article dict | reports listlengths 1 3.97k |
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{
"abstract": "BACKGROUND\nCardiac allograft vasculopathy (CAV), a major cause of graft failure and mortality at >3 years after orthotopic heart transplantation (OHT), is commonly evaluated using dobutamine stress echocardiography (DSE). We sought to study: (a) the incidence of positive results and diagnostic accuracy of DSE; and (b) the predictors of adverse outcomes in OHT patients.\n\n\nMETHODS\nWe studied 497 consecutive patients (63 ± 10 years, 78% men) with OHT who had undergone DSE as part of routine surveillance at our center between 1998 and 2013. Every DSE and coronary angiogram performed during follow-up was reviewed. CAV was regraded according to the 2010 recommendations of the International Society for Heart and Lung Transplantation. Composite events (death, coronary revascularization, myocardial infarction and retransplantation) were recorded.\n\n\nRESULTS\nThere were 1,243 DSE studies performed during a median of 8.7 (6.2 to 11.9) years after transplantation. Only 22 studies (1.8%) were positive, 978 (78.7%) were negative and 243 (19.5%) were non-diagnostic (sub-maximal heart rate response) for ischemia. Among 497 patients, only 20 (4%) had at least one positive DSE study. There were 310 diagnostic DSEs with coronary angiograms performed within 1 year of one another other. In this subgroup, the sensitivity, specificity, positive predictive value and negative predictive value of DSE were 7%, 98%, 82% and 41%, respectively, to detect any CAV, and 28%, 98%, 71% and 89% to detect CAV Grades 2 or 3, respectively. There were no deaths during DSE. At 5.6 ± 3.6 years after DSE, there were 201 (40%) events. Degree of CAV (and not DSE-based ischemia, p = 0.3) independently predicted outcomes (p < 0.001).\n\n\nCONCLUSIONS\nThe incidence of a positive result is very low in OHT patients undergoing surveillance DSE. DSE is insufficiently sensitive for detection of early CAV. Degree of CAV and not DSE-based ischemia independently predicted outcomes.",
"affiliations": "Kaufman Center for Heart Failure; Section of Cardiovascular Imaging, Department of Cardiovascular Medicine, Heart and Vascular Institute, Cleveland Clinic, Cleveland, Ohio; Division of Cardiology, Department of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand.;Kaufman Center for Heart Failure.;Kaufman Center for Heart Failure.;Section of Cardiovascular Imaging, Department of Cardiovascular Medicine, Heart and Vascular Institute, Cleveland Clinic, Cleveland, Ohio.;Section of Cardiovascular Imaging, Department of Cardiovascular Medicine, Heart and Vascular Institute, Cleveland Clinic, Cleveland, Ohio. Electronic address: desaim2@ccf.org.",
"authors": "Chirakarnjanakorn|Srisakul|S|;Starling|Randall C|RC|;Popović|Zoran B|ZB|;Griffin|Brian P|BP|;Desai|Milind Y|MY|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1053-2498",
"issue": "34(5)",
"journal": "The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation",
"keywords": "accuracy; cardiac allograft vasculopathy; dobutamine stress echocardiography; heart transplantation; outcomes",
"medline_ta": "J Heart Lung Transplant",
"mesh_terms": "D025401:Echocardiography, Stress; D005260:Female; D005500:Follow-Up Studies; D006084:Graft Rejection; D006333:Heart Failure; D016027:Heart Transplantation; D006801:Humans; D015994:Incidence; D008297:Male; D008875:Middle Aged; D011237:Predictive Value of Tests; D011379:Prognosis; D015203:Reproducibility of Results; D012189:Retrospective Studies; D015996:Survival Rate; D013785:Thailand; D066027:Transplant Recipients; D016276:Ventricular Function",
"nlm_unique_id": "9102703",
"other_id": null,
"pages": "710-7",
"pmc": null,
"pmid": "25682552",
"pubdate": "2015-05",
"publication_types": "D016428:Journal Article; D064888:Observational Study",
"references": null,
"title": "Dobutamine stress echocardiography during follow-up surveillance in heart transplant patients: Diagnostic accuracy and predictors of outcomes.",
"title_normalized": "dobutamine stress echocardiography during follow up surveillance in heart transplant patients diagnostic accuracy and predictors of outcomes"
} | [
{
"companynumb": "US-BAXTER-2015BAX034922",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "DEXTROSE MONOHYDRATE\\DEXTROSE MONOHYDRATE\\DOBUTAMINE HYDROCHLORI... |
{
"abstract": "The purpose of the study was to review the recurrent posterior reversible encephalopathy syndrome (PRES) and emphasize the possibility of repeated attacks on the basis of particular clinical situations. 32 children, diagnosed with PRES were included in our study. The recurrent cases were determined; their radiological features such as involved localizations and clinical information such as presenting symptoms, underlying diseases and clinical prognosis are retrospectively assessed. Of the 32 children (8 months to 18 years old; mean age 11), four of the patients had recurrent episodes of PRES. They had different underlying diseases. One had Chediak-Higashi syndrome, one had ALL, one had chronic renal disease on hemodialysis and one was a renal transplant recipient. Three of the children recovered with no residual neurological deficits, one of them passed away due to multiorgan failure. Three of them had high blood pressures at the time of either one or both PRES, and the renal transplant recipient had also high blood levels of Tacrolimus. Recurrent PRES is encountered most commonly because of repeated increasing blood pressures due to various underlying diseases, immune system disorders or side effects of the treatments.",
"affiliations": "Department of Radiology, Baskent University Medical Faculty, 44. Sokak No: 11/8, Bahcelievler, Ankara, Turkey, fuldemyildirim@yahoo.com.",
"authors": "Donmez|Fuldem Yildirim|FY|;Agildere|Ahmet Muhtesem|AM|",
"chemical_list": null,
"country": "Italy",
"delete": false,
"doi": "10.1007/s10072-015-2212-3",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1590-1874",
"issue": "36(9)",
"journal": "Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology",
"keywords": null,
"medline_ta": "Neurol Sci",
"mesh_terms": "D000293:Adolescent; D001794:Blood Pressure; D001921:Brain; D002648:Child; D002675:Child, Preschool; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007223:Infant; D008279:Magnetic Resonance Imaging; D008297:Male; D054038:Posterior Leukoencephalopathy Syndrome; D011379:Prognosis; D012008:Recurrence; D012189:Retrospective Studies",
"nlm_unique_id": "100959175",
"other_id": null,
"pages": "1603-9",
"pmc": null,
"pmid": "25894844",
"pubdate": "2015-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "21074464;19021847;24613735;12063238;18403560;22577937;23093975;25114439;22835573;21043390;25293448;23084334;11058630;23726785;18268188;17259848;22919196;19061161;18356474;25022403",
"title": "Recurrent childhood PRES.",
"title_normalized": "recurrent childhood pres"
} | [
{
"companynumb": "PHHY2015TR048082",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "MYCOPHENOLATE MOFETIL\\MYCOPHENOLATE MOFETIL HYDROCHLORIDE"
},
... |
{
"abstract": "We present a case of acute upper gastrointestinal haemorrhage in a patient with systemic vasculitis immunosuppressed on cyclophosphamide and prednisolone. The patient presented with a diffuse haemorrhagic oesophagitis and a non-specific duodenitis. Biopsies taken from the oesophagus and duodenum demonstrated infection with herpes simplex virus (HSV) and cytomegalovirus (CMV) respectively. Viral infection of the upper gastrointestinal tract is a recognised complication of immunosuppression and HSV is one of the most common pathogens. CMV on the other hand most commonly causes a colitis or less commonly oesophagitis. CMV enteritis is rare as is the synchronous infection with two viral agents in an immunocompromised patient having being described in a few case series only. Viral infection of the gastrointestinal tract in immunocompromised patients should be treated with systemic anti-viral medication and consideration to withdrawal of the immunosuppressive therapy if possible and appropriate. The authors highlight the need for a high suspicion of viral infection in immunosuppressed patients presenting with upper gastrointestinal bleeding.",
"affiliations": "Lyn Alexandra Smith, Daniel R Gaya, Gastroenterology Unit, Glasgow Royal Infirmary, G4 0SF Glasgow, United Kingdom.;Lyn Alexandra Smith, Daniel R Gaya, Gastroenterology Unit, Glasgow Royal Infirmary, G4 0SF Glasgow, United Kingdom.;Lyn Alexandra Smith, Daniel R Gaya, Gastroenterology Unit, Glasgow Royal Infirmary, G4 0SF Glasgow, United Kingdom.",
"authors": "Smith|Lyn Alexandra|LA|;Gangopadhyay|Mitali|M|;Gaya|Daniel R|DR|",
"chemical_list": "D000998:Antiviral Agents; D007166:Immunosuppressive Agents; D003520:Cyclophosphamide; D011239:Prednisolone",
"country": "United States",
"delete": false,
"doi": "10.3748/wjg.v21.i8.2542",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1007-9327",
"issue": "21(8)",
"journal": "World journal of gastroenterology",
"keywords": "Cytomegalovirus; Endoscopy; Gastrointestinal haemorrhage; Herpes simplex virus; Immunosuppression",
"medline_ta": "World J Gastroenterol",
"mesh_terms": "D000368:Aged; D000998:Antiviral Agents; D001706:Biopsy; D003520:Cyclophosphamide; D003586:Cytomegalovirus Infections; D004382:Duodenitis; D016099:Endoscopy, Gastrointestinal; D004941:Esophagitis; D017809:Fatal Outcome; D005260:Female; D006471:Gastrointestinal Hemorrhage; D006561:Herpes Simplex; D006801:Humans; D016867:Immunocompromised Host; D007166:Immunosuppressive Agents; D009894:Opportunistic Infections; D011239:Prednisolone; D056647:Systemic Vasculitis; D016896:Treatment Outcome",
"nlm_unique_id": "100883448",
"other_id": null,
"pages": "2542-5",
"pmc": null,
"pmid": "25741165",
"pubdate": "2015-02-28",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "18627655;10923360;11864149",
"title": "Catastrophic gastrointestinal complication of systemic immunosuppression.",
"title_normalized": "catastrophic gastrointestinal complication of systemic immunosuppression"
} | [
{
"companynumb": "GB-BAUSCH-BL-2015-025868",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CYCLOPHOSPHAMIDE"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nThe optimal timing of pharmacological treatment for patent ductus arteriosus (PDA) in extremely preterm infants is unknown.\n\n\nOBJECTIVE\nTo investigate whether timing of pharmacological PDA treatment is associated with a risk of secondary PDA surgery or death before 3 months of age, or bronchopulmonary dysplasia (BPD) in extremely preterm infants.\n\n\nMETHODS\nIn this population-based cohort of infants born before 27 gestational weeks in Sweden in 2004-2007, 290/585 infants (50%) received pharmacological PDA treatment. Cox proportional hazards regression estimated the hazard ratio (HR, with 95% confidence interval, CI) of secondary PDA surgery or death as a composite outcome in relation to postnatal age at the start of pharmacological treatment: early (0-2 days); intermediate (3-6 days); late (≥7 days). Furthermore, the odds ratio (OR, with 95% CI) of BPD was estimated in relation to postnatal age at PDA treatment by conditional logistic regression.\n\n\nRESULTS\nThe median postnatal age at the start of pharmacological PDA treatment was 4 days. 102 infants had secondary PDA surgery. Timing of PDA treatment was not associated with risk of PDA surgery or death; adjusted HRs were 0.89 (95% CI 0.57-1.39) after an intermediate start and 1.10 (95% CI 0.53-2.28) after a late start, compared to an early start of treatment. Compared to the early start of PDA treatment, the intermediate start was not associated with any risk of BPD, while late PDA treatment was associated with a lower BPD risk; adjusted ORs were 0.83 (95% CI 0.42-1.64) and 0.28 (95% CI 0.13-0.61), respectively.\n\n\nCONCLUSIONS\nTiming of pharmacological PDA treatment after extremely preterm birth is not associated with the risk of secondary PDA surgery or death. Moreover, expectant PDA management is not associated with an increased risk of BPD.",
"affiliations": "Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.",
"authors": "Gudmundsdottir|Anna|A|;Johansson|Stefan|S|;Håkansson|Stellan|S|;Norman|Mikael|M|;Källen|Karin|K|;Bonamy|Anna-Karin|AK|",
"chemical_list": "D016861:Cyclooxygenase Inhibitors; D007052:Ibuprofen; D007213:Indomethacin",
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000367887",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1661-7800",
"issue": "107(2)",
"journal": "Neonatology",
"keywords": null,
"medline_ta": "Neonatology",
"mesh_terms": "D001997:Bronchopulmonary Dysplasia; D015331:Cohort Studies; D016861:Cyclooxygenase Inhibitors; D004374:Ductus Arteriosus, Patent; D005260:Female; D005865:Gestational Age; D006801:Humans; D007052:Ibuprofen; D007213:Indomethacin; D062071:Infant, Extremely Premature; D007231:Infant, Newborn; D016015:Logistic Models; D008297:Male; D013548:Sweden; D061665:Time-to-Treatment",
"nlm_unique_id": "101286577",
"other_id": null,
"pages": "87-92",
"pmc": null,
"pmid": "25412681",
"pubdate": "2015",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Timing of pharmacological treatment for patent ductus arteriosus and risk of secondary surgery, death or bronchopulmonary dysplasia: a population-based cohort study of extremely preterm infants.",
"title_normalized": "timing of pharmacological treatment for patent ductus arteriosus and risk of secondary surgery death or bronchopulmonary dysplasia a population based cohort study of extremely preterm infants"
} | [
{
"companynumb": "SE-JNJFOC-20150318446",
"fulfillexpeditecriteria": "1",
"occurcountry": "SE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "IBUPROFEN"
},
"drugadditional": null,
"... |
{
"abstract": "Anti-glutamic acid decarboxylase (GAD) antibody-associated autoimmune encephalitis has been reported mostly as limbic encephalitis. Only few cases with extralimbic involvement are reported with limited investigation. Here, we report an extensive investigation with MRI, PET, and pathological examination. A 66-year-old Japanese female with a history of hypothyroidism, colon cancer, pheochromocytoma, and thymoma-associated myasthenia gravis presented with generalised tonic-clonic seizures. MRI showed multiple hyperintense lesions and PET showed hypermetabolic lesions in the brain. Biopsy showed non-specific gliosis, microglial proliferation, and perivascular lymphohistiocytic infiltrates. Various neuronal antibodies were negative, except for anti-GAD antibody. Anti-GAD antibody-associated encephalitis is an increasingly recognised CNS disease. Pathophysiology of this encephalitis is unclear. While PET showed hypermetabolic lesions, the biopsy showed non-specific changes. The treatments may include immunosuppressants, IVIg, and plasma exchange. One should consider to measure this antibody, in addition to others, when autoimmune encephalitis is suspected [Published with video sequences] .",
"affiliations": "The John A. Hartford Foundation Center of Excellence in Geriatrics, Department of Geriatric Medicine, John A. Burns School of Medicine, University of Hawaii, Honolulu, Hawaii, Japan Green Medical Centre, London, UK.;The John A. Hartford Foundation Center of Excellence in Geriatrics, Department of Geriatric Medicine, John A. Burns School of Medicine, University of Hawaii, Honolulu, Hawaii.;Neuroscience Institute, Queen's Medical Center, Honolulu, Hawaii, USA.",
"authors": "Kojima|Gotaro|G|;Inaba|Michiko|M|;Bruno|Michiko K|MK|",
"chemical_list": "D001323:Autoantibodies; D005968:Glutamate Decarboxylase",
"country": "France",
"delete": false,
"doi": "10.1684/epd.2014.0666",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1294-9361",
"issue": "16(3)",
"journal": "Epileptic disorders : international epilepsy journal with videotape",
"keywords": "anti-GAD antibody; autoimmune encephalitis; generalized seizure; glutamic acid decarboxylase; limbic encephalitis; palatal myoclonus",
"medline_ta": "Epileptic Disord",
"mesh_terms": "D000368:Aged; D001323:Autoantibodies; D001921:Brain; D004660:Encephalitis; D005260:Female; D005968:Glutamate Decarboxylase; D006801:Humans; D007091:Image Processing, Computer-Assisted; D008279:Magnetic Resonance Imaging; D059906:Neuroimaging; D011877:Radionuclide Imaging",
"nlm_unique_id": "100891853",
"other_id": null,
"pages": "358-61",
"pmc": null,
"pmid": "25042574",
"pubdate": "2014-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D059040:Video-Audio Media",
"references": null,
"title": "PET-positive extralimbic presentation of anti-glutamic acid decarboxylase antibody-associated encephalitis.",
"title_normalized": "pet positive extralimbic presentation of anti glutamic acid decarboxylase antibody associated encephalitis"
} | [
{
"companynumb": "US-UCBSA-2014017597",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LEVETIRACETAM"
},
"drugadditional": null,
... |
{
"abstract": "Local anesthetic systemic toxicity characteristically occurs after inadvertent intravascular injection of local anesthetics; however, it is unclear if similar symptoms arise after intrathecal adminstration. Intrathecal use of local anesthetics for chronic pain is increasing and carries a potential risk of toxicity. Experience with the presenting symptoms and appropriate treatment for intrathecal local anesthetic toxicity is limited.\n\n\n\nA 74-year-old woman with an intrathecal bupivacaine/morphine pump developed lower extremity sensory neuropathy followed by obtundation, hypotension, and lower extremity flaccidity after an intrathecal pump refill. Her condition evolved to status epilepticus (SE) refractory to standard treatment. Intravenous fat emulsion (IFE) was administered, but was not immediately effective thus necessitating phenobarbital loading and propofol infusion. Despite significant bupivacaine neurotoxicity, no cardiotoxicity developed.\n\n\n\nThe patient developed intrathecal local anesthetic and opioid toxicity after a malfunction of her intrathecal pump during a refill. We hypothesize that no cardiotoxicity developed secondary to sequestration of bupivacaine within the central nervous system. Likewise, poor CNS penetration of intravenous lipid emulsion may have negated or delayed any antidotal effect.\n\n\n\nWe present a case of intrathecal toxicity leading to prolonged spinal anesthesia, progressive encephalopathy, and SE refractory to intravenous lipid emulsion. Management of SE with benzodiazepines and barbiturates may be more effective than lipids in cases of toxicity from intrathecal administration of bupivacaine.",
"affiliations": "Division of Medical Toxicology, Department of Emergency Medicine, University of Pittsburgh School of Medicine, USA. Electronic address: sidlakam2@upmc.edu.;Division of Medical Toxicology, Department of Emergency Medicine, University of Pittsburgh School of Medicine, USA.;Division of Medical Toxicology, Department of Emergency Medicine, University of Pittsburgh School of Medicine, USA; Pittsburgh Poison Center, Pittsburgh, PA, USA.",
"authors": "Sidlak|Alexander M|AM|;Yanta|Joseph H|JH|;Lynch|Michael J|MJ|",
"chemical_list": "D000701:Analgesics, Opioid; D000779:Anesthetics, Local; D001463:Barbiturates; D005217:Fat Emulsions, Intravenous; D001569:Benzodiazepines; D009020:Morphine; D002045:Bupivacaine",
"country": "United States",
"delete": false,
"doi": "10.1016/j.ajem.2019.12.055",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0735-6757",
"issue": "38(5)",
"journal": "The American journal of emergency medicine",
"keywords": "Bupivacaine; Intrathecal drug delivery pump; Intravenous fat emulsion; Morphine",
"medline_ta": "Am J Emerg Med",
"mesh_terms": "D000368:Aged; D000701:Analgesics, Opioid; D000775:Anesthesia, Spinal; D000779:Anesthetics, Local; D001463:Barbiturates; D001569:Benzodiazepines; D002045:Bupivacaine; D005217:Fat Emulsions, Intravenous; D005260:Female; D006801:Humans; D007022:Hypotension; D007278:Injections, Spinal; D009020:Morphine; D013226:Status Epilepticus",
"nlm_unique_id": "8309942",
"other_id": null,
"pages": "1046.e5-1046.e7",
"pmc": null,
"pmid": "31952869",
"pubdate": "2020-05",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Intrathecal bupivacaine and morphine toxicity leading to transient hypotension and delayed status epilepticus.",
"title_normalized": "intrathecal bupivacaine and morphine toxicity leading to transient hypotension and delayed status epilepticus"
} | [
{
"companynumb": "US-CADILA HEALTHCARE LIMITED-US-ZYDUS-055457",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MORPHINE"
},
"drugaddition... |
{
"abstract": "Glomerulopathies affect kidney glomeruli and can lead to end-stage renal disease if untreated. Clinical and experimental evidence have identified numerous (>20) genetic mutations in the mitochondrial coenzyme Q8B protein (COQ8B) primarily associated with nephrotic syndrome. Yet, little else is understood about COQ8B activity in renal pathogenesis and its role in mitochondrial dysfunction. We identified additional novel COQ8B mutations in a glomerulopathy patient and aimed to define the potential structural and functional defects of COQ8B mutations.\n\n\n\nWhole exome sequencing was performed on a Hispanic female presenting with proteinuria. Novel mutations in the COQ8B gene were identified. The effects of mutation on protein function, mitochondrial morphology, and disease progression were investigated by histopathology, transmission electron microscopy, homology modeling, and in silico structural analysis.\n\n\n\nWe have characterized the pathophysiology of novel COQ8B mutations, compound heterozygous for two alterations c.1037T>G (p.I346S), and c.1560G>A (p.W520X), in the progression of proteinuria in a Hispanic female. Histopathology revealed defects in podocyte structure and mitochondrial morphology. In silico and computation analyses highlight possible structural origins of COQ8B dysfunction in the presence of mutations.\n\n\n\nNovel mutations in COQ8B present promising biomarkers for the early detection and therapeutic targeting of mitochondrial glomerulopathy. Insights from structural modeling suggest roles of mutation-dependent alterations in COQ8B allosteric regulation, protein folding, or stability in renal pathogenesis.",
"affiliations": "Department of Pediatrics, Division of Nephrology, University of Arizona, Tucson, Arizona, USA.;Department of Chemistry and Biochemistry, University of Arizona, Tucson, Arizona, USA.;Department of Chemistry and Biochemistry, University of Arizona, Tucson, Arizona, USA.;Department of Medicine, Division of Nephrology, University of Arizona, Tucson, Arizona, USA.;Center for Applied Genetics and Genomic Medicine and Department of Pediatrics, University of Arizona College of Medicine, Tucson, Arizona, USA.;Center for Applied Genetics and Genomic Medicine and Department of Pediatrics, University of Arizona College of Medicine, Tucson, Arizona, USA.",
"authors": "AbuMaziad|Asmaa S|AS|0000-0001-5093-3405;Thaker|Tarjani M|TM|;Tomasiak|Thomas M|TM|;Chong|Chyi Chyi|CC|;Galindo|Maureen K|MK|;Hoyme|H Eugene|HE|",
"chemical_list": "C586096:COQ8B protein, human; D011494:Protein Kinases",
"country": "United States",
"delete": false,
"doi": "10.1002/ajmg.a.61909",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1552-4825",
"issue": "185(1)",
"journal": "American journal of medical genetics. Part A",
"keywords": "ADCK4; COQ8B; FSGS; mitochondria; nephrotic syndrome; proteinuria",
"medline_ta": "Am J Med Genet A",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D003198:Computer Simulation; D005260:Female; D005923:Glomerulosclerosis, Focal Segmental; D006801:Humans; D007223:Infant; D007668:Kidney; D007676:Kidney Failure, Chronic; D008297:Male; D008928:Mitochondria; D009154:Mutation; D009404:Nephrotic Syndrome; D010375:Pedigree; D011494:Protein Kinases; D013329:Structure-Activity Relationship; D000073359:Whole Exome Sequencing; D055815:Young Adult",
"nlm_unique_id": "101235741",
"other_id": null,
"pages": "60-67",
"pmc": null,
"pmid": "33084234",
"pubdate": "2021-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural",
"references": null,
"title": "The role of novel COQ8B mutations in glomerulopathy and related kidney defects.",
"title_normalized": "the role of novel coq8b mutations in glomerulopathy and related kidney defects"
} | [
{
"companynumb": "US-009507513-2101USA005100",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "LOSARTAN POTASSIUM"
},
"drugadditional": nul... |
{
"abstract": "Abnormal change on the tongue is a potential complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT). The exact pathogenesis remains unclear and several risk factors include chemoradiotherapy, infection, graft-versus-host disease, disease relapse, and secondary malignancy. Our case described a 42-year-old woman with B-cell acute lymphoblastic leukemia treated by allo-HSCT 2 months later followed by a rare and atypical tongue neoplasia without oral pain, dysphagia, and dysgeusia. The biopsy was operated which showed granulation tissue with no evidence on typical graft-versus-host disease or malignancy, and no specific infection had been identified. Cyclosporine and mycophenolate mofetil, which were used for immunosuppression after allo-HSCT accompanying with the rapid growth of the tongue neoplasia, was then replaced by sirolimus. One month later, the patient underwent a complete remission unexpectedly.",
"affiliations": "Department of Hematology, the Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China.",
"authors": "Qiu|Xi|X|;Yu|Teng|T|;Xu|Yang|Y|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1097/SCS.0000000000007290",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1049-2275",
"issue": "32(5)",
"journal": "The Journal of craniofacial surgery",
"keywords": null,
"medline_ta": "J Craniofac Surg",
"mesh_terms": "D000328:Adult; D001402:B-Lymphocytes; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma; D014059:Tongue; D014184:Transplantation, Homologous",
"nlm_unique_id": "9010410",
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"title": "A Rare Case of Tongue Neoplasia Treated Successfully in a Patient With B-Cell Acute Lymphoblastic Leukemia Following Allogeneic Hematopoietic Stem Cell Transplantation.",
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"abstract": "BACKGROUND\nPain is the fifth vital sign of human beings. Morphine is the first choice for relieving moderate to severe cancer pain. Most of the previous studies merely focused on the analgesic effect of high-dose or ultra-high-dose morphine in patients with advanced cancers but did not report any cases related to successful morphine withdrawal.\nA 42-year-old woman was admitted to our hospital in March 2019.\n\n\nMETHODS\nShe was diagnosed with progressive aggravation of headache for 1 month, which was meningeal metastasis of lung cancer.\n\n\nMETHODS\nSymptomatic treatments like dehydration, hormone, intrathecal injection chemotherapy and an increased dose of osimertinib to 160 mg/day were applied but showed poor curative effects. The patient refused whole-brain radiotherapy. Pain intensity level was re-evaluated and the patient scored 9 based on numerical rating scale, which suggested that the patient suffered from severer cancerous pain. Thus, the patient started to receive morphine for treating headache.\n\n\nRESULTS\nThe patient's headache was alleviated after receiving high-dose morphine treatment, and she continued to undergo anti-cancer treatment. After tumor remission, the patient's morphine dose gradually decreased and eventually stopped, without any withdrawal symptoms. In addition, the quality of life of the patient was greatly improved with performance status scored 2 and limb muscle strength increased from Grade 2 to Grade 5.\n\n\nCONCLUSIONS\nFor patients with advanced cancers, the application of ultra-high-dose morphine may significantly relieve cancerous pain, improve survival and quality of life, and overcome their fear for death and desperation, which contributes to the establishment of a basis for subsequent anticancer treatments. Thus, timely effective pain management and routine anticancer treatments are the key to addressing the cancer pain problem.",
"affiliations": "Department of Oncology, Changzhi People's Hospital.;Department of Anesthesiology, Changzhi People's Hospital.;Department of Oncology, Changzhi People's Hospital.;Department of Oncology, Changzhi People's Hospital.;Department of Oncology, Changzhi People's Hospital.;Quality Control Department, Changzhi People's Hospital, Changzhi, Shanxi.;Department of Pathophysiology, College of Basic Medical Sciences, Zhengzhou University.;Department of Oncology, Changzhi People's Hospital.",
"authors": "Zhang|Xiaoling|X|;Zhang|Jialei|J|;Du|Yunyi|Y|;Wang|Mei|M|;Gao|Yangjun|Y|;Zhou|Lurong|L|;Lu|Jing|J|;Zhao|Jun|J|",
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"fulltext": "\n==== Front\nMedicine (Baltimore)\nMedicine (Baltimore)\nMEDI\nMedicine\n0025-7974 1536-5964 Lippincott Williams & Wilkins Hagerstown, MD \n\nMD-D-19-09547\n10.1097/MD.0000000000022919\n22919\n3300\nResearch Article\nClinical Case Report\nIntravenous analgesia with ultra-high-dose morphine for the treatment of headache and successful withdrawal of morphine\nA case report and literature reviewZhang Xiaoling MMeda Zhang Jialei MMedb Du Yunyi MMeda Wang Mei MMeda Gao Yangjun MMeda Zhou Lurong MMedc Lu Jing MD, PhDde∗ Zhao Jun MD, PhDa∗ Saranathan. Maya a Department of Oncology, Changzhi People's Hospital\nb Department of Anesthesiology, Changzhi People's Hospital\nc Quality Control Department, Changzhi People's Hospital, Changzhi, Shanxi\nd Department of Pathophysiology, College of Basic Medical Sciences, Zhengzhou University\ne Collaborative Innovation Center of Henan Province for Cancer Chemoprevention, Zhengzhou, Henan, China.\n∗ Correspondence: Jun Zhao, Department of Oncology, Changzhi People's Hospital, Changzhi, Shanxi 046000, China (e-mail: zhaojun380@163.com); Jing Lu, Department of Pathophysiology, College of Basic Medical Sciences, Zhengzhou University, Collaborative Innovation Center of Henan Province for Cancer Chemoprevention, Zhengzhou, Henan 450001 (e-mail: lujing@zzu.edu.cn).\n30 10 2020 \n30 10 2020 \n99 44 e229192 12 2019 24 7 2020 25 9 2020 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:\nPain is the fifth vital sign of human beings. Morphine is the first choice for relieving moderate to severe cancer pain. Most of the previous studies merely focused on the analgesic effect of high-dose or ultra-high-dose morphine in patients with advanced cancers but did not report any cases related to successful morphine withdrawal.\n\nPatient concerns:\nA 42-year-old woman was admitted to our hospital in March 2019.\n\nDiagnosis:\nShe was diagnosed with progressive aggravation of headache for 1 month, which was meningeal metastasis of lung cancer.\n\nInterventions:\nSymptomatic treatments like dehydration, hormone, intrathecal injection chemotherapy and an increased dose of osimertinib to 160 mg/day were applied but showed poor curative effects. The patient refused whole-brain radiotherapy. Pain intensity level was re-evaluated and the patient scored 9 based on numerical rating scale, which suggested that the patient suffered from severer cancerous pain. Thus, the patient started to receive morphine for treating headache.\n\nOutcomes:\nThe patient's headache was alleviated after receiving high-dose morphine treatment, and she continued to undergo anti-cancer treatment. After tumor remission, the patient's morphine dose gradually decreased and eventually stopped, without any withdrawal symptoms. In addition, the quality of life of the patient was greatly improved with performance status scored 2 and limb muscle strength increased from Grade 2 to Grade 5.\n\nLessons:\nFor patients with advanced cancers, the application of ultra-high-dose morphine may significantly relieve cancerous pain, improve survival and quality of life, and overcome their fear for death and desperation, which contributes to the establishment of a basis for subsequent anticancer treatments. Thus, timely effective pain management and routine anticancer treatments are the key to addressing the cancer pain problem.\n\nKeywords\ncancerous painmorphine withdrawalultra-high-dose morphinePostgraduate Education Innovation Research Project of Shanxi Province2019JG183Jun ZhaoOPEN-ACCESSTRUE\n==== Body\n1 Introduction\nPain is the fifth vital sign of human beings. Statistically, ∼25% of newly diagnosed cancer patients suffer from cancerous pain. Moreover, the incidence rate rises to 60% to 80% in patients with advanced cancers, among which one third of patients experience severe pain.[1] Morphine is the first choice for relieving moderate to severe cancer pain.[2,3] Most of the previous studies merely focused on the analgesic effect of high-dose or ultra-high-dose morphine in patients with advanced cancers but did not report any cases related to successful morphine withdrawal. This study reported a case of a patient with meningeal metastatic lung cancer who was administrated ultra-high-dose morphine (the patient received injection of 480-mg morphine daily, which was equivalent to 1440 mg of oral morphine) for treating headache. After achieving efficient pain relief by morphine, the patient continued her anticancer therapies and cancerous pain was significantly reduced. Then morphine was gradually withdrawn without inducing any withdrawal symptoms. In addition, the quality of life of the patient was greatly improved with performance status (PS) scored 2 and limb muscle strength increased from Grade 2 to Grade 5.\n\n2 Case presentation\nA 42-year-old woman was admitted to our hospital in May 2017 due to progressive aggravation of lumbodorsal pain for 1 month. The patient was diagnosed with peripheral lung adenocarcinoma in the apicoposterior segment of superior lobe of left lung (cTxNxM1, quantification type IV, EGFR 19del) with multiple bone metastases in the fifth, seventh, and twelfth thoracic vertebrae and the second and fourth lumbar vertebrae. Herein, the patient was orally administrated 250 mg of gefitinib once daily and injected with zoledronic acid. In March 2018, the patient complained about head distention and ache. Results of peripheral blood genetic test showed T790M mutation. Thus, the patient was orally administrated 80 mg of osimertinib once daily and headache was found to be effectively relieved. In October 2018, the patient reported a relapse of headache and was diagnosed with meningeal metastases by pathological examination of cerebrospinal fluid. Hence, the patient received intrathecally injection of 10-mg methotrexate and 5-mg dexamethasone for three times and was administrated an increased dose of osimertinib to 160 mg/day.[4] Headache symptom was alleviated after the treatment. However, headache returned to the patient after 2 months and further intensified. The patient refused whole-brain radiotherapy (WBRT) but accepted pemetrexed as a chemotherapy for 1 week. Headache was relieved after the treatment. Then, the patient herself discontinued routine chemotherapy. In March 2019, the patient reported an aggravation of headache symptom, which was improved after dehydration therapy. Then, the patient was administrated pemetrexed and carboplatin as chemotherapies in combination with a single intrathecal injection. One week later, the patient developed a sudden severe headache with general numbness, dysphoria, projectile vomit, and decreased limb muscle strength to Grade 1 or Grade 2. Pain intensity of the patient scored 7, which suggested severe pain according to the numerical rating scale (NRS). Physicians speculated that pain could be caused by elevated intracranial pressure associated with meningeal metastases. Symptomatic treatments like dehydration and hormone therapies were applied but showed poor curative effects. Pain intensity level was re-evaluated and the patient scored 9 based on NRS, which suggested that the patient suffered from severer cancerous pain. Thus, the patient started to receive morphine treatment.\n\n2.1 Morphine treatment\n2.1.1 Dose titration during morphine intolerance\nThe U.S. Food and Drug Administration identifies opioid tolerance as receiving 25 mcg/h fentanyl patch, at least 60 mg of morphine daily, at least 30 mg of oral oxycodone daily, at least 8 mg of oral hydromorphone daily, 25 mg of oxymorphone daily, or an equivalent dose of another opioid for a week or longer; otherwise, it may be classified as opioid intolerance.[5] Accordingly, the patient was defined as opioid-naïve before receiving morphine treatment in this study. According to the “Guidelines for Diagnosis and Treatment of Cancer Pain (2018 Edition)” issued by the National Health Commission of the People's Republic of China (hereinafter referred to as the guidelines), all doses should be titrated to appropriate effect. On this basis, the patient with severe cancerous pain received hypodermic injection of 5-mg morphine on March 12, 2019 (Day 1, the first day of morphine treatment). The doses of morphine extended-release tablet were adjusted based on the doses of morphine immediate-release tablet that were used for relieving breakthrough pain (BTP) occurring in the initial 24 h. The dosage of morphine extended-release tablet reached 660 mg (330 mg Q12 h) on the sixth day of morphine treatment (Table 1).\n\nTable 1 Dose titration during morphine intolerance.\n\n2.1.2 Pain management after morphine tolerance by multi-disciplinary team\nThe dose of morphine reached a peak on the sixth day of treatment. Morphine-caused adverse effects occurred in the patient, including general numbness, decreased limb muscle strength, uroschesis, nausea, emesis, and pruritus. Based on the patient's condition, our hospital held a multi-disciplinary team (MDT) consultation in order to determine superior therapeutic strategies that could achieve favorable analgesic effects as well as reduce adverse effects. In view of the poor condition of the patient, radiologists recommended WBRT if intracranial pressure could be reduced after curative care. Neurosurgeons refused ventriculo-peritoneal (pleural) shunt because of meningeal metastatic lung cancer. Pain clinicians recommended establishing an intrathecal drug delivery system by lumbar catheterization to decrease the dose of morphine. Neurologists noticed that the intracranial pressure of the patient reached 500 to 550 mm H2O and thereby speculated that anticancer treatments could be the key to pain relief for that the increase in intracranial pressure could be mainly attributed to direct stimulation by tumor cells or pain related to meningeal metastases. According to oncologists, an oral dose equivalent to 10% to 20% of total morphine taken in the initial 24 h should be administrated once BTP occurred for effectively relieving pain and improving the quality of life of the patient. The patient had taken 30 mg of oral morphine for 1 week, which made her a morphine-tolerant patient. Besides, the patient did not receive routine chemotherapy or antiangiogenic therapy. Thus, the oncologists recommended performing pemetrexed and bevacizumab combination treatment and closely monitoring the adverse effects of morphine. After serious consideration and discussion, the patient and her dependents refused lumbar cistern catheterization but agreed to receive anticancer treatment 1 week later.\n\n2.1.3 Intravenous infusion of ultra-high-dose morphine for relieving cancer pain and successful morphine withdrawal after anticancer treatment\nThe patient developed frequent vomit, which caused an inaccuracy in oral morphine intake. According to the National Comprehensive Cancer Network Guidelines for Adult Cancer Pain, oral morphine can be conversed into intramuscular or intravenous at a conversion ratio of 3:1. Hence, in order to maintain a stable plasma concentration, reduce adverse effects of oral morphine and maximize pain relief, the patient began to receive 240 mg/d morphine via infusion pump since Day 22. The doses of morphine were dynamically adjusted according to the guidelines. The dose of morphine used on Day 28 was increased to 480 mg/day. The clinical signs of the patient and adverse effects were continuously observed and results showed that cancerous pain was significantly relieved and no recurrence of BTP was observed. In addition to several adverse effects like nausea, vomit and constipation, no toxic symptoms such as dizziness, respiratory depression were observed.\n\nOn Day 42, the patient developed lethargy with mild nausea. Considering that the patient was experiencing unmanageable adverse effects and cancerous pain had been partially relieved by anticancer treatment, opioid dose reduction was warranted for alleviating the adverse effects caused by opioids. As described in the guidelines, the dose should be gradually tapered down. The analgesic dose may be reduced by 10% to 25% daily until the dose is equivalent to 30 mg of oral morphine for ameliorating opioid-related withdrawal symptoms. The effective dose above may be continued for 2 days and then withdrawn. Accordingly, the dose of morphine was reduced once every 2 days since Day 43. By Day 71, the dosage of morphine had been adjusted to intravenous infusion of 10 mg/d morphine. This morphine dose was continued for 2 days and then withdrawn on Day 73 (Fig. 1). Two-week follow-up showed no symptoms of morphine withdrawal. Re-evaluation of the condition of the patient demonstrated that limb muscle strength was enhanced to Grade 5 and no BTP occurred. The patient began routine anticancer treatment.\n\nFigure 1 The processes of intravenous analgesia with ultra-high dose of morphine and drug withdrawal.\n\n3 Discussion\nWorld Health Organization (WHO) identifies morphine consumption as one of the golden criteria used for evaluating pain management. Morphine is characterized by no ceiling effect, which means that morphine doses may be unlimitedly adjusted on the basis of pain intensity levels. According to Edmonton Classification Scale, the doses of oral morphine include: regular doses (<300 mg/d), high doses (300–600 mg/d), and ultra-high doses (>600 mg/d).[6] Although with treatments under the guidance of the three-step “ladder” for cancer pain relief developed by WHO, ∼10% to 20% of patients still developed refractory cancer pain, among which 5% to 8% of patients required high doses of opioids. According to the statistics in a previous retrospective study, cancer patients receiving ultra-high-dose morphine treatment accounted for only 1.6%.[3,7] Berevitch et al retrospectively analyzed the medical records of 651 patients hospitalized in Tel Hashomer Hospital between January 1, 1996 and December 31, 1997, and concluded that 453 patients received regular doses of morphine as the first-line therapy. A total of 55 patients took doses higher than 299 mg/d, among which 19 patients received doses between 300 and 599 mg/d and the rest received doses higher than 599 mg.[8] Plentiful previous publications reported the application of high-dose or ultra-high-dose morphine for pain relief in patients with advanced cancers. However, the patients recruited all suffered from advanced cancers with poor prognoses and short survivals. Thus, none of these studies addressed the survival issue of patients receiving ultra-high-dose morphine or reported any cases of successful withdrawal from ultra-high-dose morphine. Berevitch et al compared the survivals between patients receiving regular doses of morphine and those receiving high doses, and found that the mean survival periods of patients receiving morphine with regular doses (<300 mg/d), high doses (300–599 mg/d), or ultra-high doses (>599 mg/d) were 14 days, 15 days, and 13 days, respectively. There were no significant differences among these groups.[8] In this study, the patient received ultra-high doses of morphine via intravenous morphine infusion pump based on the comprehensive assessment results for the patient's condition. The doses of morphine were tapered down to withdrawal after cancerous pain had been significantly reduced by anticancer treatment. Follow-up results showed that no symptoms of withdrawal occurred. The quality of life of the patient was greatly improved with PS scored 2 and limb muscle strength elevated from Grade 2 to Grade 5. Altogether, these results suggested that effective pain management may be a prerequisite for anticancer interventions, which in turn determine the withdrawal of analgesics. Thus, pain management is necessary for patients with advanced cancers to continue their anticancer treatments for that effective pain control not only reduces cancerous pain in patients but also strives for the precious time for further anticancer treatments.\n\nLu et al[9,10] demonstrated that the combination therapy involving intrathecal morphine pump and wireless-controlled analgesic pump achieved favorable analgesic effects in patients with advanced cancers. Programmable morphine pump, also known as intrathecal drug delivery system, is an efficient analgesic device for pain management by continuously delivering low-dose morphine. The pump is filled with morphine and implanted under the covering of the abdominal muscles of patients. A small catheter is inserted into the subarachnoid space and is threaded upward. Then the catheter is tunneled under the skin to the abdomen and is connected to the pump. The most distinct advantage of morphine pump is that it can exert an equivalent pain-relieving effect to oral morphine with a much lower dose. However, the patient refused morphine pump implantation after fully communicating with physicians. Instead, the patient received morphine treatment on ultra high doses for 73 days. Initially, several adverse effects such as nausea, vomit, dizziness, pruritus, uroschesis, constipation, and decreased limb muscle strength of limbs occurred in the morphine-intolerant patient, whereas the symptoms were gradually relieved and disappeared with the development of morphine tolerance, except for constipation. Morphine doses were titrated to appropriate effect according to the guidelines, and results showed that no symptoms of morphine overdose (such as respiratory depression) occurred in the morphine-intolerant patient. The withdrawal of morphine should obey the principle of “slow-rapid-slow.” Accordingly, in this report, ultra-high-dose morphine was gradually withdrawn without triggering any symptoms of withdrawal, which suggested that no morphine addiction was developed in the morphine-tolerant patient in spite of ultra-high-dose morphine treatment. These results consistently indicated the safety of ultra-high-dose morphine in the management of cancer pain. However, more clinical trials should be performed for further verifying the current findings.\n\nIn conclusion, although ultra-high dose of morphine has not been widely used in clinical practices, it may be generally considered safe on the basis of strict application ranges and close monitoring of adverse reactions. For patients with advanced cancers, the application of ultra-high-dose morphine may significantly relieve cancerous pain, improve survival and quality of life, and overcome their fear for death and desperation, which contributes to the establishment of a basis for subsequent anticancer treatments. Thus, timely effective pain management and routine anticancer treatments are the key to addressing the cancer pain problem.\n\nAuthor contributions\nConceptualization: Xiaoling Zhang, Jialei Zhang, Jing Lu, Jun Zhao.\n\nData curation: Yunyi Du.\n\nInvestigation: Mei Wang.\n\nResources: Yangjun Gao.\n\nSoftware: Lurong Zhou.\n\nWriting – original draft: Xiaoling Zhang, Jialei Zhang.\n\nWriting – review & editing: Jing Lu, Jun Zhao.\n\nAbbreviations: BTP = breakthrough pain, MDT = multi-disciplinary team, NRS = numerical rating scale, PS = performance status, WBRT = whole-brain radiotherapy, WHO = World Health Organization.\n\nHow to cite this article: Zhang X, Zhang J, Du Y, Wang M, Gao Y, Zhou L, Lu J, Zhao J. Intravenous analgesia with ultra-high-dose morphine for the treatment of headache and successful withdrawal of morphine: A case report and literature review. Medicine. 2020;99:44(e22919).\n\nXZ and JZ contributed equally to this work.\n\nEthics approval: The work was conducted under the guidance of Declaration of Helsinki 1975. The study was reviewed and approved by the Ethics Committee of Changzhi People's Hospital.\n\nInformed consent: Written informed consent was obtained from the patient for the purpose of publication of case details and accompanying images.\n\nThis work was supported by the Postgraduate Education Innovation Research Project of Shanxi Province (2019JG183).\n\nThe authors have no conflicts of interest to disclose.\n\nThe datasets generated during and/or analyzed during the present study are available from the corresponding author on reasonable request.\n==== Refs\nReferences\n[1] Vadalouca A Moka E Argyra E \nOpioid rotation in patients with cancer: a review of the current literature\n. J Opioid Manag \n2008 ;4 :213 –50\n.18837204 \n[2] Li X Li C Zhou X \nPharmacoeconomic analysis of four opioid analgesics in treatment of cancer pain\n. Mod Oncol \n2013 ;21 :169 –71\n.\n[3] Morasco BJ Cavanagh R Gritzner S \nCare management practices for chronic pain in veterans prescribed high doses of opioid medications\n. Fam Pract \n2013 ;30 :671 –8\n.23901065 \n[4] Yang JCH Cho BC Kim DW \nOsimertinib for patients (pts) with leptomeningeal metastases (LM) from EGFR-mutant non-small cell lung cancer (NSCLC): updated results from the BLOOM study\n. J Clin Oncol \n2017 ;35 :2020 .\n[5] Swarm RA Abernethy AP Anghelescu DL \nAdult cancer pain\n. J Natl Compr Canc Netw \n2013 ;11 :992 –1022\n.23946177 \n[6] Pei B Zhang Y Yang Y \nManagement of high-dose continuous intravenous infusion of morphine in patients with advanced cancer\n. Chin J Drug Appl Monit \n2011 ;8 :193 –4\n.\n[7] Yang Y Wu L Liu Y \nRetrospective study on the conversion coefficient of high dose of morphine injection continuous PCA pump delivery for the patients with advanced cancer pain\n. Chin Pharm \n2017 ;20 :1061 –4\n.\n[8] Bercovitch M Waller A Adunsky A \nHigh dose morphine use in the hospice setting. A database survey of patient characteristics and effect on life expectancy\n. Cancer \n1999 ;86 :871 –7\n.10463988 \n[9] Abdel-Ghaffar HS Mohamed SA Fares KM \nCombined intrathecal morphine and dexmedetomidine for postoperative analgesia in patients undergoing major abdominal cancer surgery\n. Pain Med \n2016 ;17 :2109 –18\n.27002003 \n[10] Lu Z Hu Z \nEffects of intrathecal morphine pump combined with wireless controlled analgesic pump on cellular immune function and survival of patients with advanced cancer pain\n. Chin Remed Clin \n2019 ;19 :750 –2\n.\n\n",
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"abstract": "OBJECTIVE\nRaoultella ornithinolytica is not well known as a clinical pathogen. We performed a retrospective review of R. ornithinolytica bacteremia to investigate its clinical features, antimicrobial susceptibility, and overall patient outcomes.\n\n\nMETHODS\nR. ornithinolytica bacteremia cases were collected from an electronic database of all cases of bacteremia over a 10-year period. Medical records were retrospectively reviewed. Demographic data, clinical information, the presence of underlying comorbidities, the results of antimicrobial susceptibility testing, and the antimicrobial regimen administered were investigated.\n\n\nRESULTS\nR. ornithinolytica was isolated from blood culture specimens in 16 cases. The majority of these patients had an underlying malignant condition of advanced stage (15 patients, 94 %). Seven of these patients had a solid tumor with lesions or metastases that extended to the bile duct or biliary tract. Neutropenic fever following hematologic stem cell transplantation was found in three cases. No resistance to piperacillin/tazobactam or imipenem was found. Four cases showed resistance to cefoxitin, while one of these cases showed resistance to multiple cephalosporins. In overall outcomes, seven patients (44 %) did not recover from the infection and subsequently expired.\n\n\nCONCLUSIONS\nR. ornithinolytica bacteremia occurs mainly in patients with underlying malignancies. The overall outcome was not favorable, despite favorable antimicrobial susceptibility test results. The findings of this study contradict those of other studies that demonstrated that infection from Raoultella species have good prognoses.",
"affiliations": "Department of Laboratory Medicine & Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Ilwon-Dong, Kangnam-Gu, Seoul, 135-710, Korea.",
"authors": "Chun|S|S|;Yun|J W|JW|;Huh|H J|HJ|;Lee|N Y|NY|",
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"title": "Clinical characteristics of Raoultella ornithinolytica bacteremia.",
"title_normalized": "clinical characteristics of raoultella ornithinolytica bacteremia"
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"abstract": "Anagrelide is a phosphodiesterase-3 inhibitor used in the treatment of essential thrombocythaemia. Cardiovascular side effects such as ventricular tachycardia and cardiomyopathy are rare but potentially fatal and should be made known to patients before starting the medication. It usually arises within the first 6 months after initiation of therapy and may be dose related. The elderly population are particularly susceptible. These cardiotoxicities result from an increase in cyclic AMP that induces positive inotropic and chronotropic effects and are often reversible with cessation of use. We report a case of a 78-year-old woman with essential thrombocythaemia and recently started on anagrelide who presented with syncope and multiple bruises and facial trauma and found to have developed ventricular tachyarrhythmia.",
"affiliations": "Internal Medicine, Einstein Medical Center, Philadelphia, Pennsylvania, USA.;Internal Medicine, Einstein Medical Center, Philadelphia, Pennsylvania, USA.;Internal Medicine, Einstein Medical Center, Philadelphia, Pennsylvania, USA.;Division of Cardiac Electrophysiology, Einstein Medical Center, Philadelphia, Pennsylvania, USA.",
"authors": "Rodriguez-Ziccardi|Mary|M|;Rubio|Manolo|M|;Lu|Marvin|M|;Greenspan|Allan|A|",
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"title": "Ventricular tachyarrhythmia in a 78-year-old woman with essential thrombocythaemia.",
"title_normalized": "ventricular tachyarrhythmia in a 78 year old woman with essential thrombocythaemia"
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"abstract": "A 20-year-old female ingested an unknown quantity of minoxidil tablets as a suicide gesture. She presented to the emergency department about 90 minutes later with tachycardia, diffuse T wave inversion, and S-T segment depression on the ECG, labile hypotension, and a substantially elevated total serum minoxidil concentration of 3140 ng/mL. She responded to supportive therapy with intravenous fluids, and was discharged 32 hours later with stable blood pressure and mild residual tachycardia. The clinical toxicology, treatment, and previous case reports of minoxidil overdose are reviewed.",
"affiliations": "Department of Emergency Medicine, University of Florida Health Science Center, Jacksonville.",
"authors": "Poff|S W|SW|;Rose|S R|SR|",
"chemical_list": "D008914:Minoxidil",
"country": "United States",
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"doi": "10.1016/0736-4679(92)90011-h",
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"issue": "10(1)",
"journal": "The Journal of emergency medicine",
"keywords": null,
"medline_ta": "J Emerg Med",
"mesh_terms": "D000328:Adult; D062787:Drug Overdose; D004562:Electrocardiography; D005260:Female; D006801:Humans; D007022:Hypotension; D008914:Minoxidil; D011041:Poisoning",
"nlm_unique_id": "8412174",
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"pages": "53-7",
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"pmid": "1629592",
"pubdate": "1992",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Minoxidil overdose with ECG changes: case report and review.",
"title_normalized": "minoxidil overdose with ecg changes case report and review"
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"activesubstancename": "MINOXIDIL"
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"abstract": "OBJECTIVE\nThe porphyrias are a defect in the biosynthesis of heme which can be associated with different neurological symptoms during acute attacks such as peripheral neuropathy, mental disturbance and seizures. So far, there have only been a few case reports of status epilepticus, none of which were of epilepsia partialis continua (EPC). We present here two cases of hereditary coproporphyria (HCP) manifesting EPC as part of the clinical presentation.\n\n\nMETHODS\nThe patients' medical charts, EEG and imaging studies were carefully reviewed.\n\n\nRESULTS\nCase 1 is a 49-year-old male who first presented a tonic-clonic seizure. Case 2 is a 30-year-old male who came to the emergency room for a convulsive status epilepticus. Both evolved to EPC over the next days. EPC persisted despite several antiepileptic drug trials. Diagnosis of HCP was confirmed by a high level of urine, fecal and serum porphyrins in both cases and by genetic testing in one. Over the last 3 years, the first patient has continued to present non-disabling EPC and has had four tonic-clonic seizures associated with alcohol consumption. The second patient died from brain edema one month and half after admission.\n\n\nCONCLUSIONS\nAcute porphyrias should be included in the differential diagnosis of new onset status epilepticus, including EPC. Their recognition is important as it modifies significantly patient management, since many anticonvulsants are porphyrogenic.",
"affiliations": "Service de Neurologie, Hôpital Notre-Dame, Centre Hospitalier Universitaire de Montréal, Montréal, Qué., Canada.",
"authors": "Tran|Thi Phuoc Yen|TP|;Leduc|Karine|K|;Savard|Martin|M|;Dupré|Nicolas|N|;Rivest|Donald|D|;Nguyen|Dang Khoa|DK|",
"chemical_list": null,
"country": "Switzerland",
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"doi": "10.1159/000353279",
"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 10.1159/000353279crn-0005-0116Published online: June, 2013Acute Porphyria Presenting as Epilepsia Partialis Continua Tran Thi Phuoc Yen aLeduc Karine bSavard Martin bDupré Nicolas bRivest Donald cNguyen Dang Khoa a*aService de Neurologie, Hôpital Notre-Dame, Centre Hospitalier Universitaire de Montréal, Montréal, Qué., CanadabService de Neurologie, Hôpital de l'Enfant-Jésus, Centre Hospitalier Universitaire de Québec, Québec City, Qué., CanadacService de Neurologie, Hôpital Hôtel-Dieu de Lévis, Centre Hospitalier Universitaire de Québec, Québec City, Qué., Canada*Prof. Dang K. Nguyen, MD, FRCPC, Service de Neurologie, Université de Montréal, CHUM Notre-Dame, 1560 Sherbrooke Est, Montreal, QC H2L 4M1 (Canada), E-Mail d.nguyen@umontreal.caMay-Aug 2013 29 6 2013 29 6 2013 5 2 116 124 Copyright © 2013 by S. Karger AG, Basel2013This is an Open Access article licensed under the terms of the Creative Commons Attribution-NonCommercial 3.0 Unported license (CC BY-NC) (www.karger.com/OA-license), applicable to the online version of the article only. Users may download, print and share this work on the Internet for noncommercial purposes only, provided the original work is properly cited, and a link to the original work on http://www.karger.com and the terms of this license are included in any shared versions.Purpose\nThe porphyrias are a defect in the biosynthesis of heme which can be associated with different neurological symptoms during acute attacks such as peripheral neuropathy, mental disturbance and seizures. So far, there have only been a few case reports of status epilepticus, none of which were of epilepsia partialis continua (EPC). We present here two cases of hereditary coproporphyria (HCP) manifesting EPC as part of the clinical presentation.\n\nMethod\nThe patients’ medical charts, EEG and imaging studies were carefully reviewed.\n\nResults\nCase 1 is a 49-year-old male who first presented a tonic-clonic seizure. Case 2 is a 30-year-old male who came to the emergency room for a convulsive status epilepticus. Both evolved to EPC over the next days. EPC persisted despite several antiepileptic drug trials. Diagnosis of HCP was confirmed by a high level of urine, fecal and serum porphyrins in both cases and by genetic testing in one. Over the last 3 years, the first patient has continued to present non-disabling EPC and has had four tonic-clonic seizures associated with alcohol consumption. The second patient died from brain edema one month and half after admission.\n\nConclusion\nAcute porphyrias should be included in the differential diagnosis of new onset status epilepticus, including EPC. Their recognition is important as it modifies significantly patient management, since many anticonvulsants are porphyrogenic.\n\nKey words\nAcute porphyriaStatus epilepticusEpilepsia partialis continua\n==== Body\nIntroduction\nThe porphyrias, a group of disorders characterized by a variable catalytic defect of one of the seven enzymes in the biosynthesis of heme, are classified clinically as acute or non-acute porphyrias based on their clinical manifestations with or without neurovisceral attacks [1, 2, 3]. The major manifestations of acute porphyrias are neurological, including neuropathic abdominal pain, peripheral neuropathy, mental disturbance and seizures. Seizures affect 10–20% of patients with acute porphyria [1]. The most commonly reported types of seizures are complex partial seizures and tonic-clonic seizures [4, 5], even though EEG documentation of such seizures have been sparse. Status epilepticus has also been rarely reported. Here, we report two patients with hereditary coproporphyria (HCP) who presented with status epilepticus and an EEG documentation.\n\nCase Summaries\nCase 1\nA 49-year-old right-handed man with a past medical history of Berger's disease presented to the emergency room on December 13, 2009, for a 1-min-long tonic-clonic seizure and increasing confusion over the past week. He was immediately started on acyclovir and phenytoin. The initial EEG, brain MRI and lumbar puncture were normal. Within 2 days, he developed continuous right hand myoclonic jerks compatible with epilepsia partialis continua (EPC). Repeat brain MRI performed 3 days after admission disclosed non-enhancing high T2 and FLAIR signal changes over the bilateral temporal lobes (fig. 1). Brain PET revealed focal hypermetabolism over the bilateral frontal and temporal lobes, predominantly over the left side. Repeat EEG revealed left frontotemporal periodic lateralized epileptiform discharges (fig. 2). A repeat lumbar puncture at day 3 was within normal limits. Bacteriological, viral serological (including herpes simplex virus PCR) workup, immunologic parameters as well as toxicology screen revealed no abnormal findings. While the confusion progressively waned, EPC persisted despite several antiepileptic drug trials (phenytoin, valproic acid, carbamazepine, clobazam, lamotrigine). A probable diagnosis of HPC was eventually made when urine coproporphyrins and fecal total porphyrins returned to twice the normal range (even when testing was made 9 days after admission while the patient was improving). These abnormal results could not be explained by other conditions which have previously been associated with secondary coproporphyrinurias such as abuse of toxic substances, liver diseases, malignancies, diverse hematological diseases, etc. [6]. Over the last 3 years, the patient has continued to present non-disabling EPC (manifesting only as very low-amplitude right hand myoclonic jerks) and has had a total of four tonic-clonic seizures in the context of alcohol consumption. He remains with mild memory problems and is currently treated with levetiracetam. On the last brain MRI (2 years after initial setting), T2 signal changes had decreased significantly (fig. 3).\n\nCase 2\nA 30-year-old man, known only for a generalized anxiety disorder, was brought to the emergency room on November 16, 2011, in convulsive status epilepticus preceded over the last 3 days by nausea, vomiting and headaches. Initial management included intravenous benzodiazepines and phenytoin followed by intubation and a perfusion of midazolam and propofol. The patient then evolved to EPC as he presented continuous left hand and mouth myoclonic jerks, very rarely associated with altered consciousness. EEG (fig. 4) showed diffuse slowing, sometime associated with right frontotemporal periodic lateralized epileptiform discharges. MRI disclosed right hemispheric gyriform increased signal on T2-weighted images, restricted diffusion on DWI/ADC images and mild midline shift to the left. Brain PET revealed focal hypermetabolism over the right frontal and temporal lobes, and to a lesser extent in the right occipital region. Two lumbar punctures were normal. As in the first patient, bacteriological, viral serological workup as well as immunologic parameters failed to disclose a plausible cause. His condition eventually worsened, with decreased level of consciousness leading to intubation, despite large spectrum antibiotics, acyclovir, several antiepileptic drug trials (phenobarbital, levetiracetam, lacosamide, topiramate, vigabatrin, gabapentin) and immunotherapy (intravenous immunoglobulins, plasma exchanges). Diagnosis of porphyria was made when results from urine, fecal and serum porphyrins returned elevated at 3 weeks after admission. One month and a half after admission and despite hematin therapy and withdrawal of porphyrinogenic drugs, the patient eventually died from brain edema secondary to the status epilepticus, after he had suffered a porphyric attack from an isoflurane trial. Later, genetic testing confirmed HCP with a rare homozygous missense G189S mutation in the coproporphyrinogen III oxidase gene.\n\nDiscussion\nPorphyrias are uncommon, complex metabolic disorders caused by deficiencies in the activities of the seven out of eight enzymes of the heme biosynthetic pathway [3]. They are generally subdivided into acute and non-acute porphyrias on the basis of their major clinical manifestations [3]. The acute porphyrias are well-defined genetic disorders of heme biosynthesis characterized by acute life-threatening attacks of nonspecific neurologic symptoms. These acute porphyrias are comprised of acute intermittent porphyria (AIP), HCP, variegate porphyria (VP) and 5-aminolevulinic acid dehydratase porphyria (ADP) in which AIP is the most frequent type. The combined prevalence of the acute porphyrias is approximately 5 cases per 100,000 persons, they are more common in women than in men, and often generally develop during adult life. Acute porphyric attacks can be exacerbated by a variety of factors, including porphyrinogenic drugs, alcohol, endogenous hormones particularly progesterone, pregnancy, cigarette smoking, metabolic stress induced by infections or surgery and reduced caloric intake [1]. Misdiagnoses of porphyrias are common because the signs and symptoms of acute attacks are variable and may mimic many other diseases. They can present with acute neurovisceral attacks, which may be accompanied by skin lesions in HCP and VP. Abdominal pain [1], reported approximately in 85–95% of patients, is often accompanied by nausea, vomiting, constipation and diarrhea. Other symptoms include acute psychiatric symptoms, seizures, tachycardia and hypertension, and peripheral neuropathy.\n\nSeizures [1] occur in approximately 10–20% of patients with symptomatic porphyrias. The most common types of seizures reported in the literature consist of complex partial or tonic-clonic seizures. Status epilepticus is less common, having been reported on five instances only. A summary of these previously reported cases is presented in table 1 [6, 7, 8, 9, 10] along with our cases. All were adult patients. Status epilepticus was part of the initial presentation for all subjects with the presence of visceral symptoms in two. Pregnancy was a precipitating factor in two. The type of status varied greatly from convulsive status epilepticus to non-convulsive status epilepticus, complex partial status and EPC. EEG revealed non-specific periodic discharges or rhythmic focal activity. Non-surprisingly, confirmation of diagnosis led to modification of the treatment regimen with good outcome for all patients except one (case 2). Out of the previously five reported cases, 3 patients had AIP, 1 patient had VP and 1 had an unknown type of acute porphyria, while both of our patients had HCP.\n\nCurrent understanding of the pathogenesis of seizures suggests the hepatic production of a neurotoxic substance, presumably ALA [a γ-aminobutyric acid (GABA) analogue] and/or PBG which may interact with GABA or glutamate receptors [2]. A combination of endothelial dysfunction, hypoperfusion, and vasoconstriction in this setting of neurotoxicity can lead to a compromise of the blood-brain barrier and brain edema [11]. MRI may help detect changes occurring in the brain at the time of the acute attack though lesions are non-specific (cortically and/or subcortically, anterior or posterior, without or with mild enhancement, generally but not always reversible) [11, 12]. Seizures, when they occur, are a therapeutic challenge because most AEDs (phenobarbital, carbamazepine, clonazepam, phenytoin, primidone, ethosuximide, valproic acid, lamotrigine, felbamate, tiagabine, topiramate) may exacerbate attack of acute porphyria [13]. Drugs reported to be relatively safe include gabapentin [6, 8, 14], levetiracetam [7], and possibly oxcarbazepine [15].\n\nConclusion\nAcute porphyrias may be a cause of new onset convulsive status epilepticus and EPC. Although rare, their recognition is important as it modifies significantly patient management and probably their outcome.\n\nFig. 1 FLAIR sequence showing hyperintensity over both mesial temporal structures (a), with mild incomplete regression after 2 years (b).\n\nFig. 2 a EEG with left frontotemporal periodic lateralized epileptiform discharges. b Left frontotemporal periodic discharges evolving into rhythmic slow activity discharge most prominent over the left frontotemporal region (HFF = 35 Hz; LFF = 1 Hz).\n\nFig. 3 FLAIR image showing right hemispheric gyriform hyperintense signal changes.\n\nFig. 4 EEG showing diffuse slowing activity, right frontal subtle/blunted periodic lateralized epileptiform discharges and left-sided muscle artifacts due to left facial jerks.\n\nTable 1 Summary of clinical, imaging, and encephalographic features of previously reported cases and our cases\n\n\tIn the literature\tOur patients\t\n\tCase 1\tCase 2\tCase 3\tCase 4\tCase 5\tCase 6\tCase 7\t\nAge, years\t42\t48\t26\t22\t22\t49\t30\t\nGender\tfemale\tfemale\tfemale\tfemale\tfemale\tmale\tmale\t\nPast medical history\tepilepsy related to L F astrocytoma (resected 5 y earlier)\tAIP diagnosed at age 20 after refractory SE; 3 other SE subsequently\tnone but family history of AIP\tnormal first pregnancy\tnormal first pregnancy\tBerger's disease\tgeneralized anxiety disorder\t\nExacerbating factors\tsurgery for presumed cholecystectomy\tleg deep venous thrombosis\talprazolam\tsecond pregnancy\tsecond pregnancy\tROH\t–\t\nVisceral symptoms\tabdominal discomfort, anorexia, episodic dark urine\t–\t–\t–\t–\t–\tnausea, vomiting\t\nNeurological symptoms\tdelirium, complex partial SE\trefractory complex partial SE\tconfusion, quadriparetic, labored respiration, convulsive SE\tdelirium, GTC seizure → convulsive SE\tpsychiatric symptoms GTC seizures → convulsive SE\tconfusion, one GTC seizure → EPC\theadache, confusion, convulsive SE → EPC → NCSE\t\nSeizure description\tstaring, altered consciousness, complex motor behavior\tR head deviation, R facial clonic jerks, R arm tonic-clonic activity, 20–120 s, ~15 to 20/h\tR facial and upper limb twitching (day 12) → convulsive SE (day 14)\tloss of consciousness, R leg clonic activity → R arm → GTC activity, 2–3 min → convulsive SE\t–\ttonic-clonic seizure evolving into continuous right hand myoclonic jerks\tfour GTC seizures → NCSE with the L hand and mouth jerks, rarely associated with altered consciousness\t\nMRI/scan\tunchanged postoperative encephalomalacia\tCT: possible L hemisphere edema\t–\tbiF ↑ diffusion coefficient\t–\tbiT T2/FLAIR\tR hemispheric gyriform T2 changes + diffusion restriction; mild L midline shift\t\nEEG\tbursts of spikes, poly-spikes, sharp waves, ±sharp/slow complexes over biFT leads L R\tL>R slowing; during seizures: rhythmic L FT theta activity\t–\tduring seizures: rhythmic L F slow activity → both hemispheres\t–\tL F PLEDs\tsevere diffuse slowing; R FT PLEDs\t\nTreatment before diagnosis\tPHT, CBZ, LZP, Pentobarbital\t–\t–\tLZP, PHT, LEV\tOXC, LEV, PHT\tayclovir, PHT, VPA, CBZ, CLB, LTG\tantibiotics, acyclovir, plasma exchange, IG, Pb, propofol, LEV, LCM, TPM, VGB,\t\nTreatment after diagnosis\thigh carbohydrate diet, hematin, GPN\thematin; GPN; OXC → LEV + Mg\thematin, propofol, GPN\tGPN, LZP, high carbohydrate intake, hematin, abortion\tabortion\tLEV\thematin, (VGB, LEV, LCM) → GPN, plasma exchange, IG\t\nOutcome\tno further delirium over next 2 years; modest ↓ in seizure frequency\tno further seizures over next 8 months of FU\tconvulsions stopped, alert, able to walk with support (day 16)\tno futher convulsion after abortion\tno further seizures as well as attack of hepatic porphyria over next 2 years of FU\tmild memory deficits, persisting but non-disabling R hand EPC; 1 GTC seizure and 1 cluster of 3 GTC seizures in the setting of ROH intake over last 3 years\tdeceased\t\nType of porphyria\tAIP\tAIP\tAIP\tVP\tacute hepatic porphyria\tHCP\tHCP\t\nReference\tYandel and Watter (1995) [7]\tZaatreh et al. (2005) [8]\tPandey et al. (2003) [9]\tEngelhardt et al. (2004) [10]\tWeinzierl et al. (2007) [11]\t\t\t\nL = Left; R = right; F = frontal; T = temporal; PHT = phenytoin; CBZ = carbamazepine; Pb = phenobarbital; LZP = lorazepam; GPN = gabapentin; SE = status epilepticus;\n\nNCSE = non-convulsive status epilepticus; PLEDs = periodic lateralized epileptiform discharges; GTC = generalized tonic-clonic; IG = immunoglobulin.\n==== Refs\nReferences\n1 Anderson KE Bloomer JR Bonkovsky HL Kushner JP Pierach CA Pimstone NR Desnick RJ Recommendations for the diagnosis and treatment of the acute porphyrias Ann Intern Med 2005 142 439 450 15767622 \n2 Balwani M Desnick RJ The porphyrias: advances in diagnosis and treatment. Blood . DOI: 10.1182/blood-2012–05–423186.\n3 Schneider-Yin X Harms J Minder EI Porphyria in Switzerland, 15 years experience Swiss Med Wkly 2009 139 198 206 19350426 \n4 Bylesjö I Forsgren L Lithner F Boman K Epidemiology and clinical characteristics of seizures in patients with acute intermittent porphyria Epilepsia 1996 37 230 235 8598180 \n5 Ghosh S Chaudhury PK Goswami HK An analysis of six cases of acute intermittent porphyria (AIP) Indian J Psychiatry 2006 48 189 192 20844651 \n6 Hift R Meissner P Kadish KM Smith KM Guilard R Miscellaneous abnormalities in porphyrin production and disposal. Medical aspect of porphyrins The porphyrin handbook 2003 14 San Diego Elsevier Science 151 165 \n7 Yandel ML Watters MR Treatment of complex partial status epilepticus unmasking acute intermittent porphyria in a patient with resected anaplastic glioma Clin Neurol Neurosurg 1995 97 261 263 7586862 \n8 Zaatreh MM Levetiracetam in porphyric status epilepticus: a case report Clin Neuropharmacol 2005 28 243 244 16239766 \n9 Pandey CK Singh N Bose N Sahay S Gabapentin and propofol for treatment of status epilepticus in acute intermittent porphyria J Postgrad Med 2003 49 285 14597800 \n10 Engelhardt K Trinka E Franz G Unterberger I Spiegel M Beer R Pfausler B Kampfl A Schmutzhard E Refractory status epilepticus due to acute hepatic porphyria in a pregnant woman: induced abortion as the sole therapeutic option? Eur J Neurol 2004 11 693 697 15469454 \n11 Weinzierl A Brezinka C Engelhardt K Unusual manifestation of acute hepatic porphyria in pregnancy Fetal Diagn Ther 2007 22 136 138 17139171 \n12 Dahlgren M Khosroshahi A Stone JH A 22-year-old woman with severe headaches, vomiting, and tonic-clonic seizures Arthritis Care Res (Hoboken) 2011 63 165 171 20506341 \n13 Kang S-Y Kang J-H Choi JC Lee JS Posterior reversible encephalopathy syndrome in a patient with acute intermittent porphyria J Neurol 2010 257 663 664 20012311 \n14 Ventura P Cappellini MD Rocchi E The acute porphyrias: a diagnostic and therapeutic challenge in internal and emergency medicine Intern Emerg Med 2009 4 297 308 19479318 \n15 Hahn M Gildemeister OS Krauss GL Pepe JA Lambrecht RW Donohue S Bonkosky HL Effects of new anticonvulsant medications on porphyrin synthesis in cultured liver cells: potential implications for patients with acute porphyria Neurology 1997 49 97 106 9222176 \n16 Gaida-Hommernick B Rieck K Runge U Oxcarbazepine in focal epilepsy and hepatic porphyria: a case report Epilepsia 2001 42 793 795 11422339\n\n",
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"issue": "5(2)",
"journal": "Case reports in neurology",
"keywords": "Acute porphyria; Epilepsia partialis continua; Status epilepticus",
"medline_ta": "Case Rep Neurol",
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"nlm_unique_id": "101517693",
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"pubdate": "2013-05",
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"title": "Acute porphyria presenting as epilepsia partialis continua.",
"title_normalized": "acute porphyria presenting as epilepsia partialis continua"
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"abstract": "We investigated the feasibility and efficacy of a fludarabine-based dose-reduced conditioning regimen followed by stem cell transplantation from related (n = 5) or unrelated HLA-matched donors (n = 7) in 12 patients with high risk MDS, who were not eligible for a standard myeloablative conditioning regimen. The conditioning regimen consisted of fludarabine 30 mg/m(2) daily for 6 days, busulfan 4 mg/kg daily for 2 days and anti-thymocyte globulin (ATG, rabbit) 10 mg/kg daily for 4 days in 11 patients, while one patient received fludarabine, ATG, cyclophosphamide and thiotepa. Graft-versus-host disease prophylaxis consisted of cyclosporine and a short course of methotrexate. The median age of the patients was 53 years (range 37-59). The median percentage of blasts in bone marrow aspirate at transplantation was 15% (range <5% to 35%). Diagnosis at transplant was RA (n = 1), RAEB (n = 5), RAEB-T (n = 5) and sAML (n = 1). A complex karyotype including monosomy 7 was noted in five patients. The reasons for using a dose-reduced conditioning regimen were prior autologous/syngeneic BMT (n = 4), active fungal infection (n = 2) or age/reduced performance status (n = 6). Engraftment was observed in all patients with complete donor chimerism. The incidence of acute GVHD (grade II-IV) was 33%. Eight patients died during follow-up due to relapse (n = 4), liver toxicity (n = 2), aspergillus (n = 1) or aGVHD grade IV (n = 1). After a median follow-up of 19 months, the 2-year estimated disease-free survival is 12% (95% CI: 2-23%) and the overall survival is 26% (95% CI: 4-52%). Fludarabine dose-reduced conditioning prior to allogeneic stem cell transplantation in high risk MDS patients, who were not eligible for standard transplantation, resulted in stable engraftment with complete chimerism, but the toxicity and relapse rate were considerable.",
"affiliations": "Bone Marrow Transplantation, University Hospital Hamburg-Eppendorf, Martinistrasse 52, D-20246 Hamburg, Germany.",
"authors": "Kröger|N|N|;Schetelig|J|J|;Zabelina|T|T|;Krüger|W|W|;Renges|H|H|;Stute|N|N|;Schrum|J|J|;Kabisch|H|H|;Siegert|W|W|;Zander|A R|AR|",
"chemical_list": "D000961:Antilymphocyte Serum; D003520:Cyclophosphamide; D014740:Vidarabine; D002066:Busulfan; C024352:fludarabine; D008727:Methotrexate",
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"mesh_terms": "D000328:Adult; D000754:Anemia, Refractory, with Excess of Blasts; D000961:Antilymphocyte Serum; D001853:Bone Marrow; D002066:Busulfan; D002452:Cell Count; D002897:Chromosomes, Human, Pair 7; D003520:Cyclophosphamide; D018572:Disease-Free Survival; D005240:Feasibility Studies; D006085:Graft Survival; D006086:Graft vs Host Disease; D018380:Hematopoietic Stem Cell Transplantation; D006504:Hepatic Veno-Occlusive Disease; D006648:Histocompatibility; D006801:Humans; D007239:Infections; D007621:Karyotyping; D008727:Methotrexate; D008875:Middle Aged; D009006:Monosomy; D009190:Myelodysplastic Syndromes; D012008:Recurrence; D015996:Survival Rate; D013601:T-Lymphocytes; D014019:Tissue Donors; D019172:Transplantation Conditioning; D014184:Transplantation, Homologous; D016896:Treatment Outcome; D014740:Vidarabine",
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"publication_types": "D016428:Journal Article",
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"title": "A fludarabine-based dose-reduced conditioning regimen followed by allogeneic stem cell transplantation from related or unrelated donors in patients with myelodysplastic syndrome.",
"title_normalized": "a fludarabine based dose reduced conditioning regimen followed by allogeneic stem cell transplantation from related or unrelated donors in patients with myelodysplastic syndrome"
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"abstract": "Following conventional chemotherapy, eight myeloma patients presenting with advanced tumor stages were treated with an intensified high-dose regimen and autologous peripheral blood stem cell transplantation. High-dose chemotherapy consisted of idarubicin 20 mg/m2 on days -13, -12 and -11, melphalan 100 mg/m2 on days -5 and -4 and cyclophosphamide 60 mg/kg (plus mesna 60 mg/kg) on days -3 and -2 (IMC). Seven patients achieved a complete remission or a very good partial remission (reduction of M-component > or =90%). There were no toxic deaths. Severe mucositis and fever of unknown origin were seen in all patients. Reversible supraventricular tachycardias without clinical signs of cardiac failure occurred in five patients. One patient developed a persistent deterioration of cardiac function. We surmise that high-dose chemotherapy with IMC is very effective and well tolerated in myeloma patients.",
"affiliations": "Clinic for Hematology and Oncology, Department of Internal Medicine, University Düsseldorf, Germany.",
"authors": "Heyll|A|A|;Söhngen|D|D|;Kobbe|G|G|;Schneider|P|P|;Bauser|U|U|;Thiele|K P|KP|;Wehmeier|A|A|;Südhoff|T|T|;Quenzel|E M|EM|;Rieth|C|C|;Wernet|P|P|;Fischer|J|J|;Frick|M|M|;Aul|C|C|",
"chemical_list": "D003520:Cyclophosphamide; D008558:Melphalan; D015255:Idarubicin",
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
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"issn_linking": "0887-6924",
"issue": "11 Suppl 5()",
"journal": "Leukemia",
"keywords": null,
"medline_ta": "Leukemia",
"mesh_terms": "D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D003520:Cyclophosphamide; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D015255:Idarubicin; D008297:Male; D008558:Melphalan; D008875:Middle Aged; D009101:Multiple Myeloma; D009367:Neoplasm Staging; D013617:Tachycardia, Supraventricular",
"nlm_unique_id": "8704895",
"other_id": null,
"pages": "S32-4",
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"pubdate": "1997-12",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article",
"references": null,
"title": "Idarubicin, melphalan and cyclophosphamide: an intensified high-dose regimen for the treatment of myeloma patients.",
"title_normalized": "idarubicin melphalan and cyclophosphamide an intensified high dose regimen for the treatment of myeloma patients"
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"abstract": "To present a case of chorea gravidarum and conduct a review of the published literature on the treatment for this condition, and on maternal and fetal prognosis.\n\n\n\nCase presentation of a 16-year-old primiparous patient admitted to a Level III public hospital at 8 weeks of gestation complaining of involuntary head and limb movements and right lower limb hyperreflexia lasting three days. The patient had a history of Sydenham chorea. Treatment with antipsychotics and benzodiazepines was given to manage symptoms, and with benzathine penicillin to address the etiology, achieving control at 14 weeks. Treatment was discontinued at 35 weeks and the patient went on to have normal delivery at 39 weeks. A search was conducted in the Medline via PubMed, UptoDate, Medscape and Google Scholar databases using the terms \"Pregnancy and Chorea Gravidarum\". The search was limited to case reports and case series or review articles published between 2000 al 2019.\n\n\n\nSeven case reports and one review of the topic were found. In 4 of the 7 cases, treatment was based on haloperidol, benzodiazepines and chlorpromazine. Penicillin was used in one of two cases with a history of Sydenham chorea. Maternal and fetal prognosis was good in 6 of 7 cases, there was 1 case of intrauterine growth restriction.\n\n\n\nTreatment of gestation chorea is primarily expectant and the goal is to reduce symptoms. Maternal and fetal prognosis is good.",
"affiliations": "Universidad Industrial de Santander, Bucaramanga (Colombia).;Docente del Departamento de Ginecobstetricia, Universidad Industrial de Santander, Unidad de Medicina Materno-Fetal del Hospital Universitario de Santander, Bucaramanga (Colombia).",
"authors": "Rengifo-Quintero|Laura Juliana|LJ|;Beltrán-Avendaño|Mónica Andrea|MA|",
"chemical_list": "D014150:Antipsychotic Agents; D001569:Benzodiazepines; D010401:Penicillin G Benzathine",
"country": "Colombia",
"delete": false,
"doi": "10.18597/rcog.3251",
"fulltext": null,
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"issn_linking": "0034-7434",
"issue": "70(3)",
"journal": "Revista colombiana de obstetricia y ginecologia",
"keywords": " chorea gravidarum; corea gravidarum ; embarazo ; Pregnancy ; enfermedades del sistema nervioso ; nervous system diseases ",
"medline_ta": "Rev Colomb Obstet Ginecol",
"mesh_terms": "D000293:Adolescent; D014150:Antipsychotic Agents; D001569:Benzodiazepines; D020150:Chorea Gravidarum; D005260:Female; D006801:Humans; D010401:Penicillin G Benzathine; D011247:Pregnancy; D011256:Pregnancy Outcome; D011379:Prognosis",
"nlm_unique_id": "0404263",
"other_id": null,
"pages": "189-194",
"pmc": null,
"pmid": "31738489",
"pubdate": "2019-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "CHOREA GRAVIDARUM: CASE REPORT AND REVIEW OF THE LITERATURE.",
"title_normalized": "chorea gravidarum case report and review of the literature"
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"abstract": "Chemotherapy has an increasing potential for cure and palliation of most forms of cancer in different stages. However, its use is associated with a multitude of side effects some very common and few very rare. We present two patients of metastatic nonsmall lung cancer who had severe forms of hand-foot syndrome with two different classes of antineoplastic drugs and have to discontinue chemotherapy.",
"affiliations": "Department of Medical Oncology, Sher-I-Kashmir Institute of Medical Sciences, Srinagar, Jammu and Kashmir, India.;Department of Medical Oncology, Sher-I-Kashmir Institute of Medical Sciences, Srinagar, Jammu and Kashmir, India.;Department of Medical Oncology, Sher-I-Kashmir Institute of Medical Sciences, Srinagar, Jammu and Kashmir, India.;Department of Medical Oncology, Sher-I-Kashmir Institute of Medical Sciences, Srinagar, Jammu and Kashmir, India.;Department of Medical Oncology, Sher-I-Kashmir Institute of Medical Sciences, Srinagar, Jammu and Kashmir, India.;Department of Medical Oncology, Sher-I-Kashmir Institute of Medical Sciences, Srinagar, Jammu and Kashmir, India.",
"authors": "Dar|Waseem|W|;Hussain|Mir|M|;Aziz|Sheikh Aijaz|SA|;Mohammad|Gul|G|;Wani|Burhan|B|;Latief|Muzamil|M|",
"chemical_list": null,
"country": "Germany",
"delete": false,
"doi": "10.4103/ijmpo.ijmpo_70_16",
"fulltext": "\n==== Front\nIndian J Med Paediatr OncolIndian J Med Paediatr OncolIJMPOIndian Journal of Medical and Paediatric Oncology : Official Journal of Indian Society of Medical & Paediatric Oncology0971-58510975-2129Medknow Publications & Media Pvt Ltd India IJMPO-38-38010.4103/ijmpo.ijmpo_70_16Case ReportUncommon Adverse Effects of Commonly Used Chemotherapeutic Agents in Medical Oncology Practice: A Series of Two Cases of Hand-Foot Syndrome Dar Waseem Hussain Mir Aziz Sheikh Aijaz Mohammad Gul Wani Burhan Latief Muzamil Department of Medical Oncology, Sher-I-Kashmir Institute of Medical Sciences, Srinagar, Jammu and Kashmir, IndiaAddress for correspondence: Dr. Waseem Dar, Department of Medical Oncology, Sher-I-Kashmir Institute of Medical Sciences, Srinagar - 190 011, Jammu and Kashmir, India. E-mail: drwaseemdar@gmail.comJul-Sep 2017 38 3 380 382 Copyright: © 2017 Indian Journal of Medical and Paediatric Oncology2017This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.Chemotherapy has an increasing potential for cure and palliation of most forms of cancer in different stages. However, its use is associated with a multitude of side effects some very common and few very rare. We present two patients of metastatic nonsmall lung cancer who had severe forms of hand-foot syndrome with two different classes of antineoplastic drugs and have to discontinue chemotherapy.\n\nKeywords\nChemotherapycancerhand-foot syndromepalliation\n==== Body\nIntroduction\nChemotherapeutic agents are potentially toxic agents that are associated with a number of side effects including cutaneous ones which include maculopapular rashes, hyperpigmentation, nail changes, Bergdorf's reaction (a form of acral erythema), palmoplantar dysesthesia (palmar-plantar erythematous [PPE]), and hand-foot syndrome (HFS).[1234] HFS is a relatively common side effect of many types of chemotherapy drugs, namely, 5-fluorouracil (FU), capecitabine, and liposomal doxorubicin. We present a series of two metastatic nonsmall cell lung cancer patients who developed HFS following vinorelbine- and docetaxel-based single agent chemotherapy which is a rare occurrence.\n\nCase Reports\nCase report 1\nA 46-year-old male, chronic smoker was diagnosed as adenocarcinoma lung stage IIIB in February 2014. His epidermal growth factor receptor was wild type. He received three cycles of chemotherapy with injection pemetrexed and carboplatin till April. In May, he was reassessed, and there was no change in the size of lung mass. He was given three cycles of injection docetaxel till July 2014. He started with pain back. His bone scan showed increased tracer uptake in D12-L3 suggestive of bone metastasis. He received 15 Gy/5# local radiotherapy to D12-L3 area and was put on monthly injection zoledronic acid. In view of progressive disease, he was treated with weekly vinorelbine single-agent chemotherapy at 30 mg/m2 weekly in October. After 3rd week of single-agent vinorelbine, he started with pain and paresthesias along with reddish discoloration of hands and feet. On examination, symmetrical diffuse erythema and swelling with tenderness were noted in the palms and soles. There was impending desquamation in sole area. Nails were normal [Figure 1a and b]. World Health Organization (WHO) grade 3/4 HFS was diagnosed in him. Chemotherapy was withheld, and patient was treated with local care with emollients and he improved and recovered.\n\nFigure 1 (a and b) Palmar and planter erythema, edema, and blisters in right sole after 3 weekly doses of single-agent vinorelbine in a nonsmall cell lung cancer patient\n\nCase report 2\nA 52-year-old male, chronic smoker was diagnosed as squamous cell carcinoma lung stage IV at presentation in April 2014. He was started on palliative chemotherapy with gemcitabine and carboplatin. After four cycles in July, he showed signs of progressive disease. He was started on single-agent docetaxel (75 mg/m2)-based chemotherapy. After second cycle of docetaxel in September, he started with pain and paresthesias along with erythema and peeling of skin. On local examination, he had symmetrical diffuse erythema with tenderness in the palms and soles. There was diffuse peeling off of skin on palms and soles. Nails were normal [Figure 2a and b]. WHO grade 4 HFS was diagnosed in him. Chemotherapy was withheld, and patient was treated with local care with emollients and he improved and recovered.\n\nFigure 2 (a and b) Palmar and planter erythema with diffuse skin desquamation after second cycle of single-agent docetaxel in a nonsmall cell lung cancer patient\n\nDiscussion\nHFS has been commonly described as a cutaneous side effect of cytotoxic chemotherapy with 5-FU, capecitabine, cytarabine, doxorubicin, liposomal daunorubicin and doxorubicin, gemcitabine and recently with tyrosine-kinase inhibitors such as sunitinib, gefitinib, and erlotinib. Vinorelbine, a promising new chemotherapy agent, has demonstrated activity in different types of tumors including nonsmall cell lung cancer and breast cancer.[5] As with other vinca alkaloids, vinorelbine acts by inhibiting microtubule assembly, but it seems to have a more acceptable safety profile than those of its predecessors.[6] This agent is known to cause granulocytopenia, neurotoxicity, asthenia, nausea, alopecia, phlebitis, and constipation, and longer infusion of higher doses of vinorelbine may be associated with HFS.[578] Acral erythrodysesthesia was noted in four of sixty patients undergoing single-agent continuous high-dose infusion with vinorelbine for metastatic breast cancer.[8] It has been postulated that continuous infusion regimens afford the skin longer exposure to the drugs used, thus facilitating drug accumulation. The occurrence of HFS is very rare with vinorelbine use. Docetaxel is a frequently used chemotherapeutic agent belonging to the taxane family. It was first discovered in 1986 and is a semi-synthetic compound derived from the needles of the European yew (Taxus baccata).[9] It exerts its anticancer effect by promoting microtubule stabilization, leading to mitotic arrest and subsequent cell death.[10] It is used alone or in combination with other chemotherapeutic agents for the management of various malignant conditions including breast, prostate, gastric, head and neck, and nonsmall cell lung cancer.[11] Docetaxel is known to cause a number of side effects including hypersensitivity reactions, alopecia, nausea, vomiting, peripheral neuropathy, myelosuppression, diarrhea, mucositis, fluid retention, myalgia, arthralgia, nail changes, and cutaneous reactions.[11] A number of skin reactions have been described in association with docetaxel, of which limb and/or PPE reactions and fixed plaque erythrodysesthesia are among the more common.[12] HFS has been reported in association with docetaxel in a number of case reports but remains rare.[13] The mechanism of HFS is still obscure. However, the high proliferation rate of epidermal basal cells in the palms could make them more sensitive to the local action of cytotoxic drugs. It may also be due to delivery of drugs through eccrine sweat glands, increased vascularization, temperature, and pressure in the hands and feet. Moreover, palms, soles, and finger tips are areas of repeated friction, grasping, and trauma, which further increases the predisposition to this syndrome.[14] HFS is characterized by paresthesiae in a sock-and-glove distribution, followed by ful swelling and erythema. The skin may break down; and in severely affected patients, it desquamates upon discontinuation of therapy. Skin biopsy may show keratinocyte vacuolar degeneration, keratinocyte damage and apoptosis, intracytoplasmic inclusion bodies, dermal perivascular lymphocytic infiltration, and dermal edema.[15] Management of HFS includes educating the patient regarding the recognition of symptoms and prompt referral. The patient should also be reassured that permanent complications do not occur after the resolution of the events. Extremes of temperature, pressure, and friction should be avoided. Regular application of topical emollients should be advised. Corticosteroids and pyridoxine are found to be effective in the treatment of HFS. In severe cases, further treatment with chemotherapeutic agents is interrupted and can be restarted at a lower dose after resolution of symptoms. Usually, HFS resolves rapidly, often without recurrence. If the symptoms recur with a higher grade, then that particular drug should be discontinued permanently, and alternative drug or treatment plan can be offered to the patient. The possibility of recurrence of symptoms after restarting the chemotherapy could not be observed in our patient as she succumbed to the disease rapidly due to metastasis to lung and liver.\n\nConclusion\nAlthough HFS is not fatal and is a manageable condition, it is essential to identify this unique syndrome at the earliest to avoid complications and inconvenience in performing day-to-day activities.\n\nFinancial support and sponsorship\nNil.\n\nConflicts of interest\nThere are no conflicts of interest.\n==== Refs\nReferences\n1 Chu CY Yang CH Yang CY Hsiao GH Chiu HC Fixed erythrodysaesthesia plaque due to intravenous injection of docetaxel Br J Dermatol 2000 142 808 11 10792238 \n2 Schrijvers D Van Den Brande J Vermorken JB Supravenous discoloration of the skin due to docetaxel treatment Br J Dermatol 2000 142 1069 70 \n3 Eich D Scharffetter-Kochanek K Eich HT Tantcheva-Poor I Krieg T Acral erythrodysesthesia syndrome caused by intravenous infusion of docetaxel in breast cancer Am J Clin Oncol 2002 25 599 602 12478008 \n4 Webster-Gandy JD How C Harrold K Palmar-plantar erythrodysesthesia (PPE): A literature review with commentary on experience in a cancer centre Eur J Oncol Nurs 2007 11 238 46 17350337 \n5 Smith GA Current status of vinorelbine for breast cancer Oncology (Williston Park) 1995 9 767 73 7577376 \n6 Hohneker JA A summary of vinorelbine (Navelbine) safety data from North American clinical trials Semin Oncol 1994 21 5 Suppl 10 42 6 \n7 Wargin WA Lucas VS The clinical pharmacokinetics of vinorelbine (Navelbine) Semin Oncol 1994 21 5 Suppl 10 21 7 \n8 Hoff PM Valero V Ibrahim N Willey J Hortobagyi GN Hand-foot syndrome following prolonged infusion of high doses of vinorelbine Cancer 1998 82 965 9 9486588 \n9 Vaishampayan U Parchment RE Jasti BR Hussain M Taxanes: An overview of the pharmacokinetics and pharmacodynamics Urology 1999 54 6A Suppl 22 9 10606281 \n10 Eisenhauer EA Vermorken JB The taxoids. Comparative clinical pharmacology and therapeutic potential Drugs 1998 55 5 30 9463787 \n11 Docetaxel Drug Information Website Last accessed on 2016 Apr 20 Available from: http://www.taxotere.com/oncology/about_Taxotere/mechanism_of_action.aspx \n12 Chew L Chuen VS Cutaneous reaction associated with weekly docetaxel administration J Oncol Pharm Pract 2009 15 29 34 18753180 \n13 Zimmerman GC Keeling JH Lowry M Medina J Von Hoff DD Burris HA Prevention of docetaxel-induced erythrodysesthesia with local hypothermia J Natl Cancer Inst 1994 86 557 8 7907667 \n14 Milano G Etienne-Grimaldi MC Mari M Lassalle S Formento JL Francoual M Candidate mechanisms for capecitabine-related hand-foot syndrome Br J Clin Pharmacol 2008 66 88 95 18341672 \n15 Yang CH Lin WC Chuang CK Chang YC Pang ST Lin YC Hand-foot skin reaction in patients treated with sorafenib: A clinicopathological study of cutaneous manifestations due to multitargeted kinase inhibitor therapy Br J Dermatol 2008 158 592 6 18070211\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "0971-5851",
"issue": "38(3)",
"journal": "Indian journal of medical and paediatric oncology : official journal of Indian Society of Medical & Paediatric Oncology",
"keywords": "Chemotherapy; cancer; hand-foot syndrome; palliation",
"medline_ta": "Indian J Med Paediatr Oncol",
"mesh_terms": null,
"nlm_unique_id": "9604571",
"other_id": null,
"pages": "380-382",
"pmc": null,
"pmid": "29200697",
"pubdate": "2017",
"publication_types": "D002363:Case Reports",
"references": "12478008;10606281;18070211;18753180;18341672;7577376;7907667;9463787;17350337;10792238;7973769;9486588;10809894;7973765",
"title": "Uncommon Adverse Effects of Commonly Used Chemotherapeutic Agents in Medical Oncology Practice: A Series of Two Cases of Hand-Foot Syndrome.",
"title_normalized": "uncommon adverse effects of commonly used chemotherapeutic agents in medical oncology practice a series of two cases of hand foot syndrome"
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"companynumb": "IN-MYLANLABS-2018M1048415",
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"activesubstancename": "ZOLEDRONIC ACID"
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... |
{
"abstract": "BACKGROUND\nUterine leiomyosarcoma is one of the most frequent uterine sarcomas. In the metastatic setting it is sensitive to doxorubicin, ifosfamide, gemcitabine, docetaxel and a few other drugs, but time to progression is generally short. For this reason prognosis is often poor and there are few reports in the literature of long responders.\n\n\nMETHODS\nWe report a case of a 40-year-old Caucasian woman with metastatic uterine leiomyosarcoma who began treatment six years before the presentation of this case report and for the following six years underwent ten lines of chemotherapy, achieving excellent results and a good quality of life. Among the treatments administered we observed a long response to temolozomide, an unconventional drug for this kind of disease.\n\n\nCONCLUSIONS\nAlthough there are few chemotherapeutic options for the management of metastatic uterine leiomyosarcoma, a small number of patients have an unexpected long lasting response to treatment. For this reason further research is needed to identify new therapeutic agents and the predictive factors for the achievement of response.",
"affiliations": "Oncology Department, 'Infermi' Hospital, Via Settembrini 2, Rimini, 47923, Italy. claudio.rid@gmail.com.",
"authors": "Ridolfi|Claudio|C|;Pasini|Giuseppe|G|;Drudi|Fabrizio|F|;Barzotti|Eleonora|E|;Santelmo|Carlotta|C|;Polselli|Antonio|A|;Ravaioli|Alberto|A|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1186/1752-1947-7-29",
"fulltext": "\n==== Front\nJ Med Case RepJ Med Case RepJournal of Medical Case Reports1752-1947BioMed Central 1752-1947-7-292334756010.1186/1752-1947-7-29Case ReportLong lasting clinical response to chemotherapy for advanced uterine leiomyosarcoma: a case report Ridolfi Claudio 12claudio.rid@gmail.comPasini Giuseppe 1gpasini@auslrn.netDrudi Fabrizio 1f.drudi1@virgilio.itBarzotti Eleonora 1eleonora.barzotti@libero.itSantelmo Carlotta 1carlotta.santelmo@alice.itPolselli Antonio 2Antonio.Polselli@auslrn.netRavaioli Alberto 13Alberto.Ravaioli@auslrn.net1 Oncology Department, ‘Infermi’ Hospital, Via Settembrini 2, Rimini, 47923, Italy2 Oncology Department, ‘Cervesi’ Hospital, Via Ludwig Van Beethoven 1, Cattolica, RN 47841, Italy3 IRST (The Cancer Institute of Romagna), Via Piero Maroncelli 40, Meldola, FC 47014, Italy2013 24 1 2013 7 29 29 25 10 2012 19 12 2012 Copyright ©2013 Ridolfi et al.; licensee BioMed Central Ltd.2013Ridolfi et al.; licensee BioMed Central Ltd.This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Introduction\nUterine leiomyosarcoma is one of the most frequent uterine sarcomas. In the metastatic setting it is sensitive to doxorubicin, ifosfamide, gemcitabine, docetaxel and a few other drugs, but time to progression is generally short. For this reason prognosis is often poor and there are few reports in the literature of long responders.\n\nCase presentation\nWe report a case of a 40-year-old Caucasian woman with metastatic uterine leiomyosarcoma who began treatment six years before the presentation of this case report and for the following six years underwent ten lines of chemotherapy, achieving excellent results and a good quality of life. Among the treatments administered we observed a long response to temolozomide, an unconventional drug for this kind of disease.\n\nConclusion\nAlthough there are few chemotherapeutic options for the management of metastatic uterine leiomyosarcoma, a small number of patients have an unexpected long lasting response to treatment. For this reason further research is needed to identify new therapeutic agents and the predictive factors for the achievement of response.\n\nAdvanced leiomyosarcomaChemotherapyResponse\n==== Body\nIntroduction\nUterine sarcomas are rare tumors with a poor prognosis; they represent less than 3% of all female genital tract malignancies and only 8.4% of uterine cancers [1,2]. They can be classified into two groups: smooth muscle tumors and endometrial stromal tumors. The first group includes benign leiomyomas, smooth muscle tumors of uncertain malignant potential, and leiomyosarcomas (LMS). The second group is composed of benign endometrial stromal nodules, endometrial stromal sarcomas and undifferentiated endometrial sarcomas [1].\n\nTreatment for early-stage disease is surgery, with total abdominal hysterectomy with or without bilateral salpingo-oophorectomy. The role of adjuvant chemotherapy or local radiotherapy is still controversial [1-3].\n\nIn the metastatic setting, treatment of a uterine sarcoma includes resection of metastases, chemotherapy, hormone therapy and targeted therapy [1,3,4]. Among the chemotherapies used, the drugs that have shown the best results are doxorubicin with or without ifosfamide, gemcitabine and docetaxel and, more recently, trabectedin and pazopanib [1,4-7]. Although literature data underline the possibility of a long lasting response to different types of therapy using drug associations, few papers report encouraging results beyond second-line chemotherapy.\n\nWe describe a case of a long-term responder to a wide variety of drugs, highlighting that it is possible to offer more than two lines of chemotherapy to some patients.\n\nCase presentation\nA 40-year-old premenopausal Caucasian woman without comorbidities underwent surgical treatment seven years before the presentation of this case report for a clinical diagnosis of uterine myoma. The postoperative histological examination revealed the presence of a LMS and a hysterectomy with lymphadenectomy was thus performed. The tumor was estrogen and progesterone receptor positive. A staging computed tomography scan detected bilateral, multiple lung metastases of about four to six mm. Six years before the presentation of this case report the patient underwent first-line chemotherapy with Adriamycin® (doxorubicin) and ifosfamide but after six cycles of therapy the lung metastases had increased in size and a new lesion had appeared in the abdomen near the right psoas muscle. It was decided to perform a partial resection of the lung metastases (with histological confirmation) and an ovariectomy.\n\nSecond-line treatment with sorafenib was begun but was rapidly discontinued because of toxicity and treatment with dacarbazine was started as third-line. After three cycles, progression in the lung metastases was detected and continuous infusion of ifosfamide was administered as fourth-line therapy for the following two months. Then the patient was discharged from a National Oncologic Centre to be treated with palliative care.\n\nWhen the patient arrived in our Department, further progression in the abdomen and chest caused an inability to walk due to nerve impingement and pain and a fifth-line of treatment was begun with docetaxel and gemcitabine. In these 11 months the patient showed a partial response and regained the ability to walk. Disease stabilization in the following six months was achieved with anastrozole (sixth line) and at the next progression the patient was treated with paclitaxel and liposomal doxorubicin (seventh line) for 19 cycles and then with trabectedin (eighth line) for eight cycles, until May of two years before the presentation of this case report. It is noteworthy that more than four years had passed since the initial diagnosis and the patient continued to feel well (with only right leg pain, and three points on visual analogue scale, VAS). After eight cycles of trabectedin the lung metastases and pelvic lesion increased to three cm and 18cm, respectively, causing bilateral ureteral compression and an increase in leg pain (VAS eight to nine).\n\nIn July of two years before the presentation of this case report the patient’s performance status (PS) was two on the Eastern Cooperative Oncology Group (ECOG) scale and a bilateral nephrostomy was performed. A ninth-line of treatment was started with temozolomide at a dose of 150mg/m2/day for five days every four weeks. Despite the negative status of O6-methylguanine-deoxyribonucleic acid (DNA)-methyltransferase promoter methylation (this kind of test is performed for patients with glioblastoma multiforme to predict response to temozolomide [8]), a rapid response to therapy was observed with a reduction in the pelvic lesion, resolution of pain and removal of the nephrostomies (Figures 1 and 2). The patient returned to her normal life and was able to use her bicycle and to perform activities without leg pain or fatigue (ECOG PS 0) that would previously have been unthinkable. Treatment with temozolomide was completed after 24 months, with very good tolerance, but further progression was detected. The patient recently began a new line of therapy (the tenth) with pazopanib and is currently doing well, six years after the start of treatment.\n\nFigure 1 Effect of temozolomide on pelvic metastasis. A: before the beginning of treatment. B: after 11 months of treatment.\n\nFigure 2 Effect of temozolomide on one of the lung metastases. A: before the beginning of treatment. B: after 11 months of treatment.\n\nDiscussion\nOur case underlines the role of conventional and unconventional drugs for the treatment of metastatic LMS. Temozolomide has been tested in numerous clinical trials on metastatic soft tissue sarcomas (STSs).\n\nIn 2011, Penel et al. [9] reported their analysis of new regimens used in patients with STSs during the past 10 years and temozolomide at a dose of 75 to 100mg/m2/day was considered a ‘promising drug’.\n\nThe Soft Tissue and Bone Sarcoma Group of the European Organization for Research and Treatment of Cancer [10] evaluated the use of 750mg/m2 of oral temozolomide divided over five days every four weeks in 31 patients with advanced STSs. One partial response for eight cycles was observed in a patient with retroperitoneal LMS metastatic to breast, skin, and liver. Nine patients of varying histologies had stable disease, and 21 patients progressed to therapy. Nausea and vomiting were the most commonly reported non-hematologic adverse events; there were no episodes of neutropenic fever or grade three or four hematologic toxicity.\n\nTalbot et al. [11] treated 25 patients with STSs with twice daily temozolomide for five days every four weeks. Two patients had partial responses (8%), three patients (12%) experienced stable disease for over six months, and two patients had mixed responses (8%). All of these responding patients had LMS. No treatment-related deaths or grade four toxicity were observed.\n\nIn their study Trent et al. [12] evaluated patients with gastrointestinal stromal tumors (GIST) and other STSs treated with temozolomide at a dose of 85mg/m2/day for 21 days followed by seven days of rest. Among 39 evaluable patients with non-GIST tumors, 18 had metastatic LMS. Two responses (11%) were observed in the other STSs subgroup and stable disease was observed in 33% of patients. One partial response lasting for seven months was seen in a patient with metastatic pelvic LMS to the lung. Grade three or four hematologic toxicity was experienced in 10% of patients. The most common non-hematologic adverse event was fatigue, which was observed in 14% of patients.\n\nGarcia del Muro et al. [13] evaluated oral temozolomide given at 75mg/m2/day for six weeks in 43 patients with STSs and 18 patients with GIST. In the first group, seven patients obtained a partial response, eight patients had stable disease and 28 patients had progressive disease. Responses were seen in five of the 11 patients who had gynecologic LMS. The median duration of response was 12.5 months. Severe hematological toxicities for the 61 patients of two groups were grade three or four granulocytopenia or thrombocytopenia (nine patients), grade four lymphocytopenia (24 patients) and grade three or four anemia (seven patients). Non-hematologic toxicity was represented by nausea and vomiting (34 patients) and fatigue (35 patients). No toxic deaths or episodes of febrile neutropenia occurred.\n\nAnderson and Aghajanian [14] evaluated patients with advanced LMS treated with temozolomide at a dose of 50 to 75mg/m2/day for six weeks followed by a two-week rest or temozolomide at a dose of 150 to 300mg/m2/day for five days every four weeks. Among 12 patients treated with continuous low-dose temozolomide, one patient had a partial response and the duration was four months, four patients demonstrated stable disease and seven patients progressed while on therapy. Among seven patients treated with bolus-dose temozolomide, one patient had a near complete response, four patients experienced stable disease and two patients progressed while on therapy. There were no toxicity-associated admissions, deaths, neutropenia or neutropenic fever for either dosing schedule.\n\nOn the basis of these works we decided to start the treatment with temozolomide and in our patient it obtained the best response and gave a good quality of life without significant toxicity, indicating that its use could be considered after failure of standard treatment options.\n\nConclusion\nThis case report highlights the fact that some patients with uterine LMS can have an exceptionally good response to chemotherapy. On the basis of our experience temozolomide should be used in these patients.\n\nConsent\nWritten informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nAbbreviations\nECOG: Eastern Cooperative Oncology Group; GIST: Gastrointestinal stromal tumors; LMS: Leiomyosarcoma; PS: Performance status; STSs: Soft tissue sarcomas; VAS: Visual analogue scale.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nAuthors’ contributions\nGP, CS, AP and AR took care of the patient. AR and CR described and wrote the case report. FD and EB revised the literature. AR and CR performed the last revision. All authors have read and approved the final manuscript.\n\nAcknowledgements\nSupported by Istituto Oncologico Romagnolo, Forlì - Italy.\n==== Refs\nSeddon BM Davda R Uterine sarcomas–Recent progress and future challenges Eur J Radiol 2011 78 30 40 10.1016/j.ejrad.2010.12.057 21247711 \nAbd-Alla HM El-Sebaie MM Ali NM Uterine sarcoma: analysis of treatment failure and survival J Egypt Natl Canc Inst 2000 12 245 251 \nD'Angelo E Prat J Uterine sarcomas: a review Gynecol Oncol 2010 116 131 139 10.1016/j.ygyno.2009.09.023 19853898 \nKanjeekal S Chambers A Fung MF Verma S Systemic therapy for advanced uterine sarcoma: a systematic review of the literature Gynecol Oncol 2005 97 624 637 10.1016/j.ygyno.2005.01.041 15863170 \nHensley ML Role of chemotherapy and biomolecular therapy in the treatment of uterine sarcomas Best Pract Res Clin Obstet Gynaecol 2011 25 773 782 10.1016/j.bpobgyn.2011.06.003 21752717 \nAksoy S Hizli D Sarici S Öcalan R Köse MF Güler N A retrospective review of metastatic or recurrent uterine sarcomas treated with ifosfamide and doxorubicin (IMA) UHOD 2008 18 129 134 \nvan der Graaf WT Blay JY Chawla SP Kim DW Bui-Nguyen B Casali PG Schöffski P Aglietta M Staddon AP Beppu Y Le Cesne A Gelderblom H Judson IR Araki N Ouali M Marreaud S Hodge R Dewji MR Coens C Demetri GD Fletcher CD Dei Tos AP Hohenberger P EORTC Soft Tissue and Bone Sarcoma Group, PALETTE study group Pazopanib for metastatic soft-tissue sarcoma (PALETTE): a randomised, double-blind, placebo-controlled phase 3 trial Lancet 2012 379 1879 1886 10.1016/S0140-6736(12)60651-5 22595799 \nHegi ME Diserens AC Gorlia T Hamou MF de Tribolet N Weller M Kros JM Hainfellner JA Mason W Mariani L Bromberg JE Hau P Mirimanoff RO Cairncross JG Janzer RC Stupp R MGMT gene silencing and benefit from temozolomide in glioblastoma N Engl J Med 2005 352 997 1003 10.1056/NEJMoa043331 15758010 \nPenel N Van Glabbeke M Marreaud S Ouali M Blay JY Hohenberger P Testing new regimens in patients with advanced soft tissue sarcoma: analysis of publications from the last 10 years Ann Oncol 2011 22 1266 1272 10.1093/annonc/mdq608 21183581 \nWoll PJ Judson I Lee SM Rodenhuis S Nielsen OS Buesa JM Lorigan PC Leyvraz S Hermans C van Glabbeke M Verweij J Temozolomide in adult patients with advanced soft tissue sarcoma: a phase II study of the EORTC Soft Tissue and Bone Sarcoma Group Eur J Cancer 1999 35 410 412 10.1016/S0959-8049(98)00403-1 10448291 \nTalbot SM Keohan ML Hesdorffer M Orrico R Bagiella E Troxel AB Taub RN A phase II trial of temozolomide in patients with unresectable or metastatic soft tissue sarcoma Cancer 2003 98 1942 1946 10.1002/cncr.11730 14584078 \nTrent JC Beach J Burgess MA Papadopolous N Chen LL Benjamin RS Patel SR A two-arm phase II study of temozolomide in patients with advanced gastrointestinal stromal tumors and other soft tissue sarcomas Cancer 2003 98 2693 2699 10.1002/cncr.11875 14669291 \nGarcia del Muro X Lopez-Pousa A Martin J Buesa JM Martinez-Trufero J Casado A Poveda A Cruz J Bover I Maurel J Spanish Group for Research on Sarcomas A phase II trial of temozolomide as a 6-week, continuous, oral schedule in patients with advanced soft tissue sarcoma: a study by the Spanish Group for Research on Sarcomas Cancer 2005 104 1706 1712 10.1002/cncr.21384 16134177 \nAnderson S Aghajanian C Temozolomide in uterine leiomyosarcomas Gynecol Oncol 2005 98 99 103 10.1016/j.ygyno.2005.03.018 15916799\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1752-1947",
