular hemorrhage (IVH) associated with enlargement of the lateral, III, and IV ventricles. On the 20th DOL the neonate was referred to our Neonatal Intensive Care Unit to undergo neurosurgery due to a progressive worsening hydrocephalus. He immediately underwent external ventricular drain (EVD), and at 1 month of life a ventriculoperitoneal shunt (VPS) was placed. The VPS was replaced subsequently for several times. It had to be externalized again for the onset of Escherichia coli meningitis, requiring 3 weeks of intravenous meropemen and amikacin therapy. The repeated meningeal infections led to a multiloculated hydrocephalus, requiring the diversion of cerebrospinal fluid (CSF) through neuro-endoscopic intra-cystic septostomy and the implantation of three Rickham reservoir devices, in the frontal sites and one in posterior cranial fossa that flowed into the peritoneum.\n\nAt 8 months of life the infant developed meningitis caused by a Staphylococcus epidermidis strain susceptible to vancomycin (MIC 2 μg/ml), to linezolid (MIC 1 μg/ml) and resistant to teicoplanin (MIC 16 μg/ml). Vancomycin therapy (15 mg/Kg, four times in a day) was immediately started but, due to poor response (CSF cultures were persistently positive), after 20 days, intravenous linezolid was added at the dosage of 10 mg/Kg three times in a day, administered in 1 h [5–7, 9]. All the 12 lead ECGs performed up to this time point and during the first days after the start of linezolid had always shown sinus rhythm with QTc interval within the normal range (340 milliseconds) (Fig. 1a and b). About 20 days later a lengthened QTc interval (430 milliseconds) was detected on the ECG (Fig. 1c and d) and confirmed by the examinations carried out in the following days. Suspecting a linezolid-related side effect and because the persistent presence of Staphylococcus epidermidis in the CSF cultures, after 24 days of therapy, linezolid was replaced by intravenous rifampicin (20 mg/kg/die) in association with intrathecal vancomycin, with resolution of the meningitis. With the discontinuation of linezolid, QTc interval values returned to the normal range (350–390 milliseconds).\nFig. 1 shows the patient’s electrocardiograms before therapy (a), at the beginning of linezolid administration (b), the progressive prolongation of the QTc tract during (c) and at the end of therapy (d)\n\n\n\nTo assess the patient’s proper linezolid exposure and rule out toxic levels, we measured plasma and CSF drug concentrations throughout therapy, by a High-Performance Liquid Chromatography (HPLC). The target to achieve a therapeutic effect was a concentration higher than MIC 90 of the bacteria considered sensitive (2–4 μg/ml; range of C max described for age: 6.8–36.7 μg/ml) [6, 7]. Linezolid plasma levels resulted within the therapeutic range, while in CSF drug levels appeared to be lower than those considered effective. CSF/plasma concentration ratios were low (Table 1) [5, 6, 10].\nTable 1 Plasma and CSF levels of linezolid at different time points\n\nLinezolid concentration (μg/ml)a\t\nTime points\tPlasma\tCSF\tCSF/Plasma ratiob\t\n1 h before the infusion\t7.93\t5.57\t0.70\t\n1 h after\t48.44\t4.91\t0.10\t\n6 h after\t11.25\t4.88\t0.43\t\naEffective range in infants: Cmax 6.8–36.7 μg/ml (ref. [6])\n\nbCSF/Plasma ratio describing a good penetration into CSF: 0.7–0.8+/− 0.3 (ref. [9])\n\n\n\nThe neonate was discharged at 1 year of life with severe neurological impairment, under anticonvulsive therapy. Currently he is following our follow up program, receiving periodical pediatric, neurosurgical and cardiologic visits. He did not show any cardiac side effects attributable to linezolid therapy.\n\nDiscussion and conclusions\nDiscussion\nLinezolid is a weak reversible monoamine oxidase inhibitor and has the potential to interact with adrenergic and serotoninergic agents. When administered with concomitant sympathomimetic agents it can cause an increase in blood pressure and induce heart palpitations. This is the reason why in 2009, the US Food and Drug Administration Agency approved an updated safety labeling for linezolid, pointing out the risks of the simultaneous administration of monoamine oxidase inhibitors, serotonergic agents, and drugs that might increase blood pressure [11].\n\nMost common side effects of Linezolid include gastrointestinal disorders, headache, rash, liver dysfunction, optic and peripheral neuropathy, thrombocytopenia, anemia, neutropenia, lactic acidosis. Those side effects usually occur after prolonged administration and disappear after linezolid discontinuation [3, 4]. To our knowledge, this is the first report describing an association between linezolid administration and a transitory ECG QTc interval prolongation in a preterm born infant. Tartarone described bradycardia in an adult patient after 48 h of therapy with linezolid, but QTc was normal [9] A single study performed in adult patients assessed the potential link between linezolid and QTc prolongation, without finding apparent relationships [12]. Rubinstein performed a Phase III study and found that QTc intervals measured before and after the administration of linezolid vs placebo were similar [13, 14]. However, there are currently no available data investigating the potential development of arrhythmias or cardiac complication among neonates or infants treated with linezolid.\n\nIn our patient, the lengthened QTc interval appeared after a prolonged administration of linezolid and disappeared after drug discontinuation. This side effect was reported as adverse event to the Italian Agency for Drug Monitoring (AIFA).\n\nFurthermore, in our patient the prolonged treatment with linezolid did not resolve the meningitis from Staphylococcus epidermidis. Although plasma levels of the drug were in the range of effectiveness, ratios between CSF and plasma concentrations were lower than the optimal value. Our patient had a multiloculated hydrocephalus and it is easy to hypothesize that the CSF circulation could be compromised by the particular anatomical feature, hindering the uniform linezolid distribution into the liquor cysts. Linezolid CSF levels assessed at different time points from the administration seem to confirm this altered drug distribution (Table 1).\n\nConclusions\nAccording to our experience, although generally well tolerated, linezolid prolonged administration seems able to cause a prolongation of the QTc interval in neonates and infants. Therefore, its administration in such patients should be limited to cases of bacterial resistance to other antibiotics. Moreover, in addition to the already known necessity for close monitoring of the platelet level, during linezolid administration we suggest serial ECG controls, before and during the therapy, in particular if the administration lasts more than 2 weeks.\n\nIn our patient therapy with linezolid did not resolve the meningitis from Staphylococcus epidermidis. Although plasma levels of the drug were in the correct range, ratios between CSF and plasma concentrations were lower than the optimal value. Well-designed studies on linezolid administration to neonates and infants are required to confirm our findings.\n\nAbbreviations\nAIFAItalian Agency for Drug Monitoring\n\nAUCArea under the curve\n\nCSFCerebro spinal fluid\n\nDOLDay of life\n\nECGElectrocardiogram\n\nEVDExternal ventricular drain\n\nHPLCHigh-performance liquid chromatography\n\nIVHIntraventricular hemorrhage\n\nMICMinimal inhibitory concentration\n\nQTcCorrected QT interval of the electrocardiogram\n\nVPSVentriculoperitoneal shunt\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAcknowledgements\nNone.\n\nAuthors’ contributions\nAll authors have been involved in the multidisciplinary diagnostic and therapeutic approach and in writing the manuscript. The author(s) read and approved the final manuscript.\n\nFunding\nNone.\n\nAvailability of data and materials\nData supporting the results reported in the article can be found in the intranet of Bambino Gesù Childrens’ Hospital.\n\nEthics approval and consent to participate\nPatient’s parents gave their informed consent before each invasive procedure and they consented to publish their child’s clinical history and data.\n\nConsent for publication\nObtained from the parents of patients.\n\nCompeting interests\nThe authors have no conflict of interest to declare.\n==== Refs\nReferences\n1. Mendes RE Deshpande LM Costello AJ Farrell DJ Molecular epidemiology of Staphylococcus epidermidis clinical isolates from US hospital Antimicrob Agents Chemother 2012 9 4656 10.1128/AAC.00279-12 \n2. Norrby R Expert Opin Pharmacother 2001 2 293 10.1517/14656566.2.2.293 11336587 \n3. Stevens DL Herr D Lampiris H Hunt JL Batts DH Hafkin B Linezolid versus vancomycin for the treatment of methicillin-resistant Staphylococcus aureus infections Clin Infect Dis 2002 34 1481 10.1086/340353 12015695 \n4. Shibata Y, Yamagishi Y, Mikamo H, Kato H, Nishiyama N, Asai N, Koizumi Y, Matsuura K, Suematsu H, Hagihara MJ. Comparative study on safety of linezolid and vancomycin in the treatment of infants and neonates for gram-positive bacterial infections. Infect Chemother. 2018. 10.1016/j.jiac.2018.04.006.\n5. Andes D van Ogtrop ML Peng J Craig WA In vivo pharmacodynamics of a new oxazolidinone (linezolid) Antimicrob Agents Chemother 2002 246 3484 10.1128/AAC.46.11.3484-3489.2002 \n6. Jungbluth GL Welshman IR Hopkins NK Linezolid pharmacokinetics in pediatric patients: an overview Pediatr Infect Dis J 2003 22 S153 10.1097/01.inf.0000086954.43010.63 14520140 \n7. Li S-C, Ye Q, Xu H, Zhang L, Wang Y. Population pharmacokinetics and dosing optimization of linezolid in pediatric patients. Antimicrob Agents Chemother. 2019, 2019. 10.1128/AAC.02387-18.\n8. Deville JG Adler S Azimi PH Jantausch BA Morfin MR Beltran S Linezolid versus vancomycin in the treatment of known or suspected resistant gram-positive infections in neonates Pediatr Infect Dis J 2003 22 Suppl 9 S158 S163 10.1097/01.inf.0000086955.93702.c7 14520141 \n9. Tartarone A Gallucci G Iodice G Romano G Coccaro M Vigliotti ML Mele G Matera R Linezolid–induced bradycardia: a case report Int J Antimicrob Agents 2004 23 412 10.1016/j.ijantimicag.2003.10.001 15081095 \n10. Dryden MS. Linezolid pharmacokinetics and pharmacodynamics in clinical treatment. J Antimicrob Chemother. 2011, 2011;66(Suppl 4). 10.1093/jac/dkr072.\n11. Waknine Y FDA safety changes: mirena, zyvox, orencia 2008 \n12. Damle B LaBadie R Cuozzo C Alvey C Chong C Choo H Lack of an effect of linezolid on QTc interval prolongation Antimicrob Agents Chemother 2011 55 4302 10.1128/AAC.01723-10 21709083 \n13. Rubinstein E Isturiz R Standiford HC Smith LG Oliphant TH Cammarata S Worldwide assessment of linezolid's clinical safety and tolerability: comparator-controlled phase III studies Antimicrob Agents Chemother 2003 47 1824 10.1128/AAC.47.6.1824-1831.2003 12760854 \n14. Vinh DC, Rubinstein E. Linezolid: a review of safety and tolerability. J Infect. 2009, 2009;59(Suppl 1). 10.1016/S0163-4453(09)60009-8.\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1720-8424",
"issue": "46(1)",
"journal": "Italian journal of pediatrics",
"keywords": "Linezolid; Neonate; QTc interval; Side effect; Staphylococcal meningitis",
"medline_ta": "Ital J Pediatr",
"mesh_terms": "D000900:Anti-Bacterial Agents; D004334:Drug Administration Schedule; D016903:Drug Monitoring; D006801:Humans; D007223:Infant; D000069349:Linezolid; D008297:Male; D016920:Meningitis, Bacterial; D013203:Staphylococcal Infections; D016896:Treatment Outcome",
"nlm_unique_id": "101510759",
"other_id": null,
"pages": "90",
"pmc": null,
"pmid": "32600437",
"pubdate": "2020-06-29",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "21709083;12015695;15081095;11336587;19766891;21521707;22687512;14520140;14520141;12384354;29807867;30642929;12760854",
"title": "Staphylococcal meningitis therapy with linezolid in a young infant: efficacy, CSF levels and side effects.",
"title_normalized": "staphylococcal meningitis therapy with linezolid in a young infant efficacy csf levels and side effects"
} | [
{
"companynumb": "IT-HQ-000062",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "LINEZOLID"
},
"drugadditional": "1",
"drugadmini... |
{
"abstract": "To determine the cause of death, in addition to routine autopsy, some assisted techniques are imperative to achieve a definite diagnosis. Herein, we report a case of 36-year-old man who was found dead in his apartment. Medical drug containers (potassium chloride, zolpidem, and propofol) and medical instruments (syringes and indwelling needles) were also found at the scene. An autopsy revealed large amounts of whitish foamy and brown liquid in the trachea and bronchi, and histopathological findings showed remarkable pulmonary congestion and edema. An injection mark with hemorrhage on the right wrist was found on external examination. Results of forensic pathology excluded the presence of mechanical injuries, mechanical asphyxia, embolism, and other fatal diseases. The data of toxicological analysis showed that concentrations of zolpidem and propofol in blood were appreciably higher than the therapeutic dose but they did not reach the absolute lethal dose. Moreover, the level of potassium in the blood and vitreous humor was higher than the expected concentration after death. A scanning electron microscope (SEM) combined with energy-dispersive X-ray microanalyzer (EDX) was subsequently applied to assess the skin samples collected from bilateral wrists. Ultrastructural observation discovered continuous visible interruption of the skin around the injection mark, and energy spectrum analysis revealed statistically significantly higher potassium content of the skin over the right wrist than the left wrist. Comprehensive analysis concluded that the deceased had died of potassium chloride intravenous injection under the zolpidem and propofol effects.",
"affiliations": "Department of Forensic Medicine, Faculty of Basic Medical Sciences, Chongqing Medical University, Chongqing, 400016, China.;Shapingba District Branch of Chongqing Public Security Bureau, Chongqing, China.;Department of Forensic Medicine, Faculty of Basic Medical Sciences, Chongqing Medical University, Chongqing, 400016, China.;Hainan Medical University, Haikou, 570000, Hainan, China.;Institute of Forensic Science Chongqing Public Security Bureau, Chongqing, China.;Department of Forensic Medicine, Faculty of Basic Medical Sciences, Chongqing Medical University, Chongqing, 400016, China. 100390@cqmu.edu.cn.",
"authors": "Zhang|Li|L|;Zhao|Qing|Q|;Wang|Qi|Q|;Zhang|Peng|P|;Li|Hongwei|H|;Li|Jianbo|J|",
"chemical_list": "D011189:Potassium Chloride; D000077334:Zolpidem; D015742:Propofol",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00414-020-02361-6",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0937-9827",
"issue": "134(5)",
"journal": "International journal of legal medicine",
"keywords": "Forensic pathology; Postmortem biochemical analyses; Potassium chloride; Scanning electron microscope (SEM)",
"medline_ta": "Int J Legal Med",
"mesh_terms": "D000328:Adult; D002423:Cause of Death; D049429:Forensic Pathology; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D008855:Microscopy, Electron, Scanning; D011189:Potassium Chloride; D015742:Propofol; D012867:Skin; D000077334:Zolpidem",
"nlm_unique_id": "9101456",
"other_id": null,
"pages": "1719-1725",
"pmc": null,
"pmid": "32607752",
"pubdate": "2020-09",
"publication_types": "D002363:Case Reports",
"references": "31637457;27942570;30770988;17126510;27459521;25394744;11534578;30883921;17567345;19299783;23406307;11924710;27855300;31378398;27932048",
"title": "Application of scanning electron microscopy in the auxiliary diagnosis of death caused by potassium chloride intravenous injection: a case report.",
"title_normalized": "application of scanning electron microscopy in the auxiliary diagnosis of death caused by potassium chloride intravenous injection a case report"
} | [
{
"companynumb": "CN-SA-2020SA186459",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "ZOLPIDEM TARTRATE"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nSecondary central nervous system lymphoma (SCNSL) is defined as lymphoma involvement within the central nervous system (CNS) that originated elsewhere, or a CNS relapse of systemic lymphoma. Prognosis of SCNSL is poor and the most appropriate treatment is still undetermined.\n\n\nMETHODS\nWe conducted a retrospective study to assess the feasibility of an R-MIADD (rituximab, high-dose methotrexate, ifosfamide, cytarabine, liposomal formulation of doxorubicin, and dexamethasone) regimen for SCNSL patients.\n\n\nRESULTS\nNineteen patients with newly diagnosed CNS lesions were selected, with a median age of 58 (range 20 to 72) years. Out of 19 patients, 11 (57.9%) achieved complete remission (CR) and 2 (10.5%) achieved partial remission (PR); the overall response rate was 68.4%. The median progression-free survival after CNS involvement was 28.0 months (95% confidence interval 11.0-44.9), and the median overall survival after CNS involvement was 34.5 months. Treatment-related death occurred in one patient (5.3%).\n\n\nCONCLUSIONS\nThese single-centered data underscore the feasibility of an R-MIADD regimen as the induction therapy of SCNSL, further investigation is warranted.",
"affiliations": "Department of Hematology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.;Department of Hematology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.;Department of Hematology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.;Department of Hematology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.;Department of Hematology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.;Department of Hematology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.;Department of Hematology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.;Department of Hematology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.;Department of Hematology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.;Department of Hematology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.;Department of Hematology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.;Department of Neurosurgery, Beijing Xuanwu Hospital, Capital Medical University, Beijing, China.;Neuroimaging Center, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.;Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.;Department of Hematology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China. yuanbol@ccmu.edu.cn.",
"authors": "Wu|Yuchen|Y|;Sun|Xuefei|X|;Bai|Xueyan|X|;Qian|Jun|J|;Zhu|Hong|H|;Cui|Qu|Q|;Xing|Ruixian|R|;Chen|Yuedan|Y|;Liu|Qing|Q|;Lai|Wenyuan|W|;Li|Junhong|J|;Wang|Yaming|Y|;Sun|Shengjun|S|;Ji|Nan|N|;Liu|Yuanbo|Y|http://orcid.org/0000-0003-1703-6774",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1186/s41016-021-00238-0",
"fulltext": "\n==== Front\nChin Neurosurg J\nChin Neurosurg J\nChinese Neurosurgical Journal\n2095-9370\n2057-4967\nBioMed Central London\n\n238\n10.1186/s41016-021-00238-0\nResearch\nTreatment of secondary central nervous system involvement in systemic aggressive B cell lymphoma using R-MIADD chemotherapy: a single-center study\nWu Yuchen 1\nSun Xuefei 1\nBai Xueyan 1\nQian Jun 1\nZhu Hong 1\nCui Qu 1\nXing Ruixian 1\nChen Yuedan 1\nLiu Qing 1\nLai Wenyuan 1\nLi Junhong 1\nWang Yaming 3\nSun Shengjun 4\nJi Nan 2\nhttp://orcid.org/0000-0003-1703-6774\nLiu Yuanbo yuanbol@ccmu.edu.cn\n\n1\n1 grid.24696.3f 0000 0004 0369 153X Department of Hematology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China\n2 grid.24696.3f 0000 0004 0369 153X Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China\n3 grid.24696.3f 0000 0004 0369 153X Department of Neurosurgery, Beijing Xuanwu Hospital, Capital Medical University, Beijing, China\n4 grid.24696.3f 0000 0004 0369 153X Neuroimaging Center, Beijing Tiantan Hospital, Capital Medical University, Beijing, China\n2 4 2021\n2 4 2021\n2021\n7 2017 9 2020\n6 2 2021\n© The Author(s) 2021\nOpen AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. 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\nSecondary central nervous system lymphoma (SCNSL) is defined as lymphoma involvement within the central nervous system (CNS) that originated elsewhere, or a CNS relapse of systemic lymphoma. Prognosis of SCNSL is poor and the most appropriate treatment is still undetermined.\n\nMethods\n\nWe conducted a retrospective study to assess the feasibility of an R-MIADD (rituximab, high-dose methotrexate, ifosfamide, cytarabine, liposomal formulation of doxorubicin, and dexamethasone) regimen for SCNSL patients.\n\nResults\n\nNineteen patients with newly diagnosed CNS lesions were selected, with a median age of 58 (range 20 to 72) years. Out of 19 patients, 11 (57.9%) achieved complete remission (CR) and 2 (10.5%) achieved partial remission (PR); the overall response rate was 68.4%. The median progression-free survival after CNS involvement was 28.0 months (95% confidence interval 11.0–44.9), and the median overall survival after CNS involvement was 34.5 months. Treatment-related death occurred in one patient (5.3%).\n\nConclusions\n\nThese single-centered data underscore the feasibility of an R-MIADD regimen as the induction therapy of SCNSL, further investigation is warranted.\n\nKeywords\n\nCentral nervous system\nB cell lymphoma\nSCNSL\nR-MIADD\nChemotherapy\nCapital’s Funds for Health Improvement and Research2020-2-2049 Liu Yuanbo issue-copyright-statement© The Author(s) 2021\n==== Body\nBackground\n\nSecondary central nervous system lymphoma (SCNSL) refers to secondary involvement of the brain, eye, spine, meningeal by systemic lymphoma [1, 2]. It is a devastating complication of systemic lymphoma, occurring in 5–10% of diffuse large B cell lymphoma (DLBCL) patients with very few long-term survivors under conventional treatment [3]. SCNSL can occur in combination with systemic disease or present as an isolated relapse. The prognosis of SCNSL is poorer than primary central nervous system lymphoma (PCNSL); in the largest cohort of SCNSL to date, less than half of the patients reached CR by the end of the induction treatment, and the median overall survival (OS) post-CNS involvement was only 3.9 months [4]. Therefore, further explorations on the treatment of SCNSL, especially initial induction, are needed to improve CR rate and outcomes.\n\nTreatment of SNCSL requires eradication of both the systemic and CNS disease. Standard first-line chemotherapy for systemic disease has limited efficacy in treating patients with CNSL [5]. High-dose methotrexate (HD-MTX)-based regimens are the most commonly used therapy in CNSL for their CNS penetration ability. HD-MTX in combination with high-dose cytarabine can improve survival significantly in patients with PCNSL [6]. Procarbazine, etoposide, ifosfamide, thiotepa, carmustine, and other drugs which can cross the blood-brain barrier have also been included in combination with HD-MTX and/or cytarabine to further improve outcomes [7]. Doxorubicin is not included in regimens for treating PCNSL because of its inability to penetrate the blood-brain barrier [8]. However, with an alternative liposomal formulation, doxorubicin has proved to be a promising drug for CNSL in several studies [9]. In addition, high-dose chemotherapy followed by autologous stem cell transplantation (ASCT) was introduced and showed a beneficial effect. However, ASCT has been offered to only a small number of younger patients but elicited a favorable response .Therefore, several studies have explored the effectiveness of non-transplant regimens for SCNSL and indicate that this could be an effective treatment for patients with SCNSL [10–12]. With this information in mind, we proceeded to treat SCNSL patients with the combination of rituximab, HD-MTX, ifosfamide, cytarabine, liposomal formulation of doxorubicin, or an R-MIADD regimen and carried out a retrospective study to explore the effectiveness and tolerance of this novel chemotherapeutic combination.\n\nMethods\n\nClinical data of a total of 19 SCNSL patients were retrospectively reviewed using electronical medical records at the Department of Hematology at Beijing Tiantan Hospital, Capital Medical University, from January 2015 to August 2019. Database was approved by Beijing Tiantan Hospital Ethics Committee; all patients gave written informed consent. Inclusion criteria were as follows: histologic diagnosis of DLBCL or mantle cell lymphoma with blast variant; CNS involvement (including brain and/or meninges and/or cranial nerves and/or eyes and/or spinal cord) determined using stereotactic biopsy, cerebrospinal fluid, cytology/flow cytometry, or brain magnetic resonance imaging (MRI) at diagnosis, or relapse after conventional chemoimmunotherapy; aged 18–70; and an Eastern Cooperative Oncology Group performance status ≤ 3. Patients with primary CNS lymphoma, hepatitis B surface antigen positivity, anti-hepatitis C virus serologic positivity, human immunodeficiency virus, or other immunodeficiency diseases were excluded. Patients were treated with an R-MAIDD regimen in 21-day cycles, specifically the following: rituximab 375 mg/m2 infusion on day 0, HD-MTX 3.5 g/m2 infusion within 3.5 h on day 1 (with folinic acid rescue), ifosfamide 1.2 g/m2 infusion on day 2, cytarabine 1 g/m2 infusion on day 3, dexamethasone 10 mg intravenously on days 1–3, and liposomal doxorubicin infusion 20–25 mg/m2 on day 4. Patients who did not achieve CR proceeded to have salvage treatment of whole brain radiotherapy with 36 Gy and a boost to tumor bed for a total of 40–50 Gy. All patients received either post-R-MIADD regimen CNS radiotherapy or consolidation chemotherapy according to clinical response.\n\nResponse assessment was performed within 4 weeks of the final R-MIADD chemotherapy. Enhanced MRI and whole-body CT with positron emission tomography scan were used for assessment. Treatment response of systemic lymphoma was graded according to the 2014 Lugano criteria. Clinical response in CNS disease was assessed using the International Workshop to Standardize Baseline Evaluation and Response Criteria for Primary CNS Lymphoma [13], and MRIs of all patients were assessed by two experienced neuroradiologists. Toxicities were assessed and recorded using the Common Terminology Criteria for Adverse Events Version 3.0 [14]. Post-CNS involvement OS was defined as the time from initiation of the CNS disease to the last follow-up or death from any cause. Post-CNS involvement progression-free survival (PFS) was calculated from initiation of the CNS disease to disease progression or last follow-up. Survival analyses were performed using the Kaplan-Meier method with SPSS Statistics, Version 24.0. There were not enough subjects to perform reliable multivariate analysis. All tests were two-sided, and a p value < 0.05 was considered statistically significant.\n\nResults\n\nClinical characteristics of systemic disease in SCNSL patients\n\nThe median age at onset of the systemic disease was 58 (20–72) years (Table 1). Among the 19 SCNSL patients, 10 (52.6%) had simultaneous involvement both inside and outside of the CNS when initially diagnosed, defined as “new disease;” five (26.3%) had CNS disease in the latter part or within 3 months of completing primary therapy, defined as “refractory disease;” and four (21.1%) had a CNS relapse that may have been combined with systemic disease, defined as “relapse disease.” Extranodal involvement as the initial systemic disease was observed in eight patients (breasts, n = 3; testis, n = 2; bone marrow, n = 1; prostate, n = 1; and stomach, n = 1). The histological findings were DLBCL in 18 (94.7%) patients, and mantle cell lymphoma was diagnosed in one (15.3%) patient. Fourteen (73.7%) patients were graded as Ann Arbor staging III–IV at initial diagnosis. Table 1 Clinical characteristics of systemic disease in SCNSL patients\n\nCharacteristics\tN\t%\t\nAge\t\n Median (range)\t58 (20–72)\t\t\n ≤ 60\t10\t52.6\t\n > 60\t9\t47.4\t\nGender\t\n Male\t9\t47.4\t\n Female\t10\t52.6\t\nInitial disease location\t\n Breasts\t3\t15.8\t\n Testis\t2\t10.5\t\n Lymph node\t11\t57.9\t\n Others\t3\t15.9\t\nAnn Arbor stage\t\n I–II\t5\t26.3\t\n III–IV\t14\t73.7\t\nTreatment of initial disease\t\n R-CHOP like regimen\t9\t47.4\t\n Other regimen\t10\t52.6\t\nCNS prophylaxis\t\n Yes\t2\t10.5\t\n No\t17\t89.5\t\n\nFor treatment after onset of systemic disease, nine (47.7%) patients received R-CHOP or similar regimens and two of these patients received intrathecal injection of methotrexate as CNS involvement prophylaxis. One patient received ASCT after achieving CR of systemic disease and developed CNS disease afterward. Ten patients with new SCNSL received CNS-targeting treatment, which is described later in this section.\n\nClinical characteristics of CNS disease in SCNSL patients\n\nThe median age at onset of CNS disease was 59 (20–76) years (Table 2). The most common symptoms at the initial stage of CNS disease were increased intracranial pressure symptoms and dizziness, seen in five (26.3%) of the SCNSL patients. Other symptoms included blurred vision (n = 2), limb weakness (n = 2), seizure (n = 1), somnolence (n = 1), and focal neurological deficits (n = 3). Regarding radiological features, brain parenchymal lesions were found in all 19 patients. Single lesions were noted in six (31.6%) patients, and 13 (68.4%) patients had multiple lesions; 10 (47.4%) patients had tumors involving the deep part of the brain, including the cerebellum, basal ganglia, corpus callosum, and brain stem. Table 2 Clinical characteristics of CNS disease in SCNSL patients\n\nCNS characteristics\tN\t%\t\nCNS age\t\n Median, range\t59, 20–76\t\t\n ≤ 60\t10\t52.6\t\n > 60\t9\t47.4\t\nInitial symptoms\t\n Headache\t5\t26.3\t\n Dizziness\t5\t26.3\t\n Blurred version\t2\t10.5\t\n Limb weakness\t2\t10.5\t\n Seizure\t1\t5.3\t\n Somnolence\t1\t5.3\t\n Focal neurological deficits\t3\t15.8\t\nECOG-PS\t\n ≤ 1\t6\t31.6\t\n > 1\t13\t68.4\t\nType of CNS relapse\t\n New disease\t10\t52.6\t\n Relapse\t4\t21.1\t\n CNS only\t3\t\t\n Combined CNS and systemic disease\t1\t\t\n Refractory\t5\t26.3\t\nMultiplicity\t\n Single\t6\t31.6\t\n Multiple\t13\t68.4\t\nEnhancement\t\n Homogenous\t11\t57.9\t\n Patchy\t7\t36.8\t\n None\t1\t5.3\t\nLocation of disease\t\n White matter\t16\t84.2\t\n Cerebellum\t3\t74.2\t\n Brain stem\t3\t15.8\t\n Deep gray matter\t10\t47.4\t\nDiagnosis approaches\t\n Biopsy\t10\t52.6\t\n Surgery section\t4\t21.1\t\n Enhanced MRI\t4\t21.1\t\n CSF cytology\t1\t5.3\t\nHistology at relapse\t\n ABC\t10\t52.6\t\n GCB\t4\t21.1\t\n NA\t5\t26.3\t\nABC activated B cell, GCB germinal center B cell, NA not available\n\nFour (21.1%) patients were diagnosed with typical radiological manifestations on enhanced MRI, 10 (52.6%) patients were diagnosed through stereotactic biopsy, four (21.1%) patients underwent tumor resection, and one (5.3%) patient was diagnosed using cerebrospinal fluid cytology. Histologically, four (4/10) cases showed germinal center B cell phenotypes (CD10 + BCL-6 +/− MUM-1+/−), and 10 (10/14) cases showed peripherally activated B cell phenotypes (CD10-BCL- 6 +/− MUM-1+ or CD10-BCL-6-MUM-l).\n\nTreatment and responses\n\nAll patients were treated with R-MIADD regimen, one with cerebrospinal fluid dissemination received intrathecal MTX (MTX 10 mg, dexamethasone 5 mg) simultaneously. After 1–3 cycles of induction, six patients reached CR, eight patients were assessed as PR, three had stable disease, and one patient had disease progression (DP) (Fig. 1). One patient died of neutropenic sepsis after the second cycle of chemotherapy. Fig. 1 Course of therapy, responses, and clinical outcomes. CR, complete response; PR, partial response; PD, progressive disease; SD, stable disease; WBRT, whole brain radiotherapy\n\nAll six patients with CR and seven patients with PR continued R-MIADD treatment. By the end of the induction treatment, 11 patients attained CR and 2 attained PR (Table 3). Patients with stable disease and DP proceeded with whole brain radiotherapy (WBRT), and one patient with PR also turned to WBRT because of financial difficulties. All five patients achieved CR after WBRT. Table 3 Response of SCNSL patients after induction therapy\n\nResponse\tTotal\tNew disease\tRefractory disease\tRelapse disease\t\nN = 19\t%\tN = 10\t%\tN = 5\t%\tN = 4\t%\t\nCR\t11\t57.9\t7\t70\t2\t40\t2\t50\t\nPR\t2\t10.5\t1\t10\t0\t0\t1\t25\t\nWBRT*\t5\t26.3\t2\t20\t2\t40\t1\t25\t\nDeath\t1\t5.3\t0\t0\t1\t20\t0\t0\t\nCR complete remission, PR partial remission, SD stable disease, PD progression disease, WBRT whole brain radiotherapy\n\n*WBRT indicated SCNSL who turned to WBRT during the induction treatment\n\nProgression-free and overall survival\n\nBy the end of the induction treatment, 11 (57.9%) patients achieved CR and 2 (10.5%) patients achieved PR for an overall response rate (ORR) of 68.4%. Of the 10 “new disease” patients, 7 attained CR and 1 attained PR. For “refractory” and “relapse” patients, ORR was 40% (CR 40%) and 75% (CR 50%), respectively.\n\nThe median follow-up time after the onset of CNS disease was 11.1 (3.2–35.5) months, the median post-CNS involvement PFS was 28.0 months (95% CI 11.0–44.9) (Fig. 2a), and the post-CNS OS was 34.5 months (95% CI N/A) (Fig. 2b). Fig. 2 a Post-CNS progression-free survival of 19 SCNSL patients. b Post-CNS Overall survival of 19 SCNSL patients\n\nPost-R-MIADD regimen treatment\n\nAfter achieving CR, 10 patients continued with chemotherapy for consolidation treatment with a combination of ifosfamide, etoposide, and cytarabine every 3 months. One patient did not receive further treatment. The five patients who did not respond to the R-MIADD regimen proceeded with WBRT and all of them attained CR. After CR, these patients proceeded with ifosfamide, etoposide and cytarabine consolidation every 3 months.\n\nToxicity, relapses, and cause of death\n\nHematologic toxicity (16 [84.2%] patients) was most the common adverse effect of the treatment, with 3 (15.8%) patients experiencing grade 4 myelosuppression. The number of patients with grade 3–4 myelosuppression with either isolated relapse or concurrent disease was 2 (20%) and 6 (66.7%), respectively, although without statistical difference (p = 0.07). Elevated aminotransferase levels were observed in 8 (42.1%) patients, and elevated bilirubin levels were found in 2 (10.5%) patients. No severe mucosa damage was observed during the treatment. Two (10.5%) patients experienced temporarily elevated creatinine after MTX administration, but their renal function returned to normal after urine alkalinization and hydration accelerated the excretion of MTX.\n\nOne patient with refractory disease died during the induction treatment because of myelosuppression and severe pneumonia after chemotherapy, which resulted in toxic shock syndrome. Of the 11 patients who obtained CR with the R-MIADD regimen alone, three had isolated relapses in the CNS (two “new disease” and one “relapse disease” patients); one relapse occurred in the spine and two relapses occurred in brain parenchyma; and one patient died of CNS DP (Fig. 3). Fig. 3 Swim lane plot of treatment duration and response for all patients. CR, complete response; PR, partial response; PD, progressive disease; SD, stable disease\n\nDiscussion\n\nWe reported the combination of an R-MAIDD regimen to treat SCNSL patients resulting in an ORR of 68.4% and a post-CNS involvement PFS of 28.0 months (95% CI 11.0–44.9). These results indicate that a non-transplant regimen of R-MIADD could potentially be an effective treatment for SCNSL.\n\nThere is currently no randomized study that defines the optimal regimen to treat SCNSL because of the rarity of this disease. Few prospective studies favoring ASCT have demonstrated improved outcome in young and fit SCNSL patients [15–19]. In a prospective study undertaken by Korfel et al., 30 SCNSL patients were treated with intravenous HD-MTX, ifosfamide, and dexamethasone with intrathecal liposomal cytarabine; patients that did not respond to this combination were then given thiotepa and cytarabine for the second cycle, while patients that did respond to it received thiotepa, carmustine, and an etoposide regimen-conditioned ASCT with a CR response of 50% and PR 7% [16]. Ferreri et al. implemented a regimen that included high doses of MTX and cytarabine, followed by rituximab, cyclophosphamide, cytarabine +/− etoposide targeting residual systemic disease prior to ASCT, and carmustine, etoposide, cytarabine, and melphalan conditioned ASCT. In patients that responded to this treatment, the CR rate was 63% with a 2-year event-free survival rate of 50% [15]. Despite the encouraging results of the chemoresponsive patients, the majority of patients with SCNSL could not proceeded to ASCT because of poor response to the initial treatment. In a large international cohort study that included 291 cases of secondary CNS involvement in DLBCL, 173 patients received systemic chemotherapy and, of these, only 25 patients received high-dose chemotherapy followed by ASCT. Moreover, the study results indicated that for patients in CR after initial therapy, ASCT consolidation did not prolong OS in cases of isolated SCNSL [4].\n\nTherefore, several studies turned to non-transplant regimens for SCNSL and focused on improving the response rate to initial treatment. Nijland et al. used methotrexate, etoposide, carmustine, and methylprednisolone combined with R-CHOP as induction therapy. After achieving remission, patients underwent whole brain radiotherapy for consolidation. The complete response rate was 57%, with 3 years PFS and an OS rate of 45% (95% CI 34–56%) and 49% (95% CI 38–60%), respectively [10]. Those findings are comparable to the figures reported herein. In another pilot study, Chihara et al. treated eight patients with DA-EPOCH-R combined with HD-MTX, and all eight patients achieved CR [11]. Nagle et al. reported HD-MTX combined with temozolomide for the treatment of SCNSL resulted in the median OS of 4.8 months and 4-year OS of 25% [12].\n\nThe regimen used in our study contained HD-MTX, cytarabine, and ifosfamide, in addition to liposomal doxorubicin, but the doses administered in our regimen were lower than those administered the study mentioned previously. Our approach led to better treatment response without additional treatment toxicity. By the end of the induction therapy, 57.9% of patients achieved CR and post-CNS PFS was 28.0 months (95% CI 11.0–44.9), which is comparable to an ASCT-containing regimen. Substantially longer survival than the median PFS was seen in two patients (Patient 6 and 7) at the ages of 39 and 20 years. Previous reports indicate that long-term survival was seen in a small, albeit clinically relevant, proportion of younger SCNSL patients. Therefore, younger patients may have better prognoses despite the overall disappointing survival rates of SCNSL patients [15]. In this study, patients with new disease possessed higher CR rates than relapse and refractory patients (70% vs 50% and 40%). We postulated that this is because patients with relapse and refractory disease were more likely to be both drug resistant and develop treatment toxicity. This would indicate that SCNSL patients require more individualized treatment regarding their disease condition and regimen prior to the onset of CNS disease.\n\nBenefits from the use of rituximab for PCNSL are controversial [20]. A meta-analysis published in 2019 that included two randomized control studies concluded that rituximab could improve PFS but did not significantly improve OS (hazard ratio 0.76; 95% CI 0.52–1.12, low certainty). Nevertheless, the majority of research on SCNSL treatments included rituximab (some as part of the peripheral lymphoma treatment) [10–12, 15, 17]. El-Galaly et al. concluded that rituximab may reduce the risk of death in patients with isolated SCNSL; they also emphasized that in this subgroup, rituximab can even play a role comparable to ASCT [4]. Thus, we also included rituximab as part of our treatment for SCNSL.\n\nThe present study had a few limitations. First, it is a single neurosurgery center retrospective study, selection bias may exist. Second, owing to the rarity of this disease, the sample size was small, and there is inconsistency in lymphoma type. Third, the study did not reach median OS. Prospective studies with larger sample size and longer follow-up were needed in the future.\n\nConclusions\n\nTreatment of SCNSL has always been challenging. This single-center study indicate that the R-MIADD regimen is effective in treating SCNSL and the outcome of patients receiving R-MIADD were comparable to previous reports of ASCT-containing regimens. Larger cohort prospective studies are needed to define the most effective treatment strategies for SCNSL.\n\nAbbreviations\n\nASCT Autologous stem cell transplantation\n\nCNS Central nervous system\n\nCR Complete remission\n\nCT Computed tomography\n\nDLBCL Diffuse large B cell lymphoma\n\nDP Disease progression\n\nMTX Methotrexate\n\nMRI Magnetic resonance imaging\n\nORR Overall response rate\n\nOS Overall survival\n\nPCNSL Primary central nervous system lymphoma\n\nPFS Progression-free survival\n\nPR Partial remission\n\nSCNSL Secondary central nervous system lymphoma\n\nWBRT Whole brain radiotherapy\n\nAcknowledgements\n\nThis manuscript has been released as a pre-print at Research Square (Yuchen Wu, Xuefei Sun, Xueyan Bai, Jun Qian, Hong Zhu, Qu Cui et al., Management of secondary central nervous system involvement in systemic aggressive B cell lymphoma using R-MIADD chemotherapy: a single-center experience [pre-print] (2020), available at Research Square, 10 March 2020).\n\nAvailability data and materials\n\nThe datasets supporting the conclusions of this study are available from the corresponding author on reasonable request.\n\nAuthors’ contributions\n\nLYB and WYC designed the study; JN and WYM provided the patient samples; SSJ revised neuroimaging; WYC analyzed the data and wrote the manuscript; SXF, CQ, ZH, and QJ performed the experiments; BXY, XRX, CYD, LQ, LJH, and WYL collected and analyzed the data; and all the authors have read the manuscript and approved its submission.\n\nFunding\n\nThis study was supported by the Capital’s Funds for Health Improvement and Research (2020-2-2049).\n\nDeclarations\n\nEthics approval and consent to participate\n\nEthical approval was provided by Beijing Tiantan Hospital Ethics Committee, Capital Medical University (ethical approval reference number KYSB2016-170). Informed consent was written obtained when patients were admitted to Department of Hematology before initiation of chemotherapy.\n\nConsent for publication\n\nNot applicable.\n\nCompeting interests\n\nThe authors declare no competing interests.\n==== Refs\nReferences\n\n1. Maciocia P Badat M Cheesman S D'Sa S Joshi R Lambert J Treatment of diffuse large B-cell lymphoma with secondary central nervous system involvement: encouraging efficacy using CNS-penetrating R-IDARAM chemotherapy British journal of haematology. 2016 172 4 545 553 10.1111/bjh.13867 26684148\n2. Villa D Connors JM Shenkier TN Gascoyne RD Sehn LH Savage KJ Incidence and risk factors for central nervous system relapse in patients with diffuse large B-cell lymphoma: the impact of the addition of rituximab to CHOP chemotherapy Ann Oncol Off J Eur Soc Med Oncol 2010 21 5 1046 10.1093/annonc/mdp432\n3. Volkmar B Norbert S Samira Z Markus L Michael P CNS events in elderly patients with aggressive lymphoma treated with modern chemotherapy (CHOP-14) with or without rituximab: an analysis of patients treated in the RICOVER-60 trial of the German High-Grade Non-Hodgkin Lymphoma Study Group (DSHNHL) Blood. 2009 113 17 3896 3902 10.1182/blood-2008-10-182253 19144985\n4. El-Galaly TC, Cheah CY, Bendtsen MD, Nowakowski GS, Kansara R, Savage KJ, et al. Treatment strategies, outcomes and prognostic factors in 291 patients with secondary CNS involvement by diffuse large B-cell lymphoma. European journal of cancer (Oxford, England : 1990). 2018;93:57-68.\n5. Bierman P Giglio P Diagnosis and treatment of central nervous system involvement in non-Hodgkin's lymphoma Hematol/Oncol Clin North Am 2005 19 4 597 609 10.1016/j.hoc.2005.05.003\n6. Ferreri AJ Reni M Foppoli M Martelli M Pangalis GA Frezzato M High-dose cytarabine plus high-dose methotrexate versus high-dose methotrexate alone in patients with primary CNS lymphoma: a randomised phase 2 trial Lancet. 2009 374 9700 1512 1520 10.1016/S0140-6736(09)61416-1 19767089\n7. Mappa S Marturano E Licata G Frezzato M Frungillo N Ilariucci F Salvage chemoimmunotherapy with rituximab, ifosfamide and etoposide (R-IE regimen) in patients with primary CNS lymphoma relapsed or refractory to high-dose methotrexate-based chemotherapy Hematological oncology. 2013 31 3 143 150 10.1002/hon.2037 23161567\n8. Wilson WH Treatment strategies for aggressive lymphomas: what works? Hematology American Society of Hematology Education Program. 2013 2013 584 590 10.1182/asheducation-2013.1.584 24319235\n9. Lionakis MS, Dunleavy K, Roschewski M, Widemann BC, Butman JA, Schmitz R, et al. Inhibition of B cell receptor signaling by ibrutinib in primary CNS lymphoma. Cancer cell. 2017;31(6):833-43.e5.\n10. Nijland M Jansen A Doorduijn JK Enting RH Bromberg JEC Kluin-Nelemans HC Treatment of initial parenchymal central nervous system involvement in systemic aggressive B-cell lymphoma Leukemia & lymphoma. 2017 58 9 1 6 10.1080/10428194.2017.1285026\n11. Chihara D Fowler NH Oki Y Fanale MA Fayad LE Westin JR Dose-adjusted EPOCH-R and mid-cycle high dose methotrexate for patients with systemic lymphoma and secondary CNS involvement British journal of haematology. 2017 179 5 851 854 10.1111/bjh.14267 27502933\n12. Nagle SJ Shah NN Ganetsky A Landsburg DJ Nasta SD Mato A Long-term outcomes of rituximab, temozolomide and high-dose methotrexate without consolidation therapy for lymphoma involving the CNS International journal of hematologic oncology. 2017 6 4 113 121 10.2217/ijh-2017-0020 30302232\n13. Abrey LE Batchelor TT Ferreri AJ Gospodarowicz M Pulczynski EJ Zucca E Report of an international workshop to standardize baseline evaluation and response criteria for primary CNS lymphoma Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2005 23 22 5034 5043 10.1200/JCO.2005.13.524 15955902\n14. Trotti A Colevas AD Setser A Rusch V Jaques D Budach V CTCAE v3.0: development of a comprehensive grading system for the adverse effects of cancer treatment Seminars in Radiation Oncology. 2003 13 3 176 181 10.1016/S1053-4296(03)00031-6 12903007\n15. Ferreri AJM Giovanni D Maria Giuseppina C Caterina P Michael M Renato Z High doses of antimetabolites followed by high-dose sequential chemoimmunotherapy and autologous stem-cell transplantation in patients with systemic B-cell lymphoma and secondary CNS involvement: final results of a multicenter phase II trial Journal of Clinical Oncology Official Journal of the American Society of Clinical Oncology. 2015 33 33 3903 3910 10.1200/JCO.2015.61.1236 26282634\n16. Korfel A Elter T Thiel E Hanel M Mohle R Schroers R Phase II study of central nervous system (CNS)-directed chemotherapy including high-dose chemotherapy with autologous stem cell transplantation for CNS relapse of aggressive lymphomas Haematologica. 2013 98 3 364 370 10.3324/haematol.2012.077917 23242601\n17. Chen YB Batchelor T Li S Hochberg E Brezina M Jones S Phase 2 trial of high-dose rituximab with high-dose cytarabine mobilization therapy and high-dose thiotepa, busulfan, and cyclophosphamide autologous stem cell transplantation in patients with central nervous system involvement by non-Hodgkin lymphoma Cancer. 2015 121 2 226 233 10.1002/cncr.29023 25204639\n18. Qualls D Sullivan A Li S Brunner AM Collier K Hochberg E High-dose thiotepa, busulfan, cyclophosphamide, and autologous stem cell transplantation as upfront consolidation for systemic non-Hodgkin lymphoma with synchronous central nervous system involvement Clinical lymphoma, myeloma & leukemia. 2017 17 12 884 888 10.1016/j.clml.2017.08.100\n19. Oh DH Chua N Street L Stewart DA Treatment of patients with secondary central nervous system lymphoma with high-dose busulfan/thiotepa-based conditioning and autologous stem cell transplant Leukemia & lymphoma. 2016 57 1 28 33 10.3109/10428194.2015.1026901 25747968\n20. Schmitt AM, Herbrand AK, Fox CP, Bakunina K, Bromberg JEC, Cwynarski K, et al. Rituximab in primary central nervous system lymphoma-a systematic review and meta-analysis. Hematol Oncol. 2019;37(5):548–57.\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2057-4967",
"issue": "7(1)",
"journal": "Chinese neurosurgical journal",
"keywords": "B cell lymphoma; Central nervous system; Chemotherapy; R-MIADD; SCNSL",
"medline_ta": "Chin Neurosurg J",
"mesh_terms": null,
"nlm_unique_id": "101672561",
"other_id": null,
"pages": "20",
"pmc": null,
"pmid": "33795020",
"pubdate": "2021-04-02",
"publication_types": "D016428:Journal Article",
"references": "19767089;28552327;30302232;24319235;16083825;26684148;19144985;31418878;23161567;27502933;25747968;26282634;15955902;28870642;29477102;28278731;12903007;19861575;25204639;23242601",
"title": "Treatment of secondary central nervous system involvement in systemic aggressive B cell lymphoma using R-MIADD chemotherapy: a single-center study.",
"title_normalized": "treatment of secondary central nervous system involvement in systemic aggressive b cell lymphoma using r miadd chemotherapy a single center study"
} | [
{
"companynumb": "CN-PFIZER INC-2021478938",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHOTREXATE SODIUM"
},
"drugadditional": "3",... |
{
"abstract": "Usually, no adverse effects are observed in breastfed infants whose mothers are treated with the anti-epileptic carbamazepine. In this article, we described unusual short-term adverse effects observed in a young infant after exposure to carbamazepine during pregnancy and lactation.\n\n\n\nA 40-day-old female infant, born at term, was admitted to the Pediatric Clinic at University of Sassari, Italy, for recurrent regurgitations and vomiting. She was breastfed since birth and her mother was under chronic carbamazepine therapy. Gastroesophageal reflux was initially suspected; therefore, thickening of feeds and postural therapy were applied without any benefit. Subsequently, high levels of carbamazepine were detected in infant serum and in maternal breast milk. After an unsuccessful attempt to combine breastfeeding with formula feeding, the switch to exclusive formula feeding was made, with subsequent rapid resolution of symptoms and body weight increase.\n\n\n\nThe use of carbamazepine is considered compatible with breastfeeding, even if the potential risk of adverse reactions in breastfed infants exists. In this case, the discontinuation of breastfeeding resulted in the complete resolution of symptoms, suggesting a correlation between the observed manifestations in the infant and her exposure to maternal therapy.",
"affiliations": "1 Pediatric Clinic, Department of Clinical and Experimental Medicine, University of Sassari , Sassari, Italy .;2 Section of Pharmacology, Department of Diagnostics and Public Health, University of Verona , Verona, Italy .;1 Pediatric Clinic, Department of Clinical and Experimental Medicine, University of Sassari , Sassari, Italy .;1 Pediatric Clinic, Department of Clinical and Experimental Medicine, University of Sassari , Sassari, Italy .;1 Pediatric Clinic, Department of Clinical and Experimental Medicine, University of Sassari , Sassari, Italy .;1 Pediatric Clinic, Department of Clinical and Experimental Medicine, University of Sassari , Sassari, Italy .",
"authors": "Antonucci|Roberto|R|;Cuzzolin|Laura|L|;Manconi|Alessandra|A|;Cherchi|Claudio|C|;Oggiano|Anna Maria|AM|;Locci|Cristian|C|",
"chemical_list": "D000927:Anticonvulsants; D002220:Carbamazepine",
"country": "United States",
"delete": false,
"doi": "10.1089/bfm.2017.0235",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1556-8253",
"issue": "13(2)",
"journal": "Breastfeeding medicine : the official journal of the Academy of Breastfeeding Medicine",
"keywords": "adverse effects; breastfeeding; carbamazepine; infant",
"medline_ta": "Breastfeed Med",
"mesh_terms": "D000328:Adult; D000927:Anticonvulsants; D001903:Bottle Feeding; D001942:Breast Feeding; D002220:Carbamazepine; D016241:Child of Impaired Parents; D004827:Epilepsy; D005260:Female; D006801:Humans; D041943:Infant Formula; D007227:Infant Nutritional Physiological Phenomena; D007231:Infant, Newborn; D007774:Lactation; D008895:Milk, Human; D009035:Mothers; D011247:Pregnancy; D016896:Treatment Outcome; D014839:Vomiting; D015430:Weight Gain",
"nlm_unique_id": "101260777",
"other_id": null,
"pages": "155-157",
"pmc": null,
"pmid": "29431474",
"pubdate": "2018-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Maternal Carbamazepine Therapy and Unusual Adverse Effects in a Breastfed Infant.",
"title_normalized": "maternal carbamazepine therapy and unusual adverse effects in a breastfed infant"
} | [
{
"companynumb": "IT-MYLANLABS-2018M1039081",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CARBAMAZEPINE"
},
"drugadditional": null,
... |
{
"abstract": "Treatment of recalcitrant warts in solid organ transplant recipients (SOTR) can pose a therapeutic challenge for dermatologists. Successful treatment of recalcitrant warts can serve as secondary prevention for skin cancer in those with chronic immunosuppression. Given the heterogeneity of associated comorbid conditions in SOTR, clinical trials are difficult to conduct in this high-risk population, therefore, our clinical practice is mostly driven by observed responses from studies in immunocompetent patients or from case reports of immunocompromised patients. The combination of systemic retinoids and candida immunotherapy likely provide the most effective treatment for recalcitrant warts in SOTR. However, many SOTR have chronic renal insufficiency and are not candidates for acitretin therapy. We provide two cases of recalcitrant warts in SOTR successfully treated with isotretinoin in the setting of impaired renal function.",
"affiliations": "College of Medicine, University of Florida, Gainesville, FL.;Department of Dermatology, University of Florida, Gainesville, FL.;Department of Dermatology, University of Florida, Gainesville, FL.",
"authors": "Herold|Mitchell|M|;Nielson|Colton|C|0000-0003-1663-625X;Longo|Maria I|MI|",
"chemical_list": "D003879:Dermatologic Agents; D015474:Isotretinoin",
"country": "United States",
"delete": false,
"doi": "10.1111/dth.12803",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1396-0296",
"issue": "32(2)",
"journal": "Dermatologic therapy",
"keywords": "accutane + recalcitrant wart; accutane + transplant; recalcitrant wart + transplant",
"medline_ta": "Dermatol Ther",
"mesh_terms": "D000328:Adult; D002175:Candida; D003131:Combined Modality Therapy; D003879:Dermatologic Agents; D006801:Humans; D007167:Immunotherapy; D015474:Isotretinoin; D008297:Male; D008875:Middle Aged; D016377:Organ Transplantation; D066027:Transplant Recipients; D014860:Warts",
"nlm_unique_id": "9700070",
"other_id": null,
"pages": "e12803",
"pmc": null,
"pmid": "30536495",
"pubdate": "2019-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Isotretinoin and candida immunotherapy for recalcitrant warts in solid organ transplant recipients.",
"title_normalized": "isotretinoin and candida immunotherapy for recalcitrant warts in solid organ transplant recipients"
} | [
{
"companynumb": "US-DRREDDYS-USA/USA/19/0107232",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "HYDROCORTISONE"
},
"drugadditional": "3"... |
{
"abstract": "To report asymptomatic progressive fundus depigmentation and choroidal thinning in the absence of intraocular inflammation in a patient treated with checkpoint inhibitors.\nA 69-year-old woman with metastatic cutaneous melanoma, treated with checkpoint inhibition (nivolumab, ipilimumab and pembrolizumab), developed asymptomatic progressive fundus depigmentation associated with choroidal thinning in both eyes over 26 months. Serial multimodal imaging was obtained over the study period including fundus photography, fundus autofluorescence and optical coherence tomography (OCT). Over 26 months, the central choroidal thickness decreased by 34% (from 270μm to 92μm, mean between both eyes). Concurrently, central retinal thickness remained stable (206μm to 214μm, mean between both eyes). There were no findings of intraocular inflammation, subretinal fluid or retinal pigment epithelium disturbance. The patient reported no visual symptoms and maintained a visual acuity of 20/25+ in the right eye and 20/30 in the left eye throughout the observation period. Concurrently, cutaneous vitiligo and poliosis, inclusive of her periorbital dermis and eyelashes also developed.\nProgressive fundus depigmentation and choroidal thinning can be observed with checkpoint inhibition in the absence of intraocular inflammation.",
"affiliations": "Ophthalmic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.;Ophthalmic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.;Ophthalmic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.;Ophthalmic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.;Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.",
"authors": "Canestraro|Julia|J|;Jaben|Korey A|KA|;Wolchok|Jedd D|JD|;Abramson|David H|DH|;Francis|Jasmine H|JH|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.ajoc.2020.100799",
"fulltext": "\n==== Front\nAm J Ophthalmol Case Rep\nAm J Ophthalmol Case Rep\nAmerican Journal of Ophthalmology Case Reports\n2451-9936 Elsevier \n\nS2451-9936(20)30135-3\n10.1016/j.ajoc.2020.100799\n100799\nCase Report\nProgressive choroidal thinning (leptochoroid) and fundus depigmentation associated with checkpoint inhibitors\nCanestraro Julia canestrj@mskcc.orga∗ Jaben Korey A. a Wolchok Jedd D. ab Abramson David H. ac Francis Jasmine H. bc a Ophthalmic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA\nb Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA\nc Weill Cornell Medical Center, New York, NY, USA\n∗ Corresponding author. Memorial Sloan Kettering Cancer Center, 16 E 60th St, Suite 480, Ophthalmic Oncology, New York, NY, 10022, USA. canestrj@mskcc.org\n26 6 2020 \n9 2020 \n26 6 2020 \n19 10079912 11 2019 6 3 2020 21 6 2020 © 2020 The Authors. Published by Elsevier Inc.2020This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Purpose\nTo report asymptomatic progressive fundus depigmentation and choroidal thinning in the absence of intraocular inflammation in a patient treated with checkpoint inhibitors.\n\nObservations\nA 69-year-old woman with metastatic cutaneous melanoma, treated with checkpoint inhibition (nivolumab, ipilimumab and pembrolizumab), developed asymptomatic progressive fundus depigmentation associated with choroidal thinning in both eyes over 26 months. Serial multimodal imaging was obtained over the study period including fundus photography, fundus autofluorescence and optical coherence tomography (OCT). Over 26 months, the central choroidal thickness decreased by 34% (from 270μm to 92μm, mean between both eyes). Concurrently, central retinal thickness remained stable (206μm to 214μm, mean between both eyes). There were no findings of intraocular inflammation, subretinal fluid or retinal pigment epithelium disturbance. The patient reported no visual symptoms and maintained a visual acuity of 20/25+ in the right eye and 20/30 in the left eye throughout the observation period. Concurrently, cutaneous vitiligo and poliosis, inclusive of her periorbital dermis and eyelashes also developed.\n\nConclusions and importance\nProgressive fundus depigmentation and choroidal thinning can be observed with checkpoint inhibition in the absence of intraocular inflammation.\n\nKeywords\nCancerCheckpoint inhibitorFundus vitiligoLeptochoroidPoliosisProgressive choroidal thinning\n==== Body\n1 Introduction\nCancer cells can elude the immune system by hijacking natural regulatory systems known as immune checkpoints and inhibit tumor specific T-cells, thereby protecting themselves from immune attack.1 There are now a number of FDA approved drugs known as checkpoint inhibitors (CPIs) that alter this immune response and have resulted in improved patient survival in metastatic cutaneous melanoma and other tumors.1\n\nThe three classes of CPIs (cytotoxic T-lymphocyte associated antigen-4 (CTLA-4), programmed cell death (PD-1) and programmed cell death protein 1 (PD-L1) inhibitors) prevent tumor cells from evading the immune system. CPIs are intended to potentiate the T-lymphocyte response against tumor cells,1 but these T-lymphocytes can also target normal tissue resulting in inflammatory adverse events. This includes ocular inflammation which occurs in approximately 1% of patients and involves various anatomical parts of the eye including the orbit/adnexa, ocular surface, uveal tract, retina, extraocular muscles, cranial nerves and optic nerve.2, 3 These ocular side effects are thought to represent inflammation in the context of a heightened off-target immune response to healthy ocular tissue. However, the following case demonstrates progressive choroidal depigmentation and choroidal thinning in a patient on long-term treatment of ipilimumab, nivolumab and pembrolizumab for metastatic melanoma, and in the absence of intraocular inflammation or visual symptoms.\n\n2 Case report\nA 69-year-old Caucasian female with a history of metastatic cutaneous melanoma that originated in the fifth metatarsal of her right foot, developed metastases to the brain, liver and lung. Biopsy of the liver metastasis revealed HRAS and SPRED1 genetic mutations. She was seen for a baseline ophthalmic examination 6 weeks after starting ipilimumab and nivolumab for her metastatic disease. Her ocular history was negative for previous surgeries or injury and she was taking atorvastatin for elevated cholesterol and escitalopram for anxiety.\n\nBest corrected visual acuities were 20/25 in the right eye and 20/30 in the left eye, attributed to nuclear sclerosis in both eyes. Intraocular pressures were 11 and 12 mmHg in each eye with no intra-ocular inflammation. External and fundus examination was unremarkable with no adverse effects noted from her immunotherapy and the patient was advised to return in 3 months for follow-up.\n\nOver the subsequent 26 months of follow up, she completed 2 months of ipilimumab and nivolumab, followed by 12 months of pembrolizumab and finally switched to her current maintenance of nivolumab monotherapy. During this treatment course, her vision was stable, her intraocular pressures remained normotensive and there was no evidence of intraocular inflammation in either the anterior or posterior segments; nor evidence of past or present subretinal fluid. However, there was a noticeable difference in the fundus exam compared to baseline, with progressive areas of depigmentation and small geographic areas of unchanged pigmentation (Fig. 1). Furthermore, she developed poliosis of her eyelid cilia and the patient reported cutaneous vitiligo. Approximately 7 months into treatment, she was treated with a two-week course of topical fluorometholone ointment for left lower eyelid blepharitis which promptly resolved. She denied auditory and neurological symptoms.Fig. 1 Change in choroidal pigmentation in both eyes (right eye on the left and left eye on the right) over a period of 26 months: note the progressive fundus depigmentation in an almost petaloid configuration around the optic nerve and involving the macula.\n\nFig. 1\n\nIn an attempt to better understand her fundus depigmentation, the optical coherence tomography (OCT) of her choroidal and retinal thickness as well as caliber of the retinal pigment epithelium (RPE) were retrospectively reviewed. Choroidal thickness was measured as the vertical distance from Bruch's membrane to the choroidal-scleral border using the caliper tool on the Heidelberg Spectralis OCT. Likewise, the average central retinal thickness (CRT) was defined by the distance between the internal limiting membrane (ILM) and the outer RPE at the border of Bruch's membrane. Over the course of 6 serial exams in a 26-month period, the central choroidal thickness decreased by 34% (from 270μm to 92μm, mean between both eyes) (Fig. 2). Conversely, the average CRT remained stable (206μm to 214μm, mean between both eyes) (Fig. 3); in addition to no observable change in the optical coherence tomography of the RPE.Fig. 2 Change in central choroidal thickness in both eyes (right eye on the left and left eye on the right) over a period of 26 months. The red vertical line highlights the approximate choroidal thickness. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)\n\nFig. 2Fig. 3 Graph demonstrating the gradual decrease in central choroidal thickness (CCT) in microns in the right eye (red dashed line) and left eye (red dotted line). While choroidal thickness declines, the mean central retinal thickness in the right eye (CRT) (black dashed line) and left eye (black dotted line) remains relatively stable throughout the visits. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)\n\nFig. 3\n\n3 Discussion\nCPIs are associated with adverse ocular events in 1% of patients and believed to be inflammatory in etiology. We describe a case of progressive fundus depigmentation and choroidal thinning (leptochoroid) over 26 months of checkpoint inhibition, and in the absence of overt intraocular inflammation. The stability in retinal thickness and absence of abnormalities in the RPE suggests an association between the fundus depigmentation and choroidal thinning.\n\nMany conditions are now recognized to be associated with choroidal thinning. These include: macular degeneration, diurnal (evening) measurements, glaucoma, retinal angiomatous proliferation, retinoblastoma after intra-arterial chemotherapy, Best's vitelliform stage 5, idiopathic subfoveal neovascularization, hypertension, nicotine, migraine, retinitis pigmentosa, increasing age and increasing axial length.4 Our patient did not fit any of the criteria aforementioned, except perhaps increasing age. However, age related thinning does not develop over this short a time span. Previous studies of normal patients found that central choroidal thickness typically changes about 1.1–3.14 microns per year.5 Our patient had an average change in choroidal thickness of 177 microns in both eyes over the span of 26 months highlighting that this degree of change in choroidal thickness is not related to aging.\n\nOne case of choroidal depigmentation has been reported with checkpoint inhibition, but in the context of Vogt-Harada-Koyanagi (VKH)-like disease (aka the “sunset glow” fundus) and with the associated inflammatory findings,6 not found in our patient. The case previously described reports fundus findings at a single time point and made no comment on the condition of the choroid, nor its thickness. It is interesting to note that other cases of CPI-associated VKH-like findings did not report fundus depigmentation, and the choroid was reportedly thickened (or normal) as would be expected with choroiditis.7, 8, 9 Clearly, our case of progressive fundus depigmentation and leptochoroid in the absence of past or present inflammation is distinct from these previously published cases.\n\nWe were intrigued by our patients’ integumentary (skin and hair) depigmentation in the context of concomitant fundus depigmentation. The literature makes an association between cutaneous vitiligo and “choroidal” hypopigmentation in healthy patients without inflammation or RPE changes (and without the use of CPIs).10 In these two cases, choroidal thickness was not measured, nor were there changes noted over time, but it offers an explanation for a possible link between cutaneous vitiligo and choroidal hypopigmentation. Both choroidal and skin melanocytes are derived from neural crest cells, unlike the RPE which is derived from the neuroectoderm.11 It would follow that the use of CPIs to eradicate melanoma cells would have similar effects on similarly-derived choroidal and skin melanocytes giving rise to fundus vitiligo and poliosis with stable retinal and RPE findings, as noted in our patient.\n\nOur case uniquely demonstrates that CPIs can be associated with an adverse ocular event that does not appear to be overtly inflammatory or symptomatic in nature. Furthermore, this case suggests an association between progressive fundus depigmentation and choroidal thinning, the implications of which warrant further investigation.\n\nPatient consent\nThe patient consented to publication of the case orally.\n\nFunding\nThe Fund for Ophthalmic Knowledge and the 10.13039/100000918New York Community Trust had no role in the design or conduct of this research.\n\nThis research was funded in part through the 10.13039/100000002NIH/10.13039/100000054NCI\n10.13039/100007345Cancer Center Support Grant (P30 CA008748), Ludwig Collaborative and Swim Across America Laboratory, Memorial Sloan Kettering 10.13039/100007345Cancer Center, New York, NY 10065, USA. Parker Institute for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA, Weill Cornell Medicine, New York, NY 10065, USA.\n\nAuthorship\nAll authors attest that they meet the current ICMJE criteria for Authorship.\n\nDeclaration of competing interest\nDr. Wolchok:\n\nConsultant for: Adaptive Biotech; Advaxis; Amgen; Apricity; Array BioPharma; Ascentage Pharma; Astellas; Bayer; Beigene; Bristol Myers Squibb; Celgene; Chugai; Elucida; Eli Lilly; F Star; Genentech; Imvaq; Janssen; Kleo Pharma; Kyowa Hakko Kirin; Linneaus; MedImmune; Merck; Neon Therapuetics; Northern Biologics; Ono; Polaris Pharma; Polynoma; Psioxus; Puretech; Recepta; Takara Bio; Trieza; Sellas Life Sciences; Serametrix; Surface Oncology; Syndax,; Syntalogic.\n\nResearch support: Bristol Myers Squibb; Medimmune; 10.13039/100004334Merck Pharmaceuticals; Genentech; Sephora.\n\nEquity in: Potenza Therapeutics; Tizona Pharmaceuticals; Adaptive Biotechnologies; Elucida; Imvaq; Beigene; Trieza; Linneaus; Honoraium: Esanex\n\nThe following authors have no financial disclosures: JC, KAJ, DHA, JHF.\n\nAcknowledgements\nNone.\n==== Refs\nReferences\n1 Villasboas J.C. Next generation immunotherapy in lymphoma: checkpoint blockade, chimeric antigen receptor T cells, and beyond The Basics of Cancer Immunotherapy 2018 Springer Rochester, NY 95 114 \n2 Dalvin L.A. Shields C.L. Orloff M. Checkpoint inhibitor immune therapy, systemic indications and ophthalmic side effects Retina 38 2018 1063 1078 29689030 \n3 Liu Catherine Y. Francis Jasmine H. Pulido Jose S. Abramson David H. Ocular side effects of systemically administered chemotherapy Available at: https://www.uptodate.com/contents/ocular-side-effects-of-systemically-administered-chemotherapy \n4 Francis J.H. Habib L.A. Abramson D.H. Peripheral leptochoroid: clinical and anatomical findings Br J Ophthalmol 2017 1 6 0 \n5 Tuncer I. Karahan E. Zengin M.O. Choroidal thickness in relation to sex, age, refractive error, and axial length in healthy Turkish subjects Int Ophthalmol 35 2015 403 410 24950905 \n6 Crosson J.N. Laird P.W. Debiec M. Vogt-Koyanagi-Harada-like syndrome after CTLA-4 inhibition with ipilimumab for metastatic melanoma J Immunother 38 2015 80 84 25658618 \n7 Mantopoulos D. Kendra K. Letson A. Cebulla C. Bilateral choroidopathy and serous retinal detachments during ipilimumab treatment for cutaneous melanoma JAMA Ophthalmology 133 8 2015 965 966 25974108 \n8 Wong R.K. Lee J.K. Huang J.J. Bilateral drug (Ipilimumab)-Induced vitritis, choroiditis, and serous retinal detachments suggestive of vogt-koyanagi-harada syndrome Retin Cases Brief Rep 6 4 2012 423 426 25389947 \n9 Bricout M. Petre A. Amini-Adle M. Vogt-Koyanagi-Harada-like syndrome complicating pembrolizumab treatment for metastatic melanoma J Immunother 40 2017 77 82 28166182 \n10 Vingerling J.R. Owens S. Van der Meijden W.I. Cutaneous vitiligo associated with choroidal hypopigmentation Eye 18 2004 939 940 15002019 \n11 Cook C.S. Ozanis V. Jakobiec F.A. Prenatal development of the eye and its adnexa Duane's Ophthalmology 1991 Lippincot-Raven Philadelphia, PA 1 93\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2451-9936",
"issue": "19()",
"journal": "American journal of ophthalmology case reports",
"keywords": "Cancer; Checkpoint inhibitor; Fundus vitiligo; Leptochoroid; Poliosis; Progressive choroidal thinning",
"medline_ta": "Am J Ophthalmol Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101679941",
"other_id": null,
"pages": "100799",
"pmc": null,
"pmid": "32637735",
"pubdate": "2020-09",
"publication_types": "D002363:Case Reports",
"references": "28625971;25974108;25389947;29689030;15002019;24950905;28166182;25658618",
"title": "Progressive choroidal thinning (leptochoroid) and fundus depigmentation associated with checkpoint inhibitors.",
"title_normalized": "progressive choroidal thinning leptochoroid and fundus depigmentation associated with checkpoint inhibitors"
} | [
{
"companynumb": "US-009507513-2007USA004041",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PEMBROLIZUMAB"
},
"drugadditional": "3",
... |
{
"abstract": "Spontaneous coronary artery dissection (SCAD) is a rare but increasingly recognised cause of acute coronary syndrome. While numerous risk factors are associated with SCAD, one potential cause is coronary artery vasospasm. The use of cabergoline-an ergot derivative and dopamine agonist that may induce vasospasm-has been associated with SCAD in one other case report worldwide. Here, we describe SCAD in a 37-year-old woman on long-term cabergoline therapy with no other cardiac risk factors. Cabergoline-induced SCAD should be considered in patients presenting with an acute coronary syndrome who are treated with this medication.",
"affiliations": "Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada.;Division of Cardiology, Grey Nuns Hospital, Edmonton, Alberta, Canada.;Division of Cardiology, Grey Nuns Hospital, Edmonton, Alberta, Canada.;Division of Cardiology, Department of Medicine, University of Alberta Hospital, Edmonton, Alberta, Canada.;Division of Cardiology, Department of Medicine, University of Alberta Hospital, University of Alberta, Edmonton, Alberta, Canada janek.senaratne@covenanthealth.ca.",
"authors": "Saleh|Zia|Z|;Koshy|Susan|S|;Sidhu|Vaninder|V|;Opgenorth|Andrea|A|;Senaratne|Janek|J|",
"chemical_list": "D018491:Dopamine Agonists; D000077465:Cabergoline",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2020-240022",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "14(2)",
"journal": "BMJ case reports",
"keywords": "cardiovascular medicine; drugs: endocrine system",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000328:Adult; D000077465:Cabergoline; D003329:Coronary Vasospasm; D003330:Coronary Vessel Anomalies; D018491:Dopamine Agonists; D005260:Female; D006801:Humans; D009377:Multiple Endocrine Neoplasia; D014652:Vascular Diseases",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "33563672",
"pubdate": "2021-02-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Spontaneous coronary artery dissection in association with cabergoline therapy.",
"title_normalized": "spontaneous coronary artery dissection in association with cabergoline therapy"
} | [
{
"companynumb": "CA-PFIZER INC-2021218632",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "PANTOPRAZOLE"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nThe epilepsy treatment during pregnancy represents a balance between teratogenic hazard and seizure control. The aim of the study was to evaluate the safety and efficacy of lacosamide (LCS) during pregnancy and breastfeeding.\n\n\nMETHODS\nPatients referred to our Epilepsy Center for pregnancy planning who became pregnant while taking LCS were prospectively followed-up. Data on seizure frequency, side effects, pregnancy course, delivery and breastfeeding, birth outcome, congenital malformation and development of newborns were collected.\n\n\nRESULTS\nThree cases of maternal exposure to LCS were reported. Treatment with LCS was continued throughout pregnancy and breastfeeding at a median daily dose of 400mg. Lacosamide was used as monotherapy in two patients and as add-on treatment in one woman. Seizure frequency did not change throughout pregnancy and two subjects remained seizure free. The median gestational age at delivery was 39 weeks. The median Apgar scores at 1 and 5min were 9 and 10, respectively; no major or minor congenital malformations were observed in the offspring. Normal developmental milestone were reached by all new-borns.\n\n\nCONCLUSIONS\nWorldwide pregnancy registries have provided consistent and increasing information about the efficacy and safety of the older antiepileptic drugs during gestation, while data are lacking for many of the newer generations. These cases could suggest a good level of efficacy and safety for LCS throughout pregnancy and breastfeeding and argue against teratogenic or toxic potentialities.",
"affiliations": "Neurological Clinic, Department of Experimental and Clinical Medicine, Marche Polytechnic University, Ancona, Italy. Electronic address: alfierelattanzisimona@gmail.com.;Neurological Clinic, Department of Experimental and Clinical Medicine, Marche Polytechnic University, Ancona, Italy.;Neurological Clinic, Department of Experimental and Clinical Medicine, Marche Polytechnic University, Ancona, Italy.;Neurological Clinic, Department of Experimental and Clinical Medicine, Marche Polytechnic University, Ancona, Italy.;Neurological Clinic, Department of Experimental and Clinical Medicine, Marche Polytechnic University, Ancona, Italy.",
"authors": "Lattanzi|Simona|S|;Cagnetti|Claudia|C|;Foschi|Nicoletta|N|;Provinciali|Leandro|L|;Silvestrini|Mauro|M|",
"chemical_list": "D000081:Acetamides; D000078334:Lacosamide",
"country": "Poland",
"delete": false,
"doi": "10.1016/j.pjnns.2017.03.003",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0028-3843",
"issue": "51(3)",
"journal": "Neurologia i neurochirurgia polska",
"keywords": "Epilepsy; Lacosamide; Pregnancy; Seizures",
"medline_ta": "Neurol Neurochir Pol",
"mesh_terms": "D000081:Acetamides; D000328:Adult; D001942:Breast Feeding; D004827:Epilepsy; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D000078334:Lacosamide; D011247:Pregnancy; D011248:Pregnancy Complications; D011256:Pregnancy Outcome; D011446:Prospective Studies; D012307:Risk Factors; D016896:Treatment Outcome",
"nlm_unique_id": "0101265",
"other_id": null,
"pages": "266-269",
"pmc": null,
"pmid": "28385340",
"pubdate": "2017",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Lacosamide during pregnancy and breastfeeding.",
"title_normalized": "lacosamide during pregnancy and breastfeeding"
} | [
{
"companynumb": "IT-SUN PHARMACEUTICAL INDUSTRIES LTD-2017R1-143913",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LACOSAMIDE"
},
"drug... |
{
"abstract": "Most childhood medulloblastoma (MB) cases are curable using multimodal treatment, including craniospinal irradiation (CSI). However, late effects are a serious problem for survivors. This prospective registry study evaluated Japanese patients to determine whether a reduced radiation dose was feasible.\n\n\n\nPatients with MB were classified as an infant group (<3 years old) and a high-risk (HR) group (≥3 years old with metastasis). The HR group received intrathecal methotrexate (IT-MTX) and high-dose chemotherapy (HDC) using thiotepa and melphalan, as well as concomitant radiotherapy with a recommended CSI dose of 18 Gy and a total local dose of 50 Gy. Radiotherapy was only considered for infants if residual tumors were present after the HDC.\n\n\n\nBetween 1997 and 2006, we identified 28 HR patients (M1: 9, M2/3: 19) and 17 infant patients (M0: 11, M1: 3, M2/3: 3). During the median follow-up of 9.4 years for the entire HR group, the 5-year progression-free survival (PFS) rate was 82.1 ± 7.2% and the 5-year overall survival (OS) rate was 85.7 ± 6.6%. Subanalyses of the patients who received the recommended treatment revealed that the 5-year PFS and OS rates were both 90.5 ± 6.4%. In the infant group, the 5-year PFS rate was 52.9 ± 12.1% and the 5-year OS rate was 51.8 ± 12.4%. There were no serious adverse events associated with the IT-MTX and HDC treatments.\n\n\n\nIntensified chemotherapy using HDC and IT-MTX might allow for a reduced prophylactic radiation dose in patients with MB with metastases. Further studies are needed to validate these findings.",
"affiliations": "Department of Pediatric Hematology and Oncology, Osaka City General Hospital, Osaka, Japan.;Department of Pediatric Hematology and Oncology, Osaka City General Hospital, Osaka, Japan.;Department of Radiation Oncology, Kobe Proton Center, Kobe, Japan.;Department of Pediatric Neurosurgery, Osaka City General Hospital, Osaka, Japan.;Department of Pediatric Hematology and Oncology, Osaka City General Hospital, Osaka, Japan.",
"authors": "Yamasaki|Kai|K|0000-0002-5701-8813;Okada|Keiko|K|0000-0003-0825-2985;Soejima|Toshinori|T|;Sakamoto|Hiroaki|H|;Hara|Junichi|J|",
"chemical_list": "D005047:Etoposide; D003520:Cyclophosphamide; D002945:Cisplatin; D008558:Melphalan; D008727:Methotrexate",
"country": "United States",
"delete": false,
"doi": "10.1002/pbc.28012",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1545-5009",
"issue": "67(1)",
"journal": "Pediatric blood & cancer",
"keywords": "chemotherapy; craniospinal irradiation; intrathecal methotrexate; medulloblastoma; radiotherapy; thiotepa",
"medline_ta": "Pediatr Blood Cancer",
"mesh_terms": "D000293:Adolescent; D000971:Antineoplastic Combined Chemotherapy Protocols; D002528:Cerebellar Neoplasms; D002648:Child; D002675:Child, Preschool; D002945:Cisplatin; D003131:Combined Modality Therapy; D016371:Cranial Irradiation; D003520:Cyclophosphamide; D005047:Etoposide; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007278:Injections, Spinal; D008297:Male; D008527:Medulloblastoma; D008558:Melphalan; D008727:Methotrexate; D011379:Prognosis; D011446:Prospective Studies; D012042:Registries; D015996:Survival Rate",
"nlm_unique_id": "101186624",
"other_id": null,
"pages": "e28012",
"pmc": null,
"pmid": "31544362",
"pubdate": "2020-01",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "Strategy to minimize radiation burden in infants and high-risk medulloblastoma using intrathecal methotrexate and high-dose chemotherapy: A prospective registry study in Japan.",
"title_normalized": "strategy to minimize radiation burden in infants and high risk medulloblastoma using intrathecal methotrexate and high dose chemotherapy a prospective registry study in japan"
} | [
{
"companynumb": "NVSC2019JP082523",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CISPLATIN"
},
"drugadditional": "3",
"drugad... |
{
"abstract": "OBJECTIVE\nTo describe a novel technique of using peripheral nerve neuromodulation (PNNM) for the treatment of refractory, mesh-induced chronic pelvic pain. Chronic pelvic pain associated with mesh can be a debilitating complication and there is currently no consensus on treatment. PNNM has been shown to be successful in the treatment of post-traumatic neuralgias but has yet to be studied in mesh complications.\n\n\nMETHODS\nWe present a case of a 50-year-old woman who had unrelenting pelvic pain after retropubic sling placement. She failed multiple therapies including medications, mesh removal, pelvic floor physical therapy, pudendal neuromodulation, and pelvic floor onabotulinumtoxinA trigger point injections.\n\n\nRESULTS\nThe only treatment that provided temporary relief of this patient's pain was transvaginal trigger point injections along with a right pudendal nerve block using 40 mg triamcinolone and 0.5% ropivacaine. To help define if treatment at the site of her pain would provide relief, a series of blocks were done by advancing a needle retropubically to her area of pain and injecting triamcinolone and 0.5% ropivacaine. This injection, which corresponded to the previous tract of her retropubic sling, provided temporary, but profound, relief. PNNM was then done with placement of the electrode in the retropubic space at the site of her pain. This provided instantaneous relief of almost all of her pain symptoms. Twelve months postoperatively, the patient continued to have >90% improvement in her pain.\n\n\nCONCLUSIONS\nFocused PNNM is a simple procedure and can provide symptomatic relief for refractory postvaginal mesh pain.",
"affiliations": "Detroit Medical Center, Detroit, MI. Electronic address: Ssuchy21@gmail.com.;Beaumont Hospital, Royal Oak, MI.;Beaumont Hospital, Royal Oak, MI; Oakland University William Beaumont School of Medicine, Auburn Hills, MI.",
"authors": "Martin|Sarah|S|;Han|Esther|E|;Peters|Kenneth M|KM|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.urology.2019.11.008",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0090-4295",
"issue": "137()",
"journal": "Urology",
"keywords": null,
"medline_ta": "Urology",
"mesh_terms": "D059350:Chronic Pain; D020878:Device Removal; D005260:Female; D006801:Humans; D008875:Middle Aged; D017699:Pelvic Pain; D010502:Perineum; D011183:Postoperative Complications; D019919:Prosthesis Implantation; D060525:Pudendal Nerve; D060545:Pudendal Neuralgia; D053825:Suburethral Slings; D013526:Surgical Mesh; D004561:Transcutaneous Electric Nerve Stimulation; D016896:Treatment Outcome; D061028:Trigger Points; D014550:Urinary Incontinence, Stress",
"nlm_unique_id": "0366151",
"other_id": null,
"pages": "196-199",
"pmc": null,
"pmid": "31738943",
"pubdate": "2020-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A Novel Approach to Managing Post Retropubic Vaginal Sling Pain.",
"title_normalized": "a novel approach to managing post retropubic vaginal sling pain"
} | [
{
"companynumb": "US-MYLANLABS-2020M1055180",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "ONABOTULINUMTOXINA"
},
"drugadditional": null... |
{
"abstract": "Hydralazine is a commonly used anti-hypertensive medication. It can, however, contribute to the development of autoimmunity, in the form of drug-induced lupus and anti-neutrophil cytoplasmic antibodies-associated vasculitis. We report a 45-year-old patient with hypertension managed with hydralazine for four years who presented with rapidly progressive glomerulonephritis (RPGN), requiring hemodialysis, and diffuse alveolar hemorrhage (DAH), requiring mechanical ventilation, and extracorporeal membrane oxygenation. The patient's autoantibody profile was consistent with a drug-induced autoimmune process and renal histology revealed focal necrotizing crescentic GN. She was treated with high-dose steroids, plasma exchange and rituximab. DAH resolved and her renal function improved, allowing discontinuation of hemodialysis. This case reveals that rituximab can be successfully used in the setting of hydralazine-induced vasculitis, including critically ill patients with severe DAH and acute kidney injury from RPGN.",
"affiliations": "Department of Medicine, Division of Rheumatology, Washington University School of Medicine, St. Louis, MO, USA.;Department of Medicine, Division of Pulmonary and Critical Care, Washington University School of Medicine, St. Louis, MO, USA.;Department of Pathology and Immunology, Division of Anatomic and Molecular Pathology, Washington University School of Medicine, St. Louis, MO, USA.;Department of Pathology and Immunology, Division of Anatomic and Molecular Pathology, Washington University School of Medicine, St. Louis, MO, USA.;Department of Medicine, Division of Rheumatology, Washington University School of Medicine, St. Louis, MO, USA.;Department of Medicine, Division of Nephrology, Washington University School of Medicine, St. Louis, MO, USA.",
"authors": "Paley|Michael A|MA|;Edrees|Fahad|F|;Kudose|Satoru|S|;Gaut|Joseph P|JP|;Ranganathan|Prabha|P|;Vijayan|Anitha|A|",
"chemical_list": "D000893:Anti-Inflammatory Agents; D000959:Antihypertensive Agents; D001323:Autoantibodies; D013256:Steroids; D006830:Hydralazine; D000069283:Rituximab",
"country": "Saudi Arabia",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1319-2442",
"issue": "30(1)",
"journal": "Saudi journal of kidney diseases and transplantation : an official publication of the Saudi Center for Organ Transplantation, Saudi Arabia",
"keywords": null,
"medline_ta": "Saudi J Kidney Dis Transpl",
"mesh_terms": "D000893:Anti-Inflammatory Agents; D056648:Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; D000959:Antihypertensive Agents; D001323:Autoantibodies; D005260:Female; D006801:Humans; D006830:Hydralazine; D006973:Hypertension; D008875:Middle Aged; D000069283:Rituximab; D013256:Steroids",
"nlm_unique_id": "9436968",
"other_id": null,
"pages": "226-230",
"pmc": null,
"pmid": "30804286",
"pubdate": "2019",
"publication_types": "D002363:Case Reports",
"references": "10693882;12140804;13176303;13183772;13183773;17582159;19424772;19678919;20647199;22895519;23871408;25943719;25986390;25999374;26044574;28274994;28450870;6432120;7973636;8162472",
"title": "Successful use of rituximab for hydralazine-induced anti-neutrophil cytoplasmic antibodies-associated vasculitis.",
"title_normalized": "successful use of rituximab for hydralazine induced anti neutrophil cytoplasmic antibodies associated vasculitis"
} | [
{
"companynumb": "US-CIPLA LTD.-2020US03666",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "HYDRALAZINE HYDROCHLORIDE"
},
"drugadditional... |
{
"abstract": "BACKGROUND\nAnti-tumor necrosis factor (TNF) agents are increasingly being used for a rapidly expanding number of rheumatic and systemic diseases. As a result of this use, and of the longer follow-up periods of treatment, there are a growing number of reports of the development of autoimmune processes related to anti-TNF agents. The use of anti-TNF agents has been associated with more and more cases of autoimmune diseases, principally cutaneous vasculitis, lupus-like syndrome, systemic lupus erythematosus and interstitial lung disease.\n\n\nMETHODS\nWe report 2 cases of autoimmune bullous skin disease occurring in patients undergoing TNF-targeted therapy: a bullous pemphigoid and a pemphigus foliaceus. Both patients were treated by anti-TNF agents for rheumatoid arthritis and showed improvement following interruption of that treatment. Here, we discuss the relationship between anti-TNF therapy and the occurrence of autoimmune bullous disease.\n\n\nCONCLUSIONS\nAnti-TNF agents should be considered as a potential cause of drug-induced autoimmune bullous skin disease.",
"affiliations": "Department of Dermatology and Venereology, Hôpital Cochin, Paris, France.",
"authors": "Boussemart|L|L|;Jacobelli|S|S|;Batteux|F|F|;Goulvestre|C|C|;Grange|P|P|;Carlotti|A|A|;Morini|J P|JP|;Gorin|I|I|;Ziza|J M|JM|;Avril|M F|MF|;Dupin|N|N|",
"chemical_list": "D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D018501:Antirheumatic Agents; D001323:Autoantibodies; D000079424:Tumor Necrosis Factor Inhibitors; D000069285:Infliximab; D000068879:Adalimumab",
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000318008",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1018-8665",
"issue": "221(3)",
"journal": "Dermatology (Basel, Switzerland)",
"keywords": null,
"medline_ta": "Dermatology",
"mesh_terms": "D000068879:Adalimumab; D000368:Aged; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D018501:Antirheumatic Agents; D001172:Arthritis, Rheumatoid; D001323:Autoantibodies; D003875:Drug Eruptions; D005260:Female; D006801:Humans; D000069285:Infliximab; D008297:Male; D008875:Middle Aged; D010391:Pemphigoid, Bullous; D010392:Pemphigus; D000079424:Tumor Necrosis Factor Inhibitors",
"nlm_unique_id": "9203244",
"other_id": null,
"pages": "201-5",
"pmc": null,
"pmid": "20720390",
"pubdate": "2010",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Autoimmune bullous skin diseases occurring under anti-tumor necrosis factor therapy: two case reports.",
"title_normalized": "autoimmune bullous skin diseases occurring under anti tumor necrosis factor therapy two case reports"
} | [
{
"companynumb": "FR-ABBVIE-10P-056-0685577-00",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "BISOPROLOL"
},
"drugadditional": null,
... |
{
"abstract": "Castration-resistant prostate cancer (CRPC) patients with liver metastases have an extremely poor prognosis. Herein, we report a rare patient who achieved a complete response by docetaxel chemotherapy for this aggressive disease. A 67-year-old Japanese male diagnosed with local prostate cancer [initial prostate specific antigen (PSA) of 10.3 ng/mL, a highest Gleason score of eight] received radical prostatectomy (RP) followed by salvage radiotherapy for PSA recurrence without distant metastases. After four years, androgen deprivation therapy was commenced for both local recurrence and elevated PSA. After a further four years, despite good control of PSA (1.2 ng/mL), other clinical findings including radiographic images revealed CRPC with multiple liver metastases. Ten cycles of docetaxel chemotherapy achieved a complete response for more than five years. In conclusion, even if a patient has CRPC with liver metastases, early diagnostic imaging irrespective of the PSA level may provide a better response to early docetaxel chemotherapy.",
"affiliations": "Department of Uro-Oncology, Saitama Medical University International Medical Center, Saitama, Japan.;Department of Uro-Oncology, Saitama Medical University International Medical Center, Saitama, Japan.;Department of Uro-Oncology, Saitama Medical University International Medical Center, Saitama, Japan.;Department of Uro-Oncology, Saitama Medical University International Medical Center, Saitama, Japan.;Department of Uro-Oncology, Saitama Medical University International Medical Center, Saitama, Japan.;Department of Uro-Oncology, Saitama Medical University International Medical Center, Saitama, Japan.;Department of Uro-Oncology, Saitama Medical University International Medical Center, Saitama, Japan.",
"authors": "Shirotake|Suguru|S|;Umezawa|Yuta|Y|;Okabe|Takashi|T|;Kaneko|Go|G|;Kanao|Kent|K|;Nishimoto|Koshiro|K|;Oyama|Masafumi|M|",
"chemical_list": null,
"country": "China",
"delete": false,
"doi": "10.21037/tau.2020.01.20",
"fulltext": "\n==== Front\nTransl Androl Urol\nTransl Androl Urol\nTAU\nTranslational Andrology and Urology\n2223-4683\n2223-4691\nAME Publishing Company\n\n32420190\ntau-09-02-819\n10.21037/tau.2020.01.20\nCase Report\nA case of castration-resistant prostate cancer with liver metastases achieved a complete response by docetaxel chemotherapy\nShirotake Suguru\nUmezawa Yuta\nOkabe Takashi\nKaneko Go\nKanao Kent\nNishimoto Koshiro\nOyama Masafumi\nDepartment of Uro-Oncology, Saitama Medical University International Medical Center, Saitama, Japan\nCorrespondence to: Suguru Shirotake, MD, PhD. 1397-1 Yamane, Hidaka, Saitama 350-1298, Japan. Email: ss6001@5931.saitama-med.ac.jp.\n4 2020\n4 2020\n9 2 819823\n24 8 2019\n06 1 2020\n2020 Translational Andrology and Urology. All rights reserved.\n2020\nTranslational Andrology and Urology.\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0.\nCastration-resistant prostate cancer (CRPC) patients with liver metastases have an extremely poor prognosis. Herein, we report a rare patient who achieved a complete response by docetaxel chemotherapy for this aggressive disease. A 67-year-old Japanese male diagnosed with local prostate cancer [initial prostate specific antigen (PSA) of 10.3 ng/mL, a highest Gleason score of eight] received radical prostatectomy (RP) followed by salvage radiotherapy for PSA recurrence without distant metastases. After four years, androgen deprivation therapy was commenced for both local recurrence and elevated PSA. After a further four years, despite good control of PSA (1.2 ng/mL), other clinical findings including radiographic images revealed CRPC with multiple liver metastases. Ten cycles of docetaxel chemotherapy achieved a complete response for more than five years. In conclusion, even if a patient has CRPC with liver metastases, early diagnostic imaging irrespective of the PSA level may provide a better response to early docetaxel chemotherapy.\n\nKeywords:\n\nCastration-resistant prostate cancer (CRPC)\nliver metastasis\ndocetaxel chemotherapy\n==== Body\npmcIntroduction\n\nThe presence of visceral disease in patients with metastatic castration-resistant prostate cancer (mCRPC) has been identified as one of the important prognostic factors for overall survival (OS) (1-3). A meta-analysis of phase III trials (4-12) of a total of about 9,000 patients with mCRPC who received docetaxel treatment revealed that visceral disease was present in 20.8% (e.g., lung 9.1%, liver 8.6%), and that the median OS time in patients with liver metastases (13.5 months) was significantly shorter than those with bone (21.3 months) or lung metastases (19.4 months) (3).\n\nAlthough the androgen receptor (AR) axis targeted therapies (ARAT), including abiraterone acetate and enzalutamide, have been commonly used for patients with mCRPC, docetaxel treatment can be considered for patients suspected of ARAT resistance or with visceral metastatic disease (13). However, even when a prostate specific antigen (PSA) response (45% to 64%) or radiological response (12% to 28%) are observed by docetaxel treatment, the progression survival time is typically at a median of 6 to 8 months (5,9).\n\nWe herein present a rare patient with CRPC and liver metastases who achieved a complete response for more than five years following docetaxel treatment.\n\nCase presentation\n\nA 67-year-old Japanese male (SIMC-Uro #542: a unique, non-sequential patient control number in the Department of Uro-Oncology, Saitama Medical University International Medical Center) had an elevated serum PSA of 10.3 ng/mL without symptoms at a check-up examination in 2005. The patient had no significant medical history. At another hospital, a prostate biopsy revealed a prostate adenocarcinoma with a highest Gleason score of eight (4+4). Radiographic imaging showed no evidence of local progression or distant metastases. A luteinizing hormone-releasing hormone (LH-RH) analogue was initiated by the attending physician (details unknown), and then he was referred to another hospital for radical treatment.\n\nIn February 2005, his preoperative PSA level was 4.90 ng/mL, and a radical prostatectomy (RP) with pelvic lymphadenectomy was performed. The pathological diagnosis was adenocarcinoma with a highest Gleason score of eight (4+4), pT2N0, and a negative resected margin. The changes in PSA level and treatments after RP are shown in Figure 1. LH-RH analogue treatment (leuprorelin 3.75 mg monthly) was re-initiated due to a postoperative PSA nadir of 7.31 ng/mL at 39 days after RP, and PSA of 0.11 ng/mL at 118 days after RP.\n\nFigure 1 PSA changes from the initial treatment. RP, radical prostatectomy; RTx, radiotherapy; LH-RH, luteinizing hormone-releasing hormone; PSA, prostate specific antigen.\n\nHe was referred to our institution in 2007 with the aim of continuing treatment for elevated PSA after RP. External irradiation (total 60 Gy/30 fractions, RTx in Figure 1) performed after confirming that there were no distant metastases, and then the LH-RH analogue was withdrawn. Unfortunately, his PSA level rapidly increased from February 2009 (PSA 1.279 ng/mL). Radiographic imaging (Figure 2) in September 2009 showed no evidence of distant metastases (Figure 2A,C), but an unidentified region was found between the bladder and rectum, which suggested local recurrence in a part of the remaining seminal vesicle (* in Figure 2B). As PSA increased to 5.739 ng/mL, maximum androgen blockade was commenced with the addition of bicalutamide (80 mg/day) and an LH-RH analogue (goserelin 10.8 mg 3-monthly) from February 2010, resulting in an immediate decrease in the PSA level. Subsequently, due to a lack of PSA response, flutamide (250 mg/day) was replaced with bicalutamide in October 2012 (PSA 0.139 ng/mL), and estradiol (1.5 mg/day) was replaced with flutamide in November 2013 (PSA 1.421 ng/mL). Almost six months after starting estradiol administration, he unexpectedly visited our outpatient center with a complaint of anorexia, and he had a PSA of 1.237 ng/mL at that time. There were no abnormal laboratory data. However, computed tomography (CT) imaging showed multiple nodules with surrounding enhancement in the liver and in the prostate bed, and a newly sclerotic lesion in the right pubis (Figure 2D,E,F). Gastrointestinal endoscopy and assessment of tumor markers including CEA and CA19-9 revealed normal findings, suggesting that multiple liver metastases, bone metastasis and local recurrence originated from prostate cancer. The serum levels of neuron-specific enolase (NSE) and pro-gastrin-releasing peptide (pro-GRP) were not examined.\n\nFigure 2 Abdominal and pelvic computed tomography imaging. (A,B,C) At post-radical prostatectomy; (D,E,F) before docetaxel treatment; (G,H,I,J,K,L) after docetaxel treatment. Yellow arrow heads show disease lesions. *, a part of the remaining seminal vesicle; RP, radical prostatectomy; Bl, bladder; Re, rectum.\n\nSubsequently, docetaxel chemotherapy (75 mg/m2 every 3 to 4 weeks, depending on the patient’s condition) with prednisolone (10 mg/day) was initiated for metastatic mCRPC in August 2014. The major complaint of anorexia gradually improved, and his PSA level also decreased (Figure 1). CT imaging showed a marked reduction of liver metastases and local recurrence after 6 and 10 cycles of docetaxel chemotherapy (Figure 2G,H,J,K). However, the sclerotic lesion in the pubis remained (Figure 2I,L). A total of 10 cycles of docetaxel chemotherapy were terminated and both blood (e.g., PSA) and radiographic examinations (e.g., CT and bone scintigraphy) were routinely performed.\n\nHis PSA level gradually increased after the last docetaxel chemotherapy (a PSA of 0.170 ng/mL in August 2016), and radiographic imaging did not show any new metastatic lesions, including in the liver. Enzalutamide was administered at an initial dose of 80 mg/day due to his general condition. His PSA level immediately decreased, and there were no abnormal radiographic findings except for the sclerotic lesion persisting in the right pubis. Ultimately, a complete response for more than five years was achieved with docetaxel chemotherapy for CRPC with multiple liver metastases.\n\nDiscussion\n\nWe encountered an extremely rare case in which a complete response to CRPC with multiple liver metastases was achieved by docetaxel chemotherapy. Of note, the intriguing issue in this case was the early radiographic diagnosis of multiple metastases in a non-metastatic CRPC patient despite a low and stable PSA level.\n\nIrrespective of the presence of metastases, CRPC patients have been recommended to be monitored by physical examinations and laboratory tests including PSA every 3 to 6 months, as well as undergoing regular imaging tests, including bone scans and CT or MRI (14,15). Nevertheless, many physicians rely on PSA and physical examinations as the principal measures of response and progression, and imaging is often reserved until the appearance of symptoms or PSA progression. The post hoc analysis of the PREVAIL study has not been validated and could result in delayed detection of disease progression if it occurs without a rise in PSA (16). Indeed, this study showed progression in 24.5% of patients on enzalutamide without any PSA progression, and that 34.3% of patients with visceral metastases had non-rising PSA levels (16). These results suggest that a disease monitoring strategy needs not only PSA measurements, but also imaging, to more accurately evaluate disease progression.\n\nRecently, 68Ga-PSMA-PET using radiolabeled prostate-specific membrane antigen (PSMA) ligands, has achieved higher specificity and sensitivity in the detection of metastases compared to standard imaging (CT, MRI and bone scintigraphy), resulting in improved detection of metastatic lesions at low serum PSA levels (17). However, it should be noted that CRPC with neuroendocrine trans-differentiation could represent loss of PSMA-expression of liver metastases in progressive disease (18). Further studies will identify the optimal modalities and imaging frequency, especially for patients with non-metastatic CRPC.\n\nCRPC tumors associated with a lack of PSA progression, such as the present case, may have become less reliant on AR for their growth and may indicate the need for chemotherapy or treatment using non-AR targeting strategies. Namely, patients with good performance status who are able to tolerate chemotherapy, are suspected to be ARAT treatment resistance (e.g., prior response to ADT <1 year), are symptomatic or have visceral metastatic disease, and should be considered for docetaxel treatment, and subsequent cabazitaxel treatment (13). However, patients with CRPC should generally be considered to have PCa variant components, including neuroendocrine prostate cancer, which presents with loss of PSA expression, symptomatic disease and visceral disease. These PCa variants may have a high likelihood of resistance to both ARAT therapy and taxane-based chemotherapy; therefore, patients with these aggressive diseases should be considered for the platinum-based chemotherapy (19). The present patient continues to receive enzalutamide for both the slight increase in PSA and the remaining pubic sclerotic lesion after docetaxel treatment, and has shown a complete response to mCRPC. In the future, if this patient develops new visceral metastases, we will select docetaxel re-challenge treatment followed by cabazitaxel treatment, considering platinum-based chemotherapy for a PCa variant disease.\n\nIn conclusion, this successful case suggests that even if a CRPC patient has visceral metastases including in the liver, early diagnostic imaging irrespective of PSA level may lead to early initiation of docetaxel chemotherapy, resulting in a favorable clinical outcome.\n\nSupplementary\n\nThe article’s supplementary files as\n\n10.21037/tau.2020.01.20\n\nAcknowledgments\n\nFunding: None.\n\nEthical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. Written informed consent was obtained from the patient for publication of this manuscript and any accompanying images.\n\nConflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/tau.2020.01.20). The authors have no conflicts of interest to declare.\n==== Refs\nReferences\n\n1 Armstrong AJ Garrett-Mayer ES Yang YC A contemporary prognostic nomogram for men with hormone-refractory metastatic prostate cancer: a TAX327 study analysis. Clin Cancer Res 2007;13 :6396-403. 10.1158/1078-0432.CCR-07-1036 17975152\n2 Halabi S Lin CY Kelly WK Updated prognostic model for predicting overall survival in first-line chemotherapy for patients with metastatic castration-resistant prostate cancer. J Clin Oncol 2014;32 :671-7. 10.1200/JCO.2013.52.3696 24449231\n3 Halabi S Kelly WK Ma H Meta-Analysis Evaluating the Impact of Site of Metastasis on Overall Survival in Men With Castration-Resistant Prostate Cancer. J Clin Oncol 2016;34 :1652-9. 10.1200/JCO.2015.65.7270 26951312\n4 Petrylak DP Tangen CM Hussain MH Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med 2004;351 :1513-20. 10.1056/NEJMoa041318 15470214\n5 Tannock IF de Wit R Berry WR Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 2004;351 :1502-12. 10.1056/NEJMoa040720 15470213\n6 Kelly WK Halabi S Carducci M Randomized, double-blind, placebo-controlled phase III trial comparing docetaxel and prednisone with or without bevacizumab in men with metastatic castration-resistant prostate cancer: CALGB 90401. J Clin Oncol 2012;30 :1534-40. 10.1200/JCO.2011.39.4767 22454414\n7 Fizazi K Higano CS Nelson JB Phase III, randomized, placebo-controlled study of docetaxel in combination with zibotentan in patients with metastatic castration-resistant prostate cancer. J Clin Oncol 2013;31 :1740-7. 10.1200/JCO.2012.46.4149 23569308\n8 Quinn DI Tangen CM Hussain M Docetaxel and atrasentan versus docetaxel and placebo for men with advanced castration-resistant prostate cancer (SWOG S0421): a randomised phase 3 trial. Lancet Oncol 2013;14 :893-900. 10.1016/S1470-2045(13)70294-8 23871417\n9 Tannock IF Fizazi K Ivanov S Aflibercept versus placebo in combination with docetaxel and prednisone for treatment of men with metastatic castration-resistant prostate cancer (VENICE): a phase 3, double-blind randomised trial. Lancet Oncol 2013;14 :760-8. 10.1016/S1470-2045(13)70184-0 23742877\n10 Araujo JC Trudel GC Saad F Docetaxel and dasatinib or placebo in men with metastatic castration-resistant prostate cancer (READY): a randomised, double-blind phase 3 trial. Lancet Oncol 2013;14 :1307-16. 10.1016/S1470-2045(13)70479-0 24211163\n11 Petrylak DP Vogelzang NJ Budnik N Docetaxel and prednisone with or without lenalidomide in chemotherapy-naive patients with metastatic castration-resistant prostate cancer (MAINSAIL): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet Oncol 2015;16 :417-25. 10.1016/S1470-2045(15)70025-2 25743937\n12 Chi KN Higano CS Blumenstein B Custirsen in combination with docetaxel and prednisone for patients with metastatic castration-resistant prostate cancer (SYNERGY trial): a phase 3, multicentre, open-label, randomised trial. Lancet Oncol 2017;18 :473-85. 10.1016/S1470-2045(17)30168-7 28283282\n13 Chi K Hotte SJ Joshua AM Treatment of mCRPC in the AR-axis-targeted therapy-resistant state. Ann Oncol 2015;26 :2044-56. 10.1093/annonc/mdv267 26101426\n14 Scher HI Morris MJ Stadler WM Trial Design and Objectives for Castration-Resistant Prostate Cancer: Updated Recommendations From the Prostate Cancer Clinical Trials Working Group 3. J Clin Oncol 2016;34 :1402-18. 10.1200/JCO.2015.64.2702 26903579\n15 Mohler JL Antonarakis ES Armstrong AJ Prostate Cancer, Version 2.2019, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw 2019;17 :479-505. 10.6004/jnccn.2019.0023 31085757\n16 Bryce AH Alumkal JJ Armstrong A Radiographic progression with nonrising PSA in metastatic castration-resistant prostate cancer: post hoc analysis of PREVAIL. Prostate Cancer Prostatic Dis 2017;20 :221-7. 10.1038/pcan.2016.71 28117385\n17 Damjanovic J Janssen JC Prasad V (68)Ga-PSMA-PET/CT for the evaluation of liver metastases in patients with prostate cancer. Cancer Imaging 2019;19 :37. 10.1186/s40644-019-0220-x 31186052\n18 Rauscher I Maurer T Fendler WP (68)Ga-PSMA ligand PET/CT in patients with prostate cancer: How we review and report. Cancer Imaging 2016;16 :14. 10.1186/s40644-016-0072-6 27277843\n19 Aparicio AM Harzstark AL Corn PG Platinum-based chemotherapy for variant castrate-resistant prostate cancer. Clin Cancer Res 2013;19 :3621-30. 10.1158/1078-0432.CCR-12-3791 23649003\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2223-4683",
"issue": "9(2)",
"journal": "Translational andrology and urology",
"keywords": "Castration-resistant prostate cancer (CRPC); docetaxel chemotherapy; liver metastasis",
"medline_ta": "Transl Androl Urol",
"mesh_terms": null,
"nlm_unique_id": "101581119",
"other_id": null,
"pages": "819-823",
"pmc": null,
"pmid": "32420190",
"pubdate": "2020-04",
"publication_types": "D002363:Case Reports",
"references": "23649003;25743937;26101426;28117385;31186052;23871417;15470214;24211163;22454414;26951312;23742877;24449231;23569308;26903579;27277843;15470213;31085757;17975152;28283282",
"title": "A case of castration-resistant prostate cancer with liver metastases achieved a complete response by docetaxel chemotherapy.",
"title_normalized": "a case of castration resistant prostate cancer with liver metastases achieved a complete response by docetaxel chemotherapy"
} | [
{
"companynumb": "JP-TOLMAR, INC.-20JP021767",
"fulfillexpeditecriteria": "2",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "LEUPROLIDE ACETATE"
},
"drugadditional": nul... |
{
"abstract": "Background: Lung cancer is a complex disease with many subtypes. However, histochemical characteristics, and genetic mutation determinations are contributing to better define therapeutic targets and new drugs. Although this guarantees patients the possibility of obtaining tailored treatment, it makes it more difficult for clinicians patient management more difficult for clinicians who have to define the most suitable therapeutic strategy and to deal with new treatment-related adverse events (TRAEs). It has been seen that the administration of a tyrosine kinase inhibitor (TKI) sequential to an immune checkpoint inhibitor (ICI) can lead to a higher rate of severe and life-threatening TRAEs. We report the case of a patient with advanced non-small cell lung cancer (NSCLC) who experienced severe hepatotoxicity and Stevens-Johnson syndrome (SJS) induced by osimertinib sequential to pembrolizumab. Case presentation: A 54-year-old woman with advanced NSCLC received one cycle of chemotherapy plus pembrolizumab after diagnosis. Ten days later she began osimertinib 80 mg daily because epidermal growth factor receptor (EGFR) analysis had revealed an exon 19 deletion. On day 23 of osimertinib the patient experienced an episode of grade (G) 3 hepatotoxicity resolved by discontinuing osimertinib and corticosteroid therapy. The patient restarted osimertinib 80 mg daily after the remission of symptoms but was hospitalized 14 days later following a second episode of severe G3 hepatotoxicity and the onset of SJS, successfully treated with high-dose corticosteroids. Despite the short exposure to osimertinib, the patient obtained a good pathological response. Conclusion: It is important to alert clinicians to carefully evaluate the sequential therapeutic strategy in patients with NSCLC who are candidates for TKI- or ICI-based treatment. Our experience suggests that the use of tyrosine kinase inhibitors (TKIs) as front-line treatment is a more reasonable and safe option for EGFR-mutated lung adenocarcinoma, with ICIs considered as a possible further treatment in sequential approaches.",
"affiliations": "Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) \"Dino Amadori\", Meldola, Italy.;Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) \"Dino Amadori\", Meldola, Italy.;Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) \"Dino Amadori\", Meldola, Italy.;Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) \"Dino Amadori\", Meldola, Italy.;Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) \"Dino Amadori\", Meldola, Italy.;Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) \"Dino Amadori\", Meldola, Italy.;Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) \"Dino Amadori\", Meldola, Italy.;Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) \"Dino Amadori\", Meldola, Italy.;Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) \"Dino Amadori\", Meldola, Italy.",
"authors": "Gianni|Caterina|C|;Bronte|Giuseppe|G|;Delmonte|Angelo|A|;Burgio|Marco Angelo|MA|;Andrikou|Kalliopi|K|;Monti|Manlio|M|;Menna|Cecilia|C|;Frassineti|Giovanni Luca|GL|;Crinò|Lucio|L|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3389/fphar.2021.672233",
"fulltext": "\n==== Front\nFront Pharmacol\nFront Pharmacol\nFront. Pharmacol.\nFrontiers in Pharmacology\n1663-9812\nFrontiers Media S.A.\n\n672233\n10.3389/fphar.2021.672233\nPharmacology\nCase Report\nCase Report: Stevens-Johnson Syndrome and Hepatotoxicity Induced by Osimertinib Sequential to Pembrolizumab in a Patient With EGFR-Mutated Lung Adenocarcinoma\nGianni et al.\nSJS, Hepatotoxicity After Osimertinib Post-Pembrolizumab\nGianni Caterina 1 †\n\nBronte Giuseppe * 1 †\n\nDelmonte Angelo\n\nBurgio Marco Angelo\nAndrikou Kalliopi\nMonti Manlio\nMenna Cecilia\nFrassineti Giovanni Luca\nCrinò Lucio\nDepartment of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, Meldola, Italy\nEdited by:Robert Clarke, University of Minnesota Twin Cities, United States\n\nReviewed by:Veronica Aran, Instituto Estadual do Cérebro Paulo Niemeyer (IECPN), Brazil\n\nLana Nezic, University of Banja Luka, Bosnia and Herzegovina\n\n*Correspondence: Giuseppe Bronte, giuseppe.bronte@irst.emr.it\n†These authors have contributed equally to this work\n\nThis article was submitted to Pharmacology of Anti-Cancer Drugs, a section of the journal Frontiers in Pharmacology\n\n12 8 2021\n2021\n12 67223325 2 2021\n02 8 2021\nCopyright © 2021 Gianni, Bronte, Delmonte, Burgio, Andrikou, Monti, Menna, Frassineti and Crinò.\n2021\nGianni, Bronte, Delmonte, Burgio, Andrikou, Monti, Menna, Frassineti and Crinò\nhttps://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.\nBackground: Lung cancer is a complex disease with many subtypes. However, histochemical characteristics, and genetic mutation determinations are contributing to better define therapeutic targets and new drugs. Although this guarantees patients the possibility of obtaining tailored treatment, it makes it more difficult for clinicians patient management more difficult for clinicians who have to define the most suitable therapeutic strategy and to deal with new treatment-related adverse events (TRAEs). It has been seen that the administration of a tyrosine kinase inhibitor (TKI) sequential to an immune checkpoint inhibitor (ICI) can lead to a higher rate of severe and life-threatening TRAEs. We report the case of a patient with advanced non-small cell lung cancer (NSCLC) who experienced severe hepatotoxicity and Stevens-Johnson syndrome (SJS) induced by osimertinib sequential to pembrolizumab.\n\nCase presentation: A 54-year-old woman with advanced NSCLC received one cycle of chemotherapy plus pembrolizumab after diagnosis. Ten days later she began osimertinib 80 mg daily because epidermal growth factor receptor (EGFR) analysis had revealed an exon 19 deletion. On day 23 of osimertinib the patient experienced an episode of grade (G) 3 hepatotoxicity resolved by discontinuing osimertinib and corticosteroid therapy. The patient restarted osimertinib 80 mg daily after the remission of symptoms but was hospitalized 14 days later following a second episode of severe G3 hepatotoxicity and the onset of SJS, successfully treated with high-dose corticosteroids. Despite the short exposure to osimertinib, the patient obtained a good pathological response.\n\nConclusion: It is important to alert clinicians to carefully evaluate the sequential therapeutic strategy in patients with NSCLC who are candidates for TKI- or ICI-based treatment. Our experience suggests that the use of tyrosine kinase inhibitors (TKIs) as front-line treatment is a more reasonable and safe option for EGFR-mutated lung adenocarcinoma, with ICIs considered as a possible further treatment in sequential approaches.\n\nnon-small cell lung cancer\npembrolizumab\nosimertinib\nstevens johnson syndrome\nliver toxicity\n==== Body\nIntroduction\n\nLung cancer is the leading cause of cancer death worldwide (Torre et al., 2016), with the majority of patients diagnosed with advanced non-small cell lung cancer (NSCLC). The prognosis for these patients is poor, with an estimated 5-year overall survival (OS) of around 15%. Recently, the identification of a number of molecular alterations has helped to identify oncogene-addicted tumors (Rosell and Karachaliou, 2016). The greatest benefit in OS has been achieved in patients harboring activating mutations in epidermal growth factor receptor (EGFR) gene or genetic rearrangements of echinoderm microtubule-associated protein-like 4 with anaplastic lymphoma kinase (EML4-ALK). Osimertinib targets both EGFR-activating and T790M mutations. A tumor response rate of 60% was reported in two single-arm trials, the phase I AURA (Jänne et al., 2015) and the phase II AURA2 (Goss et al., 2016) trials. In November 2015, the drug was approved by the Food and Drug Administration (FDA) for the treatment of patients with metastatic NSCLC and EGFR T790M mutation progressing during EGFR TKI treatment. The phase III AURA3 study (Mok et al., 2017) reported significantly longer progression-free survival (PFS) and a higher objective response rate (ORR) for osimertinib with respect to platinum plus pemetrexed combination chemotherapy in this population of patients. Hence, osimertinib was approved by the FDA and the European Medicines Agency (EMA) for use in NSCLC with sensitizing EGFR mutations (National Comprehensive Ca, 2021). Osimertinib is more tolerable than chemotherapy and can penetrate the blood brain barrier (Colclough et al., 2021).\n\nThe main treatment for patients with metastatic NSCLC and no evidence of oncogene drivers is a combination of an immune checkpoint inhibitor (ICI) with platinum-based chemotherapy (Gandhi et al., 2018). The combined use of pembrolizumab with pemetrexed and cisplatin or carboplatin has already been approved for clinical practice in patients with non-oncogene-addicted advanced NSCLC. A recent meta-analysis on chemoimmunotherapy highlighted that it does not induce a higher risk of high-grade hematological or gastrointestinal adverse effects, with the exception of high-grade diarrhea (Abdel-Rahman, 2019).\n\nThe use of these new biological treatments has also meant that oncologists have had to deal with rare new toxicities other than those deriving from chemotherapy. never experienced before. Of note, the sequential use of ICIs (especially PD-1 inhibitors) followed by TKIs for EGFR-mutated adenocarcinoma has been shown to increase the risk of severe and life-threatening side-effects, toxicities as seen in clinical trials with combination regimens (Schoenfeld et al., 2019; De-Rui Huang and Chih-Hsin Yang, 2020). Hence, a pressing challenge now facing clinicians is that one of the new challenges consists of being able to combine these new therapies in the right way to maximize therapeutic success and limit potentially dangerous adverse events.\n\nCase Presentation\n\nA 54-year-old woman with NSCLC (ALK-negative, ROS 1-negative, PDL1 expression <1%, EGFR not available) without comorbidities presented with disseminated disease involving lymph nodes, adrenal glands, bones, and brain. She immediately began carboplatin 5AUC, pemetrexed 500 mg/m2 and pembrolizumab 200 mg q21 because of rapid disease spread. After the first therapy cycle, EGFR status was evaluated and showed an exon 19 deletion. Ten days later the patient started osimertinib 80 mg daily. On day 23 of osimertinib she interrupted treatment because of fever, grade (G) 3 hypertransaminasemia (Common Terminology Criter, 2020), with negative abdomen ultrasonography, suspected pancreatitis, and concomitant G2 mucositis. Upon suspicion of drug-induced hepatotoxicity, the patient began steroid therapy, slowly tapering off it. After an 8-day discontinuation the patient was re-started on osimertinib 8 mg/die because of the complete remission of symptoms and the improvement in liver serum enzymes to G1 (AstraZeneca Pharmaceuticals, 2018).\n\nFourteen days after the rechallenge with osimertinib, the patient was hospitalized in a state of hypovolemic shock with fever >39°C, diffuse painful G3 cutaneous erythema with confluent macules, pruritus and diffuse flaking. Laboratory tests showed hepatotoxicity with a G3 increase in liver serum enzymes (Figure 1). Viral hepatitis was excluded and blood cultures were negative. After 24 h, the cutaneous toxicity worsened and was accompanied by diffuse mucositis with oral blisters, nasal ulcers and conjunctivitis. Nikolsky’s sign was negative. Finally, a clinical diagnosis of Stevens-Johnson syndrome was made (Figure 2).\n\nFIGURE 1 Serum enzyme trend during treatment with osimertinib after chemotherapy + pembrolizumab and concomitant steroid therapy. The modification of liver enzymes indicated grade (G) 3 liver injury, with important alterations in alkaline phosphatase (ALP), gamma-glutamyltransferase (GGT), aspartate transaminase (AST) and alanine transaminase (ALT). Although the interruption of osimertinib and the concomitant use of steroids reduced the altered enzyme values, an insufficient interval between the adverse event and osimertinib rechallenge rapidly induced new toxicity that took several days to resolve.\n\nFIGURE 2 Cutaneous and mucosal involvement in Stevens-Johnson syndrome (day 45 of osimertinib). (A) Diffuse painful G3 erythema over the entire body upon hospital admission. The patient also had mucositis of the oral cavity (with blisters), pharynx (causing dysphagia), eyes, vagina, and nose (with ulcers causing episodes of epistaxis). SCORTEN score 3 (Bastuji-Garin, et al., 2000). (B) Reduction in the diffuse erythema, with areas of flaking and depigmentation (day 60).\n\nMethylprednisolone (1 mg/kg/die) in association with an antihistamine were started, with rapid defervescence, and then increased to 2 mg/kg/die when the skin conditions got worse. An antimycotic (fluconazole) and empirical antibiotic therapies (piperacillin-tazobactam) were started intravenously, as were hyaluronate ocular drops, sucralfate oral granules, a ceramide-containing topical body cream and parenteral nutrition. Liver enzymes showed a slow downtrend and the cutaneous erythema began to resolve with, however, residual areas of depigmentation due to cutaneous flaking.\n\nA total body contrast-enhanced CT scan showed disease stability and complete response of brain lesions (day 60) (Figure 3). The patient was discharged and continued the tapering off of oral steroid therapy. The skin returned to normal, with residual areas of depigmentation that showed further cutaneous flaking, and liver enzymes slowly reached normal values. The patient was monitored closely for the next 3 months.\n\nFIGURE 3 Brain response at CT scan. Comparison between baseline brain lesion at diagnosis and the impressive complete response after 3 months following chemoimmunotherapy and osimertinib. Osimertinib was only taken for a total of 37 days and then suspended because of severe toxicity.\n\nA subsequent positron emission tomography (PET) scan showed a slight increase in disease progression. In agreement with the patient, after receiving patient informed consent, osimertinib was resumed at a dose of 80 mg daily combined with prednisone 25 mg, with close clinical surveillance. The patient successfully continued osimertinib, slowly reducing corticosteroid therapy, with good tolerance and maintaining disease stability.\n\nDiscussion\n\nIn our case report, we present an unusual combination of rare and life-threating adverse events. Although a few postmarketing cases of SJS have been reported in patients receiving osimertinib (AstraZeneca Pharmaceutica, 2018), elevation in liver enzymes is considered uncommon (5% G1-2, <1% G3) (Goss et al., 2016). In particular, osimertinib-induced acute liver injury is an extremely rare event and described in few case reports (Yoshida and Kim, 2017; Hirabayashi et al., 2018; González and Chatterjee, 2019). Conversely, immune-related hepatotoxicity has been documented as a more common ICI- mediated adverse event, as have as well for cutaneous reactions. SJS is a rare event that are described too (Schoenfeld et al., 2019; National Comprehensive Ca, 2021). There are several therapeutic options for lung cancer are various to date and finding the right treatment sequence is critical given that the association between ICIs and TKIs may be lethal (De-Rui Huang and Chih-Hsin Yang, 2020). In a recent study, the sequential use of ICIs (especially PD-1 inhibitors) and osimertinib appeared to increase the risk of toxicity, including pneumonitis and colitis (Sharp and Corp, 2021). Toxicity occurred irrespective of the duration of the PD-1 blockade treatment, usually a few weeks after beginning osimertinib (as in the case of our patient). The half-life of osimertinib is 55 h (Jänne et al., 2015), whereas the receptor occupancy of anti PD-1 antibodies can last for months and may also vary among patients (Brahmer et al., 2010). This may explain the long-term effectiveness of ICIs on disease response and thus, given this durable action, severe TREAs may also occur after several months of latency.\n\nThe mechanism behind the synergism between ICIs and TKI that is responsible for higher toxicity is still not clearly understood. As seen from histological findings in conditions of immune-related adverse events (iRAEs), pembrolizumab induces a modification of the immune activity in the tissue microenvironment, with an increase in infiltrating T-lymphocytes CD3+, especially CD8+ (Saw et al., 2017; Zen and Yeh, 2018). This may create a favorable environment for a cytotoxic reaction when osimertinib is administered. It can be hypothesized that osimertinib may have undefined immune effects capable of triggering an immune response in conditions of susceptibility induced by ICIs.\n\nAlthough the association of TKIs and ICIs may have a therapeutic rationale (Karachaliou et al., 2017; Latif and Liu, 2019) given the potential impact of EGFR in immune signaling and induction of PD-L1 expression, no clear benefit have been reported for their sequential or combined use. Starting immunotherapy +/− chemotherapy as front-line treatment could prove a good choice when molecular results are not rapidly available, with the intention of switching to targeted therapy as soon as possible. However, the first administration of immunotherapy may compromise the further possibility of treatment with osimertinib or other TKIs. This is important because ICIs are currently used in various settings such as locally advanced unresectable stage III NSCLC, regardless of EGFR status, and as adjuvant/neoadjuvant treatment (Remon et al., 2020).\n\nA safe wash-out period of at least 12 months between the last infusion of ICIs and the start of osimertinib should be considered to reduce the risk of severe toxicity (Brahmer et al., 2010) when this treatment sequence is needed. As PD-L1 has long-lasting receptor occupancy, its evaluation before starting TKIs could be useful to identify the minimum wash-out latency time after ICIs. When osimertinib is the best option for the patient, a desensitization method could be taken into account (Yoshida and Kim, 2017), but this attempt could also be dangerous when ICI therapy has already been administered.\n\nHypothesizing the involvement of an immune-mediated mechanism in the genesis of the toxicity, we successfully treated the adverse events of our patient with corticosteroid therapy, enabling her to continue treatment assuming an immune-mediated mechanism involved in the genesis of the toxicity (Coleman and Pontefract, 2016). One of the limits of our approach was that invasive investigations such as skin or liver biopsies were not carried out, as these would have been useful for a complete analysis of the case. A sequential approach with TKIs as a first treatment option appears to be the safest strategy in EGFR-mutant metastatic NSCLC to avoid severe immune.-mediated TRAEs, with ICIs reserved as possible further treatment.\n\nConclusion\n\nWe reported a case of SJS and G3 hepatotoxicity induced by osimertinib administered sequentially to pembrolizumab plus chemotherapy and successfully treated with high-dose steroid therapy. There are still a great many uncertainties about the correct sequencing timing of sequence of ICIs and EGFR TKIs, and also about the correct management of potential toxicities. The identification of a patient population with fewer toxicity risks and safer TKIs should be considered is needed to reduce the risk of toxicity from sequential approaches. Further research is thus warranted into toxicity pathogenesis and safe treatment associations to maximize therapeutic success.\n\nThe authors thank Gráinne Tierney and Cristiano Verna for editorial assistance.\n\nData Availability Statement\n\nThe original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding author.\n\nEthics Statement\n\nWritten informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.\n\nAuthor Contributions\n\nCG wrote the first draft of the manuscript; GB, GF, and LC contributed to conception and design of the study; AD, MB, KA, CM, and MM collected data and wrote sections of the manuscript. All authors contributed to manuscript revision, read, and approved the submitted version.\n\nConflict of Interest\n\nThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\n\nPublisher’s Note\n\nAll claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.\n==== Refs\nReferences\n\nAbdel-Rahman O. (2019). Toxicity Patterns Associated with Chemotherapy/immune Checkpoint Inhibitor Combinations: a Meta-Analysis. Immunotherapy 11 (6 ), 543–554. 10.2217/imt-2018-0186 31135244\nAstraZeneca Pharmaceuticals (2018). Tagrisso (Osimertinib) [package Insert]. U.S. Food and Drug Administration website. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/208065s008lbl.pdf (Revised April 2018, Accessed March 03 2020).\nBastuji-Garin S. Fouchard N. Bertocchi M. Roujeau J. C. Revuz J. Wolkenstein P. (2000). SCORTEN: a Severity-Of-Illness Score for Toxic Epidermal Necrolysis. J. Invest. Dermatol. 115 (2 ), 149–153. 10.1046/j.1523-1747.2000.00061.x 10951229\nBrahmer J. R. Drake C. G. Wollner I. Powderly J. D. Picus J. Sharfman W. H. (2010). Phase I Study of Single-Agent Anti-programmed Death-1 (MDX-1106) in Refractory Solid Tumors: Safety, Clinical Activity, Pharmacodynamics, and Immunologic Correlates. J. Clin. Oncol. 28 (19 ), 3167–3175. 10.1200/JCO.2009.26.7609 20516446\nColclough N. Chen K. Johnström P. Strittmatter N. Yan Y. Wrigley G. L. (2021). Preclinical Comparison of the Blood-Brain Barrier Permeability of Osimertinib with Other EGFR TKIs. Clin. Cancer Res. 27 (1 ), 189–201. 10.1158/1078-0432.CCR-19-1871 33028591\nColeman J. J. Pontefract S. K. (2016). Adverse Drug Reactions. Clin. Med. (Lond) 16 (5 ), 481–485. 10.7861/clinmedicine.16-5-481 27697815\nCommon Terminology Criteria for Adverse Events (CTCAE) | Protocol Development | CTEP. Available at: https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. (Accessed April 15, 2020).\nDe-Rui Huang D. Chih-Hsin Yang J. (2020). Checkpoint Inhibitor Combined with Tyrosine Kinase Inhibitor-The End or Beginning? J. Thorac. Oncol. 15 (3 ), 305–307. 10.1016/j.jtho.2019.12.121 32093849\nGandhi L. Rodríguez-Abreu D. Gadgeel S. Esteban E. Felip E. De Angelis F. (2018). Pembrolizumab Plus Chemotherapy in Metastatic Non-Small Cell Lung Cancer. N. Engl. J. Med. 378 , 2078–2092. 10.1056/NEJMoa1801005 29658856\nGonzález I. Chatterjee D. (2019). Histopathological Features of Drug-Induced Liver Injury Secondary to Osimertinib. ACG Case Rep. J. 6 (2 ), e00011. 10.14309/crj.0000000000000011 31616716\nGoss G. Tsai C. M. Shepherd F. A. Bazhenova L. Lee J. S. Chang G. C. (2016). Osimertinib for Pretreated EGFR Thr790Met-Positive Advanced Non-Small Cell Lung Cancer (AURA2): a Multicentre, Open-Label, Single-Arm, Phase 2 Study. Lancet Oncol. 17 (12 ), 1643–1652. 10.1016/S1470-2045(16)30508-3 27751847\nHirabayashi R. Fujimoto D. Satsuma Y. Hirabatake M. Tomii K. (2018). Successful Oral Desensitization with Osimertinib Following Osimertinib-Induced Fever and Hepatotoxicity: A Case Report. Invest. New Drugs 36 (5 ), 952–954. 10.1007/s10637-018-0608-7 29721756\nJänne P. A. Yang J. C. Kim D. W. Planchard D. Ohe Y. Ramalingam S. S. (2015). AZD9291 in EGFR Inhibitor-Resistant Non-Small Cell Lung Cancer. N. Engl. J. Med. 372 (18 ), 1689–1699. 10.1056/NEJMoa1411817 25923549\nKarachaliou N. Gonzalez-Cao M. Sosa A. Berenguer J. Bracht J. W. P. Ito M. (2017). The Combination of Checkpoint Immunotherapy and Targeted Therapy in Cancer. Ann. Transl Med. 5 (19 ), 1–10. 10.21037/atm.2017.06.47 28164086\nLatif H. Liu S. V. (2019). Combining Immunotherapy and Epidermal Growth Factor Receptor Kinase Inhibitors: worth the Risk? Ann. Transl Med. 7 (S3 ), S76. 10.21037/atm.2019.03.6 31576285\nMok T. S. Wu Y-L. Ahn M-J. Garassino M. C. Kim H. R. Ramalingam S. S. (2017). Osimertinib or Platinum-Pemetrexed in EGFR T790M-Positive Lung Cancer. N. Engl. J. Med. 376 (7 ), 629–640. 10.1056/NEJMoa1612674 27959700\nNational Comprehensive Cancer Network (2021). Non-Small Cell Lung Cancer Guidelines. Version 5. Available at: https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf (Accessed March 03, 2021).\nRemon J. Passiglia F. Ahn M. J. Barlesi F. Forde P. M. Garon E. B. (2020). Immune Checkpoint Inhibitors in Thoracic Malignancies: Review of the Existing Evidence by an IASLC Expert Panel and Recommendations. J. Thorac. Oncol. 15 (20 ), 914–947. 10.1016/j.jtho.2020.03.006 32179179\nRosell R. Karachaliou N. (2016). Large-scale Screening for Somatic Mutations in Lung Cancer. Lancet 387 (10026 ), 1354–1356. 10.1016/S0140-6736(15)01125-3 26777918\nSaw S. Lee H. Y. Ng Q. S. (2017). Pembrolizumab-induced Stevens-Johnson Syndrome in Non-melanoma Patients. Eur. J. Cancer 81 , 237–239. 10.1016/j.ejca.2017.03.026 28438440\nSchoenfeld A. J. Arbour K. C. Rizvi H. Iqbal A. N. Gadgeel S. M. Girshman J. (2019). Severe Immune-Related Adverse Events Are Common with Sequential PD-(L)1 Blockade and Osimertinib. Ann. Oncol. 30 (5 ), 839–844. 10.1093/annonc/mdz077 30847464\nSharp M. Corp D. (2021). Keytruda (Pembrolizumab) [package Insert]. U.S. Food and Drug Administration website. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/125514s096lbl.pdf (Accessed March 2021, July 20 2021).\nTorre L. A. Siegel R. L. Ward E. M. Jemal A. (2016). Global Cancer Incidence and Mortality Rates and Trends--An Update. Cancer Epidemiol. Biomarkers Prev. 25 (1 ), 16–27. 10.1158/1055-9965.EPI-15-0578 26667886\nYoshida H. Kim Y. H. (2017). Successful Osimertinib Rechallenge after Severe Osimertinib-Induced Hepatotoxicity. J. Thorac. Oncol. 12 (5 ), e61–e63. 10.1016/j.jtho.2017.01.026 28291724\nZen Y. Yeh M. M. (2018). Hepatotoxicity of Immune Checkpoint Inhibitors: a Histology Study of Seven Cases in Comparison with Autoimmune Hepatitis and Idiosyncratic Drug-Induced Liver Injury. Mod. Pathol. 31 , 965–973. 10.1038/s41379-018-0013-y 29403081\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1663-9812",
"issue": "12()",
"journal": "Frontiers in pharmacology",
"keywords": "liver toxicity; non-small cell lung cancer; osimertinib; pembrolizumab; stevens johnson syndrome",
"medline_ta": "Front Pharmacol",
"mesh_terms": null,
"nlm_unique_id": "101548923",
"other_id": null,
"pages": "672233",
"pmc": null,
"pmid": "34456717",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": "29403081;10951229;29114546;32093849;26777918;27697815;31576285;25923549;31616716;27959700;29658856;29721756;31135244;20516446;32179179;28438440;33028591;26667886;28291724;30847464;27751847",
"title": "Case Report: Stevens-Johnson Syndrome and Hepatotoxicity Induced by Osimertinib Sequential to Pembrolizumab in a Patient With EGFR-Mutated Lung Adenocarcinoma.",
"title_normalized": "case report stevens johnson syndrome and hepatotoxicity induced by osimertinib sequential to pembrolizumab in a patient with egfr mutated lung adenocarcinoma"
} | [
{
"companynumb": "IT-SUN PHARMACEUTICAL INDUSTRIES LTD-2022RR-334733",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PEMETREXED"
},
"drug... |
{
"abstract": "We report a case of facial paresis and profound hearing loss from post-transplant lymphoproliferative disorder (PTLD) in a pediatric patient with neuroblastoma.\n\n\n\nThree-year-old boy with rapidly progressive right facial paresis and sensorineural hearing loss. High-risk neuroblastoma had been diagnosed 1 year earlier, treated with chemotherapy and resection of the adrenal primary tumor. Two months after two autologous hematopoietic stem cell transplantations (HSCT), the patient developed facial paralysis. Magnetic resonance imaging (MRI) showed bilateral progressive internal auditory canal (IAC) enhancing lesions with a mass lesion on the right and wispy enhancement on the left and enhancement within the right cochlea. Lumbar puncture (LP) was positive for Epstein-Barr virus (EBV) making the diagnosis of PTLD most probable. Biopsy of the right IAC lesion was deferred because of potential procedural risks including intradural spread of tumor or fungus. The patient was treated with anti-fungal therapy and systemic rituximab without improvement. Subsequent intrathecal rituximab resulted in improvement of lesions on MRI and clearance of EBV from the cerebrospinal fluid (CSF).\n\n\n\nMastoidectomy for biopsies from the mastoid and middle ear. Intrathecal treatment with rituximab.\n\n\n\nImaging assessment of IAC lesion, CSF EBV titers, facial nerve function.\n\n\n\nGradual resolution of IAC mass lesions, remission of PTLD, and facial improvement from House-Brackmann score of 4 to 3.\n\n\n\nPTLD causing facial paresis after autologous HSCT has not been previously reported and may be considered in the differential diagnosis of lesions causing facial paresis in patients who have received a stem cell or solid organ transplant.",
"affiliations": "Department of Otolaryngology and Communication Enhancement, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.;Pediatric Oncology, Dana-Farber/Boston Children's Cancer and Blood Disorders Center.;Pediatric Oncology, Dana-Farber/Boston Children's Cancer and Blood Disorders Center.;Department of Radiology, Boston Children's Hospital.;Pediatric Physicians' Organization at Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.;Department of Otolaryngology and Communication Enhancement, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.",
"authors": "Toivonen|Joonas|J|;Shulman|David S|DS|;Shusterman|Suzanne|S|;Robson|Caroline D|CD|;Saillant|Meredith|M|;Poe|Dennis|D|",
"chemical_list": "D000069283:Rituximab",
"country": "United States",
"delete": false,
"doi": "10.1097/MAO.0000000000003041",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1531-7129",
"issue": "42(5)",
"journal": "Otology & neurotology : official publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology",
"keywords": null,
"medline_ta": "Otol Neurotol",
"mesh_terms": "D002675:Child, Preschool; D020031:Epstein-Barr Virus Infections; D005158:Facial Paralysis; D018380:Hematopoietic Stem Cell Transplantation; D004854:Herpesvirus 4, Human; D006801:Humans; D008232:Lymphoproliferative Disorders; D008297:Male; D000069283:Rituximab",
"nlm_unique_id": "100961504",
"other_id": null,
"pages": "e605-e608",
"pmc": null,
"pmid": "33443973",
"pubdate": "2021-06-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Facial Paralysis From Post-transplant Lymphoproliferative Disorder.",
"title_normalized": "facial paralysis from post transplant lymphoproliferative disorder"
} | [
{
"companynumb": "US-CELLTRION INC.-2021US000703",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RITUXIMAB"
},
"drugadditional": "3",
... |
{
"abstract": "Cocaine can cause a myriad of changes in the lung, which can range from bronchoconstriction to destruction of the alveolar-capillary membrane and acute lung injury. Cocaine-induced bronchospasm is a diagnosis of exclusion that should be considered when the clinical presentation of acute hypoxic and hypercapneic respiratory failure cannot be explained by chronic obstructive pulmonary disease or asthma exacerbation, anaphylaxis to food or medications, exercise, or infection. Here, we present two patients with acute hypoxic and hypercapneic respiratory failure that was ultimately attributed to cocaine use shortly prior to symptom onset.",
"affiliations": "Department of Medicine, Campbell University School of Osteopathic Medicine, Lillington, North Carolina, USA.;Department of Pulmonary and Critical Care, Atrium Health, Charlotte, North Carolina, USA.;Department of Pulmonary and Critical Care, WakeMed Hospitals and Health System, Raleigh, North Carolina, USA drvikaspathak@gmail.com.",
"authors": "Zhou|Christine Y|CY|;Ricker|Melissa|M|;Pathak|Vikas|V|",
"chemical_list": "D003042:Cocaine",
"country": "United States",
"delete": false,
"doi": "10.3121/cmr.2019.1447",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1539-4182",
"issue": "17(1-2)",
"journal": "Clinical medicine & research",
"keywords": "Asthma exacerbation; Cocainem Bronchospasm",
"medline_ta": "Clin Med Res",
"mesh_terms": "D000208:Acute Disease; D001249:Asthma; D001986:Bronchial Spasm; D003042:Cocaine; D019970:Cocaine-Related Disorders; D003937:Diagnosis, Differential; D005260:Female; D006801:Humans; D008875:Middle Aged",
"nlm_unique_id": "101175887",
"other_id": null,
"pages": "34-36",
"pmc": null,
"pmid": "31160477",
"pubdate": "2019-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "16236840;19081448;17307630;8874243;3674585;7813284;10807818;17620460;9118711;18299233;12171843",
"title": "Cocaine-Induced Bronchospasm Mimicking Acute Asthma Exacerbation.",
"title_normalized": "cocaine induced bronchospasm mimicking acute asthma exacerbation"
} | [
{
"companynumb": "US-GENUS_LIFESCIENCES-USA-POI0580202000198",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "COCAINE HYDROCHLORIDE"
},
"... |
{
"abstract": "Previous references suggesting a high mortality of propofol addiction in medical personnel were mostly based on surveys of the heads of medical departments or case reports; therefore, a questionnaire was sent to 48 forensic medicine departments in Germany, Austria and Switzerland concerning the number of autopsies carried out between 2002-2112 on medical personnel with the suspicion of abuse of propofol or other analgesics. The response rate was 67%. In 16 out of the 32 responding departments 39 deaths (27 males) were observed with previous connections to anesthesiology, intensive care or emergency departments of which 22 were physicians, 13 nurses, 2 other personnel and 2 were unknown. Propofol was the major cause of death in 33 cases (85%), in 8 cases including 7 with propofol, an unintentional accident was recorded and 29 were determined to be suicide. In 14 cases chronic abuse was denied but actually excluded by toxicological analysis in only 2 cases. In 11 cases involving suicide the question of abuse was not investigated. This survey confirmed previous data about the central role of propofol for the fatal outcome of addiction and suicide of anesthetists and other medical personnel. A dual prevention strategy with low-threshold offers for persons at risk and strategies for early detection is urgently needed including a stricter control of dispensing, improvement in forensic medical documentation and the use of toxicological investigations in every case of suspected abuse.",
"affiliations": "Abteilung für Schmerzmedizin, Berufsgenossenschaftliches Universitätsklinikum Bergmannsheil gGmbH, Bürkle-de-la-Camp-Platz 1, 44789, Bochum, Deutschland. christoph.maier@rub.de.;Abteilung für Schmerzmedizin, Berufsgenossenschaftliches Universitätsklinikum Bergmannsheil gGmbH, Bürkle-de-la-Camp-Platz 1, 44789, Bochum, Deutschland.;Institut für Rechtsmedizin, Charité - Universitätsmedizin Berlin, Berlin, Deutschland.;Forensisch-Toxikologisches Centrum München GmbH, München, Deutschland.",
"authors": "Maier|C|C|;Iwunna|J|J|;Tsokos|M|M|;Mußhoff|F|F|",
"chemical_list": "D018686:Anesthetics, Intravenous; D015742:Propofol",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00101-016-0260-6",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0003-2417",
"issue": "66(2)",
"journal": "Der Anaesthesist",
"keywords": "Anesthetists; Autopsies; Drug abuse; Non-intended death; Respiratory arrest; Suicide",
"medline_ta": "Anaesthesist",
"mesh_terms": "D000328:Adult; D018686:Anesthetics, Intravenous; D000072077:Anesthetists; D001317:Austria; D002423:Cause of Death; D004282:Documentation; D005260:Female; D005858:Germany; D006282:Health Personnel; D006801:Humans; D008297:Male; D008875:Middle Aged; D009726:Nurses; D010815:Physician Impairment; D010820:Physicians; D015742:Propofol; D019966:Substance-Related Disorders; D013405:Suicide; D013557:Switzerland; D055815:Young Adult",
"nlm_unique_id": "0370525",
"other_id": null,
"pages": "109-114",
"pmc": null,
"pmid": "28091758",
"pubdate": "2017-02",
"publication_types": "D016428:Journal Article",
"references": "22467544;18175094;22120100;8368554;1416157;22714402;18946304;21921842;17898389;25579298;21297050;15237574;23771527;8403816;19512913;20960369;12359667;17868199;19299783;24302092;17065900;15967611;18946282;2342218;22880547;19514884",
"title": "Deaths from propofol abuse : Survey of institutes of forensic medicine in Germany, Austria and Switzerland.",
"title_normalized": "deaths from propofol abuse survey of institutes of forensic medicine in germany austria and switzerland"
} | [
{
"companynumb": "DE-TEVA-777777GER",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "THIOPENTAL SODIUM"
},
"drugadditional": null,
... |
{
"abstract": "We describe a case of a man affected by colon adenocarcinoma with metachronous nodes and liver metastases (resected), exposed to first line therapy with FOLFOX-cetuximab. After disease progression, a second line based on FOLFIRI-aflibercept was started achieving an initial partial response followed by a long-lasting disease stability with a good tolerability.",
"affiliations": null,
"authors": "Aroldi|Francesca|F|;Zaniboni|Alberto|A|",
"chemical_list": "D009944:Organoplatinum Compounds; D011993:Recombinant Fusion Proteins; C533178:aflibercept; D066246:ErbB Receptors; D040262:Receptors, Vascular Endothelial Growth Factor; D000068818:Cetuximab; D002955:Leucovorin; D005472:Fluorouracil; D002166:Camptothecin",
"country": "Italy",
"delete": false,
"doi": "10.1701/2094.22666",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0034-1193",
"issue": "106(12)",
"journal": "Recenti progressi in medicina",
"keywords": null,
"medline_ta": "Recenti Prog Med",
"mesh_terms": "D000230:Adenocarcinoma; D000971:Antineoplastic Combined Chemotherapy Protocols; D002166:Camptothecin; D000068818:Cetuximab; D003110:Colonic Neoplasms; D018450:Disease Progression; D066246:ErbB Receptors; D005472:Fluorouracil; D006801:Humans; D002955:Leucovorin; D008113:Liver Neoplasms; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D009944:Organoplatinum Compounds; D040262:Receptors, Vascular Endothelial Growth Factor; D011993:Recombinant Fusion Proteins; D016896:Treatment Outcome",
"nlm_unique_id": "0401271",
"other_id": null,
"pages": "653e-6e",
"pmc": null,
"pmid": "26780078",
"pubdate": "2015-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Efficacy and safety of antivascular drugs after anti-EFGR: aflibercept after cetuximab, a clinical case.",
"title_normalized": "efficacy and safety of antivascular drugs after anti efgr aflibercept after cetuximab a clinical case"
} | [
{
"companynumb": "IT-MYLANLABS-2017M1010510",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "OXALIPLATIN"
},
"drugadditional": "3",
... |
{
"abstract": "Transient gestation hypertension is a contributor to adverse pregnancy outcomes particularly when it progresses to pre-eclampsia (PE). This requires frequent monitoring. We illustrate the need for stringent monitoring of gestational hypertension, transient gestational hypertension (TGH) and PE without severe features and conducted a brief rapid review of the literature. Two cases are presented: Firstly, a 25-year-old primigravida at 30 gestational weeks who had an isolated TGH with high blood pressure (BP) of 141/87 mmHg, which was not investigated. Four weeks later, she presented with a BP of 202/128 mmHg, imminent eclampsia and intrauterine foetal death and had an uncomplicated induction of labour and delivered a 1400 g macerated male stillborn. Secondly, a 30-year-old primigravida at 30 gestational weeks who developed PE but her monitoring was compromised initially by inadequate healthcare capacity including unavailability of hospital bed-space for inpatient care and later by poor clinic attendance as a result of poor finances. At 32 gestational weeks, she presented with decreased foetal movement and was diagnosed as haemolysis, elevated liver enzymes, low platelet count (HELLP) syndrome and intrauterine foetal death. She was stabilised, had induction of labour and delivered a 1400 g male macerated stillborn. Thereafter, the need for her to go home to complete the cultural burial rites of her baby and the pressure from her workplace resulted in an inadequate postpartum follow-up care. In conclusion, transient gestational hypertension is associated with adverse maternal and foetal outcomes, including foetal demise. Unavailability of hospital bed-space and poor personal finances interfere with stringent monitoring of hypertensive disorders and can be associated with adverse pregnancy outcomes. Stringent laboratory monitoring in these cases is defined by the authors as testing at least blood levels of serum Creatinine, Haemoglobin concentration, Alanine transaminase and Platelet count (abbreviated as 'CHAP') weekly.",
"affiliations": "Department of Obstetrics and Gynaecology, Faculty of Health Sciences, School of Clinical Medicine, University of the Witwatersrand, Johannesburg, South Africa; and, Department of Obstetrics and Gynaecology, Leratong Hospital, Krugersdorp. ngenenc@gmail.com.",
"authors": "Ngene|Nnabuike C|NC|;Daef|Ghadah|G|",
"chemical_list": null,
"country": "South Africa",
"delete": false,
"doi": "10.4102/safp.v63i1.5236",
"fulltext": "\n==== Front\nS Afr Fam Pract (2004)\nS Afr Fam Pract (2004)\nSAFP\nSouth African Family Practice\n2078-6190\n2078-6204\nAOSIS\n\n33764141\nSAFP-63-5236\n10.4102/safp.v63i1.5236\nScientific Letters\nTransient gestational hypertension and pre-eclampsia: Two case reports and literature review on the need for stringent monitoring\nhttps://orcid.org/0000-0002-2278-5836\nNgene Nnabuike C. 12\nhttps://orcid.org/0000-0001-9653-0708\nDaef Ghadah 13\n1 Department of Obstetrics and Gynaecology, Faculty of Health Sciences, School of Clinical Medicine, University of the Witwatersrand, Johannesburg, South Africa\n2 Department of Obstetrics and Gynaecology, Leratong Hospital, Krugersdorp, South Africa\n3 Department of Obstetrics and Gynaecology, Klerksdorp Hospital, Klerksdorp, South Africa\nCorresponding author: Nnabuike Ngene, ngenenc@gmail.com\n16 3 2021\n2021\n63 1 523603 10 2020\n10 2 2021\n© 2021. The Authors\n2021\nhttps://creativecommons.org/licenses/by/4.0/ Licensee: AOSIS. This work is licensed under the Creative Commons Attribution License.\nTransient gestation hypertension is a contributor to adverse pregnancy outcomes particularly when it progresses to pre-eclampsia (PE). This requires frequent monitoring. We illustrate the need for stringent monitoring of gestational hypertension, transient gestational hypertension (TGH) and PE without severe features and conducted a brief rapid review of the literature. Two cases are presented: Firstly, a 25-year-old primigravida at 30 gestational weeks who had an isolated TGH with high blood pressure (BP) of 141/87 mmHg, which was not investigated. Four weeks later, she presented with a BP of 202/128 mmHg, imminent eclampsia and intrauterine foetal death and had an uncomplicated induction of labour and delivered a 1400 g macerated male stillborn. Secondly, a 30-year-old primigravida at 30 gestational weeks who developed PE but her monitoring was compromised initially by inadequate healthcare capacity including unavailability of hospital bed-space for inpatient care and later by poor clinic attendance as a result of poor finances. At 32 gestational weeks, she presented with decreased foetal movement and was diagnosed as haemolysis, elevated liver enzymes, low platelet count (HELLP) syndrome and intrauterine foetal death. She was stabilised, had induction of labour and delivered a 1400 g male macerated stillborn. Thereafter, the need for her to go home to complete the cultural burial rites of her baby and the pressure from her workplace resulted in an inadequate postpartum follow-up care. In conclusion, transient gestational hypertension is associated with adverse maternal and foetal outcomes, including foetal demise. Unavailability of hospital bed-space and poor personal finances interfere with stringent monitoring of hypertensive disorders and can be associated with adverse pregnancy outcomes. Stringent laboratory monitoring in these cases is defined by the authors as testing at least blood levels of serum Creatinine, Haemoglobin concentration, Alanine transaminase and Platelet count (abbreviated as ‘CHAP’) weekly.\n\nhypertensive disorders of pregnancy\nintrauterine foetal death\npre-eclampsia\nstringent monitoring\ntransient gestational hypertension\n==== Body\nIntroduction\n\nHypertensive disorders of pregnancy (HDP) occur in 5% – 10% of pregnancies and account for 14% of maternal deaths worldwide.1,2 The burden of the disease is highest in low- and middle-income countries.1 In South Africa for instance, HDP accounts for 18% of maternal deaths3 and this is because of high prevalence (9.6% for pre-eclampsia [PE]),4 the propensity for the severe forms of the disease5 and avoidable factors associated with their management.6 In 2018, the International Society for the Study of Hypertension in Pregnancy (ISSHP) categorised HDP into chronic hypertension, PE, which may be de novo or superimposed on chronic hypertension, white coat hypertension, masked hypertension, transient gestational hypertension (TGH) and gestational hypertension.7 The ISSHP definition of these categories are recognised in the South African 2019 National guidelines on HDP.3\n\nTransient gestational hypertension is the brief occurrence of hypertension (systolic blood pressure [BP] of ≥ 140 mmHg and or diastolic BP of ≥ 90 mmHg) at ≥ 20 gestational weeks, followed by normalisation of BP without treatment.1,7 Unfortunately, clinical management of TGH is rarely reported. Transient gestational hypertension progresses to gestational hypertension in 20% of cases and PE in 19% of cases8 and may result in maternal and foetal complications such as placental insufficiency. In 25% of cases, gestational hypertension also develops into PE.7 Therefore, TGH, gestational hypertension and PE require regular and frequent monitoring. Notably, their outcomes can be dramatic5 and there is no single laboratory test or variable that predicts the disease progression and outcomes with certainty.9,10 Stringent laboratory monitoring, defined by the authors as testing at least blood levels of serum Creatinine, Haemoglobin concentration, Alanine transaminase (ALT) and Platelet count (CHAP) weekly in patients already diagnosed to have gestational hypertension, TGH or PE without severe features, may offer the best pregnancy outcomes. Recent reports indicate that the quantity of multiple maternal vascular malperfusion lesions in the placenta in gestational hypertension and PE may be similar,11 and this underscores the ability of gestational hypertension to cause adverse pregnancy outcomes. In this article, we present two case reports to demonstrate the risk of unrecognised and poorly monitored TGH and illustrate the influence of socioeconomic challenges in the monitoring of PE.\n\nCase 1\n\nA 25-year-old primigravida commenced antenatal care in a primary healthcare clinic (PHC) at eight gestational weeks. During the first antenatal clinic visit, she had the following: BP 129/69 mmHg, pulse rate 61 bpm, weight 85 kg and normal body mass index (BMI). She subsequently had five uneventful antenatal clinic visits and a ‘normal’ foetal structural anomaly ultrasonography at 24 weeks’ gestation.\n\nOn the 6th antenatal clinic visit at 30 gestational weeks, she had an isolated BP of 141/87 mmHg (measured on two different occasions 15 min apart as recommended in the 2019 South African guidelines on HDP),3 treated with no medication and was referred to the hospital for further assessment. The patient presented to the hospital in the afternoon of the same day with no complaint, BP of 133/63 mmHg that was re-checked on two different occasions, normal spot urine dipstick and symphysio-fundal height (SFH) of 28 cm. Her BPs in the previous antenatal clinic visits were normal (systolic BP < 130 mmHg and diastolic BP < 80 mmHg). No further workup was performed. The patient was discharged home from the hospital and advised to continue antenatal care in the PHC in 4 weeks.\n\nDuring the next scheduled antenatal clinic visit at 34 gestational weeks, the patient presented with headache and a BP of 202/128 mmHg. She was treated with rapid-acting nifedipine 10 mg orally, methyldopa 500 mg orally and loaded with MgSO4 and referred to the hospital for further management as a case of PE with severe features. On arrival at the hospital, the patient had headache, epigastric pain and history further revealed that she had not felt foetal movements for 2 days before presentation. She was also found to have BP of 168/106 mmHg, +1 proteinuria, bilateral pitting pedal oedema, soft abdomen, SFH of 30 cm, no foetal heart sound on auscultation and was not in labour. Ultrasonography showed intrauterine foetal death and anhydramnios. The patient was diagnosed as TGH that has progressed to PE.\n\nThe patient was admitted to the obstetric high-care unit, where she received MgSO4 for 24 h, rapid-acting nifedipine 10 mg stat, methyldopa 500 mg thrice a day and amlodipine 10 mg once daily. The renal function, full blood count and liver function tests were normal. Labour was induced with oral misoprostol and 14 h following hospital admission, she delivered a 1400 g macerated male stillborn, a placenta that weighed 220 g and retroplacental clot was observed. Post-delivery, the BP was controlled with amlodipine 10 mg daily, and the results of blood investigation remained normal. The patient received grief counselling and was discharged home in satisfactory condition on 3 days after childbirth and had a normal postpartum period. The placental histology confirmed retroplacental haematoma, infarction and high grade foetal vascular malperfusion.\n\nCase 2\n\nA 27-year-old primigravida commenced antenatal care in a PHC at eight gestational weeks. She had no complaint at booking and her BMI was 50 kg/m2 (weight 136 kg). Her subsequent four antenatal care clinic visits were uneventful. The structural anomaly ultrasound scan at 21 gestational weeks was normal. The patient presented to the PHC at 30 gestational weeks, with facial puffiness, bilateral pitting oedema and a BP of 143/103 mmHg. She was commenced on methyldopa and referred to the regional hospital for BP control and further investigation. At the regional hospital, she had a BP of 152/88 mmHg, 4+ proteinuria, normal blood investigations for PE and a normal foetal heart rate. The patient was continued on methyldopa, planned for outpatient care because of unavailability of hospital bed-space. She was booked for an ultrasound scan with a sonologist in the next available space in 2 days’ time (as there were too many patients waiting to access prenatal ultrasonography), and to be followed-up afterwards at the regional hospital. Unfortunately, the patient failed to follow-up because it was economically inconvenient.\n\nAt 32 gestational weeks, the patient presented to the PHC with decreased foetal movements of 3 days duration and a cramping lower abdominal pain with no other symptom and was referred to the regional hospital where physical examination revealed bilateral pitting pedal oedema, BP of 195/132 mmHg, 3+ proteinuria and an absent foetal heart sound. Other physical examinations were normal. Rapid-acting antihypertensive therapy (nifedipine) was given to control BP. The patient was admitted to the obstetric high care unit and received MgSO4 infusion to prevent eclampsia. The blood investigations showed features of HELLP Syndrome: ALT 220 U/L, aspartate transaminase (AST) 523 U/L, lactate dehydrogenase (LDH) 2075 U/L, platelets 31 × 109/L. The haemoglobin was 12.7 g/dL and obstetric ultrasonography confirmed foetal demise. Ultrasonography of the kidney and liver were normal. These were carried out because early-onset PE (i.e. PE developing before 34 gestational weeks) are usually severe10 and in our setting, therefore, ultrasonographic assessment of maternal liver and kidney is usually performed to detect any pathology that may be contributory to the clinical features and to exclude complications of the HDP. Nonetheless, the patient was stabilised, had induction of labour with oral misoprostol and delivered 1400 g male macerated stillborn.\n\nPostpartum, she received counselling and was planned for further inpatient care. On day 2 postpartum, the patient requested to be discharged home to complete the traditional burial rites of her baby. Despite counselling about the need for inpatient care, she signed ‘refusal of in-hospital treatment’ and agreed to return to the hospital the next day but defaulted. Her blood investigation results were serum creatinine 85 µmol/L, urea 3 mmol/L, ALT 108 U/L, AST 119 U/L and LDH 1758 U/L. She was followed-up on an outpatient basis but defaulted clinic visits to attend to responsibilities at her workplace. She made a complete recovery with normal blood results and was discharged from the postnatal clinic on week 7 postpartum. During the last postnatal clinic visit, she had BMI 40.8 kg/m2, BP 137/88 mmHg, pulse 89 bpm, serum creatinine 59 µmol/L, haemoglobin 12.6 g/dl, ALT 17 U/L and platelet 283 × 109/L.\n\nDiscussion\n\nThe pathogenesis of new-onset hypertension during pregnancy is not well understood12,13 but we do know that all categories of HDP have the propensity to progress to PE. Of note, PE causes more adverse perinatal and maternal morbidity and mortality than other categories of HDP. Till date, the pathogenesis of PE has been studied more extensively than those of other categories of HDP. In an attempt to explain the pathogenesis of PE, many theories have been proposed and one of the most popular amongst them is the two-stage theory.12 In the first stage of the disease, there is a lack of cytotrophoblastic invasion of the uterine spiral artery and this prevents widening of the lumen of these arteries as seen in normal pregnancy. The lumen therefore remains narrow and causes abnormal blood flow through these arteries and results in vascular malperfusion of the placenta. In the second stage of the disease, the malperfusion in conjunction with maternal susceptibility results in damage to the syncytiotrophoblast, which culminates in excessive release of inflammatory mediators, including anti-angiogenic factors known as soluble fms-like tyrosine kinase-1 (sFlt-1). In the absence of maternal susceptibility, lack of spiral artery remodelling will not cause PE but may result in any other placental mediated diseases, that is, great obstetric syndromes such as foetal growth restriction. Nonetheless, the concentration of the anti-angiogenic factors become higher than the concentration of pro-angoiogenic factors such as placental growth factor (PIGF), which is amongst the seven members in the family of vascular endothelial growth factors (VEGF).13 The imbalance between the anti- and pro-angiogenic factors (represented as sFlt-1/PIGF ratio), sFlt-1 and PIGF are biomarkers used in clinical practice for predicting, screening and diagnosing PE12,14 and has great potential for predicting postpartum antihypertensive drug requirements.10 The sFlt-1 damages the vascular endothelium whose healthy state is usually maintained by VEGF. The damage to the vascular endothelium results in the clinical features of PE.12,13 The preceding description applies to early-onset-PE. The understanding is that in late onset-PE, the placenta overgrows its blood supply or becomes old and these cause damage to the syncytiotrophoblast and result in the release of the same type of inflammatory mediators, including sFlt-1.12,13 The disease causes lesions in the placenta, but heterogeneity was noticed in many placental histopathological reports.\n\nIn a meeting held in September 2014 in Amsterdam, 26 pathologists adopted a standardised guideline, which was published in 2016.15 Using the consensus terminology,15 the groups of histopathological placental lesions that may be caused by PE or foetal growth restriction are: (1) vascular lesions (such as maldevelopment, malperfusion and loss of integrity) in maternal, foetal or feto-maternal side; (2) immunoinflammatory lesions (including infectious and immune types); and (3) other lesions (for instance, massive perivillous fibrin[oid] deposition otherwise known as maternal floor infarction).16 The vascular malperfusion lesions in the maternal placental side is associated with ultrasonographic foetoplacental dopplers such as uterine artery dopplers, and this supports the use of foetal dopplers as a means of assessing placental insufficiency.16 Recently, it was reported that both gestational hypertension and PE may manifest similar maternal vascular malperfusion lesions in the placenta.11\n\nUnfortunately, there is no clear recommendation in the literature on how TGH should be monitored. It is prudent in the authors’ opinion that TGH should be followed-up and managed as gestational hypertension. Therefore, antenatal clinic visit for foetal and maternal surveillance (including laboratory investigations) should be at short intervals not longer than a week17 but determined by maternal and foetal well-being measures such as BP, obstetric ultrasonography and screening for the development of features of PE including proteinuria, signs of imminent eclampsia and deranged laboratory tests results. The first case in the present report demonstrates a failure in recognition and follow-up of TGH.\n\nPre-eclampsia may also be associated with inadequate monitoring. The National Institute for Health and Care Excellence (NICE) in the United Kingdom recommends that women with PE should have an assessment of full blood count, renal and liver function tests at least twice a week.17 Based on expert opinion, the American College of Obstetricians and Gynaecologists (ACOG) recommends that laboratory test for monitoring gestational hypertension and PE without severe features should be performed one to two times weekly.18 Because of the latter and given that TGH may progress to PE or gestational hypertension, the laboratory test for monitoring TGH should be carried out at least once weekly. In low resource settings, this schedule is difficult to comply with because of financial constraints and poor educational enlightenment, poor access to healthcare services, poorly skilled healthcare providers and inefficient referral pathways. In South Africa, the 2019 guidelines on HDP recommend that gestational hypertension should be followed-up weekly in the antenatal clinic after initial evaluation with serum creatinine, haemoglobin concentration, ALT, platelet counts and ultrasonography for foetal evaluation to excluded PE.3 Unfortunately, the follow-up laboratory tests and frequency of the testing in gestational hypertension and PE are not clearly stated in the same guidelines. However, the South Africa maternity care guidelines recommend less stringent monitoring of weekly platelet and twice-weekly cardiotocography in PE.19 Despite the controversies about the ‘ideal’ list of investigations for PE,20 the authors’ suggest that at least serum creatinine, haemoglobin concentration, AST, LDH, ALT, platelets and urine protein:creatinine ratio (CHALAPU) should be performed when the diagnosis of gestational hypertension, TGH or PE is being made or excluded. Where available, Angiogenic factors (ratio of sFlt-1/PIGF) may be used to diagnose PE if the clinical features are uncertain12 and the mnemonic ‘A-CHALAPU’ instead of ‘CHALAPU’ may be used to remember the necessary laboratory investigations listed here. Serum electrolyte and urate (EU) should then be assessed in patients diagnosed to have PE. Subsequently, serum CHAP should be performed at least once a week in gestational hypertension, TGH and PE without severe features. See Figure 1 for a schematic flow diagram of the recommended laboratory investigations. The minimum basic set of laboratory investigations that we have recommended are informed by the current criteria used in the definition of PE7 and laboratory markers that predict poor pregnancy outcomes in PE such as urate, serum creatinine, platelet count and AST.21,22,23 Where more than one laboratory test can identify a complication, we have chosen a single test, for example, the choice of LDH over bilirubin to identify haemolysis resulting from HELLP syndrome. Our recommendations are pragmatic, cost-saving in resource-limited settings and are supported by recent evidence from Canada where Thompson and colleagues in 2020 reported original research findings affirming that basic blood tests required to monitor PE without severe features are complete blood count, ALT and serum creatinine.24 Our recommendation is not a disregard for other rare derangements including hypokalaemia that may occur in PE.25,26 Generally, laboratory abnormalities occur only in a minority of patients (7.3%) with HDP but the rate increases with the severity of the disease.27 Of note, other investigations should be performed as the need arises such as the development of target organ dysfunction typical of PE with severe features. For instance, clotting profile (including international normalised ratio, fibrinogen and activated partial thromboplastin time) should be assessed in patients who develop evidence of thrombocytopenia or coagulopathy.\n\nFIGURE 1 Minimum laboratory tests for a suspected hypertensive disorder of pregnancy and stringent monitoring of gestational hypertension, transient gestational hypertension and pre-eclampsia without severe features.\n\nIt is pertinent to draw further attention to the laboratory investigations used for monitoring already diagnosed cases of PE without severe feature, gestational hypertension and TGH. Serum creatinine helps with monitoring of renal function and levels above 120 mmol/L is an indication to consider delivery.3 Haemoglobin concentration is usually elevated because of volume depletion in PE13 but may be decreased if there is haemolysis. ALT is a good marker of hepatic disease24 although in PE-related hepatic dysfunction, AST is the initial transaminase preferentially released into peripheral circulation such that the circulatory concentration of AST dominates ALT (at least initially) and levels of these transaminases may be part of the evidence used to exclude other differential diagnosis of PE.28 Platelet count is aimed at detecting thrombocytopenia, which is a complication of PE but may be a part of criteria for diagnosing HELLP syndrome.\n\nConcerning obstetric ultrasonography in gestational hypertension and PE without severe features, the NICE guidelines recommend once 2 weekly evaluation.17 The ACOG guidelines of June 2020 recommends that ultrasonography should be performed every week to assess amniotic fluid index and every 3–4 weeks to assess foetal growth.28 In low resource settings, the frequency of ultrasonography for foetal evaluation should be at least once every 2 weeks particularly in PE without severe features. The frequency should also not be longer than once every 2 weeks in gestational hypertension and TGH. If there is foetal growth restriction for instance, the severity including abnormalities in the umbilical and other foetal artery dopplers will determine the frequency of ultrasonography.29 Non-stress test should be performed at least once weekly. The second case in the present report demonstrates a lack of ready access to prenatal ultrasonography because of the high volume of patients waiting for the imaging and lack of hospital bed-space for inpatient care. As a result of socioeconomic challenges, the patient defaulted the scheduled appointment for ultrasonography and foetal demise occurred within 2 weeks following the diagnosis of PE. It also shows how cultural and socioeconomic challenges can interfere with postnatal care given that the second patient went home on day 2 postpartum against medical advice to perform traditional burial rite of her baby but did not return as planned and subsequently defaulted postnatal clinic visits because of the pressure from her workplace. These failings increase the risk of perinatal and maternal complications. Although the clinical issues are paramount, understanding the patients’ health beliefs is also important for carrying patients along during clinical encounters. The refusal of hospital treatment requires the clinicians to explore the patient’s agenda and negotiate any disparity. Patients’ behaviours and choices are often influenced by their perceptions and may not agree with the doctors’. Exploring the reason(s) for encounter therefore becomes critical. Unfortunately, the patient was not referred for further counselling by a social worker or clinical psychologist.30\n\nKey take-home messages are shown in Table 1. Of note, the primary care providers help in preventing complications of HDP31 and the flow diagram shown in Figure 1 is a good guide that may assist with follow-up (intervals and the basic investigations to be performed at each visit to promote good outcomes). Further research on our recommendations is also suggested. Nonetheless, following arrival of a stable pregnant woman to a PHC, the following should be performed to diagnose or manage HDP: (1) measure the BP using a validated device and approved technique1; (2) use available tests such as dipstick to assess spot urine for proteinuria (3) provide health education on importance of antenatal care, self-awareness of symptoms of HDP and where possible the value of using validated home device to monitor BP1; (4) ascertain if there are symptoms or complaints and address them; (5) perform physical examination including cardiovascular and abdominal exam; (6) make diagnosis and risk categorise clients into low- or high-risk pregnancy with stable patients placed on prenatal vitamins including calcium whilst those at increased risk of HDP should also receive calcium and prophylactic aspirin starting early in the second trimester; (7) high-risk women should also receive calcium and emergency treatment where appropriate such as rapid-acting antihypertensive drug for severe hypertension and referred to a higher level of care32,33,34; (8) low-risk women should be managed and followed-up in the PHC clinic and or level 1 hospitals; (9) patients with pre-hypertension (BP 135–139/85–89 mmHg) should be followed-up within 3–7 days to repeat their BPs3 as they tend to develop hypertension (BP ≥ 140/90 mmHg) and are as well likely to have poor pregnancy outcomes including eclampsia35; (10) patients with HDP should be investigated and followed-up as illustrated in Figure 1. Additional algorithms on approach to HDP for the primary care physician is freely available online at https://safpj.co.za/index.php/safpj/article/view/5095/6009.36 To successfully implement our recommendations there has to be support and changes in the health policy, health system, levels of community involvement and accessibility to healthcare facilities. And the actions that may evolve before institutionalisation of the new recommendation are creation of awareness, commitment to implement, preparation to implement, implementation of the recommendations, integration of the new recommendation into routine practice and sustenance of the new practice. The details of actions required from different stakeholders to successfully implement the recommendations on HDP are contained in a table in the South African 2019 guidelines on HDP.3\n\nTABLE 1 Key take-home messages.\n\nSerial No.\tKey points\t\n1.\tTransient gestational hypertension and pre-eclampsia increase the risk of adverse pregnancy outcomes.\t\n2.\tSocioeconomic challenges interfere with the management of hypertensive disorders of pregnancy.\t\n3.\tStringent laboratory monitoring of a newly diagnosed new-onset hypertensive disorder of pregnancy should include at least testing blood levels of serum Creatinine, Haemoglobin concentration, Alanine transaminase and Platelets (CHAP) weekly.\t\n4.\tThe use of recommendations in Figure 1, increase of in-hospital bed-spaces, ready access to obstetric ultrasonography and public health education on the value of antenatal clinic follow-up visits are important measures to improve pregnancy outcomes in hypertensive disorders of pregnancy.\t\n5.\tRobust studies are required to guide the frequency and types of routine laboratory testing in hypertensive disorders of pregnancy.\t\n\nConclusion\n\nThe outcomes of HDP are often unpredictable and dramatic and the use of stringent recommendations in Figure 1 for monitoring the patients is valuable. However, an increase in the number of bed-spaces available in the hospital, ready access to obstetric ultrasonography and public health education on the value of antenatal clinic follow-up visits are important measures to improve pregnancy outcomes in HDP.\n\nAcknowledgements\n\nThe authors are thankful to the patients for giving written informed consent for the case reports to be published.\n\nCompeting interests\n\nThe authors declare that they have no financial or personal relationships that may have inappropriately influenced them in writing this article.\n\nAuthors’ contributions\n\nN.C.N. conceptualised the study and drafted the initial manuscript except case 1. G.D. drafted case 1 in the initial manuscript. Both N.C.N. and G.D. revised and approved the final manuscript submitted.\n\nEthical considerations\n\nEthical clearance was not needed for the study. The patients gave written informed consent for the case reports to be published.\n\nFunding information\n\nThis research received no specific grant from any funding agency in the public, commercial or not-for-profit sector.\n\nData availability\n\nData sharing is not applicable to this article as no new data were created or analysed in this study.\n\nDisclaimer\n\nThe views and opinions expressed in this article are those of the authors and do not necessarily reflect the official policy or position of any affiliated agency of the authors.\n\nHow to cite this article: Ngene NC, Daef G. Transient gestational hypertension and pre-eclampsia: Two case reports and literature review on the need for stringent monitoring. S Afr Fam Pract. 2021;63(1), a5236. https://doi.org/10.4102/safp.v63i1.5236\n==== Refs\nReferences\n\n1. NgeneNC, MoodleyJ. Blood pressure measurement in pregnancy and in hypertensive disorders of pregnancy: Devices, techniques, and challenges. Cardiovasc J Afr. 2019;30 (2 ):120–129. 10.5830/CVJA-2018-067 30720845\n2. HutcheonJA, LisonkovaS, JosephKS. Epidemiology of pre-eclampsia and the other hypertensive disorders of pregnancy. Best Pract Res Clin Obstet Gynaecol. 2011;25 (4 ):391–403. 10.1016/j.bpobgyn.2011.01.006 21333604\n3. MoodleyJ, Soma-PillayP, BuchmannE, PattinsonRC. Hypertensive disorders in pregnancy: 2019 National guideline. S Afr Med J. 2019;109 (9 ):S3–S16. 10.7196/SAMJ.2019.v109i3.14104\n4. AbalosE, CuestaC, GrossoAL, ChouD, SayL. Global and regional estimates of preeclampsia and eclampsia: A systematic review. Eur J Obstet Gynaecol Reprod Biol. 2013;170 (1 ):1–7. 10.1016/j.ejogrb.2013.05.005\n5. MoodleyJ, NgeneNC. Spontaneous liver haematoma rupture associated with pre-eclampsia in a low- to middle-income country: Lessons to be learnt from maternal death assessments. S Afr Med J. 2018;108 (10 ):809–812. 10.7196/SAMJ.2018.v108i10.13280\n6. National committee on the confidential enquiries into maternal deaths. Saving mothers 2014–2016: Seventh triennial report on confidential enquiries into maternal deaths in South Africa: Short report. Pretoria: South African Department of Health; 2018.\n7. BrownMA, MageeLA, KennyLC, et al . Hypertensive disorders of pregnancy: ISSHP classification, diagnosis, and management recommendations for international practice. Hypertension. 2018;72 (1 ):24–43. 10.1161/HYPERTENSIONAHA.117.10803 29899139\n8. Lee-Ann HawkinsT, BrownMA, MangosGJ, DavisGK. Transient gestational hypertension: Not always a benign event. Pregnancy Hypertens. 2012;2 (1 ):22–27. 10.1016/j.preghy.2011.09.001 26104985\n9. UkahUV, De SilvaDA, PayneB, et al . Prediction of adverse maternal outcomes from pre-eclampsia and other hypertensive disorders of pregnancy: A systematic review. Pregnancy Hypertens. 2018;11 :115–123. 10.1016/j.preghy.2017.11.006 29198742\n10. NgeneNC, MoodleyJ, NaickerT. The performance of pre-delivery serum concentrations of angiogenic factors in predicting postpartum antihypertensive drug therapy following abdominal delivery in severe preeclampsia and normotensive pregnancy. PLoS One. 2019;14 (4 ):e0215807. 10.1371/journal.pone.0215807 31022243\n11. AviramA, BarrettJ, ZaltzA, ShermanC, MelamedN. Differences in placental findings between pregnancies complicated by gestational hypertension versus preeclampsia. J Obstet Gynaecol Can. 2020;42 (5 ):666. 10.1016/j.jogc.2020.02.014\n12. NgeneNC, MoodleyJ. Role of angiogenic factors in the pathogenesis and management of pre-eclampsia. Int J Gynaecol Obstet. 2018;14 (1 ):5–13. 10.1002/ijgo.12424\n13. NgeneNC, MoodleyJ. Physiology of blood pressure relevant to managing hypertension in pregnancy. J Matern Fetal Neonatal Med. 2019;32 (8 ):1368–1377. 10.1080/14767058.2017.1404569 29172798\n14. The Fetal Medicine Foundation. Risk assessment: Risk for preeclampsia [homepage on the Internet]. 2021 [cited 2020 Jul 23]. Available from: https://fetalmedicine.org/research/assess/preeclampsia/second-trimester\n15. KhongTY, MooneyEE, ArielI, et al . Sampling and definitions of placental lesions: Amsterdam placental workshop group consensus statement. Arch Pathol Lab Med. 2016;140 (7 ):698–713. 10.5858/arpa.2015-0225-CC 27223167\n16. PaulesC, YoussefL, RoviraC, et al . Distinctive patterns of placental lesions in pre-eclampsia vs. small-for-gestational age and their association with fetoplacental Doppler. Ultrasound Obstet Gynaecol. 2019;54 (5 ):609–616. 10.1002/uog.20350\n17. National Institute for Health and Care Excellence. Hypertension in pregnancy: Diagnosis and management [homepage on the Internet]. [cited 2020 Aug 27]. Available from: https://www.nice.org.uk/guidance/ng133/resources/hypertension-in-pregnancy-diagnosis-and-management-pdf-66141717671365\n18. ACOG. Practice bulletin no. 202: Gestational hypertension and pre-eclampsia. Obstet Gynaecol. 2019;133 (1 ):e1–e25. 10.1097/AOG.0000000000003018\n19. South African National Maternity Guidelines Committee. Guidelines for maternity care in South Africa: A manual for clinics, community health centres and district hospitals. Pretoria: Department of Health; 2016.\n20. JainV. Choosing wisely-bloodwork for pre-eclampsia. J Obstet Gynaecol Can. 2018;40 (6 ):723–725. 10.1016/j.jogc.2018.02.019 29861083\n21. Von DadelszenP, PayneB, LiJ, et al . Prediction of adverse maternal outcomes in pre-eclampsia: Development and validation of the fullPIERS model. Lancet. 2011;377 (9761 ):219–227. 10.1016/S0140-6736(10)61351-7 21185591\n22. UkahUV, PayneB, LeeT, et al . External validation of the fullPIERS model for predicting adverse maternal outcomes in pregnancy hypertension in low- and middle-income countries. Hypertension. 2017;69 (4 ):705–711. 10.1161/HYPERTENSIONAHA.116.08706 28167685\n23. MageeLA, Von DadelszenP. Hypertension. In: ArulkumaranS, LedgerW, DennyL, DoumouchtsisS, editors. Oxford textbook of obstetrics and gynaecology. Oxford: Oxford University Press, 2020; pp. 268–283.\n24. ThompsonX, SullivanMB, MathuraP, WongA, CrawfordJ, SiaW. Implementation of a clinical decision laboratory ordering algorithm for preeclampsia: A quality improvement initiative. J Obstet Gynaecol Can. 2020;42 (10 ):1223–1229.e3. 10.1016/j.jogc.2020.03.016 32654980\n25. Paulino-MorenteJMA, Cacas-DavidIG, PenolioVVL. Association of hypokalemia and preeclampsia and correlation of levels of serum potassium to blood pressure severity in preeclampsia. Philipp J Obstet Gynaecol. 2018;42 (2 ):9–16.\n26. DhanjalMK, OwenEP, AnthonyJA, DavidsonJS, RaynerdBL. Association of pre-eclampsia with the R563Q mutation of the b-subunit of the epithelial sodium channel. Br J Obstet Gynaecol. 2006;113 (5 ):595–598. 10.1111/j.1471-0528.2006.00899.x\n27. CantuJ, CliftonRG, RobertsJM, et al . Laboratory abnormalities in pregnancy-associated hypertension: Frequency and association with pregnancy outcomes. Obstet Gynaecol. 2014;124 (5 ):933–940. 10.1097/AOG.0000000000000509\n28. American College of Obstetricians and Gynaecologists’ Committee on Practice Bulletins – Obstetrics. Gestational hypertension and preeclampsia: ACOG practice bulletin, number 222. Obstet Gynaecol. 2020;135 (6 ):e237–e260. 10.1097/AOG.0000000000003891\n29. Society for Maternal-Fetal Medicine (SMFM), MartinsJG, BiggioJR, AbuhamadA. Society for Maternal-fetal medicine consult series #52: Diagnosis and management of fetal growth restriction. Am J Obstet Gynaecol. 2020;223 (4 ):B2–B17. 10.1016/j.ajog.2020.05.010\n30. NgeneNC, BodibaT. Challenges in obtaining consent for caesarean delivery in minors in South Africa. S Afr J Obstet Gynaecol. 2020;26 (1 ):38–41. 10.7196/SAJOG.2020.v26i1.1532\n31. MoodleyJ, JugnandenP, NaidooM, NgeneNC. Primary care providers and hypertension in pregnancy: Reflections on a patient encounter. S Afr Fam Pract. 2020;62 (1 ):a5086. 10.4102/safp.v62i1.5086\n32. NgeneNC, MoodleyJ. Blood pressure measurement and rapid acting antihypertesnsives for severe hypertension in pregnancy. Obstet Gynaecol Forum. 2016;26 (3 ):35–40.\n33. MoodleyJ, NgeneNC. Severe hypertension in pregnancy: Using dynamic checklist to save lives. S Afr Med J. 2016;106 (8 ):767–770. 10.7196/SAMJ.2016.v106i8.10908 27499397\n34. NgeneNC, MoodleyJ. Pre-eclampsia with severe features: Management of antihypertensive therapy in the postpartum period. Pan Afr Med J. 2020;36 :216. 10.11604/pamj.2020.36.216.19895 32963682\n35. MoodleyJ, NgeneNC. Maternal deaths due to eclampsia in teenagers: Lessons from assessment of maternal deaths in South Africa. Afr J Prim Health Care Fam Med. 2020;12 (1 ):a2305. 10.4102/phcfm.v12i1.2305\n36. NaidooM, PattinsonRC. An approach to hypertensive disorders in pregnancy for the primary care physician. S Afr Fam Pract. 2020;62 (1 ):e1–e6. 10.4102/safp.v62i1.5095\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2078-6190",
"issue": "63(1)",
"journal": "South African family practice : official journal of the South African Academy of Family Practice/Primary Care",
"keywords": "hypertensive disorders of pregnancy; intrauterine foetal death; pre-eclampsia; stringent monitoring; transient gestational hypertension",
"medline_ta": "S Afr Fam Pract (2004)",
"mesh_terms": null,
"nlm_unique_id": "9701104",
"other_id": null,
"pages": "e1-e6",
"pmc": null,
"pmid": "33764141",
"pubdate": "2021-03-16",
"publication_types": "D016428:Journal Article",
"references": "26104985;29172798;32787402;23746796;31022243;29198742;32443079;27499397;27223167;32407785;29861083;16579800;30575675;31635598;32654980;21185591;32148059;29222938;25437721;21333604;32963682;29899139;30720845;31115105;28167685;32787388",
"title": "Transient gestational hypertension and pre-eclampsia: Two case reports and literature review on the need for stringent monitoring.",
"title_normalized": "transient gestational hypertension and pre eclampsia two case reports and literature review on the need for stringent monitoring"
} | [
{
"companynumb": "ZA-SUN PHARMACEUTICAL INDUSTRIES LTD-2021RR-298753",
"fulfillexpeditecriteria": "1",
"occurcountry": "ZA",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "AMLODIPINE BESYLATE"
},
... |
{
"abstract": "OBJECTIVE\nAdvanced unresectable and metastatic non-melanoma skin cancers (NMSC) are rare, but often arise in elderly patients. When surgery or irradiation are no longer feasible, chemotherapy is often precluded by the patient's age and comorbidities. Whether low-dose multi-agent chemotherapy could be an alternative for this vulnerable population in an outpatient setting was the issue examined in this retrospective analysis.\n\n\nMETHODS\nTwenty-six patients with advanced unresectable or metastatic NMSC received weekly multi-agent chemotherapy with carboplatin at an area under the curve of 2 or 40 mg total dose of cisplatin, with 15 IU total dose of bleomycin, 40 mg total dose of methotrexate, and 500 mg total dose of 5-fluorouracil (CMF-b) until best response, toxicity, or progression of their disease.\n\n\nRESULTS\nTwenty-four patients were treated as outpatients; two were hospitalized. Twenty-three patients were previously treated with surgery or radiotherapy. The median age was 68 years (range=44-100 years). The median number of cycles was 6 (range=1 to 17). The overall response rate was 61.5% (seven complete remissions, nine partial remissions) for the entire cohort and 63.6% (two complete remissions and five partial remissions) for patients >80 years. The median duration of response was 6.1 months (range=1.6-63 months). Responses longer than 6 months were obtained in 11/26 (42.3%) of the entire cohort and in 4/11 (36.3%) patients >80 years. Symptom improvement was observed in 17 patients (65.3%). Toxicity was acceptable, with grade 3 renal failure (n=1) and grade 3 or 4 myelotoxicity (n=2).\n\n\nCONCLUSIONS\nCMF-b is a safe, weekly low-dose multi-agent regimen that offers palliation for vulnerable patients with NMSC.",
"affiliations": "Centre of Oncology, Geneva University Hospitals and University of Geneva, Geneva, Switzerland vittoria.espeli@eoc.ch pierre-yves.dietrich@hcuge.ch.;Plastic and Reconstructive Surgery, Geneva University Hospitals and University of Geneva, Geneva, Switzerland.;Department of Oncology, University Hospital of Lausanne, Lausanne, Switzerland.;Plastic and Reconstructive Surgery, Geneva University Hospitals and University of Geneva, Geneva, Switzerland.;Centre of Oncology, Geneva University Hospitals and University of Geneva, Geneva, Switzerland vittoria.espeli@eoc.ch pierre-yves.dietrich@hcuge.ch.",
"authors": "Espeli|Vittoria|V|;Ruegg|Eva|E|;Hottinger|Andreas F|AF|;Modarressi|Ali|A|;Dietrich|Pierre-Yves|PY|",
"chemical_list": "D001761:Bleomycin; D016190:Carboplatin; D002945:Cisplatin; D005472:Fluorouracil; D008727:Methotrexate",
"country": "Greece",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0250-7005",
"issue": "36(5)",
"journal": "Anticancer research",
"keywords": "Advanced non-melanoma skin cancer; chemotherapy; elderly",
"medline_ta": "Anticancer Res",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D001761:Bleomycin; D001855:Bone Marrow Diseases; D016190:Carboplatin; D002280:Carcinoma, Basal Cell; D002294:Carcinoma, Squamous Cell; D002945:Cisplatin; D004334:Drug Administration Schedule; D004341:Drug Evaluation; D005260:Female; D005472:Fluorouracil; D006801:Humans; D008297:Male; D008727:Methotrexate; D008875:Middle Aged; D012074:Remission Induction; D051437:Renal Insufficiency; D012189:Retrospective Studies; D016879:Salvage Therapy; D012878:Skin Neoplasms",
"nlm_unique_id": "8102988",
"other_id": null,
"pages": "2359-64",
"pmc": null,
"pmid": "27127144",
"pubdate": "2016-05",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Weekly Multi-agent Chemotherapy (CMF-b) for Advanced Non-melanoma Skin Cancer.",
"title_normalized": "weekly multi agent chemotherapy cmf b for advanced non melanoma skin cancer"
} | [
{
"companynumb": "PHHY2017CH028133",
"fulfillexpeditecriteria": "1",
"occurcountry": "CH",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHOTREXATE"
},
"drugadditional": "3",
"dru... |
{
"abstract": "Intra-vesical instillation of bacillus Calmette-Guérin (BCG) is an important treatment modality of superficial bladder cancer. It is usually well tolerated, although some adverse reactions can occur. One possible yet rare complication is granulomatous hepatitis, that is thought to be caused either by BCG infection or a hypersensitivity reaction to the bacillus. We present a case of a 79-year-old apparently immunocompetent patient who developed granulomatous hepatitis a few months after BCG administration for bladder cancer immunotherapy. It is important to notice that acid-fast smears and cultures are often negative, and these should not exclude diagnosis nor delay treatment. Our case highlights the importance of clinical suspicion and prompt initiation of appropriate treatment.",
"affiliations": "Infectious Diseases Department, Centro Hospitalar e Universitário de São João, 4099-002 Porto, Portugal.;Infectious Diseases Department, Centro Hospitalar e Universitário de São João, 4099-002 Porto, Portugal.;Internal Medicine Department, Centro Hospitalar e Universitário de São João, 4099-002 Porto, Portugal.;Infectious Diseases Department, Centro Hospitalar e Universitário de São João, 4099-002 Porto, Portugal.",
"authors": "Branco|Elsa Alves|EA|;Duro|Raquel|R|;Brito|Teresa|T|;Sarmento|António|A|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3390/idr13030057",
"fulltext": "\n==== Front\nInfect Dis Rep\nInfect Dis Rep\nidr\nInfectious Disease Reports\n2036-7430\n2036-7449\nMDPI\n\n10.3390/idr13030057\nidr-13-00057\nCase Report\nGranulomatous Hepatitis Following Intra-Vesical Instillation of Bacillus Calmette–Guérin for Treatment of Bladder Cancer\nBranco Elsa Alves 1*\nDuro Raquel 1\nBrito Teresa 2\nSarmento António 1\nPetrosillo Nicola Academic Editor\n1 Infectious Diseases Department, Centro Hospitalar e Universitário de São João, 4099-002 Porto, Portugal; raquel.duro@gmail.com (R.D.); antonio.sarmento@chsj.min-saude.pt (A.S.)\n2 Internal Medicine Department, Centro Hospitalar e Universitário de São João, 4099-002 Porto, Portugal; mtapbrito@gmail.com\n* Correspondence: elsa.alves.branco@gmail.com\n01 7 2021\n9 2021\n13 3 611618\n13 5 2021\n28 6 2021\n© 2021 by the authors.\n2021\nhttps://creativecommons.org/licenses/by/4.0/ Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).\nIntra-vesical instillation of bacillus Calmette–Guérin (BCG) is an important treatment modality of superficial bladder cancer. It is usually well tolerated, although some adverse reactions can occur. One possible yet rare complication is granulomatous hepatitis, that is thought to be caused either by BCG infection or a hypersensitivity reaction to the bacillus. We present a case of a 79-year-old apparently immunocompetent patient who developed granulomatous hepatitis a few months after BCG administration for bladder cancer immunotherapy. It is important to notice that acid-fast smears and cultures are often negative, and these should not exclude diagnosis nor delay treatment. Our case highlights the importance of clinical suspicion and prompt initiation of appropriate treatment.\n\ngranulomatous hepatitis\nbacillus Calmette–Guérin\nbladder cancer\n==== Body\n1. Introduction\n\nBladder instillations with bacillus Calmette–Guérin (BCG), an attenuated live strain of Mycobacterium bovis, are commonly used as immunotherapy for bladder carcinoma [1,2]. The mechanism by which BCG exerts its antitumour activity is unknown, but it has been suggested that a non-specific immune response to BCG might also destroy tumour cells. Another suggested mechanism is that the severe inflammation caused by BCG leads to local ischaemia, thereby killing tumour cells [1].\n\nAlthough usually well tolerated, both local and systemic BCG-related complications may occur following instillation, with early (in a few hours) or late (in several months) presentation [2,3]. Local side effects are frequent (90%), and may include urinary frequency, cystitis, fever and haematuria [4,5]. Although serious complications are rare, patients can develop severe, life-threatening sepsis with disseminated mycobacterial infection [5]. Various other local and systemic side effects have been reported, such as acute respiratory failure and septic shock, isolated renal tuberculosis and granulomatous hepatitis [4].\n\nGranulomatous hepatitis is a rare serious side effect, which has been considered a hypersensitivity reaction to BCG or a BCG infection [1]. Steg et al. and Lamm et al. described a 3% and 0.7% incidence, respectively, of BCG-related granulomatous hepatitis after intra-vesical instillation [4,6,7]. Hepatitis usually presents with fever, anorexia, jaundice and alteration of liver function tests, typically with a cholestatic pattern of serum liver tests; liver biopsy reveals granulomas in all cases [2]. The pathogenic mechanisms underlying the development of these complications remain not fully understood, and considerable debate exists about whether it represents a form of hypersensitivity reaction, based on the histologic finding of granulomas in the absence of recoverable microorganisms, or an active mycobacterial infection, since some authors have demonstrated viable bacilli in a variety of tissues [2].\n\n2. Case Presentation\n\nWe present a case of a 79-year-old male patient, with history of dyslipidaemia medicated with statins, moderate alcohol consumption (half a bottle of red wine a day) and ischaemic heart failure. He was diagnosed with high-grade papillary urothelial carcinoma in 2016 and was submitted to immunotherapy with intra-vesical instillation of BCG for a full year (last instillation in February 2018).\n\nRoutine bloodwork documented hepatic cytolysis and cholestasis for the first time in January of 2018 (aspartate transaminase (AST) 74 U/L (normal range: 10–37 U/L); alanine transaminase (ALT) 55 U/L (normal range: 10–37 U/L), gamma-glutamyl transferase (GGT) 273 U/L (normal range: 10–49 U/L); alkaline phosphatase (AP) 176 U/L (normal range: 30–120 U/L)), without hyperbilirubinaemia. Figure 1 describes the evolution of liver enzymes. He complained of fatigue and diminished appetite. On physical examination, the liver was palpable 4 cm bellow the right costal margin. Blood tests showed mild hepatic cytolysis. Three months later, he had aggravated liver enzymes, with AST and ALT up to 2.5 x/upper normal limit and cholestasis of 3–7 x/UNL with normal bilirubin. At that time, he stopped statin therapy and alcohol consumption.\n\nHe was previously evaluated at outpatient internal medicine appointments. An abdominal ultrasound performed in November 2018 showed a globous hepatic parenchyma with no focal lesions. In April of 2019, he complained about weight loss (about 4 kg) in the previous few months and colangio-magnetic resonance was performed that showed homogeneous mild hepatomegaly and splenomegaly, without nodules or other lesions, and the absence of biliary duct dilatation. In November 2019, he was electively admitted to undergo a hepatic biopsy. Histology showed granulomatous hepatitis and fibrotic septation of the parenchyma, with some multinucleated cells but without the typical aspects of Langhans cells and negative Ziehl–Neelsen stain (Figure 2). PCR of Mycobacterium tuberculosis complex was negative in the liver biopsy paraffined specimen. HIV and viral hepatitis serologies were all negative. Serology and polymerase chain reaction (PCR) for Coxiella burnetii and Brucella spp., as well as mycobacterial examination of urine, were also negative. Thoracic computed tomography was performed and revealed multiple mediastinal and hilar lymph nodes without adenomegaly criteria, some with gross calcifications, and lung parenchyma with evident emphysema, without masses, nodules or consolidations. An immune panel for autoimmune hepatitis was normal, and the serum angiotensin conversion enzyme (ACE) was negative.\n\nThe patient was then referred to the infectious diseases outpatient clinic, where he was first observed in June 2020. Given the existence of a granulomatous hepatitis in a patient previously submitted to BCG intra-vesical instillation, with accompanying complaints of anorexia and weight loss, the diagnosis of granulomatous hepatitis caused by BCG infection was postulated. The hepatic cytolysis and cholestasis started 1–2 months after discontinuation of the intra-vesical immunotherapy, which was consistent with the suspected diagnosis. Empirical treatment with isoniazid 300 mg/day and rifampicin 600 mg/day was started in late June. After treatment initiation, there was a progressive improvement of the liver enzymes, full normalisation of the cytolysis in November and a considerable decrease in cholestasis. The patient received 9 months of dual anti-bacillary treatment, with complete recovery, and was discharged in March 2021.\n\n3. Discussion\n\nDisseminated BCG disease is a rare but life-threatening complication of BCG administration [5]. The adverse effects of intra-vesical BCG instillations can appear early or several years after the treatment [8]. The spectrum of symptoms may be similar to that of tuberculosis infection, including persistent fever, night sweats and weight loss [5]. There is still controversy relating to whether the clinical presentation of BCG systemic disease is caused by actual dissemination of M. bovis in the involved tissues or is secondary to a hypersensitivity reaction [3]. Noticeably, in the majority of cases, hypersensitivity and infection cannot be differentiated histopathologically and clinically [4].\n\nBCG-related hepatitis is a rare complication, and most authors suggest that it is caused by a hypersensitivity reaction to BCG, based on negative Ziehl–Neelsen staining and negative cultures of liver tissue [1]. BCG-related granulomatous hepatitis should be considered in cases of abnormal liver function tests and persistent fever following BCG therapy [4]. Table 1, Table 2, and Table 3 summarise some reported cases of granulomatous hepatitis following intra-vesical instillation of BCG published in the literature over the last 3 decades. Liver biopsy reveals granulomas in all hepatitis cases, and a direct smear for mycobacteria plays an important role. However, the detection of acid-fast bacilli in liver, blood and bone marrow specimens is quite difficult. Even though acid-fast bacilli are positive in 10% of all liver tuberculosis biopsy samples, DNA hybridisation studies are often negative [4]. The exclusion of other entities and the prompt response to antituberculous treatment should be considered the cornerstones of diagnosis of BCG infection since cultures often remain negative [2]. In cases with an appropriate clinical presentation, negative culture tests should not be a cause for treatment delay. It should be remembered that early treatment improves the chance of success [4]. Treatment should consist of isoniazid (300 mg daily) and rifampicin (600 mg daily) with or without ethambutol and/or corticosteroids [1,5,8]. Treatment with pyrazinamide is not recommended, as all forms of M. bovis are resistant. Clinical response is monitored by the decline and normalisation of liver function tests [4]. In the case of our patient, he had a consistent clinical scenario and positive histology, although a direct smear for acid-fast bacilli and PCR of the biopsy specimen were both negative. Although no samples were sent to culture, prompt favourable response to treatment further corroborated the diagnosis. Overall, the prognosis of BCG infection is good [2]. Our case is an illustrative example of how time-consuming and laborious the diagnosis of granulomatous hepatitis following BCG administration can be if clinical suspicion is low, highlighting the need for high clinical suspicion in patients with an appropriate clinical scenario who were previously treated with intra-vesical BCG, in order to promptly initiate appropriate treatment.\n\nAcknowledgments\n\nThe authors are grateful to the Pathology Department of Centro Hospitalar e Universitário de São João.\n\nAuthor Contributions\n\nConceptualisation, E.A.B. and R.D.; writing—original draft preparation, E.A.B.; writing—review and editing, E.A.B., R.D., T.B. and A.S.; visualisation, E.A.B. and T.B.; supervision, R.D. and A.S. All authors have read and agreed to the published version of the manuscript.\n\nFunding\n\nThis research received no external funding.\n\nInformed Consent Statement\n\nWritten informed consent has been obtained from the patient to publish.\n\nConflicts of Interest\n\nThe authors declare no conflict of interest.\n\nFigure 1 Evolution of liver enzymes over the years (in U/L).\n\nFigure 2 Histopathological findings of the liver biopsy sample revealed epithelioid granulomas (haematoxylin and eosin).\n\nidr-13-00057-t001_Table 1 Table 1 Summary of some cases of granulomatous hepatitis following intra-vesical BCG therapy published in the literature.\n\nPublication\tNo. Cases\tSex\tAge\tTime Interval Between BCG Instillation and Diagnosis\tIsolation of M. bovis on Culture\tMolecular Detection of M. bovis\tAcid-Fast Staining on Liver Biopsy\tTherapy\tOutcome\t\nHillel Y. Marans and Huseyin M. Bekirov; Granulomatous Hepatitis following intravesical Bacillus Calmette-Guerin therapy for bladder Carcinoma; The Journal of Urology, 1987; 0022-~34 7 /8'7 /1871-0111$02.00/0\t1\tM\t62 y\t2 y\tNo\tNo\tNegative\t300 mg isoniazid + 600 mg rifampin (duration unknown)\tResolution\t\nDino A. Graziano et al; A case of granulomatous hepatitis after intravesical Bacillus Calmette-Guerin administration; The Journal of Urology, 1991; 0022-5347/91/1464-1118$03.00/0\t1\tM\t61 y\t39 days\tNo\tYes (bone marrow)\tNegative\t300 mg isoniazid + 600 mg rifampin + 40 mg prednisone (duration unknown)\tResolution\t\nProctor DD, Chopra S, Rubenstein SC, Jokela JA, Uhl L. Mycobacteremia and granulomatous hepatitis following initial intravesical bacillus Calmette-Guerin instillation for bladder carcinoma. Am J Gastroenterol. 1993 Jul;88(7):1112-5. PMID: 8317415.\t1\tM\t72 y\t8 days\tYes (blood)\tNo\tPositive (rare)\tEthambutol (2 months) + isoniazid and rifampin (12 months)\tNot mentioned\t\nArzt MR, Forouhar F. Granulomatous hepatitis as a complication of intravesical Bacillus Calmette-Guerin therapy for bladder carcinoma. Ann Clin Lab Sci. 1995 Sep-Oct;25(5):409-13. PMID: 7486816\t1\tM\t74 y\t2 months\tNo\tNo\tNegative\t300 mg isoniazid + 600 mg rifampin (6 months)\tResolution\t\nFWG Leebeek et al. Granulomatous hepatitis caused by Bacillus Calmette-Guerin (BCG) infection after BCG bladder instillation. Gut 1996;38: 616-618\t1\tM\t69 y\t14 days\tNo\tYes (liver biopsy)\tNegative\tIsoniazid + rifampin (duration unknown)\tResolution\t\n\nidr-13-00057-t002_Table 2 Table 2 Summary of some cases of granulomatous hepatitis following intra-vesical BCG therapy published in the literature.\n\nPublication\tNo. Cases\tSex\tAge\tTime Interval Between BCG Instillation and Diagnosis\tIsolation of M. bovis on Culture\tMolecular Detection of M. bovis\tAcid-Fast Staining on Liver Biopsy\tTherapy\tOutcome\t\nRobert E. Scully, Eugene J. Mark, William F. McNeely, Sally H. Ebeling; Weekly Clinicopathological Exercises. Case Records of the Massachusetts General Hospital. 1998. Volume 339, Number 12\t1\tM\t57 y\t6 weeks\tYes (blood)\tNo\tNegative\tOfloxacin + ethambutol + amikacin (6 months) + 60 mg prednisone (tapered for 3 months)\tRecurrence\t\nB. Ozbakkaloglu et al. Granulomatous Hepatitis Following Intravesical Bacillus Calmette-Guerin Therapy. International Urology and Nephrology; 1999.31(1), pp.49-53\t1\tM\t46 y\t1 week\tNo\tNo\tNegative\t300 mg isoniazid + 600 mg rifampin (6 months)\tResolution\t\nSteven M. Van Outryve et al. Bacillus Calmette–Guerin-induced granulomatous hepatitisin a patient with a superficial bladder carcinoma. European Journal of Gastroenterology & Hepatology 2004, 16:1027–1032\t1\tM\t71 y\t26 days\tNo\tNo\tNegative\t300 mg isoniazid + 600 mg rifampin (12 months) + 32 mg prednisone (tapered for 6 months)\tResolution\t\nAliye Soylu et al. Peritoneal tuberculosis and granulomatous hepatitis secondary to treatment of bladder cancer with Bacillus Calmette-Guerin. Annals of Clinical Microbiology and Antimicrobials 2009:8:12 doi: 10.1186/1476-0711-8-12\t1\tM\t46 y\tNot specified\tNo\tNo\tNegative\tIsoniazid + rifampin + ethambutol (6 months) + 60 mg methylprednisolone (tapered for 1,5 months)\tResolution\t\n\nidr-13-00057-t003_Table 3 Table 3 Summary of some cases of granulomatous hepatitis following intra-vesical BCG therapy published in the literature.\n\nPublication\tNo. Cases\tSex\tAge\tTime Interval Between BCG Instillation and Diagnosis\tIsolation of M. bovis on Culture\tMolecular Detection of M. bovis\tAcid-Fast Staining on Liver Biopsy\tTherapy\tOutcome\t\nMaddalena Adami et al. Granulomatous hepatitis after intravesical bacillus Calmette – Guérin treatment. Scandinavian Journal of Infectious Diseases, 2011; 43: 55–57\t1\tM\t78 y\t6 weeks\tNo\tNo\tNegative\tIsoniazid + rifampin + ethambutol (6 months)\tResolution\t\nY Eso, A Takai, S Arasawa, Y Ueda and H Seno. Hepatobiliary and Pancreatic: Granulomatous hepatitis due to disseminated bacillus Calmette–Guérin disease. Journal of Gastroenterology and Hepatology 32 (2017) 1538. doi:10.1111/jgh.13831\t1\tM\t66 y\t17 days\tNo\tNo\tNegative\tIsoniazid + rifampin + ethambutol (6 months)\tResolution\t\nM. Moussa, M. Abou Chakra. Granulomatous hepatitis caused by Bacillus Calmette-Guerin (BCG) infection after BCG bladder instillation: a case report. Urology Case Reports 2018. http://doi.org/10.1016/j.eucr.2018.05.012, accessed on 1 July 2021\t1\tM\t52 y\t7 days\tNo\tYes (liver biopsy)\tNegative\tIsoniazid + rifampin + ethambutol (6 months)\tResolution\t\n\nPublisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. Leebeek F.W. Ouwendijk R.J. Kolk A.H. Dees A. Meek J.C. Nienhuis J.E. Dingemans-Dumas A.M. Granulomatous hepatitis caused by Bacillus Calmette-Guerin (BCG) infection after BCG bladder instillation Gut 1996 38 616 618 10.1136/gut.38.4.616 8707098\n2. Asín M.A.P.-J. Fernández-Ruiz M. López-Medrano F. Lumbreras C. Ángel T. Juan R.S. Arrebola-Pajares A. Lizasoain M. Prieto S. Aguado J.M. Bacillus Calmette-Guérin (BCG) Infection Following Intravesical BCG Administration as Adjunctive Therapy For Bladder Cancer Medicine 2014 93 236 254 10.1097/MD.0000000000000119 25398060\n3. ElZein F. Albogami N. Saad M. El Tayeb N. Alghamdi A. ElYamany G. Disseminated Mycobacterium bovis Infection Complicating Intravesical BCG Instillation for the Treatment of Superficial Transitional Cell Carcinoma of the Bladder Clin. Med. Insights Case Rep. 2016 9 71 73 10.4137/CCRep.S39904 27559301\n4. Soylu A. Ince A.T. Polat H. Yasar N. Ciltas A. Özkara S. Tasci A.I. Peritoneal tuberculosis and granulomatous hepatitis secondary to treatment of bladder cancer with Bacillus Calmette-Guérin Ann. Clin. Microbiol. Antimicrob. 2009 8 12 10.1186/1476-0711-8-12 19368735\n5. Moussa M. Chakra M.A. Granulomatous hepatitis caused by Bacillus Calmette-Guerin (BCG) infection after BCG bladder instillation: A case report Urol. Case Rep. 2018 20 3 4 10.1016/j.eucr.2018.05.012 29984182\n6. Lamm D.L. Van Der Meijden A.P. Morales A. Brosman S.A. Catalona W.J. Herr H.W. Soloway M.S. Steg A. Debruyne F.M. Incidence and treatment of complications of Bacillus Calmette-Guérin intravesical therapy in superficial bladder cancer J. Urol. 1992 147 596 600 10.1016/S0022-5347(17)37316-0 1538436\n7. Steg A. Leleu C. Debré B. Boccon-Gibod L. Sieard D. Systemic bacillus Calmette-Guérin infection, ’BCGitis’, in patients treated by intravesical Bacillus Calmette-Guérin therapy for bladder cancer Eur. Urol. 1989 16 161 164 10.1159/000471561 2744050\n8. Marquez-Batalla S. Fraile-Villarejo E. Belhassen-García M. Gutierrez-Zubiaurre N. Cordero-Sánchez M. Disseminated infection due to Mycobacterium bovis after intravesical BCG instillation World J. Clin. Cases 2014 2 301 303 10.12998/wjcc.v2.i7.301 25032208\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2036-7430",
"issue": "13(3)",
"journal": "Infectious disease reports",
"keywords": "bacillus Calmette–Guérin; bladder cancer; granulomatous hepatitis",
"medline_ta": "Infect Dis Rep",
"mesh_terms": null,
"nlm_unique_id": "101537203",
"other_id": null,
"pages": "611-618",
"pmc": null,
"pmid": "34287340",
"pubdate": "2021-07-01",
"publication_types": "D002363:Case Reports",
"references": "25032208;29984182;25398060;27559301;1538436;2744050;8707098;19368735",
"title": "Granulomatous Hepatitis Following Intra-Vesical Instillation of Bacillus Calmette-Guérin for Treatment of Bladder Cancer.",
"title_normalized": "granulomatous hepatitis following intra vesical instillation of bacillus calmette gu rin for treatment of bladder cancer"
} | [
{
"companynumb": "PT-009507513-2107PRT008593",
"fulfillexpeditecriteria": "1",
"occurcountry": "PT",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "BACILLUS CALMETTE-GUERIN SUBSTRAIN TICE LIVE ANTIGEN"
... |
{
"abstract": "There have been a few reports of successful lung transplantation (LTx) in patients with SARS-CoV-2-induced acute respiratory distress syndrome (ARDS); however, all reports were with rather short follow-up. Here we present a 62-year-old man without prior lung diseases. Following SARS-CoV-2-induced ARDS and 6 months of extracorporeal membrane oxygenation, he underwent LTx. 3 months post-transplantation he developed acute hypoxia requiring emergency intubation. Chest imaging showed acute rejection, and de novo DQ8-DSA was discovered. He was treated with a high dose of corticosteroids and plasmapheresis and was extubated 4 days later, yet the de novo DQ8-DSA remained. After sessions of plasmapheresis and rituximab, the levels of de novo DQ8-DSA remained unchanged. Nine months post-transplantation the patient died of respiratory failure. We herein discuss the decision to transplant, the transplantation itself and the postoperative course with severe antibody-mediated rejection. In addition, we evaluated the histological changes of the explanted lungs and compared these with end-stage idiopathic pulmonary fibrosis tissue, where both similarities and differences are seen. With the current case experience, one might consider close monitoring regarding DSA, and gives further support that LTx should only be considered for very carefully selected patients.",
"affiliations": "Department of Cardiothoracic Surgery and Transplantation, Skåne University Hospital Lund, Lund, Sweden sandra.lindstedt.ingemansson@gmail.com.;Department of Cardiothoracic Anaesthesia and Intensive Care, Lund University Hospital, Lund, Sweden.;Department of Pulmonology and Transplantation, Lund University Hospital, Lund, Sweden.;Department of Cardiothoracic Surgery and Transplantation, Skåne University Hospital Lund, Lund, Sweden.;Department of Clinical Sciences, Lund University, Lund, Sweden.;Wallenberg Center for Molecular Medicine, Lund University, Lund, Sweden.;Department of Cardiothoracic Anaesthesia and Intensive Care, Lund University Hospital, Lund, Sweden.;Wallenberg Center for Molecular Medicine, Lund University, Lund, Sweden.;Department of Cardiothoracic Surgery and Transplantation, Skåne University Hospital Lund, Lund, Sweden.;Department of Pulmonology and Transplantation, Skåne University Hospital Lund, Lund, Sweden.;Department of Cardiothoracic Anaesthesia and Intensive Care, Lund University Hospital, Lund, Sweden.;Department of Cardiothoracic Surgery and Transplantation, Skåne University Hospital Lund, Lund, Sweden.",
"authors": "Lindstedt|Sandra|S|0000-0003-4484-6473;Grins|Edgar|E|;Larsson|Hillevi|H|;Nilsson|Johan|J|;Akbarshahi|Hamid|H|;Silva|Iran|I|;Hyllen|Snejana|S|;Wagner|Darcy|D|0000-0003-3794-1309;Sjögren|Johan|J|;Hansson|Lennart|L|;Ederoth|Per|P|;Gustafsson|Ronny|R|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1136/bmjresp-2021-001036",
"fulltext": "\n==== Front\nBMJ Open Respir Res\nBMJ Open Respir Res\nbmjresp\nbmjopenrespres\nBMJ Open Respiratory Research\n2052-4439\nBMJ Publishing Group BMA House, Tavistock Square, London, WC1H 9JR\n\nbmjresp-2021-001036\n10.1136/bmjresp-2021-001036\nPerspective\n1506\n2474\nLung transplant after 6 months on ECMO support for SARS-CoV-2-induced ARDS complicated by severe antibody-mediated rejection\nhttp://orcid.org/0000-0003-4484-6473\nLindstedt Sandra 12\nGrins Edgar 34\nLarsson Hillevi 5\nNilsson Johan 14\nAkbarshahi Hamid 45\nSilva Iran 26\nHyllen Snejana 34\nhttp://orcid.org/0000-0003-3794-1309\nWagner Darcy 27\nSjögren Johan 14\nHansson Lennart 8\nEderoth Per 34\nGustafsson Ronny 1\n1 Department of Cardiothoracic Surgery and Transplantation, Skåne University Hospital Lund, Lund, Sweden\n2 Wallenberg Center for Molecular Medicine, Lund University, Lund, Sweden\n3 Department of Cardiothoracic Anaesthesia and Intensive Care, Lund University Hospital, Lund, Sweden\n4 Department of Clinical Sciences, Lund University, Lund, Sweden\n5 Department of Pulmonology and Transplantation, Lund University Hospital, Lund, Sweden\n6 Department of Experimental Medical Sciences, Lung Bioengineering and Regeneration, Lund University, Lund, Sweden\n7 Lund Stem Cell Center, Lund University, Lund, Sweden\n8 Department of Pulmonology and Transplantation, Skåne University Hospital Lund, Lund, Sweden\nCorrespondence to Dr Sandra Lindstedt; sandra.lindstedt.ingemansson@gmail.com\n2021\n20 9 2021\n20 9 2021\n8 1 e00103625 6 2021\n03 9 2021\n© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.\n2021\nhttps://creativecommons.org/licenses/by-nc/4.0/ This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.\n\nThere have been a few reports of successful lung transplantation (LTx) in patients with SARS-CoV-2-induced acute respiratory distress syndrome (ARDS); however, all reports were with rather short follow-up. Here we present a 62-year-old man without prior lung diseases. Following SARS-CoV-2-induced ARDS and 6 months of extracorporeal membrane oxygenation, he underwent LTx. 3 months post-transplantation he developed acute hypoxia requiring emergency intubation. Chest imaging showed acute rejection, and de novo DQ8-DSA was discovered. He was treated with a high dose of corticosteroids and plasmapheresis and was extubated 4 days later, yet the de novo DQ8-DSA remained. After sessions of plasmapheresis and rituximab, the levels of de novo DQ8-DSA remained unchanged. Nine months post-transplantation the patient died of respiratory failure. We herein discuss the decision to transplant, the transplantation itself and the postoperative course with severe antibody-mediated rejection. In addition, we evaluated the histological changes of the explanted lungs and compared these with end-stage idiopathic pulmonary fibrosis tissue, where both similarities and differences are seen. With the current case experience, one might consider close monitoring regarding DSA, and gives further support that LTx should only be considered for very carefully selected patients.\n\nCOVID-19\nlung transplantation\nhttp://dx.doi.org/10.13039/501100004063 Knut och Alice Wallenbergs Stiftelse 2018SLDEW http://dx.doi.org/10.13039/501100004158 Marcus Wallenbergs Stiftelse för Internationellt Vetenskapligt Samarbete 2018SL special-featureunlocked\n==== Body\npmcIntroduction\n\nDespite major clinical advances in treating SARS-CoV-2-induced acute respiratory distress syndrome (ARDS), a large proportion of patients still experience severe and life-threatening conditions. Similar to ARDS, extracorporeal membrane oxygenation (ECMO) can be life-saving in patients with SARS-CoV-2-induced ARDS. Of these ECMO patients, a small proportion will progress to end-stage lung disease and ECMO weaning will not be possible. There have been reports of successful lung transplantation (LTx) in patients with SARS-CoV-2-induced end-stage lung disease, but with rather short follow-up and in most of the cases shorter time on ECMO support before transplantation.1–5 The worldwide experience with this matter is however limited and it is unknown if and when such a treatment should be offered.6 Given the poor long-term survival outcome in LTx, in combination with donor lung shortage and ethical questioning of graft allocation, all healing potentials need to be excluded before taking the decision to transplant.7\n\nCase\n\nHere we present a 62-year-old man with a history of diabetes mellitus, minor myocardial infarction with preserved ventricular function, with ejection fraction of >55% (documented using echocardiography 3 months before the SARS-CoV-2 infection), and without prior lung diseases. He presented to the emergency room with 7 days of dyspnoea, cough and fever and tested positive for SARS-CoV-2 at the time of admission. He received treatment with Veklury. Within 4 days he deteriorated and was transferred to the intensive care unit (ICU) and intubated. He was treated with lung protective ventilation and placed on prone position. On hospital day 17 he was placed on venovenous extracorporeal membrane oxygenation (VV-ECMO) and a percutaneous tracheostomy was also placed. At the time he was put on VV-ECMO support, he was SARS-CoV-2 negative. Despite aggressive supportive care, with repeated doses of both cortisone and dornase alfa, his condition progressed to end-stage lung disease along with the development of cor pulmonale. Interval chest imaging and CT scan revealed progressive lung disease (figure 1A). During 6 months of VV-ECMO support, the patient suffered numerous complications, including minor cerebral haemorrhage without neurological sequels, cor pulmonale and bloodstream infections. The ECMO cannulation strategy, femoral-jugular VV-ECMO, was kept during the entire treatment course. The patient suffered from being on mechanical ventilation and was therefore weaned off mechanical ventilation after 3 months and was spontaneously breathing while on VV-ECMO support.\n\nFigure 1 (A) Serial chest X-rays from time of presentation and diagnosis to just prior to transplantation (CT scan). Imaging displays progression of disease with increasing bilateral airspace opacities, diffuse consolidation and air bronchograms. (B) A chest X-ray and a CT scan 3 months post-transplantation with signs suspicious for acute rejection with ground-glass opacities, consolidation and interstitial thickening. (C) Gross images of explanted native lungs at the time of lung transplantation. Both lungs were small with cobblestoned visceral pleura. (D) All lungs were subjected to standard tissue processing followed by paraffin embedding. Sections from a healthy control (normal donor lung tissue), a patient with idiopathic pulmonary fibrosis (IPF) and from the current patient with COVID-19 (SARS-CoV-2-induced end-stage lung disease) were stained in parallel with H&E, Masson’s trichrome (MT), and periodic acid Schiff and Alcian blue (PAS-AB) and were compared.\n\nDecision to transplant\n\nThe network within the European Cardio Thoracic Transplant Association, a part of the European Society for Organ Transplantation, was consulted prior to the decision to transplant. Given the relative contraindications for LTx, the decision for LTx was mainly based on the ethics with a neurologically intact, awake patient in combination with the lack of experience of LTx outcome in SARS-CoV-2-induced end-stage lung disease. At the time of transplantation, the patient was mobilised on a daily basis and was able to stand for a short while with a mobiliser and with extensive help from healthcare workers. He was communicable and was able to give consent for transplantation. At the time of transplantation the patient had a normal kidney function with Pt-eGFR of 83 mL/min/1.73 kvm. He had no pretransplant HLA antibodies. With regard to his heart function, echocardiography showed cor pulmonale with an HK/HF gradient of 63 mm Hg.\n\nSurgical description\n\nSuitable donor lungs, with a negative crossmatch, were allocated. With ongoing ECMO support, the patient underwent median sternotomy. No major signs of adherence between the chest wall and the lungs were seen and therefore central cannulation and conversion to cardiopulmonary bypass (CPB) were done. Hilar dissection was completed and the lungs were explanted. Donor lungs were then implanted in sequential standard fashion. The patient was separated from CPB, without the need to reinitiate ECMO support.\n\nPostoperative course\n\nThe patient received standard triple immunosuppressive therapy with ciclosporin, prednisone and mycophenolate mofetil and induction therapy with antithymocyte globulin (ATG). The ATG was given as an infusion 8 hours post-transplantation at 1.5 mg/kg bodyweight (100 mg) in combination with hydrocortisone, clemastine and paracetamol according to local clinical guidelines. He had no signs of primary graft dysfunction and was extubated 3 days after the transplant. Post-transplant he suffered a long (2.5 months) postoperative course in the ICU with post-transplant heart failure related to cor pulmonale, infectious diseases and kidney insufficiency. He was treated with levosimendan, temporary haemodialysis and diverse types of antibiotics. He had stable levels of ciclosporin at 200–300 ng/mL and Mycophenolate mofetil (MMF) at 40–50 mg/L/hour, even during haemodialysis. At the time of transfer from the ICU to the ward, he was not dependent on oxygen support.\n\nAcute antibody-mediated rejection\n\nThree months post-transplantation, the patient without considerable prior signs shocked down at the hospital ward with acute hypoxia requiring emergency intubation and transfer back to the ICU. Chest imaging showed signs suspicious for acute rejection (figure 1B). De novo DQ8-DSA (mean fluorescence intensity 5000) was discovered. No C1q binding could be confirmed. He was successfully treated with a high dose of corticosteroids and plasmapheresis and was extubated 4 days later, yet the de novo DQ8-DSA remained. After 10 initial sessions of plasmapheresis, the levels of de novo DQ8-DSA remained unchanged. Immunosuppression was changed to tacrolimus and he received Intravenous immunoglobulin (IVIG) and corticosteroids. He received additional 10 sessions of plasmapheresis due to the refractory antibody-mediated rejection (AMR) and rituximab. To determine the nature of histological involvement, a transbronchial biopsy was done 6 months after transplantation and showed non-specific inflammation, scattered fibrosis deposits and 50% C4d positive staining. No transbronchial biopsy was done earlier due to the frailty of the patient and fear of complications. Eight months post-transplantation the patient’s level of de novo DQ8-DSA has increased despite aggressive therapy, which overlapped with a progressive decline in lung function. A spirometry was done 6 and 8 months post-transplantation and revealed VC of 1.7 (39% of expected) at 6 months and 1.2 (29% of expected) at 8 months, and FEV1 of 1.1 (predicted 3.3) at 6 months and 0.7 later at 8 months. Nine months after the transplant, the patient died of respiratory failure. Given the family’s request no autopsy was done.\n\nHistology findings\n\nGross morphology of the explanted lungs is shown in figure 1C. The explanted lungs were fixed within 1 hour and subsequently processed for routine histology. Similar to other recent reports, we observed noticeable interstitial fibrosis in the distal lung tissue of the explanted COVID-19 lungs (figure 1D). However, unlike other recent histological reports,1 we did not observe significant infiltration of immune cells in the airspaces, major evidence of diffuse alveolar damage or signs of organising pneumonia. This is likely due to the fact that the patient was beyond the acute phase of the disease and was not known to have any secondary pulmonary infection around the time of transplantation, as reported in the previous cases. The histological changes observed in the distal regions of the present COVID-19 explanted tissue had both histological similarities and differences to end-stage idiopathic pulmonary fibrosis (IPF) tissue. Parenchymal remodelling in IPF is characterised by interstitial fibrosis from mostly collagenous protein deposition, as well as deposition of both Alcian blue (AB) (acidic) and periodic acid Schiff (PAS+) (neutral) mucopolysaccharides (eg, mucins and glycoproteins) in fibroblastic foci. In contrast, alveolar thickening in this patient with COVID-19 was characterised by deposition of both collagenous and non-collagenous proteins and a pronounced increase of mostly AB positive staining.8 9 Interestingly, we observed little to no evidence of PAS+ staining in the distal lung, but the proximal lung tissue processed at the same time from this patient did contain both AB and PAS+ staining (data not shown), suggesting that alterations in mucopolysaccharides occurred in the distal lung only. We also observed evidence of abnormal epithelial repair with the appearance of honeycomb cysts lined with cuboidal epithelial cells, similar to what is observed in IPF. Taken together, this indicates that the patient did not have significant ongoing inflammation in the airspaces at the time of transplantation, but that the lung had undergone dysregulated repair resulting in significant interstitial fibrosis and aberrant re-epithelialisation (figure 1D).\n\nConclusions\n\nLTx is feasible for SARS-CoV-2-induced end-stage lung disease; however, long-term results are unknown. Knowledge will increase with increasing number of patients transplanted and longer follow-up data. Only then we will know if these patients are more predisposed to AMR, and if so if it is caused by the long preoperative ECMO support or it is the systemic inflammatory response induced by COVID-19 itself. With the current case experience, one might consider close monitoring regarding DSA, and gives further support that LTx should only be considered for very carefully selected patients. The explanted lungs of this patient demonstrated some of the stereotypical histological changes seen in patients with IPF, including collagen deposition and honeycombing. Whether or not currently approved antifibrotic therapies could be used in these patients to slow down disease progression remains unknown but will be important to explore in the future.10\n\nEthics statements\n\nPatient consent for publication\n\nObtained.\n\nContributors: All authors contributed to the study design and acquisition of data. SL, EG, HL, PE, IS, DW and RG contributed to the analysis and interpretation of data and drafted the manuscript. All authors read and approved the final manuscript.\n\nFunding: This work was supported by Knut and Alice Wallenberg (2018SLDEW) and Marcus Wallenberg Foundation (2018SL).\n\nCompeting interests: None declared.\n\nProvenance and peer review: Not commissioned; externally peer reviewed.\n==== Refs\nReferences\n\n1 LangC, JakschP, HodaMA, et al . Lung transplantation for COVID-19-associated acute respiratory distress syndrome in a PCR-positive patient. Lancet Respir Med 2020;8 :1057–60. 10.1016/S2213-2600(20)30361-1 32857987\n2 BharatA, MachucaTN, QuerreyM, et al . Early outcomes after lung transplantation for severe COVID-19: a series of the first consecutive cases from four countries. Lancet Respir Med 2021;9 :487–97. 10.1016/S2213-2600(21)00077-1 33811829\n3 GuenthartBA, KrishnanA, AlassarA, et al . First lung and kidney multi-organ transplant following COVID-19 infection. J Heart Lung Transplant 2021;40 :856–9. 10.1016/j.healun.2021.02.015 34059432\n4 LepperPM, LangerF, WilkensH, et al . Lung transplantation for COVID-19-associated ARDS. Lancet Respir Med 2021;9 :e88. 10.1016/S2213-2600(21)00278-2 34224673\n5 MessikaJ, SchmidtM, Tran-DinhA, et al . Lung transplantation for COVID-19-associated ARDS. Lancet Respir Med 2021;9 :e89. 10.1016/S2213-2600(21)00279-4 34224676\n6 CypelM, KeshavjeeS. When to consider lung transplantation for COVID-19. Lancet Respir Med 2020;8 :944–6. 10.1016/S2213-2600(20)30393-3 32857989\n7 VerledenGM, GlanvilleAR, LeaseED, et al . Chronic lung allograft dysfunction: definition, diagnostic criteria, and approaches to treatment-A consensus report from the pulmonary Council of the ISHLT. J Heart Lung Transplant 2019;38 :493–503. 10.1016/j.healun.2019.03.009 30962148\n8 TiittoL, BloiguR, HeiskanenU, et al . Relationship between histopathological features and the course of idiopathic pulmonary fibrosis/usual interstitial pneumonia. Thorax 2006;61 :1091–5. 10.1136/thx.2005.055814 16769713\n9 LiK, YuY, LiD, et al . The histopathological features of the explanted lungs from an end-stage COVID-19 patient. Forensic Sci Res 2020;5 :348–50. 10.1080/20961790.2020.1807128 33457054\n10 GeorgePM, WellsAU, JenkinsRG. Pulmonary fibrosis and COVID-19: the potential role for antifibrotic therapy. Lancet Respir Med 2020;8 :807–15. 10.1016/S2213-2600(20)30225-3 32422178\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2052-4439",