"issue": "7()",
"journal": "Journal of medical case reports",
"keywords": null,
"medline_ta": "J Med Case Rep",
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"nlm_unique_id": "101293382",
"other_id": null,
"pages": "29",
"pmc": null,
"pmid": "23347560",
"pubdate": "2013-01-24",
"publication_types": "D016428:Journal Article",
"references": "21183581;14669291;21247711;15758010;15916799;22595799;10448291;14584078;15863170;16134177;19853898;21752717",
"title": "Long lasting clinical response to chemotherapy for advanced uterine leiomyosarcoma: a case report.",
"title_normalized": "long lasting clinical response to chemotherapy for advanced uterine leiomyosarcoma a case report"
} | [
{
"companynumb": "IT-CIPLA LTD.-2018IT02989",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "GEMCITABINE\\GEMCITABINE HYDROCHLORIDE"
},
"d... |
{
"abstract": "Gefitinib is a selective inhibitor of epidermal growth factor receptor (EGFR) tyrosine kinases, and shows favorable antitumor activity against chemorefractory non-small cell lung cancer (NSCLC). The majority of responders (patients who are sensitive to gefitinib), however, relapse within 1.5 years, indicating an acquired resistance to gefitinib. Here we report three chemotherapy refractory NSCLC patients who were retreated with gefitinib. All three cases were nonsmokers and showed an adenocarcinoma histology. While they had experienced successful control from their initial treatment with gefitinib for more than 12 months, gefitinib therapy was terminated because two cases (cases 1 and 3) relapsed during the therapy and case 2 suffered alveolar hemorrhage. After more than 7 months from the time of discontinuation of the initial gefitinib treatment, they were retreated with gefitinib, as further tumor progression was observed. Of the three cases, cases 1 and 2 were well controlled by retreatment with gefitinib monotherapy for more than 7 months, suggesting sensitivity to retreatment. Case 3 also showed a regression in size of several tumors, while some other lesions progressively enlarged and developed a malignant pleural effusion after 4 months. These observations suggest the possibility that retreatment with gefitinib might be useful when 1) initial treatment shows a favorable clinical response, and 2) there has been a period of time following the termination of the initial gefitinib treatment.",
"affiliations": "Department of Internal Medicine and Molecular Therapeutics, The University of Tokushima Graduate School, 3-18-15 Kuramoto-cho, Tokushima, Japan. manae@clin.med.tokushima-u.ac.jp",
"authors": "Yano|Seiji|S|;Nakataki|Emiko|E|;Ohtsuka|Shinsaku|S|;Inayama|Mami|M|;Tomimoto|Hideki|H|;Edakuni|Nobutaka|N|;Kakiuchi|Soji|S|;Nishikubo|Naoki|N|;Muguruma|Hiroaki|H|;Sone|Saburo|S|",
"chemical_list": "D000970:Antineoplastic Agents; D011799:Quinazolines; D066246:ErbB Receptors; D000077156:Gefitinib",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0965-0407",
"issue": "15(2)",
"journal": "Oncology research",
"keywords": null,
"medline_ta": "Oncol Res",
"mesh_terms": "D000230:Adenocarcinoma; D000368:Aged; D000970:Antineoplastic Agents; D002289:Carcinoma, Non-Small-Cell Lung; D045744:Cell Line, Tumor; D018450:Disease Progression; D066246:ErbB Receptors; D005260:Female; D000077156:Gefitinib; D006801:Humans; D008175:Lung Neoplasms; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D010996:Pleural Effusion; D011799:Quinazolines; D012008:Recurrence; D019233:Retreatment; D013997:Time Factors",
"nlm_unique_id": "9208097",
"other_id": null,
"pages": "107-11",
"pmc": null,
"pmid": "16119008",
"pubdate": "2005",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Retreatment of lung adenocarcinoma patients with gefitinib who had experienced favorable results from their initial treatment with this selective epidermal growth factor receptor inhibitor: a report of three cases.",
"title_normalized": "retreatment of lung adenocarcinoma patients with gefitinib who had experienced favorable results from their initial treatment with this selective epidermal growth factor receptor inhibitor a report of three cases"
} | [
{
"companynumb": "JP-ASTRAZENECA-2003AP01219",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "GEFITINIB"
},
"drugadditional": null,
... |
{
"abstract": "Sacubitril/valsartan is the first drug from a new class of angiotensin receptor neprilysin inhibitors (ARNIs) recommended in the new European Society of Cardiology guidelines instead of angiotensin converting enzyme inhibitors (ACEI), or angiotensin receptor blockers (ARB) that are used if ACEI are not tolerated. Sacubitril/valsartan is recommended for further reduction in the risk of hospitalisation or death in outpatients with heart failure with reduced ejection fraction (HFrEF) if symptoms continue despite optimal treatment with ACEI/ARB, beta-blockers, and mineralocorticoid antagonists.\n\n\n\nThe aim of this study is to present the initial experience with regard to the effectiveness, tolerance, and safety of sacubitril/valsartan in the outpatient cardiology practice in Poland.\n\n\n\nThe study is a retrospective analysis of data obtained through a questionnaire filled in by the physicians who initiated the sacubitril/valsartan treatment in patients with HFrEF between 1 June 2016 and 30 September 2016. Patients were followed-up for three months.\n\n\n\nThe analysis included data on 28 patients aged 61 ± 16 years, of whom 85.7% were males. The drug was used in patients in New York Heart Association (NYHA) class I-III. In 25 (89.2%) patients sacubitril/valsartan was started at the lowest dose (24/26 mg BID). During follow-up the sacubitril/valsartan-treated patients had a reduction in HF symptoms assessed using the NYHA functional class (p = 0.001), a significant drop in N-terminal-pro B-type natriuretic peptide levels (mean, from 2900 to 2270 pg/mL; p = 0.008), and improved exercise tolerance, which occurred shortly after treatment initiation - after a mean of 28 days.\n\n\n\nIt was demonstrated that the use of sacubitril/valsartan in outpatients with HFrEF is safe and is associated with a significant clinical improvement.",
"affiliations": "1st Department of Cardiology, University of Medical Sciences, Poznan, Poland. marta.kaluzna@wp.pl.",
"authors": "Kałużna-Oleksy|Marta|M|;Kolasa|Jolanta|J|;Migaj|Jacek|J|;Pawlak|Agnieszka|A|;Lelonek|Małgorzata|M|;Nessler|Jadwiga|J|;Straburzyńska-Migaj|Ewa|E|",
"chemical_list": "D000613:Aminobutyrates; D057911:Angiotensin Receptor Antagonists; D001713:Biphenyl Compounds; D004338:Drug Combinations; D010446:Peptide Fragments; D013777:Tetrazoles; C109794:pro-brain natriuretic peptide (1-76); D020097:Natriuretic Peptide, Brain; D000068756:Valsartan; C549068:sacubitril and valsartan sodium hydrate drug combination",
"country": "Poland",
"delete": false,
"doi": "10.5603/KP.a2017.0230",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0022-9032",
"issue": "76(2)",
"journal": "Kardiologia polska",
"keywords": "ARNI; heart failure with reduced ejection fraction; sacubitril/valsartan",
"medline_ta": "Kardiol Pol",
"mesh_terms": "D000368:Aged; D000613:Aminobutyrates; D057911:Angiotensin Receptor Antagonists; D001713:Biphenyl Compounds; D004338:Drug Combinations; D005260:Female; D006333:Heart Failure; D006801:Humans; D008297:Male; D008875:Middle Aged; D020097:Natriuretic Peptide, Brain; D010045:Outpatients; D061214:Patient Safety; D010446:Peptide Fragments; D011044:Poland; D012189:Retrospective Studies; D013318:Stroke Volume; D013777:Tetrazoles; D016896:Treatment Outcome; D000068756:Valsartan; D018487:Ventricular Dysfunction, Left",
"nlm_unique_id": "0376352",
"other_id": null,
"pages": "381-387",
"pmc": null,
"pmid": "29192956",
"pubdate": "2018",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Initial clinical experience with the first drug (sacubitril/valsartan) in a new class - angiotensin receptor neprilysin inhibitors in patients with heart failure with reduced left ventricular ejection fraction in Poland.",
"title_normalized": "initial clinical experience with the first drug sacubitril valsartan in a new class angiotensin receptor neprilysin inhibitors in patients with heart failure with reduced left ventricular ejection fraction in poland"
} | [
{
"companynumb": "PHHY2018PL034561",
"fulfillexpeditecriteria": "1",
"occurcountry": "PL",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "SACUBITRIL\\VALSARTAN"
},
"drugadditional": "3",
... |
{
"abstract": "We present a case of hypersensitivity pneumonitis caused by intranasal abuse of the prescription narcotic hydrocodone. The patient's clinical course was complicated by acute respiratory failure. A chest radiograph showed diffuse bilateral opacities. The patient was treated with noninvasive ventilation, a high dose of intravenous steroids, and bronchodilators, resulting in improvement of symptoms and radiographic appearance.",
"affiliations": "Department of Hospital Medicine, Sanford Medical Centre, Fargo, North Dakota (Pathak), and Department of Medicine, University of West Indies, Trinidad (Vijayaraghavan).;Department of Hospital Medicine, Sanford Medical Centre, Fargo, North Dakota (Pathak), and Department of Medicine, University of West Indies, Trinidad (Vijayaraghavan).",
"authors": "Pathak|Lakshmi Kant|LK|;Vijayaraghavan|Vimala|V|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1080/08998280.2016.11929438",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0899-8280",
"issue": "29(3)",
"journal": "Proceedings (Baylor University. Medical Center)",
"keywords": null,
"medline_ta": "Proc (Bayl Univ Med Cent)",
"mesh_terms": null,
"nlm_unique_id": "9302033",
"other_id": null,
"pages": "288-9",
"pmc": null,
"pmid": "27365873",
"pubdate": "2016-07",
"publication_types": "D002363:Case Reports",
"references": "12842854;17525776;18344808;2809034",
"title": "Hydrocodone snorting leading to hypersensitivity pneumonitis.",
"title_normalized": "hydrocodone snorting leading to hypersensitivity pneumonitis"
} | [
{
"companynumb": "US-CURRAX PHARMACEUTICALS LLC-US-2019PER000096",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "HYDROCODONE BITARTRATE"
},
... |
{
"abstract": "A 36-year-old woman presented with diminution of vision and floaters in both the eyes. Both eyes had disc oedema, multiple pockets of neurosensory detachments along with vitritis. Fluorescein angiography and optical coherence tomography showed characteristic features of Vogt-Koyanagi-Harada (VKH) syndrome (figure 1). She was started on corticosteroid pulse therapy and immunosuppressants following which her VKH lesions resolved. However, she developed chickenpox after 2 weeks and after 1 month she developed discrete yellowish white retinitis patches in the periphery of the right eye which were consistent with a diagnosis of acute retinal necrosis. She was started on oral antivirals for the same and immunosuppressants were withheld in view of immunocompromised state potentially acting as a trigger for reactivation of latent virus. Retinitis patches started to resolve and showed a favourable response to the treatment.",
"affiliations": "Smt. Kanuri Santhamma Centre for Vitreo Retinal Diseases, LV Prasad Eye Institute, Hyderabad, India.;Smt. Kanuri Santhamma Centre for Vitreo Retinal Diseases, LV Prasad Eye Institute, Hyderabad, India.;Smt. Kanuri Santhamma Centre for Vitreo Retinal Diseases, LV Prasad Eye Institute, Hyderabad, India.;Smt. Kanuri Santhamma Centre for Vitreo Retinal Diseases, LV Prasad Eye Institute, Hyderabad, India.",
"authors": "Gupta|Rajan|R|http://orcid.org/0000-0003-4925-6456;Tyagi|Mudit|M|;Balakrishnan|Divya|D|;Rani|Padmaja Kumari|PK|",
"chemical_list": "D000998:Antiviral Agents; D007166:Immunosuppressive Agents",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2018-227290",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "11(1)",
"journal": "BMJ case reports",
"keywords": "infectious diseases; retina",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000328:Adult; D000998:Antiviral Agents; D002644:Chickenpox; D003937:Diagnosis, Differential; D005260:Female; D005451:Fluorescein Angiography; D014645:Herpesvirus 3, Human; D006801:Humans; D007166:Immunosuppressive Agents; D015882:Retinal Necrosis Syndrome, Acute; D041623:Tomography, Optical Coherence; D016896:Treatment Outcome; D014607:Uveomeningoencephalitic Syndrome",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "30567136",
"pubdate": "2018-11-28",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "8090452;23235944;22741031;8172275;23658473;2378860;22997354;2038718;12353186;8924252",
"title": "Acute retinal necrosis (ARN) following chickenpox in a patient of Vogt-Koyanagi-Harada (VKH) syndrome using immunosuppressants.",
"title_normalized": "acute retinal necrosis arn following chickenpox in a patient of vogt koyanagi harada vkh syndrome using immunosuppressants"
} | [
{
"companynumb": "IN-MYLANLABS-2019M1003525",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "AZATHIOPRINE"
},
"drugadditional": "1",
... |
{
"abstract": "Donepezil, an acetylcholinesterase inhibitor, is approved for the treatment of mild to moderate dementia secondary to Alzheimer's disease. Although most prescribers are aware of the common gastrointestinal side effects of donepezil, cardiovascular side effects are rarely observed. Cardiovascular side effects of donepezil have almost always been observed in patients with a history of conduction defects or sick sinus syndrome. We report a case of a woman with early onset Alzheimer's disease and no history of cardiac disease who developed second-degree heart block after a few weeks of therapy with donepezil. Withdrawal of donepezil led to resolution of the atrioventricular block.",
"affiliations": "Department of Internal Medicine (Hundae), Division of Cardiology (Afzal, Schussler), Baylor University Medical Center at Dallas; and the Department of Internal Medicine, Texas A&M College of Medicine (Schussler).;Department of Internal Medicine (Hundae), Division of Cardiology (Afzal, Schussler), Baylor University Medical Center at Dallas; and the Department of Internal Medicine, Texas A&M College of Medicine (Schussler).;Department of Internal Medicine (Hundae), Division of Cardiology (Afzal, Schussler), Baylor University Medical Center at Dallas; and the Department of Internal Medicine, Texas A&M College of Medicine (Schussler).;Department of Internal Medicine (Hundae), Division of Cardiology (Afzal, Schussler), Baylor University Medical Center at Dallas; and the Department of Internal Medicine, Texas A&M College of Medicine (Schussler).",
"authors": "Hundae|Aneley|A|;Afzal|Aasim|A|;Assar|Manish D|MD|;Schussler|Jeffrey M|JM|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1080/08998280.2014.11929146",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0899-8280",
"issue": "27(4)",
"journal": "Proceedings (Baylor University. Medical Center)",
"keywords": null,
"medline_ta": "Proc (Bayl Univ Med Cent)",
"mesh_terms": null,
"nlm_unique_id": "9302033",
"other_id": null,
"pages": "325-6",
"pmc": null,
"pmid": "25484499",
"pubdate": "2014-10",
"publication_types": "D002363:Case Reports",
"references": "11198060;15863734;16060718;16858101",
"title": "Syncope secondary to second-degree atrioventricular block with donepezil use.",
"title_normalized": "syncope secondary to second degree atrioventricular block with donepezil use"
} | [
{
"companynumb": "US-EISAI MEDICAL RESEARCH-EC-2014-002540",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "DONEPEZIL"
},
"drugadditional"... |
{
"abstract": "Dermatomyositis is a myopathic or amyopathic autoimmune connective tissue disease that presents with classic dermatologic findings ranging from: poikilodermatous photosensitivity (shawl sign), eyelid edema and violaceous-pigmentation (heliotrope sign), lichenoid eruptions on the knuckles and elbows (Gottron's sign), periungual telangiectasias, and ragged cuticles (Samitz sign). Up to 30 percent of adult-onset cases of dermatomyositis may represent a paraneoplastic syndrome warranting a thorough work-up for malignancy. The authors present a case report of paraneoplastic dermatomyositis associated with triple negative, BRCA-1 positive, invasive intraductal carcinoma of the breast, whose myopathic and cuteanous symptoms were recalcitrant to high-dose corticosteroid therapy. Herein, the authors describe the first reported case of the use of an injectable adrenocorticotropic hormone agonist gel in a patient with myopathic paraneoplastic disease that achieved clinical resolution of both myopathic and cutaneous symptoms, but subseuqently developed significant hyperpigmentation of her face suspected to be secondary to a chemotherapeutic-induced pigmentary change which was augmented by adrenocorticotropic hormone therapy.",
"affiliations": "St. Barnabas Hospital Dermatology Residency, Bronx, New York.;St. Barnabas Hospital Dermatology Residency, Bronx, New York.;New York College of Osteopathic Medicine-NYIT, Old Westbury, New York.;Pathology Associate Pc, Dermatopathology, Portchester, New York.;St. Barnabas Hospital Dermatology Residency, Bronx, New York;; Mount Sinai School of Medicine Manhattan, New York.",
"authors": "Wolff|Marisa|M|;Mancuso|Christopher|C|;Lal|Karan|K|;Dicostanzo|Damian|D|;Gropper|Charles|C|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1941-2789",
"issue": "10(1)",
"journal": "The Journal of clinical and aesthetic dermatology",
"keywords": null,
"medline_ta": "J Clin Aesthet Dermatol",
"mesh_terms": null,
"nlm_unique_id": "101518173",
"other_id": null,
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"abstract": "Down's syndrome (DS), the most common genetic cause of significant intellectual disability in children and adults is caused by the trisomy of either all or a part of human chromosome 21 (HSA21). Patients with DS mostly suffer from characteristic tumor types. Although individual patients of DS are at a higher risk for acute leukemia and testicular cancers, other types of solid tumors including breast cancers are mostly uncommon and have significantly lower-than-expected age-adjusted incidence rates. Except for an increased risk of retinoblastomas, and lymphomas, the risk of developing solid tumors has been found to be lower in both children and adults, and breast cancer was found to be almost absent (Hasle H., The Lancet Oncology, 2001). A study conducted in the United States found only one death when 11.65 were expected (Scholl T et al., Dev Med Child Neurol. 1982). A recent study examined mammogram reports of women with DS treated in the largest medical facility specifically serving adults with DS in the United States. It was found that only 0.7% women with DS had been diagnosed with breast cancers (Chicoine B et al., Intellect Dev Disabil. 2015). Here we describe a case of breast cancer in a 25-year-old patient with DS. The disease was presented as lymph node positive carcinoma with alterations of tumor suppressor genes characteristic to the triple negative breast cancer subtype. Comprehensive Genomic Profiling (CGP) revealed a wild-type status for BRCA1. The CGP report showed a frameshift mutation, A359fs*10 of the tumor suppressor gene INPP4B and another frameshift mutation, R282fs*63 of tumor suppressor gene TP53 in the tumor biopsy as characteristically found in triple-negative breast cancers. The VUS (Variance of Unknown Significance) alteration(s) were identified in ASXL1 (L1395V), NTRK1 (G18E), DDR2 (I159T), RUNX1 (amplification), ERG (amplification), SOX2 (T26A), FAM123B (G1031D), and HNF1A (A301T). Bonafide cancer-related genes of chromosome 21 amplified in the patient's tumor are RUNX1 and ERG genes. After the completion of the radiation, the patient was placed on everolimus which was based on the result of her CGP report. Thus, post-mastectomy radiation therapy was completed with a recommendation for everolimus for one year. During the time of writing of this report, no metastatic lesions were identified. The patient currently has no evidence of disease.",
"affiliations": "Center for Precision Oncology, Department of Molecular and Experimental Medicine, Avera Cancer Institute, Sioux Falls, SD 57105, USA. nandini.dey@avera.org.;Center for Precision Oncology, Department of Molecular and Experimental Medicine, Avera Cancer Institute, Sioux Falls, SD 57105, USA. Amy.Krie@avera.org.;Center for Precision Oncology, Department of Molecular and Experimental Medicine, Avera Cancer Institute, Sioux Falls, SD 57105, USA. Jessica.Klein@avera.org.;Center for Precision Oncology, Department of Molecular and Experimental Medicine, Avera Cancer Institute, Sioux Falls, SD 57105, USA. Kirstin.Williams@avera.org.;Center for Precision Oncology, Department of Molecular and Experimental Medicine, Avera Cancer Institute, Sioux Falls, SD 57105, USA. Amanda.McMillan@avera.org.;Center for Precision Oncology, Department of Molecular and Experimental Medicine, Avera Cancer Institute, Sioux Falls, SD 57105, USA. Rachel.Elsey@avera.org.;Center for Precision Oncology, Department of Molecular and Experimental Medicine, Avera Cancer Institute, Sioux Falls, SD 57105, USA. Yuliang.Sun@avera.org.;Center for Precision Oncology, Department of Molecular and Experimental Medicine, Avera Cancer Institute, Sioux Falls, SD 57105, USA. Casey.Williams@avera.org.;Center for Precision Oncology, Department of Molecular and Experimental Medicine, Avera Cancer Institute, Sioux Falls, SD 57105, USA. Pradip.De@avera.org.;Center for Precision Oncology, Department of Molecular and Experimental Medicine, Avera Cancer Institute, Sioux Falls, SD 57105, USA. brian.leylandjones@avera.org.",
"authors": "Dey|Nandini|N|;Krie|Amy|A|;Klein|Jessica|J|;Williams|Kirstin|K|;McMillan|Amanda|A|;Elsey|Rachel|R|;Sun|Yuliang|Y|;Williams|Casey|C|;De|Pradip|P|;Leyland-Jones|Brian|B|",
"chemical_list": "D014408:Biomarkers, Tumor",
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"doi": "10.3390/ijms18061218",
"fulltext": "\n==== Front\nInt J Mol SciInt J Mol SciijmsInternational Journal of Molecular Sciences1422-0067MDPI 10.3390/ijms18061218ijms-18-01218Case ReportDown’s Syndrome and Triple Negative Breast Cancer: A Rare Occurrence of Distinctive Clinical Relationship Dey Nandini 12Krie Amy 1Klein Jessica 1Williams Kirstin 1McMillan Amanda 1Elsey Rachel 1Sun Yuliang 1Williams Casey 12De Pradip 12Leyland-Jones Brian 1*Piva Terrence Academic Editor1 Center for Precision Oncology, Department of Molecular and Experimental Medicine, Avera Cancer Institute, Sioux Falls, SD 57105, USA; nandini.dey@avera.org (N.D.); Amy.Krie@avera.org (A.K.); Jessica.Klein@avera.org (J.K.); Kirstin.Williams@avera.org (K.W.); Amanda.McMillan@avera.org (A.M.); Rachel.Elsey@avera.org (R.E.); Yuliang.Sun@avera.org (Y.S.); Casey.Williams@avera.org (C.W.); Pradip.De@avera.org (P.D.)2 Departmental of Internal Medicine, Sanford School of Medicine, University of South Dakota, Sioux Falls, SD 57105, USA* Correspondence: brian.leylandjones@avera.org; Tel.: +1-605-322-329607 6 2017 6 2017 18 6 121817 4 2017 05 6 2017 © 2017 by the authors.2017Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).Down’s syndrome (DS), the most common genetic cause of significant intellectual disability in children and adults is caused by the trisomy of either all or a part of human chromosome 21 (HSA21). Patients with DS mostly suffer from characteristic tumor types. Although individual patients of DS are at a higher risk for acute leukemia and testicular cancers, other types of solid tumors including breast cancers are mostly uncommon and have significantly lower-than-expected age-adjusted incidence rates. Except for an increased risk of retinoblastomas, and lymphomas, the risk of developing solid tumors has been found to be lower in both children and adults, and breast cancer was found to be almost absent (Hasle H., The Lancet Oncology, 2001). A study conducted in the United States found only one death when 11.65 were expected (Scholl T et al., Dev Med Child Neurol. 1982). A recent study examined mammogram reports of women with DS treated in the largest medical facility specifically serving adults with DS in the United States. It was found that only 0.7% women with DS had been diagnosed with breast cancers (Chicoine B et al., Intellect Dev Disabil. 2015). Here we describe a case of breast cancer in a 25-year-old patient with DS. The disease was presented as lymph node positive carcinoma with alterations of tumor suppressor genes characteristic to the triple negative breast cancer subtype. Comprehensive Genomic Profiling (CGP) revealed a wild-type status for BRCA1. The CGP report showed a frameshift mutation, A359fs*10 of the tumor suppressor gene INPP4B and another frameshift mutation, R282fs*63 of tumor suppressor gene TP53 in the tumor biopsy as characteristically found in triple-negative breast cancers. The VUS (Variance of Unknown Significance) alteration(s) were identified in ASXL1 (L1395V), NTRK1 (G18E), DDR2 (I159T), RUNX1 (amplification), ERG (amplification), SOX2 (T26A), FAM123B (G1031D), and HNF1A (A301T). Bonafide cancer-related genes of chromosome 21 amplified in the patient’s tumor are RUNX1 and ERG genes. After the completion of the radiation, the patient was placed on everolimus which was based on the result of her CGP report. Thus, post-mastectomy radiation therapy was completed with a recommendation for everolimus for one year. During the time of writing of this report, no metastatic lesions were identified. The patient currently has no evidence of disease.\n\nDown’s syndrometriple negative breast cancertumor suppressor genesPI3K-mTOR pathway\n==== Body\n1. Background\nDown’s syndrome (DS) is a hereditary disease of chromosomal rearrangement(s). Patients with DS are known to exhibit rearrangement(s) of chromosomal material between chromosome 21 and another chromosome. As a result of this rearrangement, a patient bears the usual two copies of chromosome 21, plus extra material from chromosome 21 attached to another chromosome (which take part in the rearrangement). However, the rearrangement or translocation trisomy 21 is not common in the people with Down’s syndrome. More than 90% of Down’s syndrome is caused by an extra copy of chromosome 21, also called trisomy 21.\n\nTriplication of the human chromosome 21 in DS is associated with an altered genetic dosage of different genes including transcription factors. Since appropriate expressions, as well as the functioning of transcription factors, are essential for regulation of different signals within cells, an altered gene dosage becomes crucial for the development of complex diseases including cancers. Patterns of development of various organ-type cancers in DS are unique and emphasize the relationship between chromosome 21 and tumorigenesis. Children with DS have a ~10- to 20-fold higher risk of developing acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML), as compared with non-DS children [1]. Certain solid tumors including lymphomas, retinoblastomas, and testicular germ cell tumors, have been reported in individuals with DS [2,3,4]. However, children with DS do not have a uniformly increased risk of developing solid tumors. A decade ago, Patja et al. reported that in a cohort of a little over 1000 women with DS there was no observed case of breast cancers [5]. A national epidemiological study on mortality over 24 years in France had been conducted by Daniel Sage and colleagues. The outcome of the study showed only five deaths from breast cancers in women with DS (68.98 expected (Fisher test; p < 0.00005)) [6]. A similar type of study conducted in the United States found comparable results; only one death when 11.65 were expected [7]. A recent study examined mammogram reports of women with DS treated in the largest medical facility specifically serving adults with DS in the United States. The study examined mammogram reports of women with DS. Records of 684 women and results of 993 mammograms were reviewed, including 902 screening and 93 diagnostic mammograms. The study found that only 0.7% women with DS had been diagnosed with breast cancer [8]. In line with the above reports, Martel-Billard et al. studied trisomy 21 and breast cancer and concluded that chromosomal abnormality of DS protects against breast cancers via genetic mechanisms [9]. The development pattern of cancer in DS patients provides a distinct model to improve our understanding of the genetic basis of tumorigenesis as well as mechanisms of sensitivity to anti-cancer drugs. Here, we describe the first case of triple negative breast cancer in a 25-year-old female patient with Down’s syndrome.\n\n2. Case Description\nA 25-year-old female with DS residing in South Dakota, USA had been found to have a firm, palpable lump in her right upper outer breast 9–10 o′clock position during a physical examination. Patient’s DS has been reported to be mild (otherwise unknown). Patient’s mother’s age was 26 years, and her father’s age was 34 years at the time of the conception. Patient’s mother is a smoker. The patient experienced menarche at the age of 14 years. No major malformations have been reported in the patient. The patient’s paternal aunt was diagnosed with breast cancer in her 70s. No other family history of cancer has been recorded. A diagnostic mammogram was performed, and a mass of 5.4 × 6.1 × 6.2 cm size was identified. The tumor type was diagnosed as breast carcinoma with 5% ER positivity, 0% PR positivity and negative for HER2 (IHC, ratio, and copy number). Ratio and copy numbers are non-detected. Comprehensive Genomic Profiling (CGP) revealed a wild-type status for BRCA1. The CGP report showed a frameshift mutation, A359fs*10 of the tumor suppressor gene INPP4B and another frameshift mutation, R282fs*63 of tumor suppressor gene TP53 in the tumor biopsy as characteristically found in triple-negative breast cancers (Figure 1). The VUS (Variance of Unknown Significance) alteration(s) was identified in ASXL1 (L1395V), NTRK1 (G18E), DDR2 (I159T), RUNX1 (amplification), ERG (amplification), SOX2 (T26A), FAM123B (G1031D), and HNF1A (A301T). Bonafide cancer-related genes of chromosome 21 amplified in the patient’s tumor have been presented in the Figure 2 which shows that RUNX1 and ERG genes are amplified in the tumor (VUS genes in gray shade from the FoundationOne; Figure 1). FoundationOne® provided us fully informative genomic profiles that are based on assays identify the molecular growth drivers of a patient’s cancer (www.foundationone.com). FoundationOne provides validated comprehensive genomic profiles and interrogates the entire coding sequence of 315 cancer-related genes plus select introns from 28 genes those are often rearranged or altered in solid tumors to a typical median depth of coverage of greater than 500×. Each covered read represents a unique DNA fragment to enable the highly sensitive and specific detection of genomic alterations that occur at low frequencies as a result of tumor heterogeneity, limited tumor purity, and a small amount of samples. FoundationOne detects genomic alterations, including base substitutions, insertions and deletions (indels), copy number alterations (CNAs), and rearrangements. The patient received carboplatin plus gemcitabine, and then the treatment was switched to taxol plus carboplatin due to an increase in her liver function test score (LFTS). Patient’s Positron emission tomography/computed tomography (PET/CT) showed an absence of adenopathy. The patient underwent a mastectomy. Right breast mastectomy and axillary lymph node dissection (ALND) showed no residual disease in the breast, but 2 out of 10 lymph nodes (2/10 LN) were found positive. The tumor was Stage III cT3N3M0 Breast Invasive Ductal Carcinoma (IDC) (Figure 3). We tested cfDNA from liquid biopsy by Guardant360. Guardant360 provides the most validated comprehensive liquid biopsy for the 73-gene panel. The digital sequencing technology of Guardant360 identifies the signal of patient’s individual genomic alterations from the noise of interfering data that is inherent to standard next-generation sequencing (NGS) techniques (www.guardanthealth.com). The cfDNA from the liquid biopsy by Guardant360 identified alterations in APC (R24*), ALK (R1120W), AR (R608Q), and MET (R417*) indicating a somatic mutation burden of 0.2%. The patient was treated with four cycles of anthracyclin (AC). We followed the Clinical Guidelines for the use of AC × 4 doses. Every two week dosing of doxorubicin and cyclophosphamide for four doses, or dose-dense AC, followed by paclitaxel therapy is listed as a preferred regimen for neoadjuvant and adjuvant treatment in HER-2 negative disease in the National Comprehensive Cancer Network (NCCN) Guidelines for Invasive Breast Cancer Version 2.2017 (NCCN Guidelines. Invasive Breast Cancer. Version 2.2017). In HER-2 positive disease, dose-dense AC followed by trastuzumab, pertuzumab, and paclitaxel or docetaxel is also considered to be a preferred regimen by the NCCN. Every three weeks is considered a lower category of recommendation for these same indications. While it is no longer a preferred regimen for recurrent or metastatic breast cancer, AC is still listed as a treatment option. The American Society of Clinical Oncology (ASCO) also considers the use of an anthracycline-taxane regimen to be the optimal strategy for adjuvant therapy of HER-2 negative or HER-2 positive breast cancers, especially in high risk disease (Selection of Optimal Adjuvant Chemotherapy Regimens for Human Epidermal Growth Factor Receptor 2 (HER2)—Negative and Adjuvant Targeted Therapy for HER2-Positive Breast Cancers: An American Society of Clinical Oncology Guideline Adaptation of the Cancer Care Ontario Clinical Practice Guideline. Journal of Clinical Oncology. 2016). The patient started at outside facility on gemcitabine 1000 mg/m2 and carboplatin AUC2 D 1, 8 every 21 days and received two cycles until it was stopped due to persistent aspartate aminotransferase/alanine aminotransferase (AST/ALT) elevation and delayed nausea and vomiting. At that time, she was switched to paclitaxel 80 mg/m2 and carboplatin AUC2 D1, 8 q21 days. The patient received four cycles of this regimen for a total of six cycles of chemotherapy. Then she went to surgery, and the pathology report showed that surgical margins were negative and there was no residual cancer in the breast because the patient had previously done an excisional biopsy, but 2 of 10 axillary lymph nodes were positive for metastatic carcinoma. After surgery had been completed, the patient’s family requested a second opinion and the patient started receiving care at Avera Cancer Institute. The risks of cardiac damage in Down’s syndrome was discussed with the family and also increased the risk of leukemia which could be increased by AC treatment for breast cancer but was considered to be beneficial overall considering her high risk of breast cancer relapse. She had a normal multiple-gated acquisition (MUGA) scan and was started on four cycles of AC in the adjuvant setting at a reduced dose of doxorubicin 50 mg/m2 and cyclophosphamide 500 mg/m2 due to Down’s syndrome. She received radiation to the right breast. After reviewing the pathology further, the ER staining was 5%, and the case was reviewed by the oncotype group and given a prior history of the clot, tamoxifen was decided to be not a right option. After the completion of the radiation, the patient was placed on everolimus which was based on the result of her CGP report. Thus, post-mastectomy radiation therapy was completed with a recommendation for everolimus for one year. The patient currently has no evidence of disease (Figure 4).\n\n3. Discussion\nOne of the privileges of working in cancer clinic is the chance to meet people from all walks of life, many of whom we never get a chance to know otherwise. We report a rare and unexpected co-occurrence of DS and triple negative breast cancer. We seek to find a link between the diseases keeping in mind their state of chromosomal rearrangements and genomic alterations. It is well documented that patients with DS have HSA21 chromosomal rearrangements in different degrees. Korbel et al., mapped HSA21 chromosomal rearrangements across 30 patients in an attempt to interrogate HSA21 at increasingly high resolution [10]. The map revealed (1) subtle translocations and (2) internal rearrangements leading to duplications and deletions of HSA21 regions. For several patients, additional copies of numerous non-contiguous regions were identified by the tiling arrays. It was reported that 30 individuals either had subtle translocations (Dup21JG, Dup21SOS, Dup21DS, Dup21JSB, Dup21NA, Dup21NO, and Dup21BA) or internal rearrangements, duplications, and deletions of HSA21 regions (Dup21JL, Dup21GY, Dup21IS, Dup21JS, Dup21KG, Dup21GP, Dup21KJ, Dup21BS, Dup21HOU, Dup21WA, Dup21SOL, Dup21SM, Dup21ZSC, and Dup21WB) [10]. Collectively, the map revealed complex rearrangements involving multiple events. In a recent study, bursts of chromosome changes have been identified to drive triple negative breast cancers [11]. The study put forward a proposal that complex genomic rearrangements in triple-negative breast cancer cells occur through a “Big Bang” model—early, short bursts of copy number aberrations, rather than progressive accumulation over time. It was postulated that these aberrations are stably maintained in a handful of clones afterward that over time grows to form an active and clinically viable tumor mass. The “Big Bang” model of tumor growth proposes that cancer grows predominantly as a single expansion populated by numerous numbers of intermixed clones. The term was used because this model implies that a signature of the early origins of the malignancy can be theoretically recovered from the present day tumor, in the same way, that the cosmic microwave background represents a signature of the birth of our universe. This implies that both public (clonal) and most private (subclonal) alterations have a distinct connection (The Darwin Cancer Blog: Keeping an evolutionary eye on cancer; https//thedarwincancerblog.com).\n\nIn our case, we observed that the tumor is of triple negative subtype. Interestingly, her comprehensive genomic profiling also showed that the tumor contains mutations of both tumor suppressor genes, TP53 and INPP4B. Both PTEN and INPP4B are often inactivated following mutations in BC, more specifically in the Triple negative breast cancers (TNBC) subtype [12,13]. A substantial number of basal/TNBC patients had an inactivating mutation or loss of INPP4B in both TCGA data set (~30%) [14] and in our Avera TNBC patient cohort. The mechanism of activation of the PI3K-AKT-mTOR pathway in basal-like BC is largely contributed by the frequent genomic alterations of tumor suppressor genes, PTEN and INPP4B phosphatases [15]. Fedele et al. reported that INPP4B protein expression was frequently lost in primary human breast carcinomas. These primary human breast carcinomas were associated with high clinical grades, tumor sizes, loss of hormone receptors, and were lost most commonly in basal-like breast carcinomas. Their study demonstrated that INPP4B protein loss was also frequently co-existed in PTEN-null tumors. Interestingly, a loss of INPP4B protein was found to be a marker of the aggressiveness in basal-like breast carcinomas [16,17]. From the view point of cell signaling, PTEN and INPP4B control the homeostasis of the activation of the PI3K-AKT signaling pathway. PTEN dephosphorylates PI (3, 4, 5) P3 to PI (4, 5) P2 while INPP4B converts PI (3, 4) P2 to PI (3) P (Figure 5). PI (4, 5) P2 and PI (3) P fail to bind to PH domain of AKT and hence fail to activate AKT which eventually restrict the growth of tumors [18,19]. The PI3K-AKT-mTOR pathway is one of the most commonly activated signaling pathways in human breast cancers. A number of small molecule inhibitors that target various nodes in the pathway have been clinically investigated. Among these agents, first generation allosteric mTOR inhibitor, everolimus has been approved for clinical uses including breast cancer [18]. We also attempted to find the status of genes those are located on the chromosome 21 in the FoundationOne report of the patient. Among many genes present on the chromosome 21 [20], RUNX1 is particularly important as VUS of our patient’s tumor showed an amplification of RUNX1 (Figure 1 and Figure 2). The transcription factor RUNX1 received considerable attention in hematopoietic malignancies [21,22]. RUNX1 was originally identified as a gene fusion in acute myeloid leukemia (AML) and is regarded to play a critical role in the earliest steps of hematopoiesis [21,22]. Importantly, RUNX1 is often expressed in breast epithelium and is deregulated during tumorigenesis. Nicola Ferrari and the team used tissue microarray data of primary breast tumors to study how RUNX1 protein expression is associated with cancer-specific survival in patients with breast cancers [23]. Their study demonstrated that a high expression of the RUNX1 protein was significantly associated with poorer cancer-specific survival in patients with breast cancers belonging to the ER-negative (p < 0.05) as well as triple-negative invasive subtypes (p < 0.05). RUNX1 alters chromatin structure in cooperation with chromatin modifier and remodeling enzymes and functions both as an oncogene and a tumor suppressor in breast cancers. Barutcu et al., recently reported that RUNX1-mediated perturbation of higher-order genome organization is functionally linked with compromised gene expression in breast cancer cells [24]. Chimge et al., recently reported the relationship between RUNX1 and AXIN1 in ER-negative versus ER-positive breast cancers. RUNX1 plays a tumor suppressor role in estrogen receptor-positive (ER+) disease while it plays an oncogenic role in ER-negative (ER-) tumors. Their study reported that RUNX1 and AXIN1 proteins are strongly correlated in ER- tumors. In their study, the unexpected correlation between RUNX1, playing an oncogenic role in ER- breast cancer, and AXIN1, a well-established tumor suppressor hub, may be related to a high ratio between the expression of variant 2 and variant 1 (v2/v1) of AXIN1 in ER- compared with ER+ breast cancer. The higher v2/v1 ratio in ER- the disease is expected to weaken the tumor suppressor activity of AXIN1 in these tumors [25]. Our study from different breast cancer cohorts has established transcriptional Wnt signaling as a hallmark of triple negative breast cancers [26,27] and the Wnt pathway has been found to be associated with specific metastatic signals [28,29]. It can be argued that an amplification of RUNX1 in our case may have contributed to triggering the Wnt pathway in the context of the genesis of a triple negative breast cancer. Considering the role of RUNX1 in the relapse and metastasis of a tumor as discussed above, we will closely monitor the disease of our patient in the future since her VUS showed amplification of RUNX1.\n\n4. Conclusions\nTo the best of our knowledge, here we describe the first case of triple negative breast cancer in a 25-year-old patient with DS. The disease was presented as lymph node positive carcinoma with alterations of tumor suppressor genes, TP53 and INPP4B, characteristic to the triple negative breast cancer subtype. During the time of writing of this report, no metastatic lesions were identified in the patient, and the PET/CT image did not show any evidence of disease.\n\nAcknowledgments\nWe acknowledge our patient and her family. We sincerely thank our clinical personnel. We acknowledge FoundationOne and Guardant360. We acknowledge the Department of Molecular and Experimental Medicine, Avera Center for Precision Oncology.\n\nConflicts of Interest\nThe authors declare no conflict of interest.\n\nFigure 1 Comprehensive genomic profile of the patient from FoundationOne and Guardant360 data is presented. Genomic alterations identified from FoundationOne data showed a frameshift mutation of INPP4B and TP53. VUS (variance of unknown significance) are shown in rows in gray. The Guardant360 Table shows the mutant allele percentage (% cfDNA) of observed somatic variants at the basal level (sample submission time point). The “Somatic Alteration Burden” value below refers to the maximum % cfDNA detected at the basal time point. The Guardant360 presents a summary of somatic alterations. The percentage of altered cell-free DNA (% cfDNA) circulating in the blood is measured. The table annotates the allele frequency of altered circulating cell-free DNA (% cfDNA) detected in the patient. Alterations are listed in descending order of % cfDNA by the gene.\n\nFigure 2 Bonafide cancer-related genes of chromosome 21 amplified in the patient’s tumor. VUS genes (Figure 1: in gray shade) from the FoundationOne results show that RUNX1 and ERG genes are amplified in the patient’s tumor.\n\nFigure 3 Photomicrograph of H&E stained invasive breast carcinoma (magnification ×40 and magnification ×200): The tumor is composed of large irregular to rounded nests of cells with pleomorphic nuclei and hyperchromasia. Mitoses and dense lymphoplasmacytic infiltration are observed.\n\nFigure 4 PET/CT of the tumor before (left panel) and after (right panel) the treatment. The right panel shows no evidence of tumor.\n\nFigure 5 Domain structure, function, and signaling of INPP4B.\n==== Refs\nReferences\n1. Xavier A.C. Ge Y. Taub J.W. Down syndrome and malignancies: A unique clinical relationship: A paper from the 2008 william beaumont hospital symposium on molecular pathology J. Mol. 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The genetic architecture of Down syndrome phenotypes revealed by high-resolution analysis of human segmental trisomies Proc. Natl. Acad. Sci. USA 2009 106 12031 12036 10.1073/pnas.0813248106 19597142 \n11. Bursts of chromosome changes drive TNBC Cancer Discov. 2016 6 1075 27599500 \n12. Pfefferle A.D. Agrawal Y.N. Koboldt D.C. Kanchi K.L. Herschkowitz J.I. Mardis E.R. Rosen J.M. Perou C.M. Genomic profiling of murine mammary tumors identifies potential personalized drug targets for p53-deficient mammary cancers Dis. Model. Mech. 2016 9 749 757 10.1242/dmm.025239 27149990 \n13. Dey N. Smith B.R. Leyland-Jones B. Targeting basal-like breast cancers Curr. Drug Targets 2012 13 1510 1524 10.2174/138945012803530116 22974394 \n14. The Cancer Genome Atlas Network Comprehensive molecular portraits of human breast tumours Nature 2012 490 61 70 23000897 \n15. Ellis M.J. Perou C.M. The genomic landscape of breast cancer as a therapeutic roadmap Cancer Discov. 2013 3 27 34 10.1158/2159-8290.CD-12-0462 23319768 \n16. Fedele C.G. Ooms L.M. Ho M. Vieusseux J. O’Toole S.A. Millar E.K. Lopez-Knowles E. Sriratana A. Gurung R. Baglietto L. Inositol polyphosphate 4-phosphatase II regulates PI3K/Akt signaling and is lost in human basal-like breast cancers Proc. Natl. Acad. Sci. USA 2010 107 22231 22236 10.1073/pnas.1015245107 21127264 \n17. De P. Carlson J.H. Leyland-Jones B. Dey N. PI3K-AKT-mTOR Pathway Cooperates with the DNA Damage Repair Pathway: Carcinogenesis in Triple-Negative Breast Cancers and Beyond Teicher B.A. Springer Heidelberg, Germany 2016 \n18. Dey N. De P. Leyland-Jones B. PI3K–AKT–mTOR inhibitors in breast cancers: From tumor cell signaling to clinical trials Pharmacol. Ther. 2017 10.1016/j.pharmthera.2017.02.037 28216025 \n19. De P. Dey N. Leyland-Jones B. Growth factor and signaling networks Brenner’s Encyclopedia of Genetics Elsevier Amsterdam, The Netherlands 2013 365 369 \n20. Hattori M. Fujiyama A. Taylor T.D. Watanabe H. Yada T. Park H.S. Park A. Toyoda K. Ishii Y. Totoki D.-K. The DNA sequence of human chromosome 21 Nature 2000 405 311 319 10830953 \n21. Janes K.A. RUNX1 and its understudied role in breast cancer Cell Cycle 2011 10 3461 3465 10.4161/cc.10.20.18029 22024923 \n22. Browne G. Taipaleenmaki H. Bishop N.M. Madasu S.C. Shaw L.M. van Wijnen A.J. Stein G.S. Lian J.B. RUNX1 is associated with breast cancer progression in MMTV–PyMT transgenic mice and its depletion in vitro inhibits migration and invasion J. Cell. Physiol. 2015 230 2522 2532 10.1002/jcp.24989 25802202 \n23. Ferrari N. Mohammed Z.M. Nixon C. Mason S.M. Mallon E. McMillan D.C. Morris J.S. Cameron E.R. Edwards J. Blyth K. Expression of RUNX1 correlates with poor patient prognosis in triple negative breast cancer PLoS ONE 2014 9 e100759 10.1371/journal.pone.0100759 24967588 \n24. Barutcu A.R. Hong D. Lajoie B.R. McCord R.P. van Wijnen A.J. Lian J.B. Stein J.L. Dekker J. Imbalzano A.N. Stein G.S. RUNX1 contributes to higher-order chromatin organization and gene regulation in breast cancer cells Biochim. Biophys. Acta 2016 1859 1389 1397 10.1016/j.bbagrm.2016.08.003 27514584 \n25. Chimge N.O. Ahmed-Alnassar S. Frenkel B. Relationship between RUNX1 and AXIN1 in ER-negative versus ER-positive breast cancer Cell Cycle 2017 16 312 318 10.1080/15384101.2016.1237325 28055379 \n26. Dey N. Barwick B.G. Moreno C.S. Ordanic-Kodani M. Chen Z. Oprea-Ilies G. Tang W. Catzavelos C. Kerstann K.F. Sledge G.W. Jr. Wnt signaling in triple negative breast cancer is associated with metastasis BMC Cancer 2013 13 537 10.1186/1471-2407-13-537 24209998 \n27. Dey N. Young B. Abramovitz M. Bouzyk M. Barwick B. De P. Differential activation of Wnt-β-catenin pathway in triple negative breast cancer increases MMP7 in a PTEN dependent manner PLoS ONE 2013 8 e77425 10.1371/journal.pone.0077425 24143235 \n28. De P. Carlson J.H. Jepperson T. Willis S. Leyland-Jones B. Dey N. RAC1 GTP-ase signals Wnt-β-catenin pathway mediated integrin-directed metastasis-associated tumor cell phenotypes in triple negative breast cancers Oncotarget 2017 8 3072 3103 27902969 \n29. De P. Carlson J.H. Wu H. Marcus A. Leyland-Jones B. Dey N. Wnt-β-catenin pathway signals metastasis-associated tumor cell phenotypes in triple negative breast cancers Oncotarget 2016 7 43124 43149 10.18632/oncotarget.8988 27281609\n\n",
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"issue": "18(6)",
"journal": "International journal of molecular sciences",
"keywords": "Down’s syndrome; PI3K-mTOR pathway; triple negative breast cancer; tumor suppressor genes",
"medline_ta": "Int J Mol Sci",
"mesh_terms": "D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D014408:Biomarkers, Tumor; D002891:Chromosomes, Human, Pair 21; D055028:Comparative Genomic Hybridization; D004314:Down Syndrome; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D009154:Mutation; D000072078:Positron Emission Tomography Computed Tomography; D064726:Triple Negative Breast Neoplasms; D014314:Trisomy",
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"title": "Down's Syndrome and Triple Negative Breast Cancer: A Rare Occurrence of Distinctive Clinical Relationship.",
"title_normalized": "down s syndrome and triple negative breast cancer a rare occurrence of distinctive clinical relationship"
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"abstract": "Leukocytoclastic vasculitis (LCV) is a small-vessel vasculitis with a reported incidence rate of 30 cases per million persons per year. It usually presents as a palpable purpuric skin rash on legs, though any part of the body can be affected. LCV rash may have an associated burning sensation or pain and in some cases may involve internal organs. In some cases, LCV rash may present as nodules, recurrent ulcerations or asymptomatic lesions. The diagnosis of LCV is usually made on skin biopsy. Etiological triggers may not be identified in as many as half of the cases. Treatment is usually conservative and includes identification and removal or treatment of the etiological trigger except in cases with internal organ involvement where systemic steroids and immunosuppressant may be necessary. In this article we present a case of indomethacin-associated LCV that improved with discontinuation of the offending agent.",
"affiliations": "Department of Internal Medicine, Saint Joseph Hospital, Chicago, Ill., USA.",
"authors": "Hussain|Nasir|N|;Mustafa|Usman|U|;Davis|James|J|;Thakkar|Shivani|S|;Ali|Alaa M|AM|;Mirrakhimov|Aibek E|AE|;Barbaryan|Aram|A|;Rowley|Guy Anthony|GA|",
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"fulltext": "\n==== Front\nCase Rep DermatolCase Rep DermatolCDECase Reports in Dermatology1662-6567S. 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 10.1159/000348240cde-0005-0033Published online: February, 2013Indomethacin-Related Leukocytoclastic Vasculitis: A Case Report and Review of Literature Hussain Nasir *Mustafa Usman Davis James Thakkar Shivani Ali Alaa M. Mirrakhimov Aibek E. Barbaryan Aram Rowley Guy Anthony Department of Internal Medicine, Saint Joseph Hospital, Chicago, Ill., USA*Nasir Hussain, MD, Saint Joseph Hospital, Resurrection Health Care, Department of Internal Medicine, 2900 North Lake Shore Drive, Chicago, IL 60657 (USA), E-Mail NHussain@reshealthcare.orgJan-Apr 2013 16 2 2013 16 2 2013 5 1 33 37 Copyright © 2013 by S. Karger AG, Basel2013This is an Open Access article distributed under the terms of the Creative Commons Attribution-Noncommercial-No-Derivative-Works License (http://creativecommons.org/licenses/by-nc-nd/3.0/). Users may download, print and share this work on the Internet for noncommercial purposes only, provided the original work is properly cited, and a link to the original work on http://www.karger.com and the terms of this license are included in any shared versions.Leukocytoclastic vasculitis (LCV) is a small-vessel vasculitis with a reported incidence rate of 30 cases per million persons per year. It usually presents as a palpable purpuric skin rash on legs, though any part of the body can be affected. LCV rash may have an associated burning sensation or pain and in some cases may involve internal organs. In some cases, LCV rash may present as nodules, recurrent ulcerations or asymptomatic lesions. The diagnosis of LCV is usually made on skin biopsy. Etiological triggers may not be identified in as many as half of the cases. Treatment is usually conservative and includes identification and removal or treatment of the etiological trigger except in cases with internal organ involvement where systemic steroids and immunosuppressant may be necessary. In this article we present a case of indomethacin-associated LCV that improved with discontinuation of the offending agent.\n\nKey words\nIndomethacinLeukocytoclastic vasculitisCeretec scan\n==== Body\nIntroduction\nLeukocytoclastic vasculitis (LCV) (hypersensitivity vasculitis) is a term commonly used to denote a small-vessel vasculitis. Many possible causes or associations have been proposed for LCV, but a cause or an associated disorder may not be found in as many as half of the cases.\n\nLCV presents clinically as a cutaneous disease with or without internal body organ involvement. The prognosis of LCV is usually good if internal organs are not affected. The internal organs most commonly involved in LCV are the joints, gastrointestinal tract, and the kidneys. Clinical presentation of LCV varies from an acute self-limiting episode to recurrent or chronic forms.\n\nIn this article we report a case of a patient who developed painful skin lesions identified to be LCV almost one and a half week after the use of indomethacin. There have been few other reports of LCV secondary to use of nonsteroidal anti-inflammatory drugs. To the best of our knowledge indomethacin-related LCV has been reported only once in the literature.\n\nCase Presentation\nA 50-year-old African-American male with a past medical history of hypertension, diabetes mellitus, peripheral vascular disease, end stage renal disease (ESRD) on hemodialysis (HD) and osteoarthritis presented for evaluation of coccyx bone pain for one week. The pain was sudden in onset, non-radiating and progressively got worse to the point (10/10 in severity) that patient was wheelchair bound for one week and had missed three consecutive sessions of HD. Patient reported history of a fall few days prior to onset of pain. There was no history of coccyx bone swelling, erythema, drainage, fever or chills. Patient had a history of recurrent methicillin-sensitive Staphylococcus aureus (MSSA) bacteremia; recent MSSA bacteremia episode was almost 2 months prior to the presentation and was due to catheter-related infection. Rest of review of symptoms was negative. Social history was significant for cigarette smoking (half pack per day for 20 years). At the time of presentation patient was taking aspirin, digoxin, ferrous sulfate, erythropoietin, insulin glargine, insulin lispro, metoprolol, magnesium oxide, pantoprazole, renal multivitamins, tramadol, colchicine (for recurrent pericarditis), senna-docusate and coumadin. Vitals at the time of presentation were: blood pressure of 124/70; pulse 110 per minute, temperature 98.7°F, respiratory rate of 18 per minute. Patient was 5 feet 10 inches tall and weighed 290 pounds. Physical examination revealed an obese male in mild distress; lungs were clear to auscultation; heart rhythm was regular, no murmur, rub or gallop. Other significant physical examination findings included presence of right upper extremity arteriovenous grafts, healed surgical scar at site of previous arteriovenous graft on left antecubital fossa, permacath right upper chest, right sacroiliac joint tenderness and point tenderness of first sacral vertebrae. Initial diagnostic workup including complete blood count and comprehensive metabolic panel revealed anemia with a hemoglobin of 7.8 g/dl (13.5–17.0), hyponatremia with a sodium of 129 mmol/l (135–145 mmol/l). White blood cell (WBC) and platelet counts were within normal limits; blood urea nitrogen and serum creatinine levels were elevated. Lumbosacral X-ray showed degenerative joint disease without any other significant abnormality. Working diagnosis of sacroiliitis was considered and patient was started on indomethacin 50 mg three times a day for anti-inflammatory and analgesic purposes along with opiate analgesics as needed. Blood culture on day 5 grew Gram-positive cocci later identified as MSSA, infection was thought to be secondary to permacath infection which was removed and the right arm graft was determined to be mature for the HD. Patient was given one dose of vancomycin followed by daily cefazolin. Patient continued to have excruciating sacroiliac and coccygeal bone pain despite of judicious use of analgesics. MRI followed by CT scan of pelvis was done on day 10 and was suggestive of possible sacral osteomyelitis. Interventional radiology team performed CT-guided aspiration of the sacroiliac joint space which returned frank pus, sample was sent for Gram stain and culture. Gram-positive cocci in clusters were identified which were later identified as MSSA. Considering history of recurrent MSSA bacteremia Ceretec-tagged WBC scan was done on day 12 which did not reveal any source of the infection. The following day after Ceretec-tagged WBC scan patient was noted to have multiple erythematous painful lesions around wrist area and violaceous erythematous papules involving metacarpophalangeal joints which progressively became generalized (as shown in fig. 1). Skin rash was thought to be a result of septic embolism or an allergic reaction to medicine or Ceretec scan. Skin punch biopsy was performed which demonstrated neutrophils surrounding and infiltrating the wall of the blood vessel, fibrin deposition in the walls of the blood vessels and loss of the endothelial cells which confirmed the diagnosis of the LCV (fig. 2). Indomethacin was discontinued on day 14 and a subsequent improvement and complete resolution of the rash was noted within a week. Additional workup including ANA, RF, ANCA antibodies, complement levels, HIV antibodies and hepatitis B and C serology was within normal limits. Subsequently transthoracic echocardiogram was negative for any evidence of infective endocarditis. Patient had a complicated course of stay but responded well to intravenous antibiotics and was discharged in a stable condition.\n\nDiscussion\nLCV is a small-vessel hypersensitivity vasculitis with a reported incidence rate of about 30 cases per million people per year [1]. LCV can occur at any age group and is thought to effect men and women in equal numbers but few studies suggest male predominance [2]. Multiple etiologic factors including drugs, infections, foods, autoimmune diseases, collagen vascular diseases and malignancies have been suggested to associate with LCV [3, 4, 5, 6]. Though exact pathogenic mechanism of LCV remains to be elucidated, circulating immune complexes are believed to be involved in the pathogenesis of LCV [7].\n\nLCV usually presents as a palpable purpuric rash associated with burning sensation or pain and is most commonly observed on the legs, but any surface may be involved. Rarely the presentation may include completely asymptomatic lesions, nodular lesions or ulcerations. Thorough history of recent infections, change in medications or food etc. along with a detailed physical examination to find etiologic trigger or an associated disorder should be performed. Identification and avoidance or treatment of the etiologic trigger may prevent recurrent episodes of LCV.\n\nDiagnosis of LCV is confirmed on histological examination of the sample obtained on biopsy of the affected area. Histologically, LCV demonstrates perivascular and vascular leukocytic infiltrates along with fibrinoid necrosis. Etiological triggers are usually identified with the temporal association.\n\nIn our patient, indomethacin was started at the day of presentation; one dose of intravenous vancomycin was given on day 5 followed by daily intravenous cefazolin; Ceretec-tagged WBC scan was done one day prior to onset of LCV rash. Considering patient had history of recurrent MSSA bacteremia and had been on vancomycin and cefazolin multiple times, chances that cefazolin or vancomycin was involved in the pathogenesis of LCV were less likely. Furthermore cefazolin was continued throughout the course of the treatment and rash resolved while patient was still on cefazolin. Since indomethacin was the only new medicine to which the patient was recently exposed to, it was thought to be the etiologic trigger for LCV in this case. Further, the LCV rash improved after the discontinuation of the indomethacin confirming our hypothesis. Gamboa et al. [8] described a case of a 22-year-old male who had three episodes of recurrent LCV which coincided with the administration of indomethacin on each occasion. Our patient had onset of LCV rash on the following day after the Ceretec-tagged WBC scan which suggests that technetium-99m might have acted as a trigger for LCV. Acute allergic rash secondary to Tc-99m have been reported to occur in less than 1% of patients but no association for LCV has been described so far in literature and our case may represent the first case of possible Tc-99m-induced LCV.\n\nTreatment of LCV is identification and removal or treatment of the offending etiologic factor, and elevation of the leg and use of compression stocking if LCV rash involves dependent areas. Colchicine [9] and dapsone [10] have been shown to be useful in cases of LCV. Urticarial lesions can be managed with the antihistaminic medicines. Systemic steroids and other immunosuppressive agents [11] may be used in cases of deep organ involvement.\n\nIn conclusion, identification of potential etiological triggers in cases of LCV can prevent significant morbidity related with recurrences. Multiple NSAIDs including indomethacin can act as a potential trigger for LCV. Tc-99m may have a role as an etiologic trigger for LCV.\n\nDisclosure Statement\nThere is no conflict of interest.\n\nFig. 1 LCV rash on various parts of the body. a, b Rash affecting hands and wrists bilaterally. c–e Rash involving both lower extremities: d shows rash effecting right buttock, c and e show rash effecting bilateral popliteal and calf regions. f Facial involvement.\n\nFig. 2 a Inflammatory cells surrounding blood vessels in dermis (4×). b, c (10×), d (20×) Neutrophils surround and infiltrate blood vessel wall, d also shows loss of endothelial cells. e, f Small blood vessels with fibrin deposition in wall and neutrophils (10× and 40×, respectively); f also shows loss of endothelial cells consistent with vasculitis.\n==== Refs\nReferences\n1 Garcia-Porrua C Gonzalez-Gay MA Comparative clinical and epidemiological study of hypersensitivity vasculitis versus Henoch-Schönlein purpura in adults Semin Arthritis Rheum 1999 28 404 412 10406408 \n2 Gonzalez-Gay MA Garcia-Porrua C Systemic vasculitis in adults in northwestern Spain, 1988–1997. Clinical and epidemiologic aspects Medicine 1999 78 292 308 10499071 \n3 Sams WM Hypersensitivity angiitis J Invest Dermatol 1989 93 78S 81S 2666526 \n4 Zurada JM Ward KM Grossman ME Henoch-Schonlein purpura associated with malignancy in adults J Am Acad Dermatol 2006 55 S65 S70 17052537 \n5 Solans-Laque R Bosch-Gil JA Perez-Bocanegra C Selva-O Callaghan A Simeon-Aznar CP Vilardell-Tarres M Paraneoplastic vasculitis in patients with solid tumors: report of 15 cases J Rheumatol 2008 35 294 304 18085729 \n6 Fain O Hamidou M Cacoub P Godeau B Wechsler B Paries J Vasculitides associated with malignancies: analysis of sixty patients Arthritis Rheum 2007 57 1473 1480 18050165 \n7 Mackel SE Jordon RE Leukocytoclastic vasculitis. A cutaneous expression of immune complex disease Arch Dermatol 1982 118 296 301 6211146 \n8 Gamboa PM Tabar AI Wong E Indomethacin induced vasculitis Allergol Immunopathol 1988 16 53 55 \n9 Sais G Vidaller A Jucgla A Gallardo F Peyri J Colchicine in the treatment of cutaneous leukocytoclastic vasculitis. Results of a prospective, randomized controlled trial Arch Dermatol 1995 131 1399 1402 7492128 \n10 Wolf R Tuzun B Tuzun Y Dapsone: unapproved uses or indications Clin Dermatol 2000 18 37 53 10701085 \n11 Keogh KA Ytterberg SR Fervenza FC Carlson KA Schroeder DR Specks U Rituximab for refractory Wegener's granulomatosis: report of a prospective, open-label pilot trial Am J Respir Crit Care Med 2006 173 180 187 16224107\n\n",
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"issue": "5(1)",
"journal": "Case reports in dermatology",
"keywords": "Ceretec scan; Indomethacin; Leukocytoclastic vasculitis",
"medline_ta": "Case Rep Dermatol",
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"title": "Indomethacin-related leukocytoclastic vasculitis: a case report and review of literature.",
"title_normalized": "indomethacin related leukocytoclastic vasculitis a case report and review of literature"
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"abstract": "Drug-induced liver injury (DILI) presents as a broad spectrum of adverse drug reactions which can range from a mild elevation in liver enzymes to fulminant liver failure. The primary goal is to identify DILI early when the patient's liver enzymes are elevated and to discontinue the offending agent as soon as possible to prevent further injury. Herbal, dietary supplements and anabolic steroids represent a significant component of the drugs thought to cause DILI in the United States. Unlike all other drugs known to cause DILI, these drugs fall into a category of injury that is neither intrinsic nor idiosyncratic due to overlapping characteristics between the two. Here, we present a case of the off-label use of androgenic anabolic steroids inducing liver injury. A combination of clinical, laboratory, and histologic workup eventually led to the diagnosis of DILI. This can be a diagnostic challenge for practitioners. The American College of Gastroenterology (ACG) published guidelines to aid the clinician in diagnosing DILI. Proving that an episode of liver injury is caused by a drug is difficult in many cases as it requires the exclusion of alternative etiologies. Some of the variables include temporal association, clinical-biochemical features, type of injury (hepatocellular and/or cholestatic), extrahepatic features, and the likelihood that a given agent is the culprit based on its known manifestations with prior cases. This case illustrates the utility of the diagnostic tools used for DILI as recommended by the ACG, along with a supplemental histopathologic diagnosis.",
"affiliations": "Department of Graduate Medical Education, NSU-COM/Palmetto General Hospital, Hialeah, Fla., USA.;Department of Graduate Medical Education, NSU-COM/Palmetto General Hospital, Hialeah, Fla., USA.;Gastroenterology Department, NSU-COM/Larkin Community Hospital, South Miami, Fla., USA.;Gastroenterology Department, NSU-COM/Larkin Community Hospital, South Miami, Fla., USA.;Department of Pathology, Palmetto General Hospital, Hialeah, Fla., USA.;Department of Graduate Medical Education, NSU-COM/Palmetto General Hospital, Hialeah, Fla., USA.",
"authors": "Cabb|Elena|E|;Baltar|Shanna|S|;Powers|David Wes|DW|;Mohan|Karthik|K|;Martinez|Antonio|A|;Pitts|Eric|E|",
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"fulltext": "\n==== Front\nCase Rep GastroenterolCase Rep GastroenterolCRGCase Reports in Gastroenterology1662-0631S. 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 10.1159/000448883crg-0010-0499Single CaseThe Diagnosis and Manifestations of Liver Injury Secondary to Off-Label Androgenic Anabolic Steroid Use Cabb Elena a*Baltar Shanna aPowers David Wes bMohan Karthik bMartinez Antonio cPitts Eric aaDepartment of Graduate Medical Education, NSU-COM/Palmetto General Hospital, Hialeah, Fla., USAbGastroenterology Department, NSU-COM/Larkin Community Hospital, South Miami, Fla., USAcDepartment of Pathology, Palmetto General Hospital, Hialeah, Fla., USA*Elena Cabb, DO, MPH, 2001 W 68th Street, Suite 202, Hialeah, FL 33016 (USA), E-Mail elenacabb@gmail.comMay-Aug 2016 12 9 2016 12 9 2016 10 2 499 505 20 7 2016 1 8 2016 Copyright © 2016 by S. Karger AG, Basel2016This article is licensed under the Creative Commons Attribution-NonCommercial-4.0 International License (CC BY-NC) (http://www.karger.com/Services/OpenAccessLicense). Usage and distribution for commercial purposes requires written permission.Drug-induced liver injury (DILI) presents as a broad spectrum of adverse drug reactions which can range from a mild elevation in liver enzymes to fulminant liver failure. The primary goal is to identify DILI early when the patient's liver enzymes are elevated and to discontinue the offending agent as soon as possible to prevent further injury. Herbal, dietary supplements and anabolic steroids represent a significant component of the drugs thought to cause DILI in the United States. Unlike all other drugs known to cause DILI, these drugs fall into a category of injury that is neither intrinsic nor idiosyncratic due to overlapping characteristics between the two. Here, we present a case of the off-label use of androgenic anabolic steroids inducing liver injury. A combination of clinical, laboratory, and histologic workup eventually led to the diagnosis of DILI. This can be a diagnostic challenge for practitioners. The American College of Gastroenterology (ACG) published guidelines to aid the clinician in diagnosing DILI. Proving that an episode of liver injury is caused by a drug is difficult in many cases as it requires the exclusion of alternative etiologies. Some of the variables include temporal association, clinical-biochemical features, type of injury (hepatocellular and/or cholestatic), extrahepatic features, and the likelihood that a given agent is the culprit based on its known manifestations with prior cases. This case illustrates the utility of the diagnostic tools used for DILI as recommended by the ACG, along with a supplemental histopathologic diagnosis.\n\nKey Words\nLiver injuryAndrogenic anabolic steroidsHistopathology\n==== Body\nIntroduction\nDrug-induced liver injury (DILI) presents as a broad spectrum of adverse drug reactions which can range from mild elevation in liver enzymes to fulminant liver failure. It is considered the most common cause of death from acute liver failure in the United States [1]. Due to the highly variable clinical spectrum of DILI, it may be difficult to identify and therefore is a diagnosis of exclusion. In 2014, the American College of Gastroenterology (ACG) published guidelines to aid the clinician in diagnosing and treating DILI. The primary goal is to identify DILI early when the patient's liver enzymes are elevated and to discontinue the offending agent as soon as possible to prevent further injury. Though challenging, early identification of DILI is vital to prevent higher morbidity and mortality associated with delayed diagnosis.\n\nIt is important to note that DILI is characterized into intrinsic (toxic) and idiosyncratic types, with the latter being much rarer [2]. This is perhaps due to the higher incidence of acetaminophen-induced intrinsic reactions compared to drugs known to cause idiosyncratic reactions (i.e., antibiotics and antiepileptics) [2, 3]. In the past, viral hepatitis was the main culprit in acute liver failure, though recent prospective studies indicate that drugs are now the most common cause [4]. Further adding to the complication of diagnosis is the fact that liver injury seen with viral hepatitis may resemble the morphology of idiosyncratic DILI [5].\n\nHerbal, dietary supplements and anabolic steroids represent a significant component of the drugs thought to cause DILI in the United States [6]. However, unlike all other drug categories known to cause DILI, these drugs fall into a category of injury that is neither intrinsic nor idiosyncratic due to overlapping characteristics between the two. Here, we present a case of the off-label use of androgenic anabolic steroids (AAS) inducing liver injury.\n\nCase Report\nA 45-year-old male with no significant past medical history presented to the hospital complaining of progressive pruritus, jaundice, and scleral icterus for the past 2 weeks. His associated signs included pale stools and dark urine. He denied change in activity, recent travel, fever, malaise, upper respiratory symptoms, or sick contacts. He had no anorexia, weight loss, abdominal pain, nausea, or vomiting. The patient denied tobacco, ethanol, or illicit drug use. However, he admitted to having taken steroids for the past 3 months (Anavar 50 mg daily and testosterone injections once weekly) but discontinued after the onset of symptoms.\n\nOn presentation, the patient was normotensive, afebrile, and in no acute distress. His physical exam was remarkable for scleral icterus, a minimally tender right upper quadrant, and slight jaundice. He had no signs of a rash, hepatosplenomegaly, tremors, edema, ascites, spider angioma, jugular venous distension, or neurological deficits. Murphy's or Courvoisier sign were not appreciated.\n\nLaboratory studies revealed alkaline phosphatase 262 IU/l, total bilirubin 4.95 mg/dl, direct bilirubin 3.8 mg/dl, indirect bilirubin 1.2 mg/dl, alanine aminotransferase 162 IU/l, aspartate aminotransferase 72 IU/l, and lipase 160 IU/l. A computed tomography (CT) of the abdomen and pelvis with contrast showed a slight prominence of the pancreatic head, which may have been normal for the patient's age. There were no definite masses or biliary dilatation. There was a questionable small 1- to 2-mm gallstone versus a tiny gallbladder polyp on ultrasonography of the abdomen, and the liver appeared unremarkable in this study. A magnetic resonance cholangiopancreatography was performed to better assess the biliary tree and pancreas. It also revealed a normal liver without masses, along with an unremarkable spleen, adrenal glands, and kidneys. In concurrence with the CT of the abdomen, a mild prominence of the head of the pancreas was seen without evidence of a mass. The intra- and extrahepatic biliary tree was without evidence of choledocolithiasis, and pancreatic ducts were unremarkable. No definite filling defects of the gallbladder were visualized.\n\nEsophagogastroduodenoscopy revealed a small clean-based ulcer in the gastric body and a normal duodenum. Endoscopic ultrasound was then performed showing a homogenous left lobe of the liver and mild fatty infiltration without mass lesions. The body of the pancreas was visualized and normal in appearance, the pancreatic duct was nondilated, and the pancreatic body and tail were without masses or cysts. The common bile duct was without dilatation, and there was no evidence of choledocholithiasis. The gallbladder was mildly contracted with a 3-mm gallstone.\n\nHistological findings from the ultrasound-guided nontargeted liver biopsy revealed mild portal chronic inflammation with few eosinophils, a few early ill-defined portal granulomas, centrilobular hepatocyte dropout (fig. 3) with scattered councilman bodies, and mild pericentral vein cholestasis (fig. 2).\n\nThroughout the hospital course, the patient's laboratory studies remained stable with slight undulation in total bilirubin. Serology testing for acute Epstein-Barr virus and cytomegalovirus infection, acute viral hepatitis, HIV, herpes simplex virus, various autoimmune diseases, and tumor markers (CEA, CA 19-9, AFP) was negative. The patient was subsequently discharged home and directed to follow-up with the gastroenterologist as an outpatient. He had two follow-up visits where a complete metabolic panel was repeated. The first visit, 4 days after hospital discharge, showed worsening laboratory values, although the patient's overall history and physical examination expressed clinical improvement: alkaline phosphatase 286 IU/l, total bilirubin 6.4 mg/dl, alanine aminotransferase 67 IU/l, and aspartate aminotransferase 46 IU/l. The second visit, 12 days after hospital discharge, showed improving laboratory values along with the patient's overall history and physical examination, expressing continued clinical improvement: alkaline phosphatase 259 IU/l, total bilirubin 3.0 mg/dl, alanine aminotransferase 66 IU/l, and aspartate aminotransferase 52 IU/l. On last contact with the patient, he reported complete resolution of signs and symptoms, and his liver function tests continued to improve.\n\nDiscussion\nA challenge often faced by physicians suspecting DILI is that it is a diagnosis of exclusion. Guidelines from the ACG recommend a stepwise approach. In this case, the patient presented with overt signs of liver injury. Upon reviewing the patient's detailed history, it was discovered that while he was not taking any prescribed medications, he was ingesting 17-alpha alkylated androgen compounds daily, along with injectable testosterone weekly for 3 months. There was a clinical suspicion for DILI from the history and presentation alone.\n\nThis case illustrates the need for additional tools to aid in the accurate diagnosis of DILI. The algorithm recommended by ACG (fig 1) begins with obtaining a thorough history. Secondly, the R value must be calculated. Based on his liver function tests, his calculated R value <2 revealed a dominant cholestatic pattern, which coincides with the histopathologic findings discussed below. Alternatively, clinicians may rely on the Roussel Uclaf Causality Assessment Method (RUCAM). This is a tool that is widely used to determine the causality attribution for suspected DILI. However, in comparison to the gold standard of expert consensus, RUCAM has low retest reliability. Though the patient's RUCAM score was 7, indicating a highly probable DILI, additional tools are needed to aid an accurate diagnosis, as RUCAM alone is suboptimal in comparison to the gold standard set in place by the Drug-Induced Liver Injury Network (DILIN) [1]. This patient had moderately severe DILI as evident by his clinical jaundice and hyperbilirubinemia [7]. For this case, the ACG algorithm (fig 1) was followed to diagnose DILI, which was further supported through liver biopsy findings.\n\nAAS, particularly the 17-alpha alkylated compounds (methyltestosterone, methandrostenolone, oxymetholone, oxandrolone, and stanozolol) have the potential to produce a wide range of hepatic disturbances [8]. The DILIN published a 2014 study in Hepatology demonstrating the most common histopathologic patterns of injury as: inflammation, cholestasis or both, and emphasized the necessity of histological diagnosis for suspected DILI [9]. This case had a pattern of cholestasis and portal inflammation on histology (fig 2, 3). Newer literature, however, has AAS categorized among the class of agents that produce a primary morphologic change of cholestasis without portal inflammation [5]. The modified hepatic activity index is an assessment designed to grade the severity of hepatic inflammation and ultimately predict patient prognosis [8]. The patient's mild portal inflammation was associated with a modified hepatic activity index score of 1, which has a more favorable prognosis.\n\nOral 17-alpha alkylated androgens are a synthetic derivative of testosterone designed to produce increasing anabolic and decreasing androgenic effects while resisting liver degradation. These 17-alpha alkylated compounds have been linked to a higher incidence of hepatotoxicity [10]. Oxandrolone, the compound used by the patient in this particular case report, is FDA approved for the treatment of bone pain associated with osteoporosis, muscle wasting syndromes, and counteracting catabolism associated with long-term corticosteroid use [11]. Oxandrolone is now being advertised on several bodybuilding websites, some of which are recommending doses at 60 mg/day for optimal results. The patient in this case report had been taking 50 mg/day for 3 months prior to experiencing symptoms of acute liver injury.\n\nProving that an episode of liver injury is caused by a drug is difficult in many cases as it requires the elimination of alternative etiologies. DILI is nearly always a presumptive diagnosis, and many other disorders produce a similar clinicopathologic picture. Thus, causality may be difficult to establish and requires several, separate supportive assessment variables in order to lead to a high level of certainty. Some of the variables include temporal association (time of onset, time to resolution), clinical-biochemical features, type of injury (hepatocellular and/or cholestatic), extrahepatic features, the likelihood that a given agent is the culprit based on its known manifestations with prior cases, and exclusion of other potential causes. This case illustrates the utility of the diagnostic tools used for DILI as recommended by the ACG, along with a supplemental histopathologic diagnosis. With the rise in off-label use of prescription medications, it is important to use guidelines to aid in the diagnosis of DILI.\n\nStatement of Ethics\nApproval from the local Ethics Committee was not required for this case report. Informed consent was obtained from the patient for publication of this case report.\n\nDisclosure Statement\nAll authors have no conflicts of interest to disclose.\n\nFig. 1 An algorithm to evaluate suspected idiosyncratic DILI. The R value cutoff numbers of 2 and 5 only serve as a guideline. Tests ordered must be based on the overall clinical picture, including risk factors for competing diagnosis [e.g., recent travel to hepatitis E virus (HEV) endemic area], associated symptoms (e.g., abdominal pain, fever), and timing of laboratory tests (i.e., the R value may change as the DILI evolves) [1]. ALT = Alanine aminotransferase; Alk P = alkaline phosphatase; CMV = cytomegalovirus; EBV = Epstein-Barr virus; HCV = hepatitis C virus; HSV = herpes simplex virus; MR = magnetic resonance; ULN = upper limit of normal.\n\nFig. 2 Centrizonal cholestasis. Red blood cells within the central vein (top left). Bile (olive green) is seen occluding bile canaliculi (white).\n\nFig. 3 Focus on lobular injury (spotty necrosis). Dying hepatocyte surrounded by inflammatory cells comprised of lymphocytes and histiocytes.\n==== Refs\nReferences\n1 Chalasani NP Hayashi PH Bonkovsky HL Navarro VJ Lee WM Fontana RJ ACG Clinical Guideline: the diagnosis and management of idiosyncratic drug-induced liver injury Am J Gastroenterol 2014 109 950 966 24935270 \n2 Kaplowitz N Idiosyncratic drug hepatotoxicity Nat Rev Drug Discov 2005 4 489 498 15931258 \n3 Maddur H Chalasani N Idiosyncratic drug-induced liver injury: a clinical update Curr Gastroenterol Rep 2011 13 65 71 21049293 \n4 Khashab M Tector AJ Kwo PY Epidemiology of acute liver failure Curr Gastroenterol Rep 2007 9 66 73 17335680 \n5 Dienstag JL Isselbacher KJ Kasper DL Braunwald E Fauci A Hauser S Longo D Jameson JL Toxic and drug-induced hepatitis Harrison's Principles of Internal Medicine 2015 ed 19 New York McGraw-Hill Professional chapt 296 \n6 Chalasani N Fontanta FJ Bonkovsky HL Watkins PB Davern T Serrano J Yang H Rochon J Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States Gastroenterology 2008 135 1924 1934 18955056 \n7 United States National Library of Medicine and the National Institute of Diabetes and Digestive and Kidney Diseases Roussel Uclaf Causality Assessment Method (RUCAM) in drug-induced liver injury United States National Library of Medicine Website http://www.livertox.nlm.nih.gov/ (retrieved June 20, 2016).\n8 Ishak K Baptista A Bianchi L Histological grading and staging of chronic hepatitis J Hepatol 1995 22 696 699 7560864 \n9 Kleiner DE Chalasani NP Lee WM Fontana RJ Hepatic histological findings in suspected drug-induced liver injury: systematic evaluation and clinical associations Hepatology 2014 59 661 670 24037963 \n10 Sánchez-Osorio M Duarte-Rojo A Martínez-Benítez B Torre A Uribe M Anabolic-androgenic steroids and liver injury Liver Int 2008 28 278 282 17900246 \n11 Oxandrolone tablets USP (package insert) 2004 Hunt Valley Pharmaceuticals International\n\n",
"fulltext_license": "CC BY-NC",
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"issue": "10(2)",
"journal": "Case reports in gastroenterology",
"keywords": "Androgenic anabolic steroids; Histopathology; Liver injury",
"medline_ta": "Case Rep Gastroenterol",
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"nlm_unique_id": "101474819",
"other_id": null,
"pages": "499-505",
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"pmid": "27721739",
"pubdate": "2016",
"publication_types": "D002363:Case Reports",
"references": "24037963;7560864;17335680;18955056;17900246;21049293;24935270;15931258",
"title": "The Diagnosis and Manifestations of Liver Injury Secondary to Off-Label Androgenic Anabolic Steroid Use.",
"title_normalized": "the diagnosis and manifestations of liver injury secondary to off label androgenic anabolic steroid use"
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"abstract": "OBJECTIVE\nCan treatment of the symptoms of uncomplicated urinary tract infection (UTI) with ibuprofen reduce the rate of antibiotic prescriptions without a significant increase in symptoms, recurrences, or complications?\n\n\nMETHODS\nWomen aged 18-65 with typical symptoms of UTI and without risk factors or complications were recruited in 42 German general practices and randomly assigned to treatment with a single dose of fosfomycin 3 g (n=246; 243 analysed) or ibuprofen 3 × 400 mg (n=248; 241 analysed) for three days (and the respective placebo dummies in both groups). In both groups additional antibiotic treatment was subsequently prescribed as necessary for persistent, worsening, or recurrent symptoms. The primary endpoints were the number of all courses of antibiotic treatment on days 0-28 (for UTI or other conditions) and burden of symptoms on days 0-7. The symptom score included dysuria, frequency/urgency, and low abdominal pain.\nThe 248 women in the ibuprofen group received significantly fewer course of antibiotics, had a significantly higher total burden of symptoms, and more had pyelonephritis. Four serious adverse events occurred that lead to hospital referrals; one of these was potentially related to the trial drug. Results have to be interpreted carefully as they might apply to women with mild to moderate symptoms rather than to all those with an uncomplicated UTI.\n\n\nCONCLUSIONS\nTwo thirds of women with uncomplicated UTI treated symptomatically with ibuprofen recovered without any antibiotics. Initial symptomatic treatment is a possible approach to be discussed with women willing to avoid immediate antibiotics and to accept a somewhat higher burden of symptoms.\nGerman Federal Ministry of Education and Research (BMBF) No 01KG1105. Patient level data are available from the corresponding author. Patient consent was not obtained but the data are anonymised and risk of identification is low.Trial registration No ClinicalTrialGov Identifier NCT01488955.",
"affiliations": "Department of General Practice, University Medical Center Göttingen, Humboldtallee 38, 37073 Göttingen, Germany igagyor@gwdg.de.;Institute of General Practice, Hannover Medical School, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany.;Department of Medicine, Division of General Practice, University Medical Centre, Elsässerstrasse 2m, 79110 Freiburg, Germany.;Institute for Public Health and Nursing Research, Department for Health Services Research, University of Bremen, Grazer Strasse 4, 28359 Bremen, Germany.;Department of Medical Biometry and Epidemiology, University Medical Centre Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany.;Department of General Practice, University Medical Center Göttingen, Humboldtallee 38, 37073 Göttingen, Germany.",
"authors": "Gágyor|Ildikó|I|;Bleidorn|Jutta|J|;Kochen|Michael M|MM|;Schmiemann|Guido|G|;Wegscheider|Karl|K|;Hummers-Pradier|Eva|E|",
"chemical_list": "D000900:Anti-Bacterial Agents; D000894:Anti-Inflammatory Agents, Non-Steroidal; D005578:Fosfomycin; D007052:Ibuprofen",
"country": "England",
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"doi": "10.1136/bmj.h6544",
"fulltext": "\n==== Front\nBMJBMJbmjThe BMJ0959-81381756-1833BMJ Publishing Group Ltd. 26698878gagi02765110.1136/bmj.h6544ResearchIbuprofen versus fosfomycin for uncomplicated urinary tract infection in women: randomised controlled trial Gágyor Ildikó senior researcher in primary care1Bleidorn Jutta senior researcher in primary care2Kochen Michael M senior investigator and emeritus professor of primary care3Schmiemann Guido senior researcher in primary care and epidemiology4Wegscheider Karl trial statistician and professor of medical biometry and epidemiology5Hummers-Pradier Eva senior investigator and professor of primary care11 Department of General Practice, University Medical Center Göttingen, Humboldtallee 38, 37073 Göttingen, Germany2 Institute of General Practice, Hannover Medical School, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany3 Department of Medicine, Division of General Practice, University Medical Centre, Elsässerstrasse 2m, 79110 Freiburg, Germany4 Institute for Public Health and Nursing Research, Department for Health Services Research, University of Bremen, Grazer Strasse 4, 28359 Bremen, Germany5 Department of Medical Biometry and Epidemiology, University Medical Centre Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, GermanyCorrespondence to: I Gágyor igagyor@gwdg.de2015 23 12 2015 351 h654429 10 2015 Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions2015BMJThis is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 3.0) 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. See: http://creativecommons.org/licenses/by-nc/3.0/.Study question Can treatment of the symptoms of uncomplicated urinary tract infection (UTI) with ibuprofen reduce the rate of antibiotic prescriptions without a significant increase in symptoms, recurrences, or complications?\n\nMethods Women aged 18-65 with typical symptoms of UTI and without risk factors or complications were recruited in 42 German general practices and randomly assigned to treatment with a single dose of fosfomycin 3 g (n=246; 243 analysed) or ibuprofen 3×400 mg (n=248; 241 analysed) for three days (and the respective placebo dummies in both groups). In both groups additional antibiotic treatment was subsequently prescribed as necessary for persistent, worsening, or recurrent symptoms. The primary endpoints were the number of all courses of antibiotic treatment on days 0-28 (for UTI or other conditions) and burden of symptoms on days 0-7. The symptom score included dysuria, frequency/urgency, and low abdominal pain.\n\nStudy answer and limitations The 248 women in the ibuprofen group received significantly fewer course of antibiotics, had a significantly higher total burden of symptoms, and more had pyelonephritis. Four serious adverse events occurred that lead to hospital referrals; one of these was potentially related to the trial drug. Results have to be interpreted carefully as they might apply to women with mild to moderate symptoms rather than to all those with an uncomplicated UTI.\n\nWhat this paper adds Two thirds of women with uncomplicated UTI treated symptomatically with ibuprofen recovered without any antibiotics. Initial symptomatic treatment is a possible approach to be discussed with women willing to avoid immediate antibiotics and to accept a somewhat higher burden of symptoms.\n\nFunding, competing interests, data sharing German Federal Ministry of Education and Research (BMBF) No 01KG1105. Patient level data are available from the corresponding author. Patient consent was not obtained but the data are anonymised and risk of identification is low.\n\nTrial registration No ClinicalTrialGov Identifier NCT01488955.\n==== Body\nIntroduction\nUncomplicated urinary tract infections are common in many clinical settings but especially in general practice, where they account for 25% of antibiotic prescriptions.1\n2 Prescription of antibiotics when many cases are self limiting contributes to increased resistance rates, posing a serious health threat.3\n4 Disease burden and treatment costs have to be considered as well.5Escherichia coli, the main causative agent, is increasingly resistant to current antibiotics,6 and the number of new antibiotics being developed is declining. Many current primary care guidelines, however, still recommend antibiotics as a first line treatment,7\n8 at least when standard measures do not lead to symptom relief. As urinary tract infection is often self limiting,9\n10\n11 and less antibiotic prescribing lowers levels of antibiotic resistance,12\n13\n14\n15 efforts should be made to reduce rates of prescription.\n\nEarlier trials assessed placebo compared with antibiotic treatment for urinary tract infection as well as delayed prescription of antibiotics.9\n11\n16 These trials reported a delayed resolution of symptoms and prolonged time to bacterial clearance but no serious complications. From qualitative studies and surveys, we know that many affected women are aware of the potential disadvantages of antibiotics and might agree to avoid or postpone such treatment.17\n18\n19\n\nIn a pilot study we compared symptomatic (ibuprofen) with antibiotic treatment (ciprofloxacin) in 79 women with uncomplicated urinary tract infection. Although this study was inadequately powered for a definitive result, it showed that ibuprofen was not inferior for symptom resolution, with 24/36 women recovering without antibiotic treatment.10 In the current study we assessed whether the number of antibiotic prescriptions issued for uncomplicated urinary tract infection can be reduced by symptomatic treatment with ibuprofen, reserving antibiotics for women who return with worsening or recurrent symptoms, and without an increase in symptom burden, recurrences, or complications.\n\nMethods\nTrial design and participants\nICUTI (Immediate versus Conditional treatment of Urinary Tract Infection) was a double blind randomised multicentre comparative effectiveness trial with two parallel active treatment arms (ibuprofen and fosfomycin). The study was conducted according to the Good Clinical Practice Guidelines and the declaration of Helsinki. Safety data were monitored throughout and assessed every six months by the data and safety monitoring board. Serious adverse events were defined as adverse events leading to admission to hospital, disability, permanent damage, or risk of dying or death.\n\nThe detailed study protocol has been published elsewhere.20 From February 2012 to February 2014 practice staff and general practitioners in 42 general practices in northern Germany systematically approached women aged 18-65 with typical symptoms of urinary tract infection for consent. The upper age limit was chosen as until 2013 fosfomycin was approved only for patients up to age 65.\n\nThe study was designed as a pragmatic trial in a general practice setting.21 Inclusion criteria were dysuria and/or frequency/urgency of micturition, with or without lower abdominal pain. The main exclusion criteria were any signs of upper urinary tract infection (fever, loin tenderness); current conditions that could increase the likelihood of potentially complicated courses (such as pregnancy or renal diseases); urinary tract infection within the past two weeks; and urinary catheterisation. We also excluded patients currently treated with non-steroidal drugs for pain or antibiotics and those with a history of gastrointestinal ulcers or severe acute or exacerbated chronic conditions.20 Dipstick tests and urine culture were performed, but the results did not affect eligibility.\n\nParticipating general practitioners were trained in good clinical practice to ensure patient safety and data quality. In addition to electronic database monitoring, an independent monitor (IFS Göttingen) made one on-site monitoring visit per practice and study nurses from the academic teams made further quality management visits to ensure correct documentation. No major or safety problems were detected; some minor corrections, for example completion of missing data, were instigated and problems with screening failures were discussed.\n\nRandomisation and masking\nWe used a computerised random number generator to carry out randomisation in blocks of six in a 3:3 ratio. The trial biometrician was not involved in patient recruitment and data collection. The block-wise randomisation implied stratification by site.\n\nAn independent pharmacy identically prepared and packed drug units, which were labelled with a code number from the random list. Practices were supplied with packs of six blinded drug units. At inclusion, general practitioners assigned the code number from the drug unit to the patient and all patient related data. Practice teams as well as academic study teams were blinded to allocation and had no access to the random list. For emergency unblinding, sealed opaque envelopes for each random number were kept in the investigator site files, and a random list was kept in the trial pharmacy.\n\nProcedures\nThe practice teams were asked to assess all women presenting with symptoms of acute urinary tract infection consecutively for inclusion and exclusion criteria. Eligible women completed a questionnaire to score severity of symptoms and impairment of activity. They also provided a urine sample for dipstick, culture, and pregnancy tests. To assess bias and external validity of study findings, symptom questionnaires were also collected from women who declined to take part in the trial or had exclusion criteria. Participating women were handed out the blinded trial drug package containing either ibuprofen tablets (3×400 mg daily for three days plus 1×1 sachet placebo granules) or fosfomycin-trometamol (1×3 g sachet plus 3×3 placebo tablets for three days), according to randomisation. After inclusion, women were asked to start drug treatment themselves. Drug packages had to be returned and were checked for residual drugs.\n\nWomen were advised to consult their general practitioners again if symptoms persisted or worsened. In this case, antibiotic treatment was initiated at the discretion of the general practitioner on the basis of the results of urine culture from the baseline visit. Participants received an emergency card providing the telephone number of the trial pharmacy in case emergency unblinding was required. Women scored their daily symptoms and activity impairment in a diary. Study nurses collected data on symptoms as well as drug intake and further antibiotic prescriptions by telephone calls on day 1, 3, 5, and 7, or until recovery. On day 28, data on antibiotic prescriptions, adverse events, and recurrent urinary tract infections were also collected. All data were recorded into a web based data entry system.\n\nOne central laboratory in Göttingen performed all urine cultures. The cut off for positive culture was bacterial count >102 cfu/mL. Susceptibility test were performed by disk diffusion according to DIN 58 940 and DIN 58 959 with European Committee on Antimicrobial Susceptibility Testing breakpoints.22\n\nOutcomes\nTwo co-primary endpoints examined both benefits and risks: the total number of courses of antibiotics on days 0-28 (for urinary tract infection or other conditions)2\n23 and burden of symptoms on days 0-7, measured as area under the curve of the sums of daily symptom scores. The symptom score included dysuria, frequency/urgency of micturition, and low abdominal pain, each on a five point scale from 0 (not at all) to 4 (strong/frequent).10 The area under the curve of symptom sum scores has been used before in other trials to measure overall severity and duration of symptoms.24\n25 The trial was to be considered as having a positive outcome if superiority in the first and non-inferiority in the second co-primary endpoint could be proved.\n\nSecondary outcomes were the numbers of severe adverse events, complications (febrile urinary tract infection, pyelonephritis, septic syndrome), all adverse events, relapses (recurrent urinary tract infection after initial resolution of symptoms) up to day 28 and within six and 12 months,7 and women without symptoms at days four and seven (defined as a symptom sum score of 0); symptom load until day four and symptom load with regard to specific symptoms until day seven (specified in the trial protocol as symptom burden until day four, related to each of the three symptoms until day seven 7), assessment of activity impairment on days 1-7, measured with a five item score (range 0-4), referring to the time during which a woman’s work or personal activities had been impaired because of urinary tract infection26; and the number of daily defined doses of antibiotics per patient (the latter will be reported in a separate paper). As the wording in the trial registry was not as specific as in the protocol, we use in this paper terms and definitions for outcomes as given in the trial protocol. To determine whether there were differences within the groups based on the results of the urine cultures, we performed a post hoc outcome analysis stratified on the basis of positive or negative results on urine culture. After publication of the protocol but before unblinding the data we decided to split the early follow-up period regarding recurrent urinary tract infections into two periods according to the German urinary tract infection guideline7: early relapse of symptoms (recurrence of symptoms up to day 14, after initial resolution) and recurrence of urinary tract infection after initial resolution from day 15 up to day 28. Rates of recurrent urinary tract infection within the prolonged follow-up at six and 12 months will be reported separately once the follow-up is finished.\n\nStatistical analysis\nThe sample size calculated for both co-primary outcomes was driven by the non-inferiority part of the trial. If we assume a coefficient of variation of 80%, we would require a sample size of 2×210=420 evaluable patients to reach a power of 90% for the proof of non-inferiority in case of equivalence of the two study arms (one sided α=0.025).27 As we assumed a dropout rate of 15%, we needed to randomise 494 women to achieve the sample size of 420 patients in the per protocol population.20\n\nThe primary analysis consisted of two statistical tests as described in the study protocol.20 The first co-primary endpoint—“number of courses of antibiotic treatment”—was tested for superiority of the ibuprofen group with an exact Mann-Whitney rank sum test with a one sided test level of 2.5%. The second co-primary endpoint was tested for non-inferiority of ibuprofen compared with fosfomycin by calculating a two sided 95% confidence interval for the ratio of the symptom burden of the ibuprofen and fosfomycin groups based on a covariance analysis of the log symptom burden with adjustment for baseline log symptom sum score. Non-inferiority was assumed if the total confidence interval was below the non-inferiority margin of 125%. As no standard was available for this kind of study, we followed the suggested margins for bioequivalence studies, which accept levels of 80-120% of the reference as bioequivalent. We analysed the first co-primary endpoint in the intention to treat population, which consisted of all randomised patients with at least one report on use or non-use of antibiotics. The second co-primary endpoint was analysed in the per protocol population, which consisted of all intention to treat patients with complete seven day follow-up symptom score and subsequently in the intention to treat population. In this population, we had to impute a small number of missing values to calculate the area under the curves. For this purpose we applied an expectation-maximisation algorithm to the available score data to estimate means and covariances based on a normality assumption and chose imputations that maximise the likelihood. As the differences to the analysis of the per protocol population were small, we have presented both endpoints in the same intention to treat population for direct comparability.\n\nThe secondary endpoints were analysed with exact Mann-Whitney U rank sum tests and χ2 tests at two sided α=0.05 without adjustment for multiplicity or analogous to the second co-primary endpoint.\n\nPatient involvement\nNo patients were involved in designing the study or explicitly setting outcome measures; however, outcomes were chosen to reflect daily practice and patient preferences described in earlier studies.18\n19 Preliminary results were disseminated to study participants through their general practitioners. A lay information flyer with final results will be sent to all participating practices and can be used to inform patients with urinary tract infections.\n\nResults\nRandomisation and baseline characteristics\nA total of 1184 women with suspected urinary tract infection were screened, 779 were considered eligible, and 494 were randomly assigned to the treatment or control groups (fig 1). On average, 12 women per practice were included in 42 practices.Ten women with exclusion criteria had been included incorrectly by general practitioners and were therefore excluded immediately after recruitment by a masked researcher. The intention to treat population comprised 241 women in the ibuprofen group and 243 in the fosfomycin group. Three women, in whom exclusion criteria were detected later after inclusion, remained in this population. Two women in the ibuprofen group and seven in the fosfomycin group refused further participation and withdrew from the trial.\n\nFig 1 \nFlow of participants through trial of ibuprofen versus fosfomycin for women with urinary tract infection\n\nThere were no major differences in baseline characteristics between both groups (table 1). Minor differences concerned duration of symptoms (110 (46%) women in the fosfomycin group versus 87 (36%) in the ibuprofen group had symptoms for more than two days) and recurrent urinary tract infections being reported more often by women assigned to the fosfomycin group (54 (23%) versus 42 (17%)).\n\nTable 1 Baseline characteristics of women with uncomplicated urinary tract infection randomised to ibuprofen or fosfomycin. Figures are numbers of women (percentage) unless stated otherwise\n\n\tIbuprofen (n=241)\tFosfomycin (n=243)\t\nMean (SD) age (years)\t37.3 (14.6)\t37.3 (14.3)\t\nMedian (IQR) age (years)\t36.0 (24.0-50.0)\t34.0 (24.0-49.0)\t\nDuration of symptoms at inclusion (days)*:\t\n <1\t50 (21)\t49 (21)\t\n 1-2\t104 (43)\t80 (34)\t\n >2-7\t66 (27)\t82 (34)\t\n >7\t21 (9)\t28 (12)\t\nSymptoms at inclusion*:\t\n Dysuria\t224 (93)\t218 (91)\t\n Frequency/urgency\t231 (96)\t232 (97)\t\n Low abdominal pain\t172 (71)\t169 (71)\t\nMean (SD) symptom severity sum score†\t6.0 (2.2)\t6.1 (2.5)\t\nMedian (IQR) symptom severity sum score†\t6.0 (4.0-8.0)\t6.0 (4.0-8.0)\t\nMean (SD) dysuria score‡\t2.3 (1.0)\t2.3 (1.1)\t\nMedian (IQR) dysuria score‡\t3.0 (2.0-3.0)\t2.0 (1.0-3.0)\t\nMean (SD) frequency/urgency score‡\t2.4 (1.1)\t2.4 (1.1)\t\nMedian (IQR) frequency/urgency score‡\t2.0 (2.0-3.0)\t2.0 (2.0-3.0)\t\nMean (SD) low abdominal pain score‡\t1.3 (1.1)\t1.4 (1.1)\t\nMedian (IQR) low abdominal pain score‡\t1.0 (0.0-2.0)\t1.0 (0.0-2.0)\t\nRecurrent UTI§\t42 (17)\t54 (23)\t\nMean (SD) activity impairment score¶\t9.6 (5)\t8.9 (6)\t\nDipstick results**:\t\n Leukocytes positive\t205 (85)\t200 (83)\t\n Erythrocytes positive\t180 (75)\t189 (78)\t\n Nitrite positive\t53 (22)\t46 (19)\t\nCulture results:\t\n Urine culture positive††\t179/237 (76)\t181/234 (77)\t\n E coli\t143/179 (80)\t142/181 (79)\t\n Proteus mirabilis\t12/179 (7)\t8/181 (4)\t\n Staphylococcus saprophyticus\t8/179 (5)\t8/181 (4)\t\n Enterococcus faecalis\t3/179 (2)\t8/181 (4)\t\n Streptococcus agalactiae\t0/179 (0)\t2/181 (1)\t\n Klebsiella pneumoniae\t3/179 (2)\t1/181 (1)\t\n Other uropathogens\t10/179 (6)\t9/181 (5)\t\n Not specified\t0/179 (0)\t3/181 (2)\t\nSusceptibility to fosfomycin (rate):\t\n All uropathogens\t168/181 (93)\t162/177 (92)\t\n E coli\t142/143 (99)\t142/142 (100)\t\nSD=standard deviation; IQR=interquartile range; UTI=urinary tract infection.\n\n*n=239 in fosfomycin group.\n\n†Range 0-12. Sum of daily symptom sum scores of dysuria, frequency/urgency of micturition, and low abdominal pain, each on a five point scale from 0 (not at all) to 4 (very strong/frequent).\n\n‡Range 0-4\n\n§UTI within past year.\n\n¶Activity impairment assessment, sum score range 0-20. \n\n**n=242 in fosfomycin group.\n\n††Bacterial count >102 cfu/mL.\n\nPrimary outcomes\nThe number of courses of antibiotic treatment within 28 days was significantly lower in the ibuprofen group. The number of all courses in the fosfomycin group was 283 (243 as part of the study plus 34 courses prescribed additionally for urinary tract infection and six courses prescribed for other reasons, such as bronchitis and otitis media) compared with 94 in the ibuprofen group (81 for urinary tract infection and 13 for other reasons). This corresponds to an incidence rate reduction of 66.5% (95% confidence interval 58.8% to 74.4%; P<0.001), showing a substantial reduction of antibiotics use. Figure 2 shows the distribution of the individual number of courses of antibiotics by randomisation group. Although significantly more women received prescriptions of antibiotics in the follow-up period (21.2%), the total number receiving antibiotics was lower in the ibuprofen group by 64.7% (P<0.001, table 2).\n\nFig 2 \nTotal number of antibiotic prescriptions by randomisation group on days 0-28 (range 0-2, intention to treat population)\n\nTable 2 Summary of primary and key secondary outcomes in women with uncomplicated urinary tract infection randomised to ibuprofen or fosfomycin. Figures are numbers (percentage) of women unless stated otherwise\n\n\tIbuprofen (n=241)\tFosfomycin (n=243)\t% mean difference (95% CI)\tP value\t\nPrimary endpoints\t\nWomen who received antibiotics:\t\n Total\t85 (35)\t243 (100)\t−64.7 (−70.7 to −58.7)\t<0.001\t\n By randomisation\t0 (0)\t243 (100)\t−100\t—\t\n During follow-up (all)*\t85 (35)\t34 (14)\t21.2 (13.8 to 28.7)\t<0.001\t\n During follow-up (for UTI)\t75 (31)\t30 (12)\t18.8 (11.6 to 25.9)\t<0.001\t\nMean (SD) symptom burden day 0-7†\t17.3 (11.0)\t12.1 (8.2)\t5.3 (3.5 to 7.0)\t<0.001\t\nSecondary endpoints\t\nAdverse events in patients:\t\n Patients reporting serious adverse events‡\t4 (2)\t0 (0)\t1.7 (0.0 to 3.3)\t0.06\t\n Serious adverse events probably drug related\t1 (0.4)\t0 (0)\t0.4 (−0.4 to 1.2)\t0.32\t\n Patients reporting adverse events‡\t42 (17)\t57 (24)\t−6.0 (−13.2 to 1.1)\t0.12\t\nRelapses/complications:\t\n All recurrent UTI until day 28\t27 (11)\t34 (14)\t−2.8 (−8.7 to 3.1)\t0.41\t\n Early relapse of symptoms (up to day 14)§\t13 (5)\t7 (3)\t2.5 (−1.0 to 6.1)\t0.18\t\n Recurrence of UTI \n(day 15-28)§\t14 (6)\t27 (11)\t−5.3 (−10.2 to −0.4)\t0.049\t\n Pyelonephritis§\t5 (2)\t1 (0.4)\t1.7 (−0.3 to 3.6)\t0.12\t\n Febrile UTI/ (day 0-7)§\t3 (1)\t0\t1.2 (−0.2 to 2.6)\t0.12\t\n Worsening symptoms (day 0-7)§\t8 (3)\t5 (2)\t1.3 (−1.6 to 4.1)\t0.42\t\nPatients without symptoms day 4§\t91/234 (39)\t129/229 (56)\t−17.4 (−26.4 to −8.5)\t<0.001\t\nPatients without symptoms day 7¶\t163/232 (70)\t186/227 (82)\t−11.7 (−19.4 to −4.0)\t0.004\t\nMean (SD) symptom duration after randomisation (days)\t5.6 (2.2)\t4.6 (2.2)\t0.98 (0.59 to 1.38)\t<0.001\t\nMean (SD) symptom burden day 0-4†\t13.1 (7.1)\t10.1 (5.9)\t3.0 (1.9 to 4.2)\t<0.001\t\nMean (SD) symptom burden with regard to dysuria day 0-7\t6.8 (4.6)\t4.5 (3.6)\t2.3 (1.5 to 3.0)\t<0.001\t\nMean (SD) symptom burden with regard to frequency/urgency day 0-7\t6.5 (4.1)\t4.6 (3.4)\t1.8 (1.1 to 2.5)\t<0.001\t\nMean (SD) symptom burden with regard to low abdominal pain day 0-7\t4.1 (4.3)\t2.9 (3.1)\t1.2 (0.5 to 1.8)\t0.001\t\nMean (SD) activity impairment assessment day 0-7\t30.3 (24.5)\t19.5 (16.7)\t10.8 (7.1 to 14.6)\t<0.001\t\nSD=standard deviation; UTI=urinary tract infection.\n\n*Including antibiotic prescriptions for other reasons—for instance, acute bronchitis, otitis.\n\n†Defined as area under curve (AUC) of daily symptom sum scores day 0-7.\n\n‡As rated by patients.\n\n§As rated by general practitioners.\n\n¶Symptom free is defined as symptom sum score=0.\n\nAs shown in figure 3, the symptom burden sum score decreased in both groups, from six points on day 0 down to less than one point on day seven, on average. Figure 4 shows the corresponding distribution of the symptom burden area under the curve by randomisation group. Table 2 shows the unadjusted mean symptom burden. With an area under the curve ratio of 140% (areaibu/areafos=140.5%, 95% confidence interval 125.4% to 157.3%) calculated by the adjusted analysis of log disease burden, the non-inferiority margin of 125% was significantly exceeded. We can therefore reject the hypothesis of non-inferiority. The reported effects were essentially the same when we restricted analyses to the per protocol population.\n\nFig 3 \nSymptom sum score for dysuria, frequency/urgency, and low abdominal pain on days 0-7by randomisation group (range 0-12, intention to treat population)\n\nFig 4 \nDistribution of area under curve (AUC) of symptom sum scores for dysuria, frequency/urgency, and low abdominal pain on days 0-7 by random group (intention to treat population)\n\nSecondary outcomes\nAll secondary outcomes related to symptoms favoured the fosfomycin group. On days 0-4, the total symptom burden (area under the curve) in the ibuprofen group was significantly higher than in the fosfomycin group. The same results were shown when we considered symptoms individually: for each symptom (dysuria, frequency/urgency, abdominal pain) a higher symptom burden on days 0-7 was seen in the ibuprofen group (table 2).\n\nWith a mean duration of 5.6 days, symptoms lasted about a day longer in the ibuprofen group. On day four, 129 (56%) women in the fosfomycin group versus 91 (39%) in the ibuprofen group were symptom free (P<0.001, table 3). Up to day seven these rates increased to 82% and 70%, respectively (P<0.001, table 3).\n\nTable 3 Patients without symptoms* on day 1-7, intention to treat population of women with uncomplicated urinary tract infection randomised to ibuprofen or fosfomycin. Figures are numbers (percentage) of women unless stated otherwise\n\nDay without symptoms\tIbuprofen (n=241)\tFosfomycin (n=243)\t% mean difference (95% CI)\tP value\t\n1\t12/240 (5)\t21/231 (9)\t−4.1 (−8.7 to 0.5)\t0.10\t\n2\t30/237 (13)\t45/230 (20)\t−6.9 (−13.6 to 0.3)\t0.045\t\n3\t57/237 (24)\t101/230 (44)\t−19.9 (−28.3 to −11.5)\t<0.001\t\n4\t91/234 (39)\t129/229 (56)\t−17.4 (−26.4 to −8.5)\t<0.001\t\n5\t118/234 (50)\t152/229 (66)\t−15.9 (−24.8 to 7.1)\t0.001\t\n6\t133/233 (57)\t178/227 (78)\t−21.3 (−29.6 to −13.0)\t<0.001\t\n7\t163/232 (70)\t186/227 (82)\t−11.7 (−19.4 to −4.0)\t0.004\t\n*Defined as symptom sum score=0.\n\nWomen in the ibuprofen group showed slightly higher scores in impairment of activity—that is, more of their work or regular activities had been impaired by the urinary tract infection (table 4, fig 5). On day seven, 2% of the women overall still felt impaired most or all the time.\n\nTable 4 Assessment of impairment of activity on day 0-7, intention to treat population of women with uncomplicated urinary tract infection randomised to ibuprofen or fosfomycin. Figures are mean (SD) scores\n\nAIA sum score day*\tIbuprofen (n=241)\tFosfomycin (n=243)\t% mean difference (95% CI)\tP value\t\n0\t9.6 (5.4) (n=241)\t8.9 (5.5) (n=238)\t0.6 (−0.3 to 1.6)\t0.20\t\n1\t7.4 (5.7) (n=240)\t6.8 (5.5) (n=231)\t0.6 (−0.4 to 1.6)\t0.24\t\n2\t5.6 (5.4) (n=237)\t3.5 (4.4) (n=230)\t2.1 (1.2 to 3.0)\t<0.001\t\n3\t3.9 (4.8) (n=237)\t1.9 (3.4) (n=230)\t2.0 (1.3 to 2.8)\t<0.001\t\n4\t3.2 (4.8) (n=234)\t1.1 (2.9) (n=229)\t2.1 (1.4 to 2.8)\t<0.001\t\n5\t2.6 (4.7) (n=234)\t0.8 (2.4) (n=229)\t1.8 (1.2 to 2.5)\t<0.001\t\n6\t2.1 (4.4) (n=233)\t0.6 (2.4) (n=227)\t1.5 (0.8 to 2.1)\t<0.001\t\n7\t1.6 (3.5) (n=232)\t0.6 (2.3) (n=227)\t1.0 (0.5 to 1.6)\t<0.001\t\n*Activity impairment assessment (AIA) sum scores for five items day 0-7 (range 0-20).\n\nFig 5 \nSum scores for assessment of activity impairment related to urinary tract infection (5 items, range 0-20, intention to treat population)\n\nSubgroup analysis\nIn women with a positive result on urine culture, an average of 0.49 antibiotic treatment courses per patient was prescribed in the ibuprofen group versus 1.18 per patient in the fosfomycin group, corresponding to a reduction by 58.5% (95% confidence interval 49.8% to 67.0%, P<0.001). In women with a negative result 0.10 antibiotic treatment courses per patient were prescribed in the ibuprofen group versus 1.11 in the fosfomycin group—that is, a reduction by 90.7% (74.3% to 99.9%, P<0.001). Symptom burden in patients with negative urine culture results did not differ significantly, whereas in patients with positive results, the ibuprofen group again showed a higher burden of symptoms (figs 6 and 7). In contrast with the ibuprofen group there was no difference in the symptom burden between those with positive and those with negative results on urine culture in the fosfomycin group (fig 8). Table 5 shows differences between women with positive and negative results on urine culture at baseline.\n\nFig 6 \nSymptom sum score for women with negative results on urine culture (subgroup analysis, n=111, intention to treat population) on days 0-7\n\nFig 7 \nSymptom sum score for women with positive results on urine culture (subgroup analysis, n=360, intention to treat population) on days 0-7\n\nFig 8 \nSymptom sum score for women in fosfomycin group with positive versus negative results on urine culture (subgroup analysis, n=234, intention to treat population) on days 0-7\n\nTable 5 Baseline data from women with proved urinary tract infection (UTI): positive versus negative results on urine culture\n\nCharacteristics\tUTI positive (n=360)\tUTI negative (n=111)\tAll (n=471)\t\nMean (SD) age (years)\t37.7 (14.5)\t35.8 (14.2)\t37.3 (14.4)\t\nMedian (IQR) age (years)\t36.0 (24.0-49.0)\t33.0 (23.0-45.0)\t35.0 (24.0-49.0)\t\nNo (%) with recurrent UTI\t66/357 (19)\t25/110 (23)\t91/467 (20)\t\nUrinary tract infection symptoms\t\nMean (SD) symptom duration score\t5.2 (2.2) (n=359)\t4.7 (2.3) (n=111)\t5.1 (2.2) (n=470)\t\nMean (SD) symptom severity score\t6.2 (2.3) (n=358)\t5.5 (2.4) (n=110)\t6.0 (2.3) (n=468)\t\nMedian (IQR) symptom severity score\t6.0 (5.0-8.0)\t5.5 (4.0-7.0)\t6.0 (4.0-8.0)\t\nMean (SD) dysuria\t2.4 (1.0) (n=358)\t1.9 (1.2) (110)\t2.3 (1.1) (n=468)\t\nMedian (IQR) dysuria\t3.0 (2.0-3.0)\t2.0 (1.0-3.0)\t3.0 (2.0-3.0)\t\nMean (SD) frequency/urgency score\t2.4 (1.1) (n=358)\t2.2 (1.0) (n=110)\t2.4 (1.1) (n=468)\t\nMedian (IQR) frequency/urgency score\t2.0 (2.0-3.0)\t2.0 (1.0-3.0)\t2.0 (2.0-3.0)\t\nMean (SD) lower abdominal pain score\t1.4 (1.1) (n=358)\t1.3 (1.1) (n=110)\t1.4 (1.1) (n=468)\t\nMedian (IQR) lower abdominal pain score\t1.0 (0-2.0)\t1.0 (0-2.0)\t1.0 (0-2.0)\t\nNo (%) with dysuria\t338/358 (94)\t92/110 (84)\t430/468 (92)\t\nNo (%) with frequency/urgency\t345/358 (96)\t107/110 (97)\t452/468 (97)\t\nNo (%) with low abdominal pain\t251/358 (70)\t80/110 (73)\t331/468 (71)\t\nMean (SD) activity impairment score\t9.4 (5.4) (n=358)\t8.8 (5.7) (n=109)\t9.3 (5.5) (n=467)\t\nMedian (IQR) activity impairment score\t10.0 (5.0-13.0)\t9.0 (4.0-12.0)\t10.0 (5.0-13.0)\t\nNo (%) with dipstick results:\t\n Leukocytes positive\t316/360 (88)\t82/111 (74)\t398/471 (85)\t\n Erythrocytes positive\t292/360 (81)\t73/111 (66)\t365/471 (78)\t\n Nitrite positive\t83/360 (23)\t12/111 (11)\t95/471 (20)\t\nSD=standard deviation; IQR=interquartile range.\n\nSafety\nThe number of complications differed between groups: there were five cases of pyelonephritis in the ibuprofen group and one in the fosfomycin group (P=0.12). Women who developed pyelonephritis had a higher initial symptom score than average (7.5 versus 6). Five women with pyelonephritis consulted their general practitioners with symptoms of upper urinary tract infection (fever, loin tenderness) in the first seven days; one at day 16. Figure 9 shows the courses of symptoms in women with pyelonephritis. All women were treated as outpatients and recovered fully.\n\nFig 9 \nSymptom scores of women with pyelonephritis according to treatment with ibuprofen or fosfomycin on days 0-7\n\nThe rate of recurrent urinary tract infection was comparable in both groups. There were, however, significantly more recurrences after day 14 in the fosfomycin group (11% versus 6% in the ibuprofen group, P=0.049, table 2). Of these, 5/14 (36%) women in the ibuprofen group had a prior history of recurrent urinary tract infections compared with 16/27 (60%) in the fosfomycin group. In contrast, more women in the ibuprofen group had early relapses of symptoms (up to day 14), but the difference was not significant. (5% versus 3%; P=0.18, table 2).\n\nThere were no significant differences between groups in adverse events not related to urinary tract infection. In the fosfomycin group 57/243 women reported 64 adverse events, whereas in the ibuprofen group 42/241 reported 51 adverse events. Gastrointestinal symptoms (nausea, diarrhoea) were reported more often in the fosfomycin group (15 versus 6). Rashes or vaginal thrush were rare (table 6).\n\nTable 6 Details on adverse events, intention to treat population of women with uncomplicated urinary tract infection randomised to ibuprofen or fosfomycin\n\nClassification*\tIbuprofen (n=241)\tFosfomycin (n=243)\t\nCertain infections and parasitic diseases—such as unspecified viral infection, worms\t3\t0\t\nDiseases of blood and blood forming organs—such as anaemia\t—\t1\t\nEndocrine, nutritional and metabolic diseases—such as goitre\t1\t —\t\nMental and behavioural disorders—such as grief, psychosomatic disorders\t2\t3\t\nDiseases of the nervous system—such as headache, migraine\t3\t2\t\nDiseases of the genitourinary system—such as vaginal thrush, local infection\t3\t1\t\nDiseases of eye and ear—such as unspecific eye lid swelling, otitis, tinnitus\t3\t5\t\nDiseases of circulatory system—such as hypertonia\t—\t1\t\nDiseases of respiratory system—such as upper/lower respiratory infections, asthma\t13\t12\t\nDiseases of digestive system—such as, nausea, diarrhoea, abdominal pain, vomiting\t6\t15\t\nDiseases of skin—such as allergy, rash, naevi, eczema, photodermatosis\t3\t4\t\nDiseases of musculoskeletal system—such as back pain, shoulder syndrome, cervical syndrome\t12\t14\t\nInjuries and other external causes—such as fall, insect bites\t1\t4\t\nSymptoms not elsewhere classified—such as abnormal transpiration, non-specific symptoms\t1\t2\t\nTotal No of adverse events\t51\t64\t\n*Classification corresponds to international statistical classification of diseases and related health problems (ICD).\n\nFour patients in the ibuprofen group reported serious adverse events that required hospital admission. One (gastrointestinal haemorrhage) was likely to be drug related; the other three were considered to be unrelated to the drugs (table 7). The woman with gastrointestinal haemorrhage turned out to have an undetected stomach ulcer and alcohol induced hepatitis. Because of a misunderstanding and curiosity, and without having symptoms, one woman unblinded herself using the pharmacy emergency number.\n\nTable 7 Details of serious adverse events in women with uncomplicated urinary tract infection randomised to ibuprofen or fosfomycin\n\nDiagnosis\tAge (years)\tBeginning (days from randomisation)\tHospital admission\tTrial drug\t\nBleeding gastric ulcer\t58\t22\tYes\tIbuprofen\t\nCardiac palpitations\t37\t1\tYes\tIbuprofen\t\nMissed miscarriage*\t18\t63\tYes\tIbuprofen\t\nAcute appendicitis\t21\t18\tYes\tIbuprofen\t\n*One woman assigned to ibuprofen group proved to be pregnant despite negative pregnancy test result at inclusion. Both GP and gynaecologist thought miscarriage was not associated treatment drug.\n\nNon-participants\nNon-participants reported higher symptom scores than participants at baseline (8.9 versus 6.0). They had symptoms for longer before visiting the practice, had more recurrent urinary tract infections, and felt more impaired in their daily activities (table 8).\n\nTable 8 Baseline data of participants and non-participants with uncomplicated urinary tract infection. Figures are number (percentage) of women unless stated otherwise\n\nCharacteristics\tParticipants (n=484)\tNon-participants (n=519)\tP value\t\nDuration of symptoms (days):\t\n <1\t99/480 (20)\t108/511 (21)\t0.84\t\n 1-2\t184/480 (38)\t147/511 (29)\t0.001\t\n >2-7\t148/480 (31)\t192/511 (38)\t0.03\t\n >7\t49/480 (10)\t64/511 (13)\t0.25\t\nMean (SD) symptom severity at baseline\t6 (2.3)\t8.9 (2.7)\t<0.001\t\nMean (SD) activity impairment assessment at baseline\t9.3 (5.5)\t14.4 (5.5)\t<0.001\t\nRecurrent UTI\t96/479 (20.0)\t127/481 (26.4)\t0.02\t\nSD=standard deviation; UTI=urinary tract infection.\n\nDiscussion\nPrincipal findings\nWhile initial symptomatic treatment with ibuprofen reduced the overall number of antibiotic treatment courses in women with uncomplicated urinary tract infection by 67%, compared with immediate antibiotic treatment with fosfomycin, this strategy resulted in higher burden of symptoms and more cases of pyelonephritis.\n\nTwo thirds of the women in the ibuprofen group, however, recovered without antibiotic treatment. Within 28 days, 34% of the ibuprofen group received antibiotic treatment for persistent or worsening symptoms compared with 14% of the fosfomycin group. These findings are similar to data in the pilot study.10 In our trial, lower antibiotic consumption was “bought” at the expense of a higher burden of symptoms until day seven in the ibuprofen group, with an area under the curve ratio of 140%. Although, to our knowledge, ibuprofen has not previously been compared with placebo in women with urinary tract infection, it is likely to be effective for symptom relief. While in our trial 67% of women in the ibuprofen group recovered without antibiotics, in a previous randomised controlled trial comparing antibiotics with placebo 54% of those in the placebo group recovered9 and in another trial 28% recovered without any antibiotics within a week.16 A protocol on a similar urinary tract infection trial has been published recently, comparing mecillinam with ibuprofen in a higher dose (3×600 mg).28\n\nAs for safety aspects, there were more cases of pyelonephritis in the ibuprofen group, and the same trend was observed in worsening symptoms, febrile urinary tract infections, and symptoms of early relapse (up to day 14). Few data exist on the epidemiology of pyelonephritis.5\n29 In a meta-analysis of randomised controlled trials comparing placebo with antibiotics, the incidence of pyelonephritis ranged from 0.4% to 2.6% of all urinary tract infections.30 The pyelonephritis rate in the ibuprofen group in our trial was comparably high (2.1%). As the study was not powered to detect significant differences for pyelonephritis, it remains unclear whether this is accidental or due to the lack of antibiotic treatment or possibly due to an effect of ibuprofen on the urogenital system. Further research on this particular outcome is needed.\n\nIn our trial, ibuprofen was used to ease symptoms of urinary tract infection. An additional antimicrobial effect against E coli has been postulated by Obad and colleagues but could not be confirmed.31 Currently the same hypothesis is being investigated by Vik and colleagues.28\n\nRecurrent urinary tract infections (day 14-28) were more common in the fosfomycin group. This could be because more women with a history of recurrent urinary tract infection were randomised into the fosfomycin group. Additionally, antimicrobial treatment might result in recurrent urinary tract infections: in a recent trial women with asymptomatic bacteriuria treated with antibiotics had significantly higher rates of subsequent symptomatic urinary tract infection during 12 months’ follow-up than untreated women.32\n\nFor external validity and to comply with routine general practice, we chose a symptomatic approach as recommended in primary care guidelines.7\n8\n33 Therefore, we did not wait for culture results before inclusion and randomisation, and women with negative results on culture remained in the trial. Symptoms and results of urine tests, including the number of negative urine cultures at inclusion, were comparable with other trials in primary care.11\n16\n34\n35 A subgroup analysis stratified for urine culture results in the ibuprofen group showed significant differences in both co-primary outcomes: women with negative results showed significantly lower symptom burden, and antibiotic use was significantly more reduced in women with positive culture results. Although this was a subgroup analysis, and hence hypothesis generating, these results suggest that urine culture results largely predict the (individual) benefit of antibiotics, though a considerable proportion of those with a positive results did not need antibiotics anyway. Proof of bacterial growth might usefully be included in future antibiotic strategies to curtail unnecessary prescriptions. If sufficiently reliable, point of care tests could reduce the time to targeted treatment compared with conventional culture results, which are available only after several days. A European trial is testing the effectiveness of a point of care test for urinary tract infection with results available within 24 hours in general practices.36 Further studies could also provide information on which women with positive test results would require antibiotics and which are likely to recover with symptomatic treatment.\n\nThe overall rates of adverse events were comparably low in both groups. The only serious adverse event related to the drug in the ibuprofen group was a gastrointestinal haemorrhage in a woman with alcohol disease, undetected stomach ulcer, and alcohol induced hepatitis. Although rare in otherwise healthy younger women, risks for this serious side effect should be assessed carefully before ibuprofen is prescribed.\n\nStrength and limitations\nWe were able to enrol more than half of all potentially eligible women, ensuring external validity. While the collection of baseline data from non-participants was a strength of our study, comparison showed that inclusion was biased towards patients with less severe symptoms. This could be caused by self selection, with women with more severe symptoms expressing a preference for antibiotics or general practitioners perceiving sicker patients as unsuitable for the trial.37 Results therefore have to be interpreted carefully as they might apply only to patients with mild to moderate symptoms rather than all women with an uncomplicated urinary tract infection.\n\nAnother limitation was that both symptom score and the resulting measurement of the area under the curve were not validated, and the relevance for affected patients was not formally proved. In our pilot study the primary outcome had been symptom resolution at day 4. This did not adequately feature the severity of symptoms or their duration beyond day 4. We therefore chose the area under the curve of symptom sum score up to day 7 as a pragmatic comprehensive outcome that summarises the aspects of symptom severity and duration relevant to patients, instead of focusing on a single aspect at a prespecified point in time. The validated disease specific activity impairment score showed similar courses.\n\nTo further improve outcome measures in future trials, patients’ experiences and preferences have to be assessed carefully. Patients should be involved in the development of scores and outcomes. As shown in previous trials, the strategy of delayed prescription could be a welcome and safe alternative for patients who are willing to try treatment other than with antibiotics but want to avoid a reconsultation. This strategy did not reduce antibiotic consumption as effectively as in our trial, but the rate of complications was lower.38\n\nThe higher rate of pyelonephritis and the fact that more women experienced worsening symptoms and febrile urinary tract infection when treated with ibuprofen needs to be assessed further in controlled trials with larger patient samples. Furthermore, factors associated with successful symptomatic treatment—particularly in patients with positive results on urine culture—should be analysed to develop a decision aid as a tool for physicians and patients to assess whether to treat symptomatically or not.\n\nConclusions\nWe have to reject the hypothesis of non-inferiority of initial symptomatic treatment, and we cannot generally recommend the ibuprofen first approach. This treatment option, however, can be discussed with women with mild to moderate symptoms in a shared decision making approach or within a strategy of delayed prescription. Future research is needed to identify patients for whom symptomatic treatment is sufficient as it has the potential to considerably reduce the number of antibiotic prescriptions for women with mild to moderate symptoms of urinary tract infection, in particular those with negative results on culture.\n\nWhat is already known on this topic\nWomen with uncomplicated urinary tract infection are usually treated with antibiotics\n\nIt is unknown if symptomatic treatment is a suitable alternative approach with regard to symptoms and to what extent such treatment can reduce the overall antibiotic prescription rate\n\nWhat this study adds\nCompared with fosfomycin, initial treatment with ibuprofen substantially reduced antibiotic use in women aged 18-65 with mild to moderate symptoms of urinary tract infection but was less effective for symptom relief, and there were more cases of pyelonephritis\n\nThis treatment regimen can be discussed with women who are willing to avoid antibiotics or to accept a delayed prescription\n\nWe thank all participating women and all general practice investigators and their teams (Drs Albrecht, Annweiler, Baumgarten, Beverungen, Borchers, Böttcher, Brockstedt, Brucker, Buck, Coutelle, Dickow, Dockhorn, Egidi, Ertel, Falkenstein, Fleige, Gemen, Gerken, Glatzel, Gosewisch, Heiken, Hermann, Hiller, Hilgenberg, Holm, Keske, Kiwit-Putzer, Klinger-Bültemann, Knöpfel, Koch, Köhler, Löber, Lückerath, Meggers, Meier-Ahrens, Menke, Müller, Neidhardt, Preiskorn, Rötterink, Schaper, Schelp, Schmiemann, Schmitz, Seker, Stegemann, Wilde, Zedler, Zimny). We are grateful to our dedicated research nurses H Schneider-Rudt, C Tomala, J Westphal, and K Jürgensen-Muziol. We also thank Ludwig Balzer for support in the statistical analysis and Frank Sullivan for checking of some English language points.\n\nData Safety and Monitoring Board: Norbert Donner-Banzhoff (Philipps-University Marburg, Department of General Practice, Preventive and Rehabilitation Medicine), Jürgen Brockmöller (University Medical Centre Göttingen, Clinical Pharmacology), Helmut Eiffert (University Medical Centre Göttingen, Institute for Medical Microbiology), Wilhelm Niebling (University Medical Centre Freiburg, Division of General Practice), Andreas Sönnichsen (Institute for General Practice and Family Medicine, Faculty of Health, Witten/Herdecke), Hans-Joachim Trampisch (Ruhr-University Bochum, Department of Medical Informatics and Epidemiology).\n\nContributors: IG and JB contributed equally to the manuscript and share first authorship. All authors conceived the concept and designed and supervised to study; acquired, analysed, and interpreted the data; and drafted and revised the manuscript. KW carried out the statistical analysis. EH-P obtained funding. The Institute for Clinical Research, Göttingen (IFS), pharmacy of the Charité (Berlin), medical laboratory AMEDES Holding AG (Göttingen) contributed administrative, material, and technical support. EH-P and IG are guarantors.\n\nFunding: The trial was funded by the German Federal Ministry of Education and Research (BMBF) No 01KG1105. The funder had no role in trial design, data collection, analysis, or reporting.\n\nCompeting interests: All authors have completed the uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declare: support from the German Federal Ministry of Education and Research for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; and no other relationships or activities that could appear to have influenced the submitted work. The University of Göttingen was responsible for the initiation, quality control and financial management the clinical study but did not participate in the collection, clinical project management, analysis, and interpretation of data.\n\nEthical approval: This study was approved by the ethics committee of Hannover Medical School (No 5986M). All participants provided written informed consent.\n\nTransparency: The guarantors affirm that the manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies are disclosed.\n\nData sharing: Patient level data are available on reasonable request from the corresponding author. Patient consent was not obtained but the presented data are anonymised and risk of identification is low.\n==== Refs\n1 Hooton TM. Clinical practice. Uncomplicated urinary tract infection. N Engl J Med 2012 ;366 : 1028-37 . 10.1056/NEJMcp1104429 22417256\n2 Ong DS, Kuyvenhoven MM, van Dijk L, Verheij TJ. Antibiotics for respiratory, ear and urinary tract disorders and consistency among GPs. J Antimicrob Chemother 2008 ;62 : 587-92 . 10.1093/jac/dkn230 18544602\n3 Centers for Disease Control and Prevention. Antibiotic Resistance Threats in the United States, 2013. www.cdc.gov/drugresistance/threat-report-2013/pdf/ar-threats-2013-508.pdf.\n4 World Health Organization. Antimicrobial resistance: Global Report on Surveillance 2014 2014. http://apps.who.int/iris/bitstream/10665/112642/1/9789241564748_eng.pdf.\n5 Foxman B. Urinary tract infection syndromes: occurrence, recurrence, bacteriology, risk factors, and disease burden. Infect Dis Clin North Am 2014 ;28 : 1-13 . 10.1016/j.idc.2013.09.003 24484571\n6 Donnan PT, Wei L, Steinke DT Presence of bacteriuria caused by trimethoprim resistant bacteria in patients prescribed antibiotics: multilevel model with practice and individual patient data. BMJ 2004 ;328 : 1297. 10.1136/bmj.328.7451.1297 15166067\n7 Epidemiology, diagnostics, therapy and management of uncomplicated bacterial community acquired urinary tract infection in adults: German S3-Guideline 2010. http://www.awmf.org/leitlinien/detail/ll/043-044.html.\n8 The Dutch College of General Practitioners. Urineweginfecties M05 2013. https://www.nhg.org/standaarden/samenvatting/urineweginfecties.\n9 Christiaens TCM, De Meyere M, Verschraegen G, Peersman W, Heytens S, De Maeseneer JM. Randomised controlled trial of nitrofurantoin versus placebo in the treatment of uncomplicated urinary tract infection in adult women. Br J Gen Pract 2002 ;52 : 729-34 . 12236276\n10 Bleidorn J, Gágyor I, Kochen MM, Wegscheider K, Hummers-Pradier E. Symptomatic treatment (ibuprofen) or antibiotics (ciprofloxacin) for uncomplicated urinary tract infection?--results of a randomized controlled pilot trial. BMC Med 2010 ;8 : 30. 10.1186/1741-7015-8-30 20504298\n11 Little P, Moore MV, Turner S Effectiveness of five different approaches in management of urinary tract infection: randomised controlled trial. BMJ 2010 ;340 : c199. 10.1136/bmj.c199 20139214\n12 Patrick DM, Hutchinson J. Antibiotic use and population ecology: how you can reduce your “resistance footprint”. CMAJ 2009 ;180 : 416-21 . 10.1503/cmaj.080626 19221355\n13 Butler CC, Dunstan F, Heginbothom M Containing antibiotic resistance: decreased antibiotic-resistant coliform urinary tract infections with reduction in antibiotic prescribing by general practices. Br J Gen Pract 2007 ;57 : 785-92 . 17925135\n14 Gyssens IC. Antibiotic policy. Int J Antimicrob Agents 2011 ;38 (Suppl ): 11-20 . 10.1016/j.ijantimicag.2011.09.002 22018989\n15 Gottesman BS, Carmeli Y, Shitrit P, Chowers M. Impact of quinolone restriction on resistance patterns of Escherichia coli isolated from urine by culture in a community setting. Clin Infect Dis 2009 ;49 : 869-75 . 10.1086/605530 19686074\n16 Ferry SA, Holm SE, Stenlund H, Lundholm R, Monsen TJ. The natural course of uncomplicated lower urinary tract infection in women illustrated by a randomized placebo controlled study. Scand J Infect Dis 2004 ;36 : 296-301 . 10.1080/00365540410019642 15198188\n17 Knottnerus BJ, Geerlings SE, Moll van Charante EP, ter Riet G. Women with symptoms of uncomplicated urinary tract infection are often willing to delay antibiotic treatment: a prospective cohort study. BMC Fam Pract 2013 ;14 : 71. 10.1186/1471-2296-14-71 23721260\n18 Leydon GM, Turner S, Smith H, Little PUTIS team . Women’s views about management and cause of urinary tract infection: qualitative interview study. BMJ 2010 ;340 : c279. 10.1136/bmj.c279 20139217\n19 Willems CS, van den Broek D’Obrenan J, Numans ME, Verheij TJ, van der Velden AW. Cystitis: antibiotic prescribing, consultation, attitudes and opinions. Fam Pract 2014 ;31 : 149-55 . 10.1093/fampra/cmt077 24317602\n20 Gágyor I, Hummers-Pradier E, Kochen MM, Schmiemann G, Wegscheider K, Bleidorn J. Immediate versus conditional treatment of uncomplicated urinary tract infection - a randomized-controlled comparative effectiveness study in general practices. BMC Infect Dis 2012 ;12 : 146. 10.1186/1471-2334-12-146 22742538\n21 Loudon K, Treweek S, Sullivan F, Donnan P, Thorpe KE, Zwarenstein M. The PRECIS-2 tool: designing trials that are fit for purpose. BMJ 2015 ;350 : h2147. 10.1136/bmj.h2147 25956159\n22 Mauch H, Podbielski A, Herrmann M, Gatermann SG, Fünfstück R, Handrick W. Harnwegsinfektionen: Qualitätsstandards in der mikrobiologisch-infektiologischen Diagnostik. 2nd ed. Urban & Fischer Verlag/Elsevier GmbH 2005.\n23 Cals JW, Butler CC, Hopstaken RM, Hood K, Dinant GJ. Effect of point of care testing for C reactive protein and training in communication skills on antibiotic use in lower respiratory tract infections: cluster randomised trial. BMJ 2009 ;338 : b1374. 10.1136/bmj.b1374 19416992\n24 Linde M, Mellberg A, Dahlöf C. The natural course of migraine attacks. A prospective analysis of untreated attacks compared with attacks treated with a triptan. Cephalalgia 2006 ;26 : 712-21 . 10.1111/j.1468-2982.2006.01097.x 16686911\n25 Hanania NA, Boota A, Kerwin E, Tomlinson L, Denis-Mize K. Efficacy and safety of nebulized formoterol as add-on therapy in COPD patients receiving maintenance tiotropium bromide: Results from a 6-week, randomized, placebo-controlled, clinical trial. Drugs 2009 ;69 : 1205-16 . 10.2165/00003495-200969090-00005 19537837\n26 Wild DJ, Clayson DJ, Keating K, Gondek K. Validation of a patient-administered questionnaire to measure the activity impairment experienced by women with uncomplicated urinary tract infection: the Activity Impairment Assessment (AIA). Health Qual Life Outcomes 2005 ;3 : 42. 10.1186/1477-7525-3-42 16022727\n27 Julious SA. Sample sizes for clinical trials with normal data. Stat Med 2004 ;23 : 1921-86 . 10.1002/sim.1783 15195324\n28 Vik I, Bollestad M, Grude N Ibuprofen versus mecillinam for uncomplicated cystitis--a randomized controlled trial study protocol. BMC Infect Dis 2014 ;14 : 693. 10.1186/s12879-014-0693-y 25516016\n29 van Pinxteren B, Knottnerus BJ, Geerlings SE NHG-Standaard Urineweginfecties (derde herziening). Huisarts Wet 2013 ;56 : 270-80 .\n30 Falagas ME, Kotsantis IK, Vouloumanou EK, Rafailidis PI. Antibiotics versus placebo in the treatment of women with uncomplicated cystitis: a meta-analysis of randomized controlled trials. J Infect 2009 ;58 : 91-102 . 10.1016/j.jinf.2008.12.009 . 19195714\n31 Obad J, Šušković J, Kos B. Antimicrobial activity of ibuprofen: new perspectives on an “Old” non-antibiotic drug. Eur J Pharm Sci 2015 ;71 : 93-8 . 10.1016/j.ejps.2015.02.011 25708941\n32 Cai T, Mazzoli S, Mondaini N The role of asymptomatic bacteriuria in young women with recurrent urinary tract infections: to treat or not to treat?Clin Infect Dis 2012 ;55 : 771-7 . 10.1093/cid/cis534 22677710\n33 Scottish Intercollegiate Guidelines Network. Management of suspected bacterial urinary tract infection in adults 2012. www.sign.ac.uk/pdf/sign88.pdf.\n34 Giesen LG, Cousins G, Dimitrov BD, van de Laar FA, Fahey T. Predicting acute uncomplicated urinary tract infection in women: a systematic review of the diagnostic accuracy of symptoms and signs. BMC Fam Pract 2010 ;11 : 78. 10.1186/1471-2296-11-78 20969801\n35 Baerheim A, Digranes A, Hunskaar S. Equal symptomatic outcome after antibacterial treatment of acute lower urinary tract infection and the acute urethral syndrome in adult women. Scand J Prim Health Care 1999 ;17 : 170-3 . 10.1080/028134399750002593 10555247\n36 Bates J, Thomas-Jones E, Pickles T Point of care testing for urinary tract infection in primary care (POETIC): protocol for a randomised controlled trial of the clinical and cost effectiveness of FLEXICULT™ informed management of uncomplicated UTI in primary care. BMC Fam Pract 2014 ;15 : 187. 10.1186/s12875-014-0187-4 25425162\n37 Donovan JL, de Salis I, Toerien M, Paramasivan S, Hamdy FC, Blazeby JM. The intellectual challenges and emotional consequences of equipoise contributed to the fragility of recruitment in six randomized controlled trials. J Clin Epidemiol 2014 ;67 : 912-20 . 10.1016/j.jclinepi.2014.03.010 24811157\n38 Little P, Stuart B, Hobbs FDDESCARTE investigators . Antibiotic prescription strategies for acute sore throat: a prospective observational cohort study. Lancet Infect Dis 2014 ;14 : 213-9 . 10.1016/S1473-3099(13)70294-9 24440616\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "0959-8138",
"issue": "351()",
"journal": "BMJ (Clinical research ed.)",
"keywords": null,
"medline_ta": "BMJ",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000900:Anti-Bacterial Agents; D000894:Anti-Inflammatory Agents, Non-Steroidal; D005260:Female; D005578:Fosfomycin; D006801:Humans; D007052:Ibuprofen; D008875:Middle Aged; D012008:Recurrence; D013997:Time Factors; D016896:Treatment Outcome; D014552:Urinary Tract Infections; D055815:Young Adult",
"nlm_unique_id": "8900488",
"other_id": null,
"pages": "h6544",
"pmc": null,
"pmid": "26698878",
"pubdate": "2015-12-23",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": "19195714;18544602;19416992;19537837;19686074;20139214;20139217;20504298;20969801;22018989;22677710;22742538;22417256;23721260;24484571;24440616;24317602;24811157;25425162;25708941;25516016;25956159;19221355;17925135;16686911;16022727;15198188;15195324;10555247;12236276;15166067",
"title": "Ibuprofen versus fosfomycin for uncomplicated urinary tract infection in women: randomised controlled trial.",
"title_normalized": "ibuprofen versus fosfomycin for uncomplicated urinary tract infection in women randomised controlled trial"
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"companynumb": "DE-JNJFOC-20160110964",
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{
"abstract": "FOLFIRINOX has shown promising results in locally advanced (LAPA) or borderline resectable (BRPA) pancreatic adenocarcinoma. We report here a cohort of patients treated with this regimen from the AGEO group.\n\n\n\nThis is a retrospective multicentre study. We included all consecutive patients with non-pre-treated LAPA or BRPA treated with FOLFIRINOX.\n\n\n\nWe included 330 patients (57.9% male, 65.4% <65 years, 96.4% PS <2). Disease was classified as BRPA in 31.1% or LAPA in 68.9%. Objective response rate with FOLFIRINOX was 29.5% and stable disease 51%. Subsequent CRT was performed in 46.4% of patients and 23.9% had curative intent surgery. Resection rates were 42.1% for BRPA and 15.5% for LAPA. Main G3/4 toxicities were fatigue (15%), neutropenia (12%) and neuropathy (G2/3 35%). After a median follow-up of 26.7 months, median OS (mOS) and PFS were 21.4 and 12.4 months, respectively. For patients treated by FOLFIRINOX alone, or FOLFIRINOX followed by CRT, or FOLFIRINOX + /- CRT + surgery, mOS was 16.8 months, 21.8 months and not reached, respectively (p < 0.0001).\n\n\n\nFOLFIRINOX for LAPA and BRPA seems to be effective with a manageable toxicity profile. These promising results in \"real-life\" patients now have to be confirmed in a Phase 3 randomised trial.",
"affiliations": "Department of Hepato-Gastroenterology and Gastrointestinal Oncology, Université de Paris, Paris Descartes University, Hôpital Européen Georges Pompidou, Paris, France.;Department of Gastroenterology, Kremlin Bicêtre Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris Sud University, Le Kremlin Bicêtre, France.;Department of Gastroenterology, Kremlin Bicêtre Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris Sud University, Le Kremlin Bicêtre, France.;Department of Gastroenterology, La Pitié-Salpêtrière Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France.;Department of Oncology, Anticancer Center A Lacassagne, Nice, France.;Department of Oncology, Anticancer Center A Lacassagne, Nice, France.;Department of Digestive Surgery, Hôpital Paul Brousse, Villejuif, France.;Department of Oncology, Besançon University Hospital, Besançon, France.;Department of Hepato-Gastroenterology and Digestive Oncology, University Hospital Trousseau, Tours, France.;Department of Gastroenterology and Digestive Oncology, Amiens University Hospital, Amiens, France.;Department of Gastrointestinal Oncology, Centre Léon Bérard, Lyon, France.;Department of Gastrointestinal Oncology, Centre Léon Bérard, Lyon, France.;Department of Oncology, Institute Salah-Azaïz, Tunis, Tunisia.;Department of Gastroenterology, Hôpital Edouard Herriot, Lyon, France.;Department of Gastroenterology, Hôpital Cochin, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France.;Department of Radiotherapy, Université de Paris, Hôpital Européen Georges Pompidou, Paris, France.;Department of GI Oncology, Institut Gustave Roussy, Villejuif, France.;Department of Gastroenterology, University Hospital of Saint-Etienne, Saint-Etienne, France.;Department of Gastroenterology, La Pitié-Salpêtrière Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France.;Department of Hepato-Gastroenterology, Poitiers University Hospital, University of Poitiers, Poitiers, France.;Department of Hepato-Gastroenterology and Gastrointestinal Oncology, Université de Paris, Paris Descartes University, Hôpital Européen Georges Pompidou, Paris, France. Jtaieb75@gmail.com.",
"authors": "Auclin|Edouard|E|;Marthey|Lysiane|L|;Abdallah|Raef|R|;Mas|Léo|L|;Francois|Eric|E|;Saint|Angélique|A|;Cunha|Antonio Sa|AS|;Vienot|Angélique|A|;Lecomte|Thierry|T|;Hautefeuille|Vincent|V|;de La Fouchardière|Christelle|C|0000-0003-2291-5693;Sarabi|Matthieu|M|;Ksontini|Feryel|F|;Forestier|Julien|J|;Coriat|Romain|R|;Fabiano|Emmanuelle|E|;Leroy|Florence|F|;Williet|Nicolas|N|0000-0002-7296-5464;Bachet|Jean-Baptiste|JB|;Tougeron|David|D|;Taieb|Julien|J|0000-0002-9955-4753",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1038/s41416-021-01341-w",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0007-0920",
"issue": "124(12)",
"journal": "British journal of cancer",
"keywords": null,
"medline_ta": "Br J Cancer",
"mesh_terms": null,
"nlm_unique_id": "0370635",
"other_id": null,
"pages": "1941-1948",
"pmc": null,
"pmid": "33772154",
"pubdate": "2021-06",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Role of FOLFIRINOX and chemoradiotherapy in locally advanced and borderline resectable pancreatic adenocarcinoma: update of the AGEO cohort.",
"title_normalized": "role of folfirinox and chemoradiotherapy in locally advanced and borderline resectable pancreatic adenocarcinoma update of the ageo cohort"
} | [
{
"companynumb": "FR-PFIZER INC-202101210633",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
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"activesubstancename": "FLUOROURACIL"
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{
"abstract": "Nodular regenerative hyperplasia (NRH) is associated with autoimmune and hematologic diseases and may lead to portal hypertension. We herein report a case of NRH diagnosed based on a liver biopsy. A 63-year-old woman developed esophageal varices and splenomegaly. She had undergone surgery for transverse colon cancer 24 years earlier and received systemic chemotherapy (FOLFOX4 including oxaliplatin) to treat lymph node metastasis 21 years after the operation. The present liver biopsy confirmed NRH, and, after two years, she received endoscopic injection sclerotherapy. Oxaliplatin was suspected to be the causative agent of NRH in this case. Therefore, physicians must consider the possibility of NRH in patients who receive chemotherapy.",
"affiliations": "Third Department of Internal Medicine, Nara Medical University, Japan.",
"authors": "Takaya|Hiroaki|H|;Kawaratani|Hideto|H|;Nakanishi|Keisuke|K|;Takeyama|Shinya|S|;Morioka|Chie|C|;Sawai|Masayoshi|M|;Toyohara|Masahisa|M|;Fujimoto|Masao|M|;Yoshiji|Hitoshi|H|;Yamao|Junichi|J|;Fukui|Hiroshi|H|",
"chemical_list": "D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin",
"country": "Japan",
"delete": false,
"doi": "10.2169/internalmedicine.54.2461",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0918-2918",
"issue": "54(4)",
"journal": "Internal medicine (Tokyo, Japan)",
"keywords": null,
"medline_ta": "Intern Med",
"mesh_terms": "D000970:Antineoplastic Agents; D003110:Colonic Neoplasms; D004932:Esophageal and Gastric Varices; D005260:Female; D006801:Humans; D006965:Hyperplasia; D006975:Hypertension, Portal; D008099:Liver; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D016896:Treatment Outcome",
"nlm_unique_id": "9204241",
"other_id": null,
"pages": "383-7",
"pmc": null,
"pmid": "25748953",
"pubdate": "2015",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Development of nodular regenerative hyperplasia (NRH) with portal hypertension following the administration of oxaliplatin for the recurrence of colon cancer.",
"title_normalized": "development of nodular regenerative hyperplasia nrh with portal hypertension following the administration of oxaliplatin for the recurrence of colon cancer"
} | [
{
"companynumb": "JP-PFIZER INC-2019069475",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "OXALIPLATIN"
},
"drugadditional": null,
... |
{
"abstract": "To identify factors that may predict and affect the risk of relapse in anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis.\n\n\n\nThis was a retrospective study of an Italian cohort of patients with paediatric (≤18y) onset anti-NMDAR encephalitis.\n\n\n\nOf the 62 children included (39 females; median age at onset 9y 10mo, range 1y 2mo-18y; onset between 2005 and 2018), 21 per cent relapsed (median two total events per relapsing patient, range 2-4). Time to first relapse was median 31.5 months (range 7-89mo). Severity at first relapse was lower than onset (median modified Rankin Scale [mRS] 3, range 2-4, vs median mRS 5, range 3-5; admission to intensive care unit: 0/10 vs 3/10). At the survival analysis, the risk of relapsing was significantly lower in patients who received three or more different immune therapies at first disease event (hazard ratio 0.208, 95% confidence interval 0.046-0.941; p=0.042). Neurological outcome at follow-up did not differ significantly between patients with relapsing and monophasic disease (mRS 0-1 in 39/49 vs 12/13; p=0.431), although follow-up duration was significantly longer in relapsing (median 84mo, range 14-137mo) than in monophasic patients (median 32mo, range 4-108mo; p=0.002).\n\n\n\nRelapses may occur in about one-fifth of children with anti-NMDAR encephalitis, are generally milder than at onset, and may span over a long period, although they do not seem to be associated with severity in the acute phase or with outcome at follow-up. Aggressive immune therapy at onset may reduce risk of relapse.\n\n\n\nRelapses of anti-N-methyl-D-aspartate receptor encephalitis may span over a long period. Relapses were not associated with severity in the acute phase or outcome at follow-up. Aggressive immune therapy at onset appears to decrease risk of relapse.",
"affiliations": "Paediatric Neurology and Neurophysiology Unit, Department of Women's and Children's Health, University Hospital of Padua, Padua, Italy.;Department of Pediatric Neuroscience, Foundation IRCCS Neurological Institute 'C. Besta', Milan, Italy.;Department of Pediatric Neuroscience, Foundation IRCCS Neurological Institute 'C. Besta', Milan, Italy.;Department of Pediatric Neuroscience, Foundation IRCCS Neurological Institute 'C. Besta', Milan, Italy.;Department of Pediatric Neuroscience, Foundation IRCCS Neurological Institute 'C. Besta', Milan, Italy.;Child Neurology Unit, Department of Neuroscience and Neurorehabilitation, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.;Paediatric Neurology and Neurophysiology Unit, Department of Women's and Children's Health, University Hospital of Padua, Padua, Italy.;Child Neurology Unit, Department of Neuroscience and Neurorehabilitation, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.;Paediatric Neurology and Neurophysiology Unit, Department of Women's and Children's Health, University Hospital of Padua, Padua, Italy.",
"authors": "Nosadini|Margherita|M|0000-0002-6395-7614;Granata|Tiziana|T|;Matricardi|Sara|S|;Freri|Elena|E|;Ragona|Francesca|F|;Papetti|Laura|L|0000-0002-3336-9205;Suppiej|Agnese|A|;Valeriani|Massimiliano|M|;Sartori|Stefano|S|;|||",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1111/dmcn.14267",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0012-1622",
"issue": "61(9)",
"journal": "Developmental medicine and child neurology",
"keywords": null,
"medline_ta": "Dev Med Child Neurol",
"mesh_terms": "D000293:Adolescent; D060426:Anti-N-Methyl-D-Aspartate Receptor Encephalitis; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D005260:Female; D006801:Humans; D007223:Infant; D007558:Italy; D008297:Male; D012008:Recurrence; D012189:Retrospective Studies; D012307:Risk Factors",
"nlm_unique_id": "0006761",
"other_id": null,
"pages": "1101-1107",
"pmc": null,
"pmid": "31175679",
"pubdate": "2019-09",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Relapse risk factors in anti-N-methyl-D-aspartate receptor encephalitis.",
"title_normalized": "relapse risk factors in anti n methyl d aspartate receptor encephalitis"
} | [
{
"companynumb": "IT-SHIRE-IT202011631",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "RITUXIMAB"
},
"drugadditional": null,
"d... |
{
"abstract": "A21-year patient initially presented with a fracture of the humerus following minor trauma. Abone scan and biopsy were done due to the suspicion of pathological fracture and the biopsy confirmed the diagnosis of Ewing Sarcoma (EWS). Two months after initial presentation, chemotherapy was started and 5 cycles were given over a span of 6 months. Surgical resection of the tumor was then performed. The post-chemotherapy resection specimen, on histological examination, showed the presence of areas of neuroblastoma-like differentiation in otherwise morphologically classic EWS. Cytogenetic analysis by FISH revealed EWSR1 gene rearrangement. Four similar cases have been reported earlier in literature, all in females below 20 years of age. Our case is unique as it is the first case of post-chemotherapy neuroblastoma-like differentiation of EWS in a 21-year male.",
"affiliations": "Department of Pathology and Laboratory Medicine, The Aga Khan University Hospital, Karachi.;Medical Student, The Aga Khan Medical College, Karachi.;Department of Pathology and Laboratory Medicine, The Aga Khan University Hospital, Karachi.",
"authors": "Din|Nasir Ud|NU|;Qasim|Amna|A|;Ahmad|Zubair|Z|",
"chemical_list": "C500986:EWSR1 protein, human; D015514:Oncogene Proteins, Fusion; D034802:RNA-Binding Protein EWS; D014157:Transcription Factors",
"country": "Pakistan",
"delete": false,
"doi": "2662",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1022-386X",
"issue": "27(7)",
"journal": "Journal of the College of Physicians and Surgeons--Pakistan : JCPSP",
"keywords": null,
"medline_ta": "J Coll Physicians Surg Pak",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D001706:Biopsy; D001859:Bone Neoplasms; D006801:Humans; D006811:Humerus; D008297:Male; D009447:Neuroblastoma; D015514:Oncogene Proteins, Fusion; D034802:RNA-Binding Protein EWS; D012512:Sarcoma, Ewing; D014157:Transcription Factors; D016896:Treatment Outcome",
"nlm_unique_id": "9606447",
"other_id": null,
"pages": "444-446",
"pmc": null,
"pmid": "28818170",
"pubdate": "2017-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Post-Chemotherapy Neuroblastoma-like Differentiation in Ewing Sarcoma of Humerus: Report of a Rare Case with Review of Literature.",
"title_normalized": "post chemotherapy neuroblastoma like differentiation in ewing sarcoma of humerus report of a rare case with review of literature"
} | [
{
"companynumb": "PK-ACCORD-059318",
"fulfillexpeditecriteria": "1",
"occurcountry": "PK",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "IFOSFAMIDE"
},
"drugadditional": null,
"drug... |
{
"abstract": "The aim of this study was to assess symptomatic recurrence in patients who underwent a laparoscopic repair of large hiatal hernia without an esophageal lengthening procedure. Patients who underwent a laparoscopic repair of a large hiatal hernia from September 2009 to September 2015 by a single surgeon were identified in the retrospective review. The patients were followed up prospectively by the operating surgeon using a structured questionnaire, administered by telephone, to assess the symptoms. Symptomatic recurrence was defined as the requirement for a reoperative procedure for symptomatic recurrent hiatal hernia. There were 215 laparoscopic repairs. Reoperations (n = 35) and type I hernias of <4 cm (n = 49) were excluded. The study population included 131 patients: 36 had type I hernia, 4 had type II hernia, 37 had type III hernia, and 54 had type IV hernia. There were 102 women and 29 men, aged 63 (56-74) years. For repair, 102 Toupet, 28 Nissen, and 1 Dor fundoplications were performed. The duration of the operation was 138 (119-172) minutes. Adequate esophageal length was obtained by mediastinal esophageal mobilization in all patients, without Collis gastroplasty. A mesh was used in 106 patients. There was 1 conversion and 2 delayed esophageal leaks. The length of stay was 2 (1-3) days. Perioperative complications included atrial fibrillation in 5 patients, gastric distension or ileus in 5 patients, reintubation in 3 patients, heparin-induced thrombocytopenia in 1 patient, and temporary dialysis in 1 patient. There was no 30-day or in-hospital mortality. The questionnaire was completed by 99 out of 131 patients (76%) at 24 (9-38) months; of the 99 patients, 85 (86%) were free of preoperative symptoms; 91 (92%) were satisfied with the operation; and 73 (74%) were off proton pump inhibitors. Reoperation for symptomatic recurrent hiatal hernia occurred in 8 of the 99 patients (8%), 2 in the perioperative period and 6 at 25 (8-31) months. Laparoscopic repair of large hiatal hernia can be performed with low morbidity and results in excellent patient satisfaction. Tension-free, intra-abdominal esophageal length can be achieved laparoscopically without Collis gastroplasty. Reoperation for symptomatic recurrence is rare.",
"affiliations": "Department of Surgery, McGovern Medical School, University of Texas Health Science Center at Houston (UTHealth), Houston, Texas; Memorial Hermann Southeast Esophageal Disease Center, Houston, Texas. Electronic address: farzaneh.banki@uth.tmc.edu.;Department of Surgery, McGovern Medical School, University of Texas Health Science Center at Houston (UTHealth), Houston, Texas.;Department of Surgery, McGovern Medical School, University of Texas Health Science Center at Houston (UTHealth), Houston, Texas.;Department of Surgery, McGovern Medical School, University of Texas Health Science Center at Houston (UTHealth), Houston, Texas.;Department of Cardiothoracic and Vascular Surgery, McGovern Medical School, University of Texas Health Science Center at Houston (UTHealth), Houston, Texas.",
"authors": "Banki|Farzaneh|F|;Kaushik|Chandni|C|;Roife|David|D|;Mitchell|Kyle G|KG|;Miller|Charles C|CC|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1053/j.semtcvs.2017.05.011",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1043-0679",
"issue": "29(3)",
"journal": "Seminars in thoracic and cardiovascular surgery",
"keywords": "esophageal lengthening; laparoscopic approach; large hiatal hernia; mediastinal mobilization",
"medline_ta": "Semin Thorac Cardiovasc Surg",
"mesh_terms": "D000368:Aged; D018572:Disease-Free Survival; D004947:Esophagus; D005260:Female; D006551:Hernia, Hiatal; D059685:Herniorrhaphy; D006801:Humans; D053208:Kaplan-Meier Estimate; D010535:Laparoscopy; D008297:Male; D008875:Middle Aged; D017060:Patient Satisfaction; D011183:Postoperative Complications; D012008:Recurrence; D012189:Retrospective Studies; D012307:Risk Factors; D011795:Surveys and Questionnaires; D013997:Time Factors; D016896:Treatment Outcome",
"nlm_unique_id": "8917640",
"other_id": null,
"pages": "418-425",
"pmc": null,
"pmid": "29031705",
"pubdate": "2017",
"publication_types": "D016428:Journal Article; D059040:Video-Audio Media",
"references": null,
"title": "Laparoscopic Repair of Large Hiatal Hernia Without the Need for Esophageal Lengthening With Low Morbidity and Rare Symptomatic Recurrence.",
"title_normalized": "laparoscopic repair of large hiatal hernia without the need for esophageal lengthening with low morbidity and rare symptomatic recurrence"
} | [
{
"companynumb": "US-PFIZER INC-2017347526",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "HEPARIN SODIUM"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nPlasmablastic lymphoma (PBL) is a rare variant of diffuse large B-cell lymphoma for which no optimal treatment has been established and prognosis remains poor. Here, we describe a human immunodeficiency virus-uninfected patient with PBL that was refractory to conventional chemotherapies but was successfully controlled with a bortezomib-based regimen followed by a lenalidomide-based regimen.\n\n\nMETHODS\nA 64-year-old man suffered from nasal bleeding and occlusion. Whole-body computed tomography results revealed a large lesion occupying his nasal cavity. He was diagnosed with PBL based on a tumor biopsy and was treated with two lines of conventional chemotherapy. A dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (EPOCH) regimen and an ifosfamide, carboplatin, and etoposide (ICE) regimen were ineffective, but the bortezomib-based regimen CyBorD (bortezomib, cyclophosphamide orally, and dexamethasone orally) provided a clinical response. Due to peripheral neuropathy, the patient was then treated with a lenalidomide-based regimen (Ld; lenalidomide and dexamethasone). Although a complete response was not achieved, the Ld regimen was tolerated and was continued with a partial response (PR) for over 2 years.\n\n\nCONCLUSIONS\nIn the present case, PBL that was refractory to conventional chemotherapies responded to the CyBorD regimen and a long-term Ld-based regimen without severe adverse effects. This strategy provided and maintained a PR for over 2 years. Despite not resulting in tumor reduction and only maintaining a PR, continued Ld treatment contributed to long-term survival of the present patient with PBL.",
"affiliations": "Department of Hematology, Atomic Bomb Disease and Hibakusha Medicine Unit, Atomic Disease Institute, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan, k-ando@nagasaki-u.ac.jp.;Department of Hematology, Nagasaki University Hospital, Nagasaki, Japan.;Department of Hematology, National Hospital Organization, Nagasaki Medical Center, Nagasaki, Japan.;Nagasaki Educational and Diagnostic Center of Pathology, Nagasaki University Hospital, Nagasaki, Japan.;Department of Hematology, Nagasaki University Hospital, Nagasaki, Japan.;Department of Hematology, Nagasaki University Hospital, Nagasaki, Japan.;Department of Hematology, Nagasaki University Hospital, Nagasaki, Japan.;Department of Hematology, Atomic Bomb Disease and Hibakusha Medicine Unit, Atomic Disease Institute, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.;Department of Pathology, School of Medicine, Kurume University, Kurume, Japan.;Department of Hematology, Atomic Bomb Disease and Hibakusha Medicine Unit, Atomic Disease Institute, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.",
"authors": "Ando|Koji|K|;Imaizumi|Yoshitaka|Y|;Kobayashi|Yuji|Y|;Niino|Daisuke|D|;Hourai|Makio|M|;Sato|Shinya|S|;Sawayama|Yasushi|Y|;Hata|Tomoko|T|;Ohshima|Koichi|K|;Miyazaki|Yasushi|Y|",
"chemical_list": "D000069286:Bortezomib; D000077269:Lenalidomide",
"country": "Netherlands",
"delete": false,
"doi": "10.1159/000504608",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2296-5270",
"issue": "43(3)",
"journal": "Oncology research and treatment",
"keywords": "Bortezomib; CyBorD; Dexamethasone; Lenalidomide; Plasmablastic lymphoma",
"medline_ta": "Oncol Res Treat",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D000069286:Bortezomib; D019008:Drug Resistance, Neoplasm; D006801:Humans; D000077269:Lenalidomide; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D000069293:Plasmablastic Lymphoma; D011379:Prognosis; D012074:Remission Induction; D016879:Salvage Therapy",
"nlm_unique_id": "101627692",
"other_id": null,
"pages": "112-116",
"pmc": null,
"pmid": "31842017",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Bortezomib- and Lenalidomide-Based Treatment of Refractory Plasmablastic Lymphoma.",
"title_normalized": "bortezomib and lenalidomide based treatment of refractory plasmablastic lymphoma"
} | [
{
"companynumb": "JP-ASPEN-GLO2020JP003090",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "DEXAMETHASONE"
},
"drugadditional": null,
... |
{
"abstract": "Data on the coincidence of tuberculosis (TB) and COVID-19 are limited, and previous observations are based on the results of just a few studies, which has led to polarized views on the course of infection with SARS-CoV-2 in patients with active TB. We present the first two cases of TB and COVID-19 coinfection in the population of patients in Poland, diagnosed shortly after the outbreak of the global pandemic. In the first patient, TB was very advanced at the time of infection with SARS-CoV-2. From the third day of hospitalisation, respiratory failure was increasing, with no improvement after the use of high-flow oxygen therapy and mechanical ventilation. On the seventh day of hospitalization, the patient died. In the second presented case, therapeutic success was achieved despite the coincidence of COVID-19, infection with HIV, and extrapulmonary and pulmonary TB. The patient had symptoms of renal failure and the SARS-CoV-2 infection was mild and asymptomatic. Because both patients were in the care of a homeless shelter, a molecular epidemiological investigation was carried out. Different DNA profiles of Mycobacterium tuberculosis complex isolates detected in clinical materials from patients ruled out the transmission of tuberculosis. Based on our analysis, it is impossible to clearly define the influence of active TB on the course of SARS-CoV-2 infection. We can only suggest that coinfection is particularly dangerous for socially disadvantaged people, the elderly, and people with other comorbidities. In the coming years, a negative impact of the current pandemic on control programmes will be observed for many infectious diseases, including TB.",
"affiliations": "Department of Microbiology, National Tuberculosis and Lung Diseases Research Institute, Plocka 26, 01-138 Warsaw, Poland.;Department of Microbiology, National Tuberculosis and Lung Diseases Research Institute, Plocka 26, 01-138 Warsaw, Poland.",
"authors": "Kozińska|Monika|M|0000-0003-1968-6818;Augustynowicz-Kopeć|Ewa|E|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3390/diagnostics11101768",
"fulltext": "\n==== Front\nDiagnostics (Basel)\nDiagnostics (Basel)\ndiagnostics\nDiagnostics\n2075-4418\nMDPI\n\n10.3390/diagnostics11101768\ndiagnostics-11-01768\nCase Report\nCOVID-19 in Patients with Active Tuberculosis\nhttps://orcid.org/0000-0003-1968-6818\nKozińska Monika *\nAugustynowicz-Kopeć Ewa\nBaraniak Anna Academic Editor\nDepartment of Microbiology, National Tuberculosis and Lung Diseases Research Institute, Plocka 26, 01-138 Warsaw, Poland; e.kopec@igichp.edu.pl\n* Correspondence: m.kozinska@igichp.edu.pl\n26 9 2021\n10 2021\n11 10 176824 8 2021\n20 9 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/).\nData on the coincidence of tuberculosis (TB) and COVID-19 are limited, and previous observations are based on the results of just a few studies, which has led to polarized views on the course of infection with SARS-CoV-2 in patients with active TB. We present the first two cases of TB and COVID-19 coinfection in the population of patients in Poland, diagnosed shortly after the outbreak of the global pandemic. In the first patient, TB was very advanced at the time of infection with SARS-CoV-2. From the third day of hospitalisation, respiratory failure was increasing, with no improvement after the use of high-flow oxygen therapy and mechanical ventilation. On the seventh day of hospitalization, the patient died. In the second presented case, therapeutic success was achieved despite the coincidence of COVID-19, infection with HIV, and extrapulmonary and pulmonary TB. The patient had symptoms of renal failure and the SARS-CoV-2 infection was mild and asymptomatic. Because both patients were in the care of a homeless shelter, a molecular epidemiological investigation was carried out. Different DNA profiles of Mycobacterium tuberculosis complex isolates detected in clinical materials from patients ruled out the transmission of tuberculosis. Based on our analysis, it is impossible to clearly define the influence of active TB on the course of SARS-CoV-2 infection. We can only suggest that coinfection is particularly dangerous for socially disadvantaged people, the elderly, and people with other comorbidities. In the coming years, a negative impact of the current pandemic on control programmes will be observed for many infectious diseases, including TB.\n\nCOVID-19\ntuberculosis\nSARS-CoV-2\nMycobacterium tuberculosis\ncoincidence\ncoinfection\n==== Body\npmc1. Introduction\n\nThe global risks of infectious diseases, including tuberculosis, have long been a concern of governmental and non-governmental institutions responsible for public health policy. Since tuberculosis as an infectious disease remains a major cause of death in the world, it requires monitoring, efficient and reliable diagnosis, contact tracing, and effective treatment. The COVID-19 pandemic has significantly changed the functioning of healthcare systems. COVID-19 and tuberculosis are both infectious diseases that primarily affect the respiratory system and cause similar symptoms, such as cough, fever, and breathing problems [1]. Both diseases are transmitted mainly by close contact and usually spread via airborne droplets. Factors influencing the course of COVID-19 include old age [2], immune response [3,4], host genetics [5], environmental factors [6], and therapeutic interventions related to comorbidities [7,8]. Mass immunization programmes in populations all over the world are now in progress, and treatment largely relies on adjuvant therapy [9].\n\nThe incidence of tuberculosis in Poland is slightly higher than the European average, and in 2019 it was 13.9/100,000. Poland, Romania, and the United Kingdom accounted for 45% of all TB cases reported in the European Union [10]. Considering the number of SARS-CoV-2 cases, Poland, until October 2020, was not a high-risk country compared to European data. However, as the pandemic continued, the domestic epidemiological situation got worse, and the notified statistics reached alarming levels. According to the ECDC update (as of 21 July 2021), 2,881,594 cases of SARS-CoV-2—including 75,219 deaths (2.6% of infected patients)—have been reported in total from Poland [11].\n\nIn the face of the global COVID-19 pandemic, other epidemiological problems important for public health have been neglected, and there have been shortfalls in the diagnosis of many serious infectious diseases, including TB.\n\nThe National Reference Laboratory for Tuberculosis (NRLT) at the Institute of Tuberculosis and Lung Diseases in Warsaw has monitored the incidence of TB and COVID-19 coinfection in Poland from the beginning of the pandemic and holds relevant records of patients. Based on notifications from regional laboratories for Mycobacterium tuberculosis, two cases of TB and COVID-19 coinfection have been documented, and they are described below.\n\n2. Case Study\n\n2.1. Case 1—Lethal COVID-19 and TB Infection\n\nA 71-year-old homeless man reported to the emergency department on 25 May 2020 due to general weakening, cough with expectoration of greenish sputum of over a week, and atrial fibrillation of undetermined duration. He had a fever of 39.6 °C and a sore throat. His general condition was moderately severe; he was conscious, in logical contact, cachectic (body mass index: 15.59), and with severe dyspnoea. Vital signs were an average heart rate of 128 beats per minute, blood pressure 91/67 mmHg, tachypnea, with a respiratory rate of 44 breaths/min, oxygen saturation (spO2) on room air 76–89%, with an increase in spO2 up to 96% after oxygen therapy through a mask with a flow of 5 Lt/min. The medical history revealed smoking (more than 20 cigarettes/day) for most of his life. The patient was treated for tuberculosis in 1981.\n\nA test for SARS-CoV-2 was performed using a throat and nasal swab taken on 27 May 2020. The Vitassay qPCR SARS-CoV-2 test was positive for SARS-CoV-2 RNA. A chest X-ray revealed bilateral areas of confluent parenchymal and interstitial densities in the lungs, predominantly in the upper and middle fields. Computed tomography, completed on 28 May 2020, showed lesions typical of pulmonary tuberculosis (Figure 1). Antimycobacterial treatment was initiated empirically in the following scheme: isoniazid (INH), rifampicin (RMP), pyrazinamide (PZA), and ethambutol (EMB).\n\nFor further TB diagnosis, sputum was sampled from the patient and sent to the NRLT. The analysis of the fluorescent-stained microscopic smear using the Ziehl–Neelsen technique revealed the presence of acid-fast bacilli (AFB+++) (Figure 2A). The GeneXpert assay confirmed the presence of genetic material from MTBC. An identification and drug sensitivity test for the isolated strain confirmed it belonged to the species Mycobacterium tuberculosis and was sensitive to streptomycin (SM), INH, RMP, EMB, and PZA.\n\nFrom the third day of hospitalisation, respiratory failure was increasing, with no improvement after the use of high-flow oxygen therapy (helmet-based CPAP/continuous positive airway pressure). Mechanical ventilation was applied, and an infusion of norepinephrine and dobutamine was initiated due to circulatory decompensation. Cardiac arrest by asystole occurred after a few hours and the patient was pronounced dead.\n\n2.2. Case 2—Asymptomatic COVID-19 in the Coexistence of Extra-Pulmonary and Pulmonary TB and HIV Infection\n\nAn HIV-positive, 64-old patient was treated in 2018–2019 for pulmonary tuberculosis and urogenital tuberculosis, which was confirmed by a positive bacteriological test in NRLT. Back then, assays revealed the presence of mycobacteria in sputum and urine smears (Figure 2B,C). In the genetic assay, Mycobacterium tuberculosis complex (MTBC) DNA was detected in clinical materials, and mycobacterial strains sensitive to SM, INH, RMP, EMB, and PZA were cultured.\n\nFrom 27 May 2020, the patient was hospitalized due to haematuria and chronic kidney disease requiring dialysis. Relevant diagnostic procedures were carried out because of the suspected relapse of urogenital TB. Histopathological examination of bladder specimens (collected on 28 May) revealed granular lesions with purulent inflammation and necrotizing purulent masses of tissue. On 19 June 2020, tissue sections fixed in paraffin were submitted to the NRLT for TB diagnosis. The genetic assay was negative for MTBC DNA.\n\nDuring hospitalization, the patient tested positive for SARS-CoV-2. The analytical material was a throat and nasal swab taken on 27 May 2020. The Vitassay qPCR SARS-CoV-2 test was positive for SARS-CoV-2 RNA. Due to mild symptoms of infection, the patient did not require clinical intervention and was discharged from the hospital in good health. He received outpatient care, with dialysis therapy recommended.\n\n2.3. Molecular Epidemiological Investigation\n\nAn interview revealed that both patients were in the care of a homeless shelter in Warsaw and had contact with each other. A molecular epidemiological investigation was carried out with a focus on the potential transmission of TB between patients. MTBC strains isolated from clinical samples from both patients were analysed using spoligotyping and MIRU-VNTR. The strain cultured from Patient 1′s sputum was classified as the spoligotype LAM9 42 with MIRU-VNTR code 233464236654438. Strains cultured from the sputum and urine of Patient 2 were identical and represented the molecular family T1 51 with MIRU-VNTR code 324443322564234 (Table 1).\n\n3. Discussion\n\nData on the coincidence of TB and COVID-19 are limited. So far, there have been a few studies describing cases of coinfection with MTBC and the SARS-CoV-2 virus [12,13,14,15]. In our research, we present the first two cases of coinfection in Poland, detected shortly after the outbreak of the global pandemic. Both of the case study patients had active TB and contracted a SARS-CoV-2 infection. However, the course of coinfection was entirely different in the first patient, and at the time of infection with the virus, the TB was very advanced. This caused worse outcomes, and the patient died as a result of both diseases. The second presented case is particularly interesting because therapeutic success was achieved despite the coincidence of COVID-19, HIV, and extrapulmonary and pulmonary TB. Hypothetically, this homeless patient, because of coinfection with TB and HIV, had better access to healthcare, and the treatment of TB did not cause damage and complications as in the first patient.\n\nPolarized views have been reported regarding the course of SARS-CoV-2 infection in patients with active TB. The first cohort analysis to assess the relationship between TB and COVID-19 was prepared through an international collaboration and included 49 cases of coinfection identified in 8 countries and revealed a higher mortality rate among the elderly with a history of tuberculosis [13]. Chen et al. reported that tuberculosis increased susceptibility to COVID-19 and exacerbated its symptoms [16]. Similarly, Italian researchers have suggested that coinfection may be more severe in the elderly or in patients with comorbidities, but that it is a clinically manageable condition [17,18]. Another study carried out in the Philippines confirmed a negative role of TB in the course of COVID-19, and linked coinfection with a higher risk of morbidity and mortality [19]. Substantial evidence for the impact of TB on COVID-19 outcomes was obtained in a South African study that compared data on more than 3 million patients treated in public healthcare institutions, with or without COVID-19, and with other comorbidities, including TB and HIV. It demonstrated that a history of tuberculosis, active tuberculosis, and tuberculosis coexisting with HIV infection all increase the risk of death in COVID-19 patients [20].\n\nContrasting conclusions were reached in another two studies, which found no direct relationship between tuberculosis and the deterioration of COVID-19 symptoms [21,22].\n\n4. Conclusions\n\nPerhaps it is too early and too small a population has been studied to draw firm conclusions on how TB affects the course of SARS-CoV-2 infection. Over time, more studies will probably be published to support these hypotheses. By consensus, it can already be inferred that coinfection is particularly dangerous for socially disadvantaged people, the elderly, and patients with other comorbidities such as diabetes and/or hypertension. However, taking into account the cases reported by us, it may not be possible to draw firm conclusions on the consequences of viral and bacterial coinfections.\n\nThe consequences of the COVID-19 pandemic pose a serious challenge to tuberculosis control programmes, mainly because of shortfalls in the diagnosis and treatment of tuberculosis [23]. Due to the similarities between the symptoms of TB and COVID-19, countries without an effective diagnostic framework are unable to correctly detect these infections. This issue has a negative effect on therapeutic decisions and, thus, on the prognosis of both diseases [24,25,26].\n\nBased on these observations, it can be predicted that the SARS-CoV-2 pandemic is likely to impact healthcare systems around the world. Deficiencies in control programs for many chronic diseases (such as diabetes, COPD, hypertension, asthma, cardiovascular disease, cancer, and depression), diagnostic delays, and drug unavailability worsened the epidemiological situation and increased the number of cases and deaths [27]. In addition, lockdowns and increased difficulty in accessing healthcare resulted in the adoption of virtualized treatments that eliminated the possibility of physical meetings between patients and healthcare providers [28].\n\nAccording to the WHO forecast, the SARS-CoV-2 pandemic will set the world programme of tuberculosis control back 5–8 years. In view of this situation, an increase in TB cases and deaths back to the level of the epidemiological indicators in 2013–2016 is expected in 2021.\n\nIt is essential for policymakers and financing institutions to recognize the seriousness of this problem and to take actions to enable the rapid implementation of innovative people-centred approaches to patients affected by TB so that the fight to end one pandemic does not aggravate another.\n\nAcknowledgments\n\nWe would like to thank the team of doctors from the IV-th Department, Hospital for Infectious Diseases, Warsaw, and the team of doctors from the Department of Diagnostic Imaging, Hospital for Infectious Diseases, Warsaw for providing medical and radiological documentation.\n\nAuthor Contributions\n\nConceptualization, M.K. and E.A.-K.; methodology, M.K.; formal analysis, M.K.; investigation, M.K. and E.A.-K.; writing—original draft preparation, M.K.; writing—review and editing, E.A.-K.; funding acquisition, E.A.-K. All authors have read and agreed to the published version of the manuscript.\n\nFunding\n\nThis research was funded by the National Science Centre of Poland (Grant Number 2019/35/B/NZ7/00942). The study was undertaken as a part of the statutory activity of the Tuberculosis and Lung Diseases Research Institute (Research Task No. 1.47).\n\nInstitutional Review Board Statement\n\nNot applicable.\n\nInformed Consent Statement\n\nPatient 1′s consent was waived due to his homelessness, death and lack of contact with relatives. The consent of Patient 2 was waived due to homelessness, lack of identification of their place of stay and lack of contact with relatives.\n\nData Availability Statement\n\nThe clinical data of the reported results have been archived in IV-th Department, Hospital for Infectious Diseases and in Department of Diagnostic Imaging, Hospital for Infectious Diseases. Microbiology data has been archived at the Department of Microbiology, National Tuberculosis and Lung Diseases Research Institute, Warsaw, Poland.\n\nConflicts of Interest\n\nThe authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.\n\nFigure 1 Figure 1. Chest CT scans. (A)—parenchymal-atelectatic lesions; thick-walled cavities filled with masses of tissue decay in the upper lobes; (B)—parenchymal-atelectatic lesions; cavities filled with tissue decay in segment 3 of the right and left lung, with the accompanying areas of tree-in-bud-appearance in segment 3 of the left lung and in the apex of segment 6 of the right and left lung; (C)—fluid in the pleural cavity; (D–F)—tree-in-bud-appearance in the apex of segment 6 of the right lung and in segments 6–9 of the left lung.\n\nFigure 2 Acid-fast bacilli visible after Ziehl–Neelsen staining; (A)—sputum (Patient 1); (B)—urine (Patient 2); (C)—sputum (Patient 2).\n\ndiagnostics-11-01768-t001_Table 1 Table 1 Clinical and microbiological characteristics of reported cases.\n\n\tPATIENT 1\nHospitalisation 25–31 May 2020\tPATIENT 2\nHospitalisation 27.05–29 May 2020\t\nSex\tMale\tMale\t\nAge\t71\t64\t\nSocial status\tHomeless\tHomeless\t\nComorbidities\tAtrial fibrillation\tHIV-positive\nRenal insufficiency\t\nSymptoms on admission\tCough, weakness, malaise, coughing up sputum\tNo data\t\nTB\t\t\t\nMedical history\t1981—pulmonary tuberculosis\tDecember 2018—pulmonary tuberculosis February 2019—urogenital tuberculosis\t\nChest X-ray, CT\t(28 May 2020) Lesions suggesting pulmonary TB\tNo data\t\nBacteriological assay\t(29 May 2020) Sputum AFB (+++)—MTBC culture\tSputum AFB (+)—MTBC culture\nUrine AFB (+++)—MTBC culture\t\nGenetic assay\t(29 May 2020) GeneXpert\nSputum (+)\t(19 June 2020) GeneXpert\nBladder specimens embedded in paraffin (-)\t\nStrain drug sensitivity\tSensitive to SM, INH, RMP, EMB, PZA\tSensitive to SM, INH, RMP, EMB, PZA\t\nStrains genotyping\nSpoligotyping\nMIRU-VNTR\t■■■■■■■■■■■■■■■■■■■■□□□□■■■■■■■■□□□□■■■■■■■\nLAM9 42\n233464236654438\t■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■□□□□■■■■■■■\nT1 51\n324443322564234\t\nTB treatment\tINH+RMP+PZA+EMB\tNo data\t\nCOVID-19\t\t\t\nDiagnostic tests\tThroat and nasal swab\tThroat and nasal swab\t\nGenetic assay\tVitassay qPCR SARS-CoV-2 (+)\n(27 May 2020)\tVitassay qPCR SARS-CoV-2 (+)\n(27 May 2020)\t\nClinical symptoms\tCough, fever of 39.6 °C, shortness of breath, and a sore throat\tNo symptoms\t\nRadiological observations\tChest X-ray: bilateral areas of fusing parenchymal-atelectatic densities in the lungs, predominant in the upper and middle fields\nCT scans: Extensive lesions parenchymal-atelectatic; thick-walled cavities filled with masses of tissue decay in the upper lobes płuc; areas of tree-in-bud-appearance in segment 3 of the left lung and in the apex of segment 6 of the right and left lung; fluid in the pleural cavity; tree-in-bud-appearance in the apex of segment 6 of the right lung and in segments 6–9 of the left lung\tNo data\t\nOther diagnostic tests\t-\tHistopathological examination of bladder specimens revealed granular lesions with purulent inflammation and necrotizing purulent masses of tissue\t\nOUTCOME\tUnsuccessful treatment, death (31 May 2020)\tSuccessful treatment, outpatient care\t\n\nPublisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. 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Studies in humanized mice and convalescent humans yield a SARS-CoV-2 antibody cocktail Science 2020 369 1010 1014 10.1126/science.abd0827 32540901\n9. Troiano G. Nardi A. Vaccine hesitancy in the era of COVID-19 Public Health 2021 194 245 251 10.1016/j.puhe.2021.02.025 33965796\n10. Korzeniewska-Koseła M. Tuberculosis and Lung Diseases in Poland in 2019 NTLDRI Publisher Warsaw, Poland 2020\n11. Latest Situation Update for the EU/EEA Available online: https://www.ecdc.europa.eu/en/cases-2019-ncov-eueea (accessed on 21 July 2021)\n12. Kumar D.R. Bhattacharya D.B. Meena D.V. Soneja D.M. Wig D.N. COVID-19 and TB co-infection—‘Finishing touch’’ in perfect recipe to ‘severity’ or ‘death’ J. Infect. 2020 81 39 40 10.1016/j.jinf.2020.06.062\n13. Tadolini M. Codecasa L.R. García-García J.M. Blanc F.X. Borisov S. Alffenaar J.W. Andréjak C. Bachez P. Bart P.A. Belilovski E. Active tuberculosis, sequelae and COVID-19 co-infection: First cohort of 49 cases Eur. Respir. J. 2020 56 2001398 10.1183/13993003.01398-2020 32457198\n14. Tham S.M. Lim W.Y. Lee C.K. Loh J. Premkumar A. Yan B. Kee A. Chai L. Tambyah P.A. Yan G. Four Patients with COVID-19 and Tuberculosis, Singapore, April-May 2020 Emerg. Infect. Dis. 2020 26 2764 2766 10.3201/eid2611.202752 32667283\n15. Kozińska M. Podlasin R. Ropelewska-Łącka K. Wojtycha-Kwaśnica B. Bajera-Mitschein I. Augustynowicz-Kopeć E. TB and COVID-19 coinfection Int. J. Tuberc. Lung Dis. 2021 25 776 10.5588/ijtld.21.0358\n16. Chen Y. Wang Y. Fleming J. Yu Y. Gu Y. Liu C. Fan L. Wang X. Cheng M. Bi L. Active or latent tuberculosis increases susceptibility to COVID-19 and disease severity MedRxiv 2020 10.1101/2020.03.10.20033795\n17. Stochino C. Villa S. Zucchi P. Parravicini P. Gori A. Raviglione M.C. Clinical characteristics of COVID-19 and active tuberculosis co-infection in an Italian reference hospital Eur. Respir. J. 2020 30 2001708 10.1183/13993003.01708-2020\n18. Motta I. Centis R. D’Ambrosio L. García-García J.M. Goletti D. Gualano G. Lipani F. Palmieri F. Sánchez-Montalvá A. Pontali E. Tuberculosis, COVID-19 and migrants: Preliminary analysis of deaths occurring in 69 patients from two cohorts Pulmonology 2020 26 233 240 10.1016/j.pulmoe.2020.05.002 32411943\n19. Sy K.T.L. Haw N.J.L. Uy J. Previous and active tuberculosis increases risk of death and prolongs recovery in patients with COVID-19 Infect. Dis. 2020 52 902 907 10.1080/23744235.2020.1806353\n20. Davies M.A. HIV and risk of COVID-19 death: A population cohort study from the Western Cape Province, South Africa medRxiv 2020 10.1101/2020.07.02.20145185\n21. Singh A. Prasad R. Gupta A. Das K. Gupta N. Severe acute respiratory syndrome coronavirus-2 and pulmonary tuberculosis: Convergence can be fatal Monaldi Arch. Chest Dis. 2020 90 10.4081/monaldi.2020.1368\n22. Gao Y. Liu M. Chen Y. Shi S. Geng J. Tian J. Association between tuberculosis and COVID-19 severity and mortality: A rapid systematic review and meta-analysis J. Med. Virol. 2021 93 194 196 10.1002/jmv.26311 32687228\n23. Nikolayevskyy V. Holicka Y. van Soolingen D. van der Werf M.J. Ködmön C. Surkova E. Hillemann D. Groenheit R. Cirillo D. Impact of COVID-19 pandemic on tuberculosis laboratory services in Europe Eur. Respir. J. 2021 57 2003890 10.1183/13993003.03890-2020 33184119\n24. Getnet F. Demissie M. Worku A. Gobena T. Tschopp R. Girmachew M. Assefa G. Seyoum B. Delay in diagnosis of pulmonary tuberculosis increases the risk of pulmonary cavitation in pastoralist setting of Ethiopia BMC Pulm. Med. 2019 19 201 10.1186/s12890-019-0971-y 31694601\n25. Togun T. Kampmann B. Stoker N.G. Lipman M. Anticipating the impact of the COVID-19 pandemic on TB patients and TB control programmes Ann. Clin. Microbiol. Antimicrob. 2020 19 21 10.1186/s12941-020-00363-1 32446305\n26. Amimo F. Lambert B. Magit A. What does the COVID-19 pandemic mean for HIV, tuberculosis, and malaria control? Trop. Med. Health 2020 48 32 10.1186/s41182-020-00219-6 32425653\n27. Chudasama Y.V. Gillies C.L. Zaccardi F. Coles B. Davies M.J. Seidu S. Khunti K. Impact of COVID-19 on routine care for chronic diseases: A global survey of views from healthcare professionals Diabetes Metab. Syndr. 2020 14 965 967 10.1016/j.dsx.2020.06.042 32604016\n28. Webster P. Virtual health care in the era of COVID-19 Lancet 2020 395 1180 1181 10.1016/S0140-6736(20)30818-7 32278374\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2075-4418",
"issue": "11(10)",
"journal": "Diagnostics (Basel, Switzerland)",
"keywords": "COVID-19; Mycobacterium tuberculosis; SARS-CoV-2; coincidence; coinfection; tuberculosis",
"medline_ta": "Diagnostics (Basel)",
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"pubdate": "2021-09-26",
"publication_types": "D002363:Case Reports",
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"title": "COVID-19 in Patients with Active Tuberculosis.",
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"abstract": "BACKGROUND\nHemophagocytic lymphohistiocytosis (HLH) is a rare multiorgan disease of toxic immune activation caused by the interaction of cytotoxic T cells and innate immune cells and frequently involves the central nervous system (CNS). Posterior reversible encephalopathy syndrome (PRES) might develop during treatment with the HLH-2004 protocol from the Histiocyte Society. The aims of this study were to evaluate clinical outcomes and putative risk factors for prediction of PRES related to HLH.\n\n\nMETHODS\nWe reviewed the medical records of 28 patients with HLH who were treated between April 2005 and April 2012. We compared various clinical and laboratory parameters in patients without or with PRES to evaluate putative risk factors related to development of PRES.\n\n\nRESULTS\nSix (21.4%) of the patients experienced PRES during treatment with the HLH-2004 protocol. Clinical and laboratory manifestations were not different compared with other conditions causing PRES. The main mechanism of PRES may be related to the HLH-2004 protocol and a high pro-inflammatory state. Most patients recovered quickly from neurologic manifestations without significant long-term sequelae. Preceding hypertension, an increase in ferritin level >50% compared with 1 week before development of PRES and hyponatremia were statistically significant factors.\n\n\nCONCLUSIONS\nPRES is clinically reversible and has a favorable outcome in patients with HLH. Awareness of PRES and a differential diagnosis of other causes of neurologic complications, including CNS involvement of HLH, can help avoid unnecessary treatment or delayed management. Patients with preceding hypertension, hyponatremia, and rising ferritin levels during HLH treatment should be closely monitored for PRES.",
"affiliations": "Department of Pediatrics, Ewha Womans University School of Medicine, Seoul, Korea.;Department of Pediatrics, Ewha Womans University School of Medicine, Seoul, Korea.;Department of Pediatrics, Ewha Womans University School of Medicine, Seoul, Korea.;Department of Pediatrics, Ewha Womans University School of Medicine, Seoul, Korea.",
"authors": "Lee|Goni|G|;Lee|Seung Eun|SE|;Ryu|Kyung-Ha|KH|;Yoo|Eun Sun|ES|",
"chemical_list": null,
"country": "Korea (South)",
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"doi": "10.5045/br.2013.48.4.258",
"fulltext": "\n==== Front\nBlood ResBlood ResBRBlood research2287-979X2288-0011Korean Society of Hematology; Korean Society of Blood and Marrow Transplantation; Korean Society of Pediatric Hematology-Oncology; Korean Society on Thrombosis and Hemostasis 10.5045/br.2013.48.4.258Original ArticlePosterior reversible encephalopathy syndrome in pediatric patients undergoing treatment for hemophagocytic lymphohistiocytosis: clinical outcomes and putative risk factors Lee Goni Lee Seung Eun Ryu Kyung-Ha Yoo Eun Sun Department of Pediatrics, Ewha Womans University School of Medicine, Seoul, Korea.Correspondence to Eun Sun Yoo, M.D., Ph.D. Department of Pediatrics, Ewha Womans University Mokdong Hospital, 1071, Anyangcheon-ro, Yangcheon-gu, Seoul 158-710, Korea. Tel: +82-2-2650-5586, Fax: +82-2-2653-3718, eunsyoo@ewha.ac.kr12 2013 24 12 2013 48 4 258 265 15 9 2013 21 10 2013 14 11 2013 © 2013 Korean Society of Hematology2013This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Background\nHemophagocytic lymphohistiocytosis (HLH) is a rare multiorgan disease of toxic immune activation caused by the interaction of cytotoxic T cells and innate immune cells and frequently involves the central nervous system (CNS). Posterior reversible encephalopathy syndrome (PRES) might develop during treatment with the HLH-2004 protocol from the Histiocyte Society. The aims of this study were to evaluate clinical outcomes and putative risk factors for prediction of PRES related to HLH.\n\nMethods\nWe reviewed the medical records of 28 patients with HLH who were treated between April 2005 and April 2012. We compared various clinical and laboratory parameters in patients without or with PRES to evaluate putative risk factors related to development of PRES.\n\nResults\nSix (21.4%) of the patients experienced PRES during treatment with the HLH-2004 protocol. Clinical and laboratory manifestations were not different compared with other conditions causing PRES. The main mechanism of PRES may be related to the HLH-2004 protocol and a high pro-inflammatory state. Most patients recovered quickly from neurologic manifestations without significant long-term sequelae. Preceding hypertension, an increase in ferritin level >50% compared with 1 week before development of PRES and hyponatremia were statistically significant factors.\n\nConclusion\nPRES is clinically reversible and has a favorable outcome in patients with HLH. Awareness of PRES and a differential diagnosis of other causes of neurologic complications, including CNS involvement of HLH, can help avoid unnecessary treatment or delayed management. Patients with preceding hypertension, hyponatremia, and rising ferritin levels during HLH treatment should be closely monitored for PRES.\n\nHemophagocytic lymphohistiocytosisPosterior reversible encephalopathy syndromeHLH-2004Risk factorsReversibleChild\n==== Body\nINTRODUCTION\nPosterior reversible encephalopathy syndrome (PRES) is a transient clinicoradiologic phenomenon characterized by seizure, headaches, altered mental status, and visual impairment with abnormal signal lesions on magnetic resonance imaging (MRI). Since it was first proposed in 1996 by Hinchey et al. [1], PRES has been reported in various conditions, such as renal disease, eclampsia, autoimmune disease, hematologic-oncologic malignancies, transplantation, and sepsis [2-14] and has developed in association with the use of medications such as chemotherapeutic agents, immunosuppressive drugs, immunoglobulin, and antiangiogenic drugs [15-17].\n\nPRES may occur in patients being treated for hemophagocytic lymphohistiocytosis (HLH), which is a life-threatening disease characterized by a generalized proliferation of histiocytes as a result of ineffective, uncontrolled activation of cytotoxic T cells and antigen-presenting cells and up-regulation of inflammatory cytokine [18, 19]. HLH has usually been treated since 2004 according to the international Histiocyte Society treatment protocol (HLH-2004), which includes etoposide, dexamethasone, and cyclosporin A (CSA) and, in selected patients, intrathecal therapy with methotrexate and corticosteroids to provide more intensive immunosuppression at the beginning of treatment [20].\n\nWe have observed significant neurologic toxicity, which is proposed to be PRES, during treatment with the HLH-2004 protocol. Because HLH is a rare multisystem disorder, in which the occurrence of PRES is even rarer, it can be difficult to distinguish PRES from other neurologic manifestations. However, careful differential diagnosis of these neurologically toxic conditions from other causes of neurologic conditions is necessary, especially with central nervous system (CNS) involvement of hemophagocytosis. HLH is frequently associated with CNS lesions with highly variable clinical manifestations at onset or during progression, and delayed diagnosis may result in permanent damage to the affected brain tissues with poorer outcomes, contrary to PRES [21].\n\nIn this study, we analyzed the clinical and laboratory findings, radiologic features, and long-term outcomes of patients with HLH who developed PRES during treatment using the HLH-2004 protocol and evaluated the role of putative risk factors for prediction of PRES related to HLH.\n\nMATERIALS AND METHODS\nPatients\nWe retrospectively reviewed the medical records of 28 patients who had a diagnosis of HLH and were treated according to the HLH-2004 protocol in the Department of Pediatrics at Ewha Womans University Mokdong Hospital, Seoul, Korea between April 2005 and April 2012. Six of these patients had a diagnosis of HLH and were treated for PRES, and they were enrolled in this study. One of these 6 patients repeatedly experienced PRES during 2 separate treatments due to reactivation of HLH, so a total of 7 events of PRES in 6 patients were reviewed.\n\nMethods\nAll 28 patients had a diagnosis of HLH according to the diagnostic criteria proposed by the HLH-2004 protocol, meeting 5 of the following 8 criteria: (1) fever; (2) splenomegaly; (3) cytopenia in 2 or more cell lines (hemoglobin level <9 g/dL, platelet count <100×109/L, and neutrophil count <1.0×109/L); (4) hypertriglyceridemia (≥265 mg/dL) or hypofibrinogenemia (≤150 mg/dL); (5) the presence of hemophagocytosis in the bone marrow, spleen, and lymph node; (6) hyperferritinemia (≥500 ng/mL); (7) an impaired function of natural killer cells or its absence; and (8) a concentration of serum soluble CD25 (soluble interleukin-2 receptor) ≥2,400 IU/mL [5]. All patients were also treated according to the HLH-2004 protocol with combinations of CSA, dexamethasone, and etoposide [20].\n\nPRES was defined by the presence of at least one of the classic clinical symptoms of seizure, headaches, altered mental status, or visual impairment in combination with typical radiologic findings on T2 and fluid attenuation inversion recovery (FLAIR) MRI, including mainly bilateral posterior subcortical hyperintensities. All patients underwent both MRI of the brain and analysis of cerebrospinal fluid (CSF) at diagnosis of HLH and at onset of PRES. None of the 6 patients had abnormal findings at diagnosis of HLH.\n\nWe reviewed the medical records of all 28 patients with HLH, including medical history, clinical characteristics, blood pressure, CSF findings, laboratory findings, MRI results, and treatment outcomes at diagnosis and during the clinical course. We compared various clinical and laboratory findings between patients without and with PRES to evaluate putative risk factors related to development of PRES.\n\nStatistical analysis\nAll analyses were performed using SPSS version 17.0. The Wilcoxon rank sum test and chi-square test were used for comparison of continuous variables between patients with and without PRES. For analysis of putative factors on the development of PRES, chi-square test, Fisher exact test, and logistic regression analysis were performed using selective parameters. Statistically significant variables on univariate analysis were included in a multivariate analysis. A P value <0.05 was considered statistically significant.\n\nRESULTS\nClinical characteristics at the onset of PRES\nSix of the 28 patients with HLH (21.4%) had documented PRES. Table 1 shows the clinical and laboratory findings of these 6 patients. One patient (patient 4), who was treated with 2 separate cycles of chemotherapy because of reactivation, experienced PRES twice during each HLH treatment. The mean time to development of PRES was 20.1 days (range, 12-29 days) from the start of chemotherapy. All patients experienced various forms of seizures, such as generalized tonic-clonic seizure of gaze deviation, suggesting partial seizure. Before the onset of seizures, all 6 patients experienced headache and altered mental status such as somnolence, drowsiness, and delirium. Four of the 6 patients developed hypertension and visual disturbances such as diplopia and cortical blindness, and 2 of the 6 patients experienced an auditory abnormality.\n\nLaboratory and radiologic findings\nThe WBCs, results of coagulation studies and fibrinogen assay, liver and kidney function, and calcium and magnesium levels were normal in all patients (data not shown) during PRES. However, hyponatremia (<135 mEq/L) was noted in 3 of the 6 patients. CSA levels were in the therapeutic range, with a mean blood level of 221.3 ng/dL (range, 145-384 ng/dL). Serum ferritin levels were variable in each patient, ranging from 350 to 8,076 ng/dL at the onset of PRES (Table 1).\n\nAll patients underwent electroencephalography (EEG), CSF analysis, and MRI immediately after neurologic symptoms developed. The results of CSF analysis were normal in all patients with PRES. All patients had abnormal findings on EEG with non-specific slow wave to multifocal spike except for 2 patients (patients 1 and 6) who were not assessed because of their worsening condition (Table 1). MRI showed a decreased signal with a T1-weighted image and hyperintense abnormalities on T2-weighted and FLAIR images typical of PRES bilaterally in the subcortical white matter and cortical gray matter of the posterior parietal and occipital lobes (Fig. 1).\n\nClinical course and long-term outcomes\nTable 2 shows a summary of the clinical course and long-term outcomes after development of PRES. All patients started treatment for acute seizures with midazolam, phenytoin, valproic acid, or levetiracetam and for hypertension with a calcium channel blocker and/or hydralazine, which succeeded in controlling these conditions. After confirming typical MRI findings for PRES and negative results of CSF analysis, we temporarily discontinued treatment with CSA for 7 to 14 days or reduced the dose because we considered CSA to be a possible cause of the convulsive encephalopathy.\n\nAfter provision of the supportive care described in the preceding text, the symptoms of headache, visual disturbance, and altered mental function slowly improved and resolved in all patients, as shown by normal findings on neurologic examinations in the subsequent 1 to 2 weeks. All patients showed no aggravation of HLH during temporal cessation of treatment with CSA. Four of the 6 patients resumed treatment with CSA within 7 or 14 days after diagnosis of PRES under careful medical observation, and 5 of the 6 patients tolerated CSA well without recurrence of neurotoxicity when CSA therapy resumed. However, 1 patient (patient 5) developed the same symptoms relating to PRES 2 days after restarting CSA therapy, and CSA was changed to FK506 after his medical condition was stabilized. This patient successfully completed chemotherapy with FK506 without recurrence of PRES and reactivation of HLH. Another patient (patient 4) experienced a second occurrence of HLH while undergoing treatment for reactivation with the same HLH-2004 protocol, and her condition was successfully managed with CSA with temporal withdrawal. Patient 1 was being treated with a 20% reduction of the original dose of CSA at diagnosis of PRES, and the dose was reduced by 10% every week to a 40% reduction of the dose until the patient's death.\n\nAll patients were able to discontinue treatment with antihypertensive drugs within 7 to 25 days after onset of PRES. Antiepileptic drug therapy was maintained for several months until confirmation of complete recovery, which was based on normal findings on follow-up EEG after full recovery from the seizure attack and seizures were well controlled even after cessation of drug therapy. One patient (patient 5) continued long-term treatment with an antiepileptic drug at the time of his last clinical follow-up visit because of repeated seizure episodes even though no epileptiform discharges were noted on EEG.\n\nFollow-up MRI showed complete recovery to normal in all patients between 1 and 2 months (median, 1.2 months) except for 2 patients (patients 1 and 6) who were not assessed by MRI (Fig. 1, D2 & E2). The patient who continued long-term treatment with an antiepileptic drug (patient 5) had normal findings on MRI 1 month later.\n\nAll patients recovered without any residual symptoms of PRES except for 1 patient who died of HLH-related complications after recovery from PRES.\n\nPutative risk factors for patients with HLH who developed PRES\nWe compared the clinical and laboratory findings at diagnosis of HLH between patients with and without PRES to determine the putative risk factors. The clinical and laboratory findings were not statistically different in both groups (Table 3). We also performed logistic regression analysis using selective clinical and laboratory parameters. Among the several factors, preceding hypertension (P=0.016), a preceding rise in ferritin level >50% compared with 1 week before development of PRES (P=0.001), and hyponatremia (<135 mEq/L) (P=0.003) were statistically significant (Table 4). These factors apparently comprise putative risk factors for PRES complicated during induction chemotherapy compared with other factors.\n\nDISCUSSION\nPRES is a neurologic complication in pediatric patients undergoing treatment for HLH with the HLH-2004 protocol, although PRES has been described in numerous medical conditions. Previous pediatric studies have reported that most cases of PRES develop during the treatment of children with various cancers, mainly leukemia, and renal dysfunction [2, 8-14].\n\nThe incidence of PRES in patients undergoing treatment of HLH is undefined, and there are only 2 reports of PRES related to treatment of HLH thus far [19, 22]. In the present study, PRES was documented in 6 of 28 patients (21.4%) undergoing treatment of HLH. Similar results were reported by Thompson et al. [19], who found that 24% (4/17) of patients treated for HLH had PRES. The overall incidence of PRES varies from 0.49% in patients undergoing solid organ transplantation [23] to 47.4% in pediatric patients with acute lymphoblastic leukemia [9]. When we consider the results of Thompson et al. [19] and our study, HLH might predispose patients to develop PRES and the estimated incidence of PRES-related HLH treatment may be fairly high compared with other conditions causing PRES.\n\nAlthough the pathophysiology that underlies the development of PRES is likely multi-factorial, the mechanism of PRES has been explained by both vasogenic and cytotoxic effects. Hypertension is one of the main mechanisms proposed [13, 24, 25]. The acute rise of blood pressure leads to vasoconstriction in the cerebral blood vessels as a result of physiologic auto-regulation. However, sustained hypertension leads to the disturbance of cerebrovascular auto-regulation, the dilation of cerebral arterioles, the opening of endothelial tight junctions, and the leakage of plasma and red blood cells into the extracellular space. Finally, edema and micro-infarcts develop (vasogenic theory).\n\nA direct toxic effect on the vascular endothelium (e.g., by different chemotherapeutic agents) is also a proposed mechanism of PRES (cytotoxic theory). Endothelial dysfunction and blood-brain barrier disruption lead to the leakage of plasma and red blood cells into the extracellular space [25, 26].\n\nIn our study, 4 of the 6 patients (66.7%) had hypertension before the development of PRES, and preceding hypertension was a significant putative risk factor for PRES (Tables 1 and 4). Therefore, we suggest that hypertension plays a crucial role in the development of PRES in patients with HLH. Hypertension always accompanies PRES as a contributory factor, but some cases of PRES have occurred in patients with normal blood pressure. Two cases of PRES occurred in patients with normal blood pressure in our study, and approximately 30% of cases of PRES were reported in patients with normal blood pressure in the literature [8].\n\nHypertension is caused by use of the HLH-2004 protocol and the highly inflammatory environment of HLH. Patients with HLH may have higher-risk environments, predisposing them to develop PRES. Our patients were treated according to the HLH-2004 protocol, which is based on etoposide, dexamethasone, and CSA, and the combination of these drugs may increase the incidence of PRES in patients with HLH. CSA, a calcineurin inhibitor, has been considered one of the promoting factors for the development of PRES. CSA neurotoxicity is frequently reported in the setting of both hematopoietic stem cell and solid organ transplantation. The mechanisms of CSA neurotoxicity are unknown, but CSA causes reversible ischemic disturbances in the brain by endothelial cell damage and vasoconstriction [27]. Furthermore, the combination of CSA and dexamethasone may potentiate the risk of developing PRES in patients with HLH via hypertension. Corticosteroids may play an indirect role in the development of PRES due to the higher risk of hypertension, and corticosteroid-induced PRES was reported by Irvin et al. [28]. The CSA level does not seem to compromise predisposing factors, because our patients who developed PRES had a therapeutic range of CSA with a blood level of 221.3 ng/dL (range, 145-384 ng/dL). High CSA blood levels are widely known to be more frequently associated with a high prevalence of PRES, but CSA-associated PRES has also been found in patients with a therapeutic range [22, 29].\n\nThompson et al. [19] proposed changing the protocol for treatment of HLH regarding early introduction of CSA, which may increase the risk of PRES (41.2% vs. 7.1%), although the difference between the 2 study groups did not quite reach statistical significance. In the HLH-2004 protocol, initiation of cyclosporine was moved from after week 8 to day 1 to provide more intense upfront immune suppression to increase the survival of patients with HLH [20]. We could not compare the risk of PRES according to different study protocols because enrolled patients were treated with the HLH-2004 protocol, not the HLH-94 protocol, but this hypothesis is quite persuasive when we consider the mechanisms of the possible predisposing factors and the higher incidence of PRES in our study compared with other groups at risk for PRES.\n\nAnother possible cause of the increased prevalence of PRES in patients with HLH is related to the highly pro-inflammatory state, because HLH is a syndrome of toxic immune activation driven by the interaction of T cells and innate immune cells. As a result, greater amounts of inflammatory cytokines may affect the blood-brain barrier, and the patient might be at greater risk for neurologic toxicity by the mechanism of the vasogenic theory. Our finding that ferritin level is a significant putative risk factor for PRES supports it (Table 4).\n\nWe demonstrated that PRES is reversible in patients with HLH and that these patients have favorable outcomes with prompt diagnosis and treatment. Our patients recovered with supportive care, including control of blood pressure, use of antiepileptic drugs, and temporarily reduced or withdrawn treatment with CSA without substitution. None of the patients were observed to have aggravation of HLH during cessation of treatment with CSA, and reintroduction of CSA was well tolerated without recurrence of neurotoxicity in all patients except one (patient 5). Patient 5 redeveloped PRES after restarting treatment with CSA, and we changed CSA to tacrolimus even though tacrolimus may be associated with similar neurotoxic adverse events [30, 31]. Nevertheless, this patient successfully completed treatment of HLH, and his condition has been stable for 42 months (Table 2). All patients with PRES except one (patient 5) discontinued follow-up. All patients had evidence on follow-up MRI 1 month after diagnosis that their brain lesions regressed completely.\n\nIn conclusion, PRES has been shown to develop in patients undergoing treatment with the HLH-2004 protocol. The mechanisms of PRES in patients with HLH are related to hypertension resulting from treatment, not disease. However, a hyper-proinflammatory condition in patients with HLH may influence the increase in risk for induction of PRES by potentiating the neurotoxic effect of CSA and dexamethasone. Therefore, our experience indicates that patients receiving treatment that follows the HLH-2004 protocol should be closely monitored for the development of PRES. Awareness of this syndrome is important to distinguish PRES from other neurologic manifestations, especially CNS involvement of hemophagocytosis, and avoid unnecessary treatment or delays and anxiety. Early recognition and proper supportive care can result in a fast recovery without significant long-term sequelae in most patients with HLH. Further evaluation in a larger population is warranted to validate the risk factors suggested in this study.\n\nNo potential conflicts of interest relevant to this article were reported.\n\nFig. 1 Magnetic resonance images (MRI) in patients with posterior reversible encephalopathy during treatment with the HLH-2004 protocol. MRI showed decreased signal on T1-weighted images and hyperintense abnormalities on T2-weighted and fluid attenuated inversion recovery (FLAIR) images (A-F) typical for PRES, bilaterally in the subcortical white matter and cortical gray matter of the posterior parietal and occipital lobes. These initial increased signal lesions completely disappeared after 1 to 2 months of treatment (D2 and E2).\n\nTable 1 Clinical and laboratory findings of patients with HLH and PRES.\n\na)Onset time of PRES from the start of treatment. b)Hypertension was defined as blood pressure that was the same as or higher than that of 95% of children who are the same gender, age, and height. c)First episode. d)Second episode.\n\nAbbreviations: HLH, hemophagocytic lymphohistiocytosis; PRES, posterior reversible encephalopathy syndrome; CSA, cyclosporin A; CSF, cerebrospinal fluid; EEG, electroencephalogram; MRI, magnetic resonance imaging; M, male; HT, hypertension; F, female.\n\nTable 2 Concurrent treatment and clinical outcomes of 6 patients with HLH and PRES.\n\na)First episode. b)Second episode.\n\nAbbreviations: HLH, hemophagocytic lymphohistiocytosis; PRES, posterior reversible encephalopathy syndrome; CSA, cyclosporin A; HT, hypertension; EEG, electroencephalogram; MRI, magnetic resonance imaging; D, day; NED, no evidence of disease.\n\nTable 3 Comparison of clinical and laboratory findings at diagnosis of HLH without or with PRES.\n\nAll values are expressed as mean±SD unless otherwise noted.\n\nAbbreviations: HLH, hemophagocytic lymphohistiocytosis; PRES, posterior reversible encephalopathy syndrome; AST, aspartate aminotransferase; ALT, alanine aminotransferase.\n\nTable 4 Putative risk factors for PRES at the development of PRES by univariate analysis.\n\nAll values are expressed as number or mean±SD unless otherwise noted.\n\na)Preceding rise of ferritin level >50% compared with 1 week before development of PRES.\n\nAbbreviations: PRES, posterior reversible encephalopathy syndrome; CNS, central nervous system; CSA, cyclosporin A; AST, aspartate aminotransferase; ALT, alanine aminotransferase.\n==== Refs\n1 Hinchey J Chaves C Appignani B A reversible posterior leukoencephalopathy syndrome N Engl J Med 1996 334 494 500 8559202 \n2 Wirrell EC Hamiwka LD Hamiwka LA Grisaru S Wei X Acute glomerulonephritis presenting with PRES: a report of 4 cases Can J Neurol Sci 2007 34 316 321 17803029 \n3 Thackeray EM Tielborg MC Posterior reversible encephalopathy syndrome in a patient with severe preeclampsia Anesth Analg 2007 105 184 186 17578974 \n4 El Karoui K Le Quintrec M Dekeyser E Posterior reversible encephalopathy syndrome in systemic lupus erythematosus Nephrol Dial Transplant 2008 23 757 763 18056072 \n5 Bartynski WS Boardman JF Zeigler ZR Shadduck RK Lister J Posterior reversible encephalopathy syndrome in infection, sepsis, and shock AJNR Am J Neuroradiol 2006 27 2179 2190 17110690 \n6 Fuchigami T Inamo Y Hashimoto K Henoch-schonlein purpura complicated by reversible posterior leukoencephalopathy syndrome Pediatr Emerg Care 2010 26 583 585 20693857 \n7 Ozcakar ZB Ekim M Fitoz S Hypertension induced reversible posterior leukoencephalopathy syndrome: a report of two cases Eur J Pediatr 2004 163 728 730 15322868 \n8 Endo A Fuchigami T Hasegawa M Posterior reversible encephalopathy syndrome in childhood: report of four cases and review of the literature Pediatr Emerg Care 2012 28 153 157 22307182 \n9 Kim SJ Im SA Lee JW Predisposing factors of posterior reversible encephalopathy syndrome in acute childhood leukemia Pediatr Neurol 2012 47 436 442 23127265 \n10 de Laat P Te Winkel ML Devos AS Catsman-Berrevoets CE Pieters R van den Heuvel-Eibrink MM Posterior reversible encephalopathy syndrome in childhood cancer Ann Oncol 2011 22 472 478 20699277 \n11 Gumus H Per H Kumandas S Yikilmaz A Reversible posterior leukoencephalopathy syndrome in childhood: report of nine cases and review of the literature Neurol Sci 2010 31 125 131 19809787 \n12 Won SC Kwon SY Han JW Choi SY Lyu CJ Posterior reversible encephalopathy syndrome in childhood with hematologic/oncologic diseases J Pediatr Hematol Oncol 2009 31 505 508 19564746 \n13 Morris EB Laningham FH Sandlund JT Khan RB Posterior reversible encephalopathy syndrome in children with cancer Pediatr Blood Cancer 2007 48 152 159 16317748 \n14 Gupta A Swaroop C Rastogi R Garg R Bakhshi S Simultaneous occurrence of posterior reversible leukoencephalopathy syndrome in two cases of childhood acute lymphoblastic leukemia induction chemotherapy Pediatr Hematol Oncol 2008 25 351 358 18484481 \n15 Saeed B Abou-Zor N Amer Z Kanani I Hilal M Cyclosporin-A induced posterior reversible encephalopathy syndrome Saudi J Kidney Dis Transpl 2008 19 439 442 18445907 \n16 Yokobori S Yokota H Yamamoto Y Pediatric posterior reversible leukoencephalopathy syndrome and NSAID-induced acute tubular interstitial nephritis Pediatr Neurol 2006 34 245 247 16504799 \n17 Hourani R Abboud M Hourani M Khalifeh H Muwakkit S L-asparaginase-induced posterior reversible encephalopathy syndrome during acute lymphoblastic leukemia treatment in children Neuropediatrics 2008 39 46 50 18504683 \n18 Filipovich AH Hemophagocytic lymphohistiocytosis and other hemophagocytic disorders Immunol Allergy Clin North Am 2008 28 293 313 18424334 \n19 Thompson PA Allen CE Horton T Jones JY Vinks AA McClain KL Severe neurologic side effects in patients being treated for hemophagocytic lymphohistiocytosis Pediatr Blood Cancer 2009 52 621 625 19137570 \n20 Henter JI Horne A Arico M HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis Pediatr Blood Cancer 2007 48 124 131 16937360 \n21 Henter JI Nennesmo I Neuropathologic findings and neurologic symptoms in twenty-three children with hemophagocytic lymphohistiocytosis J Pediatr 1997 130 358 365 9063409 \n22 Yakushijin K Mizuno I Sada A Cyclosporin neurotoxicity with Epstein-Barr virus-associated hemophagocytic syndrome Haematologica 2005 90 ECR11 15753052 \n23 Bartynski WS Tan HP Boardman JF Shapiro R Marsh JW Posterior reversible encephalopathy syndrome after solid organ transplantation AJNR Am J Neuroradiol 2008 29 924 930 18272559 \n24 Pavlakis SG Frank Y Chusid R Hypertensive encephalopathy, reversible occipitoparietal encephalopathy, or reversible posterior leukoencephalopathy: three names for an old syndrome J Child Neurol 1999 14 277 281 10342593 \n25 Eguchi K Kasahara K Nagashima A Two cases of malignant hypertension with reversible diffuse leukoencephalopathy exhibiting a reversible nocturnal blood pressure \"riser\" pattern Hypertens Res 2002 25 467 473 12135328 \n26 Norman JK Parke JT Wilson DA McNall-Knapp RY Reversible posterior leukoencephalopathy syndrome in children undergoing induction therapy for acute lymphoblastic leukemia Pediatr Blood Cancer 2007 49 198 203 16123992 \n27 Truwit CL Denaro CP Lake JR DeMarco T MR imaging of reversible cyclosporin A-induced neurotoxicity AJNR Am J Neuroradiol 1991 12 651 659 1882738 \n28 Irvin W MacDonald G Smith JK Kim WY Dexamethasone-induced posterior reversible encephalopathy syndrome J Clin Oncol 2007 25 2484 2486 17557962 \n29 Torelli GF Natalino F Barberi W Early onset of posterior reversible encephalopathy syndrome (PRES) during Cyclosporine-A infusion Leuk Res 2011 35 1423 1424 21397327 \n30 Bechstein WO Neurotoxicity of calcineurin inhibitors: impact and clinical management Transpl Int 2000 13 313 326 11052266 \n31 Wong R Beguelin GZ de Lima M Tacrolimus-associated posterior reversible encephalopathy syndrome after allogeneic haematopoietic stem cell transplantation Br J Haematol 2003 122 128 134 12823354\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2287-979X",