"issue": "8(1)",
"journal": "BMJ open respiratory research",
"keywords": "COVID-19; lung transplantation",
"medline_ta": "BMJ Open Respir Res",
"mesh_terms": "D000086382:COVID-19; D015199:Extracorporeal Membrane Oxygenation; D017809:Fatal Outcome; D006084:Graft Rejection; D006801:Humans; D016040:Lung Transplantation; D008297:Male; D008875:Middle Aged; D012128:Respiratory Distress Syndrome",
"nlm_unique_id": "101638061",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34544734",
"pubdate": "2021-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "32857989;33811829;32422178;16769713;30962148;34059432;33457054;34224673;32857987;34224676",
"title": "Lung transplant after 6 months on ECMO support for SARS-CoV-2-induced ARDS complicated by severe antibody-mediated rejection.",
"title_normalized": "lung transplant after 6 months on ecmo support for sars cov 2 induced ards complicated by severe antibody mediated rejection"
} | [
{
"companynumb": "SE-STRIDES ARCOLAB LIMITED-2021SP031011",
"fulfillexpeditecriteria": "1",
"occurcountry": "SE",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional... |
{
"abstract": "Autoimmune hepatitis is an infrequent but significant side effect of infliximab treatment. Diagnosis of autoimmune hepatitis is based on clinical, laboratory, and histological findings. Initial treatment involves cessation of infliximab and trial of prednisone. We present a rare case of infliximab-induced autoimmune hepatitis leading to liver failure requiring transplantation.",
"affiliations": "Division of Gastroenterology Department of Internal Medicine Western University London Ontario Canada.;Division of Gastroenterology Department of Internal Medicine Western University London Ontario Canada.;Department of Pathology and Laboratory Medicine Western University London Ontario Canada.;Division of Gastroenterology Department of Internal Medicine Western University London Ontario Canada.",
"authors": "Wong|Frederick|F|https://orcid.org/0000-0002-7799-6083;Al Ibrahim|Bashaar|B|;Walsh|Joanna|J|;Qumosani|Karim|K|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1002/ccr3.2456",
"fulltext": "\n==== Front\nClin Case RepClin Case Rep10.1002/(ISSN)2050-0904CCR3Clinical Case Reports2050-0904John Wiley and Sons Inc. Hoboken 10.1002/ccr3.2456CCR32456Case ReportCase ReportsInfliximab‐induced autoimmune hepatitis requiring liver transplantation WONG et al.Wong Frederick https://orcid.org/0000-0002-7799-6083\n1\nfwong2020@meds.uwo.ca Al Ibrahim Bashaar \n1\n\n2\nWalsh Joanna \n3\nQumosani Karim \n1\n\n1 \nDivision of Gastroenterology\nDepartment of Internal Medicine\nWestern University\nLondon\nOntario\nCanada\n\n2 \nDepartment of Medicine\nKing Faisal Special Hospital and Research Centre\nRiyadh\nSaudi Arabia\n\n3 \nDepartment of Pathology and Laboratory Medicine\nWestern University\nLondon\nOntario\nCanada\n* Correspondence\n\nFrederick Wong, Schulich School of Medicine and Dentistry, Western University, Mailbox 198, 1151 Richmond Street, London, Ontario N6A 3K7, Canada.\n\nEmail: fwong2020@meds.uwo.ca\n27 9 2019 11 2019 7 11 10.1002/ccr3.v7.112135 2139 16 6 2019 07 8 2019 18 8 2019 © 2019 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.Abstract\nAutoimmune hepatitis is an infrequent but significant side effect of infliximab treatment. Diagnosis of autoimmune hepatitis is based on clinical, laboratory, and histological findings. Initial treatment involves cessation of infliximab and trial of prednisone. We present a rare case of infliximab‐induced autoimmune hepatitis leading to liver failure requiring transplantation.\n\nAutoimmune hepatitis is an infrequent but significant side effect of infliximab treatment. Diagnosis of autoimmune hepatitis is based on clinical, laboratory, and histological findings. Initial treatment involves cessation of infliximab and trial of prednisone. We present a rare case of infliximab‐induced autoimmune hepatitis leading to liver failure requiring transplantation.\n\n\nautoimmune hepatitisCrohn's diseaseinfliximabliver transplantation source-schema-version-number2.0component-idccr32456cover-dateNovember 2019details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:5.7.2 mode:remove_FC converted:26.11.2019\n\n\nWong \nF \n, \nAl Ibrahim \nB \n, \nWalsh \nJ \n, \nQumosani \nK \n. Infliximab‐induced autoimmune hepatitis requiring liver transplantation . Clin Case Rep . 2019 ;7 :2135 –2139 . 10.1002/ccr3.2456\n==== Body\n1 INTRODUCTION\nInfliximab, a monoclonal antibody that inhibits tumor necrosis factor α (TNF‐α), is commonly used in the treatment of inflammatory conditions such as Crohn's disease and rheumatoid arthritis. A rare but significant side effect of infliximab treatment is autoimmune hepatitis. Other autoimmune conditions induced by infliximab include systemic lupus erythematosus, psoriasis, and vasculitis.1, 2 Autoimmune hepatitis following infliximab treatment has been previously described in the treatment of patients with Crohn's disease,3, 4, 5, 6, 7 ulcerative colitis,8, 9 rheumatoid arthritis,10 psoriasis,11, 12, 13 ankylosing spondylitis,14 and psoriatic arthritis.15 Most of these cases resolved with cessation of infliximab, but some required additional steroid therapy. Here, we present the second case reported in the literature of a patient with Crohn's disease treated with infliximab that developed autoimmune hepatitis requiring liver transplantation.16\n\n\n2 CASE\nWe present a 69‐year‐old woman with a history of fistulizing Crohn's disease for over 13 years. She had multiple previous small bowel surgeries including resections and fistulectomy. The patient was started on infliximab because of the development of new fistulas. Her past medical history included hypertension, osteoarthritis, gastroesophageal reflux disease, and sigmoid diverticular disease. Her medications were amlodipine, rabeprazole, vitamin D, and furosemide. She had no significant social history and rarely consumed alcohol.\n\nApproximately 3 months into infliximab treatment after three separate doses of 5mg/kg of infliximab, she was found to be jaundiced on physical examination prior to her fourth dose at the infusion clinic. Blood work confirmed an elevated total bilirubin 392.5 µmol/L, which was mainly direct > 236.0 µmol/L. Liver enzymes were also significantly elevated (Table 1) and were previously documented as normal 6 months prior to her presentation. Her synthetic liver function was abnormal with a low albumin and elevated INR. Her autoimmune markers showed an elevated IgG and slightly elevated IgA. Antismooth muscle antibodies (ASMAs) were positive, antinuclear antibodies (ANAs) were positive, and antimitochondrial antibodies (AMAs) were negative. Hepatitis B and C serology, ferritin, ceruloplasmin, and alpha‐1‐antitrypsin were negative.\n\nTable 1 Laboratory data on presentation\n\nLiver Enzymes\t\nALT (<33 U/L)\t647\t\nAST (<33 U/L)\t1115\t\nGGT (≤31 U/L)\t400\t\nALP (35‐104 U/L)\t256\t\nSynthetic liver function\t\nTotal bilirubin (3.4‐17.1 µmol/L)\t392.5\t\nDirect bilirubin (0.0‐5.0 µmol/L)\t>236.0\t\nINR (0.9‐1.1)\t3.9\t\nPTT (23‐32 s)\t42\t\nAlbumin (35‐52 g/L)\t27\t\nImmunology\t\nImmunoglobulin G (6.4‐13.8 g/L)\t27.9\t\nImmunoglobulin A (0.9‐4.6 g/L)\t6.0\t\nImmunoglobulin M (0.6‐2.7 g/L)\t1.4\t\nANA (Neg < 1 in 40)\t<1:80\t\nAMA (Neg < 1 in 20)\t<1:20\t\nASMA (Neg < 1 in 20)\t1:40\t\nInfectious serology\t\nHepatitis B surface antigen\tNonreactive\t\nHepatitis B core antibody\tNonreactive\t\nHepatitis C antibody\tNonreactive\t\nHematology\t\nHemoglobin (115‐160 g/L)\t107\t\nLeukocytes (4.0‐10.0 × 109 g/L)\t7.6\t\nPlatelets (150‐400 × 109 g/L)\t269\t\nAbbreviations: ALP, alkaline phosphatase; ALT, alanine aminotransferase; AMA, antimitochondrial antibody; ANA, antinuclear antibody; ASMA, antismooth muscle antibody; AST, aspartate aminotransferase; GGT, gamma‐glutamyl transferase; INR, international normalized ratio; PTT, partial thromboplastin time.\n\nJohn Wiley & Sons, LtdUltrasound of the liver showed nonspecific diffuse heterogeneous coarse hepatic parenchyma with no focal lesions and no extra hepatic biliary obstruction. Magnetic resonance cholangiopancreatography was done and showed no evidence of intrahepatic or extrahepatic duct dilatation. Liver biopsy revealed extensive multiacinar hepatocyte necrosis with areas of surviving hepatocytes, a periportal and lobular infiltrate of lymphocytes and plasma cells, and interface hepatitis, morphologically consistent with autoimmune hepatitis. There was no evidence of chronic fibrosis (Figure 1).\n\nFigure 1 Liver biopsy revealing (A) acute hepatitis with parenchymal necrosis (H&E, 4×), B,Hepatocyte injury and apoptosis with dense plasma cell infiltrate (H&E, 20×). C, Interface hepatitis with plasma cells (H&E, 10×)\n\nThe patient was admitted to the hospital for further evaluation and liver transplant assessment. She was started on prednisone 30 mg daily; however, there was no improvement. During her hospitalization, her liver enzymes continued to increase (Figure 2). Her synthetic liver function also continued to deteriorate. The patient developed acute kidney injury which was attributed to hepatorenal syndrome. Her condition continued to worsen, and she developed hepatic encephalopathy.\n\nFigure 2 Clinical course since admission\n\nThe liver transplant team evaluated the patient and deemed her a good candidate for liver transplantation. Two weeks after her admission, the patient underwent liver transplantation. Further examination of the explanted liver confirmed the findings of the initial biopsy with parenchymal collapse and the presence of portal plasma cells (Figure 3). The patient was discharged home 2 weeks after her transplant and was doing well at the 3‐, 6‐, and 12‐month visits after transplantation. Repeated antibody panel showed seroconversion of ASMA and ANA from positive to negative 3 months after the liver transplant. Colonoscopy one year following the liver transplant revealed mild recurrent Crohn's disease. Subsequent colonoscopy performed two and a half years postliver transplantation showed recurrent Crohn's with stricturing and moderate neoterminal ileitis. Ustekinumab was offered at this time due to prior infliximab treatment leading to autoimmune hepatitis.\n\nFigure 3 Liver explant (A) parenchymal collapse (H&E, 10×). B, Parenchymal collapse (reticulin, 10×).C, Portal plasma cells (H&E, 20×)\n\n3 DISCUSSION\nWe present a rare case of infliximab‐induced autoimmune hepatitis requiring liver transplantation here. There are only a few cases of liver transplantation following infliximab treatment previously described in the literature.16, 17, 18, 19 However, several of these patients had factors that could have contributed to the transplantation including prior cirrhosis and hepatitis infection.17, 18 One case involved a 39‐year‐old female patient with rheumatoid arthritis who was treated with infliximab and later required a liver transplantation.17 Liver biopsy revealed underlying cirrhosis in this patient, possibly contributing to the need for transplantation. Another case is a 28‐year‐old adult‐onset Still's patient with prior hepatitis B infection treated with infliximab that developed fulminant hepatitis requiring liver transplantation.18 The patient was positive for hepatitis B surface antigen and antihepatitis B e‐antigen antibodies at the time of presentation, but negative for hepatitis B virus DNA. The underlying hepatitis B may have possibly contributed to the need for liver transplant. In fact, multiple cases of hepatitis B reactivation following infliximab treatment have been previously reported20, 21 with one case even leading to fulminant liver failure.22 Another case of fulminant hepatic failure in a patient with Crohn's disease treated with infliximab has been reported; however, the liver failure was attributed to herpes simplex virus reactivation.23 Thus, our case of autoimmune hepatitis following infliximab treatment requiring transplantation is unique in that our patient did not have prior cirrhosis or hepatic infection that would have contributed to needing a liver transplantation.\n\nThe diagnosis of autoimmune hepatitis is made based on clinical, laboratory, and histological findings. The simplified autoimmune hepatitis score is a useful tool developed by the international autoimmune hepatitis group in 2008 based on ANA levels (<1:40 = 1 point, <1:80 = 2 points), IgG (upper normal limit = 1 point, >1.10 times normal limit = 2 points), liver histology (compatible with autoimmune hepatitis = 1 point, typical for autoimmune hepatitis = 2 points), and absence of viral hepatitis (yes = 2 points, no = 0 point) to calculate the probability of autoimmune hepatitis. A score of greater or equal to 7 is definite autoimmune hepatitis, and a score of greater or equal to 6 is probable autoimmune hepatitis. Our patient in this case report received a score of 7 with ANA of < 1:80, IgG > 1.10 times normal limit, histology compatible with autoimmune hepatitis, and absence of viral hepatitis.24\n\n\nElevated autoimmune antibodies, histological findings consistent with autoimmune hepatitis, and lack of other causal factors strongly suggest that this patient presented with infliximab‐induced autoimmune hepatitis. Additionally, the findings were felt to be more consistent with autoimmune hepatitis than drug‐induced liver injury. Liver biopsy results for autoimmune hepatitis classically reveal interface hepatitis, focal necrosis, portal inflammation, and plasma cells which were present in this case.25 Meanwhile, findings with drug‐induced liver injury are more likely to show portal neutrophils and hepatocellular cholestasis.26 There is also the possibility that autoimmune hepatitis developed independently of infliximab treatment since autoimmune hepatitis is often associated with other autoimmune conditions including celiac disease and rheumatoid arthritis.27 This is unlikely in this case given the development of autoimmune hepatitis immediately after infliximab treatment and the fact that normal liver enzymes were detected several months prior to starting infliximab treatment. It is also crucial to rule out other potential causes of hepatitis including alcohol use, viral infection, and hepatotoxic medications which were all not present in this case.\n\nOther TNF‐α inhibitors including etanercept28 and adalimumab29, 30 have reportedly also resulted in autoimmune hepatitis. Some of the mechanisms proposed include underlying genetic susceptibility, a selective effect of T helper cells and immune complex formation, and the induction of an immune system imbalance from cytokine blockade.30 It is likely that the autoimmune response to TNF‐α inhibitors is individualized since there have also been reports of patients who developed autoimmune hepatitis following infliximab treatment that did not exhibit any liver dysfunction after switching to etanercept10 and adalimumab.31 Proposed monitoring for liver impairment during TNF‐α inhibitor treatment includes regular liver function tests every two to eight weeks with a referral to a hepatologist recommended when ALT is >3 times the upper limit of normal or when there is an increase in bilirubin or onset of jaundice.32\n\n\nIn conclusion, clinicians must be aware of the rare possibility of developing autoimmune hepatitis following infliximab treatment. Treatment involves discontinuation of infliximab and trial of steroids. In severe cases with liver failure, transplantation may be necessary.\n\nCONFLICT OF INTEREST\nThe authors do not have any conflicts of interest to declare.\n\nAUTHOR CONTRIBUTIONS\nFrederick Wong: involved in drafting and finalizing the manuscript. Bashaar Al Ibrahim: involved with collecting the data and drafting the manuscript. Joanna Walsh: involved with preparing the descriptions for the figures and editing the manuscript. Karim Qumosani: involved with editing the manuscript.\n\nCONSENT\nInformed consent was obtained.\n==== Refs\nREFERENCES\n1 \n\nRamos‐Casals \nM \n, \nBrito‐Zeron \nP \n, \nMunoz \nS \n, et al. Autoimmune diseases induced by TNF‐targeted therapies: analysis of 233 cases . Medicine . 2007 ;86 (4 ):242 ‐251 .17632266 \n2 \n\nSeckin \nD \n, \nDurusoy \nC \n, \nSahin \nS \n. Concomitant vitiligo and psoriasis in a patient treated with interferon alfa‐2a for chronic hepatitis B infection . Pediatr Dermatol . 2004 ;21 (5 ):577 ‐579 .15461767 \n3 \n\nCravo \nM \n, \nSilva \nR \n, \nSerrano \nM \n. Autoimmune hepatitis induced by infliximab in a patient with Crohn's disease with no relapse after switching to adalimumab . BioDrugs . 2010 ;14 (24 Suppl 1 ):25 ‐27 .\n4 \n\nGoldfeld \nDA \n, \nVerna \nEC \n, \nLefkowitch \nJ \n, \nSwaminath \nA \n. Infliximab‐induced autoimmune hepatitis with successful switch to adalimumab in a patient with Crohn's disease: the index case . Dig Dis Sci . 2011 ;56 (11 ):3386 ‐3388 .21597977 \n5 \n\nDoyle \nA \n, \nForbes \nG \n, \nKontorinis \nN \n. Autoimmune hepatitis during infliximab therapy for Crohn's disease: a case report . J Crohns Colitis . 2011 ;5 (3 ):253 ‐255 .21575891 \n6 \n\nRicciuto \nA \n, \nKamath \nBM \n, \nWalters \nTD \n, et al. New onset autoimmune hepatitis during anti‐tumor necrosis factor‐alpha treatment in children . J Pediatr . 2018 ;194 (128–35 ):e1 .\n7 \n\nSubramaniam \nK \n, \nChitturi \nS \n, \nBrown \nM \n, \nPavli \nP \n. Infliximab‐induced autoimmune hepatitis in Crohn's disease treated with budesonide and mycophenolate . Inflamm Bowel Dis . 2011 ;17 (11 ):E149 ‐E150 .21987301 \n8 \n\nIerardi \nE \n, \nDella Valle \nN \n, \nCosimo Nacchiero \nM \n, \nDe Francesco \nV \n, \nStoppino \nG \n, \nPanella \nC \n. Onset of liver damage after a single administration of infliximab in a patient with refractory ulcerative colitis . Clin Drug Investig . 2006 ;26 (11 ):673 ‐676 .\n9 \n\nMarques \nM \n, \nMagro \nF \n, \nCardoso \nH \n, et al. Infliximab‐induced lupus‐like syndrome associated with autoimmune hepatitis . Inflamm Bowel Dis . 2008 ;14 (5 ):723 ‐725 .17929297 \n10 \n\nCarlsen \nKM \n, \nRiis \nL \n, \nMadsen \nOR \n. Toxic hepatitis induced by infliximab in a patient with rheumatoid arthritis with no relapse after switching to etanercept . Clin Rheumatol . 2009 ;28 (8 ):1001 ‐1003 .19370307 \n11 \n\nPoulin \nY \n, \nTherien \nG \n. Drug‐induced hepatitis and lupus during infliximab treatment for psoriasis: case report and literature review . J Cutan Med Surg . 2010 ;14 (2 ):100 ‐104 .20338127 \n12 \n\nMancini \nS \n, \nAmorotti \nE \n, \nVecchio \nS \n, \nPonz de Leon \nM \n, \nRoncucci \nL \n. Infliximab‐related hepatitis: discussion of a case and review of the literature . Intern Emerg Med . 2010 ;5 (3 ):193 ‐200 .20107930 \n13 \n\nDang \nLJ \n, \nLubel \nJS \n, \nGunatheesan \nS \n, \nHosking \nP \n, \nSu \nJ \n. Drug‐induced lupus and autoimmune hepatitis secondary to infliximab for psoriasis . Australas J Dermatol . 2014 ;55 (1 ):75 ‐79 .23651182 \n14 \n\nOzorio \nG \n, \nMcGarity \nB \n, \nBak \nH \n, \nJordan \nAS \n, \nLau \nH \n, \nMarshall \nC \n. Autoimmune hepatitis following infliximab therapy for ankylosing spondylitis . Med J Aust . 2007 ;187 (9 ):524 ‐526 .17979620 \n15 \n\nGermano \nV \n, \nPicchianti Diamanti \nA \n, \nBaccano \nG \n, et al. Autoimmune hepatitis associated with infliximab in a patient with psoriatic arthritis . Ann Rheum Dis . 2005 ;64 (10 ):1519 ‐1520 .16162908 \n16 \n\nSzeto \nW \n, \nKingsley \nM \n, \nJulio \nP \n, \nThiago \nB \n, \nDeshpande \nAR \n. Unique immediate post‐operative management of Crohn's disease in a patient with autoimmune hepatitis‐like drug‐induced liver injury from infliximab requiring liver transplantation . 82nd Annual Scientific Meeting of the American College of Gastroenterology; United States. 2017 .\n17 \n\nTobon \nGJ \n, \nCanas \nC \n, \nJaller \nJJ \n, \nRestrepo \nJC \n, \nAnaya \nJM \n. Serious liver disease induced by infliximab . Clin Rheumatol . 2007 ;26 (4 ):578 ‐581 .16547695 \n18 \n\nMichel \nM \n, \nDuvoux \nC \n, \nHezode \nC \n, \nCherqui \nD \n. Fulminant hepatitis after infliximab in a patient with hepatitis B virus treated for an adult onset still's disease . J Rheumatol . 2003 ;30 (7 ):1624 ‐1625 .12858469 \n19 \n\nParra \nRS \n, \nForesto Machado \nV \n, \nRibeiro Feitosa \nM \n, et al. Fulminant hepatic failure requiring transplantation after initiation of infliximab therapy in Ulcerative Colitis . 10th Congress of the European Crohn's and Colitis Organisation, ECCO 2015.\n20 \n\nZingarelli \nS \n, \nFrassi \nM \n, \nBazzani \nC \n, \nScarsi \nM \n, \nPuoti \nM \n, \nAiro \nP \n. Use of tumor necrosis factor‐alpha‐blocking agents in hepatitis B virus‐positive patients: reports of 3 cases and review of the literature . J Rheumatol . 2009 ;36 (6 ):1188 ‐1194 .19447932 \n21 \n\nOjiro \nK \n, \nNaganuma \nM \n, \nEbinuma \nH \n, et al. Reactivation of hepatitis B in a patient with Crohn's disease treated using infliximab . J Gastroenterol . 2008 ;43 (5 ):397 ‐401 .18592158 \n22 \n\nOlfa \nH \n, \nAroua \nG \n, \nWissem \nM \n, et al. Fulminant acute hepatitis B after infliximab treatment in Crohn's disease . Tunis Med . 2014 ;92 (5 ):349 ‐350 .\n23 \n\nGolds \nG \n, \nWorobetz \nL \n. Fulminant hepatic failure in a patient with crohn's disease on infliximab possibly related to reactivation of herpes simplex virus 2 infection . Case Reports Hepatol . 2016 ;2016 :2132056 .27818806 \n24 \n\nHennes \nEM \n, \nZeniya \nM \n, \nCzaja \nAJ \n, et al. International autoimmune hepatitis group. simplified criteria for the diagnosis of autoimmune hepatitis . Hepatology . 2008 ;48 (1 ):169 ‐176 .18537184 \n25 \n\nTiniakos \nDG \n, \nBrain \nJG \n, \nBury \nYA \n. Role of histopathology in autoimmune hepatitis . Dig Dis . 2015 ;33 (Suppl 2 ):53 ‐64 .26642062 \n26 \n\nKleiner \nDE \n, \nChalasani \nNP \n, \nLee \nWM \n, et al. Hepatic histological findings in suspected drug‐induced liver injury: systematic evaluation and clinical associations . Hepatology . 2014 ;59 (2 ):661 ‐670 .24037963 \n27 \n\nKrawitt \nEL \n. Autoimmune hepatitis . N Engl J Med . 2006 ;354 (1 ):54 ‐66 .16394302 \n28 \n\nFathalla \nBM \n, \nGoldsmith \nDP \n, \nPascasio \nJM \n, \nBaldridge \nA \n. Development of autoimmune hepatitis in a child with systemic‐onset juvenile idiopathic arthritis during therapy with etanercept . J Clin Rheumatol . 2008 ;14 (5 ):297 ‐298 .18824922 \n29 \n\nAdar \nT \n, \nMizrahi \nM \n, \nPappo \nO \n, \nScheiman‐Elazary \nA \n, \nShibolet \nO \n. Adalimumab‐induced autoimmune hepatitis . J Clin Gastroenterol . 2010 ;44 (1 ):e20 ‐e22 .19593165 \n30 \n\nRodrigues \nS \n, \nLopes \nS \n, \nMagro \nF \n, \nCardoso \nH \n, et al. Autoimmune hepatitis and anti‐tumor necrosis factor alpha therapy: A single center report of 8 cases . World J Gastroenterol . 2015 ;21 (24 ):7584 ‐7588 .26140007 \n31 \n\nHaennig \nA \n, \nBonnet \nD \n, \nThebault \nS \n, \nAlric \nL \n. Infliximab‐induced acute hepatitis during Crohn's disease therapy: absence of cross‐toxicity with adalimumab . Gastroenterol Clin Biol . 2010 ;34 (8–9 ):e7 ‐8 .20189334 \n32 \n\nRossi \nRE \n, \nParisi \nI \n, \nDespott \nEJ \n, et al. Anti‐tumour necrosis factor agent and liver injury: literature review, recommendations for management . World J Gastroenterol . 2014 ;20 (46 ):17352 ‐17359 .25516646\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2050-0904",
"issue": "7(11)",
"journal": "Clinical case reports",
"keywords": "Crohn's disease; autoimmune hepatitis; infliximab; liver transplantation",
"medline_ta": "Clin Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101620385",
"other_id": null,
"pages": "2135-2139",
"pmc": null,
"pmid": "31788265",
"pubdate": "2019-11",
"publication_types": "D002363:Case Reports",
"references": "18592158;25504398;17632266;27818806;21175232;17163303;16394302;24037963;25516646;21987301;16547695;20189334;17979620;26642062;26140007;20338127;21597977;29274889;19447932;23651182;15461767;16162908;12858469;18537184;19370307;19593165;21575891;17929297;18824922;20107930",
"title": "Infliximab-induced autoimmune hepatitis requiring liver transplantation.",
"title_normalized": "infliximab induced autoimmune hepatitis requiring liver transplantation"
} | [
{
"companynumb": "CA-CELLTRION INC.-2019CA027531",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "VITAMIN D NOS"
},
"drugadditional": "3",... |
{
"abstract": "We present a case of a male patient with severe recurrence of focal and segmental glomerulosclerosis (FSGS) after transplant.\n\n\n\nBefore the transplant he was treated with plasma exchange. Massive proteinuria was detected post-transplantation and plasma exchanges were performed without response. We administered 5 doses of Rituximab (375 mg/m2) and partial remission was achieved. Proteinuria relapse occurred 1 year post-transplant, so Immunoadsorption (IA) was started instead of plasma exchange with reduction of proteinuria. Later, 2 new episodes of proteinuria relapse were detected and treated by increasing the number of IA sessions and administering new cycles of Rituximab. After achieving partial remission, IA was reduced to one session every 7-10 days as maintenance therapy.\n\n\n\nDespite the fact of the severe recurrence, renal function and proteinuria remain stable over 8 years after the transplantation was performed.\n\n\n\nCombination of maintenance IA and cycles of Rituximab is an effective treatment for aggressive forms of FSGS recurrence after renal transplantation.",
"affiliations": "Department of Nephrology, Clinica Universidad de Navarra, Pamplona, Spain.;Department of Hematology, Clinica Universidad de Navarra, Pamplona, Spain.;Department of Nephrology, Clinica Universidad de Navarra, Pamplona, Spain.",
"authors": "Martin-Moreno|Paloma L|PL|;Rifon|Jose|J|;Errasti|Pedro|P|",
"chemical_list": "D000069283:Rituximab",
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000488638",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0253-5068",
"issue": "46(2)",
"journal": "Blood purification",
"keywords": "Adsorption; Glomerular diseases; Recurrence; Rituximab; Transplantation",
"medline_ta": "Blood Purif",
"mesh_terms": "D005923:Glomerulosclerosis, Focal Segmental; D006801:Humans; D007163:Immunosorbent Techniques; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D010951:Plasma Exchange; D011507:Proteinuria; D012008:Recurrence; D012074:Remission Induction; D000069283:Rituximab; D016896:Treatment Outcome",
"nlm_unique_id": "8402040",
"other_id": null,
"pages": "90-93",
"pmc": null,
"pmid": "29672314",
"pubdate": "2018",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Efficacy of the Combination of Immunoadsorption and Rituximab for Treatment in a Case of Severe Focal and Segmental Glomerulosclerosis Recurrence after Renal Transplantation.",
"title_normalized": "efficacy of the combination of immunoadsorption and rituximab for treatment in a case of severe focal and segmental glomerulosclerosis recurrence after renal transplantation"
} | [
{
"companynumb": "ES-ASTELLAS-2018US045036",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "MYCOPHENOLATE MOFETIL"
},
"drugadditional": nu... |
{
"abstract": "OBJECTIVE\nOur objectives were to confirm the activity of O-MAX chemotherapy in adenocarcinoma of the stomach and esophagus, particularly the high rate of complete remission (CR) and the relation of subclinical hemolysis to CR.\n\n\nMETHODS\nTwenty-five patients with metastatic esophagogastric adenocarcinoma were treated with O-MAX. Two developed cancer-related hemolytic-uremic syndrome (C-HUS); both achieved CR. Subsequent patients were monitored for serum haptoglobin for subclinical hemolysis.\n\n\nRESULTS\nMedian survival was 16.5 months. The objective response rate was 90%, with 38% CR. Three patients achieving CR relapsed in the central nervous system and died (2 without systemic disease). Four patients have remained alive, off therapy, the longest for 20 years. Two patients developed clinical C-HUS and 5 of 8 monitored patients developed subclinical hemolysis based on abnormal serum haptoglobin. Four of the patients with subclinical hemolysis achieved CR. Of the 7 patients developing clinical C-HUS or subclinical hemolysis, 6 (86%) achieved CR.\n\n\nCONCLUSIONS\nO-MAX appears highly active in esophagogastric adenocarcinoma. A few long-term survivors of metastatic disease are being seen. CR and long-term survival appear to correlate with the development of hemolysis. Although highly promising, these results should be considered only as hypothesis-generating and require confirmation in a prospective trial.",
"affiliations": "Division of Hematology and Oncology, The George Washington University Medical Center, Washington, D.C., USA.",
"authors": "Ahlgren|James|J|;Patel|Nihar|N|;Simmens|Samuel|S|;Akin|Esma|E|;Bishop|Catherine|C|;Kirkel|Dean|D|;Siegel|Paula|P|;Schuck|Suzanne|S|;Guebre-Xabiher|Hiwot|H|;Siegel|Robert|R|",
"chemical_list": "D006242:Haptoglobins; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D003841:Deoxycytidine; D016685:Mitomycin; D000069287:Capecitabine; D004317:Doxorubicin; D005472:Fluorouracil",
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000366425",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0030-2414",
"issue": "87(6)",
"journal": "Oncology",
"keywords": null,
"medline_ta": "Oncology",
"mesh_terms": "D000230:Adenocarcinoma; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D000069287:Capecitabine; D003841:Deoxycytidine; D004317:Doxorubicin; D004334:Drug Administration Schedule; D004938:Esophageal Neoplasms; D005260:Female; D005472:Fluorouracil; D006242:Haptoglobins; D006402:Hematologic Diseases; D006463:Hemolytic-Uremic Syndrome; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D016685:Mitomycin; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D012074:Remission Induction; D013274:Stomach Neoplasms; D016896:Treatment Outcome",
"nlm_unique_id": "0135054",
"other_id": null,
"pages": "371-80",
"pmc": null,
"pmid": "25227924",
"pubdate": "2014",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "O-MAX chemotherapy: high activity in metastatic esophagogastric adenocarcinoma and possible relation to subclinical hemolysis.",
"title_normalized": "o max chemotherapy high activity in metastatic esophagogastric adenocarcinoma and possible relation to subclinical hemolysis"
} | [
{
"companynumb": "US-ROCHE-1579135",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MITOMYCIN"
},
"drugadditional": null,
"druga... |
{
"abstract": "Adverse drug reactions (ADRs) are a major problem in modern medicine, representing up to the fourth-highest cause of mortality. Pharmacogenomic tests are 1 of the most promising methods to tackle the challenge of ADRs. The objective of this study was to analyze the clinical and demographic information of the pan-Canadian active surveillance network, Canadian Pharmacogenomics Network for Drug Safety (CPNDS). Information entered into the database by trained active surveillors between May 15, 2005 and May 9, 2017 was collected and analyzed. Specific data included for analysis were number of ADR reports, reports of drug use without ADRs, date of onset of ADR, suspected drugs, concomitant drugs, and fatal ADR cases. The CPNDS database consisted of 93,974 reports of medication use, including 10,475 reports of ADRs, of which 72.6% occurred in pediatric patients (≤21 years old). Self-reported ancestries were predominantly Europe (38.2%), Canada (9.6%), and East Asia (4.9%). The 5 most frequent ADRs were cutaneous ADRs, peripheral neuropathy, cardiotoxicity, central nervous system toxicity, and ototoxicity. The 5 drugs most commonly suspected to cause ADRs were methotrexate, vincristine, doxorubicin, cisplatin, and L-asparaginase. The CPNDS database is a valuable resource to identify clinical and genomic predictors of ADRs. The database also highlights our candidate ADRs for pharmacogenomic discovery research to identify additional ADR biomarkers. Additionally, the database provides information that can be used for developing strategies to prevent ADRs and raises awareness of ADRs among Canadian healthcare professionals.",
"affiliations": "Division of Translational Therapeutics, Department of Pediatrics, Faculty of Medicine, The University of British Columbia, Vancouver, British Columbia, Canada.;Division of Translational Therapeutics, Department of Pediatrics, Faculty of Medicine, The University of British Columbia, Vancouver, British Columbia, Canada.;Division of Translational Therapeutics, Department of Pediatrics, Faculty of Medicine, The University of British Columbia, Vancouver, British Columbia, Canada.;Division of Translational Therapeutics, Department of Pediatrics, Faculty of Medicine, The University of British Columbia, Vancouver, British Columbia, Canada.;British Columbia Children's Hospital Research Institute, Vancouver, British Columbia, Canada.;British Columbia Children's Hospital Research Institute, Vancouver, British Columbia, Canada.;British Columbia Children's Hospital Research Institute, Vancouver, British Columbia, Canada.;Division of Translational Therapeutics, Department of Pediatrics, Faculty of Medicine, The University of British Columbia, Vancouver, British Columbia, Canada.;Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, British Columbia, Canada.;Division of Translational Therapeutics, Department of Pediatrics, Faculty of Medicine, The University of British Columbia, Vancouver, British Columbia, Canada.",
"authors": "Tanoshima|Reo|R|0000-0003-4361-6967;Khan|Amna|A|;Biala|Agnieszka K|AK|;Trueman|Jessica N|JN|;Drögemöller|Britt I|BI|;Wright|Galen E B|GEB|;Hasbullah|Jafar S|JS|;Groeneweg|Gabriella S S|GSS|;Ross|Colin J D|CJD|;Carleton|Bruce C|BC|;|||",
"chemical_list": "D014750:Vincristine; D004317:Doxorubicin; D001215:Asparaginase; D008727:Methotrexate",
"country": "England",
"delete": false,
"doi": "10.1002/jcph.1336",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0091-2700",
"issue": "59(3)",
"journal": "Journal of clinical pharmacology",
"keywords": "active surveillance; adverse drug reaction; network; pharmacogenomics",
"medline_ta": "J Clin Pharmacol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D016907:Adverse Drug Reaction Reporting Systems; D000368:Aged; D000369:Aged, 80 and over; D001215:Asparaginase; D002170:Canada; D002648:Child; D002675:Child, Preschool; D062313:Databases, Pharmaceutical; D004317:Doxorubicin; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008727:Methotrexate; D008875:Middle Aged; D010597:Pharmacogenetics; D014750:Vincristine; D055815:Young Adult",
"nlm_unique_id": "0366372",
"other_id": null,
"pages": "356-363",
"pmc": null,
"pmid": "30452777",
"pubdate": "2019-03",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Analyses of Adverse Drug Reactions-Nationwide Active Surveillance Network: Canadian Pharmacogenomics Network for Drug Safety Database.",
"title_normalized": "analyses of adverse drug reactions nationwide active surveillance network canadian pharmacogenomics network for drug safety database"
} | [
{
"companynumb": "CA-TEVA-2019-CA-1035510",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "ETOPOSIDE"
},
"drugadditional": null,
... |
{
"abstract": "Hodgkin lymphoma (HL) commonly presents as nodal disease, but in a subset of cases, the disease primarily develops in extranodal sites. Primary classical HL of the gastrointestinal (GI) tract is an extremely rare occurrence. Primary nature of the disease is confirmed after a complete lymphoma work up including chest radiograph, computed tomography scan, peripheral blood, and bone marrow studies. Only a few cases of primary GI lymphomas with limited immunohistochemical or molecular confirmation have been reported in literature. We report the case of a 64-year-old immunocompetent woman with primary rectal HL. She presented with constipation, and on sigmoidoscopy examination, she was detected to have an ulceroproliferative circumferential growth in the rectum. Considering the possibility of rectal carcinoma, a low anterior resection was done. Histology was suggestive of mixed cellularity classical HL. She was started on combination chemotherapy, and she responded well to treatment. However, she developed pulmonary complication after the fourth cycle of chemotherapy and succumbed to the illness. Primary rectal HL is extremely rare, and to the best of our knowledge, only 16 cases have been reported previously. We believe that reporting this case will add to the scarce data about this unusual presentation in immunocompetent patients.",
"affiliations": "Division of Pathology, Regional Cancer Centre, Thiruvananthapuram, Kerala, India.;Division of Pathology, Regional Cancer Centre, Thiruvananthapuram, Kerala, India.;Division of Medical Oncology, Regional Cancer Centre, Thiruvananthapuram, Kerala, India.",
"authors": "Vasudevan|Jayasudha Arundhathi|JA|;Nair|Rekha A|RA|;Nambiar|K Rakul|KR|",
"chemical_list": "D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor",
"country": "India",
"delete": false,
"doi": "10.4103/IJPM.IJPM_767_16",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0377-4929",
"issue": "60(3)",
"journal": "Indian journal of pathology & microbiology",
"keywords": null,
"medline_ta": "Indian J Pathol Microbiol",
"mesh_terms": "D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D017809:Fatal Outcome; D005260:Female; D006651:Histocytochemistry; D006689:Hodgkin Disease; D006801:Humans; D007150:Immunohistochemistry; D008171:Lung Diseases; D008853:Microscopy; D008875:Middle Aged; D012004:Rectal Neoplasms; D012007:Rectum; D016896:Treatment Outcome",
"nlm_unique_id": "7605904",
"other_id": null,
"pages": "412-414",
"pmc": null,
"pmid": "28937385",
"pubdate": "2017",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Primary classical Hodgkin lymphoma of rectum: Report of an extremely rare case and review of the literature.",
"title_normalized": "primary classical hodgkin lymphoma of rectum report of an extremely rare case and review of the literature"
} | [
{
"companynumb": "IN-JNJFOC-20171027975",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "DACARBAZINE"
},
"drugadditional": null,
... |
{
"abstract": "In 2011 a 76 year-old man with a medical history of diabetes, hypertension and autoimmune pancreatitis was admitted to our hospital because of anorexia, general malaise and repeated hypoglycemia. When he was 72 years old, he suffered from pancreatitis, and pancreas head tumor was operated. IgG4-related pancreatitis was diagnosed histopathologically. On admission anterior pituitary function test revealed impaired response of ACTH and cortisol to CRH, and no response of GH, TSH and gonadotropin to GHRH, TRH and LHRH, respectively. Baseline PRL level was elevated. Serum IgG and IgG4 levels were markedly elevated. Pituitary MRI showed significant enlargement of pituitary gland and stalk. Chest CT suggested IgG4-related lung disease. IgG4-related infundibulo-hypophysitis was diagnosed based on the above mentioned past history and results of present examinations. Twenty mg of hydrocortisone, followed by 20 mg of prednisolone (PSL) and 25 μg of levothyroxine markedly reduced serum IgG4 levels and ameliorated the symptom, the size of pituitary and stalk, and anterior pituitary function (TSH, GH and gonadotropin), although diabetes insipidus became apparent due to glucocorticoid administration. This is a typical case of IgG4-related hypophysitis in which PSL causes marked improvement of pituitary mass and pituitary function along with the reduction of serum IgG4 levels.",
"affiliations": "Department of Diabetology and Metabolism, National Hospital Organization Okayama Medical Center, Okayama 701-1192, Japan.",
"authors": "Iseda|Izumi|I|;Hida|Kazuyuki|K|;Tone|Atsuhiko|A|;Tenta|Masafumi|M|;Shibata|Yusuke|Y|;Matsuo|Kiyoshi|K|;Yamadori|Ichiro|I|;Hashimoto|Kozo|K|",
"chemical_list": "D007074:Immunoglobulin G; D011239:Prednisolone; D013974:Thyroxine; D006854:Hydrocortisone",
"country": "Japan",
"delete": false,
"doi": "10.1507/endocrj.ej13-0407",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0918-8959",
"issue": "61(2)",
"journal": "Endocrine journal",
"keywords": null,
"medline_ta": "Endocr J",
"mesh_terms": "D000368:Aged; D001327:Autoimmune Diseases; D020790:Diabetes Insipidus, Neurogenic; D006801:Humans; D006854:Hydrocortisone; D007018:Hypopituitarism; D007074:Immunoglobulin G; D008279:Magnetic Resonance Imaging; D008297:Male; D010195:Pancreatitis; D010900:Pituitary Diseases; D010902:Pituitary Gland; D011239:Prednisolone; D013974:Thyroxine",
"nlm_unique_id": "9313485",
"other_id": null,
"pages": "195-203",
"pmc": null,
"pmid": "24335007",
"pubdate": "2014",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Prednisolone markedly reduced serum IgG4 levels along with the improvement of pituitary mass and anterior pituitary function in a patient with IgG4-related infundibulo-hypophysitis.",
"title_normalized": "prednisolone markedly reduced serum igg4 levels along with the improvement of pituitary mass and anterior pituitary function in a patient with igg4 related infundibulo hypophysitis"
} | [
{
"companynumb": "PHHY2014JP037913",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LEVOTHYROXINE SODIUM"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nTo determine the more effective dosing sequence of intermittent erlotinib and docetaxel for treating chemotherapy-naive patients with advanced Non-Small Cell Lung Cancer (NSCLC).\n\n\nMETHODS\nPatients were randomized to receive daily erlotinib for 12 consecutive days prior to docetaxel (Arm A) or after docetaxel (Arm B). Progression-free survival (PFS) was the primary end-point; secondary end-points were overall survival (OS) and objective response rate (ORR).\n\n\nRESULTS\nFifty eligible patients received a total of 226 treatment cycles (median: 3). Median PFS and OS were 3.6 months and 10.5 months, respectively (differences were not statistically significant between the two arms). Neutropenia grade 3 and 4 occurred in 15 patients, while two patients developed grade 3 diarrhea. There were two treatment-related deaths (pulmonary embolism and non-neutropenic sepsis).\n\n\nCONCLUSIONS\nIntermittent administration of erlotinib does not appear to improve the clinical outcome of single-agent docetaxel chemotherapy in unselected patients with NSCLC in the first-line setting.",
"affiliations": "Department of Medical Oncology, \"Papageorgiou\" Hospital, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece.;Second Department of Medical Oncology, Hygeia Hospital, Athens, Greece.;Oncology Unit GPP, \"Sotiria\" General Hospital, Athens School of Medicine, Athens, Greece.;Department of Radiology, AHEPA Hospital, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece.;Department of Clinical Therapeutics, \"Alexandra\" Hospital, University of Athens School of Medicine, Athens, Greece.;Department of Pathology, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece.;Oncology Section, Second Department of Internal Medicine, \"Hippokration\" Hospital, Athens, Greece.;Department of Medical Oncology, \"Theagenio\" Cancer Hospital, Thessaloniki, Greece.;Second Department of Medical Oncology, \"Metropolitan\" Hospital, Piraeus, Greece.;Department of Radiology, AHEPA Hospital, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece.;Department of Medical Oncology, University Hospital of Larissa, University of Thessaly School of Medicine, Larissa, Greece.;Department of Medical Oncology, \"Papageorgiou\" Hospital, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece.;Department of Hematology, University of Ioannina School of Medicine, Ioannina, Greece ebriasou@otenet.gr.",
"authors": "Karavasilis|Vasilios|V|;Kosmidis|Paris|P|;Syrigos|Konstantinos N|KN|;Mavropoulou|Polyxeni|P|;Dimopoulos|Meletios A|MA|;Kotoula|Vassiliki|V|;Pectasides|Dimitrios|D|;Boukovinas|Ioannis|I|;Klouvas|George|G|;Kalogera-Fountzila|Anna|A|;Papandreou|Christos N|CN|;Fountzilas|George|G|;Briasoulis|Evangelos|E|",
"chemical_list": "D011799:Quinazolines; D043823:Taxoids; D000077143:Docetaxel; D000069347:Erlotinib Hydrochloride",
"country": "Greece",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0250-7005",
"issue": "34(10)",
"journal": "Anticancer research",
"keywords": "Erlotinib; docetaxel; non-small cell lung cancer",
"medline_ta": "Anticancer Res",
"mesh_terms": "D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D002289:Carcinoma, Non-Small-Cell Lung; D000077143:Docetaxel; D000069347:Erlotinib Hydrochloride; D005260:Female; D006801:Humans; D008175:Lung Neoplasms; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D009362:Neoplasm Metastasis; D011799:Quinazolines; D012307:Risk Factors; D043823:Taxoids; D016896:Treatment Outcome",
"nlm_unique_id": "8102988",
"other_id": null,
"pages": "5649-55",
"pmc": null,
"pmid": "25275069",
"pubdate": "2014-10",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D016449:Randomized Controlled Trial",
"references": null,
"title": "Docetaxel and intermittent erlotinib in patients with metastatic Non-Small Cell Lung Cancer; a phase II study from the Hellenic Cooperative Oncology Group.",
"title_normalized": "docetaxel and intermittent erlotinib in patients with metastatic non small cell lung cancer a phase ii study from the hellenic cooperative oncology group"
} | [
{
"companynumb": "GR-SA-2014SA178808",
"fulfillexpeditecriteria": "1",
"occurcountry": "GR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ERLOTINIB"
},
"drugadditional": null,
"dru... |
{
"abstract": "A young patient experienced a generalized seizure during the placement of an axillary plexus block. The mechanisms, essentially the presumed intravascular administration, which led to the local anesthetic toxicity as the cause of this event, are discussed. This case is an example of how visualization of the anatomy by ultrasound can give a false impression when certain details are not respected. It is assumed that the main mechanism in this case was venous compression by the ultrasound transducer.",
"affiliations": "Institut für Anästhesiologie, Spital Bülach, Bülach, Schweiz. thomas.hillermann@spitalbuelach.ch.;Institut für Anästhesiologie, Spital Bülach, Bülach, Schweiz.;Klinikbetreuung, Pharm. Dienstleistungen, Kantonsapotheke Zürich, Zürich, Schweiz.;Chirurgische Klinik, Handchirurgie, Spital Bülach, Bülach, Schweiz.",
"authors": "Hillermann|T|T|;Homburg|K|K|;Rainer|M|M|;Budde|U|U|",
"chemical_list": null,
"country": "Germany",
"delete": false,
"doi": "10.1007/s00101-021-01055-x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0003-2417",
"issue": null,
"journal": "Der Anaesthesist",
"keywords": "Anamnesis; Local anesthetic; Peripheral regional anaesthetics; Pre-existing illness; Toxicity",
"medline_ta": "Anaesthesist",
"mesh_terms": null,
"nlm_unique_id": "0370525",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34648045",
"pubdate": "2021-10-14",
"publication_types": "D004740:English Abstract; D016428:Journal Article",
"references": "29303925",
"title": "Generalized seizure during placement of an axillary plexus block.",
"title_normalized": "generalized seizure during placement of an axillary plexus block"
} | [
{
"companynumb": "CH-Fresenius Kabi-FK202205103",
"fulfillexpeditecriteria": "1",
"occurcountry": "CH",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ROPIVACAINE"
},
"drugadditional": "1",
... |
{
"abstract": "BACKGROUND\nPeripheral artery disease and critical limb ischemia are common in patients undergoing chronic hemodialysis treatment and are associated with a high rate of amputation and mortality. The effect of treatment with prostanoids in this specific group of patients is unknown.\n\n\nMETHODS\nA retrospective single-center analysis of hemodialysis patients with critical limb ischemia was performed who were treated with the prostanoid analogue alprostadil as an infusion during hemodialysis in the period from 2000 to 2013. The primary study outcome was a combined end-point including amputation and death 1 year after start of alprostadil. Kaplan-Meier curves were used to describe amputation-free survival and overall survival. A multivariable adjusted Cox proportional hazards model was calculated for the primary outcome.\n\n\nRESULTS\nA total of 86 patients (60 males, 69.7%) were studied. The median alprostadil treatment period was 1.8 months. The 1‑year amputation-free survival was 41%. In 36% of patients an amputation was necessary and 35% died. Despite alprostadil treatment, 36% of the study patients additionally underwent an endovascular procedure and 16% had bypass surgery. Men had a significantly higher amputation rate (45%) than women (15%) (P = 0.009). Male sex and dialysis vintage were significantly associated with an increased risk for primary outcome CONCLUSIONS: Despite treatment with alprostadil the mortality, amputation rate and the need for revascularization procedures in hemodialysis patients with critical limb ischemia remained high. The outcome, however, was comparable with that of other treatment, such as endovascular procedures and bypass surgery. The effect of any current treatment strategy on amputation rate or mortality in that patient group remains uncertain.",
"affiliations": "Department of Internal Medicine 3, Academic Teaching Hospital Feldkirch, Carinagasse 47, 6800, Feldkirch, Austria.;Department of Internal Medicine 3, Academic Teaching Hospital Feldkirch, Carinagasse 47, 6800, Feldkirch, Austria.;Department of Internal Medicine 3, Academic Teaching Hospital Feldkirch, Carinagasse 47, 6800, Feldkirch, Austria.;Department of Internal Medicine 3, Academic Teaching Hospital Feldkirch, Carinagasse 47, 6800, Feldkirch, Austria.;Department of Internal Medicine 3, Academic Teaching Hospital Feldkirch, Carinagasse 47, 6800, Feldkirch, Austria. karl.lhotta@lkhf.at.",
"authors": "Popp|Wolfgang|W|;Knoll|Florian|F|;Sprenger-Mähr|Hannelore|H|;Zitt|Emanuel|E|;Lhotta|Karl|K|http://orcid.org/0000-0002-8156-7775",
"chemical_list": "D000527:Alprostadil",
"country": "Austria",
"delete": false,
"doi": "10.1007/s00508-018-1407-z",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0043-5325",
"issue": "131(9-10)",
"journal": "Wiener klinische Wochenschrift",
"keywords": "Amputation; Arteriosclerosis; Bypass surgery; Mortality; Peripheral artery disease; Revascularisation",
"medline_ta": "Wien Klin Wochenschr",
"mesh_terms": "D000527:Alprostadil; D000671:Amputation; D016638:Critical Illness; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D007511:Ischemia; D053208:Kaplan-Meier Estimate; D023821:Limb Salvage; D035002:Lower Extremity; D008297:Male; D016016:Proportional Hazards Models; D006435:Renal Dialysis; D012189:Retrospective Studies; D012307:Risk Factors; D013997:Time Factors; D016896:Treatment Outcome",
"nlm_unique_id": "21620870R",
"other_id": null,
"pages": "209-215",
"pmc": null,
"pmid": "30421286",
"pubdate": "2019-05",
"publication_types": "D016428:Journal Article",
"references": "12422107;14717932;14732743;15262830;15461062;15461065;15780133;1699814;17060384;1720403;17215445;17267538;17699220;17699501;2104964;23067047;25281532;25443571;26254454;26324203;26668023;26843355;27236250;7692455;7878539;8192993;9652467",
"title": "Alprostadil treatment of critical limb ischemia in hemodialysis patients : A retrospective single-center analysis.",
"title_normalized": "alprostadil treatment of critical limb ischemia in hemodialysis patients a retrospective single center analysis"
} | [
{
"companynumb": "AT-MYLANLABS-2019M1044128",
"fulfillexpeditecriteria": "1",
"occurcountry": "AT",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "ALPROSTADIL"
},
"drugadditional": null,
... |
{
"abstract": "Non-bullous neutrophilic lupus erythematosus is a rare form of cutaneous lupus erythematosus (LE). We hereby present a case of 24-year-old female, known case of discoid LE (DLE) with negative ANA stabilized on hydroxychloroquine for 2 years. She reported new occurrence of erythematous, mildly pruritic, papular lesions and painful mucosal ulceration. The ANA became strongly positive by ELISA and urine showed proteinuria. A provisional diagnosis of Rowell syndrome was made, skin biopsy was taken, and patient started on steroids. Histopathology showed interface vacuolar change and many neutrophils in the dermis with leukocytoclasia without any bulla formation. The skin lesions responded promptly to addition of dapsone following biopsy report. We conclude that the presence of neutrophils associated with interface pathology on biopsy represents a muted form of bullous LE, especially in patients on immunosuppression. This case highlights the importance of histopathologic examination in the evaluation of any new skin lesions in a patient of lupus on therapy.",
"affiliations": "Department of Pathology, ABVIMS and Dr. RML Hospital, New Delhi, India.;Department of Pathology, ABVIMS and Dr. RML Hospital, New Delhi, India.;Department of Medicine, ABVIMS and Dr. RML Hospital, New Delhi, India.;Department of Pathology, ABVIMS and Dr. RML Hospital, New Delhi, India.",
"authors": "Malhotra|Purnima|P|;Singh|Preeti|P|;Kundu|Bijit K|BK|;Bhardwaj|Minakshi|M|",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": "10.4103/IJPM.IJPM_704_19",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0377-4929",
"issue": "63(2)",
"journal": "Indian journal of pathology & microbiology",
"keywords": "Dapsone; neutrophilic dermatoses; non-bullous neutrophilic lupus erythematosus",
"medline_ta": "Indian J Pathol Microbiol",
"mesh_terms": "D000328:Adult; D001706:Biopsy; D001768:Blister; D005260:Female; D006801:Humans; D008178:Lupus Erythematosus, Cutaneous; D009504:Neutrophils; D012867:Skin; D055815:Young Adult",
"nlm_unique_id": "7605904",
"other_id": null,
"pages": "305-308",
"pmc": null,
"pmid": "32317541",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Non-bullous neutrophilic lupus erythematosus-Muted bullous disease?",
"title_normalized": "non bullous neutrophilic lupus erythematosus muted bullous disease"
} | [
{
"companynumb": "IN-MYLANLABS-2021M1009652",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "HYDROXYCHLOROQUINE"
},
"drugadditional": "3",... |
{
"abstract": "A 54-year-old man was presented at our hospital with weight loss.He diagnosed with colorectal cancer, multiple liver metastases and para-aortic lymph node metastasis.After undergoing colostomy, he was treated sequentially with mFOLFOX6 plus bevacizumab(Bmab), FOLFIRI plus Bmab or Pmab, according to the guideline.Since these chemotherapy resulted in progressive disease, regorafenib was administered as a salvage-line treatment.PET -CT showed only para-aortic lymph node swelling with high FDG uptake.Severe adverse effects were developed shortly after regorafenib treatment so he requireda reduction in dose.Three years after treatment with regorafenib, the response of the target lesion was stable disease according to the RECIST criteria.Tumor growth had been controlled for a long time.",
"affiliations": "Dept. of Surgery, North Medical Center Kyoto Prefectural University of Medicine.",
"authors": "Watanabe|Nobuyuki|N|;Akagi|Shigenori|S|;Inoue|Hiroyuki|H|;Nakatsuji|Hiroki|H|;Ito|Hiroshi|H|;Toma|Atsushi|A|;Nakamura|Kenji|K|;Ochiai|Toshiya|T|;Otsuji|Eigo|E|",
"chemical_list": "D010671:Phenylurea Compounds; D011725:Pyridines; C559147:regorafenib",
"country": "Japan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0385-0684",
"issue": "44(12)",
"journal": "Gan to kagaku ryoho. Cancer & chemotherapy",
"keywords": null,
"medline_ta": "Gan To Kagaku Ryoho",
"mesh_terms": "D000230:Adenocarcinoma; D001011:Aorta; D006801:Humans; D008113:Liver Neoplasms; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D010671:Phenylurea Compounds; D011725:Pyridines; D012811:Sigmoid Neoplasms; D013997:Time Factors",
"nlm_unique_id": "7810034",
"other_id": null,
"pages": "1732-1734",
"pmc": null,
"pmid": "29394758",
"pubdate": "2017-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Long-Term Survival of a Patient with Metastatic Liver and Para-Aortic Lymph Node Cancer from Colon Cancer Treated with Regorafenib.",
"title_normalized": "long term survival of a patient with metastatic liver and para aortic lymph node cancer from colon cancer treated with regorafenib"
} | [
{
"companynumb": "JP-MYLANLABS-2018M1046655",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "IRINOTECAN"
},
"drugadditional": "1",
... |
{
"abstract": "Neuroleptics can induce not only physical adverse effects but also mental effects that produce deficit status in thought, affect, cognition, and behavior. This condition is known as neuroleptic-induced deficit syndrome (NIDS), which includes apathy, lack of initiative, anhedonia, indifference, blunted affect, and reduced insight into disease. Although this old concept now appears almost forgotten, neuroleptics, whether typical or atypical, can make depression or bipolar disorder resemble other more refractory conditions, readily leading to mistaken diagnosis and inappropriate treatment. The authors describe three cases of NIDS superimposed on depressive phase in bipolar disorder with psychosis, where the attending psychiatrist's failure to recognize NIDS prevented patients from receiving effective treatment and achieving remission. All cases achieved remission after reduction of neuroleptics and intensive therapy, including electroconvulsive therapy, for bipolar depression. The concept of NIDS was originally introduced for schizophrenia, and it has rarely been highlighted in other diseases. In recent years, however, atypical antipsychotics are being more often administered to patients with bipolar disorder. Psychiatrists, therefore, should also remember and exercise caution regarding NIDS in the pharmacotherapy of bipolar disorder with and without psychosis. The authors believe that the concept of NIDS needs to be reappraised in current psychiatry.",
"affiliations": "Department of Neuropsychiatry, Nippon Medical School, Tokyo, Japan.;Department of Neuropsychiatry, Nippon Medical School, Tokyo, Japan.;Tamachuo Hospital, Tokyo, Japan.;Kurumegaoka Hospital, Tokyo, Japan.;Kurumegaoka Hospital, Tokyo, Japan.;Department of Neuropsychiatry, Nippon Medical School, Tokyo, Japan.;Saijo Clinic, Tokyo, Japan.;Department of Neuropsychiatry, Nippon Medical School, Tokyo, Japan.",
"authors": "Ueda|Satoshi|S|;Sakayori|Takeshi|T|;Omori|Ataru|A|;Fukuta|Hajime|H|;Kobayashi|Takashi|T|;Ishizaka|Kousuke|K|;Saijo|Tomoyuki|T|;Okubo|Yoshiro|Y|",
"chemical_list": null,
"country": "New Zealand",
"delete": false,
"doi": "10.2147/NDT.S99577",
"fulltext": "\n==== Front\nNeuropsychiatr Dis TreatNeuropsychiatr Dis TreatNeuropsychiatric Disease and TreatmentNeuropsychiatric Disease and Treatment1176-63281178-2021Dove Medical Press 10.2147/NDT.S99577ndt-12-265Case SeriesNeuroleptic-induced deficit syndrome in bipolar disorder with psychosis Ueda Satoshi 1Sakayori Takeshi 1Omori Ataru 2Fukuta Hajime 3Kobayashi Takashi 3Ishizaka Kousuke 1Saijo Tomoyuki 4Okubo Yoshiro 11 Department of Neuropsychiatry, Nippon Medical School, Tokyo, Japan2 Tamachuo Hospital, Tokyo, Japan3 Kurumegaoka Hospital, Tokyo, Japan4 Saijo Clinic, Tokyo, JapanCorrespondence: Satoshi Ueda, Department of Neuropsychiatry, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8603, Japan, Tel +81 3 3822 2131, Fax +81 3 5814 6287, Email sat333@nms.ac.jp2016 02 2 2016 12 265 268 © 2016 Ueda et al. This work is published and licensed by Dove Medical Press Limited2016The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.Neuroleptics can induce not only physical adverse effects but also mental effects that produce deficit status in thought, affect, cognition, and behavior. This condition is known as neuroleptic-induced deficit syndrome (NIDS), which includes apathy, lack of initiative, anhedonia, indifference, blunted affect, and reduced insight into disease. Although this old concept now appears almost forgotten, neuroleptics, whether typical or atypical, can make depression or bipolar disorder resemble other more refractory conditions, readily leading to mistaken diagnosis and inappropriate treatment. The authors describe three cases of NIDS superimposed on depressive phase in bipolar disorder with psychosis, where the attending psychiatrist’s failure to recognize NIDS prevented patients from receiving effective treatment and achieving remission. All cases achieved remission after reduction of neuroleptics and intensive therapy, including electroconvulsive therapy, for bipolar depression. The concept of NIDS was originally introduced for schizophrenia, and it has rarely been highlighted in other diseases. In recent years, however, atypical antipsychotics are being more often administered to patients with bipolar disorder. Psychiatrists, therefore, should also remember and exercise caution regarding NIDS in the pharmacotherapy of bipolar disorder with and without psychosis. The authors believe that the concept of NIDS needs to be reappraised in current psychiatry.\n\nKeywords\nneuroleptic-induced deficit syndrome (NIDS)bipolar disorderpsychosisatypical antipsychoticselectroconvulsive therapy\n==== Body\nIntroduction\nIt is well known that neuroleptics can induce physical adverse effects such as extrapyramidal symptoms and oversedation, but they can also induce mental adverse effects, which involve deficit status in thought, affect, cognition, and behavior, the typical phenomena of which are apathy, lack of initiative, anhedonia, indifference, blunted affect, and reduced insight into disease. They very much resemble negative symptoms of schizophrenia. Such effects are known as neuroleptic-induced deficit syndrome (NIDS), which was proposed in order to promote interest in the mental adverse effects of neuroleptics by Lader1 and Lewander.2 Their original intention was that NIDS should be strictly differentiated from disease-related negative symptoms in schizophrenia patients taking typical antipsychotics. Recent studies,3,4 however, have indicated that some atypical antipsychotics also might well induce NIDS. This old concept appears almost forgotten in current psychiatry.\n\nNIDS also occurs in patients with psychiatric disorders other than schizophrenia, often making them resemble schizophrenia, chronic psychiatric condition, or even dementia.5 This means that a disease with better prognosis, such as depression or bipolar disorder, might be misdiagnosed as other refractory disorders, which would then prevent patients from receiving optimal treatment. We describe three cases of NIDS in bipolar disorder with psychosis, where the attending psychiatrists’ failure to recognize NIDS prolonged their treatment course, delaying remission. This study was deemed exempt from full review according to the ethics committee of Nippon Medical School, Japan as this was a naturalistic study. Written, informed consent was obtained from all patients.\n\nCase 1\nA 50-year-old married man with no personal and family history of psychiatric disease had recurrent depression and psychotic mania since his 20s and visited a psychiatric hospital. He ran a retail trade after graduation from university. From his late 30s, he had several relapses. Flight of ideas, irritability, and grandiose delusion occurred in his manic periods, while psychomotor inhibition, hypothymia, and self-reproach occurred in his depressive periods. He was usually treated with fluvoxamine and low-dose haloperidol, but developed mania with psychosis at age 48 and was hospitalized. Haloperidol was increased to 9 mg/d, and risperidone at 12 mg/d was added to fluvoxamine at 75 mg/d. Psychotic mania was resolved, but apathy, lack of initiative, blunted affect, and anxiety appeared, while his appetite was still good. He talked with an expressionless, low voice, and walked slowly dragging his feet with a slouched posture. Muscle rigidity and tremor were mild. Although he developed neither mania nor agitation, he often complained that his future was hopeless and that he felt lonely. Thus, he was suspected of chronic anxious depression.\n\nAfter 2 years of no improvement, he went to a general hospital. He appeared strangely indifferent to his current illness and potential treatment. Physical examinations detected no abnormalities. Diagnosed with bipolar disorder with psychosis, he was successfully treated with nine sessions of electroconvulsive therapy (ECT). Antipsychotics were greatly reduced to risperidone at only 3 mg/d. He became lively and free of anxiety. His actions, including walking, became as quick and smooth as before. Lithium carbonate at 800 mg/d and valproate at 1,000 mg/d were started. He successfully returned to work, and has remained in remission for 6 years.\n\nCase 2\nA 49-year-old married woman with no personal and family history of psychiatric disease had worked steadily for a company. After a month of extravagant living, she complained of depressive mood and inability to cook, eat, and sleep. She also complained that a tsunami would come and that the whole world would be destroyed. This was followed by a period of delusion of possession. She was admitted to the psychiatry department of a hospital. Five sessions of ECT improved her psychosis, but not the depression. Suspected of schizoaffective disorder at first, she was given blonanserin at 12 mg/d. Reduced initiative, apathy, and blunted affect developed. Because neuropsychological tests indicated reduced memory retention, inhibited reaction, and change in character from being a methodical to an untidy person, she was suspected of having frontotemporal dementia. She was discharged, but she could not work in the house or at her workplace, as she was demonstrating great anxiety and little vitality.\n\nAfter 8 months of no change, she was admitted to another hospital. Detailed examinations revealed no organic abnormalities except moderate extrapyramidal symptoms. She moved slowly, showed very little facial expression, had poor insight into her disease, and displayed reduced desire to improve. She underwent 12 sessions of ECT, and blonanserin was stopped. She gradually became lively, motivated, and rich in emotional expression, with absence of extrapyramidal symptoms. She recovered her originally tidy personality. Lithium carbonate at 800 mg/d and quetiapine at 200 mg/d have maintained her in remission for 5 years.\n\nCase 3\nAfter his divorce, a 42-year-old man with no personal and family history of psychiatric disease, showing a lack of motivation and suicidal ideation, visited the psychiatric department in a hospital, and took antidepressants for only 2 weeks. He had successfully run an independent business since his late 20s. At age 46, he relapsed into a depressive state and revisited the same department. He complained of a feeling of having worms on his back and of being watched by someone from outside his home. He was suspected of suffering from some psychosis in addition to depression. Olanzapine at 10 mg/d was started and increased to 20 mg/d. His symptoms remained unresolved. He withdrew progressively and developed blunted affect and poor rapport with others. At every examination in the hospital, he only complained of insomnia, showing poor speech, thought, and responsiveness. Because these conditions were considered to be natural negative symptoms of schizophrenia, he was diagnosed with schizophrenia. The prescribed neuroleptics were changed from olanzapine to risperidone 6 mg/d, and then risperidone was changed to the combination of aripiprazole at 12 mg/d, levomepromazine (150 mg/d at the maximum), and quetiapine (500 mg/d at the maximum); but they had no effect.\n\nAt age 52, his diagnosis was changed to depression by new attending psychiatrists, because they considered that none of his symptoms were typical of schizophrenia and because the onset and progression of his illness was more likely to correspond to the treatment course of depression than to that of schizophrenia. Neuroleptics were drastically reduced: quetiapine at 500 mg/d was decreased to 200 mg/d, while 150 mg/d of levomepromazine and 12 mg/d of aripiprazole were stopped. Mirtazapine was administered up to 45 mg/d. He gradually became lively and active. His speech and response on examinations also became more organized and smooth. Hallucinations and delusions were entirely absent. He started a part-time job after 6 years of unemployment. A year later, however, he showed inflated self-esteem and exaggerated elation and became engaged in unrestrained business activities. Mirtazapine was stopped, quetiapine was increased to 350 mg/d, and his mood and behavior became normal.\n\nTable 1 shows the clinical profiles of three cases.\n\nIn Cases 1 and 2, ECT at the second hospital, with bilateral frontotemporal electrode placement, was performed three times a week using a Thymatron System IV brief-pulse square-wave apparatus (Somatics, LLC, Lake Bluff, IL, USA). Stimulus dosing was done according to “Clinical Manual of Electroconvulsive Therapy”.6 Thiamylal or propofol was intravenously administered as anesthetic agent, and succinylcholine was given as muscle relaxant.\n\nDiscussion\nThese three cases appeared to exhibit deficit status superimposed on the depressive phase. The deficit status was probably induced by several kinds of potent neuroleptics, and this condition was identified as NIDS. The major NIDS in these cases included apathy, lack of initiative, blunted affect, indifference, poor insight into disease, and reduced desire to improve. It had not been recognized that these symptoms were neuroleptic-induced, superimposed symptoms. All three cases presented good reasons for a diagnosis of bipolar disorder: Cases 1 and 2 had exhibited both manic and depressive states before admission, and Case 3 exhibited depressive state with psychosis for years, followed by a manic state that was not resolved by discontinuation of antidepressant. However, they were described as appearing like several refractory conditions with poorer prognosis. Case 1 was falsely suspected of chronic depression, Case 2 of frontotemporal dementia, and Case 3 of chronic schizophrenia. NIDS may well have masked the patients’ original symptoms and seemingly changed their psychopathology. The attending psychiatrist’s failure to recognize NIDS resulted in persistent inadequate treatment and delayed remission. After NIDS was treated with reduction of neuroleptics and intensive therapy, including ECT, for bipolar depression, all cases eventually had remission.\n\nOnce patients, who have had psychosis, are suspected of refractory diseases, neuroleptics are very often not discontinued in case of possible relapse, as shown in the present cases. Swartz and Shorter7 warned that antipsychotic drugs are two-edged swords: at first swing they cut psychosis, but when taken in sufficient duration (2 years in young patients, 2 months in elderly) antipsychotic drugs cause psychosis or depression. Then the antipsychotic is continued to cut the symptoms it brought on.\n\nPatients with NIDS, however, do not always improve with only discontinuation of neuroleptics, because the discontinuation may actually again elicit their original symptoms such as psychosis or mania. In such cases, ECT may be a very useful and effective option, as observed in Cases 1 and 2. After ECT, maintenance pharmacotherapy for bipolar disorder, and not only for psychosis, must be intensively undertaken.\n\nThe concept of NIDS was proposed more than 20 years ago with the aim of differentiating it from negative symptoms in schizophrenia. Some attention has long been paid to this concept when treating schizophrenia patients, where the subjective dysphoric response to neuroleptics and negative influence on their well-being have been focused on.8,9 However, there have been only a few reports in the literature on NIDS developing in diseases other than schizophrenia. Among those rare but valuable studies is a case report by Machida et al,5 where the authors’ recognition of NIDS allowed a patient with obsessive–compulsive disorder to be successfully treated. As observed in the cases discussed in the present study, NIDS seems much more likely to occur in patients with psychotic bipolar disorder for whom neuroleptics tend to be more readily prescribed. On the other hand, in the treatment of nonpsychotic bipolar disorder or depression, among neuroleptics, atypical antipsychotics have very often been administered in both labeled and off-labeled use or as augmentation. In recent years, atypical antipsychotics have been appearing one after another as new, better-tolerated agents. These “milder” neuroleptics are more often being administered to patients with bipolar disorder. Psychiatrists, therefore, need to remember and exercise caution concerning NIDS in the pharmacotherapy of bipolar disorder.\n\nNIDS has been considered to be pharmacologically caused by the inhibition of the central dopaminergic reward system; dopamine D2 receptor antagonism of antipsychotics may reduce activation of the system.9 Moreover, the specific sedative effects mediated via its antagonism may cause inactivity, apathy, and indifference, related to some extrapyramidal symptoms.2 Although atypical antipsychotics show a weaker binding to dopamine D2 receptors, recent studies have presented evidence that some potent atypical antipsychotics might well cause NIDS.3,4 In the present study, haloperidol (Case 1), risperidone (Cases 1 and 3), blonanserin (Case 2), and olanzapine (Case 3) were mainly used. Haloperidol is potent typical antipsychotics, and the other agents are described as potent among atypical antip-sychotics, which have dopamine D2 receptor antagonism to a certain degree.\n\nA recent study10 indicated that disease-related deficit status might also occur in patients with bipolar disorder, not only in those with schizophrenia. As long as antipsychotics are clinically used, whether typical or atypical, the recognition and differentiation of deficit status is needed for the treatment of bipolar disorder as well as schizophrenia. When taking this problem into consideration, it is clear that NIDS is becoming an increasingly important issue in pharmacotherapy. The authors believe that its concept should be reappraised in current clinical psychiatry.\n\nDisclosure\n\nThe abstract of this paper was presented at the 13th International Forum on Mood and Anxiety Disorders as a poster presentation with interim findings. The poster’s abstract was published in “Poster Abstracts” in International Journal of Psychiatry in Clinical Practice.\n\nSatoshi Ueda received an honorarium from Meiji Seika Pharma Co., Ltd. The authors report no other conflicts of interest in this work.\n\nTable 1 Clinical profile\n\nCase\tSex/age (years)\tAP associated with NIDS (mg)\tTime to recover from NIDS\tPharmacotherapy after NIDS (mg)\t\n1\tM/50\tHPD 9, RIS 12\t2 years\tLi 800, VPA 1000\t\n2\tF/49\tBNS 12\t10 months\tLi 800, QTP 200\t\n3\tM/52\tOLZ 10–20/QTP 500, LPZ 150, APZ 12\t6 years\tMTZ 45, QTP 200\t\nAbbreviations: AP, antipsychotics; NIDS, neuroleptic-induced deficit syndrome; HPD, haloperidol; RIS, risperidone; Li, lithium carbonate; VPA, valproate; BNS, blonanserin; QTP, quetiapine; OLZ, olanzapine; LPZ, levomepromazine; APZ, aripiprazole; MTZ, mirtazapine; M, male; F, female.\n==== Refs\nReferences\n1 Lader M Neuroleptic-induced deficit syndrome: old problem, new challenge J Psychopharmacol 1993 7 4 392 393 22291004 \n2 Lewander T Neuroleptic and the neuroleptic-induced deficit syndrome Acta Psychiatr Scand Suppl 1994 380 8 13 7914056 \n3 Artaloytia JF Arango C Lahti A Negative signs and symptoms secondary to antipsychotics: a double-blind, randomized trial of a single dose of placebo, haloperidol, and risperidone in healthy volunteers Am J Psychiatry 2006 163 3 488 493 16513871 \n4 Park CH Park TW Yang JC No negative symptoms in healthy volunteers after single doses of amisulpride, aripiprazole, and haloperidol: a double-blind placebo-controlled trial Int Clin Psychopharmacol 2012 27 2 114 120 22241281 \n5 Machida N Shiotsuka S Semba J A case of obsessive-compulsive disorder associated with neuroleptic-induced deficit syndrome (NIDS): successfully treated by discontinuation of neuroleptics followed by SSRI Seishin Shinkeigaku Zasshi 2005 107 7 667 673 Japanese 16146185 \n6 Mankad MV Beyer JL Weiner RD Krystal AD Clinical Manual of Electroconvulsive Therapy Washington, DC American Psychiatric Publishing Inc 2010 \n7 Swartz CM Shorter E Psychotic Depression Cambridge, UK Cambridge University Press 2007 \n8 Gervin M Browne S Garavan J Roe M Larkin C O’Callanghan E Dysphoric subjective response to neuroleptics in schizophrenia; relationship to extrapyramidal side effects and symptomatology Eur Psychiatry 1999 14 7 405 409 10683626 \n9 Karamatskos E Mulert C Lambert M Naber D Subjective well-being of patients with schizophrenia as a target of drug treatment Curr Pharm Biotechnol 2012 13 8 1490 1499 22283757 \n10 Nio S Suzuki T Uchida H Watanabe K Mimura M Deficit status in bipolar disorder: investigation on prevalence rate and description of seven cases J Affect Dis 2012 143 1–3 248 252 22840466\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1176-6328",
"issue": "12()",
"journal": "Neuropsychiatric disease and treatment",
"keywords": "atypical antipsychotics; bipolar disorder; electroconvulsive therapy; neuroleptic-induced deficit syndrome (NIDS); psychosis",
"medline_ta": "Neuropsychiatr Dis Treat",
"mesh_terms": null,
"nlm_unique_id": "101240304",
"other_id": null,
"pages": "265-8",
"pmc": null,
"pmid": "26893564",
"pubdate": "2016",
"publication_types": "D016428:Journal Article",
"references": "22283757;7914056;10683626;16146185;22241281;16513871;22840466;22291004",
"title": "Neuroleptic-induced deficit syndrome in bipolar disorder with psychosis.",
"title_normalized": "neuroleptic induced deficit syndrome in bipolar disorder with psychosis"
} | [
{
"companynumb": "JP-ALEMBIC PHARMACUETICALS LIMITED-2016SCAL000177",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "MIRTAZAPINE"
},
"dru... |
{
"abstract": "Rivaroxaban is a newer anticoagulant initially approved by the Food and Drug Administration to treat nonvalvular atrial fibrillation. Rivaroxaban has several characteristics that are more favorable than warfarin. One of the characteristics is decreased risk of hemorrhage. We report one of the first case reports of severe intracranial hemorrhage associated with rivaroxaban in an elderly patient with decreased renal function. We aim to alert emergency medicine providers regarding the likelihood of encountering these patient as newer anticoagulants rise in popularity.",
"affiliations": "Loma Linda University, Department of Emergency Medicine, Loma Linda, California.;University of California San Francisco, Department of Laboratory Medicine, San Francisco, California.",
"authors": "Lo|Jean Chin-Yu|JC|;Gerona|Roy R|RR|",
"chemical_list": "D065427:Factor Xa Inhibitors; D009025:Morpholines; D013876:Thiophenes; D000069552:Rivaroxaban",
"country": "United States",
"delete": false,
"doi": "10.5811/westjem.2014.2.19440",
"fulltext": "\n==== Front\nWest J Emerg MedWest J Emerg MedWestJEMWestern Journal of Emergency Medicine1936-900X1936-9018Department of Emergency Medicine, University of California, Irvine School of Medicine 2503573610.5811/westjem.2014.2.19440wjem-15-375Diagnostic AcumenCase ReportA Case of Rivaroxaban Associated Intracranial Hemorrhage Lo Jean Chin-Yu MD*Gerona Roy R. PhD†* Loma Linda University, Department of Emergency Medicine, Loma Linda, California† University of California San Francisco, Department of Laboratory Medicine, San Francisco, CaliforniaAddress for Correspondence: Jean Chin-Yu Lo, Loma Linda University, Department of Emergency Medicine, 11234 Anderson Street, Loma Linda, CA 92354. Email: jeanloem@hotmail.comSupervising Section Editor: Rick A. McPheeters, DO\n\n7 2014 15 4 375 377 30 8 2013 10 2 2014 14 2 2014 Copyright © 2014 the authors.2014This is an open access article distributed in accordance with the terms of the Creative Commons\nAttribution (CC BY 4.0) License. See: http://creativecommons.org/licenses/by-nc/4.0/.Rivaroxaban is a newer anticoagulant initially approved by the Food and Drug Administration to treat nonvalvular atrial fibrillation. Rivaroxaban has several characteristics that are more favorable than warfarin. One of the characteristics is decreased risk of hemorrhage. We report one of the first case reports of severe intracranial hemorrhage associated with rivaroxaban in an elderly patient with decreased renal function. We aim to alert emergency medicine providers regarding the likelihood of encountering these patient as newer anticoagulants rise in popularity.\n==== Body\nINTRODUCTION\nRivaroxaban (Xarelto) is an oral factor Xa inhibitor that has been approved by the Food and Drug Administration (FDA) in 2010 to treat nonvalvular atrial fibrillation. New anticoagulants emerge as warfarin requires frequent monitoring, and has multiple drug and food interaction. Rivaroxaban was developed with the goal of predictable pharmacokinetics that eliminates the need for monitoring the international normalized ratio.1–5 Several characteristics have made rivaroxaban an attractive alternative to warfarin; once daily dosing, obviate the need for monitoring the international normalized ratio, noninferiority to warfarin in treating atrial fibrillation, and decreased risk of bleeding in comparison to warfarin.6 Although the risk of bleeding is decreased in comparison, the risk remains. We believe this is the first case report of intracranial hemorrhage secondary to rivaroxaban use.\n\nCASE REPORT\nCJ is a 92-year-old man with a past medical history of atrial fibrillation and ischemic stroke five months prior to emergency department (ED) presentation. He presented to the ED with left upper extremity and left lower extremity weakness, left facial droop and slurred speech. His initial vital signs in the ED at 9:38AM were temperature 97.4°Fahrenheit, blood pressure 175/59 mmHg, heart rate 111 beats per minutes, respiratory rate 28 times per minutes, oxygen saturation 97% on room air. On physical exam the patient was alert and followed commands intermittently, extraocular movement was intact bilaterally, pupils were equal and reactive bilaterally. Cranial nerve exam revealed left facial droop. Strength exam were 5/5 in right upper extremity and right lower extremities and 1/5 in left upper extremity and left lower extremity. Patient was transported to computed tomography (CT) immediately. CT head revealed an acute 6.7 cm × 5.3 cm right parasylvian and right basal ganglia hemorrhage with surrounding edema, as well as 7 mm leftward midline shift at the level of the septum pellucidum. When the patient returned from CT, his eyes deviated to the right side. Fosphenytoin was initiated for likely seizure. His blood pressure was elevated to 230/100 mmHg. Labetalol 20 mg was administered intravenously with improvement of blood pressure. The patient became progressively lethargic while in the emergency department. He was intubated under rapid sequence intubation at 10:20AM. Since the patient was on rivaroxaban, the plan was to administer prothrombin complex concentrate (PCC). However, PCC was not available at the facility. Two units of fresh frozen plasma were administered intravenously at 10:58AM.\n\nLaboratory result revealed white blood cell 12.93 bil/L, hemoglobin 11.3 g/dL, hematocrit 33.4%, platelet 135 bil/L, sodium 137 mMol/L, potassium 4.2 mMol/L, chloride 101 mMol/L, CO2 22 mMol/L, BUN 30 mg/dL, creatinine 1.3 mg/dL, protime 11.3 seconds, INR 1.1 IU, PTT 23.8 seconds, plasma rivaroxaban level 95 ng/mL. Neurosurgery service was consulted, and recommended no surgical intervention at this time. The patient was admitted to the intensive care unit (ICU). Two days after ICU admission, the family withdrew care.\n\nAccording to the patient’s family members, the patient was on warfarin for many years. However, due to warfarin’s interaction with food and frequent need for clinic visits to assess patient’s coagulation panel, the patient’s physician switched him to dabagatrin nine months prior to this ED presentation. The patient had difficulty swallowing the dabagatrin’s capsule, so his physician switched him to rivaroxaban four months prior to the ED presentation.\n\nDISCUSSION\nRivaroxaban (Xarelto) is a new anticoagulant that was approved by the FDA in 2011 for stroke and systemic embolism prophylaxis in patients with nonvalvular atrial fibrillation. Rivaroxaban is also indicated for treatment and prevention of pulmonary embolism and deep vein thrombosis.7,8 The Factor Xa inhibitor is a major new anticoagulant drug class that emerged as warfarin requires frequent monitoring, and has multiple drug and food interaction. Rivaroxaban was developed with the goal of predictable pharmacokinetics that eliminates the need for monitoring the international normalized ratio.1,2,3,4,5 Several characteristics have made rivaroxaban an attractive alternative to warfarin; once daily dosing, obviate the need for monitoring the international normalized ratio, noninferiority to warfarin for preventing stroke in patients with atrial fibrillation, lower risk of intracranial hemorrhage compared with warfarin.6\n\nRivaroxaban inhibits factor Xa activity and prolonging plasma clotting time.2 Traditional coagulation studies do not determine the degree of anticoagulation of rivaroxaban.9 Methods that measure the degree of anticoagulation of rivaroxaban include tissue factor-activated clotting time.10 In overdose situations, rivaroxaban does increase INR. Study by Mueck et al reveals that rivaroxaban plasma concentrations and prothrombin time (PT) correlates with a linear model.11 APTT prolongation also occurs in dose-dependent fashion.12 The coagulation panel was within normal limit in our patient. Furthermore, the measured rivaroxaban level was 95 ng/mL, (the range of level of 0–666 ng/ml was found in patients on therapeutic dose of rivaroxaban by van Veen).13 The level was measured from the first set of blood that was drawn when the patient presented to the ED. The rivaroxaban level was measured by time of flight (TOF) at the University of California, San Francisco laboratory several weeks subsequent to the event. The intracranial hemorrhage in this patient is most likely associated with therapeutic dosing.\n\nAlthough the study lead by Patel6 revealed statistically significant reduction in intracranial hemorrhage with rivaroxaban versus warfarin (0.5% vs. 0.7%, p=0.02), some characteristics of rivaroxaban may prevent its wide application. In the EINSTEIN DVT, PE, and Extension clinical studies, both thrombotic and bleeding event rates were higher in patients over the age of 65 than in those under the age of 65.7 Furthermore, rivaroxaban is not recommended in patient with decreased creatinine clearance as drug exposure is increased, and the risk of bleeding is elevated.14–16 Rivaroxaban is also contraindicated in patients with hepatic disease associated with coagulopathy.17 In addition, rivaroxaban is associated with increased risk of gastrointestinal bleeding compare to warfarin.18 Our patient was 92 years old with mild renal dysfunction. The recommended dose of rivaroxaban per package insert is 20 mg once daily for CrCl >50 mL/min, and 15 mg once daily for patient with CrCl 15 to 50 mL/min (Table 1). The patient’s CrCl was 46.15 mL/min. Therefore, his recommended daily dose of rivaroxaban was 15 mg once daily. According to his family member, the patient was compliant with his medications. Therefore, rivaroxaban may not be the optimal choice of anticoagulant for him.\n\nAccording to ISMP (Institute for Safe Medication Practices), rivaroxaban was associated with 356 adverse event in the first quarter of 2012. Of those, 158 cases were associated with serious thrombus, ie pulmonary embolism. One hundred and twenty one cases were associated with hemorrhage. Possible suboptimal anticoagulation due to the predominance of thromboembolic event, in additional to the risk of bleeding, should be balanced against the favorable characteristics of rivaroxaban in patients who plan to use this newer anticoagulant.\n\nEmergency medicine (EM) clinicians are more likely to care for these patients as newer anticoagulants rise in popularity. Recommended reversal agents for rivaroxaban associated hemorrhage are included in Table 2 for EM providers.\n\nCONCLUSION\nRivaroxaban is a newer anticoagulant that has several advantages to traditional anticoagulants. However, adverse effect does occur rarely. We report the first case report documenting intracranial hemorrhage associated with rivaroxaban. Caution should be used in selective patient populations, such as elder’s and patients with hepatic or renal dysfunction.\n\nFull text available through open access at http://escholarship.org/uc/uciem_westjem\n\nConflicts of Interest: By the WestJEM 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\nTable 1 Recommended dose of rivaroxaban per package insert.\n\nRecommended dose of rivaroxaban\tRenal function for recommended dose\t\n20 mg once daily\tCrCl >50 mL/min\t\n15 mg once daily\tCrCl 15 to 50 mL/min\t\nTable 2 Recommended reversal agents for hemorrhage associated with rivaroxaban.\n\nRecommended reversal agents\t\nProthrombin complex concentrate (PCC)\t\nFactor VIII\t\nFactor eight inhibitor bypass activity (FEIBA)\t\nFresh frozen plasma (FFP)\n==== Refs\nREFERENCES\n1 Kubitza D Becka M Voith B Safety, pharmacodynamics, and pharmacokinetics of single doses of BAY 59-7939, an oral, direct factor Xa inhibitor Clin Pharmacol Ther 2005 78 412 421 16198660 \n2 Perzborn E Roehrig S Straub A Rivaroxaban: A New Oral Factor Xa Inhibitor Arterioscler Thromb Vasc Bio 2010 30 376 381 20139357 \n3 Winstanley L Chen R New thrombin and factor Xa inhibitors for primary and secondary prevention of ischaemic stroke CNS Neurol Disord Drug Targets 2013 12 242 251 23394539 \n4 Kakar P Watson T Lip GY Rivaroxaban Drugs Today (Barc) 2007 43 129 136 17380210 \n5 Turpie AG New oral anticoagulants in atrial fibrillation Eur Heart J 2008 29 155 165 18096568 \n6 Patel MR Mahaffey KW Garg J Rivaroxaban versus warfarin in nonvalvular atrial fibrillation N Engl J Med 2011 365 883 891 21830957 \n7 EINSTEIN Investigators Bauersachs R Berkowitz SD Oral rivaroxaban for symptomatic venous thromboembolism N Engl J Med 2010 363 2499 2510 21128814 \n8 Prandoni P Anticoagulant treatment of pulmonary embolism: impact and implications of the EINSTEIN PE study Eur J Haematol 2012 89 281 287 22834998 \n9 Brem E Koyfman A Foran M Review of recently approved alternatives to anticoagulation with warfarin for emergency clinicians J Emerg Med 2013 45 143 149 23375217 \n10 Körber MK Langer E Ziemer S Measurement and Reversal of Prophylactic and Therapeutic Peak Levels of Rivaroxaban: An In Vitro Study Clin Appl Thromb Hemost 2013 7 5 [Epub ahead of print] \n11 Mueck W Becka M Kubitza D Population model of the pharmacokinetics and pharmacodynamics of rivaroxaban--an oral, direct factor Xa inhibitor--in healthy subjects Int J Clin Pharmacol Ther 2007 45 335 344 17595891 \n12 Helin TA Pakkanen A Lassila R Laboratory Assessment of Novel Oral Anticoagulants: Method Suitability and Variability Between Coagulation Laboratories Clin Chem 2013 59 807 814 23378569 \n13 van Veen J Smith J Kitchen S Normal prothrombin time in the presence of therapeutic levels of rivaroxaban Br J Haematol 2013 160 859 861 23278675 \n14 Kubitza D Becka M Mueck W Effects of renal impairment on the pharmacokinetics, pharmacodynamics and safety of rivaroxaban, an oral, direct Factor Xa inhibitor Br J Clin Pharmacol 2010 70 703 712 21039764 \n15 Hori M Matsumoto M Tanahashi N Safety and efficacy of adjusted dose of rivaroxaban in Japanese patients with non-valvular atrial fibrillation-subanalysis of J-ROCKET AF for patients with moderate renal impairment Circ J 2013 77 632 638 23229461 \n16 Samama MM Use of low-molecular-weight heparins and new anticoagulants in elderly patients with renal impairment Drugs Aging 2011 28 177 193 21329400 \n17 Graff J Harder S Anticoagulant Therapy with the Oral Direct Factor Xa Inhibitors Rivaroxaban, Apixaban and Edoxaban and the Thrombin Inhibitor Dabigatran Etexilate in Patients with Hepatic Impairment Clin Pharmacokinet 2013 52 243 254 23389892 \n18 Alberts MJ Eikelboom JW Hankey GJ Antithrombotic therapy for stroke prevention in non-valvular atrial fibrillation Lancet Neurol 2012 11 1066 1081 23153406\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1936-900X",
"issue": "15(4)",
"journal": "The western journal of emergency medicine",
"keywords": null,
"medline_ta": "West J Emerg Med",
"mesh_terms": "D000369:Aged, 80 and over; D001281:Atrial Fibrillation; D065427:Factor Xa Inhibitors; D017809:Fatal Outcome; D006801:Humans; D020300:Intracranial Hemorrhages; D008297:Male; D009025:Morpholines; D000069552:Rivaroxaban; D020521:Stroke; D013876:Thiophenes",
"nlm_unique_id": "101476450",
"other_id": null,
"pages": "375-7",
"pmc": null,
"pmid": "25035736",
"pubdate": "2014-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "23378569;23394539;21128814;17380210;23229461;18096568;21329400;20139357;23153406;16198660;22834998;23375217;23389892;21039764;21830957;17595891;23832064;23278675",
"title": "A case of rivaroxaban associated intracranial hemorrhage.",
"title_normalized": "a case of rivaroxaban associated intracranial hemorrhage"
} | [
{
"companynumb": "US-JNJFOC-20140803392",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RIVAROXABAN"
},
"drugadditional": null,
... |
{
"abstract": "Sitosterolaemia is a rare, autosomal recessive dyslipidaemia with increased absorption of dietary plant sterol and often presents with hypercholesterolaemia, xanthomas, and haematologic manifestations. If left untreated, sitosterolaemia can lead to high symptomatic burden and coronary artery disease (CAD).\nWe describe a case of a young female who initially presented at 4 years of age with classic manifestations of sitosterolaemia. She was misdiagnosed and treated for both juvenile arthritis and later familial hypercholesterolaemia until adulthood, when venous blood samples showed significantly elevated concentrations of plant sterols. DNA analyses showed that the patient was homozygous for a mutation in the ABCG5 gene, [c.1336C>T, p.(Arg446*)], which is known to be associated with sitosterolaemia.\nSitosterolaemia presents with multiple manifestations, which can initially be misinterpreted leading to prolonged misdiagnosis. Early diagnosis is key in order to relieve symptoms and prevent CAD.",
"affiliations": "Department of Cardiology, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, 8200 Aarhus, Denmark.;Department of Cardiology, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, 8200 Aarhus, Denmark.;Department of Cardiology, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, 8200 Aarhus, Denmark.",
"authors": "Frederiksen|Tanja Charlotte|TC|https://orcid.org/0000-0003-3338-9297;Mortensen|Martin Bødtker|MB|https://orcid.org/0000-0003-2693-4154;Kanstrup|Helle Lynge|HL|https://orcid.org/0000-0002-3693-4871",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1093/ehjcr/ytab188",
"fulltext": "\n==== Front\nEur Heart J Case Rep\nEur Heart J Case Rep\nehjcr\nEuropean Heart Journal: Case Reports\n2514-2119\nOxford University Press\n\n10.1093/ehjcr/ytab188\nytab188\nCase Report\nAcademicSubjects/MED00200\nSeventeen years of misdiagnosis in rare dyslipidaemia: a case report of sitosterolaemia in a young female\nhttps://orcid.org/0000-0003-3338-9297\nFrederiksen Tanja Charlotte\nhttps://orcid.org/0000-0003-2693-4154\nMortensen Martin Bødtker\nhttps://orcid.org/0000-0002-3693-4871\nKanstrup Helle Lynge\nDepartment of Cardiology, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, 8200 Aarhus, Denmark\nSia Ching-Hui Handling Editor\nGiampatzis Vasilios Editor\nMancusi Constantino Editor\nTardo Daniel Editor\nJakstaite Aiste Monika Editor\nCorresponding author. Tel: +45 60147406, Email: tanja_charlotte@clin.au.dk\n5 2021\n19 5 2021\n19 5 2021\n5 5 ytab18801 12 2020\n23 12 2020\n16 4 2021\n© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.\n2021\nhttps://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com\n\nAbstract\n\nBackground \n\nSitosterolaemia is a rare, autosomal recessive dyslipidaemia with increased absorption of dietary plant sterol and often presents with hypercholesterolaemia, xanthomas, and haematologic manifestations. If left untreated, sitosterolaemia can lead to high symptomatic burden and coronary artery disease (CAD).\n\nCase summary \n\nWe describe a case of a young female who initially presented at 4 years of age with classic manifestations of sitosterolaemia. She was misdiagnosed and treated for both juvenile arthritis and later familial hypercholesterolaemia until adulthood, when venous blood samples showed significantly elevated concentrations of plant sterols. DNA analyses showed that the patient was homozygous for a mutation in the ABCG5 gene, [c.1336C>T, p.(Arg446*)], which is known to be associated with sitosterolaemia.\n\nDiscussion \n\nSitosterolaemia presents with multiple manifestations, which can initially be misinterpreted leading to prolonged misdiagnosis. Early diagnosis is key in order to relieve symptoms and prevent CAD.\n\nDyslipidaemias\nGenetics\nHypercholesterolaemia\nCase report\nSitosterolaemia\n==== Body\nFor the podcast associated with this article, please visit https://academic.oup.com/ehjcr/pages/podcast\n\nLearning points\n\nSitosterolaemia is a rare dyslipidaemia that often presents with hypercholesterolaemia, xanthomas, and haematological disorders.\n\nSitosterolaemia is an autosomal recessive disorder, thus parental consanguinity increases the risk significantly.\n\nSitosterolaemia should be considered in hypercholesterolemic patients with poor effect of statin treatment, normocholesterolemic xanthomas, great effect of dietary changes on cholesterol levels and xanthomas, or unexplained haemolytic anaemia and macrothrombocytopenia.\n\nEzetimibe and a diet low in plant sterols are recommended treatments of sitosterolaemia, and compliance to treatment is essential to reduce cholesterol levels.\n\nIntroduction\n\nSitosterolaemia is a rare, autosomal recessive dyslipidaemia. Patients often present with hypercholesterolaemia, xanthomas, and haematologic manifestations.1 Current guidelines recommend testing for familial hypercholesterolaemia (FH) in children with a family history of elevated low-density lipoprotein (LDL) cholesterol, premature coronary artery disease (CAD), and/or positive genetic testing,2 but there are no guideline recommendations on diagnostic evaluation of sitosterolaemia. There are no clinical trial data on management of sitosterolaemia, but a diet low in plant sterols and treatment with Ezetimibe are recommended.3 However, recommendations are based on low level of evidence.4,5 This report describes a young female with symptoms of sitosterolaemia, who was misdiagnosed during her childhood leading to a high symptomatic burden.\n\nTimeline\n\nDate\tMedical information, treatment, or investigation\t\n1999\tPatient born\t\n2003–2008\tSeveral tumours related to joints surgically removed\t\n2008\tPathological examination of joint-related tumour interpreted as granulomatous inflammation\t\n2008\tDiagnosis of juvenile idiopathic arthritis. Treatment with methotrexate initiated\t\n2009\tProgression of joint pain\t\n2009\tBlood cholesterol measurement for the first time. Total cholesterol, high-density lipoprotein (HDL), and low-density lipoprotein (LDL) cholesterol all significantly increased\t\n2009\tPrevious biopsy from tumour was revised and found compatible with xanthoma\t\n2009\tGenetic testing negative for any known mutations in the LDL receptor and apolipoprotein B genes\t\n2009\tDiagnosis of familial hypercholesterolaemia. Initiation of treatment with Simvastatin 10 mg/day. No significant response\t\n2010\tSimvastatin increased to 20 mg/day with no significant response\t\n2012\tChange to Atorvastatin 80 mg/day\t\n2012\tPatient admitted to the hospital with acute liver failure. Ultrasound of the abdomen revealed an enlarged spleen. Side effects to the statin treatment was suspected and treatment was discontinued\t\n2012\tTreatment with Ezetimibe 10 mg/day initiated\t\n2019\tPatient referred to the haematology department with prolonged thrombocytopenia and reticulocytosis. Folic acid treatment for 3 months was initiated\t\n2019\tPatient referred to our department wishing to discontinue Ezetimibe. Total cholesterol was 6.1 mmol/L (236 mg/dL), HDL 2.2 mmol/L (85 mg/dL), and LDL was 2.8 mmol/L (108 mg/dL)\t\n2019\tVenous blood samples with significantly elevated concentrations of plant sterols, campesterole, and sitosterole\t\n2019\tDNA analyses. Patient homozygous for a mutation in the ABCG5 gene, [c.1336C>T, p.(Arg446*)], known to be associated with sitosterolaemia\t\n2019\tEzetimibe 10 mg/day continued and dietary consulting initiated\t\n2020\tOne-year follow-up. Increased total cholesterol and LDL. Patient admitted being inconsistent with treatment and diet\t\n\nCase presentation\n\nA 21-year-old woman was referred to the cardiology department by her general practitioner. Ten years prior she had been diagnosed with FH and was taking Ezetimibe 10 mg once a day. Her total cholesterol was 6.1 mmol/L (236 mg/dL), high-density lipoprotein (HDL) cholesterol was 2.2 mmol/L (85 mg/dL), and LDL cholesterol was 2.8 mmol/L (108 mg/dL). The patient wished to discontinue the medication. When she came to the outpatient clinic, she had not taken her Ezetimibe for 2 weeks. Her total cholesterol increased to 7.0 mmol/L (271 mg/dL) and LDL 4.0 mmol/L (155 mg/dL). The patient was a never smoker and had a normal body mass index. Her blood pressure was normal, and she had no signs of diabetes [haemoglobin A1c 23 mmol/mol (4.3%)]. Clinical examination revealed a xanthoma on the left hand (Figure 1). She had no complaints of chest pain or shortness of breath.\n\nFigure 1 Xanthoma on third finger. At her first visit in the outpatient clinic, the patient presented with a xanthoma on the left hand.\n\nAt age 4, the patient presented with an excrescence at the intergluteal cleft, which was surgically removed. At same age, she was admitted to the hospital with the suspicion of reactive arthritis. From age 4 to 10 years, she often had complaints of joint pain and presented with several joint-related tumours, some of which were surgically removed. One was sent for pathological examination and interpreted as granulomatous inflammation. She was then diagnosed with juvenile idiopathic arthritis at age 10 and treated with methotrexate for 1.5 years. Despite the treatment, her symptoms progressed. At that time, her blood cholesterol was measured for the first time. Total cholesterol was 9.8 mmol/L (379 mg/dL), HDL 7.8 mmol/L (302 mg/dL), and LDL 7.6 mmol/L (294 mg/dL). The previous biopsy was revised and found compatible with a xanthoma. She was diagnosed with clinical FH and had genetic testing done, which was negative for any known mutations in the LDL receptor and apolipoprotein B genes. Her parents were cousins and neither of them had hypercholesterolaemia. Her mother’s father suffered from stroke at age 58 and had a coronary artery bypass at age 65. His brother had acute myocardial infarction at 50 years of age. The patient’s brother was apparently healthy (Figure 2). When she was diagnosed with FH, she changed her diet, which had some effect on her cholesterol levels and symptoms. Furthermore, she was started on Simvastatin 10 mg/day, which had little effect despite a later increase in dose to 20 mg/day and consequently a change to Atorvastatin 80 mg/day. Shortly after, she was admitted to the hospital with nausea and vomiting. She was icteric and had impaired liver function with alanine transaminase of ∼1600 U/L. Ultrasound of the abdomen revealed an enlarged spleen (length of 13.7 cm). Side effects to the statin treatment were suspected and the treatment was discontinued. After the hospitalization, treatment with Ezetimibe 10 mg/day was initiated. Eventually, her liver function normalized completely.\n\nFigure 2 Pedigree. The patient was the only family member with sitosterolaemia, which is an autosomal recessive disorder. Her parents were cousins. Consanguinity is indicated by a double line. Males are represented by squares and females by circles. A clear symbol shows an unaffected individual, while a black symbol shows an affected individual. Deceased individuals are presented with a diagonal line. The arrow shows the proband. AMI, acute myocardial infarction; CABG, coronary artery bypass grafting.\n\nAfter 5 years of mild thrombocytopenia on routine blood samples, the patient was referred to the haematology department with a platelet count of 139 × 109/L and reticulocytosis (reticulocyte count of 114 × 109/L). She had no symptoms of haematological disorders. On clinical examination there was no lymphadenopathy. Haemoglobin was normal (8.4 mmol/L), haptoglobin was slightly decreased (0.30 g/L), free haemoglobin was mildly increased (4 µmol/L), and direct antiglobulin test was negative. The cause of thrombocytopenia was not identified, and the patient was prescribed a folic acid treatment for 3 months, which had no effect on her platelet count (122 × 109/L after treatment).\n\nAt the cardiology outpatient clinic, blood samples were analysed for concentrations of plant sterols, campesterole, and sitosterole using a gas chromatographic/mass spectrometric method.6 The concentration of campesterole was 170 μg/mL and sitosterole was 270 μg/mL. Normal values for both are <15 μg/mL.\n\nDNA analyses showed that the patient was homozygous for a mutation in the ABCG5 gene [c.1336C>T, p.(Arg446*)], which is known to be associated with sitosterolaemia.7\n\nThe patient was referred to a dietary consultant and Ezetimibe 10 mg/day was again prescribed.\n\nAt the most recent follow-up, ∼15 months after diagnosis, the patient had a total cholesterol level of 6.4 mmol/L (248 mg/dL) and LDL 4.0 mmol/L (155 mg/dL). The patient admitted being inconsistent with the medical therapy and having difficulties with diet adherence.\n\nDiscussion\n\nThis case report describes a 21-year-old female with manifestations of sitosterolaemia, including increased levels of total cholesterol, LDL and plant sterols, xanthomas, and thrombocytopenia. The patient was misdiagnosed with juvenile idiopathic arthritis and later FH until adulthood, when she was finally diagnosed with sitosterolaemia.\n\nSitosterolaemia is an autosomal recessive disorder characterized by increased plasma levels of plant sterols. It is associated with a mutation in either the ABCG5 or ABCG8 gene both encoding proteins, which help transport sterols to intestinal lumen or into bile.7 This results in increased intestinal absorption and decreased biliary excretion of plant sterols leading to extreme plasma levels.1 Patients often present with increased levels of total and LDL cholesterol, since cholesterol absorption can be increased as well.1 However, cholesterol levels can be normal, as in the first cases of sitosterolaemia described in 1974.8\n\nDifferential diagnoses are other rare dyslipidaemias such as heterozygous FH, homozygous FH, autosomal recessive hypercholesterolaemia (LDLRAP1 mutations), lysosomal acid lipase deficiency, and cerebrotendinous xanthomatosis.\n\nThe major clinical manifestation of sitosterolaemia is xanthomas,9 often tendinous or tuberous xanthomas formed on the extensor areas. However, intertriginous xanthomas have also been described.10 Another known manifestation of sitosterolaemia is haemolytic anaemia and macrothrombocytopenia.1 In several cases of sitosterolaemia, splenomegaly was present, sometimes leading to splenectomy.11 In our case, the patient had acute liver dysfunction, which has previously been described in sitosterolaemia.12\n\nPremature CAD has been described in young patients with sitosterolaemia, both in patients with hypercholesterolaemia13 but also in normocholesterolemic patients.14 However, there is no evidence regarding causality between sitosterolaemia and cardiovascular disease (CVD). A report of five sitosterolaemia patients with hypercholesterolaemia showed no signs of clinical or subclinical CVD and the authors suggested that premature CVD in sitosterolaemia is independent of circulating plant sterols.15\n\nNon-invasive imaging techniques such as detection of coronary artery calcification with computed tomography and assessment of carotid or femoral plaque burden have been proven to predict cardiovascular events beyond traditional risk factors in asymptomatic individuals.16,17 Guidelines suggest that such imaging techniques may be used in low- or moderate-risk patients in order to guide treatment strategy.2 However, the benefits of screening asymptomatic patients, already receiving pharmacological treatment, are somewhat unclear. A possible benefit could be motivation to medication and lifestyle adherence, while there are some disadvantages such as radiation hazards and lack of long-term reassurance even if imaging shows no signs of atherosclerosis, especially in young individuals. In our case, we chose not to screen the patient with non-invasive imaging techniques since the results would most likely have no consequences for the current management.\n\nIndications for plant sterol measurement in clinical practice could be hypercholesterolaemia with poor effect of statin treatment, normocholesterolemic xanthomas, unexpected effect of dietary changes, or unexplained haemolytic anaemia and macrothrombocytopenia.1\n\nHyperlipidaemia in sitosterolaemia responds well to reduction in dietary sterol intake,9 while there is often a poor response to statin treatment.1 The lack of improvement on statin treatment could have been a diagnostic clue in our case. Ezetimibe has been shown to reduce levels of total cholesterol and plant sterols in sitosterolaemia.3 In some cases, treatment with Ezetimibe has significantly reduced xanthomas4 and improved platelet count.3 Thus, early initiation of treatment and compliance seem important in order to reduce symptoms and prevent CVD.\n\nConclusion\n\nSitosterolaemia is a rare form of dyslipidaemia characterized by increased levels of plant sterols. The condition often presents with hypercholesterolaemia, xanthomas, and haematologic manifestations and can initially be misinterpreted leading to prolonged misdiagnosis. Early diagnosis and prompt treatment with Ezetimibe and reduction in dietary sterol intake are essential to reduce cholesterol levels.\n\nLead author biography\n\nTanja Charlotte Frederiksen is an MD and PhD Student in Cardiology at Aarhus University Hospital. Her interest areas are genetic heart disease, electrophysiology, and personalized medicine.\n\nSupplementary material\n\nSupplementary material is available at European Heart Journal - Case Reports online.\n\nSlide sets: A fully edited slide set detailing this case and suitable for local presentation is available online as Supplementary data.\n\nConsent: The authors confirm that written consent for submission and publication of this case report including images and associated text has been obtained from the patient in line with COPE guidance.\n\nConflict of interest: None declared.\n\nFunding: None declared.\n==== Refs\nReferences\n\n1 Yoo EG. Sitosterolemia: a review and update of pathophysiology, clinical spectrum, diagnosis, and management. Ann Pediatr Endocrinol Metab 2016;21 :7–14.27104173\n2 Mach F , BaigentC, CatapanoAL, KoskinasKC, CasulaM, BadimonL et al ; ESC Scientific Document Group. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk: the Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS). Eur Heart J 2020;41 :111–188.31504418\n3 Othman RA , MyrieSB, MyminD, MerkensLS, RoulletJ-B, SteinerRD et al Ezetimibe reduces plant sterol accumulation and favorably increases platelet count in sitosterolemia. J Pediatr 2015;166 :125–131.25444527\n4 Veit L , Allegri MachadoG, BürerC, SpeerO, HäberleJ. Sitosterolemia-10 years observation in two sisters. JIMD Rep 2019;48 :4–10.31392106\n5 Huang D , ZhouQ, ChaoYQ, ZouCC. Clinical features and genetic analysis of childhood sitosterolemia: two case reports and literature review. Medicine (Baltimore) 2019;98 :e15013.30985648\n6 Acimovic J , Lövgren-SandblomA, MonostoryK, RozmanD, GolicnikM, LutjohannD et al Combined gas chromatographic/mass spectrometric analysis of cholesterol precursors and plant sterols in cultured cells. J Chromatogr B Analyt Technol Biomed Life Sci 2009;877 :2081–2086.\n7 Lu K , LeeMH, HazardS, Brooks-WilsonA, HidakaH, KojimaH et al Two genes that map to the STSL locus cause sitosterolemia: genomic structure and spectrum of mutations involving sterolin-1 and sterolin-2, encoded by ABCG5 and ABCG8, respectively. Am J Hum Genet 2001;69 :278–290.11452359\n8 Bhattacharyya AK , ConnorWE. Beta-sitosterolemia and xanthomatosis. A newly described lipid storage disease in two sisters. J Clin Invest 1974;53 :1033–1043.4360855\n9 Hegele RA , BorénJ, GinsbergHN, ArcaM, AvernaM, BinderCJ et al Rare dyslipidaemias, from phenotype to genotype to management: a European Atherosclerosis Society task force consensus statement. Lancet Diabetes Endocrinol 2020;8 :50–67.31582260\n10 Park JH , ChungIH, KimDH, ChoiMH, GargA, YooEG. Sitosterolemia presenting with severe hypercholesterolemia and intertriginous xanthomas in a breastfed infant: case report and brief review. J Clin Endocrinol Metab 2014;99 :1512–1518.24423340\n11 Wang Z , CaoL, SuY, WangG, WangR, YuZ et al Specific macrothrombocytopenia/hemolytic anemia associated with sitosterolemia. Am J Hematol 2014;89 :320–324.24166850\n12 Bazerbachi F , ConboyEE, MounajjedT, WattKD, Babovic-VuksanovicD, PatelSB et al Cryptogenic cirrhosis and sitosterolemia: a treatable disease if identified but fatal if missed. Ann Hepatol 2017;16 :970–978.29055934\n13 Kwiterovich P , SmithH, ConnorW, BachorikP, McKusickV, TengB et al Hyperapobetalipoproteinaemia in two families with xanthomas and phytosterolaemia. Lancet 1981;317 :466–469.\n14 Kolovou G , VoudrisV, DrogariE, PalatianosG, CokkinosDV. Coronary bypass grafts in a young girl with sitosterolemia. Eur Heart J 1996;17 :965–966.8781841\n15 Hansel B , CarriéA, Brun-DrucN, LeclertG, ChantepieS, CoiffardA-S et al Premature atherosclerosis is not systematic in phytosterolemic patients: severe hypercholesterolemia as a confounding factor in five subjects. Atherosclerosis 2014;234 :162–168.24657386\n16 Sillesen H , SartoriS, SandholtB, BaberU, MehranR, FusterV. Carotid plaque thickness and carotid plaque burden predict future cardiovascular events in asymptomatic adult Americans. Eur Heart J Cardiovasc Imaging 2018;19 :1042–1050.29059296\n17 McClelland RL , JorgensenNW, BudoffM, BlahaMJ, PostWS, KronmalRA et al 10-Year coronary heart disease risk prediction using coronary artery calcium and traditional risk factors: derivation in the MESA (Multi-Ethnic Study of Atherosclerosis) with validation in the HNR (Heinz Nixdorf Recall) study and the DHS (Dallas Heart Study). J Am Coll Cardiol 2015;66 :1643–1653.26449133\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2514-2119",