"issue": "48(4)",
"journal": "Blood research",
"keywords": "Child; HLH-2004; Hemophagocytic lymphohistiocytosis; Posterior reversible encephalopathy syndrome; Reversible; Risk factors",
"medline_ta": "Blood Res",
"mesh_terms": null,
"nlm_unique_id": "101605247",
"other_id": null,
"pages": "258-65",
"pmc": null,
"pmid": "24466550",
"pubdate": "2013-12",
"publication_types": "D016428:Journal Article",
"references": "10342593;18424334;17110690;21397327;16937360;9063409;1882738;20693857;18056072;8559202;12135328;19809787;18445907;15322868;16123992;18504683;16317748;20699277;18484481;11052266;17803029;19564746;15753052;23127265;16504799;18272559;19137570;17578974;12823354;17557962;22307182",
"title": "Posterior reversible encephalopathy syndrome in pediatric patients undergoing treatment for hemophagocytic lymphohistiocytosis: clinical outcomes and putative risk factors.",
"title_normalized": "posterior reversible encephalopathy syndrome in pediatric patients undergoing treatment for hemophagocytic lymphohistiocytosis clinical outcomes and putative risk factors"
} | [
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"abstract": "Hydralazine is a medication that has been used to manage hypertension and heart failure. In this case series, we report 4 patients who presented to a large, Midwestern academic medical center on chronic hydralazine therapy with acute kidney injury, nephritic urine sediment on urine microscopy, and the simultaneous presence of autoantibodies suggesting both drug-induced lupus and drug-induced vasculitis. All of them had evidence of pauci-immune glomerulonephritis on kidney biopsy. All the patients reported in our series are white women older than 60 years who were receiving hydralazine for more than 12 months at a dose of 150 mg or more. On initial presentation, all had evidence of acute kidney injury with nephritic sediment. These patients also had high titers of serum anti-neutrophil cytoplasmic antibodies of the antimyeloperoxidase subtype and simultaneous presence of multiple autoantibodies. All of them subsequently underwent a kidney biopsy, which revealed pauci-immune glomerulonephritis. This case series draws rheumatologists' attention to the possibility of pauci-immune glomerulonephritis in patients taking hydralazine, highlights the presence of multiple antibodies in these cases, and questions the long-term use of hydralazine especially in an elderly female population.",
"affiliations": "From the Divisions of *Nephrology and †Allergy/Rheumatology, Department of Internal Medicine, University of Iowa Hospitals and Clinics, Iowa City, IA.",
"authors": "Suneja|Manish|M|;Baiswar|Shalanki|S|;Vogelgesang|Scott A|SA|",
"chemical_list": "D019268:Antibodies, Antineutrophil Cytoplasmic; D000959:Antihypertensive Agents; D017311:Amlodipine; D006830:Hydralazine",
"country": "United States",
"delete": false,
"doi": "10.1097/RHU.0000000000000049",
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"issue": "20(2)",
"journal": "Journal of clinical rheumatology : practical reports on rheumatic & musculoskeletal diseases",
"keywords": null,
"medline_ta": "J Clin Rheumatol",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D017311:Amlodipine; D056648:Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; D019268:Antibodies, Antineutrophil Cytoplasmic; D000959:Antihypertensive Agents; D001706:Biopsy; D005260:Female; D005921:Glomerulonephritis; D006801:Humans; D006830:Hydralazine; D006973:Hypertension; D007668:Kidney; D008875:Middle Aged; D016896:Treatment Outcome; D028761:Withholding Treatment",
"nlm_unique_id": "9518034",
"other_id": null,
"pages": "99-102",
"pmc": null,
"pmid": "24561415",
"pubdate": "2014-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Hydralazine associated pauci-immune glomerulonephritis.",
"title_normalized": "hydralazine associated pauci immune glomerulonephritis"
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"abstract": "We discuss a case of an 81-year-old man who presented to hospital with a case of severe hypercalcaemia (5.07 mmol/L). The two most common causes of hypercalcaemia, making up around 90% of the cases, are malignancy and primary hyperparathyroidism. Initial investigations are guided by this knowledge. In this case, no underlying malignancy or evidence of a parathyroid adenoma causing primary hyperparathyroidism was found. Instead, on further history, it was found that this patient had troublesome dyspepsia symptoms for which he had ingested 10-12 calcium carbonate tablets a day for the preceding 2 years. This amounts to 6.6-7.9 g of calcium carbonate per day compared with the guideline daily intake of calcium of 1 g. His presentation of severe hypercalcaemia was therefore diagnosed as milk-alkali syndrome secondary to calcium carbonate tablet abuse.",
"affiliations": "Acute Medical Unit, Russells Hall Hospital, Dudley, UK.;Acute Medical Unit, Russells Hall Hospital, Dudley, UK.",
"authors": "Stoney|Ben|B|http://orcid.org/0000-0002-0261-9603;Bagchi|Gautam|G|",
"chemical_list": "D000863:Antacids; D002119:Calcium Carbonate",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2017-219611",
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"issue": "2017()",
"journal": "BMJ case reports",
"keywords": "Calcium and bone; Drugs: endocrine system; Endocrine system",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000369:Aged, 80 and over; D000863:Antacids; D002119:Calcium Carbonate; D003937:Diagnosis, Differential; D006801:Humans; D006934:Hypercalcemia; D008297:Male; D013577:Syndrome",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "28473363",
"pubdate": "2017-05-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "10878206;15804228;17699269;17717370;19252114;20413609;21954111;24288027;26037642;7891547",
"title": "Antacid abuse: a rare cause of severe hypercalcaemia.",
"title_normalized": "antacid abuse a rare cause of severe hypercalcaemia"
} | [
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"companynumb": "PHHY2017GB080996",
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"activesubstancename": "DOXAZOSIN\\DOXAZOSIN MESYLATE"
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"abstract": "BACKGROUND\nGlioblastoma multiforme (GBM) is a rapid-growing central nervous system neoplasm. We report a case of GBM with extensive intramedullary lumbar drop metastasis and highly unusual osseous spine metastasis from a primary infratentorial GBM occurring 10 years after the initial diagnosis, which to our knowledge has not been described previously.\n\n\nMETHODS\nThis 37-year-old man presented with new-onset headaches of increasing severity. Brain magnetic resonance imaging (MRI) demonstrated a heterogeneously enhancing mass in the left superior temporal lobe with adjacent edema. The lesion was initially biopsied in December 2006 and diagnosed as GBM (World Health Organization grade IV) with characteristic features of a highly cellular infiltrating glial neoplasm with nuclear pleomorphism, abundant microvascular proliferation, and abundant necrosis with pseudopalisading nuclei. Ki-67 immunostaining revealed that 15%-20% tumor cell nuclei were positive, indicating a high proliferative index. Histologically, this neoplasm demonstrated characteristic \"cell wrapping.\" Immunoreactivity was variably but strongly positive for glial fibrillary acidic protein in neoplastic cells. In 2018, additional MRI revealed disease throughout the spine and bone biopsy of the thoracic spine showed the same glial neoplasm with primitive neuroectodermal tumor-like components (GBM-PNET).\n\n\nCONCLUSIONS\nThis case is meant to highlight that, although rare, infratentorial GBM-PNET has a higher frequency of isocitrate dehydrogenase 1 (IDH1) mutation and may metastasize to the spine years after the initial diagnosis despite the likely better prognosis.",
"affiliations": "Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota, USA. Electronic address: ricar029@umn.edu.;Department of Neurosurgery, University of Minnesota, Minneapolis, Minnesota, USA.;Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota, USA.;Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota, USA.;Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota, USA.;Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota, USA.;Department of Neurosurgery, University of Minnesota, Minneapolis, Minnesota, USA.;Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota, USA.",
"authors": "Ricard|Jocelyn A|JA|;Cramer|Samuel W|SW|;Charles|River|R|;Gil Tommee|Carolina|C|;Le|An|A|;Bell|W Robert|WR|;Chen|Clark C|CC|;Flanagan|Margaret E|ME|",
"chemical_list": "D007521:Isocitrate Dehydrogenase",
"country": "United States",
"delete": false,
"doi": "10.1016/j.wneu.2019.07.142",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1878-8750",
"issue": "131()",
"journal": "World neurosurgery",
"keywords": "Glioblastoma multiforme; Isocitrate dehydrogenase (IDH1/IDH2); Metastasis; Spine",
"medline_ta": "World Neurosurg",
"mesh_terms": "D000328:Adult; D001859:Bone Neoplasms; D005909:Glioblastoma; D006801:Humans; D015192:Infratentorial Neoplasms; D007521:Isocitrate Dehydrogenase; D008279:Magnetic Resonance Imaging; D008297:Male; D018241:Neuroectodermal Tumors, Primitive, Peripheral; D013125:Spinal Neoplasms; D013904:Thoracic Vertebrae",
"nlm_unique_id": "101528275",
"other_id": null,
"pages": "90-94",
"pmc": null,
"pmid": "31356980",
"pubdate": "2019-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Infratentorial Glioblastoma Metastasis to Bone.",
"title_normalized": "infratentorial glioblastoma metastasis to bone"
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"activesubstancename": "TEMOZOLOMIDE"
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{
"abstract": "In this observational, retrospective, multicenter study, we aimed to assess the safety of the combination of local metastasis-directed radiotherapy (RT) and immunotherapy (IT) in a cohort of advanced non-small-cell lung cancer (aNSCLC) patients.\n\n\n\nWe collected clinical data of aNSCLC patients who received concomitant RT and anti-PD-1/PD-L1 inhibitors in seven Italian centers from September 2015 to June 2019. Concomitant RT was defined as delivered ≤4 weeks before or after the first or last administration of immunotherapy, or within two consecutive cycles of ICI. All adverse events apparently related to RT and/or IT were graded according to the Common Terminology Criteria for Adverse Events, version 4.0, and reported in terms of incidence and severity as immune related or RT related, or combined.\n\n\n\nWe analyzed the clinical charts of 187 patients. Median follow-up time was 23 months, and median overall survival was 16.5 months (range, 3-162). Thirteen patients developed pure RT-related side effects, and 43 patients (23.9%) developed immune-related side effects. No additive toxic effects were observed. A case of grade 5 pulmonary toxicity was recorded as a possible consequence of a combined effect.\n\n\n\nThis analysis suggests that the combination of concomitant RT and anti-PD-1/PD-L1 agents is safe, and the two toxicity profiles are independent.",
"affiliations": "Department of Radiation Oncology, Azienda Ospedaliero Universitaria Careggi, University of Florence, Florence, Italy.;Department of Radiation Oncology, Azienda Ospedaliero Universitaria Careggi, University of Florence, Florence, Italy.;Radiation Oncology Unit, Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, Italy.;Radiation Oncology Department, University and Spedali Civili of Brescia, Brescia, Italy.;Radiotherapy Unit, Department of Oncology and Hematology, University Hospital of Modena, Modena, Italy.;Advanced Radiation Oncology Department, IRCCS Sacro Cuore Don Calabria, Negrar, Italy.;Radiotherapy Unit, SS Antonio e Biagio e Cesare Arrigo Hospital, Alessandria, Italy.;Department of Radiation Oncology, Azienda Ospedaliero Universitaria Careggi, University of Florence, Florence, Italy. Electronic address: matteo.mariotti88@gmail.com.;Department of Radiation Oncology, Azienda Ospedaliero Universitaria Careggi, University of Florence, Florence, Italy.;Department of Oncology and Hematology, University Hospital of Modena, Modena, Italy.;Radiation Oncology Department, IRCCS Ospedale Policlinico San Martino, Genova, Italy.;Radiation Oncology Unit, \"SS Annunziata\" Hospital, \"G. D'Annunzio\" University, Chieti, Italy.;Radiation Oncology Section, Perugia General Hospital, Perugia, Italy.;Radiation Oncology Department, University and Spedali Civili of Brescia, Brescia, Italy.;Radiation Oncology Unit, Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, Italy.;Radiation Oncology Department, University and Spedali Civili of Brescia, Brescia, Italy.;Radiotherapy Unit, Department of Oncology and Hematology, University Hospital of Modena, Modena, Italy.;Radiation Oncology, Fondazione IRCCS Policlinico San Matteo and University of Pavia, Pavia, Italy.;Radiation Oncology, Campus Bio-Medico University, Rome, Italy.;IRCCS Humanitas Research Hospital, via Manzoni 56, 20089 Rozzano, Milan, Italy.;Radiation Oncology Unit, \"SS Annunziata\" Hospital, \"G. D'Annunzio\" University, Chieti, Italy.;Radiotherapy Unit, Department of Oncology and Hematology, University Hospital of Modena, Modena, Italy.;Radiation Oncology Department, University and Spedali Civili of Brescia, Brescia, Italy.;Advanced Radiation Oncology Department, IRCCS Sacro Cuore Don Calabria, Negrar, Italy; University of Brescia, Brescia, Italy.;Department of Radiation Oncology, Azienda Ospedaliero Universitaria Careggi, University of Florence, Florence, Italy.;Radiotherapy Unit, Department of Oncology and Hematology, University Hospital of Modena, Modena, Italy.",
"authors": "Perna|Marco|M|;Scotti|Vieri|V|;Ciammella|Patrizia|P|;Borghetti|Paolo|P|;D'angelo|Elisa|E|;Levra|Niccolò Giaj|NG|;Fozza|Alessandra|A|;Mariotti|Matteo|M|;Salvestrini|Viola|V|;Bertolini|Federica|F|;Vagge|Stefano|S|;Taraborrelli|Maria|M|;Falcinelli|Lorenzo|L|;Taddeo|Alessandra|A|;Rossi|Roberto|R|;Costantino|Gianluca|G|;Frassinelli|Luca|L|;Filippi|Andrea Riccardo|AR|;Greco|Carlo|C|;Franceschini|Davide|D|;Genovesi|Domenico|D|;Lohr|Frank|F|;Magrini|Stefano Maria|SM|;Alongi|Filippo|F|;Livi|Lorenzo|L|;Bruni|Alessio|A|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.cllc.2021.02.005",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1525-7304",
"issue": "22(5)",
"journal": "Clinical lung cancer",
"keywords": "Advanced NSCLC; Concomitant treatment; Immunotherapy",
"medline_ta": "Clin Lung Cancer",
"mesh_terms": null,
"nlm_unique_id": "100893225",
"other_id": null,
"pages": "e767-e773",
"pmc": null,
"pmid": "33766477",
"pubdate": "2021-09",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "The NIPRO Study: An Observational, Retrospective, Multicenter Study on the Safety of the Radiotherapy and Immunotherapy Combination for Advanced-Stage NSCLC.",
"title_normalized": "the nipro study an observational retrospective multicenter study on the safety of the radiotherapy and immunotherapy combination for advanced stage nsclc"
} | [
{
"companynumb": "IT-BRISTOL-MYERS SQUIBB COMPANY-BMS-2021-035587",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "NIVOLUMAB"
},
"drugaddi... |
{
"abstract": "Zoledronic acid is an intravenous bisphosphonate used to increase bone mineral density and reduce the risk of fractures. Its safety profile compares well with pamidronate in pediatric patients. We describe an acute, severe, life-threatening, inflammatory reaction in a child.\n\n\n\nA 7-year-old boy with complex medical problems and chronic ventilator requirements was admitted to the pediatric intensive care unit (due to ventilator needs) for zoledronic acid infusion and subsequent monitoring. His history was significant for osteoporosis secondary to immobilization with multiple fractures since 2 years of age, hypoxic-ischemic encephalopathy, quadriplegic cerebral palsy, seizure disorder, ventilator dependence, and pulmonary hypertension. He had previously been treated with four cycles of pamidronate without adverse events. He received 0.013 mg/kg of zoledronic acid infused over 30 minutes. Beginning 3 hours after completion of the infusion, he developed progressive tachycardia, fever, hypotension requiring vasopressor infusion, and increasing oxygen requirements. Laboratory studies revealed leukopenia, thrombocytopenia, elevated C-reactive protein, abnormal coagulation profile, metabolic acidosis, and negative cultures. The following day, he developed moderate acute respiratory distress syndrome and pulmonary hemorrhage requiring higher ventilatory settings, and subsequently diarrhea and abdominal distension. Initial clinical resolution was noted from the third day onward, and he was discharged on the sixth day after zoledronate administration.\n\n\n\nOur pediatric patient demonstrated an acute, severe, life-threatening reaction to zoledronic acid requiring intensive cardiorespiratory support without an underlying pre-existing inflammatory disorder.\n\n\n\nOur case highlights the importance of careful monitoring of children following zoledronic acid therapy. We recommend inpatient observation after an initial infusion of zoledronic acid in medically complex children. Children and their parents should be thoroughly counseled on the potential risks of bisphosphonate treatment, which can sometimes be severe and life threatening.",
"affiliations": "Department of Pediatric and Adolescent Medicine, Division of Pediatric Critical Care, Mayo Clinic, Rochester, MN, USA.;Department of Pediatric and Adolescent Medicine, Division of Pediatric Endocrinology, Mayo Clinic, Rochester, MN, USA.;Department of Pediatric and Adolescent Medicine, Division of Pediatric Endocrinology, Mayo Clinic, Rochester, MN, USA.;Department of Pediatric and Adolescent Medicine, Division of Pediatric Critical Care, Mayo Clinic, Rochester, MN, USA.;Department of Pediatric and Adolescent Medicine, Division of Pediatric Critical Care, Mayo Clinic, Rochester, MN, USA.;Department of Pediatric and Adolescent Medicine, Division of Pediatric Endocrinology, Mayo Clinic, Rochester, MN, USA. tebben.peter@mayo.edu.",
"authors": "Trivedi|S|S|;Al-Nofal|A|A|;Kumar|S|S|;Tripathi|S|S|;Kahoud|R J|RJ|;Tebben|P J|PJ|",
"chemical_list": "D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D007093:Imidazoles; D000077211:Zoledronic Acid",
"country": "England",
"delete": false,
"doi": "10.1007/s00198-016-3528-4",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0937-941X",
"issue": "27(7)",
"journal": "Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA",
"keywords": "Adverse drug reaction; Bisphosphonates; Inflammation; Low bone density; Osteoporosis; Serious adverse reaction",
"medline_ta": "Osteoporos Int",
"mesh_terms": "D050071:Bone Density Conservation Agents; D002648:Child; D004164:Diphosphonates; D006801:Humans; D007093:Imidazoles; D008297:Male; D010024:Osteoporosis; D018746:Systemic Inflammatory Response Syndrome; D000077211:Zoledronic Acid",
"nlm_unique_id": "9100105",
"other_id": null,
"pages": "2379-2382",
"pmc": null,
"pmid": "26892041",
"pubdate": "2016-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "15207762;12682500;18504549;19344075;15655696;17574945;23074158;15520785;9366759;25757207;12629073;16785077;1597042;12410192;21298747;20808669;15792214;22876543;9753709",
"title": "Severe non-infective systemic inflammatory response syndrome, shock, and end-organ dysfunction after zoledronic acid administration in a child.",
"title_normalized": "severe non infective systemic inflammatory response syndrome shock and end organ dysfunction after zoledronic acid administration in a child"
} | [
{
"companynumb": "US-ACTAVIS-2015-28264",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "SODIUM CHLORIDE"
},
"drugadditional": null,
... |
{
"abstract": "Here, we report a complex case that involved a pediatric patient who experienced recalcitrant multidrug-resistant Pseudomonas aeruginosa infection complicated by bacteremia/sepsis; our antibacterial options were limited because of resistance, allergies, and suboptimal source control. A cocktail of 2 bacteriophages targeting the infectious organism introduced on 2 separate occasions sterilized the bacteremia.",
"affiliations": "Enteric Disease Department, Infectious Disease Directorate, Naval Medical Research Center, Silver Spring, Maryland.;Biological Defense Research Directorate, Naval Medical Research Center, Fort Detrick, Maryland.;Pediatric Infectious Diseases, Children's National Medical Center, Washington, DC.;Walter Reed National Military Medical Center, Bethesda, Maryland.;Biological Defense Research Directorate, Naval Medical Research Center, Fort Detrick, Maryland.;Biological Defense Research Directorate, Naval Medical Research Center, Fort Detrick, Maryland.;Biological Defense Research Directorate, Naval Medical Research Center, Fort Detrick, Maryland.;Biological Defense Research Directorate, Naval Medical Research Center, Fort Detrick, Maryland.;Biological Defense Research Directorate, Naval Medical Research Center, Fort Detrick, Maryland.",
"authors": "Duplessis|C|C|;Biswas|B|B|;Hanisch|B|B|;Perkins|M|M|;Henry|M|M|;Quinones|J|J|;Wolfe|D|D|;Estrella|L|L|;Hamilton|T|T|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1093/jpids/pix056",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2048-7193",
"issue": "7(3)",
"journal": "Journal of the Pediatric Infectious Diseases Society",
"keywords": null,
"medline_ta": "J Pediatric Infect Dis Soc",
"mesh_terms": "D016470:Bacteremia; D002675:Child, Preschool; D024901:Drug Resistance, Multiple, Bacterial; D017809:Fatal Outcome; D006801:Humans; D008297:Male; D000071059:Phage Therapy; D011552:Pseudomonas Infections",
"nlm_unique_id": "101586049",
"other_id": null,
"pages": "253-256",
"pmc": null,
"pmid": "28992111",
"pubdate": "2018-08-17",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Refractory Pseudomonas Bacteremia in a 2-Year-Old Sterilized by Bacteriophage Therapy.",
"title_normalized": "refractory pseudomonas bacteremia in a 2 year old sterilized by bacteriophage therapy"
} | [
{
"companynumb": "US-CHIESI USA, INC.-US-2018CHI000520",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TOBRAMYCIN"
},
"drugadditional": "... |
{
"abstract": "OBJECTIVE\nTo describe the clinical course and outcome of 10 patients with Kawasaki disease (KD) treated with a calcineurin inhibitor after failing to respond to multiple therapies.\n\n\nMETHODS\nDemographic and clinical data were prospectively collected using standardized case report forms. T-cell phenotypes were determined by flow cytometry, and KD risk alleles in ITPKC (rs28493229), CASP3 (rs72689236), and FCGR2A (rs1801274) were genotyped.\n\n\nRESULTS\nIntravenous followed by oral therapy with cyclosporine (CSA) or oral tacrolimus was well tolerated and resulted in defervescence and resolution of inflammation in all 10 patients. There were no serious adverse events, and a standardized treatment protocol was developed based on our experiences with this patient population. Analysis of T-cell phenotype by flow cytometry in 2 subjects showed a decrease in circulating activated CD8(+) and CD4(+) T effector memory cells after treatment with CSA. However, suppression of regulatory T-cells was not seen, suggesting targeting of specific, proinflammatory T-cell compartments by CSA.\n\n\nCONCLUSIONS\nTreatment of refractory KD with a calcineurin inhibitor appears to be a safe and effective approach that achieves rapid control of inflammation associated with clinical improvement.",
"affiliations": "Department of Pediatrics, University of California at San Diego and Rady Children's Hospital, La Jolla, CA, USA.",
"authors": "Tremoulet|Adriana H|AH|;Pancoast|Paige|P|;Franco|Alessandra|A|;Bujold|Matthew|M|;Shimizu|Chisato|C|;Onouchi|Yoshihiro|Y|;Tamamoto|Alyson|A|;Erdem|Guliz|G|;Dodd|Debra|D|;Burns|Jane C|JC|",
"chemical_list": "D016756:Immunoglobulins, Intravenous; D007155:Immunologic Factors; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D016559:Tacrolimus",
"country": "United States",
"delete": false,
"doi": "10.1016/j.jpeds.2012.02.048",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0022-3476",
"issue": "161(3)",
"journal": "The Journal of pediatrics",
"keywords": null,
"medline_ta": "J Pediatr",
"mesh_terms": "D002648:Child; D002675:Child, Preschool; D002985:Clinical Protocols; D016572:Cyclosporine; D005260:Female; D006801:Humans; D016756:Immunoglobulins, Intravenous; D007155:Immunologic Factors; D007166:Immunosuppressive Agents; D007223:Infant; D008297:Male; D009080:Mucocutaneous Lymph Node Syndrome; D013601:T-Lymphocytes; D016559:Tacrolimus; D017211:Treatment Failure",
"nlm_unique_id": "0375410",
"other_id": null,
"pages": "506-512.e1",
"pmc": null,
"pmid": "22484354",
"pubdate": "2012-09",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "19786535;20166878;6502354;15041378;9723362;19132087;9877364;11528596;18482216;18174868;19504733;21244766;20423928;20981092;15505111;20024653;12502728;18260334;18672254;19915573;14523200;21383649;22081228;17335804;21160486;16455648;18571548;21587094;3321081;1709446;11419513;18084290;15131473;21987091;8551407;15928679;19018092;21958311;9884249",
"title": "Calcineurin inhibitor treatment of intravenous immunoglobulin-resistant Kawasaki disease.",
"title_normalized": "calcineurin inhibitor treatment of intravenous immunoglobulin resistant kawasaki disease"
} | [
{
"companynumb": "US-PFIZER INC-2017076656",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE SODIUM SUCCINATE"
},
"druga... |
{
"abstract": "To report a case of a full-thickness macular hole (MH) that developed after cryotherapy and intravitreal bevacizumab injection (IVB) to treat a retinal vasoproliferative tumor (VPT).\nCase report of a man with a retinal VPT.\nA 64-year-old Japanese man complained of blurred vision in his right eye. At the initial examination, his best-corrected visual acuity (BCVA) was 20/25 in the right eye and 20/20 in the left eye. Ophthalmoscopy showed a VPT in the lower peripheral retina of the right eye. An exudative retinal detachment and hard exudates were seen around the tumor. Cryotherapy and intravitreal injections of bevacizumab (IVB) were performed. Although the exudative changes were reduced, a MH developed two months after the initial IVB treatment. He underwent 25-gauge pars plana vitrectomy, and the MH was closed. His postoperative BCVA was 20/32 and the VPT was inactive. The reduced BCVA was due to damage of the outer retinal layers.\nOur findings indicate that cryotherapy and IVB are effective treatments for VPT although the possibility of developing a MH should be considered.",
"affiliations": "Department of Ophthalmology, Matsumoto Dental University, Shiojiri, Nagano, Japan.;Department of Ophthalmology, Matsumoto Dental University, Shiojiri, Nagano, Japan.;Department of Ophthalmology, Matsumoto Dental University, Shiojiri, Nagano, Japan.",
"authors": "Sato|Atsuko|A|;Fukui|Emi|E|;Ohta|Kouichi|K|",
"chemical_list": null,
"country": "New Zealand",
"delete": false,
"doi": "10.2147/IMCRJ.S266986",
"fulltext": "\n==== Front\nInt Med Case Rep J\nInt Med Case Rep J\nimcrj\nimcrj\nInternational Medical Case Reports Journal\n1179-142X Dove \n\n266986\n10.2147/IMCRJ.S266986\nCase Report\nMacular Hole Formation in Eye After Cryotherapy and Intravitreal Bevacizumab Treatment for Vasoproliferative Tumor\nSato et alSato et alSato Atsuko 1 Fukui Emi 1 Ohta Kouichi 1 1 Department of Ophthalmology, Matsumoto Dental University, Shiojiri, Nagano, Japan\nCorrespondence: Atsuko Sato Department of Ophthalmology, Matsumoto Dental University, 1780 Gobara, Hirooka, Shiojiri, Nagano399-0781, JapanTel/Fax +81-263-51-2210 Email atsuko.sato@mdu.ac.jp\n14 9 2020 \n2020 \n13 419 423\n09 6 2020 31 7 2020 © 2020 Sato et al.2020Sato et al.This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php).Purpose\nTo report a case of a full-thickness macular hole (MH) that developed after cryotherapy and intravitreal bevacizumab injection (IVB) to treat a retinal vasoproliferative tumor (VPT).\n\nMethods\nCase report of a man with a retinal VPT.\n\nResults\nA 64-year-old Japanese man complained of blurred vision in his right eye. At the initial examination, his best-corrected visual acuity (BCVA) was 20/25 in the right eye and 20/20 in the left eye. Ophthalmoscopy showed a VPT in the lower peripheral retina of the right eye. An exudative retinal detachment and hard exudates were seen around the tumor. Cryotherapy and intravitreal injections of bevacizumab (IVB) were performed. Although the exudative changes were reduced, a MH developed two months after the initial IVB treatment. He underwent 25-gauge pars plana vitrectomy, and the MH was closed. His postoperative BCVA was 20/32 and the VPT was inactive. The reduced BCVA was due to damage of the outer retinal layers.\n\nConclusion\nOur findings indicate that cryotherapy and IVB are effective treatments for VPT although the possibility of developing a MH should be considered.\n\nKeywords\nintravitreal bevacizumab injectionmacular holeoptical coherence tomographyvasoproliferative tumorvitrectomy\n==== Body\nIntroduction\nA vasoproliferative tumor (VPT) is a benign retinal vascular tumor.1–3 The tumor is characterized by yellowish-pink lesions and can be classified as a primary or a secondary tumor. Shields reported that primary VPTs occurred in 80% and secondary in 20% of the patients.2 Secondary VPTs occur in patients with retinitis pigmentosa, pars planitis, Coats’ disease, and other retinal disorders.4,5 Many complications are associated with VPT including intraocular hemorrhages, macular edema, macular exudation, epiretinal membrane (ERM), and exudative retinal detachment, but macular hole (MH) formation is rare.6 The purpose of this report is to present our findings in a case of VPT that developed a MH after treatment.\n\nCase Presentation\nA 64-year-old Japanese man complained of blurred vision in his right eye in January 2015. At his initial examination, his best-corrected visual acuity (BCVA) was 20/25 in the right eye and 20/20 in the left eye. Ophthalmoscopy showed an approximately 3-disc diameter (DD) yellowish-pink elevated lesion with retinal hemorrhages in the lower peripheral retina. There was vitreomacular traction in his right eye (Figure 1A and B). A shallow exudative retinal detachment was also present in the inferior quadrant, and hard exudates were seen around the tumor. In addition, hard exudates had also accumulated around the inferior vascular arcade and optic disc.Figure 1 Ultra-widefield fundus photograph (A), optical coherence tomographic (OCT) image (B), fluorescein angiogram (C), and indocyanine green angiograms (D) of the right eye of a patient with a vasoproliferative tumor (VPT) before treatment. (A) Fundus photograph showing a VPT (arrow) in the lower peripheral retina. (B) OCT image showing vitreomacular traction. (C) Fluorescein angiogram of the right eye showing early leakage within the tumor. (D) Indocyanine green angiographic image showing no hypofluorescence or late granular hyperfluorescence which are characteristics of metastatic choroidal tumors.\n\nAbbreviations: OCT, optical coherence tomography; VPT, vasoproliferative tumor.\n\nThe differential diagnosis of retinal tumors includes secondary tumor such as von Hippel-Lindau (VHL) syndrome and other systemic hemangiomas. In VHL syndrome, the tumors are usually multiple and bilateral which were not present in our case. Fluorescein angiography (FA) and indocyanine green angiography (ICGA) were performed. A dilated feeder vessel was not seen as is usually seen in eyes with VHL syndrome. FA showed early leakage from the tumor (Figure 1C), and ICGA showed no hypofluorescence or late granular hyperfluorescence which are characteristics of metastatic choroidal tumors (Figure 1D). The patient did not have any family history for VHL syndrome or other systemic hamartomas. General systemic screening by MRI and PET-CT showed the presence of renal cancer and thyroid cancer. In addition, no other tumors such as malignant melanomas and metastatic tumors were detected.\n\nWith time, the hard exudates extended to macula leading to an increase in the vitreomacular traction. The BCVA was reduced to 20/63. Before the surgery for renal cancer in April 2015, he was diagnosed with primary VPT, and transscleral cryotherapy and an intravitreal injection of bevacizumab (IVB) were performed in March 2015. However, the hard exudates remained and the subretinal fluid (SRF) increased after these treatments. A secondary IVB was performed one month later prior to the surgery for renal cancer at another university hospital. One month after the second IVB, the vitreomacular traction was released, and the level of subfoveal fluid was decreased.\n\nHowever, a full-thickness MH developed with exudates in May 2015, but he did not complain of a further decrease in his vision (Figure 2A and B). Although pars plana vitrectomy for the MH was considered, his highest priority was surgery for another thyroid tumor which was scheduled for August 2015 in another hospital.Figure 2 Ultra-widefield fundus image (A) and OCT image (B) of the right eye of a patient with VPT after a second IVB injection. (A) Fundus image shows mild reduction of exudative changes of the VPT. (B) OCT showing full-thickness macular hole with subfoveal exudates in the right eye.\n\nAbbreviations: OCT, optical coherence tomography; VPT, vasoproliferative tumor; IVB, intravitreal bevacizumab.\n\nThe hard exudates and subretinal fluid were resolved after the eighth IVB injection in November 2015. (Figure 3A and B). The size of the VPT was also decreased after the IVB injection. The BCVA remained 20/63. The ellipsoid zone (EZ) and external limiting membrane (ELM) were not detected over the MH. After successful resections of the 2 cancerous lesions, he decided to undergo 25-gauge pars plana vitrectomy combined with cataract surgery and intraocular lens implantation in February 2016. Internal limiting membrane peeling and gas tamponade with 25% sulfur hexafluoride were performed. After the surgery, the MH was completely closed (Figure 4A and B). His BCVA was still reduced to 20/63 at 1 year after the vitrectomy. The reduced BCVA was probably related to the 8 months during which the MH remained open. A disruption of the ellipsoid zone (EZ) and thinning of the outer nuclear layer (ONL) were observed beyond the edge of the original MH. However, his BCVA gradually improved, and it was 20/32 at 4 years after the MH surgery. Both the renal cancer and thyroid tumor were successfully excised without metastasis. Both surgeons for the renal and the thyroid carcinomas stated that there was no association between the renal and thyroid tumor and the VPT. Unfortunately, genetic testing was not performed.Figure 3 Ultra-widefield fundus image (A) and OCT image (B) before vitrectomy for the MH after one cryotherapy and 8 IVBs. (A) Fundus photograph showing a further reduction of the exudative changes and scarring of the VPT. (B) OCT image showing a full-thickness MH and absence of exudates.\n\nAbbreviations: OCT, optical coherence tomography; MH, macular hole; IVB, intravitreal bevacizumab; VPT, vasoproliferative tumor.Figure 4 Ultra-widefield fundus image (A) and OCT image (B) after vitrectomy for the MH. (A) Fundus photograph showing a further reduction of the exudative changes after a vitrectomy. (B) OCT image showing a closed MH without exudates. A disruption of the EZ and thinning of the ONL can be seen beyond the edge of the original MH.\n\nAbbreviations: OCT, optical coherence tomography; MH, macular hole; EZ, ellipsoid zone; ONL, outer nuclear layer.\n\nDiscussion and Conclusions\nIt has been reported that VPTs can lead to severe vision reduction because of ocular complications such as intraocular hemorrhages (35%), macular edema (32%), macular exudation (23%), and ERM formation (20%).2 However, the formation of a MH is a rare complication in eyes with a VPT.6\n\nThe various treatments for VPT include laser photocoagulation,7 cryotherapy,3,8 photodynamic therapy,9 and intravitreal injections of anti-vascular endothelial growth factor (VEGF) including bevacizumab.10 Cryotherapy is also known to be an effective treatment for VPT, and it has been reported that the tension created by a VPT-related epiretinal membrane (ERM) was released in 63% of the cases after cryotherapy.8 In our case, the cryotherapy released the vitreoretinal traction but a MH still developed.\n\nThe formation of a MH has been reported in eyes with VPT6 and also eyes with von VHL syndrome.11,12 In our case, a MH developed after cryotherapy and two IVB injections. The IVB could have been the cause of the MH because there have been several reports of MH formation after anti-VEGF therapy.13–16 Other possible mechanisms for the MH formation include an increase in the anterior-posterior transvitreal traction, vitreous incarceration at the injection site, and anti-VEGF-induced contraction of the target of the disease. In our case, the exudative changes were reduced after the combined therapy which could then increase the degree of vitreoretinal traction. It has also been reported that MH can form after an air injection and cryotherapy for a retinal detachment.17,18 We suggest that the MH formation in our case was related to the cryotherapy and/or anti-VEGF therapy rather than the VPT.\n\nThe MH was successfully closed by the initial vitrectomy with ILM peeling. The postoperative poorer BCVA may be related to the delayed MH surgery and also the disruption of the EZ and thinning of the ONL beyond the original MH edge by the exudates from the VPT. Although subretinal exudations can extend rapidly to the macula, they have been absorbed after IVB treatment. The outer retinal layer was damaged by these exudates in our case. In the end, the original VPT was completely scarred without any recurrence for 4 years after the treatments.\n\nIn conclusion, a MH developed after cryotherapy and IVB injections in a case of VPT. Our findings indicate that cryotherapy with IVB is effective in treating VPT, although ophthalmologists should be aware of the risk of MH formation.\n\nAcknowledgments\nWe thank Professor Emeritus Duco Hamasaki of the Bascom Palmer Eye Institute for discussions and editing the manuscript.\n\nEthics Approval and Consent to Participate\nEthics approval was provided by the Institutional Review Board of the Matsumoto Dental University, Shiojiri, Japan. The patient provided a written informed consent for the case details and images to be published.\n\nDisclosure\nThe authors report no conflicts of interest in this work.\n==== Refs\nReferences\n1. Shields \nJA , Decker \nWL , Sanborn \nGE , Augsburger \nJJ , Goldberg \nRE . Presumed acquired retinal hemangiomas\n. Ophthalmology . 1983 ;90 (11 ):1292 –1300\n. doi:10.1016/S0161-6420(83)34389-X 6664668 \n2. Shields \nCL , Kaliki \nS , Al-Dahmash \nS , et al. Retinal vasoproliferative tumors: comparative clinical features of primary vs secondary tumors in 334 cases\n. JAMA Ophthalmol . 2013 ;131 (3 ):328 –334\n. doi:10.1001/2013.jamaophthalmol.524 23494037 \n3. Jain \nK , Berger \nAR , Yucil \nYH , McGowan \nHD . Vasoproliferative tumor of the retina\n. Eye (Lond) . 2003 ;17 (3 ):364 –368\n. doi:10.1038/sj.eye.6700311 12724700 \n4. Shields \nCL , Shields \nJA , Barrett \nJ , De Potter \nP . Vasoproliferative tumors of the ocular fundus. Classification and clinical manifestations in 103 patients\n. Arch Ophthalmol . 1995 ;113 (5 ):615 –623\n. doi:10.1001/archopht.1995.01100050083035 7748132 \n5. Mori \nK , Ohta \nK , Murata \nT . Vasoproliferative tumors of the retina secondary to ocular toxocariasis\n. Can J Ophthalmol . 2007 ;42 (5 ):758 –759\n. doi:10.3129/i07-137 17891207 \n6. Clare \nG , Yorston \nD , Charteris \nDH , Aylward \nGW . Successful treatment of macular holes associated with peripheral retinal vascular tumours\n. Eye (Lond) . 2007 ;21 (3 ):419 –420\n. doi:10.1038/sj.eye.6702423 16710432 \n7. Krivosic \nV , Massin \nP , Desjardins \nL , Le Hoang \nP , Tadayoni \nR , Gaudric \nA . Management of idiopathic retinal vasoproliferative tumors by slit-lamp laser or endolaser photocoagulation\n. Am J Ophthalmol . 2014 ;158 (1 ):154 –161\n. doi:10.1016/j.ajo.2014.03.005 24631475 \n8. Manjandavida \nFP , Shields \nCL , Kaliki \nS , Shields \nJA . Cryotherapy-induced release of epiretinal membrane associated with retinal vasoproliferative tumor\n. Retina . 2014 ;34 (8 ):1644 –1650\n. doi:10.1097/IAE.0000000000000137 24752009 \n9. Blasi \nMA , Scupola \nA , Tiberti \nAC , Sasso \nP , Balestrazzi \nE . Photodynamic therapy for vasoproliferative retinal tumors\n. Retina . 2006 ;26 (4 ):404 –409\n.16603958 \n10. Kenawy \nN , Groenwald \nC , Damato \nB . Treatment of a vasoproliferative tumour with intravitreal bevacizumab (Avastin)\n. Eye . 2007 ;21 (6 ):893 –894\n. doi:10.1038/sj.eye.6702782 17347676 \n11. Loewestein \nJI . Bilateral macular holes in von Hippel-Lindau disease\n. Arch Ophthalmol . 1995 ;113 (2 ):143 –144\n. doi:10.1001/archopht.1995.01100020021016 7864744 \n12. Inoue \nM , Yamazaki \nK , Shinoda \nK , et al. A clinicopathologic case report on macular hole associated with von Hippel-Lindau disease: a novel ultrastructural finding of wormlike, wavy tangles of filaments\n. Graefes Arch Clin Exp Ophthalmol . 2004 ;242 (10 ):881 –886\n. doi:10.1007/s00417-004-0908-9 15052488 \n13. Querques \nG , Souied \nEH , Soubrane \nG . Macular hole following intravitreal ranibizumab injection for choroidal neovascular membrane caused by age-related macular degeneration\n. Acta Ophthalmol . 2009 ;87 (2 ):235 –237\n. doi:10.1111/j.1755-3768.2008.01226.x \n14. Grigoropoulos \nV , Emfietzoglou \nJ , Nikolaidis \nP , Theodossiadis \nG , Theodossiadis \nP . Full-thickness macular hole after intravitreal injection of ranibizumab in a patient with retinal pigment epithelium detachment and tear\n. Eur J Ophthalmol . 2010 ;20 (2 ):469 –472\n. doi:10.1177/112067211002000235 20037902 \n15. Moisseiev \nE , Goldstein \nM , Loewenstein \nA , Moisseiev \nJ . Macular hole following Intravitreal bevacizumab injection in choroidal neovascularization caused by age-related macular degeneration\n. Case Rep Ophthalmol . 2010 ;1 (1 ):36 –41\n.21369348 \n16. Miura \nM , Iwasaki \nT , Goto \nH . Macular hole formation after intravitreal bevacizumab administration in a patient with myopic choroidal neovascularization\n. Retin Cases Brief Rep . 2011 ;5 (2 ):149 –152\n. doi:10.1097/ICB.0b013e3181cd1da1 25389887 \n17. Hilton \nGF , Tornambe \nPE , Brinton \nDA , et al. The complication of pneumatic retinopexy\n. Trans Am Ophthalmol Soc . 1990 ;88 :191 –210\n.2095021 \n18. Boscia \nF , Recchimurzo \nN , Cardascia \nN , Sborgia \nL , Furino \nC , Sborgia \nC . Macular hole following conventional repair of bullous retinal detachment using air injection (D-ACE procedure)\n. Eur J Ophthalmol . 2004 ;14 (6 ):572 –574\n. doi:10.1177/112067210401400621 15638111\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1179-142X",
"issue": "13()",
"journal": "International medical case reports journal",
"keywords": "intravitreal bevacizumab injection; macular hole; optical coherence tomography; vasoproliferative tumor; vitrectomy",
"medline_ta": "Int Med Case Rep J",
"mesh_terms": null,
"nlm_unique_id": "101566269",
"other_id": null,
"pages": "419-423",
"pmc": null,
"pmid": "32982482",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": "7864744;20037902;19292858;7748132;17347676;15638111;16603958;15052488;16710432;2095021;6664668;25389887;21369348;12724700;23494037;24752009;24631475;17891207",
"title": "Macular Hole Formation in Eye After Cryotherapy and Intravitreal Bevacizumab Treatment for Vasoproliferative Tumor.",
"title_normalized": "macular hole formation in eye after cryotherapy and intravitreal bevacizumab treatment for vasoproliferative tumor"
} | [
{
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"patient": {
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{
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"activesubstance": {
"activesubstancename": "BEVACIZUMAB"
},
"drugadditional": "3",
"drug... |
{
"abstract": "Buprenorphine is a semi-synthetic opioid derivative commonly used in the treatment of heroin addiction. Life-threatening complications have been described following overdoses while few cases of hepatotoxicity due to drug use at therapeutic doses have been recently described in hepatitis C virus carriers. In these cases, however, histological assessment was not exhaustive and no extra-hepatic organ failure was observed. We describe herein a case of acute liver and kidney failure in a patient with previously latent hepatitis C virus chronic infection following recommended doses of buprenorphine. Histology did not demonstrate any feature compatible with hepatitis C virus reactivation or liver cirrhosis and suspension of the treatment led to the resolution of both liver and kidney failure. Causality criteria fulfillment indicates a high probability of buprenorphine-induced liver toxicity. No signs of pre-existant kidney impairment or of pre- or post-renal causes were observed. Since buprenorphine is metabolized through cytochrome P450 3A4, we genotyped six genetic polymorphisms previously described in poor metabolizers but could not confirm these pharmacogenetic bases in this case. In conclusion, we surmise that buprenorphine at suggested doses can induce liver and kidney failure in susceptible individuals, possibly through direct mitochondrial toxicity.",
"affiliations": "Department of Medicine, Division of Internal Medicine, San Paolo School of Medicine, University of Milan, Milan, Italy. massimo.zuin@unimi.it",
"authors": "Zuin|M|M|;Giorgini|A|A|;Selmi|C|C|;Battezzati|P M|PM|;Cocchi|C A|CA|;Crosignani|A|A|;Benetti|A|A|;Invernizzi|P|P|;Podda|M|M|",
"chemical_list": "D009292:Narcotic Antagonists; D002047:Buprenorphine",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.dld.2007.12.014",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1590-8658",
"issue": "41(7)",
"journal": "Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver",
"keywords": null,
"medline_ta": "Dig Liver Dis",
"mesh_terms": "D058186:Acute Kidney Injury; D000328:Adult; D002047:Buprenorphine; D006556:Heroin Dependence; D006801:Humans; D017114:Liver Failure, Acute; D008297:Male; D009292:Narcotic Antagonists",
"nlm_unique_id": "100958385",
"other_id": null,
"pages": "e8-e10",
"pmc": null,
"pmid": "18294936",
"pubdate": "2009-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Acute liver and renal failure during treatment with buprenorphine at therapeutic dose.",
"title_normalized": "acute liver and renal failure during treatment with buprenorphine at therapeutic dose"
} | [
{
"companynumb": "IT-PFIZER INC-2018392428",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
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{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ACETAMINOPHEN"
},
"drugadditional": "1",
... |
{
"abstract": "Disseminated fungal infections due to Magnusiomyces capitatus are rare, occurring exclusively in immunocompromised patients. We report the first case in a liver transplant patient with chronic rejection and portal thrombosis who had a M. capitatus fungemia with a refractory septic shock. Despite an antibacterial and antifungal treatment with caspofungin empirical treatment, the patient died from multiple organ failure. Subsequently, mycological examinations of blood cultures, bronchoalveolar lavage fluid and urine were positive to M. capitatus identified by mass spectrometry and confirmed by sequencing respectively. The stain was resistant to caspofungin and fluconazole. The best treatment appears to be the combination of amphotericin B and voriconazole or amphotericin B and 5 fluorocytosine.",
"affiliations": "Laboratoire de parasitologie-mycologie, hôpital de l'Archet 2, centre hospitalier universitaire de Nice, 151, route Saint-Antoine-de-Ginestière, CS 23079, 06202 Nice cedex 3, France. Electronic address: kouadiocha@yahoo.fr.;Laboratoire de parasitologie-mycologie, hôpital de l'Archet 2, centre hospitalier universitaire de Nice, 151, route Saint-Antoine-de-Ginestière, CS 23079, 06202 Nice cedex 3, France.;Unité de réanimation médico-chirurgicale et transplantations d'organes, hôpital de l'Archet 2, centre hospitalier universitaire de Nice, 151, route Saint-Antoine-de-Ginestière, 06202 Nice cedex 3, France.;Laboratoire de parasitologie-mycologie, hôpital de l'Archet 2, centre hospitalier universitaire de Nice, 151, route Saint-Antoine-de-Ginestière, CS 23079, 06202 Nice cedex 3, France.",
"authors": "Yapo-Kouadio|C G|CG|;Hasseine|L|L|;Goubaux|B|B|;Gari-Toussaint|M|M|",
"chemical_list": null,
"country": "France",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1156-5233",
"issue": "26(3)",
"journal": "Journal de mycologie medicale",
"keywords": "Caspofungine; Disseminated fungal infection; Geotrichum; Infection fongique disséminée; Magnusiomyces capitatus; Transplantation hépatique; Transplanted liver",
"medline_ta": "J Mycol Med",
"mesh_terms": "D017809:Fatal Outcome; D016469:Fungemia; D006084:Graft Rejection; D006801:Humans; D016867:Immunocompromised Host; D016031:Liver Transplantation; D008297:Male; D008875:Middle Aged; D004718:Saccharomycetales; D018805:Sepsis",
"nlm_unique_id": "9425651",
"other_id": null,
"pages": "261-4",
"pmc": null,
"pmid": "27289448",
"pubdate": "2016-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Disseminated fungal infection due to Magnusiomyces capitatus in a liver graft patient.",
"title_normalized": "disseminated fungal infection due to magnusiomyces capitatus in a liver graft patient"
} | [
{
"companynumb": "FR-STRIDES ARCOLAB LIMITED-2017SP000944",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE SODIUM SUCCINATE"
},
... |
{
"abstract": "A 74-year-old female patient was admitted to hospital following a road accident with pains in the chest, abdomen, waist, back, nose, left wrist and lower limbs. After 1 week, the patient presented with gastrointestinal bleeding, and thus was treated with protein pump inhibitors (PPIs), including lansoprazole, esomeprazole and omeprazole enteric-coated tablets, in order to inhibit acid secretion and attenuate bleeding. However, the patient developed skin rashes on the chest and right lower limb and foot 28 days following treatment initiation. The skin rashes spread and ulcerated after 3 days, and were associated with tracheal mucosal injury and hemoptysis. Subsequently, treatment of the patient with PPIs was terminated, after which the tracheal hemoptysis and skin rashes markedly improved. In addition, no new skin rashes appeared following termination of the PPI treatment. In the present case, long-term treatment of an elderly patient with PPIs may have induced exfoliative dermatitis, due to hepatic ischemia, hypoxia and acute renal failure, which may have decreased the metabolism of PPIs, resulting in the accumulation of PPI metabolites.",
"affiliations": "Department of Pharmacy, Hebei General Hospital, Shijiazhuang, Hebei 050051, P.R. China.;Department of Pharmacy, Hebei General Hospital, Shijiazhuang, Hebei 050051, P.R. China.;Department of Pharmacy, Hebei General Hospital, Shijiazhuang, Hebei 050051, P.R. China.;Department of Pharmacy, Hebei General Hospital, Shijiazhuang, Hebei 050051, P.R. China.;Department of Pharmacy, Hebei General Hospital, Shijiazhuang, Hebei 050051, P.R. China.;Department of Pharmacy, Hebei General Hospital, Shijiazhuang, Hebei 050051, P.R. China.;Department of Pharmacy, The First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui 233004, P.R. China.",
"authors": "Qiu|Zhihong|Z|;Liu|Hongtao|H|;He|Lien|L|;Ma|Yinling|Y|;Song|Haojing|H|;Bai|Wanjun|W|;Yu|Meiling|M|",
"chemical_list": null,
"country": "Greece",
"delete": false,
"doi": "10.3892/etm.2015.2926",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1792-0981",
"issue": "11(2)",
"journal": "Experimental and therapeutic medicine",
"keywords": "exfoliative dermatitis; proton pump inhibitors",
"medline_ta": "Exp Ther Med",
"mesh_terms": null,
"nlm_unique_id": "101531947",
"other_id": null,
"pages": "543-546",
"pmc": null,
"pmid": "26893644",
"pubdate": "2016-02",
"publication_types": "D016428:Journal Article",
"references": "24640269;20420046;23877017;25550719;8827397;22648560;22848226;22744268;16135140;20654868;1530819;14693020;22005822;24550106;23062394;24074057;2524907;24527247;23229306;23006222;23414543",
"title": "Proton pump inhibitor-induced exfoliative dermatitis: A case report.",
"title_normalized": "proton pump inhibitor induced exfoliative dermatitis a case report"
} | [
{
"companynumb": "CN-DEXPHARM-20160072",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "LANSOPRAZOLE"
},
"drugadditional": null,
... |
{
"abstract": "Primary aldosteronism (PA) is a rare disorder. The majority of patients with PA present with typical features and are easily diagnosed. This disorder is usually diagnosed with hypokalemia, hypertension or an adrenal mass. However, patients with atypical symptoms may present a challenge for diagnosis and treatment. In the present study, a case of PA is described that presented with hypokalemic myopathy simulating polymyositis. The patient was a 44-year-old woman who presented with weakness and difficulty walking. The patient was initially suspected to have PM and was treated with methylprednisolone. The patient was found to have hypokalemia which persisted despite high-dose supplementation of potassium. Adrenal computed tomography revealed a right adrenal mass. Surgical adrenalectomy was conducted. The final pathological diagnosis was benign adrenocortical adenoma. The serum tests remained normal and the patient's symptoms were resolved during the 8-month follow-up.",
"affiliations": "Department of Nephrology, Qingyuan People's Hospital, Lishui, Zhejiang 323000, P.R. China.;Department of Urology, The First Hospital of Quanzhou Affiliated to Fujian Medical University, Quanzhou, Fujian 362000, P.R. China.;Department of Urology, The First Hospital of Quanzhou Affiliated to Fujian Medical University, Quanzhou, Fujian 362000, P.R. China.;Department of Nephrology, Lishui Hospital Affiliated to Zhejiang University, Lishui, Zhejiang 323000, P.R. China.;Department of Nephrology, Lishui Hospital Affiliated to Zhejiang University, Lishui, Zhejiang 323000, P.R. China.;Department of Nephrology, Lishui Hospital Affiliated to Zhejiang University, Lishui, Zhejiang 323000, P.R. China.;Department of Nephrology, Lishui Hospital Affiliated to Zhejiang University, Lishui, Zhejiang 323000, P.R. China.",
"authors": "Wu|Chuifen|C|;Xin|Jun|J|;Xin|Minghua|M|;Zou|Hai|H|;Jing|Lie|L|;Zhu|Caoyong|C|;Lei|Wenhui|W|",
"chemical_list": null,
"country": "Greece",
"delete": false,
"doi": "10.3892/etm.2016.3864",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1792-0981",
"issue": "12(6)",
"journal": "Experimental and therapeutic medicine",
"keywords": "hypokalemic myopathy; primary aldosteronism",
"medline_ta": "Exp Ther Med",
"mesh_terms": null,
"nlm_unique_id": "101531947",
"other_id": null,
"pages": "4064-4066",
"pmc": null,
"pmid": "28101185",
"pubdate": "2016-12",
"publication_types": "D016428:Journal Article",
"references": "22000401;19218772;19829865;11002726;26934393;3659246;18552288;27311223;21724734;3430508",
"title": "Hypokalemic myopathy in primary aldosteronism: A case report.",
"title_normalized": "hypokalemic myopathy in primary aldosteronism a case report"
} | [
{
"companynumb": "CN-MYLANLABS-2017M1001516",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "INDAPAMIDE"
},
"drugadditional": "1",
... |
{
"abstract": "BACKGROUND\nOsteonecrosis is a benign condition characterised by necrotic exposed bone, and is associated with bisphosphonate use. Osteonecrosis of the external auditory canal is rare, with only a few reported cases.\n\n\nMETHODS\nTwo case reports of temporal bone osteonecrosis are presented.\n\n\nRESULTS\nA 64-year-old man with a history of immunoglobulin G kappa multiple myeloma developed a right external auditory canal ulcer 6 years after commencement on clodronate. A 72-year-old woman taking alendronate for osteoporosis, initially diagnosed and treated for right-sided otitis externa, was found to have underlying exposed bone in the right external auditory canal, with a computed tomography scan confirming destruction of the temporal bone.\n\n\nCONCLUSIONS\nWith increasing use of both oral and intravenous bisphosphonates in the community for benign conditions such as osteoporosis and for malignant conditions such as breast cancer and multiple myeloma, the diagnosis of bisphosphonate-associated osteonecrosis should always be considered in patients with a temporal bone lesion, and a relevant drug history taken.",
"affiliations": "Department of Haematology, Adelaide Cancer Centre, Adelaide, South Australia, Australia.",
"authors": "Wickham|N|N|;Crawford|A|A|;Carney|A S|AS|;Goss|A N|AN|",
"chemical_list": "D019386:Alendronate",
"country": "England",
"delete": false,
"doi": "10.1017/S002221511300100X",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0022-2151",
"issue": "127 Suppl 2()",
"journal": "The Journal of laryngology and otology",
"keywords": null,
"medline_ta": "J Laryngol Otol",
"mesh_terms": "D000368:Aged; D019386:Alendronate; D059266:Bisphosphonate-Associated Osteonecrosis of the Jaw; D003937:Diagnosis, Differential; D004424:Ear Canal; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D012307:Risk Factors; D013701:Temporal Bone",
"nlm_unique_id": "8706896",
"other_id": null,
"pages": "S51-3",
"pmc": null,
"pmid": "23673152",
"pubdate": "2013-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Bisphosphonate-associated osteonecrosis of the external auditory canal.",
"title_normalized": "bisphosphonate associated osteonecrosis of the external auditory canal"
} | [
{
"companynumb": "SE-ACTAVIS-2015-07501",
"fulfillexpeditecriteria": "1",
"occurcountry": "SE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ALENDRONIC ACID"
},
"drugadditional": null,
... |
{
"abstract": "Lamotrigine is a commonly prescribed anticonvulsant medication. It is an infrequently reported agent of intentional acute ingestion to poison centers. The spectra of clinical effects of lamotrigine in acute overdose are not well established. We report a case of acute ingestion of lamotrigine and ethanol that resulted in coma requiring ventilatory support, paradoxic seizure activity, and mild rhabdomyolysis.",
"affiliations": "Georgia Poison Center/Emory University School of Medicine, Atlanta, Georgia, USA. aeo8@cdc.gov",
"authors": "Schwartz|Michael D|MD|;Geller|Robert J|RJ|",
"chemical_list": "D000927:Anticonvulsants; D014227:Triazines; D000077213:Lamotrigine",
"country": "United States",
"delete": false,
"doi": "10.1097/FTD.0b013e31815bf239",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0163-4356",
"issue": "29(6)",
"journal": "Therapeutic drug monitoring",
"keywords": null,
"medline_ta": "Ther Drug Monit",
"mesh_terms": "D000328:Adult; D000927:Anticonvulsants; D003243:Consciousness; D062787:Drug Overdose; D006801:Humans; D000077213:Lamotrigine; D012640:Seizures; D014227:Triazines",
"nlm_unique_id": "7909660",
"other_id": null,
"pages": "843-4",
"pmc": null,
"pmid": "18043485",
"pubdate": "2007-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
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"abstract": "Six-minute walk test (6MWT) is a submaximal exercise test applied for evaluation of adults with pulmonary arterial hypertension (PAH). It was widely used as an endpoint in the clinical trials. The aim of the study was to assess the usefulness of 6MWT in management of children with PAH and to establish correlations with other clinical features. 164 6MWT were performed in 15 children between 5 and 18 years with PAH confirmed by right heart catheterization (102 in patients with shunt, 62 without shunt). Distance in 6MWT (6MWD)-% of predicted for age and gender, desaturation at the maximum effort, peak heart rate (HR)-% of maximal HR, were compared to the level of NTproBNP, WHO-FC, echocardiography parameters, and events of PAH treatment intensification. 6MWD had low negative correlation with peak HR (τ -0.1 p = 0,03), negative correlation with NTproBNP (τ -0.17 p = 0.002), and no dependence on echocardiography parameters. The presence of shunt was associated with lower 6MWD, lower blood saturation at rest, and higher desaturation after effort. Patients in III/IV WHO-FC achieved higher rest HR and maximal HR in comparison to patients in I/II WHO-FC (63.1 vs. 55.2% p < 0.01) and lower 6MWD (64.3 vs. 77.5% p < 0.01). In 14 out of 20 6MWT performed after treatment intensification, increase of distance was observed. The results of 6MWT were consistent with clinical status (WHO-FC, NTproBNP) but not with echocardiography parameters. 6MWT may be the source of additional information in management of children with PAH.",
"affiliations": "Department of Cardiology, The Children's Memorial Health Institute, Al. Dzieci Polskich 20, 04-730, Warsaw, Poland.;Department of Cardiology, The Children's Memorial Health Institute, Al. Dzieci Polskich 20, 04-730, Warsaw, Poland. a.migdal@ipczd.pl.;Department of Cardiology, The Children's Memorial Health Institute, Al. Dzieci Polskich 20, 04-730, Warsaw, Poland.;Department of Cardiology, The Children's Memorial Health Institute, Al. Dzieci Polskich 20, 04-730, Warsaw, Poland.;Department of Cardiology, The Children's Memorial Health Institute, Al. Dzieci Polskich 20, 04-730, Warsaw, Poland.;Department of Cardiology, The Children's Memorial Health Institute, Al. Dzieci Polskich 20, 04-730, Warsaw, Poland.",
"authors": "Zuk|Malgorzata|M|;Migdal|Anna|A|http://orcid.org/0000-0003-4103-500X;Jagiellowicz-Kowalska|Dorota|D|;Mazurkiewicz|Katarzyna|K|;Sadel-Wieczorek|Anna|A|;Brzezinska-Rajszys|Grazyna|G|",
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"doi": "10.1007/s00246-017-1575-z",
"fulltext": "\n==== Front\nPediatr CardiolPediatr CardiolPediatric Cardiology0172-06431432-1971Springer US New York 157510.1007/s00246-017-1575-zOriginal ArticleSix-Minute Walk Test in Evaluation of Children with Pulmonary Arterial Hypertension Zuk Malgorzata http://orcid.org/0000-0003-4103-500XMigdal Anna a.migdal@ipczd.pl Jagiellowicz-Kowalska Dorota Mazurkiewicz Katarzyna Sadel-Wieczorek Anna Brzezinska-Rajszys Grazyna grid.413923.eDepartment of Cardiology, The Children’s Memorial Health Institute, Al. Dzieci Polskich 20, 04-730 Warsaw, Poland 27 2 2017 27 2 2017 2017 38 4 754 761 16 10 2016 19 1 2017 © The Author(s) 2017\nOpen AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.Six-minute walk test (6MWT) is a submaximal exercise test applied for evaluation of adults with pulmonary arterial hypertension (PAH). It was widely used as an endpoint in the clinical trials. The aim of the study was to assess the usefulness of 6MWT in management of children with PAH and to establish correlations with other clinical features. 164 6MWT were performed in 15 children between 5 and 18 years with PAH confirmed by right heart catheterization (102 in patients with shunt, 62 without shunt). Distance in 6MWT (6MWD)—% of predicted for age and gender, desaturation at the maximum effort, peak heart rate (HR)—% of maximal HR, were compared to the level of NTproBNP, WHO-FC, echocardiography parameters, and events of PAH treatment intensification. 6MWD had low negative correlation with peak HR (τ −0.1 p = 0,03), negative correlation with NTproBNP (τ −0.17 p = 0.002), and no dependence on echocardiography parameters. The presence of shunt was associated with lower 6MWD, lower blood saturation at rest, and higher desaturation after effort. Patients in III/IV WHO-FC achieved higher rest HR and maximal HR in comparison to patients in I/II WHO-FC (63.1 vs. 55.2% p < 0.01) and lower 6MWD (64.3 vs. 77.5% p < 0.01). In 14 out of 20 6MWT performed after treatment intensification, increase of distance was observed. The results of 6MWT were consistent with clinical status (WHO-FC, NTproBNP) but not with echocardiography parameters. 6MWT may be the source of additional information in management of children with PAH.\n\nKeywords\nPulmonary arterial hypertensionChildrenSix-minute walk testCongenital heart diseaseissue-copyright-statement© Springer Science+Business Media New York 2017\n==== Body\nIntroduction\n6-minute walk test (6MWT) is a submaximal exercise test applied for evaluation of adults with pulmonary arterial hypertension (PAH) [1]. It was widely used as an endpoint in the clinical studies [2]. According to European Society of Cardiology guidelines (2015 [1] and previous), distance reached in 6MWT (6MWD) is one of the factors in risk assessment in pulmonary arterial hypertension. In children, 6MWD is not used as a prognostic parameter [3] due to the difficult cooperation, dependence on age, height, and gender. However, it remains the only exercise test easy to perform and accepted by children with exercise limitations [4].\n\nThe aim of this study was to assess the usefulness of 6MWT for evaluation of children with pulmonary arterial hypertension and to establish correlations with other clinical features.\n\nMaterials and Methods\nAnalysis includes 164 6 MW tests performed every 3 months in 15 children with PAH confirmed in right heart catheterization. The number of tests per 1 patient ranged from 1 to 23 (mean 11 ± 7, median 9). The age during the test was 5–18 years (mean 13.4 ± 4.0; median 14.8), and there were no patients with Down syndrome and physical or mental disability. Distribution of tests performed in patients in I/II WHO functional class (WHO-FC) and III/IV WHO-FC was 129 to 35. 102 tests were done in patients with shunt—multiple ventricular septal defects, atrial septal defect ostium secundum, partial anomalous pulmonary venous drainage, tricuspid atresia, atrio-ventricular septal defect, idiopathic PAH after Potts shunt, and 62 in children without shunt—idiopathic PAH, postoperative congenital heart defect (Table 1). All patients had no bradycardia in 24-h Holter electrocardiography monitoring performed before 6MWT. The 6MWT were performed according to American Thoracic Society standard [5]. Distance, blood oxygen saturation before test (rest SAT) and desaturation at the maximum effort (rest SAT–SAT 6′), initial and maximal heart rate (rest HR, peak HR) were analyzed. Distance was shown as percentage of predicted for age and gender. Normal value of distance was calculated using gender-specific, age-adjusted reference equations [6] (Table 2). Heart rate was analyzed as percentage of median for age [7] (rest HR) and percentage of maximal heart rate for age (220-age)—peak HR. Submaximal exercise was defined as reaching no more than 85% of maximal heart rate [8]. Additionally ratio peak heart rate (% of max HR) to distance (% of predicted) was calculated. Obtained data were compared with the WHO-FC, level of N-terminal pro-brain natriuretic peptide (NTproBNP), echocardiographic parameters: left ventricular diastolic dimension—percentage of mean value for body surface area (LVDd%N), systolic gradient right ventricle-right atrium (∆RV/RA) (Table 3), and events of PAH treatment intensification (first administration, uptitration, or addition of new PAH-specific drug; Potts shunt) (Fig. 1). In order to determine the relationship between distance and clinical parameters, 6 MW tests were divided for three groups: with good, medium, and poor results according to percent of predicted distance (PPD >80%, 60–80%, and <60%) (Table 4).\n\n\nTable 1 Clinical characteristics of the study population\n\nID\tGender\tDiagnosis\tShunt\tNumber of 6MWT\tFirst 6MWT\tLast 6MWT\tΔdistance\t∆ PPD\tTreatment intensification\t\nAge\tWHO-FC\tNTproBNP (pg/ml)\tTreatment\tAge\tWHO-FC\tNTproBNP (pg/ml)\tTreatment\tImprovement\tNo change\tDeterioration–intervention\t\n1\tF\tIPAH\t\t9\t13.2\tII\t797\tbos\t15\tIV\t2428\tbos. sild\t−270\t−41\t\t\t1 − LTx\t\n2\tF\tAPAH CHD\tAVSD\t15\t14.7\tIII\t220\t\t18\tII\t365\tbos\t121\t23\t2\t\t\t\n3\tF\tIPAH\t\t16\t14.8\tIII\t2988\t\t17.9\tII\t60\tbos. tad\t225\t39\t2\t\t\t\n4\tF\tHPAH\t\t12\t16.3\tIII\t1144\t\t18\tIII\t1368\tbos. sild. ilo\t15\t4\t2\t2\t\t\n5\tM\tAPAH CHD\tmVSD\t23\t8.7\tII\t170\tbos. sild\t15.8\tII\t29\tbos. sild\t120\t9\t\t\t\t\n6\tM\tAPAH CHD postop\t\t8\t7.2\tII\t235\t\t9\tII\t118\tbos\t131\t17\t1\t\t\t\n7\tF\tIPAH\tPotts shunt*\t6\t5.1\tIV\t17,272\tbos. sild. epo\t5.8\tIII\t6557\tbos. sild. Potts\t10\t0\t1\t\t1 − Potts shunt\t\n8\tF\tAPAH CHD\tASD II\t23\t6.4\tII\t\tsild\t13.5\tII\t306\tbos. sild\t60\t−3\t1\t\t\t\n9\tF\tAPAH CHD\tAT\t7\t16.7\tII\t122\t\t18\tII\t168\tbos\t42\t8\t1\t\t\t\n10\tF\tIPAH\t\t15\t13.1\tII\t\tsild\t18\tII\t60\tbos\t95\t20\t1\t\t\t\n11\tF\tIPAH\t\t1\t16.1\tIV\t5000\tDeath after RHC\t\t\t\t\t\t\t\t\t\t\n12\tF\tAPAH CHD\tASD II\t15\t14.6\tII\t316\t\t18\tIII\t194\tbos. sild\t−90\t−11\t1\t\t\t\n13\tM\tAPAH CHD\tASD. PAPVD\t7\t6.4\tIII\t1908\t\t7.7\tIII\t4718\tbos. sild\t185\t31\t2\t1\t1 − dose escalation\t\n14\tF\tIPAH\tPotts shunt\t4\t5.4\tI\t78\tbos. sild. Potts\t6.1\tI\t109\tbos. sild. Potts\t−31\t−8\t\t\t\t\n15\tF\tAPAH CHD\tmVSD\t3\t5\tII\t192\tbos\t5.4\tII\t206\tbos\t30\t5\t\t\t\t\n\n6MWT six-minute walk test, PPD percent of predicted distance, IPAH idiopathic pulmonary arterial hypertension, HPAH heritable pulmonary arterial hypertension, APAH pulmonary arterial hypertension associated with, CHD congenital heart defect, CHD postop congenital heart defect after shunt closure, AVSD atrio-ventricular septal defect, mVSD multiple ventricular septal defects, ASD II atrial septal defect ostium secundum, AT tricuspid atresia, PAPVD partial anomalous pulmonary venous drainage, RHC right heart catheterization, bos bosentan, sild sildenafil, tad tadalafil, ilo iloprost, epo epoprostenol, LTx lung transplantation\n\n*1st test before Potts shunt\n\n\n\n\n\nTable 2 Equations to predict the 6MWD in children and adolescents—age-adjusted model [6]\n\nBoys\t\n <13 yo\t24.18 × y + 385.18\t\n >13 yo\t13.08 × y + 476.69\t\nGirls\t\n <12 yo\t20.83 × y + 413.94\t\n >12 yo\t−8.66 × y + 757.42\t\n\n\n\n\nFig. 1 Change of 6MWD after treatment intensification (PPD—% of predicted distance for age and gender)\n\n\n\n\n\nTable 3 Results of all analyzed 6MWT (data presented as mean ± SD and median)\n\nParameters\tUnits\tAll 6MWT\tShunt\tNo shunt\t\np\n\tWHO-FC I/II\tWHO-FC III/IV\t\np\n\t\n\nN\n\t\t\n164\n\t\n102\n\t\n62\n\t\t\n124\n\t\n40\n\t\t\n6MWD\t% of predicted\t74.3 ± 12.6\n76.5\t\n72.8 ± 12.4\n\n\n75.2\n\t\n76.9 ± 12.5\n\n\n79.3\n\t\n0.02\n\t\n77.5 ± 8.9\n\n\n78.0\n\t\n64.3 ± 16.4\n\n\n70.6\n\t<0.01\n\t\nRest SAT\t%HbO2\t92.6 ± 6.3\n96\t\n89.6 ± 6.4\n\n\n91\n\t\n97.5 ± 1.1\n\n\n98\n\t<0.01\n\t93.1 ± 5.7\n6.0\t90.9 ± 7.8\n95.0\tNS\t\nDesaturation\t%HbO2\t11.8 ± 11.2\n10.0\t\n17.5 ± 10.4\n\n\n17.5\n\t\n2.6 ± 4.3\n\n\n1\n\t<0.01\n\t11.8 ± 11.4\n10.0\t11.7 ± 10.6\n9.0\tNS\t\nRest HR\t% of median for age\t101 ± 21\n101\t99.3 ± 2.119\n9.3\t102.9 ± 18.6\n103.3\tNS\t\n96.6 ± 20.9\n\n\n96.5\n\t\n113.1 ± 18.5\n\n\n110.3\n\t<0.01\n\t\nPeak HR\t% of max HR for age\t57.1 ± 11.9\n56.9\t57.3 ± 11.1\n58.2\t56.9 ± 13.3\n54.9\tNS\t\n55.1 ± 11.2\n\n\n54.3\n\t\n63.1 ± 12.35\n\n\n9.4\n\t<0.01\n\t\nPeak HR/6MWD\t\t0.79 ± 0.33\n0.75\t0.81 ± 0.35\n0.77\t0.77 ± 0.29\n0.7\tNS\t\n0.71 ± 0.2\n\n\n0.7\n\t\n1.12 ± 0.56\n\n\n1.05\n\t<0.01\n\t\nNTproBNP\tpg/ml\t875 ± 1904\n255\t804 ± 1612\n271\t995 ± 2336\n176\tNS\t\n244 ± 244\n\n\n165\n\t\n2766 ± 3120\n\n\n1832\n\t<0.01\n\t\nΔRV-RA\tmmHg\t95 ± 25\n100\t\n101.7 ± 21.8\n\n\n103\n\t\n83.9 ± 25\n\n\n82\n\t<0.01\n\t94.2 ± 27.5\n101.0\t95.8 ± 17\n90.5\tNS\t\nLVDd %N\t% of mean normal value\t90.8 ± 11.5\n92\t92.8 ± 10.5\n94\t88.7 ± 12.3\n91.5\tNS\t91.1 ± 10.9\n93.0\t90.2 ± 12.1\n91.0\tNS\t\nHb\tg/l\t146 ± 18\n149\t\n152 ± 15\n\n\n152\n\t\n136 ± 17\n\n\n132\n\t<0.01\n\t145 ± 19\n149\t149 ± 14\n152\tNS\t\nBold values indicate statistically significant (p < 0.05)\n\n\n\n\n\nTable 4 6MWTs divided into groups: good, medium and poor result (data presented as mean ± SD)\n\n\nGroup\tAll\n\nN = 164\nMean PPD 74.3 ± 12.6%\tGood\nPPD >80%\n\nN = 51\nMean PPD 85.6 ± 5.2%\tMedian\nPPD 60–80%\n\nN = 93\nMean PPD 73.8 ± 4.8%\tPoor\nPPD <60%\n\nN = 20\nMean PPD 48.1 ± 10.1%\t\np\n\t\nClinical data\t\n Shunt\t102 (62%)\t\n23 (45%)\n\t64 (69%)\t\n15 (75%)\n\t<0.01\t\n Age (years)\t13.4 ± 4.0\t14.7 ± 3.4\t13.5 ± 3.6\t\n9.4 ± 4.6\n\t<0.01\t\n WHO-FC\t2.2\t1.9\t2.2\t\n2.9\n\t<0.01\t\n Rest HR\t80.0 ± 17.7\t77.2 ± 14.2\t75.9 ± 13.6\t\n106.3 ± 20.7\n\t<0.01\t\n Rest SAT (%HbO2)\t92.6 ± 6.3\t93.9 ± 5.7\t92.8 ± 5.9\t\n88.9 ± 8.2\n\t<0.01\t\n NTproBNP (pg/ml)\t899.9 ± 1946.9\t\n431.1 ± 762.2\n\t666.9 ± 1952.8\t\n3108.5 ± 2495.4\n\t<0.01\t\nEcho\t\n LVDd%N\t90.8 ± 11.5\t89.5 ± 9.9\t91.4 ± 12.3\t90.8 ± 11.6\tNS\t\n ΔRV-RA\t94.7 ± 24.7\t88.7 ± 26.9\t96.6 ± 25.4\t96.2 ± 19.3\tNS\t\n6MWT\t\n Peak HR\t117.9 ± 24.4\t114.0 ± 23.3\t117.2 ± 25.0\t\n131.4 ± 20.5\n\t0.02\t\n HR% max\t57.1 ± 11.9%\t55.6 ± 11.4%\t56.8 ± 12.4%\t62.5 ± 10.0%\tNS\t\n ΔHR\t38.6 ± 25.1\t36.8 ± 24.0\t42.3 ± 24.1\t\n25.5 ± 28.5\n\t0.02\t\n Peak SAT (%HbO2)\t80.7 ± 14.6\t\n85.5 ± 13.7\n\t78.4 ± 14.5\t78.7 ± 14.6\t0.01\t\n Desaturation (%HbO2)\t11.8 ± 11\t\n7.8 ± 9.7\n\t14.4 ± 11.7\t10.2 ± 9.5\t<0.01\t\nAbbreviations description in the text\n\n\n\n\n Procedures analyzed in this study are the part of standard care of patients with pulmonary hypertension. All are required by the National Health Fund to reimbursement of pharmacotherapy. Informed consent to participate in the therapeutic program of the National Health Fund was obtained in all patients.\n\nStatistical Analysis\nContinuous data were presented as values with an average, a standard deviation, and a median. Normal distribution was determined using Shapiro–Wilk test. To compare of distribution in groups, parametric (T-student) and non-parametric (Whitney–Mann) tests were used. The limit for statistical significance was set at p < 0.05. Obtained data were shown on the boxplot. Differences among three groups of tests (good, medium, poor result) were analyzed using analysis of variance (ANOVA). To measure the association between two measured quantities, Kendall’s rank correlation coefficient (tau) was used.\n\nResults\n In all tests, reached distance adjusted to age and gender ranged from 22 to 109% of predicted value (mean 74.3 ± 12.6%; median 76.5%). 11 patients in 51 tests reached distance more than 80% predicted (good result group). In this group, a lower WHO-FC (92% WHO-FC I/II) and a lower level of NTproBNP (431.1 ± 762.2) were found. 55% of tests were performed by patients with PAH without shunt therefore with higher saturation, and lower mean desaturation. 7 patients in 20 tests did not achieve 60% PPD (poor result group). Mean age during tests was lower than in other groups. 75% tests in this group were performed by patients with shunt therefore the rest saturation was lower. Patients were in higher WHO-FC (80% WHO-FC III/IV), with higher level of NTproBNP (3108.5 ± 2495.4), rest HR, and peak HR despite the increase heart rate (ΔHR) was lower. There were no differences in echocardiography parameters irrespectively of 6MWT results (good, medium, and poor).\n\nIn whole material, the walk distance had low negative correlation with peak heart rate (τ −0.1 p = 0.03) (Fig. 2) and negative correlation with NTproBNP (τ −0.17 p = 0.002) (Fig. 3). No dependence on echocardiography parameters was found. All results of 6MWT are shown in (Table 4).\n\n\nFig. 2 Correlation between 6MWD and peak heart rate (peak HR)\n\n\n\n\n\nFig. 3 Correlation between 6MWD and NTproBNP level\n\n\n\n\n20 events of treatment intensification were detected in 11 patients (Fig. 1). In 17 cases, it was associated with at least 5% change of distance in the next 6MWT (after 1–3 months). Increase in percentage of predicted value (7–25%, mean 13 ± 6, median 10.5%) was observed in 14 events in 10 patients. In 3 patients, the percentage of predicted value decreased by 6–25%. In those cases further intensification of treatment was taken: dose escalation with good results in 1 patient, Potts shunt in 1 and lung transplantation in 1 (Table 1).\n\nShunt Versus No Shunt (Table 3)\nThe percentage of patients in WHO-FC III/IV was similar in both groups (shunt 27.2%; no shunt 22.5%). Walk distance in patients with shunt was lower than without shunt (73 vs. 77% p = 0.02) (Fig. 4). No differences in heart rate (initial and peak) were observed. The presence of shunt was associated with lower blood saturation at rest (90 vs. 98% p < 0.01) (Fig. 5) and higher desaturation after effort (17.5%HbO2 vs. 3%HbO2 p < 0.01) (Fig. 6).\n\n\nFig. 4 6MWD in patients with shunt and no shunt\n\n\n\n\n\nFig. 5 Blood saturation at rest (rest SAT) in patients with shunt and with no shunt\n\n\n\n\n\nFig. 6 Desaturation after effort in patients with shunt and with no shunt\n\n\n\n\nWHO III/IV Versus I/II (Table 3)\nThe percentage of patients with shunt was similar in both groups (III/IV 57.5%; I/II 63.7%). Patients in III/IV WHO-FC achieved significantly lower walk distance than children with I/II WHO-FC (64.3 vs. 77.5% p < 0.01) (Fig. 7). They had higher rest HR (113 vs. 97% of normal value p < 0.01) (Fig. 8), similar increase of HR during effort (38 vs. 39 beats NS), and higher peak HR (63.1 vs. 55.2% of maximal heart rate for age p < 0.01) (Fig. 9). Only in six tests criteria of submaximal exercise was exceeded or was only slightly below limit (81–84%). Five of them were performed by patients in III WHO-FC with the average distance 69 vs. 74% in the rest of the tests (too small group for statistical analysis). Peak heart rate-to-distance ratio in patients with III/IV WHO-FC was significantly higher than in patients in I/II WHO-FC (1.1 vs. 0.7 p < 0.01) (Fig. 10).\n\n\nFig. 7 6MWD in patients in I/II WHO-FC in comparison to patients in III/IV WHO-FC\n\n\n\n\n\nFig. 8 Rest heart rate (rest HR) in patients in I/II WHO-FC in comparison to patients in III/IV WHO-FC\n\n\n\n\n\nFig. 9 Peak heart rate (peak HR) in patients in I/II WHO-FC in comparison to patients in III/IV WHO-FC\n\n\n\n\n\nFig. 10 Peak heart rate (peak HR) to 6MWD ratio in patients in I/II WHO-FC in comparison to patients in III/IV WHO-FC\n\n\n\n\nDiscussion\nThis study demonstrated that the results of 6MWT in children with pulmonary hypertension are associated with clinical status, especially with WHO-FC and NTproBNP which are unquestioned prognostic factors in this disease [3]. No dependence on echocardiography parameters was detected, but only basic measurements were included. Similarly Placido et al. [9] reported no correlation between conventional parameters of the RV function and 6 MWD in adults with pulmonary arterial hypertension. It is possible that more detail examination of systolic and diastolic function in echo using advanced methods will be more useful to detect correlation between echo and 6MWD and this needs further investigation, especially in children.\n\nThe usefulness of the 6MWT was confirmed in many studies in adults [10–12], so in ESC guidelines 2015 [1] and previous, 6MWD is recommended as one of prognosis determinants. There are many doubts regarding the usefulness of 6MWT in children because the results depend on age, gender, and developmental parameters. Additionally, reproducibility of this test in children depends on proper cooperation, which is not always possible. In our study, we use percentage of normal value adjusted for age and gender to eliminate developmental differences. Martins et al. [13] have verified the reproducibility of the 6-min walk test in healthy children at the age of 6–14 years. No effect of learning on the distance in second test was observed. Similar results were obtained by Morinder et al [14], who examined a group of 49 obese and 97 healthy children. Taking into account the above evidence, analysis of the individual tests (not individual patients) seems reasonable and should not be fraught with bias resulting from age and the effect of learning.\n\nMany authors evaluated the results of 6MWT in children with chronic diseases (for example, pulmonary diseases [15], obesities [14], connective tissue diseases, and hematological and neurological abnormalities [16]). In most studies, 6MWT was recognized as a useful in the evaluation of chronically ill children. However, standards of performance of 6MWT are different, so comparison between studies is difficult and conclusion should be interpreted with caution [17].\n\nThere are limited data concerning the usefulness of 6MWT in children with PAH.\n\nBased on recent studies, where baseline 6MWD was not a predictor of survival in children with pulmonary hypertension, Ivy et al. [18] concluded that 6MWT should not be consider in risk assessment in PAH children in contrast to adults. However, the results of other studies suggest that 6MWT can be useful in the management of pediatric PAH. Lammers et al. [19] published data of 47 children with PAH at the mean age of 11.4 years, where 6 MW distance in single measurement was one of the predictors of death or need for transplantation. The same author [20] evaluated results of 6MWT in PAH children. In this study, 6MWD was significantly shorter than predicted (47.7 ± 16.7%). 6MWT was a submaximal test in most of patients. Heart rate limit for maximal effort was reached only by children with a 6MWT distance of less than 300 m. That is compatible with our observation—distance in all tests was less than predicted, and criteria of submaximal effort exceeded patients with WHO-FC III/IV with shorter 6MWD.\n\nWe observed shorter 6MWD in PAH patients with shunt compare to patients with IPAH or PAH after shunt closure. The same results, but without statistical significance, were published by Lammers [20] and Douwes [21]. Additionally, Lammers demonstrated lower exercise capacity measured in CPET in patients with Eisenmenger syndrome compare to patient after shunt closure. As explained by Dimopoulos [22], it may be abnormal ventilatory response to exercise due to cyanosis. In the presented material, patients with Eisenmenger syndrome characterized by ventilation to perfusion mismatch. They have lower peak oxygen uptake (VO2max) and significantly higher ventilation per unit of CO2 production (VE/VCO2) slope, and lower expiratory exchange ratio at peak exercise.\n\nStudy published by Douwes [21] contains two issues—evaluation of 6MWT as a prognostic factor and as a determinant of disease severity. 6MWD was negatively correlated with NTproBNP and WHO-FC (similarly to our results and Van Albada study [23]). Patients with shunt had higher desaturation on the peak of effort. No correlation between heart rate and WHO-FC was observed. On the contrary, our study showed higher heart rate during 6MWT, baseline and maximal, in patients in III/IV WHO-FC. The results of both studies (Douwes’ and ours) conducted using different methods indicate that 6MWT may be useful in monitoring of disease severity.\n\nStudy Limitation\nWe analyzed the tests independently which were repeated several times by the same patients, however, in different clinical conditions. The study group does not have limitations associated with the physical development or intellectual disability or pathology of other systems. The bias related to age and the effect of learning seems to be irrelevant of the reasons mentioned above. However, the individual differences in exercise capacity of patients may affect the results. On the other hand, the studies assessing 1 test in each patient do not take into account the changes of clinical status and treatment. Thus, the predictive value of identical result of the test in child before treatment vs child receiving the combination therapy is different. Therefore it would be rational to apply advanced statistical modeling methods in a larger group of patients who have performed many tests to achieve more satisfactory results.\n\nConclusions\nThe results of the 6MWT in children with pulmonary hypertension reflect clinical status (WHO-FC, NTproBNP), but not echocardiography parameters. 6MWT may be the source of additional information in assessment and management of children with PAH. 6MWT repeated in routine control may be helpful in treatment decisions.\n\nAbbreviations\n6MWT6-minute walk test\n\n6MWD6-minute walk distance\n\nHRHeart rate\n\nLVDd%NLeft ventricular diastolic dimension—percentage of mean value for body surface area\n\nNTproBNPN-terminal pro-brain natriuretic peptide\n\nPAHPulmonary arterial hypertension\n\n∆RV/RASystolic gradient right ventricle-right atrium\n\nSATBlood oxygen saturation\n\nWHO-FCWHO functional class\n\nAcknowledgements\nMalgorzata Zuk takes responsibility for the content of the manuscript, including the data and analysis. MZ and AM have made substantial contributions to the conception and design, analysis and interpretation of data, have drafted the submitted article and revised it critically for important intellectual content, have provided final approval of the version to be published, and have agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. DJK, KMA, and ASW have made substantial contributions to acquisition of data, have revised submitted article critically for important intellectual content, and have agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. GBR has made substantial contributions to interpretation of data, has revised submitted article critically for important intellectual content, and has provided final approval of the version to be published.\n\nCompliance with Ethical Standards\nConflict of interest\nThe authors declare that they have no conflict of interest.\n==== Refs\nReferences\n1. Galie N Humbert M Vachiery JL 2015 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension Eur Heart J 2016 37 1 67 119 10.1093/eurheartj/ehv317 26320113 \n2. Peacock A Keogh A Humbert M Endpoints in pulmonary arterial hypertension: the role of clinical worsening Curr Opin Pulm Med 2010 16 suppl S1 S9 10.1097/01.mcp.0000370205.22885.98 20375659 \n3. Ploegstra MJ Zijlstra WM Douwes JM Hillege HL Berger RM Prognostic factors in pediatric pulmonary arterial hypertension: a systematic review and meta-analysis Int J Cardiol 2015 184 198 207 10.1016/j.ijcard.2015.01.038 25706327 \n4. Geiger R Strasak A Treml B Six-minute walk test in children and adolescents J Pediatr 2007 150 4 395 399 10.1016/j.jpeds.2006.12.052 17382117 \n5. American Thoracic Society ATS statement: guidelines for the six-minute walk test Am J Respir Crit Care Med 2002 166 1 111 117 10.1164/ajrccm.166.1.at1102 12091180 \n6. Ulrich S Hildenbrand FF Treder U Reference values for the 6-minute walk test in healthy children and adolescents in Switzerland BMC Pulm Med 2013 13 49 10.1186/1471-2466-13-49 23915140 \n7. Fleming S Thompson M Stevens R Normal ranges of heart rate and respiratory rate in children from birth to 18 years: a systematic review of observational studies The Lancet 2011 377 9770 1011 1018 10.1016/S0140-6736(10)62226-X \n8. Fletcher GF Balady GJ Amsterdam EA Exercise standards for testing and training: a statement for healthcare professionals from the American Heart Association Circulation 2001 104 1694 1740 10.1161/hc3901.095960 11581152 \n9. Plácido R Martins S Marques JS Kovell L Predictors of functional capacity in patients with pulmonary hypertension J Pulm Respir Med 2015 5 5 10.4172/2161-105X.1000290 \n10. Fritz JS Blair C Oudiz RJ Baseline and follow-up 6-min walk distance and brain natriuretic peptide predict 2-year mortality in pulmonary arterial hypertension Chest 2013 143 2 315 323 10.1378/chest.12-0270 22814814 \n11. Mathai SC Puhan MA Lam D Wise RA The minimal important difference in the 6-minute walk test for patients with pulmonary arterial hypertension Am J Respir Crit Care Med 2012 186 5 428 433 10.1164/rccm.201203-0480OC 22723290 \n12. Farber HW Miller DP McGoon MD Frost AE Benton WW Benza RL Predicting outcomes in pulmonary arterial hypertension based on the 6-min walk distance J Heart Lung Transplant 2015 34 362 368 10.1016/j.healun.2014.08.020 25312386 \n13. Martins R Goncalves RM Mayer AF Santos Schivinski CI Reliability and reproducibility of six-minute walk test in healthy children Fisioter Pesqui 2014 21 3 279 284 \n14. Morinder G Mattsson E Sollander C Marcus C Larsson UE Six-minute walk test in obese children and adolescents: reproducibility and validity Physiother Res Int 2009 14 91 104 10.1002/pri.428 19003813 \n15. Ghofraniha L Dalir Sani Z Vakilian F The six-minute walk test (6MWT) for the evaluation of pulmonary diseases J Cardiothorac Med 2015 3 2 284 287 \n16. Hassan J van der Net J Helders PJM Prakken BJ Takken T Six-minute walk test in children with chronic conditions Br J Sports Med 2010 44 270 274 10.1136/bjsm.2008.048512 18487250 \n17. Bartels B de Groot JF Terwee CB The six-minute walk test in chronic pediatric conditions: a systematic review of measurement properties Phys Ther 2013 93 4 529 541 10.2522/ptj.20120210 23162042 \n18. Ivy D Abman SH Barst RJ Pediatric pulmonary hypertension J Am Coll Cardiol 2013 62 25 Suppl D117-D126 24355636 \n19. Lammers AE Munnery E Hislop AA Haworth SG Heart rate variability predicts outcome in children with pulmonary arterial hypertension Int J Cardiol 2010 142 159 165 10.1016/j.ijcard.2008.12.087 19176261 \n20. Lammers AE Diller GP Odendaal D Tailor S Derrick G Haworth SG Comparison of 6-min walk test distance and cardiopulmonary exercise test performance in children with pulmonary hypertension Arch Dis Child 2011 96 141 147 10.1136/adc.2009.169904 20930016 \n21. Douwes JM Hegeman AK van der Krieke MB Roofthooft MT Hillege HL Berger RM Six-minute walking distance and decrease in oxygen saturation during the six-minute walk test in pediatric pulmonary arterial hypertension Int J Cardiol 2016 202 34 39 10.1016/j.ijcard.2015.08.155 26386916 \n22. Dimopoulos K Okonko DO Diller G-P Abnormal ventilatory response to exercise in adults with congenital heart disease relates to cyanosis and predicts survival Circulation 2006 113 2796 2802 10.1161/CIRCULATIONAHA.105.594218 16769913 \n23. Van Albada ME Loot FG Fokkema R Roofthooft MT Berger RM Biological serum markers in the management of pediatric pulmonary arterial hypertension Pediatr Res 2008 63 321 327 10.1203/PDR.0b013e318163a2e7 18287971\n\n",
"fulltext_license": "CC BY",
"issn_linking": "0172-0643",
"issue": "38(4)",
"journal": "Pediatric cardiology",
"keywords": "Children; Congenital heart disease; Pulmonary arterial hypertension; Six-minute walk test",
"medline_ta": "Pediatr Cardiol",
"mesh_terms": "D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D017079:Exercise Tolerance; D005260:Female; D006801:Humans; D006976:Hypertension, Pulmonary; D008297:Male; D000070857:Walk Test",
"nlm_unique_id": "8003849",
"other_id": null,
"pages": "754-761",
"pmc": null,
"pmid": "28239753",
"pubdate": "2017-04",
"publication_types": "D016428:Journal Article",
"references": "17382117;18487250;26386916;21411136;25312386;25706327;19176261;12091180;23915140;22723290;22814814;18287971;20930016;19003813;26320113;24355636;11581152;20375659;23162042;16769913",
"title": "Six-Minute Walk Test in Evaluation of Children with Pulmonary Arterial Hypertension.",
"title_normalized": "six minute walk test in evaluation of children with pulmonary arterial hypertension"
} | [
{
"companynumb": "PL-ACTELION-A-CH2018-168424",
"fulfillexpeditecriteria": "1",
"occurcountry": "PL",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "SILDENAFIL"
},
"drugadditional": null,
... |
{
"abstract": "Pegloticase is a highly effective treatment for refractory gouty arthropathy. Unfortunately, the medication is also highly immunogenic, leading to infusion reactions, loss of drug efficacy and anaphylaxis. Desensitisation, a procedure to tolerise a patient to a medication previously causing a hypersensitivity reaction, has been used successfully in oncology for chemotherapy treatment. The same principle can be applied to other specialties. Presented is a 48-year-old man who experienced multiple, severe infusion reactions to pegloticase administered for gouty arthropathy. A rapid desensitisation was performed using an outpatient, 3-bag, 12-step protocol, which allowed multiple additional pegloticase infusions to be performed without incident. This is the first reported case of a patient successfully desensitised after an infusion reaction to pegloticase. Though additional patients are needed to confirm these results, this represents a significant opportunity to recapture and continue pegloticase therapy in patients treated for refractory gouty arthropathy.",
"affiliations": "Orthopedic Physicians Alaska, Anchorage, Alaska, USA jbotson@opaak.com.",
"authors": "Botson|John K|JK|http://orcid.org/0000-0002-9552-3351",
"chemical_list": "D006074:Gout Suppressants; D011092:Polyethylene Glycols; D014503:Urate Oxidase; C031545:Pegloticase",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2020-234721",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "13(6)",
"journal": "BMJ case reports",
"keywords": "immunology; rheumatology",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000553:Ambulatory Care; D002985:Clinical Protocols; D003888:Desensitization, Immunologic; D004342:Drug Hypersensitivity; D006073:Gout; D006074:Gout Suppressants; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D011092:Polyethylene Glycols; D016896:Treatment Outcome; D014503:Urate Oxidase",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "32565437",
"pubdate": "2020-06-21",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Pegloticase hypersensitivity desensitisation: an outpatient, 3-bag, 12-step protocol.",
"title_normalized": "pegloticase hypersensitivity desensitisation an outpatient 3 bag 12 step protocol"
} | [
{
"companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-286106",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drug... |
{
"abstract": "OBJECTIVE\nA case report of a sharp rise in International Normalized Ratio (INR) values during a patient's concomitant use of warfarin and the antineoplastic agent vismodegib is presented.\n\n\nCONCLUSIONS\nAbout three weeks after he was prescribed vismodegib for skin cancer, a 78-year-old Caucasian man whose INR had been stable during nine months of warfarin use was found to have a critical INR value (9.5) during a visit to a pharmacy anticoagulation clinic. After clinic interventions including brief suspensions of warfarin therapy and an incremental 36% decrease in the weekly dose, the patient's INR returned to a high-normal value over the next few weeks, and treatment with warfarin was resumed. One week later, the man was admitted to the emergency department for altered mental status and loss of consciousness, which were thought to be unrelated to anticoagulation therapy. The patient died in the hospital shortly thereafter of unknown causes. At the time of death, laboratory values were stable, the most recent INR was 1.8, and the patient was hemodynamically stable and on a non-intensive care ward. Assessment with the Drug Interaction Probability Scale indicated a probable interaction between warfarin and vismodegib. Since its introduction in 2012, vismodegib has been implicated as a possible factor in seven reports of patient deaths.\n\n\nCONCLUSIONS\nConcurrent use of vismodegib and warfarin was deemed the probable cause of acute INR elevation in this case, suggesting the need for close monitoring of INR values in patients receiving this combination of drugs.",
"affiliations": "Shannon Lim is a Pharm.D. candidate at the University of Arizona College of Pharmacy, Tucson. Jenna Houranieh, Pharm.D., is Clinical Pharmacy Specialist in Hematology/Oncology, Lexington Veterans Affairs (VA) Medical Center, Lexington, KY; at the time of writing, she was Postgraduate Year 2 (PGY2) Oncology Pharmacy Resident; and Russell Crawford, B.S.Pharm., BCOP, is Clinical Pharmacy Specialist in Hematology/Oncology and PGY2 Oncology Pharmacy Residency Program Director, Southern Arizona VA Healthcare System, Tucson.",
"authors": "Lim|Shannon|S|;Houranieh|Jenna|J|;Crawford|Russell|R|",
"chemical_list": "D000813:Anilides; D000925:Anticoagulants; D000970:Antineoplastic Agents; C538724:HhAntag691; D011725:Pyridines; D014859:Warfarin",
"country": "England",
"delete": false,
"doi": "10.2146/ajhp130093",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1079-2082",
"issue": "71(3)",
"journal": "American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists",
"keywords": null,
"medline_ta": "Am J Health Syst Pharm",
"mesh_terms": "D000368:Aged; D000813:Anilides; D000925:Anticoagulants; D000970:Antineoplastic Agents; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D016903:Drug Monitoring; D006801:Humans; D019934:International Normalized Ratio; D008297:Male; D011725:Pyridines; D012878:Skin Neoplasms; D014859:Warfarin",
"nlm_unique_id": "9503023",
"other_id": null,
"pages": "200-3",
"pmc": null,
"pmid": "24429012",
"pubdate": "2014-02-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Elevated International Normalized Ratio in a patient concurrently using warfarin and vismodegib.",
"title_normalized": "elevated international normalized ratio in a patient concurrently using warfarin and vismodegib"
} | [
{
"companynumb": "US-IPCA LABORATORIES LIMITED-IPC-2020-US-000224",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "HYDROCHLOROTHIAZIDE"
},
... |
{
"abstract": "Acute promyelocytic leukemia (APL) manifesting during pregnancy is a very rare but highly challenging gestational complication in part due to its associated profound coagulopathy. We present the case of a 23-year-old Gravida 3 Para 2002 woman admitted to our hospital at 26 weeks of gestation for severe pre-eclampsia with documentation of intrauterine fetal demise (IUFD), thrombocytopenia, and placental abruption. A peripheral blood smear revealed promyelocytes with azure granules, highly concerning for APL. Additional peripheral blood studies confirmed APL. Placental examination also revealed circulating blasts in decidual vessels and scattered blast entrapment in diffuse perivillous fibrinoid deposits, but none in the chorionic villi. Treatment for APL was initiated immediately and she is in complete molecular remission. Our case underscores the importance of close collaboration among obstetric, hematology, and pathology teams in the care of patients with pre-eclampsia, thrombocytopenia, and postpartum coagulopathy. We also describe five additional cases of gestations complicated by hematologic malignancies identified upon a 10-year institutional retrospective review.",
"affiliations": "Department of Pathology, Divisions of Anatomic and Clinical Pathology, The University of Alabama at Birmingham, Birmingham, AL 35249, USA.;Department of Pathology, Divisions of Anatomic and Clinical Pathology, The University of Alabama at Birmingham, Birmingham, AL 35249, USA.;Department of Medicine, Division of Hematology/Oncology, The University of Alabama at Birmingham, Birmingham, AL 35249, USA.;Department of Medicine, Division of Hematology/Oncology, The University of Alabama at Birmingham, Birmingham, AL 35249, USA.;Department of Pathology, Divisions of Anatomic and Clinical Pathology, The University of Alabama at Birmingham, Birmingham, AL 35249, USA. Electronic address: vreddy@uabmc.edu.",
"authors": "Fei|Fei|F|;Faye-Petersen|Ona M|OM|;Vachhani|Pankit|P|;Jamy|Omer|O|;Reddy|Vishnu V|VV|",
"chemical_list": "D000970:Antineoplastic Agents; D014212:Tretinoin",
"country": "Germany",
"delete": false,
"doi": "10.1016/j.prp.2019.152672",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0344-0338",
"issue": "215(12)",
"journal": "Pathology, research and practice",
"keywords": "Acute promyelocytic leukemia; Disseminated intravascular coagulation; Pregnancy",
"medline_ta": "Pathol Res Pract",
"mesh_terms": "D000037:Abruptio Placentae; D000970:Antineoplastic Agents; D004211:Disseminated Intravascular Coagulation; D005260:Female; D005313:Fetal Death; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute; D049590:Postpartum Period; D011225:Pre-Eclampsia; D011247:Pregnancy; D011252:Pregnancy Complications, Neoplastic; D012189:Retrospective Studies; D016896:Treatment Outcome; D014212:Tretinoin; D055815:Young Adult",
"nlm_unique_id": "7806109",
"other_id": null,
"pages": "152672",
"pmc": null,
"pmid": "31587825",
"pubdate": "2019-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Acute promyelocytic leukemia during pregnancy: A case report and 10-year institutional review of hematologic malignancies during pregnancy.",
"title_normalized": "acute promyelocytic leukemia during pregnancy a case report and 10 year institutional review of hematologic malignancies during pregnancy"
} | [
{
"companynumb": "US-PFIZER INC-2019558384",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "TRETINOIN"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nThis is a prospective clinical study aimed at assessing the success rate of osteotomy and primary wound closure in patients with bisphosphonate-associated osteonecrosis of the jaw (BONJ).\n\n\nMETHODS\nFifty patients who had received bisphosphonates intravenously and subsequently suffered from BONJ were included in the study. All patients underwent osteotomy of the affected jaw bone region and primary wound closure under general anaesthesia. They were followed up bimonthly for a period of 12 months.\n\n\nRESULTS\nMacroscopically altered bone could be completely removed in all cases. In two patients with plasmocytoma, major bleeding occurred postoperatively that required monitoring in an intensive care unit. In two cases, recurrence of BONJ was diagnosed during the first 2 months. In three patients, recurrence appeared between the fourth and the sixth month. In these cases, an additional osteotomy had to be performed. Six patients died during the follow-up period. In the remaining 39 patients, no signs of recurrence could be detected during the follow-up of 12 months. The success rate of the surviving patients was 89% after 1 year.\n\n\nCONCLUSIONS\nDue to the high success rate of osteotomy and primary wound closure, it should be checked for every patient suffering from BONJ if osteotomy is a viable treatment option.",
"affiliations": "Department of Oral and Maxillofacial Surgery, Friedrich-Alexander University Erlangen-Nuremberg, Glückstrasse 11, 91054 Erlangen, Germany. philipp.stockmann@uk-erlangen.de",
"authors": "Stockmann|Philipp|P|;Vairaktaris|Eleftherios|E|;Wehrhan|Falk|F|;Seiss|Martin|M|;Schwarz|Stephan|S|;Spriewald|Bernd|B|;Neukam|Friedrich-Wilhelm|FW|;Nkenke|Emeka|E|",
"chemical_list": "D050071:Bone Density Conservation Agents; D004164:Diphosphonates",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00520-009-0688-1",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0941-4355",
"issue": "18(4)",
"journal": "Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer",
"keywords": null,
"medline_ta": "Support Care Cancer",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007571:Jaw Diseases; D008297:Male; D008875:Middle Aged; D010020:Osteonecrosis; D010027:Osteotomy; D010954:Plasmacytoma; D011446:Prospective Studies; D012008:Recurrence; D012086:Reoperation; D013536:Suture Techniques; D016896:Treatment Outcome",
"nlm_unique_id": "9302957",
"other_id": null,
"pages": "449-60",
"pmc": null,
"pmid": "19609572",
"pubdate": "2010-04",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article",
"references": "9332325;18558816;14586868;12966493;17663640;16957978;10321934;18282788;17307580;8950879;17307613;17118761;17123911;12966490;12915606;16982320;15122554;17768133;14738134;16243172;15356460;17172192;11858359;17912085;17545793;11564110;17606496;17482847;10525729;6810448;18642292;18336375;17524535;10780527;16901034;16702591;11289137;16383047;18506174",
"title": "Osteotomy and primary wound closure in bisphosphonate-associated osteonecrosis of the jaw: a prospective clinical study with 12 months follow-up.",
"title_normalized": "osteotomy and primary wound closure in bisphosphonate associated osteonecrosis of the jaw a prospective clinical study with 12 months follow up"
} | [
{
"companynumb": "PHHY2010DE49614",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "IBANDRONIC ACID"
},
"drugadditional": "3",
"d... |
{
"abstract": "Alemtuzumab is FDA-approved for the treatment of chronic lymphocytic leukemia (CLL). Nonetheless, its use for this indication has fallen out of favor due to serious concerns for infectious complications and increased risks of second malignancies from the profound and lasting immunosuppression. We report here in a patient with a rapidly progressive metastatic Merkel cell carcinoma (MCC) who was previously treated with alemtuzumab and fludarabine for CLL. He developed profound lymphopenia and hypogammaglobulinemia. While the risk of MCC is increased in CLL, its rapid dissemination has not been previously reported with fludarabine alone. In light of the rapidly fatal outcome in our patient due to MCC, we advise caution with the use of alemtuzumab. In patients treated with alemtuzumab for nononcologic indications, aggressive surveillance for cutaneous malignancies should be implemented until its safety profile can be further characterized.",
"affiliations": null,
"authors": "Yu|Kenneth K|KK|;Dasanu|Constantin A|CA|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D000074323:Alemtuzumab; D014740:Vidarabine; C024352:fludarabine",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0010-6178",
"issue": "80(6)",
"journal": "Connecticut medicine",
"keywords": null,
"medline_ta": "Conn Med",
"mesh_terms": "D000361:Agammaglobulinemia; D000368:Aged; D000074323:Alemtuzumab; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols; D002280:Carcinoma, Basal Cell; D015266:Carcinoma, Merkel Cell; D002294:Carcinoma, Squamous Cell; D017809:Fatal Outcome; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell; D008231:Lymphopenia; D008297:Male; D008545:Melanoma; D016609:Neoplasms, Second Primary; D012878:Skin Neoplasms; D014740:Vidarabine",
"nlm_unique_id": "0372745",
"other_id": null,
"pages": "353-8",
"pmc": null,
"pmid": "27509643",
"pubdate": "2016",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Rapidly Fatal Dissemination of Merkel Cell Carcinoma in a Patient Treated with Alemtuzumab for Chronic Lymphocytic Leukemia.",
"title_normalized": "rapidly fatal dissemination of merkel cell carcinoma in a patient treated with alemtuzumab for chronic lymphocytic leukemia"
} | [
{
"companynumb": "US-MYLANLABS-2016M1040216",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "VITAMINS"
},
"drugadditional": null,
... |
{
"abstract": "A sprightly 79-year-old woman was treated for high blood pressure with indapamide (2.5 mg/day) and the angiotensin converting enzyme (ACE) inhibitor lisinopril (5 mg/day). About 12 months after starting treatment a blood count carried out because of a syncopal attack revealed pancytopenia (haemoglobin 3.3 g/dl, erythrocytes 1.0 x 10(6)/microliters, leucocytes 1100/microliters, platelets 8000/microliters). Until then the blood count had been unremarkable. The bone marrow showed severe hypoplasia of all three cell lines with reactive plasmocytosis. Malignant cells were not present. The patient received a total of nine units of erythrocytes and seven units of platelets. Her care included reverse barrier nursing and antibiotic treatment. She was also given high dose steroid therapy (methylprednisone up to 150 mg/day) and granulocyte colony stimulating factor (filgrastim 300 micrograms/day subcutaneously for 25 days), and after a latent period of several weeks juvenile myeloid precursors reappeared in the blood. Before discharge from hospital the results rose to subnormal levels without further transfusions (haemoglobin 8.5/dl, erythrocytes 3.1 x 10(6)/microliters, leucocytes 3900/microliters, platelets 21.000/microliters). In the bone marrow, all three cell lines were beginning to recover. The final diagnosis was incompletely reversible pancytopenia resulting from secondary aplastic anaemia during ACE inhibitor therapy.",
"affiliations": "I. Medizinische Abteilung, Krankenhauses Bogenhausen, München.",
"authors": "Schratzlseer|G|G|;Lipp|T|T|;Riess|G|G|;Antoni|D|D|;Delius|W|W|",
"chemical_list": "D000806:Angiotensin-Converting Enzyme Inhibitors; D011994:Recombinant Proteins; D016179:Granulocyte Colony-Stimulating Factor; D017706:Lisinopril; D007190:Indapamide; D000069585:Filgrastim; D008775:Methylprednisolone",
"country": "Germany",
"delete": false,
"doi": "10.1055/s-2008-1058798",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0012-0472",
"issue": "119(30)",
"journal": "Deutsche medizinische Wochenschrift (1946)",
"keywords": null,
"medline_ta": "Dtsch Med Wochenschr",
"mesh_terms": "D000368:Aged; D000741:Anemia, Aplastic; D000806:Angiotensin-Converting Enzyme Inhibitors; D017707:Erythrocyte Transfusion; D005260:Female; D000069585:Filgrastim; D016179:Granulocyte Colony-Stimulating Factor; D006801:Humans; D006973:Hypertension; D007190:Indapamide; D017706:Lisinopril; D008775:Methylprednisolone; D017713:Platelet Transfusion; D011994:Recombinant Proteins",
"nlm_unique_id": "0006723",
"other_id": null,
"pages": "1029-33",
"pmc": null,
"pmid": "7519541",
"pubdate": "1994-07-29",
"publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article",
"references": null,
"title": "Severe pancytopenia in old age after 12-month ACE inhibitor therapy.",
"title_normalized": "severe pancytopenia in old age after 12 month ace inhibitor therapy"
} | [
{
"companynumb": "DE-AMGEN-DEUSP2020194693",
"fulfillexpeditecriteria": "2",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FILGRASTIM"
},
"drugadditional": "3",
... |
{
"abstract": "OBJECTIVE\nBortezomib-melphalan-prednisone (VMP) has improved overall survival in multiple myeloma. This randomized trial compared VMP plus thalidomide (VMPT) induction followed by bortezomib-thalidomide maintenance (VMPT-VT) with VMP in patients with newly diagnosed multiple myeloma.\n\n\nMETHODS\nWe randomly assigned 511 patients who were not eligible for transplantation to receive VMPT-VT (nine 5-week cycles of VMPT followed by 2 years of VT maintenance) or VMP (nine 5-week cycles without maintenance).\n\n\nRESULTS\nIn the initial analysis with a median follow-up of 23 months, VMPT-VT improved complete response rate from 24% to 38% and 3-year progression-free-survival (PFS) from 41% to 56% compared with VMP. In this analysis, median follow-up was 54 months. The median PFS was significantly longer with VMPT-VT (35.3 months) than with VMP (24.8 months; hazard ratio [HR], 0.58; P < .001). The time to next therapy was 46.6 months in the VMPT-VT group and 27.8 months in the VMP group (HR, 0.52; P < .001). The 5-year overall survival (OS) was greater with VMPT-VT (61%) than with VMP (51%; HR, 0.70; P = .01). Survival from relapse was identical in both groups (HR, 0.92; P = .63). In the VMPT-VT group, the most frequent grade 3 to 4 adverse events included neutropenia (38%), thrombocytopenia (22%), peripheral neuropathy (11%), and cardiologic events (11%). All of these, except for thrombocytopenia, were significantly more frequent in the VMPT-VT patients.\n\n\nCONCLUSIONS\nBortezomib and thalidomide significantly improved OS in multiple myeloma patients not eligible for transplantation.",
"affiliations": "Antonio Palumbo, Sara Bringhen, Alessandra Larocca, Valeria Magarotto, Paola Omedé, Roberto Mina, Mario Boccadoro, and Giulia Benevolo, Azienda Ospedaliera (A.O.) Città della Salute e della Scienza di Torino; Daniela Gottardi, A.O. Ordine Mauriziano; Roberto Passera, San Giovanni Battista Hospital, University of Torino, Torino; Davide Rossi and Gianluca Gaidano, Amedeo Avogadro University of Eastern Piedmont, Novara; Francesco Di Raimondo, Ferrarotto Hospital, University of Catania, Catania; Francesca Patriarca, A.O. Universitaria, Udine; Anna Levi and Maria Teresa Petrucci, Sapienza University of Rome; Luca Franceschini, Tor Vergata University Hospital, Rome; Iolanda Donatella Vincelli, A.O. Bianchi-Melacrino-Morelli, Reggio Calabria; Mariella Grasso, S. Croce e Carle Hospital, Cuneo; Renato Zambello, Università degli Studi di Padova, Padova; Vittorio Montefusco, Istituto Di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Nazionale dei Tumori Milano, University of Milano, Milan; Antonietta Pia Falcone, IRCCS Casa Sollievo della Sofferenza and Unità di Ematologia, San Giovanni Rotondo; Roberto Marasca, University of Modena, Modena; Fortunato Morabito, A.O. di Cosenza, Cosenza; Tommasina Guglielmelli, \"S. Luigi Gonzaga\" Hospital, Orbassano; Chiara Nozzoli, A.O. Universitaria Careggi, Firenze; Massimo Offidani, Ospedali Riuniti, Ancona; Roberto Ria, University of Bari \"Aldo Moro\" Medical School, Bari; Pellegrino Musto, IRCCS-Centro Regionale Oncologico Basilicata, Rionero in Vulture; and Michele Cavo, Università degli Studi di Bologna, Policlinico S. Orsola-Malpighi, Bologna, Italy.",
"authors": "Palumbo|Antonio|A|;Bringhen|Sara|S|;Larocca|Alessandra|A|;Rossi|Davide|D|;Di Raimondo|Francesco|F|;Magarotto|Valeria|V|;Patriarca|Francesca|F|;Levi|Anna|A|;Benevolo|Giulia|G|;Vincelli|Iolanda Donatella|ID|;Grasso|Mariella|M|;Franceschini|Luca|L|;Gottardi|Daniela|D|;Zambello|Renato|R|;Montefusco|Vittorio|V|;Falcone|Antonietta Pia|AP|;Omedé|Paola|P|;Marasca|Roberto|R|;Morabito|Fortunato|F|;Mina|Roberto|R|;Guglielmelli|Tommasina|T|;Nozzoli|Chiara|C|;Passera|Roberto|R|;Gaidano|Gianluca|G|;Offidani|Massimo|M|;Ria|Roberto|R|;Petrucci|Maria Teresa|MT|;Musto|Pellegrino|P|;Boccadoro|Mario|M|;Cavo|Michele|M|",
"chemical_list": "D001897:Boronic Acids; D011719:Pyrazines; D013792:Thalidomide; D000069286:Bortezomib; D008558:Melphalan; D011241:Prednisone",
"country": "United States",
"delete": false,
"doi": "10.1200/JCO.2013.52.0023",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0732-183X",
"issue": "32(7)",
"journal": "Journal of clinical oncology : official journal of the American Society of Clinical Oncology",
"keywords": null,
"medline_ta": "J Clin Oncol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D001897:Boronic Acids; D000069286:Bortezomib; D018572:Disease-Free Survival; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D060828:Induction Chemotherapy; D053208:Kaplan-Meier Estimate; D060046:Maintenance Chemotherapy; D008297:Male; D008558:Melphalan; D008875:Middle Aged; D009101:Multiple Myeloma; D009503:Neutropenia; D010523:Peripheral Nervous System Diseases; D011241:Prednisone; D011719:Pyrazines; D013792:Thalidomide; D013921:Thrombocytopenia; D016896:Treatment Outcome",
"nlm_unique_id": "8309333",
"other_id": null,
"pages": "634-40",
"pmc": null,
"pmid": "24449241",
"pubdate": "2014-03-01",
"publication_types": "D016428:Journal Article; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Bortezomib-melphalan-prednisone-thalidomide followed by maintenance with bortezomib-thalidomide compared with bortezomib-melphalan-prednisone for initial treatment of multiple myeloma: updated follow-up and improved survival.",
"title_normalized": "bortezomib melphalan prednisone thalidomide followed by maintenance with bortezomib thalidomide compared with bortezomib melphalan prednisone for initial treatment of multiple myeloma updated follow up and improved survival"
} | [
{
"companynumb": "IT-TAKEDA-2017MPI007090",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "MELPHALAN"
},
"drugadditional": null,
... |
{
"abstract": "Graves' disease is the predominant cause of hyperthyroidism in the pediatric age group. Other disorders must be recognized, however, because adequate management relies on a precise diagnosis. Careful monitoring of the thyroid status is required during this active phase of growth and development.",
"affiliations": "Section of General Pediatrics, Mayo Clinic, Rochester, Minnesota, USA.",
"authors": "Zimmerman|D|D|;Lteif|A N|AN|",
"chemical_list": "D011989:Receptors, Thyrotropin; D013972:Thyrotropin",
"country": "United States",
"delete": false,
"doi": "10.1016/s0889-8529(05)70302-9",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0889-8529",
"issue": "27(1)",
"journal": "Endocrinology and metabolism clinics of North America",
"keywords": null,
"medline_ta": "Endocrinol Metab Clin North Am",
"mesh_terms": "D000236:Adenoma; D002648:Child; D002675:Child, Preschool; D006111:Graves Disease; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D009154:Mutation; D010911:Pituitary Neoplasms; D011989:Receptors, Thyrotropin; D013971:Thyrotoxicosis; D013972:Thyrotropin",
"nlm_unique_id": "8800104",
"other_id": null,
"pages": "109-26",
"pmc": null,
"pmid": "9534032",
"pubdate": "1998-03",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": null,
"title": "Thyrotoxicosis in children.",
"title_normalized": "thyrotoxicosis in children"
} | [
{
"companynumb": "SK-US-PROVELL PHARMACEUTICALS LLC-9229041",
"fulfillexpeditecriteria": "1",
"occurcountry": "SK",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "LEVOTHYROXINE SODIUM"
},
"dru... |
{
"abstract": "Regulatory decisions may be enhanced by incorporating patient preferences for drug benefit and harms. This study demonstrates a method of weighting clinical evidence by patients' benefit-risk preferences. Preference weights, derived from discrete choice experiments, were applied to clinical trial data to estimate the expected utility of alternative drugs. In a case study, the rank ordering of antiepileptic drugs (AEDs), as indicated from clinical studies, was compared with ordering based on weighting clinical evidence by patients' preferences. A statistically significant change in rank ordering of AEDs was observed for women of childbearing potential who were prescribed monotherapy for generalized or unclassified epilepsy. Rank ordering inferred from trial data, valproate > topiramate > lamotrigine, was reversed. Modeling the expected utility of drugs might address the need to use more systematic, methodologically sound approaches to collect patient input that can further inform regulatory decision making.",
"affiliations": "Centre for Health Economics and Medicines Evaluation, Bangor University, Bangor, UK.;Centre for Health Economics and Medicines Evaluation, Bangor University, Bangor, UK.;Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK.;Department of Public Health and Policy, University of Liverpool, Liverpool, UK.;Institute of Psychology, Health and Society, University of Liverpool, Liverpool, UK.;Medical Research Council North West Hub for Trials Methodology Research, Department of Biostatistics, University of Liverpool, Liverpool, UK.;Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK.;Centre for Health Economics and Medicines Evaluation, Bangor University, Bangor, UK.",
"authors": "Holmes|Emily A F|EAF|;Plumpton|Catrin|C|;Baker|Gus A|GA|;Jacoby|Ann|A|;Ring|Adele|A|;Williamson|Paula|P|;Marson|Anthony|A|;Hughes|Dyfrig A|DA|",
"chemical_list": "D000927:Anticonvulsants",
"country": "United States",
"delete": false,
"doi": "10.1002/cpt.1231",
"fulltext": "\n==== Front\nClin Pharmacol TherClin. Pharmacol. Ther10.1002/(ISSN)1532-6535CPTClinical Pharmacology and Therapeutics0009-92361532-6535John Wiley and Sons Inc. Hoboken 3020425210.1002/cpt.1231CPT1231ArticleResearchArticlesPatient‐Focused Drug Development Methods for Benefit–Risk Assessments: A Case Study Using a Discrete Choice Experiment for Antiepileptic Drugs Holmes Emily A.F. \n1\nPlumpton Catrin \n1\nBaker Gus A. \n2\nJacoby Ann \n3\nRing Adele \n4\nWilliamson Paula \n5\nMarson Anthony \n2\n\n6\nHughes Dyfrig A. d.a.hughes@bangor.ac.uk \n1\n\n2\n\n1 \nCentre for Health Economics and Medicines Evaluation\nBangor University\nBangor\nUK\n\n2 \nDepartment of Molecular and Clinical Pharmacology\nUniversity of Liverpool\nLiverpool\nUK\n\n3 \nDepartment of Public Health and Policy\nUniversity of Liverpool\nLiverpool\nUK\n\n4 \nInstitute of Psychology, Health and Society\nUniversity of Liverpool\nLiverpool\nUK\n\n5 \nMedical Research Council North West Hub for Trials Methodology Research\nDepartment of Biostatistics\nUniversity of Liverpool\nLiverpool\nUK\n\n6 \nWalton Centre National Health Service Foundation Trust\nLiverpool\nUK\n* Correspondence: Dyfrig A. Hughes (d.a.hughes@bangor.ac.uk)25 10 2018 3 2019 25 10 2018 105 3 10.1111/cpt.2019.105.issue-3From Molecule to Patient672 683 10 5 2018 24 8 2018 © 2018 The Authors Clinical Pharmacology & Therapeutics published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and TherapeuticsThis 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.Regulatory decisions may be enhanced by incorporating patient preferences for drug benefit and harms. This study demonstrates a method of weighting clinical evidence by patients’ benefit–risk preferences. Preference weights, derived from discrete choice experiments, were applied to clinical trial data to estimate the expected utility of alternative drugs. In a case study, the rank ordering of antiepileptic drugs (AEDs), as indicated from clinical studies, was compared with ordering based on weighting clinical evidence by patients’ preferences. A statistically significant change in rank ordering of AEDs was observed for women of childbearing potential who were prescribed monotherapy for generalized or unclassified epilepsy. Rank ordering inferred from trial data, valproate > topiramate > lamotrigine, was reversed. Modeling the expected utility of drugs might address the need to use more systematic, methodologically sound approaches to collect patient input that can further inform regulatory decision making.\n\nNational Institute for Health ResearchPB‐PG‐0909‐20161Medical Research Council North West Hub for Trials Methodology ResearchMR/K025635/1NIHR Collaboration for Leadership in Applied Health Research and Care North West CoastHealth and Care Research Wales Senior Research LeaderSRL/15/029 source-schema-version-number2.0component-idcpt1231cover-dateMarch 2019details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:5.6.2.1 mode:remove_FC converted:01.05.2019\n==== Body\nStudy Highlights\n\n\nWHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?\n\n\n\n\n\nDiscrete choice experiments have been recognized as a suitable method for eliciting evidence on patients’ preferences to inform regulatory benefit–risk assessments.\n\n\n\nWHAT QUESTION DID THIS STUDY ADDRESS?\n\n\n\n\n\nWhat is the impact of weighting clinical evidence by patients’ benefit–risk preferences, and how can this be achieved in practice?\n\n\n\nWHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?\n\n\n\n\n\nOn the basis of a case study of antiepileptic drugs (AEDs), patients were willing to accept a reduction in the chance of seizure remission in exchange for a reduction in the risk of adverse effects. This resulted in changes to the trial‐based rank ordering of AEDs, determined from time to treatment failure.\n\n\n\nHOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?\n\n\n\n\n\nExplicit consideration of patient preferences could lead to different conclusions relating to the benefit–risk profiles of medicines. This has implications for drug development and regulation, in how patient values and clinical attributes may be integrated to inform benefit–risk assessments.\n\n\n\n\nDrug development and regulatory decision making require explicit evaluation of benefits and risks. In balancing the benefits and risks of drugs, judgements are required on the maximum acceptable risk (MAR) of harm for an expected health benefit. Traditionally, these judgements have relied on expert clinical opinion of the available evidence. More recently, however, there is increasing acknowledgment that patients’ preferences with respect to trade‐offs in harms for benefits may differ from those of clinical experts and that patient perspectives need to be considered in benefit–risk assessments.1, 2\n\n\nThe US Food and Drug Administration (FDA) Center for Drug Evaluation and Research currently implements a qualitative approach via the Patient‐Focused Drug Development Program under the fifth and sixth authorizations of the Prescription Drug User Fee Act. This involves patients in the approvals process by convening public meetings to discuss the impact of disease on patients’ daily lives and patients’ perspectives on treatment benefits and adequacy.3 The European Medicines Agency's Committee for Medicinal Products for Human Use piloted patient involvement in benefit–risk discussions through their participation in expert group meetings and the scientific advice/protocol assistance procedure.4 The Committee for Medicinal Products for Human Use continues to involve patients in oral explanations when it is believed this could be of benefit. The FDA's Center for Devices and Radiological Health (CDRH), by contrast, has adopted a more quantitative approach and considers evidence relating to patients’ perspectives of what constitutes meaningful benefit–risk.2, 5\n\n\nMoving forward, the 21st Century Cures Act (section 3002) requires the FDA to develop guidance (by quarter 4 2021) for integrating relevant patient experience data in benefit–risk assessments for new drugs and biological agents.6 Although specific details are currently unknown, it is worth noting the CDRH's guidance includes 11 recommendations for the conduct of quantitative patient preference studies,5, 7 and a project coordinated by the European Medicines Agency outlined a range of methods.8 Both organizations identify discrete choice experiments (DCEs) among potential options for use in benefit–risk assessments of medicines.\n\nStated preference DCEs are a method for quantifying the relative importance of different treatment characteristics (attributes), trade‐offs between these attributes, and respondents’ total satisfaction (utility) with specified treatments.9 The method has been used extensively for the evaluation of health services and health technologies,10, 11 and there is increasing application in the determination of benefit–risk trade‐off for medicines.12, 13 In DCEs, respondents are asked to choose their preferred option from a set of hypothetical (but realistic) alternatives, on the basis of attributes and their respective levels determined using established qualitative methods.14\n\n\nModeling the expected utility of drugs, on the basis of patient‐defined benefit–risk trade‐offs, offers a quantitative approach to inform drug development and regulatory decision making. The present study demonstrates the potential for the DCE method in benefit–risk assessment. Patient priorities for drug outcomes are first identified using qualitative interviews and ranking exercises. Patient preferences for the most important outcomes are then valued using a DCE. This generates preference weights for each selected outcome that are applied to observed data from a clinical trial. The expected utilities of alternative drugs are then modeled to generate patient‐defined benefit–risk preferences for a selection of alternative drugs.\n\nThe case study is based on antiepileptic drugs (AEDs), selected because of the particular need to balance benefits against the risks of harm.15 Although two thirds of patients treated with AEDs will achieve remission from seizures within 5 years of diagnosis, at least 40% of patients will experience treatment‐related adverse effects.16, 17 Patient‐determined levels of acceptable harm for improved seizure control are rarely considered in clinical trials.18 However, they are essential considerations, especially for women of childbearing potential with generalized epilepsy, in whom choices need to be made between the most effective yet teratogenic treatment, valproate, and less teratogenic (but less effective) alternatives.17, 19 In this case study, we aimed to compare patient‐defined benefit–risk preferences with the results of a clinical trial of AEDs16, 17 and to assess differences between patient subgroups.\n\nResults\nBenefit and risk attribute selection\nFifty‐four patients and nine physicians (34% and 90% of those invited, respectively) participated in the qualitative study to identify the most important benefit and risk outcomes for use in the DCE. Reduction in seizure frequency was the most important treatment outcome (benefit) across all groups (Table \n\nS1\n), and discussions surrounding this outcome focused on seizures stopping and patients achieving remission. The importance of adverse effects (risks) varied by patient group: recently diagnosed patients were most concerned about feelings of aggression and depression, whereas those with an established diagnosis were most concerned about memory problems. Women of childbearing potential also ranked memory problems highest, followed by the risk of fetal abnormality if they became pregnant while taking the drug. Physicians ranked memory problems and depression highly. Patients and physicians valued life impacts (e.g., reduced independence), but in the context of the decision to initiate or switch an AED, physicians considered them to be consequences of epilepsy, or the adverse events (AEs) of treatment, rather than independent treatment outcomes. As such, they were excluded from the DCE. Attributes selected for the DCE are presented in Table \n1. Two versions of the DCE were developed to represent the most important attributes selected by patients with a recent or established diagnosis (DCE‐1) and women of childbearing potential (DCE‐2) (Figure \n\nS1\n).\n\nTable 1 Attributes and levels of the discrete choice experiment\n\nDCE attributea\n\tDCE levels (coding)\tLevel selection\tDescription (before choice questions)\t\n\nSeizures stop\n\n\nOne year after starting this medication\n\t\n5 in 10 people (0.5)\n\n3 in 10 people (0.3)\n\tPlausible estimates based on:\nSeizure frequency16, 17\n\n\nClinical expert opinion (research team, scientific advisory group, and group discussion meeting with prescribing physicians)\n\n\n\t\nWe would like you to imagine you have the choice between two medications: medication A and medication B. We will give you the same information about each medication.\n\nThe chance of responding well:\n\n‐ Seizures stop\n\n‐ Fewer seizures\n\t\n\nFewer seizures\n\n\nOne year after starting this medication\n\t\n3 in 10 people (0.3)\n\n1 in 10 people (0.1)\n\t\n\nMemory problems\n\n\nThese problems frequently affect activities of daily life\n\t\n1 in 100 people (0.01)\n\n7 in 100 people (0.07)\n\tPlausible estimates based on:\nClinically important adverse events and patient‐reported quality of life outcomes16, 17\n\n\nSection 4.8 of the summary of product characteristics of AEDs used in the SANAD trial16, 17\n\n\nClinical expert opinion (research team, scientific advisory group, and group discussion meeting with prescribing physicians)\n\n\n\t\nThe risk of severe adverse effects.\n\n‐ Memory problems\n\n‐ Depression\n\n‐ Feelings of aggressionb\n\n\nThese adverse effectsc would be so severe that you would need to change to a different antiepileptic medication\n\t\n\nDepression\n\n\nA feeling of low mood that often affects activities of daily life\n\t\n1 in 100 people (0.01)\n\n8 in 100 people (0.08)\n\t\n\nFeelings of aggression\nb\n\n\nThis can be verbal or physical and often affects relationships and activities of daily life\n\t\n1 in 100 people (0.01)\n\n8 in 100 people (0.08)\n\t\n\nHarm to your fetus if you get pregnant while taking this medication\nd\n\n\nCausing problems from birth, such as spina bifida or low IQ\n\t\n2 in 100 pregnant women (0.02)\n\n9 in 100 pregnant women (0.09)\n\tMinimum and maximum risk of AED‐related fetal abnormality reported to patients via the Epilepsy Action charity website at the time of the survey.\t\nFinally, we will also give you information on the risk of harm to the fetus if you get pregnant while taking this medication.\n\nThis may cause problems, such as spina bifida, a hole in the heart, and a cleft palate (where the roof of the mouth is not correctly joined). This may also cause neurodevelopment problems, such as poor memory, poor language and social skills, and low IQ.\n\t\nAED, antiepileptic drug; DCE, discrete choice experiment; IQ, intelligence quotient; SANAD, Standard vs. New Antiepileptic Drugs. aAs described in each of the eight choice questions. bOnly in DCE for patients with a recent or established diagnosis. cTerm “adverse effects” used to describe adverse events, as per findings of our qualitative study. dOnly in DCE for women of childbearing potential.\n\nJohn Wiley & Sons, LtdDiscrete choice experiment\nAmong those who consented to the survey, 4 withdrew before randomization and 29 did not start their DCE, leaving 280 patients for this analysis (Table \n2).\n\nTable 2 Patient characteristics\n\nCharacteristics\tDCE‐1 (N = 177)\tDCE‐2 (N = 103)\t\nExcluding women of childbearing potential\tWomen of childbearing potential\t\n\nn/N\n\t% or rangea\n\t\nn/N\n\t% or rangea\n\t\nDemographics\t\nAge, median, yearsb\n\t45\t18–79\t29\t18–55\t\nFemale sex\t95/177\t54\t103/103\t100\t\nWhite British\t140/149\t94\t84/86\t98\t\nLive alone\t28/149\t19\t6/87\t7\t\nEmployed\t76/149\t51\t69/87\t79\t\nTime since diagnosis, years\t\n<1\t9/176\t5\t3/103\t3\t\n1–10\t40/176\t23\t40/103\t39\t\n>10\t127/176\t72\t60/103\t58\t\nSeizure types\t\nFocal\t56/157\t36\t40/96\t42\t\nComplex focal\t70/157\t45\t45/96\t47\t\nAbsences\t64/157\t41\t46/96\t48\t\nTonic clonic\t102/157\t65\t73/96\t76\t\nTime since last seizure (<1 month)\t88/159\t56\t48/95\t51\t\nSeizure frequency compared with 1 year ago\t\nIncreased\t39/157\t25\t17/96\t18\t\nConstant\t69/157\t44\t48/96\t50\t\nDecreased\t49/157\t31\t31/96\t32\t\nChange to antiepileptic medication (changes in past 3 months)\t66/151\t44\t43/93\t46\t\nChange reason seizures\t43/65\t66\t31/42\t74\t\nChange reason adverse effects\t19/65\t29\t15/42\t36\t\nChange reason remission\t5/65\t8\t2/42\t5\t\nSelf‐reported nonadherence to antiepileptic medicationc\n\t37/66\t56\t24/42\t57\t\nExperience of adverse effects\t\nAggressionc\n\t15/66\t23\t11/42\t26\t\nDepressionc\n\t15/66\t23\t16/42\t38\t\nMemory problemsc\n\t22/66\t33\t14/42\t33\t\nChange antiepileptic medication because of pregnancy concern\tNA\tNA\t31/97\t32\t\nDCE‐1, discrete choice experiment for patients with a recent or established diagnosis; DCE‐2, DCE for women of childbearing potential; NA, not applicable. aPercentage of eligible responses (excluding missing data). b\nN = 177 (DCE‐1), N = 103 (DCE‐2). cNumber restricted to patients who reported a change in the type or amount of antiepileptic drug in the past 3 months, because of a routing error in the online survey.\n\nJohn Wiley & Sons, LtdAll patients preferred the AED offering the greatest benefits and the lowest risk of harm, as indicated by direction of the signs on the coefficients (+/−) (Table \n3). Patients had stronger preferences for reductions in the risk of AEs than improvements in 12‐month seizure remission, as shown by the greater magnitude of the harm coefficients. Experiencing fewer seizures did not have a significant influence on AED preferences of women of childbearing potential (P = 0.685).\n\nTable 3 Results of the DCE random‐effects logistic regression model\n\nAttribute\tDCE‐1: excluding women of childbearing potentiala\n\tDCE‐2: women of childbearing potentiala\n\t\nCoefficient (95% CI)b\n\t\nP value\tMaximum acceptable incremental risk (%) per 1% increase in 12‐month remission (95% CI)b\n\tCoefficient (95% CI)b\n\t\nP value\tMaximum acceptable incremental risk (%) per 1% increase in 12‐month remission (95% CI)b\n\t\nRemission\t0.03 (0.03 to 0.05)\t<0.001\tNA\t0.05 (0.04 to 0.07)\t<0.001\tNA\t\nFewer seizures\t0.01 (0.00 to 0.02)\t0.010\tNA\t−0.00 (−0.01 to 0.01)\t0.685\tNA\t\nDepression\t−0.11 (−0.15 to −0.10)\t<0.001\t0.31 (0.24 to 0.39)\t−0.08 (−0.13 to −0.06)\t<0.001\t0.56 (0.38 to 0.88)\t\nMemory problems\t−0.11 (−0.16 to −0.10)\t<0.001\t0.30 (0.23 to 0.40)\t−0.14 (−0.21 to −0.11)\t<0.001\t0.34 (0.26 to 0.45)\t\nAggression/fetal abnormality\t−0.13 (−0.18 to −0.13)\t<0.001\t0.25 (0.20 to 0.31)\t−0.23 (−0.32 to −0.21)\t<0.001\t0.20 (0.16 to 0.24)\t\nConstant\t0.03 (−0.19 to 0.12)\t0.689\tNA\t0.47 (0.25 to 0.92)\t<0.001\tNA\t\nNumber of observations\t1,339\t\t\t790\t\t\t\nNumber of groups\t177\t\t\t103\t\t\t\nWald χ2 (5 degrees of freedom)\t321.27\t\t\t154.55\t\t\t\nLog likelihood\t−674.71\t\t\t−360.77\t\t\t\nPseudo R\n2\n\t0.27\t\t\t0.34\t\t\t\n\nP value\t<0.000\t\t\t<0.000\t\t\t\nCI, confidence interval; DCE, discrete choice experiment; DCE‐1, DCE for patients with a recent or established diagnosis; DCE‐2, DCE for women of childbearing potential; NA, not applicable. aA total of 159 respondents to DCE‐1 (90%) and 97 respondents to DCE‐2 (94%) passed the dominance check question included for internal validity, by selecting the antiepileptic drug aligned with a priori expectations and thus indicating they comprehended the task. A model excluding respondents who failed the dominance check for internal validity did not differ significantly. bCIs generated by 1000 bootstrap replications.\n\nJohn Wiley & Sons, LtdThe maximum acceptable increase in risks of adverse effects for an AED that increases the chance of 12‐month remission by 10% (in DCE‐1) were as follows: 3.1% for depression, 3.0% for memory problems, and 2.5% for aggression. For women of childbearing potential, the MAR of fetal abnormality was 2.0% for a 10% increase in probability of remission, compared with 5.6% for depression and 3.4% for memory problems.\n\nPatient utility associated with selected AEDs\nThe preference‐weighted outcomes (remission, reduction, memory problems, depression, aggression/fetal abnormality) for four alternative drugs for focal epilepsy (carbamazepine, lamotrigine, gabapentin, and topiramate) and three alternative drugs for generalized and unclassified epilepsy (valproate, lamotrigine, and topiramate)16, 17 are displayed in Figure \n1. On the basis of total utility (sum of the weighted outcomes), respondents to DCE‐1 indicated carbamazepine would be the most preferred AED for focal epilepsy, and topiramate the least. The disutility associated with topiramate (−0.67) suggests these patients would prefer to avoid it. For generalized or unclassified epilepsy, valproate yielded higher utility than both lamotrigine and topiramate. In both cases, ranking based on utility differed from ranking based on time to treatment failure, as observed in clinical trials (Figure \n1\na); however, this did not reach statistical significance.\n\nFigure 1 AED, antiepileptic drug; DCE‐1, discrete choice experiment for patients with a recent or established diagnosis; DCE‐2, DCE for women of childbearing potential. Preference‐weighted outcomes of AEDs by DCE‐1 (a) and DCE‐2 (b). *High utility is most preferred. AEDs presented in order of highest to lowest utility, left to right by indication. **Clinical rank based on primary outcome in Standard vs. New Antiepileptic Drugs (SANAD) I (time to treatment failure). Rank 1 = high (i.e., longest time to treatment failure).\n\nWomen of childbearing potential responding to DCE‐2 favored lamotrigine over carbamazepine for focal epilepsy, in agreement with trial‐based ranking; however, gabapentin ranked second when the trial outcomes were weighted in the utility model. Topiramate was associated with the lowest utility. Lamotrigine was also favored for generalized or unclassified epilepsy, with valproate being the least preferred; thus, weighting by patient preferences for benefit and harm outcomes resulted in a statistically significant reversal of rankings.20 The combined risk and preference weighting for fetal abnormality heavily influenced the disutility of valproate (Figure \n1\nb).\n\nThe improvement in benefit associated with a switch to valproate did not outweigh the increase in risk for women of childbearing potential. A switch from topiramate to valproate for generalized or unclassified epilepsy, for instance, increased the risk of fetal abnormality by 6.65%,19 which exceeds the 1.41% MAR that corresponds to the 7% improvement in 12‐month remission seen with valproate17 (Table \n\nS2\n).\n\nDiscussion\nDCEs represent a valid and reliable method to quantify patient‐focused outcomes.10, 11, 12, 13 The utility model demonstrated how quantitative data on patient preferences can be integrated with clinical evidence to provide a patient‐focused benefit–risk analysis that could be used to inform regulatory decision making. The case study illustrates how DCEs can provide an explicit estimate of patient‐defined MAR, which may differ from value judgements based on clinical evidence alone.\n\nThe FDA implemented changes after the fifth authorization of the Prescription Drug User Fee Act, to increase the clarity, transparency, and consistency of its benefit–risk assessments. With the passage of the 21st Century Cures Act, the FDA now has an imperative to consider how relevant patient experience data and related information can be incorporated into the structured benefit–risk assessment framework to inform regulatory decision making.6 Our proposed method is one approach that might address the FDA's recognized need to use more systematic, methodologically sound approaches to collect patient input so that it becomes data that can further inform regulatory decision making21 (Figure \n2).\n\nFigure 2 DCE, discrete choice experiment; FDA, US Food and Drug Administration. Adaptation of the FDA Benefit–Risk Framework, highlighting opportunities for consideration of patient‐focused evidence across each dimension, and linking to methods described for stages 1, 2, and 3 in the context of antiepileptic drug assessment.\n\nPatients have an important role alongside all other stakeholders in determining relevant outcomes and priorities, acceptable uncertainty, as well as benefit–risk and value of a medicine.1, 2 However, patients believe that decision makers, particularly regulators, do not always have a complete understanding of the risks that patients with some illnesses are willing to accept, and that this benefit–risk assessment will vary by disease.22 Our DCE‐based approach linked with clinical trial evidence addresses this, by generating patient‐defined benefit–risk thresholds for drugs for specific clinical indications.\n\nThere are several examples of what could be interpreted as different levels of acceptance of risk among some patients, regulators, or other stakeholders–most notably, in the context of HIV, where “patient experts” successfully challenged the drug development and licensing paradigms, leading up to the FDA's Accelerated Approval pathway. The antiparkinsonian drug, tolcapone, was marketed in the European Union in 1997, but cases of fatal hepatotoxicity led to its marketing authorization being suspended the following year.23 Patients and physicians argued that some patients experience improved quality of life and pleaded to gain access to the drug while explicitly accepting the risk of hepatotoxicity. Their lobbying led to the lifting of the suspension in 2004. Both natalizumab (for patients with relapsing forms of multiple sclerosis) and alosetron (for irritable bowel syndrome) were voluntarily withdrawn by their manufacturers because of safety concerns.23 However, the FDA recommended their reintroduction to the market at the request of patients and family members. The use of methods to support regulatory benefit‐risk assessments that consider patient preferences explicitly might have lessened the likelihood of misaligned preferences between the various stakeholders. Benefit–risk assessments are a qualitative exercise grounded in quantitative evidence, but just because patient perspectives are subjective does not mean that they cannot be quantified and analyzed accordingly.\n\nOur case study showed that although seizure freedom was ranked the most important treatment outcome by patients during qualitative interviews, patients also prioritized reduction in the risk of adverse effects, and the importance of these effects differed by patient subgroup. The results of the DCE, however, suggest that patients are willing to accept a reduction in the chance of remission in exchange for a reduction in the risk of adverse effects—and that they attach a higher value on improving risk reduction than benefit. Women of childbearing potential would accept 5% reduction in the probability of 12‐month remission to reduce the risk of fetal abnormality by 1%. The potential for our method to identify both MAR, and willingness to forego benefit, is particularly important with respect to prescribing valproate, which is considered the most effective treatment for certain epilepsy syndromes, such as juvenile myoclonic epilepsy, but is associated with the highest risk of teratogenicity.24\n\n\nThis study provides quantitative evidence on women's strength of preference to avoid valproate, which aligns with recent advice from regulatory authorities.25, 26, 27 Understanding the balance between benefit and harm, and the extent to which women are willing to forego benefit for this reduction in harm, could assist in the development of recommendations of alternative treatments to valproate and inform parameters of equivalence for new drugs.\n\nWe are aware of previous use of DCE to elicit preferences for AEDs.28, 29, 30, 31 Lloyd et al.28 found that UK patients were willing to forego 4.85% seizure control for a 1% reduction in risk of hair loss, 4.45% seizure control for a 1% reduction in risk of skin rash, and 1.37% seizure control for a 1‐lb (0.45‐kg) reduction in weight gain. Manjunath et al.29 measured US patient preferences for add‐on AEDs in terms of seizure frequency and AEs; and they found that seizure reduction was the top priority when ranked against the reduction or elimination of AEs. Powell et al.30 compared patients’ and neurologists’ preferences for a carbamazepine pharmacogenetic testing service. Ettinger et al.31 also conducted a DCE in patients and neurologists, and they found that, although both ranked seizure control most important, neurologists’ preferences were more influenced by seizure reduction compared with adverse effects for patients. None of these studies, however, assessed preferences in the context of trial data pertaining to actual AEDs; in fact, we are unaware of any other studies that integrate benefit–risk preference weights, estimated using DCE methods, and trial data.\n\nThe key strengths of our study are in meeting the recommended qualities of patient preference studies specified by the CDRH5: (i) Patient centeredness: the DCE measured patient preferences for outcomes. Furthermore, the study encompassed the views of both patients and physicians at appropriate stages of developing the DCE, to ensure the hypothetical task was relevant to the context of clinical decisions. (ii) Representativeness of the sample and generalizability of results: the study used an appropriate sample size in each clinically well‐defined group; however, there may be limitations in generalizability because of the sampling. (iii) Capturing heterogeneity of patients’ preferences: we identified clinically important subgroups a priori and tailored individual DCEs in response to heterogeneity in preferences at the qualitative phase. (iv) Established good research practices by recognized professional organizations: we adhered to good practice guidelines.14, 32 (v) Effective communication of benefit, harm, risk, and uncertainty: attribute levels were displayed as natural frequencies with pictographs, as recommended.5 (vi) Minimal cognitive bias: cognitive interviewing was used to minimize framing effects and choices ordered randomly. (vii) Logical soundness: we demonstrated a high level of internal validity with a dominance test. (viii) Relevance: potential attributes identified from validated outcome measures, reduced systematically using a qualitative study and defined by clinically meaningful thresholds. (ix) Robustness of analysis of results: analysis adhered to good practice guidelines9, 32 with uncertainty represented by bootstrapped confidence intervals. (x) Study conduct: trained and experienced researchers interviewed patients, and the DCE questionnaire was verified by patients and healthcare professionals. (xi) Comprehension by study participants: robust application of cognitive interviews and questionnaire piloting to ensure face validity and optimal comprehension choice tasks.14\n\n\nThere were, however, limitations to our approach. Bias arising from patients self‐selecting to complete the questionnaire will limit the generalizability of the results. We also acknowledge that although DCE is a recommended approach to benefit–risk assessment, other methods exist, including multicriteria decision analysis33 and health outcome modeling.8, 34 Our methods highlighted differences in responses linked to the methods used. The ranking of single outcomes identified seizure remission as the most important, whereas the DCE identified that reductions in the risk of AEs were more highly valued than improvements in seizure control. Although ranking exercises do not consider trade‐offs explicitly, DCEs benefit from capturing this to assess the MAR for a given level of benefit. DCEs are inherently limited by the potential for patients’ stated preferences not reflecting their revealed preferences accurately and the cognitive burden placed on respondents, which increases rapidly with the number of attributes. Consequently, differences between studies in benefit and risk attributes are inevitable,28, 29, 30, 31 although in mitigation, our study used a robust approach to attribute selection.5, 14, 32\n\n\nIn conclusion, our case study findings indicate that accounting for patient preferences, in addition to clinical variables, could lead to different treatment choices or regulatory decisions. The most substantive results for AEDs are that women of childbearing potential show a clear preference for lamotrigine over valproate, principally driven by a preference to avoid the risk of teratogenicity (major malformation rate, ≈11%19). This is despite clinical trial results showing valproate to be significantly more effective than lamotrigine in generalized onset seizures,17 and aligns with recommendations from regulators.25, 26\n\n\nThe study demonstrates how patients’ preference for treatment benefits and risks can be incorporated into benefit–risk assessments by obtaining quantitative evidence using a DCE. Our method represents a transparent and valid approach to examining a patient‐oriented perspective in support of regulatory assessments of medicines.1 It also builds on previous research that highlighted that, although studies quantifying preferences may allow for formal evidence‐based appraisal of benefit–risk values, more is required to ensure best practice and to develop methods that combined stated preferences and clinical data.35 Certainly, drug regulators will need to be cognizant of the evolving methods of preference‐based benefit–risk, including DCEs.36\n\n\nMethods\nThe study comprised three stages (Table \n4): (i) identification of the most important outcomes of AED treatment using qualitative interviews and ranking exercises with patients and a focus discussion group meeting of physicians; (ii) elicitation of patient preferences for these outcomes using a DCE; and (iii) estimation of the expected utility associated with alternative AEDs by combining preference weights with data from a clinical trial.\n\nTable 4 Summary of the stages involved in development of the case study\n\nStage\tStage 1: benefit–risk outcome selection\tStage 2: DCE\tStage 3: modeling‐expected utility of alternative AEDs\t\nPrincipal (supplementary) method\tInterviews with patients\tMeeting with physicians (cognitive interviews with patients)\tWeb‐based survey (pilot questionnaire)\tObtain observed data for outcomes\tCalculate expected utility model\t\nAim\tTo identify the outcomes of AEDs that are most important to patients and their priorities for these outcomes\tTo assess the plausibility of the benefit–risk outcomes selected by patients in stage 1, for use in a DCE (to confirm the face validity of the highest rank outcomes in the format of a DCE)\tTo value the patient preferences for five benefit–risk outcomes of AEDs\tObtain trial data on outcome event rates for four alternative drugs for focal epilepsy (carbamazepine, lamotrigine, gabapentin, and topiramate) and three alternative drugs for generalized and unclassified epilepsy (valproate, lamotrigine, and topiramate)\tEstimate the expected utility associated with each AED for both indications\t\nSample\tAdult patients with epilepsy recruited via three specialist neurology secondary and tertiary care referral centers in England (n = 41). Subgroups: patients with a recent diagnosis (3–12 months), patients with an established diagnosis (>12 months), and women of childbearing age (18–50 years)\tNine physicians responsible for prescribing AEDs to adults with epilepsy (a further 13 patients from sampling frame used in stage 1)\tAdult patients self‐reporting as aged ≥18 years and diagnosed with epilepsy by a physician (n = 280). Subgroups: women self‐identifying as being of childbearing potential and other responders (Epilepsy Action staff and volunteers, clinical and academic researchers, and members of the scientific advisory group)\tSANAD clinical trial and Cochrane review of monotherapy treatment of epilepsy in pregnancy\t\t\nMethod\tSemistructured interview and ranking exercise: Which outcomes are most important to you? Rank your top four (highest = 4, lowest = 1). Analysis: Mean rank score per outcome by subgroup. Outputs: Most important outcomes from patients’ perspective\tGroup discussion and individual ranking exercises: Which outcomes are most important to you? Define the frequency and seriousness at which an adverse event becomes “clinically important.” Analysis: Mean rank score per outcome by time since patient diagnosis, early or established. Outputs: Most plausible outcomes from the prescribers’ perspective (think aloud experiment)\tRandom‐effects logit model with 1,000 bootstrap replications. Outputs: preference weights for outcomes, maximum acceptable risk of harm for a gain in benefit (Online: invitation to complete the questionnaire and supply comments)\tParameter uncertainty represented by drawing from β distributions for the number of events in the observed data. 1,000 replications were simulated, and the confidence intervals were taken to be the 25th and 975th percentile of the variable\tUtility = Σ(β_outcome*events). Confidence intervals generated from simulated preference and event data. Outputs: Total utility and rank order of AEDs by preference‐weighted rank\t\nOutcomes assessed at each stage\t\nBenefits: reduction in seizure frequency, reduction in seizure severityAdverse events: memory problems, depression, fetal abnormality, anger and aggression, headache, sleepiness and drowsiness, difficulty concentrating, weight gain, skin rash, dizziness, nervousness and/or agitation, tiredness\n\nLife impacts: limits ability to work in paid employment, reduces independence, negative impacts on relationships with family and/or friends, makes you feel less in control of the things that happen to you, limits hopes and plans for the future, limits social life and activities, increases the worry about having a seizure, causes problems with everyday memory and/or concentration, extent to which other people treat you like an inferior person, makes you feel more negative about yourself\n\nPatients could also self‐nominate any outcome they considered to be missing\n\t\nBenefits: reduction in seizure frequency\n\nAdverse events: memory problems, depression, fetal abnormality, anger and aggression, headache\n\nLife impacts: limits ability to work in paid employment, reduces independence, negative impacts on relationships with family and/or friends, makes you feel less in control of the things that happen to you, limits hopes and plans for the future\n\t\nBenefits: remission, reduction in seizure frequency\n\nAdverse events: memory problems, depression, anger and aggression, fetal abnormality\n\t\nBenefits: remission, reduction in seizure frequency\n\nAdverse events: memory problems, depression, anger and aggression, fetal abnormality\n\t\nBenefits: remission, reduction in seizure frequency\n\nAdverse events: memory problems, depression, anger and aggression, fetal abnormality\n\nTotal utility per AED\n\t\nAED, antiepileptic drug; DCE, discrete choice experiment; SANAD, Standard vs. New Antiepileptic Drugs.\n\nJohn Wiley & Sons, LtdEthical approval was granted by the UK National Health Service Research (reference number: 11/NW/0191).\n\nStage 1: benefit–risk outcome selection\nThe first stage in the method was to identify patients’ most important outcomes of AED treatment for inclusion in the DCE. A qualitative study was designed according to good practice guidelines.14, 32, 37 All interviews were conducted in patients’ own homes, and consent was requested to audiotape record for subsequent transcription. Patients were asked to consider predefined treatment outcomes, which were categorized according to whether they were treatment benefits, adverse effects, or life impacts, and selected from clinical trials16, 17 and validated outcome measures.38, 39, 40, 41 Patients were first asked to nominate any additional outcomes, on the basis of their own experiences, that they considered were missing from each category. Next, they were asked to select the outcomes that were most important to them from each category. Finally, considering all the outcomes they had selected, across the three categories, they were asked to choose their top four, and rank them in order of importance.\n\nThe face validity and plausibility of the 10 most important attributes overall were examined using cognitive interviews with patients and a meeting with prescribing physicians. The meeting of physicians responsible for prescribing AEDs to adults with epilepsy was convened at the Walton Centre National Health Service Foundation Trust. Participants were first asked to rank the 10 treatment outcomes that patients had considered the most important. They then participated in semistructured discussions to share their practical experience of discussing treatment outcomes with patients and, in particular, their distinction between “adverse effects” and “life impacts” relating to AEDs. They were asked to independently record the frequency and seriousness at which an AE becomes a “clinically important” AE that required a change in treatment. For example, clinically important depression was described as “low mood which often affects activities of daily life.” The purpose of this exercise was to ensure parity between DCE descriptions of treatment outcomes and clinically important AE data recorded in clinical trials,16, 17 to ensure optimal integration of preferences with clinical evidence. Prescribers were also asked to draw on their experience of communicating benefit–risk to patients and to provide feedback on the formatting of the patient DCE questionnaire. Discussions were audiotape recorded, and ranking results were noted in workbooks that were self‐completed during the session.\n\nStage 2: DCE\nThe DCE was conducted, analyzed, and reported according to good practice guidelines.32, 42 The five treatment outcomes ranked highest by patients, and which were considered clinically plausible, were included as attributes in the DCE. Each attribute was assigned two levels on the basis of data from a clinical trial16, 17 and information on the risk of AED‐related fetal abnormality available to patients on the Epilepsy Action charity website at the time of the survey. Levels represent the frequency of events observed in clinical trials and were presented in the questionnaire as a “1 in X people experience…”, supplemented with pictograms that used a traffic light color coding for positive and negative effects.\n\nThe DCE consisted of eight binary choice scenarios (Figure \n\nS1\n), which asked: Which medication would you prefer? A partially dominant choice was used to test the internal validity of the DCE, in which “medication A” had a higher chance of remission and lower risk of AEs; therefore, it was assumed respondents would prefer this option.\n\nPatient DCE questionnaire\nAdults self‐reporting as being aged ≥18 years and diagnosed as having epilepsy by a physician were eligible to complete the survey. Respondents were required to consent to participate in the study before they accessed the questionnaire, and there was no compensation for their time. Recruitment was via publicity from the charity, Epilepsy Action, an advertisement in local press, and posters in 113 National Health Service outpatient clinics across England and Wales. The survey was implemented online (Snap Surveys, London, UK) between June and October 2013 and hosted by the Epilepsy Action website. Estimated completion time was 30 minutes. Target sample size was a minimum of 63 respondents per DCE, based on each main effect level of interest being represented across the design at least 500 times.43 A random sample of 25% was directed to a DCE designed to compare patients’ with physicians’ preferences for pharmacogenetic testing prior treatment with carbamazepine, which is reported elsewhere.30 Remaining respondents were directed to one of the two DCEs reported herein via a series of filter questions (DCE‐2 for women of childbearing potential; DCE‐1 for everyone else).\n\nThe questionnaire was piloted in a convenience sample of Epilepsy Action staff and volunteers, clinical and academic research staff, physicians who agreed to be contacted after the focus group, and members of our scientific advisory group. These individuals provided feedback on aspects such as the phrasing of the attributes and the selection criteria for women of childbearing potential, which was changed from being defined by age to a single question that asked, “Is there any chance, however remote, that you may become pregnant in the future?”\n\nStatistical analysis\nResponses to the DCE were analyzed in STATA, version 13 (StataCorp LP, College Station, TX) using a random‐effects logit model that allowed for multiple observations (eight binary choices) from the same respondent.44 The regression model estimated preference weights for each attribute that indicate the importance of attributes and the direction of effect. The coefficients (β) from the regression were used to calculate the MAR of an AE that respondents were willing to accept in exchange for a percentage point improvement in benefit (12‐month remission) (Figure \n\nS2\n).\n\nConfidence intervals (95%) were determined from 1000 bootstrap replications.\n\nStage 3: estimating the utility for a given AED\nThe expected utility model was parameterized using the preference weights elicited in the DCE and data on the number of events for each outcome assessed in the DCE, from the Standard vs. New Antiepileptic Drugs (SANAD) clinical trial of AEDs16, 17 and from a meta‐analysis of the effects of prenatal exposure to commonly prescribed AEDs on the prevalence of congenital malformations in the child19 (Table \n5). The β coefficients for each outcome (derived in stage 2) were multiplied by the corresponding clinical trial event rate and summed to estimate the total utility for each AED42 (Figure \n\nS2\n). The ranking of AEDs by total utility was compared with ranking by time to treatment failure (because of inadequate seizure control or AEs), chosen to reflect the benefit–harm trade‐off observed in the clinical trial.16, 17\n\n\nTable 5 Clinical event data used to calculate preference weights and total utility by AED\n\nVariable\tPartial epilepsy\tGeneralized and unclassified epilepsy\t\nCarbamazepine\tGabapentin\tLamotrigine\tTopiramate\tRef.\tValproate\tTopiramate\tLamotrigine\tRef.\t\n12‐Month remission at year 2 observation (PP)\t44\t35\t44\t38\t\n16\n\t55\t48\t46\t\n17\n\t\nSeizure reduction at year 2 observationa\n\t13\t14\t21\t10\t\n16\n\t12\t5\t15\t\n17\n\t\nClinically important adverse effects\t\nDepression\t2.23\t2.79\t3.58\t6.70\t\n16\n\t0.44\t0.88\t2.64\t\n17\n\t\nMemory problems\t3.35\t5.31\t2.75\t5.31\t\n16\n\t0.00\t4.42\t0.88\t\n17\n\t\nBehavior/personality change/aggression\t1.12\t1.68\t1.93\t5.31\t\n16\n\t1.75\t7.96\t1.76\t\n17\n\t\nMajor congenital malformation outcomes in the children of women receiving AED treatment while pregnant\t4.93\t1.47\t2.31\t4.28\t\n19\n\t10.93\t4.28\t2.31\t\n19\n\t\nData are given as events per 100 patients.\n\nAED, antiepileptic drug; PP, trial per‐protocol analysis.\n\na Calculated as the number of patients still receiving randomized drug at year 2 observation, minus the number of patients who had achieved 12‐month remission at year 2 observation (based on PP).\n\nJohn Wiley & Sons, LtdSupporting information\nSupplementary information accompanies this paper on the Clinical Pharmacology & Therapeutics website (www.cpt-journal.com).\n\nFunding\nFunded by the National Institute for Health Research (NIHR), under its Research for Patient Benefit Programme (Grant Reference Number PB‐PG‐0909‐20161). P.W., A.M., and D.A.H. are also supported by the Medical Research Council North West Hub for Trials Methodology Research (Reference Number MR/K025635/1). A.M. is partly funded by the NIHR Collaboration for Leadership in Applied Health Research and Care North West Coast; and D.A.H. is a Health and Care Research Wales Senior Research Leader (SRL/15/029).\n\nConflict of Interest\nThe authors declared no competing interests for this work. The funder had no role in study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the paper for publication.\n\nAuthor Contributions\nE.H. and D.H. wrote the manuscript; A.M., D.H., E.H., A.J., P.W., and G.B. designed the research; E.H., A.R., D.H., and A.M. performed the research; E.H. and C.P. analyzed the data.\n\nSupporting information\n\nTable S1 Results of the ranking exercises, presented as standardized weighed rank scoresa.Table S2 Maximum acceptable risk (MAR) and difference in total utility associated with a change to AED with better seizure control.Figure S1 Example binary DCE question.Figure S2 Model specification and analysis.\n\nClick here for additional data file.\n\n Acknowledgments\nThe authors thank the study participants; and acknowledge the contributions of Angie Pullen (Epilepsy Services Manager, Epilepsy Action), Margaret Rawnsley (Research Administration Officer, Epilepsy Action), and Joanna Coast (Professor in the Economics of Health and Care, University of Bristol) to the design and conduct of this research. We also thank the members of our study Advisory Group: Carole Brown, Jeff Canning, Joanna Coast, Paul Cooper, Margaret Jackson, Andrew Kirkham, Doug McCorry, and Rajiv Mohanraj.\n==== Refs\n1 \n\nMühlbacher , A.C. \n, \nJuhnke , C. \n, \nBeyer , A.R. \n & \nGarner , S. \n\nPatient‐focused benefit‐risk analysis to inform regulatory decisions: the European Union perspective . Value Health \n19 , 734 –740 (2016 ).27712699 \n2 \n\nJohnson , F.R. \n & \nZhou , M. \n\nPatient preferences in regulatory benefit‐risk assessments: a US perspective . Value Health \n19 , 741 –745 (2016 ).27712700 \n3 \nFederal Drug Administration \n. Prescription drug user fee act patient‐focused drug development: announcement of disease areas for meetings conducted in fiscal years 2013–2015 . Fed. Regist . 78 , 21613 –21614 (2013 ) <https://www.gpo.gov/fdsys/pkg/FR-2013-04-11/pdf/2013-08441.pdf>. Accessed 26 April 2018.\n4 \nEuropean Medicines Agency \n. 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Epilepsy Res. \n16 , 83 –88 (1993 ).8243442 \n41 \n\nBaker , G.A. \n, \nSmith , D.F. \n, \nJacoby , A. \n, \nHayes , J.A. \n & \nChadwick , D.W. \n\nLiverpool seizure severity scale revisited . Seizure \n30 , 201 –205 (1998 ).\n42 \n\nLancsar , E. \n, \nFiebig , D.G. \n & \nHole , A.R. \n\nDiscrete choice experiments: a guide to model specification, estimation and software . Pharmacoeconomics \n35 , 697 –716 (2017 ).28374325 \n43 \n\nOrme , B.K. \n\nGetting Started With Conjoint Analysis: Strategies for Product Design and Pricing Research (Research Publishers , Madison, WI , 2010 ).\n44 \n\nRyan , M. \n, \nGerard , R.K. \n, \nWatson , V. \n, \nStreet , D.J. \n & \nBurgess , L. \n\nPractical issues in conducting a discrete choice experiment In: Using Discrete Choice Experiments to Value Health and Health Care (eds. Ryan M. , Gerard K. & Amaya‐Amaya M. ). 73 –88 . (Springer Science & Business Media , Dordrecht , The Netherlands, 2007 ).\n\n",
"fulltext_license": "CC BY",
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"issue": "105(3)",
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"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000927:Anticonvulsants; D000076722:Drug Development; D005260:Female; D017144:Focus Groups; D006801:Humans; D008297:Male; D008875:Middle Aged; D018802:Patient-Centered Care; D036301:Qualitative Research; D018570:Risk Assessment; D012640:Seizures; D055815:Young Adult",
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"pubdate": "2019-03",
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"references": "27712716;21669364;27819746;18620460;19444531;17628557;21511198;23637054;26138622;21557381;25552232;29669717;17382828;27665373;27712699;17632534;8243442;28374325;25005924;16277551;22770879;27832461;22503427;17382827;29433949;22223558;12919340;24821575;27712700;24852596;28061040;9700832;28597374;24232377",
"title": "Patient-Focused Drug Development Methods for Benefit-Risk Assessments: A Case Study Using a Discrete Choice Experiment for Antiepileptic Drugs.",
"title_normalized": "patient focused drug development methods for benefit risk assessments a case study using a discrete choice experiment for antiepileptic drugs"
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"abstract": "Bipolar disorder is characterized by persistent and/or recurrent mood changes between depressive and manic poles. Rapid cycling is a frequent, although underrecognized, condition in bipolar disorder, and it is known to worsen the prognosis of the disease. With regard to the treatment of bipolar depression, there is a shortage of evidence-supported treatment choices, and the literature on the subject includes few references to cases of manic switch induced by lamotrigine. The authors describe a case of a rapid cycling bipolar patient who presented manic symptoms after initiating treatment with lamotrigine.",
"affiliations": "Psychiatry, University Hospital Center of Sao Joao, Oporto, PRT.;Psychiatry, University Hospital Center of Sao Joao, Oporto, PRT.;Psychiatry, University Hospital Center of Sao Joao, Oporto, PRT.",
"authors": "Ramos|Ana Lúcia|AL|;Salgado|Henrique|H|;Bragança|Miguel|M|",
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"doi": "10.7759/cureus.16184",
"fulltext": "\n==== Front\nCureus\nCureus\n2168-8184\nCureus\n2168-8184\nCureus Palo Alto (CA)\n\n10.7759/cureus.16184\nPsychiatry\nManic Episode Induced by Lamotrigine in Rapid Cycling Bipolar Disorder\nMuacevic Alexander\nAdler John R\nRamos Ana Lúcia 1\nSalgado Henrique 1\nBragança Miguel 1\n1 Psychiatry, University Hospital Center of Sao Joao, Oporto, PRT\nAna Lúcia Ramos analuciacr29@gmail.com\n5 7 2021\n7 2021\n13 7 e161845 7 2021\nCopyright © 2021, Ramos et al.\n2021\nRamos et al.\nhttps://creativecommons.org/licenses/by/3.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.\nThis article is available from https://www.cureus.com/articles/63014-manic-episode-induced-by-lamotrigine-in-rapid-cycling-bipolar-disorder\nBipolar disorder is characterized by persistent and/or recurrent mood changes between depressive and manic poles. Rapid cycling is a frequent, although underrecognized, condition in bipolar disorder, and it is known to worsen the prognosis of the disease. With regard to the treatment of bipolar depression, there is a shortage of evidence‐supported treatment choices, and the literature on the subject includes few references to cases of manic switch induced by lamotrigine.\n\nThe authors describe a case of a rapid cycling bipolar patient who presented manic symptoms after initiating treatment with lamotrigine.\n\nbipolar disorder\nrapid cycling\nlamotrigine\nbipolar depression\nmania\nThe content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus.\n==== Body\nIntroduction\n\nBipolar disorder is a chronic psychiatric disorder characterized by persistent and/or recurrent mood changes between depressive and manic poles [1]. The course of the disease is complex and heterogeneous, with a highly variable frequency of mood and energy transitions. About one in six patients who seek treatment for bipolar disorder present with a rapid-cycling pattern [2]. Rapid-cycling bipolar disorder refers to the presence of at least food mood episodes in the previous 12 months that meet the criteria for manic, hypomanic, or major depressive episodes [3]. Rapid-cycling bipolar disorder is associated with poorer treatment response, worse long-term prognosis, and probable higher suicide risk than bipolar disorder without rapid cycling [4]. Regarding the response to pharmacological measures, treatment resistance for each episode appears to increase with each additional recurrence [5]. Hypothyroidism, antidepressant use, and substance abuse are often associated with rapid cycling [6].\n\nThe treatment of bipolar disorder comprehends different strategies, which include the maintenance treatment and the approach of acute mania or depression. There are multiple factors that make the treatment of acute depression the most challenging step [7] and, in addition, there is a paucity of evidence‐supported treatment choices for bipolar depression [8]. The risk of manic switch is commonly feared, especially concerning rapid-cycling patients.\n\nLamotrigine is an effective treatment for acute bipolar depression [9], and it has a lower risk of adverse effects (although potentially severe rash) compared with alternatives as lithium and quetiapine [8]. Furthermore, in two large 18‐month trials, lamotrigine did not increase the risk of mania compared with placebo [8]. On the other hand, there are some described cases of manic episodes that occurred after the introduction of lamotrigine [9-12]. Therefore, although unlikely, we must be aware of this risk in clinical practice.\n\nIn this case report, we describe the clinical features of a patient with rapid cycling bipolar disorder that suffered a manic switch after lamotrigine introduction.\n\nCase presentation\n\nA 59-year-old man, diagnosed with bipolar disorder I for many years, presented with an episode of bipolar depression with symptoms such as anhedonia, depressed mood, reduced energy, psychomotor retardation, demotivation, anxiety, and decreased social activity, which had been gradually worsening for two weeks. Significant impairment in his usual functioning was noted, given that the patient lost the interest and ability to work in the projects that excited him the most, for example, he abandoned the writing of a new book (months before, when stable, he managed to translate a book he had already published). He also stopped taking care of his diet, with less and less elaborate meals. These symptoms were interpreted as an episode of bipolar depression. At that time, he was being treated at the day hospital of the psychiatric department and was medicated with semisodium valproate 1500 mg id, olanzapine 10 mg 2id, aripiprazole 10 mg id, and lorazepam 2.5 mg 3id.\n\nAbout six months before this episode, the patient was hospitalized for a period of six weeks following a suicide attempt through self-induced deep cuts in the upper limbs, with severe bleeding that motivated hospitalization in the intensive care unit. This event occurred in the context of severe depression with psychotic characteristics (with delusional ideas of guilt and ruin). In that time, medication was adjusted with the introduction of fluoxetine 20 mg id, olanzapine 10 mg id, and diazepam 5 mg 2id (in addition to semisodium valproate and lorazepam, which he was already taking). Initially, a clinical improvement was noticed, but, soon after discharge, he had a subsequent manic switch, with elevated mood, increased energy, psychomotor agitation, verborrea, disinhibition, involvement in new projects, and regular cocaine consumption. Thus, the medication was progressively readjusted and cessation of cocaine consumption was promoted, with progressive clinical improvement, until he turned to the depressive mood described at the beginning of this case report.\n\nIn addition to this recent psychiatric history, the patient had already been hospitalized six times in psychiatry wards due to decompensation of his bipolar disorder. In some of these hospitalizations, he also presented with mental and behavioral disorders induced by psychoactive substance use, which normally takes place after the installation of elevated mood and disinhibition. In fact, he has a history of drug abuse, mainly cocaine but also cannabinoids, heroin, and alcohol. His medical history also includes hypertension, treated with lisinopril 10 mg id and amlodipine 5 mg id.\n\nFacing the current depressive episode, lab tests were carried out and no abnormalities were found in blood cell count, renal function, electrolytes, liver function, folic acid, B12 vitamin, total cholesterol, and glucose. Valproate levels were 61.7 mg/L and urine drug screening was negative. Regarding the treatment, it must be taken into account that, in previous depressive episodes, the patient responded poorly to quetiapine and reported serious adverse effects of lithium, such as muscle twitch and trembling, pointing out his low tolerability to the drug. Given this background, the decision was to start lamotrigine in titration up to 25 mg id, in addition to the semisodium valproate he was already taking. We also decided to suspend aripiprazole.\n\nAbout three to four weeks after initiating lamotrigine, the patient presented with an expansive mood, sudden involvement in new projects (intention of publishing new books), increased energy, easy social interactions, disinhibition, fast speech, and insomnia. At that time, the dose of lamotrigine was 25 mg id, and the taking of the medication was supervised by the nurses in the day hospital. The patient himself early recognized that his mood was unwell, explaining his clinical condition with the introduction of lamotrigine: \"lamotrigine is like methamphetamine, I am no longer depressed.\" After the onset of this manic episode, the patient resumed cocaine use and, at this point, we must highlight that the consumption only began after the exacerbation of manic symptoms, given that the previous drug screenings, regularly performed, were consistently negative. Therefore, lamotrigine was gradually discontinued, aripiprazole 10 mg was reintroduced, sodium valproate dose was increased to 2 g id, and flurazepam 30mg id was started. At the same time, cocaine use was discouraged again, and the patient stopped using it. About two weeks after the discontinuation of lamotrigine, a gradual clinical stabilization was observed, with a return to euthymic mood and normal speech debt, stable sleep and appetite, and clear absence of psychotic activity or suicidal ideation, overlapping his previous functioning.\n\nDiscussion\n\nThis case report presents a patient who had two depressive episodes and two manic episodes in the period of one year, making him suitable for the diagnosis of rapid cycling bipolar disorder I. Rapid cycling is a frequent, although underrecognized, condition in bipolar disorder, and it contributes to a worse prognosis [3]. The literature suggests that rapid cycling affects a significant portion of bipolar patients and is related to a longer course of illness, earlier age at onset, more illegal drug and alcohol abuse, and increased suicidality [3], clinical features that were accessed in this patient. \n\nDespite the variety of clinical manifestations exhibited by the patient, it was clearly noticed that the biggest damage to his way of acting was caused by depressive episodes, as proven by the history of serious suicide attempts. Indeed, in bipolar disorder, symptoms of depression have been shown to account for more impairment than symptoms of mania [13]. Thus, early treatment of the acute depressive episode, as well as prevention of relapses, was of supreme importance in this case. As the patient had a history of manic switches induced by antidepressants, as well as poor response to quetiapine and low tolerance to lithium, we opted for the introduction of lamotrigine in his therapeutic scheme. In fact, in a previous study, lamotrigine was generally effective and well-tolerated in a group of previously non-responsive rapid cycling bipolar patients [14].\n\nAlthough there is sparse evidence about the potential risk of a manic switch related to lamotrigine therapy, in this case, the manic symptoms were distinctly observed after the patient initiated lamotrigine. At the time, the interference of illicit psychoactive drugs in the symptoms was suspected, given the patient's history of substance abuse. However, urinary drug screenings were performed every two days, and since the results were consistently negative, the possibility that the patient was using drugs was ruled out. At the onset of the manic episode, the drug screening was negative for cocaine, opiates, cannabinoids, and amphetamines. By the way, it was interesting to note that the patient himself had a perception of the potential risk of a manic switch caused by lamotrigine, an understanding that was evident when he compared taking lamotrigine with being under the effect of stimulating drugs, such as amphetamines, in order to justify his elevated mood and energy.\n\nSince we started to taper off lamotrigine soon after the first manic symptoms, it is questionable if a sufficient dose of lamotrigine was reached. However, the possibility of an insufficient dose is less likely, as the patient was taking semisodium valproate at the same time, which is known to raise the blood concentration of lamotrigine. On Naranjo Adverse Drug Reaction Probability Scale, the total score for lamotrigine was 3, which means that the symptoms were a possible adverse reaction to lamotrigine [15]. Nevertheless, we cannot rule out the possible contribution of aripiprazole withdrawal to the beginning of the manic symptoms.\n\nFinally, despite the possible association between lamotrigine and the occurrence of the reported manic switch, we cannot exclude that this abrupt mood transition may have occurred in the context of the natural course of the disease, especially considering the rapid-cycling pattern and the history of drug use relapses.\n\nConclusions\n\nEven though the episodes of manic switch are not consistently linked to the therapy with lamotrigine, the number of cases described in the literature is not insignificant. In this case report, we describe a patient who presented with depressive symptoms and turned manic after the introduction of lamotrigine. This article aims to draw the attention of the scientific community to this possibility, highlighting the need for future studies on the subject.\n\nHuman Ethics\n\nThe authors have declared that no competing interests exist.\n\nConsent was obtained or waived by all participants in this study\n==== Refs\nReferences\n\n1 Biomarkers for bipolar disorder: current status and challenges ahead Expert Rev Neurother Teixeira AL Colpo GD Fries GR Bauer IE Selvaraj S 67 81 19 2019 30451546\n2 Rapid cycling bipolar disorder: clinical characteristics and treatment options CNS Drugs Coryell W 557 569 19 2005 15984894\n3 Rapid cycling in bipolar disorder: a systematic review J Clin Psychiatry Carvalho AF Dimellis D Gonda X Vieta E Mclntyre RS Fountoulakis KN 0 86 75 2014\n4 Treatment of rapid-cycling bipolar disorder J Clin Psychiatry Schneck CD 22 27 67 Suppl 11 2006 https://pubmed.ncbi.nlm.nih.gov/17029493/\n5 Complexity of pharmacologic treatment required for sustained improvement in outpatients with bipolar disorder J Clin Psychiatry Post RM Altshuler LL Frye MA 1176 1186 71 2010 20923622\n6 Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) 2018 guidelines for the management of patients with bipolar disorder Bipolar Disord Yatham LN Kennedy SH Parikh SV 97 170 20 2018 29536616\n7 Antidepressants in bipolar depression: an enduring controversy Int J Bipolar Disord Gitlin MJ 25 6 2018 30506151\n8 The Psychopharmacology Algorithm Project at the Harvard South Shore Program: an update on bipolar depression Bipolar Disord Wang D Osser DN 472 489 22 2020 31650675\n9 A case of hypomania with low-dose lamotrigine Indian J Psychiatry Oflaz S Yıldızhan E Tatar ZB Akyuz F 217 57 2015 26124534\n10 Lamotrigine-induced manic switch: a report of 2 cases Prim Care Companion CNS Disord Bhagyalakshmi Subodh N Jayarajan D Chand PK Benegal V Murthy P 0 13 2011\n11 Can lamotrigine induce a switch into mania? [Article in Portuguese] Rev Psiquiatr Rio Gd Sul Cheniaux E Dias A Lessa JLM Versiani M 206 209 27 2005\n12 A case of hypomania induced by lamotrigine augmentation Prim Care Companion CNS Disord Sansone RA Sansone LA 0 13 2011 https://pubmed.ncbi.nlm.nih.gov/21731836/\n13 Aripiprazole in bipolar depression: a pooled, post-hoc analysis by severity of core depressive symptoms Int J Psychiatry Clin Pract Thase ME Bowden CL Nashat M Eudicone JM Marcus R McQuade RD Carlson BX 121 131 16 2012 22296512\n14 The efficacy of lamotrigine in rapid cycling and non-rapid cycling patients with bipolar disorder Biol Psychiatry Bowden CL Calabrese JR McElroy SL 0 8 45 1999\n15 A method for estimating the probability of adverse drug reactions Clin Pharmacol Ther Naranjo CA Busto U Sellers EM 239 245 30 1981 7249508\n\n",
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"title": "Manic Episode Induced by Lamotrigine in Rapid Cycling Bipolar Disorder.",
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"abstract": "Management of nonobstetric pain in the pregnant patient presents unique challenges related to transplacental fetal exposure to opioids and the subsequent risk of neonatal withdrawal syndrome. We present the case of a pregnant patient suffering from the pain of a progressively enlarging thoracoabdominal sarcoma. Epidural analgesia (using local anesthetics with minimal opioid) was utilized over a span of weeks to manage oncologic pain, limiting fetal opioid exposure and culminating in the birth of a healthy infant. While nonobstetric abdominal pain during pregnancy is not that uncommon, neoplastic abdominal pain does appear to be rare. Combined local anesthetic and opioid continuous epidural infusion should be considered a viable option in the pain management approach to obstetric patients with nonobstetric pain associated with malignancy.",
"affiliations": "Department of Anesthesiology, UT Health, McGovern Medical School, Houston, TX, USA.;Orlando Health, Orlando, FL, USA.;UT Health, McGovern Medical School, Houston, TX, USA.;Department of Anesthesiology, UT Health, McGovern Medical School, Houston, TX, USA.",
"authors": "Mehta|Jaideep H|JH|;Gibson|Mary Elizabeth|ME|;Amaro-Driedger|David|D|;Hussain|Mahammad N|MN|",
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"fulltext": "\n==== Front\nJ Pain ResJ Pain ResJournal of Pain ResearchJournal of Pain Research1178-7090Dove Medical Press 10.2147/JPR.S97155jpr-9-357Case ReportThoracic epidural analgesia to control malignant pain until viability in a pregnant patient Mehta Jaideep H 1Gibson Mary Elizabeth 2Amaro-Driedger David 3Hussain Mahammad N 11 Department of Anesthesiology, UT Health, McGovern Medical School, Houston, TX, USA2 Orlando Health, Orlando, FL, USA3 UT Health, McGovern Medical School, Houston, TX, USACorrespondence: Jaideep H Mehta, Department of Anesthesiology, UT Health, McGovern Medical School, 6431 Fannin Street, MSB 5.020, Houston, TX 77030, USA, Tel +1 713 500 6200, Fax +1 713 500 6201, Email Jaideep.H.Mehta@gmail.com2016 13 6 2016 9 357 360 © 2016 Mehta 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.Management of nonobstetric pain in the pregnant patient presents unique challenges related to transplacental fetal exposure to opioids and the subsequent risk of neonatal withdrawal syndrome. We present the case of a pregnant patient suffering from the pain of a progressively enlarging thoracoabdominal sarcoma. Epidural analgesia (using local anesthetics with minimal opioid) was utilized over a span of weeks to manage oncologic pain, limiting fetal opioid exposure and culminating in the birth of a healthy infant. While nonobstetric abdominal pain during pregnancy is not that uncommon, neoplastic abdominal pain does appear to be rare. Combined local anesthetic and opioid continuous epidural infusion should be considered a viable option in the pain management approach to obstetric patients with nonobstetric pain associated with malignancy.\n\nKeywords\nepiduralpregnancymalignantsarcoma\n==== Body\nIntroduction\nNonobstetric pain management in the gravid patient presents the challenge of safely and effectively managing two patients simultaneously and requires consideration of potential risk and benefit to mother, fetus, and the course of pregnancy.1–3 Traditional pain management approaches, specifically the use of high-dose opioids, place the fetus at risk for withdrawal symptoms after delivery.4 We describe a case of a pregnant woman with malignancy-related pain treated for 3 weeks with an epidural infusion of low-dose ropivacaine and fentanyl. The Committee for the Protection of Human Subjects approved the retrospective review of this case, and written consent from the patient for the publication of this case report was obtained, prior to her passing.\n\nCase description\nA 32-year-old G2P1 female presented to the acute pain medicine (APM) service with a history of uncontrolled thoracoabdominal pain secondary to an aggressively growing sarcoma. Pain was first reported at 10 weeks of pregnancy. Imaging studies at that time revealed a 5.8 cm craniocaudal ×3.6 cm transverse ×3.7 cm lobulated retroperitoneal mass. At 22 weeks, the patient underwent laparoscopic excision of a left-sided retroperitoneal mass. The patient was discharged home with a diagnosis of a benign tumor, and her pain was controlled with one hydrocodone/acetaminophen 10 mg/325 mg tablet every 4–6 hours. In addition, the obstetrician prescribed high-dose oral steroids, in an attempt to halt the growth of the mass.\n\nShe was readmitted to the hospital at 26 weeks 3 days of pregnancy complaining of worsening, unrelenting pain. Magnetic resonance imaging from the Emergency Department indicated a suboptimal resection of a retroperitoneal mass. The patient’s pain was controlled overnight by the APM service with 5–10 mg oxycodone as needed every 4 hours for breakthrough pain. She was discharged home the following day with prescriptions for oxycodone extended release 10 mg every 8 hours and one to two tablets of hydrocodone/acetaminophen 10 mg/325 mg every 4 hours for breakthrough pain. However, she returned to the Emergency Department 3 days later with uncontrolled pain, at which point an abdomen/pelvis computed tomography with contrast revealed an increase in the size of the soft tissue mass in the left retroperitoneum, extending posteriorly to the kidney and superiorly to the spleen. Multiple separate lesions were also invading the spleen, left hemidiaphragm, peritoneum, bilateral pulmonary parenchyma, and left ventricle. The patient was discharged home with a prescription for a fentanyl 12.5 mg/hr patch in addition to her prior oral regimen.\n\nThe patient returned again 2 days later and was admitted with 10/10 pain. During this admission, the patient recog-nized the lack of relief from her increasingly large narcotic regimen and expressed a desire to avoid opioids to improve fetal outcome. The obstetrics and neonatal services stated their desire to continue the pregnancy until a planned delivery at 30 weeks in order to improve the outcome for the fetus. The APM team determined that neuraxial analgesia was a viable option, with potential for more targeted segmental pain control and minimal fetal risk.\n\nA thoracic epidural catheter was inserted via the T8/9 space, and a bolus of 10 mL of 0.1% ropivacaine with 2 µg/mL fentanyl was administered, resulting in a sensory block from T4 to L2. An occlusive transparent sterile dressing with chlorhexidine-impregnated gel was placed over the site to maintain sterility. The patient reported significant pain relief, with her pain score dropping from 8/10 to 2/10. A patient-controlled epidural analgesia of 0.1% ropivacaine with 2 µg/mL fentanyl epidural infusion was started at 10 mL/hr, with patient-controlled bolus option of 5 mL every 20 minutes with a maximum of 20 mL/hr. The pain relief provided by this epidural allowed the patient to rest comfortably, tolerate oral intake, and ambulate. Over the subsequent 2 weeks, the epidural catheter was replaced twice as per the APM service protocol, on Day 5 and Day 12, in an attempt to continue to cover breakthrough pain in the left abdomen and chest wall, as well as reduce the likelihood of epidural site infection.\n\nDespite excellent pain control, aggressive nutrition, hydration, and electrolyte management, the patient became increasingly tachypneic, lethargic, and cachectic over the following 2 weeks. The obstetrics service induced labor at 29 weeks 2 days of pregnancy in response to an overall decline in the patient’s clinical picture. A combined spinal epidural anesthetic, with 1 mL of 0.25% bupivacaine in the spine and a 0.1% ropivacaine with 2 µg/mL of fentanyl infusion at 8 mL/hr in the epidural space at L3/4, was used to control pain in the final stages of labor. The thoracic epidural was maintained in place at T8/9 and continued in order to manage the cancer pain during labor. The patient had an uncomplicated vaginal delivery of a 1,410 g infant, with Apgar scores of 6.0 and 8.0, without complication or signs of neonatal withdrawal, as the patient had received minimal opioids for ∼3 weeks. Both epidural catheters were removed shortly after delivery without complications. On postpartum day 1, the patient was started on a multimodal pain management regimen, consisting of acetaminophen, ibuprofen, methadone for long-acting pain control, and oxycodone for breakthrough pain.5 She was subsequently discharged that afternoon to a quaternary oncology facility for the initiation of chemotherapy for her cancer, which was ultimately clinically diagnosed as a rare rhabdomyosarcoma by the oncologist without additional biopsies. No additional information was available to the team regarding additional workup for congenital rhabdomyosarcoma in either of the surviving children, nor was there information on follow-up after prolonged high-dose administration of opioids early in pregnancy. Although the patient underwent aggressive chemotherapy, she ultimately succumbed to the cancer.\n\nDiscussion\nThis case deals with the difficult question of how to appropriately manage severe, progressive, oncologic pain in a patient with a viable pregnancy. Rathmell et al3 focused on fetal risks associated with in utero exposure to specific drug classes and discussed management of headache, back pain, and sickle cell crisis, as examples of chronic pain in the obstetric patient. Fetal risks can include dependence on narcotics used to alleviate the mother’s pain; in this case, the male baby showed no signs of opioid withdrawal after delivery.\n\nOur case is unique because our patient’s pain was a direct result of an aggressively growing metastatic malignancy, which was initially misdiagnosed as a benign tumor. It is likely that pregnancy-associated hormones may have contributed to the aggressive nature of the tumor, while the physical changes of pregnancy, as implicated in the case reported by Samlaska and Dews,6–8 were not the causes of pain in this case. Their case involved long-term epidural analgesia for an intercostal neuralgia. Moreover, in the case described by Samlaska and Dews,8 the patient was discharged home, epidural in place, with home nursing care for dressing changes and infusion pump management, and the epidural was discontinued at the onset of spontaneous labor per the patient’s desire for natural childbirth. Considering the volatile nature of our patient’s condition and the dynamic nature of the pain of oncologic origin, treating the patient at home using epidural analgesia was not a prudent or feasible option. Palliative chemotherapy could have also been considered, but it was not used due to the risks to the viable fetus and the lack of pathology confirming malignancy.9 While genetics and heritability of the condition may have played a role in the development of the tumor, no cytogenetic analysis was performed during either the pregnancy or delivery hospitalization.\n\nIn this case, many pharmaceutical options were eliminated because of concern regarding transplacental transfer to the fetus. Fetal exposure to nonsteroidal anti-inflammatory drugs (NSAIDs) may cause premature constriction of the ductus arteriosus, which may result in fetal pulmonary hypertension.10–12 Other reported effects of in utero exposure to NSAIDs include intracranial hemorrhage, necrotizing enterocolitis, oligohydramnios, and renal dysfunction; additionally, there is increased risk of peripartum and postpartum hemorrhage.13\n\nIncreased incidences of fetal structural abnormalities and other manifestations of developmental toxicity, including lethality, growth restriction, and nervous and reproductive system functional impairment were demonstrated in studies of pregabalin in rats.14 Decreased fetal weights, skeletal ossification, and developmental delays were demonstrated in animal studies of tramadol; neonatal seizures, neonatal withdrawal syndrome, fetal death, and stillbirth have all been reported during postmarketing surveillance.15 Opioids, including morphine, hydromorphone, methadone, oxycodone, and hydrocodone, do cross the placenta and may cause respiratory depression and life-threatening neonatal withdrawal syndrome.3,16,17 A newborn infant in opioid withdrawal is usually small for gestational age, often shows signs of intrauterine growth retardation, and demonstrates the following: yawning, sneezing, decreased Moro reflex, hunger with an uncoordinated sucking action, jitteriness, tremor, constant movement, a shrill protracted cry, increased tendon reflexes, convulsions, vomiting, fever, watery diarrhea, cyanosis, dehydration, vasomotor instability, seizure, and cardio vascular collapse.18,19 No specific treatment protocol has been shown to be effective for neonatal withdrawal syndrome, and these infants often have chronic neurobehavioral handicaps.19 As previously mentioned, there was no evidence that this baby underwent opioid withdrawal after delivery.\n\nWe elected to use a 0.1% ropivacaine with 2 µg/mL fentanyl epidural infusion for management of the severe pain, in an effort to reduce the risk of neonatal withdrawal syndrome and postdelivery apnea in the preterm infant. Spinal or epidural opioids, especially when combined with dilute solutions of local anesthetics, can provide excellent analgesia for thoracic, abdominal, or pelvic pain without the side effects associated with large doses of systemically administered opioids.20 As fentanyl is a lipophilic opioid, it is frequently preferred for its ability to provide segmental analgesia as opposed to hydrophilic morphine, which has a more rostral spread. The APM team elected to use a dilute ropivacaine with low-dose fentanyl epidural infusion under the premise that the addition of fentanyl would offer better pain control than plain ropivacaine for the dynamic, spasmodic episodes of thoracoabdominal pain, by inhibiting pain transmission at the dorsal horn of the spinal cord.4,21 The major advantages of using a combination of opioid and local anesthetic in epidural infusion are the rapid onset of pain relief, a decrease in shivering, and less dense motor blockade.22\n\nWe demonstrate that high thoracic epidural analgesia, in lieu of systemic opioids, provided adequate pain control for the patient with severe thoracoabdominal pain, with resultant healthy neonatal outcome. Combined local anesthetic and opioid continuous epidural infusion can be a safe and viable option in the pain management approach to obstetric patients with nonobstetric pain.\n\nAcknowledgments\nThis study did not receive any external funding.\n\nAuthor contributions\n\nAll authors contributed toward data analysis, drafting and critically revising the paper and agree to be accountable for all aspects of the work.\n\nDisclosure\n\nThe authors report no conflicts of interest in this work.\n==== Refs\nReferences\n1 Epstein FB Acute abdominal pain in pregnancy Emerg Med Clin North Am 1994 12 1 151 165 8306930 \n2 Spalluto LB Woodfield CA DeBenedectis CM Lazarus E MR imaging evaluation of abdominal pain during pregnancy: appendicitis and other nonobstetric causes Radiographics 2012 32 2 317 334 22411935 \n3 Rathmell JP Viscomi CM Ashburn MA Management of non-obstetric pain during pregnancy and lactation Anesth Analg 1997 85 1074 1087 9356103 \n4 Schumacher MA Basbaum AI Way WL Chapter 31. Opioid analgesics and antagonists Katzung BG Masters SB Trevor AJ Basic and Clinical Pharmacology 12th ed New York McGraw-Hill 2012 \n5 American Society of Anesthesiologists Task Force on Chronic Pain Management American Society of Regional Anesthesia and Pain Medicine Practice guidelines for chronic pain management: an updated report by the American Society of Anesthesiologists Task Force on Chronic Pain Management and the American Society of Regional Anesthesia and Pain Medicine Anesthesiology 2010 112 4 810 833 20124882 \n6 Yazigi R Driscoll SG Sarcoma complicating pregnancy Gynecol Oncol 1986 25 1 125 127 3732912 \n7 Jafari K Lash AF Webster A Pregnancy and Sarcoma Acta Obstet Gynecol Scand 1978 57 3 265 271 665173 \n8 Samlaska S Dews TE Long-term epidural for pregnancy-induced intercostal neuralgia Pain 1995 62 2 245 248 8545151 \n9 Taghavi K Sykes P Innes C Wrong place at the wrong time: a case of cervical embryonal rhabdomyosarcoma in pregnancy Gynecol Oncol Rep 2015 12 77 79 26076166 \n10 Prefumo F Marasini M De Biasio P Venturini PL Acute premature constriction of the ductus arteriosus after maternal self-medication with nimesulide Fetal Diagn Ther 2008 24 35 38 18504378 \n11 Lubetzky R Mandel D Mimouni FB Indomethacin-induced early patent ductus arteriosus closure cannot be predicted by a decrease in pulse pressure Am J Perinatol 2004 21 257 261 15232757 \n12 Gewillig M Brown SC De Catte L Premature foetal closure of the arterial duct: clinical presentations and outcome Eur Heart J 2009 30 12 1530 1536 19389789 \n13 Rella JG Carter WA Chapter 185. Nonsteroidal Anti-Inflammatory Drugs Tintinalli JE Stapczynski JS Cline DM Ma OJ Cydulka RK Meckler GD Tintinalli’s Emergency Medicine: A Comprehensive Study Guide 7th ed New York McGraw-Hill 2011 \n14 Lyrica (full prescribing information) [webpage on the Internet] New York, NY Pfizer Pharmaceuticals, LLC., Division of Pfizer, Inc 2012 Available from: http://labeling.pfizer.com/ShowLabeling.aspx?id=561 Accessed January 26, 2013 \n15 Ultram (full prescribing information) [webpage on the Internet] Raritan, NJ PriCara, Division of Ortho-McNeil-Janssen Pharmaceuticals, Inc 2009 Available from: http://www.janssenpharmaceuticalsinc.com/assets/ultram.pdf Accessed January 26, 2013 \n16 OxyContin (full prescribing information) [webpage on the Internet] Stamford, CT Purdue Pharma, L.P. 2011 Available from: http://www.purduepharma.com/pi/prescription/OxycontinPI.pdf Accessed January 26, 2013 \n17 Vicodin (full prescribing information) [webpage on the Internet] North Chicago, IL Abbott Laboratories 2012 Available from: http://www.rxabbvie.com/pdf/vicodin_apap_300mg_hydrocodone_5mg-7.5mg-10mg_PI.pdf Accessed January 26, 2013 \n18 Rumack BH Dart RC Chapter 13. Poisoning Hay WW Jr Levin MJ Deterding RR Ross JJ Sondheimer JM CURRENT Diagnosis and Treatment: Pediatrics 21st ed New York McGraw-Hill 2012 \n19 Thilo EH Rosenberg AA Chapter 2. The Newborn infant Hay WW Jr Levin MJ Deterding RR Ross JJ Sondheimer JM CURRENT Diagnosis and Treatment: Pediatrics 21st ed New York McGraw-Hill 2012 \n20 Catterall WA Mackie K Chapter 20. Local anesthetics Brunton LL Chabner BA Knollmann BC Goodman and Gilman’s the Pharmacological Basis of Therapeutics 12th ed New York McGraw-Hill 2011 \n21 Adams MC Tighe PJ Hurley RW Chapter 96. Pain Lawry GV McKean SC Matloff J Ross JJ Dressler DD Brotman DJ Ginsberg JS Principles and Practice of Hospital Medicine New York McGraw-Hill 2012 \n22 Cunningham FG Leveno KJ Bloom SL Hauth JC Rouse DJ Spong CY Chapter 19. Obstetrical Anesthesia Cunningham FG Leveno KJ Bloom SL Hauth JC Rouse DJ Spong CY Williams Obstetrics 23rd ed New York McGraw-Hill 2010\n\n",
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"issn_linking": "1178-7090",
"issue": "9()",
"journal": "Journal of pain research",
"keywords": "epidural; malignant; pregnancy; sarcoma",
"medline_ta": "J Pain Res",
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"pages": "357-60",
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"title": "Thoracic epidural analgesia to control malignant pain until viability in a pregnant patient.",
"title_normalized": "thoracic epidural analgesia to control malignant pain until viability in a pregnant patient"
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"abstract": "Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited.\n\n\n\nTo determine whether hydrocortisone improves outcome for patients with severe COVID-19.\n\n\n\nAn ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020.\n\n\n\nThe corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108).\n\n\n\nThe primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%).\n\n\n\nAfter excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively.\n\n\n\nAmong patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions.\n\n\n\nClinicalTrials.gov Identifier: NCT02735707.",
"affiliations": "The Clinical Research Investigation and Systems Modeling of Acute Illness (CRISMA) Center, Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.;Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands.;Division of Anaesthetics, Pain Medicine and Intensive Care Medicine, Department of Surgery and Cancer, Imperial College London and Imperial College Healthcare NHS Trust, London, United Kingdom.;Intensive Care Unit, Raymond Poincaré Hospital (AP-HP), Paris, France.;Intensive Care Department, College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, King Abdullah International Medical Research Center, King Abdulaziz Medical City, Riyadh, Saudi Arabia.;Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom.;Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands.;Berry Consultants LLC, Austin, Texas.;Li Ka Shing Knowledge Institute, St Michael's Hospital, Toronto, Ontario, Canada.;Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands.;Bristol Royal Informatory, Bristol, United Kingdom.;Center for Clinical Studies and Center for Sepsis Control and Care (CSCC), Department of Anesthesiology and Intensive Care Medicine, Jena University Hospital, Jena, Germany.;Global Coalition for Adaptive Research, San Francisco, California.;Helix, Monash University, Melbourne, Victoria, Australia.;Infection Prevention and Healthcare Epidemiology Unit, Alfred Health, Melbourne, Victoria, Australia.;Department of Medical Microbiology, Amsterdam University Medical Center, University of Amsterdam, the Netherlands.;Berry Consultants LLC, Austin, Texas.;NHS Blood and Transplant, Bristol, United Kingdom.;Berry Consultants LLC, Austin, Texas.;Department of Microbiology, Antwerp University Hospital, Antwerp, Belgium.;Australian and New Zealand Intensive Care Research Centre, School of Epidemiology and Preventive Medicine, Monash University, Melbourne, Victoria, Australia.;Network for Improving Critical Care Systems and Training, Colombo, Sri Lanka.;Australian and New Zealand Intensive Care Research Centre, School of Epidemiology and Preventive Medicine, Monash University, Melbourne, Victoria, Australia.;The Clinical Research Investigation and Systems Modeling of Acute Illness (CRISMA) Center, Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.;Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands.;Intensive Care Unit, Princess Alexandra Hospital, Brisbane, Queensland, Australia.;Université de Sherbrooke, Sherbrooke, Quebec, Canada.;Cardiac Intensive Care Unit, Peter Munk Cardiac Centre, University Health Network, Interdepartmental Division of Critical Care Medicine, University of Toronto, Toronto, Ontario, Canada.;The Clinical Research Investigation and Systems Modeling of Acute Illness (CRISMA) Center, Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.;School of Medicine and Pharmacology, University of Western Australia, Crawley, Western Australia, Australia.;Berry Consultants LLC, Austin, Texas.;Li Ka Shing Knowledge Institute, St Michael's Hospital, Toronto, Ontario, Canada.;Centre for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, United Kingdom.;Berry Consultants LLC, Austin, Texas.;Australian and New Zealand Intensive Care Research Centre, School of Epidemiology and Preventive Medicine, Monash University, Melbourne, Victoria, Australia.;Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.;The Clinical Research Investigation and Systems Modeling of Acute Illness (CRISMA) Center, Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.;Clinical Trials Unit, Intensive Care National Audit & Research Centre (ICNARC), London, United Kingdom.;University of British Columbia School of Medicine, Vancouver, Canada.;Australian and New Zealand Intensive Care Research Centre, School of Epidemiology and Preventive Medicine, Monash University, Melbourne, Victoria, Australia.;Cardiothoracic and Vascular Intensive Care Unit, Auckland City Hospital, Auckland, New Zealand.;Australian and New Zealand Intensive Care Research Centre, School of Epidemiology and Preventive Medicine, Monash University, Melbourne, Victoria, Australia.;Clinical Trials Unit, Intensive Care National Audit & Research Centre (ICNARC), London, United Kingdom.;Berry Consultants LLC, Austin, Texas.;Li Ka Shing Knowledge Institute, St Michael's Hospital, Toronto, Ontario, Canada.;Berry Consultants LLC, Austin, Texas.;The Clinical Research Investigation and Systems Modeling of Acute Illness (CRISMA) Center, Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.;Medical Research Institute of New Zealand, Wellington, New Zealand.;Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, the Netherlands.;Southside Clinical Unit, Princess Alexandra Hospital, Brisbane, Queensland, Australia.;Department of Medicine, Critical Care and Hematology/Medical Oncology, University of Manitoba, Winnipeg, Manitoba, Canada.;Berry Consultants LLC, Austin, Texas.;Berry Consultants LLC, Austin, Texas.;Medical Research Institute of New Zealand, Wellington, New Zealand.;Australian and New Zealand Intensive Care Research Centre, School of Epidemiology and Preventive Medicine, Monash University, Melbourne, Victoria, Australia.;Division of Anaesthetics, Pain Medicine and Intensive Care Medicine, Department of Surgery and Cancer, Imperial College London and Imperial College Healthcare NHS Trust, London, United Kingdom.",