"issue": "5(5)",
"journal": "European heart journal. Case reports",
"keywords": "Case report; Dyslipidaemias; Genetics; Hypercholesterolaemia; Sitosterolaemia",
"medline_ta": "Eur Heart J Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101730741",
"other_id": null,
"pages": "ytab188",
"pmc": null,
"pmid": "34268478",
"pubdate": "2021-05",
"publication_types": "D002363:Case Reports",
"references": "4360855;11452359;8781841;24166850;24657386;19525158;26449133;27104173;29055934;25444527;30985648;31392106;24423340;6110091;29059296;31504418;31582260",
"title": "Seventeen years of misdiagnosis in rare dyslipidaemia: a case report of sitosterolaemia in a young female.",
"title_normalized": "seventeen years of misdiagnosis in rare dyslipidaemia a case report of sitosterolaemia in a young female"
} | [
{
"companynumb": "DK-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-309125",
"fulfillexpeditecriteria": "1",
"occurcountry": "DK",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ATORVASTATIN CALCIUM"
},
... |
{
"abstract": "BACKGROUND Pasteurella multocida is a gram negative-penicillin sensitive bacterium and is part of normal respiratory microbiota of animals (e.g., cats and dogs) and some birds. Various infections in humans, such as cellulitis, rarely bacteremia, endocarditis, meningitis, and septic arthritis, are a result of domestic cat or dog bites. These infections are rarely seen in an immunocompetent person, without an associated animal bite. CASE REPORT We present a case of refractory Pasteurella multocida bacteremia without any animal bite in an immunocompetent person. CONCLUSIONS Pasteurella multocida bacteremia has been seen in immunocompromised patients and mostly after a cat or dog bite or scratch but might also happen in immunocompetent humans with only pet licking rather than biting, which might increase hospital and emergency department visits or admissions in the future.",
"affiliations": "Department of Medicine, Our Lady of Lourdes Hospital, Binghamton, NY, USA.;Department of Medicine, Our Lady of Lourdes Hospital, Binghamton, NY, USA.",
"authors": "Zarlasht|Fnu|F|;Khan|Muzammil|M|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.12659/ajcr.907251",
"fulltext": "\n==== Front\nAm J Case RepAm J Case RepamjcaserepThe American Journal of Case Reports1941-5923International Scientific Literature, Inc. 2936758510.12659/AJCR.907251907251ArticlesA Case of Recurrent Pasteurella Bacteremia in an Immunocompetent Patient with No Animal Bite Zarlasht Fnu DEFKhan Muzammil EFDepartment of Medicine, Our Lady of Lourdes Hospital, Binghamton, NY, U.S.A.Authors’ Contribution:\n\nA Study Design\n\nB Data Collection\n\nC Statistical Analysis\n\nD Data Interpretation\n\nE Manuscript Preparation\n\nF Literature Search\n\nG Funds Collection\n\nConflict of interest: None declared\n\nCorresponding Author: Fnu Zarlasht, e-mail: linnyc777@yahoo.com2018 25 1 2018 19 95 98 22 9 2017 20 10 2017 © Am J Case Rep, 20182018This work is licensed under Creative Common Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)Patient: Male, 61\n\nFinal Diagnosis: Recurrent pasteurella bacteremia\n\nSymptoms: Ankle pain\n\nMedication: —\n\nClinical Procedure: —\n\nSpecialty: Infectious Diseases\n\nObjective:\nRare disease\n\nBackground:\nPasteurella multocida is a gram negative-penicillin sensitive bacterium and is part of normal respiratory microbiota of animals (e.g., cats and dogs) and some birds. Various infections in humans, such as cellulitis, rarely bacteremia, endocarditis, meningitis, and septic arthritis, are a result of domestic cat or dog bites. These infections are rarely seen in an immunocompetent person, without an associated animal bite.\n\nCase Report:\nWe present a case of refractory Pasteurella multocida bacteremia without any animal bite in an immunocompetent person.\n\nConclusions:\nPasteurella multocida bacteremia has been seen in immunocompromised patients and mostly after a cat or dog bite or scratch but might also happen in immunocompetent humans with only pet licking rather than biting, which might increase hospital and emergency department visits or admissions in the future.\n\nMeSH Keywords:\nBacteremiaPasteurella MultocidaThrombophilia\n==== Body\nBackground\nPasteurella multocida is a gram negative-penicillin sensitive bacterium and is part of normal respiratory microbiota of animals (e.g., cats and dogs) and some birds. Usually systemic infections occur after an animal bite or a scratch. Most of the resulting systemic infections, such as cellulitis, septic arthritis, endocarditis, and meningitis, are observed in immunocompromised patients [1–3]. We present a case of Pasteurella multocida bacteremia in an immunocompetent patient with only cat licking [3].\n\nCase Report\nA 61-year-old male presented due to chief complaint of left foot and ankle swelling and generalized body aches with intermittent chills. The patient had no shortness of breath, chest pain, abdominal pain, urinary symptoms, diarrhea, headaches, runny nose, sore throat, tick bites, or skin rashes. The patient had a healthy cat which licks him, but he had no cat bites or any other bites. The cat’s immunization status was up-to-date as per the patient. This patient had no significant past medical history and his outpatient primary care clinic visits were up-to-date. He was not taking any medications at home.\n\nOn presentation, the patient was not in any acute respiratory distress, but was tachycardiac (heart rate 128 beats/minute), blood pressure 86/53 mm Hg, saturation was 95% on room air and he was afebrile. The patient was alert and oriented to time, place, and person. His cardio-pulmonary and gastrointestinal examination was unremarkable. His left ankle was tender but not erythematous or warm and his left foot was swollen; other extremities were unremarkable. He had good and equal bilateral pulses.\n\nHis laboratory tests revealed white cell count (WBC) of 7.5 K/uL with 10% bandemia, hemoglobin 13.5 gm/dL, and platelets 72 K/mcL. He had acute kidney injury (creatinine 1.41 mg/dL, glomerular filtration rate 51 mL/min/1.73 m2), low potassium at 3.4, and lactic acidosis of 4.1 mmol/L. Red blood cell morphology did not show any schistocytes. Urinalysis was negative for any infections, and only showed high specific gravity of 1.031. Liver function test was positive for mildly deranged AST/ALT at 74/72 U/L and total bilirubin 1.4 mg/dL. Procalcitonin was 29.83 ng/mL.\n\nDuring the next 20 days, his WBC continued to worsen, peaked to 20 K/µL on day 6 then trended down. Hemoglobin remained stable, sepsis-induced thrombocytopenia improved from 72 K/mcL to 262 on day 8. Mild acute kidney injury resolved. Liver function tests initially worsened but then resolved and lactic acidosis also resolved. A detailed follow-up of these tests is shown in Table 1.\n\nA computed topography (CT) chest-abdomen-pelvis did not show any pulmonary consolidations but it showed multiple prominent mesenteric lymph nodes largest measuring 3.8×2.6 cm in central mesentery, which was likely infectious, and their sizes improved upon follow-up repeat CT scan. An ultrasound of the left lower extremity was done, which ruled out deep venous thrombosis on presentation.\n\nBlood cultures were drawn; the patient was started on broad spectrum intravenous antibiotics meropenem (500 mg three times a day), vancomycin (1 gm two times a day) and admitted to the intensive care unit.\n\nOn day 2, magnet resonance imaging (MRI) of his left ankle-foot was done which showed diffuse soft tissue edema and reticulation around the ankle. A trans-thoracic echocardiogram ruled out endocarditis. The patient was sent for arthrocentesis but due to lack of fluid in the ankle joint, a tap was not possible.\n\nHis blood cultures came back positive for Pasteurella multocida for which the intravenous antibiotic meropenem was continued and ciprofloxacin was added for double coverage. Pasteurella multocida cultures showed very good sensitivity to ciprofloxacin, meropenem, and piperacillin-tazobactam.\n\nDue to worsening left lower extremity edema, an ultrasound of the left lower extremity was repeated on day 6, which showed new partially occlusive deep venous thrombus in the left popliteal vein and the left posterior tibial vein, for which he was started on enoxaparin treatment on day 8 once his sepsis-induced thrombocytopenia was resolved.\n\nDuring follow-up, the patient continued to be in the intensive care unit; his mental status remained stable. He started to have purplish discoloration of all finger and toe tips.\n\nExtensive workup for disseminated intravascular coagulation, vasculitis, hypercoagulable syndrome, and autoimmunity was done, which showed moderately positive lupus anticoagulant antibodies, decreased protein-C activity, and positive anti-cardiolipin IgM antibodies; details are shown in Table 2.\n\nThis patient was diagnosed with thrombophilia (causing left lower extremity DVT) secondary to positive anticardiolipin antibodies, moderately positive lupus anticoagulants and low protein-C activity. Due to low-normal complements level, ANA and DsDNA, lupus, vasculitis, connective tissue disease, and rheumatoid arthritis were of low suspicion. Multiple blood cultures were negative prior to discharge.\n\nMultiple sub-specialties were involved in this case, including rheumatologist, vascular surgeon, orthopedic, and infectious disease and it was mutually decided to complete antibiotics for four weeks once blood cultures are negative and to continue anticoagulation for thrombophilia. The patient was discharged to a rehabilitation center after his prolonged hospital stay.\n\nIn the outpatient setting, the patient continued to have digital ulcerations and his right forefoot turned into wet gangrene despite of being on antibiotics.\n\nHe was readmitted for right fore-foot amputation and his blood cultures were sent again. He underwent right fore-foot amputation and his blood cultures came back positive again for Pasteurella multocida. He was started again on intravenous antibiotic piperacillin-tazobactam (3.375 gm three times a day) for recurrent Pasteurella multocida bacteremia. Deep tissue cultures and bone biopsy from the gangrenous, infected toes were sent out and results showed enterococcus group-D and staphylococcus coagulase negative for which he was started on daptomycin intravenously (4 mg/kg every 24 hours) according to culture sensitivity. Further workup showed he had left ankle-knee osteomyelitis for which he underwent below knee amputation. The patient was discharged again to a rehabilitation center.\n\nDuring this whole course of stay, it was not clear why this patient had recurrent Pasteurella bacteremia without any clear source.\n\nDiscussion\nPasteurella multocida infections are usually seen in cat (75%) and dog (50%) bites. Licking of non-intact wounds can also lead to various infections. A literature review showed direct transmission occurs through contact with these animals or indirect transmission through infected blood transfusion, trans-placental or close contact with a colonized person.\n\nThis bacteremia causes a variety of infections like cellulitis, skin abscesses, septic joints, bacteremia, endocarditis, meningitis, and spontaneous bacterial peritonitis in cirrhotic patients [1–4]. Mortality from Pasteurella multocida bacteremia has been documented as 30% [5–7].\n\nUsually these diseases have been documented in immunocompromised patients like patients with active cancer, HIV positive, cirrhotic, chronic kidney diseases, or patients after chemotherapy and radiotherapy [8,9]. In this case, the patient was completely immunocompetent and there was no pet bite.\n\nConclusions\nThe number of domestic animals is increasing day by day in the USA. We should consider this organism as a differential diagnosis not only in immunocompromised patients but in immunocompetent patients as well. This case also shows that this organism can cause diseases not only with pet bites or scratches but also with licking, due to which emergency department visits or hospital admissions will likely increase in the future.\n\nConflicts of interest\n\nNone.\n\nTable 1. Laboratory follow up of the patient during first hospital stay.\n\n\tDay 1\tDay 4\tDay 6\tDay 8\tDay 10\tDay 20\t\nWBC (k/ul)\t7.5\t15.8\t21\t18\t13.8\t9.9\t\nHemoglobin (gm/dl)\t13.5\t13.2\t13.6\t12.1\t10.5\t11.1\t\nPlatelet (k/mcl)\t72\t36\t99\t262\t587\t661\t\nCreatinine/GFR (mg/dl)/(ml/min/1.73 m2)\t1.41/51\t1.03/>60\t–\t–\t–\t0.54/>60\t\nAST (unit/liter)\t74\t223\t93\t71\t62\t\t\nALT (unit/liter)\t72\t167\t82\t69\t89\t\t\nBilirubin (mg/dl)\t1.4\t1.6\t1.2\t0.8\t0.6\t\t\nLactic acid (mmol/L)\t4.1\t2.1\t\t\t\t\t\nTable 2. Rheumatologic Laboratory investigations.\n\nFibrinogen\t744 mg/dl (range 180–440)\t\nProthrombin time\t11.9 sec (range 9–12.5)\t\nActivated partial prothrombin time\t27 sec (24–33)\t\nAnti-thrombin III\t78% (range 76–128)\t\nLupus-anticoagulant\tModerately present\t\nFactor V Leiden\tNegative\t\nHIT antibody\t0.146 (normal <0.399)\t\nComplement C3\t114 mg/dl (range 90–180)\t\nComplement C4\t29 mg/dl (range 10–40)\t\nProtein C activated\t77% (range 83–168)\t\nProtein S Free\t89% (range 74–147)\t\nMethylene tetrahydrafolate reductase(MTHFR c. 1286 A>C)\tNegative\t\nMethylene tetrahydrafolate reductase(MTHFR c. 665 C>T)\tNegative\t\nAntinuclear antibody (ANA)\tNegative\t\nDouble stranded DNA antibody (DsDNA)\tNegative\t\nCardiolipin IgM\t144 MPL (range 0–12)\t\nCardiolipin IgA\t7 APL (range 0–11)\t\nCardiolipin IgG\t22 GPL (range 0–14)\t\nRNP antibody\tNegative\t\nSmith antibody\tNegative\t\nSSA antibody\tNegative\t\nSSB antibody\tNegative\t\nSCL-70 antibody\tNegative\t\nCentromere antibody\tNegative\t\nA phagocyte antibody IgG and IgM\tNormal\t\nIgA total\t455 mg/dl (range 66–436)\t\nIgM total\t51 mg/dl (range 43–279)\t\nIgG total\t921 mg/dl (range 791–1643)\t\nHepatitis C antibody and B core antigen\tNegative\t\nCryoglobulin\tNegative\t\nLyme IgM and immunoblot\tNegative\t\nMalaria smear\tRuled out malaria and babesia\n==== Refs\nReferences:\n1. Narsana N Farhat F Septic shock due to Pasteurella multocida bacteremia: A case report J Med Case Rep 2015 9 159 26163266 \n2. Hendrie J Pasteurella multocida bacteremia in humans: A clinical report Can Fam Physician 1974 20 4 79 81 \n3. Kawashima S Matsukawa N Ueki Y Pasteurella multocida meningitis caused by kissing animals: A case report and review of the literature J Neurol 2010 257 4 653 54 19997925 \n4. Weber DJ Wolfson JS Swartz MN Hooper DC Pasteurella multocida infections: Report of 34 cases and review of the literature Medicine (Baltimore) 1984 63 3 133 54 6371440 \n5. Tseng HK Su SC Liu CP Lee CM Pasteurella multocida bacteremia due to non-bite animal exposure in cirrhotic patients: Report of two cases J Microbiol Immunol Infect 2001 34 293 96 11825011 \n6. O’Neill E Moloney A Hickey M Pasteurella multocida meningitis: Case report and review of the literature J infect 2005 50 4 344 45 15845433 \n7. Bryant BJ Conry-Cantilena C Ahlgren A Pasteurella multocida bacteremia in asymptomatic plateletpheresis donors: A tale of two cats Transfusion 2007 47 11 1984 89 17958526 \n8. Yokose N Dan K Pasteurella multocida sepsis due to a scratch from a pet cat, in a post-chemotherapy neutropenic patient with non-hodgkin lymphoma Int J Hematol 2007 85 2 146 48 17321993 \n9. Randhawa E Woytanowski JR Schultz S Bluen B Pasteurella multocida bacteremia and osteomyelitis from a diabetic foot ulcer American J Med Case Rep 2017 5 8 229 31\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "1941-5923",
"issue": "19()",
"journal": "The American journal of case reports",
"keywords": null,
"medline_ta": "Am J Case Rep",
"mesh_terms": "D000818:Animals; D016470:Bacteremia; D001733:Bites and Stings; D002415:Cats; D006801:Humans; D007121:Immunocompetence; D008297:Male; D008875:Middle Aged; D010326:Pasteurella Infections; D016979:Pasteurella multocida; D057805:Pets",
"nlm_unique_id": "101489566",
"other_id": null,
"pages": "95-98",
"pmc": null,
"pmid": "29367585",
"pubdate": "2018-01-25",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "19997925;6371440;11825011;20469060;26163266;15845433;17321993;17958526",
"title": "A Case of Recurrent Pasteurella Bacteremia in an Immunocompetent Patient with No Animal Bite.",
"title_normalized": "a case of recurrent pasteurella bacteremia in an immunocompetent patient with no animal bite"
} | [
{
"companynumb": "US-009507513-1803USA002499",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "DAPTOMYCIN"
},
"drugadditional": null,
... |
{
"abstract": "An increasing number of patients with medication-related osteonecrosis of the jaws (MRONJ) has recently been reported. It is still being debated whether the presence or placement of dental implants can lead to MRONJ, so the aim of this study was to find out whether dental implants are a risk factor for MRONJ. From January 2003-January 2019 180 patients with MRONJ were seen at the Leiden University Medical Center. Luxating moments for the onset of MRONJ were calculated retrospectively. We collected clinical data and details of antiresorptive medication and found 22 patients with both dental implants and MRONJ. In 18 patients the implants were in the region of the MRONJ and they were included in this study, 14 who had had implants before using antiresorptive drugs and four who had had antiresorptive drugs before or at the time that the implants were placed. The median times between the placement of implants and the diagnosis of MRONJ in these two groups were 24 months and 6 months, respectively. Among the 47 implants, 30 were located in the necrotic region, and all 30 were either lost spontaneously or had to be removed during treatment of MRONJ. Our results show an increased risk for developing MRONJ in patients with dental implants. Both peri-implantitis around previously placed implants, and insertion of dental implants, are risk factors. Prevention of peri-implantitis and caution when inserting dental implants in patients who take antiresorptive medication are therefore important.",
"affiliations": "Department of Oral & Maxillofacial Surgery (Chair: Prof. Dr. JPR van Merkesteyn), Leiden University Medical Center, PO BOX 9600, 2300 RC Leiden, The Netherlands; Center for Bone Quality Leiden, Leiden University Medical Center, PO BOX 9600, 2300 RC Leiden, The Netherlands.;Department of Oral & Maxillofacial Surgery (Chair: Prof. Dr. JPR van Merkesteyn), Leiden University Medical Center, PO BOX 9600, 2300 RC Leiden, The Netherlands.;Department of Biomedical Data Sciences, Leiden University Medical Center, P.O. Box 9512, 2300 RA Leiden, The Netherlands; Mathematical Institute, Leiden University, P.O. Box 9512, 2300 RA Leiden, Leiden The Netherlands.;Department of Internal Medicine, Leiden University Medical Center, PO BOX 9600, 2300 RC Leiden, The Netherlands; Center for Bone Quality Leiden, Leiden University Medical Center, PO BOX 9600, 2300 RC Leiden, The Netherlands.;Department of Oral & Maxillofacial Surgery (Chair: Prof. Dr. JPR van Merkesteyn), Leiden University Medical Center, PO BOX 9600, 2300 RC Leiden, The Netherlands; Center for Bone Quality Leiden, Leiden University Medical Center, PO BOX 9600, 2300 RC Leiden, The Netherlands. Electronic address: j.p.r.van_merkesteyn@lumc.nl.",
"authors": "Pichardo|S E C|SEC|;van der Hee|J G|JG|;Fiocco|M|M|;Appelman-Dijkstra|N M|NM|;van Merkesteyn|J P R|JPR|",
"chemical_list": "D050071:Bone Density Conservation Agents; D015921:Dental Implants; D004164:Diphosphonates",
"country": "Scotland",
"delete": false,
"doi": "10.1016/j.bjoms.2020.03.022",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0266-4356",
"issue": "58(7)",
"journal": "The British journal of oral & maxillofacial surgery",
"keywords": "BRONJ; DRONJ; Dental implants; MRONJ; bisphosphonates; denosumab; osteomyelitis; osteonecrosis; risk factor",
"medline_ta": "Br J Oral Maxillofac Surg",
"mesh_terms": "D059266:Bisphosphonate-Associated Osteonecrosis of the Jaw; D050071:Bone Density Conservation Agents; D015921:Dental Implants; D004164:Diphosphonates; D006801:Humans; D012189:Retrospective Studies; D012307:Risk Factors",
"nlm_unique_id": "8405235",
"other_id": null,
"pages": "771-776",
"pmc": null,
"pmid": "32631756",
"pubdate": "2020-09",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Dental implants as risk factors for patients with medication-related osteonecrosis of the jaws (MRONJ).",
"title_normalized": "dental implants as risk factors for patients with medication related osteonecrosis of the jaws mronj"
} | [
{
"companynumb": "NL-AMGEN-NLDSP2020112755",
"fulfillexpeditecriteria": "2",
"occurcountry": "NL",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "DENOSUMAB"
},
"drugadditional": null,
... |
{
"abstract": "Final data are presented for the ORAL Sequel long-term extension (LTE) study evaluating the safety and efficacy of tofacitinib 5 mg and 10 mg twice daily (BID) for up to 9.5 years in patients with rheumatoid arthritis (RA).\n\n\n\nEligible patients had previously completed a phase 1, 2, or 3 qualifying index study of tofacitinib and received open-label tofacitinib 5 mg or 10 mg BID. Stable background therapy, including csDMARDs, was continued; adjustments to tofacitinib or background therapy were permitted at investigators' discretion. Assignment to dose groups (5 mg or 10 mg BID) was based on patients' average total daily dose. The primary objective was to determine the long-term safety and tolerability of tofacitinib 5 mg and 10 mg BID; the key secondary objective was to evaluate the long-term persistence of efficacy.\n\n\n\nBetween February 5, 2007, and November 30, 2016, 4481 patients were enrolled. Total tofacitinib exposure was 16,291 patient-years. Safety data are reported up to month 114 for all tofacitinib; efficacy data are reported up to month 96 for tofacitinib 5 mg BID and month 72 for 10 mg BID (with low patient numbers limiting interpretation beyond these time points). Overall, 52% of patients discontinued (24% due to adverse events [AEs] and 4% due to insufficient clinical response); the safety profile remained consistent with that observed in prior phase 1, 2, 3, or LTE studies. The incidence rate (IR; number of patients with events per 100 patient-years) for AEs leading to discontinuation was 6.8. For all-cause AEs of special interest, IRs were 3.4 for herpes zoster, 2.4 for serious infections, 0.8 for malignancies excluding non-melanoma skin cancer, 0.4 for major adverse cardiovascular events, and 0.3 for all-cause mortality. Clinically meaningful improvements in the signs and symptoms of RA and physical functioning, which were observed in the index studies, were maintained.\n\n\n\nTofacitinib 5 mg and 10 mg BID demonstrated a consistent safety profile (as monotherapy or combination therapy) and sustained efficacy in this open-label LTE study of patients with RA. Safety data are reported up to 9.5 years, and efficacy data up to 8 years, based on adequate patient numbers to support conclusions.\n\n\n\nNCT00413699 , funded by Pfizer Inc (date of trial registration: December 20, 2006).",
"affiliations": "Rheumatologie Hamburg, Struenseehaus, Hamburg, Germany.;Seoul National University, Seoul, Republic of Korea.;University of Alabama at Birmingham, Birmingham, AL, USA.;Healthpoint Medical Group, Tampa, FL, USA.;Pfizer Inc, Groton, CT, USA.;Pfizer Inc, New York, NY, USA.;Pfizer Inc, New York, NY, USA.;Pfizer Inc, Collegeville, PA, USA.;Pfizer Inc, Capelle aan den Ijssel, Netherlands.;Pfizer Inc, New York, NY, USA.;IQVIA Canada, Montréal, Quebec, Canada.;Pfizer Inc, Groton, CT, USA. Lisy.Wang@pfizer.com.;Metroplex Clinical Research Center and University of Texas Southwestern Medical Center, Dallas, TX, USA.",
"authors": "Wollenhaupt|Jürgen|J|;Lee|Eun-Bong|EB|;Curtis|Jeffrey R|JR|;Silverfield|Joel|J|;Terry|Ketti|K|;Soma|Koshika|K|;Mojcik|Chris|C|;DeMasi|Ryan|R|;Strengholt|Sander|S|;Kwok|Kenneth|K|;Lazariciu|Irina|I|;Wang|Lisy|L|;Cohen|Stanley|S|",
"chemical_list": "D018501:Antirheumatic Agents; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011758:Pyrroles; C479163:tofacitinib",
"country": "England",
"delete": false,
"doi": "10.1186/s13075-019-1866-2",
"fulltext": "\n==== Front\nArthritis Res TherArthritis Res. TherArthritis Research & Therapy1478-63541478-6362BioMed Central London 186610.1186/s13075-019-1866-2Research ArticleSafety and efficacy of tofacitinib for up to 9.5 years in the treatment of rheumatoid arthritis: final results of a global, open-label, long-term extension study Wollenhaupt Jürgen wollenhaupt@rheumatologikum.de 1Lee Eun-Bong leb7616@snu.ac.kr 2Curtis Jeffrey R. jrcurtis@uabmc.edu 3Silverfield Joel agbeard1@aol.com 4Terry Ketti ketti.k.terry@pfizer.com 5Soma Koshika Koshika.Soma@pfizer.com 6Mojcik Chris mojcik@aol.com 6DeMasi Ryan Ryan.DeMasi@pfizer.com 7Strengholt Sander Sander.Strengholt@pfizer.com 8Kwok Kenneth Kenneth.Kwok@pfizer.com 6Lazariciu Irina irina.lazariciu@iqvia.com 9Wang Lisy Lisy.Wang@pfizer.com 5Cohen Stanley arthdoc@aol.com 101 Rheumatologie Hamburg, Struenseehaus, Hamburg, Germany 2 0000 0004 0470 5905grid.31501.36Seoul National University, Seoul, Republic of Korea 3 0000000106344187grid.265892.2University of Alabama at Birmingham, Birmingham, AL USA 4 Healthpoint Medical Group, Tampa, FL USA 5 0000 0000 8800 7493grid.410513.2Pfizer Inc, Groton, CT USA 6 0000 0000 8800 7493grid.410513.2Pfizer Inc, New York, NY USA 7 0000 0000 8800 7493grid.410513.2Pfizer Inc, Collegeville, PA USA 8 grid.487416.8Pfizer Inc, Capelle aan den Ijssel, Netherlands 9 IQVIA Canada, Montréal, Quebec Canada 10 0000 0000 9482 7121grid.267313.2Metroplex Clinical Research Center and University of Texas Southwestern Medical Center, Dallas, TX USA 5 4 2019 5 4 2019 2019 21 898 6 2018 18 3 2019 © The Author(s). 2019Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nFinal data are presented for the ORAL Sequel long-term extension (LTE) study evaluating the safety and efficacy of tofacitinib 5 mg and 10 mg twice daily (BID) for up to 9.5 years in patients with rheumatoid arthritis (RA).\n\nMethods\nEligible patients had previously completed a phase 1, 2, or 3 qualifying index study of tofacitinib and received open-label tofacitinib 5 mg or 10 mg BID. Stable background therapy, including csDMARDs, was continued; adjustments to tofacitinib or background therapy were permitted at investigators’ discretion. Assignment to dose groups (5 mg or 10 mg BID) was based on patients’ average total daily dose. The primary objective was to determine the long-term safety and tolerability of tofacitinib 5 mg and 10 mg BID; the key secondary objective was to evaluate the long-term persistence of efficacy.\n\nResults\nBetween February 5, 2007, and November 30, 2016, 4481 patients were enrolled. Total tofacitinib exposure was 16,291 patient-years. Safety data are reported up to month 114 for all tofacitinib; efficacy data are reported up to month 96 for tofacitinib 5 mg BID and month 72 for 10 mg BID (with low patient numbers limiting interpretation beyond these time points). Overall, 52% of patients discontinued (24% due to adverse events [AEs] and 4% due to insufficient clinical response); the safety profile remained consistent with that observed in prior phase 1, 2, 3, or LTE studies. The incidence rate (IR; number of patients with events per 100 patient-years) for AEs leading to discontinuation was 6.8. For all-cause AEs of special interest, IRs were 3.4 for herpes zoster, 2.4 for serious infections, 0.8 for malignancies excluding non-melanoma skin cancer, 0.4 for major adverse cardiovascular events, and 0.3 for all-cause mortality. Clinically meaningful improvements in the signs and symptoms of RA and physical functioning, which were observed in the index studies, were maintained.\n\nConclusions\nTofacitinib 5 mg and 10 mg BID demonstrated a consistent safety profile (as monotherapy or combination therapy) and sustained efficacy in this open-label LTE study of patients with RA. Safety data are reported up to 9.5 years, and efficacy data up to 8 years, based on adequate patient numbers to support conclusions.\n\nTrial registration\nNCT00413699, funded by Pfizer Inc (date of trial registration: December 20, 2006)\n\nElectronic supplementary material\nThe online version of this article (10.1186/s13075-019-1866-2) contains supplementary material, which is available to authorized users.\n\nKeywords\nRheumatoid arthritisTofacitinibLong-term extensionPfizer Incissue-copyright-statement© The Author(s) 2019\n==== Body\nBackground\nRheumatoid arthritis (RA) is a chronic and debilitating autoimmune disease characterized by systemic inflammation, persistent synovitis, and joint destruction, and affects an estimated 0.24% of the global population [1].\n\nTofacitinib is an oral Janus kinase inhibitor for the treatment of RA. The efficacy and safety of tofacitinib 5 mg and 10 mg twice daily (BID) administered as monotherapy or in combination with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), mainly methotrexate (MTX), in patients with moderately to severely active RA, have been demonstrated in phase 2 [2–6] and phase 3 [7–13] randomized controlled trials (RCTs) of up to 24 months’ duration.\n\nThe efficacy and safety of therapy is typically evaluated via double-blind RCTs. As RA is a chronic disease requiring long-term treatment, it is important to assess the long-term effectiveness and safety of RA therapies to understand the potential lifelong impact on patients’ health and quality of life. Of note, long-term extension (LTE) studies, with their controlled setting and rigorous safety reporting, offer the ability to observe and evaluate long-latency safety events, such as malignancies and cardiovascular events, as well as short-latency events, such as infections. Efficacy and safety data from LTE studies of tofacitinib treatment in global (Study A3921024; ORAL Sequel) and Japanese (Study A3921041) populations are part of the largest clinical development program undertaken for any RA treatment to date [14–16].\n\nInterim results from the LTE studies have been regularly reported, and final results from Study A3921041, the LTE study conducted in Japanese patients, have been published [15]. Here, we report the final data from the global LTE ORAL Sequel study and describe the safety and efficacy of treatment with tofacitinib 5 mg and 10 mg BID for up to 9.5 years in patients with RA.\n\nMethods\nStudy design and treatment\nORAL Sequel (NCT00413699; Study A3921024) was an open-label follow-up LTE study conducted in 414 centers across 43 countries (further details provided in Additional file 1: Table S1). Eligible patients had previously completed a prior qualifying index study of tofacitinib (Additional file 1: Table S1), which included two phase 1 studies, eight phase 2 studies, and six phase 3 studies.\n\nAcross qualifying index studies, tofacitinib was dosed at 1, 3, 5, 10, 15, and 30 mg BID, or 20 mg once daily, as monotherapy or in combination with background csDMARDs (mostly MTX).\n\nThe majority of enrolled patients from phase 2 qualifying index studies initiated open-label tofacitinib at 5 mg BID, and the majority of patients from phase 3 qualifying index studies initiated open-label tofacitinib at 10 mg BID, except for patients from China who initiated tofacitinib 5 mg BID as per the protocol. After LTE study baseline, the tofacitinib dose could be increased or decreased at the discretion of the investigator (e.g., increased in the case of inadequate control of RA symptoms [5 mg to 10 mg BID] or decreased in response to adverse events [AEs] or laboratory anomalies [10 mg to 5 mg BID]).\n\nPatients receiving tofacitinib were also eligible for temporary discontinuation if deemed necessary by the investigator. In addition, patients participating in a vaccine sub-study (data not reported) underwent temporary withdrawal from tofacitinib treatment.\n\nPatients were allowed to continue or add stable background arthritis therapy (including non-steroidal anti-inflammatory drugs, COX2 inhibitors, and opioids at ≤ 30 mg oral morphine/day potency), certain csDMARDs (MTX, leflunomide, sulfasalazine, anti-malarials, auranofin, and injectable gold preparations at approved doses), and corticosteroids (≤ 10 mg prednisone or equivalent/day), with adjustment permitted at the investigator’s discretion for reasons of inadequate efficacy, or tapering/discontinuation with disease improvement. Patients taking MTX must also have been taking folic acid (according to local standards). Prohibited concomitant medications included moderate/potent cytochrome P450 3A4 inhibitors or inducers.\n\nThis study was conducted in accordance with the International Ethical Guidelines for Biomedical Research Involving Human Subjects, the Declaration of Helsinki, and the Good Clinical Practice Guidelines, along with applicable local regulatory requirements and laws. The study protocol was approved by the Institutional Review Boards and/or Independent Ethics Committee at each study center. An independent Data Safety Monitoring Board external to the study sponsor reviewed unblinded safety data on a cumulative basis, and Safety Endpoint Adjudication Committees, blinded to treatment assignment of prior randomized double-blind index studies, supported with standardized safety endpoint assessment for selected events as described below. All patients provided written, informed consent.\n\nPatients\nPatients who met the criteria for the index studies, which included a diagnosis of RA based on the American College of Rheumatology (ACR) 1987 Revised Criteria, and had completed the index studies were eligible for enrollment in ORAL Sequel. For those enrolling > 14 days after completion of their prior qualifying index study, the investigator must have deemed that their RA disease activity warranted treatment with tofacitinib and that no evidence of active or inadequately treated Mycobacterium tuberculosis infection be present. Key exclusion criteria for this LTE study included the following for all patients enrolling from the index studies: current/recent history of uncontrolled clinically significant renal, hepatic, hematologic, gastrointestinal, endocrine, pulmonary, cardiac, or neurologic disease; lifetime history of lymphoproliferative disorder, lymphoma, leukemia, or signs and symptoms suggestive of lymphatic disease; history of recurrent herpes zoster infection, current human immunodeficiency virus or hepatitis B/C infection, or any infection requiring hospitalization (including herpes zoster), parenteral antimicrobial therapy, or judged to be opportunistic by the investigator within 6 months prior to the first study drug dose (including those that occurred during the prior qualifying index study); current or history of malignancy (with the exception of adequately treated or excised non-metastatic basal/squamous cell skin cancer or cervical carcinoma in situ); or use of prohibited concomitant medications. For patients enrolling > 14 days after completion of their prior qualifying index study, additional exclusion criteria included hemoglobin levels < 9 g/dL or hematocrit < 30%; absolute white blood cell count < 3.0 × 109/L, absolute neutrophil count (ANC) < 1.2 × 109/L, or absolute lymphocyte count (ALC) < 0.5 × 109/L (< 0.75 × 109/L for patients in Croatia, Czech Republic, Denmark, Ireland, Korea, Germany, Spain, Sweden, and the UK); thrombocytopenia (platelet count < 100 × 109/L); estimated creatinine clearance < 40 mL/min (Cockcroft-Gault calculation); and total bilirubin, aspartate aminotransferase (AST), or alanine aminotransferase (ALT) > 1.5 times the upper limit of normal (ULN).\n\nObjectives and endpoints\nThe primary objective was to determine the long-term safety and tolerability of tofacitinib 5 mg and 10 mg BID, via evaluation of AE reports, clinical laboratory data, physical examinations, vital signs, and electrocardiogram (ECG) values. The key secondary objective was to evaluate the long-term persistence of efficacy with tofacitinib 5 mg and 10 mg BID, via endpoints including ACR20/50/70 response rates; observed mean score over time in Health Assessment Questionnaire-Disability Index (HAQ-DI) and proportion of patients reporting improvements ≥ the minimum clinically important difference (≥ 0.22) in HAQ-DI; observed mean score over time in Disease Activity Score in 28 joints using erythrocyte sedimentation rate (DAS28-4[ESR]), and proportions of patients achieving DAS28-4(ESR)-defined remission (scores < 2.6) and DAS28-4(ESR)-defined low disease activity (LDA; scores ≤ 3.2); and the observed proportions of patients achieving remission defined by Clinical (CDAI) and Simplified (SDAI) Disease Activity Indices (scores ≤ 2.8 and ≤ 3.3, respectively). Exploratory ACR20/50/70 response maintenance analyses and CDAI/SDAI remission maintenance analyses were also conducted.\n\nStatistical methods\nStatistical analyses of safety and efficacy data are descriptive in nature, and no formal comparisons between tofacitinib treatment groups were performed.\n\nBaseline values for safety and efficacy endpoints were those of the qualifying index study (index baseline) for patients who enrolled in the LTE study within ≤ 14 days of index study completion, or the LTE baseline for patients who enrolled > 14 days after index study completion. The safety analysis set comprised all patients who received at least one dose of study medication.\n\nAssignment to the tofacitinib 5 mg or 10 mg BID arm for analysis of efficacy and safety outcomes in this LTE study was based on the study average total daily dose (TDD) for each patient (i.e., sum of all doses received divided by number of days of treatment over the entire study duration for each patient): tofacitinib 5 mg BID if TDD < 15 mg and tofacitinib 10 mg BID if TDD ≥ 15 mg. Patients were assigned to “stay-on monotherapy” (received tofacitinib monotherapy) or “stay-on background csDMARDs” (received tofacitinib plus csDMARD combination therapy) subgroups for analysis of safety outcomes if they remained on their initial study-start therapy for the entire duration of the study (irrespective of tofacitinib or csDMARD dose adjustments), with the exception of a ≤ 28-day break in csDMARD use allowed for stay-on csDMARD patients. Patients who switched from csDMARD to monotherapy, or vice versa, were not included in these subgroup analyses and, therefore, they do not sum to total number of patients treated with tofacitinib. Equivalent subgroup analyses for efficacy outcomes, including data pooled from ORAL Sequel, have been previously published [17].\n\nExposure-adjusted event rates of the number of patients with events per 100 patient-years (EAERs per 100 patient-years) were calculated for AEs, and incidence rates of the number of patients with events per 100 patient-years (IRs per 100 patient-years) and 95% confidence intervals (CI; calculated via the Exact Poisson method) were calculated for AEs of special interest. EAERs were based on the number of unique patients with events per 100 patient-years over all patients’ exposures between their first dose of tofacitinib and their last dose (excluding any temporary treatment breaks in between). IRs were based on the number of unique patients with events during the time between the first and last tofacitinib dose plus 28 days, divided by the time accruing during the risk period (i.e., between the first and last tofacitinib dose plus 28 days, or the time accruing to the first event, whichever occurred earlier). The recurrence rate of herpes zoster was also calculated for patients with at least one event within the risk period.\n\nIn relation to IRs for AEs of special interest, cardiovascular events were adjudicated from February 2009, opportunistic infections from February 2013, hepatic events from December 2012, gastrointestinal events from December 2014, and interstitial lung disease events from April 2014. Events prior to these dates were not adjudicated and were identified by clinical review of AEs. For malignancies, the central histopathological review of AEs was initiated in July 2009, with events adjudicated from February 2014. Events prior to this were subsequently reviewed and adjudicated.\n\nThe efficacy analyses were conducted for all patients who received at least one dose of study medication and had at least one post-index/LTE baseline efficacy measurement available. All analyses were based on observed data with no imputation for missing data.\n\nResults\nPatients\nBetween February 5, 2007, and November 30, 2016, 4481 patients were enrolled in the main study of ORAL Sequel (Additional file 2: Figure S1a). A total of 2340 patients discontinued (see Kaplan-Meier time to discontinuation curve in Additional file 2: Figure S1b). For all tofacitinib, the median time to discontinuation was 1785 days (approximately 4.9 years), as estimated by the Kaplan-Meier method. After 5 years, 49% of patients were still in the study.\n\nPatient baseline demographic and disease characteristics (Additional file 3: Table S2) were generally similar between treatment arms. In total, 90.2% (n = 4041/4481) of patients had baseline data from their index study (i.e., patients enrolled ≤ 14 days after index study completion) and 9.8% (n = 440/4481) had baseline data re-assessed and reported at the time of enrollment into the LTE study (i.e., patients enrolled > 14 days after index study completion).\n\nThe majority of patients (76.6% [3432/4481]) remained on their initial tofacitinib dose (5 mg or 10 mg BID) throughout the study.\n\nSafety\nAll-cause adverse events\nAE data are presented for all patients up to month 114 of the LTE period for tofacitinib 5 mg and 10 mg BID. Total tofacitinib exposure was 16,291 patient-years (4683 patient-years in the 5 mg BID population and 11,608 patient-years in the 10 mg BID population). A summary of all-cause treatment-emergent AEs (hereafter referred to as AEs), including the most common all-cause AEs by system organ class (SOC) and preferred term, is presented in Table 1. The majority of all-cause AEs were mild (59%) or moderate (36%) in severity for all tofacitinib; corresponding data for tofacitinib 5 mg BID were 57% and 36%, respectively, and for tofacitinib 10 mg BID were 59% and 36%, respectively.Table 1 Patients with all-cause treatment-emergent AEs\n\n\tTofacitinib 5 mg BID (n = 1123)\tTofacitinib 10 mg BID (n = 3358)\tAll tofacitinib (n = 4481)\t\nAEs, n (%) [IRs; patients with events per 100 patient-years; 95% CI]\t\n AEs\t1015 (90.4)\n[98.69; 92.71, 104.96]\t3021 (90.0)\n[118.54; 114.35, 122.84]\t4036 (90.1)\n[112.83; 109.38, 116.37]\t\n SAEs\t346 (30.8)\n[8.16; 7.31, 9.07]\t997 (29.7)\n[9.37; 8.80, 9.98]\t1343 (30.0)\n[9.03; 8.55, 9.53]\t\n Discontinued due to AEs\t315 (28.0)\n[6.67; 5.95, 7.45]\t805 (24.0)\n[6.83; 6.36, 7.32]\t1120 (25.0)\n[6.78; 6.39, 7.20]\t\nDose reduction or temporary discontinuation due to AEs\t518 (46.1)\n[16.85; 15.43, 18.36]\t1329 (39.6)\n[15.70; 14.87, 16.57]\t1847 (41.2)\n[16.01; 15.29, 16.76]\t\n Dose reduction only\t75 (14.5)\t86 (6.5)\t161 (8.7)\t\n Temporary discontinuation only\t372 (71.8)\t1147 (86.3)\t1519 (82.2)\t\n Dose reduction and temporary discontinuation\t71 (13.7)\t96 (7.2)\t167 (9.0)\t\n Permanent discontinuationa\t275 (53.1)\t615 (46.3)\t890 (48.2)\t\nAEs, n (%) [EAERs; patients with events per 100 patient-years]\nMost frequently reported AEs by SOC (≥ 20% in any treatment group) and within-SOC preferred term (≥ 5% in any treatment group)\t\nInfections and infestations\t738 (65.7)\n[15.90]\t2299 (68.5)\n[20.04]\t3037 (67.8)\n[18.84]\t\n Upper respiratory tract infection\t228 (20.3)\n[4.91]\t614 (18.3)\n[5.35]\t842 (18.8)\n[5.22]\t\n Nasopharyngitis\t138 (12.3)\n[2.97]\t518 (15.4)\n[4.51]\t656 (14.6)\n[4.07]\t\n Urinary tract infection\t166 (14.8)\n[3.57]\t453 (13.5)\n[3.94]\t619 (13.8)\n[3.84]\t\n Bronchitis\t143 (12.7)\n[3.08]\t434 (12.9)\n[3.78]\t577 (12.9)\n[3.58]\t\n Herpes zoster\t119 (10.6)\n[2.56]\t386 (11.5)\n[3.36]\t505 (11.3)\n[3.13]\t\n Sinusitis\t70 (6.2)\n[1.50]\t242 (7.2)\n[2.10]\t312 (7.0)\n[1.93]\t\n Influenza\t81 (7.2)\n[1.74]\t199 (5.9)\n[1.73]\t280 (6.2)\n[1.73]\t\n Pharyngitis\t58 (5.2)\n[1.24]\t148 (4.4)\n[1.29]\t206 (4.6)\n[1.27]\t\nMusculoskeletal and connective tissue disorders\t447 (39.8)\n[9.63]\t1373 (40.9)\n[11.96]\t1820 (40.6)\n[11.29]\t\n Rheumatoid arthritis\t111 (9.9)\n[2.39]\t309 (9.2)\n[2.69]\t420 (9.4)\n[2.60]\t\n Back pain\t109 (9.7)\n[2.34]\t301 (9.0)\n[2.62]\t410 (9.1)\n[2.54]\t\n Arthralgia\t88 (7.8)\n[1.89]\t271 (8.1)\n[2.36]\t359 (8.0)\n[2.22]\t\n Osteoarthritis\t66 (5.9)\n[1.42]\t196 (5.8)\n[1.70]\t262 (5.8)\n[1.62]\t\nGastrointestinal disorders\t406 (36.2)\n[8.74]\t1045 (31.1)\n[9.10]\t1451 (32.4)\n[9.00]\t\n Diarrhea\t74 (6.6)\n[1.59]\t218 (6.5)\n[1.90]\t292 (6.5)\n[1.81]\t\n Nausea\t57 (5.1)\n[1.22]\t175 (5.2)\n[1.52]\t232 (5.2)\n[1.43]\t\nInvestigations\t404 (36.0)\n[8.70]\t1007 (30.0)\n[8.77]\t1411 (31.5)\n[8.75]\t\n Blood creatine phosphokinase increased\t91 (8.1)\n[1.96]\t249 (7.4)\n[2.17]\t340 (7.6)\n[2.11]\t\n ALT increased\t63 (5.6)\n[1.35]\t122 (3.6)\n[1.06]\t185 (4.1)\n[1.14]\t\n Blood creatinine increased\t60 (5.3)\n[1.29]\t116 (3.5)\n[1.01]\t176 (3.9)\n[1.09]\t\nInjury, poisoning, and procedural complications\t267 (23.8)\n[5.75]\t783 (23.3)\n[6.82]\t1050 (23.4)\n[6.51]\t\n Fall\t70 (6.2)\n[1.50]\t217 (6.5)\n[1.89]\t287 (6.4)\n[1.78]\t\nNervous system disorders\t232 (20.7)\n[4.99]\t687 (20.5)\n[5.98]\t919 (20.5)\n[5.70]\t\n Headache\t67 (6.0)\n[1.44]\t203 (6.0)\n[1.76]\t270 (6.6)\n[1.67]\t\nRespiratory, thoracic, and mediastinal disorders\t223 (19.9)\n[4.80]\t671 (20.0)\n[5.84]\t894 (20.0)\n[5.54]\t\n Cough\t65 (5.8)\n[1.40]\t203 (6.0)\n[1.76]\t268 (6.0)\n[1.66]\t\nSafety analysis set: all patients who received at least one dose of study medication. Database lock: March 2, 2017\n\nAE adverse event, ALT alanine aminotransferase, BID twice daily, CI confidence interval, EAER exposure-adjusted event rate, IR incidence rate, SAE serious adverse event, SOC system organ class\n\naPatients who had dose reduction or temporary discontinuation due to AEs and eventually discontinued from the study\n\nEAERs represent rates of events/100 patient-years of exposure. Total tofacitinib exposure was 16,291 patient-years (4683 patient-years in the 5 mg BID population and 11,608 patient-years in the 10 mg BID population). Exposure for EAER calculations was 16,113 patient-years for all tofacitinib (4641 patient-years in the 5 mg BID population and 11,472 patient-years in the 10 mg BID population). Data for herpes zoster reflect only AEs reported using preferred term “Herpes zoster”\n\n\n\nAll-cause adverse events leading to discontinuation\nThe proportion of patients with all-cause AEs decreased from baseline over time, while the proportion with all-cause AEs leading to discontinuation remained consistent over time (Additional file 4: Figure S2). For all tofacitinib, the most common all-cause AEs by SOC leading to discontinuation included infections and infestations (9.4% [n = 423/4481]), investigations (4.6% [n = 206/4481]), and benign, malignant, and unspecified neoplasms (3.7% [n = 165/4481]), and by preferred term included pneumonia (1.8% [n = 80/4481]), blood creatinine increased (1.5% [n = 69/4481]), and herpes zoster (0.7% [n = 32/4481]). The IR (95% CI) for all-cause AEs leading to discontinuation was 6.78 (6.39, 7.20) for all tofacitinib. The corresponding IR data for patients receiving tofacitinib as combination therapy (n = 656/2464) was 7.73 (7.15, 8.35), and for patients receiving tofacitinib as monotherapy (n = 279/1298) was 5.88 (5.21, 6.61).\n\nSerious adverse events\nFor all tofacitinib, the most common (≥ 5% in any treatment group) all-cause serious AEs (SAEs) by SOC included infections and infestations (9.0% [n = 405/4481]) and musculoskeletal and connective tissue disorders (5.5% [n = 246/4481]), and by preferred term included pneumonia (2.1% [n = 96/4481]), osteoarthritis (1.9% [n = 86/4481]), and RA (0.8% [n = 34/4481]), noting that 1.1% (n = 51/4481) also reported “condition aggravated” as an SAE. The IR (95% CI) for SAEs was 9.03 (8.55, 9.53) for all tofacitinib. The corresponding SAE IR (95% CI) for patients receiving tofacitinib as combination therapy (n = 726/2464) was 9.48 (8.80, 10.20), and for patients receiving tofacitinib as monotherapy (n = 349/1298) was 8.11 (7.28, 9.01).\n\nDeaths\nA total of 88 deaths occurred in the study; 44 within the risk period (excluding one fetal death [pregnancy in partner of enrolled patient with in utero fetal death reported after diagnosis of Down syndrome]) and 43 outside of the risk period. A total number of 84 all-cause SAEs (5 mg BID n = 39, 10 mg BID n = 45) resulted in death. The IR (95% CI) for all-cause mortality was 0.26 (0.19, 0.36) for all tofacitinib. The corresponding all-cause mortality IR (95% CI) for patients receiving tofacitinib as combination therapy (n = 23/2464) was 0.27 (0.17, 0.40), and for patients receiving tofacitinib as monotherapy (n = 18/1298) was 0.37 (0.22, 0.59). Further details (incidence of mortality and mortality listings) are provided in Additional file 5: Table S3.\n\nAll-cause adverse events of special interest\nIRs for all-cause AEs of special interest are summarized in Table 2, including data for patients receiving tofacitinib as combination therapy and as monotherapy. The majority of malignancy-, cardiovascular-, mortality-, and infection-related events had IRs < 0.5; exceptions were herpes zoster, all serious infections, malignancies excluding non-melanoma skin cancer (NMSC), and NMSC. Figure 1a–c presents serious infections, malignancies excluding NMSC, and herpes zoster over time, showing they remained generally stable. IRs for malignancies excluding NMSC, lymphoma, melanomas, breast cancer (female patients only), lung cancer, tuberculosis, composite major adverse cardiovascular event (MACE), gastrointestinal perforation, interstitial lung disease, deep vein thrombosis (DVT), pulmonary embolism (PE), and mortality were comparable between patients receiving tofacitinib 5 mg and 10 mg BID.Table 2 Incidence rates for all-cause AEs of special interest\n\n\tAll patients (IR (95% CI) [n/N])\tPatients receiving tofacitinib as combination therapy (stay-on background csDMARDs) (IR (95% CI) [n/N])\tPatients receiving tofacitinib as monotherapy (stay-on monotherapy) (IR (95% CI) [n/N])\t\nTofacitinib 5 mg BID\tTofacitinib 10 mg BID\tAll tofacitinib\tTofacitinib 5 mg BID\tTofacitinib 10 mg BID\tAll tofacitinib\tTofacitinib 5 mg BID\tTofacitinib 10 mg BID\tAll tofacitinib\t\nMalignancy related\t\n NMSC\t0.6 (0.4, 0.9)\n[28/1123]\t0.8 (0.6, 0.9)\n[88/3358]\t0.7 (0.6, 0.9)\n[116/4481]\t0.4 (0.2, 0.7)\n[9/630]\t0.9 (0.6, 1.1)\n[51/1834]\t0.7 (0.5, 0.9)\n[60/2464]\t0.8 (0.4, 1.4)\n[10/305]\t0.4 (0.2, 0.6)\n[13/993]\t0.5 (0.3, 0.7)\n[23/1298]\t\n Malignancies excluding NMSC\t0.8 (0.6, 1.1)\n[38/1123]\t0.8 (0.7, 1.0)\n[100/3358]\t0.8 (0.7, 1.0)\n[138/4481]\t1.0 (0.7, 1.5)\n[25/630]\t0.8 (0.6, 1.0)\n[48/1834]\t0.9 (0.7, 1.1)\n[73/2464]\t0.8 (0.4, 1.4)\n[10/305]\t0.9 (0.6, 1.3)\n[31/993]\t0.9 (0.6, 1.2)\n[41/1298]\t\n Lymphoma\t0.0 (0.0, 0.1)\n[1/1123]\t0.1 (0.0, 0.1)\n[8/3358]\t0.1 (0.0, 0.1)\n[9/4481]\t0.0 (0.0, 0.2)\n[1/630]\t0.1 (0.0, 0.2)\n[5/1834]\t0.1 (0.0, 0.2)\n[6/2464]\t0 (0.0, 0.3)\n[0/305]\t0.0 (0.0, 0.2)\n[1/993]\t0.0 (0.0, 0.1)\n[1/1298]\t\n Melanomas\t0.1 (0.0, 0.2)\n[3/1123]\t0.1 (0.0, 0.2)\n[10/3358]\t0.1 (0.0, 0.1)\n[13/4481]\t0.1 (0.0, 0.3)\n[2/630]\t0.1 (0.0, 0.2)\n[4/1834]\t0.1 (0.0, 0.2)\n[6/2464]\t0.1 (0.0, 0.4)\n[1/305]\t0.1 (0.1, 0.3)\n[5/993]\t0.1 (0.1, 0.3)\n[6/1298]\t\n Breast cancera\t0.2 (0.1, 0.3)\n[6/927]\t0.2 (0.1, 0.3)\n[17/2744]\t0.2 (0.1, 0.3)\n[23/3671]\t0.3 (0.1, 0.6)\n[5/512]\t0.2 (0.1, 0.4)\n[10/1498]\t0.2 (0.1, 0.4)\n[15/2010]\t0 (0.0, 0.3)\n[0/261]\t0.1 (0.0, 0.3)\n[3/798]\t0.1 (0.0, 0.2)\n[3/1059]\t\n Lung cancer\t0.1 (0.1, 0.3)\n[6/1123]\t0.2 (0.1, 0.3)\n[20/3358]\t0.2 (0.1, 0.2)\n[26/4481]\t0.1 (0.0, 0.4)\n[3/630]\t0.2 (0.1, 0.3)\n[12/1834]\t0.2 (0.1, 0.3)\n[15/2464]\t0.2 (0.0, 0.6)\n[2/305]\t0.2 (0.1, 0.4)\n[6/993]\t0.2 (0.1, 0.3)\n[8/1298]\t\nInfection related\t\n All serious infections\t1.9 (1.6, 2.4)\n[91/1123]\t2.6 (2.3, 2.9)\n[304/3358]\t2.4 (2.2, 2.6)\n[395/4481]\t1.9 (1.4, 2.5)\n[46/630]\t3.0 (2.6, 3.5)\n[184/1834]\t2.7 (2.4, 3.1)\n[230/2464]\t2.1 (1.4, 3.0)\n[27/305]\t2.3 (1.9, 2.9)\n[81/993]\t2.3 (1.9, 2.7)\n[108/1298]\t\n Tuberculosis\t0.1 (0.0, 0.2)\n[5/1123]\t0.2 (0.1, 0.3)\n[20/3358]\t0.2 (0.1, 0.2)\n[25/4481]\t0.2 (0.0, 0.4)\n[4/630]\t0.2 (0.1, 0.3)\n[12/1834]\t0.2 (0.1, 0.3)\n[16/2464]\t0.1 (0.0, 0.4)\n[1/305]\t0.2 (0.1, 0.4)\n[6/993]\t0.2 (0.1, 0.3)\n[7/1298]\t\n Herpes zoster\t2.3 (2.3, 3.3)\n[120/1123]\t3.7 (3.4, 4.1)\n[406/3358]\t3.4 (3.2, 3.7)\n[526/4481]\t2.2 (1.7, 2.9)\n[52/630]\t4.1 (3.6, 4.7)\n[233/1834]\t3.6 (3.2, 4.0)\n[285/2464]\t2.4 (1.6, 3.5)\n[29/305]\t2.3 (1.8, 2.9)\n[77/993]\t2.4 (1.9, 2.8)\n[106/1298]\t\n Opportunistic infections excluding tuberculosis\t0.1 (0.0, 0.2)\n[4/1123]\t0.5 (0.4, 0.7)\n[60/3358]\t0.4 (0.3, 0.5)\n[64/4481]\t0.0 (0.0, 0.2)\n[1/630]\t0.6 (0.4, 0.8)\n[36/1834]\t0.4 (0.3, 0.6)\n[37/2464]\t0.2 (0.0, 0.6)\n[2/305]\t0.4 (0.2, 0.7)\n[14/993]\t0.3 (0.2, 0.5)\n[16/1298]\t\nMortality related\t\n Mortality attributed to a cardiovascular event\t0.2 (0.1, 0.3)\n[7/1046]\t0.1 (0.1, 0.2)\n[12/3358]\t0.1 (0.1, 0.2)\n[19/4404]\t0.1 (0.0, 0.4)\n[3/572]\t0.1 (0.1, 0.3)\n[8/1834]\t0.1 (0.1, 0.2)\n[11/2406]\t0.3 (0.1, 0.8)\n[4/289]\t0.1 (0.0, 0.2)\n[2/993]\t0.1 (0.1, 0.3)\n[6/1282]\t\n Mortality due to infections\t0.1 (0.0, 0.2)\n[4/1123]\t0.1 (0.0, 0.1)\n[9/3358]\t0.1 (0.0, 0.1)\n[13/4481]\t0.1 (0.0, 0.3)\n[2/630]\t0.1 (0.0, 0.2)\n[4/1834]\t0.1 (0.0, 0.2)\n[6/2464]\t0.1 (0.0, 0.4)\n[1/305]\t0.1 (0.0, 0.3)\n[4/993]\t0.1 (0.0, 0.2)\n[5/1298]\t\n Mortality due to malignancy\t0.0 (0.0, 0.1)\n[1/1123]\t0.0 (0.0, 0.1)\n[3/3358]\t0.0 (0.0, 0.1)\n[4/4481]\t0 (0.0, 0.2)\n[0/630]\t0.0 (0.0, 0.1)\n[2/1834]\t0.0 (0.0, 0.1)\n[2/2464]\t0.1 (0.0, 0.4)\n[1/305]\t0.0 (0.0, 0.2)\n[1/993]\t0.0 (0.0, 0.2)\n[2/1298]\t\nOther\t\n Composite MACE\t0.5 (0.3, 0.7)\n[20/1046]\t0.4 (0.3, 0.5)\n[42/3358]\t0.4 (0.3, 0.5)\n[62/4404]\t0.5 (0.3, 0.9)\n[11/572]\t0.5 (0.3, 0.7)\n[29/1834]\t0.5 (0.4, 0.7)\n[40/2406]\t0.5 (0.2, 1.1)\n[6/289]\t0.2 (0.1, 0.4)\n[6/993]\t0.3 (0.1, 0.4)\n[12/1282]\t\n Gastrointestinal perforation\t0.1 (0.0, 0.2)\n[3/1123]\t0.2 (0.1, 0.3)\n[20/3358]\t0.1 (0.1, 0.2)\n[23/4481]\t0.0 (0.0, 0.2)\n[1/630]\t0.2 (0.1, 0.4)\n[13/1834]\t0.2 (0.1, 0.3)\n[14/2464]\t0.1 (0.0, 0.4)\n[1/305]\t0.1 (0.1, 0.3)\n[5/993]\t0.1 (0.1, 0.3)\n[6/1298]\t\n Interstitial lung disease\t0.2 (0.1, 0.4)\n[10/1123]\t0.2 (0.1, 0.3)\n[22/3358]\t0.2 (0.1, 0.3)\n[32/4481]\t0.2 (0.0, 0.4)\n[4/630]\t0.3 (0.1, 0.4)\n[15/1834]\t0.2 (0.1, 0.4)\n[19/2464]\t0.3 (0.1, 0.8)\n[4/305]\t0.1 (0.0, 0.3)\n[3/993]\t0.2 (0.1, 0.3)\n[7/1298]\t\n Deep vein thrombosis\t0.1 (0.1, 0.3)\n[6/1123]\t0.1 (0.1, 0.2)\n[17/3358]\t0.1 (0.1, 0.2)\n[23/4481]\t0.1 (0.0, 0.4)\n[3/630]\t0.1 (0.1, 0.3)\n[8/1834]\t0.1 (0.1, 0.2)\n[11/2464]\t0.1 (0.0, 0.4)\n[1/305]\t0.2 (0.1, 0.4)\n[6/993]\t0.2 (0.1, 0.3)\n[7/1298]\t\n Pulmonary embolism\t0.1 (0.0, 0.3)\n[5/1123]\t0.1 (0.1, 0.2)\n[16/3358]\t0.1 (0.1, 0.2)\n[21/4481]\t0.1 (0.0, 0.3)\n[2/630]\t0.1 (0.1, 0.3)\n[8/1834]\t0.1 (0.1, 0.2)\n[10/2464]\t0.1 (0.0, 0.4)\n[1/305]\t0.2 (0.1, 0.4)\n[6/993]\t0.2 (0.1, 0.3)\n[7/1298]\t\nIR is the number of patients with events per 100 patient-years. Tofacitinib was dosed at 1, 3, 5, 10, 15, and 30 mg BID, or 20 mg QD, as monotherapy or in combination with background csDMARDs (mostly MTX). Total tofacitinib exposure was 16,291 patient-years (4683 patient-years in the 5 mg BID population and 11,608 patient-years in the 10 mg BID population). Tofacitinib exposure for female patients was 13,476 patient-years (3888 patient-years in the 5 mg BID population and 9587 patient-years in the 10 mg BID population). Tofacitinib exposure for patients in the cardiac event analysis population was 15,823 patient-years (4257 patient-years in the 5 mg BID population and 11,566 patient-years in the 10 mg BID population). As per the protocol, cardiovascular events were adjudicated from February 2009, opportunistic infections from February 2013, hepatic events from December 2012, gastrointestinal events from December 2014, and interstitial lung disease events from April 2014. Events prior to these dates were not adjudicated and were identified by clinical review of AEs. For malignancies, central histopathological review of AEs was initiated in July 2009, with events adjudicated from February 2014. Events prior to this were subsequently reviewed and adjudicated. Data for herpes zoster reflect AEs reported using any preferred term including “Herpes zoster”. Database lock: March 2, 2017\n\nAE adverse event, BID twice daily, CI confidence interval, csDMARD conventional synthetic disease-modifying antirheumatic drug, IR incidence rate, MACE major adverse cardiovascular event, MTX methotrexate, NMSC non-melanoma skin cancer, QD once daily\n\naFemale patients only\n\nFig. 1 Incidence rates for notable safety events of special interest over time. Including serious infections (a), malignancies excluding NMSC (b), and herpes zoster (c). IR is the number of patients with events per 100 patient-years. Total tofacitinib exposure was 16,291 patient-years (4683 patient-years in the 5 mg BID population and 11,608 patient-years in the 10 mg BID population). Database lock: March 2, 2017. BID twice daily, CI confidence interval, IR incidence rate, NMSC non-melanoma skin cancer, PY patient-years of exposure\n\n\n\nAcross all patients, IRs were higher (per non-overlapping CI) with tofacitinib 10 mg BID versus 5 mg BID for herpes zoster (3.7 versus 2.3, respectively) and opportunistic infections excluding tuberculosis (0.5 versus 0.1); numerical differences (per marginally overlapping CI) in IRs were also observed for all serious infections (Table 2). The majority of cases of herpes zoster were non-serious (96% [503/526]); 30 patients had recurrent herpes zoster, including 1 patient with recurrent ophthalmic herpes zoster. The recurrence rate for herpes zoster (per 100 patient-years) was 2.6.\n\nIn addition, IRs were higher for patients receiving tofacitinib as combination therapy versus monotherapy for herpes zoster (3.6 versus 2.4, respectively). Within the subgroup of patients receiving tofacitinib as combination therapy, IRs were higher with tofacitinib 10 mg BID versus 5 mg BID for all serious infections (3.0 versus 1.9, respectively), herpes zoster (4.1 versus 2.2), and opportunistic infections excluding tuberculosis (0.6 versus 0.0) (Table 2).\n\nLaboratory variables of interest\nLaboratory variables of interest, including total cholesterol and low-density lipoprotein (LDL) (Fig. 2a, b), ALT (Additional file 6: Figure S3a), AST (Additional file 6: Figure S3b), and serum creatinine (Additional file 6: Figure S3d) remained generally stable over time, with variability attributable to smaller patient numbers at later time points. Changes over time were observed in lymphocytes (ALC levels gradually declined until month 48, whereafter the level stabilized; Fig. 2c) and neutrophils (Fig. 2d); furthermore, slight increases in hemoglobin (Additional file 6: Figure S3c) were observed until month 24, which then remained stable. Laboratory data are reported up to month 96 of the LTE study period only, due to low patient numbers after this time point.Fig. 2 Mean (SE) laboratory variables of interest over time. Including total cholesterol (a), LDL (b), lymphocyte counts (c), and neutrophil counts (d). Baseline qualifying index study data were used for approximately 90% of patients. Data for 12-month intervals are reported in the tables. Database lock: March 2, 2017. BID twice daily, BL baseline, LDL low-density cholesterol, SE standard error\n\n\n\nFor all tofacitinib, values for confirmed neutropenia at any time were mild, 1.5 × 103/mm3 ≤ ANC < 2 × 103/mm3, 6.0% (271/4481); moderate, 1.0 × 103/mm3 ≤ ANC < 1.5 × 103/mm3, 1.3% (58/4481); severe, 0.5 × 103/mm3 ≤ ANC < 1.0 × 103/mm3, 0.2% (7/4481); and potentially life-threatening, ANC < 0.5 × 103/mm3, 0%). No patients with confirmed neutropenia developed serious infections within 30 days of their lowest neutrophil count. For confirmed lymphopenia at any time, values were mild, 1.5 × 103/mm3 ≤ ALC < 2 × 103/mm3, 17.5% (782/4481); moderate, 1.0 × 103/mm3 ≤ ALC < 1.5 × 103/mm3, 40.6% (1820/4481); severe, 0.5 × 103/mm3 ≤ ALC < 1.0 × 103/mm3, 30.1% (1351/4481); and potentially life-threatening, ALC < 0.5 × 103/mm3, 1.3% (58/4481). Of the patients with mild, moderate, and severe lymphopenia, 0.9% (7/782), 0.3% (5/1820), and 0.3% (4/1351), respectively, developed serious infections within 30 days of their lowest ALC. Of the 58 patients with potentially life-threatening lymphopenia at any time (with ALC < 0.5 × 103 cells/mm3), five cases were potentially associated with serious infections; two (3.4%) occurred within 30 days of the patients’ lowest ALC. In addition, 52 of the 58 patients eventually returned to ALC ≥ 0.5 × 103 cells/mm3, and 29 of the 58 patients with ALC < 0.5 × 103 cells/mm3 eventually returned to within 20% of their respective baseline value, following treatment discontinuation. For all tofacitinib, the IRs (95% CI) for neutropenia (n = 86/4481) and lymphopenia (n = 181/4481) were 0.52 (0.42, 0.65) and 1.11 (0.95, 1.28), respectively.\n\nThe proportions of patients with confirmed ALT and AST > 1×, ≥ 2×, and ≥ 3× ULN are shown in Additional file 7: Table S4. The IR (95% CI) for ALT ≥ 3× ULN was 1.71 (1.51, 1.92) for all tofacitinib; the corresponding IR for patients receiving tofacitinib as combination therapy (n = 133/2464) was 1.59 (1.33, 1.88), and for patients receiving tofacitinib as monotherapy (n = 70/1298) was 1.50 (1.17, 1.90). For AST ≥ 3× ULN, IRs (95% CI) were 0.98 (0.84, 1.15), 1.04 (0.83, 1.28), and 0.93 (0.68, 1.25) for all tofacitinib, patients receiving tofacitinib as combination therapy (n = 88/2464), and patients receiving tofacitinib as monotherapy (n = 44/1298), respectively.\n\nThe summary of actions taken with tofacitinib and MTX during elevated AST or ALT levels ≥ 3× ULN is shown in Table 3.Table 3 Summary of actions taken with tofacitinib and MTX during ALT or AST elevations ≥ 3× ULN\n\nPatients with ≥ 3× ULN ALT or AST (N = 109), n (%)\t\nActions taken with MTX\tActions taken with tofacitinib\t\nContinued tofacitinib (n = 40)\tPermanently discontinued tofacitinib (n = 39)\tDiscontinued tofacitinib due to AEsa (n = 2)\tTemporarily discontinued tofacitinib and resumed same dose (n = 10)\tTemporarily discontinued tofacitinib and resumed reduced doseb (n = 7)\tReduced tofacitinib doseb (n = 11)\t\nPermanently discontinued MTX\t4 (3.7)\t14 (12.8)\t1 (0.9)\t1 (0.9)\t0\t2 (1.8)\t\nTemporarily discontinued MTX\t1 (0.9)\t0\t0\t0\t0\t0\t\nReduced MTX dose\t2 (1.8)\t0\t0\t0\t1 (0.9)\t0\t\nContinued MTX\t20 (18.3)\t11 (10.1)\t0\t4 (3.7)\t4 (3.7)\t2 (1.8)\t\nPatients were not receiving MTX\t13 (11.9)\t14 (12.8)\t1 (0.9)\t5 (4.6)\t2 (1.8)\t7 (6.4)\t\nAE adverse event, ALT alanine aminotransferase, AST aspartate aminotransferase, BID twice daily, MTX methotrexate, ULN upper limit of normal\n\naAEs occurring prior to AST elevations\n\nbReduction in tofacitinib dose from 10 mg BID to 5 mg BID\n\n\n\nFor all tofacitinib, laboratory values that met with protocol criteria for monitoring included any single ALT and/or AST elevation > 3× ULN regardless of total bilirubin (7.1% [317/4481]); any single hemoglobin value < 8.0 g/dL, or one that drops ≥ 2 gm/dL below baseline (14.3% [640/4481]); and transient increases in serum creatinine > 50% over the average screening and baseline values leading to discontinuation (4.5% [201/4481] patients). Of note, no patients had confirmed ANC < 500 mm3. No clinically notable changes were observed in systolic or diastolic blood pressure or ECG values, from baseline to month 96 (data not shown).\n\nEfficacy\nEfficacy data are presented up to month 96 of the LTE study period for tofacitinib 5 mg BID, and up to month 72 of the LTE study period for tofacitinib 10 mg BID (data were censored due to low patient numbers after these time points; although these patients contributed to all tofacitinib exposure).\n\nACR\nACR20 (Fig. 3), ACR50 (Additional file 8: Figure S4a), and ACR70 (Additional file 8: Figure S4b) response rates were maintained over time between months 1 and 96 and were generally similar with tofacitinib 5 mg (months 1 to 96) and 10 mg BID (months 1 to 72).Fig. 3 ACR20 response over time (observed). ACR calculated with respect to qualifying index study data available for approximately 90% of patients. Italicized data not reported in figure due to low patient numbers. Data for 12-month intervals are reported in the table. Database lock: March 2, 2017. ACR American College of Rheumatology, BID twice daily\n\n\n\nHAQ-DI\nAcknowledging appreciable attrition in the sample size over time, improvements in mean HAQ-DI scores at month 1 remained stable over time with tofacitinib 5 mg and 10 mg BID (Fig. 4). HAQ-DI ≥ 0.22 improvement from baseline was observed in 64.8% (n = 103/159) of patients with all tofacitinib at month 96; in 63.6% (n = 91/143) of patients with tofacitinib 5 mg BID at month 96; and in 70.3% (n = 201/286) of patients with tofacitinib 10 mg BID at month 72.Fig. 4 Mean (SE) HAQ-DI scores over time (observed). Baseline qualifying index study data were used for approximately 90% of patients. Italicized data not reported in figure due to low patient numbers. Data for 12-month intervals are reported in the table. Database lock: March 2, 2017. BID twice daily, BL baseline, HAQ-DI Health Assessment Questionnaire-Disability Index, SE standard error\n\n\n\nDAS28-4(ESR), CDAI, and SDAI\nMean DAS28-4(ESR) (Fig. 5) decreased at month 1 and then remained consistent over time with tofacitinib 5 mg and 10 mg BID. DAS28-4(ESR)-defined remission was observed in 24.7% (n = 39/158) of patients with all tofacitinib at month 96, in 25.4% (n = 36/142) of patients with tofacitinib 5 mg BID at month 96, and in 25.0% (n = 71/284) of patients with tofacitinib 10 mg BID at month 72. Corresponding data for DAS28-4(ESR)-defined LDA were 46.8% (n = 74/158), 47.2% (n = 67/142), and 48.2% (n = 137/284), respectively.Fig. 5 Mean (SE) DAS28-4(ESR) over time (observed). Baseline qualifying index study data were used for approximately 90% of patients. Italicized data not reported in figure due to low patient numbers. Data for 12-month intervals are reported in the table. Database lock: March 2, 2017. BID twice daily, BL baseline, DAS28-4(ESR) Disease Activity Score in 28 joints using erythrocyte sedimentation rate, SE standard error\n\n\n\nCDAI- and SDAI-defined remission was observed in approximately a third of patients at month 96 (Additional file 9: Figure S5a and S5b). Rates of CDAI and SDAI remission were maintained over time, with the majority (> 85%) of patients maintaining or improving their CDAI or SDAI category (CDAI ≤ 2.8; 2.8 < CDAI ≤ 10; CDAI > 10) from the end of their index study to month 96 of the LTE.\n\nDiscussion\nThe ORAL Sequel LTE study of tofacitinib is part of the largest clinical development program undertaken for any RA treatment to date. Up to 9.5 years of treatment with tofacitinib in more than 4000 patients worldwide with RA is represented in this study, with a combined tofacitinib exposure of > 16,000 patient-years.\n\nSafety data up to 114 months for all tofacitinib, and efficacy data up to 96 months for tofacitinib 5 mg BID and 72 months for 10 mg BID, are reported, with low patient numbers limiting interpretation beyond these time points. Patient baseline demographic and disease characteristics were generally similar between the tofacitinib 5 mg and 10 mg BID treatment arms, although a greater proportion of patients enrolled from prior phase 3 studies compared with phase 2 studies and then initiated the LTE at 10 mg BID, per protocol (the exception to this was that all phase 3 patients from China initiated the LTE at 5 mg BID, also per protocol). Most (> 90%) patients were enrolled in the LTE study within ≤ 14 days of index study completion, and so their baseline index data were used, per protocol.\n\nIn all, the safety profile remained consistent with that observed in prior phase 2 [2–6] or phase 3 [7, 9–13] tofacitinib studies, or prior combined analyses including LTE data [16, 18]. The IRs for AEs leading to discontinuation were comparable for all tofacitinib, tofacitinib 5 mg BID, and tofacitinib 10 mg BID (6.8, 6.7, and 6.8, respectively), as were the IRs for SAEs (9.0, 8.2, and 9.4, respectively). Overall in ORAL Sequel, 52% of patients discontinued by month 114 (24% due to AEs and 4% due to insufficient clinical response) and the incidence of AEs leading to discontinuation remained stable over time. These data are consistent with a recent integrated analysis of safety data over 8.5 years for tofacitinib (5 mg and 10 mg BID combined, with or without background csDMARDs) across 17 phase 1/2/3 studies and two LTE studies, including ORAL Sequel, in which the IR for discontinuation due to AEs was 7.5 and the IR for SAEs was 9.0, for all tofacitinib [18]. Furthermore, in pooled LTE safety analyses from ORAL Sequel and Japanese Study A3921041 (tofacitinib 5 mg and 10 mg BID combined, with or without background DMARDs), 51% of patients discontinued by month 114 (24% due to AEs and 4% due to insufficient clinical response) and the IR for SAEs was 9.1 for all tofacitinib [16].\n\nMost malignancy-, cardiovascular-, mortality-, and infection-related events had IRs < 0.5; exceptions were herpes zoster, all serious infections, malignancies excluding NMSC, and NMSC. IRs for herpes zoster, all serious infections, and malignancies excluding NMSC remained generally stable over time. Recurrent herpes zoster was observed in 30 patients. IRs were higher (CI non-overlapping) with tofacitinib 10 mg BID versus 5 mg BID for herpes zoster and opportunistic infections excluding tuberculosis and numerically higher (CI marginally overlapping) for all serious infections; no dose-dependencies were indicated for other events.\n\nInfections and infestations were anticipated to represent the most common class of overall AEs. IRs for serious infections were consistent between ORAL Sequel, the integrated analysis of safety data for tofacitinib [18], and pooled ORAL Sequel and Study A3921041 data [16], at 2.4, 2.7, and 2.5, respectively, as were IRs for herpes zoster between ORAL Sequel and the integrated analysis of safety data, at 3.4 and 3.9, respectively (data not reported for the pooled ORAL Sequel and Study A3921041 analysis; IR was 7.4 for herpes zoster in the Japanese population of Study A3921041 alone [15]). With respect to tuberculosis, the IR for all tofacitinib (0.2) was slightly lower compared with the IR for other opportunistic infections excluding tuberculosis (0.4) in ORAL Sequel. In the integrated analysis of safety data for tofacitinib, IRs were similar between tuberculosis (0.2) and other opportunistic infections excluding tuberculosis (0.3), and concordant with ORAL Sequel data [18]. Prior evaluation has supported the understanding that the risk of tuberculosis in patients receiving tofacitinib treatment directly varies with background tuberculosis prevalence in different geographic sub-populations [19]. ORAL Sequel IR data for tuberculosis are comparable with data for biologic DMARDs [20–22].\n\nOf interest, the long-latency events MACE and lymphoma had IRs at 0.4 and 0.1, respectively. IRs for other AEs of interest reported in both ORAL Sequel and the integrated analysis of safety data for tofacitinib [18] were consistent: 0.8 and 0.9 for malignancies excluding NMSC, 0.7 and 0.6 for NMSC, and both 0.1 for gastrointestinal perforation (which is also comparable with tumor necrosis factor inhibitors [TNFi] [23]). Furthermore, the IRs for DVT and PE in patients receiving tofacitinib (both 0.1) were comparable to those reported in data pooled from phase 2 and phase 3 studies of tofacitinib as monotherapy or in combination with DMARDs (DVT IR of 0.1 for both tofacitinib 5 and 10 mg BID, and PE IR of 0.1 for tofacitinib 5 mg BID and 0.2 for tofacitinib 10 mg BID [24]) and in the literature for patients with RA, including those treated with DMARDs (DVT IRs of 0.45 [25] and 0.62 [26], and PE IRs of 0.26 [25] and 0.20 [26]).\n\nIn support of the consistencies noted above, safety data from LTE studies and meta-analyses of biologic and targeted synthetic DMARDs are comparable with those reported for tofacitinib. Considering discontinuation from biologic DMARDs, 62% of patients discontinued by year 10 of treatment in an LTE study of adalimumab (23% due to AEs and 12% due to lack of efficacy/disease progression) [27]; and 31% of patients discontinued by year 5 in an LTE study of subcutaneous abatacept (31% due to AEs and 7% due to lack of efficacy) [28]. Considering safety events of special interest, previous LTE studies have reported IRs for serious infections of 3.1 and 1.7 events for adalimumab (across 10 years of treatment) and subcutaneous abatacept (across 5 years of treatment), respectively [27, 28]. In the integrated analysis of safety data for baricitinib, event IRs were reported for serious infections (3.0), herpes zoster (3.3), tuberculosis (0.1), MACE (0.5), DVT (0.4), PE (0.2), malignancies excluding NMSC (0.8), lymphoma (0.08), NMSC (0.4), and gastrointestinal perforation (0.04) [29, 30]. Meta-analysis data showed that in a dataset comprising RCTs and LTE studies, the IRs for tofacitinib (serious infection 2.74; malignancies excluding NMSC 0.89) were comparable to those reported for biologic and targeted synthetic DMARDs, including abatacept, adalimumab, baricitinib, certolizumab pegol, etanercept, golimumab, infliximab, rituximab, and tocilizumab (serious infection 3.04–7.59; malignancies excluding NMSC 0.75–1.06) [31, 32], which in turn are concordant with data reported for ORAL Sequel. In addition, serious infection IRs for tofacitinib were observed to be congruous with IRs previously calculated in a 2017 meta-analysis of RCTs for biologic DMARDs, including abatacept (3.0), rituximab (3.5), tocilizumab (5.4), and TNFi (5.5), and the targeted synthetic DMARD baricitinib (4.8 for 2 mg, 3.7 for 4 mg) [31]. Taking the findings of ORAL Sequel and these data together, this supports the work of other groups concluding that the rates of serious infections for tofacitinib are within the range of those reported for biologic DMARDs (up to 12 weeks only) [33] and the targeted synthetic DMARD, baricitinib (versus placebo) [29].\n\nAE data in ORAL Sequel indicated some differences between tofacitinib monotherapy and combination therapy. IRs for AEs leading to discontinuation in ORAL Sequel were higher (CI non-overlapping) in patients receiving tofacitinib combination therapy (7.7) compared with patients receiving tofacitinib monotherapy (5.9); SAE IRs were also numerically different (CI marginally overlapping) between patients receiving combination therapy (9.5) and tofacitinib monotherapy (8.1). In terms of AEs of special interest, IRs were higher (CI non-overlapping) in patients receiving tofacitinib as combination therapy versus monotherapy for herpes zoster. Within the subgroup of patients receiving tofacitinib as combination therapy, IRs were higher (CI non-overlapping) with tofacitinib 10 mg BID versus 5 mg BID for all serious infections, herpes zoster, and opportunistic infections excluding tuberculosis.\n\nLaboratory variables of interest, including cholesterol, LDL, ALT, AST, and serum creatinine, remained generally stable over time. ALC levels gradually declined until month 48, whereafter the level stabilized. Overall, 40.6% of patients experienced moderate lymphopenia, and 30.1% of patients experienced severe lymphopenia; these events did not meet with study discontinuation criteria, per protocol. Approximately 1% of patients had a drop in lymphocyte count to < 500 cells/mm3 (potentially life-threatening lymphopenia); however, nearly all recovered to above 500 cells/mm3 upon treatment discontinuation. Additionally, five of these patients experienced a serious infection during the study; two occurred within 30 days of the patients’ lowest lymphocyte count. Although the proportion of patients who developed a serious infection within 30 days of the lowest lymphocyte count was highest among patients with potentially life-threatening lymphopenia, these results should be interpreted with caution due to the low number of patients with ALC < 500 cells/mm3. As per the tofacitinib prescribing information, routine clinical practice should involve evaluation of lymphocyte count at baseline, monitoring every 3 months during tofacitinib treatment, and consideration of the following actions: discontinuation if ALC reaches < 500 cells/mm3 (a level associated with increased risk of serious infections [18, 34]), dose reduction or interruption if ALC reaches 500–750 cells/mm3, and dose maintenance if ALC is ≥ 750 cells/mm3 [35, 36].\n\nClinically meaningful improvements in the signs and symptoms of RA as measured by ACR response rates, DAS28-4(ESR) improvements from baseline, and CDAI- and SDAI-defined remission rates, as well as improvements in physical functioning as measured by HAQ-DI improvements from baseline, were also maintained over time in patients who remained on tofacitinib treatment. Efficacy data for patients receiving tofacitinib monotherapy or tofacitinib plus csDMARD combination therapy were not available here, but have been previously published [17]; in this earlier analysis of data pooled from ORAL Sequel and Study A3921041, efficacy was maintained through to month 72, regardless of treatment regimen.\n\nIt is acknowledged that LTE studies are limited by enrolling eligible patients who completed preceding index studies and excluding those who developed tofacitinib treatment-related SAEs and so were discontinued from preceding index studies. As per the protocol, significant opportunistic infections or serious infection events, and certain malignancies, precluded enrollment to ORAL Sequel. LTE study populations, therefore, represent patients in whom the study drug is known to be efficacious and well tolerated, restricting full evaluation of the benefit to risk profile. It is important to note that a greater exposure (patient-years) occurred with tofacitinib 10 mg BID compared with 5 mg BID, as a result of the majority of patients enrolling from large phase 3 studies and initiating the LTE study at 10 mg BID per protocol (except for patients from China, bringing a geographic skew). Caution should be taken when interpreting results for patients with the longest tofacitinib exposure due to the relatively small patient numbers at later months. Furthermore, tofacitinib dose assignment based on using average TDD does not account for cumulative treatment exposure or dose changes over time. It also does not provide the actual dose when the event occurred; therefore, although 77% of patients remained on their study-start dose, this may have attenuated any between-dose differences for the 5 mg versus 10 mg BID tofacitinib dose. We also recognize that there may be limitations to the interpretation of efficacy results, given that all analyses were conducted “as observed” and patients not achieving an effect on treatment in the qualifying study were more likely to not enroll in the LTE study or discontinue. To this point, it should be noted that only < 4% of patients discontinued from the LTE study due to insufficient clinical response. The lack of a placebo or comparator arm also restricts benefit to risk profile evaluation. Finally, comparisons of data for combination versus monotherapy should be treated with caution because each prior qualifying index study defined the regimen for all patients within that study, and patients were not randomized to dose for the LTE study or to one regimen versus the other (monotherapy versus combination therapy). The monotherapy subgroup was also smaller (n = 1298) than the combination therapy subgroup (n = 2464).\n\nNevertheless, open-label LTE studies provide valuable information. A controlled setting with rigorous safety reporting, including independent adjudication of events, is facilitated. Data for drug exposure are collected over months or years, yielding a long-term safety profile. Indeed, additional long-term studies of tofacitinib are ongoing: Study A3921133 (NCT02092467), an ongoing post-marketing surveillance study, was initiated to compare the safety of tofacitinib versus TNFi in patients with RA in an open-label design. With final enrollment estimated at ~ 4400 patients, outcomes are event-driven, with malignancies excluding NMSC and the incidence of MACE being the primary outcome measures. Study A3921133 is, therefore, anticipated to provide further insights that will contribute further to the evaluation of the benefit to risk profile of tofacitinib. Furthermore, a recent publication on post-marketing surveillance experience with tofacitinib showed that no new safety risks were revealed in this real-world setting compared with the safety profile identified in the RA clinical development program [37]. As of December 2017, it is estimated that over 115,000 patients with RA worldwide have received tofacitinib (Pfizer data on file).\n\nConclusions\nTofacitinib 5 mg and 10 mg BID demonstrated a consistent safety profile and sustained efficacy in this open-label LTE ORAL Sequel study of patients with RA. Safety data are reported up to 9.5 years, and efficacy data up to 8 years, based on adequate patient numbers to support conclusions. Observed IRs for SAEs, serious infections, malignancies, MACE, DVT, and PE were similar to those observed in pooled data from phase 1, 2, 3, and LTE studies, and comparable to those seen with TNFi and other biologic DMARDs. Patient-level laboratory safety data were consistent with findings from prior tofacitinib phase 2, phase 3, and LTE studies. Furthermore, the safety profile of tofacitinib in patients who initiated tofacitinib as monotherapy was generally similar to that observed when tofacitinib was initiated in combination with csDMARDs. Tofacitinib 5 mg and 10 mg BID provided sustained improvement in signs and symptoms of RA and improvements in physical function.\n\nAdditional files\n\nAdditional file 1: Table S1. Summary of qualifying index studies associated with ORAL Sequel (NCT00413699).\n\n \nAdditional file 2: Figure S1. Patient disposition (a) and discontinuation over time (b). aFour patients in the tofacitinib 10 mg BID arm had a missing end-of-study page. bEvaluable for AEs (evaluable for laboratory data: tofacitinib 5 mg BID n = 1118, tofacitinib 10 mg BID n = 3346, and all tofacitinib n = 4464). cTwo patients in the tofacitinib 10 mg BID arm did not have recorded AEs. Safety analysis set: all patients who received at least one dose of study medication; efficacy analysis set: all patients who received at least one dose of study medication and had at least one post-baseline efficacy measurement available. Time to discontinuation: difference between the end-of-study date and first tofacitinib dose date plus 1 day; completers are censored at the end-of-study date. Study discontinuation occurred with the following scenarios: serious infections requiring antimicrobial therapy or hospitalization; opportunistic infections judged to be significant by the investigator; two sequential lymphocyte or neutrophil counts < 500 mm3 (neutrophil counts < 1000 mm3 for patients from Croatia, Czech Republic, Denmark, Germany, Ireland, Korea, Spain, Sweden, and the UK); two sequential platelet counts < 75,000 mm3; two sequential AST or ALT elevations > 3 times the ULN with ≥ 1 total bilirubin value > 2 times the ULN, abnormal International Normalized Ratio liver function test, or symptoms consistent with hepatic injury (or elevations > 5 times the ULN regardless); single positive HBcAb and a negative HBsAb; two sequential hemoglobins < 8.0 g/dL or a decrease > 30% from baseline; two sequential increases in serum creatinine > 100% of the average baseline/screening values (> 50% for Korea); other serious or severe AEs. Database lock: March 2, 2017. AE adverse event, ALT alanine aminotransferase, AST aspartate aminotransferase, BID twice daily, HBcAb hepatitis B core antibody, HBsAb hepatitis B surface antibody, ULN upper limit of normal.\n\n \nAdditional file 3: Table S2. Patient baseline demographic and disease characteristics.\n\n \nAdditional file 4: Figure S2. All-cause AEs (a) and all-cause AEs leading to discontinuation (b) over time. Baseline qualifying index study data were used for approximately 90% of patients. Database lock: March 2, 2017. AE adverse event, BID twice daily.\n\n \nAdditional file 5: Table S3. Incidence of all mortality (a) and mortality listings (b).\n\n \nAdditional file 6: Figure S3. Mean (SE) ALT (a), AST (b), hemoglobin (c), and serum creatinine (d) over time. Baseline qualifying index study data were used for approximately 90% of patients. Data for 12-month intervals are reported in the tables . Database lock: March 2, 2017. ALT alanine aminotransferase, AST aspartate aminotransferase, BID twice daily, SE standard error.\n\n \nAdditional file 7: Table S4. Confirmed AST and ALT > 1×, ≥ 2×, and ≥ 3× ULN.\n\n \nAdditional file 8: Figure S4. ACR50 (a) and ACR70 (b) response rates over time (observed). ACR calculated with respect to qualifying index study data available for approximately 90% of patients. Italicized data not reported in figure due to low patient numbers. Data for 12-month intervals are reported in the tables. Database lock: March 2, 2017. ACR American College of Rheumatology, BID twice daily.\n\n \nAdditional file 9: Figure S5. Remission as defined by CDAI (score ≤ 2.8) (a) and SDAI (score ≤ 3.3) (b) (observed). Baseline qualifying index study data were used for approximately 90% of patients. Italicized data not reported in figure due to low patient numbers. Data for 12-month intervals are reported in the tables. Database lock: March 2, 2017. BID twice daily, BL baseline, CDAI Clinical Disease Activity Index, SDAI Simplified Disease Activity Index, SE standard error.\n\n \n\n\nAbbreviations\nACRAmerican College of Rheumatology\n\nAEAdverse event\n\nALCAbsolute lymphocyte count\n\nALTAlanine aminotransferase\n\nANCAbsolute neutrophil count\n\nASTAspartate aminotransferase\n\nBIDTwice daily\n\nBLBaseline\n\nBMIBody mass index\n\nCDAIClinical Disease Activity Index\n\nCIConfidence interval\n\nCRPC-reactive protein\n\ncsDMARDConventional synthetic disease-modifying antirheumatic drug\n\nDAS28-4(ESR)Disease Activity Score in 28 joints using erythrocyte sedimentation rate\n\nDMARDDisease-modifying antirheumatic drug\n\nEAERExposure-adjusted event rate\n\nECGElectrocardiogram\n\nESRErythrocyte sedimentation rate\n\nHAQ-DIHealth Assessment Questionnaire-Disability Index\n\nHBcAbHepatitis B core antibody\n\nHBsAbHepatitis B surface antibody\n\nIRIncidence rate\n\nLDALow disease activity\n\nLDLLow-density cholesterol\n\nLTELong-term extension\n\nMACEMajor adverse cardiovascular event\n\nMTXMethotrexate\n\nNMSCNon-melanoma skin cancer\n\nPYPatient-years of exposure\n\nQ2WEvery 2 weeks\n\nQDOnce daily\n\nRARheumatoid arthritis\n\nRCTRandomized controlled trial\n\nSAESerious adverse event\n\nSCSubcutaneous\n\nSDStandard deviation\n\nSDAISimplified Disease Activity Index\n\nSEStandard error\n\nSOCSystem organ class\n\nTDDTotal daily dose\n\nTNFiTumor necrosis factor inhibitor\n\nULNUpper limit of normal\n\nAcknowledgements\nMedical writing support, under the guidance of authors, was provided by Louise Brown, at CMC Connect, a division of McCann Health Medical Communications Inc, Radnor, PA, USA, and was funded by Pfizer Inc, New York, NY, USA, in accordance with Good Publication Practice (GPP3) guidelines (Battisti WP, Wager E, Baltzer L, Bridges D, Cairns D, Carswell CI, et al. Good Publication Practice for Communicating Company-Sponsored Medical Research: GPP3. Ann Intern Med. 2015;163:461–4).\n\nFunding\nThis study was sponsored by Pfizer Inc.\n\nAvailability of data and materials\nUpon request, and subject to certain criteria, conditions, and exceptions (see https://www.pfizer.com/science/clinical-trials/trial-data-and-results for more information), Pfizer will provide access to individual de-identified participant data from Pfizer-sponsored global interventional clinical studies conducted for medicines, vaccines, and medical devices (1) for indications that have been approved in the US and/or EU or (2) in programs that have been terminated (i.e., development for all indications has been discontinued). Pfizer will also consider requests for the protocol, data dictionary, and statistical analysis plan. Data may be requested from Pfizer trials 24 months after study completion. The de-identified participant data will be made available to researchers whose proposals meet the research criteria and other conditions, and for which an exception does not apply, via a secure portal. To gain access, data requestors must enter into a data access agreement with Pfizer.\n\nAuthors’ contributions\nLW was involved in the conception and design of the study/analyses. KK and IL performed the data and statistical analyses. JW, EBL, JRC, JS, SC, LW, and JC were involved in patient recruitment, study monitoring, and/or data acquisition (conducted the experiment). All authors were involved in data interpretation and manuscript drafting, reviewing, and development. The views and opinions expressed within this manuscript are those of all authors and do not necessarily represent those of the sponsor. All authors read and approved the final manuscript.\n\nEthics approval and consent to participate\nThis study was conducted in accordance with the International Ethical Guidelines for Biomedical Research Involving Human Subjects, the Declaration of Helsinki, and the Good Clinical Practice Guidelines, along with applicable local regulatory requirements and laws. The study protocol was approved by the Institutional Review Boards and/or Independent Ethics Committee at each study center. All patients provided written, informed consent.\n\nConsent for publication\nNot applicable.\n\nCompeting interests\nJW and SC are consultants for, and have received speaker fees and honoraria from, Pfizer Inc. EBL is a consultant for Pfizer Inc and has received grant/research support from Green Cross Corporation and Hammi Pharm. JRC has received grant/research support and consultant fees from Pfizer Inc. JS has received grant/research support and speaker fees from Pfizer Inc. KT, KS, CM, RD, SS, KW, and LW are employees of, and hold shares in, Pfizer Inc. IL is an employee of IQVIA and a consultant for Pfizer Inc.\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. Cross M Smith E Hoy D Carmona L Wolfe F Vos T The global burden of rheumatoid arthritis: estimates from the global burden of disease 2010 study Ann Rheum Dis 2014 73 1316 1322 10.1136/annrheumdis-2013-204627 24550173 \n2. Fleischmann R Cutolo M Genovese MC Lee EB Kanik KS Sadis S Phase IIb dose-ranging study of the oral JAK inhibitor tofacitinib (CP-690,550) or adalimumab monotherapy versus placebo in patients with active rheumatoid arthritis with an inadequate response to disease-modifying antirheumatic drugs Arthritis Rheum 2012 64 617 629 10.1002/art.33383 21952978 \n3. Kremer JM Bloom BJ Breedveld FC Coombs JH Fletcher MP Gruben D The safety and efficacy of a JAK inhibitor in patients with active rheumatoid arthritis: results of a double-blind, placebo-controlled phase IIa trial of three dosage levels of CP-690,550 versus placebo Arthritis Rheum 2009 60 1895 1905 10.1002/art.24567 19565475 \n4. Kremer JM Cohen S Wilkinson BE Connell CA French JL Gomez-Reino J A phase IIb dose-ranging study of the oral JAK inhibitor tofacitinib (CP-690,550) versus placebo in combination with background methotrexate in patients with active rheumatoid arthritis and an inadequate response to methotrexate alone Arthritis Rheum 2012 64 970 981 10.1002/art.33419 22006202 \n5. Tanaka Y, Suzuki M, Nakamura H, Toyoizumi S, Zwillich SH, Tofacitinib Study Investigators. Phase II study of tofacitinib (CP-690,550) combined with methotrexate in patients with rheumatoid arthritis and an inadequate response to methotrexate. Arthritis Care Res (Hoboken). 2011;63:1150–8.\n6. Tanaka Y Takeuchi T Yamanaka H Nakamura H Toyoizumi S Zwillich S Efficacy and safety of tofacitinib as monotherapy in Japanese patients with active rheumatoid arthritis: a 12-week, randomized, phase 2 study Mod Rheumatol 2015 25 514 521 10.3109/14397595.2014.995875 25496464 \n7. Burmester GR Blanco R Charles-Schoeman C Wollenhaupt J Zerbini C Benda B Tofacitinib (CP-690,550) in combination with methotrexate in patients with active rheumatoid arthritis with an inadequate response to tumour necrosis factor inhibitors: a randomised phase 3 trial Lancet. 2013 381 451 460 10.1016/S0140-6736(12)61424-X 23294500 \n8. Fleischmann R Mysler E Hall S Kivitz AJ Moots RJ Luo Z Efficacy and safety of tofacitinib monotherapy, tofacitinib with methotrexate, and adalimumab with methotrexate in patients with rheumatoid arthritis (ORAL strategy): a phase 3b/4, double-blind, head-to-head, randomised controlled trial Lancet. 2017 390 457 468 10.1016/S0140-6736(17)31618-5 28629665 \n9. Fleischmann R Kremer J Cush J Schulze-Koops H Connell CA Bradley JD Placebo-controlled trial of tofacitinib monotherapy in rheumatoid arthritis N Engl J Med 2012 367 495 507 10.1056/NEJMoa1109071 22873530 \n10. Kremer J Li Z-G Hall S Fleischmann R Genovese M Martin-Mola E Tofacitinib in combination with nonbiologic disease-modifying antirheumatic drugs in patients with active rheumatoid arthritis: a randomized trial Ann Intern Med 2013 159 253 261 10.7326/0003-4819-159-4-201308200-00006 24026258 \n11. Lee EB Fleischmann R Hall S Wilkinson B Bradley J Gruben D Tofacitinib versus methotrexate in rheumatoid arthritis N Engl J Med 2014 370 2377 2386 10.1056/NEJMoa1310476 24941177 \n12. van der Heijde D Tanaka Y Fleischmann R Keystone E Kremer J Zerbini C Tofacitinib (CP-690,550) in patients with rheumatoid arthritis receiving methotrexate: twelve-month data from a twenty-four-month phase III randomized radiographic study Arthritis Rheum 2013 65 559 570 10.1002/art.37816 23348607 \n13. van Vollenhoven RF Fleischmann R Cohen S Lee EB García Meijide JA Wagner S Tofacitinib or adalimumab versus placebo in rheumatoid arthritis N Engl J Med 2012 367 508 519 10.1056/NEJMoa1112072 22873531 \n14. Wollenhaupt J Silverfield J Lee EB Curtis JR Wood SP Soma K Safety and efficacy of tofacitinib, an oral Janus kinase inhibitor, for the treatment of rheumatoid arthritis in open-label, longterm extension studies J Rheumatol 2014 41 837 852 10.3899/jrheum.130683 24692527 \n15. Yamanaka H Tanaka Y Takeuchi T Sugiyama N Yuasa H Toyoizumi S Tofacitinib, an oral Janus kinase inhibitor, as monotherapy or with background methotrexate, in Japanese patients with rheumatoid arthritis: an open-label, long-term extension study Arthritis Res Ther 2016 18 34 10.1186/s13075-016-0932-2 26818974 \n16. Wollenhaupt J Silverfield J Lee EB Terry K Kwok K Strengholt S Tofacitinib, an oral Janus kinase inhibitor, in the treatment of rheumatoid arthritis: safety and efficacy in open-label, long-term extension studies over 9 years Arthritis Rheumatol. 2017 69 683 684 10.1002/art.39972 27788282 \n17. Fleischmann R Wollenhaupt J Takiya L Maniccia A Kwok K Wang L Safety and maintenance of response for tofacitinib monotherapy and combination therapy in rheumatoid arthritis: an analysis of pooled data from open-label long-term extension studies RMD Open 2017 3 e000491 10.1136/rmdopen-2017-000491 29435359 \n18. Cohen SB Tanaka Y Mariette X Curtis JR Lee EB Nash P Long-term safety of tofacitinib for the treatment of rheumatoid arthritis up to 8.5 years: integrated analysis of data from the global clinical trials Ann Rheum Dis 2017 76 1253 1262 10.1136/annrheumdis-2016-210457 28143815 \n19. Winthrop KL Park SH Gul A Cardiel MH Gomez-Reino JJ Tanaka Y Tuberculosis and other opportunistic infections in tofacitinib-treated patients with rheumatoid arthritis Ann Rheum Dis 2016 75 1133 1138 10.1136/annrheumdis-2015-207319 26318385 \n20. Alten R Kaine J Keystone E Nash P Delaet I Genovese MC Long-term safety of subcutaneous abatacept in rheumatoid arthritis: integrated analysis of clinical trial data representing more than four years of treatment Arthritis Rheumatol. 2014 66 1987 1997 10.1002/art.38687 24782324 \n21. Dixon WG Hyrich KL Watson KD Lunt M Galloway J Ustianowski A Drug-specific risk of tuberculosis in patients with rheumatoid arthritis treated with anti-TNF therapy: results from the British Society for Rheumatology Biologics Register (BSRBR) Ann Rheum Dis 2010 69 522 528 10.1136/ard.2009.118935 19854715 \n22. Schiff MH Burmester GR Kent JD Pangan AL Kupper H Fitzpatrick SB Safety analyses of adalimumab (HUMIRA) in global clinical trials and US postmarketing surveillance of patients with rheumatoid arthritis Ann Rheum Dis 2006 65 889 894 10.1136/ard.2005.043166 16439435 \n23. Xie F Yun H Bernatsky S Curtis JR Brief report: risk of gastrointestinal perforation among rheumatoid arthritis patients receiving tofacitinib, tocilizumab, or other biologic treatments Arthritis Rheumatol. 2016 68 2612 2617 10.1002/art.39761 27213279 \n24. Mease PJ Kremer J Cohen S Curtis JR Charles-Schoeman C Loftus EV Incidence of thromboembolic events in the tofacitinib rheumatoid arthritis, psoriasis, psoriatic arthritis and ulcerative colitis development programs Arthritis Rheumatol 2017 69 52 55 \n25. Kim SC Schneeweiss S Liu J Solomon DH Risk of venous thromboembolism in patients with rheumatoid arthritis Arthritis Care Res (Hoboken) 2013 65 1600 1607 23666917 \n26. Ogdie A, Kay McGill N, Shin DB, Takeshita J, Jon Love T, Noe MH, et al. Risk of venous thromboembolism in patients with psoriatic arthritis, psoriasis and rheumatoid arthritis: a general population-based cohort study. Eur Heart J. 2018;39:3608–14.\n27. Furst DE Kavanaugh A Florentinus S Kupper H Karunaratne M Birbara CA Final 10-year effectiveness and safety results from study DE020: adalimumab treatment in patients with rheumatoid arthritis and an inadequate response to standard therapy Rheumatology (Oxford) 2015 54 2188 2197 26199453 \n28. Genovese MC Pacheco-Tena C Covarrubias A Leon G Mysler E Keiserman M Longterm safety and efficacy of subcutaneous abatacept in patients with rheumatoid arthritis: 5-year results from a phase IIIb trial J Rheumatol 2018 45 1085 1092 10.3899/jrheum.170344 29657147 \n29. Genovese MC Smolen JS Takeuchi T Rooney TP Dickson CL Yang X-Y Safety profile of baricitinib for the treatment of rheumatoid arthritis up to 6 years: an updated integrated safety analysis Arthritis Rheumatol. 2018 70 abstract 962 10.1002/art.40580 \n30. Weinblatt M Taylor P Burmester G Saifan C Walls C Issa M Cardiovascular safety - update from up to 6 years of treatment with baricitinib in rheumatoid arthritis clinical trials Arthritis Rheumatol. 2018 70 abstract 2815 \n31. Strand V Ahadieh S DeMasi R Krishnaswami S Geier J Menon S Meta-analysis of serious infections with baricitinib, tofacitinib and biologic DMARDs in rheumatoid arthritis Ann Rheum Dis 2017 76 284 10.1136/annrheumdis-2015-209055 \n32. Gomez-Reino JJ Checchio T Geier J Boy M Ahadieh S Menon S Systematic review and meta-analysis of malignancies, excluding non-melanoma skin cancer, in patients with rheumatoid arthritis treated with tofacitinib or biologic disease-modifying antirheumatic drugs Ann Rheum Dis 2017 76 277 10.1136/annrheumdis-2015-209064 27457515 \n33. Vieira MC Zwillich SH Jansen JP Smiechowski B Spurden D Wallenstein GV Tofacitinib versus biologic treatments in patients with active rheumatoid arthritis who have had an inadequate response to tumor necrosis factor inhibitors: results from a network meta-analysis Clin Ther 2016 38 2628 2641 10.1016/j.clinthera.2016.11.004 27889300 \n34. van Vollenhoven R, Lee EB, Strengholt S, Mojcik C, Valdez H, Krishnaswami S, et al. Evaluation of the short-, mid-, and long-term effects of tofacitinib on lymphocytes in patients with rheumatoid arthritis. Arthritis Rheumatol. 2018. 10.1002/art.40780.\n35. European Medicines Agency. Xeljanz (tofacitinib citrate) - summary of product characteristics. 2017. https://www.medicines.org.uk/emc/medicine/33167. Accessed 15 Mar 2019.\n36. Pfizer Inc. XELJANZ prescribing information. 2012. http://labeling.pfizer.com/ShowLabeling.aspx?id=959. Accessed 15 Mar 2019.\n37. Cohen S Curtis JR DeMasi R Chen Y Fan H Soonasra A Worldwide, 3-year, post-marketing surveillance experience with tofacitinib in rheumatoid arthritis Rheumatol Ther 2018 5 283 291 10.1007/s40744-018-0097-3 29470834\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1478-6354",
"issue": "21(1)",
"journal": "Arthritis research & therapy",
"keywords": "Long-term extension; Rheumatoid arthritis; Tofacitinib",
"medline_ta": "Arthritis Res Ther",
"mesh_terms": "D000284:Administration, Oral; D000328:Adult; D000368:Aged; D018501:Antirheumatic Agents; D001172:Arthritis, Rheumatoid; D002318:Cardiovascular Diseases; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D005500:Follow-Up Studies; D006562:Herpes Zoster; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011758:Pyrroles; D013997:Time Factors; D016896:Treatment Outcome",
"nlm_unique_id": "101154438",
"other_id": null,
"pages": "89",
"pmc": null,
"pmid": "30953540",
"pubdate": "2019-04-05",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't",
"references": "22873530;24941177;26199453;28444172;24782324;16439435;22006202;21584942;27889300;28143815;22873531;19565475;26818974;24550173;27213279;21952978;29435359;26318385;23294500;30427585;19854715;23666917;24026258;24692527;29657147;23348607;28629665;25496464;29470834",
"title": "Safety and efficacy of tofacitinib for up to 9.5 years in the treatment of rheumatoid arthritis: final results of a global, open-label, long-term extension study.",
"title_normalized": "safety and efficacy of tofacitinib for up to 9 5 years in the treatment of rheumatoid arthritis final results of a global open label long term extension study"
} | [
{
"companynumb": "JP-PFIZER INC-2013137119",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CLOPIDOGREL BISULFATE"
},
"drugadditional": n... |
{
"abstract": "A case is presented of a male with drug rash with eosinophilia and systemic symptoms (DRESS) syndrome induced by carbamazepine intake. The patient presented all the elements of DRESS syndrome: Skin reaction, fever, enlargement of the lymph nodes, increased eosinophils and lymphocytes, with associated organ dysfunctions. The patient was admitted with acute laryngeal edema and imminence of respiratory insufficiency. The escalation of symptoms for this syndrome is typical, even after the administering of the the culprit medicine has ceased. However, in this case, the most difficult aspect was the complex treatment scheme prior to admission. All medical compounds involved in the background treatment were substituted with other substances in order to control the immune response. Current knowledge regarding DRESS is reviewed and possible influence of various etiologies over the present case are discussed. Clinicians should be aware of this rare situation with life-threatening potential. We benefited from the advantage of reuniting the knowledge of a complex team of experts from various tertiary emergency units in Romania.",
"affiliations": "ENT Department, Bucharest Emergency University Hospital, 010271 Bucharest, Romania.;Department of Anatomy, 'Carol Davila' University of Medicine and Pharmacy, 050474 Bucharest, Romania.;ENT Department, Bucharest Emergency University Hospital, 010271 Bucharest, Romania.;ENT Department, Târgu Mureş University of Medicine and Pharmacy, 540139 Târgu Mureş, Romania.;ENT Department, 'Sânta Maria' Clinical Hospital, 011172 Bucharest, Romania.;Department of Anesthesia and ICU, Bucharest Emergency University Hospital, 020021 Bucharest, Romania.",
"authors": "Vrinceanu|Daniela|D|;Dumitru|Mihai|M|;Stefan|Adrian|A|;Neagos|Adriana|A|;Musat|Gabriela|G|;Nica|Elena Adriana|EA|",
"chemical_list": null,
"country": "Greece",
"delete": false,
"doi": "10.3892/etm.2020.8894",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1792-0981",
"issue": "20(3)",
"journal": "Experimental and therapeutic medicine",
"keywords": "DRESS syndrome; addiction; carbamazepine; eosinophilia; respiratory distress",
"medline_ta": "Exp Ther Med",
"mesh_terms": null,
"nlm_unique_id": "101531947",
"other_id": null,
"pages": "2377-2380",
"pmc": null,
"pmid": "32765718",
"pubdate": "2020-09",
"publication_types": "D016428:Journal Article",
"references": "27996289;32099824;27126302;27134114;29255708;28868484;25360193;29242946;28296768;21359537;26418832;28598363",
"title": "Severe DRESS syndrome after carbamazepine intake in a case with multiple addictions: A case report.",
"title_normalized": "severe dress syndrome after carbamazepine intake in a case with multiple addictions a case report"
} | [
{
"companynumb": "RO-ALLERGAN-2044808US",
"fulfillexpeditecriteria": "1",
"occurcountry": "RO",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "AMOXICILLIN"
},
"drugadditional": "3",
... |
{
"abstract": "Anabolic steroid use is prevalent among athletes and bodybuilders. There are known cardiovascular, reproductive, musculoskeletal and neuropsychiatric risks associated with their prolonged use. Although there have been very few documented cases of strokes associated with anabolic steroid use, cardiomyopathy and secondary erythropoiesis can increase the risk of strokes in users with no other risk factors. We present a 49-year-old man with left parietal ischaemic stroke with haemorrhagic conversion resulting in Gerstmann syndrome secondary to a hypercoagulable state from chronic anabolic steroid use.",
"affiliations": "School of Osteopathic Medicine, Touro University Nevada, Henderson, Nevada, USA.;Internal Medicine Residency, MountainView Hospital, Las Vegas, Nevada, USA.;Internal Medicine Residency, MountainView Hospital, Las Vegas, Nevada, USA.;Internal Medicine Residency, MountainView Hospital, Las Vegas, Nevada, USA.",
"authors": "Long|Nina|N|;Bassi|Satnaam|S|;Pepito|Don|D|;Akhondi|Hossein|H|http://orcid.org/0000-0001-5035-8295",
"chemical_list": "D045930:Anabolic Agents; D013256:Steroids",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2018-229004",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "12(6)",
"journal": "BMJ case reports",
"keywords": "neurological injury; public health; stroke",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D045930:Anabolic Agents; D002545:Brain Ischemia; D002543:Cerebral Hemorrhage; D005862:Gerstmann Syndrome; D006801:Humans; D008297:Male; D008875:Middle Aged; D018962:Phlebotomy; D011086:Polycythemia; D013256:Steroids; D014891:Weight Lifting",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "31175112",
"pubdate": "2019-06-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "18382179;15793561;19337562;30403310;3408335;29150164;30410343;24574525;12534854;30460728",
"title": "Gerstmann syndrome complicating polycythemia secondary to anabolic steroid use.",
"title_normalized": "gerstmann syndrome complicating polycythemia secondary to anabolic steroid use"
} | [
{
"companynumb": "US-PFIZER INC-2019274159",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TRENBOLONE ACETATE"
},
"drugadditional": "3",
... |
{
"abstract": "Urachal carcinoma is a rare type of non-urothelial malignancy that arises from the urachal ligament, a remnant of fetal development. It frequently involves the dome of the bladder or its midline, with adenocarcinoma being the most common histological type. This malignancy is generally diagnosed in advanced stages and is associated with poor prognosis.\n\n\n\nA 40-year-old woman was referred to hospital due to recurrent urinary tract infections. Imaging studies showed the presence of a 3.7 cm tumor in the bladder dome that extended to the posterior region of the umbilicus. A biopsy through cystoscopy confirmed the diagnosis of urachal carcinoma. Since there were no metastases, the patient underwent partial cystectomy and resection of the urachal ligament and the umbilicus. Surgical margins were negative and it was considered a complete resection. Nine months later, disease progression occurred, with peritoneal carcinomatosis, multiple adenopathies and a 4 cm mass in the pelvic cavity with invasion of the vagina, rectum, and sigmoid colon. She began palliative chemotherapy with cisplatine and 5-fluorouracil. After 7 cycles, progression was again observed, with an increase of the pelvic mass, vaginal and rectal hemorrhage, multiple intramuscular implants, bilateral axillary adenopathies, as well as lesion in the right breast, which was compatible with metastasis from urachal carcinoma. She underwent hemostatic radiotherapy to the pelvic mass and second line palliative chemotherapy with gemcitabine and paclitaxel. After 4 cycles, the patient clinically deteriorated and eventually died.\n\n\n\nUrachal carcinoma is an aggressive malignancy. Although systemic treatment may be effective in disease control, a standard chemotherapy regimen is yet to be determined. Multicenter trials are needed to clarify the best treatment approach in these patients.",
"affiliations": "Oncology Department, Portuguese Institute of Oncology Francisco Gentil, Porto, Portugal. Electronic address: ines.almeida.moreira@ipoporto.min-saude.pt.;Oncology Department, Portuguese Institute of Oncology Francisco Gentil, Porto, Portugal.;Pathology Department, Portuguese Institute of Oncology Francisco Gentil, Porto, Portugal.;Oncology Department, Portuguese Institute of Oncology Francisco Gentil, Porto, Portugal.;Oncology Department, Portuguese Institute of Oncology Francisco Gentil, Porto, Portugal.",
"authors": "Moreira|Inês|I|;Coelho|Sara|S|;Rodrigues|Ângelo|Â|;Patrão|Ana Sofia|AS|;Maurício|Maria Joaquina|MJ|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.currproblcancer.2021.100711",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0147-0272",
"issue": "45(6)",
"journal": "Current problems in cancer",
"keywords": "Chemotherapy; Metastatic; Multimodal treatment; Urachal carcinoma",
"medline_ta": "Curr Probl Cancer",
"mesh_terms": null,
"nlm_unique_id": "7702986",
"other_id": null,
"pages": "100711",
"pmc": null,
"pmid": "33541722",
"pubdate": "2021-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Urachal carcinoma: A case of a rare neoplasm.",
"title_normalized": "urachal carcinoma a case of a rare neoplasm"
} | [
{
"companynumb": "PT-MYLANLABS-2022M1039949",
"fulfillexpeditecriteria": "1",
"occurcountry": "PT",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "GEMCITABINE"
},
"drugadditional": null,
... |
{
"abstract": "Stroke is an uncommon but serious potential complication of pregnancy. The management of acute ischemic stroke in pregnant women remains a complex challenge that extends beyond the limits of clinical trial evidence. Patient 1 was a 29-year-old woman 27 weeks into her first pregnancy, without remarkable past medical history or vascular risk factors. She was admitted 1 h after sudden onset of a left total anterior circulation syndrome (National Institute of Health Stroke Scale [NIHSS] score of 23). CT and angio-CT scans were normal. Thrombolysis was performed, with mild clinical improvement. Brain MRI showed multi-territorial embolic events. Extended blood panel, cervical-transcranial ultrasound, 48-h ECG monitoring, and transthoracic echocardiogram were unremarkable. She was started on aspirin and low-molecular-weight heparin (LMWH), giving birth to a healthy child 10 weeks later. Patient 2 was a 45-year-old woman 34 weeks into her pregnancy, without remarkable past medical history or vascular risk factors. She was admitted 30 min after sudden onset of a left partial anterior circulation syndrome, already partially recovered (NIHSS score of 4). The CT scan showed only a subacute right incidental middle cerebral artery infarct, while the angio-CT confirmed a left M3 branch occlusion. Thrombolysis and thrombectomy were contraindicated by the recent contralateral infarct, mild deficits, and distal occlusion site. Brain MRI also suggested an embolic etiology and LMWH was started. Extended blood panel, 48-h ECG monitoring, and transthoracic echocardiogram were normal. She gave birth to a healthy baby 4 weeks later. These cases emphasize the growing real-world evidence of the emergent use of CT, IV contrast, and recombinant tissue plasminogen activator in pregnant women with acute stroke, while also illustrating the importance of an individualized management, accounting for the safety of both mother and child.",
"affiliations": "Neurology Department, Centro Hospitalar de Entre Douro e Vouga, Santa Maria da Feira, Portugal.;Neurology Department, Centro Hospitalar de Entre Douro e Vouga, Santa Maria da Feira, Portugal.;Neurology Department, Centro Hospitalar de Entre Douro e Vouga, Santa Maria da Feira, Portugal.;Neurology Department, Centro Hospitalar de Entre Douro e Vouga, Santa Maria da Feira, Portugal.;Neurology Department, Centro Hospitalar de Entre Douro e Vouga, Santa Maria da Feira, Portugal.",
"authors": "Rodrigues|Rita|R|;Silva|Renata|R|;Fontão|Luís|L|;Ruano|Luís|L|;Roriz|José Mário|JM|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000496386",
"fulltext": "\n==== Front\nCase Rep NeurolCase Rep NeurolCRNCase Reports in Neurology1662-680XS. Karger AG Allschwilerstrasse 10, P.O. Box · Postfach · Case postale, CH-4009, Basel, Switzerland · Schweiz · Suisse, Phone: +41 61 306 11 11, Fax: +41 61 306 12 34, karger@karger.ch 10.1159/000496386crn-0011-0037Case ReportAcute Ischemic Stroke in Pregnancy Rodrigues Rita a*Silva Renata aFontão Luís aRuano Luís abRoriz José Mário aaNeurology Department, Centro Hospitalar de Entre Douro e Vouga, Santa Maria da Feira, PortugalbDepartamento de Ciências da Saúde Pública e Forenses e Educação Médica, Faculdade de Medicina, Universidade do Porto, Porto, Portugal*Rita Rodrigues, Neurology Department, Centro Hospitalar de Entre Douro e Vouga, Rua Dr. Cândido de Pinho, PT–4520-211 Santa Maria da Feira (Portugal), E-Mail arodrigues.rita@gmail.comJan-Apr 2019 8 2 2019 8 2 2019 11 1 37 40 17 10 2018 17 12 2018 2019 Copyright © 2019 by S. Karger AG, Basel2019This 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.Stroke is an uncommon but serious potential complication of pregnancy. The management of acute ischemic stroke in pregnant women remains a complex challenge that extends beyond the limits of clinical trial evidence. Patient 1 was a 29-year-old woman 27 weeks into her first pregnancy, without remarkable past medical history or vascular risk factors. She was admitted 1 h after sudden onset of a left total anterior circulation syndrome (National Institute of Health Stroke Scale [NIHSS] score of 23). CT and angio-CT scans were normal. Thrombolysis was performed, with mild clinical improvement. Brain MRI showed multi-territorial embolic events. Extended blood panel, cervical-transcranial ultrasound, 48-h ECG monitoring, and transthoracic echocardiogram were unremarkable. She was started on aspirin and low-molecular-weight heparin (LMWH), giving birth to a healthy child 10 weeks later. Patient 2 was a 45-year-old woman 34 weeks into her pregnancy, without remarkable past medical history or vascular risk factors. She was admitted 30 min after sudden onset of a left partial anterior circulation syndrome, already partially recovered (NIHSS score of 4). The CT scan showed only a subacute right incidental middle cerebral artery infarct, while the angio-CT confirmed a left M3 branch occlusion. Thrombolysis and thrombectomy were contraindicated by the recent contralateral infarct, mild deficits, and distal occlusion site. Brain MRI also suggested an embolic etiology and LMWH was started. Extended blood panel, 48-h ECG monitoring, and transthoracic echocardiogram were normal. She gave birth to a healthy baby 4 weeks later. These cases emphasize the growing real-world evidence of the emergent use of CT, IV contrast, and recombinant tissue plasminogen activator in pregnant women with acute stroke, while also illustrating the importance of an individualized management, accounting for the safety of both mother and child.\n\nKeywords\nAcute ischemic strokePregnancyThrombolysis\n==== Body\nIntroduction\nStroke is an uncommon but serious potential complication of pregnancy and puerperium [1, 2]. According to the recent American Heart Association/American Stroke Association (AHA/ASA) guidelines, the treatment of acute ischemic stroke with intravenous alteplase during pregnancy may be considered when the anticipated benefits of treating moderate to severe stroke outweigh the anticipated increased risks of uterine bleeding (Class IIb) [3]. Several case reports have documented successful reperfusion, in addition to satisfactory maternal and fetal outcomes [4]. However, management of an acute ischemic stroke during pregnancy remains a clinical challenge concerning the safety of both the mother and the unborn child [5].\n\nHerein, we present two clinical cases of stroke in pregnant women with different individualized therapeutic approaches.\n\nPatient 1\nPatient 1 was a 29-year-old woman 27 weeks into her first pregnancy, without remarkable past medical history or known vascular risk factors. Recently emigrated from Brazil, she was admitted to the emergency department 1 h after sudden onset of mutism and right-sided motor deficit. On initial neurological examination, she had global aphasia, left gaze deviation, right homonymous hemianopsia, a right-sided hemiplegia and hypoesthesia with facial involvement, and a right Babinski sign, suggesting a left total anterior circulation syndrome. A noncontrast CT scan was normal. She was clinically diagnosed with an acute ischemic stroke in the left middle cerebral artery (MCA) territory, with a National Institute of Health Stroke Scale (NIHSS) score of 23. No contraindications to intravenous recombinant tissue plasminogen activator (rtPA) were identified, so the bolus was administered on the CT table with 15-min door-to-needle time. CT angiogram was then performed, excluding large-vessel occlusion or stenosis, cerebral venous thrombosis, or arterial dissection. The rtPA perfusion was completed without complications. A mild improvement of her right hemiparesis was observed in the first 24 h, but the aphasia and right hemianopsia persisted. We were not able to perform a CT perfusion or an MRI angiography in the acute phase because these technologies are not available in our stroke unit.\n\nThe control CT scan at 24 h showed an established left MCA infarct, with apparent involvement of the ipsilateral anterior cerebral artery (ACA). Brain MRI, performed 5 days after the stroke, confirmed an extensive recent ischemic lesion in the left MCA and left ACA territories, with interhemispheric extension through the genu of the corpus callosum. Angio-MRI revealed complete occlusion of the proximal left MCA and partially recanalized bilateral ACA thrombosis, suggesting recurrent multi-territorial embolism after the initially unremarkable angio-CT. She was started on aspirin 100 mg/day about 24 h after thrombolysis and low-molecular-weight heparin (LMWH) 60 mg b.i.d. only 12 days after stroke because of the extension of the ischemic lesion and the high NIHSS score.\n\nAn extended blood panel was unremarkable for thrombophilia, autoimmune diseases, occult neoplasia, hemoglobinopathies, HIV, malaria, dengue, or drugs. Cervical-transcranial ultrasound, 48-h ECG monitoring, and transthoracic echocardiogram were normal, except for persistent left M1 occlusion. A search for patent foramen ovale, monitoring for shunted air-microbubbles with transcranial Doppler, was negative. Serial obstetric ultrasonography also showed no signs of placental displacement or obstetric complication consistent with amniotic embolism.\n\nAt the time of discharge, 44 days after the vascular event, she had recovered from the initial comprehension deficits, agraphia, and hemianopsia. While motor aphasia and right hemiparesis persisted, she was already capable of gait with bilateral support, scoring NIHSS 14. She gave birth to a healthy child 10 weeks after the stroke, by cesarean delivery.\n\nPatient 2\nPatient 2 was a 45-year-old woman at 34 weeks' gestation, G2P1, without remarkable past medical history or known vascular risk factors. She was admitted to the emergency department 30 min after sudden onset of slurred speech, facial asymmetry, and weakness of the right arm. She reported partial spontaneous improvement during the transportation to the hospital. Neurological examination on admission detected only mild anomic aphasia, slight dysarthria, and right supranuclear facial palsy, scoring NIHSS 4. A noncontrast brain CT scan revealed a subacute infarct in the right MCA territory, without acute signs of left hemispheric ischemia. CT angiogram, however, confirmed a left M3 segment occlusion. Considering the presence of a subacute infarct and the minor deficits, thrombolysis was not performed. The distal branch occlusion of the left MCA was deemed inaccessible to endovascular treatment.\n\nBrain MRI and angio-MRI, done 2 days later, confirmed both the acute infarct in the left inferior frontal gyrus and the subacute infarct in the right fronto-insular cortex, with an occlusion of the insular branch of the left MCA. The multiple infarcts in different vascular territories, suggesting a central embolic etiology, and the small extension of the acute stroke supported the decision to start a therapeutic dose of LMWH (60 mg b.i.d.) 3 days after the stroke.\n\nAn extended blood panel workup revealed only mild anemia (Hb 10.3 g/dL) and dyslipidemia (total cholesterol 224 mg/dL, LDL 115 mg/dL, HDL 41 mg/dL), without other relevant changes. Serum markers for thrombophilia, autoimmune diseases, and occult neoplasia were negative. ECG monitoring and transthoracic echocardiogram were also normal. Serial obstetric ultrasonography was unremarkable.\n\nShe remained neurologically stable and was discharged home 1 week after admission, completely recovered except for very mild anomic aphasia, corresponding to an NIHSS score of 1. She gave birth to a healthy baby 4 weeks after the stroke, by eutocic delivery.\n\nDiscussion\nThere are only limited data comparing the therapeutic approaches and clinical outcomes of pregnant with nonpregnant women of the same age range. Pregnancy was an exclusion criterion in all clinical trials that assessed the use of alteplase in acute stroke, so our knowledge about its efficacy and safety comes exclusively from case reports and case series [6, 7]. According to the recent AHA/ASA guidelines, the use of intravenous alteplase seems to be relatively safe during pregnancy and can be considered in acute stroke cases with moderate to severe deficits [3].\n\nIn most patients, the evaluation and treatment of stroke during pregnancy should, thus, be the same as in the nonpregnant state [3, 8]. Whenever stroke is suspected in a pregnant woman, the stroke protocol should be activated immediately, considering the currently available time-dependent treatments.\n\nBoth our patients performed an acute-phase CT and CT angiogram, which were essential to support the diagnosis and the therapeutic decisions. Despite the theoretical risks of ionizing radiation and IV contrast for the fetus, it is important to demystify its use in acute stroke, since delayed diagnosis precludes an effective treatment and can lead to worse outcomes for both mother and child. Additionally, the fetal irradiation risk can be minimized by the use of a lead apron.\n\nIn our first patient, the stroke team decided to perform thrombolysis, considering the potential benefits of treatment seemed to outweigh the risks of uterine bleeding. In the second patient, the mild deficits and the presence of an established subacute contralateral infarction led to a more conservative attitude.\n\nThese cases emphasize the importance of a careful and individualized management of stroke in pregnant women, since it is a very complex process that extends beyond the limits of clinical trial evidence. It is important that further cumulative real-world evidence can be gathered and that specific clinical guidelines are developed on this topic, to reduce the morbidity associated with this potentially devastating event.\n\nStatement of Ethics\nThe authors have no ethical conflicts to declare.\n\nDisclosure Statement\nThe publication fee for this paper was supported by Boehringer Ingelheim.\n==== Refs\nReferences\n1 Terón I Eng MS Katz JM Causes and treatment of acute ischemic stroke during pregnancy Curr Treat Options Neurol 2018 5 20 (6) 21 29785465 \n2 Sells CM Feske SK Stroke in Pregnancy Semin Neurol 2017 12 37 (6) 669 78 29270940 \n3 Powers WJ Rabinstein AA Ackerson T Adeoye OM Bambakidis NC Becker K American Heart Association Stroke Council 2018 Guidelines for the Early Management of Patients With Acute Ischemic Stroke: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association Stroke 2018 3 49 (3) e46 110 29367334 \n4 Tettenborn B Stroke and pregnancy Neurol Clin 2012 8 30 (3) 913 24 22840796 \n5 van Alebeek ME de Heus R Tuladhar AM de Leeuw FE Pregnancy and ischemic stroke: a practical guide to management Curr Opin Neurol 2018 2 31 (1) 44 51 29120921 \n6 Tassi R Acampa M Marotta G Cioni S Guideri F Rossi S Systemic thrombolysis for stroke in pregnancy Am J Emerg Med 2013 2 31 (2) 448.e1 3 \n7 Tversky S Libman RB Reppucci ML Tufano AM Katz JM Thrombolysis for Ischemic Stroke during Pregnancy: a case report and review of the literature J Stroke Cerebrovasc Dis 2016 10 25 (10) e167 70 27523596 \n8 O'Neal MA Feske SK Stroke in pregnancy: a case-oriented review Pract Neurol 2016 2 16 (1) 23 34 26349835\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1662-680X",
"issue": "11(1)",
"journal": "Case reports in neurology",
"keywords": "Acute ischemic stroke; Pregnancy; Thrombolysis",
"medline_ta": "Case Rep Neurol",
"mesh_terms": null,
"nlm_unique_id": "101517693",
"other_id": null,
"pages": "37-40",
"pmc": null,
"pmid": "31543784",
"pubdate": "2019",
"publication_types": "D002363:Case Reports",
"references": "22840796;22867835;26349835;27523596;29120921;29270940;29367334;29785465",
"title": "Acute Ischemic Stroke in Pregnancy.",
"title_normalized": "acute ischemic stroke in pregnancy"
} | [
{
"companynumb": "PT-BAYER-2019-042509",
"fulfillexpeditecriteria": "1",
"occurcountry": "PT",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "HEPARIN SODIUM"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nTo report the clinical course of a patient with acute retinal necrosis resulting from a multidrug-resistant strain of herpes simplex virus 2.\n\n\nMETHODS\nObservational case report.\n\n\nRESULTS\nA 17-year-old man with no identifiable immune deficiency presented with pain and decreased vision in his left eye. He had dense anterior and posterior segment inflammation with retinal whitening suggestive of acute retinal necrosis, which progressed despite treatment with intravenous acyclovir, methylprednisolone, and ganciclovir. A transition to intravitreal and intravenous foscarnet led to clinical improvement. Genetic analysis revealed the etiology to be a multidrug-resistant strain of herpes simplex virus 2.\n\n\nCONCLUSIONS\nAntiviral resistance is an uncommon finding among viruses causing acute retinal necrosis in immunocompetent patients. Patients with these infections may be adequately treated with prompt recognition and a change in therapy to alternative antiviral agents such as foscarnet.",
"affiliations": "*Department of Ophthalmology, California Pacific Medical Center, San Francisco, California; †West Coast Retina Medical Group, San Francisco, California; ‡Department of Ophthalmology, Stanford University School of Medicine, Palo Alto, California; and §Department of Vision Science, Berkeley School of Optometry, University of California, Berkeley, California.",
"authors": "Dokey|Adrian T|AT|;Haug|Sara J|SJ|;McDonald|H Richard|HR|;Cunningham|Emmett T|ET|;Lujan|Brandon J|BJ|;Fu|Arthur D|AD|;Jumper|J Michael|JM|",
"chemical_list": "D000998:Antiviral Agents; D017245:Foscarnet",
"country": "United States",
"delete": false,
"doi": "10.1097/ICB.0000000000000096",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1935-1089",
"issue": "8(4)",
"journal": "Retinal cases & brief reports",
"keywords": null,
"medline_ta": "Retin Cases Brief Rep",
"mesh_terms": "D000293:Adolescent; D000998:Antiviral Agents; D024882:Drug Resistance, Viral; D015828:Eye Infections, Viral; D017245:Foscarnet; D006561:Herpes Simplex; D018258:Herpesvirus 2, Human; D006801:Humans; D008297:Male; D015882:Retinal Necrosis Syndrome, Acute; D016896:Treatment Outcome",
"nlm_unique_id": "101298744",
"other_id": null,
"pages": "260-4",
"pmc": null,
"pmid": "25372523",
"pubdate": "2014",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Acute retinal necrosis secondary to multidrug-resistant herpes simplex virus 2 in an immunocompetent adolescent.",
"title_normalized": "acute retinal necrosis secondary to multidrug resistant herpes simplex virus 2 in an immunocompetent adolescent"
} | [
{
"companynumb": "US-MYLANLABS-2015M1033465",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ACYCLOVIR"
},
"drugadditional": null,
... |
{
"abstract": "Hemophagocytic lymphohistiocytosis (HLH) is a rare and life-threatening syndrome of immune system dysregulation characterized by the phagocytosis of various cells by histiocytes in the bone marrow. HLH can present in one of the two ways: primary HLH, which is caused by mutations in genes essential to T and NK-cell function, and secondary HLH, typically caused by Epstein-Barr virus (EBV) infection or malignancy. Because of the rapid progression and high mortality of this disease, prompt diagnosis is essential to good outcomes. Here, we report the 2-month clinical course of a patient who presented with altered mental status and recurrent fever of unknown origin. Initially, he did not meet diagnostic criteria for HLH and had a negative bone marrow biopsy; however, he eventually progressed to full-blown HLH secondary to occult Hodgkin lymphoma. This case is unusual for the slow and smoldering course of the patient's disease and highlights the importance of aggressively searching for potential malignancies to ensure the initiation of definitive therapy as soon as possible.",
"affiliations": "Department of Medicine, University of Rochester Medical Center, 601 Elmwood Avenue Box MED, Rochester, NY 14642, USA.;Department of Medicine, University of Rochester Medical Center, 601 Elmwood Avenue Box MED, Rochester, NY 14642, USA.;Department of Medicine, University of Rochester Medical Center, 601 Elmwood Avenue Box MED, Rochester, NY 14642, USA.;Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, 601 Elmwood Avenue Box 626, Rochester, NY 14642, USA.;Department of Medicine, University of Rochester Medical Center, 601 Elmwood Avenue Box MED, Rochester, NY 14642, USA.",
"authors": "Komisarof|Justin|J|https://orcid.org/0000-0002-3591-4625;McGann|Kevin|K|;Huston|Alissa|A|;Katerji|Hani|H|https://orcid.org/0000-0002-6105-8092;Morgan|Mary Anne|MA|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1155/2021/6672257",
"fulltext": "\n==== Front\nCase Rep Hematol\nCase Rep Hematol\nCRIHEM\nCase Reports in Hematology\n2090-6560\n2090-6579\nHindawi\n\n10.1155/2021/6672257\nCase Report\nAn Atypical Presentation of Hemophagocytic Lymphohistiocytosis (HLH) Secondary to Occult Hodgkin Lymphoma\nhttps://orcid.org/0000-0002-3591-4625\nKomisarof Justin justin_komisarof@urmc.rochester.edu\n1\nMcGann Kevin 1\nHuston Alissa 1\nhttps://orcid.org/0000-0002-6105-8092\nKaterji Hani 2\nMorgan Mary Anne 1\n1Department of Medicine, University of Rochester Medical Center, 601 Elmwood Avenue Box MED, Rochester, NY 14642, USA\n2Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, 601 Elmwood Avenue Box 626, Rochester, NY 14642, USA\nAcademic Editor: Kiyotaka Kawauchi\n\n2021\n24 7 2021\n2021 66722573 10 2020\n5 7 2021\n19 7 2021\nCopyright © 2021 Justin Komisarof et al.\n2021\nhttps://creativecommons.org/licenses/by/4.0/ This 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.\nHemophagocytic lymphohistiocytosis (HLH) is a rare and life-threatening syndrome of immune system dysregulation characterized by the phagocytosis of various cells by histiocytes in the bone marrow. HLH can present in one of the two ways: primary HLH, which is caused by mutations in genes essential to T and NK-cell function, and secondary HLH, typically caused by Epstein–Barr virus (EBV) infection or malignancy. Because of the rapid progression and high mortality of this disease, prompt diagnosis is essential to good outcomes. Here, we report the 2-month clinical course of a patient who presented with altered mental status and recurrent fever of unknown origin. Initially, he did not meet diagnostic criteria for HLH and had a negative bone marrow biopsy; however, he eventually progressed to full-blown HLH secondary to occult Hodgkin lymphoma. This case is unusual for the slow and smoldering course of the patient's disease and highlights the importance of aggressively searching for potential malignancies to ensure the initiation of definitive therapy as soon as possible.\n==== Body\n1. Introduction\n\nHemophagocytic lymphohistiocytosis (HLH) is a rare life-threatening syndrome of immune system dysregulation characterized by hypersecretion of inflammatory cytokines due to persistent overactivation of cytotoxic T cells and NK cells, ultimately leading to phagocytosis of hematopoietic cells by histiocytes throughout the reticuloendothelial system [1–3]. While HLH was initially described as a genetic disorder of childhood and much of what is known regarding its pathophysiology, presentation, and management has originated from the pediatric literature, our understanding of secondary HLH in adults continues to grow [4]. While the potential etiologic underpinnings of secondary HLH are exceedingly broad [5–10], principal among them are EBV infection and lymphoma [1, 11–14]. The presentation of HLH is variable and nonspecific, overlapping with many conditions such as sepsis, thereby posing significant challenges for early diagnosis and treatment in what is often a rapidly progressive and fatal picture [15–21].\n\nDiagnostic criteria developed from pediatric patients with familial HLH were first proposed in 1991 [22] and later revised in 2004 [23] to include eight criteria of which a patient must meet at least five: fever (≥38.5°C for ≥7 days), cytopenias (≥2 cell lines affected), splenomegaly (>3 cm below costal margin), hypertriglyceridemia (≥2 mmol/L) and/or hypofibrinogenemia (≤150 mg/dL), hemophagocytosis in the bone marrow, spleen, or lymph nodes, elevated ferritin (≥500 μg/l), elevated soluble IL-2 receptor levels (≥2400 U/mol), and low/absent NK-cell activity. More recently, novel diagnostic criteria known as the HScore have also been developed and validated in a small population of adult patients [24]. These diagnostic criteria align with the most common presenting symptoms of HLH and include fever, splenomegaly, and cytopenias. However, an array of other presenting findings, including skin rash [3, 25, 26], pulmonary symptoms such as dyspnea and cough [27], and neurologic features including encephalopathy, seizure, ataxia, and cranial nerve abnormalities have been reported [28–31]. Treatment of secondary HLH must be initiated early and aims to address the underlying precipitating disorder, with the most commonly used HLH protocol relying on etoposide, dexamethasone, and hematopoietic stem cell transplantation as mainstays of therapy [32]. For HLH secondary to Hodgkin lymphoma, brentuximab therapy has been reported to be successful [33, 34].\n\n2. Case Presentation\n\nA 63-year-old man with a history of remote Hodgkin lymphoma at age 19 years, coronary artery disease (CAD), and recent urothelial carcinoma presented to Highland Hospital with 2-3 months of intermittent fevers and confusion. His initial laboratory values were notable for anemia (hemoglobin 9.0 g/dL) and thrombocytopenia (63,000 platelets/μL) with a normal white blood cell count (5700 WBC/μL). He was hyponatremic with a sodium of 125 mmol/L and had an elevated alkaline phosphatase (300 U/L). He underwent an extensive infectious workup which was notable only for positive Epstein–Barr virus (EBV) viral PCR (7800 copies/mL) but negative EBV IgM. Hematology was consulted out of concern for a hemolytic anemia, but hemolysis labs were unremarkable with normal serum haptoglobin (93 mg/dL) and total bilirubin (0.9 mg/dL). Reticulocyte count was not elevated (2.3%), and schistocytes were not seen on a peripheral smear. The possibility of hemophagocytic lymphohistiocytosis (HLH) was raised at this time due to the patient's cytopenias and recurrent fever. At this time, his ferritin was elevated at 1089 ng/mL and triglycerides were elevated at 153 mg/dL but below the diagnostic cutoff for HLH. However, fibrinogen was normal, and the patient was not observed to have splenomegaly. A bone marrow biopsy was performed and did not show phagocytic histiocytes or evidence of malignancy (Figure 1). NK functional assay was sent but cancelled due to insufficient lymphocyte count. Soluble IL-2 receptor assay was ordered. The patient was treated with a 5-day course of antibiotics, and his fever curve gradually downtrended. His encephalopathy improved with the resolution of his fevers. The patient was afebrile for 72 hours and was able to be discharged from the hospital.\n\nOne month later, the patient was admitted to Strong Memorial Hospital with ongoing intermittent fevers and confusion. In the interim, he underwent a positron emission tomography (PET) scan which revealed a hypermetabolic focus in the left palatine tonsil (Figure 2). On admission, triglycerides were slightly higher at 173 mg/dL and ferritin was also slightly higher at 1407 ng/mL. He had a positive blood culture for Staphylococcus epidermidis which was believed to be a contaminant. Tonsillar biopsy demonstrated an atypical clonal lymphoid population but no morphologically abnormal lymphoid cells and no Hodgkin Reed–Sternberg (HRS) cells or other evidence for lymphoma. Soluble IL-2 receptor assay from the earlier hospitalization had still not resulted at this time. Ferritin continued to rise climbing steadily to 9573 ng/mL two weeks after admission. The patient became hypotensive and was transferred to the ICU for vasopressor support. He developed acute hypoxic respiratory failure requiring intubation thought to be due to pleural effusions and atelectasis. Soluble IL-2 receptor came back extremely elevated at 17,375 U/mL. Repeat EBV viral PCR was now 40,400 copies/mL. The patient underwent repeat bone marrow biopsy which showed Hodgkin lymphoma with hemophagocytic lymphohistiocytosis (Figure 3), confirming the diagnosis of HLH. Karyotype analysis was 46XY with no apparent clonal chromosomal aberrations, and EBER-ISH was positive. The patient was started on high-dose dexamethasone (20 mg) daily as well as etoposide (100 mg/mL) twice weekly. At this point, ferritin was now 12,130 ng/mL. Dexamethasone was increased shortly after to 40 mg daily, and the patient received a single dose of brentuximab (1.8 mg/kg). After receiving brentuximab, the patient developed progressive renal failure with creatinine increasing from 1.4 to 3.0 mg/dL over the course of a week as well as a lactic acidosis. After discussion with the family, the patient was terminally extubated and passed away.\n\n3. Discussion\n\nHemophagocytic lymphohistiocytosis (HLH) is a rare life-threatening syndrome of immune system dysregulation typically seen secondary to EBV infection or blood malignancy. Herein, we describe the detailed 2-month course of a 63-year-old male who presented with altered mental status, recurrent fevers, and fatigue and who was ultimately found to have HLH secondary to occult Hodgkin lymphoma.\n\nThis case is unusual for its slow and smoldering presentation. Typically, patients with active HLH present acutely ill, often in multiple organ system failure and requiring ICU level of care. This patient's symptoms fluctuated to an extent that he met criteria for hospital discharge, only to be readmitted four weeks later with ongoing subacute and intermittent symptoms. Although the diagnosis of HLH secondary to new lymphoma was entertained during the patient's first hospital stay, the bone marrow biopsy was unrevealing. During his second hospital stay, despite multidisciplinary subspecialty consultation and interdepartmental review, the diagnosis was clinched only when the bone marrow aspirate was repeated. As no malignant cells were found outside the bone marrow, it is possible that this represented primary bone marrow Hodgkin lymphoma. While this is quite rare and typically associated with HIV infection, for which our patient tested negative, several previous cases have been described of HIV-negative primary bone marrow Hodgkin lymphoma [35, 36]. Alternatively, it is possible that the tonsillar biopsy was a false negative and that this represented stage 4 Hodgkin lymphoma.\n\nThe most notable feature of this case that delayed diagnosis was the first bone marrow biopsy which did not show any evidence of phagocytic histiocytes or underlying malignancy. While HLH is characterized by hemophagocytosis, it is important to note that the sensitivity of bone marrow biopsy for HLH is relatively low at 83% and that hemophagocytosis can be seen in the bone marrow of patients without HLH [37]. Similarly, it is becoming clear that bone marrow biopsy false negatives are fairly common in Hodgkin lymphoma and that patients should undergo PET/CT as part of their initial workup [38]. HLH is treated primarily with a regimen of dexamethasone and etoposide, and HLH secondary to malignancy must be treated by addressing the underlying cancer [39]. In all cases where HLH is suspected, an aggressive approach must be taken both to work up all HLH diagnostic criteria as well as to identify any underlying malignancy present and initiate definitive treatment as quickly as possible.\n\nAcknowledgments\n\nThe authors would like to thank Dr. Andrew Evans for assistance with pathology figures.\n\nData Availability\n\nThe imaging, laboratory, and pathologic data used to support the findings of this case study are included within the article.\n\nConflicts of Interest\n\nAll authors are employed by the University of Rochester Medical Center.\n\nFigure 1 Hematoxylin and eosin (H&E) section of the hypocellular bone marrow with no definitive infiltration by lymphoma.\n\nFigure 2 PET scan revealing the hypermetabolic focus localized to the left palatine tonsil.\n\nFigure 3 H&E section of the bone marrow revealing hemophagocytosis (a). High-powered H&E section (b) and chloracetate esterase section (c) demonstrating binucleated Reed–Sternberg (RS) cells. Immunohistochemistry showed positivity for CD30 (d) and CD15 (e) in RS cells. Epstein–Barr encoding region in situ hybridization (EBER-ISH) (f).\n==== Refs\n1 Al-Samkari H. Berliner N. Hemophagocytic lymphohistiocytosis Annual Review of Pathology: Mechanisms of Disease 2018 13 1 27 49 10.1146/annurev-pathol-020117-043625 2-s2.0-85041748803\n2 Bhatt N. S. Oshrine B. An Talano J. Hemophagocytic lymphohistiocytosis in adults Leukemia & Lymphoma 2019 60 1 19 28 10.1080/10428194.2018.1482543 2-s2.0-85061376634 29966474\n3 Maus M. V. Leick M. B. Cornejo K. M. Nardi V. Case 35-2019: a 66-year-old man with pancytopenia and rash New England Journal of Medicine 2019 381 20 1951 1960 10.1056/nejmcpc1909627\n4 Campo M. Berliner N. Hemophagocytic lymphohistiocytosis in adults Hematology/Oncology Clinics of North America 2015 29 5 915 925 10.1016/j.hoc.2015.06.009 2-s2.0-84942365818 26461151\n5 Bailey C. Dearden C. Ardeshna K. Haemophagocytic lymphohistiocytosis as a consequence of untreated B-cell chronic lymphocytic leukaemia Case Reports 2017 2017 10.1136/bcr-2016-219057 2-s2.0-85018794202\n6 Chen J. Wang X. He P. Viral etiology, clinical and laboratory features of adult hemophagocytic lymphohistiocytosis Journal of Medical Virology 2016 88 3 541 549 10.1002/jmv.24359 2-s2.0-84955174999 26287378\n7 Assi R. Boddu P. Kadia T. M. Estrov Z. E. Garcia-Manero G. Abou Zahr A. Characteristics and outcomes of patients (pts) with malignancy-associated hemophagocytic lymphohistiocytosis (M-HLH) in adults: a single-center, prospective analysis of 36 pts Blood 2018 132 1 p. 3689 10.1182/blood-2018-99-117366\n8 Dumancas C. Y. Reyes H. A. G. Cosico J. Savadkar A. Lah S. Streptococcus pneumoniae-related hemophagocytic lymphohistiocytosis treated with IVIG and steroids American Journal of Case Reports 2018 19 25 28 10.12659/ajcr.906590 2-s2.0-85040911884\n9 Elzein F. E. Al Sherbini N. Alotaibi M. M. Al-Hassan W. M. Brucellosis accompanied by haemophagocytic lymphohistiocytosis and multiple splenic abscesses in a patient with depression Case Reports 2018 2018 10.1136/bcr-2017-224018 2-s2.0-85044670912\n10 Kennedy‐Snodgrass C. Obayomi M. Muddasani R. Slonim L. B. Braunstein M. Hemophagocytic lymphohistiocytosis secondary to babesia in an immunocompetent adult American Journal of Hematology 2019 94 3 379 383 30478854\n11 Lai W. Wang Y. Wang J. Wu L. Jin Z. Wang Z. Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis in adults and adolescents-a life-threatening disease: analysis of 133 cases from a single center Hematology 2018 23 10 810 816 10.1080/10245332.2018.1491093 2-s2.0-85049218992 29957156\n12 Bigenwald C. Fardet L. Coppo P. A comprehensive analysis of Lymphoma-associated haemophagocytic syndrome in a large french multicentre cohort detects some clues to improve prognosis British Journal of Haematology 2018 183 1 68 75 10.1111/bjh.15506 2-s2.0-85055081270 30043391\n13 Iardino A. Amar Z. Ahmed Y. Epstein-barr-positive classical hodgkin lymphoma-associated haemophagocytic lymphohistocytiosis: a rare case Case Reports 2018 2018 10.1136/bcr-2018-225262 2-s2.0-85051588157\n14 Jin Z. Wang Y. Wei N. Wang Z. Hodgkin lymphoma-associated hemophagocytic lymphohistiocytosis-a dangerous disease Annals of Hematology 2020 99 7 1575 1581 10.1007/s00277-020-04093-4 32500223\n15 Rosado F. G. N. Kim A. S. Hemophagocytic lymphohistiocytosis American Journal of Clinical Pathology 2013 139 6 713 727 10.1309/ajcp4zdkj4icouat 2-s2.0-84878384497 23690113\n16 Otrock Z. K. Eby C. S. Clinical characteristics, prognostic factors, and outcomes of adult patients with hemophagocytic lymphohistiocytosis American Journal of Hematology 2015 90 3 220 224 10.1002/ajh.23911 2-s2.0-84923083822 25469675\n17 Otrock Z. K. Daver N. Kantarjian H. M. Eby C. S. Diagnostic challenges of hemophagocytic lymphohistiocytosis Clinical Lymphoma Myeloma and Leukemia 2017 17 S105 S110 10.1016/j.clml.2017.02.017 2-s2.0-85026539664\n18 Birndt S. Schenk T. Heinevetter B. Hemophagocytic lymphohistiocytosis in adults: collaborative analysis of 137 cases of a nationwide German registry Journal of Cancer Research and Clinical Oncology 2020 146 4 1065 1077 10.1007/s00432-020-03139-4 32076823\n19 Zhou M. Li L. Zhang Q. Clinical features and outcomes in secondary adult hemophagocytic lymphohistiocytosis QJM: An International Journal of Medicine 2018 111 1 23 31 10.1093/qjmed/hcx183 2-s2.0-85051315322 29025045\n20 Carcillo J. A. Podd B. Simon D. W. From febrile pancytopenia to hemophagocytic lymphohistiocytosis-associated organ dysfunction Intensive Care Medicine 2017 43 12 1853 1855 10.1007/s00134-017-4853-6 2-s2.0-85021245161 28649693\n21 Prokesch B. C. Nagalla S. Ezzati F. What’s in a name? the heterogeneous clinical spectrum and prognostic factors in a cohort of adults with hemophagocytic lymphohistiocytosis Transfusion and Apheresis Science 2018 57 6 779 784 10.1016/j.transci.2018.10.001 2-s2.0-85054743671 30327177\n22 Henter J. I. Elinder G Ost A Diagnostic guidelines for hemophagocytic lymphohistiocytosis. The FHL study group of the histiocyte society Seminars in Oncology 1991 18 29 33 1992521\n23 Henter J.-I. Horne A. Aricó M. HLH-2004: diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis Pediatric Blood & Cancer 2007 48 2 124 131 10.1002/pbc.21039 2-s2.0-33845619137 16937360\n24 Fardet L. Galicier L. Lambotte O. Development and validation of the HScore, a score for the diagnosis of reactive hemophagocytic syndrome Arthritis & Rheumatology 2014 66 9 2613 2620 10.1002/art.38690 2-s2.0-84907408074 24782338\n25 Khairoun M. Meynen F. Vercoutere W. Leavis H. L. Case series of three adult patients with exceptional clinical presentations of haemophagocytic lymphohistiocytosis The Netherlands Journal of Medicine 2020 78 3 136 141 10.1007/s40278-020-83256-3 32332189\n26 Schram A. M. Comstock P. Campo M. Haemophagocytic lymphohistiocytosis in adults: a multicentre case series over 7 years British Journal of Haematology 2016 172 3 412 419 10.1111/bjh.13837 2-s2.0-84955735455 26537747\n27 Seguin A. Galicier L. Boutboul D. Lemiale V. Azoulay E. Pulmonary involvement in patients with hemophagocytic lymphohistiocytosis Chest 2016 149 5 1294 1301 10.1016/j.chest.2015.11.004 2-s2.0-84966658494 26836913\n28 Cai G. Wang Y. Liu X. Han Y. Wang Z. Central nervous system involvement in adults with haemophagocytic lymphohistiocytosis: a single-center study Annals of Hematology 2017 96 8 1279 1285 10.1007/s00277-017-3035-5 2-s2.0-85020282687 28589450\n29 Pastula D. M. Burish M. Reis G. F. Adult-onset central nervous system hemophagocytic lymphohistiocytosis: a case report BMC Neurology 2015 15 1 p. 203 10.1186/s12883-015-0470-6 2-s2.0-84944406567\n30 Magaki S. Ostrzega N. Ho E. Yim C. Wu P. Vinters H. V. Hemophagocytic lymphohistiocytosis associated with epstein-barr virus in the central nervous system Human Pathology 2017 59 108 112 10.1016/j.humpath.2016.07.033 2-s2.0-84997228883 27574808\n31 Song Y. Pei R.-J. Wang Y.-N. Zhang J. Wang Z. Central nervous system involvement in hemophagocytic lymphohistiocytosis in adults Chinese Medical Journal 2018 131 7 776 783 10.4103/0366-6999.228234 2-s2.0-85044479248 29578120\n32 Schram A. M. Berliner N. How i treat hemophagocytic lymphohistiocytosis in the adult patient Blood 2015 125 19 2908 2914 10.1182/blood-2015-01-551622 2-s2.0-84929190350 25758828\n33 Nagaharu K. Masuya M. Kageyama Y. Successful treatment of primary bone marrow hodgkin lymphoma with brentuximab vedotin: a case report and review of the literature Journal of Medical Case Reports 2018 12 1 p. 151 10.1186/s13256-018-1693-0 2-s2.0-85047737070\n34 Knox B. Singh D. Mai H. Mirza K. Hodgkin’s lymphoma with HLH and complete remission with brentuximab-based therapy BMJ Case Reports 2019 12 12 e231629 10.1136/bcr-2019-231629\n35 Morita Y. Emoto M. Serizawa K. HIV-negative primary bone marrow hodgkin lymphoma manifesting with a high fever associated with hemophagocytosis as the initial symptom: a case report and review of the previous literature Internal Medicine 2015 54 11 1393 1396 10.2169/internalmedicine.54.3770 2-s2.0-84939537874 26027994\n36 Laurent C. Arber D. A. Johnston P. Fend F. Zamo A. Attygalle A. D. Diagnosis of classic hodgkin lymphoma on bone marrow biopsy Histopathology 2020 76 7 934 941 10.1111/his.14085 32092168\n37 Goel S. Polski J. M. Imran H. Sensitivity and specificity of bone marrow hemophagocytosis in hemophagocytic lymphohistiocytosis Annals of Clinical and Laboratory Science 2012 42 1 21 25 22371906\n38 Voltin C.-A. Goergen H. Baues C. Value of bone marrow biopsy in hodgkin lymphoma patients staged by FDG PET: results from the german hodgkin study group trials HD16, HD17, and HD18 Annals of Oncology 2018 29 9 1926 1931 10.1093/annonc/mdy250 2-s2.0-85054333270 30010775\n39 Ehl S. Astigarraga I. von Bahr Greenwood T. Recommendations for the use of etoposide-based therapy and bone marrow transplantation for the treatment of HLH: consensus statements by the HLH steering committee of the histiocyte society The Journal of Allergy and Clinical Immunology: In Practice 2018 6 5 1508 1517 10.1016/j.jaip.2018.05.031 2-s2.0-85049320659 30201097\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2090-6579",
"issue": "2021()",
"journal": "Case reports in hematology",
"keywords": null,
"medline_ta": "Case Rep Hematol",
"mesh_terms": null,
"nlm_unique_id": "101576456",
"other_id": null,
"pages": "6672257",
"pmc": null,
"pmid": "34341690",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": "29025045;32092168;29843820;30201097;31722157;29578120;32076823;26537747;28934563;29966474;26287378;28446487;30043391;27574808;25469675;32332189;22371906;28649693;16937360;26461151;29307884;26836913;23690113;28760295;30010775;25758828;29588282;26467435;30108117;24782338;1992521;28589450;30478854;32500223;31818889;29957156;26027994;30327177",
"title": "An Atypical Presentation of Hemophagocytic Lymphohistiocytosis (HLH) Secondary to Occult Hodgkin Lymphoma.",
"title_normalized": "an atypical presentation of hemophagocytic lymphohistiocytosis hlh secondary to occult hodgkin lymphoma"
} | [
{
"companynumb": "US-SEATTLE GENETICS-2021SGN05261",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "BRENTUXIMAB VEDOTIN"
},
"drugadditiona... |
{
"abstract": "Liquid chromatography-tandem mass spectrometry (LC-MS/MS) and multiple reaction monitoring mass spectrometry (MRM-MS) proteomics analyses were performed on eccrine sweat of healthy controls, and the results were compared with those from individuals diagnosed with schizophrenia (SZ). This is the first large scale study of the sweat proteome. First, we performed LC-MS/MS on pooled SZ samples and pooled control samples for global proteomics analysis. Results revealed a high abundance of diverse proteins and peptides in eccrine sweat. Most of the proteins identified from sweat samples were found to be different than the most abundant proteins from serum, which indicates that eccrine sweat is not simply a plasma transudate and may thereby be a source of unique disease-associated biomolecules. A second independent set of patient and control sweat samples were analyzed by LC-MS/MS and spectral counting to determine qualitative protein differential abundances between the control and disease groups. Differential abundances of selected proteins, initially determined by spectral counting, were verified by MRM-MS analyses. Seventeen proteins showed a differential abundance of approximately 2-fold or greater between the SZ pooled sample and the control pooled sample. This study demonstrates the utility of LC-MS/MS and MRM-MS as a viable strategy for the discovery and verification of potential sweat protein disease biomarkers.",
"affiliations": "The Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, Virginia 20110, United States. mraisza3@gmu.edu",
"authors": "Raiszadeh|Michelle M|MM|;Ross|Mark M|MM|;Russo|Paul S|PS|;Schaepper|Mary Ann|MA|;Zhou|Weidong|W|;Deng|Jianghong|J|;Ng|Daniel|D|;Dickson|April|A|;Dickson|Cindy|C|;Strom|Monica|M|;Osorio|Carolina|C|;Soeprono|Thomas|T|;Wulfkuhle|Julia D|JD|;Petricoin|Emanuel F|EF|;Liotta|Lance A|LA|;Kirsch|Wolff M|WM|",
"chemical_list": "D015415:Biomarkers; D020543:Proteome",
"country": "United States",
"delete": false,
"doi": "10.1021/pr2007957",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1535-3893",
"issue": "11(4)",
"journal": "Journal of proteome research",
"keywords": null,
"medline_ta": "J Proteome Res",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D015415:Biomarkers; D002853:Chromatography, Liquid; D004439:Eccrine Glands; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D020543:Proteome; D040901:Proteomics; D012559:Schizophrenia; D013542:Sweat; D053719:Tandem Mass Spectrometry",
"nlm_unique_id": "101128775",
"other_id": null,
"pages": "2127-39",
"pmc": null,
"pmid": "22256890",
"pubdate": "2012-04-06",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "16354654;19131956;8068938;17027767;15181200;12734009;19540723;13052810;10973933;9516668;3924408;16226876;2421395;13633369;8732586;6497428",
"title": "Proteomic analysis of eccrine sweat: implications for the discovery of schizophrenia biomarker proteins.",
"title_normalized": "proteomic analysis of eccrine sweat implications for the discovery of schizophrenia biomarker proteins"
} | [
{
"companynumb": "US-JNJFOC-20120904602",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "QUETIAPINE"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nTo review our experiences with high-dose infliximab (IFX) to treat juvenile idiopathic arthritis (JIA). We routinely use high doses of IFX (10-20 mg/kg) in children with recalcitrant or highly active JIA. Although biologics have revolutionized treatment of JIA, many patients have active disease despite therapy. Studies have shown benefits of high-dose IFX in several conditions, including inflammatory bowel disease, psoriasis, and idiopathic uveitis. The safety and effectiveness of high-dose IFX have not been evaluated in JIA.\n\n\nMETHODS\nWe performed a retrospective review of children with JIA who received IFX ≥ 10 mg/kg. We recorded all serious adverse events (SAE), medically important infections, and infusion reactions. We also recorded the physician global assessment of disease activity (MD global) and active joint count (AJC) at initiation of high-dose IFX and 3, 6, and 12 months thereafter.\n\n\nRESULTS\nFifty-eight subjects received a total of 1064 infusions over 95 person-years. There were a total of 9 SAE (9.5/100 person-yrs), 7 of which were potentially related to therapy, and 6 infusion reactions (0.5%), none constituting anaphylaxis. Statistically significant improvements were observed in the AJC (median 0, range 0-31, vs 2, 0-39) and MD global (12, 2-31, vs 22, 5-80) over the first year.\n\n\nCONCLUSIONS\nHigh-dose IFX appears safe in the management of JIA. Future prospective controlled studies are necessary to evaluate its safety and efficacy.",
"affiliations": "From the University of Alabama at Birmingham (UAB), Department of Pediatrics, Division of Rheumatology, Birmingham, Alabama, USA.",
"authors": "Tambralli|Ajay|A|;Beukelman|Timothy|T|;Weiser|Peter|P|;Atkinson|Thomas Prescott|TP|;Cron|Randy Quentin|RQ|;Stoll|Matthew Laurence|ML|",
"chemical_list": "D000911:Antibodies, Monoclonal; D018501:Antirheumatic Agents; D000069285:Infliximab; D008727:Methotrexate",
"country": "Canada",
"delete": false,
"doi": "10.3899/jrheum.130133",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0315-162X",
"issue": "40(10)",
"journal": "The Journal of rheumatology",
"keywords": "INFLIXIMAB; JUVENILE IDIOPATHIC ARTHRITIS; THERAPEUTICS",
"medline_ta": "J Rheumatol",
"mesh_terms": "D000293:Adolescent; D000911:Antibodies, Monoclonal; D018501:Antirheumatic Agents; D001171:Arthritis, Juvenile; D002648:Child; D002675:Child, Preschool; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007223:Infant; D000069285:Infliximab; D008297:Male; D008727:Methotrexate; D012189:Retrospective Studies; D016896:Treatment Outcome",
"nlm_unique_id": "7501984",
"other_id": null,
"pages": "1749-55",
"pmc": null,
"pmid": "23950184",
"pubdate": "2013-10",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "High doses of infliximab in the management of juvenile idiopathic arthritis.",
"title_normalized": "high doses of infliximab in the management of juvenile idiopathic arthritis"
} | [
{
"companynumb": "US-JNJFOC-20131015246",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "INFLIXIMAB"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nCarbapenem-resistant Klebsiella pneumonia (CRKP) infections have been a concerning threat, especially in organ transplant patients with very high mortality. Allograft hemorrhage associated with CRKP infection has never been described.\nA total of 6 recipients tested positive for CRKP were identified in 297 adult kidney transplant recipients who received kidney from donors according to Chinese type donation after cardiac death (DCD) at our center between January 2006 and December 2017.\nCRKP identification was performed via Vitek 2 system, and the susceptibility was tested by broth microdilution and disk diffusion. Based on the signs of infection and the positive culture, the diagnosis of CRKP infection was established.\n\n\nMETHODS\nTherapy with antibiotic such as including ceftazidime-avibactam or tigecycline and surgical control of primary infection source including allograft nephrectomy and/or thorough debridement was administrated.\n\n\nRESULTS\nThe most striking aspect was that spontaneous recurrent hemorrhage occurred in all the 6 patients. The mortality of CRKP infection in our study was 50%.\n\n\nCONCLUSIONS\nCRKP infection possibly due to donor-to-recipient transmission in DCD kidney transplants was essentially a necrotic hemorrhagic inflammation and characterized by recurrent hemorrhage and high mortality. The pre-donation screening for CRKP colonization should be mandatory and, if positive, donation should be contraindicated. And, the effective infection source control such as allograft nephrectomy and/or thorough debridement was important to improve outcomes. Further investigation will be required to further characterize the clinical efficacy of new pharmacotherapeutic schemes including ceftazidime-avibactam.",
"affiliations": "Institute of Organ Transplant, The 8th Medical Center of Chinese People's Liberation Army General Hospital, Beijing, 100091, China.",
"authors": "Wang|Zhen|Z|;Qian|Yeyong|Y|;Bai|Hongwei|H|;Yang|Jintao|J|;Li|Xiang|X|",
"chemical_list": "D015780:Carbapenems",
"country": "United States",
"delete": false,
"doi": "10.1097/MD.0000000000018982",
"fulltext": "\n==== Front\nMedicine (Baltimore)\nMedicine (Baltimore)\nMEDI\nMedicine\n0025-7974 1536-5964 Wolters Kluwer Health \n\n32221060\nMD-D-19-03212\n10.1097/MD.0000000000018982\n18982\n4900\nResearch Article\nClinical Case Report\nAllograft hemorrhage as a manifestation of carbapenem-resistant Klebsiella pneumonia infection in kidney transplant recipients\nCase seriesWang Zhen MD, PhD∗ Qian Yeyong MD Bai Hongwei MD Yang Jintao MD Li Xiang MD NA. Institute of Organ Transplant, The 8th Medical Center of Chinese People's Liberation Army General Hospital, Beijing, 100091, China.\n∗ Correspondence: Zhen Wang, Institute of Organ Transplant, The 8th Medical Center of Chinese People's Liberation Army General Hospital, Beijing, 100091, China (e-mail: wangzhentransplant@163.com).\n27 3 2020 \n3 2020 \n99 13 e189828 5 2019 28 11 2019 30 12 2019 Copyright © 2020 the Author(s). Published by Wolters Kluwer Health, Inc.2020This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0Abstract\nRationale:\nCarbapenem-resistant Klebsiella pneumonia (CRKP) infections have been a concerning threat, especially in organ transplant patients with very high mortality. Allograft hemorrhage associated with CRKP infection has never been described.\n\nPatient concerns:\nA total of 6 recipients tested positive for CRKP were identified in 297 adult kidney transplant recipients who received kidney from donors according to Chinese type donation after cardiac death (DCD) at our center between January 2006 and December 2017.\n\nDiagnoses:\nCRKP identification was performed via Vitek 2 system, and the susceptibility was tested by broth microdilution and disk diffusion. Based on the signs of infection and the positive culture, the diagnosis of CRKP infection was established.\n\nInterventions:\nTherapy with antibiotic such as including ceftazidime-avibactam or tigecycline and surgical control of primary infection source including allograft nephrectomy and/or thorough debridement was administrated.\n\nOutcomes:\nThe most striking aspect was that spontaneous recurrent hemorrhage occurred in all the 6 patients. The mortality of CRKP infection in our study was 50%.\n\nLessons:\nCRKP infection possibly due to donor-to-recipient transmission in DCD kidney transplants was essentially a necrotic hemorrhagic inflammation and characterized by recurrent hemorrhage and high mortality. The pre-donation screening for CRKP colonization should be mandatory and, if positive, donation should be contraindicated. And, the effective infection source control such as allograft nephrectomy and/or thorough debridement was important to improve outcomes. Further investigation will be required to further characterize the clinical efficacy of new pharmacotherapeutic schemes including ceftazidime-avibactam.\n\nKeywords\nallograft hemorrhagecarbapenem resistancekidney transplantationKlebsiella pneumonia infectionOPEN-ACCESSTRUE\n==== Body\n1 Introduction\nThe recent worldwide outbreaks of multidrug-resistant (MDR) bacteria infections have been a concerning threat, especially in immunocompromised patients.[1,2] Carbapenem-resistant Klebsiella pneumonia (CRKP) was identified in 2001,[3] spread to hospitals and became one of the most important pathogens of MDR bacteria.[4] Recently, the increasing threat of CRKP infection in organ-transplanted patients has been highlighted, due to difficulty in treatment and high mortality.[5–8] Clinical studies have shown that infections with CRKP were consisted of bloodstream infections,[9] urinary tract infections,[10] pneumonia,[11] central venous catheter-associated infection,[12] and surgical site infections.[13,14]\n\nAllograft hemorrhage was a severe and potentially lethal complication of renal transplantation. Previous studies reported that allograft infection, such as Mucoraceous[15] and Aspergillus,[16] was a rare cause of allograft renal artery rupture and hemorrhage in kidney recipients. Unlike previous cases of allograft hemorrhage associated with fungal infections, we describe 6 cases of allograft hemorrhage in kidney recipients caused by CRKP infections. According to our knowledge, the allograft hemorrhage due to CRKP has never been described in transplant recipients.\n\n2 Case description\nThe retrospective cohort study included 297 adult (older than 18 years of age) kidney transplant recipients who received kidney from donors according to Chinese type donation after cardiac death (DCD)[17] at our center between January 2006 and December 2017. CRKP identification was performed via Vitek 2 system, and the susceptibility was tested by broth microdilution and disk diffusion. CRKP were confirmed as resistant to carbapenem antibiotic. The pre-donation screening for CRKP colonization in donors and recipients was routinely performed. None of the donors were confirmed to be infected or colonized with CKRP prior to the donation. And, none of the recipients have positive cultures for CRKP around the time of transplant.\n\nA total of 6 recipients tested positive for CRKP were identified, with an incidence of 2.0% (6/297). All the patients’ main clinical–pathological characteristics were described in Tables 1 and 2. Also, the antibiotic susceptibility was summarized in Table 3.\n\nTable 1 Clinical characteristics of recipients with CRKP infections.\n\nTable 2 Treatment and outcomes of transplant recipients with CRKP infection.\n\nTable 3 Mean inhibitory concentrations (mg/L) for Klebsiella pneumonia isolated from patients.\n\n2.1 Case 1\nA 55-year-old man with end-stage renal disease (ERSD) resulting from glomerulonephritis underwent kidney transplant in July 2016. His initial posttransplant course was good with proper allograft function. On posttransplant week 1, the patient had a persistent fever and bacteriuria, associated with a progressively increased level of creatinine (Cr, 2.36 mg/dL) and infectious parameters (C-reactive protein [CRP], 137 mg/L; procalcitonin [PCT], 1.0 ng/mL), was empirically treated with meropenem. Because of the condition deterioration, the patient was transferred to our hospital on posttransplant day (PT) 14. Blood and urine grew CRKP, which was extensively drug resistant and sensitive only to amikacin and tigecycline on PT 20. Thereafter, tigecycline was immediately given. The fever was not relieved, and a severe leukocytosis, anaemia, and leukocyturia were found. Magnetic resonance imaging showed an enlarge kidney with a moderate perirenal hematoma, which was suggestive of the allograft infection (Fig. 1A). On PT 42, the possibility of acute renal hemorrhage is considered due to the pain in the kidney transplantation area and the decrease of blood pressure. The emergency exploration surgery showed that the artery of transplanted kidney was pale, poorly elastic, and severely damaged in the vessel wall. A rupture at the anastomotic stoma of the renal artery and the external iliac artery was found, and allograft nephrectomy and resection and re-anastomosis of external iliac artery were performed. Pathological examination showed acute inflammatory cell infiltration accompanied by massive hemorrhage and infarction; thrombus formation in the renal portal vessels; mucoid degeneration of the intima of the arteries and microabscess in the transplanted kidney (Fig. 2). During the next 2 weeks after nephrectomy, a large number of purulent exudates were drained in the allograft area and CRKP was positive. After 2 weeks of nephrectomy, the drainage was gradually reduced. On PT 63, the blood and drainage fluid culture of CRPK were negative. The patient was recovered and discharged from the hospital.\n\nFigure 1 (A) Magnetic resonance imaging from patient 1 showed an enlarged renal graft, abdominal and pelvic soft tissues with stripe and grid high signal (black arrow), and pelvic peritoneal fluid signal (white arrow); which was suggestive of the transplanted kidney and perirenal tissue infection. (B) Computerized tomographic scanning of case 5 showed big low density shape shadow in the iliac fossa (black arrow) and soft tissue defects at the incision (white arrow), indicating massive fluid and incision infection.\n\nFigure 2 Pathological features of case 1 showed presence of acute inflammatory cell infiltration accompanied by massive hemorrhage and infarction (A); thrombus formation in the renal portal vessels (B); mucoid degeneration of the intima of the arteries (C), and microabscess (D) in the transplanted kidney under the light microscope after hematoxylin–eosin stain.\n\n2.2 Case 2\nA 44-year-old woman with ERSD resulting from glomerulonephritis underwent kidney transplant in July 2016. On PT 3, level of Cr was normal. On PT7, the patient had mild fever. Because of the blood CRKP-positive, she was administered tigecycline plus with meropenem. On PT 13, severe pain and hematogenic shock suddenly occurred. The ultrasound examination showed the thrombosis of the renal allograft artery without blood flow and the signs of hemorrhage of allograft. The emergency surgery showed ischemia and necrosis of graft, renal hemorrhage, and no obvious vascular defects. And, nephrectomy was performed. After nephrectomy, a great deal of hemorrhagic purulent liquid that grew CRKP and Bauman Acinetobacter was continuously drained. Therefore, the antibiotics adjusted to cefoperazone tazobactam plus tigecycline. On PT 23 after hemodialysis, the additional hemorrhage was considered because of the durative bloody drainage volume associated with hemodynamic instability. The external iliac artery stent implantation was performed in the emergency digital subtraction angiography (DSA) to stop bleeding (Fig. 3). On the second day, the third hemorrhagic shock occurred again. Multiple tissue hemorrhage characterized with osmotic blood in the iliac fossa was found in the third emergency surgery. She ultimately died on PT 25.\n\nFigure 3 Comparison of angiography images from patient 6 obtained before (A) and after (B) the external iliac artery covered stent implantation (white arrow) to resolve emergency hemostasis. (A) Large hemorrhage from the right external iliac artery. (B) No evidence of hemorrhage.\n\n2.3 Case 3\nA 44-year-old woman with ERSD resulting from glomerulonephritis underwent kidney transplant at our hospital in July 2016. Post-transplantation, the recipient showed good general condition without fever, but higher infectious index (CRP, 110 mg/L; PCT, 1.2 ng/mL). On PT 14, severe pain and hematogenic shock suddenly occurred. An emergency exploratory operation revealed bleeding from a rupture with a diameter of approximately 5 mm in the renal artery. The kidney and fascia surrounding the graft appeared normal. Based on the suspicion for mucormycosis, allograft nephrectomy was performed, immunosuppression was stopped, and liposomal amphotericin B was administered. On PT 23, the second exploratory operation because of another hemorrhagic shock revealed another rupture with a diameter of approximately 2 mm at the proximal end of external iliac artery. An amount of dead muscle was encountered and the peritoneal layer appeared dusky. Surgical debridement and re-anastomosis of the external iliac artery were performed. And, the necrotic abdominal tissues and blood grew CRKP. Acinetobacter baumannii was cultured in the blood on PT30, and the antibiotics were adjusted to cefoperazone tazobactam and tigecycline. Despite intensive drugs, the patient died on PT51.\n\n2.4 Case 4\nA 37-year-old male patient with ERSD caused by chronic glomerulonephritis underwent renal transplantation in our hospital in May, 2017. On PT 2, the donor's blood cultures grew CRKP only sensitive to tigecycline and compound sulfamethoxazole. Then, tigecycline combined with ceftazidime-avibactam was immediately applied to the patient. On PT3, level of serum creatinine was normal. Within 1 week after transplant, routine urinalysis showed bacteriuria with normal leukocyte. 1 week after transplant, he had a persistent leukocytosis and fevers. Ultrasound due to an elevated Cr showed persistent hydronephrosis. Therefore, percutaneous nephropyelostomy was performed, and a pyelostomy tube was placed. The hemorrhage in puncturing area was found, the blood pressure dropped and the hemorrhagic shock occurred on PT18. Emergency exploration showed severe bleeding in the surrounding tissue of the transplanted kidney and no vascular rupture. So, nephrectomy and thorough debridement were performed. A great deal of hemorrhagic purulent liquid was continuously drained from the transplanted kidney area, and was positive for CRKP in the following week. On the 10th day after nephrectomy, the drainage fluid disappeared. Eventually completing 1 month's tigecycline plus ceftazidime-avibactam therapy, the infection was cured without evidence of CRKP in the culture of urine and blood.\n\n2.5 Case 5\nA 44-year-old man with ERSD caused by diabetes mellitus and hypertension received the donor kidney from the same donor as the case 4. Because of delayed graft function, hemodialysis was required. On PT2, tigecycline plus with ceftazidime-avibactam was used in the prevention and treatment of CRKP. The same as case 4, allograft hydronephrosis was detected and the percutaneous transplanting renal puncture and fistula drainage was performed on PT8, and CRKP grew in the urine drainage. In the next week, the patient had fever accompanied by a continuous increase of bacteriuria and leukocytosis. On PT 18, bleeding was coincidentally found at the puncture and drainage area. The rupture of the anastomotic stoma of the transplanted renal artery and the external iliac artery was revealed in the emergency exploratory operation, and the graft nephrectomy combined with debridement was performed. On PT28, the recurrence of acute massive hemorrhage occurred after hemodialysis. Therefore, the external iliac artery covered stent was used for emergency hemostasis. A large number of hemorrhagic purulent drainage and incisional infection (Fig. 1B) were found within the next 2 weeks. CRKP were recovered from both the drainage and incisional infection secretions. After 8 weeks of tigecycline plus with ceftazidime-avibactam treatment, the infection was cured without evidence of CRKP.\n\n2.6 Case 6\nA 37-year-old female patient with uremia caused by chronic glomerulonephritis underwent kidney transplant in our hospital in May, 2017. Hemodialysis was necessary because of delayed graft function. The results of renal perfusion and donor blood bacteria culture were negative. On PT3, the patients suffered fever with the increase of leukocyte and neutrophils ratio. On PT6, the blood culture confirmed CRKP-positive. And, the drug sensitivity test showed that it was sensitive only to tigecycline and sulfamethoxazole. The antibiotics were changed to tigecycline plus meropenem. There was a large area ecchymosis in the recipient's right lower abdomen and lower back. Subsequently, the skin was marked by inflammation and necrosis, and diagnosed as necrotizing fascia tissue inflammation. On PT10, the signs of renal allograft hemorrhage were detected by ultrasonography. In the ensuing days, a great deal of hemorrhagic fluid which culture was positive for CRKP was continuously drained in the transplanted kidney area. However, the results of blood and drainage culture showed that CRPK was negative on PT30. Eventually, the patient continued to deteriorate, suffered from severe septic shock, and died on PT60.\n\n3 Discussion\nCRKP infections in our study occurred during different time periods, suggesting not relation to infection outbreak. Most of CRKP infections (5/6) developed immediately in the first moth after transplant, were more likely to occur within 2 weeks after transplant. Within the same time period, none of recipients from living donor kidney developed CRKP infection. It was noteworthy that the 2 kidney recipients from the same donor who was confirmed to be colonized with CRKP after donation developed infection. Additionally, the risk of donor-derived infections has also been previously described in deceased-donor renal transplant.[18] Therefore, donor-to-recipient transmission (probably via allograft) was considered to be the most likely cause of the infection. Moreover, it was assumed that donors were at high risk for acquiring multidrug-resistant pathogens including CRKP infection because of poor functional debilitated status, prolonged intensive care units admissions, mechanical ventilation, more exposure to multiple antimicrobials that may fostered the selection of resistant strains.[19] Given the risk of transmission of infection from donor, pre-donation screening for CRKP colonization in donors is of paramount importance for the prevention of subsequent infections in transplant.[20,21] In times of delay the currently culture-based techniques, screening performed on the day of donation cannot be taken into account the bacteremia carrier status.[22] Therefore, the clinical risk stratification strategy in conjunction with systematic screening may be helpful in identifying risk of donor bacteria carriage and prevention of donor-derived infections.\n\nThe most common clinical presentation of our case series included systemic inflammatory response syndrome (SIRS) associated with infection, septic shock, and recurrent hemorrhage. Intraoperative findings revealed ruptures in the renal artery or iliac artery, dead fascia, and muscle. Post-nephrectomy, a large amount of purulent bloody fluid was persistently obtained from the drainage tube in the iliac fossa. All cultures (blood, urine, drainage, subcutaneous fluid) in the 6 aforementioned cases were positive for CRKP. In addition, CRKP also grew in the perirenal dead tissue obtained from nephrectomy and biopsy specimens. Pathological examinations confirmed the presence of diffuse hemorrhagic necrotic lesions with lymphocyte infiltration, vascular wall inflammation cells erosion (vasculitis), and thrombosis in the blood vessels. In times of clinical manifestations, pathological findings and evidence of positive microbiological finding, we firstly elucidated that CRKP infection was essentially a necrotic hemorrhagic inflammation. This was line with results from previous studies in which the necrotizing inflammation associated with CRKP including abscesses and necrotizing soft tissue infection developed in organ recipients.[13,14] The necrotizing fasciitis associated with CRKP was also reported in a heart transplant case.[23] Furthermore, another case showed that CRKP pyelonephritis caused perirenal hematoma.[24]\n\nThe most striking aspect was that recurrent hemorrhage occurred in all the 6 recipients, suggesting that the anastomotic dehiscence and arterial rupture were associated with CRKP infection. CRKP infections had different clinical presentations due to the anatomic location of infection, was characterized by strong local invasion and low probability of distant organ proliferation. When the infection only involved in the allograft within about 1 week, the patients presented with fever, urinary tract infections, elevated white blood cells, or asymptomatic symptoms. With the massive bacterial replication, CRKP rapidly spread from kidney to the contiguous tissue by direct inoculation within 2 to 3 weeks after transplantation. Eventually, tissues around allograft including deep fascia, subcutaneous tissue, and arteries were infected by CRKP. Subsequently, this resulted in multiple necrotic inflammatory lesions, multiple abscess cavities filled purulent fluid, and persistent drainage. Mechanical destruction of vessel wall by infiltration of inflammatory cells and endothelial cell contributed to spontaneous arteries rupture, sudden hemorrhage, and hemorrhagic shock. To our knowledge, this was the first reported cause of spontaneous recurrent allograft hemorrhage in kidney recipients due to CRKP infection. In order to avoid the serious consequences of later vascular complications, the anastomosis of the donor renal artery to the internal iliac artery should be preferred when the donor was suspected to be infected. Optimization of anticoagulants might reduce the risk of hemorrhage during hemodialysis in CRKP infected recipients.\n\nThe mortality of CRKP infection in our study was 50%, and almost of the deaths occurred within 4 weeks after the infection. Previous studies also demonstrated that the total CRKP infection mortality rate of the transplant recipients was as high as 40% to 75%,[5,6] and the 30-days mortality rate was 50% to 60%.[7,8] CRKP was resistant to most of the antibiotics, but sensitive only to polymyxin and tigecycline,[2,5] which was the main cause of high lethality. We found that CRKP was only partly sensitive to tigecycline (sensitivity 50%). Early diagnosis of CRKP infection was difficult, and sensitive antibiotic treatment was often delayed,[4] which was another important factor leading to high mortality. The accuracy rate of early application of antibiotics in accordance with the drug sensitive results was only 50% in our study, which was line with the previous reported result that the early treatment rate of sensitive antibiotics was only 35% in CRKP infection.[25] Moreover, the toxic side effects of antibiotics, the immunocompromised state, graft insufficiency required hemodialysis, and concurrent mixed infections were also important causes of high mortality. Previous clinical trials reported that allograft resection improved the success rate of infection cure.[11,26] Moreover, the study of liver transplant recipients showed that completely debridement was essential to CRKP necrotizing soft tissue infections.[14] All the 3 surviving recipients in our study underwent allograft nephrectomy, thorough debridement, and drainage. In addition, no distant infection in the lungs, liver, and brain was found in our study. At the same time, Simkins et al also reported 13 cases of CRKP infection without the diffusion of distant organs.[26] The most possible likely explanation was that the patient had died before the infection of the distant organs. Therefore, the effective infection source control was great significance to improve the survival rate in recipients with CRKP infection.\n\nThe clinical efficacy of ceftazidime-avibactam against CRKP was corroborated by our observations. The resistance rate of CRKP to polymyxin and tigecycline was increasing.[27,28] The research in New York confirmed that the resistance rate of CRKP to polymyxin was 9% to 27%.[29] And, the existence of CRKP resistant to tigecycline was also found in the study of Greece.[28] Two survived patients in our series survived were treated with ceftazidime-avibactam in conjunction with surgical source control, indicating that ceftazidime-avibactam represented a great potential agent for the treatment of CRKP. Recent clinical trials have proved that the CRKP infection in immunocompromised hosts was successfully treated with a ceftazidime-avibactam-based therapy.[30] However, more clinical data are available to better evaluate the clinical efficacy.[31]\n\nSome limitations of our study should be noted. First, this study was only a retrospective single center study including a small number of infections, and may have introduced bias. Second, the culture method to confirm CRKP infection in our study was less sensitive than molecular biology and may lead to false negatives. The lack of gene identification of strains and the mechanism of drug resistance in our study were the third shortcoming.\n\nTo summarize, CRKP infection possibly due to donor-to-recipient transmission in DCD kidney transplants was essentially a necrotic hemorrhagic inflammation and characterized by recurrent hemorrhage and high mortality. These data provided that pre-donation screening for CRKP colonization should be mandatory and, if positive, donation should be contraindicated. Furthermore, the effective infection source control such as allograft nephrectomy and/or thorough debridement was important to improve outcomes. Nevertheless, further investigation will be required to explore new pharmacotherapeutic scheme including ceftazidime-avibactam.\n\nAuthor contributions\nZhen wang, Yeyong Qian, Hongwei Bai, Xiang Li, and Jintao Yang performed transplants.\n\nZhen wang, Xiang Li, and Jintao Yang collected, analyzed data, and interpreted results.\n\nZhen Wang prepared figures, drafted manuscript, and edited manuscript.\n\nConceptualization: Zhen Wang.\n\nData curation: Zhen Wang, Yeyong Qian, Xiang Li, and Jintao Yang.\n\nFormal analysis: Zhen Wang.\n\nInvestigation: Zhen Wang.\n\nMethodology: Zhen Wang, Xiang Li.\n\nResources: Zhen wang, Yeyong Qian, Hongwei Bai, Xiang Li, Jintao Yang.\n\nWriting – original draft: Zhen Wang.\n\nWriting – review & editing: Zhen Wang.\n\nAbbreviations: CRKP = carbapenem-resistant Klebsiella pneumonia, CRP = C-reactive protein, DCD = donation after cardiac death, DSA = digital subtraction angiography, ERSD = end-stage renal disease, MDR = multidrug-resistant, PCT = procalcitonin, PT = posttransplant day, SIRS = systemic inflammatory response syndrome.\n\nHow to cite this article: Wang Z, Qian Y, Bai H, Yang J, Li X. Allograft hemorrhage as a manifestation of Carbapenem-resistant Klebsiella pneumonia infection in kidney transplant recipients: case series. Medicine. 2020;99:13(e18982).\n\nWritten informed consents were obtained from the patients or the kins of died patients for the use of anonymous data and medical pictures for publication purposes.\n\nThe authors have no conflicts of interest to disclose.\n==== Refs\nReferences\n[1] Pouch SM Satlin MJ \nCarbapenem-resistant Enterobacteriaceae in special populations: solid organ transplant recipients, stem cell transplant recipients, and patients with hematologic malignancies\n. Virulence \n2017 ;8 :391 –402\n.27470662 \n[2] Barchiesi F Montalti R Castelli P \nCarbapenem-resistant Klebsiella pneumoniae influences the outcome of early infections in liver transplant recipients\n. BMC Infect Dis \n2016 ;16 :538 .27716164 \n[3] Yigit H Queenan AM Anderson GJ \nNovel carbapenem hydrolyzing beta-lactamase, KPC-1, from a carbapenem-resistant strain of Klebsiella pneumoniae\n. Antimicrob Agents Chemother \n2001 ;45 :1151 –61\n.11257029 \n[4] Satlin MJ Chen L Patel G \nMulticenter clinical and molecular epidemiological analysis of bacteremia due to carbapenem-resistant Enterobacteriaceae (CRE) in the CRE Epicenter of the United States\n. Antimicrob Agents Chemother \n2017 ;61 : pii:e02349-16 .\n[5] Bias TE Malat GE Lee DH \nClinical outcomes associated with carbapenem resistant Klebsiella pneumonia (CRKP) in abdominal solid organ transplant (SOT) recipients\n. Infect Dis (Lond) \n2018 ;50 :67 –70\n.28714754 \n[6] Mazza E Prosperi M Panzeri MF \nCarbapenem-resistant Klebsiella pneumoniae infections early after liver transplantation: a single-center experience\n. Transplant Proc \n2017 ;49 :677 –81\n.28457370 \n[7] Pouch SM Kubin CJ Satlin MJ \nEpidemiology and outcomes of carbapenem-resistant Klebsiella pneumonia bacteriuria in kidney transplant recipients\n. Transpl Infect Dis \n2015 ;17 :800 –9\n.26341757 \n[8] Varotti G Dodi F Terulla A \nImpact of carbapenem-resistant Klebsiella pneumoniae (CR-KP) infections in kidney transplantation\n. Transpl Infect Dis \n2017 ;19 :e12757 .\n[9] Trecarichi EM Pagano L Martino B \nBloodstream infections caused by Klebsiella pneumoniae in onco-hematological patients: clinical impact of carbapenem resistance in a multicentre prospective survey\n. Am J Hematol \n2016 ;91 :1076 –81\n.27428072 \n[10] Brizendine KD Richter SS Cober ED \nCarbapenem-resistant Klebsiella pneumoniae urinary tract infection following solid organ transplantation\n. Antimicrob Agents Chemother \n2015 ;59 :553 –7\n.25385105 \n[11] Clancy CJ Chen L Shields RK \nEpidemiology and molecular characterization of bacteremia due to carbapenem-resistant Klebsiella pneumoniae in transplant recipients\n. Am J Transplant \n2013 ;13 :2619 –33\n.24011185 \n[12] Piano S Romano A Rosi S \nSpontaneous bacterial peritonitis due to carbapenemase-producing Klebsiella pneumoniae: the last therapeutic challenge\n. Eur J Gastroenterol Hepatol \n2012 ;24 :1234 –7\n.22713510 \n[13] Mathers AJ Cox HL Bonatti H \nFatal cross infection by carbapenem-resistant Klebsiella in two liver transplant recipients\n. Transpl Infect Dis \n2009 ;11 :257 –65\n.19254325 \n[14] Rana MM Sturdevant M Patel G \nKlebsiella necrotizing soft tissue infections in liver transplant recipients: a case series\n. Transpl Infect Dis \n2013 ;15 :E157 –63\n.23782431 \n[15] Zhu X Liu H Wang W \nTwo cases of transplant renal artery thrombosis and spontaneous rupture caused by mucormycosis\n. Transpl Infect Dis \n2015 ;17 :442 –8\n.25846151 \n[16] Wang Z Qian Y Shi B \nDonor-derived renal mixed fungal infections in cardiac death donor kidney transplant recipients\n. Nephrology \n2017 ;22 :926 .\n[17] Huang J Millis JM Mao Y \nA pilot programme of organ donation after cardiac death in China\n. Lancet \n2012 ;379 :862 –5\n.22078722 \n[18] Ariza-Heredia EJ Patel R Blumberg EA \nOutcomes of transplantation using organs from a donor infected with Klebsiella pneumonia carbapenemase (KPC)-producing K. pneumoniae\n. Transpl Infect Dis \n2012 ;14 :229 –36\n.22624726 \n[19] Liu P Li X Luo M \nRisk factors for carbapenem-resistant Klebsiella pneumoniae infection: a meta-analysis\n. Microb Drug Resist \n2018 ;24 :190 –8\n.28749714 \n[20] Geladari A Karampatakis T Antachopoulos C \nEpidemiological surveillance of multidrug-resistant gram-negative bacteria in a solid organ transplantation department\n. Transpl Infect Dis \n2017 ;19 :e12686 .\n[21] Giannella M Bartoletti M Morelli MC \nRisk factors for infection with carbapenem-resistant Klebsiella pneumoniae after liver transplantation: the importance of pre- and posttransplant colonization\n. Am J Transplant \n2015 ;15 :1708 –15\n.25754742 \n[22] Demiraslan H Cevahir F Berk E \nIs surveillance for colonization of carbapenem-resistant gram-negative bacteria important in adult bone marrow transplantation units?\n\nAm J Infect Control \n2017 ;45 :735 –9\n.28214159 \n[23] Greer-Bayramoglu R Matic DB Kiaii B \nKlebsiella oxytoca necrotizing fasciitis after orthotopic heart transplant\n. J Heart Lung Transplant \n2008 ;27 :1265 –7\n.18971102 \n[24] Mancio J Oliveira M Gonçalves M \nPerirenal haematoma with Klebsiella pneumonia pyelonephritis\n. BMJ Case Reports \n2013 ;pii:bcr2012007523 .\n[25] Girmenia C Rossolini GM Piciocchi A \nInfections by carbapenem-resistant Klebsiella pneumoniae in SCT recipients: a nationwide retrospective survey from Italy\n. Bone Marrow Transplant \n2015 ;50 :282 –8\n.25310302 \n[26] Simkins J Muggia V Cohen HW \nCarbapenem-resistant Klebsiella pneumoniae infections in kidney transplant recipients: a case–control study\n. Transpl Infect Dis \n2014 ;16 :775 –82\n.25092500 \n[27] Antoniadou A Kontopidou F Poulakou G \nColistin-resistant isolates of Klebsiella pneumoniae emerging in intensive care unit patients: first report of a multiclonal cluster\n. J Antimicrob Chemother \n2007 ;59 :786 –90\n.17307769 \n[28] Castanheira M Sader HS Deshpande LM \nAntimicrobial activities of tigecycline and other broad-spectrum antimicrobials tested against serine carbapenemase- and metallobeta-lactamase-producing Enterobacteriaceae: report from the SENTRY Antimicrobial Surveillance Program\n. Antimicrob Agents Chemother \n2008 ;52 :570 –3\n.18070960 \n[29] Bratu S Tolaney P Karumudi U \nCarbapenemase-producing Klebsiella pneumoniae in Brooklyn, NY: molecular epidemiology and in vitro activity of polymyxin B and other agents\n. J Antimicrob Chemother \n2005 ;56 :128 –32\n.15917285 \n[30] Satlin MJ Walsh TJ \nMultidrug-resistant Enterobacteriaceae, Pseudomonas aeruginosa, and vancomycin-resistant Enterococcus: three major threats to hematopoietic stem cell transplant recipients\n. Transpl Infect Dis \n2017 ;19 doi: 10.1111/tid.12762 .\n[31] Mills JP Wilck MB Weikert BC \nSuccessful treatment of a disseminated infection with extensively drug-resistant Klebsiella pneumoniae in a liver transplant recipient with a fosfomycin-based multidrug regimen\n. Transpl Infect Dis \n2016 ;18 :777 –81\n.27458980\n\n",
"fulltext_license": "CC BY",
"issn_linking": "0025-7974",
"issue": "99(13)",
"journal": "Medicine",
"keywords": null,
"medline_ta": "Medicine (Baltimore)",
"mesh_terms": "D000328:Adult; D064591:Allografts; D015780:Carbapenems; D002681:China; D005260:Female; D006470:Hemorrhage; D006801:Humans; D016030:Kidney Transplantation; D007710:Klebsiella Infections; D007711:Klebsiella pneumoniae; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies",
"nlm_unique_id": "2985248R",
"other_id": null,
"pages": "e18982",
"pmc": null,
"pmid": "32221060",
"pubdate": "2020-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Allograft hemorrhage as a manifestation of carbapenem-resistant Klebsiella pneumonia infection in kidney transplant recipients: Case series.",
"title_normalized": "allograft hemorrhage as a manifestation of carbapenem resistant klebsiella pneumonia infection in kidney transplant recipients case series"
} | [
{
"companynumb": "CN-PFIZER INC-2020151242",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "TIGECYCLINE"
},
"drugadditional": null,
... |
{
"abstract": "New antibiotic options are urgently needed for the treatment of carbapenem-resistant Enterobacteriaceae infections. We report a 64-year-old female with prolonged hospitalization following an intestinal transplant who developed refractory bacteremia due to a serine carbapenemase-producing pandrug-resistant isolate of Klebsiella pneumoniae. After failing multiple antimicrobial regimens, the patient was successfully treated.",
"affiliations": "Department of Medicine, Division of Infectious Diseases, University of Miami Miller School of Medicine, Miami, Florida, USA jfc31@med.miami.edu rafael.canton@salud.madrid.org.;Department of Medicine, Division of Infectious Diseases, University of Miami Miller School of Medicine, Miami, Florida, USA.;Miami Transplant Institute and Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida, USA.;Miami Transplant Institute and Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida, USA.;Department of Pharmacy, Jackson Memorial Hospital, Miami, Florida, USA.;Department of Microbiology, Jackson Memorial Hospital, Miami, Florida, USA.;Department of Microbiology, University of Miami, Miami, Florida, USA.;Department of Medicine, Division of Infectious Diseases, University of Miami Miller School of Medicine, Miami, Florida, USA.;Department of Medicine, Division of Infectious Diseases, University of Miami Miller School of Medicine, Miami, Florida, USA.;Servicio de Microbiología, Hospital Universitario Ramón y Cajal and Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain Red Española de Investigación en Patología Infecciosa (REIPI), Madrid, Spain jfc31@med.miami.edu rafael.canton@salud.madrid.org.",
"authors": "Camargo|Jose F|JF|;Simkins|Jacques|J|;Beduschi|Thiago|T|;Tekin|Akin|A|;Aragon|Laura|L|;Pérez-Cardona|Armando|A|;Prado|Clara E|CE|;Morris|Michele I|MI|;Abbo|Lilian M|LM|;Cantón|Rafael|R|",
"chemical_list": "D000900:Anti-Bacterial Agents; D000998:Antiviral Agents; D053961:Azabicyclo Compounds; D001426:Bacterial Proteins; D015780:Carbapenems; D004338:Drug Combinations; D007166:Immunosuppressive Agents; D013845:Thienamycins; C000595613:avibactam, ceftazidime drug combination; D000078304:Tigecycline; D015662:Trimethoprim, Sulfamethoxazole Drug Combination; D002442:Ceftazidime; D001618:beta-Lactamases; C063912:carbapenemase; D000077731:Meropenem; D008911:Minocycline; D000077562:Valganciclovir; D015774:Ganciclovir; D003091:Colistin",
"country": "United States",
"delete": false,
"doi": "10.1128/AAC.00655-15",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0066-4804",
"issue": "59(10)",
"journal": "Antimicrobial agents and chemotherapy",
"keywords": null,
"medline_ta": "Antimicrob Agents Chemother",
"mesh_terms": "D000900:Anti-Bacterial Agents; D000998:Antiviral Agents; D053961:Azabicyclo Compounds; D016470:Bacteremia; D001426:Bacterial Proteins; D015780:Carbapenems; D002442:Ceftazidime; D003082:Colectomy; D003091:Colistin; D004338:Drug Combinations; D024901:Drug Resistance, Multiple, Bacterial; D005260:Female; D015774:Ganciclovir; D006801:Humans; D007166:Immunosuppressive Agents; D007421:Intestine, Small; D007710:Klebsiella Infections; D007711:Klebsiella pneumoniae; D000077731:Meropenem; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D008911:Minocycline; D013845:Thienamycins; D000078304:Tigecycline; D015662:Trimethoprim, Sulfamethoxazole Drug Combination; D000077562:Valganciclovir; D001618:beta-Lactamases",
"nlm_unique_id": "0315061",
"other_id": null,
"pages": "5903-8",
"pmc": null,
"pmid": "26386029",
"pubdate": "2015-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "25542050;25597275;1244564;6413485;3060240;10223931;16080071;17328735;21118912;21396529;21422205;22467668;25305144;22752516;23145859;23253318;23231088;23371303;23439635;23391714;23571536;23733463;24183799;24521856;24562613;24890393;24930781;22700698;25542051",
"title": "Successful Treatment of Carbapenemase-Producing Pandrug-Resistant Klebsiella pneumoniae Bacteremia.",
"title_normalized": "successful treatment of carbapenemase producing pandrug resistant klebsiella pneumoniae bacteremia"
} | [
{
"companynumb": "US-ACCORD-041821",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BASILIXIMAB"
},
"drugadditional": null,
"dru... |
{
"abstract": "Macrolide resistance in Mycoplasma genitalium (MG) exceeds 50% in many regions, and quinolone resistance is increasing. We recently reported that resistance-guided therapy (RGT) using doxycycline followed by sitafloxacin or 2.5 g azithromycin cured 92% and 95% of macrolide-resistant and macrolide-susceptible infections, respectively. We present data on RGT using doxycycline-moxifloxacin, the regimen recommended in international guidelines, and extend data on the efficacy of doxycycline-2.5 g azithromycin and de novo macrolide resistance.\n\n\n\nPatients attending Melbourne Sexual Health Centre between 2017 and 2018 with sexually transmitted infection syndromes were treated with doxycycline for 7 days and recalled if MG-positive. Macrolide-susceptible cases received 2.5 g azithromycin (1 g, then 500 mg daily for 3 days), and resistant cases moxifloxacin (400 mg daily, 7 days). Test of cure was recommended 14-28 days post-antimicrobials.\n\n\n\nThere were 383 patients (81 females/106 heterosexual males/196 men who have sex with men) included. Microbial cure following doxycycline-azithromycin was 95.4% (95% confidence interval [CI], 89.7-98.0) and doxycycline-moxifloxacin was 92.0% (95% CI, 88.1-94.6). De novo macrolide resistance was detected in 4.6% of cases. Combining doxycycline-azithromycin data with our prior RGT study (n = 186) yielded a pooled cure of 95.7% (95% CI, 91.6-97.8). ParC mutations were present in 22% of macrolide-resistant cases.\n\n\n\nThese findings support the inclusion of moxifloxacin in resistance-guided strategies and extend the evidence for 2.5 g azithromycin and presumptive use of doxycycline. These data provide an evidence base for current UK, Australian, and European guidelines for the treatment of MG.",
"affiliations": "Central Clinical School, Faculty of Medicine, Nursing and Health Sciences, Monash University, Melbourne, Australia.;Central Clinical School, Faculty of Medicine, Nursing and Health Sciences, Monash University, Melbourne, Australia.;Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, Victoria, Australia.;Melbourne Sexual Health Centre, Alfred Health, Carlton, Victoria, Australia.;Central Clinical School, Faculty of Medicine, Nursing and Health Sciences, Monash University, Melbourne, Australia.;Central Clinical School, Faculty of Medicine, Nursing and Health Sciences, Monash University, Melbourne, Australia.;Central Clinical School, Faculty of Medicine, Nursing and Health Sciences, Monash University, Melbourne, Australia.;Melbourne Sexual Health Centre, Alfred Health, Carlton, Victoria, Australia.;SpeeDx Pty Ltd, National Innovation Centre, Eveleigh, New South Wales, Australia.;SpeeDx Pty Ltd, National Innovation Centre, Eveleigh, New South Wales, Australia.;Central Clinical School, Faculty of Medicine, Nursing and Health Sciences, Monash University, Melbourne, Australia.;Central Clinical School, Faculty of Medicine, Nursing and Health Sciences, Monash University, Melbourne, Australia.",
"authors": "Durukan|Duygu|D|;Read|Tim R H|TRH|;Murray|Gerald|G|;Doyle|Michelle|M|;Chow|Eric P F|EPF|;Vodstrcil|Lenka A|LA|;Fairley|Christopher K|CK|;Aguirre|Ivette|I|;Mokany|Elisa|E|;Tan|Lit Y|LY|;Chen|Marcus Y|MY|;Bradshaw|Catriona S|CS|",
"chemical_list": "D000900:Anti-Bacterial Agents; D018942:Macrolides; D017963:Azithromycin; D004318:Doxycycline; D000077266:Moxifloxacin",
"country": "United States",
"delete": false,
"doi": "10.1093/cid/ciz1031",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1058-4838",
"issue": "71(6)",
"journal": "Clinical infectious diseases : an official publication of the Infectious Diseases Society of America",
"keywords": "\n Mycoplasma genitalium\n ; antimicrobial resistance; moxifloxacin; sexually transmitted infections; treatment",
"medline_ta": "Clin Infect Dis",
"mesh_terms": "D000900:Anti-Bacterial Agents; D001315:Australia; D017963:Azithromycin; D004318:Doxycycline; D024881:Drug Resistance, Bacterial; D005260:Female; D018451:Homosexuality, Male; D006801:Humans; D018942:Macrolides; D008297:Male; D000077266:Moxifloxacin; D009175:Mycoplasma Infections; D045704:Mycoplasma genitalium; D000072339:Sexual and Gender Minorities",
"nlm_unique_id": "9203213",
"other_id": null,
"pages": "1461-1468",
"pmc": null,
"pmid": "31629365",
"pubdate": "2020-09-12",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Resistance-Guided Antimicrobial Therapy Using Doxycycline-Moxifloxacin and Doxycycline-2.5 g Azithromycin for the Treatment of Mycoplasma genitalium Infection: Efficacy and Tolerability.",
"title_normalized": "resistance guided antimicrobial therapy using doxycycline moxifloxacin and doxycycline 2 5 g azithromycin for the treatment of mycoplasma genitalium infection efficacy and tolerability"
} | [
{
"companynumb": "AU-BAYER-2020-257767",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "MOXIFLOXACIN"
},
"drugadditional": null,
... |
{
"abstract": "Japanese average sleeping time is decreasing year by year. The National Sleep Foundation of United States of America released that Japan reports the least amount of sleep. Japanese reports sleeping about 30 to 40 minutes less on workdays than those in the other countries surveyed, averaging 6 hours 22 minutes of sleep. There are many reports that insomnia has been suggested to cause depression and other mental disorders. And epidemiological evidence supports a link between sleep loss and obesity. Obesity is one of risk factors of obstructive sleep apnea syndrome which causes cognitive dysfunction, mood disorders and so on. Sleep loss and sleep insufficiency can cause mental disorders and be impaired cognitive function and performance.",
"affiliations": "Department of Neuropsychiatry, Kurume University of School of Medicine.",
"authors": "Hashizume|Yuji|Y|",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0047-1852",
"issue": "72(2)",
"journal": "Nihon rinsho. Japanese journal of clinical medicine",
"keywords": null,
"medline_ta": "Nihon Rinsho",
"mesh_terms": "D000328:Adult; D003863:Depression; D006801:Humans; D008297:Male; D008603:Mental Health; D012890:Sleep; D012891:Sleep Apnea Syndromes; D007319:Sleep Initiation and Maintenance Disorders",
"nlm_unique_id": "0420546",
"other_id": null,
"pages": "341-6",
"pmc": null,
"pmid": "24605538",
"pubdate": "2014-02",
"publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article",
"references": null,
"title": "The importance of sleep in the mental health.",
"title_normalized": "the importance of sleep in the mental health"
} | [
{
"companynumb": "PHHY2014JP117117",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ZOLPIDEM\\ZOLPIDEM TARTRATE"
},
"drugadditional": null... |
{
"abstract": "BACKGROUND\nInvasive aspergillosis (IA) of the central nervous system (CNS) is an uncommon condition that usually occurs in immunocompromised patients. This illness can manifest as meningitis, or as a micotic aneurism, stroke or abscess. The infection affects the CNS either primarily or, more often, secondarily via blood dissemination from a distant focus, and has a poor prognosis. We present a patient with IA primarily affecting the cervical bones, with later spread into the brain.\n\n\nMETHODS\nA 25-year old male was receiving chemotherapy for acute lymphocytic leukemia when he developed pneumonitis secondary to methotrexate and was started on corticosteroids. He subsequently developed cervicalgia, prompting a needle biopsy of the fourth vertebrae, after which a diagnosis of osteomyelitis was made. Even though the biopsy culture was negative, empirical antibiotics were initiated. A parietal lobe lesion was treated surgically months later after the patient presented with three episodes of transient aphasia. After A. fumigatus grew in culture, the patient's antibiotic regimen was changed to treat the specific agent with a good response.\n\n\nCONCLUSIONS\nIA must be considered a possibility whenever an immunocompromised patient presents with a new brain lesion. These lesions require surgical evacuation, a procedure that allows for diagnostic confirmation and enhances prognosis. Appropriate anti-fungal therapy must be started as soon as the diagnosis is confirmed. In addition, the patient's neurological exam must be repeated and images obtained periodically to monitor treatment and detect possible recurrences.",
"affiliations": "Neurocirujanos del Departamento de Neurocirugía de FLENI, Buenos Aires, Argentina.;Traumatólogos (Neurortopedistas) del Departamento de Neurocirugía de FLENI, Buenos Aires, Argentina.;Infectólogos del Departamento de Infectología de FLENI, Buenos Aires, Argentina.;Infectólogos del Departamento de Infectología de FLENI, Buenos Aires, Argentina.;Neurocirujanos del Departamento de Neurocirugía de FLENI, Buenos Aires, Argentina.;Neurocirujanos del Departamento de Neurocirugía de FLENI, Buenos Aires, Argentina.;Neurocirujanos del Departamento de Neurocirugía de FLENI, Buenos Aires, Argentina.;Neurocirujanos del Departamento de Neurocirugía de FLENI, Buenos Aires, Argentina.",
"authors": "Vergara|Guillermo Enrique|GE|;Roura|Natalia|N|;Del Castillo|Marcelo|M|;Mora|Andrea|A|;Alcorta|Santiago Condomi|SC|;Mormandi|Rubén|R|;Cervio|Andrés|A|;Salvat|Jorge|J|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.4103/2152-7806.167203",
"fulltext": "\n==== Front\nSurg Neurol IntSurg Neurol IntSNISurgical Neurology International2229-50972152-7806Medknow Publications & Media Pvt Ltd India SNI-6-52410.4103/2152-7806.167203Case ReportAspergilosis cervical con diseminación al sistema nervioso central. Presentación de un caso y revisión de bibliografía Cervical aspergillosis with dissemination to the central nervous system: Case reports and review of the literature Vergara Guillermo Enrique vergaraguien@gmail.com*Roura Natalia nroura@fleni.org.ar1del Castillo Marcelo mdelcastillo@fleni.org.ar2Mora Andrea amora@fleni.org.ar2Alcorta Santiago Condomi scondomi@fleni.org.arMormandi Rubén rmormandi@fleni.org.arCervio Andrés acervio@fleni.org.arSalvat Jorge jsalvat@fleni.org.arrNeurocirujanos del Departamento de Neurocirugía de FLENI, Buenos Aires, Argentina1 Traumatólogos (Neurortopedistas) del Departamento de Neurocirugía de FLENI, Buenos Aires, Argentina2 Infectólogos del Departamento de Infectología de FLENI, Buenos Aires, Argentina* Corresponding author\n2015 12 10 2015 6 Suppl 20 SNI: Revista Argentina de Neurocirugia, a supplement to SNIS524 S529 13 3 2015 19 3 2015 Copyright: © 2015 Vergara GE.2015This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Introducción:\nla Aspergilosis Invasiva (AI) del Sistema Nervioso Central (SNC) es infrecuente y ocurre generalmente en pacientes inmunocomprometidos. Puede presentarse con cuadros de meningitis, aneurismas micóticos, infartos o abscesos. Es una infección con pronóstico reservado y puede afectar el SNC de forma primaria o secundaria a partir de un foco que se disemina por vía hematógena. Presentamos el caso de un paciente con AI con invasión primaria a nivel óseo y diseminación posterior al cerebro.\n\nCaso clínico:\nPaciente masculino de 25 años con diagnóstico de leucemia linfática aguda en tratamiento quimioterápico que presentó neumonitis por metotrexate por lo que inicia tratamiento con corticoides. Posteriormente agregó cervicalgia y con el diagnóstico de osteomielitis cervical se realiza punción bajo tomografía computada (TC) sin aislarse gérmenes. Se colocó Halo Vest e inició tratamiento antibiótico empírico. Posteriormente presentó afasia de expresión secundaria a lesión frontal izquierda. Se realizó evacuación de absceso cerebral aislando A. fumigatus. El tratamiento antibiótico específico posterior permitió una buena respuesta clínica y radiológica.\n\nConclusión:\nLa presencia de lesiones en el SNC de pacientes inmunocomprometidos debe incluir a las micosis como diagnóstico diferencial. La evacuación quirúrgica permite llegar rápidamente al diagnóstico mejorando la respuesta posterior al tratamiento antibiótico. Para evaluar la respuesta terapéutica y posibles recaídas se debe realizar un seguimiento periódico clínico radiológico. Palabras clave: Aspergilosis cerebral; Aspergilosis cervical; Aspergilosis invasiva; Voriconazol.\n\nBackground:\nInvasive aspergillosis (IA) of the central nervous system (CNS) is an uncommon condition that usually occurs in immunocompromised patients. This illness can manifest as meningitis, or as a micotic aneurism, stroke or abscess. The infection affects the CNS either primarily or, more often, secondarily via blood dissemination from a distant focus, and has a poor prognosis. We present a patient with IA primarily affecting the cervical bones, with later spread into the brain.\n\nCase Description:\nA 25-year old male was receiving chemotherapy for acute lymphocytic leukemia when he developed pneumonitis secondary to methotrexate and was started on corticosteroids. He subsequently developed cervicalgia, prompting a needle biopsy of the fourth vertebrae, after which a diagnosis of osteomyelitis was made. Even though the biopsy culture was negative, empirical antibiotics were initiated. A parietal lobe lesion was treated surgically months later after the patient presented with three episodes of transient aphasia. After A. fumigatus grew in culture, the patient's antibiotic regimen was changed to treat the specific agent with a good response.\n\nConclusion:\nIA must be considered a possibility whenever an immunocompromised patient presents with a new brain lesion. These lesions require surgical evacuation, a procedure that allows for diagnostic confirmation and enhances prognosis. Appropriate anti-fungal therapy must be started as soon as the diagnosis is confirmed. In addition, the patient's neurological exam must be repeated and images obtained periodically to monitor treatment and detect possible recurrences.\n\nBrain aspergillosiscervical aspergillosisinvasive aspergillosisvoriconazolAspergilosis cerebralaspergilosis cervicalaspergilosis invasivavoriconazol\n==== Body\nINTRODUCCIÓN\nLa Aspergillosis Invasiva (AI) es una de las infecciones oportunistas más agresivas. Los sitios más frecuentemente afectados son los pulmones y los senos paranasales. El sistema nervioso central (SNC) se compromete en forma primaria o secundaria a partir de un foco que se disemina vía hematógena.\n\nLa AI del SNC es un cuadro poco frecuente con una incidencia menor al 5%. Generalmente ocurre en pacientes inmunocomprometidos, aunque hay casos descriptos en pacientes inmunocompetentes.[1113] Su incidencia se incrementó en los últimos tiempos[18] debido al aumento de pacientes con SIDA y transplantados, de enfermedades autoinmunes y granulomatosas crónicas y del uso de drogas inmunosupresoras y corticoides.\n\nEl éxito en el tratamiento de esta patología depende del diagnóstico temprano, un tratamiento agresivo y un seguimiento posterior adecuado.\n\nNuestro objetivo es la presentación de un paciente con AI con invasión primaria a nivel óseo y diseminación posterior al cerebro.\n\nCASO CLÍNICO\nPaciente de sexo masculino de 25 años de edad con antecedentes de leucemia linfática aguda desde 2007. Realizó quimioterapia hasta 2008 con remisión completa (8 ciclos de HyperCVAD). En julio de 2008 inició tratamiento de mantenimiento con metrotexato, vincristina y 6 mercaptopurina intercurriendo con neumonitis interpretada como secundaria a metrotexato. Se suspendió el mismo e inició tratamiento con corticoides (prednisona 4 mg/día). En noviembre de 2008 comenzó con cervicalgia, la resonancia magnética (RM) realizada evidenció lesión compatible con osteomielitis cervical [Figura 1]. Se realizó punción bajo control tomográfico sin obtenerse rescate de microorganismos.\n\nFigura 1 RM columna cervical. Secuencia T1 con gadolinio. Corte sagital. Pérdida parcial de la lordosis cervical e hiperintensidad leve en discos y vértebras C2 - C5. Realce homogéneo de los discos y vértebras de C2 – C5\n\nSe decidió tratamiento conservador con collar de Philadelfia, luego una ortesis cervical (Minerva) y por último HALO VEST, e inició tratamiento empírico con teicoplanina/ciprofloxacina 750 mg cada 12 hs + rifampicina 300 mg cada 12 hs.\n\nA finales de 2008 y comienzos de 2009, presentó 3 episodios compatibles con afasia de expresión de segundos de duración, se realizó una tomografía computada (TC) de cerebro que evidenció la existencia de una lesión a nivel frontal izquierdo.\n\nSe retiró el HALO VEST y se colocó collar de Philadelfia para realizar RM [Figura 2] de cerebro que evidenció lesión cortical con abundante edema vasogénico perilesional con marcado refuerzo posterior al contraste en región parieto temporal posterior. Teniendo en cuenta antecedentes clínicos, sintomatología y hallazgos radiológicos se decidió realizar evacuación quirúrgica guiada con neuronavegación. Posteriormente se medicó con vancomicina 1 gr cada 12 hs + cefepime 2 gr cada 12 hs + metronidazol 500 mg cada 6 hs + aciclovir 750 mg cada 8 hs. Frente a las hifas evidenciadas en el examen histológico inició tratamiento con anfotericina 5 mg/kg/día por 24 hs y luego, con diagnóstico de certeza de Aspergilosis, se rotó el tratamiento a voriconazol 300 mg cada 12 hs. Se efectuaron cada 3 meses controles periódicos de columna cervical y cerebro con RM, con buena respuesta al tratamiento, sin cervicalgia ni trastornos del lenguaje, durante 20 meses de seguimiento [Figuras 3 y 4].\n\nFigura 2 RM pre operatoria cerebro. Secuencia T1 con gadolinio. Corte axial. Lesión nodular intraxial que capta contraste de forma heterogénea con abundante edema perilesional a nivel parietal izquierdo\n\nFigura 3 RM columna cervical 20 meses de seguimiento. Secuencia T1 con gadolinio. Corte sagital. Pérdida parcial de la lordosis cervical, no se observa realce en los discos C2 - C5 tras el contraste\n\nFigura 4 RM de cerebro 20 meses post operatoria. Secuencia T1 con gadolinio. Corte axial. Sin realce a nivel parietal izquierdo en zona de evacuación de lesión abscedada y sin edema\n\nDISCUSIÓN\nEl Aspergillus es un hongo que se encuentra en la tierra, agua y restos orgánicos y es reconocido como patógeno humano desde 1847.[18] La inhalación de esporas de Aspergillus es sumamente frecuente, sin embargo casi nunca produce enfermedad. La forma infecciosa del hongo son las conidias, las cuales también colonizan el tracto respiratorio y el conducto auditivo externo lo que explica por qué los pulmones y los senos paranasales son los lugares más frecuentemente afectados. De las 19 especies de Aspergillus, el A. fumigatus es el patógeno humano más frecuente, considerado responsable del 90% de los casos.[17] Sin embargo, hay casos descriptos de A. flavus, A. niger y A. oxyzae.[24] La incidencia es mayor en climas secos y cálidos, principalmente India y Arabia Saudita.\n\nUn vez producida la primo infección, por vía hematógena o por contigüidad el hongo invade el SNC causando abscesos intraparenquimatosos y epidurales, vasculitis, infartos, granulomas y/o meningitis. La mayor parte de los estudios identifica al Cryptococcus, Aspergillus y la Candida como las especies micóticas más frecuentes en afectar el SNC y reconoce al Aspergillus como la principal especie formadora de granulomas.[21]\n\nLos factores de riesgo más frecuentemente asociados con infección del SNC son el trasplante de médula ósea, los tumores hematológicos, la terapia inmunosupresora y la neutropenia. Otros grupos de riesgo son los pacientes con trasplante de órganos sólidos y los pacientes con SIDA, insuficiencia hepática, síndrome de Cushing, asma y alcoholismo.[10]\n\nLa sintomatología que presentan los pacientes con AI es variable y poco específica. En el 25-33% de los casos la AI es asintomática.[5] Déficit neurológico focal, cambios en el estado de conciencia y convulsiones son los síntomas neurológicos más comunes, y se caracterizan por una progresión rápida.\n\nEl diagnóstico de AI es establecido mediante la combinación de datos histológicos (visualización de hifas compatibles con las de Aspergillus) y microbiológicos (visualización de hifas en el examen en fresco y aislamiento de Aspergillus en cultivo), dado que ninguno de ellos puede asegurar el diagnóstico por sí solo. Las tinciones histológicas más utilizadas son: La metenamina de plata o tinción de Grocot y la hematoxilina-eosina, aunque esta última no es útil cuando los tejidos están necrosados. La visualización histológica debe ser confirmada con el aislamiento en cultivo, ya que las hifas de Aspergillus son indistinguibles de las de Pseudallescheria boydii o Fusarium spp. El Aspergillus crece bien en casi todos los medios de cultivo. La temperatura óptima de crecimiento es de 37° C y los micelios pueden ser visibles a las 48 horas de incubación.\n\nEl diagnóstico es difícil de realizar por pruebas de laboratorio basadas en cultivos sanguíneos y de líquido cefalorraquídeo (LCR).[25] El análisis del LCR generalmente es negativo pero sirve para hacer diagnóstico diferencial con otras patologías que afectan las meninges.[1] Los test serológicos en sangre y en LCR como la contrainmunoelectroforesis, la inmunofluorecencia y la enzimo inmuno ensayo (ELISA) pueden ayudar al diagnóstico. La detección de anticuerpos en sangre para el diagnóstico de la AI resulta útil en el caso de pacientes no inmunosuprimidos, pero es de de muy baja utilidad en pacientes inmunosuprimidos. Si los anticuerpos se encuentran al inicio de la enfermedad suelen estar causados por la exposición al hongo previa a la enfermedad. Si se encuentran al final suelen indicar la recuperación del individuo de su AI, por lo que podemos dar a estos datos un valor pronóstico, pero no diagnóstico.\n\nDebido a la dificultad en el diagnóstico de la AI, la realización de PCR en busca del ADN del hongo causante de la enfermedad constituye una alternativa.[1] La posibilidad de encontrar ADN de Aspergillus en suero es mayor que la de hallar hemocultivos positivos a Aspergillus. Esto se debe a la mayor sensibilidad de PCR o bien a que las hifas que se liberen al torrente sanguíneo estén muertas y por tanto no puedan crecer en medios de cultivos, mientras que sí podemos detectar el ADN. Sin embargo, esta última teoría choca con la demostrada capacidad de diseminación del hongo. La detección de Galactomananos, un carbohidrato componente de la pared del Aspergillus, en orina, suero y LCR ha mejorado el diagnóstico en pacientes inmunodeprimidos. Por lo expuesto, el diagnóstico definitivo se realiza con el estudio anatomopatológico.\n\nLos métodos de imágenes para el diagnóstico son TC, RM y tomografía por emisión de positrones (PET-TC).[8] Las lesiones en TC son hiperdensas con efecto de masa y pueden o no captar contraste; en RM se presentan habitualmente irregulares, hipo o isointensas en T1 e hipointensas en T2, con realce en anillo u homogéneo posterior al gadolineo. Una señal hiperintensa en Difusión puede ser observada debido a células inflamatorias y tejido necrótico rico en proteínas. Las imágenes en T1 son secundarias a necrosis por compromiso vascular y la señal en T2 se debe a la densa cantidad de hifas de Aspergillus pero también puede ser explicada por la presencia de hierro,[16] manganeso y magnesio que presentan las paredes micóticas del Aspergillus o bien por hemorragias que ocurren en el 25% de las lesiones.[23] Un anillo hipointenso circundante está asociado con una mayor frecuencia de hemorragia, y la presencia de una gruesa pared irregular alrededor de la lesión indica mecanismos de defensa del huésped que tienden a encapsular la infección.[15] Las imágenes cambian según la inmunidad del paciente: En pacientes severamente comprometidos se observa poco o nada de refuerzo con contraste en RM, en cambio en pacientes inmunocompetentes o con leve alteración de su inmunidad se observa una gran captación de contraste. Esto sugiere la ausencia de respuesta inflamatoria para el primer paciente y por consiguiente, un peor pronóstico.[14] Todas las imágenes descriptas pueden corresponder a Aspergilosis pero también a otros microorganismos como Criptococos, Nocardia, Toxoplasmosis y Tuberculosis. Por esto resulta difícil realizar el diagnóstico de certeza por medio de las imágenes. Las principales formas de presentación de esta patología en imágenes son: Infartos, infiltración dural o vascular y lesiones ocupantes de espacio intra o extraaxial.[21] Generalmente, los infartos producidos por AI involucran los núcleos de la base mostrando su predilección por arterias perforantes lentículo estriadas. Las lesiones granulomatosas o abscesos, son frecuentes de observar a nivel del lóbulo frontal o temporal en regiones córtico subcorticales. El PET-TC con F-fluordeoxyglucosa (FDG) se usa para diferenciar patología inflamatoria/infecciosa de patología maligna, mostrando captación de FDG en patología inflamatoria. Sin embargo, si la lesión tiene mucho componente necrótico esta captación puede disminuir.[3]\n\nDistintos estudios han probado mayor eficacia y menor toxicidad del voriconazol sobre otros medicamentos, por lo que se ha transformado en la droga de elección para el inicio del tratamiento.[136722] Se pueden usar otros fármacos como la anfotericina B (su compuesto liposomal), itraconazol, fluconazol y 5 fluorcitocina o una combinación de ellas.[19] Las distintas combinaciones continúan siendo estudiadas sin evidencias claras de superioridad de una sobre las otras.[12] Hay reportes de tratamiento de abscesos cerebrales por Aspergilosis con anfotericina intracavitaria de manera continua con buena respuesta. Otros tratamientos experimentales propuestos son el factor estimulante de colonias y el interferón gama recombinante.\n\nEn cuanto a la técnica quirúrgica a utilizar no hay recomendaciones, los datos son solo tomados de reportes y series de casos. Lo que sí se puede establecer es que el tratamiento quirúrgico permite un diagnóstico de certeza en aquellos casos que no se llega a diagnóstico con exámenes de laboratorios y de imágenes. Permite, además, una mejor respuesta al tratamiento con antimicóticos y en casos de masas intracraneales de gran tamaño, evita déficits neurológicos y síndrome de hipertensión endocraneana. En una revisión bibliográfica realizada por Kourkoumpetis y col.[12] se analizaron pacientes tratados solo con terapia antibiótica y pacientes que realizaron tratamiento quirúrgico y antibiótico observándose una mortalidad del 67% y 28% respectivamente. Debido a la existencia de múltiples lesiones cerebrales, el tratamiento quirúrgico resectivo no siempre es posible, en ese caso se utiliza la esterotaxia para la toma de biopsia.[24] En lesiones por Aspergilosis en áreas elocuentes, donde la exéresis total provocaría déficit neurológico, la resección parcial y hasta la toma de una biopsia otorgaría mejor pronóstico y mayor respuesta al tratamiento en comparación con casos tratados con antimicóticos solamente. Si la lesión se encuentra en un área no elocuente, la exéresis quirúrgica completa es la meta.\n\nLuego del tratamiento quirúrgico, el paciente debe continuar con un tratamiento antimicótico agresivo. Siddiqui ha planteado una clasificación que pone de manifiesto la evolución clínica con respecto al tipo de invasión producida por el hongo.[1921]\n\n\nTipo 1: Pacientes con aspergilosis intracerebral (peor pronóstico)\n\nTipo 2: Pacientes con aspergilosis orbital y de base de cráneo (buena respuesta al tratamiento)\n\nTipo 3: Pacientes con aspergilosis intracranana extradural (pronóstico intermedio).\n\n\n\n\nEl pronóstico es distinto según las publicaciones y depende principalmente del estado inmunológico del paciente. En pacientes inmunocomprometidos la mortalidad llega a ser del 95-100%[7171820] y baja al 40-60% en pacientes inmunocompetentes.[718] Pacientes con enfermedad nasosinusal con o sin invasión de órbita o base de cráneo tienen buen pronóstico (mortalidad <20%). Pacientes con lesiones intraparenquimatosas presentan peor pronóstico que aquellos con lesiones extradurales.\n\nCONCLUSIÓN\nLa AI y más precisamente la afección del SNC es una infección micótica poco frecuente que afecta predominantemente a pacientes inmunodeprimidos. Debido al aumento de su incidencia en los últimos tiempos y al mal pronóstico que acarrea, el diagnóstico rápido es de suma importancia. Los síntomas y signos neurológicos y las imágenes que se pueden observar en pacientes con Aspergilosis cerebral son inespecíficos, por lo que no se puede llegar a un diagnóstico a través de los mismos. Sin embargo, ante un paciente inmunodeprimido que presente sintomatología neurológica y las imágenes muestren lesiones compatibles, es un diagnóstico diferencial a considerar. Ya que es difícil diagnosticar esta patología por medio de técnicas no invasivas (cultivo y análisis de sangre y LCR), se hace necesaria la toma de biopsia para estudios microbiológicos e histológicos. El tratamiento antimicótico de elección es el voriconazol y la segunda opción es la anfotericina liposomal o los tratamientos combinados. Se recomienda un estricto seguimiento clínico – radiológico para evaluar la respuesta al tratamiento y detectar posibles recidivas.\n\nhttp://surgicalneurologyint.com/Aspergilosis-cervical-con-diseminación-al-sistema-nervioso-central.-Presentación-de-un-caso-y-revisión-de-bibliografía/\n==== Refs\nBIBLIOGRAFÍA\n1 Al-Abdely HM Alothman AF Salman JA Al-Musawi T Almaslamani M Butt AA Clinical practice guidelines for the treatment of invasive Aspergillus infections in adults in the Middle East region: Expert panel recommendations J Infect Public Health 2014 7 20 31 24029495 \n2 Alapatt JP Kutty RK Gopi PP Challissery J Middle and posterior fossa aspergilloma Surg Neurol 2006 6675 8 discussion 78-9 \n3 Azarpira N Esfandiari M Bagheri MH Rakei S Salari S Cerebral Aspergillosis Presenting as a Mass Lesion Braz J Infect Dis 2008 12 349 51 19030740 \n4 Chi CY Fung CP Liu CY Aspergillus flavus epidural abscess and osteomyelitis in a diabetic patient J Microbiol Immunol Infect 2003 36 145 8 12886968 \n5 Dubey A Patwardhan RV Sampth S Santosh V Kolluri S Nanda A Intracranial Fungal Granuloma: Analysis of 40 patients and review of the literature Surg Neurol 2005 63 254 60 15734518 \n6 Gallien S Fournier S Porcher R Bottero J Ribaud P Sulahian A Therapeutic Outcome and Prognostic Factor of Invasive Aspergilolosis in an Infectious Disease Department: A review of 34 cases Infection 2008 36 533 8 19011743 \n7 Herbrecht R Denning DW Patterson TF Bennett JE Greene RE Oestmann JW Voriconazol versus amphotericin B for primary therapy of invasive aspergillosis N Engl J Med 2002 347 408 15 12167683 \n8 Oh IS Seo JY Ha KY Kim YC Treatment for Multiple Aspergillus Spondylitis Including a Hip Joint Asian Spine J 2009 3 106 12 20404956 \n9 Kirby A Hassan I Burnie J Recommendations for managing Aspergillus osteomyelitis and joint infections based on a review of the literature J Infect 2006 52 405 14 16239033 \n10 Kleinschmidt-DeMasters BK Central nervous system aspergilosis: A 20-year retrospective series Hum Pathol 2002 33 116 24 11823982 \n11 Koshy R Malhotra P Treatment of primary aspergilloma of the central nervous system in a diabetic immunocompetent patient with surgical resection and voriconazole: A case report and review of the literature Turk Neurosurg 2011 21 641 4 22194129 \n12 Kourkoumpetis TK Desalermos A Muhammed M Mylonakis E Central nervous system aspergillosis: A series of 14 cases from a general hospital and review of 123 cases from the literature Medicine (Baltimore) 2012 91 328 36 23117848 \n13 Lee JC Lim DJ Ha SK Kim SD Kim SH Fatal case of cerebral aspergillosis: A case report and literature review J Korean Neurosurg Soc 2012 52 420 2 23133737 \n14 Okafuji T Yabuuchi H Nagatoshi Y Hattanda Y Fukuya T CT and MR findings of brain aspergillosis Comput Med Imaging Graph 2003 27 489 92 14575782 \n15 Phutharak W Hesselink JR Wixon C MR feactures of cerebral aspergillosis in an inmunocompetent patient: Correlation with histology and elemental analysis AJNR Am J Neuroradiol 2005 26 835 8 15814930 \n16 Pollack E Bhaya A Law M Differentiating Intracranial Aspergillosis from a High Grade Glioma Using MRI and MR Spectroscopic Imaging J Neuroimaging 2007 17 361 6 17894631 \n17 Ruhnke M Kofla G Otto K Schwartz S CNS Aspergillosis. Recognition, Diagnosis and Management CNS Drugs 2007 21 659 76 17630818 \n18 Shamim MS Enam SA Ali R Answar S Cranicerebral Aspergillosis: A review of advances in diagnosis and management J Pak Med Assoc 2010 60 573 9 20578611 \n19 Siddiqui AA Bashir SH Ali Shah A Sajjad Z Ahmed N Jooma R Diagnostic MR imaging feactures of craniocerebral Aspergillosis of sino-nasal origin in immunocompetent patients Acta Neurochir (Wien) 2006 148 155 66 16283103 \n20 Son JM Jee WH Jung CK Kim SI Ha KY Aspergillus Spondylitis involving the Cervico-Thoraco-Lumbar Spine in an Immunocompromised Patient: A case report Korean J Radiol 2007 8 448 51 17923789 \n21 Srinivasan US Intracranial Aspergilloma in Inmunocompetent Patients Successfully Treatment with Radical Surgical Intervention and Antifungal Therapy - Case Report Ann Acad Med Singapore 2008 37 783 7 18989496 \n22 Stratov I Korman TM Johnson PD Management of Aspergillus Osteomyelitis: Report of Failure of Liposomal Amphotericin B and Response to Voriconazole in an Immunocompetent Host and Literature Review Eur J Clin Microbiol Infect Dis 2003 22 277 83 12734721 \n23 Tempkin AD Sobonya RE Seeger JF Oh ES Cerebral Aspergillosis: Radiologic and pathologic findings Radiographics 2006 26 1239 42 16844943 \n24 Turgut M Ozsunar Y Oncü S Akyüz O Ertuğrul MB Tekin C Invasive fungal granuloma of the brain cause by Aspergillus fumigatus: A case report and review of the literature Surg Neurol 2008 69 169 74 17825367 \n25 Walsh TJ Hier DB Caplan LR Aspergillosis of the Central Nervous System: Clinicopathological Analysis of 17 Patients Ann Neurol 1985 18 574 82 3935042\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "2152-7806",