"authors": "Angus|Derek C|DC|;Derde|Lennie|L|;Al-Beidh|Farah|F|;Annane|Djillali|D|;Arabi|Yaseen|Y|;Beane|Abigail|A|;van Bentum-Puijk|Wilma|W|;Berry|Lindsay|L|;Bhimani|Zahra|Z|;Bonten|Marc|M|;Bradbury|Charlotte|C|;Brunkhorst|Frank|F|;Buxton|Meredith|M|;Buzgau|Adrian|A|;Cheng|Allen C|AC|;de Jong|Menno|M|;Detry|Michelle|M|;Estcourt|Lise|L|;Fitzgerald|Mark|M|;Goossens|Herman|H|;Green|Cameron|C|;Haniffa|Rashan|R|;Higgins|Alisa M|AM|;Horvat|Christopher|C|;Hullegie|Sebastiaan J|SJ|;Kruger|Peter|P|;Lamontagne|Francois|F|;Lawler|Patrick R|PR|;Linstrum|Kelsey|K|;Litton|Edward|E|;Lorenzi|Elizabeth|E|;Marshall|John|J|;McAuley|Daniel|D|;McGlothin|Anna|A|;McGuinness|Shay|S|;McVerry|Bryan|B|;Montgomery|Stephanie|S|;Mouncey|Paul|P|;Murthy|Srinivas|S|;Nichol|Alistair|A|;Parke|Rachael|R|;Parker|Jane|J|;Rowan|Kathryn|K|;Sanil|Ashish|A|;Santos|Marlene|M|;Saunders|Christina|C|;Seymour|Christopher|C|;Turner|Anne|A|;van de Veerdonk|Frank|F|;Venkatesh|Balasubramanian|B|;Zarychanski|Ryan|R|;Berry|Scott|S|;Lewis|Roger J|RJ|;McArthur|Colin|C|;Webb|Steven A|SA|;Gordon|Anthony C|AC|;|||;Al-Beidh|Farah|F|;Angus|Derek|D|;Annane|Djillali|D|;Arabi|Yaseen|Y|;van Bentum-Puijk|Wilma|W|;Berry|Scott|S|;Beane|Abigail|A|;Bhimani|Zahra|Z|;Bonten|Marc|M|;Bradbury|Charlotte|C|;Brunkhorst|Frank|F|;Buxton|Meredith|M|;Cheng|Allen|A|;De Jong|Menno|M|;Derde|Lennie|L|;Estcourt|Lise|L|;Goossens|Herman|H|;Gordon|Anthony|A|;Green|Cameron|C|;Haniffa|Rashan|R|;Lamontagne|Francois|F|;Lawler|Patrick|P|;Litton|Edward|E|;Marshall|John|J|;McArthur|Colin||;McAuley|Daniel|D|;McGuinness|Shay|S|;McVerry|Bryan|B|;Montgomery|Stephanie|S|;Mouncey|Paul|P|;Murthy|Srinivas|S|;Nichol|Alistair|A|;Parke|Rachael|R|;Rowan|Kathryn|K|;Seymour|Christopher|C|;Turner|Anne|A|;van de Veerdonk|Frank|F|;Webb|Steve|S|;Zarychanski|Ryan|R|;Campbell|Lewis|L|;Forbes|Andrew|A|;Gattas|David|D|;Heritier|Stephane|S|;Higgins|Lisa|L|;Kruger|Peter|P|;Peake|Sandra|S|;Presneill|Jeffrey|J|;Seppelt|Ian|I|;Trapani|Tony|T|;Young|Paul|P|;Bagshaw|Sean|S|;Daneman|Nick|N|;Ferguson|Niall|N|;Misak|Cheryl|C|;Santos|Marlene|M|;Hullegie|Sebastiaan|S|;Pletz|Mathias|M|;Rohde|Gernot|G|;Rowan|Kathy|K|;Alexander|Brian|B|;Basile|Kim|K|;Girard|Timothy|T|;Horvat|Christopher|C|;Huang|David|D|;Linstrum|Kelsey|K|;Vates|Jennifer|J|;Beasley|Richard|R|;Fowler|Robert|R|;McGloughlin|Steve|S|;Morpeth|Susan|S|;Paterson|David|D|;Venkatesh|Bala|B|;Uyeki|Tim|T|;Baillie|Kenneth|K|;Duffy|Eamon|E|;Fowler|Rob|R|;Hills|Thomas|T|;Orr|Katrina|K|;Patanwala|Asad|A|;Tong|Steve|S|;Netea|Mihai|M|;Bihari|Shilesh|S|;Carrier|Marc|M|;Fergusson|Dean|D|;Goligher|Ewan|E|;Haidar|Ghady|G|;Hunt|Beverley|B|;Kumar|Anand|A|;Laffan|Mike|M|;Lawless|Patrick|P|;Lother|Sylvain|S|;McCallum|Peter|P|;Middeldopr|Saskia|S|;McQuilten|Zoe|Z|;Neal|Matthew|M|;Pasi|John|J|;Schutgens|Roger|R|;Stanworth|Simon|S|;Turgeon|Alexis|A|;Weissman|Alexandra|A|;Adhikari|Neill|N|;Anstey|Matthew|M|;Brant|Emily|E|;de Man|Angelique|A|;Lamonagne|Francois|F|;Masse|Marie-Helene|MH|;Udy|Andrew|A|;Arnold|Donald|D|;Begin|Phillipe|P|;Charlewood|Richard|R|;Chasse|Michael|M|;Coyne|Mark|M|;Cooper|Jamie|J|;Daly|James|J|;Gosbell|Iain|I|;Harvala-Simmonds|Heli|H|;Hills|Tom|T|;MacLennan|Sheila|S|;Menon|David|D|;McDyer|John|J|;Pridee|Nicole|N|;Roberts|David|D|;Shankar-Hari|Manu|M|;Thomas|Helen|H|;Tinmouth|Alan|A|;Triulzi|Darrell|D|;Walsh|Tim|T|;Wood|Erica|E|;Calfee|Carolyn|C|;O’Kane|Cecilia|C|;Shyamsundar|Murali|M|;Sinha|Pratik|P|;Thompson|Taylor|T|;Young|Ian|I|;Bihari|Shailesh|S|;Hodgson|Carol|C|;Laffey|John|J|;McAuley|Danny|D|;Orford|Neil|N|;Neto|Ary|A|;Detry|Michelle|M|;Fitzgerald|Mark|M|;Lewis|Roger|R|;McGlothlin|Anna|A|;Sanil|Ashish|A|;Saunders|Christina|C|;Berry|Lindsay|L|;Lorenzi|Elizabeth|E|;Miller|Eliza|E|;Singh|Vanessa|V|;Zammit|Claire|C|;van Bentum Puijk|Wilma|W|;Bouwman|Wietske|W|;Mangindaan|Yara|Y|;Parker|Lorraine|L|;Peters|Svenja|S|;Rietveld|Ilse|I|;Raymakers|Kik|K|;Ganpat|Radhika|R|;Brillinger|Nicole|N|;Markgraf|Rene|R|;Ainscough|Kate|K|;Brickell|Kathy|K|;Anjum|Aisha|A|;Lane|Janis-Best|JB|;Richards-Belle|Alvin|A|;Saull|Michelle|M|;Wiley|Daisy|D|;Bion|Julian|J|;Connor|Jason|J|;Gates|Simon|S|;Manax|Victoria|V|;van der Poll|Tom|T|;Reynolds|John|J|;van Beurden|Marloes|M|;Effelaar|Evelien|E|;Schotsman|Joost|J|;Boyd|Craig|C|;Harland|Cain|C|;Shearer|Audrey|A|;Wren|Jess|J|;Clermont|Giles|G|;Garrard|William|W|;Kalchthaler|Kyle|K|;King|Andrew|A|;Ricketts|Daniel|D|;Malakoutis|Salim|S|;Marroquin|Oscar|O|;Music|Edvin|E|;Quinn|Kevin|K|;Cate|Heidi|H|;Pearson|Karen|K|;Collins|Joanne|J|;Hanson|Jane|J|;Williams|Penny|P|;Jackson|Shane|S|;Asghar|Adeeba|A|;Dyas|Sarah|S|;Sutu|Mihaela|M|;Murphy|Sheenagh|S|;Williamson|Dawn|D|;Mguni|Nhlanhla|N|;Potter|Alison|A|;Porter|David|D|;Goodwin|Jayne|J|;Rook|Clare|C|;Harrison|Susie|S|;Williams|Hannah|H|;Campbell|Hilary|H|;Lomme|Kaatje|K|;Williamson|James|J|;Sheffield|Jonathan|J|;van’t Hoff|Willian|W|;McCracken|Phobe|P|;Young|Meredith|M|;Board|Jasmin|J|;Mart|Emma|E|;Knott|Cameron|C|;Smith|Julie|J|;Boschert|Catherine|C|;Affleck|Julia|J|;Ramanan|Mahesh|M|;D’Souza|Ramsy|R|;Pateman|Kelsey|K|;Shakih|Arif|A|;Cheung|Winston|W|;Kol|Mark|M|;Wong|Helen|H|;Shah|Asim|A|;Wagh|Atul|A|;Simpson|Joanne|J|;Duke|Graeme|G|;Chan|Peter|P|;Cartner|Brittney|B|;Hunter|Stephanie|S|;Laver|Russell|R|;Shrestha|Tapaswi|T|;Regli|Adrian|A|;Pellicano|Annamaria|A|;McCullough|James|J|;Tallott|Mandy|M|;Kumar|Nikhil|N|;Panwar|Rakshit|R|;Brinkerhoff|Gail|G|;Koppen|Cassandra|C|;Cazzola|Federica|F|;Brain|Matthew|M|;Mineall|Sarah|S|;Fischer|Roy|R|;Biradar|Vishwanath|V|;Soar|Natalie|N|;White|Hayden|H|;Estensen|Kristen|K|;Morrison|Lynette|L|;Smith|Joanne|J|;Cooper|Melanie|M|;Health|Monash|M|;Shehabi|Yahya|Y|;Al-Bassam|Wisam|W|;Hulley|Amanda|A|;Whitehead|Christina|C|;Lowrey|Julie|J|;Gresha|Rebecca|R|;Walsham|James|J|;Meyer|Jason|J|;Harward|Meg|M|;Venz|Ellen|E|;Williams|Patricia|P|;Kurenda|Catherine|C|;Smith|Kirsy|K|;Smith|Margaret|M|;Garcia|Rebecca|R|;Barge|Deborah|D|;Byrne|Deborah|D|;Byrne|Kathleen|K|;Driscoll|Alana|A|;Fortune|Louise|L|;Janin|Pierre|P|;Yarad|Elizabeth|E|;Hammond|Naomi|N|;Bass|Frances|F|;Ashelford|Angela|A|;Waterson|Sharon|S|;Wedd|Steve|S|;McNamara|Robert|R|;Buhr|Heidi|H|;Coles|Jennifer|J|;Schweikert|Sacha|S|;Wibrow|Bradley|B|;Rauniyar|Rashmi|R|;Myers|Erina|E|;Fysh|Ed|E|;Dawda|Ashlish|A|;Mevavala|Bhaumik|B|;Litton|Ed|E|;Ferrier|Janet|J|;Nair|Priya|P|;Buscher|Hergen|H|;Reynolds|Claire|C|;Santamaria|John|J|;Barbazza|Leanne|L|;Homes|Jennifer|J|;Smith|Roger|R|;Murray|Lauren|L|;Brailsford|Jane|J|;Forbes|Loretta|L|;Maguire|Teena|T|;Mariappa|Vasanth|V|;Smith|Judith|J|;Simpson|Scott|S|;Maiden|Matthew|M|;Bone|Allsion|A|;Horton|Michelle|M|;Salerno|Tania|T|;Sterba|Martin|M|;Geng|Wenli|W|;Depuydt|Pieter|P|;De Waele|Jan|J|;De Bus|Liesbet|L|;Fierens|Jan|J|;Bracke|Stephanie|S|;Reeve|Brenda|B|;Dechert|William|W|;Chassé|Michaël|M|;Carrier|François Martin|FM|;Boumahni|Dounia|D|;Benettaib|Fatna|F|;Ghamraoui|Ali|A|;Bellemare|David|D|;Cloutier|Ève|È|;Francoeur|Charles|C|;Lamontagne|François|F|;D’Aragon|Frédérick|F|;Carbonneau|Elaine|E|;Leblond|Julie|J|;Vazquez-Grande|Gloria|G|;Marten|Nicole|N|;Wilson|Maggie||;Albert|Martin|M|;Serri|Karim|K|;Cavayas|Alexandros|A|;Duplaix|Mathilde|M|;Williams|Virginie|V|;Rochwerg|Bram|B|;Karachi|Tim|T|;Oczkowski|Simon|S|;Centofanti|John|J|;Millen|Tina|T|;Duan|Erick|E|;Tsang|Jennifer|J|;Patterson|Lisa|L|;English|Shane|S|;Watpool|Irene|I|;Porteous|Rebecca|R|;Miezitis|Sydney|S|;McIntyre|Lauralyn|L|;Brochard|Laurent|L|;Burns|Karen|K|;Sandhu|Gyan|G|;Khalid|Imrana|I|;Binnie|Alexandra|A|;Powell|Elizabeth|E|;McMillan|Alexandra|A|;Luk|Tracy|T|;Aref|Noah|N|;Andric|Zdravko|Z|;Cviljevic|Sabina|S|;Đimoti|Renata|R|;Zapalac|Marija|M|;Mirković|Gordan|G|;Baršić|Bruno|B|;Kutleša|Marko|M|;Kotarski|Viktor|V|;Vujaklija Brajković|Ana|A|;Babel|Jakša|J|;Sever|Helena|H|;Dragija|Lidija|L|;Kušan|Ira|I|;Vaara|Suvi|S|;Pettilä|Leena|L|;Heinonen|Jonna|J|;Kuitunen|Anne|A|;Karlsson|Sari|S|;Vahtera|Annukka|A|;Kiiski|Heikki|H|;Ristimäki|Sanna|S|;Azaiz|Amine|A|;Charron|Cyril|C|;Godement|Mathieu|M|;Geri|Guillaume|G|;Vieillard-Baron|Antoine|A|;Pourcine|Franck|F|;Monchi|Mehran|M|;Luis|David|D|;Mercier|Romain|R|;Sagnier|Anne|A|;Verrier|Nathalie|N|;Caplin|Cecile|C|;Siami|Shidasp|S|;Aparicio|Christelle|C|;Vautier|Sarah|S|;Jeblaoui|Asma|A|;Fartoukh|Muriel|M|;Courtin|Laura|L|;Labbe|Vincent|V|;Leparco|Cécile|C|;Muller|Grégoire|G|;Nay|Mai-Anh|MA|;Kamel|Toufik|T|;Benzekri|Dalila|D|;Jacquier|Sophie|S|;Mercier|Emmanuelle|E|;Chartier|Delphine|D|;Salmon|Charlotte|C|;Dequin|PierreFrançois|P|;Schneider|Francis|F|;Morel|Guillaume|G|;L’Hotellier|Sylvie|S|;Badie|Julio|J|;Berdaguer|Fernando Daniel|FD|;Malfroy|Sylvain|S|;Mezher|Chaouki|C|;Bourgoin|Charlotte|C|;Megarbane|Bruno|B|;Voicu|Sebastian||;Deye|Nicolas|N|;Malissin|Isabelle|I|;Sutterlin|Laetitia|L|;Guitton|Christophe|C|;Darreau|Cédric|C|;Landais|Mickaël|M|;Chudeau|Nicolas|N|;Robert|Alain|A|;Moine|Pierre|P|;Heming|Nicholas|N|;Maxime|Virginie|V|;Bossard|Isabelle|I|;Nicholier|Tiphaine Barbarin|TB|;Colin|Gwenhael|G|;Zinzoni|Vanessa|V|;Maquigneau|Natacham|N|;Finn|André|A|;Kreß|Gabriele|G|;Hoff|Uwe|U|;Friedrich Hinrichs|Carl|C|;Nee|Jens|J|;Pletz|Mathias|M|;Hagel|Stefan|S|;Ankert|Juliane|J|;Kolanos|Steffi|S|;Bloos|Frank|F|;Petros|Sirak|S|;Pasieka|Bastian|B|;Kunz|Kevin|K|;Appelt|Peter|P|;Schütze|Bianka|B|;Kluge|Stefan|S|;Nierhaus|Axel|A|;Jarczak|Dominik|D|;Roedl|Kevin|K|;Weismann|Dirk|D|;Frey|Anna|A|;Klinikum Neukölln|Vivantes|V|;Reill|Lorenz|L|;Distler|Michael|M|;Maselli|Astrid|A|;Bélteczki|János|J|;Magyar|István|I|;Fazekas|Ágnes|Á|;Kovács|Sándor|S|;Szőke|Viktória|V|;Szigligeti|Gábor|G|;Leszkoven|János|J|;Collins|Daniel|D|;Breen|Patrick|P|;Frohlich|Stephen|S|;Whelan|Ruth|R|;McNicholas|Bairbre|B|;Scully|Michael|M|;Casey|Siobhan|S|;Kernan|Maeve|M|;Doran|Peter|P|;O’Dywer|Michael|M|;Smyth|Michelle|M|;Hayes|Leanne|L|;Hoiting|Oscar|O|;Peters|Marco|M|;Rengers|Els|E|;Evers|Mirjam|M|;Prinssen|Anton|A|;Bosch Ziekenhuis|Jeroen|J|;Simons|Koen|K|;Rozendaal|Wim|W|;Polderman|F|F|;de Jager|P|P|;Moviat|M|M|;Paling|A|A|;Salet|A|A|;Rademaker|Emma|E|;Peters|Anna Linda|AL|;de Jonge|E|E|;Wigbers|J|J|;Guilder|E|E|;Butler|M|M|;Cowdrey|Keri-Anne|KA|;Newby|Lynette|L|;Chen|Yan|Y|;Simmonds|Catherine|C|;McConnochie|Rachael|R|;Ritzema Carter|Jay|J|;Henderson|Seton|S|;Van Der Heyden|Kym|K|;Mehrtens|Jan|J|;Williams|Tony|T|;Kazemi|Alex|A|;Song|Rima|R|;Lai|Vivian|V|;Girijadevi|Dinu|D|;Everitt|Robert|R|;Russell|Robert|R|;Hacking|Danielle|D|;Buehner|Ulrike|U|;Williams|Erin|E|;Browne|Troy|T|;Grimwade|Kate|K|;Goodson|Jennifer|J|;Keet|Owen|O|;Callender|Owen|O|;Martynoga|Robert|R|;Trask|Kara|K|;Butler|Amelia|A|;Schischka|Livia|L|;Young|Chelsea|C|;Lesona|Eden|E|;Olatunji|Shaanti|S|;Robertson|Yvonne|Y|;José|Nuno|N|;Amaro dos Santos Catorze|Teodoro|T|;de Lima Pereira|Tiago Nuno Alfaro|TNA|;Neves Pessoa|Lucilia Maria|LM|;Castro Ferreira|Ricardo Manuel|RM|;Pereira Sousa Bastos|Joana Margarida|JM|;Aysel Florescu|Simin|S|;Stanciu|Delia|D|;Zaharia|Miahela Florentina|MF|;Kosa|Alma Gabriela|AG|;Codreanu|Daniel|D|;Marabi|Yaseen|Y|;Al Qasim|Eman|E|;Moneer Hagazy|Mohamned|M|;Al Swaidan|Lolowa|L|;Arishi|Hatim|H|;Muñoz-Bermúdez|Rosana|R|;Marin-Corral|Judith|J|;Salazar Degracia|Anna|A|;Parrilla Gómez|Francisco|F|;Mateo López|Maria Isabel|MI|;Rodriguez Fernandez|Jorge|J|;Cárcel Fernández|Sheila|S|;Carmona Flores|Rosario|R|;León López|Rafael|R|;de la Fuente Martos|Carmen|C|;Allan|Angela|A|;Polgarova|Petra|P|;Farahi|Neda|N|;McWilliam|Stephen|S|;Hawcutt|Daniel|D|;Rad|Laura|L|;O’Malley|Laura|L|;Whitbread|Jennifer|J|;Kelsall|Olivia|O|;Wild|Laura|L|;Thrush|Jessica|J|;Wood|Hannah|H|;Austin|Karen|K|;Donnelly|Adrian|A|;Kelly|Martin|M|;O’Kane|Sinéad|S|;McClintock|Declan|D|;Warnock|Majella|M|;Johnston|Paul|P|;Gallagher|Linda Jude|LJ|;Mc Goldrick|Clare|C|;Mc Master|Moyra|M|;Strzelecka|Anna|A|;Jha|Rajeev|R|;Kalogirou|Michael|M|;Ellis|Christine|C|;Krishnamurthy|Vinodh|V|;Deelchand|Vashish|V|;Silversides|Jon|J|;McGuigan|Peter|P|;Ward|Kathryn|K|;O’Neill|Aisling|A|;Finn|Stephanie|S|;Phillips|Barbara|B|;Mullan|Dee|D|;Oritz-Ruiz de Gordoa|Laura|L|;Thomas|Matthew|M|;Sweet|Katie|K|;Grimmer|Lisa|L|;Johnson|Rebekah|R|;Pinnell|Jez|J|;Robinson|Matt|M|;Gledhill|Lisa|L|;Wood|Tracy|T|;Morgan|Matt|M|;Cole|Jade|J|;Hill|Helen|H|;Davies|Michelle|M|;Antcliffe|David|D|;Templeton|Maie|M|;Rojo|Roceld|R|;Coghlan|Phoebe|P|;Smee|Joanna|J|;Mackay|Euan|E|;Cort|Jon|J|;Whileman|Amanda|A|;Spencer|Thomas|T|;Spittle|Nick|N|;Kasipandian|Vidya|V|;Patel|Amit|A|;Allibone|Suzanne|S|;Genetu|Roman Mary|RM|;Ramali|Mohamed|M|;Ghosh|Alison|A|;Bamford|Peter|P|;London|Emily|E|;Cawley|Kathryn|K|;Faulkner|Maria|M|;Jeffrey|Helen|H|;Smith|Tim|T|;Brewer|Chris|C|;Gregory|Jane|J|;Limb|James|J|;Cowton|Amanda|A|;O’Brien|Julie|J|;Nikitas|Nikitas|N|;Wells|Colin|C|;Lankester|Liana|L|;Pulletz|Mark|M|;Williams|Patricia|P|;Birch|Jenny|J|;Wiseman|Sophie|S|;Horton|Sarah|S|;Alegria|Ana|A|;Turki|Salah|S|;Elsefi|Tarek|T|;Crisp|Nikki|N|;Allen|Louise|L|;McCullagh|Iain|I|;Robinson|Philip|P|;Hays|Carole|C|;Babio-Galan|Maite|M|;Stevenson|Hannah|H|;Khare|Divya|D|;Pinder|Meredith|M|;Selvamoni|Selvin|S|;Gopinath|Amitha|A|;Pugh|Richard|R|;Menzies|Daniel|D|;Mackay|Callum|C|;Allan|Elizabeth|E|;Davies|Gwyneth|G|;Puxty|Kathryn|K|;McCue|Claire|C|;Cathcart|Susanne|S|;Hickey|Naomi|N|;Ireland|Jane|J|;Yusuff|Hakeem|H|;Isgro|Graziella|G|;Brightling|Chris|C|;Bourne|Michelle|M|;Craner|Michelle|M|;Watters|Malcolm|M|;Prout|Rachel|R|;Davies|Louisa|L|;Pegler|Suzannah|S|;Kyeremeh|Lynsey|L|;Arbane|Gill|G|;Wilson|Karen|K|;Gomm|Linda|L|;Francia|Federica|F|;Brett|Stephen|S|;Sousa Arias|Sonia|S|;Elin Hall|Rebecca|R|;Budd|Joanna|J|;Small|Charlotte|C|;Birch|Janine|J|;Collins|Emma|E|;Henning|Jeremy|J|;Bonner|Stephen|S|;Hugill|Keith|K|;Cirstea|Emanuel|E|;Wilkinson|Dean|D|;Karlikowski|Michal|M|;Sutherland|Helen|H|;Wilhelmsen|Elva|E|;Woods|Jane|J|;North|Julie|J|;Sundaran|Dhinesh|D|;Hollos|Laszlo|L|;Coburn|Susan|S|;Walsh|Joanne|J|;Turns|Margaret|M|;Hopkins|Phil|P|;Smith|John|J|;Noble|Harriet|H|;Depante|Maria Theresa|MT|;Clarey|Emma|E|;Laha|Shondipon|S|;Verlander|Mark|M|;Williams|Alexandra|A|;Huckle|Abby|A|;Hall|Andrew|A|;Cooke|Jill|J|;Gardiner-Hill|Caroline|C|;Maloney|Carolyn|C|;Qureshi|Hafiz|H|;Flint|Neil|N|;Nicholson|Sarah|S|;Southin|Sara|S|;Nicholson|Andrew|A|;Borgatta|Barbara|B|;Turner-Bone|Ian|I|;Reddy|Amie|A|;Wilding|Laura|L|;Chamara Warnapura|Loku|L|;Agno Sathianathan|Ronan|R|;Golden|David|D|;Hart|Ciaran|C|;Jones|Jo|J|;Bannard-Smith|Jonathan|J|;Henry|Joanne|J|;Birchall|Katie|K|;Pomeroy|Fiona|F|;Quayle|Rachael|R|;Makowski|Arystarch|A|;Misztal|Beata|B|;Ahmed|Iram|I|;KyereDiabour|Thyra|T|;Naiker|Kevin|K|;Stewart|Richard|R|;Mwaura|Esther|E|;Mew|Louise|L|;Wren|Lynn|L|;Willams|Felicity|F|;Innes|Richard|R|;Doble|Patricia|P|;Hutter|Joanne|J|;Shovelton|Charmaine|C|;Plumb|Benjamin|B|;Szakmany|Tamas|T|;Hamlyn|Vincent|V|;Hawkins|Nancy|N|;Lewis|Sarah|S|;Dell|Amanda|A|;Gopal|Shameer|S|;Ganguly|Saibal|S|;Smallwood|Andrew|A|;Harris|Nichola|N|;Metherell|Stella|S|;Lazaro|Juan Martin|JM|;Newman|Tabitha|T|;Fletcher|Simon|S|;Nortje|Jurgens|J|;Fottrell-Gould|Deirdre|D|;Randell|Georgina|G|;Zaman|Mohsin|M|;Elmahi|Einas|E|;Jones|Andrea|A|;Hall|Kathryn|K|;Mills|Gary|G|;Ryalls|Kim|K|;Bowler|Helen|H|;Sall|Jas|J|;Bourne|Richard|R|;Borrill|Zoe|Z|;Duncan|Tracey|T|;Lamb|Thomas|T|;Shaw|Joanne|J|;Fox|Claire|C|;Moreno Cuesta|Jeronimo|J|;Xavier|Kugan|K|;Purohit|Dharam|D|;Elhassan|Munzir|M|;Bakthavatsalam|Dhanalakshmi|D|;Rowland|Matthew|M|;Hutton|Paula|P|;Bashyal|Archana|A|;Davidson|Neil|N|;Hird|Clare|C|;Chhablani|Manish|M|;Phalod|Gunjan|G|;Kirkby|Amy|A|;Archer|Simon|S|;Netherton|Kimberley|K|;Reschreiter|Henrik|H|;Camsooksai|Julie|J|;Patch|Sarah|S|;Jenkins|Sarah|S|;Pogson|David|D|;Rose|Steve|S|;Daly|Zoe|Z|;Brimfield|Lutece|L|;Claridge|Helen|H|;Parekh|Dhruv|D|;Bergin|Colin|C|;Bates|Michelle|M|;Dasgin|Joanne|J|;McGhee|Christopher|C|;Sim|Malcolm|M|;Hay|Sophie Kennedy|SK|;Henderson|Steven|S|;Phull|Mandeep-Kaur|MK|;Zaidi|Abbas|A|;Pogreban|Tatiana|T|;Rosaroso|Lace Paulyn|LP|;Harvey|Daniel|D|;Lowe|Benjamin|B|;Meredith|Megan|M|;Ryan|Lucy|L|;Hormis|Anil|A|;Walker|Rachel|R|;Collier|Dawn|D|;Kimpton|Sarah|S|;Oakley|Susan|S|;Rooney|Kevin|K|;Rodden|Natalie|N|;Hughes|Emma|E|;Thomson|Nicola|N|;McGlynn|Deborah|D|;Walden|Andrew|A|;Jacques|Nicola|N|;Coles|Holly|H|;Tilney|Emma|E|;Vowell|Emma|E|;Schuster-Bruce|Martin|M|;Pitts|Sally|S|;Miln|Rebecca|R|;Purandare|Laura|L|;Vamplew|Luke|L|;Spivey|Michael|M|;Bean|Sarah|S|;Burt|Karen|K|;Moore|Lorraine|L|;Day|Christopher|C|;Gibson|Charly|C|;Gordon|Elizabeth|E|;Zitter|Letizia|L|;Keenan|Samantha|S|;Baker|Evelyn|E|;Cherian|Shiney|S|;Cutler|Sean|S|;Roynon-Reed|Anna|A|;Harrington|Kate|K|;Raithatha|Ajay|A|;Bauchmuller|Kris|K|;Ahmad|Norfaizan|N|;Grecu|Irina|I|;Trodd|Dawn|D|;Martin|Jane|J|;Wrey Brown|Caroline|C|;Arias|Ana-Marie|AM|;Craven|Thomas|T|;Hope|David|D|;Singleton|Jo|J|;Clark|Sarah|S|;Rae|Nicola|N|;Welters|Ingeborg|I|;Hamilton|David Oliver|DO|;Williams|Karen|K|;Waugh|Victoria|V|;Shaw|David|D|;Puthucheary|Zudin|Z|;Martin|Timothy|T|;Santos|Filipa|F|;Uddin|Ruzena|R|;Somerville|Alastair|A|;Tatham|Kate Colette|KC|;Jhanji|Shaman|S|;Black|Ethel|E|;Dela Rosa|Arnold|A|;Howle|Ryan|R|;Tully|Redmond|R|;Drummond|Andrew|A|;Dearden|Joy|J|;Philbin|Jennifer|J|;Munt|Sheila|S|;Vuylsteke|Alain|A|;Chan|Charles|C|;Victor|Saji|S|;Matsa|Ramprasad|R|;Gellamucho|Minerva|M|;Creagh-Brown|Ben|B|;Tooley|Joe|J|;Montague|Laura|L|;De Beaux|Fiona|F|;Bullman|Laetitia|L|;Kersiake|Ian|I|;Demetriou|Carrie|C|;Mitchard|Sarah|S|;Ramos|Lidia|L|;White|Katie|K|;Donnison|Phil|P|;Johns|Maggie|M|;Casey|Ruth|R|;Mattocks|Lehentha|L|;Salisbury|Sarah|S|;Dark|Paul|P|;Claxton|Andrew|A|;McLachlan|Danielle|D|;Slevin|Kathryn|K|;Lee|Stephanie|S|;Hulme|Jonathan|J|;Joseph|Sibet|S|;Kinney|Fiona|F|;Senya|Ho Jan|HJ|;Oborska|Aneta|A|;Kayani|Abdul|A|;Hadebe|Bernard|B|;Orath Prabakaran|Rajalakshmi|R|;Nichols|Lesley|L|;Thomas|Matt|M|;Worner|Ruth|R|;Faulkner|Beverley|B|;Gendall|Emma|E|;Hayes|Kati|K|;Hamilton-Davies|Colin|C|;Chan|Carmen|C|;Mfuko|Celina|C|;Abbass|Hakam|H|;Mandadapu|Vineela|V|;Leaver|Susannah|S|;Forton|Daniel|D|;Patel|Kamal|K|;Paramasivam|Elankumaran|E|;Powell|Matthew|M|;Gould|Richard|R|;Wilby|Elizabeth|E|;Howcroft|Clare|C|;Banach|Dorota|D|;Fernández de Pinedo Artaraz|Ziortza|Z|;Cabreros|Leilani|L|;White|Ian|I|;Croft|Maria|M|;Holland|Nicky|N|;Pereira|Rita|R|;Zaki|Ahmed|A|;Johnson|David|D|;Jackson|Matthew|M|;Garrard|Hywel|H|;Juhaz|Vera|V|;Roy|Alistair|A|;Rostron|Anthony|A|;Woods|Lindsey|L|;Cornell|Sarah|S|;Pillai|Suresh|S|;Harford|Rachel|R|;Rees|Tabitha|T|;Ivatt|Helen|H|;Sundara Raman|Ajay|A|;Davey|Miriam|M|;Lee|Kelvin|K|;Barber|Russell|R|;Chablani|Manish|M|;Brohi|Farooq|F|;Jagannathan|Vijay|V|;Clark|Michele|M|;Purvis|Sarah|S|;Wetherill|Bill|B|;Dushianthan|Ahilanandan|A|;Cusack|Rebecca|R|;de Courcy-Golder|Kim|K|;Smith|Simon|S|;Jackson|Susan|S|;Attwood|Ben|B|;Parsons|Penny|P|;Page|Valerie|V|;Zhao|Xiao Bei|XB|;Oza|Deepali|D|;Rhodes|Jonathan|J|;Anderson|Tom|T|;Morris|Sheila|S|;Xia Le Tai|Charlotte|C|;Thomas|Amy|A|;Keen|Alexandra|A|;Digby|Stephen|S|;Cowley|Nicholas|N|;Wild|Laura|L|;Southern|David|D|;Reddy|Harsha|H|;Campbell|Andy|A|;Watkins|Claire|C|;Smuts|Sara|S|;Touma|Omar|O|;Barnes|Nicky|N|;Alexander|Peter|P|;Felton|Tim|T|;Ferguson|Susan|S|;Sellers|Katharine|K|;Bradley-Potts|Joanne|J|;Yates|David|D|;Birkinshaw|Isobel|I|;Kell|Kay|K|;Marshall|Nicola|N|;Carr-Knott|Lisa|L|;Summers|Charlotte|C|",
"chemical_list": "D000305:Adrenal Cortex Hormones; D000893:Anti-Inflammatory Agents; D006854:Hydrocortisone",
"country": "United States",
"delete": false,
"doi": "10.1001/jama.2020.17022",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0098-7484",
"issue": "324(13)",
"journal": "JAMA",
"keywords": null,
"medline_ta": "JAMA",
"mesh_terms": "D000305:Adrenal Cortex Hormones; D000328:Adult; D000893:Anti-Inflammatory Agents; D000073640:Betacoronavirus; D000086382:COVID-19; D018352:Coronavirus Infections; D057239:Early Termination of Clinical Trials; D005260:Female; D006801:Humans; D006854:Hydrocortisone; D007362:Intensive Care Units; D008297:Male; D008875:Middle Aged; D058873:Pandemics; D011024:Pneumonia, Viral; D012121:Respiration, Artificial; D000086402:SARS-CoV-2; D012769:Shock; D016896:Treatment Outcome",
"nlm_unique_id": "7501160",
"other_id": null,
"pages": "1317-1329",
"pmc": null,
"pmid": "32876697",
"pubdate": "2020-10-06",
"publication_types": "D016428:Journal Article; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": "31808551;26305643;32876694;28798016;32425234;32427279;32539990;32732190;32267771;32224769;32445440;25835432;29067406;31577035;32043983;31939808;32678530;32409522;32372026;32696006",
"title": "Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.",
"title_normalized": "effect of hydrocortisone on mortality and organ support in patients with severe covid 19 the remap cap covid 19 corticosteroid domain randomized clinical trial"
} | [
{
"companynumb": "US-PFIZER INC-2020356386",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "HYDROCORTISONE SODIUM SUCCINATE"
},
"drugaddit... |
{
"abstract": "Flecainide is a class 1c antiarrhythmic that acts by blocking sodium channels to reduce intracardiac conduction and is used mainly in the treatment of supraventricular arrhythmias. Dizziness, visual disturbances, headache, and nausea are commonly associated with flecainide, but severe central nervous system toxicity is rare. Here, we report the case of a 71-year-old woman with a history of renal transplantation who developed severe myoclonus 24 hours after being started on flecainide, 100 mg 2 times a day, because of atrial fibrillation. This symptom completely disappeared once the drug was removed. Only 2 patients presenting with flecainide-induced myoclonus have been previously reported. Although the exact pathophysiologic explanation of this phenomenon remains unclear, it is well known that the susceptibility to severe flecainide toxicity is increased in patients with chronic kidney disease.",
"affiliations": "*Neurology Department, Hospital Universitario 12 de Octubre, Madrid, Spain; and †Instituto de Investigación Hospital 12 de Octubre (i + 12), Madrid, Spain.",
"authors": "Velasco|Sara Llamas|SL|;Sierra-Hidalgo|Fernando|F|;Rodríguez|Rosa María Ceballos|RM|;Guerreo|Antonio José Méndez|AJ|;Morales|Juan Ruiz|JR|",
"chemical_list": "D000889:Anti-Arrhythmia Agents; D005424:Flecainide",
"country": "United States",
"delete": false,
"doi": "10.1097/WNF.0000000000000025",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0362-5664",
"issue": "37(2)",
"journal": "Clinical neuropharmacology",
"keywords": null,
"medline_ta": "Clin Neuropharmacol",
"mesh_terms": "D000368:Aged; D000889:Anti-Arrhythmia Agents; D005260:Female; D005424:Flecainide; D006801:Humans; D009207:Myoclonus",
"nlm_unique_id": "7607910",
"other_id": null,
"pages": "65-6",
"pmc": null,
"pmid": "24614665",
"pubdate": "2014",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Flecainide-induced myoclonus.",
"title_normalized": "flecainide induced myoclonus"
} | [
{
"companynumb": "ES-RANBAXY-2014R1-80434",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "FLECAINIDE"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nImmediate hypersensitivity reactions to clavulanic acid (CLV) seem to be on the increase. Diagnosis is mainly based on skin testing and the drug provocation test (DPT), procedures that are not risk free. The aim of this study was to evaluate whether the histamine release test (HRT) could help evaluate patients with selective hypersensitivity to CLV.\n\n\nMETHODS\nEighteen patients with immediate selective hypersensitivity reactions to CLV (positive skin tests to CLV but negative to the major and minor determinants of benzylpenicillin and amoxicillin; negative DPT to benzylpenicillin and amoxicillin) and 21 controls with tolerance to CLV were included. Direct and passive HRT, using patient whole blood or 'IgE-stripped' donor blood sensitized by patient serum, respectively, were performed by stimulating the blood with CLV, and basophil histamine release was detected by fluorometric determination.\n\n\nRESULTS\nThe clinical symptoms were anaphylaxis (n = 6), urticaria (n = 9) and urticaria-angioedema (n = 3). The median time interval between the reaction and the study was 225 days (interquartile range, IQR: 120-387.5) and between drug intake and the development of symptoms 30 min (IQR: 6.25-30). We obtained similar data for both the direct and passive HRT, with a sensitivity and specificity of 55 and 85%, respectively, a positive predictive value of 76% and a negative predictive value of 69%.\n\n\nCONCLUSIONS\nThe sensitivity of both the direct and passive HRT for diagnosing patients with immediate allergy to CLV is less than 60%. However, the passive HRT has the advantage that it is based on the testing of serum samples that can be handled more easily than fresh blood samples.",
"affiliations": "DIATER Laboratories, Madrid, Spain.",
"authors": "Pineda|Fernando|F|;Ariza|Adriana|A|;Mayorga|Cristobalina|C|;Arribas|Francisca|F|;González-Mendiola|Rosario|R|;Blanca-López|Natalia|N|;Davila|Galicia|G|;Cabañes|Nieves|N|;Canto|Gabriela|G|;Laguna|José Julio|JJ|;Senent|Carlos|C|;Stahl-Skov|Per|P|;Palacios|Ricardo|R|;Blanca|Miguel|M|;Torres|María José|MJ|",
"chemical_list": "D000900:Anti-Bacterial Agents; D019818:Clavulanic Acid",
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000443274",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1018-2438",
"issue": "168(4)",
"journal": "International archives of allergy and immunology",
"keywords": null,
"medline_ta": "Int Arch Allergy Immunol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000707:Anaphylaxis; D000799:Angioedema; D000900:Anti-Bacterial Agents; D001681:Biological Assay; D016022:Case-Control Studies; D019818:Clavulanic Acid; D005260:Female; D006636:Histamine Release; D006801:Humans; D008297:Male; D008875:Middle Aged; D015166:Monitoring, Immunologic; D012680:Sensitivity and Specificity; D012882:Skin Tests; D013997:Time Factors",
"nlm_unique_id": "9211652",
"other_id": null,
"pages": "233-40",
"pmc": null,
"pmid": "26894754",
"pubdate": "2015",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Role of Histamine Release Test for the Evaluation of Patients with Immediate Hypersensitivity Reactions to Clavulanic Acid.",
"title_normalized": "role of histamine release test for the evaluation of patients with immediate hypersensitivity reactions to clavulanic acid"
} | [
{
"companynumb": "ES-SUN PHARMACEUTICAL INDUSTRIES LTD-2016RR-125916",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "AMOXICILLIN\\CLAVULANIC ACID"
... |
{
"abstract": "Radiation-induced sarcoma (RIS) has been reported as a late secondary malignancy following radiotherapy for various types of cancer with a median latency of 10 years. We describe an early RIS that developed in an adolescent within three years of treatment (including PD-L1 check-point inhibitor Nivolumab) of a relapsed classic Hodgkin lymphoma (HL) and was diagnosed post-mortem. The patient died of the progressive RIS that was misleadingly assumed to be a resistant HL based on the positive PET/CT scan. Repetitive tumor biopsies are warranted in cases of aggressive and multi-drug resistant HL to validate imaging findings, ensure correct diagnosis and avoid overtreatment.",
"affiliations": "Faculty of Medicine, Vilnius University, 03101 Vilnius, Lithuania.;Faculty of Medicine, Vilnius University, 03101 Vilnius, Lithuania.;Center for Pediatric Oncology and Hematology, Vilnius University, 08406 Vilnius, Lithuania.;Center of Pediatric Oncology and Hematology at Pediatric Department and Hospital of Kauno Klinikos, Lithuanian University of Health Sciences, 44307 Kaunas, Lithuania.;National Center of Pathology, 08406 Vilnius, Lithuania.;Institute of Biomedical Sciences, Department of Radiology, Nuclear Medicine and Medical Physics, Vilnius University, 03101 Vilnius, Lithuanian.;Radiology Clinic, Nuclear Medicine Department of Kauno Klinikos, Lithuanian University of Health Sciences, 44307 Kaunas, Lithuania.;Faculty of Medicine, Vilnius University, 03101 Vilnius, Lithuania.",
"authors": "Šalaševičius|Lukas|L|;Vaitkevičienė|Goda Elizabeta|GE|;Pasaulienė|Ramunė|R|;Kiudelienė|Rosita|R|;Ivanauskaitė-Didžiokienė|Ernesta|E|;Vajauskas|Donatas|D|;Jurkienė|Nemira|N|;Rascon|Jelena|J|",
"chemical_list": "D000074322:Antineoplastic Agents, Immunological; D000077594:Nivolumab",
"country": "Switzerland",
"delete": false,
"doi": "10.3390/medicina56040155",
"fulltext": "\n==== Front\nMedicina (Kaunas)\nmedicina\nMedicina\n1010-660X 1648-9144 MDPI \n\n10.3390/medicina56040155\nmedicina-56-00155\nCase Report\nEarly Radiation-Induced Sarcoma in an Adolescent Treated for Relapsed Hodgkin Lymphoma with Nivolumab\nŠalaševičius Lukas 1 Vaitkevičienė Goda Elizabeta 12 Pasaulienė Ramunė 2 Kiudelienė Rosita 3 Ivanauskaitė-Didžiokienė Ernesta 4 Vajauskas Donatas 56 Jurkienė Nemira 7 Rascon Jelena 12* 1 Faculty of Medicine, Vilnius University, 03101 Vilnius, Lithuania; lukassalasevicius@gmail.com (L.Š.); GodaElizabeta.Vaitkeviciene@santa.lt (G.E.V.)\n2 Center for Pediatric Oncology and Hematology, Vilnius University, 08406 Vilnius, Lithuania; ramune.pasauliene@santa.lt\n3 Center of Pediatric Oncology and Hematology at Pediatric Department and Hospital of Kauno Klinikos, Lithuanian University of Health Sciences, 44307 Kaunas, Lithuania; rosita.kiudeliene@kaunoklinikos.It\n4 National Center of Pathology, 08406 Vilnius, Lithuania; Ernesta.IvanauskaiteDidziokiene@vpc.lt\n5 Institute of Biomedical Sciences, Department of Radiology, Nuclear Medicine and Medical Physics, Vilnius University, 03101 Vilnius, Lithuanian; donatas.vajauskas@kaunoklinkikos.lt\n6 Radiology and Nuclear Medicine Center, Department of Nuclear Medicine, Vilnius University Hospital Santaros Klinikos, 08661 Vilnius, Lithuania\n7 Radiology Clinic, Nuclear Medicine Department of Kauno Klinikos, Lithuanian University of Health Sciences, 44307 Kaunas, Lithuania; nemira.jurkiene@kaunoklinikos.lt\n* Correspondence: jelena.rascon@santa.lt\n31 3 2020 \n4 2020 \n56 4 15519 1 2020 25 3 2020 © 2020 by the authors.2020Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).Radiation-induced sarcoma (RIS) has been reported as a late secondary malignancy following radiotherapy for various types of cancer with a median latency of 10 years. We describe an early RIS that developed in an adolescent within three years of treatment (including PD-L1 check-point inhibitor Nivolumab) of a relapsed classic Hodgkin lymphoma (HL) and was diagnosed post-mortem. The patient died of the progressive RIS that was misleadingly assumed to be a resistant HL based on the positive PET/CT scan. Repetitive tumor biopsies are warranted in cases of aggressive and multi-drug resistant HL to validate imaging findings, ensure correct diagnosis and avoid overtreatment.\n\nHodgkin lymphomapost-radiation sarcomaNivolumabchildrenobesity\n==== Body\n1. Introduction\nCurrent five-year overall survival in pediatric Hodgkin lymphoma (HL) exceeds 90% [1]. However, secondary malignant neoplasms (SMNs) are the most relevant long-term sequelae comprising of 75%–80% of late effects [2]. Median latency period of SMNs development varies from 10 to 17.5 years [2,3]. Radiotherapy is one of the main risk factors for development of SMNs, often arising in the radiation field [3]. Even low-dose irradiation harbors a significant risk for SMNs with a cumulative incidence of 17% at 20 years [4]. Cancer of the breast, lung, and thyroid of various morphologies are the most common radiotherapy associated SMNs [5,6,7]. Secondary sarcomas are considered to be rare. Several small series reported radiotherapy associated sarcoma diagnosed 4 to 31 years following pediatric HL [4,8,9]\n\nWe describe a case of a relapsed classic HL that was treated with several lines of chemotherapy including PD-L1 check-point inhibitor Nivolumab. An early radiation-induced sarcoma (RIS) developed within three years after initial presentation and was diagnosed only post-mortem. Written informed consent from both parents was obtained before writing this study.\n\n2. Case Report\nA 13 year old girl started to complain of persistent cough. Her physical examination at diagnosis was unremarkable except for obesity: weight and height were over 95 age and gender-specific percentile and body mass index (BMI) was 31.0. Endocrinological work-up did not reveal any potential cause of obesity. Neither palpable lymph nodes nor B symptoms were present. Imaging studies including positron emission tomography–computed tomography with 18 fluorine labeled fluorodeoxyglucose (18FDG-PET/CT) revealed an 18FDG-avid, bulky mediastinal mass of 13 cm, enlarged periclavicular lymph nodes, and a focus in the left femur that showed a moderate 18FDG uptake (Figure 1a). The biopsy taken from a periclavicular lymph node confirmed a classic HL, nodular sclerosis subtype, expressing immune phenotype CD30+, CD15+, CD20/CD3 (Figure 2a).\n\nTaking the PET-positive focus in the left femur into consideration, the patient was assigned to the Lugano stage IV. Chemotherapy was initiated according to the EuroNet-PHL-C1 protocol as per stage IVa. Two OEPA (prednisone, vincristine, doxorubicin, etoposide) followed by 4 COPDAC (prednisone, dacarbazine, vincristine, cyclophosphamide) courses were successfully completed. An early response assessment by 18FDG-PET/CT after 2 OEPA courses showed Deauville 4 (Figure 3). After six chemotherapy cycles, a complete metabolic response was achieved (Deauville 2) with residual mediastinal mass of 6.2 × 8.6 cm. However, the focus in the left femur still showed metabolic activity with unchanged 18FDG uptake as compared to the diagnostic images. Radiotherapy of 30 Gy to the mediastinum was delivered. Thereafter, an overall unconfirmed complete remission (as per EuroNet-PHL-C1 protocol definition) was documented. A control 18FDG-PET/CT scan showed persistent moderate metabolic activity in the left femur. The biopsy taken from the femoral focus revealed a non-malignant enchondroma (Figure 2b).\n\nNineteen months after initial diagnosis a control magnetic resonance imaging (MRI) visualized an enlargement of the mediastinal masses. The biopsy showed the same histologic subtype of the classic HL-expressing diagnostic immune phenotype (Figure 2c). The PET/CT confirmed a 18FDG-avid relapse (Deauville 5b, Figure 1b). The patient received two ESHAP (etoposide, methylprednisolone, cytarabine, cisplatin) courses that decreased metabolic activity to Deauville 4 (Figure 3). After the third ESHAP cycle (23 months after the disease onset) the patient developed dyspnea and neuropathic pain in both arms due to compression of the brachial plexus. After the fourth ESHAP cycle, 18FDG-PET/CT showed new metabolically active masses in the neck and below the diaphragm and progressive disease in the mediastinum and bilaterally in the hilar lymph nodes (Deauville 5b).\n\nFacing rapid disease progression, the second-line salvage therapy regimen IGEV (ifosfamide, gemcytabine, prednisone, vinorelbine) was administered. Following 4 cycles, the pain relieved, however, the control PET/CT showed no metabolic response, Deauville 4–5. The third-line salvage therapy of six cycles of Brentuximab vedotin (BV) was initiated. After four cycles of BV the 18FDG-PET/CT remained Deauville 5. Moreover, new foci with increased uptake in the mediastinum, lungs, and neck lymph nodes were documented. Given no metabolic response, DHAP (dexamethasone, high-dose cytarabine, cisplatin) chemotherapy was added to BV. After two cycles of immunochemotherapy, 18FDG-PET/CT remained Deauville 5. Therefore, the fourth salvage chemotherapy BGD (bendamustine, gemcytabine, dexamethasone) was administered (Figure 3). After two cycles, 18FDG-PET/CT revealed Deauville 4 (Figure 1c), however, after the third cycle, the patient experienced clinical and metabolic progression with newly onset fever, dysphagia, and pain in both arms.\n\nSubsequently, Nivolumab was administered every two weeks (in total, four doses were infused). Before the second infusion, the patient developed an acute episode of air-way obstruction and asystolia provoked by dysphagia and choking. After resuscitation, persistent airway obstruction required intubation and prolonged ventilation, thus, an attempt of a tracheostomy was undertaken. The intervention was unsuccessful due to bulky tumor masses compressing the upper airways. The masses were partially excised: histologic evaluation showed no lymphoma cells in the tumor. Two days after the intervention, the patient passed away due to progressive airway obstruction (38th month of treatment). The autopsy confirmed the absence of HL cells and revealed an undifferentiated sarcoma infiltrating the neck, trachea, esophagus, and the naso- and oropharynx (Figure 2d). Extensive immune staining ruled out the classic HL and could not identify any specific type of sarcoma.\n\n3. Discussion\nRadio- and chemotherapy induced SMNs have a cumulative incidence rate of 19% after 30 years of diagnosis with a median latency period of 10 years [2,3]. Radiotherapy to the mediastinum of a cumulative dosage over 30 Gy is known to cause secondary cancer [5,6,10]. Our patient developed a secondary sarcoma (most probably radiation-induced) within 3 years after the initial diagnosis that is unusually early. The first two biopsies confirmed classic HL, therefore, RIS developed during the relapse therapy. It is impossible to determine the exact time-point of the tumor conversion as the imaging findings were unspecific for RIS or HL. 18FDG-PET/CT has demonstrated high negative-predictive value but substantially low positive-predictive value for prediction of outcomes in pediatric HL [11]. One can only speculate that neuropathic pain could be the first manifestation of RIS, which has a poor prognosis with estimated five-year survival of 12%–58% [12].\n\nThe patient was treated according to the EuroNet-PHL-C1 protocol where 18FDG-PET/CT is used to deliver a response-adapted therapy in an attempt to minimize exposure to radiotherapy. As per protocol, 30 Gy were delivered to the mediastinum based on the insufficient early response after two OEPA courses. A recent study confirmed an adverse prognostic value of a strongly enhanced residual 18FDG uptake in early PET-response for treatment outcome [13]. Adversely, the disease was overstaged to Lugano stage IV instead of II based on the positive 18FDG uptake in the benign enchondroma of the femur that caused initial overtreatment. A retrospective review of knee MRIs reported the prevalence of incidental enchodromas of 2.8%–2.9% in the adult population [14,15]. While benign bone tumors are less 18FDG-avid than malignant ones [16], enchondromas can demonstrate a high 18FDG uptake [17]. In our case, the enchondroma focus showed a stable moderate 18FDG uptake (as compared to fluctuant 18FDG-avid HL-derived lesions) that ultimately drove the decision to perform a biopsy.\n\nSeveral studies in adults demonstrated an increased risk for HL development in the overweight population [18,19]. However, there are no convincing data whether high BMI compromises the disease outcome. Results of meta-analysis in children with hematological malignancies and osteosarcoma suggested that obesity was associated with worse survival: weight excess negatively affected the toxicity profile and increased the risk of treatment related mortality [20,21,22]. The impact of high BMI on disease progression in childhood leukemia remains unclear [20]. Some studies showed that excessive amounts of adipose tissue promoted resistances of leukemic cells to chemotherapy and facilitated tumor spread [21,23]. In contrast, in sarcoma patients, obesity did not appear to exacerbate the protumorigenic environment and aggravate a predisposition to tumor progression [24]. A recent case-control study suggested that obesity during childhood cancer treatment might be associated with increased risk for SMNs [25]. In view of scarce and inconsistent data, we can only speculate if obesity contributed negatively to the unfavorable outcome in our case.\n\nA recent study on HL reported 5%–10% of patients will be refractory to initial treatment and 10%–30% will relapse after achieving an initial complete remission [26]. Despite multimodal treatment, the cure rate for relapsed or refractory disease does not exceed 49% [27]. In the adult population Nivolumab showed a remission rate of 65% in relapsed or progressive classic HL [28]. The evidence on efficacy in children is scarce. In our case, Nivolumab was administered as the fifth line of salvage therapy. It is impossible to prove whether Nivolumab or other cytotoxic drugs eradicated HL, which was undetectable on the third biopsy. The treatment was guided based on the response assessment on 18FDG-PET/CT. However, the 18FDG is a nonspecific radiotracer representing metabolic tissue activity that in our case was unspecific for HL, enchondroma, and RIS.\n\n4. Conclusions\nThis case demonstrates that a SMN, in particular RIS, can develop early within the treatment and should be considered as a differential diagnosis in resistant malignancy. One should always take into account potential PET-positivity of non-malignant tissues, e.g., enchondroma that could erroneously lead to upstaging and overtreatment. Finally, additional biopsies and histological verification are warranted in cases of persistent 18FDG-avid uptake.\n\nAuthor Contributions\nL.Š. and J.R. wrote and outlined the manuscript, G.E.V., R.P., and R.K. provided clinical data and treatment details. D.V. and N.J. provided and described images. E.I.-D. selected and prepared pathology slides for visualization. J.R. corrected, reviewed, and supervised the manuscript preparation. All authors have read and agreed to the published version of the manuscript.\n\nFunding\nThis research received no external funding.\n\nConflicts of Interest\nThe authors declare no conflict of interest.\n\nFigure 1 Whole body 18FDG PET/CT. (a) At diagnosis. Left supraclavicular and mediastinal 18FDG-avid lesions (arrows), 18FDG-avid lesion in the left femur (red line), according to lymphoma staging Lugano IV; (b) Relapse. 18FDG-avid relapse in the mediastinum (arrows). According to lymphoma response, Deauville 5b. No metabolic changes in the left femur after the biopsy of enchondroma; (c) One month prior to death. 18FDG-avid lesions in neck, mediastinum, and hilar lymph nodes bilaterally. According to lymphoma response, Deauville 4.\n\nFigure 2 Pathology. (a) Diagnostic lymph node biopsy: classic Hodgkin lymphoma, nodular sclerosis, immune phenotype CD30+, CD15+, CD20/CD−. (b) Enchondroma on the left femur. (c) Relapse lymph node specimen: classic Hodgkin lymphoma, nodular sclerosis, immune phenotype CD30+, CD15+, CD20/CD3−, EBV LMP1−, ALK1−. (d) Autopsy. Secondary undifferentiated sarcoma. The tumor is formed of nodules composed of epithelioid or spindle cells with eosinophilic cytoplasm and large, hyperchromic, round or irregular nuclei expressing CD30+, CD15+/−, CD20/CD3−, VIM+ immune phenotype.\n\nFigure 3 Disease evolution and treatment: BV—brentuximab vedotin 1.8 mg/kg every three weeks; COPDAC—prednisone 40 mg/m2 on days 1–15, dacarbazine 250 mg/m2 on days 1–3, vincristine 1.5 mg/m2 on days 1 and 15, cyclophosphamide 500 mg/m2 on days 1 and 8; DHAP—dexamethasone 40 mg on days 1–4, high-dose cytarabine 2.000 mg/m2 on day 2, cisplatin 100 mg/m2 on day 1; ESHAP—etoposide 40 mg/m2 on days 1–4, methylprednisolone 500 mg on days 1–5, cytarabine 2000 mg/m2 on day 5, cisplatin 25 mg/m2 on days 1–4; BGD—bendamustine 90 mg/m2 on days 1 and 2, gemcytabine gemcytabine 800 mg/m2 on days 1 and 4, dexamethasone 40 mg on days 1–4; IGEV—ifosfamide 2000 mg/m2 on days 1 and 4, vinorelbine 20 mg/m2 on day 1, gemcytabine 800 mg/m2 on days 1 and 4, prednisone 100 mg on days 1 and 4; OEPA—prednisone 60 mg/m2 on days 1–15, vincristine 1.5 mg/m2 on days 1, 8 and 15, doxorubicin 40 mg/m2 on days 1 and 15, etoposide 125 mg/m² on days 1–5; Nivolumab 240 mg every two weeks, RT—radiotherapy.\n==== Refs\nReferences\n1. Mauz-Korholz C. Metzger M.L. Kelly K.M. Schwartz C.L. Castellanos M.E. Dieckmann K. Kluge R. Korholz D. Pediatric Hodgkin Lymphoma J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol. 2015 33 2975 2985 10.1200/JCO.2014.59.4853 26304892 \n2. Ng A.K. Mauch P.M. Late effects of Hodgkin’s disease and its treatment Cancer J. 2009 15 164 168 10.1097/PPO.0b013e31819e30d7 19390314 \n3. Dorffel W. Riepenhausen M. Luders H. Bramswig J. Late Effects Following Treatment of Hodgkin Lymphoma During Childhood and Adolescence. Results of the Hodgkin Lymphoma Late Effects Research Project Klin. Padiatr. 2016 228 286 293 10.1055/s-0042-110406 27846658 \n4. O’Brien M.M. Donaldson S.S. Balise R.R. Whittemore A.S. Link M.P. Second malignant neoplasms in survivors of pediatric Hodgkin’s lymphoma treated with low-dose radiation and chemotherapy J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol. 2010 28 1232 1239 10.1200/JCO.2009.24.8062 20124178 \n5. Travis L.B. Hill D.A. Dores G.M. Gospodarowicz M. van Leeuwen F.E. Holowaty E. Glimelius B. Andersson M. Wiklund T. Lynch C.F. Breast cancer following radiotherapy and chemotherapy among young women with Hodgkin disease Jama 2003 290 465 475 10.1001/jama.290.4.465 12876089 \n6. Travis L.B. Gospodarowicz M. Curtis R.E. Clarke E.A. Andersson M. Glimelius B. Joensuu T. Lynch C.F. van Leeuwen F.E. Holowaty E. Lung cancer following chemotherapy and radiotherapy for Hodgkin’s disease J. Natl. Cancer Inst. 2002 94 182 192 10.1093/jnci/94.3.182 11830608 \n7. Sklar C. Whitton J. Mertens A. Stovall M. Green D. Marina N. Greffe B. Wolden S. Robison L. Abnormalities of the thyroid in survivors of Hodgkin’s disease: Data from the Childhood Cancer Survivor Study J. Clin. Endocrinol. Metab. 2000 85 3227 3232 10.1210/jc.85.9.3227 10999813 \n8. Smith J. Postradiation sarcoma of bone in Hodgkin disease Skelet. Radiol. 1987 16 524 532 10.1007/BF00351266 \n9. Wolden S.L. Lamborn K.R. Cleary S.F. Tate D.J. Donaldson S.S. Second cancers following pediatric Hodgkin’s disease J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol. 1998 16 536 544 10.1200/JCO.1998.16.2.536 \n10. Hodgson D.C. Gilbert E.S. Dores G.M. Schonfeld S.J. Lynch C.F. Storm H. Hall P. Langmark F. Pukkala E. Andersson M. Long-term solid cancer risk among 5-year survivors of Hodgkin’s lymphoma J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol. 2007 25 1489 1497 10.1200/JCO.2006.09.0936 \n11. Isik E.G. Kuyumcu S. Kebudi R. Sanli Y. Karakas Z. Cakir F.B. Unal S.N. Prediction of outcome in pediatric Hodgkin lymphoma based on interpretation of (18)FDG-PET/CT according to DeltaSUVmax, Deauville 5-point scale and IHP criteria Ann. Nucl. Med. 2017 31 660 668 10.1007/s12149-017-1196-x 28741053 \n12. Gladdy R.A. Qin L.X. Moraco N. Edgar M.A. Antonescu C.R. Alektiar K.M. Brennan M.F. Singer S. Do radiation-associated soft tissue sarcomas have the same prognosis as sporadic soft tissue sarcomas? J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol. 2010 28 2064 2069 10.1200/JCO.2009.25.1728 20308666 \n13. Kurch L. Hasenclever D. Kluge R. Georgi T. Tchavdarova L. Golombeck M. Sabri O. Eggert A. Brenner W. Sykora K.W. Only strongly enhanced residual FDG uptake in early response PET (Deauville 5 or qPET >/= 2) is prognostic in pediatric Hodgkin lymphoma: Results of the GPOH-HD2002 trial Pediatric Blood Cancer 2019 66 e27539 10.1002/pbc.27539 30426671 \n14. Walden M.J. Murphey M.D. Vidal J.A. Incidental enchondromas of the knee AJR Am. J. Roentgenol. 2008 190 1611 1615 10.2214/AJR.07.2796 18492914 \n15. Stomp W. Reijnierse M. Kloppenburg M. de Mutsert R. Bovee J.V. den Heijer M. Bloem J.L. Group NEOs Prevalence of cartilaginous tumours as an incidental finding on MRI of the knee Eur. Radiol. 2015 25 3480 3487 10.1007/s00330-015-3764-6 25994192 \n16. Costelloe C.M. Chuang H.H. Madewell J.E. FDG PET/CT of primary bone tumors AJR Am. J. Roentgenol. 2014 202 W521 W531 10.2214/AJR.13.11833 24848845 \n17. Dobert N. Menzel C. Ludwig R. Berner U. Diehl M. Hamscho N. Grunwald F. Enchondroma: A benign osseous lesion with high F-18 FDG uptake Clin. Nucl. Med. 2002 27 695 697 10.1097/00003072-200210000-00001 12352108 \n18. Strongman H. Brown A. Smeeth L. Bhaskaran K. Body mass index and Hodgkin’s lymphoma: UK population-based cohort study of 5.8 million individuals Br. J. Cancer 2019 120 768 770 10.1038/s41416-019-0401-1 30808991 \n19. Li Q. Chang E.T. Bassig B.A. Dai M. Qin Q. Gao Y. Zhang Y. Zheng T. Body size and risk of Hodgkin’s lymphoma by age and gender: A population-based case-control study in Connecticut and Massachusetts Cancer Causes Control CCC 2013 24 287 295 10.1007/s10552-012-0100-1 23208661 \n20. Amankwah E.K. Saenz A.M. Hale G.A. Brown P.A. Association between body mass index at diagnosis and pediatric leukemia mortality and relapse: A systematic review and meta-analysis Leuk. Lymphoma 2016 57 1140 1148 10.3109/10428194.2015.1076815 26453440 \n21. Sheng X. Mittelman S.D. The role of adipose tissue and obesity in causing treatment resistance of acute lymphoblastic leukemia Front. Pediatrics 2014 2 53 10.3389/fped.2014.00053 24926474 \n22. Altaf S. Enders F. Jeavons E. Krailo M. Barkauskas D.A. Meyers P. Arndt C. High-BMI at diagnosis is associated with inferior survival in patients with osteosarcoma: A report from the Children’s Oncology Group Pediatric Blood Cancer 2013 60 2042 2046 10.1002/pbc.24580 23955975 \n23. Cha Y.J. Koo J.S. Roles of omental and bone marrow adipocytes in tumor biology Adipocyte 2019 8 304 317 10.1080/21623945.2019.1643189 31334678 \n24. Buchta C.M. Boi S.K. Miller B.J. Milhem M.M. Norian L.A. Obesity Does Not Exacerbate the Protumorigenic Systemic Environment in Sarcoma Subjects ImmunoHorizons 2017 1 20 28 10.4049/immunohorizons.1700001 29202127 \n25. Moke D.J. Hamilton A.S. Chehab L. Deapen D. Freyer D.R. Obesity and Risk for Second Malignant Neoplasms in Childhood Cancer Survivors: A Case-Control Study Utilizing the California Cancer Registry Cancer Epidemiol. Biomark. Prev. Publ. Am. Assoc. Cancer Res. Cosponsored Am. Soc. Prev. Oncol. 2019 28 1612 1620 10.1158/1055-9965.EPI-19-0466 \n26. Ansell S.M. Hodgkin lymphoma: 2018 update on diagnosis, risk-stratification, and management Am. J. Hematol. 2018 93 704 715 10.1002/ajh.25071 29634090 \n27. Sirohi B. Cunningham D. Powles R. Murphy F. Arkenau T. Norman A. Oates J. Wotherspoon A. Horwich A. Long-term outcome of autologous stem-cell transplantation in relapsed or refractory Hodgkin’s lymphoma Ann. Oncol. Off. J. Eur. Soc. Med. Oncol. 2008 19 1312 1319 10.1093/annonc/mdn052 \n28. Kasamon Y.L. de Claro R.A. Wang Y. Shen Y.L. Farrell A.T. Pazdur R. FDA Approval Summary: Nivolumab for the Treatment of Relapsed or Progressive Classical Hodgkin Lymphoma Oncologist 2017 22 585 591 10.1634/theoncologist.2017-0004 28438889\n\n",
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"keywords": "Hodgkin lymphoma; Nivolumab; children; obesity; post-radiation sarcoma",
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"mesh_terms": "D000293:Adolescent; D000074322:Antineoplastic Agents, Immunological; D005260:Female; D006689:Hodgkin Disease; D006801:Humans; D009381:Neoplasms, Radiation-Induced; D000077594:Nivolumab; D049268:Positron-Emission Tomography; D012509:Sarcoma",
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"title": "Early Radiation-Induced Sarcoma in an Adolescent Treated for Relapsed Hodgkin Lymphoma with Nivolumab.",
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"abstract": "Perioral myoclonia with absences (POMA) is not recognized as a unique electro-clinical syndrome and studies suggest its inclusion under the genetic generalized epilepsy (GGE) spectrum. The aim of this study was to explore the prevalence and electro-clinical homogeneity of this disorder in an epilepsy monitoring unit. Between 2013 and 2019, among drug-resistant epilepsy patients who were referred for video-telemetry, those diagnosed with POMA based on the presence of documented absences with prominently observed peri-oral muscular contractions accompanied by generalized EEG features were included. Among 62 patients who were diagnosed with absence epilepsy, five finally met the criteria for POMA (8.1%) with late childhood or adolescent onset of epilepsy. Four (80%) had a referral diagnosis of focal epilepsy based on historical focal features with exacerbation of seizures on oxcarbazepine. All five patients demonstrated brief absences with orbicularis oris muscle contractions accompanied by subtle focal phenomenology. One patient had concurrent axial-appendicular myoclonic jerks precipitated by hyperventilation. While four patients had strikingly identical interictal and ictal characteristics of typical absence epilepsy, one patient demonstrated additional atypical generalized polyspike discharges without a \"dart-dome\" morphology. Therapeutic response to introduction of sodium valproate was noted in all five patients. Features that were not consistent with the diagnosis were apparent in one patient who was re-classified with combined focal and generalized epilepsy. Differentiating aspects in this patient included multifocal discharges, background slowing, fast-recruiting ictal rhythms and valproate resistance. This is one of the largest case series of POMA. This entity, which falls under the spectrum of GGE, remains under-diagnosed and its distinctive electro-clinical features need to be recorded in order to prevent misclassification as focal epilepsy of probable opercular origin. Background-slowing, atypical ictal rhythms and valproate unresponsiveness are not consistent with the diagnosis of this unique absence epilepsy. [Published with video sequences].",
"affiliations": "Sree Chitra Tirunal Institute for Medical Sciences and Technology, Dept of Neurology, Thiruvananthapuram, Kerala, India.;Sree Chitra Tirunal Institute for Medical Sciences and Technology, Dept of Neurology, Thiruvananthapuram, Kerala, India.;Sree Chitra Tirunal Institute for Medical Sciences and Technology, Dept of Neurology, Thiruvananthapuram, Kerala, India.;Sree Chitra Tirunal Institute for Medical Sciences and Technology, Dept of Neurology, Thiruvananthapuram, Kerala, India.",
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"title": "Unmasking the entity of 'drug-resistant' perioral myoclonia with absences: the twitches, darts and domes!",
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"abstract": "Extranodal nature killer (NK)/T cell lymphoma (ENKL), nasal type, is a highly aggressive and heterogeneous disease. Here we report a retrospective study of 38 newly-diagnosed ENKL patients treated with pegaspargase, gemcitabine, oxaliplatin (P-Gemox) and sandwiched radiotherapy in our department during 2012-2016. A median of 4 (range, 2-6) (total=141) cycles of P-Gemox were administered. Interim restaging after at least 2 cycles showed complete remission (CR) rate of 23.68%, partial remission (PR) rate of 63.16%, giving an overall response rate (ORR) of 86.84%. On treatment completion, the ORR became 92.1% (CR=86.84%, PR=5.26%). Only one patient experienced disease progression during therapy. Multivariate analysis showed gender was a significant independent factor impacting on CR. Hematologic toxicity was common yet nonhematologic toxicity was mild, both of them can be well controlled by supportive treatments and only one treatment-related death was observed. At a median follow-up of 15.5 months, 4 patients (10.53%) experienced disease progression and died of disease. 1-year progression-free survival (PFS) rate and 1-year overall survival (OS) rate for the whole cohort were 86.7% and 86.6%. The P-Gemox regimen with sandwiched radiotherapy may be a promising option in the treatment of newly-diagnosed ENKL due to its high efficacy yet low toxicity.",
"affiliations": "Department of Lymphoma, Sichuan Cancer Hospital, Chengdu, People's Republic of China.;Department of Lymphoma, Sichuan Cancer Hospital, Chengdu, People's Republic of China.;Department of Lymphoma, Sichuan Cancer Hospital, Chengdu, People's Republic of China.;Department of Radiotherapy, Sichuan Cancer Hospital, Chengdu, People's Republic of China.;Department of Lymphoma, Sichuan Cancer Hospital, Chengdu, People's Republic of China.;Department of Lymphoma, Sichuan Cancer Hospital, Chengdu, People's Republic of China.;Department of Lymphoma, Sichuan Cancer Hospital, Chengdu, People's Republic of China.;Department of Lymphoma, Sichuan Cancer Hospital, Chengdu, People's Republic of China.;Department of Lymphoma, Sichuan Cancer Hospital, Chengdu, People's Republic of China. Electronic address: 490608418@qq.com.",
"authors": "Jing|Xiao-Mei|XM|;Zhang|Zhi-Hui|ZH|;Wu|Ping|P|;Zhang|Shi-Chuan|SC|;Ren|Yuan-Rong|YR|;Xiong|Zhu-Juan|ZJ|;Wei|Wen|W|;Luo|Lei|L|;Li|Li|L|",
"chemical_list": "D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D003841:Deoxycytidine; D011092:Polyethylene Glycols; C042705:pegaspargase; C056507:gemcitabine; D001215:Asparaginase",
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0145-2126",
"issue": "47()",
"journal": "Leukemia research",
"keywords": "Extranodal nature killer (NK)/T cell lymphoma; Gemcitabine; Oxaliplatin; Pegaspargase; Radiotherapy",
"medline_ta": "Leuk Res",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D001215:Asparaginase; D003131:Combined Modality Therapy; D003841:Deoxycytidine; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D054391:Lymphoma, Extranodal NK-T-Cell; D008297:Male; D008875:Middle Aged; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D011092:Polyethylene Glycols; D012074:Remission Induction; D012189:Retrospective Studies; D015996:Survival Rate; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "7706787",
"other_id": null,
"pages": "26-31",
"pmc": null,
"pmid": "27239738",
"pubdate": "2016-08",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Efficacy and tolerance of pegaspargase, gemcitabine and oxaliplatin with sandwiched radiotherapy in the treatment of newly-diagnosed extranodal nature killer (NK)/T cell lymphoma.",
"title_normalized": "efficacy and tolerance of pegaspargase gemcitabine and oxaliplatin with sandwiched radiotherapy in the treatment of newly diagnosed extranodal nature killer nk t cell lymphoma"
} | [
{
"companynumb": "CN-FRESENIUS KABI-FK201605294",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "GEMCITABINE\\GEMCITABINE HYDROCHLORIDE"
},
... |
{
"abstract": "OBJECTIVE\nThe broader and prolonged use of anti-tumor necrosis factor (TNF) agents in inflammatory bowel disease (IBD) could expose patients to an increased risk of adverse reactions, including dermatological complications. We assessed the cumulative incidence of anti-TNF-induced cutaneous adverse reactions in IBD patients, their risk factors, their dermatological management, and their outcome in a large cohort of IBD patients.\n\n\nMETHODS\nIn a single-center observational retrospective study, including all consecutive adult IBD patients treated with an anti-TNF agent between 2001 and 2014, all patients with dermatological complications under anti-TNF therapy were identified in a well-defined cohort of IBD patients. We conducted a survival analysis to determine the cumulative incidence of dermatological complications and risk factors for developing any dermatological complications, cutaneous infections, and psoriasiform lesions. Survival curves were estimated by the Kaplan-Meier method, and we used a Cox proportional hazards model to test the association between parameters and time to each event: any dermatological complication, cutaneous infections, and psoriasis lesions.\n\n\nRESULTS\nAmong 583 IBD patients, 176 dermatological complications occurred, involving 20.5% of patients. Median duration of follow-up was 38.2 months (range: 1-179). Psoriasiform lesions (10.1%; 59/583) and cutaneous infections (11.6%, 68/583) were the most frequently observed, with a cumulative incidence of, respectively, 28.9% and 17.6% at 10 years. They led to anti-TNF discontinuation, respectively, in 18.6% and 2.9% of patients. In case of switching to another anti-TNF agent for psoriasiform lesions, recurrence occurred in 57% of patients. Ulcerative colitis was associated with a lower risk of developing cutaneous infections than Crohn's disease (hazard ratio (HR)=0.25; 95% confidence interval (CI)=0.09-0.68; P=0.007). Higher dosing of anti-TNF agent was associated with a higher risk of developing cutaneous infections (HR=1.99; 95% CI=1.09-3.64; P=0.025). A younger age at time of anti-TNF initiation was associated with a higher risk of dermatological complications (HR=2.25; 95% CI=1.39-3.62; P<0.001).\n\n\nCONCLUSIONS\nDermatological complications involve one of five patients treated with anti-TNF therapy after a 14-year follow-up. Association of cutaneous infections with higher anti-TNF dosing suggests a dose-dependent effect. Discontinuation of anti-TNF therapy due to dermatological complications is required in one out of five patients with psoriasiform lesions, but specific dermatological treatment allows to continue anti-TNF therapy in half of them.",
"affiliations": "Department of Dermatology and Allergy, University Hospital of Nancy, Lorraine University, Vandoeuvre-Les-Nancy, France.;ESPRI-BIOBASE Unit, PARC, University Hospital of Nancy, Vandoeuvre-Les-Nancy, France.;Department of Dermatology and Allergy, University Hospital of Nancy, Lorraine University, Vandoeuvre-Les-Nancy, France.;Inserm U954, Department of Hepato-Gastroenterology, University Hospital of Nancy, Lorraine University, Vandoeuvre-Les-Nancy, France.;Department of Dermatology and Allergy, University Hospital of Nancy, Lorraine University, Vandoeuvre-Les-Nancy, France.;Department of Dermatology and Allergy, University Hospital of Nancy, Lorraine University, Vandoeuvre-Les-Nancy, France.;Inserm U954, Department of Hepato-Gastroenterology, University Hospital of Nancy, Lorraine University, Vandoeuvre-Les-Nancy, France.",
"authors": "Fréling|Estelle|E|;Baumann|Cédric|C|;Cuny|Jean-François|JF|;Bigard|Marc-André|MA|;Schmutz|Jean-Luc|JL|;Barbaud|Annick|A|;Peyrin-Biroulet|Laurent|L|",
"chemical_list": "D000894:Anti-Inflammatory Agents, Non-Steroidal; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D014409:Tumor Necrosis Factor-alpha; D000069285:Infliximab; D000068879:Adalimumab",
"country": "United States",
"delete": false,
"doi": "10.1038/ajg.2015.205",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0002-9270",
"issue": "110(8)",
"journal": "The American journal of gastroenterology",
"keywords": null,
"medline_ta": "Am J Gastroenterol",
"mesh_terms": "D000068879:Adalimumab; D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000894:Anti-Inflammatory Agents, Non-Steroidal; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D002648:Child; D003093:Colitis, Ulcerative; D003424:Crohn Disease; D004305:Dose-Response Relationship, Drug; D003875:Drug Eruptions; D005260:Female; D006801:Humans; D015994:Incidence; D000069285:Infliximab; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D015995:Prevalence; D016016:Proportional Hazards Models; D011565:Psoriasis; D012189:Retrospective Studies; D012307:Risk Factors; D012874:Skin Diseases, Infectious; D014409:Tumor Necrosis Factor-alpha; D055815:Young Adult",
"nlm_unique_id": "0421030",
"other_id": null,
"pages": "1186-96",
"pmc": null,
"pmid": "26195181",
"pubdate": "2015-08",
"publication_types": "D016428:Journal Article; D064888:Observational Study",
"references": "18674945;18603161;20580412;20728573;16424222;17300238;17310002;16705109;23468464;17631151;19880688;15899052;14682196;18285688;19628303;22559024;15899041;21506984;22751454;23435403;15728381;24918318;16148729;22139830;16255017;15192172;24613021;18576309;22398059;22887849;19681863;24268978;23474780;19210297;21228429;14699483;22469155;24099467;12922954;23777821;18832524;21957906;17911986",
"title": "Cumulative incidence of, risk factors for, and outcome of dermatological complications of anti-TNF therapy in inflammatory bowel disease: a 14-year experience.",
"title_normalized": "cumulative incidence of risk factors for and outcome of dermatological complications of anti tnf therapy in inflammatory bowel disease a 14 year experience"
} | [
{
"companynumb": "FR-JNJFOC-20151105260",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "METHOTREXATE"
},
"drugadditional": null,
... |
{
"abstract": "Objective: This study aims to examine potentially inappropriate medication (PIM) prevalence and factors that affect the use of PIMs in a military treatment facility. Method: Admission and discharge medication lists of 60 patients aged ≥65 years were retrospectively reviewed by a clinical pharmacist and a member of the study team for the presence of PIM using the 2012 Beers Criteria. Patients included were those discharged between December 2012 and September 2013 from the Womack Army Medical Center, Internal Medicine unit. Results: Among the 60 patients evaluated, 44 (73%) were on at least one PIM at admission, whereas the prevalence of PIM at discharge (30 patients) was 50% (p < .001). The top three classes of PIM at admission were antihistamines (11, 15.3%), nonsteroidal anti-inflammatory drugs (10, 13.9%), and benzodiazepines (6, 8.3%). Patients on >10 medications at admission (37, 62%) were 4 times more likely to have a PIM (p < .001). Conclusion: Data showed a high and a previously unknown PIM prevalence among older adults in a U.S. military treatment facility.",
"affiliations": "Baumholder/Kaiserslautern Army Health Clinic, Baumholder, Germany.;Womack Army Medical Center, Fort Bragg, NC, USA.;Womack Army Medical Center, Fort Bragg, NC, USA.;Womack Army Medical Center, Fort Bragg, NC, USA.",
"authors": "Osei|Edward K|EK|;Berry-Cabán|Cristóbal S|CS|;Haley|Chelsey L|CL|;Rhodes-Pope|Heather|H|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1177/2333721416637790",
"fulltext": "\n==== Front\nGerontol Geriatr MedGerontol Geriatr MedGGMspggmGerontology and geriatric medicine2333-7214SAGE Publications Sage CA: Los Angeles, CA 10.1177/233372141663779010.1177_2333721416637790ArticlePrevalence of Beers Criteria Medications Among Elderly Patients in a Military Hospital Osei Edward K. CPT, PharmD1Berry-Cabán Cristóbal S. PhD2Haley Chelsey L. MSCR2Rhodes-Pope Heather PharmD21 Baumholder/Kaiserslautern Army Health Clinic, Baumholder, Germany2 Womack Army Medical Center, Fort Bragg, NC, USAChelsey L. Haley, Research Coordinator, Henry M. Jackson Foundation, Womack Army Medical Center, 2817 Reilly Rd., Bldg. 2517, Fort Bragg, NC 28310, USA. Email: chelsey.l.haley.ctr@mail.mil16 3 2016 Jan-Dec 2016 2 233372141663779017 3 2015 23 12 2015 9 2 2016 © The Author(s) 20162016SAGE PublicationsThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial 3.0 License (http://www.creativecommons.org/licenses/by-nc/3.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access page(https://us.sagepub.com/en-us/nam/open-access-at-sage).Objective: This study aims to examine potentially inappropriate medication (PIM) prevalence and factors that affect the use of PIMs in a military treatment facility. Method: Admission and discharge medication lists of 60 patients aged ≥65 years were retrospectively reviewed by a clinical pharmacist and a member of the study team for the presence of PIM using the 2012 Beers Criteria. Patients included were those discharged between December 2012 and September 2013 from the Womack Army Medical Center, Internal Medicine unit. Results: Among the 60 patients evaluated, 44 (73%) were on at least one PIM at admission, whereas the prevalence of PIM at discharge (30 patients) was 50% (p < .001). The top three classes of PIM at admission were antihistamines (11, 15.3%), nonsteroidal anti-inflammatory drugs (10, 13.9%), and benzodiazepines (6, 8.3%). Patients on >10 medications at admission (37, 62%) were 4 times more likely to have a PIM (p < .001). Conclusion: Data showed a high and a previously unknown PIM prevalence among older adults in a U.S. military treatment facility.\n\npotentially inappropriate medicationBeers Criteriamilitaryinappropriate prescribingcover-dateJanuary-December 2016\n==== Body\nIntroduction\nAccording to IMS Institute for Healthcare Informatics estimates, health care costs caused by improper and unnecessary use of medicines exceeded $200 billion in 2012 (IMS Institute for Healthcare Informatics, 2013). In 2013, the estimated health care expenditures related to potentially inappropriate medications (PIMs) was $1.3 billion, with a range of $900 million to $1.7 billion (IMS Institute for Healthcare Informatics, 2013). PIMs are medications with risks that outweigh their therapeutic benefit and should be avoided in people aged 65 or older (Campanelli, 2012; O’Connor, Gallagher, & O’Mahony, 2012). The prevalence of PIM reported in the literature ranges from 35% to 47% (Gallagher et al., 2011; Gallagher & O’Mahony, 2008) in hospitalized older adult patients and up to 73% in nursing homes (Byrne et al., 2011; Clyne et al., 2013).\n\nA similar study in Ireland attributed 9% of the overall expenditure on pharmaceuticals to PIMs (Cahir et al., 2010). PIMs such as nonsteroidal anti-inflammatory drugs (NSAIDs) are the most common cause of gastropathy among geriatrics, with an average admission cost of over $14,000 (Fick et al., 2003). These numbers are expected to only increase with rising health care costs and the use of multiple specialty physicians that increases the likelihood of polypharmacy and the prescribing of PIMs (Takane, Balignasay, & Nigg, 2013).\n\nInappropriate prescribing is associated with negative outcomes including adverse drug events, readmission rates, higher mortality rates, medication nonadherence, increased risk of falls, and increased health care costs (O’Connor et al., 2012). A 2005 study estimated that more than 4.3 million health care visits were attributed to an adverse drug event as a result of polypharmacy (Maher, Hanlon, & Hajjar, 2014). Furthermore, polypharmacy and PIMs are estimated to cause adverse drug events in up to 35% of outpatients and 40% of inpatient older adults (Maher et al., 2014). There are no clear guidelines for prescribers to determine what type of PIM should be used; clinicians must therefore consider multiple factors when choosing such agents for geriatric use (Campanelli, 2012).\n\nEfficient use of medication among older military beneficiaries represents a significant challenge for the Department of Defense (DoD). Many older DoD beneficiaries use both TRICARE (military health care service) and Medicare for their medical needs. TRICARE is the Health Maintenance Organization (HMO) equivalent for military service members, including retirees and their qualified dependents. As civilian and government hospitals do not have combined medical records, it is difficult for the DoD to properly manage medications. In one study of 123,682 TRICARE beneficiaries 65 years and older, 50% obtained six or more medications, and 3% obtained 16 or more medications from the pharmacy during a 90-day period (Linton, Garber, Fagan, & Peterson, 2007).\n\nThe Beers Criteria for Potentially Inappropriate Medications Use in Older Adults (the Beers Criteria), devised by Beers and his colleagues in 1991 for use in nursing homes, was subsequently expanded and revised in 1997, 2003, and 2012, and consists of 53 medications or classes of medications that are divided into three groups: PIMs to avoid in older adults, PIMs to avoid in older adults with diseases and syndromes that the drugs can exacerbate, and medications to be used with caution (Campanelli, 2012). The Beers Criteria (mainly designed for use in the United States) is a well-validated tool that allows easy comparison with other studies (Fick et al., 2003). It is a well-known, comprehensive list endorsed by the American Geriatrics Society, creating a standard list of medications that may be deemed potentially inappropriate. Among community-dwelling older adults, a systemic review identified an association between medications listed on the Beers Criteria and hospitalizations (Jano & Aparasu, 2007). The Beers Criteria is currently being updated and is set for release in 2015 (The John A. Hartford Foundation, 2015).\n\nThe aim of this study is to determine the prevalence and types of PIMs at admission and upon discharge, and to compare these findings with the national average. In addition, the factors that affect the number of PIMs at admission and discharge were also evaluated using the 2012 Beers Criteria.\n\nMethod\nA retrospective study was conducted by a clinical pharmacist and a member of the study team. Data were collected at a large military hospital between December 2012 and September 2013. Three electronic record systems were used: the Composite Health Care System (CHCS), the Armed Forces Health Longitudinal Technology Application (AHLTA), and ESSENTRIS (an inpatient system). All admission and discharge medications were assessed for PIM using the 2012 Beers Criteria. In this study, medications in the patient’s record that were listed on the Beers Criteria were considered PIMs. Medications were not assessed for appropriateness.\n\nInclusion criteria included patients 65 years and older who had been discharged from the Internal Medicine unit, patients with at least one medication prescribed at time of admission, patients with medications who had been in active status with or without multiple refills within 180 days of admission, patients with medications of sufficient quantity to warrant chronic use (at least a 30-day supply), patients who received medical care for chronic disease management, and patients with available medication records. All readmissions within 30 days of initial discharge from the Internal Medicine unit were also examined.\n\nAll patient medications were evaluated and verified 6 months prior to admission and at discharge. Medications used during hospitalization were excluded from the study. Patients who died during hospitalization and/or left against medical advice were excluded from the study; patients admitted and discharged from other clinics such as Family Medicine, Step Down, Intensive Care, Surgery, and Psychiatry units were also excluded. Patients were also excluded if they had no medication history prior to admission and had expired or discontinued medications. It was assumed that patients were not taking expired or discontinued medications. A total of 285 charts were linked to the Internal Medicine unit for the study period; after exclusion criteria were assessed, a random sample of 60 patients was included in the study due to time limitations and a stringent inclusion criterion.\n\nThe PIM prevalence was determined by dividing the total number of patients with at least one PIM by the total number of patients. Only medications listed in the hospital electronic medical record that were covered by TRICARE were reviewed. Over-the-counter (OTC) medications were not reviewed because they are not kept in the electronic medical record. Contraindicated diseases/conditions at admission were identified to determine both acute and chronic disease state, and compared with the 2012 Beers Criteria for potential drug–disease interactions.\n\nFactors affecting number of PIMs at admission and discharge were determined by fitting regression using two models. The first model was fitted for number of PIMs at admission, with gender, age, and total number of medications used by the patient at admission as independent variables. The second model fitted a global model with number of PIMs at discharge, with gender, age, length of stay at hospital, total number of medications used by the patient at admission, total number of medications used by the patient at discharge, and number of PIMs at admission as independent variables.\n\nDescriptive data were analyzed to determine differences in baseline characteristics. A two-tailed t test was used to compare continuous variables. Chi-square test was used to compare categorical variables. Statistical significance was established at a p value of ≤.05.\n\nAll data were analyzed using SAS version 9.4 (www.sas.com). This study was approved by the Womack Army Medical Center Institutional Review Board.\n\nResults\nTable 1 provides an overview of population characteristics including age, gender, and length of hospital stay. An examination of polypharmacy found that 93% of patients at admission and 90% of patients at discharge had at least five medications. Among the 60 patients evaluated, 44 (73%) were on at least one PIM at admission; the prevalence at discharge was 50% (p < .001). Overall, 11% (77/722) of medications at admission and 7.1% (46/647) of discharge medications were found to be potentially inappropriate (Table 2).\n\nTable 1. Patient Demographics at Admissions.\n\nPopulation characteristics\tInternal medicine unit\t\nTotal patients\t60\t\nAge, years (M, range)\t76.5 (66-92)\t\nGender, female (n, %)\t32 (52)\t\nLength of hospital stay, days (M, range)\t2.3 (0-12)\t\nMedication group\tAdmission\t\nNumber of patients (n, %)\tNumber of medications (n, %)\t\n≤5 drugs\t7 (11)\t26 (4)\t\n6-10 drugs\t15 (25)\t120 (17)\t\n11-16 drugs\t25 (42)\t328 (45)\t\n>16 drugs\t13 (22)\t248 (34)\t\nTable 2. Results of Primary Endpoints Showing PIMs Prevalence and PIMs Index.\n\nMedications\tAdmission\tDischarge\t\nTotal medications\t722\t647\t\nM number of medications (range)\t12 (2-23)\t10.8 (2-23)\t\nPatients on ≥5 medications (n, %)\t56 (93)\t54 (90)\t\nNumber of PIM (n, %)\t77 (11)\t46 (7.1)\t\nPIM index\t0.11 (95% CI = [0.084, 0.13]; p < .001)\t0.071 (95% CI = [0.051, 0.091]; p < .001)\t\nPIM prevalence\t73% (95% CI = [62.1, 84.5]; p < .001)\t50% (95% CI = [37.4, 62.7]; p < .001)\t\nNote. PIM = potentially inappropriate medication; CI = confidence interval.\n\nThe top three classes of PIM at admission were antihistamines (15.3%), NSAIDs (13.9%), and benzodiazepines (8.3%); whereas antihistamines (18.6%), central alpha blockers (11.6%), and antiarrhythmics (9.6%) were the most frequently prescribed PIMs at discharge. Several other drugs and drug classes accounted for the remaining PIM at admission and include calcium channel blockers (8.3%), central alpha blockers (6.9%), opioids (5.6%), antidepressants (5.6%), antiarrhythmics (5.6%), hypnotic (4.2%), alpha blockers (4.2%), skeletal muscle relaxants (4.2%), antimuscarinic (4.2%), and medications less frequently prescribed (tricyclic antidepressants, antispasmodics, antiparkinson, sulfonylurea, thiazolidinedione, mirtazapine, and megestrol; Table 3).\n\nTable 3. Common PIM Identified at Admission and Discharge Based on the 2012 Beers Criteria.\n\nAdmission\tDischarge\t\nAntihistamines\n● Diphenhydramine, chlorpheniramine, meclizine, loratadine\tAntihistamines\n● Diphenhydramine, chlorpheniramine, meclizine, loratadine, hydroxyzine\t\nNSAIDs\n● Ibuprofen, naproxen, meloxicam, indomethacin\tAlpha blockers\n● Terazosin, clonidine\t\nBenzodiazepines\n● Alprazolam, clonazepam, diazepam\tAntiarrhythmics\n● Propafenone, amiodarone\t\nSource.\nCampanelli (2012).\n\nNote. PIM = potentially inappropriate medication; NSAIDs = nonsteroidal anti-inflammatory drugs.\n\nGender did not make a statistically significant difference in number of PIMs at either admission or discharge (Table 4). Length of hospital stay did not affect number of PIMs at discharge. The length of hospital stay ranged from 0 to a maximum of 12 days. Age was negatively related to number of PIMs at admission meaning older patients were likely to have smaller number of PIMs. However, this relationship was not found between number of PIMs at discharge and total number of medications at discharge. Number of PIMs at both admission and discharge were positively related with total number of medications at admissions and discharge, respectively. At admission, each increase in number of medications was associated with .1 PIMs. At discharge, each increase in number of medications was associated with .07 PIMs.\n\nTable 4. Regression Coefficients With Associated p Values for Each Regression Model.\n\nDependent variable\tIndependent variable\tRegression coefficient\tp\t95% CI\t\nPIMs at admission\tGender\t.327\t.23\t[−0.21, 0.87]\t\nAge\t−.047\t.03\t[−0.09, 0.00]\t\nTotal number of medications at admission\t.109\t<.01\t[0.06, 0.16]\t\nPIMs at discharge\tGender\t−.071\t.67\t[−0.41, 0.26]\t\nAge\t.024\t.09\t[−0.00, 0.05]\t\nLength of hospital stay\t−.009\t.81\t[−0.09, 0.07]\t\nNumber of PIMs at admission\t.757\t<.01\t[0.59, 0.92]\t\nTotal number of medications at admission\t−.130\t<.01\t[−0.17, −0.07]\t\nTotal number of medications at discharge\t.121\t<.01\t[0.07, 0.17]\t\nNote. CI = confidence interval; PIM = potentially inappropriate medication.\n\nAccording to the global model, number of PIMs at discharge was positively associated with the number of PIMs at admission as well as the total number of medications used at discharge. However, somewhat surprisingly, number of PIMs at discharge was negatively associated with the total number of medications used at admission. The reason for this may be that those who are known to use a larger number of medications at admission are assumed to be more likely users of PIMs and as such may be given more intensive scrutiny and care in reducing the number of PIMs.\n\nThree patients were readmitted within 30 days of discharge; only one had a PIM (meclizine), but the PIM was unrelated to the readmission diagnosis (pleural effusion).\n\nPIMs identified at admission were grouped into three categories using the 2012 Beers Criteria. The frequencies based on this group classification at admission were as follows: medications to avoid (61%), medications that cause disease interaction (20.3%), and medications to be used with caution (2.7%). Similar results, although slightly lower, were observed at discharge.\n\nPIM with potential drug–disease interaction identified at admission include zolpidem (hypnotic), verapamil and diltiazem (calcium channel blockers), terazosin (alpha blocker), and pseudoephedrine and theophylline (central nervous system [CNS] stimulants). Two antipsychotics, risperidone and paliperidone, were identified at both admission and discharge as medications to use with caution.\n\nDiscussion\nThis study found a high prevalence of PIM use at both admission and discharge among older adult patients in a U.S. military hospital. Among the 60 patients evaluated, 44 (73%) were on at least one PIM at admission, whereas the prevalence of PIM at discharge (30 patients) was 50% (p < .001). The top three classes of PIM at admission were antihistamines (11, 15.3%), NSAIDs (10, 13.9%), and benzodiazepines (6, 8.3%). Patients on >10 medications at admission (37, 62%) were 4 times more likely to have a PIM (p < .001). Several studies that examined the prevalence of PIMs using solely the Beers Criteria reported lower rates of 30%, 32%, and 34%, respectively (Jones & Bhandari, 2013). However, studies conducted at long-term care facilities show similar or higher prevalence rates (Clyne et al., 2013).\n\nAntihistamines (diphenhydramine, chlorpheniramine, loratadine, meclizine) were identified as the predominant PIM followed by analgesics (NSAIDs; ibuprofen, naproxen, indomethacin, meloxicam) at admission. These classes of PIMs were similar to that reported in other studies (Gallagher et al., 2011; Gallagher & O’Mahony, 2008). Various studies show a clear and positive association between polypharmacy and PIM use (Akazawa, Imai, Igarashi, & Tsutani, 2010; Bao, Shao, Bishop, Schackman, & Bruce, 2012; Nixdorff et al., 2008; Varallo, Capucho, Planeta, & de Carvalho Mastroianni, 2011). We observed a similar association in our study. Approximately 93% of patients at admission had ≥5 medications, and the mean number of medications used per day prior to admission was 12.3 (range = 2-23). PIM use increased from 3.8% with ≤4 drugs to 11.7% with 5 to 9 drugs and to 47% with >15 drugs (Figure 1). Patients taking >10 medications at admission were 4 times more likely to have a PIM (p < .001). Although hospital readmissions have been linked with PIM use among older adult patients, our study did not find any association between PIM and readmission diagnosis within 30 days of discharge. This finding may be due in part to the small sample size.\n\nFigure 1. Relationship between polypharmacy and PIMs at admission.\n\nNote. PIM = potentially inappropriate medication.\n\nIt is interesting to report that seven patients (11.7%) had admission diagnosis that could potentially be attributed to PIM use. One patient diagnosed with weakness was on diazepam at the time of admission, another patient with syncope was on clonazepam, one patient with gastrointestinal reflux disease was on ibuprofen, one patient with dizziness was on both alprazolam and zolpidem, one patient with anemia was on naproxen, and two patients with chest pain and hypertension were on ibuprofen.\n\nIn our study, the prescribing of PIMs may have been the result of patients taking many medications and having multiple comorbidities, hospitalizations, and visits with multiple providers. The lack of a geriatric specialty clinic, the proliferation of newer medications, easy access to OTC medications, and misdiagnosing the side effect of drugs as symptoms of another clinical condition and treating with additional drugs (prescription cascade) can further increase the prevalence of PIM among such vulnerable population (Hunt, Kreiner, & Brody, 2012).\n\nThis study is the first to examine the prevalence and types of PIMs among older adult patients in a U.S. military hospital. The population used was unique in the fact that a military hospital serves a predominantly young population. Furthermore, this study is one of the first studies that used the revised 2012 Beers Criteria (Campanelli, 2012). At the time of this writing, a 2015 version of the Beers Criteria was being updated and set for release (The John A. Hartford Foundation, 2015).\n\nThis study has several limitations. One limitation of the study is the small sample size, this is due in part that only 6,500 adults >60 years old were seen at the hospital annually. The small sample size is attributed to a stringent inclusion criterion and time limitations that did not evaluate all patients receiving regular medical care for managing chronic disease states at other clinics, hence limiting the generalizability of this study. The results of this study must therefore be interpreted with caution. Data were obtained from only one department in the hospital, thus introducing selection bias. The prevalence and types of PIMs found in our results are most likely lower than the actual amount due to only including medications covered by TRICARE. For example, an OTC antihistamine taken by a patient would not have been evaluated. In addition, in our sample, only 52% of women were included. This is significantly lower than the national average of 56% of the population >65 years old who are women. Another limitation is providers’ knowledge and awareness of the latest Beers Criteria. The period from which data for the study were compiled (December 2012-September 2013) may have been too close to the introduction of the revised Beers Criteria (April 2012), thus not providing health professionals sufficient time to adapt and incorporate the new evidence into their practice. We also recognize that there are other reasons for admission other than PIM and polypharmacy.\n\nFinally, the list and number of medications captured were those paid for by TRICARE; filled at Womack Army Medical Center, other military hospitals, and non-network pharmacies; and documented in various hospital record systems. Any medication purchased out of pocket and not provided by the patient at admission was not evaluated and could be a limitation to this study.\n\nConclusion\nOur study shows a high prevalence of PIM among older adult patients who receive care at a U.S. military hospital.\n\nHealth care providers should screen medications to minimize polypharmacy, a major risk factor for PIM, and address PIMs and justification for their use at each hospital visit. Furthermore, health care managers must also look at ways to incorporate the Beers list into electronic prescribing systems to alert providers. Providers must be aware of the Beers Criteria and minimize PIM use except where clinically warranted to help mitigate potential harms that may be associated with using these types of medications.\n\nThe results of this study may help create awareness, and provide knowledge and understanding of the importance of the application of the Beers Criteria and PIM prevalence in the Military Health System.\n\nFuture studies should involve larger sample size, investigate justification for PIM use, analyze any association between PIM and readmission, and address comorbidity and PIM association if any.\n\nAuthors’ Note: The views expressed herein are those of the authors and do not reflect the official policy of the Department of the Army, Department of Defense, or the U.S. Government.\n\nDeclaration of Conflicting Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.\n\nFunding: The authors received no financial support for the research, authorship, and/or publication of this article.\n==== Refs\nReferences\n\nAkazawa M. Imai H. Igarashi A. Tsutani K. (2010 ). Potentially inappropriate medication use in elderly Japanese patients . The American Journal of Geriatric Pharmacotherapy , 8 , 146 -160 . Retrieved from http://www.sciencedirect.com/science/article/pii/S154359461000024320439064 \n\nBao Y. Shao H. Bishop T. F. Schackman B. R. Bruce M. L. (2012 ). Inappropriate medication in a national sample of US elderly patients receiving home health care . Journal of General Internal Medicine , 27 , 304 -310 . Retrieved from http://link.springer.com/article/10.1007/s11606-011-1905-4#21975822 \n\nByrne S. O’Sullivan D. Hughes C. O’Mahony D. Parsons C. Patterson S. . . . Finn F. (2011 ). An evaluation of the inappropriate prescribing in older residents in long term care facilities in the greater Cork and Northern Ireland regions using the STOPP and Beers’ criteria . Dublin : Centre for Ageing Research and Development in Ireland .\n\nCahir C. Fahey T. Teeling M. Teljeur C. Feely J. Bennett K. (2010 ). Potentially inappropriate prescribing and cost outcomes for older people: A national population study . British Journal of Clinical Pharmacology , 69 , 543 -552 .20573091 \n\nCampanelli C. M. (2012 ). American Geriatrics Society updated Beers Criteria for potentially inappropriate medication use in older adults (The American Geriatrics Society 2012 Beers Criteria Update Expert Panel) . Journal of the American Geriatrics Society , 60 , 616 -631 . Retrieved from http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3571677/22376048 \n\nClyne B. Bradley M. C. Hughes C. M. Clear D. McDonnell R. Williams D. . . . Smith S. M. (2013 ). Addressing potentially inappropriate prescribing in older patients: Development and pilot study of an intervention in primary care (the OPTI-SCRIPT study) . BMC Health Services Research , 13 , Article 307.\n\nFick D. M. Cooper J. W. Wade W. E. Waller J. L. Maclean J. R. Beers M. H. (2003 ). Updating the Beers criteria for potentially inappropriate medication use in older adults: Results of a US consensus panel of experts . Archives of Internal Medicine , 163 , 2716 -2724 . Retrieved from http://archinte.jamanetwork.com/article.aspx?articleid=757456&;quizId=1787&atab=714662625 \n\nGallagher P. Lang P. O. Cherubini A. Topinková E. Cruz-Jentoft A. Errasquín B. M. . . . Baeyens J.-P. (2011 ). Prevalence of potentially inappropriate prescribing in an acutely ill population of older patients admitted to six European hospitals . European Journal of Clinical Pharmacology , 67 , 1175 -1188 . Retrieved from http://link.springer.com/article/10.1007/s00228-011-1061-0#page-121584788 \n\nGallagher P. O’Mahony D. (2008 ). STOPP (Screening Tool of Older Persons’ potentially inappropriate Prescriptions): Application to acutely ill elderly patients and comparison with Beers’ criteria . Age and Ageing , 37 , 673 -679 . Retrieved from http://ageing.oxfordjournals.org/content/37/6/673.short18829684 \n\nHunt L. M. Kreiner M. Brody H. (2012 ). The changing face of chronic illness management in primary care: A qualitative study of underlying influences and unintended outcomes . The Annals of Family Medicine , 10 , 452 -460 . Retrieved from http://www.annfammed.org/content/10/5/452.short22966109 \n\nIntercontinental Marketing Services (IMS) Institute for Healthcare Informatics . (2013 ). Avoidable costs in U.S. healthcare: The $200 billion opportunity from using medicines more responsibly . Parsippany, NJ .\n\nJano E. Aparasu R. R. (2007 ). Healthcare outcomes associated with beers’ criteria: A systematic review . Annals of Pharmacotherapy , 41 , 438 -448 .17311835 \n\nThe John A. Hartford Foundation . (2015 ). Draft for 2015 updated Beers criteria for potentially inappropriate medication use in older adults available for public comment [Press release]. Retrieved from http://www.jhartfound.org/news-events/events/2015-updated-beers-criteria-for-potentially-inappropriate-medication-use-in\n\nJones S. A. Bhandari S. (2013 ). The prevalence of potentially inappropriate medication prescribing in elderly patients with chronic kidney disease . Postgraduate Medical Journal , 89 , 247 -250 . Retrieved from http://pmj.bmj.com/content/89/1051/247.short23417370 \n\nLinton A. Garber M. Fagan N. K. Peterson M. R. (2007 ). Examination of multiple medication use among TRICARE beneficiaries aged 65 years and older . Journal of Managed Care Pharmacy , 13 , 155 -162 . Retrieved from http://www.amcp.org/JMCP/2007/March/March_PDFs/7537/1033.html17330976 \n\nMaher R. L. Hanlon J. Hajjar E. R. (2014 ). Clinical consequences of polypharmacy in elderly . Expert Opinion on Drug Safety , 13 , 57 -65 . Retrieved from http://informahealthcare.com/doi/abs/10.1517/14740338.2013.82766024073682 \n\nNixdorff N. Hustey F. M. Brady A. K. Vaji K. Leonard M. Messinger-Rapport B. J. (2008 ). Potentially inappropriate medications and adverse drug effects in elders in the ED . The American Journal of Emergency Medicine , 26 , 697 -700 . Retrieved from http://www.sciencedirect.com/science/article/pii/S073567570800028418606325 \n\nO’Connor M. N. Gallagher P. O’Mahony D. (2012 ). Inappropriate prescribing . Drugs & Aging , 29 , 437 -452 . Retrieved from http://link.springer.com/article/10.2165/11632610-000000000-00000#22642779 \n\nTakane A. K. Balignasay M.-D. Nigg C. R. (2013 ). Polypharmacy reviews among elderly populations project: Assessing needs in patient-provider communication . Hawai’i Journal of Medicine & Public Health , 72 , 15 -22 . Retrieved from http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3555477/\n\nVarallo F. R. Capucho H. C. Planeta C. S. de Carvalho Mastroianni P. (2011 ). Safety assessment of potentially inappropriate medications use in older people and the factors associated with hospital admission . Journal of Pharmacy & Pharmaceutical Sciences , 14 , 283 -290 . Retrieved from http://wigan-ojs.library.ualberta.ca/index.php/JPPS/article/view/979521733416\n\n",
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"title": "Prevalence of Beers Criteria Medications Among Elderly Patients in a Military Hospital.",
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"abstract": "A 16-year-old female patient was admitted to our hospital due to progressive renal dysfunction with an increased serum creatinine (sCr) level of 1.7 mg/dL. Her clinical course without any ocular manifestations and results of drug-induced, lymphocyte-stimulating tests, in addition to a renal histological assessment, initially encouraged us to ascribe the patient's renal abnormalities to drug-induced acute interstitial nephritis (AIN). Four months later, she started to complain about reduced visual acuity when she was found to have anterior bilateral uveitis despite the recovered renal function with almost constant sCr levels around 0.7 mg/dL. Thus, a diagnosis of tubulointerstitial nephritis and uveitis (TINU) syndrome was finally made. Our case illustrates the difficulties in distinguishing late-onset uveitis TINU syndrome from drug-induced AIN at the time of the renal biopsy, thereby suggesting the importance of a longitudinal follow-up to overcome the potential underdiagnosis of the disease. Several diagnostic conundrums that emerged in this case are also discussed.",
"affiliations": "Division of Nephrology, Department of Internal Medicine, Jichi Medical University, Tochigi, Japan.;Division of Nephrology, Department of Internal Medicine, Jichi Medical University, Tochigi, Japan.;Division of Nephrology, Department of Internal Medicine, Jichi Medical University, Tochigi, Japan.;Division of Nephrology, Department of Internal Medicine, Jichi Medical University, Tochigi, Japan.;Division of Nephrology, Department of Internal Medicine, Jichi Medical University, Tochigi, Japan.;Division of Nephrology, Department of Internal Medicine, Jichi Medical University, Tochigi, Japan.;Division of Nephrology, Department of Internal Medicine, Jichi Medical University, Tochigi, Japan.;Division of Nephrology, Department of Internal Medicine, Jichi Medical University, Tochigi, Japan.;Division of Nephrology, Department of Internal Medicine, Jichi Medical University, Tochigi, Japan.;Division of Nephrology, Department of Internal Medicine, Jichi Medical University, Tochigi, Japan.",
"authors": "Kawamata|Mutsumi|M|;Akimoto|Tetsu|T|;Sugase|Taro|T|;Otani-Takei|Naoko|N|;Miki|Takuya|T|;Masuda|Takahiro|T|;Kobayashi|Takahisa|T|;Takeda|Shin-Ichi|S|;Muto|Shigeaki|S|;Nagata|Daisuke|D|",
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"doi": "10.4137/CCRep.S36862",
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"issue": "9()",
"journal": "Clinical medicine insights. Case reports",
"keywords": "DLST; HLA; TINU syndrome; acute interstitial nephritis; uveitis",
"medline_ta": "Clin Med Insights Case Rep",
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"title": "Tubulointerstitial Nephritis and Uveitis Syndrome: Are Drugs Offenders or Bystanders?",
"title_normalized": "tubulointerstitial nephritis and uveitis syndrome are drugs offenders or bystanders"
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"abstract": "The inflammation-mediated comorbidities in myelofibrosis (MF) and related neoplasms (MPNs) likely reflect the concurrent immune deregulation and systemic inflammatory nature of the MPNs, emphasizing the link between chronic systemic inflammation, immune deregulation, and the malignant clone. JAK1-2 inhibitors in MF-patients reduce constitutional symptoms and splenomegaly, but also taget autoimmune and inflammation-mediated comorbidities.",
"affiliations": "Department of Hematology, Roskilde University Hospital, Roskilde Denmark ; Institute for Inflammation Research (IIR), Department of Infectious Diseases and Rheumatology, Copenhagen University Hospital Rigshospitalet, Denmark.;Department of Hematology, Roskilde University Hospital, Roskilde Denmark.",
"authors": "Bjørn|Mads Emil|ME|;Hasselbalch|Hans Carl|HC|",
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"doi": "10.1002/ccr3.281",
"fulltext": "\n==== Front\nClin Case RepClin Case Repccr3Clinical Case Reports2050-09042050-0904John Wiley & Sons, Ltd Chichester, UK 10.1002/ccr3.281Case ReportsThe impact of ruxolitinib treatment on inflammation-mediated comorbidities in myelofibrosis and related neoplasms Bjørn Mads Emil 12Hasselbalch Hans Carl 11 Department of Hematology, Roskilde University Hospital, RoskildeDenmark2 Institute for Inflammation Research (IIR), Department of Infectious Diseases and Rheumatology, Copenhagen University HospitalRigshospitalet, DenmarkCorrespondence Mads Emil Bjørn, Department of Hematology, Roskilde University Hospital, Køgevej 7-13, 4000 Roskilde, Denmark. Tel: +45 47 32 48 00; Fax: +45 46 35 34 39; E-mail: meb@c.dkFunding Information No sources of funding were declared for this study.\n\nBoth authors contributed to the writing and editing of the article.\n\n6 2015 04 5 2015 3 6 499 503 19 2 2015 17 3 2015 19 3 2015 © 2015 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.2015This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.Key clinical message\nThe inflammation-mediated comorbidities in myelofibrosis (MF) and related neoplasms (MPNs) likely reflect the concurrent immune deregulation and systemic inflammatory nature of the MPNs, emphasizing the link between chronic systemic inflammation, immune deregulation, and the malignant clone. JAK1-2 inhibitors in MF-patients reduce constitutional symptoms and splenomegaly, but also taget autoimmune and inflammation-mediated comorbidities.\n\nAutoimmunitycomorbiditiesinflammationmyelofibrosismyeloproliferative neoplasmremissionruxolitinib\n==== Body\nIntroduction\nThe classical Philadelphia negative chronic myeloproliferative neoplasms (MPNs) encompass mainly essential thrombocythemia (ET), polycythemia vera (PV), and myelofibrosis 1. These diseases are clonal, as evidenced by mutations such as the JAK2V617, MPL, and CALR\n2–5. The clinical MPN-phenotype is often accompanied by an inflammation-mediated comorbidity burden 6,7. This is most clearly demonstrated by the increased frequency of cardiovascular diseases, but also several other inflammatory diseases such as psoriasis, giant cell arteritis, and Crohn's disease 8,9. It has also been shown, that some rheumatological diseases increase the risk of hematological as well as non-hematological cancers, and that the risk of having a coincident second malignancy increases when suffering from an MPN 8–10. Furthermore, patients with MPNs exhibit biochemical evidence of low-grade chronic inflammation as evidenced by elevated levels of C-reactive protein 11 and elevated levels of circulating YKL-40 12,13, which is considered a biomarker of chronic inflammation 14. To this end, several inflammatory cytokines are elevated in patients with MPNs, in particular in myelofibrosis 15,16. Most recently, it has been shown that the elevated levels of cytokines are secreted by both malignant MPN-cells as well as nonmalignant cells 17 and that both subsets are affected by JAK inhibition. Furthermore, transcriptional profiling studies have unravelled a massive deregulation of inflammation and immune genes 18–22 - all supportive of the concept that disease progression in these neoplasms may at least partly be driven by chronic inflammation 6,7,16,23 and concomitant immune deregulation 18–21,24. JAK-inhibitors have demonstrated anti-inflammatory and anti-proliferative potential. Consequently JAK-inhibitors are being extensively tested within several other areas, including dermatology and rheumatology 25–27. The rationale in MPNs is the constitutively activated JAK-STAT signaling pathway giving rise to clonal myeloproliferation with an enhanced proinflammatory cytokine profile, excessive formation of ROS, immune deregulation, and ultimately marrow fibrosis 2–7,28,29. The cytokine profile is normalized in MF-patients during treatment with the JAK1-2 inhibitor ruxolitinib, and the clinical benefits for the majority of MF-patients are prompt with resolution of constitutional symptoms within days in concert with resolution of splenomegaly within months. The rapid improvement of constitutional symptoms is most likely attributed to normalization of the cytokine-profile 30–35.\n\nTofacitinib – a JAK1-3 inhibitor – is approved for the treatment of rheumatoid arthritis (RA) and phase 3 studies are ongoing investigating the role of JAK-inhibition in psoriasis. Furthermore, a topical form of ruxolitinib is being tested in the treatment of psoriasis, emphasizing the role for JAK-inhibitors in inflammatory and autoimmune diseases as well 25,27. In addition, a role in infectious diseases has also been suggested, indicated by the observation that ruxolitinib and tofacitinib – in vitro – inhibits HIV-1 36.\n\nImportantly, none of these inhibitors are strictly selective. They are rather promiscuous in nature and both have some activity with all the 3 different JAK's, their activities applying to both mutated and wild-type JAK's. This promiscuity explains the great potential in targeting several crucial points in MPN disease and inflammation-mediated comorbidities 37. This phenomenon has recently been described in a few cases 38–40. Herein, we wish to report on 3 additional patients suffering from MPN and receiving ruxolitinib, who during therapy experienced rapid and profound resolution of their non-hematological comorbidities. The perspectives for ruxolitinib in future studies will also be discussed.\n\nCase reports\nCase 1 – porphyria cutanea tarda (PCT)\nA 76-year-old female suffering from PMF had received treatment with hydroxycarbamide for 3 years and was started on ruxolitinib due to constitutional symptoms (unintended weight loss) and progressive splenomegaly. The JAK2 allelic burden was 40%. Prior to the PMF-diagnosis the patient had been treated with percutaneous coronary intervention due to a stenosis and also suffered from hypertension. Seven years before the diagnosis of PMF the patient was diagnosed with PCT and treated with phlebotomies. Within 3 months of ruxolitinib therapy the patient experienced total resolution of the PCT in concert with resolution of constitutional symptoms and subsequently experienced a weight gain (intended). The allelic burden declined over 2 years of therapy from 40% to 21% at last follow-up, but the thrombocytopenia was worsened reaching 27 × 109/L as nadir at last follow-up but without any bleeding episodes. The detrimental effect on the platelets was accompanied by an increase in the hemoglobin and the patient remained transfusion-independent.\n\nCase 2 – polymyalgia rheumatica (PMR)\nA 73-year-old male suffering from PV had received treatment with interferon-alpha2a (IFN) and was started on a combination therapy with IFN and ruxolitinib based on signs of progressive disease with a persisting need of phlebotomies combined with thrombocytopenia, JAK2 allelic burden reaching 96%, constitutional symptoms (unintended weight loss) and progressive splenomegaly. Thus, the patient was likely in the transitional stage between PV and MF. Prior to ruxolitinib the patient had experienced deep vein thrombosis and paroxysmal atrial flutter. Two years prior to ruxolitinib therapy the patient had suffered from PMR and was treated in the rheumatological setting with steroids, which were associated with partial symptomatic improvement and a normalization of the sedimentation rate. Accordingly, it was concluded that the PMR was treated successfully and that the remaining symptoms (persisting morning stiffness and aches in the shoulder region) were due to age and not inflammatory activity. However, on treatment with ruxolitinib, the patient experienced a marked clinical improvement with disappearance of constitutional symptoms and – most remarkably – also total resolution of “age-related rheumatism” – the PMR-symptoms. This response was obtained in less than a month. The patient spontaneously expressed, that he now remembered the feeling of being healthy. Furthermore, both the hemoglobin levels and platelet counts initially dropped and subsequently increased during combination therapy, which was well tolerated.\n\nCase 3 – psoriasis and psoriasis arthritis (PA)\nA 61-year-old male suffering from post-PV-MF and intolerant to hydroxycarbamide and anagrelide was started on ruxolitinib due to progressive disease with constitutional symptoms and splenomegaly. The JAK2 allelic burden was 25%. The patient was also suffering from psoriasis and PA and was treated with sulfasalazine and methotrexate (MTX), but without proper disease control. The patient also suffered from severe hypertension receiving 4 different drugs to obtain normal blood-pressure. When the patient was started on ruxolitinib, the psoriasis lesions disappeared and itching virtually resolved as well. The arthritis also totally vanished within 3 weeks, and the methotrexate was discontinued without subsequent relapse of the arthritis. The splenomegaly also totally resolved within 2 months and the JAK2 allelic burden was reduced from the initial 25% to 5% within 7 months. The patient obtained a complete hematologic response within 2 months and the response was sustained at last follow-up after approximately 2 years of therapy. The patient stated that the therapy was the best that ever happened to him since he had also been able to start working again, which before ruxolitinib was impossible due to the severe constitutional symptoms, but also due to the severe psoriasis lesions in his hands which now had resolved. Furthermore, the patient experienced reduction of his blood-pressure, even below normal range. Consequently reduction and subsequent discontinuation of several of the anti-hypertensive drugs is ongoing with the hope of discontinuing them all.\n\nDiscussion\nThe highly impressive impact of ruxolitinib therapy on associated comorbidities in our patients reflects that JAK1-2 inhibition not only dampens the strict MPN-associated state with resolution of splenomegaly and constitutional symptoms but also – in general – has a huge impact upon MPN-associated inflammation-driven diseases as well. Thus, the common denominator for these diseases – chronic systemic inflammation and immune deregulation – is also being addressed by ruxolitinib therapy. Importantly, the successful outcome of ruxolitinib treatment in our patient with psoriasis also emphasizes that ruxolitinib may actually improve the performance status substantially and to a degree enabling the patient to start working again. Recently, this particular issue – the socioeconomic consequences for MPN-patients on ruxolitinib treatment – has been described 6. Furthermore, the proposed improved survival in patients with myelofibrosis treated with ruxolitinib may likely be explained by improvement in inflammation-mediated comorbidities, which should also be carefully considered and addressed in future studies 6,31,33,35.\n\nThe PCT case also illustrates the association (and in this case detrimental synergistic effect) between the inflammatory dermatological disorder and the MPN, accounting for increased cell counts and accordingly cell-turnover, thus challenging heme-metabolism beyond its natural boundaries. This happens in a patient already being stressed by an overwhelming immune-reaction towards photo-toxic metabolites accumulated over time due to insufficiency to metabolize heme within the normal range. In this setting, ruxolitinib addresses both the myeloproliferation, thereby reducing the amount of heme that has to be metabolized and also targets the inflammatory reaction towards the remaining photo-toxic heme-metabolites.\n\nThe PA case demonstrates several important aspects. Firstly, an important advantage of the anti-inflammatory potential of ruxolitinib is discontinuation or reduction in the use of disease modifying anti-rheumatic drugs (DMARD's), steroids and other medication prescribed for the nonmalignant inflammatory disease(s) accompanying MF. This is of major importance to the MF-patients since they are often thrombocytopenic and cannot handle further declines in platelet counts due to methotrexate treatment which is associated with many side-effects, including thrombocytopenia. Secondly, the ruxolitinib treatment is superior in regard to disease control in this patient, highlighting a possible role as 2nd line therapy in MTX-nonresponders 41. Thirdly, a possible link between cardiovascular diseases and MPN – exemplified by hypertension – is demonstrated and apparently addressed by ruxolitinib therapy.\n\nThe PMR-case illustrates 2 important observations. Firstly the initial decline in platelet counts can be reversible during combination therapy – even in a thrombocytopenic patient receiving 2 drugs both having myelosuppressive potential. The subsequent increase in platelets is probably due to the reduced pooling and sequestration of platelets in the enlarged spleen 42, which resolves during ruxolitinib therapy. Secondly this case also substantiates the observation that combination therapy with ruxolitinib and IFN is feasible despite the theoretical concerns regarding safety and efficacy with combined therapy 43.\n\nIn conclusion, this report highlights the ability of ruxolitinib to improve the clinical course of MF-patients by alleviating their burden of comorbidities and also serves to illustrate the association between MPNs and inflammatory/autoimmune diseases. Further studies are urgently needed to substantiate our observations on several inflammation-driven diseases being efficaciously addressed by a single agent.\n\nConflict of Interest\nHans Carl Hasselbalch has received research grants from Novartis Oncology. Mads Emil Bjørn has received partial funding for his PhD from Novartis Oncology. Novartis had no knowledge regarding this article and consequently had no influence on the manuscript.\n==== Refs\nReferences\nTefferi A Vardiman JW Classification and diagnosis of myeloproliferative neoplasms: the 2008 World Health Organization criteria and point-of-care diagnostic algorithms Leukemia 2008 22 14 22 17882280 \nBaxter EJ Scott LM Campbell PJ East C Fourouclas N Swanton S Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders Lancet 2005 365 1054 1061 15781101 \nNangalia J Massie CE Baxter EJ Nice FL Gundem G Wedge DC Somatic CALR mutations in myeloproliferative neoplasms with nonmutated JAK2 N. Engl. J. Med 2013 369 2391 2405 24325359 \nCazzola M Kralovics R From Janus kinase 2 to calreticulin: the clinically relevant genomic landscape of myeloproliferative neoplasms Blood 2014 123 3714 3719 24786775 \nTefferi A Thiele J Vannucchi AM Barbui T An overview on CALR and CSF3R mutations and a proposal for revision of WHO diagnostic criteria for myeloproliferative neoplasms Leukemia 2014 28 1407 1413 24441292 \nHasselbalch HC Perspectives on the impact of JAK-inhibitor therapy upon inflammation-mediated comorbidities in myelofibrosis and related neoplasms Expert Rev. Hematol 2014 7 203 216 24524202 \nHasselbalch HC Perspectives on chronic inflammation in essential thrombocythemia, polycythemia vera, and myelofibrosis: is chronic inflammation a trigger and driver of clonal evolution and development of accelerated atherosclerosis and second cancer? Blood 2012 119 3219 3225 22318201 \nKristinsson SY Landgren O Samuelsson J Björkholm M Goldin LR Autoimmunity and the risk of myeloproliferative neoplasms Haematologica 2010 95 1216 1220 20053870 \nNewberry KJ Naqvi K Nguyen KT Cardenas-Turanzas M Florencia Tanaka M Pierce S Comorbidities predict worse prognosis in patients with primary myelofibrosis Cancer 2014 120 2996 3002 24917509 \nFrederiksen H Farkas DK Christiansen CF Hasselbalch HC Sørensen HT Chronic myeloproliferative neoplasms and subsequent cancer risk: a Danish population-based cohort study Blood 2011 118 6515 6520 22039256 \nBarbui T Carobbio A Finazzi G Vannucchi AM Barosi G Antonioli E Inflammation and thrombosis in essential thrombocythemia and polycythemia vera: different role of C-reactive protein and pentraxin 3 Haematologica 2011 96 315 318 21173097 \nAndersen CL Bjørn ME McMullin MF Harrison C Samuelsson J Ejerblad E Circulating YKL-40 in patients with essential thrombocythemia and polycythemia vera treated with the novel histone deacetylase inhibitor vorinostat Leuk. Res 2014 38 816 821 24836761 \nBjørn ME Andersen CL Jensen MK Hasselbalch HC Circulating YKL-40 in myelofibrosis a potential novel biomarker of disease activity and the inflammatory state Eur. J. Haematol 2014 93 224 228 24689875 \nJohansen JS Studies on serum YKL-40 as a biomarker in diseases with inflammation, tissue remodelling, fibroses and cancer Dan. Med. Bull 2006 53 172 209 17087877 \nTefferi A Vaidya R Caramazza D Finke C Lasho T Pardanani A Circulating interleukin (IL)-8, IL-2R, IL-12, and IL-15 levels are independently prognostic in primary myelofibrosis: a comprehensive cytokine profiling study J. Clin. Oncol 2011 29 1356 1363 21300928 \nHasselbalch HC The role of cytokines in the initiation and progression of myelofibrosis Cytokine Growth Factor Rev 2013 24 133 145 23415024 \nKleppe M Kwak M Koppikar P Riester M Keller M Bastian L JAK-STAT pathway activation in malignant and non-malignant cells contributes to MPN pathogenesis and therapeutic response Cancer Discov 2015 5 316 331 25572172 \nSkov V Larsen TS Thomassen M Riley CH Jensen MK Bjerrum OW Molecular profiling of peripheral blood cells from patients with polycythemia vera and related neoplasms: identification of deregulated genes of significance for inflammation and immune surveillance Leuk. Res 2012 36 1387 1392 22877729 \nSkov V Riley CH Thomassen M Larsen TS Jensen MK Bjerrum OW Whole blood transcriptional profiling reveals significant down-regulation of human leukocyte antigen class I and II genes in essential thrombocythemia, polycythemia vera and myelofibrosis Leuk. Lymphoma 2013 54 2269 2273 23302045 \nSkov V Larsen TS Thomassen M Riley CH Jensen MK Bjerrum OW Whole-blood transcriptional profiling of interferon-inducible genes identifies highly upregulated IFI27 in primary myelofibrosis Eur. J. Haematol 2011 87 54 60 21447007 \nSkov V Thomassen M Riley CH Jensen MK Bjerrum OW Kruse TA Gene expression profiling with principal component analysis depicts the biological continuum from essential thrombocythemia over polycythemia vera to myelofibrosis Exp. Hematol 2012 40 771 80 e19 22659388 \nHasselbalch HC Thomassen M Riley CH Kjær L Larsen TS Jensen MK Whole blood transcriptional profiling reveals deregulation of oxidative and antioxidative defence genes in myelofibrosis and related neoplasms. Potential implications of downregulation of Nrf2 for genomic instability and disease progression PLoS ONE 2014 9 e112786 25397683 \nHasselbalch HC Chronic inflammation as a promotor of mutagenesis in essential thrombocythemia, polycythemia vera and myelofibrosis. A human inflammation model for cancer development? Leuk. Res 2013 37 214 220 23174192 \nBarosi G An immune dysregulation in MPN Curr. Hematol. Malig. Rep 2014 9 331 339 25139710 \nHsu L Armstrong AW JAK inhibitors: treatment efficacy and safety profile in patients with psoriasis J. Immunol. Res 2014 2014 283617 24883332 \nGhoreschi K Gadina M Jakpot! New small molecules in autoimmune and inflammatory diseases Exp. Dermatol 2014 23 7 11 24131352 \nYazici Y Regens AL Inhibitors TK Promising new treatments for rheumatoid arthritis - the kinase inhibitors Bull. NYU Hosp. Jt. Dis 2011 69 233 237 22035435 \nVener C Novembrino C Catena FB Fracchiolla NS Gianelli U Savi F Oxidative stress is increased in primary and post-polycythemia vera myelofibrosis Exp. Hematol 2010 38 1058 1065 20655352 \nMarty C Lacout C Droin N Le Couédic J-P Ribrag V Solary E A role for reactive oxygen species in JAK2 V617F myeloproliferative neoplasm progression Leukemia 2013 27 2187 2195 23558526 \nMesa RA Gotlib J Gupta V Catalano JV Deininger MW Shields AL Effect of ruxolitinib therapy on myelofibrosis-related symptoms and other patient-reported outcomes in COMFORT-I: a randomized, double-blind, placebo-controlled trial J. Clin. Oncol 2013 31 1285 1292 23423753 \nPassamonti F Vannucchi AM Cervantes F Harrison C Morra E Kantarjian H Ruxolitinib and survival improvement in patients with myelofibrosis Leukemia 2015 29 739 740 25249013 \nOstojic A Vrhovac R Verstovsek S Ruxolitinib for the treatment of myelofibrosis: its clinical potential Ther. Clin. Risk Manag 2012 8 95 103 22399854 \nVerstovsek S Gotlib J Levy RS Gupta V Dipersio JF Catalano JV Long-term outcomes of ruxolitinib therapy in patients with myelofibrosis: 3-year update from COMFORT-I Blood 2013 122 396 \nMascarenhas J Hoffman R A comprehensive review and analysis of the effect of ruxolitinib therapy on the survival of patients with myelofibrosis Blood 2013 121 4832 4837 23570800 \nVerstovsek S Mesa RA Gotlib J Levy RS Gupta V Dipersio JF Efficacy, safety and survival with ruxolitinib in patients with smyelofibrosis: Results of a median 2-year follow-up of COMFORT-I Haematologica 2013 98 1865 1871 24038026 \nGavegnano C Detorio M Montero C Bosque A Planelles V Schinazi RF Ruxolitinib and tofacitinib are potent and selective inhibitors of HIV-1 replication and virus reactivation in vitro Antimicrob. Agents Chemother 2014 58 1977 1986 24419350 \nMesa RA Ruxolitinib, a selective JAK1 and JAK2 inhibitor for the treatment of myeloproliferative neoplasms and psoriasis IDrugs 2010 13 394 403 20506062 \nHornung T Janzen V Wenzel J Remission of recalcitrant dermatomyositis treated with ruxolitinib N. Engl. J. Med 2014 371 2537 2538 25539124 \nPieri L Guglielmelli P Vannucchi AM Ruxolitinib-induced reversal of alopecia universalis in a patient with essential thrombocythemia Am. J. Hematol 2015 90 82 83 25307179 \nXing L Dai Z Jabbari A Cerise JE Higgins CA Gong W Alopecia areata is driven by cytotoxic T lymphocytes and is reversed by JAK inhibition Nat. Med 2014 20 1043 1049 25129481 \nGadina M Janus Kinases: an ideal target for the treatment of autoimmune diseases J. Investig. Dermatol. Symp. Proc 2013 16 S70 S72 \nGrunwald MR Spivak JL Ruxolitinib enhances platelet production in patients with thrombocytopenic myelofibrosis J. Clin. Oncol 2014 32 2013 2015 \nBjørn ME de Stricker K Kjær L Ellemann K Hasselbalch HC Combination therapy with interferon and JAK1-2 inhibitor is feasible: Proof of concept with rapid reduction in JAK2V617F-allele burden in polycythemia vera Leuk. Res. Rep 2014 3 73 75 25379406\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2050-0904",
"issue": "3(6)",
"journal": "Clinical case reports",
"keywords": "Autoimmunity; comorbidities; inflammation; myelofibrosis; myeloproliferative neoplasm; remission; ruxolitinib",
"medline_ta": "Clin Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101620385",
"other_id": null,
"pages": "499-503",
"pmc": null,
"pmid": "26185657",
"pubdate": "2015-06",
"publication_types": "D002363:Case Reports",
"references": "25572172;25249013;23302045;24524202;24836761;21300928;17882280;24326567;20655352;23570800;24419350;22318201;22035435;24038026;24325359;24958831;21447007;22659388;21173097;22877729;23174192;25539124;17087877;25307179;25129481;24131352;24441292;20506062;15781101;24689875;23423753;23415024;24917509;20053870;22399854;22039256;25379406;23558526;25139710;24883332;25397683;24786775",
"title": "The impact of ruxolitinib treatment on inflammation-mediated comorbidities in myelofibrosis and related neoplasms.",
"title_normalized": "the impact of ruxolitinib treatment on inflammation mediated comorbidities in myelofibrosis and related neoplasms"
} | [
{
"companynumb": "DK-SHIRE-DK201619990",
"fulfillexpeditecriteria": "1",
"occurcountry": "DK",
"patient": {
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{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ANAGRELIDE HYDROCHLORIDE"
},
"drugadditional": "1"... |
{
"abstract": "A second-line treatment protocol including plasma exchange (PE) in addition to the standard therapies was scheduled and utilized in our hospital with the intent of improving the outcome of high risk pregnancies of women with primary antiphospholipid syndrome (APS). This paper chronologically reports and discusses the results obtained in these patients over a 15-year period. Between April 1991 and September 2006, 142 pregnancies of patients with APS were followed by us. Nine of these (6.3%), who did not respond to the conventional procedures or showed complications during the treatments were shifted to a PE protocol management. All these women had a history of previous thromboembolism associated to triple antiphospholipid antibody positivity. Nine pregnancies of 7 patients (2 women were treated twice) were thus followed using PE therapy, which has undergone modification over the years. In the cases studied the outcome of pregnancy varied according to the different PE therapy conditions. This study suggests that prophylactic PE treatment administered along with full anticoagulation and IVIG therapy could be a valuable therapeutic option in high risk pregnant APS women. Further studies in this type of patients are certainly warranted.",
"affiliations": "Rheumatology Unit, Department of Clinical and Experimental Medicine, University of Padova, Padova, Italy. amelia.ruffatti@unipd.it <amelia.ruffatti@unipd.it>",
"authors": "Ruffatti|Amelia|A|;Marson|Piero|P|;Pengo|Vittorio|V|;Favaro|Maria|M|;Tonello|Marta|M|;Bortolati|Maria|M|;Minucci|Daria|D|;De Silvestro|Giustina|G|",
"chemical_list": "D000925:Anticoagulants; D016756:Immunoglobulins, Intravenous; D017762:Nadroparin",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.autrev.2006.11.002",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1568-9972",
"issue": "6(3)",
"journal": "Autoimmunity reviews",
"keywords": null,
"medline_ta": "Autoimmun Rev",
"mesh_terms": "D000328:Adult; D000925:Anticoagulants; D016736:Antiphospholipid Syndrome; D005260:Female; D006801:Humans; D016756:Immunoglobulins, Intravenous; D017762:Nadroparin; D010951:Plasma Exchange; D011247:Pregnancy; D011248:Pregnancy Complications; D011256:Pregnancy Outcome; D012189:Retrospective Studies; D016896:Treatment Outcome",
"nlm_unique_id": "101128967",
"other_id": null,
"pages": "196-202",
"pmc": null,
"pmid": "17289557",
"pubdate": "2007-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Plasma exchange in the management of high risk pregnant patients with primary antiphospholipid syndrome. A report of 9 cases and a review of the literature.",
"title_normalized": "plasma exchange in the management of high risk pregnant patients with primary antiphospholipid syndrome a report of 9 cases and a review of the literature"
} | [
{
"companynumb": "IT-BEH-2020121041",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "NADROPARIN"
},
"drugadditional": null,
"dr... |
{
"abstract": "OBJECTIVE\nTo describe biologic treatment patterns and effectiveness among patients with psoriasis who initiated biologic therapy.\n\n\nMETHODS\nA chart review was conducted for 169 patients with psoriasis initiating biologic treatment between 1 July 2005 and 30 June 2009 from six dermatology clinics. Severity was measured by the Psoriasis Area and Severity Index (PASI) at baseline and time of treatment change. Biologic treatment patterns in the 12 months following initiation (discontinuation, switching, dose increase, and persistence) were collected.\n\n\nRESULTS\nMean (SD) PASI score at initiation was 18.4 (7.8). Eighteen percent of patients discontinued biologic use, 12% switched, and 7% increased biologic dose within the first 12 months. Patients persistent on initial biologic therapy (64%) achieved a mean PASI score of 3.8 at 12 months; 69% achieved PASI ≥75. For patients who discontinued due to lack of effectiveness, mean PASI score was 22.6; no patient reached PASI ≥75. Among patients who switched, mean PASI was 15.7 (0% PASI ≥75) at the time of switch. In those who increased their dose, mean PASI score was 9.1 (43% reached PASI ≥75) at the time of dose increase.\n\n\nCONCLUSIONS\nA large proportion (36%) of patients changed or discontinued biologic therapy within the first year. These patients experienced limited PASI response, if any, suggesting an unmet need for this population.",
"affiliations": "United Biosource Corporation , London , UK.",
"authors": "Khalid|Javaria Mona|JM|;Fox|Kathleen M|KM|;Globe|Gary|G|;Maguire|Andrew|A|;Chau|Dina|D|",
"chemical_list": "D001688:Biological Products",
"country": "England",
"delete": false,
"doi": "10.3109/09546634.2013.768762",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0954-6634",
"issue": "25(1)",
"journal": "The Journal of dermatological treatment",
"keywords": null,
"medline_ta": "J Dermatolog Treat",
"mesh_terms": "D000328:Adult; D001688:Biological Products; D004739:England; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D011565:Psoriasis; D012189:Retrospective Studies; D012720:Severity of Illness Index",
"nlm_unique_id": "8918133",
"other_id": null,
"pages": "67-72",
"pmc": null,
"pmid": "23336246",
"pubdate": "2014-02",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Treatment patterns and therapy effectiveness in psoriasis patients initiating biologic therapy in England.",
"title_normalized": "treatment patterns and therapy effectiveness in psoriasis patients initiating biologic therapy in england"
} | [
{
"companynumb": "GB-JNJFOC-20160921329",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "INFLIXIMAB"
},
"drugadditional": null,
... |
{
"abstract": "A 34-year-old man with history of Hodgkin lymphoma presented 7 months after allogeneic stem cell transplantation with an unexplained severe musculoskeletal pain syndrome. A Tc-MDP bone SPECTCT showed multiple foci with moderate to intense bone uptake across the axial and appendicular skeleton consistent with periostitis. The patient had been on voriconazole daily for 4 months to treat an Aspergillus pneumonia, and in the absence of other causes, a drug-induced periostitis was suspected. Voriconazole was changed to posaconazole with complete resolution of the musculoskeletal symptoms within 3 weeks.",
"affiliations": "From the Departments of Nuclear Medicine and Molecular Imaging, and.;From the Departments of Nuclear Medicine and Molecular Imaging, and.",
"authors": "Haemels|Maarten|M|;Pans|Steven|S|;Schoemans|Hélène|H|;Goffin|Karolien|K|;Gheysens|Olivier|O|;Jentjens|Sander|S|",
"chemical_list": "D000935:Antifungal Agents; D065819:Voriconazole",
"country": "United States",
"delete": false,
"doi": "10.1097/RLU.0000000000002383",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0363-9762",
"issue": "44(2)",
"journal": "Clinical nuclear medicine",
"keywords": null,
"medline_ta": "Clin Nucl Med",
"mesh_terms": "D000328:Adult; D000935:Antifungal Agents; D006689:Hodgkin Disease; D006801:Humans; D008297:Male; D010522:Periostitis; D000072098:Single Photon Emission Computed Tomography Computed Tomography; D033581:Stem Cell Transplantation; D065819:Voriconazole",
"nlm_unique_id": "7611109",
"other_id": null,
"pages": "159-160",
"pmc": null,
"pmid": "30516686",
"pubdate": "2019-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Voriconazole-Induced Periostitis After Allogeneic Stem Cell Transplantation.",
"title_normalized": "voriconazole induced periostitis after allogeneic stem cell transplantation"
} | [
{
"companynumb": "BE-AUROBINDO-AUR-APL-2019-001106",
"fulfillexpeditecriteria": "1",
"occurcountry": "BE",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "VORICONAZOLE"
},
"drugadditional": "1"... |
{
"abstract": "A 49 years old woman (weight 68 kg, BMI 27.3 kg/m2 ) with heterozygous familial hypercholesterolemia (HeFH) and multiple statin intolerance with muscle aches and creatine kinase elevation, presented at the Outpatient Lipid Clinic of Verona University Hospital in May 2015. Hypercholesterolemia was firstly diagnosed during adolescence, followed in adulthood by a diagnosis of Cogan's syndrome, a rheumatologic disorder characterized by corneal and inner ear inflammation. No xanthomas, corneal arcus, or vascular bruits were detectable at physical examination. Screening for macrovascular complications did not reveal relevant damages. Ongoing medical therapy included salicylic acid, methylprednisolone, methotrexate, and protonic-pump inhibitor. In the absence of specific lipid-lowering therapy, plasma lipid levels at first visit were: total-cholesterol = 522 mg/dL, LDL-cholesterol = 434 mg/dL, HDL-cholesterol = 84 mg/dL, triglycerides = 120 mg/dL, Lp(a) = 13 mg/dL. On December 2015, evolocumab 140 mg sc every 2 weeks was initiated. After a 24-week treatment, the LDL-cholesterol levels decreased by an average of 21.2% to 342 ± 22 mg/dL (mean ± SD). On May 2016, LDL-apheresis (H.E.L.P.system) was started as add-on therapy. Compared to the average levels obtained during the evolocumab monotherapy period, the LDL-cholesterol was reduced by 49.4%, thus reaching an inter-apheresis level (mean ± SD) of 173 ± 37 mg/dL. This report suggests that a combination therapy with evolocumab and lipoprotein-apheresis may have synergic effects on circulating lipid levels. Its relevance as a highly effective treatment option for hyperlipidemia in HeFH patients warrants further investigation in larger datasets.",
"affiliations": "Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University Hospital of Verona, Verona, Italy.;Extracorporeal Therapeutic Techniques Unit, Lipid Clinic and Atherosclerosis Prevention Centre, Immunohematology and Transfusion Medicine, Department of Molecular Medicine, ''Sapienza'' University of Rome, ''Umberto I'' Hospital, Rome, Italy.;Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University Hospital of Verona, Verona, Italy.;Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University Hospital of Verona, Verona, Italy.;Section of Nephrology, Department of Medicine, University Hospital of Verona, Verona, Italy.;Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University Hospital of Verona, Verona, Italy.;Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University Hospital of Verona, Verona, Italy.",
"authors": "Zenti|M G|MG|http://orcid.org/0000-0002-2963-3990;Stefanutti|C|C|;Sanga|V|V|;Altomari|A|A|;Fabris|A|A|;Dauriz|M|M|http://orcid.org/0000-0002-5542-5941;Bonora|E|E|",
"chemical_list": "D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000924:Anticholesteremic Agents; D008078:Cholesterol, LDL; D008074:Lipoproteins; C577155:evolocumab",
"country": "United States",
"delete": false,
"doi": "10.1002/jca.21632",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0733-2459",
"issue": "33(4)",
"journal": "Journal of clinical apheresis",
"keywords": "anti-PCSK9 antibody; evolocumab; heterozygous familial hypercholesterolemia; lipoprotein apheresis; statin intolerance",
"medline_ta": "J Clin Apher",
"mesh_terms": "D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000924:Anticholesteremic Agents; D001781:Blood Component Removal; D008078:Cholesterol, LDL; D003131:Combined Modality Therapy; D005260:Female; D006801:Humans; D006938:Hyperlipoproteinemia Type II; D008074:Lipoproteins; D008875:Middle Aged",
"nlm_unique_id": "8216305",
"other_id": null,
"pages": "546-550",
"pmc": null,
"pmid": "29638018",
"pubdate": "2018-08",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Evolocumab and lipoprotein apheresis combination therapy may have synergic effects to reduce low-density lipoprotein cholesterol levels in heterozygous familial hypercholesterolemia: A case report.",
"title_normalized": "evolocumab and lipoprotein apheresis combination therapy may have synergic effects to reduce low density lipoprotein cholesterol levels in heterozygous familial hypercholesterolemia a case report"
} | [
{
"companynumb": "IT-SUN PHARMACEUTICAL INDUSTRIES LTD-2017RR-134245",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ATORVASTATIN"
},
"dr... |
{
"abstract": "Objective: A 15-year-old pediatric male patient was influenza A positive and started on oseltamivir at an outpatient clinic. Method: The next morning the patient presented to the emergency department (ED) with a chief complaint of visual disturbances including decreased central vision. Prior to presenting to the ED the patient was evaluated by his optometrist and his eye exam tested 20/400 bilaterally. His previous year's eye exam was normal, 20/25 bilaterally. Results: In the ED, the patient had an MRI which showed a normal appearing optic nerve, chiasm, and optic tracts. The oseltamivir therapy was discontinued, and the patient followed up with an ophthalmologist outpatient. Conclusion: At a 10-week follow-up visit the patient had 90% recovery of his vision.",
"affiliations": "Stormont-Vail Healthcare, Topeka, KS, USA.;Stormont-Vail Healthcare, Topeka, KS, USA.",
"authors": "Carson|Laura|L|;Price|John E|JE|https://orcid.org/0000-0003-4363-6976",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1177/0018578720942225",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0018-5787",
"issue": "56(6)",
"journal": "Hospital pharmacy",
"keywords": "adverse drug reactions; anti-infectives; disease management; ear; eye; infectious diseases; medication safety; nose; throat",
"medline_ta": "Hosp Pharm",
"mesh_terms": null,
"nlm_unique_id": "0043175",
"other_id": null,
"pages": "678-680",
"pmc": null,
"pmid": "34732921",
"pubdate": "2021-12",
"publication_types": "D016428:Journal Article",
"references": "7249508;23479534;25276813;23571265;22989339;15802939;19743581;29541690;29563955;29090056;31697568;26243850;17884292;25943730;23054689",
"title": "Temporary Central Vision Blindness After Oseltamivir Administration in a 15-Year-Old Pediatric Male Positive for Influenza A.",
"title_normalized": "temporary central vision blindness after oseltamivir administration in a 15 year old pediatric male positive for influenza a"
} | [
{
"companynumb": "US-MACLEODS PHARMACEUTICALS US LTD-MAC2020027610",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "OSELTAMIVIR"
},
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"abstract": "In solid organ transplant recipients, Epstein-Barr virus (EBV) can cause active central nervous system (CNS) infection or malignant transformation of latently infected cells in the CNS, known as post-transplant lymphoproliferative disease (PTLD). Reduction of T-cell immunosuppression is the cornerstone of management. The role of antivirals with in-vitro activity against herpesviruses in EBV-related CNS syndromes is controversial, as they have no effect on latent virus. We report an unusual case of relapsing EBV encephalitis in a donor-positive, EBV-negative renal transplant recipient, with response to valganciclovir. Our report supports the utility of antiviral treatment for EBV encephalitis, as adjunct to reducing immunosuppression, and highlights the need for a systematic approach and long-term, multi-disciplinary follow-up of such patients.",
"affiliations": "Department of Neurology, Rhode Island Hospital and Warren Alpert Medical School of Brown University, Providence, RI, United States.;Transplant Infectious Diseases, Westchester Medical Center and New York Medical College, Valhalla, NY, United States.;Division of Infectious Diseases, Department of Internal Medicine, Rhode Island Hospital and Warren Alpert Medical School of Brown University, Providence, RI, United States.",
"authors": "Stone|Joshua A|JA|;Knoll|Bettina M|BM|;Farmakiotis|Dimitrios|D|",
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"doi": "10.1016/j.idcr.2017.09.009",
"fulltext": "\n==== Front\nIDCasesIDCasesIDCases2214-2509Elsevier S2214-2509(17)30149-X10.1016/j.idcr.2017.09.009ArticleRelapsing EBV encephalitis in a renal transplant recipient Stone Joshua A. a1Knoll Bettina M. b1Farmakiotis Dimitrios Dimitrios.Farmakiotis@lifespan.orgc⁎1a Department of Neurology, Rhode Island Hospital and Warren Alpert Medical School of Brown University, Providence, RI, United Statesb Transplant Infectious Diseases, Westchester Medical Center and New York Medical College, Valhalla, NY, United Statesc Division of Infectious Diseases, Department of Internal Medicine, Rhode Island Hospital and Warren Alpert Medical School of Brown University, Providence, RI, United States⁎ Corresponding author at: 593 Eddy Street, Gerry House 113, Providence, RI, 02903, United States. Dimitrios.Farmakiotis@lifespan.org1 J.A.S. and B.M.K. contributed equally to this work.\n\n28 9 2017 2017 28 9 2017 10 83 87 16 8 2017 26 9 2017 26 9 2017 © 2017 Published by Elsevier Ltd.2017This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).In solid organ transplant recipients, Epstein-Barr virus (EBV) can cause active central nervous system (CNS) infection or malignant transformation of latently infected cells in the CNS, known as post-transplant lymphoproliferative disease (PTLD). Reduction of T-cell immunosuppression is the cornerstone of management. The role of antivirals with in-vitro activity against herpesviruses in EBV-related CNS syndromes is controversial, as they have no effect on latent virus. We report an unusual case of relapsing EBV encephalitis in a donor-positive, EBV-negative renal transplant recipient, with response to valganciclovir. Our report supports the utility of antiviral treatment for EBV encephalitis, as adjunct to reducing immunosuppression, and highlights the need for a systematic approach and long-term, multi-disciplinary follow-up of such patients.\n\nKeywords\nEpstein-Barr virusEBVEncephalitisTransplantationAcyclovirValacyclovirGanciclovirValganciclovir\n==== Body\nCase report\nA 53-year-old women with history of living, unrelated donor kidney transplant one year prior, due to diabetic nephropathy, was admitted to the hospital with decline in executive functioning. The patient was previously independent, but in the weeks leading to admission had difficulty calculating her insulin dose, recognizing the day of the week, and using the telephone or the microwave. The patient also experienced frequent falls. For her transplant, the patient had received induction immunosuppression with anti-thymocyte globulin (ATG), as part of steroid-sparing regimen due to diabetes. Cytomegalovirus (CMV) and EBV serology status were donor positive, recipient negative. The patient had completed 6 months of CMV prophylaxis with valganciclovir. Maintenance immunosuppression consisted of tacrolimus, with an admission level of 13.5 ng/dL, and mycophenolate 720 mg twice daily. The patient had no history of recent travel, sick contacts, or rural exposures.\n\nOn admission, the patient was febrile to 101.3 °F, perseverative and inattentive, and not oriented to person, place or time. There were no cranial nerve or other focal deficits. Laboratory work-up is summarized in Table 1. Lumbar puncture (LP) revealed pleiocytosis with lymphocyte predominance and elevated protein (Table 1). Magnetic resonance imaging (MRI) with gadolinium contrast showed abnormal signal in the left insular region, left pons, and right cerebellum (Fig. 1A–C), but no enhancing lesions. Electroencephalogram (EEG) showed left frontotemporal slowing with occasional embedded sharp waves. The patient was empirically started on intravenous (IV) acyclovir and ampicillin, for herpetic and Listeria encephalitis, respectively. On day 2, the patient had a generalized tonic-clonic seizure and was started on levatiracetam. Mycophenolate was decreased to 360 mg bid and tacrolimus dose was also reduced, to a trough goal of 5–7 ng/mL. Plasma EBV viral load (VL) was 285 IU/mL. EBV serologies were negative for both antiviral capsid antigen IgM and nuclear antigen (NA) IgG. EBV VL in the CSF was 1100 IU/mL. CSF cytology and flow cytometry were negative for lymphoma.Fig. 1 Magnetic resonance imaging (MRI) showing diffuse multi-focal hyperintense lesions on axial T2 fluid-attenuated inversion recovery (FLAIR) sequences on initial presentation (A–C), 3 weeks after presentation (D–F), 6 weeks after presentation (G–I), 5 (J–L) and 8 (M–O) months after presentation.\n\nFig. 1Table 1 Admission laboratory results.\n\nTable 1Test\tLaboratory Value\tReference Range\t\nBlood\t\nWhite blood cell count\t3.9 × 109/L\t3.5–11.0 × 109/L\t\nHemoglobin\t13.1 g/dL\t11.0–15.0 g/dL\t\nPlatelets\t240 × 109/L\t150–400 × 109/L\t\nGlucose\t306 mg/dL\t67–99 mg/dL\t\nSodium\t122 mEq/L\t135–145 mEq/L\t\nPotassium\t4.5 mEq/L\t3.6–5.1 mEq/L\t\nChloride\t88 mEq/L\t98–110 mEq/L\t\nCarbon dioxide\t26 mEq/L\t22–32 mEq/L\t\nBlood urea nitrogen\t14 mg/dL\t6–24 mg/dL\t\nCreatinine\t0.87 mg/dL\t0.44–1.03 mg/dL\t\nMagnesium\t1.4 mEq/L\t1.3–1.9 mEq/L\t\nALT\t21 IU/L\t6–45 IU/L\t\nAST\t20 IU/L\t10–42 IU/L\t\nAlkaline phosphatase\t38 IU/L\t34–104 IU/L\t\nTotal bilirubin\t0.7 mg/dL\t0.2–1.3 mg/dL\t\nAmmonia\t34 μmol/L\t2–50 μmol/L\t\nOsmolality\t274 mOsm/kg\t290–300 mOsm/kg\t\nUric acid\t2.8 mg/dL\t2.6-6.0 mg/dL\t\nTSH\t0.894 μIU/mL\t0.350-5.500 μIU/mL\t\nVitamin B12\t1647 pg/mL\t211–911 pg/mL\t\nRapid plasma reagin\tNonreactive\tNonreactive\t\nTacrolimus level\t13.5 ng/mL\t5.0-20.0 ng/mL\t\nBlood culture ×2\tNo growth\t\t\nLyme reflex\t0.1\t0.00−0.91\t\nEBV IgG\t0.3\t0.0−0.8\t\nEBV IgM\t0.2\t0.0−0.8\t\nEBV qPCR (Viracor)\t285 IU/mL\tTND, 49-1.69 × 108 IU/mL\t\nCryptococcal antigen\tNegative\tNegative\t\nHIV 1 and 2 antibodies\tNegative\tNegative\t\nJC virus qPCR\tTND\t40–1 × 108 copies/mL\t\n\n\n\t\nCSF\t\nCell count, 1st tube\t191 cells/μL\t0–5 cells/μL\t\nCell count, last tube\t157 cells/μL\t0–5 cells/μL\t\nRBC, 1st tube\t8 cells/μL\t0–5 cells/μL\t\nRBC, last tube\t3 cells/μL\t0–5 cells/μL\t\nDifferential\t84% lymphocytes\t63–99%\t\n2% polys\t0–2%\t\n14% monocytes\t3–37%\t\nProtein\t136 mg/dL\t15–45 mg/dL\t\nGlucose\t141 mg/dL\t38–85 mg/dL\t\nGram stain\tNo organisms\t\t\nBacterial culture\tNo growth\t\t\nEnterovirus PCR\tNegative\t\t\nHSV I and II PCR\tNegative\t\t\nWest Nile IgG\t<1.3\t<1.3\t\nWest Nile IgM\t<0.9\t<0.9\t\nCMV PCR\tNegative\t\t\nJC virus qPCR\tTND\t72–1 × 108 copies/mL\t\nVZV PCR\tNegative\t\t\nEBV qPCR\t1100 IU/mL\t52-1.69 × 108 IU/mL\t\nFungal stain and culture\tNo fungus isolated\t\t\nAFB stain and culture\tNo AFB isolated at 6 weeks\t\t\nAFB, acid-fast bacilli; ALT, alanine aminotransferase, AST, aspartate aminotransferase; CMV, cytomegalovirus; CSF, cerebrospinal fluid; EBV, Epstein-Barr Virus; HIV, human immunodeficiency virus; HSV, herpes simplex virus; (q)PCR, (quantitative) polymerase chain reaction; RBC, red blood cells; TND, target not detected; TSH, thyroid-stimulating hormone; VZV, varicella-zoster virus.\n\n\n\nThe patient’s mental status improved and she was discharged, after a 2 week course of IV acyclovir, on oral acyclovir 800 mg 5 times daily. Re-admission was prompted 11 days later by mental status decline without changes in immunosuppression (Fig. 2). EEG was consistent with nonconvulsive status epilepticus, and the patient was loaded with phenytoin. MRI revealed worsening diffuse periventricular hyperintensities with more extensive pontine and cerebellar involvement (Figs. 1D–F, 2). Repeat EBV viral load in the CSF was 37,300 IU/mL. Intravenous ganciclovir was initiated with resultant improvement in mental status and decrease in CSF EBV VL (Fig. 2). The patient was discharged on oral valganciclovir 900 mg two times daily.Fig. 2 Clinical course, respective interventions, laboratory values and imaging.\n\nLaboratory values and images have been linked to the closest timepoint of clinical assessment. Grey marks represent clinical or laboratory deterioration and black ones improvement. CSF, cerebrospinal fluid; EBV, Epstein-Barr Virus; FLAIR, fluid-attenuated inversion recovery; IV, intravenous; MRI, magnetic resonance imaging; TND, target not detected; <49 (plasma), EBV detected, below quantification cut-off.\n\nFig. 2\n\nOne month later, valganciclovir was discontinued as her mental status had returned to baseline and the patient had developed neutropenia. CSF EBV VL had decreased to 5400 IU/mL, CSF pleiocytosis had resolved, MRI was improved (Figs. 1G–I & 2), and the patient had developed anti-EBV nuclear antigen IgG. After discontinuation of valganciclovir, progressive mental status changes and gait instability ensued. Three months later, MRI and LP findings were consistent with progressive infection (Figs. 1J–L & 2), and the patient was found to be viremic with EBV viral load of 900 IU/mL. Mycophenolate was discontinued, and oral valganciclovir 900 mg two times daily was resumed. The patient soon returned to her functional baseline, with resolution of viremia and MRI improvement (Fig. 1 M-O). Treatment was complicated by neutropenia, so therapy was transitioned to high-dose oral valacyclovir (1 gm three times daily). This was followed by lethargy and confusion three weeks into the course. The patient was re-started on valganciclovir with rapid recovery; after one month, the dose was decreased to 450 mg two times daily. After six additional months, she underwent repeat lumbar puncture that showed normalization of cell count and protein, and EBV viral of 61 IU/mL (limit of detection: 52 IU/mL), at which point valganciclovir was discontinued. Serum creatinine has been <1 mg/dL, and she is receiving tacrolimus single-agent immunosuppression with trough levels of 5–7 ng/dL. Plasma EBV viral load has remained undetectable with monthly checks. The patient is off anti-epileptics, without clinical evidence of relapse, and she is able to drive.\n\nDiscussion\nIn solid organ transplant (SOT) recipients, symptoms and signs of encephalopathy, such as altered mental status, motor or sensory deficits, behavioral or personality changes, speech or movement disorders, and seizures are common. The differential diagnosis is broad, and causes classified as infectious and non-infectious. Non-infectious causes are drug toxicities (neurotoxicity from calcineurin inhibitors), vascular events (stroke, uncontrolled hypertension) and metabolic abnormalities (hepatic or uremic encephalopathy) [1], [2]. Encephalitis is the term describing encephalopathy from viral [3], bacterial (bacterial meningo-encephalitis or Listeria rhomboid encephalitis), fungal (Cryptococcus) or parasitic (Toxoplasma, Trypanosoma) infection of the CNS [1]. CSF evaluation is paramount to diagnosis and, in viral encephalitis, reveals pleiocytosis with lymphocytic predominance, elevated protein, and normal glucose (Table 1) [3]. Imaging findings may depend on the etiology, but often include nonspecific white matter changes, as demonstrated in our case (Fig. 1, Fig. 2) [3]. Specific serologies and PCR are used to identify the causative agent [3]. It should be noted that, in the setting of immunosuppression, EBV viremia and positive PCR in the CSF can be reactive. Therefore, if another pathogen has been identified, the clinical significance of EBV in the CSF is unclear.\n\nPrimary EBV infection occurs in over 90% of the world population and is either asymptomatic, or manifests as infectious mononucleosis (IM), followed by latency of the virus in B-lymphocytes [4]. EBV affects the central nervous system (CNS) in 1–18% of patients [2]. Up to 22% of viral encephalitis cases have been reported as EBV-related [5]. Neurologic sequelae of EBV infection are due to the virus-host immunity interaction, and include encephalitis, meningitis, cerebellitis, polyradiculomyelitis, transverse myelitis, and cranial and peripheral neuropathies [2], [6]. Outside of primary EBV infection, reactivation of latent virus is a prerequisite for CNS involvement and is most likely to occur in T-cell immunosuppressed hosts [1], [2], [7], [8], [9]. In the current case, donor derived primary EBV infection is most likely, given the sero-discordance at time of transplantation.\n\nEBV latently infected B-cells can be oncogenically transformed, giving rise to lymphoproliferative disorders, especially post-transplant lymphoproliferative disorder (PTLD) in the setting of decreased immune surveillance secondary to T-cell immunosuppression [10], [11]. Therefore, an important diagnostic consideration in SOT recipients with CNS manifestations is EBV-related CNS-PTLD [12]. In renal transplant recipients, the incidence of PTLD is approximately 1% [12]; CNS involvement is estimated in 10–15% of all PTLD cases [12], [13], 12% among renal transplant recipients with PTLD [13]. The World Health Organization classifies PTLD into early, polymorphic and monomorphic lesions [11]. These conditions lie along a continuum of disease. Early lesions can have relatively nonspecific manifestations such as IM-type illness and no signs of space-occupying malignancy. Both polymorphic and monomorphic lesions demonstrate malignant transformation, but only the latter meets all the diagnostic criteria for a B-cell lymphoma recognized in immunocompetent patients [11].\n\nEBV serostatus and the depth of T-cell immunosuppression are risk factors for the development of PTLD: EBV sero-negative recipients of an EBV sero-positive organ have a 10- to 76-fold greater incidence of PTLD, compared to those who are seropositive [12]. EBV-infected B-lymphocytes are controlled by cytotoxic T-cells [14]. ATG induction therapy depletes T-cells and has been associated with 5-fold increase in the incidence of PTLD [13]. Calcineurin inhibitors (i.e. tacrolimus) inhibit T-cell activation and therefore add to the risk. Mycophenolate targets both T and B-cells, but does not confer significant risk for development of PTLD [15].\n\nIn addition to clinical features, the diagnosis of CNS-PTLD is supported by imaging and evidence of malignant transformation. In our patient, no brain biopsy was performed and the possibility of PTLD could not be excluded. MRI imaging features favoring encephalitis rather than PTLD were absence of well-circumscribed lesions and, most importantly, lack of contrast enhancement (Fig. 1, Fig. 2) [12]. CSF cytology was negative, though it can be negative in up to 60% of primary CNS lymphomas in immunocompetent hosts [16]. Most convincingly, our patient responded to antiviral treatment, which is only active against lytic virus, and should, therefore, have no effect on CNS-PTLD [12].\n\nDistinguishing between EBV encephalitis and CNS-PTLD in SOT recipients could be important for initiation of appropriate treatment. For both, reduction of immunosuppression should be attempted, to the maximum feasible degree without endangering vital transplant organ function that cannot be replaced otherwise. Additional treatment options for PTLD include rituximab, radiation, and combination chemotherapy [12]. In our patient, tacrolimus was dose-reduced and mycophenolate dose-reduced and eventually discontinued, in order to remove an additional myelo- and immunosuppressive agent and to help maintain a higher neutrophil count while on treatment with valganciclovir.\n\nTreatment with antivirals has no role in management of PTLD, as it does not affect latently-infected tumor cells [12]. Antivirals are not routinely recommended for primary EBV infection, including encephalitis [4], given their lack of efficacy in IM [7]. In immunocompetent hosts however, there are case reports [6] and small case series [17] of the use of antivirals for the treatment of EBV-related neurologic complications, often with adjunct steroids [6], [7], [8]. Based on this limited data and the experienced gained from the current case, antiviral treatment against actively proliferating, lytic virus should be considered as an adjunct to decreased immunosuppression in cases of EBV-encephalitis in immunocompromised hosts. Both acyclovir and ganciclovir target the viral DNA-polymerase, potentially halting active EBV infection. Valganciclovir would be the preferred drug of choice, given its ten-fold increased in-vitro activity against EBV compared to valacyclovir [9], [18]. Myelosuppression may occur after prolonged valganciclovir treatment. Contingent upon clinical circumstance, treatment discontinuation, growth factor administration, or dose adjustment can be considered. Given the paucity of published data available for review, optimal antiviral treatment duration is unknown. In the current case, the decision for maintenance therapy was based on clinical, radiographic and virologic relapse or persistence, with valganciclovir discontinuation despite reduced maintenance immunosuppressive therapy (Fig. 2).\n\nThe risk of developing CNS-PTLD in the future for a patient with EBV-encephalitis is unclear, as both syndromes are rare. EBV-positive CNS lymphoma, 10 years after EBV encephalitis has been reported in a renal transplant recipient. Prospective monitoring of EBV PCRs on blood [19] and monoclonal protein secretion in serum or urine have been proposed [20].\n\nOur case study has limitations, specifically lack of tissue diagnosis, few follow-up LPs due to patient preference, and overlap between changes in immunosuppression and antiviral treatment.\n\nIn conclusion, valganciclovir treatment for EBV encephalitis in immunocompromised patients should be considered as an adjunct to immunosuppression reduction. Transplant recipients with EBV encephalitis benefit from long-term, multi-disciplinary follow-up.\n==== Refs\nReferences\n1 Wright A.J. Fishman J.A. Central nervous system syndromes in solid organ transplant recipients Clin Infect Dis 59 7 2014 1001 1011 (PubMed PMID: 24917660) 24917660 \n2 Ponticelli C. Campise M.R. Neurological complications in kidney transplant recipients J Neprhol 18 5 2005 521 528 (PubMed PMID: 16299677) \n3 Tunkel A.R. Glaser C.A. Bloch K.C. Sejvar J.J. Marra C.M. Roos K.L. The management of encephalitis: clinical practice guidelines by the Infectious Diseases Society of America Clin Infect Dis 47 3 2008 303 327 (PubMed PMID: 18582201) 18582201 \n4 Luzuriaga K. Sullivan J.L. Infectious mononucleosis N Engl J Med 362 21 2010 1993 2000 (PubMed PMID: 20505178) 20505178 \n5 Bastos M.S. Lessa N. Naveca F.G. Monte R.L. Braga W.S. Figueiredo L.T. Detection of Herpesvirus, Enterovirus, and Arbovirus infection in patients with suspected central nervous system viral infection in the Western Brazilian Amazon J Med Virol 86 9 2014 1522 1527 (PubMed PMID: 24760682) 24760682 \n6 Celik T. Celik U. Tolunay O. Komur M. Baspinar H. Yilmaz C. Epstein-Barr virus encephalitis with substantia nigra involvement J Pediatr Neurosci 10 4 2015 401 403 (PubMed PMID: 26962357; PubMed Central PMCID: PMC4770663) 26962357 \n7 Barberi W. Perrone S. Iori A.P. Torelli G.F. Testi A.M. Moleti M.L. Proven Epstein-Barr encephalitis with negative EBV-DNA load in cerebrospinal fluid after allogeneic hematopoietic stem cell transplantation in a child with acute lymphoblastic leukemia Pediatr Transplant 19 1 2015 E19 E24 (PubMed PMID: 25388950) 25388950 \n8 Raman L. Nelson M. Cerebral vasculitis and encephalitis due to Epstein-Barr virus in a patient with newly diagnosed HIV infection J Clin Virol 59 4 2014 264 267 (PubMed PMID: 24568965) 24568965 \n9 Babik J.M. Katrak S. Miller S. Shah M. Chin-Hong P. Epstein-Barr virus encephalitis in a renal transplant recipient manifesting as hemorrhagic, ring-enhancing mass lesions Transpl Infect Dis 17 5 2015 744 750 (PubMed PMID: 26252540) 26252540 \n10 Liebowitz D. Epstein-Barr virus and a cellular signaling pathway in lymphomas from immunosuppressed patients N Engl J Med 338 20 1998 1413 1421 (PubMed PMID: 9580648) 9580648 \n11 Swerdlow S. Campo E. Harris N. World Health Organization classification of tumours of haematopoietic and lymphoid tissues 2008 WHO Lyon, France \n12 Cavaliere R. Petroni G. Lopes M.B. Schiff D. International Primary Central Nervous System Lymphoma Collaborative G. Primary central nervous system post-transplantation lymphoproliferative disorder: an international primary central nervous system lymphoma collaborative group report Cancer 116 4 2010 863 870 (PubMed PMID: 20052713; PubMed Central PMCID: PMC4113953.) 20052713 \n13 Opelz G. Naujokat C. Daniel V. Terness P. Dohler B. Disassociation between risk of graft loss and risk of non-Hodgkin lymphoma with induction agents in renal transplant recipients Transplantation 81 9 2006 1227 1233 (PubMed PMID: 16699447) 16699447 \n14 Lim W.H. Russ G.R. Coates P.T. Review of Epstein-Barr virus and post-transplant lymphoproliferative disorder post-solid organ transplantation Nephrology 11 4 2006 355 366 (PubMed PMID: 16889577) 16889577 \n15 Caillard S. Dharnidharka V. Agodoa L. Bohen E. Abbott K. Posttransplant lymphoproliferative disorders after renal transplantation in the United States in era of modern immunosuppression Transplantation 80 9 2005 1233 1243 (PubMed PMID: 16314791) 16314791 \n16 Fine H.A. Mayer R.J. Primary central nervous system lymphoma Ann Intern Med 119 11 1993 1093 1104 (PubMed PMID: 8239229) 8239229 \n17 Bathoorn E. Vlaminckx B.J. Schoondermark-Stolk S. Donders R. van der Meulen M. Thijsen S.F. Primary Epstein-Barr virus infection with neurological complications Scand J Infect Dis 43 2 2011 136 144 (PubMed PMID: 21070089) 21070089 \n18 Allen U.D. Preiksaitis J.K. Practice ASTIDCo Epstein-Barr virus and posttransplant lymphoproliferative disorder in solid organ transplantation Am J Transplant 13 Suppl. 4 2013 107 120 (PubMed PMID: 23465004) 23465004 \n19 Stevens S.J. Verschuuren E.A. Pronk I. van Der Bij W. Harmsen M.C. The T.H. Frequent monitoring of Epstein-Barr virus DNA load in unfractionated whole blood is essential for early detection of posttransplant lymphoproliferative disease in high-risk patients Blood 97 5 2001 1165 1171 (PubMed PMID: 11222357) 11222357 \n20 Lemoine A. Pham P. Azoulay D. Saliba F. Emile J.F. Saffroy R. Detection of gammopathy by serum protein electrophoresis for predicting and managing therapy of lymphoproliferative disorder in 911 recipients of liver transplants Blood 98 5 2001 1332 1338 (PubMed PMID: 11520779) 11520779\n\n",
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"journal": "IDCases",
"keywords": "Acyclovir; EBV; Encephalitis; Epstein-Barr virus; Ganciclovir; Transplantation; Valacyclovir; Valganciclovir",
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"pages": "83-87",
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"pubdate": "2017",
"publication_types": "D016428:Journal Article; D002363:Case Reports",
"references": "20052713;20505178;11520779;23465004;26252540;16299677;16889577;24760682;26962357;8239229;21070089;18582201;16314791;24917660;25388950;9580648;11222357;24568965;16699447",
"title": "Relapsing EBV encephalitis in a renal transplant recipient.",
"title_normalized": "relapsing ebv encephalitis in a renal transplant recipient"
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"abstract": "This case of sarcoidosis mimicking metastatic breast cancer serves as a reminder of the need to consider differential diagnoses even when the clinical scenario and imaging findings are highly suggestive of metastases.",
"affiliations": "Department of Radiation Oncology University of Nebraska Medical Center Omaha NE USA.;Department of Radiation Oncology University of Nebraska Medical Center Omaha NE USA.;Department of Radiation Oncology University of Nebraska Medical Center Omaha NE USA.;Department of Radiology University of Nebraska Medical Center Omaha NE USA.;Department of Internal Medicine University of Nebraska Medical Center Omaha NE USA.;Department of Internal Medicine University of Nebraska Medical Center Omaha NE USA.;Department of Radiation Oncology University of Nebraska Medical Center Omaha NE USA.;Department of Radiation Oncology University of Nebraska Medical Center Omaha NE USA.",
"authors": "Vieira|Heidi|H|https://orcid.org/0000-0003-1555-2281;Neilsen|Beth K|BK|https://orcid.org/0000-0002-4859-6486;Sleightholm|Richard|R|;Hankins|Jordan|J|;Freifeld|Alison|A|;Moore|Gerald|G|;Wahl|Andrew|A|;Baine|Michael J|MJ|",
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"fulltext": "\n==== Front\nClin Case Rep\nClin Case Rep\n10.1002/(ISSN)2050-0904\nCCR3\nClinical Case Reports\n2050-0904 John Wiley and Sons Inc. Hoboken \n\n10.1002/ccr3.3561\nCCR33561\nCase Report\nCase Reports\nDiffuse lesions secondary to sarcoidosis mimicking widespread metastatic breast cancer: A case report\nVIEIRA et al.Vieira Heidi https://orcid.org/0000-0003-1555-2281\n1\n Neilsen Beth K. https://orcid.org/0000-0002-4859-6486\n1\n Sleightholm Richard \n1\n Hankins Jordan \n2\n Freifeld Alison \n3\n Moore Gerald \n3\n Wahl Andrew \n1\n Baine Michael J. \n1\nmbaine@unmc.edu \n1 \nDepartment of Radiation Oncology\nUniversity of Nebraska Medical Center\nOmaha\nNE\nUSA\n\n\n2 \nDepartment of Radiology\nUniversity of Nebraska Medical Center\nOmaha\nNE\nUSA\n\n\n3 \nDepartment of Internal Medicine\nUniversity of Nebraska Medical Center\nOmaha\nNE\nUSA\n\n* Correspondence\n\nMichael J. Baine, Department of Radiation Oncology, University of Nebraska Medical Center, 986861 Nebraska Medical Center, Omaha, NE 68198‐686, USA.\n\nEmail: mbaine@unmc.edu\n\n01 12 2020 \n1 2021 \n9 1 10.1002/ccr3.v9.1477 481\n15 6 2020 22 8 2020 19 9 2020 © 2020 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\nThis case of sarcoidosis mimicking metastatic breast cancer serves as a reminder of the need to consider differential diagnoses even when the clinical scenario and imaging findings are highly suggestive of metastases.\n\nThis case of sarcoidosis mimicking metastatic breast cancer serves as a reminder of the need to consider differential diagnoses even when the clinical scenario and imaging findings are highly suggestive of metastases.\n\n\n\ninfectious diseasesoncology source-schema-version-number2.0cover-dateJanuary 2021details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:5.9.6 mode:remove_FC converted:18.01.2021\n\n\nVieira \nH \n, \nNeilsen \nBK \n, \nSleightholm \nR \n, et al. Diffuse lesions secondary to sarcoidosis mimicking widespread metastatic breast cancer: A case report\n. Clin Case Rep .2021 ;9 :477 –481\n. 10.1002/ccr3.3561\n==== Body\n1 INTRODUCTION\nA 71‐year‐old woman with a history of breast cancer presented with back pain and diffuse PET‐avid lesions consistent with diffuse metastatic disease but was found to represent biopsy‐proven sarcoidosis. This highlights the need for a broad differential even when the clinical scenario and imaging findings are highly suggestive of metastases.\n\nBreast cancer frequently metastasizes to lymphatics, bone, lung, liver, and brain, with bone being the most common hematogenous route and representing more than 70% of distant metastases.\n1\n Risk factors for bone metastasis include advanced clinical stage, lymph node metastases, negative progesterone receptor status, and tumor subtype.\n2\n On CT imaging, metastatic bone lesions can appear as either osteolytic or osteoblastic, or they can have a mix of osteolytic and osteoblastic features; they are most commonly located in the vertebrae and pelvis owing to the rich vascularization of these areas.\n3\n There are, however, several other conditions that can mimic the imaging findings of metastatic cancer and should be ruled out prior to ascribing the changes seen on imaging to metastatic spread.\n\nOne such condition is sarcoidosis, an inflammatory condition with highly variable clinical presentation and a hallmark pathological finding of non‐caseating epithelioid granulomatous inflammation. Sarcoid granulomas most often affect the lungs and lymph nodes in >90% of cases, but can be present in almost any tissue in the body.\n4\n Bone lesions are present in an estimated 3%‐13% of cases, most commonly in the small bones of the hands and feet; vertebral involvement is rare but has been reported.\n5\n Vertebral lesions have variable appearance on CT, with existing reports describing lytic, mixed lytic with sclerotic features, and sclerotic appearance.\n6\n, \n7\n Much like metastases and some infectious granulomas, sarcoid granulomas display increased avidity for fluorodeoxyglucose (FDG) during PET/CT imaging.\n8\n\n\n\nHerein, we present a case of a 71‐year‐old female with past medical history significant for breast cancer who was thought to have widely metastatic disease based on clinical picture and imagining findings, but was instead found to have an inflammatory cause for her widespread hypermetabolic bone and soft tissue lesions on biopsy.\n\n2 CASE PRESENTATION\nA 71‐year‐old Caucasian female presented with a chief complaint of acutely worsened lower back pain. The pain had come on over the previous two months and was localized over the upper lumbar spine. She reported an increase in intensity of the pain when lying flat. The patient had a longstanding history of chronic back pain, and two previous surgeries for adult tethered cord syndrome, but reported this pain to be significantly worse than what she had experienced before.\n\nNotably, her past medical history included a diagnosis 13 months prior of infiltrating ductal adenocarcinoma of the breast, which had been identified on routine screening mammogram. The tumor was determined on core needle biopsy to be ER (90%), PR (95%), and Her2 (3+) positive, with a Ki67 of 13%. She had undergone a left breast lumpectomy and sentinel lymph node biopsy with negative surgical margins. Final pathology from lumpectomy demonstrated the tumor was grade 2 and 1.2 cm in greatest dimension. Focal DCIS was present with high nuclear grade. The sample was without lymphovascular invasion. Pathology showed one of six sentinel nodes was positive for macrometastatic disease with associated extracapsular extension. Final pathological staging after lumpectomy and sentinel lymph node biopsy was pT1N1aMx.\n\nAfter lumpectomy, the patient had been treated with adjuvant chemotherapy followed by radiation therapy and hormonal therapy. Her chemotherapy regimen consisted of dose dense paclitaxel, cyclophosphamide, and trastuzumab for a total of six cycles, which was complicated by neutropenic fever following the first dose as well as a persistently infected wound of the toe prompting a dose reduction of paclitaxel and cyclophosphamide for the remaining five cycles, with plans to continue trastuzumab therapy for one year. Her radiation treatment was initiated five weeks following completion of her cyclophosphamide and paclitaxel treatment. Radiation treatment was delivered to the whole breast with high tangents using a hypofractionated course to a total dose of 4256 cGy delivered over 16 fractions followed by a 1000 cGy boost to the tumor bed delivered over five fractions. Given the ER‐positive status of her tumor, the patient was also started on anastrozole at the conclusion of her radiation therapy. Ten months after initial diagnosis and three months after the completion of radiation therapy, a diagnostic mammogram showed no evidence of disease in either breast. The patient was continued on trastuzumab and anastrozole.\n\nHer presentation with acutely worsened back pain occurred one week after completion of the one‐year of adjuvant trastuzumab therapy, and approximately 13 months after breast cancer diagnosis. A review of systems was negative for constitutional symptoms. Physical examination at the time of presentation showed tenderness to palpation midline in the upper lumbar spine, with limited range of motion bidirectionally due to pain. Neurological examination, including assessment of strength and gait, was normal. No laboratories were drawn at this time.\n\nAn MRI of the spine was ordered, which showed an abnormal signal and enhancement at L2, L4, and S1 in addition to iliac and sacral lesions consistent with metastatic disease (Figure 1). A follow‐up PET scan demonstrated multifocal hypermetabolic lesions in the mediastinum, hila, spleen, liver, abdominal and inguinal lymph nodes, as well as in multiple bones (SUVmax(range): 3‐5.75) suggestive of widespread and distant metastatic involvement (Figure 2). A biopsy of a liver lesion was planned for confirmation of metastatic disease but results from this failed to confirm the diagnosis of metastasis and showed no signs of malignancy, instead unexpectedly showing granulomatous hepatitis with multiple non‐caseating epithelioid granulomas.\n\nFigure 1 Representative sagittal (A) and coronal (B) MRI sections demonstrating lesions at L2/3 and L4\n\nFigure 2 Representative images from PET/CT scan. (A) PET/CT composite. (B) Coronal section on PET/CT. (C) Axial section of L2/3 lesion. (D) Axial section of L4 lesion\n\nDue to these non‐confirmatory findings on biopsy, the case was reviewed by a multidisciplinary tumor board comprising diagnostic radiology, pathology, oncology, and radiation oncology. The consensus from this session was that, despite the nondiagnostic biopsy results, the patient's imaging findings, clinical findings, and history of breast cancer were most consistent with metastatic disease and palliative radiation therapy with repeat biopsy of a separate site was recommended.\n\nTwo weeks later, the patient underwent a CT‐guided biopsy of the left iliac and right side of the L4 vertebral body. These biopsies again failed to demonstrate any evidence of malignancy but instead consistently demonstrated a non‐necrotizing granulomatous pattern of disease. Therefore, metastatic disease was no longer considered the likely diagnosis due to the biopsies of multiple sites failing to demonstrate any evidence of metastatic disease.\n\nA comprehensive workup was performed to evaluate for a possible infectious source for the lesions. A quantiferon test as well as urine and serum Ag/Ab tests for histoplasma, blastomycosis, coccidiomycosis, and treponema was completed with all tests coming back negative. PCR testing of the liver was also negative for acid‐fast bacilli and fungi. On further evaluation, it was noted that one year prior to her breast cancer diagnosis, the patient had complained of a persistent cough with evaluation demonstrating imaging evidence of possible sarcoidosis. She did not receive treatment for sarcoidosis at the time, and instead was instructed to return if her cough worsened. As a result of this additional information and her recent biopsy results demonstrating non‐necrotizing granulomas, the patient was referred to a rheumatologist, and her imaging findings were evaluated for their potential to represent widespread sarcoidosis. However, she still refrained from initiating steroid treatment for sarcoidosis as her back pain was thought to be more consistent with worsening osteoarthritis after consultation with a rheumatologist. A repeat MRI of the lumbar spine four months later demonstrated that the PET‐avid bone and soft tissue lesions were stable and comparable in size with what was seen in the previous MRI, providing further reassurance against a metastatic etiology for these lesions.\n\n3 DISCUSSION\nThis case report should serve as a cautionary tale describing alternative potential causes of imaging findings consistent with malignancy. Multiple groups have previously described additional cases or highlighted other causes of PET‐avid lesions that mimic malignancy on PET/CT scan that were largely observed during initial cancer staging or incidental findings on imaging. In this case, the patient presented with numerous lesions more than a year after her initial breast cancer diagnosis mimicking a more recurrent/metastatic clinical picture. Our patient presented with back pain, a common presenting symptom in patients with bone metastasis, and was then found to have multiple bone lesions on spine MRI and additional soft tissue involvement on subsequent PET imaging. Based on her past medical history, clinical picture, and corroborating imaging findings, this patient was believed to have metastatic disease for several weeks while awaiting biopsy results that revealed a nonmalignant etiology.\n\nKnown nonmalignant causes of FDG‐avid lesions include anything that induces inflammation or increased glucose uptake in tissue, which are commonly of infectious or autoimmune origin. Other groups have reported false positive PET scan findings can be caused by infectious diseases (including mycobacterial, fungal, or bacterial), sarcoidosis, trauma, and post‐operative surgical conditions in the absence of malignancy.\n9\n, \n10\n, \n11\n, \n12\n, \n13\n, \n14\n, \n15\n, \n16\n, \n17\n, \n18\n, \n19\n, \n20\n In fact, a concurrent diagnosis of sarcoidosis has been described in a case report when additional lesions were identified during initial cancer staging workup, but the additional lesions were subsequently determined to be nonmalignant.\n21\n Other alternative nonmalignant etiologies of bone lesions include fibrous dysplasia of bone, osteonecrosis, osteitis fibrosa cystica, and Paget's disease of bone, among others, can present with PET‐avid lesions on imaging and characteristic laboratory findings including hypercalcemia.\n10\n, \n13\n, \n14\n, \n15\n, \n22\n Infectious etiologies also need to be ruled out when PET‐avid bone lesions are identified as disseminated tuberculosis and multifocal osteomyelitis have both been reported to be mistaken for metastases on PET scan.\n12\n, \n16\n, \n18\n\n\n\nMultiple cutoff values have been proposed to distinguish between benign and malignant origins for increased FDG‐avidity. One group proposed an SUV cutoff of 3 for bone metastases with sensitivities ranging from 95.2% to 99.6% and specificity ranging from 75% to 100% for various primary malignancies including breast.\n23\n Another group evaluating rib metastases found the max SUV was higher in malignancy (3.0 ± 1.8) than in benign causes (2.5 ± 1.1), but had significant overlap and recommended a cutoff of 2.4.\n24\n Finally, in an evaluation for axillary metastasis as part of the initial workup for newly diagnosed breast cancer, a max SUV cutoff of 2.3 had a sensitivity of 60% and a specificity of 100%. However, no single cutoff is reliable in all circumstances and the range for benign vs. malignant causes overlap. For example, in our patient the SUVmax was 5.75 and 4.91 in two of her bone lesions with numerous areas of soft tissue and lymph nodes having an SUVmax above 3.\n\nWhile more qualitative metrics, the pattern of disease and other specific imaging findings can be used to try to distinguish between possible etiologies. For example, while the radiographic findings in sarcoidosis are highly variable, it tends to favor a symmetric and central distribution. Another radiographic finding that is commonly attributed to metastatic disease is increasing lymph node size. However, increasing size of lymph nodes on imaging can also have a range of non‐metastatic causes including sarcoidosis, fibrosing mediastinitis, or even a second, primary lymphoma.\n11\n, \n17\n, \n25\n\n\n\nIn this case, the patient's clinical presentation and history were consistent with metastatic disease, but her back pain and hypermetabolic lesions were ultimately determined to be nonmalignant in nature representing likely musculoskeletal and sarcoid‐related findings, respectively. Thus, the differential diagnoses in a patient with newly identified lesions on PET/CT should be evaluated according to the clinical scenario as well as specific imaging findings (level of SUVmax, CT or MRI findings). However, without confirmation from tissue biopsy there will always be at least a small amount of uncertainty. Therefore, lymph node and other image‐identified lesions should be biopsied whenever possible to confirm suspected metastases. Unfortunately, such a biopsy may not always be feasible due to complex anatomic location, patient history, or other complicating factors, could delay treatment, and therefore may be omitted in the setting of a clear clinical picture, patient history, and/or inability to obtain tissue biopsy.\n\n4 CONCLUSIONS\nIn this case, the consistency of the patient's clinical and imaging findings with metastatic disease and the much higher likelihood of metastatic disease vs. other causes in this clinical scenario supported the use of empiric therapy. Regardless, the possibility of another etiology causing similar findings on imaging should be considered and ruled out if at all possible prior to treatment. Empiric radiation therapy is commonly used in the setting of previously biopsy‐proven malignant disease for the purpose of pain palliation or for the prevention of impending anatomic damage (ie, spinal cord compression). However, the likelihood of metastatic disease and urgency of the clinical scenario should drive decision‐making in these situations. Ideally, timely imaging in conjunction with pathologic evidence of malignant disease should be obtained prior to any treatment if at all possible. Unfortunately, however, this is not always possible or routinely practiced in the setting of probable metastatic disease inducing significant pain or impending spinal cord compression.\n\nOverall, this case highlights the need to consider a wide differential of potential diagnoses even when the clinical scenario and imaging findings are highly suggestive of metastases. In addition, prompt biopsy confirmation of metastatic disease provides significant value through confirmation of the diagnosis even when the clinical and imaging data are suggestive thereby ensuring appropriate treatment.\n\nCONFLICT OF INTEREST\nThe authors declare no conflicts of interest.\n\nAUTHOR CONTRIBUTIONS\nHV, BN, and RS: reviewed patient records, drafted the case report, and revised the final manuscript. JH, AF, GM, AW, and MB: participated in direct patient care and provided the patient background and presentation. All authors: revised the final manuscript and gave final approval for publication.\n\nACKNOWLEDGMENT\nPublished with written consent of the patient.\n==== Refs\nREFERENCES\n1 \n\nSavci‐Heijink \nCD \n, \nHalfwerk \nH \n, \nHooijer \nGK \n, \nHorlings \nHM \n, \nWesseling \nJ \n, \nvan de Vijver \nMJ \n. Retrospective analysis of metastatic behaviour of breast cancer subtypes\n. 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Paget's disease mimicking bone metastasis in a patient with neuroendocrine tumor on (68)Ga‐DOTANOC PET/CT\n. J Belg Soc Radiol . 2016 ;100 (1 ):66 \n10.5334/jbr-btr.903 \n30151468 \n11 \n\nHua \nF \n, \nFeng \nX \n, \nGuan \nY \n, \nZhao \nJ \n, \nHuang \nZ \n. Non‐Hodgkin's lymphoma of supraclavicular lymph nodes can mimic metastasis of breast cancer during chemotherapy on FDG PET/CT\n. Clin Nucl Med . 2009 ;34 (9 ):594 ‐595\n. 10.1097/RLU.0b013e3181b06c2f \n19692820 \n12 \n\nJoo \nHS \n, \nHa \nJK \n, \nHwang \nCJ \n, \nLee \nDH \n, \nLee \nCS \n, \nCho \nJH \n. Lumbar cryptococcal osteomyelitis mimicking metastatic tumor\n. Asian Spine J . 2015 ;9 (5 ):798 ‐802\n. 10.4184/asj.2015.9.5.798 \n26435802 \n13 \n\nSchnyder \nMA \n, \nStolzmann \nP \n, \nHuber \nGF \n, \nSchmid \nC \n. A patient with a history of breast cancer and multiple bone lesions: a case report\n. 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Intern Med . 2014 ;53 (21 ):2555 ‐2556\n. 10.2169/internalmedicine.53.3333 \n25366024 \n18 \n\nAlexiou \nE \n, \nGeorgoulias \nP \n, \nValotassiou \nV \n, \nGeorgiou \nE \n, \nFezoulidis \nI \n, \nVlychou \nM \n. Multifocal septic osteomyelitis mimicking skeletal metastatic disease in a patient with prostate cancer\n. Hell J Nucl Med . 2015 ;18 (1 ):77 ‐78\n. 10.1967/s002449910168 \n25679079 \n19 \n\nConte \nG \n, \nZugni \nF \n, \nColleoni \nM \n, \nRenne \nG \n, \nBellomi \nM \n, \nPetralia \nG \n. Sarcoidosis with bone involvement mimicking metastatic disease at (18)F‐FDG PET/CT: problem solving by diffusion whole‐body MRI\n. Ecancermedicalscience . 2015 ;9 :537 \n10.3332/ecancer.2015.537 \n26015806 \n20 \n\nAshamalla \nM \n, \nKoutroumpakis \nE \n, \nMcCarthy \nL \n, \nHegener \nP \n, \nGrimm \nR \n, \nMehdi \nS \n. Osseous sarcoidosis mimicking metastatic cancer on positron emission tomography\n. J Oncol Pract . 2016 ;12 (7 ):697 ‐698\n. 10.1200/JOP.2016.012807 \n27407163 \n21 \n\nSpiekermann \nC \n, \nKuhlencord \nM \n, \nHuss \nS \n, \nRudack \nC \n, \nWeiss \nD \n. Coexistence of sarcoidosis and metastatic lesions: a diagnostic and therapeutic dilemma\n. Oncol Lett . 2017 ;14 (6 ):7643 ‐7652\n. 10.3892/ol.2017.7247 \n29344212 \n22 \n\nGaze \nMN \n, \nNeville \nE \n, \nRooke \nHW \n. Bone scan hot spots in a patient with lung cancer: ischaemic necrosis of bone mimicking metastatic carcinoma\n. Clin Oncol (R Coll Radiol) . 1991 ;3 (3 ):177 ‐179\n.2069879 \n23 \n\nWafaie \nAKH \n, \nKotb \nM \n, \nZeitoun \nR \n, \nIsmail \nS \n. Evaluation of the efficiency of FDG PET/CT in detection and characterization of skeletal metastases\n. Egypt J Radiol Nucl Med . 2014 ;45 (1 ):181 ‐190\n. 10.1016/j.ejrnm.2013.11.007 \n\n24 \n\nChoi \nHS \n, \nYoo Ie \nR \n, \nPark \nHL \n, \nChoi \nEK \n, \nKim \nSH \n, \nLee \nWH \n. Role of (1)(8)F‐FDG PET/CT in differentiation of a benign lesion and metastasis on the ribs of cancer patients\n. Clin Imaging . 2014 ;38 (2 ):109 ‐114\n. 10.1016/j.clinimag.2013.11.011 \n24361174 \n25 \n\nOkamoto \nK \n, \nIchinose \nM \n. Idiopathic fibrosing mediastinitis mimicking nodal metastasis from breast cancer\n. Asian Cardiovasc Thorac Ann . 2017 ;25 (9 ):663 ‐664\n. 10.1177/0218492317691156 \n28114793\n\n",
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"title": "Diffuse lesions secondary to sarcoidosis mimicking widespread metastatic breast cancer: A case report.",
"title_normalized": "diffuse lesions secondary to sarcoidosis mimicking widespread metastatic breast cancer a case report"
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"abstract": "OBJECTIVE\nTo establish an appropriate administration schedule for oxaliplatin in FOLFOX plus bevacizumab therapy for a hemodialytic patient.\n\n\nMETHODS\nA 50-year-old man on chronic hemodialysis was treated for colon cancer and synchronous hepatic metastasis with modified FOLFOX-6 plus bevacizumab therapy every 3 weeks. The plasma concentration of free platinum was measured at eight points, before and within the first 50 h after oxaliplatin administration. A dose escalation study of oxaliplatin was performed at doses of 60, 70, and 85 mg/m(2). A 4-h dialysis session was begun at the end of the oxaliplatin treatment.\n\n\nRESULTS\nThe pharmacokinetics of free platinum showed a bimodal pattern at each dose: The serum concentration decreased rapidly soon after dialysis, then increased, and remained at a high level for 24 h. The areas under the curves (AUC) for free platinum were 17.6, 23.6, and 32.6 μg h/mL after doses of 60, 70, and 85 mg/m(2) oxaliplatin, respectively. These exceeded the AUC when 90 mg/m(2) was given to a patient with normal renal function (7.9 μg h/mL). Treatment was safely continued for 6 months without severe toxicity.\n\n\nCONCLUSIONS\nFOLFOX plus bevacizumab therapy can be given safely to hemodialytic patients with no reduction in the dose of oxaliplatin if hemodialysis is performed soon after the administration of oxaliplatin and the dosing interval is extended to 3 weeks.",
"affiliations": "Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, 54 Shogoinkawaharacho, Sakyo-ku, Kyoto 606-8507, Japan.",
"authors": "Horimatsu|Takahiro|T|;Miyamoto|Shin'ichi|S|;Morita|Shuko|S|;Mashimo|Yoko|Y|;Ezoe|Yasumasa|Y|;Muto|Manabu|M|;Chiba|Tsutomu|T|",
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"mesh_terms": "D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D000971:Antineoplastic Combined Chemotherapy Protocols; D000068258:Bevacizumab; D015179:Colorectal Neoplasms; D005472:Fluorouracil; D006801:Humans; D002955:Leucovorin; D008113:Liver Neoplasms; D008297:Male; D008875:Middle Aged; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D006435:Renal Dialysis",
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"title": "Pharmacokinetics of oxaliplatin in a hemodialytic patient treated with modified FOLFOX-6 plus bevacizumab therapy.",
"title_normalized": "pharmacokinetics of oxaliplatin in a hemodialytic patient treated with modified folfox 6 plus bevacizumab therapy"
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... |
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"abstract": "Hysterectomy has a limited role in the management of gestational trophoblastic neoplasia because of the high effectiveness of chemotherapy and the young age of patients. In selected patients, it is believed to help in reducing the number of chemotherapy cycles, overcoming chemo-resistance, and treating acute haemorrhagic events. The present study aimed to evaluate the indications and outcomes of hysterectomy in patients with GTN at a tertiary care centre in India. Between 2012 and 2019, we identified all patients with GTN from the hospital database. Demographic, clinical, and follow-up details of patients who underwent hysterectomy were obtained from the electronic medical records. During the study period, 98 cases of GTN were treated at our centre of which 54% were low-risk and 46% were high-risk cases. Twenty-six patients (26%) underwent hysterectomy as part of their management for GTN. The patients belonging to the high-risk group had more hysterectomies (65%) with an odds ratio of 2.96. The common pathological diagnosis was choriocarcinoma in 44% and an invasive mole in 30% of patients. Bleeding, either intraperitoneal or vaginal, was the most common indication for hysterectomy (48%). The median number of chemotherapy cycles received was 5 in patients who had primary hysterectomy and 6 in patients who did not have hysterectomy. The majority of patients received EMACO (57.7%) chemotherapy. The mean duration of follow-up was 18 months (range 1-67). After treatment, complete remission was achieved in 94 out of 98 (95.9%) and also in all patients (100%) who had undergone hysterectomy as adjuvant procedure. Three patients died during treatment (3.06%), all belonging to the high-risk group, and one patient had a recurrence (0.01%). In selected cases of GTN, hysterectomy may be an effective means to reduce or eliminate tumour bulk, to overcome chemoresistance and manage acute bleeding events.",
"affiliations": "Department of Gynaecologic Oncology, Christian Medical College, CMC Hospital, Vellore, Tamil Nadu 632004 India.;Department of Gynaecologic Oncology, Christian Medical College, CMC Hospital, Vellore, Tamil Nadu 632004 India.;Department of Gynaecologic Oncology, Christian Medical College, CMC Hospital, Vellore, Tamil Nadu 632004 India.;Department of Gynaecologic Oncology, Christian Medical College, CMC Hospital, Vellore, Tamil Nadu 632004 India.;Department of Gynaecologic Oncology, Christian Medical College, CMC Hospital, Vellore, Tamil Nadu 632004 India.;Department of Gynaecologic Oncology, Christian Medical College, CMC Hospital, Vellore, Tamil Nadu 632004 India.;Department of Gynaecologic Oncology, Christian Medical College, CMC Hospital, Vellore, Tamil Nadu 632004 India.",
"authors": "Ramesan|C K|CK|;Thomas|Dhanya Susan|DS|;Sebastian|Ajit|A|;Thomas|Vinotha|V|;Thomas|Anitha|A|0000-0002-5533-0184;George|Rachel|R|;Peedicayil|Abraham|A|",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": "10.1007/s13193-021-01328-2",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0975-7651",
"issue": "12(2)",
"journal": "Indian journal of surgical oncology",
"keywords": "Gestational trophoblastic neoplasia; Hysterectomy",
"medline_ta": "Indian J Surg Oncol",
"mesh_terms": null,
"nlm_unique_id": "101532448",
"other_id": null,
"pages": "386-390",
"pmc": null,
"pmid": "34295083",
"pubdate": "2021-06",
"publication_types": "D016428:Journal Article",
"references": "16816073;29887485;20739008;30306586;18851873;13379512;18720927;20626174;30612545",
"title": "Role of Hysterectomy in Gestational Trophoblastic Neoplasia.",
"title_normalized": "role of hysterectomy in gestational trophoblastic neoplasia"
} | [
{
"companynumb": "IN-MYLANLABS-2021M1088787",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "ETOPOSIDE"
},
"drugadditional": null,
... |
{
"abstract": "The aim of the presentation of this case is to discuss whether there is an association with eosinophilic granulomatosis with polyangiitis (EGPA) and the use of montelukast, and clarithromycin and to discuss a successful treatment course. A 4-year-old girl with a preceding history of asthma attacks and increased eosinophil counts was admitted. She had been using clarithromycin for five days and montelucast for a month. She was eventually diagnosed with EGPA with detailed examination. Clinicians should remember EGPA in children with asthma and hypereosinophilia. Patients receiving leukotriene receptor antagonists and/or macrolides should be monitored for developing a multisystem disease. Treatment with immunosuppressive agents may be required to ensure a good prognosis.",
"affiliations": "Department of Pediatrics, Dr. Sami Ulus Maternity and Children's Health and Diseases Training and Research Hospital, Ankara, Turkey.;Department of Pediatric Nephrology/rheumatology, Dr. Sami Ulus Maternity/ Children's Health and Diseases Training and Research Hospital, Ankara, Turkey.;Department of Dermatology, Dr. Sami Ulus Maternity and Children's Health and Diseases Training and Research Hospital, Ankara, Turkey.;Department of Pediatrics, Dr. Sami Ulus Maternity and Children's Health and Diseases Training and Research Hospital, Ankara, Turkey.;Department of Pediatrics, Dr. Sami Ulus Maternity and Children's Health and Diseases Training and Research Hospital, Ankara, Turkey.;Department of Pediatrics, Dr. Sami Ulus Maternity and Children's Health and Diseases Training and Research Hospital, Ankara, Turkey.",
"authors": "Altinel Acoglu|Esma|E|;Yazilitas|Fatma|F|;Gurkan|Asuman|A|;Sari|Eyup|E|;Senel|Saliha|S|;Akcaboy|Meltem|M|",
"chemical_list": "D000085:Acetates; D018927:Anti-Asthmatic Agents; D003521:Cyclopropanes; D011804:Quinolines; D013440:Sulfides; C093875:montelukast",
"country": "Iran",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1029-2977",
"issue": "22(3)",
"journal": "Archives of Iranian medicine",
"keywords": "Children; Churg strauss syndrome (CSS); Clarithromycin; Eosinophilic granulomatosis with polyangiitis; Montelukast",
"medline_ta": "Arch Iran Med",
"mesh_terms": "D000085:Acetates; D018927:Anti-Asthmatic Agents; D001249:Asthma; D002675:Child, Preschool; D003521:Cyclopropanes; D004804:Eosinophils; D005260:Female; D014890:Granulomatosis with Polyangiitis; D006801:Humans; D011804:Quinolines; D013440:Sulfides",
"nlm_unique_id": "100889644",
"other_id": null,
"pages": "161-163",
"pmc": null,
"pmid": "31029073",
"pubdate": "2019-03-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Eosinophilic Granulomatosis with Polyangiitis in a 4-Year-Old Child: Is Montelukast and/or Clarithromycin a Trigger?",
"title_normalized": "eosinophilic granulomatosis with polyangiitis in a 4 year old child is montelukast and or clarithromycin a trigger"
} | [
{
"companynumb": "TR-TEVA-2019-TR-1083966",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
},
"drugadditional": "1",
... |
{
"abstract": "A 72-year-old Japanese woman with rheumatoid arthritis whose activity decreased with previous treatments had recurrent thunderclap headaches during an atovaquone regimen for the treatment of pneumocystis pneumonia. The recurrent headaches disappeared after discontinuation of the drug. Brain magnetic resonance images showed multiple cerebral vasoconstrictions of cerebral arteries with vasogenic cerebral white matter edema, which diminished several weeks later. We diagnosed the patient's headaches as reversible cerebral vasoconstriction syndrome due to atovaquone.",
"affiliations": "Department of Neurology, Chibaken Saiseikai Narashino Hospital, Narashino, Japan.;Department of Neurology, Chibaken Saiseikai Narashino Hospital, Narashino, Japan.;Office of Medical Education, Graduate School of Medicine, Chiba University, Chiba, Japan.",
"authors": "Makino|Takahiro|T|;Kamitsukasa|Ikuo|I|;Ito|Shoichi|S|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000484551",
"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 10.1159/000484551crn-0009-0304Case ReportReversible Cerebral Vasoconstriction Syndrome due to Atovaquone Makino Takahiro a*Kamitsukasa Ikuo aIto Shoichi baDepartment of Neurology, Chibaken Saiseikai Narashino Hospital, Narashino, JapanbOffice of Medical Education, Graduate School of Medicine, Chiba University, Chiba, Japan*Takahiro Makino, Department of Neurology, Chibaken Saiseikai Narashino Hospital, 1-1-1 Izumi Chou, Narashino 275-8580 (Japan), E-Mail takamkt2@gmail.comSep-Dec 2017 19 12 2017 19 12 2017 9 3 304 308 4 8 2017 19 10 2017 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.A 72-year-old Japanese woman with rheumatoid arthritis whose activity decreased with previous treatments had recurrent thunderclap headaches during an atovaquone regimen for the treatment of pneumocystis pneumonia. The recurrent headaches disappeared after discontinuation of the drug. Brain magnetic resonance images showed multiple cerebral vasoconstrictions of cerebral arteries with vasogenic cerebral white matter edema, which diminished several weeks later. We diagnosed the patient's headaches as reversible cerebral vasoconstriction syndrome due to atovaquone.\n\nKeywords\nReversible cerebral vasoconstriction syndromePosterior reversible encephalopathy syndromeAtovaquone\n==== Body\nIntroduction\nReversible cerebral vasoconstriction syndrome (RCVS) is characterized by severe headaches with diffuse segmental constrictions of cerebral arteries, and the nature of the headaches is usually recurrent thunderclap headaches. There are various precipitants of RCVS including catecholamine-secreting tumors, eclampsia, and the use of illicit drugs, antidepressants, triptans, intravenous immunoglobulin, or red-blood-cell transfusion [1]. RCVS is often accompanied by vasogenic edema in cerebral white matter, which can be considered posterior reversible encephalopathy syndrome (PRES), and the coexistence of RCVS and PRES suggests that there is a dysfunction of vascular endothelium in the development of those conditions [1].\n\nPneumocystis infection can occur in association with immunosuppressants including prednisolone and methotrexate in rheumatoid arthritis (RA) patients. Atovaquone is one member of the class of hydroxynaphtoquinones that has potent activity against Pneumocystis carinii [2]. Although headaches can be observed as an adverse effect of atovaquone use [2], to our knowledge, RCVS associated with atovaquone has not been reported previously. Here, we report the case of a woman who had recurrent thunderclap headaches while taking atovaquone, with cerebral vasoconstrictions that diminished over 8 weeks following the discontinuation of atovaquone.\n\nCase Presentation\nA 72-year-old Japanese woman with hypertension and diabetes mellitus had been suffering from RA for 20 years when she was admitted to our hospital for the treatment of pneumocystis pneumonia. Her immune condition was probably suppressed due to 20 mg prednisolone and 8 mg methotrexate (MTX) which she had been taking for her RA. We discontinued MTX, but 20 mg prednisolone was continued. For the treatment of the patient's pneumonia, 2 g sulfamethoxazole trimethoprim was started, but it was switched to 1,500 mg atovaquone because severe diarrhea was observed.\n\nThe patient's blood pressure was normal (130/80 mm Hg) on admission. However, excessive hypotension was observed after admission, and antihypertensive drugs including 10 mg amlodipine, 100 mg irbesartan, and 50 mg eplerenone were discontinued. Her diabetes mellitus was continuously treated with 50 mg sitagliptin and 0.5 mg glimepiride.\n\nSixteen days after the patient had started taking atovaquone, thunderclap headaches lasting several hours repeatedly occurred twice a day. She had no medical history of recurrent headaches. No remarkable elevation of blood pressure was observed during the headache attacks. The recurrent headache could not be relieved by nonsteroidal anti-inflammatory drugs. No abnormal neurological signs or arthralgia were observed.\n\nThe duration and the intensity of the recurrent headache increased for 3 days after the onset of the headache. Blood tests, CT, and MRI of the brain were examined. The blood tests showed an elevated white blood cell count and erythrocyte sedimentation rate (11,000/μL and 90 mm/h, respectively). The brain CT showed no abnormal findings including subarachnoid hemorrhage, cerebral hemorrhage, and infarction, but the brain MRI showed multiple vasoconstrictions with vasogenic white matter edema (Fig. 1). As the headache of the patient was considered to occur and increase in relation with taking atovaquone, we stopped administrating it. Three days after discontinuing this drug, the patient's headache disappeared. Lumbar puncture was not performed because the headache did not recur after the discontinuation of atovaquone. Eight weeks after the initial MR images, the white matter abnormalities and the vasoconstrictions of the cerebral arteries disappeared except for slight necrotic white matter lesions on follow-up brain MRI (Fig. 2). She was diagnosed with RCVS with PRES due to atovaquone.\n\nDiscussion\nThe recurring thunderclap headaches of our patient occurred during the atovaquone regimen, we continued her other medications except for MTX, which was discontinued 3 weeks before the onset of the headaches. There was no obvious elevation of blood pressure when the headaches occurred despite the discontinuation of antihypertensive drugs for the patient's excessive low blood pressure. The headaches disappeared within 3 days after discontinuing atovaquone. A brain MR angiography showed reversible cerebral vasoconstrictions that had improved on follow-up MRI scans. Our patient's recurrent thunderclap headaches could thus be diagnosed as RCVS in association with the atovaquone regimen.\n\nIt is important to identify causes of RCVS based on the medication history and the time course of the clinical symptoms such as headache. In the presented case, the headache successfully improved several days after the discontinuation of atovaquone along with the disappearance of RCVS on MRI, so it is speculated that the headache was caused by RCVS due to atovaquone. Regarding the clinical outcome of RCVS in general, women are at a high risk of RCVS with intracranial hemorrhage which determines long-term prognosis of RCVS [3]; though most patients with RCVS have a good clinical outcome [1, 3]. Although the recurrence of thunderclap headache is not significantly related to RCVS with intracranial hemorrhage [3], early diagnosis of RCVS as a cause of headache and appropriate treatment result in good clinical outcome. The primary treatment of patients with RCVS should be the identification and elimination of aggravating factors including drugs, the recommendation of rest, and the administration of drugs targeting vasospasms, such as nimodipine and verapamil, in addition to symptomatic management including analgesics, antiepileptic drugs for seizures, and antihypertensive agents with monitoring of the patient's blood pressure [1].\n\nThe mechanism by which the use of atovaquone induces RCVS is not clear. Though the exact mechanisms of RCVS are unknown, it is possible that endothelial dysfunction [1] or alterations in vascular tone [4] may have a role in the occurrence of RCVS. In addition, PRES has been speculated to have underlying mechanisms similar to those of RCVS, e.g., specific alterations of vascular endothelial function. It has been reported that nearly half of the patients with PRES have autoimmune disorders [5]. In the presented case, it is possible that any alterations of endothelial functions, associated with some pharmacological effects of atovaquone, or comorbid autoimmune disorders, such as RA, may induce an abnormality of vascular tone, and subsequently cause RCVS with PRES.\n\nThe probability of the association between headaches and the administration of atovaquone is scaled as “likely” by the Naranjo Adverse Drug Reactions Probability Scale, which is used to objectively evaluate adverse drug effects [6]. In a review, adverse effects of atovaquone on the central nervous system, such as headaches, dizziness, and insomnia, have been observed in 14% [2]. RCVS may account for some of the headaches associated with the administration of atovaquone.\n\nWe have presented the case of a patient with recurrent thunderclap headaches due to RCVS associated with the administration of atovaquone. When recurrent headaches are experienced by an individual who is taking atovaquone, RCVS should be considered.\n\nStatement of Ethics\nThe patient provided informed consent to participate in this study and for publication of this paper with figures. This case report was approved by the institutional review board.\n\nDisclosure Statement\nThe authors declare no conflicts of interest.\n\nFig. 1. The initial fluid-attenuated inversion recovery image (A) and the apparent diffusion coefficient map (B) show vasogenic white matter edema in the parietal lobe. Time of flight MR angiography (C–E) shows multiple vasoconstrictions in bilateral anterior communicating, middle, and posterior cerebral arteries. Enlarged images of the posterior cerebral artery (D) and the anterior communicating artery (E) show multiple vasoconstrictions (arrows).\n\nFig. 2. On follow-up images obtained 8 weeks after the initial images, parietal white matter lesions (A, B) and vasoconstrictions of the cerebral arteries (C–E) are not found except for slight necrotic white matter lesions.\n==== Refs\nReferences\n1 Ducros A Reversible cerebral vasoconstriction syndrome. Lancet Neurol 2012 11 906 917 22995694 \n2 Haile LG Flaherty JF Atovaquone: a review. Ann Pharmacother 1993 27 1488 1494 8305784 \n3 Ducros A Fiedler U Porcher R Hemorrhagic manifestations of reversible cerebral vasoconstriction syndrome: frequency, features, and risk factors. Stroke 2010 41 2505 2511 20884871 \n4 Calabrese LH Dodick DW Schwedt TJ Narrative review: reversible cerebral vasoconstriction syndromes. Ann Intern Med 2007 146 34 44 17200220 \n5 Fugate JE Rabinstein AA Posterior reversible encephalopathy syndrome: clinical and radiological manifestations, pathophysiology, and outstanding questions. Lancet Neurol 2015 14 914 925 26184985 \n6 Naranjo CA Busto U Sellers EM A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther 1981 30 239 245 7249508\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1662-680X",
"issue": "9(3)",
"journal": "Case reports in neurology",
"keywords": "Atovaquone; Posterior reversible encephalopathy syndrome; Reversible cerebral vasoconstriction syndrome",
"medline_ta": "Case Rep Neurol",
"mesh_terms": null,
"nlm_unique_id": "101517693",
"other_id": null,
"pages": "304-308",
"pmc": null,
"pmid": "29422854",
"pubdate": "2017",
"publication_types": "D002363:Case Reports",
"references": "17200220;22995694;26184985;20884871;7249508;8305784",
"title": "Reversible Cerebral Vasoconstriction Syndrome due to Atovaquone.",
"title_normalized": "reversible cerebral vasoconstriction syndrome due to atovaquone"
} | [
{
"companynumb": "JP-MYLANLABS-2018M1060791",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "IRBESARTAN"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nLymphomatoid drug reactions can mimic endogenous T and B cell lymphoproliferative diseases.\n\n\nOBJECTIVE\nWe present a novel form of cutaneous drug reaction with features of pityriasis lichenoides (PL), a recognized form of T cell dyscrasia.\n\n\nMETHODS\nTen cases were studied where a cutaneous eruption exhibiting semblance to PL within a few weeks to months after starting a particular drug.\n\n\nRESULTS\nThe patient cohort comprised 7 females and 3 males with the mean age of 60 years. Widely distributederythematous cutaneous lesions were present in 6 cases whereas a more localized distribution was seen in three cases. The most frequently implicated drugsassociated with the eruption were antidepressants and statins. Histologic examination showed a morphologic picture identical to PL including marked epitheliotropism of mildly atypical lymphocytes, psoriasiform epidermal hyperplasia, dyskeratosis, hemorrhage, and a thick parakeratotic scale. Therewas a significant reduction in the expression of CD7 and CD62L amid the T cells. Regression of the eruption occurred in all cases excluding one.\n\n\nCONCLUSIONS\nThefindings conform the categorization of this process as a form of T-cell dyscrasia albeit one that is reversible, dependent on the drug withdrawal. The limitationof our study includes the retrospective design of the study.",
"affiliations": "Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, New York. cym2003@med.cornell.edu.",
"authors": "Magro|Cynthia|C|;Guo|Ruifeng|R|;Nguyen|Giang Huong|GH|;Tsang|Hamilton|H|;Momtahen|Shabnam|S|",
"chemical_list": "D000928:Antidepressive Agents; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1087-2108",
"issue": "23(11)",
"journal": "Dermatology online journal",
"keywords": null,
"medline_ta": "Dermatol Online J",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000928:Antidepressive Agents; D003937:Diagnosis, Differential; D003875:Drug Eruptions; D005260:Female; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D017512:Lichenoid Eruptions; D008297:Male; D008875:Middle Aged; D017514:Pityriasis Lichenoides; D012189:Retrospective Studies; D012867:Skin; D013601:T-Lymphocytes",
"nlm_unique_id": "9610776",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "29447634",
"pubdate": "2017-11-15",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Pityriasis lichenoides-like drug reaction: A clinical histopathologic study of 10 cases.",
"title_normalized": "pityriasis lichenoides like drug reaction a clinical histopathologic study of 10 cases"
} | [
{
"companynumb": "US-MYLANLABS-2018M1021314",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "GABAPENTIN"
},
"drugadditional": "1",
... |
{
"abstract": "The escalated BEACOPP (escBEACOPP) regimen improves the outcome of patients with advanced-stage Hodgkin lymphoma (HL) but is associated with cumbersome toxicity. We analyzed the survival outcome of high-risk, advanced-stage HL patients treated with response-adapted therapy. escBEACOPP was administered for 2 cycles, and after complete remission (CR) or partial remission (PR) was observed on FDG-PET/CT, treatment was de-escalated to 4 cycles of ABVD. Sixty-nine patients were evaluated, of them 45 participated in the multicenter, phase II prospective study between 2001 and 2007. Sixty patients had an international prognostic score ≥3. At a median follow-up of 5.6 years, 4 patients had died, 2 of them due to advanced HL. After the initial 2 cycles of escBEACOPP, 52 (75%) patients were in CR and 17 (25%) had a PR. Progression-free survival and overall survival (OS) were 79 and 93%, respectively. OS was predicted from the results of early-interim FDG-PET/CT: 98% of the patients in CR and 79% of those with a PR (p = 0.015). Hematological toxicity was more frequent during the first 2 cycles of escBEACOPP than in the ABVD phase. In conclusion, this retrospective analysis indicates that combined escBEACOPP-ABVD therapy is well tolerated and efficacious in HL patients who achieve negative early-interim PET results, while a positive PET result partially identified those with a worse prognosis.",
"affiliations": "Division of Hematology and Bone Marrow Transplantation, Chaim Sheba Medical Center and Sackler School of Medicine, Tel Aviv University, Tel Hashomer, Israel.",
"authors": "Kedmi|Meirav|M|;Apel|Arie|A|;Davidson|Tima|T|;Levi|Itai|I|;Dann|Eldad J|EJ|;Polliack|Aaron|A|;Ben-Bassat|Isaac|I|;Nagler|Arnon|A|;Avigdor|Abraham|A|",
"chemical_list": "D019788:Fluorodeoxyglucose F18; D001761:Bleomycin; D011344:Procarbazine; D014750:Vincristine; D014747:Vinblastine; D005047:Etoposide; D003606:Dacarbazine; D004317:Doxorubicin; D003520:Cyclophosphamide; D011241:Prednisone",
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000441962",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0001-5792",
"issue": "135(3)",
"journal": "Acta haematologica",
"keywords": null,
"medline_ta": "Acta Haematol",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D001761:Bleomycin; D003520:Cyclophosphamide; D003606:Dacarbazine; D004317:Doxorubicin; D005047:Etoposide; D005260:Female; D019788:Fluorodeoxyglucose F18; D005500:Follow-Up Studies; D006689:Hodgkin Disease; D006801:Humans; D008297:Male; D009367:Neoplasm Staging; D016609:Neoplasms, Second Primary; D049268:Positron-Emission Tomography; D011241:Prednisone; D011344:Procarbazine; D012074:Remission Induction; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome; D014747:Vinblastine; D014750:Vincristine",
"nlm_unique_id": "0141053",
"other_id": null,
"pages": "156-61",
"pmc": null,
"pmid": "26588173",
"pubdate": "2016",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "High-Risk, Advanced-Stage Hodgkin Lymphoma: The Impact of Combined Escalated BEACOPP and ABVD Treatment in Patients Who Rapidly Achieve Metabolic Complete Remission on Interim FDG-PET/CT Scan.",
"title_normalized": "high risk advanced stage hodgkin lymphoma the impact of combined escalated beacopp and abvd treatment in patients who rapidly achieve metabolic complete remission on interim fdg pet ct scan"
} | [
{
"companynumb": "IL-BAXTER-2016BAX035478",
"fulfillexpeditecriteria": "1",
"occurcountry": "IL",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "BLEOMYCIN SULFATE"
},
"drugadditional": null,
... |
{
"abstract": "Histoplasma capsulatum can rarely affect the trachea. We report the case of a 68-year-old woman with rheumatoid arthritis on immunosuppressive therapy who presented with fevers, worsening shortness of breath, nonproductive cough and subjective throat hoarseness and fullness. Chest computed tomography demonstrated no tracheal findings. Bronchoscopy found mucosal irregularity, nodularity and vesicular regions in the proximal trachea extending seven centimeters distal to the vocal cords. Also seen was an edematous, exudative left vocal cord with polyps and an ulcerative lesion. Silver staining and culture and wash of the tracheal biopsy revealed Histoplasma capsulatum. She was treated with oral itraconazole then briefly on intravenous amphotericin for rising Histoplasma urinary antigen levels. She continued treatment 24 months following diagnosis with minimal dyspnea. Histoplasma tracheitis has been proposed as an indicator of disseminated infection. However, our patient did not demonstrate other organ manifestations. Histoplasma tracheitis should be considered in a differential diagnosis of tracheal lesions even in the absence of systemic involvement.",
"affiliations": "Department of Radiology, University Hospitals Case Medical Center, Cleveland, OH, USA.;School of Medicine, Case Western Reserve University, Cleveland, OH, USA.;Department of Pathology, Mount Carmel Health System, Columbus, OH, USA.;Department of Infectious Disease, Mount Carmel Health System, Columbus, OH, USA.;Department of Pulmonary and Critical Care Medicine, Mount Carmel Health System, Columbus, OH, USA.",
"authors": "Bhojwani|Nicholas|N|http://orcid.org/0000-0002-7998-4131;Hartman|Jason Brett|JB|;Taylor|David C|DC|;Herbert|Mark|M|;Corriveau|Michael|M|",
"chemical_list": "D000935:Antifungal Agents; D017964:Itraconazole; D000666:Amphotericin B",
"country": "England",
"delete": false,
"doi": "10.1111/crj.12185",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1752-6981",
"issue": "10(2)",
"journal": "The clinical respiratory journal",
"keywords": "Histoplasma; bronchoscopy; immunosuppression; trachea",
"medline_ta": "Clin Respir J",
"mesh_terms": "D061605:Administration, Intravenous; D000368:Aged; D000666:Amphotericin B; D000935:Antifungal Agents; D003937:Diagnosis, Differential; D005260:Female; D006658:Histoplasma; D006660:Histoplasmosis; D006801:Humans; D017964:Itraconazole; D014132:Trachea; D016896:Treatment Outcome",
"nlm_unique_id": "101315570",
"other_id": null,
"pages": "255-8",
"pmc": null,
"pmid": "25043266",
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"abstract": "Despite compelling evidence that cannabis use is associated with neurocognitive deficits, loss of cerebral gray matter, relapse and rehospitalization, a substantial number of individuals with early psychosis continue to use recreational or medicinal marijuana. One identified pathway to relapse is non-adherence. Recurrent relapses modify the trajectory of illness and culminate in long-term disability. Long-acting antipsychotic medications are superior to oral equivalents in preventing relapse.\nThe current paper sought to examine the role of long-acting antipsychotics in preventing relapse in cannabis using early psychosis patients.\nThe present retrospective study, which was based in an early psychosis program in mid-Michigan, examined the association between patient perceptions of antipsychotic medication and subsequent rehospitalization, among cannabis users (n = 24) and non-users (n = 27). Patient perceptions of antipsychotic medications were assessed using a single question from the NAVIGATE Patient Self-Rating Form: \"Between now and your next visit, do you think we should keep your medication the same, or consider changing the medication?\".\nCannabis users were substantially more likely to report dissatisfaction with antipsychotic medication (Pearson Chi-square 9.67, df = 1.0, p < 0.002), and more likely to experience rehospitalization (Pearson Chi-square 4.40, df = 1.0, p = 0.036). Those maintained on long-acting injectable antipsychotic medications were rehospitalized less frequently when compared to others maintained on oral formulations (Pearson Chi-square 4.61, df = 1.0, p = 0.032).\nDissatisfaction with antipsychotics may predict non-adherence and subsequent rehospitalization in early psychosis patients who use cannabis. Long-acting antipsychotics may prevent rehospitalization.",
"affiliations": "College of Osteopathic Medicine, Michigan State University, United States.;Department of Psychiatry, Michigan State University, United States.;Department of Psychiatry, Michigan State University, United States.;Early Treatment & Cognitive Health, United States.;Early Treatment & Cognitive Health, United States.",
"authors": "Rozin|Emily|E|;Vanaharam|Vivek|V|;D'Mello|Dale|D|;Palazzolo|Scott|S|;Adams|Cathy|C|",
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"doi": "10.1016/j.abrep.2019.100221",
"fulltext": "\n==== Front\nAddict Behav RepAddict Behav RepAddictive Behaviors Reports2352-8532Elsevier S2352-8532(19)30056-210.1016/j.abrep.2019.100221100221Research PaperA retrospective study of the role of long-acting injectable antipsychotics in preventing rehospitalization in early psychosis with cannabis use Rozin Emily rozinemi@msu.edua⁎Vanaharam Vivek bc1D'Mello Dale bcPalazzolo Scott cAdams Cathy ca College of Osteopathic Medicine, Michigan State University, United Statesb Department of Psychiatry, Michigan State University, United Statesc Early Treatment & Cognitive Health, United States⁎ Corresponding author: 264 Lake Ridge Dr, Kalamazoo, MI 49006, USA. rozinemi@msu.edu1 Deceased.\n\n16 10 2019 12 2019 16 10 2019 10 1002216 4 2019 16 9 2019 17 9 2019 © 2019 The Authors2019This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Highlights\n• Cannabis use in early psychosis is associated with rehospitalization.\n\n• Individuals with early psychosis commonly use recreational marijuana.\n\n• Non-adherence is an identified pathway to rehospitalization.\n\n• Long-acting antipsychotic medications are superior in preventing rehospitalization.\n\n• Long-acting injectable antipsychotics prevented rehospitalization in cannabis users.\n\n\n\nBackground\nDespite compelling evidence that cannabis use is associated with neurocognitive deficits, loss of cerebral gray matter, relapse and rehospitalization, a substantial number of individuals with early psychosis continue to use recreational or medicinal marijuana. One identified pathway to relapse is non-adherence. Recurrent relapses modify the trajectory of illness and culminate in long-term disability. Long-acting antipsychotic medications are superior to oral equivalents in preventing relapse.\n\nPurpose\nThe current paper sought to examine the role of long-acting antipsychotics in preventing relapse in cannabis using early psychosis patients.\n\nMethods\nThe present retrospective study, which was based in an early psychosis program in mid-Michigan, examined the association between patient perceptions of antipsychotic medication and subsequent rehospitalization, among cannabis users (n = 24) and non-users (n = 27). Patient perceptions of antipsychotic medications were assessed using a single question from the NAVIGATE Patient Self-Rating Form: “Between now and your next visit, do you think we should keep your medication the same, or consider changing the medication?”.\n\nResults\nCannabis users were substantially more likely to report dissatisfaction with antipsychotic medication (Pearson Chi-square 9.67, df = 1.0, p < 0.002), and more likely to experience rehospitalization (Pearson Chi-square 4.40, df = 1.0, p = 0.036). Those maintained on long-acting injectable antipsychotic medications were rehospitalized less frequently when compared to others maintained on oral formulations (Pearson Chi-square 4.61, df = 1.0, p = 0.032).\n\nConclusions\nDissatisfaction with antipsychotics may predict non-adherence and subsequent rehospitalization in early psychosis patients who use cannabis. Long-acting antipsychotics may prevent rehospitalization.\n\nKeywords\nCannabisFirst-episode psychosisSchizophrenia\n==== Body\n1 Introduction\nIn patients with first episode psychosis cannabis use is associated with neurocognitive deficits and loss of cerebral gray matter (Nunez et al., 2016, Rais et al., 2008). Continued cannabis use after first episode psychosis is associated with a dose-dependent increase in the risk, frequency and severity of relapse (Schoeler et al., 2017). It is estimated that a third of all patients with schizophrenia (Starr, Bermak, Mao, Rodriguez, & Alphs, 2018), and two thirds of patients who have experienced a first psychotic episode (Hahn, 2018) use cannabis. For many, cannabis-induced psychosis represents a step in the overall progression towards schizophrenia. Nearly 50% of patients who experience a first episode of cannabis-induced psychosis convert to schizophrenia over the ensuing 2–4 years (Starzer, Nordentoft, & Hjorthoj, 2018). Unfortunately, individuals who have experienced a first episode of psychosis, and those who are at extremely high risk for developing psychosis, have a proclivity for cannabis abuse (Shrivastava, Johnston, Terpstra, & Bureau, 2015).\n\nThe RAISE-ETP (Early Treatment Program) study, which enrolled patients between the ages of 15 and 40, who had experienced a single episode of schizophrenia and related disorders, established that early detection and coordinated specialty care of first episode psychosis can modify the trajectory of illness, enabling patients to achieve a better quality of life, minimizing overall symptom burden (Kane, Robinson, & Schooler, 2016). Relapse during the first few years after first psychotic episode predicts long term disability. Relapse occurs twice as commonly among those who continue to smoke marijuana as compared to those that stop smoking (Schoeler et al., 2017). The UK Schizophrenia Commission (Schizophrenia Commission, 2012) identified cannabis use as the “single most preventable risk factor in the development of a psychotic disorder.”\n\nIt is estimated that 30% of adverse outcomes associated with cannabis use in schizophrenia are related to medication non-adherence (Schoeler et al., 2017). It follows, therefore, that interventions directed at enhancing medication adherence may prevent relapse. Long-acting injectable antipsychotics are superior to oral equivalents in preventing relapse in patients with early psychosis (Kishi, Oya, & Iwata, 2016), and in dually diagnosed patients with psychosis and comorbid substance use disorder (Starr et al., 2018, Viala et al., 2007). We are unaware of any study that examined the role of long-acting antipsychotics in preventing relapse in patients with early psychosis and concurrent cannabis use disorder.\n\n2 Objective\nThe purpose of this study was to examine the role of long-acting injectable antipsychotics in preventing relapse in a cohort of early psychosis patients with concurrent cannabis use disorder. Our hypothesis was that long-acting antipsychotics would prove to be superior to oral formulations in this population.\n\n3 Methods\nWe completed a retrospective chart review of all patients diagnosed with early psychosis at the Early Treatment & Cognitive Health (ETCH) Program in East Lansing, over 12 consecutive calendar months (2017). At ETCH, a treatment program that specializes in the management of early psychosis, we employ the NAVIGATE ETP model of Coordinated Specialty Care. For the purpose of our study “early psychosis” was defined as having experienced a duration of psychosis of 18 months or less. The Institutional Review Board at Michigan State University was apprised of the study, and considered it exempt. Sources of data included the NAVIGATE Patient Self-Rating Form, the Practice Fusion web-based electronic medical record platform, and the ETCH program’s hospitalization log. Item 36 on the NAVIGATE Patient Self-Rating Form inquires: “Since your last visit have you used any marijuana?” Patients who had at least a single positive answer on this item, during calendar year 2017, were considered as cannabis users. Patients who had negative responses on this item but were reported to be users by their therapists at ETCH were also categorized as cannabis users. Urine drug screening was not used. The prescriber’s role in the NAVIGATE ETP treatment model is based on Shared Decision Making. Hence, Item 38 on the NAVIGATE Patient Self-Rating Form asks: “Between now and your next visit, do you think we should keep your medication the same, or consider changing the medication?” A request to change the medication was considered to represent dissatisfaction with the prescribed regimen. Antipsychotic prescription information was gleaned from the Practice Fusion electronic medical record. All data were abstracted anonymously and entered into the MYSTAT statistical software program for analysis. Differences in the mean values of relapse (defined as rehospitalization) between patients maintained on long acting injectable antipsychotics were compared to others maintained on oral antipsychotics or those not taking any recommended antipsychotic.\n\n4 Results\nFifty-one patients, ages 17–31 years, were included in the study. These included 39 men and 12 women. Twenty-seven (53%) were cannabis non-users. Twenty-four (47%) were cannabis users. Twenty-two (56%) of the men, but only two (17%) of the women were cannabis users; Pearson Chi-square 5.81, df = 1.0, p = 0.016. The study did not address socioeconomic status or level of education. Users and non-users did not differ in severity of illness, measured using Clinical Global Impression (Severity) rating completed at every visit (Table 1). Long-acting antipsychotics used included aripiprazole extended-release injection, haloperidol decanoate, paliperidone palmitate (1-month and 3-month formulations). Overall, 17 patients were maintained on long-acting injectable antipsychotics. Eight patients received long-acting injectable aripiprazole (1-month formulation). Six patients received long-acting paliperidone palmitate (1-month formulation). Three received long-acting paliperidone palmitate (3-month formulation). Oral antipsychotics included haloperidol, aripiprazole, ziprasidone, lurasidone, risperidone. olanzapine, quetiapine and clozapine. The cannabis users were more likely to express dissatisfaction with antipsychotics and request a medication change when compared to non-users. Sixteen (59%) of the users requested a change. Only four (16%) of the non-users requested a change; Pearson Chi-square 9.67, df = 1.0, p < 0.002. Eleven (46%) of the cannabis users were hospitalized during the calendar year. Only 5 (21%) of the non-users were hospitalized. Differences in rates of rehospitalization were statistically significant: Pearson Chi-square 4.40, df = 1.0, p = 0.036 (Table 2). Of the 10 cannabis users who were maintained on long-acting injectable antipsychotics, only 2 (20%) were hospitalized. Six patients were maintained on long-acting injectable aripiprazole (1-month formulation), 3 were maintained on long-acting paliperidone palmitate (1-month formulation), and 1 was maintained on paliperidone palmitate (3-month formulation). By comparison, 9 (64%) of 14 cannabis users on either oral or no antipsychotics were hospitalized. Differences in relapse rates were significant: Pearson Chi-square = 4.61, df = 1.0, p = 0.032 (Table 3).Table 1 Demographic and clinical characteristics of patient sample (n = 51).\n\n\tNon-users (n = 27)\tUsers (n = 24)\tStatistical significance\t\nAge\t23.0 (SD = 3.3) years\t21.9 (SD = 2.5) years\tTwo sample t-test\n= 1.3, df = 49, p = 0.194\t\nGender\t10 women, 17 men\t2 women, 22 men\tPearson Chi square 5.818, df = 1, p = 0.016\t\nCGI (S)\t3.3 (SD + 1.0)\t3.2 (SD = 1.0)\tTwo sample t-test\n= 0.5, df = 48, p = 0.637\t\nTable 2 Effect of cannabis use on rates of re-hospitalization in early psychosis patients (n = 51).\n\n\tNon-users\tUsers\tTotal\t\nNot hospitalized\t22\t11\t35\t\nHospitalized\t5\t11\t16\t\nTotal\t27\t24\t51\t\nEleven (46%) of the cannabis users were hospitalized vs only 5 (21%) of the non-users.\n\nPearson Chi-square 4.40, df = 1.0, p = 0.036.\n\nTable 3 Influence of antipsychotic formulation on re-hospitalization rates in cannabis users (n = 24).\n\n\tNot-hospitalized\tHospitalized\tTotal\t\nOral antipsychotics\t5\t9\t14\t\nLong-acting antipsychotics\t8\t2\t10\t\nTotal\t13\t11\t24\t\nOnly 2 (20%) of cannabis users maintained on long-acting injectable antipsychotics were hospitalized compared to 9 (64%) of 14 cannabis users on either oral or no antipsychotics were hospitalized.\n\nPearson Chi-square = 4.61, df = 1.0, p = 0.032.\n\n\n\n5 Discussion\nWorldwide, frequent use of high potency cannabis during adolescence is the single most important preventable cause of schizophrenia (The Health and Social Effects of Non-Medical Cannabis, 2016). High potency cannabis is more likely to induce enduring psychosis than other abused substances (Starzer et al., 2018). The pathogenic mechanisms implicated are unique, and not exclusively related to a perturbation of the dopamine circuits typically associated with psychosis (D’Souza, Sewell, & Ranganathan, 2009). Cannabinoid-1 receptors play a modulatory role in the delicate neuroplastic sculpting of the adolescent brain. Long-term use of exogenous cannabinoids such as tetrahydrocannabinol (THC) derail this delicate process, producing persistent impairments of cognitive and executive function (Atkinson & Abbott, 2018). The endogenous cannabinoid (anandamide) is a retrograde “stress responsive” neurotransmitter. Released “on-demand” from post-synaptic neurons it modulates the activity of pre-synaptic neurons. It is thought to serve the purpose of erasing unnecessary and undesirable memories (e.g. traumatic events). In contrast, exogenous cannabinoids (e.g. THC) induce global memory deficits, loss of hippocampal gray matter volume and enduring down-regulation of cannabinoid-1 receptors in the hippocampus (Atkinson & Abbott, 2018). Additionally, disruption of balance between the dentate gyrus and CA3 areas of the hippocampus increases generation of associations (creativity) and decreased error-checking, leading to false beliefs (delusions) (Atkinson & Abbott, 2018).\n\nIn patients with schizophrenia cannabis use is associated with symptom exacerbation, relapse and rehospitalization. A third of the adverse outcomes is attributed to medication non-adherence (Schoeler et al., 2017).\n\nIn the present study cannabis users were more likely to express dissatisfaction with antipsychotic medication. They were also more likely to experience rehospitalization than non-users. Cannabis users who were maintained on long-acting injectable antipsychotic agents were less likely to be rehospitalized than those maintained on oral compounds. Conversely, it is conceivable that the more serious cannabis users were more likely to decline injectable long-acting antipsychotics, and express a preference for oral formulations, which enabled non-adherence, resulting in subsequent rehospitalization. There are few studies that suggest effective strategies for managing patients with early psychosis and concurrent cannabis use disorder (Bosanac, Lusicic, & Castle, 2018). Psychosocial interventions that combine motivational interviewing and cognitive behavior therapy are more effective than treatment as usual (Bosanac et al., 2018, Cooper et al., 2015). Randomized controlled trials of cannabinoid receptor agonists (e.g. dronabinol), the opioid υ receptor antagonist (naltrexone) and antidepressants (e.g. bupropion) have proven inconclusive. Gabapentin and N-acetylcysteine have modest effects on curbing the use of cannabis. Among antipsychotics, second generation compounds as a group, and clozapine in particular, provide a modest advantage over first generation antipsychotics, in decreasing cannabis use in patients with schizophrenia and concurrent cannabis use disorder (Bosanac et al., 2018). Long-acting injectable antipsychotics are superior to oral equivalents in preventing relapse in dually diagnosed patients with psychosis and comorbid substance use disorder (Starr et al., 2018, Viala et al., 2007).\n\nLong-acting antipsychotic medications are generally reserved for patients who are non-adherent with recommended oral preparations. A naturalistic study reflected that the difference in efficacy between long-acting antipsychotics and oral compounds was equivalent to the difference in efficacy between oral antipsychotics and placebo (Tiihonen, Mittendorfer-Rutz, & Majak, 2017). A recent real-world prospective study of patients with schizophrenia and concurrent substance use disorders, who were recently released from prison, demonstrated that long-acting antipsychotics reduced rates of rehospitalization when compared to oral equivalent compounds (Starr et al., 2018).\n\nThe present study suggests that long-acting injectable antipsychotics may play a critical role in preventing rehospitalization in cannabis using early psychosis patients.\n\nThe limitations of this study include the small (n = 51) sample size, the retrospective rather than prospective nature, and the single rather than multiple site design. It was assumed that a participant’s expressed desire for “a change in medication” implied “dissatisfaction” with prescribed medication. It is plausible that an individual’s desire for a change did not necessarily represent a desire to decrease or stop the antipsychotic medication. Rather, it may have represented a desire for an increase in dosage of the antipsychotic for better symptom control, or the addition of an antidepressant or antianxiety agent. Additionally, the subsample of cannabis users was identified using a single question on the NAVIGATE Self-Rating Form. Routine toxicology urine drug screening may have provided a more reliable measure of cannabis use. All participants were attending an early psychosis treatment program in a university town located in the US Mid-West. This may not be representative of the general population. The proportion of females to males was low, and the proportion of female cannabis users was even less. Therefore, it would be necessary to replicate this study with a larger, more diverse sample.\n\n6 Conclusion\nThe present study affirms that cannabis use is common in patients with early psychosis. Cannabis use is associated with dissatisfaction with antipsychotic medication, discontinuation of recommended treatment and subsequent rehospitalization. Cannabis using patients who were maintained on long-acting antipsychotics were rehospitalized less frequently as compared to those maintained on oral compounds.\n\nFuture prospective studies of long-acting antipsychotic medications in this vulnerable population may shed further light on the growing enigma of cannabis use in early psychosis. Finally, among cannabis using early psychosis patients, expression of dissatisfaction with antipsychotic medication may be an early warning sign of impending non-adherence and subsequent relapse.\n\nDeclaration of Competing Interest\nThe authors declare that there is no conflict of interest.\n\nAppendix A Supplementary material\nThe following are the Supplementary data to this article:Supplementary data 1\n \n\nAcknowledgement\nThe authors wish to thank Dr. Eric Achtyes who reviewed the manuscript and provided critical comments.\n\nAppendix A Supplementary data to this article can be found online at https://doi.org/10.1016/j.abrep.2019.100221.\n==== Refs\nReferences\nAtkinson, D. L., Abbott, J. K. (2018). Cannabinoids and the brain: The effects of endogenous and exogenous cannabinoids on brain systems and function. In: Compton, M. T., Manseau, M. W. (Eds.): The Complex Connection between Cannabis and Schizophrenia. 2018. (pp. 37–74). London, UK, Elsevier Press.\nBosanac P. Lusicic A. Castle D.J. The Treatment of Cannabis Use Disorder Among Individuals With a Psychotic Disorder Compton M.T. Manseau M.W. The Complex Connection between Cannabis and Schizophrenia 2018 Elsevier Press London, UK \nCooper K. Chatters R. Kaltenhaler E. Wong R. Psychological and psychosocial interventions for cannabis cessation in adults: A systematic review show report Health Technology Assessment 19 56 2015 \nD’Souza D.C. Sewell R.A. Ranganathan M. Cannabis and psychosis/schizophrenia: Human studies European Archives of Psychiatry and Clinical Neuroscience 259 7 2009 413 431 19609589 \nHahn B. The potential of cannabidiol treatment for cannabis users with recent-onset psychosis Schizophrenia Bulletin 44 1 2018 46 53 https://academic.oup.com/schizophreniabulletin/article/44/1/46/4080751 29083450 \nKane J.M. Robinson D.G. Schooler N.R. Comprehensive versus usual community care for first-episode psychosis: 2-year outcomes from the NIMH RAISE early treatment program The American Journal of Psychiatry 173 2016 362 372 https://ajp.psychiatryonline.org/doi/full/10.1176/appi.ajp.2015.15050632 26481174 \nKishi, T., Oya, K., Iwata N. (2016). Long-acting injectable antipsychotics for the prevention of relapse in patients with recent-onset psychotic disorders: A systematic review and meta-analysis of randomized controlled trials. Psychiatry Research, 246, 750–755. <https://www.deepdyve.com/lp/elsevier/long-acting-injectable-antipsychotics-for-the-prevention-of-relapse-in-HYAX7OXLa6>.\nNunez C. Achoa S. Huerta-Ramos E. Banos I. Barajas A. Dolz M. Cannabis use and cognitive function in first episode psychosis: Differential effect of heavy use Psychopharmacology 233 2016 809 821 https://link.springer.com/article/10.1007/s00213-015-4160-2 26621349 \nRais M. Cahn W. Van Haren N. Schnack H. Caspers E. Hulshoff Pol H. Excessive brain volume loss over time in cannabis-using first-episode schizophrenia patients The American Journal of Psychiatry 165 2008 490 496 https://ajp.psychiatryonline.org/doi/full/10.1176/appi.ajp.2007.07071110 18281413 \nSchizophrenia Commission (2012). The abandoned illness: A report by the Schizophrenia Commission. London: Rethink Mental Illness <https://www.rethink.org/about-us/the-schizophrenia-commission>.\nSchoeler T. Petros N. Di Forti M. Klamerus E. Foglia E. Murray R. Poor medication adherence and risk of relapse associated with continued cannabis use in patients with FEP: A prospective analysis Lancet Psychiatry 4 2017 627 633 28705600 \nShrivastava A. Johnston M. Terpstra K. Bureau Y. Pathways to psychosis in cannabis abuse Clinical Schizophrenia & Related Psychosis 9 1 2015 30 35 https://clinicalschizophrenia.org/doi/abs/10.3371/CSRP.SHJO.030813 \nStarr H.L. Bermak J. Mao L. Rodriguez S. Alphs L. Comparison of long-acting and oral antipsychotic treatment effects in patient with schizophrenia, comorbid substance abuse, and a history of recent incarceration: An exploratory analysis of the PRIDE study Schizophrenia Research 194 2018 39 46 https://www.sciencedirect.com/science/article/pii/S0920996417302645 28601497 \nStarzer M.S.K. Nordentoft M. Hjorthoj C. Rates and predictors of conversion to schizophrenia or bipolar disorder following substance-induced psychosis The American Journal of Psychiatry 175 2018 343 350 https://ajp.psychiatryonline.org/doi/10.1176/appi.ajp.2017.17020223 29179576 \nThe Health and Social Effects of Non-Medical Cannabis (2016). World Health Organization Publications. Geneva, Switzerland. http://www.who.int.\nTiihonen J. Mittendorfer-Rutz E. Majak M. Real-world effectiveness of antipsychotic treatments in a nationwide cohort of 29,823 patients with schizophrenia JAMA Psychiatry 74 2017 686 693 28593216 \nViala A. Vacheron M.N. Baldacci C. Bardou H. Choudey M. Ekbatani A. Psychotic patients addicted to cannabis and other substances treated with risperidone long acting injectable: Follow-up and reintegration European Psychiatry 22 Suppl 1 2007 S171\n\n",