"issue": "6(Suppl 20)",
"journal": "Surgical neurology international",
"keywords": null,
"medline_ta": "Surg Neurol Int",
"mesh_terms": null,
"nlm_unique_id": "101535836",
"other_id": null,
"pages": "S524-9",
"pmc": null,
"pmid": "26600985",
"pubdate": "2015",
"publication_types": "D002363:Case Reports",
"references": "17894631;16283103;20404956;3935042;17923789;15734518;11823982;23133737;22194129;15814930;23117848;19030740;17825367;18989496;14575782;20578611;12734721;12886968;16793449;12167683;16239033;16844943;17630818;19011743;24029495",
"title": "Cervical aspergillosis with dissemination to the central nervous system: Case reports and review of the literature.",
"title_normalized": "cervical aspergillosis with dissemination to the central nervous system case reports and review of the literature"
} | [
{
"companynumb": "AR-FRESENIUS KABI-FK201602178",
"fulfillexpeditecriteria": "1",
"occurcountry": "AR",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "VINCRISTINE"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nPostmastectomy chest wall radiation therapy has historically used bolus to increase dose at the skin surface. Despite the theoretical benefits of bolus, the clinical implications of locoregional tumor control, cosmesis, and the incidence of radiodermatitis are less well characterized. We hypothesized that treatment in the presence or absence of bolus results in equivalent chest wall recurrence rates, but its presence results in more severe acute dermatologic toxicity.\n\n\nMETHODS\nLocally advanced breast cancer patients undergoing chest wall radiation therapy were retrospectively reviewed from 2005 to 2015 (n = 106; 53 with bolus, 53 without). Outcomes including local failure, acute skin toxicity, and treatment interruptions were recorded. Median age was 59 years (range, 28-91) and median follow-up was 34 months. Histology was invasive ductal carcinoma (73%), invasive lobular carcinoma (20%), inflammatory (6%), and neuroendocrine (1%). Fifty-nine percent were T3/T4 primary tumors and 29.2% had clinical/pathologic skin involvement. Node-positive patients accounted for 80.2%. Chemotherapy was administered in 84.0%. All patients had 3-dimensional conformal radiation therapy and received a median dose of 61Gy (range, 50-63 Gy).\n\n\nRESULTS\nLocal failure was 6.6% (n = 7) overall, with 4 failures in the bolus group and 3 in the no bolus group. No pathological factors were associated with local failure. Acute grade 2 and 3 skin toxicities (37 vs 22) and treatment interruptions (20 vs 3) were more common in the bolus group (P < .05). Mean treatment interruption (14.5 vs 5 days) was longer for patients receiving bolus. Patients undergoing treatment interruption were more likely to fail locally than patients not requiring a treatment interruption (17.4% vs 3.6%, P = .0322).\n\n\nCONCLUSIONS\nBolus omission in adjuvant chest wall radiation therapy may be a reasonable approach to avoid acute skin toxicity and treatment interruptions while preserving local control; however, further study will be needed to reach a definitive conclusion.",
"affiliations": "Lake Erie College of Osteopathic Medicine, Bradenton, Florida.;Allegheny General Hospital, Pittsburgh, Pennsylvania.;Allegheny General Hospital, Pittsburgh, Pennsylvania; Drexel University College of Medicine, Pittsburgh Campus, Pittsburgh, Pennsylvania. Electronic address: Mark.Trombetta@ahn.org.;Allegheny General Hospital, Pittsburgh, Pennsylvania.;Allegheny General Hospital, Pittsburgh, Pennsylvania; Drexel University College of Medicine, Pittsburgh Campus, Pittsburgh, Pennsylvania.;Allegheny General Hospital, Pittsburgh, Pennsylvania; Drexel University College of Medicine, Pittsburgh Campus, Pittsburgh, Pennsylvania.;Allegheny General Hospital, Pittsburgh, Pennsylvania.",
"authors": "Abel|Stephen|S|;Renz|Paul|P|;Trombetta|Mark|M|;Cowher|Michael|M|;Day Werts|E|E|;Julian|Thomas B|TB|;Wegner|Rodney|R|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.prro.2016.10.018",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1879-8500",
"issue": "7(3)",
"journal": "Practical radiation oncology",
"keywords": null,
"medline_ta": "Pract Radiat Oncol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001943:Breast Neoplasms; D017024:Chemotherapy, Adjuvant; D005260:Female; D006801:Humans; D008408:Mastectomy; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D011855:Radiodermatitis; D011878:Radiotherapy; D012189:Retrospective Studies; D035441:Thoracic Wall; D017211:Treatment Failure",
"nlm_unique_id": "101558279",
"other_id": null,
"pages": "167-172",
"pmc": null,
"pmid": "28395915",
"pubdate": "2017",
"publication_types": "D018848:Controlled Clinical Trial; D016428:Journal Article",
"references": null,
"title": "Local failure and acute radiodermatological toxicity in patients undergoing radiation therapy with and without postmastectomy chest wall bolus: Is bolus ever necessary?",
"title_normalized": "local failure and acute radiodermatological toxicity in patients undergoing radiation therapy with and without postmastectomy chest wall bolus is bolus ever necessary"
} | [
{
"companynumb": "US-JNJFOC-20170526738",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DOXORUBICIN HYDROCHLORIDE"
},
"drugadditional": "... |
{
"abstract": "A 55-year-old woman presented to the emergency department following an episode of severe visual impairment, headache, dizziness and confusion. The patient had been taking quinine sulfate as long-term medication for leg cramps. During an episode of sleepwalking, the patient had taken an overdose of quinine sulfate. Following a thorough investigation and assessment, a diagnosis of ocular quinine toxicity was made. We present this case and highlight the risks of quinine prescription.",
"affiliations": "Birmingham Heartlands Hospital, Birmingham, UK.",
"authors": "Sinha|Amit|A|;Al Husainy|Sahar|S|",
"chemical_list": "D009125:Muscle Relaxants, Central; D011803:Quinine",
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2013()",
"journal": "BMJ case reports",
"keywords": null,
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D003937:Diagnosis, Differential; D062787:Drug Overdose; D005128:Eye Diseases; D005260:Female; D006801:Humans; D008875:Middle Aged; D009120:Muscle Cramp; D009125:Muscle Relaxants, Central; D011803:Quinine; D013009:Somnambulism",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "24287479",
"pubdate": "2013-11-28",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "14676522;21407799;7425057;9226770",
"title": "Ocular quinine toxicity in a sleepwalker.",
"title_normalized": "ocular quinine toxicity in a sleepwalker"
} | [
{
"companynumb": "GB-WATSON-2014-14522",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "QUININE SULFATE"
},
"drugadditional": null,
... |
{
"abstract": "The curative role of sugammadex has been challenged in several observations of rocuronium-induced anaphylaxis because sugammadex may not completely encapsulate the molecule of rocuronium. In such conditions, rocuronium remains able to cause immunoglobulin E cross-linkage and the anaphylaxis mechanism can continue. We describe a case of rocuronium-induced anaphylaxis in which clinical improvement followed sugammadex administration. Intradermic skin tests confirmed rocuronium immunoglobulin E-mediated anaphylaxis but also showed intradermal injection of mixing in equal molecular ratio of sugammadex with rocuronium preventing rocuronium anaphylactic skin reaction. This observation demonstrates the efficacy of sugammadex to prevent rocuronium interaction with the skin immune system.",
"affiliations": "From the Department of Anesthesiology, Hospital Foch, Suresnes, France.;From the Department of Anesthesiology, Hospital Foch, Suresnes, France.;From the Department of Anesthesiology, Hospital Foch, Suresnes, France.",
"authors": "Binczak|Marie|M|;Fischler|Marc|M|;Le Guen|Morgan|M|",
"chemical_list": "D000077122:Sugammadex; D007073:Immunoglobulin E; D000077123:Rocuronium",
"country": "United States",
"delete": false,
"doi": "10.1213/XAA.0000000000000973",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2575-3126",
"issue": "13(1)",
"journal": "A&A practice",
"keywords": null,
"medline_ta": "A A Pract",
"mesh_terms": "D000368:Aged; D000707:Anaphylaxis; D005260:Female; D006801:Humans; D007073:Immunoglobulin E; D000077123:Rocuronium; D000077122:Sugammadex; D016896:Treatment Outcome",
"nlm_unique_id": "101714112",
"other_id": null,
"pages": "17-19",
"pmc": null,
"pmid": "30720535",
"pubdate": "2019-07-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Efficacy of Sugammadex in Preventing Skin Test Reaction in a Patient With Confirmed Rocuronium Anaphylaxis: A Case Report.",
"title_normalized": "efficacy of sugammadex in preventing skin test reaction in a patient with confirmed rocuronium anaphylaxis a case report"
} | [
{
"companynumb": "FR-MYLANLABS-2019M1068732",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "EPINEPHRINE"
},
"drugadditional": null,
... |
{
"abstract": "Purpose: To report a case of acute retinal necrosis (ARN) caused by varicella-zoster virus (VZV) in an elderly patient with ocular sarcoidosis after oral corticosteroid indication. Methods: Retrospective case report. Results: A 75-year-old male with a past history of ocular sarcoidosis came with blurred left vision. Ocular findings in the left eye were consistent with ocular sarcoidosis, while no inflammation in the right eye. On day 14, intraocular inflammation in the left eye resolved by topical corticosteroid, but inflammatory cells were found in the right eye. Suspecting recurrence of ocular sarcoidosis, systemic corticosteroid was initiated. On day 21, inflammation worsened, and the presence of extended yellowish white peripheral retinal lesion in the right eye suggested ARN. Polymerase chain reaction (PCR) testing using ocular fluid detected 3.0 × 107 copies/ml of VZV DNA. Conclusions: In the case of poor response to immunosuppressive therapy in elderly uveitis, infection including ARN should be considered. Immediate PCR testing for pathogen screening is required.",
"affiliations": "Department of Ophthalmology, National Defense Medical College , Tokorozawa , Japan.;Department of Ophthalmology, Tokyo University Graduate School of Medicine , Tokyo , Japan.;Department of Ophthalmology, National Defense Medical College , Tokorozawa , Japan.",
"authors": "Takayama|Kei|K|;Kaburaki|Toshikatsu|T|;Takeuchi|Masaru|M|",
"chemical_list": "D004279:DNA, Viral",
"country": "England",
"delete": false,
"doi": "10.1080/09273948.2019.1635168",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0927-3948",
"issue": "27(7)",
"journal": "Ocular immunology and inflammation",
"keywords": "Acute retinal necrosis; corticosteroid; immunosuppressive; sarcoidosis; varicella-zoster virus",
"medline_ta": "Ocul Immunol Inflamm",
"mesh_terms": "D000368:Aged; D001082:Aqueous Humor; D004279:DNA, Viral; D003937:Diagnosis, Differential; D015828:Eye Infections, Viral; D005451:Fluorescein Angiography; D005654:Fundus Oculi; D006563:Herpes Zoster Ophthalmicus; D014645:Herpesvirus 3, Human; D006801:Humans; D008297:Male; D015882:Retinal Necrosis Syndrome, Acute; D012507:Sarcoidosis; D041623:Tomography, Optical Coherence; D014605:Uveitis",
"nlm_unique_id": "9312169",
"other_id": null,
"pages": "1067-1070",
"pmc": null,
"pmid": "31414927",
"pubdate": "2019",
"publication_types": "D002363:Case Reports; D016422:Letter",
"references": null,
"title": "Development of Acute Retinal Necrosis in a Patient with Ocular Sarcoidosis: A Case Report.",
"title_normalized": "development of acute retinal necrosis in a patient with ocular sarcoidosis a case report"
} | [
{
"companynumb": "JP-TEVA-2019-JP-1159064",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
},
"drugadditional": "3",
... |
{
"abstract": "With the increasing use of chemotherapy for many different primary malignancies, secondary or therapy-related acute myeloid leukaemias (AML) and myelodysplastic syndromes (MDS) are becoming more common. The risk of developing sAML has been estimated to be between 2% and 10%, depending upon the type, duration and dosage of previous therapy (Michels et al, 1985; Shulman, 1993; Robinson & Mertens, 1993; Ballen & Antin, 1993). It is therefore one of the most serious long-term complications of current cancer treatment and is likely to increase as longer survival rates for the primary tumour are achieved. An increasing range of drugs have been reported to cause sAML, including the alkylating agents, the epipodophyllotoxins and the anthracyclines, both as single agents and in combination (Pedersen-Bjergaard & Philip, 1991; Pedersen-Bjergaard & Rowley, 1994). We report two cases of secondary AML in which platinum compounds were the sole prior chemotherapy.",
"affiliations": "Department of Academic Haematology and Cytogenetics, Royal Marsden Hospital, London.",
"authors": "Philpott|N J|NJ|;Elebute|M O|MO|;Powles|R|R|;Treleaven|J G|JG|;Gore|M|M|;Dainton|M G|MG|;Min|T|T|;Swansbury|G J|GJ|;Catovsky|D|D|",
"chemical_list": "D000970:Antineoplastic Agents; D016190:Carboplatin; D002945:Cisplatin",
"country": "England",
"delete": false,
"doi": "10.1046/j.1365-2141.1996.d01-1716.x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0007-1048",
"issue": "93(4)",
"journal": "British journal of haematology",
"keywords": null,
"medline_ta": "Br J Haematol",
"mesh_terms": "D000208:Acute Disease; D000230:Adenocarcinoma; D000328:Adult; D000970:Antineoplastic Agents; D016190:Carboplatin; D002945:Cisplatin; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D007951:Leukemia, Myeloid; D008875:Middle Aged; D010051:Ovarian Neoplasms",
"nlm_unique_id": "0372544",
"other_id": null,
"pages": "884-7",
"pmc": null,
"pmid": "8703821",
"pubdate": "1996-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Platinum agents and secondary myeloid leukaemia: two cases treated only with platinum-based drugs.",
"title_normalized": "platinum agents and secondary myeloid leukaemia two cases treated only with platinum based drugs"
} | [
{
"companynumb": "GB-PFIZER INC-2018512344",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CISPLATIN"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nAdult-onset Still's disease (AOSD) is a rare systemic inflammatory disease, which is characterized by daily fever and arthritis, with an evanescent rash and neutrophilic leukocytosis. To date, there has been no definite laboratory or imaging test available for diagnosing AOSD; the diagnosis is one of exclusion, which can be very challenging. In particular, AOSD patients may experience different complications affecting their clinical picture, management, and prognosis. The treatment of AOSD remains largely empirical and involves therapeutic agents.\n\n\nMETHODS\nWe report the case of a 36-year-old woman who presented with fever, red rash, arthralgia, and sore throat. Her serum ferritin level and white blood cell count were markedly elevated, and the first diagnosis 22 years prior was \"juvenile rheumatoid arthritis of systemic type\". The patient was treated with prednisone, sulfasalazine, methotrexate, and leflunomide. After remission of her symptoms, the patient stopped taking the medications, and the disease recurred. Ultimately, the patient was diagnosed with adult-onset Still's disease. Relapse occurred several times due to self-medication withdrawal, and an interleukin-6 antagonist (tocilizumab/Actemra) was administered to control the disease. Recently, she was hospitalized because an incision did not heal, and the patient suddenly developed high fever and diarrhea during hospitalization. The patient's disease progressed violently and quickly developed into macrophage activation syndrome, disseminated intravascular coagulation, shock, and multiple organ failure. The patient had sudden cardiac arrest, and she died despite emergency rescue efforts.\n\n\nCONCLUSIONS\nAOSD patients need regular follow-up in the long-term treatment process, and must press formulary standard medication, and do not voluntarily withdraw or reduce the dose. Otherwise it may cause disease back-and-forth or serious life-threatening complications. Meanwhile, strict management of trauma, infections, tumors, and other diseases may contribute to improved outcomes in patients with complications.",
"affiliations": "Department of Surgery, Affiliated Zhongshan Hospital of Dalian University, Dalian 116001, Liaoning Province, China.;Department of Surgery, Affiliated Zhongshan Hospital of Dalian University, Dalian 116001, Liaoning Province, China.;Department of ICU, Affiliated Zhongshan Hospital of Dalian University, Dalian 116001, Liaoning Province, China.;Department of Oncology, Affiliated Zhongshan Hospital of Dalian University, Dalian 116001, Liaoning Province, China.;Department of Surgery, Second People's Hospital of Jinzhong City, Jinzhong 030600, Shanxin Province, China.;Department of ICU, Affiliated Zhongshan Hospital of Dalian University, Dalian 116001, Liaoning Province, China. 13704119600@163.com.",
"authors": "Han|Zhong-Bin|ZB|;Wu|Ju|J|;Liu|Jing|J|;Li|He-Ming|HM|;Guo|Kai|K|;Sun|Tong|T|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.12998/wjcc.v9.i4.886",
"fulltext": "\n==== Front\nWorld J Clin Cases\nWJCC\nWorld Journal of Clinical Cases\n2307-8960 Baishideng Publishing Group Inc \n\njWJCC.v9.i4.pg886\n10.12998/wjcc.v9.i4.886\nCase Report\nAdult-onset Still's disease evolving with multiple organ failure and death: A case report and review of the literature\nHan ZB et al. Adult-onset Still's diseaseHan Zhong-Bin Department of Surgery, Affiliated Zhongshan Hospital of Dalian University, Dalian 116001, Liaoning Province, China\n Wu Ju Department of Surgery, Affiliated Zhongshan Hospital of Dalian University, Dalian 116001, Liaoning Province, China\n Liu Jing Department of ICU, Affiliated Zhongshan Hospital of Dalian University, Dalian 116001, Liaoning Province, China\n Li He-Ming Department of Oncology, Affiliated Zhongshan Hospital of Dalian University, Dalian 116001, Liaoning Province, China\n Guo Kai Department of Surgery, Second People's Hospital of Jinzhong City, Jinzhong 030600, Shanxin Province, China\n Sun Tong Department of ICU, Affiliated Zhongshan Hospital of Dalian University, Dalian 116001, Liaoning Province, China. 13704119600@163.com\n Author contributions: Han ZB and Sun T were the patient’s managing physician, reviewed the literature, and contributed to manuscript drafting; Wu J, Liu J, and Guo K collected the patient’s past medical histories, reviewed the literature, and contributed to manuscript drafting; Li HM was responsible for the revision of the manuscript for important intellectual content; all authors issued final approval for the version to be submitted.\n\nCorresponding author: Tong Sun, MAMS, Associate Professor, Director, Doctor, Department of ICU, Affiliated Zhongshan Hospital of Dalian University, No. 6 Jiefang Street, Dalian 116001, Liaoning Province, China. 13704119600@163.com\n\n\n6 2 2021 \n6 2 2021 \n9 4 886 897\n5 9 2020 28 11 2020 10 12 2020 ©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.2021This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial.BACKGROUND\nAdult-onset Still’s disease (AOSD) is a rare systemic inflammatory disease, which is characterized by daily fever and arthritis, with an evanescent rash and neutrophilic leukocytosis. To date, there has been no definite laboratory or imaging test available for diagnosing AOSD; the diagnosis is one of exclusion, which can be very challenging. In particular, AOSD patients may experience different complications affecting their clinical picture, management, and prognosis. The treatment of AOSD remains largely empirical and involves therapeutic agents.\n\nCASE SUMMARY\nWe report the case of a 36-year-old woman who presented with fever, red rash, arthralgia, and sore throat. Her serum ferritin level and white blood cell count were markedly elevated, and the first diagnosis 22 years prior was \"juvenile rheumatoid arthritis of systemic type\". The patient was treated with prednisone, sulfasalazine, methotrexate, and leflunomide. After remission of her symptoms, the patient stopped taking the medications, and the disease recurred. Ultimately, the patient was diagnosed with adult-onset Still's disease. Relapse occurred several times due to self-medication withdrawal, and an interleukin-6 antagonist (tocilizumab/Actemra) was administered to control the disease. Recently, she was hospitalized because an incision did not heal, and the patient suddenly developed high fever and diarrhea during hospitalization. The patient's disease progressed violently and quickly developed into macrophage activation syndrome, disseminated intravascular coagulation, shock, and multiple organ failure. The patient had sudden cardiac arrest, and she died despite emergency rescue efforts.\n\nCONCLUSION\nAOSD patients need regular follow-up in the long-term treatment process, and must press formulary standard medication, and do not voluntarily withdraw or reduce the dose. Otherwise it may cause disease back-and-forth or serious life-threatening complications. Meanwhile, strict management of trauma, infections, tumors, and other diseases may contribute to improved outcomes in patients with complications.\n\nAdult-onset Still's diseaseMacrophage activation syndromeDisseminated intravascular coagulopathyMultiple organ failureDeathCase report\n==== Body\nCore Tip: Adult-onset Still’s disease (AOSD) is a rare systemic inflammatory disease, and the lack of disease-specific symptoms and laboratory markers hinders the diagnosis and assessment of its progression. More importantly, the treatment of AOSD remains largely empirical, with a lack of controlled clinical trials. Few cases of the disease with multiple complications have been reported. The present case highlights the characteristics of AOSD and severe complications and shares our experience in its diagnosis and treatment to provide experience for the effective recognition and treatment of this disease. The authors also note the link between the biopsychosocial model and autoimmune diseases.\n\nINTRODUCTION\nAdult-onset Still's disease (AOSD) is a rare systemic inflammatory disease, which is characterized by fever, arthritis, an evanescent rash, and neutrophilic leukocytosis. Other nonspecific symptoms may be observed in AOSD, such as sore throat, cardiopulmonary features, kidney disease, and neurological manifestations[1,2]. AOSD was definitively described in 1971 by Eric Bywaters, who named the disease on account of its close resemblance to the pediatric syndrome systemic-onset juvenile idiopathic arthritis (SoJIA), which was formerly called “Still's disease” for the reason that it was described by Dr George Still in 1897[3,4]. The etiology is unknown, and both infectious triggers and genetic factors have been suggested, but there is no clear evidence of an infectious etiology[5].\n\nAvailable epidemiologic results show that the incidence of AOSD ranges between 0.16 and 0.4/100000 people, with an estimated prevalence rate between 1 and 34 cases/1 million people[2,6,7]. Based on some reports, females seem to be more affected than males; however, AOSD is considered to be evenly distributed between the sexes. AOSD usually afflicts young people, with a bimodal peak at ages 15-25 and 36-46 years[2,8]. Diagnosis is based on clinical grounds, following the exclusion of mimickers of autoimmune, infectious, and neoplastic disorders, with the additional consideration of nonspecific laboratory abnormalities such as elevation of serum ferritin (SF), peripheral leukocytosis, and other acute-phase reactants[9]. In general, the absence of disease-specific symptoms and laboratory markers hinders its diagnosis, and the lack of established disease activity markers makes the determination of treatment efficacy problematic. More importantly, AOSD-related complications are significantly associated with mortality. These patients may also experience different complications that affect their clinical symptoms, management, and prognosis. Moreover, clinical progression is also unpredictable, with 60%-70% of those patients developing a chronic form of the disease[2].\n\nCASE PRESENTATION\nChief complaints\nA 36-year-old woman presented to the Outpatient Department of our hospital complaining of poor wound healing of an incision in her right hip and AOSD.\n\nHistory of present illness\nShe had developed steroid-induced femoral head osteonecrosis caused by long-term prednisone therapy for AOSD, and the incision had not healed by 2 mo after bilateral prosthetic replacement. She was hospitalized for treatment in a stable condition. During hospitalization, the patient suddenly developed high fever and diarrhea, with the highest temperature reaching 38.2 °C, accompanied by nausea, vomiting, poor appetite, and mild dehydration. The patient was transferred to the intensive care unit (ICU) after refusing fluid rehydration therapy with deep-vein puncture. After further inquiry about the patient's history, her husband said that her AOSD was greatly affected by her mood, and the patient had a high fever of 41 °C lasting for 1 mo due to depression\". The next day, her condition suddenly deteriorated, blood pressure decreased, and her dyspnea, oliguria, and disease rapidly worsened.\n\nHistory of past illness\nTwenty-two years prior (at 14 years old, 1998), fever occurred due to overfright, with the highest body temperature reaching 40 °C; her body temperature often increased in the morning. This was accompanied by a red rash on her back, sore throat, migratory swelling, and pain of multiple joints and muscle in the whole body, mainly affecting the proximal interphalangeal joint of both hands, metacarpophalangeal joint, double wrist joint, double elbow joint, and bilateral temporomandibular joint. Her symptoms associated with morning stiffness eased slightly after 1 h of activity. Test results showed that SF was increased and white blood cells (WBCs) obviously increased. The first diagnosis was \"juvenile rheumatoid arthritis of systemic type\", and the patient was treated with prednisone up to 30 mg/d, sulfasalazine, methotrexate, and leflunomide. After her symptoms improved, the patient stopped taking the medicines. The disease then recurred, and she was diagnosed with \"AOSD\" and was treated with prednisone at a dose up to 60 mg (1 mg/kg), methotrexate, and traditional Chinese medicine, resulting in short-term improvement of symptoms. In 2002, bilateral alternating hip pain began to appear. After that, movement of both hip joints and knee joints was limited, with overflexion of the proximal interphalangeal joints of fingers and feet. In 2015, X-ray of her hands was performed, showing a narrow joint space of the hands and wrists. X-ray of the hip joint revealed a flattened femoral head on both sides, with multiple transparent shadows and hyperosteogeny and sclerosis, and the acetabular bone on both sides was obviously thinner; some bones were discontinuous, with hyperosteogeny and cystic shadow, and the joint space of both hips became obviously narrow. During this period, the disease recurred many times, and the patient took oral prednisone, lothorofan, and leflumide intermittently. Methotrexate, iguratimod, and Tripterygium wilfordii were discontinued due to adverse effects. In April 2016, the patient began treatment with etanercept. After that, due to frequent recurrence of the disease, the patient began to receive regular monthly intravenous administration of an interleukin (IL)-6 antagonist (Actemra) at 320 mg, and the dose of prednisone was reduced to 10 mg/d. In April 2020, she was hospitalized with the aggravation of pain in both hip joints and a limp. The test results showed that WBC count, C-reactive protein (CRP), and SF were normal. Bilateral femoral head necrosis was definitively diagnosed, and bilateral prosthetic replacement was performed. Two months after the surgery, the patient did withdrawal of Actemra and immuno-suppressive agents on her own.\n\nPhysical examination\nAfter her second day in the ICU, the patient’s temperature was 36.5 °C, her heart rate was 96 bpm, her respiratory rate was 26 breaths per minute, her blood pressure was 80/41 mmHg, and her oxygen saturation in room air was 88%-96%. The patient was under some type of sedation but responded to painful stimuli. A 1 cm unhealed incision was seen on the right hip, with seepage of a reddish fluid. Other physical examinations showed no abnormal signs.\n\nLaboratory examinations\nOn the first day in the ICU, laboratory parameters showed abnormalities of routine blood examination, coagulation function, hepatic function, and serum electrolytes (Table 1, Day 1).\n\nTable 1 Main laboratory findings (Day 1 to Day 4)\n\n\nMain laboratory finding\n\n\t\nValue\n\n\t\nNormal range\n\n\t\n\nDay 1\n\n\t\nDay 2\n\n\t\nDay 3\n\n\t\nDay 4\n\n\t\nWhite blood cell count\t5.0\t5.6\t20.5\t28.3\t(3.5-9.5) × 109/L\t\nLymphocyte percentage\t6.6\t10.1\t8.9\t15.6\t20%-50%\t\nNeutrophil percentage\t90\t86.7\t90.1\t81\t40%-75%\t\nHemoglobin\t80\t99\t112\t98\t(115-150) g/L\t\nPlatelets\t30\t32\t52\t35\t(125-350) × 109/L\t\nProthrombin time\t18.1\t18.8\t18.2\t16.4\t(9-14) s\t\nInternational normalized ratio \t1.6\t1.68\t1.62\t1.42\t\t\nProthrombin activity\t54.9\t51.8\t54.2\t63\t%\t\nActivated partial thromboplastin time standardization\t61\t55.3\t54.1\t56.8\t(20-40) s\t\nThrombin time\t39.7\t37.1\t50.6\tChyle blood, no test\t(14-21) s\t\nFibrinogen\t1.37\t1.0\t0.77\tChyle blood, no test\t(2-4) g/L\t\nD-Dimer\t\t4.88\t\t5.96\t(0-0.5) μg/L\t\nFibrinogen degradation products\t\t272.9\t\t90.6\t(0-5) μg/L\t\nErythrocyte sedimentation rate\t\t\t10\t\t(0-20) mm/L\t\nC-reactive protein\t\t121.01\t111.7\t104.2\t(0-10) mg/L\t\nHemolytic index\t15\t15\t60\t55\t0-15\t\nBlood lipid index\t2\t2\t2\t225\t0-2\t\nTotal protein\t57.1\t53.5\t46.8\t55.7\t(65-85) g/L\t\nAlbumin\t28.8\t26.3\t26.3\t23.2\t(40-55) g/L\t\nGlobin\t28.3\t27.3\t26.2\t24.4\t(20-40) g/L\t\nTotal bilirubin\t35.9\t42.9\t49.6\t62.1\t(0-21) μmol/L\t\nConjugated bilirubin\t14.6\t19.5\t27.3\t35.2\t(0-5) μmol/L\t\nUnconjugated hyperbilirubinemia\t3.5\t3.5\t2.6\t4.2\t(0-19) μmol/L\t\nGlutamic-pyruvic transaminase\t84.9\t90.9\t139.8\t153.8\t(0-40) U/L\t\nAspartate aminotransferase\t295\t329\t593\t589\t(0-40) U/L\t\nAlkaline phosphatase\t366\t510\t508\t453\t(38-126) U/L\t\nγ-Glutamyl transpeptidase\t118\t161\t185\t183\t(6-35) U/L\t\nCholinesterase\t3584.3\t3395.1\t3476.1\t4351.8\t(4650-12220) U/L\t\nLactate dehydrogenase\t5292\t5616\t9299\t8746\t(313-618) U/L\t\nK+\t4.9\t4.57\t4.42\t5.3\t(3.6-5) mm/L\t\nNa+\t127.8\t128.9\t142.6\t146.2\t(137-145) mm/L\t\nCl-\t102\t103.9\t111.8\t106.7\t(98-107) mm/L\t\nCreatinine\t288.1\t299.2\t298.8\t311.5\t(41-73) μmol/L\t\nCarbamide\t16.19\t17.79\t22.38\t28.01\t(2.6-7.5) mm/L\t\nUric acid\t683\t706.4\t487.4\t510.4\t(155-357) μmol/L\t\nHypersensitive troponin\t0.012\t0.138\t13\t52\t(0-0.034) ng/L\t\nNT-ProBNP\t4120\t9910\t35000\t35000\t(0-125) pg/L\t\nMyoglobin\t\t145.7\t\t936.4\t(0-110) ng/moL\t\nProcalcitonin\t\t10.479\t\t24.025\t(0-0.05) ng/mL\t\nThis table shows the main laboratory findings of the patient during the intensive care unit.\n\nImaging examinations\nAbdominal B-ultrasonography revealed splenomegaly. X-ray of the hip joints showed that the shape and position of bilateral prosthesis were normal, and there were no signs of infection.\n\nFurther diagnostic work-up\nOver the next 3 d in the ICU, the laboratory parameters of routine blood examination, coagulation function, hepatic function, and serum electrolyte deteriorated further (Table 1, Day 2, 3 and 4).\n\nThe level of SF was more than 10000 ng/mL (normal range: 13-150 ng/mL). The level of general cortisol was more than 1649.9 mmol/L (101.2-535.7 mmol/L), and that of adrenocorticotrophic hormone was less than 1.54 mL/L (7.2-63.6 mL/L). Serum κ and λ light chain levels were 60.9 mg/L (6.7-22.4 mg/L) and 1.62 (0.31-1.56 mg/L), respectively, and the ratio of κ/λ was 1.62 (0.31-1.56). Other immunological tests were almost within the normal range, including anti-phospholipid antibodies, immunoglobulin, complement, rheumatoid factor (RF), antistreptolysin O test, anti-CCP antibody, autoimmune antibody tests, and Coombs test (MGCT). No bacteria or fungi were found in blood culture, sputum culture, or secretions of surgical wound. Routine urine tests indicated urine protein 2+, occult blood 2+, and WBCs 188.5 mL/L, with no other abnormality found. Fecal flora analysis indicated 100% Enterobacter spp. The examination of lymphocyte subpopulations and cytokines was ongoing.\n\nMULTIDISCIPLINARY EXPERT CONSULTATION\nGiven the multiple organ involvement and high SF and WBC levels, and the patient's history of stopping Actemra and immunosuppressive agents on her own for 2 mo, the diagnosis of active AOSD was confirmed by multidisciplinary expert consultation. It was discussed whether the diarrhea was a second hit. Diarrhea may trigger a pathologic process in genetically susceptible patients, finally leading to an uncontrollable increase in proinflammatory cytokines, with a severe systemic inflammatory reaction, which is responsible for AOSD development. It was agreed that the large dose of cortisol impulse therapy up to 200 mg per day was a reasonable treatment and that immunomodulatory and inflammatory suppression should be continued. Hemodialysis should also be performed to remove metabolic wastes and inflammatory factors from the blood. Furthermore, the examination of lymphocyte subpopulations and cytokines should be carried out to detect disease activity. If necessary, the patient should undergo bone marrow biopsy, flow cytometry, and chromosome testing. Treatment with cortisol at a dose of 200 mg/d was re-commended, and hemodialysis was performed. In the case of nonresponse, it was decided to consider treatment with Actemra and cyclosporine.\n\nFINAL DIAGNOSIS\nThe final diagnoses of the presented case were shock, multiple organ dysfunction syndrome (acute heart failure, acute liver failure, acute respiratory dysfunction, and abnormal coagulation function), AOSD, acute gastroenteritis, postoperative nonunion of the right hip, electrolyte disorder, anemia, and hypoproteinemia.\n\nTREATMENT\nAfter comprehensive treatment, such as anti-shock, blood transfusion, auxiliary ventilation, plasma exchange, and cortisol impulse treatment, the patient’s body temperature returned to normal, but her diarrhea was not relieved.\n\nOUTCOME AND FOLLOW-UP\nOn the third day in the ICU, the patient’s condition worsened; her blood pressure suddenly dropped to 50/30 mmHg, and she did not respond to increased epinephrine and dopamine doses or intravenous epinephrine. In the end, the patient had sudden cardiac arrest, and she died despite emergency rescue efforts.\n\nDISCUSSION\nAOSD is classified as a multigenic autoinflammatory disease because of its complex pathogenesis, involving both the innate and adaptive immune systems. It is generally considered that some unknown factors, playing as second hits, may startup a pathologic procedure in genetically susceptible patients, eventually leading to the activation of an aberrant inflammatory response, which leads to the development of AOSD. Although the pathogenesis is mostly unknown, the pivotal role of proinflammatory cytokines, including IL-1β, IL-6, IL-8, IL-10, IL-17, IL-18, interferon-γ, tumor necrosis factor, and ferritin in developing the inflammatory vicious circle has been reported[10-13]. There are six sets of criteria for the diagnosis of AOSD currently, and Yamaguchi's criteria are the most sensitive as well as the most widely used. The criteria include fever evanescent rash, arthralgia, and leukocytosis as major items and other nonspecific symptoms, such as sore throat, lymphadenopathy, splenomegaly, deterioration of liver function, negative rheumatoid factor, and antinuclear antibody as minor items; more than five items including at least two major criteria are necessary for the diagnosis and to exclude malignancy or infectious disease[14].\n\nAOSD typically manifests with a symptomatic triad characterized by fever (60%-100%), red rash (60%-80%), and arthralgia and arthritis (70%-100%) which may develop to destructive symmetric polyarthritis[1]. In AOSD, fever always precedes other manifestations' onset, and the fever shows an abrupt onset usually, commonly once or twice the quotidian pattern, with the highest temperature detected in the early evening or late afternoon. The temperature may sometimes return to a normal value without any antipyretic treatment. The rash is usually observed on the proximal trunk and limbs, appearing during the febrile attacks, and its typically histopathology shows a mixed inflammatory infiltrate, surrounding the perivascular areas without epidermal changes. Joint disease is also a common sign. Arthritis and arthralgia mostly affect knees, wrists, and ankles. Some patients may gradually develop chronic destructive symmetrical polyarthritis and ankylosis in subsequent years. Laboratory test of joint fluid may show an inflammatory fluid with neutrophil predominance. Other nonspecific symptoms may be found in AOSD, such as sore throat, cardiopulmonary features, kidney disease, neurological manifestations, enlargement of cervical lymph nodes (LNs), splenomegaly, hepatomegaly, liver dysfunction, and increased hepatic enzymes[15].\n\nLaboratory tests commonly show increased SF, CRP, and erythrocyte sedimentation rate (ESR), neutrophilic leukocytosis, anemia, and thrombocytopenia. The levels of SF are higher than those observed in other autoimmune, infectious, inflammatory, or neoplastic diseases. It has been reported that SF is an acute-phase protein released from impaired hepatocytes; the levels may be elevated in inflammatory disorders, alcohol abuse, liver disease, infectious diseases such as HIV infection, or malignancy[16]. Eighty percent of AOSD patients were reported to have increased ferritin levels, 70% of which were more than five times the normal upper limit[17]. The median level of SF in AOSD patients is reportedly 4752 ng/mL. A SF level higher than 10000 ng/mL can be a specific marker for AOSD if there is no severe liver dysfunction or history of multiple blood transfusions, but the SF level itself is only a nonspecific marker for inflammation[18-20]. Due to its low specificity, elevated SF is not included in this disease's diagnostic criteria, but we consider that this association is worth highlighting, given that younger age and the nonspecific nature of most presentations often lead to delayed diagnosis[21-23]. It has been reported that proinflammatory cytokine levels are significantly increased in both the pathological tissues and sera of patients with active or untreated AOSD, and that ferritin synthesis is regulated by proinflammatory cytokines at various levels during cellular differentiation, proliferation, and inflammation. Cytokines may also have an effect on ferritin translation indirectly by their ability to increase inducible nitric oxide synthase (iNOS) and hence increase the levels of NO. NO in turn induces ferritin expression. These reports suggest that the level of ferritin might be a good biomarker to monitor the disease activity of AOSD[10,24]. Furthermore, thrombocytopenia and leukocytosis are reportedly promoted along with rises in SF levels, which is associated with AOSD's disease activity strongly and may also be a biomarker of AOSD[25,26]. Some studies have confirmed that SF and heme oxygenase 1 can serve as highly sensitive and specific biomarkers for AOSD[27].\n\nAOSD patients may experience different complications affecting their clinical manifestations, management, and prognosis. The major cause of death is infection, followed by severe complications. Important systemic complications of AOSD reported until now include macrophage activation syndrome (MAS), thrombotic thrombocytopenic purpura (TTP), disseminated intravascular coagulopathy (DIC), thrombotic microangiopathy, diffuse alveolar hemorrhage, respiratory distress syndrome, pulmonary arterial hypertension, shock, multiple organ failure, myocarditis, tamponade, constrictive endocarditis, pericarditis, fulminant hepatitis, and amyloidosis[9,15,28].\n\nMAS or reactive hemophagocytic syndrome (HPS) is a potentially life-threatening complication characterized by excessive macrophage activity and cytokine production leading to multiple organ failure[29,30]. Primary MAS commonly occurs in children with MAS-associated genetic defects or a family history of MAS, while secondary MAS occurs after exposure to immunological trigger factors of underlying autoimmune diseases, infections, malignancies, or flares of AOSD[31]. It is reported that the incidence of MAS is up to 15% among those AOSD patients and it is considered the most severe complication, with a high mortality rate ranging from 10% to 41%[9,32]. The criteria for diagnosing MAS according to the 2004 guidelines are as follows: (1) Fever > 38.5 °C or lasting more than 7 d; (2) Cytopenia affecting at least two of three lineages in the peripheral blood (Hb < 90 g/L, absolute neutrophil count < 1.0 × 109/L, platelet < 100 × 109/L); (3) Splenomegaly; (4) Hypofibrinogenemia or hypertriglyceridemia; (5) Hyperferritinemia (SF ≥ 500 µg/L); (6) Hemophagocytosis in bone marrow, lymph nodes, or the spleen; (7) High levels of sIL-2r (s-CD25 ≥ 500 µg/L); and (8) Low or absent NK-cell activity. MAS can be diagnosed if five of the eight criteria are fulfilled[33]. However, the diagnosis of MAS is often delayed due to possible differential diagnoses. These include conditions that can present with similar clinical manifes-tations and laboratory abnormalities, such as systemic inflammatory response syndromes or sepsis. However, the level of SF is usually obviously higher in MAS patients and considered a highly characteristic feature of MAS by most scholars[34]. Bone marrow aspiration is considered the gold standard and is usually required in some untypical cases where there may be a diagnostic dilemma. In the present case, the patient presented a high fever with a body temperature of 38.3 °C, splenomegaly, hemopenia, hypertriglyceride, hypofibrinemia, and SF greater than 10000 µg/L. Inflammatory factors and bone marrow puncture were not examined, and the patient died. Although her body temperature did not meet the diagnostic criteria, the continued increase in SF and hypofibrinogenemia reflected worsening of the disease.\n\nDIC is also a lethal complication characterized by uninhibited activation of the coagulation system. Some reports suggest that its diagnosis can be challenging, even for some experienced clinicians[35]. A precipitous decrease in ESR in the context of persistent hyperferritinemia and worsening clinical condition may be a danger sign and raise the index of suspicion for the presence of DIC. Some specialists have suggested that anakinra may be recommended for patients with severe flares of AOSD and DIC[36,37].\n\nThe treatment of AOSD remains largely empirical, and therapeutic agents for AOSD include nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) such as methotrexate, and biological disease-modifying anti-rheumatic drugs (bDMARDs). Some studies have shown that NSAIDs may fail to control the symptoms of AOSD, and a large percentage of patients may afflict drug adverse reactions. According to some reports, only 15%-20% of AOSD patients respond to NSAIDs treatment, and a corticosteroid is required to control disease manifestations in most cases. Corticosteroids have been suggested as the first-line treatment for AOSD, producing a clinical response in approximately 60% of cases. Corticosteroids should be started at a dosage of 0.51 mg/kg per day, but intravenous high-dose corticosteroids may be considered if MAS and/or severe visceral involvement occur. Some cases may relapse over chronic treatment or tapering of the corticosteroid dosage[38]. High-dose corticosteroids seem to be more efficient in controlling those disease, but the maintenance of long-term corticosteroids can induce many potential adverse reactions[15,39]. In the present case, the patient developed femoral head necrosis due to long-term glucocorticoid use, and she experienced relapse due to repeated spontaneous reduction or withdrawal of the drug. Cyclosporine and methotrexate (MTX) are the most frequently administered sDMARDs in AOSD, mainly owning to their steroid-sparing effects. Other agents, such as azathioprine, leflunomide, cyclophosphamide, tacrolimus, hydroxychorquine sulfate, and intravenous immunoglobulin, have also been widely applied, producing various response rates. In a study, after adding MTX, 70% of patients achieved complete remission, and 39% of patients discontinued corticosteroids. Thus, csDMARDs have been used to prevent AOSD relapse and allow for reduction of the corticosteroid dosage simultaneously[39-41]. Some researchers also have found that cyclosporine can be used in patients with severe MAS as well as AOSD[42,43]. Biologic agents or biologic DMARDs (bDMARDs) targeting specific cytokines are suggested for the treatment of those cases that are refractory to csDMARDs and corticosteroids. Some studies have revealed a key role of proinflammatory cytokines such as IL-1, IL-6, IL-8, IL-18 and tumor necrosis factor-α (TNF-α) in disease pathogenesis, promoting the development of novel targeted therapies aimed at the optimum method of disease control[44]. It has been reported that bDMARDs are an important option for relapsed patients or as a first-line regimen, which may help to reduce the dosage in terms of glucocorticoid and other cDMARD exposure[45,46]. Some researchers have shown that most patients (84.4%) are able to achieve clinical remission initially by using bDMARDs[47]. It has also been reported that a case of glucocorticoid and cyclosporine refractory AOSD complicated by DIC was successfully managed with a humanized anti-IL-6 receptor monoclonal antibody. IL-6 inhibition can lead to a rapid response, symptomatic improvement, and corticosteroid sparing[48]. Wang et al[49] have found that anti-IL-6 antibody combined with MTX have significant therapeutic effects for refractory AOSD, is conducive to the reduction and discontinuation of prednisone, and may allow stabilization of the patient’s condition after reducing the dosage of anti-IL-6 antibody, with good safety.\n\nIn this case, the patient experienced relapse of the disease due to voluntary drug withdrawal or dosage reduction several times, and her WBC and SF levels were significantly increased. Because of the frequent recurrence of the disease, the patient received anti-IL-6 antibody, and the frequency of disease recurrence was significantly reduced; glucocorticoid dosage was also reduced. The recurrence of her disease was caused by the spontaneous cessation of Actemra and leflunomide at 2 mo after surgery. Diarrhea was the main factor that caused the rapid progression of the disease. The most frequently implicated triggering factors include infections, medications, and disease flares[50]. This may induce T cell activation and proliferation with cytokine secretion (interferon-gamma and granulocyte macrophage colony-stimulating factor) and macrophage hyperactivation. The final result is an uncontrollable increase in IL-1, TNFα, and IL-6 production, with a severe systemic inflammatory reaction[51]. Rituximab may suppress the triggering factor effectively, but the severe AOSD flare and subsequent cytokine release required more T-cell-specific immunosuppression (i.e., cyclosporine) for effective control[52]. Furthermore, the diarrhea resulted in a large amount of fluid loss, electrolyte disturbance, and malnutrition, which aggravated the development of the disease and eventually resulted in DIC and MODS. The mortality rate of MODS patients with two-organ failure is 50%-60%, and the mortality rate of MODS patients with failure of more than four organs is 100%. In addition, a large prospective study identified an increased risk of death in patients with continued platelet depletion and poor response to treatment[53]. Our patient simultaneously developed five-organ failure, and glucocorticoid shock therapy and blood purification failed; the disease progressed violently, and the patient died before the use of cyclosporine and Actemra. In particular, attention should be paid to the signature value of the biopsychosocial model in the process of patient management, which may have great potential value, and mental health may be related to the occurrence, progression, and prognosis of the disease. The patient experienced a high fever lasting 1 mo due to bad mood. Some scholars have found the levels of ESR, CRP, and PLT in patients with rheumatoid arthritis combined with depression to be significantly higher than those in patients with no depression. Psychological intervention for rheumatoid arthritis with depression has obvious effects in improving patients' treatment compliance, as well as improving their primary symptoms and depressive state[54]. Several cross-sectional studies have revealed that those exhibiting depressive manifestations have increased levels of IL-1, IL-6, IL-2, TNF-α, and CRP, which are associated with depression in patients being treated for clinical depression[55,56]. Figueiredo-Braga et al reported that anxiety and depression in lupus are influenced by a complicated mix of biological, social, and psychological factors. Their study also found that IL-6 and IL-10 correlated with increased Hospital Anxiety and Depression Scale (HADS) depression scores in depressed patients. IL-10 is responsible for helping drive the Th2-mediated response that results in increased B cell activation, immunoglobulin G class switching, and increased antibody production. It is also strongly associated with disease activity in patients with systemic lupus erythematosus (SLE)[57]. Overall, the relationship between AOSD and psychology remains to be further studied.\n\nCONCLUSION\nAOSD is an exclusionary diagnosis that can be very challenging. It requires an extensive workup and multidisciplinary evaluation. Despite access to many imaging technologies and medical tests, a detailed history and good physical examination are still two powerful tools that can guide an accurate diagnosis. Importantly, more clinical studies will be useful to increase our knowledge about AOSD and complications and offer tailoring for more effective therapies. The biopsychosocial model has great potential value and should also be taken seriously.\n\nACKNOWLEDGEMENTS\nWe thank Li HM for her technical assistance.\n\nInformed consent statement: Informed written consent was obtained from the patient for publication of this report and any accompanying images. \n\nConflict-of-interest statement: The authors declare that they have no conflict of interest to report. \n\nCARE Checklist (2016) statement: The authors have read the CARE Checklist (2016), and the manuscript was prepared and revised according to the CARE Checklist (2016).\n\nManuscript source: Unsolicited manuscript\n\nPeer-review started: September 5, 2020\n\nFirst decision: November 20, 2020\n\nArticle in press: December 10, 2020\n\nSpecialty type: Medicine, research and experimental\n\nCountry/Territory of origin: China\n\nPeer-review report’s scientific quality classification\n\nGrade A (Excellent): A\n\nGrade B (Very good): 0\n\nGrade C (Good): C\n\nGrade D (Fair): D\n\nGrade E (Poor): 0\n\nP-Reviewer: Losurdo G, Velázquez-Soto H S-Editor: Gao CC L-Editor: Wang TQ P-Editor: Yuan YY\n==== Refs\n1 Reihl Crnogaj M Čubelić D Babić A Mayer M Anić B Treatment of refractory adult onset Still's disease with tocilizumab-a single centre experience and literature review Rheumatol Int 2020 40 1317 1325 32506202 \n2 Giacomelli R Ruscitti P Shoenfeld Y A comprehensive review on adult onset Still's disease J Autoimmun 2018 93 24 36 30077425 \n3 MIDDLEMISS JH Juvenile rheumatoid arthritis (Still's disease) Proc R Soc Med 1951 44 805 816 14891783 \n4 Bywaters EG Still's disease in the adult Ann Rheum Dis 1971 30 121 133 5315135 \n5 Mehta BY Ibrahim S Briggs W Efthimiou P Racial/Ethnic variations in morbidity and mortality in Adult Onset Still's Disease: An analysis of national dataset Semin Arthritis Rheum 2019 49 469 473 31109638 \n6 Magadur-Joly G Billaud E Barrier JH Pennec YL Masson C Renou P Prost A Epidemiology of adult Still's disease: estimate of the incidence by a retrospective study in west France Ann Rheum Dis 1995 54 587 590 7668903 \n7 Wakai K Ohta A Tamakoshi A Ohno Y Kawamura T Aoki R Kojima M Lin Y Hashimoto S Inaba Y Minowa M Aizawa S Ichikawa Y Miyasaka N Estimated prevalence and incidence of adult Still's disease: findings by a nationwide epidemiological survey in Japan J Epidemiol 1997 7 221 225 9465547 \n8 Sfriso P Priori R Valesini G Rossi S Montecucco CM D'Ascanio A Carli L Bombardieri S LaSelva G Iannone F Lapadula G Alivernini S Ferraccioli G Colaci M Ferri C Iacono D Valentini G Costa L Scarpa R LoMonaco A Bagnari V Govoni M Piazza I Adami S Ciccia F Triolo G Alessandri E Cutolo M Cantarini L Galeazzi M Ruscitti P Giacomelli R Caso F Galozzi P Punzi L Adult-onset Still's disease: an Italian multicentre retrospective observational study of manifestations and treatments in 245 patients Clin Rheumatol 2016 35 1683 1689 27207567 \n9 Efthimiou P Kadavath S Mehta B Life-threatening complications of adult-onset Still's disease Clin Rheumatol 2014 33 305 314 24435354 \n10 Lee SW Park YB Song JS Lee SK The mid-range of the adjusted level of ferritin can predict the chronic course in patients with adult onset Still's disease J Rheumatol 2009 36 156 162 19040301 \n11 Chen DY Lan JL Lin FJ Hsieh TY Proinflammatory cytokine profiles in sera and pathological tissues of patients with active untreated adult onset Still's disease J Rheumatol 2004 31 2189 2198 15517632 \n12 Priori R Colafrancesco S Alessandri C Minniti A Perricone C Iaiani G Palazzo D Valesini G Interleukin 18: a biomarker for differential diagnosis between adult-onset Still's disease and sepsis J Rheumatol 2014 41 1118 1123 24786926 \n13 Sun Y Wang Z Chi H Hu Q Ye J Liu H Cheng X Shi H Zhou Z Teng J Yang C Su Y Elevated serum levels of interleukin-10 in adult-onset Still's disease are associated with disease activity Clin Rheumatol 2019 38 3205 3210 31236746 \n14 Yamaguchi M Ohta A Tsunematsu T Kasukawa R Mizushima Y Kashiwagi H Kashiwazaki S Tanimoto K Matsumoto Y Ota T Preliminary criteria for classification of adult Still's disease J Rheumatol 1992 19 424 430 1578458 \n15 Kadavath S Efthimiou P Adult-onset Still's disease-pathogenesis, clinical manifestations, and new treatment options Ann Med 2015 47 6 14 25613167 \n16 Koperdanova M Cullis JO Interpreting raised serum ferritin levels BMJ 2015 351 h3692 26239322 \n17 Ohta A Yamaguchi M Tsunematsu T Kasukawa R Mizushima H Kashiwagi H Kashiwazaki S Tanimoto K Matsumoto Y Akizuki M Adult Still's disease: a multicenter survey of Japanese patients J Rheumatol 1990 17 1058 1063 2213780 \n18 Yamashita S Furukawa NE Matsunaga T Hirakawa Y Tago M Yamashita SI Extremely High Serum Ferritin: An Instrumental Marker of Masquerading Adult-Onset Still's Disease with Hemophagocytic Syndrome Am J Case Rep 2017 18 1296 1301 29208852 \n19 Coffernils M Soupart A Pradier O Feremans W Nève P Decaux G Hyperferritinemia in adult onset Still's disease and the hemophagocytic syndrome J Rheumatol 1992 19 1425 1427 1433011 \n20 Moore C Jr Ormseth M Fuchs H Causes and significance of markedly elevated serum ferritin levels in an academic medical center J Clin Rheumatol 2013 19 324 328 23965472 \n21 Evensen KJ Swaak TJ Nossent JC Increased ferritin response in adult Still's disease: specificity and relationship to outcome Scand J Rheumatol 2007 36 107 110 17476616 \n22 Wang W Knovich MA Coffman LG Torti FM Torti SV Serum ferritin: Past, present and future Biochim Biophys Acta 2010 1800 760 769 20304033 \n23 Fautrel B Ferritin levels in adult Still's disease: any sugar? Joint Bone Spine 2002 69 355 357 12184429 \n24 Torti FM Torti SV Regulation of ferritin genes and protein Blood 2002 99 3505 3516 11986201 \n25 Gerfaud-Valentin M Jamilloux Y Iwaz J Sève P Adult-onset Still's disease Autoimmun Rev 2014 13 708 722 24657513 \n26 Ichikawa T Shimojima Y Otuki T Ueno KI Kishida D Sekijima Y Acquired Amegakaryocytic Thrombocytopenia in Adult-onset Still's Disease: Successful Combination Therapy with Tocilizumab and Cyclosporine Intern Med 2019 58 3473 3478 31391399 \n27 Kirino Y Kawaguchi Y Tada Y Tsukamoto H Ota T Iwamoto M Takahashi H Nagasawa K Takei S Horiuchi T Ichida H Minota S Ueda A Ohta A Ishigatsubo Y Beneficial use of serum ferritin and heme oxygenase-1 as biomarkers in adult-onset Still's disease: A multicenter retrospective study Mod Rheumatol 2018 28 858 864 29278009 \n28 Ruscitti P Cipriani P Masedu F Iacono D Ciccia F Liakouli V Guggino G Carubbi F Berardicurti O Di Benedetto P Valenti M Triolo G Valentini G Giacomelli R Adult-onset Still's disease: evaluation of prognostic tools and validation of the systemic score by analysis of 100 cases from three centers BMC Med 2016 14 194 27903264 \n29 Janka GE Familial and acquired hemophagocytic lymphohistiocytosis Annu Rev Med 2012 63 233 246 22248322 \n30 Schulert GS Grom AA Pathogenesis of macrophage activation syndrome and potential for cytokine- directed therapies Annu Rev Med 2015 66 145 159 25386930 \n31 Favara BE Feller AC Pauli M Jaffe ES Weiss LM Arico M Bucsky P Egeler RM Elinder G Gadner H Gresik M Henter JI Imashuku S Janka-Schaub G Jaffe R Ladisch S Nezelof C Pritchard J Contemporary classification of histiocytic disorders. The WHO Committee On Histiocytic/Reticulum Cell Proliferations. Reclassification Working Group of the Histiocyte Society Med Pediatr Oncol 1997 29 157 166 9212839 \n32 Sawar H Espinoza LR Gedalia A Macrophage activation syndrome and etanercept in children with systemic juvenile rheumatoid arthritis J Rheumatol 2004 31 623; author reply 623 623; author reply 624 14994420 \n33 Henter JI Horne A Aricó M Egeler RM Filipovich AH Imashuku S Ladisch S McClain K Webb D Winiarski J Janka G HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis Pediatr Blood Cancer 2007 48 124 131 16937360 \n34 Ravelli A Minoia F Davì S Horne A Bovis F Pistorio A Aricò M Avcin T Behrens EM De Benedetti F Filipovic L Grom AA Henter JI Ilowite NT Jordan MB Khubchandani R Kitoh T Lehmberg K Lovell DJ Miettunen P Nichols KE Ozen S Pachlopnik Schmid J Ramanan AV Russo R Schneider R Sterba G Uziel Y Wallace C Wouters C Wulffraat N Demirkaya E Brunner HI Martini A Ruperto N Cron RQ Paediatric Rheumatology International Trials Organisation; Childhood Arthritis and Rheumatology Research Alliance; Pediatric Rheumatology Collaborative Study Group; Histiocyte Society 2016 Classification Criteria for Macrophage Activation Syndrome Complicating Systemic Juvenile Idiopathic Arthritis: A European League Against Rheumatism/American College of Rheumatology/Paediatric Rheumatology International Trials Organisation Collaborative Initiative Ann Rheum Dis 2016 75 481 489 26865703 \n35 Arai Y Handa T Mitani K [Adult-onset Still disease presenting with disseminated intravascular coagulation] Rinsho Ketsueki 2004 45 316 318 15168449 \n36 Kötter I Wacker A Koch S Henes J Richter C Engel A Günaydin I Kanz L Anakinra in patients with treatment-resistant adult-onset Still's disease: four case reports with serial cytokine measurements and a review of the literature Semin Arthritis Rheum 2007 37 189 197 17583775 \n37 Mori T Tanigawa M Iwasaki E Tamaki S Ono T Wada H Deguchi K Shirakawa S [Cyclosporine therapy of adult onset Still's disease with disseminated intravascular coagulation] Rinsho Ketsueki 1993 34 147 152 8492412 \n38 Jamilloux Y Gerfaud-Valentin M Henry T Sève P Treatment of adult-onset Still's disease: a review Ther Clin Risk Manag 2015 11 33 43 25653531 \n39 Yoo DH Treatment of adult-onset still's disease: up to date Expert Rev Clin Immunol 2017 13 849 866 28540751 \n40 Plaçais L Mekinian A Bornes M Poujol-Robert A Bigé N Maury E Fain O Adult onset Still's disease occurring during pregnancy: Case-report and literature review Semin Arthritis Rheum 2018 47 575 577 28781105 \n41 Franchini S Dagna L Salvo F Aiello P Baldissera E Sabbadini MG Efficacy of traditional and biologic agents in different clinical phenotypes of adult-onset Still's disease Arthritis Rheum 2010 62 2530 2535 20506370 \n42 Mitamura M Tada Y Koarada S Inoue H Suematsu R Ohta A Nagasawa K Cyclosporin A treatment for Japanese patients with severe adult-onset Still's disease Mod Rheumatol 2009 19 57 63 18839270 \n43 Mehta MV Manson DK Horn EM Haythe J An atypical presentation of adult-onset Still's disease complicated by pulmonary hypertension and macrophage activation syndrome treated with immunosuppression: a case-based review of the literature Pulm Circ 2016 6 136 142 27162622 \n44 Castañeda S Blanco R González-Gay MA Adult-onset Still's disease: Advances in the treatment Best Pract Res Clin Rheumatol 2016 30 222 238 27886796 \n45 Zhou S Qiao J Bai J Wu Y Fang H Biological therapy of traditional therapy-resistant adult-onset Still's disease: an evidence-based review Ther Clin Risk Manag 2018 14 167 171 29416343 \n46 Ruscitti P Ursini F Cipriani P De Sarro G Giacomelli R Biologic drugs in adult onset Still's disease: a systematic review and meta-analysis of observational studies Expert Rev Clin Immunol 2017 13 1089 1097 28870100 \n47 Hu QY Zeng T Sun CY Luo CN Liu S Ding TT Ji ZF Lu A Yimaiti K Teng JL Cheng XB Ye JN Su YT Shi H Sun Y Chi HH Zhou ZC Chen LJ Xu J Jiang LD Wu LJ Lin J Yang CD Liu HL Clinical features and current treatments of adult-onset Still's disease: a multicentre survey of 517 patients in China Clin Exp Rheumatol 2019 37 Suppl 121 52 57 \n48 Matsumoto K Nagashima T Takatori S Kawahara Y Yagi M Iwamoto M Okazaki H Minota S Glucocorticoid and cyclosporine refractory adult onset Still's disease successfully treated with tocilizumab Clin Rheumatol 2009 28 485 487 19184270 \n49 Wang CY Guo SH Wang LP Shen HL Refractory adult-onset Still disease treated by tocilizumab combined with methotrexate: A STROBE-compliant article Medicine (Baltimore) 2019 98 e16682 31393368 \n50 Ravelli A Magni-Manzoni S Pistorio A Besana C Foti T Ruperto N Viola S Martini A Preliminary diagnostic guidelines for macrophage activation syndrome complicating systemic juvenile idiopathic arthritis J Pediatr 2005 146 598 604 15870661 \n51 Tristano AG Macrophage activation syndrome: a frequent but under-diagnosed complication associated with rheumatic diseases Med Sci Monit 2008 14 RA27 RA36 18301366 \n52 Schäfer EJ Jung W Korsten P Combination Immunosuppressive Therapy Including Rituximab for Epstein-Barr Virus-Associated Hemophagocytic Lymphohistiocytosis in Adult-Onset Still's Disease Case Rep Rheumatol 2016 2016 8605274 28018698 \n53 Moreau D Timsit JF Vesin A Garrouste-Orgeas M de Lassence A Zahar JR Adrie C Vincent F Cohen Y Schlemmer B Azoulay E Platelet count decline: an early prognostic marker in critically ill patients with prolonged ICU stays Chest 2007 131 1735 1741 17475637 \n54 Zhang YF Ci CZ Wang XD Meng S Su YH An investigation of depression and related factors in rheumatoid arthritis patients Weifang Yixueyuan Xuebao 2017 3 233 235 \n55 Dowlati Y Herrmann N Swardfager W Liu H Sham L Reim EK Lanctôt KL A meta-analysis of cytokines in major depression Biol Psychiatry 2010 67 446 457 20015486 \n56 Howren MB Lamkin DM Suls J Associations of depression with C-reactive protein, IL-1, and IL-6: a meta-analysis Psychosom Med 2009 71 171 186 19188531 \n57 Figueiredo-Braga M Cornaby C Cortez A Bernardes M Terroso G Figueiredo M Mesquita CDS Costa L Poole BD Depression and anxiety in systemic lupus erythematosus: The crosstalk between immunological, clinical, and psychosocial factors Medicine (Baltimore) 2018 97 e11376 29995777\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2307-8960",
"issue": "9(4)",
"journal": "World journal of clinical cases",
"keywords": "Adult-onset Still's disease; Case report; Death; Disseminated intravascular coagulopathy; Macrophage activation syndrome; Multiple organ failure",
"medline_ta": "World J Clin Cases",
"mesh_terms": null,
"nlm_unique_id": "101618806",
"other_id": null,
"pages": "886-897",
"pmc": null,
"pmid": "33585636",
"pubdate": "2021-02-06",
"publication_types": "D002363:Case Reports",
"references": "2213780;23965472;25386930;32506202;9212839;31393368;31391399;22248322;1433011;29416343;15517632;29208852;19184270;18301366;27886796;20304033;14891783;25613167;17583775;12184429;8492412;19188531;5315135;11986201;29278009;15870661;31573475;27207567;28018698;16937360;28540751;27162622;9465547;20506370;30077425;28781105;24657513;7668903;29995777;17476616;14994420;20015486;26865703;27903264;24435354;1578458;26239322;31109638;19040301;25653531;18839270;17475637;15168449;24786926;28870100;31236746",
"title": "Adult-onset Still's disease evolving with multiple organ failure and death: A case report and review of the literature.",
"title_normalized": "adult onset still s disease evolving with multiple organ failure and death a case report and review of the literature"
} | [
{
"companynumb": "CN-SA-2021SA058668",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "TOCILIZUMAB"
},
"drugadditional": null,
"d... |
{
"abstract": "We aim to evaluate prevalence and characteristics of CTS in routine daily practice over a 5-year period, with a review of the literature.\n\n\n\nPatients treated with endocrine therapy (441) were retrospectively analyzed looking for CTS cases in aromatase inhibitors (219, 49.6%) and in tamoxifen (222, 50.3%) patients. We described patient's characteristics and CTS management. We also reviewed the literature reporting CTS in aromatase inhibitors clinical trials.\n\n\n\nSix cases of CTS were diagnosed, all in patients on aromatase inhibitors given in the adjuvant setting. Prevalence was 2.7%. Median age was 54 years. CTS occurred under anastrozole in four cases and letrozole in two cases. One patient had severe intensity presentation. Median time to symptoms onset was 14 months, and resolution was obtained within 4 months after a nonsurgical treatment.\n\n\n\nAromatase inhibitor-induced CTS is rare. It should be recognized and treated in order to avoid endocrine therapy discontinuation.",
"affiliations": "Medical Oncology Department, Abderrahmane Mami Hospital, Rue de l'Hopital, Ariana, Tunisia.;Medical Oncology Department, Abderrahmane Mami Hospital, Rue de l'Hopital, Ariana, Tunisia. nesrinemejriturki@yahoo.fr.;Medical Oncology Department, Abderrahmane Mami Hospital, Rue de l'Hopital, Ariana, Tunisia.;Medical Oncology Department, Abderrahmane Mami Hospital, Rue de l'Hopital, Ariana, Tunisia.;Medical Oncology Department, Abderrahmane Mami Hospital, Rue de l'Hopital, Ariana, Tunisia.;Medical Oncology Department, Abderrahmane Mami Hospital, Rue de l'Hopital, Ariana, Tunisia.",
"authors": "Labidi|Soumaya|S|;Mejri|Nesrine|N|;El Benna|Houda|H|;Afrit|Mehdi|M|;Lakhdhar|Sarra|S|;Boussen|Hamouda|H|",
"chemical_list": "D047072:Aromatase Inhibitors",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00280-016-3190-8",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0344-5704",
"issue": "78(6)",
"journal": "Cancer chemotherapy and pharmacology",
"keywords": "Aromatase inhibitors; Breast cancer; Carpal tunnel syndrome",
"medline_ta": "Cancer Chemother Pharmacol",
"mesh_terms": "D047072:Aromatase Inhibitors; D001943:Breast Neoplasms; D002349:Carpal Tunnel Syndrome; D005260:Female; D006801:Humans; D008875:Middle Aged; D015995:Prevalence; D012189:Retrospective Studies",
"nlm_unique_id": "7806519",
"other_id": null,
"pages": "1311-1315",
"pmc": null,
"pmid": "27817058",
"pubdate": "2016-12",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Aromatase inhibitor-induced carpal tunnel syndrome: prevalence in daily practice.",
"title_normalized": "aromatase inhibitor induced carpal tunnel syndrome prevalence in daily practice"
} | [
{
"companynumb": "TN-INDICUS PHARMA-000461",
"fulfillexpeditecriteria": "1",
"occurcountry": "TN",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "TAMOXIFEN"
},
"drugadditional": "1",
... |
{
"abstract": "We describe the case of a female patient, 52 years old, with dizziness and left motor incoordination for 2 weeks. Brain MRI magnetic resonance imaging) revealed a hyperintense lesion on T2-weighted images, without restricted diffusion, in the left middle cerebellar peduncle. Spectroscopy demonstrated peak of lipids and perfusion did not show any elevation in relative cerebral blood volume (rCBV). The patient underwent an open biopsy and resection, and the diagnosis of diffuse large B-cell lymphoma (DLBCL) was established. The patient received intravenous dexamethasone with symptoms remission, followed by four cycles of methotrexate plus cytarabine. After 3 months, the patient returned with decreased consciences level and a new MRI revealed a right superior frontal gyrus lesion with features suggesting a lymphomatous lesion. The patient died five days after her relapse.",
"affiliations": "Department of Radiology, Faculty of Medical Sciences, University of Campinas, Campinas, São Paulo, SP, Brasil.;Department of Internal Medicine, Faculty of Medical Sciences, University of Campinas, Campinas, São Paulo, SP, Brasil.;Department of Internal Medicine, Faculty of Medical Sciences, University of Campinas, Campinas, São Paulo, SP, Brasil.;Department of Internal Medicine, Faculty of Medical Sciences, University of Campinas, Campinas, São Paulo, SP, Brasil.;Department of Internal Medicine, Faculty of Medical Sciences, University of Campinas, Campinas, São Paulo, SP, Brasil.;Department of Pathology, Faculty of Medical Sciences, University of Campinas, Campinas, São Paulo, SP, Brasil.;Department of Pathology, Faculty of Medical Sciences, University of Campinas, Campinas, São Paulo, SP, Brasil.;Department of Radiology, Faculty of Medical Sciences, University of Campinas, Campinas, São Paulo, SP, Brasil.",
"authors": "Beraldo|Gabriel Laverdi|GL|http://orcid.org/0000-0002-9191-737X;Brito|Angelo Borsarelli Carvalho|ABC|http://orcid.org/0000-0001-9424-0010;Delamain|Márcia Torresan|MT|http://orcid.org/0000-0001-9071-4397;Souza|Carmino Antonio de|CA|http://orcid.org/0000-0001-8656-8374;Lima|Carmen Silvia Passos|CSP|http://orcid.org/0000-0002-1314-2345;Bonfitto|João Felipe Leite|JFL|http://orcid.org/0000-0002-8450-0744;Queiroz|Luciano de Souza|LS|http://orcid.org/0000-0001-8648-6846;Reis|Fabiano|F|http://orcid.org/0000-0003-2256-4379",
"chemical_list": null,
"country": "Brazil",
"delete": false,
"doi": "10.1590/1806-9282.65.2.136",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0104-4230",
"issue": "65(2)",
"journal": "Revista da Associacao Medica Brasileira (1992)",
"keywords": null,
"medline_ta": "Rev Assoc Med Bras (1992)",
"mesh_terms": "D001932:Brain Neoplasms; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D007121:Immunocompetence; D016403:Lymphoma, Large B-Cell, Diffuse; D008279:Magnetic Resonance Imaging; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local",
"nlm_unique_id": "9308586",
"other_id": null,
"pages": "136-140",
"pmc": null,
"pmid": "30892435",
"pubdate": "2019-02",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Primary infratentorial diffuse large b-cell lymphoma: a challenging diagnosis in an immunocompetent patient.",
"title_normalized": "primary infratentorial diffuse large b cell lymphoma a challenging diagnosis in an immunocompetent patient"
} | [
{
"companynumb": "BR-SUN PHARMACEUTICAL INDUSTRIES LTD-2019R1-207588",
"fulfillexpeditecriteria": "1",
"occurcountry": "BR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CYTARABINE"
},
"drug... |
{
"abstract": "Clostridium difficile-associated disease seems to be increasing worldwide. A wide spectrum of clinical manifestations, ranging from asymptomatic to life-threatening disease, has been described. A case of pseudomembranous colitis with massive ascites as the main presenting manifestation is described in order to illustrate the changing clinical pattern of antibiotic-associated colitis.",
"affiliations": "Department of Internal Medicine, Mediterraneo Hospital, Glyfada, Athens, Greece.",
"authors": "Tsourous|George I|GI|;Raftopoulos|Leonidas G|LG|;Kafe|Eleni E|EE|;Manoleris|Eleftherios K|EK|;Makaritsis|Kostas P|KP|;Pinis|Sotirios G|SG|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.ejim.2006.09.034",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0953-6205",
"issue": "18(4)",
"journal": "European journal of internal medicine",
"keywords": null,
"medline_ta": "Eur J Intern Med",
"mesh_terms": null,
"nlm_unique_id": "9003220",
"other_id": null,
"pages": "328-30",
"pmc": null,
"pmid": "17574110",
"pubdate": "2007-07",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "A case of pseudomembranous colitis presenting with massive ascites.",
"title_normalized": "a case of pseudomembranous colitis presenting with massive ascites"
} | [
{
"companynumb": "GR-PFIZER INC-2011140931",
"fulfillexpeditecriteria": "1",
"occurcountry": "GR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CLINDAMYCIN HYDROCHLORIDE"
},
"drugadditional"... |
{
"abstract": "We describe the clinical outcome of 17 patients with secondary Acinetobacter bacteremia whose isolates had a tigecycline MIC of ≤2 mg/liter and who received tigecycline within 2 days of bacteremia onset. The 14-day mortality rate of the tigecycline cohort was 41.2% (7/17), which was significantly higher than that of those receiving other appropriate antimicrobial agents (13.8%, 9/65; P = 0.018). However, the percentages of end-stage renal disease and congestive heart failure were higher in the tigecycline cohort. The efficacy of tigecycline was contingent upon the illness severity and bacterial species. Tigecycline should be applied cautiously for treatment of Acinetobacter bacteremia.",
"affiliations": "Division of Infectious Diseases, Department of Medicine, Hsinchu Mackay Memorial Hospital, Hsinchu City, Taiwan.;Department of Emergency Medicine, Taipei Veterans General Hospital, Taipei, Taiwan Institute of Clinical Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan.;Institute of Clinical Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan Division of Infectious Diseases, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Zhunan, Taiwan ludwigvantw@gmail.com.;Division of Infectious Diseases, Department of Medicine, Taichung Veterans General Hospital, Taichung, Taiwan.;Institute of Clinical Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan Division of Infectious Diseases, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.",
"authors": "Liou|Bo-Huang|BH|;Lee|Yi-Tzu|YT|;Kuo|Shu-Chen|SC|;Liu|Po-Yu|PY|;Fung|Chang-Phone|CP|",
"chemical_list": "D000900:Anti-Bacterial Agents; D000078304:Tigecycline; D008911:Minocycline",
"country": "United States",
"delete": false,
"doi": "10.1128/AAC.04987-14",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0066-4804",
"issue": "59(6)",
"journal": "Antimicrobial agents and chemotherapy",
"keywords": null,
"medline_ta": "Antimicrob Agents Chemother",
"mesh_terms": "D000151:Acinetobacter Infections; D040981:Acinetobacter baumannii; D016954:Acinetobacter calcoaceticus; D000368:Aged; D000369:Aged, 80 and over; D000900:Anti-Bacterial Agents; D016470:Bacteremia; D024901:Drug Resistance, Multiple, Bacterial; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D008911:Minocycline; D012189:Retrospective Studies; D000078304:Tigecycline",
"nlm_unique_id": "0315061",
"other_id": null,
"pages": "3637-40",
"pmc": null,
"pmid": "25824230",
"pubdate": "2015",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "18508226;20025527;21595793;21653602;21193494;22495546;16080072;16080073;18990531",
"title": "Efficacy of tigecycline for secondary Acinetobacter bacteremia and factors associated with treatment failure.",
"title_normalized": "efficacy of tigecycline for secondary acinetobacter bacteremia and factors associated with treatment failure"
} | [
{
"companynumb": "TW-PFIZER INC-2015183113",
"fulfillexpeditecriteria": "1",
"occurcountry": "TW",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "TIGECYCLINE"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nKetorolac is an effective analgesic but the potential for acute kidney injury (AKI) is concerning, particularly in geriatric \"G-60 trauma\" patients. The objectives of this study are to report the incidence of AKI in patients who receive ketorolac, identify risk factors for AKI, and develop a risk factor-guided algorithm for safe utilization.\n\n\nMETHODS\nThis retrospective cohort study included trauma patients age 60 years and older who received intravenous ketorolac. The primary endpoint was the incidence of AKI.\n\n\nRESULTS\nAmong 316 patients evaluated, the incidence of AKI was 2.5%. Patients with AKI received more nephrotoxins, had more comorbidities, and higher use of loop diuretics or vasopressors. Loop diuretic therapy and number of comorbidities were independent predictors of AKI.\n\n\nCONCLUSIONS\nRisk for AKI with ketorolac was low, being more prevalent with comorbidities or receipt of loop diuretics.",
"affiliations": "Department of Pharmacy, Mayo Clinic Health System, 700 West Avenue South, La Crosse, WI, 54601, USA. hall.scott2@mayo.edu.;Trauma and Acute Care Surgery, HonorHealth John C. Lincoln Medical Center, 250 E Dunlap Ave, Phoenix, AZ, 85020, USA.;College of Pharmacy, Midwestern University, 19555 N 59th Avenue, Glendale, AZ, 85308, USA.",
"authors": "Hall|Scott T|ST|;Mangram|Alicia J|AJ|;Barletta|Jeffrey F|JF|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1007/s00268-021-06320-z",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0364-2313",
"issue": null,
"journal": "World journal of surgery",
"keywords": null,
"medline_ta": "World J Surg",
"mesh_terms": null,
"nlm_unique_id": "7704052",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34553259",
"pubdate": "2021-09-22",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Identification of Risk Factors for Acute Kidney Injury from Intravenous Ketorolac in Geriatric Trauma Patients.",
"title_normalized": "identification of risk factors for acute kidney injury from intravenous ketorolac in geriatric trauma patients"
} | [
{
"companynumb": "US-APOTEX-2022AP007999",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "KETOROLAC TROMETHAMINE"
},
"drugadditional": "3"... |
{
"abstract": "BACKGROUND\nCurrent guidelines recommend direct-acting oral anticoagulants (DOACs) over warfarin in patients with atrial fibrillation (AF) and valvular heart disease (VHD) without a mechanical valve or moderate to severe mitral stenosis. However, real-world data to support the safety and efficacy of DOACs in this patient population are lacking.\n\n\nOBJECTIVE\nOur objective was to assess the safety and effectiveness of DOACs in patients with AF and VHD.\n\n\nMETHODS\nThis retrospective chart review evaluated patients aged ≥ 18 years with a diagnosis of AF and at least moderate VHD on echocardiogram. Patients were included if they received ≥ 1 month of DOAC therapy from December 2016 to December 2018. Patients were excluded if they received dual antiplatelet therapy or had additional indications for anticoagulation. The primary outcomes were incidence of stroke or systemic embolism (SSE) and major bleeding.\n\n\nRESULTS\nIn total, 200 patients were included (disease type: aortic, n = 50; mitral, n = 50; tricuspid, n = 50; multivalve, n = 50). Most patients received apixaban (n = 133 [66.5%]) followed by rivaroxaban (n = 50 [25%]) and dabigatran (n = 17 [8.5%]). No patients received edoxaban. The mean CHA2DS2-VASc score was 4.25 and was similar among DOAC cohorts (p = 0.380). The overall SSE rate was 3.5% and was highest for dabigatran (n = 3 [17.6%]) compared with the other DOACs (apixaban, n = 1 [0.8%]; rivaroxaban, n = 3 [6%]; p = 0.001). Rates were similar among different valve types (aortic, n = 3 [6%]; mitral, n = 1 [2%]; tricuspid, n = 2 [4%]; multivalve, n = 1 [2%]; p = 0.653). The overall rate of major bleeding was 5.5% and did not differ among the DOACs (apixaban, n = 5 [3.8%]; rivaroxaban, n = 4 [8%]; dabigatran, n = 2 [11.8%]; p = 0.264) or valve type (aortic, n = 3 [6%]; mitral, n = 2 [4%]; tricuspid, n = 2 [4%]; multivalve, n = 4 [8%]; p = 0.787).\n\n\nCONCLUSIONS\nIn patients with AF and VHD, rates of major bleeding were similar among the DOACs and valve types; however, more patients receiving dabigatran experienced SSE. Further studies are needed to validate these findings.",
"affiliations": "Missouri Baptist Medical Center, St. Louis, MO, USA.;St. Louis College of Pharmacy, St. Louis, MO, USA. Katie.Tellor@stlcop.edu.;St. Louis College of Pharmacy, St. Louis, MO, USA.;BJC Medical Group Cardiology, St. Louis, MO, USA.;BJC Medical Group Cardiology, St. Louis, MO, USA.",
"authors": "Hampton|Meredith L|ML|;Tellor|Katie B|KB|http://orcid.org/0000-0003-0980-9888;Armbruster|Anastasia L|AL|http://orcid.org/0000-0002-1516-4118;Theodos|Gus|G|;Schwarze|Martin W|MW|",
"chemical_list": "D065427:Factor Xa Inhibitors",
"country": "New Zealand",
"delete": false,
"doi": "10.1007/s40256-020-00398-x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1175-3277",
"issue": "20(6)",
"journal": "American journal of cardiovascular drugs : drugs, devices, and other interventions",
"keywords": null,
"medline_ta": "Am J Cardiovasc Drugs",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D001281:Atrial Fibrillation; D004617:Embolism; D065427:Factor Xa Inhibitors; D005260:Female; D006349:Heart Valve Diseases; D006470:Hemorrhage; D006801:Humans; D008297:Male; D012189:Retrospective Studies; D020521:Stroke",
"nlm_unique_id": "100967755",
"other_id": null,
"pages": "611-617",
"pmc": null,
"pmid": "32043243",
"pubdate": "2020-12",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Evaluation of the Safety and Effectiveness of Direct-Acting Oral Anticoagulants in Patients with Atrial Fibrillation and Coexisting Valvular Heart Disease.",
"title_normalized": "evaluation of the safety and effectiveness of direct acting oral anticoagulants in patients with atrial fibrillation and coexisting valvular heart disease"
} | [
{
"companynumb": "US-BRISTOL-MYERS SQUIBB COMPANY-BMS-2021-026901",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "APIXABAN"
},
"drugaddit... |
{
"abstract": "Immune-checkpoint inhibitors (ICIs) are transforming the modern era of cancer therapy. As new treatment options are becoming available, new patterns of disease behavior are manifesting. One such phenomenon, known as hyperprogressive disease (HPD), is a rare complication resulting in exponential disease progression on exposure to an ICI. Herein, we report an uncommon case of a patient who experienced HPD on 2 different occasions with 2 different immunotherapy agents.\nA 77-year-old black man was diagnosed with stage IV squamous cell carcinoma of the lung. He was enrolled in a clinical trial that involved viral transduction and stereotactic body radiation followed by pembrolizumab administration. His disease progressed markedly after the first cycle of immunotherapy. He was switched to carboplatin and protein-bound paclitaxel. He continued to have steady disease progression. After the third cycle of chemotherapy, he was again given immunotherapy, this time with atezolizumab. Again, after a single infusion, he exhibited substantial disease progression and further clinical deterioration.\nHPD is a rare yet disturbing complication of immunotherapy with devastating effects on morbidity and mortality. Although there is accumulating literature supporting the phenomenon of HPD, to our knowledge, this is the first reported case of HPD occurring with 2 different ICIs in the same patient. This case suggests that the presence of HPD during treatment with 1 checkpoint inhibitor may preclude the use of another one. It also raises concerns about using other forms of immunomodulating agents. As immunotherapy becomes a major form of cancer therapy, more data are needed to better understand HPD and determine which patients are at risk.",
"affiliations": "Department of Medicine, Houston Methodist Hospital, Houston, Texas.;Cancer Center, Houston Methodist Hospital, Houston, Texas.;Department of Medicine, Houston Methodist Hospital, Houston, Texas.;Cancer Center, Houston Methodist Hospital, Houston, Texas.",
"authors": "Kasparian|Saro|S|;Gentille|Cesar|C|;Burns|Ethan|E|;Bernicker|Eric H|EH|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.jtocrr.2020.100017",
"fulltext": "\n==== Front\nJTO Clin Res Rep\nJTO Clin Res Rep\nJTO Clinical and Research Reports\n2666-3643\nElsevier\n\nS2666-3643(20)30017-5\n10.1016/j.jtocrr.2020.100017\n100017\nBrief Report\nHyperprogressive NSCLC With Two Immune-Checkpoint Inhibitors\nKasparian Saro MD saro.kasparian@gmail.com\na∗\nGentille Cesar MD b\nBurns Ethan MD a\nBernicker Eric H. MD b\na Department of Medicine, Houston Methodist Hospital, Houston, Texas\nb Cancer Center, Houston Methodist Hospital, Houston, Texas\n∗ Corresponding author. Address for correspondence: Saro Kasparian, MD, Department of Medicine, Houston Methodist Hospital, 6550 Fannin St., Houston, Texas 77030. saro.kasparian@gmail.com\n22 2 2020\n6 2020\n22 2 2020\n1 2 10001720 1 2020\n8 2 2020\n10 2 2020\n© 2020 The Authors\n2020\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).\nIntroduction\n\nImmune-checkpoint inhibitors (ICIs) are transforming the modern era of cancer therapy. As new treatment options are becoming available, new patterns of disease behavior are manifesting. One such phenomenon, known as hyperprogressive disease (HPD), is a rare complication resulting in exponential disease progression on exposure to an ICI. Herein, we report an uncommon case of a patient who experienced HPD on 2 different occasions with 2 different immunotherapy agents.\n\nCase Presentation\n\nA 77-year-old black man was diagnosed with stage IV squamous cell carcinoma of the lung. He was enrolled in a clinical trial that involved viral transduction and stereotactic body radiation followed by pembrolizumab administration. His disease progressed markedly after the first cycle of immunotherapy. He was switched to carboplatin and protein-bound paclitaxel. He continued to have steady disease progression. After the third cycle of chemotherapy, he was again given immunotherapy, this time with atezolizumab. Again, after a single infusion, he exhibited substantial disease progression and further clinical deterioration.\n\nConclusions\n\nHPD is a rare yet disturbing complication of immunotherapy with devastating effects on morbidity and mortality. Although there is accumulating literature supporting the phenomenon of HPD, to our knowledge, this is the first reported case of HPD occurring with 2 different ICIs in the same patient. This case suggests that the presence of HPD during treatment with 1 checkpoint inhibitor may preclude the use of another one. It also raises concerns about using other forms of immunomodulating agents. As immunotherapy becomes a major form of cancer therapy, more data are needed to better understand HPD and determine which patients are at risk.\n\nKeywords\n\nHyperprogressive disease\nNon−small cell lung cancer\nStage IV\nPembrolizumab\nAtezolizumab\nImmunotherapy\n==== Body\npmcIntroduction\n\nImmune-checkpoint inhibitors (ICIs) have transformed the landscape of modern cancer therapy, particularly in advanced disease. Melanoma and NSCLC are 2 of the many malignancies in which patients have greatly benefited from this innovative therapy. The therapeutic response is measured by the Response Evaluation Criteria in Solid Tumors and includes complete response, partial response, stable disease, and disease progression.1 Nevertheless, a small population of patients in clinical trials who received ICI had an unanticipated early crossing of progression-free survival and overall survival curves compared with those in standard chemotherapy.2\n\nThis phenomenon is associated with a rapid increase in tumor burden or growth and is now termed hyperprogressive disease (HPD). Although debate exists on whether patients truly experience accelerated growth versus ineffective therapy and typical disease progression, certain patients do experience tumor enlargement response that is consistent with hyperprogression. This case report describes the unusual scenario of a patient with metastatic NSCLC who developed HPD with 2 different ICIs on 2 different occasions.\n\nCase Presentation\n\nA 77-year-old black man with history of chronic obstructive pulmonary disease (COPD) and 40-plus pack-years of smoking was admitted to the hospital with acute COPD exacerbation. Computed tomography (CT) of the chest revealed a 1.2-cm right lower lobe nodule and left-sided atelectasis. He was followed clinically, and 2 months later, a noncontrast CT revealed a necrotic mass in the superior segment of the left lower lobe measuring approximately 4 cm × 5 cm × 5 cm, along with a small left-sided, complex loculated effusion with pleural thickening (Fig. 1A and B). Subsequent bronchoscopy and biopsy revealed a fungating mass consistent with squamous cell carcinoma, and a bronchoalveolar lavage cytology specimen was positive for malignancy. Programmed cell death-ligand 1 (PD-L1) expression was present in 1% to 5% of the cells. Staging workup with positron emission tomography (PET) with CT revealed a similar-sized mass with increased uptake in the left lower lobe, an additional uptake in the left pleura, left pleural effusion, and a 2.7 cm nodule in the right adrenal gland, consistent with stage IV squamous cell carcinoma.Figure 1 (A) Axial and (B) coronal views of the noncontrast computed tomography scan images before the initiation of pembrolizumab. [Yellow Arrow] A 5-cm mass-like area in the superior segment of the left lower lobe can be seen. (C) Axial and (D) coronal views of the noncontrast computed tomography scan images 3 months later (3 weeks after his first and only dose of pembrolizumab). [Red Arrow] Progression of the disease now at 10.8 cm in size and with new right lower lobe nodules.\n\nHe was enrolled in a clinical trial consisting of an oncolytic viral transduction plus stereotactic body radiation therapy followed by pembrolizumab. He received his viral transduction a month later and was followed by 5 fractions of stereotactic body radiation therapy. Two weeks later, he received his first infusion of pembrolizumab. This was complicated by a hospitalization 3 weeks later owing to pneumonia. A repeat CT scan revealed interval hyperprogression of the cancer with the mass now measuring 10.7 cm × 10.8 cm, along with the development of several subcentimeter right lower lobe pulmonary nodules and an increase in the right adrenal mass to 3.9 cm (Fig. 1C and D). Given this rapid progression and clinical deterioration, he was taken off the trial and transitioned to systemic chemotherapy with carboplatin and protein-bound paclitaxel.\n\nHe tolerated the chemotherapy well, and after 2 cycles, he had another PET with CT scan. Although reduction in the primary mass was found, a new 7.6 cm mass in the posterior left lung base, which had invaded the adjacent pleura and pericardium, had developed. Additional subcentimeter nodules were also found in the right lung, along with growth of the adrenal mass and multiple new osseous lesions throughout the body. Although the disease progressed, its rate of growth was significantly lower and there was improvement in several of the metastatic sites. After an extensive discussion with the patient, it was decided to proceed with a third cycle of the chemotherapy.\n\nOne month later, he developed progressive dyspnea and chest pain. A repeat CT scan revealed steady progression of the disease with enlargement in both the lung and adrenal masses (Fig. 2A and B). Cell-free DNA analysis revealed positive findings for nontargetable mutations, including FGFR3-TACO3 fusion, PIK3CA amplification, and TP53 E287. Given the chemotherapy resistance and minimal intervention with the previous immunotherapy, it was decided to attempt a second trial of immunotherapy with atezolizumab. However, after 1 cycle, he was readmitted for confusion, lethargy, weakness, shortness of breath, hypercalcemia of the malignancy, and pneumonia. He developed acute hypoxic and hypercapnic respiratory failure that required endotracheal intubation and mechanical ventilation. A chest CT scan now revealed rapid enlargement of the primary mass, innumerable nodules, significant growth of the existing nodules, and extensive peritoneal involvement; all of which at a faster rate than the scans indicated during chemotherapy (Fig. 2C and D). Given his performance status, he was not a candidate for further therapy, and it was decided to proceed with hospice care 10 months after the initial discovery of the mass.Figure 2 (A) Axial and (B) coronal view contrast CT after 3 cycles of carboplatin and paclitaxel, revealing further progression of the disease with enlarging mass and [Yellow Arrow] increased number of pulmonary nodules. (C) Axial and (D) coronal view of the noncontrast CT scan 5 weeks later (2 weeks post atezolizumab infusion) showing [Red Arrow] increasing in both size and number of lung lesions.\n\nDiscussion and Conclusions\n\nImmune evasion is an evolutionary necessity developed by cancer cells to thrive in the body. Although traditional chemotherapy limits cellular division and growth, checkpoint inhibitors attempt to stop and reverse cancer-mediated immune suppression.3 As new treatment options become available, new patterns of disease behavior are manifesting.\n\nThough anecdotally reported in the literature, HPD was first defined by Champiat et al.4 as a twofold or greater increase in tumor growth rate (TGR) compared with pretreatment and progression as evaluated by the Response Evaluation Criteria in Solid Tumors. Although theoretically a sound definition, the subtleties of TGR vary among different studies; some frequently used definitions are as follows: the sum of the longest diameters of the target lesions,4,5 the change in the diameter of the target lesions,6 tumor volume,7 or time-to-treatment failure, total tumor burden, or increase in progression pace.8,9 Regardless of the definition used, the clinical phenomenon is unchanged: rapid progression of the disease while on ICI. The incidence of this paradoxical phenomenon also varies among study results ranging from 4% to 15% in mixed solid tumors, 8% to 21% in NSCLC, and 29% in head and neck cancers.4,5 Contributing clinical factors, such as age more than 65 years, a higher number of metastatic lesions at diagnosis, and locoregional disease recurrence, have been reported but should be considered with caution because they have not been used consistently in all analyses. Interestingly, PD-L1 expression, number of previous therapies, and advanced stage, or poor performance status at baseline have not been linked to HPD.4 The manifestation of HPD is associated with a poorer overall survival in retrospective and prospective trials5 and may explain why some phase III clinical trials were terminated early.7\n\nThere are increasing data from retrospective studies arguing in favor of HPD.10 A study by Ferrara et al.7 analyzed a cohort of pretreated patients with advanced NSCLC who received programmed cell death protein-1 (PD-1)/PD-L1 inhibitors or single-agent chemotherapy and assessed the rate of HPD in both groups by calculating TGR before and during treatment. HPD was noted in 13.8% of the patients treated with ICIs compared with 5.1% of the patients treated with chemotherapy. Their definition of HPD included tumor growth of more than 10% per month before ICIs and more than 60% after therapy, or more than 80% per month after therapy if tumor growth was 30% before ICIs. The inclusion of these strict criteria supports a negative effect of PD-1/PD-L1 inhibition instead of progression, which could solely be explained by the natural history of the disease. Other authors argue against the existence of this phenomenon. Pearson et al.11 cite the lack of placebo-controlled cohort studies as one of the reasons that HPD cannot be adequately described; they also argue that the crossing of survival curves found in the clinical trials does not reveal a change in TGR but rather more of disease control with chemotherapy than with ICIs. In addition, a biological basis for HPD has not been fully described yet.\n\nNevertheless, several preclinical studies have formulated various hypotheses with postulated pathophysiology. These are dutifully summarized in the review by Champiat et al.4 The proposed mechanisms include the following: T regulatory cell expansions secondary to checkpoint blockade leading to immune suppression; increased T-cell exhaustion owing to alternative checkpoint pathways; checkpoint blockade resulting in immunosuppressive cytokine release from macrophages, dendritic cells, or other myeloid-derived cells; an uncontrolled inflammatory response; and direct activation of oncogenic pathways by the checkpoint blockade.10 The actual cause is likely a combination of these pathways along with yet other unrecognized cell processes. Even though the association between HPD and ICIs must still be clearly defined, it is difficult to ignore the data and reports that reveal that a group of patients treated with ICIs had accelerated progression and poor outcomes.\n\nOur patient was diagnosed with an aggressive squamous cell lung carcinoma. The initial CT scan after his COPD exacerbation revealed a 4 cm × 5 cm × 5 cm mass in the left lower lobe. The PET with CT scan done approximately 3 weeks later revealed a similar-sized mass along with the initial metastatic sites in the left pleura, pleural effusion, and the right adrenal gland. He tolerated the research protocol and had no major issues for 6 weeks until immunotherapy administration. Three weeks after administration of pembrolizumab, the imaging revealed that the primary mass had nearly doubled in size, the adrenal mass had enlarged, and several new right-sided pulmonary nodules had developed. There was a profound change in the tumor burden, and it was decided to stop the immunotherapy. Traditional cytotoxic chemotherapy reduced the size of the primary mass but he had stable disease progression. The use of atezolizumab resulted in yet another HPD as revealed by imaging a few weeks later, with innumerable lung nodules, significant growth in all previous metastatic sites and the primary site, and significant worsening of pleural and peritoneal involvement, all at a rate that was markedly worse than that of the stable disease progression found during traditional chemotherapy.\n\nTo our knowledge, this is the first reported case of a significant progression after treatment with 2 different ICIs on different occasions. The temporal relation between tumor progression and decline in performance status supports and argues in favor of the existence of HPD after PD-1/PD-L1 inhibition. As checkpoint inhibitors become a major treatment option for many cancers, the phenomenon of HPD must be considered as a possible outcome and studied further to determine who would be at risk. Furthermore, the presence of HPD after a single exposure to a checkpoint inhibitor suggests the preclusion of all future checkpoint inhibitors.\n\nAcknowledgments\n\nThe authors thank the patient and his family for allowing them to write this case report. The authors would also like to thank the radiology department at the Houston Methodist Hospital for their help in reviewing the imaging findings. Dr. Kasparian provided substantial contributions to the conception and design of the manuscript, chart review, literature search, drafting the article, and revising it critically for important intellectual content. Dr. Gentille provided substantial contributions to the conception and design of the manuscript, chart review, literature search, drafting the article, and revising it critically for important intellectual content. Dr. Burns provided substantial contributions to chart review, literature search, drafting the article, and revising it critically for important intellectual content. Dr. Bernicker provided substantial contributions to the conception and design of the manuscript, literature search, drafting the article, and revising it critically for important intellectual content. All the authors approved of the final version to be published.\n\nDisclosure: Dr. Bernicker reports personal fees from AstraZeneca, Pfizer, and Guardant Health outside of the submitted work. The remaining authors declare no conflict of interest. Dr. Kasparian provided substantial contributions to the conception and design of the manuscript, chart review, literature search, drafting the article, and revising it critically for important intellectual content. Dr. Gentille provided substantial contributions to the conception and design of the manuscript, chart review, literature search, drafting the article, and revising it critically for important intellectual content. Dr. Burns provided substantial contributions to chart review, literature search, drafting the article, and revising it critically for important intellectual content. Dr. Bernicker provided substantial contributions to the conception and design of the manuscript, literature search, drafting the article, and revising it critically for important intellectual content. All the authors approved of the final version to be published.\n==== Refs\nReferences\n\n1 Borcoman E. Nandikolla A. Long G. Goel S. Le Tourneau C. Patterns of response and progression to immunotherapy Am Soc Clin Oncol Educ Book 38 2018 169 178 30231380\n2 Popat S. Hyperprogression with immunotherapy: is it real? Cancer 125 2019 1218 1220 30768797\n3 Pardoll D.M. The blockade of immune checkpoints in cancer immunotherapy Nat Rev Cancer 12 2012 252 264 22437870\n4 Champiat S. Dercle L. Ammari S. Hyperprogressive disease is a new pattern of progression in cancer patients treated by anti-PD-1/PD-L1 Clin Cancer Res 23 2017 1920 1928 27827313\n5 Kanjanapan Y. Day D. Wang L. Hyperprogressive disease in early-phase immunotherapy trials: clinical predictors and association with immune-related toxicities Cancer 125 2019 1341 1349 30768786\n6 Saâda-bouzid E. Defaucheux C. Karabajakian A. Hyperprogression during anti-PD-1/PD-L1 therapy in patients with recurrent and/or metastatic head and neck squamous cell carcinoma Ann Oncol 28 2017 1605 1611 28419181\n7 Ferrara R. Mezquita L. Texier M. Hyperprogressive disease in patients with advanced non-small cell lung cancer treated with PD-1/PD-L1 inhibitors or with single-agent chemotherapy JAMA Oncol 4 2018 1543 1552 30193240\n8 Kato S. Goodman A. Walavalkar V. Barkauskas D.A. Sharabi A. Kurzrock R. Hyperprogressors after immunotherapy: analysis of genomic alterations associated with accelerated growth rate Clin Cancer Res 23 2017 4242 4250 28351930\n9 Valle J.W. Borbath I. Rosbrook B. Fernandez K. Raymond E. Sunitinib in patients with pancreatic neuroendocrine tumors: update of safety data Future Oncol 15 2019 1219 1230 30701988\n10 Champiat S. Ferrara R. Massard C. Hyperprogressive disease: recognizing a novel pattern to improve patient management Nat Rev Clin Oncol 15 2018 748 762 30361681\n11 Pearson A.T. Sweis R.F. Hyperprogression-immunotherapy-related phenomenon vs intrinsic natural history of cancer JAMA Oncol 5 2019 743 30896751\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2666-3643",
"issue": "1(2)",
"journal": "JTO clinical and research reports",
"keywords": "Atezolizumab; Hyperprogressive disease; Immunotherapy; Non−small cell lung cancer; Pembrolizumab; Stage IV",
"medline_ta": "JTO Clin Res Rep",
"mesh_terms": null,
"nlm_unique_id": "101769967",
"other_id": null,
"pages": "100017",
"pmc": null,
"pmid": "34589924",
"pubdate": "2020-06",
"publication_types": "D016428:Journal Article",
"references": "30361681;30231380;30768797;27827313;30768786;22437870;30193240;30896751;30701988;28351930;28419181",
"title": "Hyperprogressive NSCLC With Two Immune-Checkpoint Inhibitors.",
"title_normalized": "hyperprogressive nsclc with two immune checkpoint inhibitors"
} | [
{
"companynumb": "US-ROCHE-2931498",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ATEZOLIZUMAB"
},
"drugadditional": "3",
"dru... |
{
"abstract": "Despite widespread public health concern regarding opioid misuse and overuse, there is a paucity of literature on the acute and chronic pulmonary vascular and cardiac implications of excipient lung disease. This case series describes the clinical presentation of five adult patients who experienced profound pulmonary hypertension and right heart failure in the setting of confirmed or suspected crushed opioid injection at a single academic center between 2012 and 2019. The clinical characteristics and right heart catheterization data presented in these cases demonstrate the acute intravascular effects of the intravenous injection of crushed opioids and potential for hemodynamic collapse. Moreover, these cases suggest that survivors of acute excipient lung disease may develop chronic pulmonary vascular disease. Further studies are needed to explore the epidemiology and outcomes of oral opioid-induced intravascular excipient lung disease to increase awareness of this life-threatening complication among health care professionals and guide treatment and prevention measures.",
"affiliations": "Division of Pulmonary, Critical Care, & Sleep Medicine, University of Kansas School of Medicine, 3901 Rainbow Boulevard, Mail Stop #3007, Kansas City, KS, 66160-7381, USA.;Division of Pulmonary, Critical Care, & Sleep Medicine, University of Kansas School of Medicine, 3901 Rainbow Boulevard, Mail Stop #3007, Kansas City, KS, 66160-7381, USA.;Division of Pulmonary, Critical Care, & Sleep Medicine, University of Kansas School of Medicine, 3901 Rainbow Boulevard, Mail Stop #3007, Kansas City, KS, 66160-7381, USA. lsatterwhite@kumc.edu.",
"authors": "Cook|Christine M|CM|0000-0002-0360-8594;Simpson|Steven Q|SQ|0000-0002-9166-2717;Satterwhite|Lewis|L|0000-0002-6743-8870",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1007/s00408-021-00456-4",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0341-2040",
"issue": "199(4)",
"journal": "Lung",
"keywords": "Excipient-induced lung disease; Opioid addiction; Pulmonary hypertension",
"medline_ta": "Lung",
"mesh_terms": null,
"nlm_unique_id": "7701875",
"other_id": null,
"pages": "363-368",
"pmc": null,
"pmid": "34313827",
"pubdate": "2021-08",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Excipient-Induced Pulmonary Vascular Disease: An Underrecognized and Deadly Complication of Opioid Addiction.",
"title_normalized": "excipient induced pulmonary vascular disease an underrecognized and deadly complication of opioid addiction"
} | [
{
"companynumb": "US-SPECGX-T202102628",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "METHADONE HYDROCHLORIDE"
},
"drugadditional": null... |
{
"abstract": "We present extensive clinical, serological, morphological and muscle imaging data of a 66-year-old man with isolated bilateral ptosis and external ophthalmoplegia secondary to Immune checkpoint inhibitors (Pembrolizumab). He had elevated CK level (>5000 UI/L). No facial, bulbar, proximal, distal or axial muscular weakness was observed. Electromyography (EMG) showed myopathic pattern, with spontaneous activity. Myositis specific antibodies and anti-striational antibodies were negative. Cardiac and respiratory functions were preserved. Skeletal muscle MRI was unremarkable, whereas extraocular muscles revealed bilateral hyperintensities in inferior rectus, medial rectus and superior oblique muscles in both T1 and STIR sequences, with mild muscle atrophy. Muscle biopsy showed endomysial inflammatory infiltrates, MHC-1 expression was observed in clusters of non-necrotic cells. CD56 positive cells were observed in perifascicular regions. Patient discontinued Pembrolizumab and received corticosteroid treatment with progressive clinical improvement and CK normalization. Our findings support this clinical entity, suggesting that isolated ocular myositis represents a subgroup of generalised myositis with predominant ocular symptoms.",
"affiliations": "Neuromuscular Disease Centre, Department of Neuroscience, Mental Health and Sensory Organs (NESMOS), SAPIENZA University of Rome, Sant'Andrea Hospital, Via di Grottarossa 1035-1039, 00189 Rome, Italy. Electronic address: matteo.garibaldi@uniroma1.it.;Department of Medical Oncology, San Camillo Forlanini Hospital, Rome, Italy.;Neuromuscular Disease Centre, Department of Neuroscience, Mental Health and Sensory Organs (NESMOS), SAPIENZA University of Rome, Sant'Andrea Hospital, Via di Grottarossa 1035-1039, 00189 Rome, Italy.;Department of Radiology, Policlinico Tor Vergata, Rome, Italy.;Rare Neuromuscular Diseases Centre, Department of Human Neuroscience, SAPIENZA University, Rome, Italy.;Department of Radiology, Istituto Dermopatico dell'Immacolata, IRCCS, Rome, Italy.;Department of Radiology, Istituto Dermopatico dell'Immacolata, IRCCS, Rome, Italy.;Department of Neuroscience, San Camillo-Forlanini Hospital, Rome, Italy.",
"authors": "Garibaldi|Matteo|M|;Calabrò|Fabio|F|;Merlonghi|Gioia|G|;Pugliese|Silvia|S|;Ceccanti|Marco|M|;Cristiano|Lara|L|;Tartaglione|Tommaso|T|;Petrucci|Antonio|A|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D000074322:Antineoplastic Agents, Immunological; D000082082:Immune Checkpoint Inhibitors; C582435:pembrolizumab",
"country": "England",
"delete": false,
"doi": "10.1016/j.nmd.2020.02.013",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0960-8966",
"issue": "30(5)",
"journal": "Neuromuscular disorders : NMD",
"keywords": "Anti-PD-1; Idiopathic inflammatory myopathies; Immune checkpoint inhibitors (ICIs); Immune checkpoint inhibitors-related Myositis (irMyositis); Ocular myositis; Pembrolizumab",
"medline_ta": "Neuromuscul Disord",
"mesh_terms": "D000368:Aged; D061067:Antibodies, Monoclonal, Humanized; D000074322:Antineoplastic Agents, Immunological; D001763:Blepharoptosis; D006801:Humans; D000082082:Immune Checkpoint Inhibitors; D007680:Kidney Neoplasms; D008297:Male; D009220:Myositis; D009801:Oculomotor Muscles; D009886:Ophthalmoplegia",
"nlm_unique_id": "9111470",
"other_id": null,
"pages": "420-423",
"pmc": null,
"pmid": "32387281",
"pubdate": "2020-05",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Immune checkpoint inhibitors (ICIs)-related ocular myositis.",
"title_normalized": "immune checkpoint inhibitors icis related ocular myositis"
} | [
{
"companynumb": "IT-009507513-1908ITA004301",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "LENVATINIB MESYLATE"
},
"drugadditional": n... |
{
"abstract": "OBJECTIVE\nTreatment with Palbociclib, a cyclin-dependent kinase 4/6 inhibitor, has demonstrated significantly improved progression-free survival in patients with hormone receptor-positive, HER2-negative, advanced breast cancer, when used in combination with letrozole or fulvestrant endocrine therapies. However, limited information exists on its cutaneous adverse effects (AE). Hence, we conducted a retrospective cohort study to investigate the prevalence and management of cutaneous AE during palbociclib and endocrine therapy.\n\n\nMETHODS\nWe included 324 adult patients with advanced breast cancer who received palbociclib between March 2016 and August 2020 within a tertiary comprehensive cancer centre. Patient demographics, details of previous and concurrent treatments, as well as treatment-related cutaneous AE were recorded from electronic records.\n\n\nRESULTS\nThe incidence of treatment-related cutaneous AE was 14.2% (46 from a total of 324 patients). The most frequent cutaneous reactions included maculopapular rash (41%), asteatosis (37%), pruritus and urticaria (20%), and bullous dermatitis reactions (9%). We identified two patients with treatment-induced subacute cutaneous lupus erythematosus, one case of bullous pemphigoid, and a single erythema multiforme. Patients received an average of 9 cycles of treatment, completing an average of 6 cycles before developing cutaneous AE, which persisted for a median of 43 days. Only 15% (n = 7) of affected patients required temporary suspension, and 4% (n = 2) required discontinuation. The majority were managed with potent topical steroids, with oral corticosteroids being required in 3 patients, and one patient required hydroxychloroquine.\n\n\nCONCLUSIONS\nOur study describes both the spectrum of cutaneous AE of palbociclib and endocrine therapy, and approaches to management. Prompt management may limit the negative impact on patients, facilitating beneficial continuation of palbociclib and endocrine therapy.",