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"issn_linking": "2352-8532",
"issue": "10()",
"journal": "Addictive behaviors reports",
"keywords": "Cannabis; First-episode psychosis; Schizophrenia",
"medline_ta": "Addict Behav Rep",
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"title": "A retrospective study of the role of long-acting injectable antipsychotics in preventing rehospitalization in early psychosis with cannabis use.",
"title_normalized": "a retrospective study of the role of long acting injectable antipsychotics in preventing rehospitalization in early psychosis with cannabis use"
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"abstract": "BACKGROUND\nCalcineurin inhibitors are widely used for the prevention and treatment of graft versus host disease in patients undergoing allogeneic hematopoietic stem cell transplantation, and successful treatment with calcineurin inhibitors is very important for the management of these cases.\n\n\nMETHODS\nA 19-year-old man with thalassemia major experienced hypersensitivity reaction to parenteral vitamin K, cyclosporine, and tacrolimus before hematopoietic stem cell transplantation. All three episodes of reaction appeared a few minutes after administration of offended drugs and cause systemic signs and symptoms of anaphylaxis, i.e. itching, flushing, difficulty in breathing, and hypotension.\nHypersensitivity reaction was fully controlled by immediately discontinuing the drug and administering hydrocortisone, chlorpheniramine, epinephrine, and intravenous fluids. During hospitalization, the patient tolerated oral tacrolimus without any complication.\n\n\nCONCLUSIONS\nIt appears that Cremophor EL (polyoxyethylated castor oil) which acts as a carrier, solubilizer, and emulsifier in intravenous calcineurin inhibitors is responsible for the occurrence of anaphylactic reaction (anaphylaxis); therefore, it is suggested that the administration of cremophor-containing drug should be avoided in patients with a previous history of hypersensitivity reaction to one of these drugs.",
"affiliations": "Department of Clinical Pharmacy, Faculty of Pharmacy, Guilan University of Medical Sciences, Rasht, Iran.;Department of Clinical Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.;Department of Clinical Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.",
"authors": "Taghvaye-Masoumi|Hamidreza|H|;Sadeghi|Kourosh|K|https://orcid.org/0000-0003-2876-4937;Hadjibabaie|Molouk|M|",
"chemical_list": "D007166:Immunosuppressive Agents; D014812:Vitamin K; D016572:Cyclosporine; D016559:Tacrolimus",
"country": "England",
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"issue": "26(4)",
"journal": "Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners",
"keywords": "Cyclosporine; anaphylaxis; cremophor EL; hypersensitivity; tacrolimus",
"medline_ta": "J Oncol Pharm Pract",
"mesh_terms": "D061605:Administration, Intravenous; D000284:Administration, Oral; D016572:Cyclosporine; D004342:Drug Hypersensitivity; D057915:Drug Substitution; D006801:Humans; D007166:Immunosuppressive Agents; D008297:Male; D016559:Tacrolimus; D014812:Vitamin K; D055815:Young Adult",
"nlm_unique_id": "9511372",
"other_id": null,
"pages": "986-988",
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"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Successful switch to oral tacrolimus in a patient with hypersensitivity reaction to parenteral vitamin K, cyclosporine, and tacrolimus: A case report.",
"title_normalized": "successful switch to oral tacrolimus in a patient with hypersensitivity reaction to parenteral vitamin k cyclosporine and tacrolimus a case report"
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{
"abstract": "BACKGROUND\nToxic epidermal necrolysis (TEN) (also known as Lyell syndrome) and Stevens-Johnson syndrome (SJS) are life-threatening mucocutaneous blistering diseases. They are characterized by generalized blisters and epidermal inflammation, most likely resulting from the administration or interaction of medicines.\n\n\nOBJECTIVE\nTo report potential new method in the treatment of TEN.\n\n\nMETHODS\nThis article presents a case report of a 35-year-old man suffering from TEN covering about 95% of his body surface. Lesions occurred in the patient during antiepileptic therapy, after taking simultaneously amoxicillin (with clavulanic acid) and naproxen followed by lamotrigine treatment. Standard general treatment was performed. Intravenous feeding was necessary. Due to acute respiratory failure, the patient required mechanical ventilation. Two methods were combined in topical treatment: application of platelet-rich plasma (PRP) and a simultaneous biostatic human amnion transplant.\n\n\nRESULTS\nIn the presented case, the combination of both methods contributed to a significant acceleration of wound healing. After the application of PRP and biostatic amnion transplantation, the healing of wounds on the back and posterior surfaces of the legs was completed after six days. The surgical treatment most probably contributed to a significant acceleration of wound healing.\n\n\nCONCLUSIONS\nThe case report shows that topical TEN/SJS treatment with biostatic human amnion and PRP has a positive clinical effect and may be a new method of treatment of TEN.",
"affiliations": "Stanislaw Sakiel Burn Treatment Centre in Siemianowice Slaskie, Siemianowice Slaskie, Poland.;Stanislaw Sakiel Burn Treatment Centre in Siemianowice Slaskie, Siemianowice Slaskie, Poland.;Stanislaw Sakiel Burn Treatment Centre in Siemianowice Slaskie, Siemianowice Slaskie, Poland.;Stanislaw Sakiel Burn Treatment Centre in Siemianowice Slaskie, Siemianowice Slaskie, Poland.;Stanislaw Sakiel Burn Treatment Centre in Siemianowice Slaskie, Siemianowice Slaskie, Poland.;Stanislaw Sakiel Burn Treatment Centre in Siemianowice Slaskie, Siemianowice Slaskie, Poland.;Stanislaw Sakiel Burn Treatment Centre in Siemianowice Slaskie, Siemianowice Slaskie, Poland.;Stanislaw Sakiel Burn Treatment Centre in Siemianowice Slaskie, Siemianowice Slaskie, Poland.;Stanislaw Sakiel Burn Treatment Centre in Siemianowice Slaskie, Siemianowice Slaskie, Poland.;Stanislaw Sakiel Burn Treatment Centre in Siemianowice Slaskie, Siemianowice Slaskie, Poland.",
"authors": "Klama-Baryła|Agnieszka|A|;Strzelec|Przemysław|P|;Pawlik-Knapik|Danuta|D|;Cholewa|Zbigniew|Z|;Szapski|Michał|M|https://orcid.org/0000-0002-5586-0812;Kitala|Diana|D|;Łabuś|Wojciech|W|;Kraut|Małgorzata|M|;Smętek|Wojciech|W|;Kucharzewski|Marek|M|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1111/jocd.13864",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1473-2130",
"issue": "20(9)",
"journal": "Journal of cosmetic dermatology",
"keywords": "Stevens-Johnson syndrome; biostatic amnion; lamotrigine; platelet-rich plasma; topical treatment; toxic epidermal necrolysis",
"medline_ta": "J Cosmet Dermatol",
"mesh_terms": "D000287:Administration, Topical; D000328:Adult; D000650:Amnion; D006801:Humans; D008297:Male; D053657:Platelet-Rich Plasma; D013262:Stevens-Johnson Syndrome; D014945:Wound Healing",
"nlm_unique_id": "101130964",
"other_id": null,
"pages": "2887-2893",
"pmc": null,
"pmid": "33232565",
"pubdate": "2021-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "The use of biostatic human amnion and platelet-rich plasma in topical treatment of toxic epidermal necrolysis-A case report.",
"title_normalized": "the use of biostatic human amnion and platelet rich plasma in topical treatment of toxic epidermal necrolysis a case report"
} | [
{
"companynumb": "PL-UNICHEM PHARMACEUTICALS (USA) INC-UCM202012-001471",
"fulfillexpeditecriteria": "1",
"occurcountry": "PL",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "FLUOXETINE HYDROCHLORIDE"
... |
{
"abstract": "OBJECTIVE\nTo report the features and clinical course of Acanthamoeba keratitis in a cosmetic contact lens wearer.\n\n\nMETHODS\nA 29-year-old man sought medical attention for severe ocular pain, blurry vision, photophobia, and a foreign body sensation in the left eye for the past 3-4 days. He had been wearing a single sapphire cosmetic soft contact lens for 1-2 months. The left upper eyelid was edematous and the conjunctiva was hyperemic; the best corrected distance visual acuity was 20/400. A slit lamp examination revealed circular and perineural linear stromal opacities and diffuse keratic precipitates. A clinical diagnosis of herpes simplex keratitis was made and the patient was started on antiviral therapy. After initial improvement, the patient returned with worsening pain and vision; the corneal lesions had exacerbated. Unresponsiveness to antiviral therapy prompted examination of corneal scrapings, which revealed Acanthamoeba developmental forms. Antimicrobial therapy was prescribed resulting in relief of symptoms despite corneal opacities and poor vision.\n\n\nCONCLUSIONS\nThis case illustrates the importance of considering Acanthamoeba keratitis in contact lens wearers at presentation, particularly in those with symptomatic keratitis unresponsive to antiviral and antifungal therapy.",
"affiliations": "Department of Pathology, Downstate Medical Center, State University of New York, and Kings County Hospital Center, Brooklyn, New York, USA.;Department of Ophthalmology, Downstate Medical Center, State University of New York, and Kings County Hospital Center, Brooklyn, New York, USA.;Department of Pathology, Downstate Medical Center, State University of New York, and Kings County Hospital Center, Brooklyn, New York, USA.;Department of Ophthalmology, Downstate Medical Center, State University of New York, and Kings County Hospital Center, Brooklyn, New York, USA.;Department of Pathology, Downstate Medical Center, State University of New York, and Kings County Hospital Center, Brooklyn, New York, USA haseeb.siddiqi@downstate.edu.",
"authors": "Gupta|Raavi|R|;Gorski|Matthew|M|;Henderson|Triona|T|;Lazzaro|Douglas|D|;Haseeb|M A|MA|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0091-7370",
"issue": "45(3)",
"journal": "Annals of clinical and laboratory science",
"keywords": "Acanthamoeba keratitis; Keratitis; contact lens; cornea; protozoa",
"medline_ta": "Ann Clin Lab Sci",
"mesh_terms": "D015823:Acanthamoeba Keratitis; D000328:Adult; D003263:Contact Lenses, Hydrophilic; D003315:Cornea; D018450:Disease Progression; D006801:Humans; D008297:Male",
"nlm_unique_id": "0410247",
"other_id": null,
"pages": "366-70",
"pmc": null,
"pmid": "26116606",
"pubdate": "2015",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Clinical Course of Unilateral Acanthamoeba Keratitis in a Cosmetic Contact Lens Wearer.",
"title_normalized": "clinical course of unilateral acanthamoeba keratitis in a cosmetic contact lens wearer"
} | [
{
"companynumb": "US-JNJFOC-20150902676",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "HEXAMIDINE DIISETHIONATE"
},
"drugadditional": nu... |
{
"abstract": "Breast cancer is the leading malignancy and the second most common cause of mortality in women. Although there have been advances in identifying biomarkers as potential targets for therapy, triple-negative breast cancer (TNBC) continues to have a poorer prognosis than the other receptor subtypes. The most common sites of metastasis are bone, liver, lung, and brain. We present a patient with known TNBC presenting with nausea and vomiting in whom computed tomography revealed a right-side pelvic mass causing hydronephrosis. Biopsy was consistent with TNBC of the ureter, an unusual site for breast cancer involvement. She required ureteral stent placement to relieve obstruction and has had good response to paclitaxel. Hydronephrosis due to malignancy presents significant risk of morbidity and mortality due to compromised renal function and must be resolved promptly to avoid compromise of renal function.",
"affiliations": "University of Florida, Jacksonville, FL, USA.;University of Florida, Jacksonville, FL, USA.;University of Florida, Jacksonville, FL, USA.;University of Florida, Jacksonville, FL, USA.;University of Florida, Jacksonville, FL, USA.",
"authors": "Chahin|Michael|M|0000-0001-9371-0252;Chhatrala|Hardik|H|;Krishnan|Nithya|N|0000-0002-2953-7288;Brow|Darren|D|;Zuberi|Lara|L|",
"chemical_list": "D017239:Paclitaxel",
"country": "United States",
"delete": false,
"doi": "10.1177/2324709620905954",
"fulltext": "\n==== Front\nJ Investig Med High Impact Case RepJ Investig Med High Impact Case RepHICsphicJournal of Investigative Medicine High Impact Case Reports2324-7096SAGE Publications Sage CA: Los Angeles, CA 10.1177/232470962090595410.1177_2324709620905954Case ReportTriple-Negative Lobular Breast Cancer Causing\nHydronephrosis https://orcid.org/0000-0001-9371-0252Chahin Michael DO1Chhatrala Hardik MD1https://orcid.org/0000-0002-2953-7288Krishnan Nithya MD1Brow Darren MD1Zuberi Lara MD11 University of Florida, Jacksonville, FL,\nUSAMichael Chahin, DO, Department of Medicine,\nDivision of Internal Medicine, University of Florida College of\nMedicine–Jacksonville, 653-1 West 8th Street, Box L-18, Jacksonville, FL 32209,\nUSA. Email: Michael.chahin@jax.ufl.edu11 2 2020 Jan-Dec 2020 8 232470962090595410 11 2019 5 12 2019 21 12 2019 © 2020 American Federation for Medical\nResearch2020American Federation for Medical\nResearchThis article is distributed under the terms of the Creative Commons\nAttribution 4.0 License (https://creativecommons.org/licenses/by/4.0/) which permits\nany use, reproduction and distribution of the work without further\npermission provided the original work is attributed as specified on the SAGE\nand Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).Breast cancer is the leading malignancy and the second most common cause of\nmortality in women. Although there have been advances in identifying biomarkers\nas potential targets for therapy, triple-negative breast cancer (TNBC) continues\nto have a poorer prognosis than the other receptor subtypes. The most common\nsites of metastasis are bone, liver, lung, and brain. We present a patient with\nknown TNBC presenting with nausea and vomiting in whom computed tomography\nrevealed a right-side pelvic mass causing hydronephrosis. Biopsy was consistent\nwith TNBC of the ureter, an unusual site for breast cancer involvement. She\nrequired ureteral stent placement to relieve obstruction and has had good\nresponse to paclitaxel. Hydronephrosis due to malignancy presents significant\nrisk of morbidity and mortality due to compromised renal function and must be\nresolved promptly to avoid compromise of renal function.\n\nbreast cancerreceptornegativetriplehydronephrosiscover-dateJanuary-December 2020typesetterts1\n==== Body\nIntroduction\nApproximately 15% of breast cancers are triple negative, in which the tumor lacks\nexpression of estrogen receptor (ER), progesterone receptor (PR), and human\nepidermal growth factor receptor 2 (HER2).1 However, the representation of triple-negative subgroup is much higher in\nthose that recur or metastasize (5-year overall survival is 77% for triple negative\nvs >90% for others). Breast cancer most commonly metastasizes to bone, liver,\nlung, and brain.2 A Surveillance, Epidemiology, and End Results database–based study\ndemonstrated triple-negative breast cancer (TNBC) has a propensity to metastasize to bone.3 In recent years, TNBC has been recognized as comprising a heterogeneous group\nof tumor types. This has revealed different potential biomarkers that may be treated\nwith targeted therapy. In general, however, TNBC is an aggressive entity that\nrequires prompt recognition and treatment.4 We present a patient with TNBC who developed bulky pelvic lymphadenopathy\nwith subsequent invasion of the right ureter.\n\nCase Report\nA 54-year-old female with a history of triple-negative grade 1 ductal adenocarcinoma\ndiagnosed 2 years prior presented to the emergency department with diffuse abdominal\npain, nausea, and vomiting that had been worsening over 2 weeks. She had pursued\nbreast cancer treatment with holistic and natural remedies only. Breast examination\nrevealed a 10-cm right inferior breast mass and peau d’orange changes. There was\nbilateral axillary lymphadenopathy.\n\nComputed tomography scan showed right distal ureteral thickening and right\nhemi-pelvic mass causing severe hydronephrosis (Figure 1). Biopsy of the right pelvic mass\nrevealed poorly differentiated adenocarcinoma that was GATA3, CKAE1/AE3, and\ncytokeratin (CK) 8/18 positive, consistent with breast primary tumor (Figures 2-4). The sample demonstrated smooth muscle indicating ureteral or bladder\ninvasion. The mass was ER negative, PR negative, HER2 negative, and Ki-67 positive.\nA core needle biopsy of left breast mass from the outside hospital 2 years prior\nrevealed invasive pleomorphic lobular carcinoma Nottingham grade 1, ER, PR, and HER2\nnegative.\n\nFigure 1. Right hemi-pelvis bulky mass.\n\nFigure 2. Metastatic poorly differentiated adenocarcinoma of the breast. Nearly entire\nbiopsy is tumor cells.\n\nFigure 3. Tumor cells at 20× with high degree of atypia and poor differentiation,\nobtained from right pelvic mass.\n\nFigure 4. Gata3 immunostaining demonstrating epithelial tissue, 96% positive in\nmetastatic breast cancer.\n\nShe underwent a right ureteral stent placed to relieve the obstruction. She received\nwhole brain radiation therapy for cerebellar metastases that were found on brain\nimaging. Positron emission tomography scan a few weeks after this presentation\nrevealed increased metabolic activity of bilateral breasts and axillary,\nretroperitoneal, mediastinal, cervical, and supraclavicular lymph nodes. The right\npelvic mass was demonstrated again, and an omental mass was present. Bone or liver\nmetastasis were not evidenced though there were hypermetabolic lower lobe pulmonary\nopacities bilaterally. Palliative chemotherapy was started in the form of\nsingle-agent weekly paclitaxel. She has had excellent response to whole brain\nradiotherapy with decrease in tumor size, and no neurologic deficits. Her clinical\ncourse was complicated by pseudomonas pyelonephritis after cycle one but has\notherwise tolerated 3 cycles of paclitaxel well.\n\nDiscussion\nInformation regarding ureteral involvement by breast cancer is limited. The available\nstudies consist largely of individual case reports and case series. An autopsy\nreview of 215 patients with breast malignancy revealed 42 cases of ureteral metastasis.5 A case series of 82 patients demonstrated cervical, prostate, breast, and\ncolorectal as the most common primary cancers with ureteral metastasis.6 Lymphoma involvement of the ureter has also been reported.7 Considering these autopsy reports, it is likely that ureteral metastasis is\nunderrepresented. A limit to these studies is that they predate widespread use of\ncomputed tomography scan, but they provide evidence for ureteral metastasis from\nbreast cancer as an entity.\n\nMetastasis of breast cancer to the ureter is unusual, though more likely to occur\nfrom breast cancer than other cancer types simply by virtue of its high incidence.\nIt has been suggested that hematogenous or lymphatic routes of metastasis occur less\nfrequently than direct invasion. This is likely due to the separate vasculature\nbetween the 3 anatomic portions of the ureter.8,9 Our patient likely had distal\nright ureteral invasion from the adjacent pelvic mass, possible extracapsular, as\nopposed to hematogenous or direct lymphatic spread. Anatomically, the likelihood of\nbreast cancer developing bulky lymphadenopathy is low, but given our patient’s\nextensive lymphatic involvement, we propose that the pelvic mass extended from a\nregional lymph node though no lymph node tissue was isolated in the biopsy. This is\nopposed to a case reported by Gabsi et al, in which breast tumor cells were found\nwithin the ureter with no regional lymph node metastasis.10\n\nBased on our literature review this is the only case demonstrating TNBC with invasion\nof the ureter. ER+/PR−; HER2+, and ER+/PR+; HER2+ breast malignancies have been reported.11 One explanation for the rarity of this is that the aggressive nature of most\nTNBCs often results in multiple sites of metastases that are more accessible for\nbiopsy. This was more a case of a neglected cancer rather than an inherently\naggressively behaving cancer given that it was low-grade and the patient had elected\nnot to pursue treatment for more than 2 years.\n\nThe management of patients of malignant urinary tract obstruction is largely\npalliative. Placement of retrograde ureteral stents or percutaneous nephrostomy have\nbeen employed.12 In addition to addressing the morbidity of renal obstruction, these patients\nshould be treated with the appropriate systemic therapy depending on receptor status\nand performance status. In solid tumors, ureteral obstruction whether through direct\ninvasion or extrinsic compression is often seen as a surrogate for advanced cancer.\nFortunately, some common chemotherapy agent classes used in the palliative setting\nfor metastatic breast cancers like taxanes, anthracyclines, and eribulin have\nminimal renal excretion.13 They can be used safely in these subgroups of patients with obstructive\nuropathy secondary to ureteral obstruction.\n\nConclusion\nHydronephrosis is a rare but significant complication in cancer patients. It poses\nrisk of worsening morbidity including the need for dialysis and the higher\nanticipated toxicity of chemotherapeutic agents and increases the therapeutic\nchallenges as in our patient who had a pseudomonas urinary tract infection. It needs\nto be addressed promptly by the treating oncologist in collaboration with a\nmultidisciplinary team of urologists and radiologists.\n\nDeclaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the\nresearch, authorship, and/or publication of this article.\n\nFunding: The author(s) received no financial support for the research, authorship, and/or\npublication of this article.\n\nEthics Approval: Our institution does not require ethical approval for reporting individual cases\nor case series.\n\nInformed Consent: Verbal informed consent was obtained from the patient or their legally authorized\nrepresentative for anonymized patient information to be published in this\narticle.\n\nORCID iDs: Michael Chahin \nhttps://orcid.org/0000-0001-9371-0252\n\nNithya Krishnan \nhttps://orcid.org/0000-0002-2953-7288\n==== Refs\nReferences\n1 \nAnders C Carey LA \nUnderstanding and treating triple-negative\nbreast cancer . Oncology (Williston Park) .\n2008 ;22 :1233 -1243 .18980022 \n2 \nJin L Han B Siegel E Cui Y Giuliano A Cui X \nBreast cancer lung metastasis: molecular biology\nand therapeutic implications . Cancer Biol\nTher .\n2018 ;19 :858 -868 .29580128 \n3 \nWu Q Li J Zhu S , et al\nBreast cancer subtypes\npredict the preferential site of distant metastasis: a SEER based\nstudy . Oncotarget .\n2017 ;8 :27990 -27996 .28427196 \n4 \nSchmadeka R Harmon B Singh M \nTriple-negative breast carcinoma: current and\nemergency concepts . Am J Clin Pathol .\n2014 ;141 :462 -477 .24619745 \n5 \nGrabstald H Kaufman R \nHydronephrosis secondary to ureteral obstruction\nby metastatic breast cancer . J Urol .\n1969 ;102 :569 -576 .4310510 \n6 \nRichie JP Withers G Ehrlich RM \nUreteral obstruction secondary to metastatic\ntumors . Surg Gynecol Obstet .\n1979 ;148 :355 -357 .419434 \n7 \nNumakura K Tsuchiya N Obara T , et al\nA case of ureteral\nmalignancy lymphoma diagnosed by laparoscopic needle biopsy .\nJpn J Clin Oncol .\n2011 ;41 :440 -442 .21109511 \n8 \nKaraosmanoglu AD Onur MR Karcaaltincaba M , et al\nSecondary tumors of the\nurinary system: an imaging conundrum . Korean J\nRadiol .\n2018 ;19 :742 -751 .29962880 \n9 \nFröber R \nSurgical anatomy of the ureter .\nBJU Int . 2007 ;100 \n949 -965 .17822477 \n10 \nGabsi A Yahiaoui Y Zenhani A , et al\nUreteral metastasis in\ncarcinoma of the breast . Urol Case Rep .\n2018 ;21 :38 -40 .30202731 \n11 \nJani K \nUreteric obstruction secondary to metastatic\nbreast carcinoma . Pak J Med Sci .\n2006 ;22 :197 -199 .\n12 \nLogothetis CJ Assikis V Sarriera JE \nAlgorithm for management of urinary\nobstruction . In: Kufe Dw Pollock RE Weichselbaum RR , et al, eds. Holland-Frei Cancer\nMedicine . 6th ed. \nHamilton, Ontario : BC\nDecker ; 2003 .\n13 \nMerchan JR Jhaveri KD \nChemotherapy nephrotoxicity and dose modification in\npatients with renal insufficiency: conventional cytotoxic agents .\nhttps://www.uptodate.com/contents/chemotherapy-nephrotoxicity-and-dose-modification-in-patients-with-renal-insufficiency-conventional-cytotoxic-agents.\nAccessed January 29, 2020 .\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2324-7096",
"issue": "8()",
"journal": "Journal of investigative medicine high impact case reports",
"keywords": "breast cancer; hydronephrosis; negative; receptor; triple",
"medline_ta": "J Investig Med High Impact Case Rep",
"mesh_terms": "D000230:Adenocarcinoma; D002528:Cerebellar Neoplasms; D005260:Female; D006801:Humans; D006869:Hydronephrosis; D008875:Middle Aged; D017239:Paclitaxel; D010386:Pelvic Neoplasms; D015607:Stents; D016896:Treatment Outcome; D064726:Triple Negative Breast Neoplasms; D014513:Ureter; D014517:Ureteral Obstruction",
"nlm_unique_id": "101624758",
"other_id": null,
"pages": "2324709620905954",
"pmc": null,
"pmid": "32043897",
"pubdate": "2020",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "17822477;29962880;28427196;29580128;4310510;419434;21109511;30202731;18980022;24619745",
"title": "Triple-Negative Lobular Breast Cancer Causing Hydronephrosis.",
"title_normalized": "triple negative lobular breast cancer causing hydronephrosis"
} | [
{
"companynumb": "US-ACCORD-173652",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PACLITAXEL"
},
"drugadditional": "3",
"druga... |
{
"abstract": "Light chain proximal tubulopathy (LCPT) is characterized by cytoplasmic inclusions of monoclonal LC within proximal tubular cells. The significance of crystalline versus noncrystalline LCPT and the effect of modern therapies are unknown. We reported the clinical-pathologic features of 40 crystalline and six noncrystalline LCPT patients diagnosed between 2000 and 2014. All crystalline LCPTs were κ-restricted and displayed acute tubular injury. One-third of noncrystalline LCPT patients displayed λ-restriction or acute tubular injury. Only crystalline LCPT frequently required antigen retrieval to demonstrate monoclonal LC by immunofluorescence. In five of 38 patients, crystals were not detectable by light microscopy, but they were visible by electron microscopy. Hematolymphoid neoplasms, known before biopsy in only 15% of patients, included 21 monoclonal gammopathies of renal significance; 15 multiple myelomas; seven smoldering multiple myelomas; and three other neoplasms. Biopsy indications included Fanconi syndrome (38%; all with crystalline LCPT), renal insufficiency (83%), and proteinuria (98%). Follow-up was available for 30 (75%) patients with crystalline LCPT and all six patients with noncrystalline LCPT, of whom 11 underwent stem cell transplant, 16 received chemotherapy only, and nine were untreated. Complete or very good partial hematologic remissions occurred in six of 22 treated crystalline LCPT patients. By multivariable analysis, the only independent predictor of final eGFR was initial eGFR, highlighting the importance of early detection. All patients with crystalline LCPT treated with stem cell transplant had stable or improved kidney function, indicating the effectiveness of aggressive therapy in selected patients.",
"affiliations": "Departments of Pathology and mbs2101@cumc.columbia.edu.;Department of Medicine, Columbia University College of Physicians and Surgeons, New York, New York;;Department of Pathology, Cleveland Clinic, Cleveland, Ohio; and.;Department of Medicine, Hackensack University Medical Center, Hackensack, New Jersey.;Department of Medicine, Hackensack University Medical Center, Hackensack, New Jersey.;Departments of Pathology and.;Departments of Pathology and.",
"authors": "Stokes|Michael B|MB|;Valeri|Anthony M|AM|;Herlitz|Leal|L|;Khan|Abdullah M|AM|;Siegel|David S|DS|;Markowitz|Glen S|GS|;D'Agati|Vivette D|VD|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1681/ASN.2015020185",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1046-6673",
"issue": "27(5)",
"journal": "Journal of the American Society of Nephrology : JASN",
"keywords": "Renal pathology; multiple myeloma; renal proximal tubule cell",
"medline_ta": "J Am Soc Nephrol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001706:Biopsy; D003460:Crystallization; D005198:Fanconi Syndrome; D005260:Female; D006801:Humans; D007668:Kidney; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies",
"nlm_unique_id": "9013836",
"other_id": null,
"pages": "1555-65",
"pmc": null,
"pmid": "26374607",
"pubdate": "2016-05",
"publication_types": "D016428:Journal Article",
"references": "16723980;7673737;22385229;22742545;24108460;21701535;7564094;22417785;19414839;20356978;15010372;17824791;16514437;15806478;23313305;25190731;12955694;8468490;10844934;10325408;17063172;163583;24439928;16855634;22997259;18971951;24359985;25268200",
"title": "Light Chain Proximal Tubulopathy: Clinical and Pathologic Characteristics in the Modern Treatment Era.",
"title_normalized": "light chain proximal tubulopathy clinical and pathologic characteristics in the modern treatment era"
} | [
{
"companynumb": "US-CELGENEUS-USA-20170602433",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "LENALIDOMIDE"
},
"drugadditional": null,
... |
{
"abstract": "Intravenous immunoglobulins (IVIg) are increasingly being used to treat a wide spectrum of dermatological and neurological autoimmune diseases. Although the administration of IVIg does not usually result in severe adverse reactions, side effects of IVIg reportedly occur in 6-13% of patients. Most reported cases were not severe, and IVIg is considered a relatively safe drug. Some reports described a vesicular eczematous eruption caused by IVIg that was cured by applying topical steroid ointments or systemic steroids. Herein, we present, to the best of our knowledge, the first case of severe vesicular eczematous eruption all over the body induced by IVIg that was unresponsive to topical steroid ointment and was subsequently treated with narrow band-ultraviolet B (NB-UVB) therapy successfully. NB-UVB was started at a dose of 400 mJ/cm2 once a week, and swift improvement was observed. The skin rash disappeared in the first 2 months, and the pathogenesis of IVIg-induced eczematous eruption remains unelucidated. No change in eosinophils and complement levels were observed in our case. Given the increase in the widespread use of IVIg, we have shown that NB-UVB therapy is a candidate choice for the treatment of IVIg-induced severe vesicular eczematous eruption.",
"affiliations": "Division of Dermatology, Department of Internal Related, Kobe University Graduate School of Medicine, Kobe, Japan.;Division of Dermatology, Department of Internal Related, Kobe University Graduate School of Medicine, Kobe, Japan.;Division of Dermatology, Department of Internal Related, Kobe University Graduate School of Medicine, Kobe, Japan.;Division of Dermatology, Department of Internal Related, Kobe University Graduate School of Medicine, Kobe, Japan.",
"authors": "Koizumi|Rina|R|;Fukumoto|Takeshi|T|;Jimbo|Haruki|H|;Nishigori|Chikako|C|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1111/phpp.12666",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0905-4383",
"issue": "37(5)",
"journal": "Photodermatology, photoimmunology & photomedicine",
"keywords": "CIDP; IVIg; NB-UVB; dermatological adverse reaction; vesicular eczematous eruption",
"medline_ta": "Photodermatol Photoimmunol Photomed",
"mesh_terms": null,
"nlm_unique_id": "9013641",
"other_id": null,
"pages": "371-373",
"pmc": null,
"pmid": "33559335",
"pubdate": "2021-09",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Intravenous immunoglobulin-induced severe vesicular eczematous eruption successfully treated with narrow band-ultraviolet B therapy.",
"title_normalized": "intravenous immunoglobulin induced severe vesicular eczematous eruption successfully treated with narrow band ultraviolet b therapy"
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"abstract": "A 23-year-old gravid Ugandan female at 26 weeks was admitted to the maternity ward with sweats, abdominal pain, feeling of apprehension and palpitations. A diagnosis of pre-eclampsia was made and treatment with magnesium sulphate initiated. She was later transferred to intensive care unit for monitoring and control of blood pressure. Due to her labile blood pressures despite intravenous hydralazine and metoprolol, the pregnancy was terminated. However, she continued to have labile blood pressures. Better control of blood pressure was achieved on oral prazocin and nifedipine. The patient was then transferred to floor and discharged home a few days later. An abdominal computed-tomography scan showed a solid lobulated right paravertebral mass superio-medial to the right kidney. An open adrenelectomy was performed and antihypertensives discontinued. Histopathology revealed a benign pheochromocytoma. The mother had good post-operative outcome; however the premature baby died 2 days later in the special care unit.",
"affiliations": "Department of Medicine, School of Medicine, College of Health Sciences, Makerere University, P. O. Box: 7072, Kampala, Uganda.",
"authors": "Lalitha|Rejani|R|;Opio|Christopher Kenneth|CK|",
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"doi": "10.11604/pamj.2013.15.29.2039",
"fulltext": "\n==== Front\nPan Afr Med JPan Afr Med JPAMJThe Pan African Medical Journal1937-8688The African Field Epidemiology Network PAMJ-15-2910.11604/pamj.2013.15.29.2039Case ReportA missed diagnosis or a masquerading disease: back to the basics Lalitha Rejani 1&Opio Christopher Kenneth 11 Department of Medicine, School of Medicine, College of Health Sciences, Makerere University, P. O. Box: 7072, Kampala, Uganda& Corresponding author: Lalitha Rejani, Department of Medicine, School of Medicine, College of Health Sciences, Makerere University, P. O. Box: 7072, Kampala, Uganda21 5 2013 2013 15 2915 9 2012 12 2 2013 © Lalitha Rejani et al.2013The Pan African Medical Journal - ISSN 1937-8688. This is an Open Access article distributed under the terms of the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.A 23-year-old gravid Ugandan female at 26 weeks was admitted to the maternity ward with sweats, abdominal pain, feeling of apprehension and palpitations. A diagnosis of pre-eclampsia was made and treatment with magnesium sulphate initiated. She was later transferred to intensive care unit for monitoring and control of blood pressure. Due to her labile blood pressures despite intravenous hydralazine and metoprolol, the pregnancy was terminated. However, she continued to have labile blood pressures. Better control of blood pressure was achieved on oral prazocin and nifedipine. The patient was then transferred to floor and discharged home a few days later. An abdominal computed-tomography scan showed a solid lobulated right paravertebral mass superio-medial to the right kidney. An open adrenelectomy was performed and antihypertensives discontinued. Histopathology revealed a benign pheochromocytoma. The mother had good post-operative outcome; however the premature baby died 2 days later in the special care unit.\n\nPre-eclampsiamagnesium sulphatepheochromocytomablood pressures\n==== Body\nIntroduction\nPheochromocytoma is rare during pregnancy however a strong index of suspicion is key to the diagnosis. Any hypertension presenting before 20 weeks of gestation should be thoroughly investigated. This case represents the lack of perception by many clinicians of other causes of hypertension in pregnancy. This patient had hypertension secondary to an adrenal tumor which was missed at initial presentation.\n\nPatient and observation\nPatient and observation We present a 23-year old African female, a primigravida and an allied health professional. She did not have any major health issues other than an appendectomy 6 months before diagnosis of her current pregnancy at 8 Weeks of Gestation (WOG). Her first antenatal contact occurred at 12 WOG, during which she was diagnosed with hypertension in pregnancy. She complained of intermittent palpitations and headache. No intervention with anti-hypertensive drugs was required at that time. Additional details regarding this visit could not be obtained.\n\nShe continued to feeling unwell over the subsequent 3 months. Finally, at 26 WOG, she sought obstetric care at a large urban hospital. Her complaints at the time included intermittent progressive palpitations, feelings of apprehension, sweating, dizziness, tremulousness, headache and occasional abdominal pain. This was not associated with any urinary symptoms, fever, or any other related symptoms. She was not on any medication or recreational drugs. She did not smoke or consume alcohol during this pregnancy. Her Physical examination was remarkable for anxious looking facies, tachycardia of 105 to 130 beats per minute, and a high systolic Blood Pressure (BP) of 140 to 200 mmHg. Her admission BP was 200/120mmHg on both arms.The rest of her cardiorespiratory examination was normal. Fundoscopy was not done at admission. Her neurological examination was normal. Abdominal examination revealed a gravid uterus with fundal height at 24/40 weeks, no renal bruit was appreciated. Her pre-pregnancy Body Mass Index (BMI) was 23.5.\n\nInvestigations during this admission showed a normal complete blood counts and differentials, normal electrolytes including calcium, magnesium and phosphate (serum potassium of 3.9mmol/L), liver and renal panels. Urine dip stick was negative for proteinuria. Her random plasma glucose was 6.5mmol/L. An obstetric ultrasound done at admission showed a gravid uterus but no mention on the state of the kidneys, adrenal glands or presence of any abnormal abdominal masses. She was managed by her obstetrician as hypertension in pregnancy and started on intra muscular magnesium sulphate for her raised BP. However her hypertension was refractory to this treatment leading to the development of hypertensive urgency. She was transferred to the medical/surgical Intensive Care Unit (ICU) for monitoring and control of her BP. Further evaluation was not very helpful. Urinalysis and renal studies remained normal while Electrocardiogram (EKG) and echocardiogram showed features of left ventricular strain and moderate left ventricular hypertrophy. Fundoscopy showed bilateral Grade IV hypertensive retinopathy (papilledema). In ICU, her BP was managed with intravenous hydralazine and metoprolol. EKG monitoring was performed every 2 days for signs of myocardial ischemia in combination with daily assessment of symptoms and clinical signs for the same. Cardiac enzymes could not be done.\n\nA decision to terminate the pregnancy at 27 WOG was made by obstetric team due to her labile BP with the hope that this would lead to better BP control and a live healthy baby. The cesarean section was uneventful leading to the birth of a premature neonate. Following the surgery, she was readmitted to ICU for monitoring. The baby died after 2 days in special care unit. She continued to experience swinging BP. This was controlled after titration with oral nifedipine and metoprolol. At this time, a diagnosis of secondary hypertension was strongly considered. Screening was undertaken for renal disease (imaging, renal function) and pheochromocytoma. A 24-hour urine metanephrine screen was negative but was inconclusive. Despite this a decision was taken to start her on medication for pheochromocytoma. The patient was transferred back to maternity with a diagnosis of secondary hypertension possibly due to pheochromocytoma and eventually discharged via the ward by the obstetric team/internists on oral prazocin 1mg once daily and oral nifedipine extended release 30mg twice daily. The plan was to continue her work up as an outpatient with further imaging and a repeat urinary vanillylmandelic acid (VMA).\n\nA chest Computed Tomography (CT) scan was performed and was normal. Abdominal CT scan showed a solid lobulated right paravertebral mass superior-medial to the right kidney with calcifications, extending from 11th, 12th thoracic vertebrae to 13th lumbar vertebra measuring 7.2 × 3.9 × 8.5 cm and compressing the inferior vena cava. The right supra renal gland was not visualized. The left supra renal gland and kidney were normal. A repeat 24 hour urinary VMA level was markedly elevated at 19.56 mg (normal range 2-7 mg/24h) with a normal creatinine clearance of 91.27 ml/min (normal range 88-128 ml/min) and 24h urine output of 2,450mls. This was sufficient to clinically confirm the diagnosis of pheochromocytoma.Her systolic BP was in the range of 150-160mmHg with oral prazocin 1mg twice daily and oral nifedipine 30mg twice daily. Oral propranolol 40mg twice daily was added to her treatment and liberal salt diet was encouraged in preparation for her surgery. She was readmitted after two weeks following her discharge for an open laparotomy and resection of the tumor. Before the surgery, her blood pressure was well controlled on the three antihypertensive drugs. The tumor was resected successfully and tissue samples were sent for histopathology using hematoxylin and eosin stain (Figure 1) and immunohistochemical staining (Figure 2). Following the surgery she spent two days in ICU for monitoring of BP and analgesia. At this point all antihypertensive were withdrawn and BP remained normal throughout her recovery and one year following her discharge from hospital.\n\nFigure 1 Section of tissue block obtained from adrenal tumor with Hematoxylin and Eosin stain, under low power, showing organoid neoplasm with large nests of tumor cells (black arrows) surrounded by rim of spindle cells or sustentacular cells (yellow arrows). These are features suggestive of an adrenal pheochromocytoma\n\nFigure 2 Immunohistochemistry of adrenal tumor showing diffuse cytoplasmic positivity of tumor cells to neuroendocrine markers namely Synaptophysin (black arrows) and Chromogranin (red arrows)\n\nDifferential diagnoses\nHypertension in pregnancy is a common problem thought to present in more than 8% of pregnancies [1]. It is classified into four categories namely: chronic hypertension, pre-eclampsia/enclampsia (hypertension and proteinuria after 20 WOG), pre-eclampsia superimposed on chronic hypertension and gestational hypertension (transient hypertension of pregnancy or chronic hypertension identified in the latter half of pregnancy). The patient described above falls into chronic hypertension, defined as hypertension (BP greater than 140/90mmHg) diagnosed at less than 20 WOG. Since the patient did not demonstrate any coexistent proteinuria/hyperuricaemia, it is unlikely that she had pre-eclampsia superimposed on chronic hypertension. The diagnosis of gestational hypertension is excluded since her hypertension was neither transient nor did it first present after 20 weeks of gestation.\n\nOne large study describing hypertensive disorders in pregnancy showed that chronic hypertension was twice as frequent as pre-eclampsia/eclampsia and 4 times more frequent than gestational hypertension or preeclampsia superimposed on chronic hypertension. In this study, chronic hypertension was twice more frequent in women of African ancestry compared to those with European or Asian origin [2]. In Uganda, one third of those with pre-eclampsia/eclampsia were shown to develop persistent hypertension; and risks factors for persistent hypertension after delivery included elevated serum creatinine, serum uric acid, and age group (20-29 years) [1]. One can postulate that many of these patients already had chronic hypertension.This collaborated by studies show the prevalence of chronic hypertension among females in this group in the community to be around 22% [3]. Chronic hypertension is mainly essential in nature, although it may be secondary to kidney diseases (primary or secondary), renal vascular diseases, adrenal diseases/disorders (primary aldosteronism, pheochromocytoma,Cushing's disease) and coarctation of the aorta. In reference to our patient, renal causes of hypertension were excluded at the time of admission on the basis of a normal creatinine, bland urinalysis and absence of renal bruit. Coarctation of aorta is unlikely based on the fact that she had the same blood pressure values on both the upper limbs and a normal cardiovascular examination. Cushing's syndrome or primary aldosteronism is also unlikely since the patient did not present with features diagnostic of Cushing's syndrome or laboratory findings of aldosteronism (low urine specific gravity, high urine PH, persistently low serum potassium and high urine potassium) except hypertension. In our patient a diagnosis of pheochromocytoma was confirmed on the basis of symptomatic paroxysmal persistent hypertension that is refractory to the usual drugs, adrenal mass, VMA greater than three times upper limit of normal, and complete remission of hypertension and removal of the need for antihypertensive medications following removal of tumor.\n\nDiscussion\nPheochromocytoma is a rare catecholamine-secreting tumor and very rare in association with pregnancy. In 85% of patients, it is derived from chromaffin cells of adrenal medulla; the rest 15% arise from extra-adrenal locations. It is a rare cause of sustained and paroxysmal hypertension. Hypertension may alternate with hypotension if the tumor predominantly secretes epinephrine. The clinical manifestations of the disease such as palpitations, generalized inappropriate sweating, feelings of impending doom or apprehension and headache arise from catecholamines released by the tumor into the circulation. Several mechanisms have been described as to why the manifestations of pheochromocytoma become clinically overt only during and probably due to the pregnancy. The increased intra-abdominal pressure owing to expanding uterus, fetal movements hemorrhage into tumor, abdominal palpation e.g., during physical examination, uterine contractions, the process of delivery, and general anesthesia induce a surge of catecholamines. Peripartum period is especially precarious due to abrupt massive outpouring of catecholamines from stress of labor, anesthesia and vaginal delivery. Pheochromocytoma in pregnancy demands special attention as there are several unusual presentations of the disease which makes diagnosis difficult with grave consequences.\n\nA high index of suspicion and a succinct history taking may help highlight the key symptoms and signs of pheochromocytoma, especially in our setting where resources are scarce, which warrants prompt evaluation. Reliable diagnosis requires a combination of biochemical tests and anatomical localization of the tumor by imaging studies. Plasma and 24-hour urinary metanephrine and normetanephrine are the most sensitive biochemical tests for making the diagnosis. Very rarely is clonidine suppression test indicated. Once the diagnosis is established, pheochromocytoma must be localized by appropriate imaging studies. A Computed Tomography (CT) can identify adrenal tumors which are 1cm or larger in 95% of the cases and localize 90% of extra-adrenal tumors larger than 2cm. Magnetic Resonance Imaging (MRI) is more sensitive and specific than CT. MRI is preferred in pregnant women and children suspected of having pheochromocytoma as it poses no radiation risk. MRI is currently not accessible by majority of the population in a low income country like ours. Tumor uptake of a radiopharmaceutical agent 131I- metaiodobenzylguanidine (MIBG) occurs in 81 to 85% of pheochromocytomas and is 95 to 100% specific for diagnosis. Imaging studies may be done before biochemical studies if familial pheochromocytoma is suspected where the tumor may not secrete significant amounts of catecholamines.\n\nTreatment of pheochromocytoma involves timely management of hypertensive emergencies and urgency. Hydralazine, a direct arteriolar vasodilator, is used primarily to treat hypertensive crisis of pregnancy. One of the adverse effects is myocardial ischemia due to a reflex increases in heart rate and stroke volume especially in patients with pheochromocytoma but this effect can be reduced by combining the agent with a beta blocker like metoprolol after achieving appropriate alpha blockade. We used intravenous hydralazine and metoprolol as these agents are readily available in a resource limited setting unlike phentolamine or phenoxybenzamine. Phentolamine, an alpha blocker, is the drug of choice in treatment of hypertensive emergency in pheochromocytoma. Preoperative alpha adrenergic blockade with phenoxybenzamine or prazocin or calcium channel blockers can usually control pheochromocytoma hypertension. Preoperative β1 blockade may be needed to control supraventricular arrhythmias or tachycardias and angina.\n\nCardioselective β1 blocking agent like the long acting metoprolol is recommended for controlling supraventricular tachycardia. Alpha blockade should always be achieved before blocking the β1 receptors as beta blockade alone can cause marked hypertension. This is more common with non- selective beta blockers as these agents block β2 receptors inhibiting any vasodilatory effects of epinephrine and thereby promoting vasoconstriction. In our patient, preoperative alpha blockade was achieved by oral prazocin and nifedipine and beta blockade by propranolol as oral metoprolol is not available in Uganda although it is recommended to use cardioselective β1 blockers like metoprolol. Preoperative sedation with diazepam helps alleviate symptoms of anxiety and catecholamine release. A muscle relaxant is recommended before endotracheal intubation to prevent any surge of catecholamines. For intraoperative control of hypertension intravenous phentolamine, nitroprusside or nitroglycerine can be used. Arrhythmias can be controlled using intravenous esmolol and/or lidocaine. Proper intra-operative intravenous fluid administration minimizes any risk for post-operative hypotension. Resection of the tumor can be done laparoscopically or by open laparotomy. Open laparotomy is preferred when the tumors are multiple, very large or difficult to be removed laparoscopically. Preservation of the adrenocortical function is important to prevent lifelong steroid replacement therapy and its complications. Pheochromocytomas in pregnancy should be removed promptly but if the pregnancy is carried to term, delivery of the fetus should be done by caesarean section to avoid the stress of labor and vaginal delivery. An experienced surgeon and anesthesiologist are paramount to a successful resection of the tumor and favorable maternal-fetal outcomes.\n\nConclusion\nThis case highlights the significance of a high index of suspicion and careful history taking in identifying these patients. This patient had hypertension secondary to an adrenal tumor which was missed at initial presentation. The importance of a broad differential diagnosis and special attention to diagnostic clues holds the key to right diagnosis and successful case management. We strongly recommend that clinicians should fully evaluate to determine other causes of hypertension among women presenting with raised blood pressure earlier than 20 weeks of gestation.\n\nAcknowledgements\nThe authors would like to thank Surgpath Medical Consultants for processing the tissue sample for histopathology and providing us with the electronic pictures of the stained tissue sections.OKC received support from Grant Number 5R24TW008886 supported by OGAC, NIH and HRSA.\n\nCompeting interests\nNone of the authors have any competing interests to declare.\n\nAuthors’ contributions\nRL conceived the idea, admitted and treated the patient, and prepared the manuscript. CKO participated in preparing and reviewing the manuscript.\n==== Refs\nReferences\n1 Ndayambagye Emmanuel Nakalembe Miriam Kaye Dan Factors associated with persistent hypertension after puerperium among women with preeclampsia/eclampsia in Mulago hospital, Uganda BMC Pregnancy and Childbirth 2010 10 12 20222993 \n2 Gaio Dea Schmidt Maria Duncan Bruce Bertoldi Luciana Matos Maria Branchtein Leandro Hypertensive disorders in pregnancy: frequency and associated factors in a cohort of Brazilian women Hypertens Pregnancy 2001 20 3 269 81 12044335 \n3 Wamala Joseph Karyabakabo Zepher Ndungutse David Guwatudde David Prevalence factors associated with hypertension in Rukungiri district, Uganda- a community-based study Afr Health Sci 2009 9 9 3 153 60 20589143\n\n",
"fulltext_license": "CC BY",
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"issue": "15()",
"journal": "The Pan African medical journal",
"keywords": "Pre-eclampsia; blood pressures; magnesium sulphate; pheochromocytoma",
"medline_ta": "Pan Afr Med J",
"mesh_terms": "D000310:Adrenal Gland Neoplasms; D000959:Antihypertensive Agents; D001794:Blood Pressure; D003951:Diagnostic Errors; D005260:Female; D006801:Humans; D006973:Hypertension; D010673:Pheochromocytoma; D011225:Pre-Eclampsia; D011247:Pregnancy; D011249:Pregnancy Complications, Cardiovascular; D011252:Pregnancy Complications, Neoplastic; D011256:Pregnancy Outcome; D014057:Tomography, X-Ray Computed; D014454:Uganda; D055815:Young Adult",
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"pages": "29",
"pmc": null,
"pmid": "24009805",
"pubdate": "2013",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't; D013487:Research Support, U.S. Gov't, P.H.S.",
"references": "12044335;20222993;20589143",
"title": "A missed diagnosis or a masquerading disease: back to the basics.",
"title_normalized": "a missed diagnosis or a masquerading disease back to the basics"
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"abstract": "Objectives: Disease progression in metastatic castration-resistant prostate cancer (mCRPC) is dependent on androgen signaling. This case describes the complex adaptive androgen signaling mechanisms in mCRPC and illustrates that caution should be exercised when treating these patients with drugs influencing the androgen axis.Methods: Single case report and review of the literature.Results: We report the case of an 86-year-old man with mCRPC, treated with the secondary antihormonal agent abiraterone acetate. Following association of spironolactone to deal with symptoms related to mineralocorticoid excess, biochemical and radiographic disease progression occurred. Spironolactone was discontinued and 8 months after withdrawal, the patient continues to show a biochemical response to abiraterone.Conclusions: Although spironolactone generally exerts anti-androgenic effects, experimental evidence exists that it acts as an androgen receptor agonist in an androgen-depleted environment, capable of inducing prostate cancer proliferation. This is supported by the observations described in this case report. Therefore, spironolactone should be avoided in prostate cancer patients suffering from treatment-associated side effects of abiraterone.",
"affiliations": "Department of Urology, Ghent University Hospital , Ghent , Belgium.;Department of Urology, Ghent University Hospital , Ghent , Belgium.;Department of Urology, Ghent University Hospital , Ghent , Belgium.;Department of Urology, Ghent University Hospital , Ghent , Belgium.;Department of Urology, Ghent University Hospital , Ghent , Belgium.;Department of Radiation Oncology and Experimental Cancer Research, Laboratory of Experimental Cancer Research, Ghent University , Ghent , Belgium.;Department of Urology, Ghent University Hospital , Ghent , Belgium.",
"authors": "Dhondt|Bert|B|https://orcid.org/0000-0001-7223-7670;Buelens|Sarah|S|https://orcid.org/0000-0002-1752-6821;Van Besien|Jeroen|J|;Beysens|Matthias|M|;De Bleser|Elise|E|;Ost|Piet|P|;Lumen|Nicolaas|N|",
"chemical_list": "D000970:Antineoplastic Agents; D000451:Mineralocorticoid Receptor Antagonists; D013148:Spironolactone; D000069501:Abiraterone Acetate",
"country": "England",
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"doi": "10.1080/17843286.2018.1543827",
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"issue": "74(6)",
"journal": "Acta clinica Belgica",
"keywords": "Abiraterone; CYP17; androgen receptor; mineralocorticoid excess; prostate cancer; spironolactone",
"medline_ta": "Acta Clin Belg",
"mesh_terms": "D000069501:Abiraterone Acetate; D000369:Aged, 80 and over; D000970:Antineoplastic Agents; D001859:Bone Neoplasms; D000075203:Contraindications, Drug; D018450:Disease Progression; D004347:Drug Interactions; D064420:Drug-Related Side Effects and Adverse Reactions; D006801:Humans; D008297:Male; D000451:Mineralocorticoid Receptor Antagonists; D009367:Neoplasm Staging; D064129:Prostatic Neoplasms, Castration-Resistant; D013148:Spironolactone; D016896:Treatment Outcome; D028761:Withholding Treatment",
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"title": "Abiraterone and spironolactone in prostate cancer: a combination to avoid.",
"title_normalized": "abiraterone and spironolactone in prostate cancer a combination to avoid"
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"abstract": "BACKGROUND\nAlthough antibody deficiency (AD) is a well-known cause of recurrent respiratory infections, there are few data on its impact in adults with asthma. The objective of the present study was to assess outcomes in adults with severe asthma and AD after treatment with either azithromycin or subcutaneous immunoglobulins (SCIg).\n\n\nMETHODS\nWe performed a 5-year, prospective, observational, two-centre study of adults with severe asthma and AD in France. Bronchiectasis was ruled out by high-resolution computed tomography. Patients were treated for one year with either azithromycin (250 mg every other day) or SCIg (0.4-0.6 g/kg/months, weekly). All patients were evaluated for exacerbations, asthma control and lung function at baseline and then one year after treatment initiation.\n\n\nRESULTS\nThirty-nine patients with severe asthma were included in the study: 14 had been treated with azithromycin and 25 had been treated with SCIg. Before the initiation of treatment for AD, all patients had an Asthma Control Questionnaire (ACQ-7) score > 1.5 (mean ± SD: 2.71 ± 0.53) despite treatment at GINA step 4 or 5, and had a high exacerbation rate requiring oral corticosteroids and/or rescue antibiotics (∼7.2 ± 2.1/patient/year). One year after treatment initiation, we observed a significantly higher FEV1 (mean: 0.18 ± 0.22 L) and ACQ-7 score (1.26 ± 0.68), and a significantly lower exacerbation rate (1.63 ± 1.24/patient/year).\n\n\nCONCLUSIONS\nTreatment of AD dramatically improved asthma outcomes - suggesting that adults with severe asthma and recurrent respiratory infections should be screened and (if appropriate) treated for AD.",
"affiliations": "Department of Pulmonology, Nancy University Hospital, Nancy, France; Development, Adaptation and Disadvantage, Cardio-Respiratory Regulations and Motor Control, University of Lorraine, Nancy, France; National Heart and Lung Institute, Airway Disease Section, Imperial College London, London, UK. Electronic address: angelica.tiotiu@yahoo.com.;Department of Airway Diseases, Foch Hospital, Suresnes, France; Foch Hospital, Paris Saclay University, Suresnes, France.;Department of Internal Medicine, Nancy University Hospital, Nancy, France; Faculty of Medicine, University of Lorraine, Nancy, France.;Faculty of Medicine, University of Lorraine, Nancy, France; ENT Department, Nancy University Hospital, Nancy, France.;Department of Airway Diseases, Foch Hospital, Suresnes, France; Foch Hospital, Paris Saclay University, Suresnes, France.;Department of Airway Diseases, Foch Hospital, Suresnes, France.;Department of Airway Diseases, Foch Hospital, Suresnes, France; Foch Hospital, Paris Saclay University, Suresnes, France.",
"authors": "Tiotiu|Angelica|A|;Salvator|Hélène|H|;Jaussaud|Roland|R|;Jankowski|Roger|R|;Couderc|Louis-Jean|LJ|;Catherinot|Emilie|E|;Devillier|Philippe|P|",
"chemical_list": "D007136:Immunoglobulins; D017963:Azithromycin",
"country": "England",
"delete": false,
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"issue": "69(2)",
"journal": "Allergology international : official journal of the Japanese Society of Allergology",
"keywords": "Antibody deficiency; Asthma; Azithromycin; Immunoglobulin replacement; Respiratory infections",
"medline_ta": "Allergol Int",
"mesh_terms": "D000368:Aged; D001249:Asthma; D017963:Azithromycin; D018450:Disease Progression; D005260:Female; D006801:Humans; D007136:Immunoglobulins; D007153:Immunologic Deficiency Syndromes; D007279:Injections, Subcutaneous; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D012129:Respiratory Function Tests; D016896:Treatment Outcome",
"nlm_unique_id": "9616296",
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"pages": "215-222",
"pmc": null,
"pmid": "31812484",
"pubdate": "2020-04",
"publication_types": "D016428:Journal Article; D064888:Observational Study",
"references": null,
"title": "Efficacy of immunoglobulin replacement therapy and azithromycin in severe asthma with antibody deficiency.",
"title_normalized": "efficacy of immunoglobulin replacement therapy and azithromycin in severe asthma with antibody deficiency"
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"companynumb": "FR-MYLANLABS-2020M1040994",
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"activesubstancename": "AZITHROMYCIN ANHYDROUS"
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"abstract": "We investigated the superiority of docetaxel plus cisplatin and S-1 compared with cisplatin and S-1 in chemotherapy-naive patients with advanced gastric cancer.\n\n\n\nIn this open-label, phase 3, randomised controlled trial, patients were recruited from 56 hospitals in Japan. We enrolled individuals aged 20-75 years who had unresectable or recurrent gastric cancer, had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, had received no previous chemotherapy (except adjuvant chemotherapy completed 24 weeks before reccurence), radiotherapy, or hormonal therapy, could take drugs orally, and had adequate organ function. Patients were randomly assigned (1:1) to receive docetaxel plus cisplatin and S-1 (docetaxel 40 mg/m2 and cisplatin 60 mg/m2 on day 1 intravenously, and S-1 40-60 mg twice a day orally for 2 weeks, every 4 weeks) or cisplatin and S-1 (cisplatin 60 mg/m2 intravenously on day 8, and S-1 40-60 mg orally twice a day for 3 weeks, every 5 weeks). Randomisation was done centrally with the minimisation method, with a random component balancing for institution, ECOG performance status (0 vs 1), disease status at enrolment (unresectable vs recurrent), measurable lesion (yes vs no), number of metastatic sites (0-1 vs ≥2), and histological type (differentiated vs undifferentiated). Neither investigators or patients were masked to the study treatment. The primary endpoint was overall survival in the intention-to-treat population. The study is registered with UMIN-CTR, number UMIN000007652.\n\n\n\nBetween April 3, 2012, and March 18, 2016, 741 patients were randomly assigned to receive docetaxel plus cisplatin and S-1 (n=370) or cisplatin and S-1 (n=371). Median overall survival was 14·2 months (95% CI 12·9-15·9) in the docetaxel plus cisplatin and S-1 group and 15·3 months (14·2-16·2) in the cisplatin and S-1 group (hazard ratio [HR] 0·99 [95% CI 0·85-1·16]; one-sided stratified log-rank p=0·47). The most common grade 3 or worse adverse events were neutropenia (209 [59%] of 357 patients in the docetaxel plus cisplatin and S-1 group vs 117 [32%] of 365 patients in the cisplatin and S-1 group), leukopenia (120 [34%] vs 60 [16%]), and anorexia (94 [26%] vs 81 [22%]). The deaths of one patient in the cisplatin and S-1 group and in three patients in the docetaxel plus cisplatin and S-1 group were deemed treatment-related.\n\n\n\nThe addition of docetaxel to cisplatin and S-1 did not improve overall survival in chemotherapy-naive Japanese patients with advanced gastric cancer. Therefore, cisplatin and S-1 remains the standard first-line chemotherapy.\n\n\n\nMinistry of Health, Labour and Welfare and Japan Agency for Medical Research and Development.",
"affiliations": "Comprehensive Cancer Center, National Center for Global Health and Medicine, Shinjuku-ku, Tokyo, Japan; Department of Medical Oncology, Hamamatsu University School of Medicine, Shizuoka, Japan; Gastrointestinal Medical Oncology Division, National Cancer Center Hospital, Chuo-ku, Tokyo, Japan. Electronic address: yayamada@hosp.ncgm.go.jp.;Gastrointestinal Medical Oncology Division, National Cancer Center Hospital, Chuo-ku, Tokyo, Japan.;Japan Clinical Oncology Group Data Center and Operations Office, National Cancer Center Hospital, Chuo-ku, Tokyo, Japan.;Gastrointestinal Medical Oncology Division, National Cancer Center Hospital, Chuo-ku, Tokyo, Japan.;Department of Clinical Oncology, Aichi Cancer Center Hospital, Chikusa-ku, Nagoya, Aichi, Japan.;Department of Gastroenterology, Kanagawa Cancer Center Hospital, Asahi-ku, Yokohama, Kanagawa, Japan.;Department of Gastroenterology, Kitasato University School of Medicine, Minami, Sagamihara, Kanagawa, Japan.;Department of Gastroenterology, Hyogo Cancer Center, Akashi, Hyogo, Japan.;Department of Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa-shi, Chiba, Japan.;Department of Medical Oncology, Kindai University, Faculty of Medicine, Osaka, Japan.;Department of Gastroenterology, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, Koto-ku, Tokyo, Japan.;Department of Surgery, National Hospital Organization Kyoto Medical Center, Fushimi-ku, Kyoto, Japan.;Second Department of Surgery, School of Medicine, Wakayama Medical University, Wakayama, Japan.;Department of Gastroenterology, Saitama Cancer Center, Inamachi, Kitaadachi-gun, Saitama, Japan.;Division of Gastrointestinal Oncology, Shizuoka Cancer Center, Nagaizumi-cho, Sunto-gun, Shizuoka, Japan.;Japan Clinical Oncology Group Data Center and Operations Office, National Cancer Center Hospital, Chuo-ku, Tokyo, Japan.;Japan Clinical Oncology Group Data Center and Operations Office, National Cancer Center Hospital, Chuo-ku, Tokyo, Japan.;Department of Gastrointestinal Surgery, Kanagawa Cancer Center Hospital, Asahi-ku, Yokohama, Kanagawa, Japan.;Department of Surgery, Hyogo College of Medicine, Fushimi-ku Mukogawa-cho, Nishinomiya-shi, Hyogo, Japan.;Division of Gastric Surgery, Shizuoka Cancer Center, Nagaizumi-cho, Sunto-gun, Shizuoka, Japan.",
"authors": "Yamada|Yasuhide|Y|;Boku|Narikazu|N|;Mizusawa|Junki|J|;Iwasa|Satoru|S|;Kadowaki|Shigenori|S|;Nakayama|Norisuke|N|;Azuma|Mizutomo|M|;Sakamoto|Takeshi|T|;Shitara|Kohei|K|;Tamura|Takao|T|;Chin|Keisho|K|;Hata|Hiroaki|H|;Nakamori|Mikihito|M|;Hara|Hiroki|H|;Yasui|Hirofumi|H|;Katayama|Hiroshi|H|;Fukuda|Haruhiko|H|;Yoshikawa|Takaki|T|;Sasako|Mitsuru|M|;Terashima|Masanori|M|",
"chemical_list": "D000077143:Docetaxel; D002945:Cisplatin",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/S2468-1253(19)30083-4",
"fulltext": null,
"fulltext_license": null,
"issn_linking": null,
"issue": "4(7)",
"journal": "The lancet. Gastroenterology & hepatology",
"keywords": null,
"medline_ta": "Lancet Gastroenterol Hepatol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D002945:Cisplatin; D000077143:Docetaxel; D005260:Female; D006801:Humans; D007564:Japan; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009364:Neoplasm Recurrence, Local; D013274:Stomach Neoplasms; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "101690683",
"other_id": null,
"pages": "501-510",
"pmc": null,
"pmid": "31101534",
"pubdate": "2019-07",
"publication_types": "D017428:Clinical Trial, Phase III; D003160:Comparative Study; D000073843:Equivalence Trial; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Docetaxel plus cisplatin and S-1 versus cisplatin and S-1 in patients with advanced gastric cancer (JCOG1013): an open-label, phase 3, randomised controlled trial.",
"title_normalized": "docetaxel plus cisplatin and s 1 versus cisplatin and s 1 in patients with advanced gastric cancer jcog1013 an open label phase 3 randomised controlled trial"
} | [
{
"companynumb": "JP-PFIZER INC-2019223793",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "DOCETAXEL"
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"drugadditional": null,
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{
"abstract": "A 74-year-old female with trigeminal neuralgia developed hypertension after the initiation of carbamazepine therapy. The time sequence of start of the suspected drug and onset of hypertension are consistent with the diagnosis. The hypertension did not resolve with antihypertensive therapy or dose reduction of carbamazepine. Patient recovered after the carbamazepine therapy was discontinued. The positive rechallenge and positive dechallenge showed association of carbamazepine therapy with hypertension as its adverse effect. This is a rare case that we report of carbamazepine-induced hypertension and this report may act as alerting mechanism to the health care professionals especially neurologists.",
"affiliations": "Department of Pharmacology, Pandit Bhagwat Dayal Sharma University of Health Sciences, Rohtak, Haryana, India.;Department of Pharmacology, Pandit Bhagwat Dayal Sharma University of Health Sciences, Rohtak, Haryana, India.;Department of Pharmacology, Pandit Bhagwat Dayal Sharma University of Health Sciences, Rohtak, Haryana, India.",
"authors": "Kharb|Preeti|P|;Mittal|Niti|N|;Gupta|Mahesh C|MC|",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": "10.4103/0976-500X.171879",
"fulltext": "\n==== Front\nJ Pharmacol PharmacotherJ Pharmacol PharmacotherJPPJournal of Pharmacology & Pharmacotherapeutics0976-500X0976-5018Medknow Publications & Media Pvt Ltd India JPP-6-21610.4103/0976-500X.171879Case ReportCarbamazepine-induced hypertension: A rare case Kharb Preeti Mittal Niti Gupta Mahesh C. Department of Pharmacology, Pandit Bhagwat Dayal Sharma University of Health Sciences, Rohtak, Haryana, IndiaAddress for correspondence: Preeti Kharb, Department of Pharmacology, Pandit Bhagwat Dayal Sharma University of Health Sciences, Rohtak - 124 001, Haryana, India. E-mail: preetikharb88@gmail.comOct-Dec 2015 6 4 216 218 25 10 2014 17 12 2014 02 8 2015 Copyright: © Journal of Pharmacology and Pharmacotherapeutics2015This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.A 74-year-old female with trigeminal neuralgia developed hypertension after the initiation of carbamazepine therapy. The time sequence of start of the suspected drug and onset of hypertension are consistent with the diagnosis. The hypertension did not resolve with antihypertensive therapy or dose reduction of carbamazepine. Patient recovered after the carbamazepine therapy was discontinued. The positive rechallenge and positive dechallenge showed association of carbamazepine therapy with hypertension as its adverse effect. This is a rare case that we report of carbamazepine-induced hypertension and this report may act as alerting mechanism to the health care professionals especially neurologists.\n\nCarbamazepinehypertensiontrigeminal neuralgia\n==== Body\nINTRODUCTION\nThe trigeminal neuralgia is defined as sudden, usually unilateral, severe, brief, stabbing, recurrent episodes of pain in the distribution of one or more branches of the trigeminal nerve (fifth cranial nerve).[1] In 80-90% of cases, it is thought to be caused by compression of the trigeminal nerve by a loop of artery or vein.[2] The annual incidence worldwide is 4 to 5 in 100,000.[3] Women are affected twice than men. The incidence increases with age and is rare in people younger than 40 years of age.[2]\n\nThe drug of choice for trigeminal neuralgia is carbamazepine.[24] Most common adverse effects observed with carbamazepine are drowsiness, unsteadiness, constipation, nausea, and vomiting. There are various side effects related to different systems.[4] It is also reported to cause hypertension;[45] however, the frequency of occurrence is rare (≥1/10,000 to < 1/1,000).[5]\n\nCASE REPORT\nA 74-year-old female presented to a private practitioner with complaint of facial pain on the left side. On examination her blood pressure (B.P) was 117/80 mmHg. Her dental examination was normal and based on the symptoms a provisional diagnosis of trigeminal neuralgia was made. She had no significant past medical or family history of similar condition. The patient was prescribed tablet carbamazepine 300 mg tablet OD. After 2 days, she complained of headache, restlessness and on examination B.P was found to be 290/110 mmHg. There was no previous history of hypertension. The drug was discontinued and the B.P. returned to 120/78 mmHg.\n\nAs the pain was persisting, she presented to the neurology OPD of the institute with complaint of left side facial pain and the diagnosis was confirmed as trigeminal neuralgia. The baseline B.P. was 118/80 mmHg. The patient was started with carbamazepine 50 mg tablet BD and was gradually titrated to 200 mg BD. The MRI findings confirmed the diagnosis of trigeminal neuralgia. On examination, her B.P. was 180/100 mmHg and there were no features suggestive of hypertensive encephalopathy. She was started with tablet telmisartan/hyrochlorthiazide and carbamazepine was continued. She was advised to get thyroid profile, random blood sugar and lipid profile done, all of which were within normal range. She presented after 4 days with severe nausea, vomiting and dizziness with persisting constipation. Home B.P. records were not done. Her facial pain had recovered. The B.P. was 146/80 mmHg. The dose of carbamazepine was reduced to 100 mg BD and rest all the medicines were continuing. She was also prescribed tablet betahistine. The ECG and fundus examination were normal, biochemistry reports revealed low uric acid 2.3 (2.5-6.2 mg/dl); low serum sodium 119 mg/dl (135-155); low chloride 96 mmol/l (98-107); high total protein 9.3 g/dl (6.3-8.2); and high serum globulin 4.3 g/dl (2.5-3.5).\n\nNext day the patient was admitted to a private hospital with complaints of severe headache, epigastric pain and vomiting. On examination B.P. was 180/99 mmHg. All her medicines were stopped and she was managed symptomatically. The patient was discharged in satisfactory condition. The B.P. records were normal and the patient is off all the antihypertensive treatment. The patient is stable now [Table 1]. The trigeminal neuralgia resolved after the carbamazepine was stopped. No other treatment modality was used.\n\nTable 1 Sequence of events summary\n\nMeanwhile, based on literature search and detailed review of the patient's medical and family history, carbamazepine was suspected to be the causal agent for this adverse reaction as there was no underlying cardiovascular disease. Sudden shoot of B.P. after oral carbamazepine high dose; and non-resolution of hypertension despite anti-hypertensive therapy confirmed that hypertension was induced by oral carbamazepine therapy as it resolved only after carbamazepine discontinuation.\n\nA causal association between hypertension and carbamazepine was assessed by World Health Organization (WHO) probability method and Naranjo's adverse drug reaction probability scale.[67] The WHO probability method and Naranjo's Adverse Drug Reaction Probability Scale showed “certain” and “definite” (Naranjo's score 10) association, respectively. As per modified Hartwig and Siegel scale, the severity of the reaction was “moderate: Level 4b”.[8]\n\nDISCUSSION\nLiterature search was conducted which showed six reports on carabamazepine-induced hypertension from various countries.[91011121314] All the cases had patients who developed hypertension during carbamazepine treatment which resolved on discontinuation. To the best of our knowledge, this is the first report of carbamazepine-induced hypertension from India.\n\nBo et al. discussed the possible role of anti-diuretic hormone in the production of this infrequent side effect.[9] The possible mechanism as to why the antihypertensive therapy is unresponsive as explained by Downey et al. is that antiepileptic agents could induce drug-metabolizing system and thus reduce the effects of antihypertensive medications.[10] Another author stated that carbamazepine induces the cytochrome P450, which catalyze the metabolism of most of the antihypertensive used.[13]\n\nThe time sequence of start of the suspected drug and onset of hypertension are consistent with the diagnosis. The rechallenge by another physician led to raised blood pressure, not successfully managed by the appropriate treatment. The symptoms recovered after withdrawal of the suspected drug and the patient did not develop hypertension further owing to cessation of carbamazepine which is suggestive of possible association between carbamazepine and hypertension.\n\nCONCLUSION\nCarbamazepine-induced hypertension is rare and this report may act as alerting mechanism to the health care professionals. Neurologists, doctors and experts in various fields, pharmacist and patients need to be aware of the potential of carbamazepine-induced hypertension.\n\nFinancial support and sponsorship\nNil.\n\nConflicts of interest\nThere are no conflicts of interest.\n==== Refs\nREFERENCES\n1 Merskey H Bogduk N Classification of Chronic Pain: Descriptions of Chronic Pain Syndromes and Definitions of Pain Terms 1994 Seattle IASP Press 59 71 \n2 Trigeminal neuralgia NICE recommendations, NPSA Last accessed on 2014 Jul 24 Available from:\nhttp://www.nice.org.uk/guidance/CG173/chapter/1.Recommendations \n3 Katusic S Williams DB Beard CM Bergstralh E Kurland LT Epidemiology and clinical features of idiopathic trigeminal neuralgia and glossopharyngeal neuralgia: Similarities and differences, Rochester, Minnesota, 1945-1984 Neuroepidemiology 1991 10 276 81 1798430 \n4 Product Information: Tegretol, Novartis Pharmaceuticals Corporation Last accessed on 2014 Jul 24 Available from:\nhttp://www.accessdata.fda.gov/drugsatfda_docs/label/2014/016608s103,018281s051,018927s044,020234s035lbl.pdf \n5 Electronic Medicines Compendium (eMC). Summary of Product Characteristics: Tegretol (Carbamazepine), Novartis Limited Last accessed on 2014 Jul 24 Available from:\nhttps://www.medicines.org.uk/emc/printfriendlydocument.aspx?documentid=1328 \n6 WHO-UMC causality assessment system Last accessed on 2014 Jul 24 Available from:\nhttp://www.who-umc.org/pdfs/Causality.pdf \n7 Naranjo CA Busto U Sellars EM Sandor P Ruiz I Roberts EA A method for estimating the probability of adverse drug reactions Clin Pharmacol Ther 1981 30 239 45 7249508 \n8 Hartwig SC Siegel J Schneider PJ Preventability and severity assessment in reporting adverse drug reactions Am J Hosp Pharm 1992 49 2229 32 1524068 \n9 Bo GP Cocito L Maffini M Perfumo P Venturi S Arterial hypertension caused by carbamazepine Riv Neurol 1987 57 333 5 3452233 \n10 Downey P Fajuri A Valdés G Refractory arterial hypertension and the use of anticonvulsant drugs. Case report Rev Med Chil 2001 129 1325 7 11836887 \n11 Jette N Veregin T Guberman A Carbamazepine-induced hypertension Neurology 2002 59 275 6 12136070 \n12 Marini AM Choi JY Labutta RJ Transient neurologic deficits associated with carbamazepine-induced hypertension Clin Neuropharmacol 2003 26 174 6 12897634 \n13 Frangos Lordos E Trombert V Kuzmanovic I Vogt-Ferrier N Perrenoud JJ Drug-induced refractory arterial hypertension Rev Med Suisse 2005 1 2522 2525 6 \n14 Furuta N Fujita Y Sekine A Ikeda M Okamoto K Reversible posterior leukoencephalopathy syndrome associated with carbamazepine-induced hypertension Rinsho Shinkeigaku 2009 49 191 3 19462818\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "0976-500X",
"issue": "6(4)",
"journal": "Journal of pharmacology & pharmacotherapeutics",
"keywords": "Carbamazepine; hypertension; trigeminal neuralgia",
"medline_ta": "J Pharmacol Pharmacother",
"mesh_terms": null,
"nlm_unique_id": "101552113",
"other_id": null,
"pages": "216-8",
"pmc": null,
"pmid": "26816475",
"pubdate": "2015",
"publication_types": "D002363:Case Reports",
"references": "1798430;12897634;3452233;12136070;1524068;16323733;7249508;19462818;11836887",
"title": "Carbamazepine-induced hypertension: A rare case.",
"title_normalized": "carbamazepine induced hypertension a rare case"
} | [
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"companynumb": "IN-JUBILANT CADISTA PHARMACEUTICALS-2016JUB00038",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
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{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CARBAMAZEPINE"
},
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{
"abstract": "BACKGROUND\nWe report a case of profound symptomatic bradycardia after a single dose of tizanidine.\n\n\nMETHODS\nA 93-year-old female became altered and was found to have hypotension and profound symptomatic bradycardia 30 min post ingestion of a single 4-mg dose of tizanidine at her physician's office. Emergency Medical Services was called to scene and patient was transported to our tertiary medical center. In the emergency department, the patient required intubation, vasopressor support, and transcutaneous pacing. An electrocardiogram revealed atrial fibrillation with slow ventricular response with a heart rate of 19 beats/min. The patient was transferred to the intensive care unit and subsequently taken for cardiac catheterization, where a transvenous pacer was placed. During the next few days, her vital signs and mental status improved, allowing for successful extubation. Before discharge, the patient received a single-chamber pacemaker.\n\n\nCONCLUSIONS\nProfound symptomatic bradycardia from a single dose of tizanidine has not been reported. A review of the patient's medications did not reveal a significant cytochrome P450 drug interaction to result in an adverse effect as previously reported in the literature.\n\n\nCONCLUSIONS\nTizanidine should be used cautiously in elderly population and drug interactions screening should be performed.",
"affiliations": "Lakeland Regional Medical Center, Lakeland, Florida.;Lakeland Regional Medical Center, Lakeland, Florida.;Lakeland Regional Medical Center, Lakeland, Florida.",
"authors": "Cortes|Jennifer|J|;Hall|Brad|B|;Redden|Danyelle|D|",
"chemical_list": "D058647:Adrenergic alpha-2 Receptor Agonists; C023754:tizanidine; D003000:Clonidine",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0736-4679",
"issue": "48(4)",
"journal": "The Journal of emergency medicine",
"keywords": "CNS; cardiac support; muscle relaxants; psychological pharmaceuticals",
"medline_ta": "J Emerg Med",
"mesh_terms": "D058647:Adrenergic alpha-2 Receptor Agonists; D000369:Aged, 80 and over; D001919:Bradycardia; D002304:Cardiac Pacing, Artificial; D003000:Clonidine; D005260:Female; D006801:Humans; D016896:Treatment Outcome",
"nlm_unique_id": "8412174",
"other_id": null,
"pages": "458-60",
"pmc": null,
"pmid": "25456780",
"pubdate": "2015-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Profound symptomatic bradycardia requiring transvenous pacing after a single dose of tizanidine.",
"title_normalized": "profound symptomatic bradycardia requiring transvenous pacing after a single dose of tizanidine"
} | [
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"companynumb": "US-DRREDDYS-USA/USA/15/0049635",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
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"actiondrug": null,
"activesubstance": {
"activesubstancename": "HYDROCHLOROTHIAZIDE\\TRIAMTERENE"
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{
"abstract": "Bisphosphonates have evolved over the past decades from oral to more potent intravenous preparations. Along with significant paradigm shift in the management of myeloma over the past years, stronger nitrogen-containing bisphosphonates, due to their antiresorptive action on the bones, have found their way as a key and integral part in the management of bone disease in myeloma. Multiple randomized controlled trials have established efficacy of bisphosphonates in reducing skeletal-related events in myeloma. Some well-documented adverse events include acute-phase reactions, esophageal irritation, and osteonecrosis of the jaw. Across all clinical indications, the incidence of inflammatory eye reactions after bisphosphonate infusion ranges from 0.046% to 1%. However, data from myeloma patients are extrapolated from few reported cases in literature with varying management strategies including discontinuation, switching to different forms, and rechallenging with steroid cover. Inflammatory eye reactions can vary from self-limiting conjunctivitis and episcleritis to serious uveitis and vision-threatening orbital inflammation. We present a similar case of a patient with IgG kappa myeloma who developed flu-like symptoms followed by severe orbital inflammation within 48-72 hours after receiving zoledronic acid infusion. The patient was successfully managed with intravenous methyl prednisolone followed by oral tapering dose of steroids and discontinuation of further bisphosphonate therapy. A complete recovery was noted in a week's time.",
"affiliations": "Haematology Department, University Hospital Galway, Galway, Ireland.;Haematology Department, University Hospital Galway, Galway, Ireland.",
"authors": "Faryal|Rehman|R|https://orcid.org/0000-0002-9823-9786;Hayat|Amjad|A|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1155/2021/6647277",
"fulltext": "\n==== Front\nCase Rep Hematol\nCase Rep Hematol\nCRIHEM\nCase Reports in Hematology\n2090-6560 2090-6579 Hindawi \n\n10.1155/2021/6647277\nCase Report\nKeeping an Eye on Bisphosphonate Therapy in Myeloma: A Case Report of Ocular Inflammation Postzoledronic Acid Infusion\nhttps://orcid.org/0000-0002-9823-9786Faryal Rehman rehman.faryal@hse.ie Hayat Amjad Haematology Department, University Hospital Galway, Galway, Ireland\nAcademic Editor: Alessandro Gozzetti\n\n\n2021 \n13 2 2021 \n2021 664727716 11 2020 4 2 2021 6 2 2021 Copyright © 2021 Rehman Faryal and Amjad Hayat.2021This 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.Bisphosphonates have evolved over the past decades from oral to more potent intravenous preparations. Along with significant paradigm shift in the management of myeloma over the past years, stronger nitrogen-containing bisphosphonates, due to their antiresorptive action on the bones, have found their way as a key and integral part in the management of bone disease in myeloma. Multiple randomized controlled trials have established efficacy of bisphosphonates in reducing skeletal-related events in myeloma. Some well-documented adverse events include acute-phase reactions, esophageal irritation, and osteonecrosis of the jaw. Across all clinical indications, the incidence of inflammatory eye reactions after bisphosphonate infusion ranges from 0.046% to 1%. However, data from myeloma patients are extrapolated from few reported cases in literature with varying management strategies including discontinuation, switching to different forms, and rechallenging with steroid cover. Inflammatory eye reactions can vary from self-limiting conjunctivitis and episcleritis to serious uveitis and vision-threatening orbital inflammation. We present a similar case of a patient with IgG kappa myeloma who developed flu-like symptoms followed by severe orbital inflammation within 48–72 hours after receiving zoledronic acid infusion. The patient was successfully managed with intravenous methyl prednisolone followed by oral tapering dose of steroids and discontinuation of further bisphosphonate therapy. A complete recovery was noted in a week's time.\n==== Body\n1. Introduction\nMultiple myeloma is a disorder of clonal plasma cells which are derived from postgerminal B cells. It accounts for around 1% of all cancers and 13% of hematological malignancies. Median age of diagnosis is around 70 years with 37% of myeloma patients younger than 65 years [1]. Alongside anemia, hypercalcemia, and renal impairment, lytic bone lesions are an important feature of myeloma, which can complicate the course of disease with severe pain and skeletal-related events (SREs) including pathological fractures and cord compression. Approximately 80% of multiple myeloma patients experience a pathological fracture over the course of their disease [2]. Introduction of immunomodulatory drugs, proteasome inhibitors, and monoclonal antibodies into the treatment algorithms have translated into better survival outcomes. Over the past decades, bisphosphonates have found central role in osteoporosis, malignancies, and Paget's disease, and now they are an integral part of the management of bone disease in myeloma. Bisphosphonates have evolved from oral therapies to more potent, dose-convenient, intravenous therapies. Generally, well tolerated, they are known to cause side effects ranging from mild acute-phase reactions, esophageal irritation, hypocalcemia, and atrial fibrillation to rare serious adverse events such as osteonecrosis of the jaw. Relatively rare adverse effects of bisphosphonate therapy are inflammatory eye reactions (IERs) ranging from conjunctivitis and episcleritis to vision-threatening uveitis, scleritis, and severe orbital inflammation. Due to their increasing indications, usage, and previously underreporting, more cases of ophthalmological adverse events have come to light in recent years.\n\n2. Case Presentation\nA 45-year-old man presented to the eye casualty with right-sided periorbital swelling, pain, epiphora, and chemosis three days after receiving zoledronic acid in hematology day ward. He had a history of recently diagnosis of IgG kappa myeloma, R-ISS stage I, with multiple lytic lesions on the ribs, and a bone-related plasmacytoma on the left-sided ninth rib. He was an ex-smoker with a smoking history of 15 pack years. He had no other significantly past medical history and was not on any regular medications prior to his diagnosis. He was started on bortezomib/lenalidomide/dexamethasone (VRD) therapy. At the start of the second cycle, he received zoledronic acid 4 mg intravenously. He started noticing flu-like symptoms 24 hours after infusion, along with mild joint pains and minimal right eyelid swelling. Over the next 48 hours, he reported worsening right eye swelling, pain, redness, and difficulty in opening his eye (Figure 1).\n\nOn examination, his visual acuity was 6/9 bilaterally. A computed tomography (CT) scan of both orbits was requested to assess any possible retrobulbar inflammation. CT findings were suggestive of right-sided orbital cellulitis (Figure 2). On suspicion of a possible infective episode, he was empirically started on IV antibiotics. His symptoms continued to worsen over the next 12 hours, and it was decided to start on IV methyl prednisolone 500 mg once daily. By day three of IV steroids, there was a significant resolution of swelling and pain. He was discharged on oral prednisolone 60 mg which was tapered down every third day. He was followed up in day ward after a week where he reported complete recovery. Based on severity of the event and ophthalmology opinion, it was agreed to discontinue any further bisphosphonate therapy.\n\n3. Types of Bisphosphonates and Mechanism of Action\nBisphosphonates are structural analogues of naturally occurring inorganic pyrophosphates, which bind to the hydroxyapatite binding site on the exposed areas of the bone, undergoing active resorption. During the resorptive process, bisphosphonates are absorbed by the osteoclasts, eventually leading to apoptosis.\n\nChemically, they are classified into two categories: nonnitrogen-containing bisphosphonates that include early first-generation bisphosphonates such as clodronate and etidronate. They are structurally very similar to naturally occurring inorganic pyrophosphates. The second category consists of nitrogen-containing bisphosphonates which include second- and third-generation compounds such as alendronate, risedronate, ibandronate, pamidronate, and zoledronic acid. The addition of nitrogen/amine group to the bisphosphonate upgrades its antiresorptive potency by 10–10,000 compared to nonnitrogen-containing bisphosphonates [3, 4]. It is important to know that, along with the antiresorptive effect, pyrophosphates (including naturally occurring inorganic pyrophosphates and bisphosphonates) also inhibit calcification and mineralization of the bone. However, the potential to inhibit mineralization differs among the bisphosphonates, for example, risedronate inhibits bone resorption and mineralization at the same concentration (therapeutic index 1 : 1). In contrast, for nitrogen-containing bisphosphonates, the potential to inhibit mineralization is 1000 times less than its antiresorptive effect at the same concentration of the drug. Therefore, it renders a favorable therapeutic index to treat conditions such as myeloma-related bone disease.\n\nOnce absorbed by the osteoclasts, nonnitrogen-containing bisphosphonates are metabolized and incorporated into newly formed adenosine triphosphate (ATP) molecules. These nonhydrolysable ATPs accumulate and are unable to drive ATP-dependent cellular processes, resulting in osteoclast apoptosis. In comparison, nitrogen-containing bisphosphonates, once absorbed by the osteoclasts, inhibit the activity of farnesyl pyrophosphate synthase, a key regulatory enzyme in the mevalonic acid pathway resulting in posttranslational modifications of key proteins and eventually resulting in osteoclast apoptosis [4].\n\n4. Pathophysiology of Ocular Inflammation\nBisphosphonate treatment has been known to trigger the release of cytokines, IL-1 and IL-6, and other acute-phase proteins. In one study, it is suggested that nitrogen-containing bisphosphonates stimulate gamma/delta T cells (γ/δ T cells) in peripheral blood. Furthermore, it is suggested that the intensity of the acute-phase reaction seemed to correlate with the magnitude of increase in γ/δ T cells [5].\n\nThe exact mechanism of underlying ocular inflammatory response largely remains unknown. One suggested mechanism is that the drug is secreted into the tears by the lacrimal gland triggering a transitory localized irritation leading to the release of cytokines and other acute-phase proteins in the eye or cause activation of gamma/delta T cells within the orbit [6–8]. Preclinical animal studies reported conjunctivitis and episcleral congestion in rabbits with very supratherapeutic doses of pamidronate (daily dose of 30 mg/kg for 6 months), and it was identified that, at these doses, pamidronate secrets tears [9, 10].\n\nThe acute cytokines or T-cell response could explain the immediate eye reactions that take place within a short window. However, it is difficult to explain very delayed reactions occurring after weeks or months. It is uncertain whether the type of bisphosphonates used or disease-related factors such as background inflammatory conditions, immune dysregulation, or progressive accumulation of bisphosphonates overtime within the eye play any possible role to illicit these delayed reactions [6].\n\n5. Discussion\nMyeloma represents a subsegment of the patients receiving bisphosphonate therapies. Over the past years, multiple randomized placebo trials have demonstrated the efficacy of clodronate, pamidronate, and zoledronic acid in reducing bone pains and skeletal-related events. One study showed zoledronic acid was found to be as effective as pamidronate in reducing pain and incidence of SREs [11]. In another study, Medical Research Council (MRC) Myeloma IX trial, it not only shows zoledronic acid to be better than clodronate in reduction of SREs but also demonstrates that addition of zoledronic acid to standard first-line myeloma treatment reduced the risk of death by 16% and prolonged median overall survival by 5.5 months compared to clodronate [12]. However, a meta-analysis from Cochrane database was not able to confirm superiority of one bisphosphonate over another, but it is important to note that zoledronic acid is the only bisphosphonate to show survival benefit in placebo-controlled trials [13, 14]. Most experts and myeloma groups recommend a 2-year duration of bisphosphonate therapy, which is extrapolated from all placebo-controlled trials, in which the maximum duration of bisphosphonate therapy was 2 years.\n\nOverall, the incidence of IERs after bisphosphonate exposure ranges from 0.046% to 1%, with onset occurring from a few hours after exposure up to more than 3 years, with a median of 3 weeks [9]. Around 1 in 10 patients receiving bisphosphonates have flu-like symptoms such as fever, arthralgia, and myalgia following the first dose. The rate of reactions reduces to half following subsequent infusions. In one study, HORIZON trial, the rate of acute-phase reactions after the third dose was suggested to be around 2.8% [9].\n\nAlthough most of the data around ocular adverse effects of bisphosphonates comes from its use in broader categories of indications such as osteoporosis, Paget's disease, and solid cancers such as breast, prostate, and lung cancers, the data of myeloma patients come from few case reports in literature with variability in the management ranging from discontinuation of bisphosphonate therapy to rechallenging with the same or different forms of bisphosphonate. Maniel et al. report a recurrence of ocular symptoms including eyelid swelling, chemosis, and diplopia on rechallenging 4 months after the first episode with the same bisphosphonate (pamidronate) [15]. Similarly, Benderson et al. reports recurrence of milder symptoms after switching from zoledronic acid to pamidronate infusion with methyl prednisolone support and continued monthly pamidronate with steroid cover thereafter with minimal symptoms [16]. Gathering data from other indications for bisphosphonate, Fraunfelder and Fraunfelder reported 17 cases of unilateral scleritis associated with intravenous pamidronate which required discontinuation of the pamidronate therapy [17].\n\nThe decisions to rechallenge should be based on the severity of the adverse event and accurate diagnosis with formal evaluation by ophthalmology. Isolated conjunctivitis or episcleritis, having good prognosis, often experiences complete resolution without specific treatment after few days. Nonspecific conjunctivitis usually decreases in intensity during subsequent exposure to a bisphosphonate [17]. In context of myeloma where benefits clearly outweigh the risks in such circumstances, retreatment with or without steroid cover is generally safe. Patients presenting with severe orbital inflammation, once septic elements are excluded, should be promptly initiated on intravenous steroids. More severe adverse events such as uveitis, scleritis, and orbital inflammation can have serious and long-lasting consequences. In case of scleritis to fully resolve, bisphosphonate must be discontinued [17]. Cases such as these should be dealt with utmost care in conjunction with ophthalmology before a decision to rechallenge is made.\n\n6. Conclusion\nBisphosphonate therapy for myeloma patients continues to be an integral part of myeloma management. Physicians and hematologists should be aware of these uncommon adverse events, and based on the severity of the events and in collaboration with ophthalmology support, a well-informed decision should be made in best interest of the patient.\n\nConflicts of Interest\nThe authors declare no conflicts of interest.\n\nFigure 1 Right eyelid and periorbital swelling and redness.\n\nFigure 2 Mild right eye proptosis and soft tissue thickening overlying the right orbit (arrow). Edema of the medial and superior rectus muscles. Postseptal involvement with inflammatory fat stranding in the intraconal fat posterior to the globe.\n==== Refs\n1 Palumbo A. Anderson K. Multiple myeloma New England Journal of Medicine 2011 364 11 1046 1060 10.1056/nejmra1011442 2-s2.0-79952781038 \n2 Melton L. J. Kyle R. A. Achenbach S. J. Oberg A. L. Rajkumar S. V. Fracture risk with multiple myeloma: a population-based study Journal of Bone and Mineral Research 2005 20 3 487 93 10.1359/jbmr.041131 2-s2.0-14344250737 15746994 \n3 Russell R. G. G. Bisphosphonates: from bench to bedside Annals of the New York Academy of Sciences 2006 1068 1 367 401 10.1196/annals.1346.041 2-s2.0-33744762777 16831938 \n4 Drake M. T. Clarke B. L. Khosla S. Bisphosphonates: mechanism of action and role in clinical practice Mayo Clinic Proceedings 2008 83 9 1032 1045 10.4065/83.9.1032 2-s2.0-51349163043 18775204 \n5 Kunzmann V. Bauer E. Wilhelm M. \nγ /δ T-cell stimulation by pamidronate New England Journal of Medicine 1999 340 9 737 738 10.1056/nejm199903043400914 2-s2.0-0033522147 \n6 Clark E. M. Durup D. Inflammatory eye reactions with bisphosphonates and other osteoporosis medications: what are the risks? Therapeutic Advances in Musculoskeletal Disease 2015 7 1 11 16 10.1177/1759720x14566424 2-s2.0-84922155743 25650170 \n7 Fraunfelder F. W. Fraunfelder F. T. Adverse ocular drug reactions recently identified by the national registry of drug-induced ocular side effects Ophthalmology 2004 111 7 1275 1279 10.1016/j.ophtha.2003.12.052 2-s2.0-3042511629 15234126 \n8 Peterson J. D. Bedrossian E. H. Bisphosphonate-associated orbital inflammation-a case report and review Orbit 2012 31 2 119 123 10.3109/01676830.2011.648818 2-s2.0-84859603015 22489855 \n9 Pazianas M. Clark E. M. Eiken P. A. Brixen K. Abrahamsen B. Inflammatory eye reactions in patients treated with bisphosphonates and other osteoporosis medications: cohort analysis using a national prescription database Journal of Bone and Mineral Research 2013 28 3 455 463 10.1002/jbmr.1783 2-s2.0-84873979722 23044864 \n10 Subramanian P. S. Kerrison J. B. Calvert P. C. Miller N. R. Orbital inflammatory disease after pamidronate treatment for metastatic prostate cancer Archives of Ophthalmology 2003 121 9 1335 1336 10.1001/archopht.121.9.1335 2-s2.0-0141610765 12963622 \n11 Rosen L. S. Gordon D. Kaminski M. Long-term efficacy and safety of zoledronic acid compared with pamidronate disodium in the treatment of skeletal complications in patients with advanced multiple myeloma or breast carcinoma Cancer 2003 98 8 1735 1744 10.1002/cncr.11701 2-s2.0-10744233021 14534891 \n12 Morgan G. J. Davies F. E. Gregory W. M. First-line treatment with zoledronic acid as compared with clodronic acid in multiple myeloma (MRC Myeloma IX): a randomised controlled trial The Lancet 2010 376 9757 1989 1999 10.1016/s0140-6736(10)62051-x 2-s2.0-78650174738 \n13 Mhaskar R. Redzepovic J. Wheatley K. Bisphosphonates in multiple myeloma: a network meta-analysis Cochrane Database of Systematic Reviews 2012 5 003188 10.1002/14651858.cd003188.pub3 \n14 Terpos E. Roodman G. D. Dimopoulos M. A. Optimal use of bisphosphonates in patients with multiple myeloma Blood 2013 121 17 3325 3328 10.1182/blood-2012-10-435750 2-s2.0-84879357838 23407550 \n15 Meaney T. P. J. Musadiq M. Corridan P. G. J. Diplopia following intravenous administration of pamidronate Eye 2004 18 1 103 104 10.1038/sj.eye.6700542 2-s2.0-0842280801 14707987 \n16 Benderson D. Karakunnel J. Kathuria S. Badros A. Scleritis complicating zoledronic acid infusion Clinical Lymphoma and Myeloma 2006 7 2 145 147 10.3816/clm.2006.n.053 2-s2.0-33750199047 17026827 \n17 Fraunfelder F. W. Fraunfelder F. T. Bisphosphonates and ocular inflammation New England Journal of Medicine 2003 348 12 1187 1188 10.1056/nejm200303203481225 2-s2.0-0037456760\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": "6647277",
"pmc": null,
"pmid": "33628538",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": "18775204;16831938;15746994;12963622;10068336;14707987;12646685;23407550;22489855;22592688;23044864;15234126;21131037;17026827;25650170;21410373;14534891",
"title": "Keeping an Eye on Bisphosphonate Therapy in Myeloma: A Case Report of Ocular Inflammation Postzoledronic Acid Infusion.",
"title_normalized": "keeping an eye on bisphosphonate therapy in myeloma a case report of ocular inflammation postzoledronic acid infusion"
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"activesubstancename": "ZOLEDRONIC ACID"
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