"affiliations": "Dermatology Department, Skin Unit, The Royal Marsden NHS Foundation Trust, Fulham Road, London, SW3 6JJ, UK.;Dermatology Department, Skin Unit, The Royal Marsden NHS Foundation Trust, Fulham Road, London, SW3 6JJ, UK.;Dermatology Department, Skin Unit, The Royal Marsden NHS Foundation Trust, Fulham Road, London, SW3 6JJ, UK.;Breast Unit, The Royal Marsden NHS FoundationTrust, Fulham Road, London, SW3 6JJ, UK.;Breast Unit, The Royal Marsden NHS FoundationTrust, Fulham Road, London, SW3 6JJ, UK.;Dermatology Department, Skin Unit, The Royal Marsden NHS Foundation Trust, Fulham Road, London, SW3 6JJ, UK. Kara.Heelan@rmh.nhs.uk.",
"authors": "Chawla|Sumir|S|http://orcid.org/0000-0002-3661-785X;Hill|Alison|A|;Fearfield|Louise|L|;Johnston|Stephen|S|;Parton|Marina|M|;Heelan|Kara|K|",
"chemical_list": "D010879:Piperazines; D011725:Pyridines; D018719:Receptor, ErbB-2; C495900:CDK4 protein, human; D051358:Cyclin-Dependent Kinase 4; C500026:palbociclib",
"country": "Netherlands",
"delete": false,
"doi": "10.1007/s10549-021-06169-9",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0167-6806",
"issue": "188(2)",
"journal": "Breast cancer research and treatment",
"keywords": "Drug reaction; Fulvestrant; Letrozole; Palbociclib; Skin rash",
"medline_ta": "Breast Cancer Res Treat",
"mesh_terms": "D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D001943:Breast Neoplasms; D051358:Cyclin-Dependent Kinase 4; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D010879:Piperazines; D011725:Pyridines; D018719:Receptor, ErbB-2; D012189:Retrospective Studies",
"nlm_unique_id": "8111104",
"other_id": null,
"pages": "535-545",
"pmc": null,
"pmid": "33683521",
"pubdate": "2021-07",
"publication_types": "D016428:Journal Article",
"references": "27067347;24002156;31724158;32222999;10212823;18381791",
"title": "Cutaneous toxicities occurring during palbociclib (CDK4/6 inhibitor) and endocrine therapy in patients with advanced breast cancer: a single-centre experience.",
"title_normalized": "cutaneous toxicities occurring during palbociclib cdk4 6 inhibitor and endocrine therapy in patients with advanced breast cancer a single centre experience"
} | [
{
"companynumb": "GB-TEVA-2021-GB-1949986",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "LETROZOLE"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nOral delayed-release dimethyl fumarate (DMF) is not recommended during pregnancy and should only be used if the potential benefit justifies the potential fetal risk. Although DMF was well tolerated in clinical trials with consistent safety results in postmarketing surveillance, data are limited in pregnant women. The objective was to provide pregnancy outcomes and DMF exposure information from an interim analysis from a prospective, international registry (TecGistry; NCT01911767).\n\n\nMETHODS\nWomen exposed to DMF from the first day of their last menstrual period before conception or during pregnancy were evaluated. Data were obtained at enrollment; 6-7 months' gestation; 4 weeks after estimated due date; and 4, 12, and 52 weeks after birth. Outcomes included live births, gestational size, pregnancy loss, birth defects, and infant or maternal death after delivery. Outcomes were analyzed cumulatively from October 30, 2013 (the start of TecGistry), to April 8, 2020.\n\n\nRESULTS\nOf 345 enrolled patients, median (range) age was 32 (20-43) years. The mean (SD) duration of gestational weeks of DMF exposure was 4.9 (3.8). Most infants were full-term at birth (n = 249/274; 91%) and of average gestational size (n = 190/232; 82%). Of 351 outcomes, 277 were live births; 17 (5%) spontaneous abortions (95% confidence interval [CI] 2.6%-7.1%), including 1 (<1%) molar and 1 (<1%) ectopic pregnancy, were reported. There were 8 (2.9% [95% CI 1.3%-5.6%]) adjudicator-confirmed birth defects among the 277 live births.\n\n\nCONCLUSIONS\nInterim results from this large registry indicate that early DMF exposure was not significantly associated with adverse pregnancy outcomes. Outcomes are consistent with previous smaller reports and with the general population.\nTecGistry; clinical trial registration number: NCT01911767.",
"affiliations": "From the Katholisches Klinikum Bochum (K.H.), Ruhr University, Germany; Manchester Centre for Clinical Neurosciences (D.R.), Salford Royal NHS Foundation Trust, United Kingdom; Department of Neurology (C.M.), St. Vincent's University Hospital & University College, Dublin, Ireland; Partners MS Center (M.K.H.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA; Adult Neurology Clinic (D.R.B.), Charlottesville, VA; and Biogen (O.M., F.B., X.P., N.J.E.), Cambridge, MA.;From the Katholisches Klinikum Bochum (K.H.), Ruhr University, Germany; Manchester Centre for Clinical Neurosciences (D.R.), Salford Royal NHS Foundation Trust, United Kingdom; Department of Neurology (C.M.), St. Vincent's University Hospital & University College, Dublin, Ireland; Partners MS Center (M.K.H.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA; Adult Neurology Clinic (D.R.B.), Charlottesville, VA; and Biogen (O.M., F.B., X.P., N.J.E.), Cambridge, MA.;From the Katholisches Klinikum Bochum (K.H.), Ruhr University, Germany; Manchester Centre for Clinical Neurosciences (D.R.), Salford Royal NHS Foundation Trust, United Kingdom; Department of Neurology (C.M.), St. Vincent's University Hospital & University College, Dublin, Ireland; Partners MS Center (M.K.H.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA; Adult Neurology Clinic (D.R.B.), Charlottesville, VA; and Biogen (O.M., F.B., X.P., N.J.E.), Cambridge, MA.;From the Katholisches Klinikum Bochum (K.H.), Ruhr University, Germany; Manchester Centre for Clinical Neurosciences (D.R.), Salford Royal NHS Foundation Trust, United Kingdom; Department of Neurology (C.M.), St. Vincent's University Hospital & University College, Dublin, Ireland; Partners MS Center (M.K.H.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA; Adult Neurology Clinic (D.R.B.), Charlottesville, VA; and Biogen (O.M., F.B., X.P., N.J.E.), Cambridge, MA.;From the Katholisches Klinikum Bochum (K.H.), Ruhr University, Germany; Manchester Centre for Clinical Neurosciences (D.R.), Salford Royal NHS Foundation Trust, United Kingdom; Department of Neurology (C.M.), St. Vincent's University Hospital & University College, Dublin, Ireland; Partners MS Center (M.K.H.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA; Adult Neurology Clinic (D.R.B.), Charlottesville, VA; and Biogen (O.M., F.B., X.P., N.J.E.), Cambridge, MA.;From the Katholisches Klinikum Bochum (K.H.), Ruhr University, Germany; Manchester Centre for Clinical Neurosciences (D.R.), Salford Royal NHS Foundation Trust, United Kingdom; Department of Neurology (C.M.), St. Vincent's University Hospital & University College, Dublin, Ireland; Partners MS Center (M.K.H.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA; Adult Neurology Clinic (D.R.B.), Charlottesville, VA; and Biogen (O.M., F.B., X.P., N.J.E.), Cambridge, MA.;From the Katholisches Klinikum Bochum (K.H.), Ruhr University, Germany; Manchester Centre for Clinical Neurosciences (D.R.), Salford Royal NHS Foundation Trust, United Kingdom; Department of Neurology (C.M.), St. Vincent's University Hospital & University College, Dublin, Ireland; Partners MS Center (M.K.H.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA; Adult Neurology Clinic (D.R.B.), Charlottesville, VA; and Biogen (O.M., F.B., X.P., N.J.E.), Cambridge, MA.;From the Katholisches Klinikum Bochum (K.H.), Ruhr University, Germany; Manchester Centre for Clinical Neurosciences (D.R.), Salford Royal NHS Foundation Trust, United Kingdom; Department of Neurology (C.M.), St. Vincent's University Hospital & University College, Dublin, Ireland; Partners MS Center (M.K.H.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA; Adult Neurology Clinic (D.R.B.), Charlottesville, VA; and Biogen (O.M., F.B., X.P., N.J.E.), Cambridge, MA.;From the Katholisches Klinikum Bochum (K.H.), Ruhr University, Germany; Manchester Centre for Clinical Neurosciences (D.R.), Salford Royal NHS Foundation Trust, United Kingdom; Department of Neurology (C.M.), St. Vincent's University Hospital & University College, Dublin, Ireland; Partners MS Center (M.K.H.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA; Adult Neurology Clinic (D.R.B.), Charlottesville, VA; and Biogen (O.M., F.B., X.P., N.J.E.), Cambridge, MA. nicholas.everage@biogen.com.",
"authors": "Hellwig|Kerstin|K|http://orcid.org/0000-0003-4467-9011;Rog|David|D|http://orcid.org/0000-0002-7262-4248;McGuigan|Christopher|C|;Houtchens|Maria K|MK|http://orcid.org/0000-0001-6077-0654;Bruen|Denise R|DR|;Mokliatchouk|Oksana|O|;Branco|Filipe|F|;Peng|Xiaomei|X|http://orcid.org/0000-0002-4488-9628;Everage|Nicholas J|NJ|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1212/NXI.0000000000001114",
"fulltext": "\n==== Front\nNeurol Neuroimmunol Neuroinflamm\nNeurol Neuroimmunol Neuroinflamm\nnnn\nNEURIMMINFL\nNeurology® Neuroimmunology & Neuroinflammation\n2332-7812\nLippincott Williams & Wilkins Hagerstown, MD\n\nNEURIMMINFL2021038953\n10.1212/NXI.0000000000001114\n3\n40\n41\n307\nArticle\nInterim Analysis of Pregnancy Outcomes After Exposure to Dimethyl Fumarate in a Prospective International Registry\nhttp://orcid.org/0000-0003-4467-9011\nHellwig Kerstin MD zirkuszelt@hotmail.com\n\nhttp://orcid.org/0000-0002-7262-4248\nRog David MD djrdjr@doctors.org.uk\n\nMcGuigan Christopher MD c.mcguigan@svhg.ie\n\nhttp://orcid.org/0000-0001-6077-0654\nHoutchens Maria K. MD mhoutchens@bwh.harvard.edu\n\nBruen Denise R. NP, RN dpr3c@virginia.edu\n\nMokliatchouk Oksana PhD oksana.mokliatchouk@biogen.com\n\nBranco Filipe MS filipe.branco@biogen.com\n\nhttp://orcid.org/0000-0002-4488-9628\nPeng Xiaomei PhD *xiaomeip@gmail.com\n\nEverage Nicholas J. PhD nicholas.everage@biogen.com\n\nFrom the Katholisches Klinikum Bochum (K.H.), Ruhr University, Germany; Manchester Centre for Clinical Neurosciences (D.R.), Salford Royal NHS Foundation Trust, United Kingdom; Department of Neurology (C.M.), St. Vincent's University Hospital & University College, Dublin, Ireland; Partners MS Center (M.K.H.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA; Adult Neurology Clinic (D.R.B.), Charlottesville, VA; and Biogen (O.M., F.B., X.P., N.J.E.), Cambridge, MA.\nCorrespondence Dr. Everage nicholas.everage@biogen.com\nGo to Neurology.org/NN for full disclosures. Funding information is provided at the end of the article.\n\n*Dr. Peng was an employee at Biogen at the time the research was conducted.\n\nThe Article Processing Charge was funded by Biogen.\n\n1 2022\n23 11 2021\n23 11 2021\n9 1 e111430 3 2021\n14 10 2021\nCopyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.\n2021\nAmerican Academy of Neurology\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.\n\nBackground and Objectives\n\nOral delayed-release dimethyl fumarate (DMF) is not recommended during pregnancy and should only be used if the potential benefit justifies the potential fetal risk. Although DMF was well tolerated in clinical trials with consistent safety results in postmarketing surveillance, data are limited in pregnant women. The objective was to provide pregnancy outcomes and DMF exposure information from an interim analysis from a prospective, international registry (TecGistry; NCT01911767).\n\nMethods\n\nWomen exposed to DMF from the first day of their last menstrual period before conception or during pregnancy were evaluated. Data were obtained at enrollment; 6−7 months' gestation; 4 weeks after estimated due date; and 4, 12, and 52 weeks after birth. Outcomes included live births, gestational size, pregnancy loss, birth defects, and infant or maternal death after delivery. Outcomes were analyzed cumulatively from October 30, 2013 (the start of TecGistry), to April 8, 2020.\n\nResults\n\nOf 345 enrolled patients, median (range) age was 32 (20–43) years. The mean (SD) duration of gestational weeks of DMF exposure was 4.9 (3.8). Most infants were full-term at birth (n = 249/274; 91%) and of average gestational size (n = 190/232; 82%). Of 351 outcomes, 277 were live births; 17 (5%) spontaneous abortions (95% confidence interval [CI] 2.6%–7.1%), including 1 (<1%) molar and 1 (<1%) ectopic pregnancy, were reported. There were 8 (2.9% [95% CI 1.3%–5.6%]) adjudicator-confirmed birth defects among the 277 live births.\n\nDiscussion\n\nInterim results from this large registry indicate that early DMF exposure was not significantly associated with adverse pregnancy outcomes. Outcomes are consistent with previous smaller reports and with the general population.\n\nTrial Registration Information\n\nTecGistry; clinical trial registration number: NCT01911767.\n\nOPEN-ACCESSTRUE\n==== Body\npmcThe global prevalence of multiple sclerosis (MS) is 2 and up to 4 times higher in women than in men1; a large proportion of women with MS are of childbearing age.1,2 Delayed-release dimethyl fumarate (DMF) is recommended for the treatment of relapsing-remitting MS, but DMF is not recommended during pregnancy. DMF should be used only if clearly needed and if the potential benefit justifies the potential risk to the fetus.3 As of June 30, 2021, >535,000 patients have been treated with DMF, representing >1,100,000 patient-years of exposure. No risk of fetal abnormalities or adverse pregnancy outcomes has been observed in relation to DMF exposure in clinical trials, which have shown 97 of 142 (68%) live births, 16 of 142 (11%) spontaneous abortions, 24 of 142 (17%) elective terminations, and 5 of 142 (4%) preterm births (Biogen, Periodic Safety Update Report, May 24, 2018). Nonetheless, additional data are needed from the postmarketing setting.4\n\nThere is no known adverse association or mechanism of action related to DMF with pregnancy outcomes. However, a large proportion of women diagnosed with MS are of childbearing age. Therefore, a global registry was established to evaluate whether DMF exposure may affect pregnancy and infant outcomes. Study coordinating centers in 8 countries are enrolling DMF-exposed pregnant women into an ongoing, prospective, observational, international registry (TecGistry; NCT01911767) to assess pregnancy and infant outcomes. We report results from an interim analysis of the registry as of April 8, 2020.\n\nMethods\n\nParticipants included pregnant women with MS exposed to DMF since the first day of their last menstrual period before conception or during pregnancy. Women were excluded if diagnosed with abnormalities in prenatal testing or the pregnancy outcome was known at enrollment. Specifically, the evidence of abnormalities found in an ultrasound, amniocentesis, or maternal serum alpha-fetoprotein/serum would exclude the patients. In addition, the following specific infectious diseases would exclude patients: rubella (by titer), toxoplasmosis (by screening), venereal disease research laboratory (rapid plasma screen), hepatitis B (by screening), or triple screen. Otherwise, patients were included and any other potential confounders or causes of abnormalities would be handled analytically. The number of pregnancy outcomes needed to detect a prevalence risk ratio of 2.9 with 80% power was 300. Evaluations consisted of live births (premature birth [<37 weeks] and full-term birth); pregnancy loss (elective or therapeutic pregnancy terminations, spontaneous abortions, and fetal death, including still birth); ectopic and molar pregnancies, birth defects, or congenital anomalies (including minor anomalies) occurring at age ≤52 weeks; any infant death occurring at age ≤52 weeks; and any maternal death occurring ≤12 weeks after delivery. Data were collected at enrollment; 6–7 months of gestation; 4 weeks after estimated delivery date; and 4, 12, and 52 weeks after birth. No information on breastfeeding with DMF or associated outcomes were collected. Outcomes were analyzed cumulatively from October 30, 2013 (the start of TecGistry), to April 8, 2020. The methods used to increase enrollment included increasing the number of coordinating centers, ensuring internal follow-up on pharmacovigilance reports as permitted by local legislation, and improving digital and social outreach to generate greater awareness of the registry in accordance with local guidance and laws.\n\nPotential birth defects were adjudicated by an external teratology expert and classified according to both the Metropolitan Atlanta Congenital Defects Program and/or the European network for the surveillance of congenital anomalies schemas. Gestational size was classified based on the World Health Organization or country-specific growth charts as small (birth weights <2,500 g), appropriate (birth weights 2,500–4,000 g), or large (birth weights >4,000 g). Percentages associated with gestational age and size were based on births with available data. This interim analysis was descriptive in nature. The prevalence of birth defects and 95% confidence intervals (CIs) for the registry population were calculated for this interim analysis. The Clopper-Pearson exact CIs were implemented.\n\nStandard Protocol Approvals, Registrations, and Patient Consents\n\nParticipating physicians obtained centralized and/or local ethics committee approval of the protocol, informed consent form, and other required study documents before starting the study. The study was conducted in accordance with the International Conference on Harmonisation and Good Pharmacovigilance Practices guidelines. In accordance with the Declaration of Helsinki, strict respect was given to the patients' privacy; physical, mental, and social integrity; and confidentiality of personal information.\n\nPatient consent (written or verbal per local regulations) was obtained by the reporting healthcare provider, investigator, or coordinating center (if permitted by local regulations) before the patient's enrollment in the registry. If the patient was a minor, written consent was obtained from the parent or legal guardian. A release of medical information was obtained from the patient to permit the coordinating center or reporting healthcare provider to contact healthcare providers related to the pregnancy (e.g., the patient's obstetric health care provider). A release of medical information was also obtained by the enrolling healthcare provider from the parent or the infant's personal representative so that the coordinating center or reporting healthcare provider could contact the pediatric healthcare provider.\n\nData Availability\n\nThis trial is registered on ClinicalTrials.gov (NCT01911767). The data sets generated during this study are available on request through the Biogen Data Request Portal (biogenclinicaldatarequest.com).\n\nResults\n\nOf 345 enrolled patients in this pregnancy registry, there were 351 known or anticipated outcomes (Figure): 243 from Germany, 65 from the United States, 16 from the United Kingdom, 9 from Italy, 8 from Australia, and 2 each from Canada and Ireland. Mean (SD) gestational week of enrollment was 11.9 (8.1). Earliest DMF exposure occurred in the first (>99%; 341/342) and second (<1%; 1/342) trimesters in the 342 women with a known exposure date (Table 1). Of 351 observed or expected pregnancy outcomes, 17 (5%) spontaneous abortions, including 1 ectopic and 1 molar pregnancy, were reported (Table 2). One neonatal death was reported, and no maternal or perinatal deaths were reported.\n\nFigure Patient Disposition\n\na Some pregnancies resulted in multiple (twin) births. b Known or anticipated outcomes; missing patients may have known pregnancy outcomes but further follow-up is in progress or not yet complete. c Percentages based on births with available birth status n = 296 because 1 patient had missing data.\n\nTable 1 Patient Characteristics at the Time of Enrollment and DMF Exposure\n\nTable 2 Incidences of Pregnancy and Infant Outcomes\n\nThe median (range) duration of gestational DMF exposure was 5 weeks (0–40), and more than 99% of pregnancies were only exposed to disease-modifying therapy in the first trimester (Table 1). There were 277 live births; of these, 7 were from 4 sets of twin pregnancies. Of live births with known results, most infants were full-term at birth (n = 249/274; 91%) and 25 (9%) were premature. Of the 232 infants with neonatal weight data, 26 (11%) were classified as small, 190 (82%) as appropriate, and 16 (7%) as large. Of 277 live births, there were 8 (2.9% [95% Clopper-Pearson exact CI 1.3%–5.6%]) confirmed birth defects (Table 2). Eighty-six percent (232/271) of women indicated they breastfed their infants at any time after birth.\n\nDiscussion\n\nInterim results from this large, international registry indicate that DMF exposure in the first trimester was not significantly associated with adverse pregnancy outcomes. The proportion of spontaneous abortions is less than that reported in MS clinical trials (8%)4 and in the general US population (12%–16%).5 Compared with the 3% of birth defects reported in the registry, birth defects are detected in 4% of people with MS6 and in 2%–5% of the general population.7 The prevalence of ventricular septal defect is estimated to range from 192 to 1,045 per 100,000 live births,8-10 whereas the prevalence in this registry was 722 per 100,000 live births.\n\nMost women indicated they breastfed their infants. Very low excretion of DMF in breast milk has been demonstrated by 2 recent case reports.11 This is currently under investigation.\n\nThere are several limitations to this analysis. At the time of this data cut and analysis, 300 pregnancy outcomes (the targeted number of patients needed to detect a prevalence risk ratio of 2.9 with 80% power, assuming an expected prevalence of birth defects of 2.2%) had not been observed, limiting the potential to draw final conclusions. Subsequent enrollment and follow-up of pregnancies will enable more detailed and robust analyses. Most exposure occurred in the first trimester with only a single pregnant woman and fetus exposed in the second trimester, suggesting minimal exposure to DMF during pregnancy and in utero in this registry. Thus, limited conclusions can be made about long-term DMF exposure during pregnancy or in utero. The results are also limited by the potential for underestimation of spontaneous abortions. Although TecGistry is an international registry, 70% of participants are from Germany, thus potentially limiting the transferability of these results to other countries.\n\nInterim results from this large, international registry indicate that DMF exposure in the first trimester was not significantly associated with adverse pregnancy outcomes. The outcomes are consistent with previous reports of smaller groups of patients.4,5 Ongoing recruitment to this registry will allow the publication of outcomes up to 1 year of age and provide essential information on pregnancy outcomes among women exposed to DMF during pregnancy.\n\nAcknowledgment\n\nThis study was sponsored by Biogen (Cambridge, MA). Cynthia C. Jones of Biogen (Cambridge, MA) was an integral part of the registry team and provided initial analysis and interpretation of the interim registry results. Gabrielle Knafler, PhD, and Karen Spach, PhD, of Excel Scientific Solutions (Fairfield, CT) provided initial editing support based on a draft from authors and incorporated author comments during revisions, and Nathaniel Hoover from Excel Scientific Solutions copyedited and styled the manuscript per journal requirements.\n\nStudy Funding\n\nThis study was sponsored by Biogen (Cambridge, MA). Funding for writing and editorial support was provided by Biogen.\n\nDisclosure\n\nK. Hellwig reports scientific advisory boards for Bayer, Biogen, Merck, Novartis, Roche, Sanofi, and Teva; speaker honoraria and research support from Bayer, Biogen, Genzyme, Merck, Novartis, Sanofi, and Teva; and support for congress participation from Bayer, Biogen, Genzyme, Merck, Roche, and Teva. D. Rog reports consulting fees from Biogen, Bristol Myers Squibb, Celgene, Hikma, MedDay, Merck Serono, Novartis, Roche, Sanofi, and Teva Neuroscience; research support from Actelion, Biogen, Merck Serono, Novartis, Sanofi, Teva Neuroscience, and TG Therapeutics; and speaker fees from Biogen, Merck Serono, Novartis, Roche, Sanofi, and Teva Neuroscience. C. McGuigan reports honoraria for consultancy work and/or research funding from Actelion, Biogen, Merck, Novartis, Roche, Sandoz, and Sanofi-Genzyme. M.K. Houtchens reports scientific advisory boards for Biogen, Merck, Novartis, Roche, Sanofi, and Teva and research support from Biogen, Genzyme, Merck, and Sanofi. D.R. Bruen reports scientific advisory boards for Biogen, Celgene, EMD Serono, Genentech, Novartis, and Sanofi-Genzyme. O. Mokliatchouk, F. Branco, X. Peng, and N.J. Everage are employees of and hold stock/stock options in Biogen. Go to Neurology.org/NN for full disclosures.\n\nAppendix Authors\n\nGlossary\n\nDMF dimethyl fumarate\n\nCI confidence interval\n\nMS multiple sclerosis\n==== Refs\nReferences\n\n1. Walton C, King R, Rechtman L, et al. Rising prevalence of multiple sclerosis worldwide: insights from the Atlas of MS. Mult Scler. 2020;26 (14 ):1816-1821.33174475\n2. Wallin MT, Culpepper WJ, Campbell JD, et al . The prevalence of MS in the United States: a population-based estimate using health claims data. Neurology. 2019;92 (10 ):e1029-e1040.30770430\n3. European Medicines Agency. Annex I Summary of Product Characterisitcs [online]. Accessed 26 March, 2021. ema.europa.eu/en/medicines/human/EPAR/tecfidera#product-information-section\n4. Gold R, Phillips JT, Havrdova E, et al . Delayed-release dimethyl fumarate and pregnancy: preclinical studies and pregnancy outcomes from clinical trials and postmarketing experience. Neurol Ther. 2015;4 (2 ):93-104.26662361\n5. Lang K, Nuevo-Chiquero A. Trends in self-reported spontaneous abortions: 1970-2000. Demography. 2012;49 (3 ):989-1009.22718315\n6. Ramagopalan SV, Guimond C, Criscuoli M, et al . Congenital abnormalities and multiple sclerosis. BMC Neurol. 2010;10 :115.21080921\n7. Centers for Disease Control and Prevention (CDC). Update on overall prevalence of major birth defects—Atlanta, Georgia, 1978-2005. MMWR Morb Mortal Wkly Rep. 2008;57 (1 ):1-5.18185492\n8. Cresti A, García-Fernández MA, De Sensi F, et al . Prevalence of auricular thrombosis before atrial flutter cardioversion: a 17-year transoesophageal echocardiographic study. Europace. 2016;18 (3 ):450-456.26017468\n9. EUROCAT. Key Public Health Indicators [online]. Accessed July 25, 2020. eu-rd-platform.jrc.ec.europa.eu/eurocat/eurocat-data/key-public-health-indicators\n10. Su XJ, Yuan W, Huang GY, Olsen J, Li J. Paternal age and offspring congenital heart defects: a national cohort study. PLoS One. 2015;10 (3 ):e0121030.25806788\n11. Ciplea AI, Datta P, Rewers-Felkins K, et al . Dimethyl fumarate transfer into human milk. Ther Adv Neurol Disord. 2020;13 :1756286420968414.33193814\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2332-7812",
"issue": "9(1)",
"journal": "Neurology(R) neuroimmunology & neuroinflammation",
"keywords": null,
"medline_ta": "Neurol Neuroimmunol Neuroinflamm",
"mesh_terms": null,
"nlm_unique_id": "101636388",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34815321",
"pubdate": "2022-01",
"publication_types": "D016428:Journal Article",
"references": "25806788;26662361;22718315;26017468;30770430;33193814;21080921;33174475;18185492",
"title": "Interim Analysis of Pregnancy Outcomes After Exposure to Dimethyl Fumarate in a Prospective International Registry.",
"title_normalized": "interim analysis of pregnancy outcomes after exposure to dimethyl fumarate in a prospective international registry"
} | [
{
"companynumb": "DE-ALKEM LABORATORIES LIMITED-DE-ALKEM-2021-07439",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "DIMETHYL FUMARATE"
},
... |
{
"abstract": "Obstetric antiphospholipid syndrome (Obs-APS) is one of the most commonly identified causes of recurrent pregnancy loss and its accurate diagnosis is a requirement for optimal treatment. Some patients do not fulfill the revised Sapporo classification criteria, the original APS classification criteria, and are considered to be non-criteria Obs-APS. In these patients with non-criteria, there is controversy about their inclusion within the spectrum of APS and eventually their treatment as having Obs-APS. A subset of patients may also have clinical characteristics of Obs-APS even though lupus anticoagulant (LA), anticardiolipin antibodies, and anti-β2-glycoprotein I (aβ2GPI) antibodies are consistently negative. These patients are recognized as seronegative Obs-APS. We reviewed evidence of non-criteria Obs-APS and discuss a case of a woman with a diagnosis of active systemic lupus erythematosus (SLE) and non-criteria Obs-APS with four consecutive pregnancy losses. After an accurate diagnosis the patient received prenatal counseling and benefited from the optimal treatment of Obs-APS that led to a successful pregnancy. The applicability of this successful experience about outcomes in women with non-criteria, or seronegative, Obs-APS is also evaluated.",
"affiliations": "Direction of Education and Research, Hospital de Especialidades Centro Médico La Raza, IMSS, Mexico City, Mexico.;Clinical Research Unit, Hospital de Especialidades Centro Médico La Raza, IMSS, Mexico City, Mexico.;Gynecology and Obstetrics Department, Hospital de Especialidades Centro Médico La Raza, IMSS, Mexico City, Mexico.;Faculty of Medicine, Universidad de Sonora, Sonora, Mexico.;Rheumatology Department, Instituto Nacional de Rehabilitación (INR), Mexico City, Mexico.;Rheumatology Department, Hospital de Especialidades Centro Médico La Raza, IMSS, Mexico City, Mexico.",
"authors": "Jara|Luis J|LJ|;Medina|Gabriela|G|;Cruz-Cruz|Polita|P|;Olivares-Rivera|Javier|J|;Duarte-Salazar|Carolina|C|;Saavedra|Miguel A|MA|",
"chemical_list": "D017153:Antibodies, Anticardiolipin; D017152:Antibodies, Antiphospholipid; D016682:Lupus Coagulation Inhibitor; D053482:beta 2-Glycoprotein I",
"country": "Israel",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": null,
"issue": "19(6)",
"journal": "The Israel Medical Association journal : IMAJ",
"keywords": null,
"medline_ta": "Isr Med Assoc J",
"mesh_terms": "D000026:Abortion, Habitual; D017153:Antibodies, Anticardiolipin; D017152:Antibodies, Antiphospholipid; D016736:Antiphospholipid Syndrome; D005260:Female; D006801:Humans; D016682:Lupus Coagulation Inhibitor; D008180:Lupus Erythematosus, Systemic; D011247:Pregnancy; D053482:beta 2-Glycoprotein I",
"nlm_unique_id": "100930740",
"other_id": null,
"pages": "382-386",
"pmc": null,
"pmid": "28647939",
"pubdate": "2017-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Non-Criteria or Seronegative Obstetric Antiphospholipid Syndrome?",
"title_normalized": "non criteria or seronegative obstetric antiphospholipid syndrome"
} | [
{
"companynumb": "MX-BAYER-2017-133952",
"fulfillexpeditecriteria": "1",
"occurcountry": "MX",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "NADROPARIN"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nLung tumors are very heterogeneous histological entities. Pulmonary sarcomatoid carcinoma is a subset of tumors characterized by specific histological features. Their poor prognosis compared to other lung tumors is due to limited responses to different types of chemotherapy.\n\n\nMETHODS\nWE REPORT TWO PATIENTS WITH SARCOMATOID TUMORS: A 53-year-old woman and a 46-year-old man who presented respiratory symptoms: Dyspnea, cough, associated with a deterioration of general condition.\n\n\nCONCLUSIONS\nPulmonary sarcomatoid carcinomas remained an unexplored entity, despite their poor prognosis. Based on these cases, we will discuss the histological and immunohistochemical features of these tumors, as well as report their responses to different chemotherapy regimens used in the course of treatment.",
"affiliations": "Department of Medical Oncology, National Institute of Oncology, Rabat, Morocco ; Jules Bordet Institute, Brussels, Belgium.;Department of Medical Oncology, National Institute of Oncology, Rabat, Morocco.;Department of Medical Oncology, National Institute of Oncology, Rabat, Morocco.;Department of Medical Oncology, National Institute of Oncology, Rabat, Morocco.;Department of Pathology, Hassan Loboratory, Rabat, Morocco.;Department of Medical Oncology, National Institute of Oncology, Rabat, Morocco.",
"authors": "Ouziane|Imane|I|;Boutayeb|Saber|S|;Mrabti|Hind|H|;Lalya|Issam|I|;Rimani|Mouna|M|;Errihani|Hassan|H|",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": "10.4103/1947-2714.136920",
"fulltext": "\n==== Front\nN Am J Med SciN Am J Med SciNAJMSNorth American Journal of Medical Sciences2250-15411947-2714Medknow Publications & Media Pvt Ltd India NAJMS-6-34210.4103/1947-2714.136920Case ReportSarcomatoid Carcinoma of the Lung: A Model of Resistance of Chemotherapy Ouziane Imane MD12Boutayeb Saber 1Mrabti Hind 1Lalya Issam 1Rimani Mouna 3Errihani Hassan 11 Department of Medical Oncology, National Institute of Oncology, Rabat, Morocco2 Jules Bordet Institute, Brussels, Belgium3 Department of Pathology, Hassan Loboratory, Rabat, MoroccoAddress for correspondence: Dr. Imane Ouziane, Department of Medical Oncology, Jules Bordet Institute, Free University of Brussels, Brussels, Belgium, and Department of Medical Oncology, National Institute of Oncology, Quartier Irfane, Hay Riad, Morocco. E-mail: ouzianeimane@gmail.com7 2014 6 7 342 345 Copyright: © North American Journal of Medical Sciences2014This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Context:\nLung tumors are very heterogeneous histological entities. Pulmonary sarcomatoid carcinoma is a subset of tumors characterized by specific histological features. Their poor prognosis compared to other lung tumors is due to limited responses to different types of chemotherapy.\n\nCase Report:\nWe report two patients with sarcomatoid tumors: A 53-year-old woman and a 46-year-old man who presented respiratory symptoms: Dyspnea, cough, associated with a deterioration of general condition.\n\nConclusion:\nPulmonary sarcomatoid carcinomas remained an unexplored entity, despite their poor prognosis. Based on these cases, we will discuss the histological and immunohistochemical features of these tumors, as well as report their responses to different chemotherapy regimens used in the course of treatment.\n\nChemotherapylungresponse to platinum saltssaromatoid carcinomasurgerytargeted therapy\n==== Body\nIntroduction\nSarcomatoid carcinomas of the lung are very uncommon tumors, comprising between 0.3 and 3% of all non-small lung carcinomas.[1] It is a heterogeneous group of poorly differentiated carcinomas with two cell types: sarcomatoid or sarcomatous morphology with giant and/or spindle cells.[1] Their clinical presentation is not specific; however, this type of neoplasm is very aggressive, with an overall 5-year survival rate of approximately 20%. Few studies have examined these tumors but chemoresistance appears to be responsible for their bad prognosis. To define the types of sarcomatoid carcinomas, clarify their immunohistochemical phenotype, and examine their therapeutic features, we herein describe two cases treated at the National Institute of Oncology in Rabat.\n\nCase Presentation\nCase 1\nA 53-year-old female presented in January 2010 with a cervical mass of gradually increasing volume that was associated with dyspnea and dry cough. Chest computed tomography (CT) scan revealed a cervico-mediastino-pulmonary lesional process of 120/80, 70/70, and 50 mm sheathing cervical and intrathoracic vascular axes and displacing the mediastinum. Pleural effusion was present [Figure 1]. A biopsy was performed and the histological examination revealed diffuse cellular water with large cells and hypertrophic irregular macro-nucleoli and macro-nuclei. We observed many mitoses, and the stroma was scant and fibro-inflammatory. Immunohistochemically, the tumor cells were positive for vimentin. However, they were negative for thyroid transcription factor-1 (TTF-1), epithelial membrane antigen (EMA), muscle actin (HHF35), cytokeratins 7, 20, and 5/6, PS100, actin, and calretinin. Abdominal CT scans and bone scintigraphy were normal. The tumor was classified as stage IV (T4N0M1) and the patient received the following chemotherapy-based platinum salts: navelbine (25 mg/m2 J1, J8) and cisplatin (80 mg/m2 J1). Toxicity was marked by nausea with grade II anemia. Evaluation after the third and sixth treatment regimens indicated stable disease.\n\nFigure 1 Chest CT scan showing a right cervicothoracic mass with vascular sheathing\n\nAfter 18 months with the stable disease, the patient clinically progressed with the onset of chest pain. A chest CT examination showed increased tumor volume (from 120 to 160 mm). Docetaxel (75 mg/m2) was administered as second-line therapy. The observed toxicity was predominantly hematological, with neutropenia and grade I anemia. Evaluation after the third and sixth courses showed significant clinical benefit with radiographic disease stabilization. The condition of the patient remained stable for 4 months and is currently being monitored routinely.\n\nCase 2\nIn February 2013, a 46-year-old male with a history of cigarette smoking for 20 years (30 cigarettes per day) presented with dyspnea stage II of the New York Heart Association classification, (NYHA), chest pain, and anorexia. Symptomatology evolved in a context of progressive deterioration of the general state and poor general condition. Upon physical examination, he appeared weak (stage II of WHO score), with a body temperature of 36.2°C. His lungs, heart, and abdomen were normal. Chest CT scans showed a large mass in the right lower lobe with spiculated contours that measured 110 mm. The mass was associated with latero-tracheal, anterior mediastinal, and right hilar lymphadenopathy. Further staging showed multiple lesions of the spine (D8), right sacroiliac joint, 4th right odds. However, no visceral lesion was observed after abdominal ultrasonographic examination. Using a scan-guided biopsy, histological and immunohistochemical evidences supported a sarcomatoid carcinoma, with carcinomatous proliferation of pleomorphic spindle and globoid cells [Figure 2a]. Tumor cells were positive for vimentin [Figure 2b], cytokeratin, and TTF1 [Figure 2c]. They did not express cytokeratins 7, 20, or 5/6. In addition, they did not express p63. The patient received cisplatin and navelbine, with a partial response after the third cycle (70 mm versus 110 mm). We decided to continue the same chemotherapy after the good clinical and radiological response; however, the patient presented with an acute kidney injury after the fourth cycle, with an estimated clearance of 25 ml/min according to the Cockroft-Gault formula. The decision was made to switch to carboplatin (AUC 5) and paclitaxel (175 mg/m2). Chest CT was performed again and showed the appearance of a lesion process in the right posterior of 7.5 cm, associated with two left hilar lymphadenopathies (20 mm and 26 mm, respectively). Therefore, we moved to a second-line therapy of docetaxel (75 mg/m2). The patient received 3 courses, and the period between these cycles of chemotherapy was marked by neuropathy grade I. A chest thoracic scan showed an increase in the size of the right posterior parietal lesion process, measuring 105/77, 5 mm vs. 75.5/36 mm. The process extended behind the 4th, 5th, and 6th dimensions, with invasion of the erector spinae muscles, trapezius invasion, and root canal. The mediastinal lymphadenopathy kept the same dimensions. We decided to go to the palliative care. The patient died a few days after.\n\nFigure 2 (a) H&E staining G× 200 carcinomatous proliferation of pleomorphic spindle and globoid cells (b) H&E staining G× 400: Tumor cells expressing the vimentin antibody (clone V9, IMMUNOTEC) (c) H&E staining G× 400: Tumor cells expressing the CK (clone AE1/AE3, DAKO) (+) and thyroid transcription factor-1 (TTF1) (clone 8G7G3 / 1 DAKO (flex). Nuclear staining (+)\n\nDiscussion\nSarcomatoid carcinoma is a rare tumor that comprises approximately 1% of all lung malignancies. They are more common among men than women with a gender ratio of 4/1. The mean age at diagnosis is between 65-75 years. The patients are usually heavy smokers or have a history of chronic smoking.[12] Some cases have been reported related to asbestos exposure. In a study by Fisbak, 3% patients with sarcomatoid carcinoma were exposed to asbestos. Thus, there could be a direct mechanism between toxicity and emergence of a sarcomatoid component.[23]\n\nThis tumor is frequent with the local advancement and has high rates of recurrence. However, there is no specific clinical presentation. Patients generally have several symptoms. Dyspnea and cough were the first symptoms to appear in our patients, which were followed by generally rapid physical deterioration. Other symptoms may occur including weakness, shortness of breath, and fever. For proximal tumors, hemoptysis is present in 50% of cases, whereas for peripheral tumors, chest pain is frequently described.[4] Radiologically, sarcomatoid carcinoma is usually a single lesion, with a large diameter (from 40 to 180 mm), and central or peripheral location in the upper lobes. The tumor is usually and locally advanced at the time of diagnosis with a large proportion of pleural invasion, either vascular or parietal (40-70% of cases).[13] Our patients had large tumors (160 and 110 mm, respectively) with vascular and nervous axis invasion (Case 1).\n\nIt is difficult to distinguish pulmonary sarcomatoid carcinomas from true sarcomas. They are defined in the World Health Organization classification as “poorly differentiated non-small cell lung carcinomas (NSCLCs) containing a sarcoma-like element (malignant spindle or giant cells) or sarcomatous component.[1] We can define five types of carcinomas based on specific histological criteria: Giant cell carcinoma, pleomorphic carcinoma, carcinosarcoma, spindle cell carcinoma, and pulmonary blastoma.[1]\n\nPleomorphic carcinoma is formed by malignant giant and/or spindle cells plus epithelial components, such as squamous cells. The spindle and/or giant cells appear as cohesive aggregates of the tumor cell, without glandular or squamous differentiation. The neoplastic spindle cells are isolated or in loose clusters, and are usually very polymorphic and elongated. Nucleoli are prominent, and nuclei are solitary, large, and spindled. Additionally, the nuclear-cytoplasmic ratio is high.[1] In some cases, multiple keratin antibodies and EMA are necessary to demonstrate epithelial differentiation in the sarcomatoid component. The tumor cells often co-express cytokeratin, vimentin, carcinoembryonic antigen, and smooth muscle markers. The TTF-1 may be positive in giant cell carcinomas. The differential diagnosis for pleomorphic carcinoma consists of other tumors as both primary and metastatic sarcomas.\n\nEpidermal growth factor receptor (EGFR) is a membrane of tyrosine kinase receptor that becomes oncogenic by acquiring a mutation within its catalytic domain. A study by Italiano suggested that a role for EGFR in SC. Indeed, in 22 surgically treated patients, EGFR expression was analyzed and EGFR gene mutations were observed. EGFR overexpression was found in all cases, with mutation analyses for EGFR exons 18, 19, 20, and 21 were obtained in 19 cases. No results could be obtained in three cases, but no EGFR mutations were detected.[6] Recently, Chang et al., reported results that confirm the existence of carcinomas with pleomorphic EGFR mutations in a Taiwanese population.[7] Sarcomatoid carcinomas have also evaluated for their K-ras status. Pelosi et al., reported 22% of patients had K-ras mutations at codon 12.[8]\n\nFor localized tumors, surgery remains adequate for treatment and appears to provide adequate local control.[3] However, for metastatic disease, no data are currently available and sarcomatoid carcinomas are usually treated as non-small cell lung cancer (NSCLCs).[9] Cytotoxic agents used for the treatment of sarcomatoid carcinomas are the same used as those used for NSCLCs. In the series of Vieira et al., study 97 patients with metastatic disease were included, of which 73% of them received chemotherapy-based platinum salts. The difference in progression-free survival (PFS) was not statistically significant between patients receiving or not a platinum-based chemotherapy, no statistically significant difference in overall survival was observed (7months with platinum versus 5.3 months without, P = 0.096).[5]\n\nOur two patients received platinum-based doublets for first-line therapy but their responses varied between stabilization and progression, but these elements remain insufficient to conclude that platinum salts possess an activity on this type of tumor or not. Other protocols have been used, such as CAV (cyclophosphamide, adriamycin, and vincristine), to target the epithelial and sarcomatous component. However, the objective response rates remain poor.[23] One study evaluated the short-term outcomes of using doxorubicin and ifosfamide in the treatment of metastatic sarcomatoid carcinoma. Among 15 patients, 50% showed partial responses to short-term chemotherapy with doxorubicin and ifosfamide. However, all patients experienced disease progression and died despite continuous treatment.[10] For targeted therapies, the study by Italiano showed that patients with lung sarcomatoid carcinoma did not benefit from anti-EGFR treatment.[6]\n\nConclusion\nSarcomatoid carcinoma of the lung remains poorly explored. The histological and immunohistochemical characteristics of this tumor type are specific and very different from non-small cell lung carcinoma, resulting in an aggressive entity. Conventional chemotherapy did not show satisfactory results, and future studies are needed to explore the molecular profile of these tumors in order to determine the best therapeutic approach.\n\nSource of Support: Nil.\n\nConflict of Interest: None declared.\n==== Refs\n1 Travis WD Brambilla E Müller-Hermelink K Harris C Kleihues C Sobin P Pathology and genetics of tumors of the lung, pleura, thymus, and heart World Health Organization Classification of Tumours 2004 Lyon IARC Press 53 58 http://www.iarc.fr/en/publications/pdfs-online/pat-gen/bb10/BB10 \n2 Ishida T Tateishi M Kaneko S Yano T Mitsudomi T Sugimachi K Carcinosarcoma and spindle cell carcinoma of the lung. Clinicopathologic and immunohistochemical studies J Thorac Cardiovasc Surg 1990 100 844 52 1701011 \n3 Davis MP Eagan RT Weiland LH Pairolero PC Carcinosarcoma of the lung: Mayo Clinic experience and response to chemotherapy Mayo Clin Proc 1984 59 598 603 6381913 \n4 Yoshino N Kubokura H Yamauchi S Ohaki Y Koizumi K Shimizu K A true pulmonary carcinosarcoma that required diagnostic differentiation from a pleomorphic adenoma: A case report Ann Thorac Cardiovasc Surg 2009 15 42 5 19262449 \n5 Vieira T Girard N Ung M Monnet I Cazes A Bonnette P Efficacy of first-line chemotherapy in patients with advanced lung sarcomatoid carcinoma J Thorac Oncol 2013 8 1574 7 24389441 \n6 Italiano A Cortot AB Ilie M Martel-Planche G Fabas T Pop D EGFR and K-RAS status of primary sarcomatoid carcinomas of the lung: Implications for anti-EGFR treatment of a rare lung malignancy Int J Cancer 2009 125 2479 82 19681124 \n7 Chang YL Wu CT Shih JY Lee YC EGFR and p53 status of pulmonary pleomorphic carcinoma: Implications for EGFR tyrosine kinase inhibitors therapy of an aggressive lung malignancy Ann Surg Oncol 2011 18 2952 60 21409490 \n8 Pelosi G Scarpa A Manzotti M Veronesi G Spaggiari L Fraggetta F K-ras gene mutational analysis supports a monoclonal origin of biphasic pleomorphic carcinoma of the lung Mod Pathol 2004 17 538 46 14990969 \n9 Mason RJ Broaddus VC Martin T King T Jr Schraufnagel D John F Murray and Nadel's Textbook of Respiratory Medicine Rare malignant primary pulmonary epithelial tumors 2010 5th ed Ch. 48, Part 4 Primary Pulmonary Sarcomas http://www.mdconsult.com/books/ \n10 Staddon AP Crawford EA Hartner L Lackman RD Ogilvie MC Treatment of metastatic sarcomatoid carcinoma with doxorubicin and ifosfamide J Clin Oncol 2008 26 21518\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "1947-2714",
"issue": "6(7)",
"journal": "North American journal of medical sciences",
"keywords": "Chemotherapy; lung; response to platinum salts; saromatoid carcinoma; surgery; targeted therapy",
"medline_ta": "N Am J Med Sci",
"mesh_terms": null,
"nlm_unique_id": "101521411",
"other_id": null,
"pages": "342-5",
"pmc": null,
"pmid": "25077084",
"pubdate": "2014-07",
"publication_types": "D002363:Case Reports",
"references": "19681124;1701011;21409490;24389441;6381913;19262449;14990969",
"title": "Sarcomatoid carcinoma of the lung: a model of resistance of chemotherapy.",
"title_normalized": "sarcomatoid carcinoma of the lung a model of resistance of chemotherapy"
} | [
{
"companynumb": "PHHY2014MA119831",
"fulfillexpeditecriteria": "1",
"occurcountry": "MA",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CISPLATIN"
},
"drugadditional": null,
"druga... |
{
"abstract": "Data regarding outcome and therapy of pregnancies in patients with homozygous antithrombin (AT) deficiency are very rare. We conducted a retrospective, descriptive investigation with emphasis on the obstetric history of eight women with homozygous AT deficiency heparin-binding site (HBS), who had at least one pregnancy. The aim of the study was to get a better insight into the outcome and identify suitable management procedures of pregnancy in this rare disease. All patients suffered from homozygous AT deficiency caused by the mutation c.391C>T p.Leu131Phe in the AT gene (SERPINC1). The women reported in total 23 pregnancies; one pregnancy was excluded because of induced abortion. We found that only seven out of the 22 analyzed pregnancies ended with a live infant, all of them were born preterm. Among the 15 negative outcomes, seven were early pregnancy losses and eight were intrauterine fetal deaths. We found no clear association between treatment protocols and outcome. Eight pregnancies were not treated at all; all of them ended with pregnancy loss. We conclude that homozygous AT deficiency HBS, a form of severe thrombophilia, is associated with high risk of pregnancy loss and preterm delivery. Rigorous anticoagulation and/or replacement of AT during pregnancy may improve the outcome.",
"affiliations": "Department of Medicine I, Clinical Division of Hematology and Hemostaseology, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria.;Department of Laboratory Medicine, Division of Medical and Chemical Laboratory Diagnostics, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria.;Department of Laboratory Medicine, Division of Medical and Chemical Laboratory Diagnostics, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria.;Department of Laboratory Medicine, Division of Medical and Chemical Laboratory Diagnostics, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria.;IVF- and Kinderwunschinstitut Wels, Kinderwunschklinik Wien, Hadikgasse 82, 1140 Vienna, Austria.;Department of Obstetrics and Fetomaternal Medicine, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria.;Department of Medicine I, Clinical Division of Hematology and Hemostaseology, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria. ingrid.pabinger@meduniwien.ac.at.",
"authors": "Kraft|Julia|J|;Sunder-Plassmann|Raute|R|;Mannhalter|Christine|C|;Quehenberger|Peter|P|;Tews|Gernot|G|;Langer|Martin|M|;Pabinger|Ingrid|I|",
"chemical_list": "D000925:Anticoagulants; C542513:SERPINC1 protein, human; D000990:Antithrombin III; D006493:Heparin",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00277-017-2965-2",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0939-5555",
"issue": "96(6)",
"journal": "Annals of hematology",
"keywords": "AT deficiency; Fetal loss; Pregnancy complications; Thrombophilia; Venous thromboembolism",
"medline_ta": "Ann Hematol",
"mesh_terms": "D000022:Abortion, Spontaneous; D000293:Adolescent; D000328:Adult; D000925:Anticoagulants; D000990:Antithrombin III; D001665:Binding Sites; D005260:Female; D006493:Heparin; D006720:Homozygote; D006801:Humans; D007231:Infant, Newborn; D050498:Live Birth; D009154:Mutation; D017063:Outcome Assessment, Health Care; D011247:Pregnancy; D011250:Pregnancy Complications, Hematologic; D047928:Premature Birth; D012189:Retrospective Studies; D012307:Risk Factors; D019851:Thrombophilia; D055815:Young Adult",
"nlm_unique_id": "9107334",
"other_id": null,
"pages": "1023-1031",
"pmc": null,
"pmid": "28361296",
"pubdate": "2017-06",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Women with homozygous AT deficiency type II heparin-binding site (HBS) are at high risk of pregnancy loss and pregnancy complications.",
"title_normalized": "women with homozygous at deficiency type ii heparin binding site hbs are at high risk of pregnancy loss and pregnancy complications"
} | [
{
"companynumb": "AT-MYLANLABS-2017M1037735",
"fulfillexpeditecriteria": "1",
"occurcountry": "AT",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "WARFARIN"
},
"drugadditional": null,
... |
{
"abstract": "Lymphangiomatosis (eg, generalized lymphatic anomaly) is an abnormal proliferation of lymphatic endothelial cells. It is often a childhood disease, but it may present in adulthood by infiltrating organs and cause obstruction, bleeding, or disruption of lymphatic flow. Pulmonary involvement may be mild or cause diffuse interstitial lung disease, airway obstruction, hemoptysis, chylothorax, chylopericardium, and culminate in respiratory failure. Treatment has been limited to surgical resection or drainage procedures because there is no accepted effective systemic therapy. This report presents a patient with lymphangiomatosis and life-threatening hemoptysis in whom positive immunostaining forc-KITsuggested upregulation of tyrosine kinase and whose disease was controlled with imatinib.",
"affiliations": "Department of Medicine, Division of Pulmonary and Critical Care Medicine, Joan and Sanford I. Weill Medical College of Cornell University and The New York-Presbyterian Hospital Weill Cornell Medical Center, New York, New York;Department of Pathology and Laboratory Medicine, Joan and Sanford I. Weill Medical College of Cornell University and The New York-Presbyterian Hospital Weill Cornell Medical Center, New York, New York;Department of Pathology and Laboratory Medicine, Joan and Sanford I. Weill Medical College of Cornell University and The New York-Presbyterian Hospital Weill Cornell Medical Center, New York, New York;Department of Radiology, Division of Body Imaging, Joan and Sanford I. Weill Medical College of Cornell University and The New York-Presbyterian Hospital Weill Cornell Medical Center, New York, New York;Department of Medicine, Division of Hematology and Oncology, Joan and Sanford I. Weill Medical College of Cornell University and The New York-Presbyterian Hospital Weill Cornell Medical Center, New York, New York;Department of Medicine, Division of Pulmonary and Critical Care Medicine, Joan and Sanford I. Weill Medical College of Cornell University and The New York-Presbyterian Hospital Weill Cornell Medical Center, New York, New York",
"authors": "Libby|Laura J|LJ|;Narula|Navneet|N|;Fernandes|Helen|H|;Gruden|James F|JF|;Wolf|David J|DJ|;Libby|Daniel M|DM|",
"chemical_list": "D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D000068877:Imatinib Mesylate",
"country": "United States",
"delete": false,
"doi": "10.6004/jnccn.2016.0045",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1540-1405",
"issue": "14(4)",
"journal": "Journal of the National Comprehensive Cancer Network : JNCCN",
"keywords": null,
"medline_ta": "J Natl Compr Canc Netw",
"mesh_terms": "D000970:Antineoplastic Agents; D001706:Biopsy; D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D000068877:Imatinib Mesylate; D008202:Lymphangioma; D008875:Middle Aged; D000072078:Positron Emission Tomography Computed Tomography; D047428:Protein Kinase Inhibitors; D019233:Retreatment; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome",
"nlm_unique_id": "101162515",
"other_id": null,
"pages": "383-6",
"pmc": null,
"pmid": "27059187",
"pubdate": "2016-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Imatinib Treatment of Lymphangiomatosis (Generalized Lymphatic Anomaly).",
"title_normalized": "imatinib treatment of lymphangiomatosis generalized lymphatic anomaly"
} | [
{
"companynumb": "US-BAYER-2016-097413",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "SORAFENIB"
},
"drugadditional": null,
"d... |
{
"abstract": "A 70-year-old man was referred to our hospital for right back pain. His past history included human immunodeficiency virus infection, which had been treated with atazanavir for 7 years. Abdominal and pelvic computed tomographic scan showed right hydronephrosis due to a strongly suspected right ureteral radiolucent stone. He underwent indwelling of a right ureteral stent because of obstructive pyelonephritis due to the ureteral stone. After improvement of the pyelonephritis, he underwent transurethral ureterolithotripsy for the right ureteral stone. Stone analysis showed the atazanavir stone. He has been followed up for 8 months without evidence of recurrence. Herein, we report this rare case of an atazanavir stone in Japan, which was confirmed by calculus analysis, and present a review of the literature.",
"affiliations": "The Department of Urology, Kyorin University School of Medicine.;The Department of Urology, Kyorin University School of Medicine.;The Department of Urology, Kyorin University School of Medicine.;The Department of Urology, Kyorin University School of Medicine.;The Department of Urology, Kyorin University School of Medicine.",
"authors": "Noma|Yasuhiro|Y|;Tambo|Mitsuhiro|M|;Kitamura|Junji|J|;Okegawa|Takatsugu|T|;Nutahara|Kikuo|K|",
"chemical_list": "D000069446:Atazanavir Sulfate",
"country": "Japan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0018-1994",
"issue": "62(1)",
"journal": "Hinyokika kiyo. Acta urologica Japonica",
"keywords": null,
"medline_ta": "Hinyokika Kiyo",
"mesh_terms": "D000368:Aged; D000069446:Atazanavir Sulfate; D006801:Humans; D008297:Male; D013055:Spectrophotometry, Infrared; D014057:Tomography, X-Ray Computed; D014514:Ureteral Calculi",
"nlm_unique_id": "0421145",
"other_id": null,
"pages": "29-32",
"pmc": null,
"pmid": "26932333",
"pubdate": "2016-01",
"publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article",
"references": null,
"title": "A Case of Atazanavir Urolithiasis Diagnosed by Stone Analysis.",
"title_normalized": "a case of atazanavir urolithiasis diagnosed by stone analysis"
} | [
{
"companynumb": "JP-ABBVIE-16P-087-1572551-00",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "RITONAVIR"
},
"drugadditional": null,
... |
{
"abstract": "A 12-year-old Hispanic boy with chronic atopic dermatitis and cushingoid features presented to our institution. He was being treated with an unknown quantity of oral prednisolone 15 mg/5 mL, equivalent to 70 mg/m2 /d of oral prednisone, purchased over the counter in El Salvador. Systemic corticosteroids are not recommended for chronic therapy of atopic dermatitis because of their significant adverse effects. Foreign-sourced pharmaceuticals account for almost half of the drugs consumed in the United States, which means that, to protect our patients, medical providers must inquire about and report unsafe medications deemed legal outside the United States to the Food and Drug Administration.",
"affiliations": "School of Medicine, Georgetown University, Washington, DC, USA.;School of Medicine, Georgetown University, Washington, DC, USA.;School of Medicine, Georgetown University, Washington, DC, USA.",
"authors": "O'Brien|Kathleen F|KF|http://orcid.org/0000-0002-2032-4040;DeKlotz|Cynthia Marie Carver|CMC|;Silverman|Robert A|RA|",
"chemical_list": "D005938:Glucocorticoids; D011239:Prednisolone; D011241:Prednisone",
"country": "United States",
"delete": false,
"doi": "10.1111/pde.13456",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0736-8046",
"issue": "35(3)",
"journal": "Pediatric dermatology",
"keywords": "atopic dermatitis; eczema; endocrine disorder; therapy-systemic",
"medline_ta": "Pediatr Dermatol",
"mesh_terms": "D002648:Child; D003480:Cushing Syndrome; D003876:Dermatitis, Atopic; D005938:Glucocorticoids; D006801:Humans; D008297:Male; D011239:Prednisolone; D011241:Prednisone",
"nlm_unique_id": "8406799",
"other_id": null,
"pages": "e196-e197",
"pmc": null,
"pmid": "29574945",
"pubdate": "2018-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Exogenous Cushing syndrome from an unexpected source of systemic steroids.",
"title_normalized": "exogenous cushing syndrome from an unexpected source of systemic steroids"
} | [
{
"companynumb": "US-VISTAPHARM, INC.-VER201806-000700",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "TRIAMCINOLONE"
},
"drugadditional... |
{
"abstract": "BACKGROUND\nAgranulocytosis is known to be a rare side effect of thionamides. This complication puts pregnant patients at particular risk for infections. Obstetricians caring for such patients have the difficult task of deciding between conservative or surgical management.\n\n\nMETHODS\nThe patient is a 37-year-old gravida 4 para 3 Hispanic woman at 11 weeks of gestation with recently diagnosed hyperthyroidism who presented with a neutropenic fever and ecthyma as a complication of thionamide use. She subsequently underwent a thyroidectomy and then had a spontaneous abortion on postoperative day 2.\n\n\nCONCLUSIONS\nThis patient had life-threatening thyrotoxicosis complicated by neutropenic fever and infection, likely caused by a reaction to thionamides. She quickly recovered with broad-spectrum antibiotics. She could not be restarted on methimazole or propylthiouracil as a result of agranulocytosis and thus underwent thyroidectomy.",
"affiliations": "University of Texas Southwestern Medical Center, Dallas, Texas.",
"authors": "Thomas|Saly K|SK|;Sheffield|Jeanne S|JS|;Roberts|Scott W|SW|",
"chemical_list": "D058671:Adrenergic beta-1 Receptor Antagonists; D013956:Antithyroid Agents; D001262:Atenolol; D008713:Methimazole; D011441:Propylthiouracil",
"country": "United States",
"delete": false,
"doi": "10.1097/AOG.0b013e3182864370",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0029-7844",
"issue": "122(2 Pt 2)",
"journal": "Obstetrics and gynecology",
"keywords": null,
"medline_ta": "Obstet Gynecol",
"mesh_terms": "D058671:Adrenergic beta-1 Receptor Antagonists; D000328:Adult; D013956:Antithyroid Agents; D001262:Atenolol; D003875:Drug Eruptions; D004473:Ecthyma; D005260:Female; D006801:Humans; D006980:Hyperthyroidism; D008713:Methimazole; D009503:Neutropenia; D011247:Pregnancy; D011248:Pregnancy Complications; D011441:Propylthiouracil; D013207:Staphylococcal Skin Infections; D013211:Staphylococcus aureus",
"nlm_unique_id": "0401101",
"other_id": null,
"pages": "490-492",
"pmc": null,
"pmid": "23884271",
"pubdate": "2013-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Thionamide-induced neutropenia and ecthyma in a pregnant patient with hyperthyroidism.",
"title_normalized": "thionamide induced neutropenia and ecthyma in a pregnant patient with hyperthyroidism"
} | [
{
"companynumb": "US-PFIZER INC-2013224956",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "METHIMAZOLE"
},
"drugadditional": "1",
... |
{
"abstract": "BACKGROUND\nAnti-melanoma differentiation-associated gene 5 antibody (anti-MDA5 Ab) is an autoantigen associated with dermatomyositis (DM). Anti-MDA5 Ab-positive DM patients frequently exhibit clinically amyopathic dermatomyositis (CADM), and develop rapidly progressive interstitial lung disease (RPILD). Even with early detection and potent combination immunosuppressive therapy, anti-MDA5 Ab-positive DM patients have a poor prognosis. In the present case report, we present a rare autopsy case of a patient with anti-MDA5 Ab DM with RPILD who exhibited diffuse alveolar damage (DAD) patterning in lung specimens, and extensive hemorrhages in multiple organs.\nAn 82-year-old Japanese man admitted with bacterial pneumonia was subsequently diagnosed with anti-MDA5 Ab-positive DM based on skin manifestations (mechanic's hand, ulcerated palmar papules, and flagellate erythema), myositis, interstitial pneumonia, and elevation of anti-MDA5 Ab titer.\n\n\nMETHODS\nThe patient was diagnosed with anti-MDA5 Ab DM, complicated with RPILD.\n\n\nMETHODS\nThe patient received potent immunosuppressive therapy consisting of pulse methylpredonisolone at a dose of 1000 mg for 3 days, followed by prednisolone at 60 mg/d, a 1000 mg pulse of intravenous cyclophosphamide (IVCY), and oral tacrolimus at 6 mg/d. Intravenous immunoglobulin (IVIG) at a dose of 400 mg/kg/d for 5 days was subsequently administered.\n\n\nRESULTS\nDespite triple immunosuppressive therapy and IVIG, the patients' respiratory status deteriorated, and the patient died of respiratory failure on the twelfth day after admission. An autopsy revealed pulmonary DAD and multiorgan hemorrhages, including the left iliopsoas muscle, gastric and bowl mucosa, spleen, and left adrenal gland.\n\n\nCONCLUSIONS\nMultiorgan hemorrhages may be a fatal complication in anti-MDA5 Ab DM patients.",
"affiliations": "Department of Rheumatology.;Department of Rheumatology.;Department of Pathology.;Department of Rheumatology.;Department of Rheumatology.;Department of Rheumatology.;Department of Pathology.;Department of Pathology.;Department of Rheumatology.;Department of Rheumatology.",
"authors": "Watanabe|Tsuyoshi|T|;Takizawa|Naoho|N|;Nagasaka|Toru|T|;Nakamura|Yoshihiro|Y|;Ikai|Hiroki|H|;Yamamoto|Mari|M|;Murai|Yukari|Y|;Takasugi|Koji|K|;Yokoyama-Kokuryo|Waka|W|;Fujita|Yoshiro|Y|",
"chemical_list": "D001323:Autoantibodies; D007166:Immunosuppressive Agents; D000072640:Interferon-Induced Helicase, IFIH1",
"country": "United States",
"delete": false,
"doi": "10.1097/MD.0000000000018600",
"fulltext": "\n==== Front\nMedicine (Baltimore)\nMedicine (Baltimore)\nMEDI\nMedicine\n0025-7974 1536-5964 Wolters Kluwer Health \n\n32011440\nMD-D-19-05234\n10.1097/MD.0000000000018600\n18600\n6900\nResearch Article\nClinical Case Report\nFatal and extensive multiorgan hemorrhages in anti-melanoma differentiation-associated gene 5 antibody-positive dermatomyositis\nAn autopsy case reportWatanabe Tsuyoshi MD, PhDa∗ Takizawa Naoho MDa Nagasaka Toru MD, PhDb Nakamura Yoshihiro MDa Ikai Hiroki MDa Yamamoto Mari MDa Murai Yukari MDb Takasugi Koji MDb Yokoyama-Kokuryo Waka MD, PhDa Fujita Yoshiro MDac NA. a Department of Rheumatology\nb Department of Pathology\nc Department of Nephrology, Chubu Rosai Hospital, Minato-ku, Nagoya, Aichi, Japan.\n∗ Correspondence: Tsuyoshi Watanabe, Department of Rheumatology, Chubu Rosai Hospital, 1-10-6, Komei-cho, Minato-ku, Nagoya, 455-8530, Japan (e-mail: tsuyoshiwatanaberhythm@yahoo.co.jp).\n17 1 2020 \n1 2020 \n99 3 e1860011 7 2019 8 11 2019 4 12 2019 Copyright © 2020 the Author(s). Published by Wolters Kluwer Health, Inc.2020This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0Abstract\nIntroduction:\nAnti-melanoma differentiation-associated gene 5 antibody (anti-MDA5 Ab) is an autoantigen associated with dermatomyositis (DM). Anti-MDA5 Ab-positive DM patients frequently exhibit clinically amyopathic dermatomyositis (CADM), and develop rapidly progressive interstitial lung disease (RPILD). Even with early detection and potent combination immunosuppressive therapy, anti-MDA5 Ab-positive DM patients have a poor prognosis. In the present case report, we present a rare autopsy case of a patient with anti-MDA5 Ab+ DM with RPILD who exhibited diffuse alveolar damage (DAD) patterning in lung specimens, and extensive hemorrhages in multiple organs.\n\nPatient concerns:\nAn 82-year-old Japanese man admitted with bacterial pneumonia was subsequently diagnosed with anti-MDA5 Ab-positive DM based on skin manifestations (mechanic's hand, ulcerated palmar papules, and flagellate erythema), myositis, interstitial pneumonia, and elevation of anti-MDA5 Ab titer.\n\nDiagnosis:\nThe patient was diagnosed with anti-MDA5 Ab+ DM, complicated with RPILD.\n\nInterventions:\nThe patient received potent immunosuppressive therapy consisting of pulse methylpredonisolone at a dose of 1000 mg for 3 days, followed by prednisolone at 60 mg/d, a 1000 mg pulse of intravenous cyclophosphamide (IVCY), and oral tacrolimus at 6 mg/d. Intravenous immunoglobulin (IVIG) at a dose of 400 mg/kg/d for 5 days was subsequently administered.\n\nOutcomes:\nDespite triple immunosuppressive therapy and IVIG, the patients’ respiratory status deteriorated, and the patient died of respiratory failure on the twelfth day after admission. An autopsy revealed pulmonary DAD and multiorgan hemorrhages, including the left iliopsoas muscle, gastric and bowl mucosa, spleen, and left adrenal gland.\n\nLessons:\nMultiorgan hemorrhages may be a fatal complication in anti-MDA5 Ab+ DM patients.\n\nKeywords\nanti-MDA5 antibodydiffuse alveolar damagemultiorgan hemorrhagesrapidly progressive interstitial lung diseaseOPEN-ACCESSTRUE\n==== Body\n1 Introduction\nDermatomyositis (DM) is an autoimmune inflammatory myopathy with characteristic cutaneous involvement. Accumulating evidence suggests that several myositis-specific autoantibodies are associated with specific clinical features, such as distinctive skin lesions, muscle involvement, interstitial lung disease (ILD), underlying malignancy, and mortality. Anti-melanoma differentiation-associated gene 5 antibody (anti-MDA5 Ab) was identified as an autoantigen associated with DM in 2009.[1] Anti-MDA5 Ab-positive (+) DM patients frequently exhibit clinically amyopathic dermatomyositis (CADM) and develop rapidly progressive interstitial lung disease (RPILD). Although a strategy of early detection and potent combination immunosuppressive therapy (high-dose glucocorticoid, cyclosporine, and intravenous cyclophosphamide pulse) can improve the survival rate of anti-MDA5 Ab+ DM patients, the mortality rate remains high at 25% even with triple therapy.[2]\n\nThe causes of death in anti-MDA5 Ab+ DM patients are significantly associated with respiratory failure via RPILD,[3,4] and lung specimens at autopsy exhibit histopathological diffuse alveolar damage (DAD).[5] However, further investigation is needed to understand the pathological conditions associated with deterioration in anti-MDA5 Ab+ DM patients with RPILD. In this case report, we present a rare autopsy case of an anti-MDA5 Ab+ DM patient with RPILD who presented with DAD in his autopsy lung specimen, and extensive hemorrhages in multiple organs.\n\n2 Case report\nAn 82-year-old Japanese man presented at the emergency department with 4 weeks of generalized weakness and 2 days of dyspnea. His medical history included hypertension and prostate cancer, which had been treated by radical prostatectomy 5 years earlier. He was taking losartan and amlodipine for the hypertension. An initial physical examination revealed bibasilar coarse crackles in both lungs, and scratch-like erythematous skin lesions on his back (Fig. 1A). On admission, his blood pressure, heart rate, respiratory rate, and oxygen saturation were 88/65 mmHg, 110 beats per minute, 22 breaths per minute, and 92% in ambient air, respectively. He was afebrile with a temperature of 36.3 °C. He had no signs of paralysis. Manual muscle testing revealed mild weakness of the iliopsoas and quadriceps muscles.\n\nFigure 1 Clinical image of flagellate erythema; widespread linear scratch-like lesions with erythema on the back on admission day (A). Palmar papules on palms and fingers (B).\n\nLaboratory evaluation revealed a white blood cell count (WBC) of 8900 cells/μL, hemoglobin (Hb) of 11.3 g/dL, and normal platelet counts (PLT). The level of creatine kinase (CK) was elevated at 924 U/L (normal range, 124–222 ng/mL). The levels of C-reactive protein (CRP), lactate dehydrogenase (LDH), aspartate aminotransferase, and alanine aminotransferase were elevated at 5.6 mg/dL, 682 U/L (normal range, 124–222 U/L), 305 U/L, and 180 U/L, respectively. Kidney dysfunction was also detected (creatinine [Cr] at 2.81 mg/dL, blood urea nitrogen [BUN] at 74.0 mg/dL). Chest radiography revealed multiple small pulmonary infiltrates in both lungs and additional high-resolution computed tomography (HRCT) of the chest revealed the presence of peripheral consolidation in the left lower lung base, and ground-glass opacities in all 6 lung fields (Fig. 2). Expectorated sputum was not good quality, and the sputum culture results were unremarkable; however, a pneumococcal urinary antigen test was positive. The patient was initially diagnosed as having community-acquired pneumonia and severe sepsis, and was subsequently started on fluid replacement and antibiotic treatment with ceftriaxone and azithromycin.\n\nFigure 2 Chest CT on admission showing the presence of peripheral consolidation in the left lower lung base and ground-glass opacities in lung fields (A). Ground-glass opacities exacerbated in the bilateral lung fields, without improvement of peripheral consolidation in the left lower lung base (B). Postmortem chest CT examination revealed widespread consolidations in both lung fields and dramatic loss of lung volume (C).\n\nAfter antibiotic and fluid replacement treatments, the patient's blood pressure and kidney function improved, but his symptoms of dyspnea and weakness worsened on the fourth day after admission. Physical examination revealed fine crackles at the lung base. The patient also developed slight skin thickening on the lateral side of the fingers (consistent with mechanic's hand) and ulcerated palmar papules (Fig. 1B) in addition to already-existing multiple vertical linear streaks with spotty crusting on his back (flagellate erythema). A chest HRCT scan revealed exacerbation of the ground-glass opacities in the bilateral lung fields, without improvement of peripheral consolidation in the left lower lung base (Fig. 2B). A bronchoscopy was performed to examine the possibility of an infectious cause, but no noteworthy colonies were isolated in bacterial or mycobacterial cultures from the bronchoalveolar lavage sample.\n\nBased on the clinical suspicion of acute interstitial pneumonia due to DM, high doses of methylprednisolone pulses (1 g/d for 3 days), 1000 mg of intravenous cyclophosphamide (IVCY), and oral tacrolimus (6 mg/d) were administered on the fourth day after admission (Fig. 3). The laboratory data showed the following results: white blood cell count (WBC 7400 cells/μL, Hb 14.3 g/dL, PLT 11.4 × 104/μL, LDH 728 U/L, CK 1208 U/L, CRP 5.78 mg/dL, and KL-6 1146 U/mL). The patient's ferritin level was also elevated at 1995 ng/mL (normal range, 30–300 ng/mL). Following immunological and serological testing, anti-MDA5 Ab was found to have a high titer index (>150; normal range, 0–39). Anti-aminoacyl tRNA synthetase (anti-ARS) antibody, anti-transcription intermediary factor 1-gamma (TIF1-γ) antibody, anti-Mi-2 antibody, antinuclear antibody (ANA), proteinase 3-anti-neutrophil cytoplasmic autoantibodies (PR3-ANCAs), and myeloperoxidase anti-neutrophil cytoplasmic autoantibodies (MPO-ANCAs) were all negative. The patient was eventually diagnosed as having anti-MDA5 Ab-positive DM with RPILD. The patient received intravenous immunoglobulin (IVIG) in addition to triple immunosuppressive therapy. However, his respiratory status exacerbated, and this was complicated by upper gastrointestinal bleeding without apparent coagulation abnormality on the ninth day after admission. Although the patient received intensive treatment with mechanical ventilatory support, continuous infusion of vasopressors, and continuous hemodiafiltration, he died of respiratory failure on the twelfth day after admission. The postmortem CT examination revealed widespread consolidations in both lung fields and dramatic loss of lung volume (Fig. 2C).\n\nFigure 3 Clinical course of the patient. AZM = azithromycin, CHDF = continuous hemodiafiltration, CK = creatine phosphokinase, CRP = C-reactive protein, CTRX = ceftriaxone, IVCY = intravenous cyclophosphamide, IVIG = intravenous immunoglobulin, MEPM = meropenem, mPSL = methylprednisolone, NPPV = noninvasive positive pressure ventilation, Tac = tacrolimus.\n\nAn autopsy was performed 2 hours after death. Both lungs revealed a congestive increase in weight (745 g for the left and 760 g for the right) with sporadic alveolar hemorrhages (Fig. 4A). Autopsy specimens taken from the lungs were consistent with DAD, with findings of hyaline membrane formation and fibrotic tissue covering the alveoli (Fig. 4B). A specimen taken from the right iliopsoas muscle showed intramuscular bleeding (Fig. 4C); however, a specimen from the quadriceps muscle showed no definitive presence of inflammatory cells (Fig. 4D). In addition, extensive intraparenchymal hemorrhages were observed, including the gastric and bowl mucosa, spleen (Fig. 4E and F), and left adrenal gland.\n\nFigure 4 Autopsy findings of lung specimens (A) were consistent with DAD, with findings of hyaline membrane formation, and fibrotic tissue covering the alveoli (arrowhead) (B, Hematoxylin and eosin stain, Bar 100 μm). A specimen obtained from the right iliopsoas muscle (C) showed intramuscular bleeding; however, a specimen from the quadriceps muscle showed no definitive inflammation (D, Hematoxylin and eosin stain, Bar 100 μm). In the spleen specimen (E), extensive intraparenchymal hemorrhages were observed (arrow) (F, Hematoxylin and eosin stain, Bar 2 mm).\n\n3 Discussion\nAnti-MDA5 Ab+ DM patients frequently develop RPILD. Due to the severity and rapid progression of the disease, the prognosis of anti-MDA5 Ab+ DM complicated by RPILD is poor, with a 90-day survival rate of 67% in Asia.[6] Although early diagnosis and treatment of anti-MDA5 Ab+ DM are important to improve patient outcomes, it is difficult to distinguish rapidly deteriorating abnormalities such as dyspnea, weakness, elevation of muscle enzymes, and pulmonary involvement associated with anti-MDA5 Ab+ DM from those caused by severe bacterial pneumonia.\n\nFor early recognition and treatment of anti-MDA5 Ab+ DM, careful attention should be focused on the unique cutaneous manifestations, which might reflect severe underlying vasculopathy. The characteristic cutaneous manifestations include cutaneous ulcers, alopecia, lateral digit hyperkeratosis or scaling, palmar papules, oral ulcers, and panniculitis.[7] In the present case, the patient had initially developed widespread linear, scratch-like lesions with erythema on his back, which was consistent with flagellate erythema. Although flagellate erythema represents an active disease state in only 5% of patients with DM, its prevalence in anti-MDA5 Ab+ DM patients is unknown.[8] In the initial evaluation of the patient in the current case, the linear streaks were not considered to be cutaneous lesions caused by DM. After admission, palmar papules and ulcer-like lesions were observed on the patient's hands, and consequently, the combination of those cutaneous manifestations and antibiotic therapy-refractory RPILD raised the probability of DM complicated with ILD, especially anti-MDA5 Ab+ DM.\n\nWe initiated potent immunosuppressive therapy on the fourth day after admission, before positive confirmation of anti-MDA5 Ab, and immediately after failure of antibiotic therapy and recognition of the distinctive skin manifestations of DM. This potent immunosuppressive therapy consisted of high-dose glucocorticoids, an IVCY pulse, and oral calcineurin inhibitors, and was previously shown to improve the survival rate of anti-MDA5 Ab+ DM patients.[2] However, approximately 25% of anti-MDA5 Ab+ DM patients did not survive even with triple therapy. In one study, a serum ferritin level of >1000 ng/mL before therapy, ground-glass opacities in all 6 lung fields before therapy, and worsening pulmonary infiltrates during therapy were identified as poor prognostic indicators, and patients with all 3 factors usually died despite receiving triple immunosuppressive therapy.[9]\n\nThe autopsy examination revealed acute and organized DAD, and invasion of macrophages into the alveoli. Although DAD is consistent with the clinical state called adult respiratory distress syndrome (ARDS), which can be caused by infection, malignancy, highly concentrated oxygen, shock, trauma, drugs, and radiation, there was no evidence of infection, malignancy, or other causes in this patient. In previous reports, 7 anti-MDA5 Ab+ DM patients, including the present case, were histopathologically examined by autopsy,[5,10–14] and lung specimens were consistent with DAD in 6 of the 7 cases. In the present case, distinctive extensive hemorrhages were also observed within the alveolae, iliopsoas muscle, gastric mucosa, spleen, and adrenal gland. We reviewed other known cases concerning anti-MDA5 Ab+ DM patients, and found only 2 previously published cases with organ bleeding.[9,12] In one case, the patient developed pneumomediastinum and intramuscular bleeding,[9] whereas in another case, diffuse alveolar damage and alveolar hemorrhage were observed by autopsy.[12] However, the mechanism responsible for organ hemorrhages in anti-MDA5 Ab+ DM cases was not determined in these previous studies. Multiorgan hemorrhages might be a rare but fatal complication in anti-MDA5 Ab+ DM patients, or might be an elusive complication, since hemorrhages were not detected before the autopsy in our case. The evidence of disseminated intravascular coagulation, which might cause multiorgan hemorrhages due to coagulation abnormality, was absent until the day before death. Therefore, further investigation would clarify the association between the anti-MDA5 Ab and extensive hemorrhages in multiple organs. We speculate that DAD caused by anti-MDA5 Ab+ DM was the major cause of death, and concurrent multiorgan hemorrhages may have affected the deteriorating condition of the patient.\n\nIn conclusion, anti-MDA5 Ab+ DM with RPILD is associated with poor prognosis even with the administration of early aggressive immunosuppressive agents. Multiorgan hemorrhages might be a rare but fatal complication in patients with anti-MDA5 Ab+ DM with RPILD.\n\nAcknowledgments\nThe authors would like to acknowledge the members of the Department of Rheumatology at the Chubu Rosai Hospital, Japan.\n\nAuthor contributions\nConceptualization: Tsuyoshi Watanabe.\n\nInvestigation: Tsuyoshi Watanabe.\n\nProject administration: Tsuyoshi Watanabe.\n\nSupervision: Naoho Takizawa, Toru Nagasaka, Yoshihiro Nakamura, Hiroki Ikai, Mari Yamamoto, Yukari Murai, Koji Takasugi, Waka Yokoyama-Kokuryo, Yoshiro Fujita.\n\nWriting – original draft: Tsuyoshi Watanabe.\n\nWriting – review & editing: Tsuyoshi Watanabe, Yoshiro Fujita.\n\nTsuyoshi Watanabe orcid: 0000-0002-5189-9584.\n\nAbbreviations: anti-MDA5 Ab = anti-melanoma differentiation-associated gene 5 antibody, CADM = clinically amyopathic dermatomyositis, DAD = diffuse alveolar damage, DM = dermatomyositis, IVCY = intravenous cyclophosphamide, IVIG = intravenous immunoglobulin, RPILD = rapidly progressive interstitial lung disease.\n\nHow to cite this article: Watanabe T, Takizawa N, Nagasaka T, Nakamura Y, Ikai H, Yamamoto M, Murai Y, Takasugi K, Yokoyama-Kokuryo W, Fujita Y. Fatal and extensive multiorgan hemorrhages in anti-melanoma differentiation-associated gene 5 antibody-positive dermatomyositis: An autopsy case report. Medicine. 2020;99:3(e18600).\n\nConsent for publication: The patient has provided informed consent for publication of the case. We also obtained the written consent from the patient for the publication of relevant medical data. Patient privacy was fully protected and personal information was handled such that the patient could not be identified.\n\nThe authors have no conflicts of interest to disclose.\n==== Refs\nReferences\n[1] Sato S Hoshino K Satoh T \nRNA helicase encoded by melanoma differentiation-associated gene 5 is a major autoantigen in patients with clinically amyopathic dermatomyositis: Association with rapidly progressive interstitial lung disease\n. Arthritis Rheum \n2009 ;60 :2193 –200\n.19565506 \n[2] Nakashima R Hosono Y Mimori T \nClinical significance and new detection system of autoantibodies in myositis with interstitial lung disease\n. Lupus \n2016 ;25 :925 –33\n.27252271 \n[3] Chen F Wang D Shu X \nAnti-MDA5 antibody is associated with A/SIP and decreased T cells in peripheral blood and predicts poor prognosis of ILD in Chinese patients with dermatomyositis\n. Rheumatol Int \n2012 ;32 :3909 –15\n.22198664 \n[4] Koga T Fujikawa K Horai Y \nThe diagnostic utility of anti-melanoma differentiation-associated gene 5 antibody testing for predicting the prognosis of Japanese patients with DM\n. Rheumatology (Oxford) \n2012 ;51 :1278 –84\n.22378718 \n[5] Yoshida N Kaieda S Tomozoe K \nAn autopsy case of anti-melanoma differentiation-associated gene-5 antibody-positive clinical amyopathic dermatomyositis complicated by rapidly progressive interstitial lung disease\n. Intern Med \n2016 ;55 :1653 –9\n.27301523 \n[6] Hozumi H Fujisawa T Nakashima R \nComprehensive assessment of myositis-specific autoantibodies in polymyositis/dermatomyositis-associated interstitial lung disease\n. Respir Med \n2016 ;121 :91 –9\n.27888997 \n[7] Kurtzman DJB Vleugels RA \nAnti-melanoma differentiation-associated gene 5 (MDA5) dermatomyositis: a concise review with an emphasis on distinctive clinical features\n. J Am Acad Dermatol \n2018 ;78 :776 –85\n.29229575 \n[8] Eichenfield DZ Paravar T \nZebra stripes in dermatomyositis: case report and review of flagellate erythema-associated dermatomyositis\n. J Eur Acad Dermatol Venereol \n2017 ;31 :e7 –9\n.26916367 \n[9] Kurasawa K Arai S Namiki Y \nTofacitinib for refractory interstitial lung diseases in anti-melanoma differentiation-associated 5 gene antibody-positive dermatomyositis\n. Rheumatology (Oxford) \n2018 ;57 :2114 –9\n.30060040 \n[10] Hibino M Nishiguchi S Akazawa K \nA case of rapid progressive interstitial pneumonia with dermatomyositis and atypical cutaneous lesions, characterized by the anti-CADM-140 antibody\n. Nihon Kokyuki Gakkaishi (Annals of The Japanese Respiratory Society) \n2012 ;1 :27 –34\n. [in Japanese, Abstract in English] .\n[11] Isoda K Kiboshi T Shoda T \nChylothorax in dermatomyositis complicated with interstitial pneumonia\n. Rheumatol Int \n2017 ;37 :671 –3\n.27885375 \n[12] Sato K Morozumi S Takeuchi Y \nCase of dermatomyositis with anti-CADM-140 antibody and alveolar hemorrhage\n. Rinsho Shinkeigaku \n2014 ;54 :408 –12\n. [in Japanese] .24943077 \n[13] Shimizu K Kojima J Hara H \nAn autopsy case of clinically amyopathic dermatomyositis accompanied by rapidly progressive interstitial pneumonia which was refractory to corticosteroids and immunosuppressive therapy\n. Jikei Idaishi (Tokyo Jikeikai Med J) \n2014 ;129 :11 –7\n. [in Japanese, Abstract in English] .\n[14] Yoshinoya K Kasamatsu Y Kida T \nA case of clinically pneumomediastinum in a patient with amyopathic dermatomyositis-associated interstitial lung disease\n. Shoujinkai Igakushi (Matsushita Med J) \n2012 ;51 :138 –44\n. [in Japanese] .\n\n",
"fulltext_license": "CC BY",
"issn_linking": "0025-7974",
"issue": "99(3)",
"journal": "Medicine",
"keywords": null,
"medline_ta": "Medicine (Baltimore)",
"mesh_terms": "D000369:Aged, 80 and over; D001323:Autoantibodies; D001344:Autopsy; D003882:Dermatomyositis; D006470:Hemorrhage; D006801:Humans; D007166:Immunosuppressive Agents; D000072640:Interferon-Induced Helicase, IFIH1; D008168:Lung; D008297:Male",
"nlm_unique_id": "2985248R",
"other_id": null,
"pages": "e18600",
"pmc": null,
"pmid": "32011440",
"pubdate": "2020-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "24943077;27885375;22198664;30060040;22378718;27252271;27301523;19565506;27888997;26916367;29229575",
"title": "Fatal and extensive multiorgan hemorrhages in anti-melanoma differentiation-associated gene 5 antibody-positive dermatomyositis: An autopsy case report.",
"title_normalized": "fatal and extensive multiorgan hemorrhages in anti melanoma differentiation associated gene 5 antibody positive dermatomyositis an autopsy case report"
} | [
{
"companynumb": "JP-PFIZER INC-2020068833",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "AZITHROMYCIN ANHYDROUS"
},
"drugadditional": "... |
{
"abstract": "Lacosamide, a new antiepileptic drug, acts at central nervous system level but may also affect the heart, increasing the risk of cardiac arrhythmias. Only few cases of lacosamide-induced cardiac dysrhythmia have been published. We report a case of several episodes of a life-threatening ventricular fibrillation requiring cardioversion following the first doses of lacosamide as adjunctive epilepsy treatment.",
"affiliations": null,
"authors": "Eleftheriou|Georgios|G|;Butera|Raffaella|R|;Gallo|Mariapina|M|;Giampreti|Andrea|A|;Faraoni|Lorella|L|;Contessa|Maria Gioia|MG|;Bacis|Giuseppe|G|",
"chemical_list": "D000927:Anticonvulsants; D000078334:Lacosamide",
"country": "Germany",
"delete": false,
"doi": "10.5414/CP203813",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0946-1965",
"issue": "58(12)",
"journal": "International journal of clinical pharmacology and therapeutics",
"keywords": null,
"medline_ta": "Int J Clin Pharmacol Ther",
"mesh_terms": "D000927:Anticonvulsants; D001145:Arrhythmias, Cardiac; D006801:Humans; D000078334:Lacosamide; D014693:Ventricular Fibrillation",
"nlm_unique_id": "9423309",
"other_id": null,
"pages": "736-739",
"pmc": null,
"pmid": "32831166",
"pubdate": "2020-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Lacosamide-induced recurrent ventricular fibrillation: A case report.",
"title_normalized": "lacosamide induced recurrent ventricular fibrillation a case report"
} | [
{
"companynumb": "NVSC2020IT254470",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "LACOSAMIDE"
},
"drugadditional": "1",
"druga... |
{
"abstract": "Transnasal humidified rapid-insufflation ventilatory exchange (THRIVE) is a novel airway technique that utilizes high-flow humidified nasal oxygen. It can extend apnea time and maintain oxygen saturation. Here we report the use of THRIVE in a 35-year-old man who required emergent surgical tracheostomy for a clinically relevant compromised airway secondary to acute supraglottic and glottic pathology. Intravenous sedation resulted in hypoventilation close to apnea. THRIVE maintained oxygen saturation for 40 minutes until transient desaturation developed after complete airway obstruction.",
"affiliations": "From the Department of Anaesthetics, Royal National Throat, Nose and Ear Hospital, Kings Cross, London, United Kingdom.",
"authors": "Desai|Neel|N|;Fowler|Anna|A|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1213/XAA.0000000000000589",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2325-7237",
"issue": "9(9)",
"journal": "A & A case reports",
"keywords": null,
"medline_ta": "A A Case Rep",
"mesh_terms": "D000328:Adult; D058109:Airway Management; D006801:Humans; D007040:Hypoventilation; D007327:Insufflation; D008297:Male; D009666:Nose; D014139:Tracheostomy",
"nlm_unique_id": "101637720",
"other_id": null,
"pages": "268-270",
"pmc": null,
"pmid": "28622152",
"pubdate": "2017-11-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Use of Transnasal Humidified Rapid-Insufflation Ventilatory Exchange for Emergent Surgical Tracheostomy: A Case Report.",
"title_normalized": "use of transnasal humidified rapid insufflation ventilatory exchange for emergent surgical tracheostomy a case report"
} | [
{
"companynumb": "GB-MYLANLABS-2018M1038778",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "FENTANYL"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nABCB4-gene mutations are responsible for several cholestatic diseases with a heterogeneous clinical spectrum.\n\n\nOBJECTIVE\nTo analyse phenotype/genotype relationships in ABCB4-mutations.\n\n\nMETHODS\nRetrospective characterization of adult patients with ABCB4-variations diagnosed between 2015 and 2020. Genotype-phenotype correlations were analysed and compared with previously reported data.\n\n\nRESULTS\nTwenty patients from 12 families were included. Thirteen patients presented recurrent elevated liver tests, eight fulfilled Low-Phospholipid-Associated-Cholelithiasis syndrome criteria, five had Intrahepatic Cholestasis of Pregnancy and three patients developed Drug-Induced-Liver-Injury. ABCB4 screening identified eight different mutations. Five patients were homozygotes to the variant c.504T > C. Ten patients had one mutation in heterozygote-state and five patients had two mutations in compound-heterozygosity. Portal fibrosis occurred in two patients. One of these patients presented progressive fibrosis and progression of cholestasis despite ursodeoxycholic-acid treatment, this patient also harbours a ABCB11 polymorphism.\n\n\nCONCLUSIONS\nAlthough, phenotype-genotype relationships have not been clearly defined, an early diagnosis of ABCB4-variants may have an important role in management decisions and patient outcomes. To our knowledge, we describe a not previously reported deletion (c.1181delT) in ABCB4. The c.504T > C polymorphism, although a silent mutation at the protein level, seems to be associated to different cholestatic diseases. The role of other genes variants, namely ABCB11, as co-factor for progression, needs to be clarified.",
"affiliations": "Largo do Prof. Abel Salazar, Centro Hospitalar Universitário do Porto, Praça D. Filipa de Lencastre n° 189, 2° frente, Porto 4050-189, Portugal. Electronic address: danielateixeirafalcao@gmail.com.;Largo do Prof. Abel Salazar, Centro Hospitalar Universitário do Porto, Praça D. Filipa de Lencastre n° 189, 2° frente, Porto 4050-189, Portugal.;Largo do Prof. Abel Salazar, Centro Hospitalar Universitário do Porto, Praça D. Filipa de Lencastre n° 189, 2° frente, Porto 4050-189, Portugal.",
"authors": "Falcão|Daniela|D|;Pedroto|Isabel|I|;Moreira|Teresa|T|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.dld.2021.07.003",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1590-8658",
"issue": null,
"journal": "Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver",
"keywords": "ABCB4; Idiopathic chronic cholestasis; Intrahepatic cholestasis of pregnancy; Low phospholipid-associated cholelithiasis syndrome; MDR3 protein",
"medline_ta": "Dig Liver Dis",
"mesh_terms": null,
"nlm_unique_id": "100958385",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34376370",
"pubdate": "2021-08-08",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "The wide phenotypic and genetic spectrum of ABCB4 gene deficiency: A case series.",
"title_normalized": "the wide phenotypic and genetic spectrum of abcb4 gene deficiency a case series"
} | [
{
"companynumb": "PT-ORGANON-O2204PRT001683",
"fulfillexpeditecriteria": "1",
"occurcountry": "PT",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ATENOLOL"
},
"drugadditional": "1",
... |
{
"abstract": "Reactive airway dysfunction syndrome (RADS) is a variant of irritant-induced asthma that develops in subjects without prior bronchoobstructive disease, following high-level exposure to nonimmunogenic irritants. Recommended maintenance treatment for RADS is not different from asthma. But in some cases, severe symptoms may persist despite the bronchodilators and corticosteroids. We describe the first case of a patient with RADS, unresponsive to all medical agents, who was successfully treated with lidocaine.",
"affiliations": "Department of Allergy and Immunology, Koç University Faculty of Medicine, İstanbul, Turkey.;Department of Chest Diseases, İstanbul University Faculty of Medicine, İstanbul, Turkey.;Department of Chest Diseases, İstanbul University Faculty of Medicine, İstanbul, Turkey.;Department of Chest Diseases, İstanbul University Faculty of Medicine, İstanbul, Turkey.;Department of Chest Diseases, İstanbul University Faculty of Medicine, İstanbul, Turkey.;Department of Chest Diseases, İstanbul University Faculty of Medicine, İstanbul, Turkey.",
"authors": "Özyiğit|Leyla Pur|LP|;Erer|Ayşen|A|;Okumuş|Gülfer|G|;Çağatay|Tülin|T|;Kıyan|Esen|E|;Erkan|Feyza|F|",
"chemical_list": null,
"country": "Turkey",
"delete": false,
"doi": "10.5578/ttj.17.2.017",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2148-7197",
"issue": "17(2)",
"journal": "Turkish thoracic journal",
"keywords": "Asthma; lidocaine; sodium hypochloride",
"medline_ta": "Turk Thorac J",
"mesh_terms": null,
"nlm_unique_id": "101648545",
"other_id": null,
"pages": "82-83",
"pmc": null,
"pmid": "29404130",
"pubdate": "2016-04",
"publication_types": "D016428:Journal Article",
"references": "15131566;8437971;4028848;18308694;24854136;15204781;10619325;9988203;472500",
"title": "Nebulized Lidocaine as an Alternative Therapy for Reactive Airway Dysfunction Syndrome.",
"title_normalized": "nebulized lidocaine as an alternative therapy for reactive airway dysfunction syndrome"
} | [
{
"companynumb": "TR-PFIZER INC-2018164412",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "THEOPHYLLINE ANHYDROUS"
},
"drugadditional": ... |
{
"abstract": "The primary Varicella Zoster Virus (VZV) infection results in varicella, a generally benign, self-limiting disease in immunocompetent children. Despite the usual course a possible fatal evolution of the primary infection is observed predominantly in immunocompromised subjects and in adults, especially emigrating from tropical regions. Two cases of fatal varicella have been investigated and discussed. Death occurred in two patients over 40 years of age, coming from South Asia and receiving chronic immunosuppressive therapy. The forensic expert must be cautious and consider all clinical records in managing fatal varicella cases, bearing in mind risk factors and pre-existing conditions such as age, geographical provenance and pathological comorbidity, which may lead to a bad prognosis irrespective of therapies. Based on the severe and fatal course observed in the reported cases, an extension of the immunization program appears advisable for immigrants from tropical countries, especially before scheduled immunotherapy.",
"affiliations": "DIMEC - Department of Medical and Surgical Sciences, Section of Legal Medicine, University of Bologna, Via Irnerio 49, 40126 Bologna, Italy.;DIMEC - Department of Medical and Surgical Sciences, Section of Legal Medicine, University of Bologna, Via Irnerio 49, 40126 Bologna, Italy.;Struttura Complessa di Medicina legale, Azienda Ospedaliera-Universitaria Policlinico di Modena, Modena, Italy.;DIMEC - Department of Medical and Surgical Sciences, Section of Legal Medicine, University of Bologna, Via Irnerio 49, 40126 Bologna, Italy.;DIMEC - Department of Medical and Surgical Sciences, Section of Legal Medicine, University of Bologna, Via Irnerio 49, 40126 Bologna, Italy.;DIMEC - Department of Medical and Surgical Sciences, Section of Legal Medicine, University of Bologna, Via Irnerio 49, 40126 Bologna, Italy. Electronic address: paolo.fais@yahoo.it.;DIMEC - Department of Medical and Surgical Sciences, Section of Legal Medicine, University of Bologna, Via Irnerio 49, 40126 Bologna, Italy.",
"authors": "Guadagnini|Gianni|G|;Lo Baido|Simone|S|;Poli|Francesca|F|;Govi|Annamaria|A|;Borin|Sveva|S|;Fais|Paolo|P|;Pelotti|Susi|S|",
"chemical_list": null,
"country": "Ireland",
"delete": false,
"doi": "10.1016/j.legalmed.2018.03.007",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1344-6223",
"issue": "32()",
"journal": "Legal medicine (Tokyo, Japan)",
"keywords": "Ancestry; Geographical provenance; Immunization; Varicella",
"medline_ta": "Leg Med (Tokyo)",
"mesh_terms": "D000328:Adult; D001208:Asia; D002644:Chickenpox; D003643:Death; D054242:Emigrants and Immigrants; D005260:Female; D049429:Forensic Pathology; D014645:Herpesvirus 3, Human; D006801:Humans; D016867:Immunocompromised Host; D007558:Italy; D008297:Male; D014329:Tropical Climate",
"nlm_unique_id": "100889186",
"other_id": null,
"pages": "83-86",
"pmc": null,
"pmid": "29605790",
"pubdate": "2018-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Fatal varicella in immigrants from tropical countries: Case reports and forensic perspectives.",
"title_normalized": "fatal varicella in immigrants from tropical countries case reports and forensic perspectives"
} | [
{
"companynumb": "IT-WEST-WARD PHARMACEUTICALS CORP.-IT-H14001-18-04656",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE"
},
... |
{
"abstract": "OBJECTIVE\nWhile hemostatic matrices are efficacious in achieving hemostasis, outcomes research is limited; therefore, this study analyzed clinical outcomes of flowable hemostatic matrices in a real-world cardiac surgical population.\n\n\nMETHODS\nRetrospective database analysis of cardiac surgical cases from 2006 to 2012.\n\n\nMETHODS\nData were extracted from Premier's United States (US) Perspective Database, developed for quality and utilization benchmarking and containing approximately 25% of US hospital discharges.\n\n\nMETHODS\nCoronary artery bypass grafting (CABG), aortic, valve, or valvular with CABG surgery cases in which FLOSEAL or SURGIFLO was included.\n\n\nMETHODS\nThree study groups were formed, given usage of hemostatic matrices: (1) FLOSEAL or SURGIFLO, exclusively; (2) FLOSEAL or SURGIFLO, with fibrin sealants, sealants, or powder hemostats; and (3) FLOSEAL or SURGIFLO, with nonflowable hemostats with or without thrombin. Outcomes included complications, transfusions, surgical revisions, mortality, length of stay (LOS) and surgery time.\n\n\nRESULTS\nGroup A included 4,480 FLOSEAL and 326 SURGIFLO cases. Results suggested SURGIFLO cases were associated with significantly higher risk of multiple adverse outcomes, including major (odds Ratio [OR] 2.12; 95% CI 1.34-3.35; p = 0.001) and minor complications (OR 1.84; 95% CI 1.33-2.55; p<0.001); surgical revisions (OR 2.01; 95% CI 1.03- 3.94; p = 0.042); transfusions for any blood products (OR 4.90; 95% CI 3.50-6.87; p<0.001); and longer surgery times (adjusted mean difference = 64 minutes, p<0.001) than the FLOSEAL group. There were no significant differences in mortality and LOS. Results were similar in groups B and C.\n\n\nCONCLUSIONS\nThese retrospective outcomes suggested FLOSEAL was associated with fewer negative consequences than SURGIFLO in this surgical population.",
"affiliations": "Baxter Healthcare Corporation, Westlake Village, CA. Electronic address: Scott_Tackett@baxter.com.;Division of Cardiothoracic Surgery, School of Medicine, Indiana University, Indianapolis, IN.;Premier Research Services, Charlotte, NC.;Division of Cardiothoracic Surgery, Department of Surgery, School of Medicine, Emory University, Atlanta, GA.",
"authors": "Tackett|Scott M|SM|;Calcaterra|Domenico|D|;Magee|Glenn|G|;Lattouf|Omar M|OM|",
"chemical_list": "D006490:Hemostatics",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1053-0770",
"issue": "28(6)",
"journal": "Journal of cardiothoracic and vascular anesthesia",
"keywords": "bleeding; cardiac surgery; hemostasis; outcomes",
"medline_ta": "J Cardiothorac Vasc Anesth",
"mesh_terms": "D000368:Aged; D016063:Blood Loss, Surgical; D001803:Blood Transfusion; D006348:Cardiac Surgical Procedures; D001026:Coronary Artery Bypass; D016208:Databases, Factual; D005260:Female; D006488:Hemostasis, Surgical; D006490:Hemostatics; D006801:Humans; D007902:Length of Stay; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D012189:Retrospective Studies; D016896:Treatment Outcome; D014481:United States",
"nlm_unique_id": "9110208",
"other_id": null,
"pages": "1558-65",
"pmc": null,
"pmid": "25245578",
"pubdate": "2014-12",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Real-world outcomes of hemostatic matrices in cardiac surgery.",
"title_normalized": "real world outcomes of hemostatic matrices in cardiac surgery"
} | [
{
"companynumb": "US-JNJFOC-20141210044",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "THROMBIN HUMAN"
},
"drugadditional": null,
... |
{
"abstract": "The mechanism of amobarbital action during the intracarotid amobarbital procedure is poorly understood. We report a patient case who underwent IAP while implanted with bilateral stereo-EEG. We analyzed the spectral power, phase amplitude coupling, and cluster-phase group synchrony during the procedure. Delta and gamma power increased bilaterally. By contrast, phase amplitude coupling increased only ipsilateral to the injection. Similarly, 4-30 Hz cluster-phase group synchrony declines and gamma cluster-phase group synchrony increases only ipsilateral to the injection. These results suggest that a possible additional mechanism for amobarbital action in the IAP is by altering the precise timing of oscillatory activity.",
"affiliations": "Department of Neurology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA.;Department of Neurology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA.;Department of Neurosurgery, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA.;Department of Neurology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA.;Department of Neurosurgery, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA.;Department of Neurosurgery, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA.;Department of Neurosurgery, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA.;Department of Neurology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA.",
"authors": "Young|James J|JJ|;Friedman|Joshua S|JS|;Oxley|Thomas J|TJ|;Palmese|Christina|C|;Panov|Fedor|F|;Ghatan|Saadi|S|;Fifi|Johanna T|JT|;Marcuse|Lara V|LV|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.ebcr.2018.04.003",
"fulltext": "\n==== Front\nEpilepsy Behav Case RepEpilepsy Behav Case RepEpilepsy & Behavior Case Reports2213-3232Elsevier S2213-3232(18)30014-810.1016/j.ebcr.2018.04.003ArticleIntracarotid amobarbital disrupts synchronous and nested oscillatory activity ipsilateral to injection☆ Young James J. james.young@mssm.eduab⁎Friedman Joshua S. aOxley Thomas J. bPalmese Christina aPanov Fedor bGhatan Saadi bFifi Johanna T. bMarcuse Lara V. aa Department of Neurology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USAb Department of Neurosurgery, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA⁎ Corresponding author at: Departments of Neurology and Neurosurgery, Icahn School of Medicine at Mount Sinai, 1468 Madison Ave, Annenberg Building, Rm. 210, New York, NY 10029, USA. james.young@mssm.edu25 4 2018 2018 25 4 2018 10 25 28 8 2 2018 5 4 2018 10 4 2018 © 2018 The Authors2018This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).The mechanism of amobarbital action during the intracarotid amobarbital procedure is poorly understood. We report a patient case who underwent IAP while implanted with bilateral stereo-EEG. We analyzed the spectral power, phase amplitude coupling, and cluster-phase group synchrony during the procedure. Delta and gamma power increased bilaterally. By contrast, phase amplitude coupling increased only ipsilateral to the injection. Similarly, 4–30 Hz cluster-phase group synchrony declines and gamma cluster-phase group synchrony increases only ipsilateral to the injection. These results suggest that a possible additional mechanism for amobarbital action in the IAP is by altering the precise timing of oscillatory activity.\n\nHighlights\n• Intracranial activity shows bilateral increases in delta and gamma activity during the IAP.\n\n• Phase amplitude coupling increases in the 2–3 Hz (phase) and 30–70 Hz (amplitude) band only ipsilateral to the injection.\n\n• 4–30 Hz synchrony declines and gamma synchrony increases only ipsilateral to the injection.\n\n• Amobarbital may alter the temporal organization of activity, rather than inactivation of the injected hemisphere.\n\n\n\nKeywords\nIntracarotid amobarbital procedureWadaStereo-EEGSynchronyPhase amplitude couplingEpilepsy surgery\n==== Body\n1 Introduction\nThe intracarotid amobarbital procedure (IAP) is used to provide prognostic information prior to epilepsy surgery, but it may also provide interesting insights into brain function. Milner and Wada, the developers of the procedure, described the function of the amobarbital as to, “temporarily inactivate,” the anterior circulation of one hemisphere of the brain [1], [2], but this mechanism does not explain some observations during the procedure. For example, EEG changes are frequently bilateral, rather than merely ipsilateral to the injection side on scalp EEG [3], [4] and intracranial EEG [5]. Although this could possibly be attributed to crossing of the drug to the contralateral hemisphere via the circle of Willis, nuclear medicine studies show that the drug passes to the other hemisphere a very small proportion of the time [6]. This suggests that the unilateral inactivation model for amobarbital action cannot adequately explain the unilateral deficits observed during the procedure. Other authors have speculated that amobarbital may function in this setting by, “deafferentation,” from cortical and subcortical structures [6]; however, this description does not clarify the physiologic mechanism for this deafferentation.\n\nTo begin to clarify the mechanism of amobarbital in producing unilateral deficits, we report a case of a patient who underwent IAP while implanted with bilateral stereo-EEG. The activity during the procedure was evaluated using measures of nested and synchronous oscillations. Measures of nested oscillations such as phase-amplitude coupling (PAC) and synchrony such as cluster-phase group synchrony were selected because existing evidence indicates their importance in cognitive function [7], [8], and dysfunction of these measures has been implicated in poor cognitive performance [9]. For example, pathological PAC has been recorded in Parkinson's disease [10].\n\n2 Materials and methods\n2.1 Consent\nThe study was conducted according to the principles of the Declaration of Helsinki, and the consent documentation and procedure were approved by the Mount Sinai Hospital Institutional Review Board.\n\n2.2 Patient\nThe patient at the time of surgery was a 41-year-old right-handed male with drug resistant epilepsy since age 17. The semiology of his events was a feeling of coldness and nausea followed by bilateral automatisms of the hands, associated with amnesia for the event. These would proceed to a generalized convulsion very infrequently. He continued to have seizures on lamotrigine, levetiracetam, and oxcarbazepine, and had failed treatment with zonisamide, lacosamide, and carbamazepine. Interictal EEG showed bilateral frontotemporal sharp waves, and multiple left frontotemporal seizures were captured on video-EGG in the epilepsy monitoring unit. His MRI was normal. Because of the presence of bilateral interictal discharges and a nonlesional MRI, it was decided that the patient should undergo bilateral stereo-EEG. The IAP was performed while the patient was implanted with bilateral stereo-EEG due to unreliable follow-up after multiple attempts pre-implantation.\n\n2.3 Data collection and pre-analysis\nElectrophysiological data was collected for all subjects using a Natus Quantum amplifier (Natus Medical Incorporated; Pleasanton, CA). The sampling rate was 1024 Hz. All pre-analysis and analysis was performed with MATLAB (Mathworks, Natick, MA) using the FieldTrip software library [11]. Recordings were referenced to the average of all electrodes. Each trace was locally detrended. AC noise was removed using a 60 Hz notch filter.\n\n2.4 Electrode localization\nLocalization of electrodes was performed using pre-operative MRIs and post-operative CTs. Coregistration of MRI and CT was performed using iELVIS [12] and the location of each electrode was selected on the post-operative CT. A parcellated image of the patient's cortical surface was generated using FreeSurfer from the T1 series of the pre-operative MRI. Cortical parcellation used the DKT40 Atlas [13].\n\n2.5 Analysis\nThe data from each electrode was divided into 10 s windows with 5 s step-size. Spectral power was calculated using a complex Morlet wavelet transformation (width = 7). Spectral power was calculated for all electrodes between 1 to 150 Hz, calculated at 1 Hz increments. Cluster-phase group synchrony – a global variable representing the phase locking of multiple signals at a given frequency — was calculated between all the electrodes in each frontal lobe between 1 to 150 Hz, calculated at 1 Hz increments [14]. Phase amplitude coupling – a measure of the tendency for high frequency oscillations to occur at particular phases of low frequency oscillations — was calculated for 1 to 20 Hz in 1 Hz increments (phase frequency) and 30 to 150 Hz in 10 Hz increments (amplitude frequency) [15].\n\n3 Results\n3.1 IAP results\nWada testing was performed during implantation with first left, then right intracarotid injection of 100 mg of amobarbital. After the left sided injection, the patient was aphasic and plegic on the right. The patient was plegic on the left after the right sided injection. Left sided memory function was 3 out of 10 exemplars. Right sided memory function was 4 out of 8 exemplars.Fig. 1 (A) A heat plot demonstrates the Z-scored spectral power for 1–150 Hz averaged over electrodes from the left and right frontal lobes. The vertical lines indicate the times of the left and right injections, respectively. (B) The mean Z-scored spectral power for the delta (1 to 3 Hz) and high gamma bands (80 to 150 Hz) are shown averaged over electrodes in the left and right frontal lobes. The vertical lines indicate the times of the left and right injections, respectively. A 12 point Gaussian filter has been on the data for clarity. (C) The 2–3 Hz (phase frequency) and 30–70 Hz (amplitude frequency) are shown averaged over electrodes in the left and right frontal lobes. The vertical lines indicate the times of the left and right injections, respectively. A 12 point Gaussian filter has been on the data for clarity. (D) The Z-score cluster-phase group synchrony for windows 5 min before, 5 min after and 10–15 min after each injection, for each hemisphere, are shown.\n\nFig. 1\n\n3.2 Electrode localization\nNinety-eight electrodes were placed bilaterally into this patient (Supplementary Fig. 1, Supplementary Table 1). Because the borders of the anterior circulation in the temporal lobe could not be clearly determined, the analysis divided electrodes that were in the frontal lobe from those in the temporal lobe. Of these, 23 electrodes were excluded because they were located more than 5 mm from a gray matter structure.\n\n3.3 Spectral power\nThe Z-score of the average spectral power for the 1–150 Hz frequencies for electrodes from each frontal lobe are depicted in Fig. 1A. At the time of both the left and the right-sided injection there is a visible increase in delta (1–3 Hz) power and high gamma (80–150 Hz) power bilaterally. The Z-scored spectral power for these bands is depicted in Fig. 1B. A similar analysis for all of the electrodes in the right and left temporal lobe produced similar results (Supplementary Fig. 2A and B). Analysis of the spectral power in the beta range (15–29 Hz) and low gamma range (30–79 Hz) show bilateral increases, but less accurate at lateralizing the side of activity (Supplementary Fig. 3).\n\n3.4 Phase amplitude coupling\nNested oscillations are speculated to support brain functions and are correlated with performance in tasks such as memory [7]. A measure of nested oscillations is the PAC, the tendency of the peaks of high frequency oscillations to cluster at a phase of a lower frequency oscillation. This measure was calculated for 1–20 Hz (phase frequency) and 30–150 (amplitude frequency) for all electrodes in the right and left frontal lobes. For the 2–3 Hz (phase frequency) and 30–70 Hz (amplitude frequency) there is an increase in PAC ipsilateral, but not contralateral to the injection (Fig. 1C). A similar analysis for all of the electrodes in the right and left temporal lobe produced similar results (Supplementary Fig. 2C).\n\n3.5 Synchrony\nSynchronous oscillations between brain regions are hypothesized to support brain function by organizing different units into functional networks [8]. A global measure of synchrony is cluster-phase group synchrony, the tendency of a group of oscillators to align to the same phase [15]. This measure was calculated between 1 to 150 Hz, calculated at 1 Hz increments for all the electrodes in the left and right frontal lobe. Fig. 1D shows a reduction in the Z-scored cluster-group synchrony in the 4–30 Hz ipsilateral to the injection and an increase in the Z-scored cluster group synchrony in the low and high gamma bands ipsilateral to the injection. These changes are present to a lesser degree contralateral to the injection. A similar analysis for all of the electrodes in the right and left temporal lobe produced similar results (Supplementary Fig. 2D). Thus, after intracarotid amobarbital, lower-frequency oscillators in the injected hemisphere tend to fall out of phase, whereas higher-frequency oscillators tend to increase phase synchrony. This pattern of synchrony closely resembles the pattern observed in poor memory performance in behavioral testing of patients implanted with intracranial EEG [9].\n\n4 Discussion\nThese results detail the electrophysiologic changes observed in a single patient who underwent IAP while implanted with bilateral stereo-EEG. As has been observed in prior scalp [3], [4] and intracranial studies [5], there was a significant bilateral increase in delta power both ipsilateral and contralateral to the injection. Although the delta power increase was more prominent ipsilateral to the injection, the relative asymmetry in delta power may not fully explain the unilateral deficits in the patient after injection. By contrast, changes in phase amplitude coupling for 2–3 Hz (phase frequency) and 30–70 (amplitude frequency) and cluster-phase group synchrony in the 4–30 Hz and 30–150 Hz bands appear in this case to more accurately lateralize the deficits observed in this patient.\n\nThe additional observation that low and high gamma power increase bilaterally is incongruous with the purported action of amobarbital in decreasing neuronal firing. It is possible that cognitive load performing the task or patient movement account for these increases. Alternatively, early studies in a dog model of amobarbital showed increased bursting activity after administration [16]. It is possible that this bursting activity is being recorded as an increase in spectral power in the gamma range.\n\nThat synchronous and nested oscillations are better at lateralizing the side of injection draws into question the hypothesis that amobarbital functions solely by, “inactivating,” the injected region. Rather, these suggest that an additional mechanism of amobarbital action may be by the disruption of the temporal structure of oscillations of the local field potential, which modifies the information encoded in nested oscillations and desynchronizes previously synchronous nodes in existing neural networks. Pathological increases in PAC have been noted in Parkinson's disease [10]. Similarly, a recent analysis of patients performing memory tasks while implanted with intracranial EEG showed that theta band synchronization and gamma desynchronization correlated with performance [9]. Our finding that the amobarbital injection causes a similar desynchronization in 4–30 Hz and synchronization in the gamma band demonstrates that the drug causes a brain state associated with poor memory performance suggests that these changes in synchrony may account for the drug's effect as an amnestic agent. Further, these quantitative observations on the intracranial signal have implications to interpretation of the scalp EEG during the procedure. It may not be possible to determine the effectiveness of the drug on the basis of qualitative evaluation of scalp EEG.\n\nThese results should be interpreted with caution as this is a single case. Other agents sometimes used in the procedure such as propofol or methohexital may have other mechanisms of action. However, if validated and repeated in a larger series, these results have broad implications for our understanding of brain function. Synchronous and nested oscillations are hypothesized to organize neural networks, yet evidence to support this hypothesis is almost exclusively correlative [17]. The results of this case study add evidence to the hypothesis that temporal synchrony of oscillatory activity is necessary for brain function.\n\n5 Conclusion\nIn this case, we show that measures of nested oscillations and synchrony may lateralize the deficits better than measures of spectral power. These results imply a possible alternative mechanism for amobarbital action and supports the hypothesis that nested and synchronous oscillations are necessary for brain function.\n\nThe following are the supplementary data related to this article.Supplementary Table 1\nEach electrode is listed with its depth beneath the cortical surface, hemisphere and location for the subject’s SEEG montage.\n\nSupplementary Table 1 Supplementary Fig. 1 Blue dots indicate the location of the SEEG electrodes in the patient's reconstructed brain.\n\nSupplementary Fig. 1Supplementary Fig. 2 (A) A heat plot demonstrates the Z-scored spectral power for 1–150 Hz averaged over electrodes from the left and right frontal lobes. The vertical lines indicate the times of the left and right injections, respectively. (B) The mean Z-scored spectral power for the delta (1 to 3 Hz) and high gamma bands (80 to 150 Hz) are shown averaged over electrodes in the left and right frontal lobes. The vertical lines indicate the times of the left and right injections, respectively. A 12 point Gaussian filter has been on the data for clarity. (C) The 2–3 Hz (phase frequency) and 30–70 Hz (amplitude frequency) are shown averaged over electrodes in the left and right frontal lobes. The vertical lines indicate the times of the left and right injections, respectively. A 12 point Gaussian filter has been on the data for clarity. (D) The Z-score cluster-phase group synchrony for windows 5 min before,5 min after and 10–15 min after each injection, for each hemisphere, are shown.\n\nSupplementary Fig. 2Supplementary Fig. 3 (Top) The mean Z-scored spectral power for the beta (15 to 29 Hz) and high gamma bands (30 to 79 Hz) are shown averaged over electrodes in the left and right frontal lobes. The vertical lines indicate the times of the left and right injections, respectively. A 12 point Gaussian filter has been on the data for clarity. (Bottom) The mean Z-scored spectral power for the beta (15 to 29 Hz) and high gamma bands (30 to 79 Hz) are shown averaged over electrodes in the left and right temporal lobes. The vertical lines indicate the times of the left and right injections, respectively. A 12 point Gaussian filter has been on the data for clarity.\n\nSupplementary Fig. 3\n\nConflict of interest\nThe authors have no conflicts of interest to declare.\n\n☆ Funding: The authors would like to acknowledge the NINDS R25 (JJY, NS8440304) and the Leon Levy Foundation (JJY).\n==== Refs\nReferences\n1 Wada J.A. Fateful encounter: sixty years later - reflections on the Wada test Epilepsia 49 2008 726 727 18366482 \n2 Milner B. Amobarbital memory testing: some personal reflections Brain Cogn 33 1997 14 17 9056273 \n3 Hong S.B. Kim K.W. Seo D.W. Contralateral EEG slowing and amobarbital distribution in Wada test: an intracarotid SPECT study Epilepsia 41 2000 207 212 10691118 \n4 Ahern G.L. Labiner D.M. Hutzler R. Quantitative analysis of the EEG in the intracarotid amobarbital procedure. I. Amplitude analysis Electroencephalogr Clin Neurophysiol 91 1994 21 32 7517841 \n5 McMackin D. Dubeau F. Jones-Gotman M. Assessment of the functional effect of the intracarotid sodium amobarbital procedure using co-registered MRI/HMPAO-SPECT and SEEG Brain and Cognition 33 1997 50 70 9056276 \n6 Soucy J.-P. Rouleau I. Roy D. Absence of correlation between amobarbital distribution as assessed with spect brain perfusion imaging and behavioral manifestations during the intracarotid amobarbital procedure (Wada test) Prog Neuro-Psychopharmacol Biol Psychiatry 23 1999 259 274 \n7 Canolty R.T. Knight R.T. The functional role of cross-frequency coupling Trends Cogn Sci 14 2010 506 515 20932795 \n8 Fries P. Rhythms for cognition: communication through coherence Neuron 88 2015 220 235 26447583 \n9 Solomon E.A. Kragel J.E. Sperling M.R. Widespread theta synchrony and high-frequency desynchronization underlies enhanced cognition Nat Commun 8 2017 1704 29167419 \n10 de Hemptinne C. Ryapolova-Webb E.S. Air E.L. Exaggerated phase-amplitude coupling in the primary motor cortex in Parkinson disease Proc Natl Acad Sci 110 2013 4780 4785 23471992 \n11 Oostenveld R. Fries P. Maris E. FieldTrip: open source software for advanced analysis of MEG, EEG, and invasive electrophysiological data Comput Intell Neurosci 2011 2011 156869 21253357 \n12 Groppe D.M. Bickel S. Dykstra A.R. iELVis: an open source MATLAB toolbox for localizing and visualizing human intracranial electrode data J Neurosci Methods 281 2017 40 48 28192130 \n13 Desikan R.S. Ségonne F. Fischl B. An automated labeling system for subdividing the human cerebral cortex on MRI scans into gyral based regions of interest (Published Online First) 2006 \n14 Özkurt T.E. Schnitzler A. A critical note on the definition of phase–amplitude cross-frequency coupling J Neurosci Methods 201 2011 438 443 21871489 \n15 Richardson M.J. Garcia R.L. Frank T.D. Measuring group synchrony: a cluster-phase method for analyzing multivariate movement time-series Front Physiol 3 OCT 2012 405 23091463 \n16 Swank R.L. Watson C.W. Effects of barbiturates and ether on spontaneous electrical activity of dog brain J Neurophysiol 12 1949 137 160 18114367 \n17 Harris A.Z. Gordon J.A. Long-range neural synchrony in behavior Annu Rev Neurosci 38 2015 171 194 25897876\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2213-3232",
"issue": "10()",
"journal": "Epilepsy & behavior case reports",
"keywords": "Epilepsy surgery; Intracarotid amobarbital procedure; Phase amplitude coupling; Stereo-EEG; Synchrony; Wada",
"medline_ta": "Epilepsy Behav Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101614202",
"other_id": null,
"pages": "25-28",
"pmc": null,
"pmid": "30013931",
"pubdate": "2018",
"publication_types": "D002363:Case Reports",
"references": "9056273;28192130;21871489;9056276;21253357;20932795;23091463;23471992;16530430;7517841;29167419;25897876;18366482;10368868;26447583;18114367;10691118",
"title": "Intracarotid amobarbital disrupts synchronous and nested oscillatory activity ipsilateral to injection.",
"title_normalized": "intracarotid amobarbital disrupts synchronous and nested oscillatory activity ipsilateral to injection"
} | [
{
"companynumb": "US-CIPLA LTD.-2019US00014",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CARBAMAZEPINE"
},
"drugadditional": "3",
... |
{
"abstract": "Systemic corticosteroids have long been the mainstay of treatment for pemphigus patients. However, the necessity of their high-dose and long-term administration has brought about a number of complications, sometimes causing significant morbidities. Maintaining a balance between therapeutic and undesirable effects of medications is not always easily achievable. Therefore, additional treatment modalities are frequently needed to control side-effects. Kaposi's sarcoma (KS) is a rare, potentially life-threatening complication in this setting. Due to the rarity of data on pemphigus-associated KS treatment, the best therapeutic approach is still undecided. Here, we report two cases of pemphigus patients who had developed extensive KS as a result of severe immunosuppressive therapy and were successfully treated with paclitaxel. In addition, we performed a review of literature to assess the results of the previously employed treatment modalities in this setting.",
"affiliations": "Autoimmune Bullous Diseases Research Centre, Razi hospital, Tehran University of Medical Sciences, Tehran, Iran.",
"authors": "Balighi|K|K|;Daneshpazhooh|M|M|;Aghazadeh|N|N|;Hejazi|P|P|;Aryanian|Z|Z|;Azizpour|A|A|;Rahbar|Z|Z|;Goodarzi|A|A|;Chams-Davatchi|C|C|",
"chemical_list": "D007166:Immunosuppressive Agents; D017239:Paclitaxel",
"country": "England",
"delete": false,
"doi": "10.1111/jdv.12348",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0926-9959",
"issue": "28(8)",
"journal": "Journal of the European Academy of Dermatology and Venereology : JEADV",
"keywords": null,
"medline_ta": "J Eur Acad Dermatol Venereol",
"mesh_terms": "D006801:Humans; D007166:Immunosuppressive Agents; D008297:Male; D008875:Middle Aged; D017239:Paclitaxel; D010392:Pemphigus; D012514:Sarcoma, Kaposi",
"nlm_unique_id": "9216037",
"other_id": null,
"pages": "987-94",
"pmc": null,
"pmid": "24341453",
"pubdate": "2014-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Pemphigus vulgaris-associated Kaposi's sarcoma: response to paclitaxel and review of the literature.",
"title_normalized": "pemphigus vulgaris associated kaposi s sarcoma response to paclitaxel and review of the literature"
} | [
{
"companynumb": "BG-PFIZER INC-2014231731",
"fulfillexpeditecriteria": "1",
"occurcountry": "BG",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE"
},
"drugadditional": null,... |
{
"abstract": "Older patients with acute myeloid leukemia (AML) have poor outcomes, with median durations of complete remission lasting less than 1 year. Increased toxicity in older patients limits the delivery of standard consolidation therapies, such as allogeneic stem cell transplant or high-dose cytarabine. Azacitidine, a nucleoside analog/DNA methyltransferase inhibitor, has demonstrated significant activity and favorable tolerability in patients unable to tolerate intensive induction chemotherapy; however, the role of azacitidine in the maintenance setting has not been fully evaluated. We undertook a pilot study of low-dose subcutaneous azacitidine [50 mg/(m(2) day)] for 5 days every 4 weeks) in AML patients ≥60 years of age in first remission following standard induction therapy. The primary objective was to determine the 1-year disease-free survival (DFS); secondary objectives were to determine safety and tolerability. We enrolled 24 patients (median age 68, range 62-81 years), the majority of whom received anthracycline-cytarabine induction regimens. From the time of first complete remission, the estimated 1-year DFS was 50% and the median overall survival was 20.4 months. Thrombocytopenia and neutropenia were the most common grade 3/4 toxicities (50 and 58%, respectively). In our study population, maintenance therapy with subcutaneous azacitidine was safe and well tolerated.",
"affiliations": "H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.;H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.;Duke University Medical Center, Durham, North Carolina.;Duke University Medical Center, Durham, North Carolina.;Florida Cancer Specialists, Tampa, Florida.;H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.;H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.",
"authors": "Griffin|Patrick T|PT|;Komrokji|Rami S|RS|;De Castro|Carlos M|CM|;Rizzieri|David A|DA|;Melchert|Magda|M|;List|Alan F|AF|;Lancet|Jeffrey E|JE|",
"chemical_list": "D018943:Anthracyclines; D000964:Antimetabolites, Antineoplastic; D003561:Cytarabine; D001374:Azacitidine",
"country": "United States",
"delete": false,
"doi": "10.1002/ajh.24087",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0361-8609",
"issue": "90(9)",
"journal": "American journal of hematology",
"keywords": null,
"medline_ta": "Am J Hematol",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D018943:Anthracyclines; D000964:Antimetabolites, Antineoplastic; D001374:Azacitidine; D003561:Cytarabine; D005260:Female; D006801:Humans; D060828:Induction Chemotherapy; D007279:Injections, Subcutaneous; D015470:Leukemia, Myeloid, Acute; D008297:Male; D008875:Middle Aged; D009503:Neutropenia; D010865:Pilot Projects; D012074:Remission Induction; D016019:Survival Analysis; D013921:Thrombocytopenia",
"nlm_unique_id": "7610369",
"other_id": null,
"pages": "796-9",
"pmc": null,
"pmid": "26089240",
"pubdate": "2015-09",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "A multicenter, phase II study of maintenance azacitidine in older patients with acute myeloid leukemia in complete remission after induction chemotherapy.",
"title_normalized": "a multicenter phase ii study of maintenance azacitidine in older patients with acute myeloid leukemia in complete remission after induction chemotherapy"
} | [
{
"companynumb": "US-CELGENE-163-50794-10070218",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "AZACITIDINE"
},
"drugadditional": null,
... |
{
"abstract": "The effectiveness of biologics has changed therapeutic strategies for psoriasis dramatically, but biologics are known to have various adverse effects. We report a 63-year-old woman with psoriatic arthritis who suddenly developed a subcutaneous hematoma after being successfully treated with adalimumab. As she had also suffered from alcoholic cirrhosis, we speculated that she had developed thrombocytopenia severe enough to cause a subcutaneous hematoma. Furthermore, we investigated the changes of platelet counts in 65 psoriatic patients treated with biologics at a single institute from 2010 to 2016. Platelet counts were found to have decreased by 17.4 ± 2.8% during adalimumab therapy (n = 16), 18.5 ± 3.8% during infliximab therapy (n = 17), 14.8 ± 2.1% during ustekinumab therapy (n = 20) and 18.5 ± 5.1% during secukinumab therapy (n = 12). Platelet counts decrease after the administration of biologics in accordance with disease activity, and there is the potential risk of subcutaneous hematoma and other adverse effects. When administrating biologics to psoriatic patients, especially to those with chronic liver disease, dermatologists should carefully monitor for thrombocytopenia.",
"affiliations": "Department of Dermatology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan.;Department of Dermatology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan.;Department of Dermatology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan.;Department of Dermatology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan.;Department of Dermatology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan.;Kobayashi Skin Clinic, Sapporo, Japan.;Department of Dermatology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan.",
"authors": "Maya|Yuka|Y|http://orcid.org/0000-0002-5649-8499;Fujita|Yasuyuki|Y|;Nakayama|Chihiro|C|;Kitamura|Shinya|S|http://orcid.org/0000-0002-4232-2943;Hata|Hiroo|H|;Arita|Ken|K|;Shimizu|Hiroshi|H|",
"chemical_list": "D018501:Antirheumatic Agents; D000068879:Adalimumab",
"country": "England",
"delete": false,
"doi": "10.1111/1346-8138.13981",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0385-2407",
"issue": "44(12)",
"journal": "The Journal of dermatology",
"keywords": "biologics; platelets; psoriasis vulgaris; psoriatic arthritis; thrombocytopenia",
"medline_ta": "J Dermatol",
"mesh_terms": "D000068879:Adalimumab; D018501:Antirheumatic Agents; D015535:Arthritis, Psoriatic; D005260:Female; D006406:Hematoma; D006801:Humans; D008104:Liver Cirrhosis, Alcoholic; D008875:Middle Aged; D010976:Platelet Count; D013921:Thrombocytopenia",
"nlm_unique_id": "7600545",
"other_id": null,
"pages": "1385-1388",
"pmc": null,
"pmid": "28733978",
"pubdate": "2017-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Severe subcutaneous hematoma in a patient with psoriatic arthritis: Changes of platelet count in psoriatic patients with biologic agents.",
"title_normalized": "severe subcutaneous hematoma in a patient with psoriatic arthritis changes of platelet count in psoriatic patients with biologic agents"
} | [
{
"companynumb": "JP-ABBVIE-15K-087-1349060-00",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "PIOGLITAZONE HYDROCHLORIDE"
},
"drugaddit... |
{
"abstract": "Obesity prior to and during pregnancy is associated with an increased risk of complications during pregnancy. One of the most common complications of pregnancy is gestational diabetes mellitus (GDM), a condition characterized by hyperglycemia and insulin resistance that is diagnosed in the third trimester of pregnancy. GDM predisposes both mothers and their children to increased obesity and cardiometabolic disorders, namely type 2 diabetes and cardiovascular disease. Current treatments include lifestyle changes and insulin injections, but oral anti-diabetic drugs such as metformin and glyburide are increasingly prescribed as they do not require injections. However, the long-term implications of therapies for diabetes during pregnancy on mothers and their offspring are not fully understood. In this review, we describe current treatments for GDM, including the first line lifestyle interventions such as exercise as well as insulin, glyburides and metformin. We also review selected natural health products that are sometimes used by individuals during pregnancy that could also be an effective therapeutic in pregnancies characterized by obesity or GDM. We focus on both the short- and long-term effects of treatments on the health of mothers and their offspring. We review the current literature from clinical research and animal studies.",
"affiliations": "Department of Pharmacology & Therapeutics, Diabetes Research Envisioned and Accomplished in Manitoba (DREAM) Research Theme of the Children's Hospital Research Institute of Manitoba and the Manitoba Developmental Origins of Chronic Diseases in Children Network (DEVOTION), University of Manitoba, Canada.;Department of Pharmacology & Therapeutics, Diabetes Research Envisioned and Accomplished in Manitoba (DREAM) Research Theme of the Children's Hospital Research Institute of Manitoba and the Manitoba Developmental Origins of Chronic Diseases in Children Network (DEVOTION), University of Manitoba, Canada. Electronic address: vdolinsky@chrim.ca.",
"authors": "Brawerman|Gabriel M|GM|;Dolinsky|Vernon W|VW|",
"chemical_list": "D001688:Biological Products; D007004:Hypoglycemic Agents; D014815:Vitamins",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.phrs.2018.02.002",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1043-6618",
"issue": "130()",
"journal": "Pharmacological research",
"keywords": "Developmental origins of health and disease; Drugs in pregnancy; Gestational diabetes mellitus; Maternal obesity; Natural health products",
"medline_ta": "Pharmacol Res",
"mesh_terms": "D000818:Animals; D001688:Biological Products; D016640:Diabetes, Gestational; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents; D008019:Life Style; D009035:Mothers; D011247:Pregnancy; D014815:Vitamins",
"nlm_unique_id": "8907422",
"other_id": null,
"pages": "52-73",
"pmc": null,
"pmid": "29421161",
"pubdate": "2018-04",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't; D016454:Review",
"references": null,
"title": "Therapies for gestational diabetes and their implications for maternal and offspring health: Evidence from human and animal studies.",
"title_normalized": "therapies for gestational diabetes and their implications for maternal and offspring health evidence from human and animal studies"
} | [
{
"companynumb": "NZ-ALKEM LABORATORIES LIMITED-NZ-ALKEM-2018-01447",
"fulfillexpeditecriteria": "2",
"occurcountry": "NZ",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "METFORMIN HYDROCHLORIDE"
},
... |
{
"abstract": "The mainstay of treatment for massive pulmonary embolism in nonpregnant individuals is urgent thrombolytic therapy, but experience with these drugs in pregnancy is limited. We report a case of a 36-year-old woman at 27 weeks' gestation who was admitted with a massive, life-threatening pulmonary embolism. The diagnosis was rapidly accomplished in the coronary care unit by transthoracic echocardiography that showed signs of pulmonary hypertension as well as a large, free-floating thrombus in the right heart. As she was hemodynamically unstable, we started treatment with tissue plasminogen activator resulting in complete resolution of cardiorespiratory symptoms. A live baby was delivered by Caesarean section at 37 weeks of gestation, and no complications were seen during the 1-year follow-up. The present case report emphasizes the pivotal role of repeat echocardiography in clinical decision-making and the life-saving potential of thrombolytic therapy without serious adverse effects.",
"affiliations": "Department of Cardiology, Kartal Kosuyolu Heart and Research Hospital, Istanbul, Turkey.",
"authors": "Açar|Göksel|G|;Şimşek|Zeki|Z|;Avci|Anl|A|;Aung|Soe M|SM|;Koca|Fatih|F|;Sağlam|Mustafa|M|;Kaymaz|Cihangir|C|",
"chemical_list": "D010959:Tissue Plasminogen Activator",
"country": "United States",
"delete": false,
"doi": "10.2459/JCM.0b013e32834036b4",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1558-2027",
"issue": "16 Suppl 1()",
"journal": "Journal of cardiovascular medicine (Hagerstown, Md.)",
"keywords": null,
"medline_ta": "J Cardiovasc Med (Hagerstown)",
"mesh_terms": "D000328:Adult; D002585:Cesarean Section; D004452:Echocardiography; D005260:Female; D006801:Humans; D011247:Pregnancy; D011655:Pulmonary Embolism; D015912:Thrombolytic Therapy; D013927:Thrombosis; D010959:Tissue Plasminogen Activator; D016896:Treatment Outcome",
"nlm_unique_id": "101259752",
"other_id": null,
"pages": "S51-4",
"pmc": null,
"pmid": "21135590",
"pubdate": "2015-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Right heart free-floating thrombus in a pregnant woman with massive pulmonary embolism: a case of 'emboli in transit'.",
"title_normalized": "right heart free floating thrombus in a pregnant woman with massive pulmonary embolism a case of emboli in transit"
} | [
{
"companynumb": "TR-ROCHE-1661009",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ALTEPLASE"
},
"drugadditional": null,
"druga... |
{
"abstract": "The purpose of this case report is to show the potential benefit of Korean medicine therapy for treating multiple metastatic breast cancer. A 45-year-old Korean woman was diagnosed with right breast invasive ductal carcinoma in August 2012 but did not receive any treatment until October 2015 when she was diagnosed with stage 4 right breast cancer with multiple liver, bone, mesentery, retroperitoneum, and axillary lymph node metastases. After chemo-port insertion, she was treated with palliative chemotherapy and the first line of trastuzumab and paclitaxel, and the port was removed due to port infection. To treat sepsis, vancomycin and tazoperan were administered, before the third line of trastuzumab and paclitaxel was carried out. However, the patient gave up chemotherapy due to vancomycin-resistant enterococci and general weakness. Later, she received Korean medicine therapy with wild ginseng pharmacopuncture, distilled Soramdan S, Hae, and Jeobgoldan for 8 months, which led to a significant decrease of the multiple metastases. The patient was able to start walking again with the help of a walking stick. However, a new metastatic lesion was found on the right adrenal gland. This case suggests that the combination of chemotherapy and Korean medicine therapy may be valuable. Further research is indicated.",
"affiliations": "Soram Korean Medicine Hospital, Seoul, Republic of Korea.;Soram Korean Medicine Hospital, Seoul, Republic of Korea.;Soram Korean Medicine Hospital, Seoul, Republic of Korea.",
"authors": "Lee|Dong-Hyun|DH|;Kim|Sung-Su|SS|;Seong|Shin|S|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000455039",
"fulltext": "\n==== Front\nCase Rep OncolCase Rep OncolCROCase Reports in Oncology1662-6575S. Karger AG Allschwilerstrasse 10, P.O. Box · Postfach · Case postale, CH–4009, Basel, Switzerland · Schweiz · Suisse, Phone: +41 61 306 11 11, Fax: +41 61 306 12 34, karger@karger.ch 10.1159/000455039cro-0010-0027Case ReportA Case Report of Metastatic Breast Cancer Treated with Korean Medicine Therapy as a Substitute for Chemotherapy Lee Dong-hyun *Kim Sung-su Seong Shin Soram Korean Medicine Hospital, Seoul, Republic of Korea*Dong-hyun Lee, Soram Korean Medicine Hospital, 458, Duklim Building Bongeunsa-ro, Gangnam-gu, Seoul 06154 (Republic of Korea), E-Mail hanvithunter@soram.krJan-Apr 2017 16 1 2017 16 1 2017 10 1 27 36 28 11 2016 9 12 2016 Copyright © 2017 by S. Karger AG, Basel2017This 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.The purpose of this case report is to show the potential benefit of Korean medicine therapy for treating multiple metastatic breast cancer. A 45-year-old Korean woman was diagnosed with right breast invasive ductal carcinoma in August 2012 but did not receive any treatment until October 2015 when she was diagnosed with stage 4 right breast cancer with multiple liver, bone, mesentery, retroperitoneum, and axillary lymph node metastases. After chemo-port insertion, she was treated with palliative chemotherapy and the first line of trastuzumab and paclitaxel, and the port was removed due to port infection. To treat sepsis, vancomycin and tazoperan were administered, before the third line of trastuzumab and paclitaxel was carried out. However, the patient gave up chemotherapy due to vancomycin-resistant enterococci and general weakness. Later, she received Korean medicine therapy with wild ginseng pharmacopuncture, distilled Soramdan S, Hae, and Jeobgoldan for 8 months, which led to a significant decrease of the multiple metastases. The patient was able to start walking again with the help of a walking stick. However, a new metastatic lesion was found on the right adrenal gland. This case suggests that the combination of chemotherapy and Korean medicine therapy may be valuable. Further research is indicated.\n\nKeywords\nKorean medicine therapyBreast cancerWild ginseng pharmacopunctureSoramdan SHaeJeobgoldan\n==== Body\nIntroduction\nBreast cancer is the second most prevalent cancer among women following thyroid cancer. In 2010, 14,277 (14.3%) out of 99,339 cancer cases found in female patients were breast cancers. The age-adjusted incidence rate of female breast cancer per 100,000 people increased from 24.5 in 1999 to 45.4 in 2010, with a 6% annual increase [1]. Breast cancer is prone to relapse and metastases: about 40% of patients who receive radical mastectomy suffer a relapse, with a high probability of developing metastases in the bones, lung, liver, lymph nodes, chest wall, and brain, among others [2].\n\nWe report the case of a HER2 3+ breast cancer patient who was diagnosed with liver, mesentery, retroperitoneum, and whole-body bone metastases. After having received chemotherapy with paclitaxel and trastuzumab, the patient decided to suspend chemotherapy due to vancomycin-resistant enterococci (VRE) and general weakness. Subsequently, she received Korean medicine therapy for 8 months, which led to a significant reduction of multiple bone and liver metastases among others.\n\nCase Presentation\nThe patient was a 45-year-old South Korean woman who was diagnosed in August 2012 with right invasive ductal carcinoma (T1N0M0) at a Medical Center in Seoul. She was recommended to undergo mastectomy but refused it. After refusing to receive any treatment for the tumor for 3 years, she was eventually hospitalized at a university hospital located in Seoul due to severe back pain, jaundice, and ascites. The PET-CT examination performed on October 19, 2015, showed right breast cancer and metastases in the liver, mesentery, retroperitoneum, both pelvic bones, cranium, whole-body bone, as well as pleural effusion and ascites. Due to the extreme probability of whole-body fractures as a result of multiple bone metastases, the patient was maintained in absolute bed rest. The biopsy results for estrogen receptor, progesterone receptor, and HER2 were +, –, and 3+, respectively. After chemo-port insertion, on October 28, 2015, first-line trastuzumab and paclitaxel treatment was performed by using palliative chemotherapy, followed by ascites and pleural effusion puncture. However, the chemo-port was removed due to port infection. From November 2, 2015, the patient began Korean medicine therapy after she was prescribed oral herbal medicine at Soram Korean Medicine Hospital. On November 20, 2015, second-line therapy was carried out with only trastuzumab, and, from December 13 to December 24, 2015, vancomycin and tazoperan were administered to treat gram-positive and gram-negative sepsis. Abdominal CT and bone scan performed on December 28, 2015, showed a reduction of multiple liver metastases in comparison to the previous result. However, it seemed to be combined with contraction of the liver parenchyma, and ascites and peritoneum metastasis were still visible. Pleural effusion on both sides increased, and, despite a slight decrease of bone metastases in some areas, new lesions were found on the sternum, left third and fourth ribs, and right acetabulum. After third-line chemotherapy with trastuzumab and paclitaxel on December 30, 2015, the patient was found to have VRE and gave up chemotherapy. Later, from January 22, 2016, to August 8, 2016, the patient received only Korean medicine therapy, which was evaluated based on CT and PET-CT performed at the university hospital where she had previously received chemotherapy. The abdominal CT image on May 30, 2016, showed a noticeable reduction of the liver metastasis lesion as well as scar and contraction of the liver parenchyma. Bone metastasis was still present. When compared to the test carried out on October 19, 2015, the PET-CT result on August 8, 2016, showed a significant reduction of the tumor size in the right breast, the primary site of the tumor, as well as of the right axillary lymph node, liver, and bone metastases. However, on the right adrenal gland, a possible new metastatic tumor appeared (Table 1; Fig. 1, Fig. 2, Fig. 3).\n\nThe Korean medicine therapy provided to the patient between November 2, 2015, and August 8, 2016, was based on oral administration of wild ginseng pharmacopuncture (WGP), distilled Soramdan S, Hae, and Jeobgoldan. WGP was used every day or every other day, while Soramdan S and Hae were administered every day or 3 times per week. Jeobgoldan was administered twice per day.\n\nDiscussion\nModern medical treatment options for breast cancer include surgery, chemotherapy, and radiotherapy. The patient reported above refused treatment, despite the early diagnosis that would have allowed her to receive the relevant surgery, and, after about 3 years, she was diagnosed with stage 4 breast cancer with multiple whole-body metastases in the lymph nodes, bones, and liver. Chemotherapy using paclitaxel and trastuzumab was carried out until the second line, and, the CT result in December 2015 showed improvement in the liver metastasis. However, the amount of pleural effusion increased, and the patient was still unable to walk due to multiple bone metastases. Also, as a result of repeated infections and fever caused by VRE, the patient's general condition severely deteriorated. After third-line chemotherapy, the patient decided to stop chemotherapy, and, instead, used only Korean medicine therapy. After 8 months of therapy, overall multiple bone metastasis as well as liver and multiple lymph node metastasic lesions were significantly reduced, allowing the patient to walk on her own with the assistance of a walking stick.\n\nFor the Korean medicine therapy, intravenous pharmacopuncture and oral herbal medicine were prescribed. For intravenous pharmacopuncture, the Korean medicine doctor injects liquid medicine made with medicinal herbs into the relevant acupuncture spot or vein. Oral herbal medicine is made by using one or more medicinal herbs in either pills or distillate that can be orally administered to the patient.\n\nAll of the intravenous pharmacopuncture and oral herbal medicine was prepared in the pharmacy of our hospital. To make WGP, 100 g cultivated wild ginseng was mixed with distilled water before distilling it for 2 h. Then, the residue was separated, and the distillate was boiled by using the extractive distiller in a white room to obtain 1,000 mL intravenous pharmacopuncture liquid, which was then filtered twice by using 0.45- and 0.2-μm filter papers. Subsequently, a measured amount of the liquid was placed into a sterilized container and sealed before being sterilized again in a sterilizer. Soramdan S was made by pulverizing wild ginseng and ginseng treated with high temperature and pressure and mixing them at a ratio of 7: 3. Then, the powder mixture was mixed with the same amount of honey, which was then prepared as 8-g pills, wrapped in gold foils. To make Hae 50 distilled medicine, milk vetch root and ginger were mixed at a 1: 1 ratio and, after mixing with distilled water, distilled for 4 h by using an extractive distiller. Then, it was diluted in the 5-times saline solution, and placed in a 50 cc glass bottle for oral administration. Jeobgoldan was made of Davallia mariesii Moore, Paeonia obovata Max., Elephas species, Cnidium officinale Makino, Zanthoxylum mantschuricum, Ligusticum acutilobum S. et Z., Chinemys reevesii (Gray), pyrite, Carthamus tinctorius L., Commiphora myrrha Engl., Angelica anomala Lallemant, Prunus humilis Bunge, and Boswellia neglecta M. Moore at a ratio of 15: 15: 15: 15: 15: 15: 15: 10: 10: 2:2: 2:2. The result was 2,000-mg round pills which are 2 mm in diameter and 100 mg per pill, and single dose of which is 20 pills (Table 2).\n\nRecently, the use of WGP and Soramdan S for tumor treatment has been reported in multiple studies. Lee et al. [3] performed Korean medicine therapy by using WGP, PVP (Prunella vulgaris pharmacopuncture), Soramdan, and Hangamdan S for treating lesions of lymph node metastasis remaining after wedge resection on the lung metastasis in a patient with stage 4 breast cancer. As a result, the lymph node metastasis was eliminated and, after 6 months of treatment, the patient did not show a relapse [3]. Soramdan S contains ginsenoside Rg3 and Rh2. It was shown that treatment of cancer cells in vivo and in vitro with Rg3 results in a reduction of proliferation, metastasis, and mortality [4, 5, 6, 7, 8]. Ginsenoside Rh2 has been shown to have an antiproliferative effect on human non-small cell lung cancer. Rh2 is able to block cell proliferation, cause G1 phase arrest, enhance the activity of capase-3, and induce apoptosis in non-small cell lung cancer A549 cells [9, 10].\n\nThe main ingredients of Hae are milk vetch root and ginger. Ye et al. [11] reported that Astragalus membranaceus polysaccharide can inhibit the proliferation of basal-like breast cancer cell line MDA-MB-468 and downregulate the expression of Akt phosphorylation. Elkady et al. [12] reported that Zingiber officinale treatment suppressed the proliferation and colony formation in breast cancer cell lines MCF-7 and MDA-MB-231.\n\nJeobgoldan is prescribed to treat fracture and bone parenchyma damage. Among its ingredients, extracts of drynariae rhizoma, paeoniae radix alba, and carthamus tinctorius have been reported in several studies to suppress osteoclast differentiation induced by receptor activator for nuclear factor κB ligand (RANKL) at bone marrow-derived macrophages without cytotoxicity in a dose-dependent manner [13, 14, 15].\n\nIn this case, during the early stage of treatment, third-line chemotherapy was carried out and part of the liver and bone metastases seemed to have been reduced. However, considering that the amount of pleural effusion had increased, with new lesions of bone metastasis, and that the patient was still unable to walk, it was unlikely that the tumor was being effectively treated. After the patient suspended chemotherapy due to VRE infection and general weakness, she received only Korean medicine therapy for 8 months without any chemotherapy or radiotherapy. As a result of the Korean medicine therapy, the multiple bone and liver metastases were significantly reduced, and the patient was able to walk again with the assistance of a walking stick. However, continuous Korean medicine therapy or chemotherapy may be necessary as new metastatic lesions were found on the right adrenal gland and could develop into a tumor in the future.\n\nIt is not reasonable to draw a decisive conclusion on the effectiveness of Korean medicine therapy for breast cancer based on this case alone. However, in case breast cancer patients refuse chemotherapy voluntarily or cannot receive chemotherapy due to general weakness, this and other similar reports can provide a clue for the active use of WGP, Soramdan S, Hae, and Jeobgoldan for treating multiple metastases including bone and liver metastases of breast cancer in the future. Future reports and clinical research will need to further demonstrate the effectiveness of Korean medicine therapy.\n\nStatement of Ethics\nThe authors have no ethical conflicts to disclose.\n\nDisclosure Statement\nThe authors have no conflicts of interest to declare.\n\nFig. 1 Radiological images showing the Korean medicine therapy and chemotherapy effects as well as those of Korean medicine therapy alone. a Abdominal CT image showing multiple liver metastases on October 18, 2015. b Abdominal CT image showing multiple liver metastases on December 28, 2015. c Abdominal CT image showing decreased multiple liver metastases on May 30, 2016. d Chest CT image showing pleural effusion on October 18, 2015. e Chest CT image showing increased pleural effusion on December 28, 2015. f Chest CT image showing that pleural effusion almost disappeared on May 30, 2016.\n\nFig. 2 Upper-body bone scan images showing the Korean medicine therapy and chemotherapy effects as well as those of Korean medicine therapy alone. a Upper-body bone scan image showing multiple bone metastases on October 20, 2015. b Upper-body bone scan image showing newly increased uptake in the sternal body as well as the left third and fourth ribs on December 28, 2015.\n\nFig. 3 PET-CT images showing the Korean medicine therapy and chemotherapy effects as well as those of Korean medicine therapy alone. a PET-CT image showing right breast tumor as well as multiple lymph node, liver, and bone metastases on October 19, 2015. b PET-CT image showing markedly decreased multiple lymph node, liver, and bone metastases in August 8, 2016.\n\nTable 1 Radiological image reading of Korean medicine therapy and chemotherapy\n\nDate and method of inspection\tImage reading\t\nOctober 18, 2015 CT\tMultiple low-attenuating lesions with rim enhancement are scattered in the liver, probably metastases\t\n\tMild swelling of the pancreatic head with peripancreatic infiltration and moderate ascites, rule out acute pancreatitis, without parenchymal necrosis\t\n\tMultiple mesenteric and left gastric LNs are probably reactive ones (differential diagnosis LN metastasis)\t\n\tMultiple osteolytic lesions involving the axial skeleton and pelvic bone, probably bone metastases Bilateral pleural effusion\t\n\t\nOctober 19, 2015 PET-CT\tMalignant tumor in the right breast\t\n\tMetastatic tumors involving both hepatic lobes\t\n\tMild pancreatitis Ascites\t\n\tLNs with increased FDG uptake in the mesentery, retroperitoneum, bilateral iliac chains are more likely to be metastatic LNs\t\n\tDiffuse skeletal metastases\t\n\tRight pleural effusion\t\n\t\nOctober 20, 2015 Bone scan\tDiffusely increased uptakes in the skull, whole axial and proximal appendicular long bones, suggestive of diffuse bone metastases\t\nDecember 28, 2015 CT Bone scan\tDecreased extent of previous multiple metastases, combined with liver parenchymal contraction Ascites with irregular peritonitis along the bilateral paracolic gutters and pelvic peritoneum; suspicion of early carcinomatosis\t\n\tIncreased amount of bilateral plural effusion\t\n\tDiffuse bone metastasis\t\n\tSlightly decreased intensity of known metastases in the skull, whole axial and proximal appendicular long bones\t\n\tNewly developed increased uptake in the right acetabulum, sternal body, and left third and fourth ribs\t\n\t\nMay 30, 2016 CT\tConsiderably decreased multiple low attenuating lesions in the liver\t\n\tScar and contraction of liver parenchyma of the right lobe of the liver\t\n\tEccentric thickening of the bowel wall from gall bladder metastasis or chronic cholecystitis\t\n\tEndurable sclerotic lesions in the spine and pelvic bone suggest bony metastasis\t\n\t\nAugust 8, 2016 PET-CT\tOverall, decrease in size of known breast cancer involvement in the right breast, right axillary LNs, liver, and bone, with viable malignancy\t\n\tSlight decrease in size of the primary tumor in the right breast\t\n\tStill intense, mass-like FDG uptake in the bones, predominantly axial skeleton\t\n\tDecreased but residual irregular uptake in the liver\t\n\tNewly developed right adrenal mass with increased FDG uptake, suggestive of metastasis\t\nLN, lymph node; FDG, fluorodeoxyglucose.\n\nTable 2 Prescription of Jeobgoldan\n\nJeobgoldan Herb\tLatin botanical name\tRelative amount, mg\t\n\tDavallia mariesii Moore\t225.5\t\n\tPaeonia obovata Max.\t225.5\t\n\tElephas Species\t225.5\t\n\tCnidium officinale Makino\t225.5\t\n\tZanthoxylum mantschuricum\t225.5\t\n\tLigusticum acutilobum S. et Z.\t225.5\t\n\tChinemys reevesii (Gray)\t225.5\t\n\tPyrite\t150.4\t\n\tCarthamus tinctorius L.\t150.4\t\n\tCommiphora myrrha Engl.\t30.1\t\n\tAngelica anomala Lallemant\t30.1\t\n\tPrunus humilis Bunge\t30.1\t\n\tBoswellia neglecta M. Moore\t30.1\t\n\t\nTotal amount (1 dose)\t1,999.7\n==== Refs\nReferences\n1 Ministry of Health and Welfare National Cancer Center Annual Report of Cancer Statistics in Korea in 2010. 2012 The Korea Central Cancer Registry \n2 Jung KH Special review: personalized therapy for advanced breast cancer using molecular signatures Korean J Med 2009 77 26 34 \n3 Lee DH Seong S Kim SS Kim NR Han JB Korean medicine therapy as a substitute for chemotherapy for metastatic breast cancer: a case report Case Rep Oncol 2015 8 64 71 25848354 \n4 Fishbein AB Wang CZ Li XL Asian ginseng enhances the anti-proliferative effect of 5-fluorouracil on human colorectal cancer: comparison between white and red ginseng Arch Pharm Res 2009 32 505 513 19407967 \n5 Wang CZ Aung HH Zhang B Chemopreventive effects of heat-processed Panax quinquefolius root on human breast cancer cells Anticancer Res 2008 28 2545 2551 19035277 \n6 Xu TM Cui MH Xin Y Inhibitory effect of ginsenoside Rg3 on ovarian cancer metastasis Chin Med J (Engl) 2008 121 1394 1397 18959116 \n7 Lishi H Tatsuta M Baba M Inhibition by ginsenoside Rg3 of bombesin-enhanced peritoneal metastasis of intestinal adenocarcinomas induced by azoxymethane in Wistar rats Clin Exp Metastasis 1997 15 603 611 9344044 \n8 Chen J Peng H Ou-Yang X Research on the antitumor effect of ginsenoside Rg3 in B16 melanoma cells Melanoma Res 2008 18 322 329 18781130 \n9 Zhang C Yu H Hou J Effects of 20 (S)-ginsenoside Rh2 and 20 (R)-ginsenoside Rh2 on proliferation and apoptosis of human lung adenocarcinoma A549 cells (in Chinese) Zhongguo Zhong Yao Za Zhi 2011 36 1670 1674 22007558 \n10 Cheng CC Yang SM Huang CY Chen JC Chang WM Hsu SL Molecular mechanisms of ginsenoside Rh2-mediated G1 growth arrest and apoptosis in human lung adenocarcinoma A549 cells Cancer Chemother Pharmacol 2005 55 531 540 15739095 \n11 Ye MN Chen HF Zhou RJ Liao MJ Effects of Astragalus polysaccharide on proliferation and Akt phosphorylation of the basal-like breast cancer cell line (in Chinese) Zhong Xi Yi Jie He Xue Bao 2011 99 1339 1346 \n12 Elkady AI Abuzinadah OA Baeshen NA Rahmy TR Differential control of growth, apoptotic activity, and gene expression in human breast cancer cells by extracts derived from medicinal herbs Zingiber officinale J Biomed Biotechnol 2012 2012 614356 22969274 \n13 Kwak SC Moon SY Kwack HB Jeon BH Min OJ Choi MK Kim JJ Jang SJ Effect of drynariae rhizoma in RANKL-induced osteoclast differentiation Korean J Orient Med Physiol Pathol 2012 26 506 510 \n14 Park BR Park GH Gu DR Ko WM Kim YC Lee SG Inhibitory effect of paeoniae radix alba ethanol extract on oseoclast differentiation and formation Korean J Orient Med Physiol Pathol 2015 29 51 57 \n15 Ann JY Kim JH Ki JY Kwak HB Oh JM Kim YK Inhibitory effects of water extract of cervi parvum cornu, carthami tinctorii fructus and their combination on osteoclast differentiation and bone resorption J Korean Orient Med Prescription 2010 18 167 182\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1662-6575",
"issue": "10(1)",
"journal": "Case reports in oncology",
"keywords": "Breast cancer; Hae; Jeobgoldan; Korean medicine therapy; Soramdan S; Wild ginseng pharmacopuncture",
"medline_ta": "Case Rep Oncol",
"mesh_terms": null,
"nlm_unique_id": "101517601",
"other_id": null,
"pages": "27-36",
"pmc": null,
"pmid": "28461813",
"pubdate": "2017",
"publication_types": "D002363:Case Reports",
"references": "18781130;19035277;22007558;15739095;18959116;22969274;9344044;19407967;25848354;22152773",
"title": "A Case Report of Metastatic Breast Cancer Treated with Korean Medicine Therapy as a Substitute for Chemotherapy.",
"title_normalized": "a case report of metastatic breast cancer treated with korean medicine therapy as a substitute for chemotherapy"
} | [
{
"companynumb": "KR-AXELLIA-001096",
"fulfillexpeditecriteria": "1",
"occurcountry": "KR",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": null,
"drugadditional": null,
"drugadministrationroute": null,
"drugauthorizatio... |
{
"abstract": "Anticoagulation after total joint arthroplasty has been demonstrated to reduce venous thromboembolism. However, anticoagulation can lead to adverse bleeding events. The purpose of this study was to assess if an association exists between specific anticoagulation modalities, such as clopidogrel, and postoperative gastrointestinal (GI) bleeding.\nA prospective cohort of Medicare patients undergoing total joint arthroplasty from 2017 to 2019 (3535 patients) was retrospectively reviewed. The baseline characteristics and anticoagulation methods were compared between the \"GI bleed\" cohort and the \"non-GI bleed cohort.\" Independent t-tests were conducted for continuous variables, while chi-squared analysis was conducted for dichotomous variables.\nThirteen patients (0.42%) sustained a postoperative complication of a GI bleed. The mean age for patients sustaining a GI bleed was 69.23 years compared with 72.30 years for the non-GI bleed cohort (P = .11). Six patients who sustained a GI bleed (46%) were on an anticoagulation therapy other than aspirin, and this trended toward significance (P = .09). Five patients who sustained a GI bleed (38%) were on clopidogrel (P < .01). Seven percent of patients on clopidogrel sustained a postoperative GI bleed (P < .01). None of the patients who sustained a postoperative GI bleed had a history of peptic ulcer disease.\nPatients on clopidogrel in the acute perioperative period demonstrated a strong association with the complication of postoperative GI bleeding. Arthroplasty surgeons should be aware of this association to educate and monitor patients on clopidogrel therapy and to work as part of interdisciplinary teams to assess the risks vs benefits of perioperative clopidogrel.",
"affiliations": "Investigation Conducted at New York University Langone Orthopaedic Hospital, New York, NY, USA.;Investigation Conducted at New York University Langone Orthopaedic Hospital, New York, NY, USA.;Investigation Conducted at New York University Langone Orthopaedic Hospital, New York, NY, USA.;Investigation Conducted at New York University Langone Orthopaedic Hospital, New York, NY, USA.;Investigation Conducted at New York University Langone Orthopaedic Hospital, New York, NY, USA.",
"authors": "Kugelman|David|D|;Teo|Greg|G|;Doran|Michael|M|;Buchalter|Daniel|D|;Long|William J|WJ|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.artd.2021.04.005",
"fulltext": "\n==== Front\nArthroplast Today\nArthroplast Today\nArthroplasty Today\n2352-3441\nElsevier\n\nS2352-3441(21)00059-5\n10.1016/j.artd.2021.04.005\nOriginal Research\nThe Association Between Clopidogrel and Gastrointestinal Bleeding After Primary Total Joint Arthroplasty\nKugelman David MD\nTeo Greg MD\nDoran Michael MD\nBuchalter Daniel MD\nLong William J. MD, FRCSC doctor_long@hotmail.com\n∗\nInvestigation Conducted at New York University Langone Orthopaedic Hospital, New York, NY, USA\n∗ Corresponding author. Department of Orthopaedics, New York University Langone Orthopaedic Hospital, 14th floor, 301 East 17 St, Manhattan New York 10003, USA. doctor_long@hotmail.com\n15 5 2021\n6 2021\n15 5 2021\n9 6164\n23 10 2020\n10 3 2021\n3 4 2021\n© 2021 The Authors\n2021\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).\nBackground\n\nAnticoagulation after total joint arthroplasty has been demonstrated to reduce venous thromboembolism. However, anticoagulation can lead to adverse bleeding events. The purpose of this study was to assess if an association exists between specific anticoagulation modalities, such as clopidogrel, and postoperative gastrointestinal (GI) bleeding.\n\nMethods\n\nA prospective cohort of Medicare patients undergoing total joint arthroplasty from 2017 to 2019 (3535 patients) was retrospectively reviewed. The baseline characteristics and anticoagulation methods were compared between the “GI bleed” cohort and the “non-GI bleed cohort.” Independent t-tests were conducted for continuous variables, while chi-squared analysis was conducted for dichotomous variables.\n\nResults\n\nThirteen patients (0.42%) sustained a postoperative complication of a GI bleed. The mean age for patients sustaining a GI bleed was 69.23 years compared with 72.30 years for the non-GI bleed cohort (P = .11). Six patients who sustained a GI bleed (46%) were on an anticoagulation therapy other than aspirin, and this trended toward significance (P = .09). Five patients who sustained a GI bleed (38%) were on clopidogrel (P < .01). Seven percent of patients on clopidogrel sustained a postoperative GI bleed (P < .01). None of the patients who sustained a postoperative GI bleed had a history of peptic ulcer disease.\n\nConclusion\n\nPatients on clopidogrel in the acute perioperative period demonstrated a strong association with the complication of postoperative GI bleeding. Arthroplasty surgeons should be aware of this association to educate and monitor patients on clopidogrel therapy and to work as part of interdisciplinary teams to assess the risks vs benefits of perioperative clopidogrel.\n\nKeywords\n\nTotal joint arthroplasty\nTotal knee arthroplasty\nTotal hip arthroplasty\nComplications following arthroplasty\nGastrointestinal bleeding\n==== Body\nIntroduction\n\nTotal joint arthroplasty (TJA) is one of the most commonly performed and fastest growing orthopedic procedures in the United States [1]. Currently, over one million total knee and total hip arthroplasties (TKA and THA) are performed in the United States on an annual basis [1]. As the population continues to age, there are estimates that by 2030, a nearly 600% increase in the number of TKAs and 200% increase in the number of THAs can be expected [1].\n\nImprovements in surgical technique and peri-operative protocols have contributed to an improvement in morbidity and mortality after TJA. However, complications after TJA are prevalent and still exist [2,3]. As the life expectancy in the United States continues to increase, TJA will be performed in older patients who may be subject to increased complications after these procedures [[4], [5], [6], [7]]. One rare, yet potentially fatal, complication after TJA is gastrointestinal (GI) bleeding [3].\n\nAs an individual ages, comorbidities increase, as seen in the Medicare patient population of those older than 65 years [[7], [8], [9], [10], [11]]. In order to treat cardiac embolic events and other venous thromboembolic events, high-risk patients are often placed on oral anticoagulation [11]. However, anticoagulation therapy does not come without dangers, which include hemorrhagic complications, such as GI bleeding.\n\nClopidogrel is an anticoagulant used in patients with cardiovascular, cerebrovascular, and peripheral vascular diseases [12]. Patients who undergo stenting procedures receive a postoperative dual antiplatelet protocol, which generally includes aspirin in addition to clopidogrel. The American Heart Association and American College of Cardiology recommend dual antiplatelet therapy for at least 1 year after stent placemen [12]. However, no specific guidelines exist with respect to clopidogrel discontinuation, with many patients remaining on the medication for life [12].\n\nClopidogrel has been associated with increased blood transfusions and major blood loss when continued during the perioperative period [13,14]. This has led to recommendations for discontinuation of the drug before elective surgery, when deemed safe by the patient’s cardiologist. However, little is known about hemorrhagic complications with respect to the timing of restarting clopidogrel in the acute perioperative period after TJA. The purpose of this study is to assess if a difference in GI bleeding occurs between patients that were restarted on clopidogrel in the early postoperative period and those that were not, after elective TJA.\n\nMaterial and methods\n\nAfter institutional review board approval, a retrospective review of prospectively collected data of Medicare patients undergoing TJA at our institution from 2017 to September 2019 was analyzed. Demographic data were collected for each patient, which included age, medical history, body mass index (BMI), and American Association of Anesthesiologists (ASA) score. Inpatient medication dispensing was collected, with specific focus on the anticoagulation medication patients received postoperatively. A chart review was performed assessing postoperative complications, including GI bleeding. Medicare patients enrolled in Bundled Payments for Care Improvement (BPCI) are monitored for 90-day complications, even if the complication and readmission are managed at another institution. This makes our GI bleeding rate accurate to monitor postoperative symptomatic complications, even if they were readmitted or seen elsewhere. Patients who underwent arthroplasty for a hip fracture, those who had a unicompartmental knee replacement, and those who had incomplete data were excluded from the analysis.\n\nAll statistical analyses were performed using SPSS software (IBM SPSS). Statistical tests were performed, using chi-squared analysis for categorical variables and students t-tests for continuous variables. Results were statistically significant if the P value < .05.\n\nResults\n\nA total of 3070 patients were included in the final analysis. Of which, 1549 patients underwent TKA, while 1507 patients underwent THA. Peptic ulcer disease was documented for 18 patients (0.59%). A postoperative complication of a GI bleed occurred in 13 patients (0.42%). No patients with a history of peptic ulcer disease sustained a postoperative GI bleed.\n\nThe average age of the cohort was 72.2 years. The average BMI of the cohort was 29.5. With respect to gender, 1023 patients were male (33.4%) while 2046 patients were female (66.6%). With respect to ethnicity, 2490 patients were Caucasian (79.2%), 235 patients were of African American ethnicity (7.7%), 244 patients were of Hispanic ethnicity (7.9%), 74 patients were of Asian ethnicity (2.4%), and 100 patients identified as “other” or refused to document their ethnicity (3.3%). No significant differences were demonstrated between patients sustaining a postoperative GI bleed and those who did not have this complication with respect to age, gender, BMI, ASA, or ethnicity (Table 1).Table 1 Demographics in patients undergoing TJA who sustained a postoperative gastrointestinal bleed and those who did not.\n\nPatient demographics/characteristics\tGastrointestinal bleed cohort (n = 13)\tNongastrointestinal bleed cohort (n = 3056)\tP value\t\nAge (mean)\t69.23 y\t72.30 y\t.36\t\nBMI (mean)\t33.17\t29.49\t.69\t\nGender\t7 males, 6 females\t1016 males, 2040 females\t.11\t\nEthnicity\tCaucasian = 10\nAfrican American = 3\tCaucasian = 2480\nAfrican American = 232\nHispanic = 244\nOther/refused to answer = 100\t.23\t\nAmerican Association of Anesthesiologists (ASA) score\t1 = 0\n2 = 5\n3 = 7\n4 = 1\t1 = 67\n2 = 1483\n3 = 1421\n4 = 85\t.61\t\n\nMost patients (2268 patients, 73.9%) were on only aspirin postoperatively. The remaining 801 patients (26.1%) were on a postoperative anticoagulation medication other than single antiplatelet therapy with aspirin. These other anticoagulants included clopidogrel, heparin, enoxaparin, apixaban, rivaroxaban, dabigatran, fondaparinux, cilastozel, ticragelor, and warfarin. A nonstatistically significant trend was demonstrated between patients who were prescribed nonaspirin chemoprophylaxis and sustaining a GI bleed (P = .09). Clopidogrel was restarted on 70 patients (2.3%) in the acute hospital setting postoperatively. The postoperative complication of a GI bleed (P < .01) was demonstrated in 5 patients on clopidogrel (7.1% of those on the drug). Patients on clopidogrel accounted for 38% of GI bleeds (P < .01).\n\nPerioperative anticoagulation history for patients sustaining a GI bleed and the time point at which the complication occurred are listed in Table 2. Aspirin was prescribed to 12 patients (92%) who sustained a GI bleed—these patients were all prescribed 81 mg bid. All patients sustaining a GI bleed received both toradol and a non-steroidal anti-inflammatory drug (NSAID) during their hospital stay. Celecoxib was given to 6 of these patients (46%), meloxicam was given to 5 patients (38%), and 2 patients (15%) were on both celecoxib and meloxicam during their hospitalization. All patients who sustained a GI bleed received at least 3 NSAIDs during their hospital stay, and 2 patients (15%) were prescribed 4 NSAIDs. GI protective medications such as protonix or famotidine were prescribed to 11 of the patients (84.6%) who sustained a GI bleed. There was no documentation on why 2 patients (15%) did not receive perioperative GI prophylaxis. All patients receiving clopidogrel who sustained a GI bleed had a history of a cardiac stent, anywhere between 2 and 15 years before their TJA (mean = 11.2 years). No patients sustaining a GI bleed had any postoperative cardiac embolic events. No patients sustained a GI bleed resulting in mortality. A single patient sustained 2 GI bleeds postoperatively.Table 2 Anticoagulation history and time-point at which postoperative gastrointestinal bleed occurred.\n\n\tAcute postoperative anticoagulation\tProcedure\tPOD gastrointestinal bleed occurred\t\nPatient 1\tAspirin 81 mg BID\tTKA\tPOD#10\t\nPatient 2\tEnoxaparin 30 mg/0.3 ml, q12\tTKA\tPOD#7\t\nPatient 3\tAspirin 81 mg BID, clopidogrel 75 mg restarted POD1\tTHA\tPOD#37\t\nPatient 4\tAspirin 81 mg BID\tTKA\tPOD#92\t\nPatient 5\tAspirin 81 mg BID\tTHA\tPOD#40, POD#50\t\nPatient 6\tAspirin 81 mg BID\tTHA\tPOD#99\t\nPatient 7\tAspirin 81 mg BID, clopidogrel 75 mg restarted POD1\tTHA\tPOD#38\t\nPatient 8\tAspirin 81 mg BID, clopidogrel 75 mg restarted POD1\tTHA\tPOD#41\t\nPatient 9\tAspirin 81 mg BID\tTHA\tPOD#53\t\nPatient 10\tAspirin 81 mg BID\tTHA\tPOD#89\t\nPatient 11\tAspirin 81 mg BID\tTHA\tPOD#76\t\nPatient 12\tAspirin 81 mg BID, clopidogrel 75 mg restarted POD1\tTHA\tPOD#88\t\nPatient 13\tAspirin 81 mg BID, clopidogrel 75 mg restarted POD1\tTKA\tPOD#121\t\n\t\tTKA = 4, THA = 9\tMean = 64.7 d\t\nBID, twice daily; POD, postoperative day.\n\nAll patients who sustained a GI bleed and on clopidogrel were restarted on the medication POD#1 (Table 2). All these patients obtained preoperative cardiology clearance. The cardiologists stated that clopidogrel should be held 5-7 days preoperatively in these 5 patients (100%). However, no cardiologist documented a safe time point to resume clopidogrel postoperatively. Documentation to start clopidogrel “ASAP” postoperatively was seen in 1 patient (20%).\n\nDiscussion\n\nOur study demonstrates that symptomatic GI bleeding after TJA in our Medicare population has a prevalence of 0.4%. The GI bleeds identified in this study were all confirmed through endoscopy. The annual incidence of GI bleeding is 0.03% - 0.09% in the general population [[15], [16], [17]]. Pulido et al. demonstrated GI bleeding was found to occur postoperatively in 0.02% of patients undergoing TJA [3]. Adeinkinju et al. demonstrated that GI bleeding occurred in 0.12% of patients in their retrospective review of over 19,000 TJA patients [18]. Our results are in contrast to a study published by Sharma, which demonstrated GI bleeding to occur in 4.5% of patients after TJA [19]. These differing rates likely reflect differences in the sample populations and perioperative anticoagulation protocols associated with TJA.\n\nThere is an increased risk for GI bleeding after surgery [[15], [16], [17], [18], [19]]. Studies have reported numerous risk factors to be associated with GI bleeding such as postoperative anticoagulation, peptic ulcer disease, and NSAID use [18,20,21]. All patients sustaining a GI bleed in this study were on postoperative anticoagulation. Strikingly, more than 7% of patients on postoperative clopidogrel sustained a GI bleed. Patients on clopidogrel accounted for nearly 40% of GI bleeds after TJA. Known peptic ulcer disease did not influence postoperative GI bleeding in this cohort, nor did age. All patients sustaining GI bleeds in our cohort were prescribed a minimum of 3 NSAIDS during their hospitalization. Sustaining a GI bleed after TJA is likely multifactorial and influenced by anticoagulation, NSAIDs, and the stress of surgery on the GI system.\n\nThis is the first study to our knowledge to identify a significant association between postoperative clopidogrel and GI bleeding. This is in contrast to a study performed by Nydick et al., which assessed 970 patients undergoing TJA, in which there was no increase in postoperative GI bleeding in patients taking clopidogrel [22]. Similarly, Nandi et al did not find a correlation with timing of clopidogrel resumption after TJA and postoperative bleeding complications, in 116 patients [23]. However, our study had a cohort size of over 3000 patients, and hence, the power increases compared with the aforementioned literature. In other areas of medicine, increased risks of postoperative bleeding complications have been demonstrated in patients on clopidogrel. In addition, our study included patients that were part of the BPCI initiative; hence, all complications within 90 days were recorded, even when presenting to another institution.\n\nWe did not find an increased risk of GI bleeding to be associated with the use of other anticoagulants besides clopidogrel. Only 1 patient in this study was on an anticoagulant other than aspirin or clopidogrel and sustained a GI bleed. This is in concordance with Faour et al. who demonstrated low-dose aspirin to be safe and effective for venous thromboembolism prophylaxis after TKA [24]. However, other reports have demonstrated potent anticoagulants other than clopidogrel to be associated with an increased risk of GI bleeding. Nielen et al. demonstrated an increased risk of GI bleeding in patients on low-molecular-weight heparin and new oral anticoagulants (direct thrombin inhibitors/direct factor Xa inhibitors) in comparison to those on solely aspirin [25]. This study did not support those findings.\n\nThis study demonstrated GI bleeding after TJA to occur at a mean of 2 months postoperatively. Lalmohamed et al. demonstrated the risk for GI bleeding to be highest during the first 2 weeks after TJA [26]. THA had a 6-fold increase in risk during the first 2 weeks after the procedure, while TKA demonstrated a 2.3-fold risk during this time period. However, the authors concluded that the risk for GI bleeding remained increased for up to 6 weeks after TKA and up to 12 weeks after THA [26]. Their study supports our results and should make physicians aware of the importance of GI bleeding risk assessment and patient education on the signs, symptoms, and prevention of this major complication.\n\nThis study has multiple limitations. First and foremost is the bias that presents with a retrospective review of large databases. In addition, our data did not assess outpatient anticoagulation after TJA; however, it is our institutional policy to continue all postoperative anticoagulation protocol after discharge through 14 days for TKAs and 28 days for THAs, which incorporates recommendations from the American Academy of Orthopedic Surgeons (AAOS), American Association of Hip and Knee Surgeons (AAHKS), and American College of Chest Physicians (ACCP) as aforementioned. A major limitation is the poor power of this analysis due to 13 patients in the GI bleed group. However, this is in concordance with other studies on the topic which demonstrate a small risk of GI bleeds after TJA. The cohort of 13 patients is a likely reason that multiple outcomes were \"trending\" toward significance, but not statistically significant as defined by a P value of <0.05. This study was performed at a major urban academic medical center that was an early participant in the BPCI initiative. Our institution concurrently focused on perioperative optimization of patients known to be at a higher risk of perioperative complications, and this is a potential source of confounding. Therefore, the rates of GI bleeding may be different in community practices with different perioperative protocols. In addition, we were only aware of patients sustaining GI bleeds within 90 days of surgery, and the number of GI bleeds may therefore be underestimated.\n\nConclusions\n\nPatients on clopidogrel in the acute perioperative period demonstrated a strong association with the complication of postoperative GI bleeding. Our study demonstrates that nearly 40% of patients sustaining GI bleeds were on postoperative clopidogrel after their TJA. For the aforementioned patients, TJA was performed at a mean of 11.2 years after their stent procedure. This study raises the following question: Are we, in joint decision-making with our medicine and cardiology colleagues, only evaluating one side of the benefit-risk profile of postoperative clopidogrel, rather than the two-sided issue of thrombosis and bleeding? This study should make physicians aware of the significantly increased risk of GI bleeding after TJA in patients on clopidogrel. We must therefore work in interdisciplinary teams, and engage in evidence-based discussions, to balance the risks and benefits of resuming clopidogrel after TJA. Arthroplasty surgeons should present this information to cardiac and medicine colleagues during patient’s preoperative evaluation, to help this joint decision-making in balancing both risks of GI bleeding and stent thrombosis.\n\nConflicts of 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 article.\n\nAppendix A Supplementary data\n\nConflict of Interest Statement for Teo\n\nConflict of Interest Statement for Kugelman\n\nConflict of Interest Statement for Long\n\nConflict of Interest Statement for Buchalter\n\nConflict of Interest Statement for Doran\n\nThis research was considered IRB exempt as part of the quality improvement initiative at our institution.\n==== Refs\nReferences\n\n1 Kurtz S. Ong K. Lau E. Mowat F. Halpern M. Projections of primary and revision hip and knee arthroplasty in the United States from 2005 to 2030 J Bone Joint Surg Am 89 4 2007 780 17403800\n2 Parvizi J. Johnson B.G. Rowland C. Ereth M.H. Lewallen D.G. Thirty-day mortality after elective total hip arthroplasty JBJS 83 10 2001 1524\n3 Pulido L. Parvizi J. Macgibeny M. In hospital complications after total joint arthroplasty J Arthroplasty 23 6 2008 139 18722311\n4 Kreder H.J. Berry G.K. McMurtry I.A. Halman S.I. Arthroplasty in the octogenarian: quantifying the risks J Arthroplasty 20 3 2005 289 15809944\n5 Berend M.E. Thong A.E. Faris G.W. Newbern G. Pierson J.L. Ritter M.A. Total joint arthroplasty in the extremely elderly: hip and knee arthroplasty after entering the 89th year of life J Arthroplasty 18 7 2003 817 14566733\n6 Kennedy J.W. Johnston L. Cochrane L. Boscainos P.J. Total knee arthroplasty in the elderly: does age affect pain, function or complications? Clin Orthop Relat Res 471 6 2013 1964 23354464\n7 Petersen W.P. Jr. Teo G.M. Friedlander S. Schwarzkopf R. Long W.J. The implications of aging population Demographics on the delivery of primary total joint arthroplasty in a bundled payment system JBJS 2020\n8 DeWilde S. Carey I.M. Emmas C. Richards N. Cook D.G. Trends in the prevalence of diagnosed atrial fibrillation, its treatment with anticoagulation and predictors of such treatment in UK primary care Heart 92 8 2006 1064 16387813\n9 Piccini J.P. Hammill B.G. Sinner M.F. Jensen P.N. Hernandez A.F. Heckbert S.R. Curtis L.H. Incidence and prevalence of atrial fibrillation and associated mortality among Medicare beneficiaries: 1993–2007 Circ Cardiovasc Qual Outcomes 5 1 2012 85 22235070\n10 Pepper A.M. Novikov D. Cizmic Z. Barrett J.T. Collins M. Iorio R. Long W.J. Age and frailty influence hip and knee arthroplasty reimbursement in a bundled payment care improvement initiative J arthroplasty 34 7 2019 S80 30803802\n11 Shroff G.R. Solid C.A. Herzog C.A. Atrial fibrillation, stroke, and anticoagulation in Medicare beneficiaries: trends by age, sex, and race, 1992–2010 J Am Heart Assoc 3 3 2014 e000756 24895161\n12 Fleisher L.A. Beckman J.A. Brown K.A. ACC/AHA 2007 guidelines on perioperative cardiovascular evaluation and care for noncardiac surgery: executive summary: a report of the American College of cardiology/American Heart association task force on practice guidelines (writing committee to revise the 2002 guidelines on perioperative cardiovascular evaluation for noncardiac surgery) Circulation 116 17 2007 1971 17901356\n13 Maltais S. Perrault L.P. Do Q.B. Effect of clopidogrel on bleeding and transfusions after off-pump coronary artery bypass graft surgery: impact of discontinuation prior to surgery Eur J Cardiothorac Surg 34 1 2008 127 18455412\n14 Jacob A.K. Hurley S.P. Loughran S.M. Wetsch T.M. Trousdale R.T. Continuing clopidogrel during elective total hip and knee arthroplasty: assessment of bleeding risk and adverse outcomes J Arthroplasty 29 2 2014 325 23856063\n15 Lanas A. Garcia-Rodriguez L.A. Polo-Tomás M. Time trends and impact of upper and lower gastrointestinal bleeding and perforation in clinical practice Am J Gastroenterol 104 7 2009 1633 19574968\n16 Laine L. Yang H. Chang S.C. Datto C. Trends for incidence of hospitalization and death due to GI complications in the United States from 2001 to 2009 Am J Gastroenterol 107 8 2012 1190 22688850\n17 Hreinsson J.P. Gumundsson S. Kalaitzakis E. Björnsson E.S. Lower gastrointestinal bleeding: incidence, etiology, and outcomes in a population-based setting Eur J Gastroenterol Hepatol 25 1 2013 37 23013623\n18 Adenikinju A.S. Feng J.E. Namba C.A. Luthringer T.A. Lajam C.M. Gastrointestinal complications warranting invasive interventions following total joint arthroplasty J Arthroplasty 34 11 2019 2780 31279602\n19 Sharma S. Upper gastrointestinal bleeding after hip and knee arthroplasty Orthopedics 29 3 2006 255 16539204\n20 Van Leerdam M.E. Epidemiology of acute upper gastrointestinal bleeding Best Pract Res Clin Gastroenterol 22 2 2008 209 18346679\n21 Madhusudhan T.R. Rangan A. Gregg P.J. Gastric protection and gastrointestinal bleeding with aspirin thromboprophylaxis in hip and knee joint replacements Ann R Coll Surg Engl 90 2008 332 18492400\n22 Nydick J.A. Farrell E.D. Marcantonio A.J. Hume E.L. Marburger R. Ostrum R.F. The use of clopidogrel (Plavix) in patients undergoing nonelective orthopaedic surgery J Orthop Trauma 24 2010 383 20502223\n23 Nandi S. Aghazadeh M. Talmo C. Robbins C. Bono J. Perioperative clopidogrel and postoperative events after hip and knee arthroplasties Clin Orthop Relat Res 470 5 2012 1436 22402810\n24 Faour M. Piuzzi N.S. Brigati D.P. Low-dose aspirin is safe and effective for venous thromboembolism prophylaxis following total knee arthroplasty J Arthroplasty 33 7 2018 S131 29656974\n25 Nielen J.T. Dagnelie P.C. Emans P.J. Veldhorst-Janssen N. Lalmohamed A. van Staa T.P. de Vries F. Safety and efficacy of new oral anticoagulants and low molecular weight heparins compared with aspirin in patients undergoing total knee and hip replacements Pharmacoepidemiol Drug Saf 25 11 2016 1245 27594378\n26 Lalmohamed A. Vestergaard P. Javaid K.M. Risk of gastrointestinal bleeding in patients undergoing total hip or knee replacement compared with matched controls: a nationwide cohort study Am J Gastroenterol 108 8 2013 1277 23629603\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2352-3441",
"issue": "9()",
"journal": "Arthroplasty today",
"keywords": "Complications following arthroplasty; Gastrointestinal bleeding; Total hip arthroplasty; Total joint arthroplasty; Total knee arthroplasty",
"medline_ta": "Arthroplast Today",
"mesh_terms": null,
"nlm_unique_id": "101681808",
"other_id": null,
"pages": "61-64",
"pmc": null,
"pmid": "34041330",
"pubdate": "2021-06",
"publication_types": "D016428:Journal Article",
"references": "18722311;31279602;22688850;15809944;24895161;23013623;22235070;23856063;18492400;27594378;18346679;14566733;17403800;30803802;20502223;22402810;18455412;16539204;23629603;29656974;11679603;23354464;19574968;33027121;17901356;16387813",
"title": "The Association Between Clopidogrel and Gastrointestinal Bleeding After Primary Total Joint Arthroplasty.",
"title_normalized": "the association between clopidogrel and gastrointestinal bleeding after primary total joint arthroplasty"
} | [
{
"companynumb": "US-BAYER-2021-153144",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CLOPIDOGREL BISULFATE"
},
"drugadditional": null,... |
{
"abstract": "Background: The use of the natural product, kratom, has increased significantly in recent years. The active compounds in kratom have been shown to produce both opioid and stimulant-like effects. While kratom is marketed as a safe, non-addictive method to treat pain and opioid withdrawal, there have been reports demonstrating that kratom is physiologically addictive and linked to overdose deaths. A limited number of case-reports are available describing treatment of kratom use disorder in middle-aged adults, generally in the context of chronic pain and in inpatient settings. Our case is unique in that we describe outpatient treatment of kratom use disorder in a young adult with comorbid attention deficit hyperactivity disorder (ADHD) and in the absence of chronic pain. Case: A 20-year-old college student with ADHD presented to an office-based opioid agonist treatment clinic (OBOT) for treatment of kratom use disorder. He was unable to attend inpatient or residential substance use treatment due to work and school obligations. Additionally, he had stopped taking his prescribed stimulant due to cardiac side effects. The OBOT team successfully initiated buprenorphine-naloxone (BUP/NAL) sublingual films via home induction to treat his kratom use disorder. The patient is being monitored monthly with plans to slowly taper his BUP/NAL dose as tolerated. Discussion: We present a case of a young adult male with kratom use disorder, complicated by a diagnosis of ADHD, successfully treated with BUP/NAL via home induction. The patient is currently kratom-free, reports improved mood and sleep patterns since initiating BUP/NAL, and is able to once again tolerate his ADHD stimulant medication. Healthcare providers should be aware of the use of kratom and consider utilizing BUP/NAL to treat dependence to this botanical drug.",
"affiliations": "The College of Pharmacy, The Ohio State University, Columbus, Ohio, USA.;The College of Medicine, The Ohio State University, Columbus, Ohio, USA.;Division of Adolescent Medicine, Nationwide Children's Hospital, Columbus, Ohio, USA.;The College of Medicine, The Ohio State University, Columbus, Ohio, USA.",
"authors": "Schmuhl|Kelsey K|KK|;Gardner|Spencer M|SM|;Cottrill|Casey B|CB|0000-0002-8126-4950;Bonny|Andrea E|AE|0000-0001-5874-1942",
"chemical_list": "D000069479:Buprenorphine, Naloxone Drug Combination; D000697:Central Nervous System Stimulants; D009292:Narcotic Antagonists; D003913:Dextroamphetamine",
"country": "United States",
"delete": false,
"doi": "10.1080/08897077.2019.1671945",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0889-7077",
"issue": "41(3)",
"journal": "Substance abuse",
"keywords": "Kratom; Mitragyna speciosa; adolescence; buprenorphine-naloxone; substance use",
"medline_ta": "Subst Abus",
"mesh_terms": "D000553:Ambulatory Care; D001289:Attention Deficit Disorder with Hyperactivity; D000069479:Buprenorphine, Naloxone Drug Combination; D000697:Central Nervous System Stimulants; D003913:Dextroamphetamine; D006801:Humans; D008297:Male; D032065:Mitragyna; D009292:Narcotic Antagonists; D019966:Substance-Related Disorders; D055815:Young Adult",
"nlm_unique_id": "8808537",
"other_id": null,
"pages": "311-314",
"pmc": null,
"pmid": "31644379",
"pubdate": "2020",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Home induction and outpatient treatment of kratom use disorder with buprenorphine-naloxone: A case report in a young adult.",
"title_normalized": "home induction and outpatient treatment of kratom use disorder with buprenorphine naloxone a case report in a young adult"
} | [
{
"companynumb": "US-DRREDDYS-USA/USA/19/0116269",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "BUPRENORPHINE\\NALOXONE"
},
"drugadditio... |
{
"abstract": "Flubromazolam is a potent triazole benzodiazepine with moderately long-lasting central nervous system-depressant effects relative to other benzodiazepines such as commonly prescribed diazepam. Flubromazolam has been studied in the living. However, there are no published reports including measured drug concentrations in post-mortem cases. We report five cases in which flubromazolam was detected in a systematic screen using high-resolution mass spectrometry and then quantified in femoral blood. In none of the five cases was the cause of death directly attributed to flubromazolam toxicity, as there was a variety of both sedative and stimulant drugs also present. However, it is important that the drug concentrations that were measured are made available for future post-mortem forensic interpretation.",
"affiliations": "University Hospital of the West Indies, Jamaica.;Forensic Toxicology Service, University Hospitals of Leicester NHS Trust, UK.;Forensic Toxicology Service, University Hospitals of Leicester NHS Trust, UK.;Analytical Services International, St George's University of London, UK.;Analytical Services International, St George's University of London, UK.;Analytical Services International, St George's University of London, UK.;Forensic Toxicology Service, University Hospitals of Leicester NHS Trust, UK.",
"authors": "Abdul|Kemba|K|;Hikin|Laura|L|;Smith|Paul|P|;Kurimbokus|Hassan|H|;Ashong|Emily|E|;Couchman|Lewis|L|;Morley|Stephen R|SR|https://orcid.org/0000-0001-9715-8936",
"chemical_list": "D015198:Designer Drugs; D001569:Benzodiazepines; C000628386:flubromazolam",
"country": "England",
"delete": false,
"doi": "10.1177/0025802420950273",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0025-8024",
"issue": "60(4)",
"journal": "Medicine, science, and the law",
"keywords": "Flubromazolam; designer benzodiazepine; post-mortem toxicology",
"medline_ta": "Med Sci Law",
"mesh_terms": "D000328:Adult; D001344:Autopsy; D001569:Benzodiazepines; D015198:Designer Drugs; D005260:Female; D053593:Forensic Toxicology; D006801:Humans; D008297:Male; D013058:Mass Spectrometry; D008875:Middle Aged; D015813:Substance Abuse Detection",
"nlm_unique_id": "0400721",
"other_id": null,
"pages": "266-269",
"pmc": null,
"pmid": "32838670",
"pubdate": "2020-10",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Flubromazolam: Detection in five post-mortem cases.",
"title_normalized": "flubromazolam detection in five post mortem cases"
} | [
{
"companynumb": "JM-PFIZER INC-2020357292",
"fulfillexpeditecriteria": "1",
"occurcountry": "JM",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CLOZAPINE"
},
"drugadditional": null,
... |
{
"abstract": "We report the first case of pregnancy in a pediatric patient with catecholiminergic polymorphic ventricular tachycardia (CPVT). Pregnant adolescents with CPVT are at high risk for NSVT and malignant VT during pregnancy, despite antiarrhythmic medication. They may receive multiple implantable cardioverter defibrillator (ICD) therapies. Such patients require close monitoring with special care during the first trimester.",
"affiliations": "Department of Pediatrics West Virginia University-Charleston Area Medical Center 830 Pennsylvania Avenue Suite 102 Charleston West Virginia 25302.;Department of Pediatric Cardiology Ruby Memorial Hospital West Virginia University-Morgantown P.O. Box 9214 Morgantown West Virginia 26506.",
"authors": "Ahmed|Aziez|A|;Phillips|John R|JR|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1002/ccr3.366",
"fulltext": "\n==== Front\nClin Case RepClin Case Rep10.1002/(ISSN)2050-0904CCR3Clinical Case Reports2050-0904John Wiley and Sons Inc. Hoboken 10.1002/ccr3.366CCR3366Case ReportCase ReportsTeenage pregnancy with catecholaminergic polymorphic ventricular tachycardia and documented ICD discharges A. Ahmed & J. R. PhillipsAhmed Aziez \n1\nPhillips John R. \n2\n1 Department of PediatricsWest Virginia University‐Charleston Area Medical Center830 Pennsylvania AvenueSuite 102CharlestonWest Virginia253022 Department of Pediatric CardiologyRuby Memorial HospitalWest Virginia University‐MorgantownP.O. Box 9214MorgantownWest Virginia26506* Correspondence\n\nAziez Ahmed, Department of Pediatrics, West Virginia University‐Charleston Area Medical Center, 830 Pennsylvania Avenue, Suite 102, Charleston, WV 25302. Tel: +14094431238; Fax: (304) 388‐9949; E‐mail: aziezahmed@hotmail.com\n02 3 2016 4 2016 4 4 10.1111/ccr3.2016.4.issue-4361 365 24 2 2015 07 6 2015 25 7 2015 © 2016 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.Key Clinical Message\nWe report the first case of pregnancy in a pediatric patient with catecholiminergic polymorphic ventricular tachycardia (CPVT). Pregnant adolescents with CPVT are at high risk for NSVT and malignant VT during pregnancy, despite antiarrhythmic medication. They may receive multiple implantable cardioverter defibrillator (ICD) therapies. Such patients require close monitoring with special care during the first trimester.\n\nAdolescentcatecholimergic polymorphic ventricular tachycardiadischargesimplantable cardioverter defibrillatorpediatricpregnancypregnantteenage pregnancy source-schema-version-number2.0component-idccr3366cover-dateApril 2016details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:4.8.6 mode:remove_FC converted:09.04.2016\n\nClinical Case Reports \n2016 ; 4 (4 ): 361 –365\n==== Body\nIntroduction\nThere is a paucity of information regarding pregnant women with an implantable cardioverter defibrillator (ICD) who have received documented discharges during pregnancy. Catecholiminergic polymorphic ventricular tachycardia (CPVT) is a calcium channelopathy that causes malignant polymorphic ventricular tachycardia (PVT) with adrenergic stimulation, and can be triggered by emotional or physical stress such as may be experienced in pregnancy 1, 2. We report a case of a pregnant teenager with CPVT who received documented ICD discharges during her pregnancy.\n\nCase Report\nIn early 2004 a 12‐year‐old female with a history of syncope during exercise was evaluated. Physical examination was normal. Her resting 12‐lead electrocardiogram and echocardiogram were within normal limits. Her cardiac MRI demonstrated normal findings without evidence of arrythmogenic right ventricular dysplasia (ARVD). Her pattern of highly malignant PVT triggered by adrenergic stimulation in the absence of structural heart disease or ECG abnormalities in a patient less than 40 years of age was thought consistent with CPVT 3.\n\nShe underwent an electrophysiologic (EP) study, which demonstrated inducible and reproducible non‐sustained polymorphic ventricular tachycardia. An ICD (Medtronic Marquis defibrillator model # 7230CX, Medtronic plc, Dublin, Ireland) was placed in the left infraclavicular area and a ventricular lead (model 6947) was implanted in the right ventricle via the left subclavian vein. Successful conversion of tachycardia with a 10 J shock was recorded. The patient was placed on daily atenolol.\n\nSince implantation, the patient has had multiple episodes of appropriate device therapy for PVT, all of which were preceded by a provoking event. This was frequently followed by a subsequent shock because of catecholamine release from the first shock.\n\nIn early 2009 the patient conceived her first child at the age of 17 years. She was seen in the pacemaker clinic at 10 weeks gestation by last menstrual period (LMP). At that time she was on atenolol, 50 mg twice a day. Her device settings that day were pacing mode VVI with a lower rate of 45 bpm, amplitude of 2.5 V, pulse width of 0.6 msec, and a sensitivity of 0.3 mV. Therapy parameters were VT zone 162–207 bpm and VF zone >207 bpm. Pacing history revealed that she was ventricularly sensed 97.5% of the time and ventricularly paced 2.5% of the time since her last visit.\n\nInterrogation revealed three events of sustained PVT requiring device therapy. The events occurred at approximately 2 weeks gestation, 4 weeks gestation and 9 weeks gestation. Each event was reversed with a single 20 J shock. All events occurred while walking and during the day time. The patient said that she forgot to take atenolol on the day of the third event. For each event, the patient stated that she felt very dizzy, and then the defibrillator went off. She continued to remain dizzy with poor exercise tolerance for approximately 30–60 sec following the discharge. Evaluation of her electrocardiograms revealed that she continued to have erratic rhythm with short bursts of ventricular tachycardia during that period before reverting to normal sinus rhythm (Fig. 1).\n\nFigure 1 \nECG lead showing a ventricular fibrillation event. Failure of antitachycardia pacing was followed by degeneration into ventricular fibrillation and ICD therapy (red arrow). Erratic rhythm with bursts of ventricular tachycardia continued after the ICD therapy before spontaneously reverting to normal sinus rhythm. TS, ventricular sensing of VT zone; FD, ventricular fibrillation detection; FS, ventricular sensing of FVT zone; TF, ventricular sensing of VF zone; TD, ventricular tachycardia detection; Rx, therapy (Defibrillation 20.2J × 1); VF, ventricular fibrillation; VT, ventricular tachycardia; VS, normal R‐wave sensing.\n\nShe additionally had thirty events of non‐sustained ventricular tachycardia (NSVT), and two which the device determined to be supraventricular tachycardia (SVT). Eighteen of these events occurred during the third month of pregnancy. At this visit she was switched to metoprolol 50 mg twice a day because of a better safety profile in pregnancy.\n\nShe called 4 days later saying metoprolol was making her feel dizzy, and she could feel her pacemaker “pacing her a lot more.” Metoprolol was decreased to 50 mg once daily. She called again a week later, saying she was still feeling unwell and her pacemaker “was pacing all the time.” Both times, she denied any defibrillator therapies. After consultation with the high‐risk obstetric staff, she was resumed on her original dose of atenolol, 50 mg twice daily.\n\nHer 23‐week ultrasound showed a fetal heart rate of 140 bpm and a PR interval of 100 msec. A biophysical profile at 34 weeks gestation revealed a 2416 g fetus which was approximately at the 35th percentile for weight. The amniotic fluid index was estimated to be adequate at 9.5–13 cm. Expected date of delivery by LMP and ultrasound differed by 4 days.\n\nShe was seen in the pacemaker clinic a week prior to her planned cesarean section, which was approximately 6 months from her previous visit. Device settings were unchanged. Pacing history revealed that she was ventricularly sensed 99.2% of the time and ventricularly paced 0.8% of the time. She had only three events of NSVT without symptoms, no ventricular fibrillation event and no ICD therapies. She was on atenolol 25 mg in the morning and 50 mg in the evening at this visit.\n\nShe underwent planned cesarean section under spinal anesthesia with 20 μg of Fentanyl delivered spinally at 38 weeks gestation. Bupivicaine 1% was used for local anesthesia at site of needle injection. 2 mg of Midazolam and 0.15 mg of Morphine were used preoperatively for mild sedation and pain control. Intravenous bicitra and phenergan were used intraoperatively to relieve patient nausea. The patient delivered a healthy male newborn with a birth weight of 3075 g. Apgar scores were 8 and 9 at 1 and 5 min, respectively. There were no complications during or after delivery, and mother and baby were discharged uneventfully. A 3‐month follow up in the gynecology and cardiac clinics of mother and baby revealed no adverse outcome except a new diagnosis of maternal post‐partum depression.\n\nDiscussion\nThe use of the ICD has allowed an increased number of young women with life‐threatening cardiac arrhythmias to reach their reproductive years. Few studies have examined pregnancy in women with ICD's 4, 5, 6, 7. All have small samples, adult populations and a narrow variety of cardiac disorders. Adolescent pregnancies have a higher propensity for adverse outcome, even in otherwise‐healthy teenagers 8. Such pregnancies may require even closer monitoring in the context of known cardiovascular disease.\n\nOnly one other case of pregnancy in a woman with CPVT and an ICD was found in the literature as part of a recent review of 12 adult patients 4. This patient did not receive any ICD discharges, and did not experience any episodes of ventricular arrhythmias or ventricular pacing during her pregnancy (Boule et al., personal communication). Other reports on arrythmogenic conditions during pregnancy such as long‐QT syndrome and ARVD have suggested ventricular events requiring ICD therapy in the second trimester, approximately around 20 weeks 9, 10. In contrast, our patient experienced three appropriate therapies and several events of antitachycardia pacing during the first trimester. Hormonal, cardiovascular and autonomic changes might play a role in exacerbation of arrhythmias during pregnancy 10, 11. In particular, circulating estrogen has been proposed to increase myocardial sensitivity to catecholamines 12. This may make patients with CPVT more sensitive to ventricular electrical events than other arrhythmogenic conditions, including other primary electrical diseases. However, the current scarcity of literature precludes any evidence‐based presumptions regarding the pattern of arrhythmias during pregnancy in CPVT on the basis of other arrhythmogenic conditions 9, 13. Important differences in physiology and endocrinology in adolescent pregnancy from adults are well‐documented 8, 14. These may all be factors in the poor control of ventricular arrhythmias in our patient. We additionally propose that the development of tolerance to the rapid cardiovascular, hormonal or autonomic changes induced by pregnancy may be different in adolescents compared to adults. Adolescent physiology may, in fact, be slower to adapt to these multiple changes thereby increasing their risk of electrical events early on. This premise is supported by our observation that the arrhythmias decreased as the pregnancy progressed despite no significant changes in medical management, possibly due to a better cardiovascular tolerance. A better and quicker adaptation may also be the reason for Boule et al.'s adult patient having a significantly different course of pregnancy.\n\nOur case indicates that the highest risk for ventricular events may be during the first trimester. Also, teenage pregnancies may behave completely differently from adults, as is suggested by the key differences between our patient and the one reported by Boule et al. Based on these observations, we recommend closer monitoring of non‐adult patients with CPVT early in pregnancy. As such, any “high‐risk pregnancy” team for such patients should include a cardiologist on all first trimester visits. These patients may be appropriate candidates for aggressive remote monitoring, suggested by recent reports to offer opportunity for faster action in case of adverse events, and also prevent inappropriate therapies 15.\n\nOur experience suggests metoprolol may not be as effective as atenolol during pregnancy in CPVT, by causing more side effects and patient discomfort. Boule et al.'s patient was maintained successfully on high dose nadolol (personal communication). Our use of atenolol did not result in adverse fetal outcome, suggesting it may be a safe alternative. However, dose optimization of beta blockers during pregnancy may be required to achieve better antiarrhythmic control, and prevent unnecessary ICD therapies. Neither our patient nor that of Boule et al. required antibradycardia pacing, despite close to maximal doses of beta blockers. The importance of adhering to medication should be emphasized at every cardiology and obstetric visit. In our case, missing a single dose may have resulted in symptomatic malignant VT requiring ICD therapy within a few hours. Sustained VT requiring device intervention within a short timeframe of discontinuing beta blockers has also been reported elsewhere 16, 17. Furthermore, it would also be reasonable to assume that nadolol may have been an important factor in preventing malignant VT in Boule et al.'s patient.\n\nPacemaker and ICD parameters should be individualized for pregnant patients based on the characteristics of their prior events. However, where such information may not be available, our settings may be effective to maintain a patient with CPVT during pregnancy. Boule et al. maintained their patient at somewhat comparable settings of VVI 40 bpm, VT zone 200–250 bpm and VF zone >250 bpm. However, their higher VF and VT thresholds are untested for appropriate response to malignant VT in such a clinical situation.\n\nICD therapies and frequent ventricular pacing did not result in adverse fetal outcome in our patient. This may be a combined effect of the low amount of current delivered by ICD's and a high fetal fibrillatory threshold 18.\n\nConclusions\nOur case report is the first report of pregnancy in a pediatric patient with CPVT. It is also the first identifiable report of ICD therapies during pregnancy in a CPVT patient of any age. This case report provides information which may be critical in managing such patients. We conclude that adolescents with CPVT are at high risk for both NSVT and malignant VT during pregnancy, despite antiarrhythmic medication. We recommend close monitoring of such patients throughout pregnancy with special care during the first trimester.\n\nConflict of Interest\nNone declared.\n==== Refs\nReferences\n1 \n\nKim , J. B. \n\n2014 \n\nChannelopathies\n . Korean J. Pediatr. \n57 :1 –18 .24578711 \n2 \n\nMiyake , C. Y. \n, \nG. \nWebster \n, \nR. J. \nCzosek \n, \nM. J. \nKantoch \n, \nA. M. \nDubin \n, \nK. \nAvasarala \n, et al. 2013 \nEfficacy of implantable cardioverter defibrillators in young patients with catecholaminergic polymorphic ventricular tachycardia: success depends on substrate . Circ. Arrhythm. Electrophysiol. \n6 :579 –587 .23667268 \n3 \n\nPriori , S. G. \n, \nA. A. \nWilde \n, \nM. \nHorie \n, \nY. \nCho \n, \nE. R. \nBehr \n, \nC. \nBerul \n, et al. 2013 \nHRS/EHRA/APHRS expert consensus statement on the diagnosis and management of patients with inherited primary arrhythmia syndromes: document endorsed by HRS, EHRA, and APHRS in May 2013 and by ACCF, AHA, PACES, and AEPC in June 2013 . Heart Rhythm \n10 :1932 –1963 .24011539 \n4 \n\nBoule , S. \n, \nL. \nOvart \n, \nC. \nMarquie \n, \nE. \nBotcherby \n, \nD. \nKlug \n, \nC. \nKouakam \n, et al. 2014 \nPregnancy in women with an implantable cardioverter‐defibrillator: is it safe? \nEuropace \n16 :1587 –1594 .24596396 \n5 \n\nNatale , A. \n, \nT. \nDavidson \n, \nM. J. \nGeiger \n, and \nK. \nNewby \n. 1997 \nImplantable cardioverter‐defibrillators and pregnancy: a safe combination? \nCirculation \n96 :2808 –2812 .9386142 \n6 \n\nSchuler , P. K. \n, \nA. \nHerrey \n, \nA. \nWade \n, \nR. \nBrooks \n, \nD. \nPeebles \n, \nP. \nLambiase \n, et al. 2012 \nPregnancy outcome and management of women with an implantable cardioverter defibrillator: a single centre experience . Europace \n14 :1740 –1745 .22744770 \n7 \n\nMiyoshi , T. \n, \nC. A. \nKamiya \n, \nS. \nKatsuragi \n, \nH. \nUeda \n, \nY. \nKobayashi \n, \nC. \nHoriuchi \n, et al. 2013 \nSafety and efficacy of implantable cardioverter‐defibrillator during pregnancy and after delivery . Circ. J. \n77 :1166 –1170 .23291990 \n8 \n\nTorvie , A. J. \n, \nL. S. \nCallegari \n, \nM. A. \nSchiff \n, and \nK. E. \nDebiec \n. 2015 \nLabor and delivery outcomes among young adolescents . Am. J. Obstet. Gynecol. \n213 :95 e1 –8 .25935776 \n9 \n\nAgir , A. \n, \nS. \nBozyel \n, \nU. \nCelikyurt \n, \nO. \nArgan \n, \nI. \nYilmaz \n, \nK. \nKarauzum \n, et al. 2014 \nArrhythmogenic right ventricular cardiomyopathy in pregnancy . Int. Heart J. \n55 :372 –376 .24898597 \n10 \n\nSilversides , C. K. \n, \nL. \nHarris \n, \nK. \nHaberer \n, \nM. \nSermer \n, \nJ. M. \nColman \n, and \nS. C. \nSiu \n. 2006 \nRecurrence rates of arrhythmias during pregnancy in women with previous tachyarrhythmia and impact on fetal and neonatal outcomes . Am. J. Cardiol. \n97 :1206 –1212 .16616027 \n11 \n\nEkholm , E. M. \n, \nS. J. \nPiha \n, \nR. U. \nErkkola \n, and \nK. J. \nAntila \n. 1994 \nAutonomic cardiovascular reflexes in pregnancy. A longitudinal study . Clin. Auton. Res. \n4 :161 –165 .7849495 \n12 \n\nPage , R. L. \n\n1995 \nTreatment of arrhythmias during pregnancy . Am. Heart J. \n130 :871 –876 .7572599 \n13 \n\nPiacenza , J. M. \n, \nG. \nKirkorian \n, \nP. H. \nAudra \n, and \nG. \nMellier \n. 1998 \nHypertrophic cardiomyopathy and pregnancy . Eur. J. Obstet. Gynecol. Reprod. Biol. \n80 :17 –23 .9758254 \n14 \n\nAguilar‐Moreno , M. \n, \nO. R. \nGalicia‐Castillo \n, \nU. \nAguilera‐Reyes \n, \nC. \nVarea‐Gonzalez \n, \nC. \nBernis‐Carro \n, and \nG. I. \nGarcia‐Lopez \n\n2015 \nHormonal state comparison (progesterone, estradiol, and leptin) of body fat and body mass indices in mexican women as a risk factor for neonatal physiologic condition . J. Pediatr. Adolesc. Gynecol. \n28 :149 –156 .26046604 \n15 \n\nGuedon‐Moreau , L. \n, \nC. \nKouakam \n, \nD. \nKlug \n, \nC. \nMarquie \n, \nF. \nBrigadeau \n, \nS. \nBoule \n, et al. 2014 \nDecreased delivery of inappropriate shocks achieved by remote monitoring of ICD: a substudy of the ECOST trial . J. Cardiovasc. Electrophysiol. \n25 :763 –770 .24602062 \n16 \n\nLee , L. C. \n, \nS. L. \nBathgate \n, and \nC. J. \nMacri \n. 2006 \nArrhythmogenic right ventricular dysplasia in pregnancy: a case report . J. Reprod. Med. \n51 :725 –728 .17039704 \n17 \n\nBonini , W. \n, \nG. L. \nBotto \n, \nT. \nBroffoni \n, and \nC. \nDondina \n. 2000 \nPregnancy with an ICD and a documented ICD discharge . Europace \n2 :87 –90 .11225601 \n18 \n\nPage , R. L. \n, \nM. H. \nHamdan \n, and \nJ. A. \nJoglar \n. 2002 \nArrhythmias occurring during pregnancy . Card. Electrophysiol. Rev. \n6 :136 –139 .11984035\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2050-0904",
"issue": "4(4)",
"journal": "Clinical case reports",
"keywords": "Adolescent; catecholimergic polymorphic ventricular tachycardia; discharges; implantable cardioverter defibrillator; pediatric; pregnancy; pregnant; teenage pregnancy",
"medline_ta": "Clin Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101620385",
"other_id": null,
"pages": "361-5",
"pmc": null,
"pmid": "27099728",
"pubdate": "2016-04",
"publication_types": "D002363:Case Reports",
"references": "24596396;25935776;24578711;16616027;22744770;11225601;11984035;9386142;23291990;7572599;27099728;24898597;24011539;23667268;17039704;26046604;24602062;9758254;7849495",
"title": "Teenage pregnancy with catecholaminergic polymorphic ventricular tachycardia and documented ICD discharges.",
"title_normalized": "teenage pregnancy with catecholaminergic polymorphic ventricular tachycardia and documented icd discharges"
} | [
{
"companynumb": "US-DRREDDYS-USA/USA/16/0079981",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METOPROLOL SUCCINATE"
},
"drugadditional... |
{
"abstract": "Verruconis gallopava is a dematiaceous mould usually causing saprophytic infection in immunosuppressed host. Only a few cases have been published even in immunocompromised states. We present a rare case of pulmonary involvement in an immunocompetent patient with recurrent disease. The mid-aged woman had no evidence of any disease causing impaired immune response. Recurrent disease shows pulmonary infiltrates and symptoms of allergic bronchopulmonary mycosis. We describe an emerging pathogen that has been found in an immunocompetent host. Eradication was not possible despite the use of several different antifungal drugs. Further recurrence of infection in the described patient is probable.",
"affiliations": "Department of Pulmonology, Klinikum Klagenfurt am Wörthersee, Feschnigstr. 11, AT 9020, Klagenfurt, Austria. christian@geltner.at.;Institute of Laboratory Diagnostics and Microbiology, Klinikum Klagenfurt, Klagenfurt, Austria.;Division of Clinical Microbiology, Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria.;Department of Pulmonology, Klinikum Klagenfurt am Wörthersee, Feschnigstr. 11, AT 9020, Klagenfurt, Austria.;Department of Pulmonology, Klinikum Klagenfurt am Wörthersee, Feschnigstr. 11, AT 9020, Klagenfurt, Austria.;Division of Hygiene and Microbiology, Medical University Innsbruck, Innsbruck, Austria.",
"authors": "Geltner|Christian|C|;Sorschag|Sieglinde|S|;Willinger|Birgit|B|;Jaritz|Thomas|T|;Saric|Zoran|Z|;Lass-Flörl|Cornelia|C|",
"chemical_list": null,
"country": "Germany",
"delete": false,
"doi": "10.1007/s15010-015-0757-y",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0300-8126",
"issue": "43(6)",
"journal": "Infection",
"keywords": null,
"medline_ta": "Infection",
"mesh_terms": "D001203:Ascomycota; D005260:Female; D006801:Humans; D008168:Lung; D008172:Lung Diseases, Fungal; D008828:Microbiological Techniques; D008853:Microscopy; D008875:Middle Aged; D009336:Necrosis; D012008:Recurrence; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "0365307",
"other_id": null,
"pages": "743-6",
"pmc": null,
"pmid": "25744338",
"pubdate": "2015-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "24687495;20631331;1498151;18177225;21955216;25232157;1955951;11083712;14690259;18694949;8824969;17710372;16157992;19356211;18651872;22548237;9114187;11008082",
"title": "Necrotizing mycosis due to Verruconis gallopava in an immunocompetent patient.",
"title_normalized": "necrotizing mycosis due to verruconis gallopava in an immunocompetent patient"
} | [
{
"companynumb": "PHHY2015AT164271",
"fulfillexpeditecriteria": "1",
"occurcountry": "AT",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "VORICONAZOLE"
},
"drugadditional": null,
"dr... |
{
"abstract": ": Hepatitis B virus (HBV) reactivation has been documented in association with multiple immunotherapy regimens . These reactivations can be life-threatening and result in fulminant hepatic failure. There are currently no reports of HBV reactivation on nivolumab treatment. This is a case of a patient with known HIV infection and previous HBV workup that revealed him to be anti-hepatitis B core antibody positive, hepatitis B surface antigen negative, and HBV DNA negative. He experienced a HBV reactivation while on therapy with nivolumab for stage IIIa poorly differentiated carcinoma of the lung, which was a recurrence from a prior surgically resected stage Ia well differentiated adenocarcinoma of the lung. He is a long-term nonprogressor in regards to his HIV and had previously had a negative HBV DNA level and had declined antiretroviral therapy until just prior to starting nivolumab. This case is also of interest as antiprogrammed death-1 receptors are involved in CD4-related HIV control , and the effects of nivolumab in a patient who was an HIV long-term nonprogressor are unknown. There was concern that he would develop increased HIV viremia and CD4-related immune dysfunction without antiretroviral therapy, and thus, he agreed to treatment prior to starting antineoplastic immunotherapy.",
"affiliations": "Lancaster General Health Family and Community Medicine Residency, Lancaster General Penn Medicine, Lancaster, Pennsylvania, USA.",
"authors": "Lake|Adam C|AC|",
"chemical_list": "D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D007155:Immunologic Factors; D000077594:Nivolumab",
"country": "England",
"delete": false,
"doi": "10.1097/QAD.0000000000001599",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0269-9370",
"issue": "31(15)",
"journal": "AIDS (London, England)",
"keywords": null,
"medline_ta": "AIDS",
"mesh_terms": "D000230:Adenocarcinoma; D000328:Adult; D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D015658:HIV Infections; D006509:Hepatitis B; D006801:Humans; D007155:Immunologic Factors; D008175:Lung Neoplasms; D008297:Male; D000077594:Nivolumab",
"nlm_unique_id": "8710219",
"other_id": null,
"pages": "2115-2118",
"pmc": null,
"pmid": "28906278",
"pubdate": "2017-09-24",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Hepatitis B reactivation in a long-term nonprogressor due to nivolumab therapy.",
"title_normalized": "hepatitis b reactivation in a long term nonprogressor due to nivolumab therapy"
} | [
{
"companynumb": "US-STRIDES ARCOLAB LIMITED-2017SP013730",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "DOLUTEGRAVIR"
},
"drugaddition... |
{
"abstract": "OBJECTIVE\nTo determine the molecular characteristics of a sequence type 338 community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) strain and the relationship among MRSA strains from various lineages and areas.\n\n\nMETHODS\nWhole-genome sequencing, genomic comparison, antimicrobial susceptibility testing, and hemolysis analysis were performed to identify the resistance determinants and virulence factors of strain ZY05 and the relationships among CC59 clones.\n\n\nRESULTS\nMRSA strain ZY05 was resistant to tetracycline, erythromycin, and clindamycin, and the resistance genes erm(B) and tet(K) were detected in the genome. ZY05 harbors the genomic islands νSaα, νSaβ, νSaγ, and ΦSa2, the pathogenicity island νSa1, and virulence factors such as Panton-Valentine leukocidin, phenol-soluble modulins, alpha-hemolysin, enterotoxin B, enterotoxin K, and enterotoxin Q, which are the same as those present in ST59 strains. In addition, the virulence potential of ST338 did not differ from that of ST59. This strain contains the staphylococcal cassette chromosome mec (SCCmec) type VT, a distinct SCCmec type previously reported from Taiwan. The results of core genome multilocus sequence typing (cgMLST) analysis showed that the gene distances between ST59 and ST338 were close among CC59 isolates, while strains from Taiwan were identical to isolates from the Chinese mainland with respect to these two sequence types.\n\n\nCONCLUSIONS\nThe ST338 strain ZY05, which has a close genetic relationship to ST59 strains, is multidrug-resistant and highly virulent. Strains of two identical lineages, ST59 and ST338, from Taiwan and the Chinese mainland may have the same genetic background.",
"affiliations": "Department of Infectious Diseases, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China; Key Laboratory of Microorganism Technology and Bioinformatics Research of Zhejiang Province, Hangzhou, Zhejiang Province, China.;State Key Laboratory for Diagnosis and Treatment of Infectious Disease, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China; Infectious Disease Department, The First People's Hospital of Wenling, Wenling, Zhejiang Province, China.;Department of Infectious Diseases, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China; Key Laboratory of Microorganism Technology and Bioinformatics Research of Zhejiang Province, Hangzhou, Zhejiang Province, China.;Department of Infectious Diseases, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China; Key Laboratory of Microorganism Technology and Bioinformatics Research of Zhejiang Province, Hangzhou, Zhejiang Province, China.;Department of Infectious Diseases, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China; Key Laboratory of Microorganism Technology and Bioinformatics Research of Zhejiang Province, Hangzhou, Zhejiang Province, China. Electronic address: yvys119@zju.edu.cn.;State Key Laboratory for Diagnosis and Treatment of Infectious Disease, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China. Electronic address: qutingting@zju.edu.cn.",
"authors": "Chen|Yiyi|Y|;Hong|Jinjing|J|;Chen|Yan|Y|;Wang|Haiping|H|;Yu|Yunsong|Y|;Qu|Tingting|T|",
"chemical_list": "D000900:Anti-Bacterial Agents; D001427:Bacterial Toxins; D005098:Exotoxins; D007956:Leukocidins; C078284:Panton-Valentine leukocidin; D037521:Virulence Factors; C025971:staphylococcal delta toxin",
"country": "Canada",
"delete": false,
"doi": "10.1016/j.ijid.2019.10.034",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1201-9712",
"issue": "90()",
"journal": "International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases",
"keywords": "CA-MRSA; China; ST338; ST59; Whole-genome sequencing",
"medline_ta": "Int J Infect Dis",
"mesh_terms": "D000328:Adult; D000900:Anti-Bacterial Agents; D001427:Bacterial Toxins; D002681:China; D002876:Chromosomes, Bacterial; D017714:Community-Acquired Infections; D005098:Exotoxins; D016680:Genome, Bacterial; D044404:Genomic Islands; D006801:Humans; D007956:Leukocidins; D008297:Male; D016106:Methicillin Resistance; D055624:Methicillin-Resistant Staphylococcus aureus; D008826:Microbial Sensitivity Tests; D058885:Multilocus Sequence Typing; D010802:Phylogeny; D013203:Staphylococcal Infections; D037521:Virulence Factors",
"nlm_unique_id": "9610933",
"other_id": null,
"pages": "181-187",
"pmc": null,
"pmid": "31682959",
"pubdate": "2020-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Characterization of a community-acquired methicillin-resistant sequence type 338 Staphylococcus aureus strain containing a staphylococcal cassette chromosome mec type VT.",
"title_normalized": "characterization of a community acquired methicillin resistant sequence type 338 staphylococcus aureus strain containing a staphylococcal cassette chromosome mec type vt"
} | [
{
"companynumb": "CN-FRESENIUS KABI-FK202004108",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "BIAPENEM"
},
"drugadditional": null,
... |
Subsets and Splits
No community queries yet
The top public SQL queries from the community will appear here once available.