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"abstract": "Bisphosphonates therapy has been shown to decrease the risk of vertebral, non-vertebral, and hip fractures in postmenopausal women. However the long-term safety of bisphosphonates use has been questioned. Recent reports have demonstrated the association between long-term alendronate therapy with low-energy subtrochanteric fracture or diaphyseal femoral fractures in a small number of patients. The author reported the first case of bilateral atypical femoral fractures in postmenopausal women with osteoporosis receiving long-term alendronate therapy.",
"affiliations": "Department of Orthopedics, Phranakhon Si Ayutthaya Hospital, Phranakhon Si Ayutthaya, Thailand.",
"authors": "Bamrungsong|Tachchai|T|;Pongchaiyakul|Chatlert|C|",
"chemical_list": "D050071:Bone Density Conservation Agents; D019386:Alendronate",
"country": "Thailand",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0125-2208",
"issue": "93(5)",
"journal": "Journal of the Medical Association of Thailand = Chotmaihet thangphaet",
"keywords": null,
"medline_ta": "J Med Assoc Thai",
"mesh_terms": "D000368:Aged; D019386:Alendronate; D044466:Asians; D050071:Bone Density Conservation Agents; D005260:Female; D005264:Femoral Fractures; D006801:Humans; D015663:Osteoporosis, Postmenopausal; D011859:Radiography; D013997:Time Factors",
"nlm_unique_id": "7507216",
"other_id": null,
"pages": "620-4",
"pmc": null,
"pmid": "20524451",
"pubdate": "2010-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Bilateral atypical femoral fractures after long-term alendronate therapy: a case report.",
"title_normalized": "bilateral atypical femoral fractures after long term alendronate therapy a case report"
} | [
{
"companynumb": "TH-ROCHE-745268",
"fulfillexpeditecriteria": "1",
"occurcountry": "TH",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ALENDRONIC ACID"
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"drugadditional": "1",
"d... |
{
"abstract": "Some lines of evidence show that D2/D3 receptor partial agonist pramipexole may be effective in the treatment of extrapyramidal symptoms (EPS) and psychiatric symptoms of schizophrenia. Therefore, we analyzed whether a low dose of pramipexole (0.375-0.75 mg/day) has efficacy on EPS and symptoms of schizophrenia while maintaining tolerability.\n\n\n\nTen subjects with EPS [including drug-induced parkinsonism (DIP) and akathisia] were recruited in a stage-1, open-label pilot study. All the subjects were treated with a low dose of pramipexole. The evaluations were performed at baseline, day 3, week 1, week 2, week 4, week 6, and week 8. The ratings of SAS, BARS, PANSS, CDSS, and CGI-S and adverse effects (AE) were recorded in every visit.\n\n\n\nSAS total scores decreased significantly during the study in patients with DIP (P<0.001), and mild AEs were detected. Treatments with pramipexole did not show an anti-akathisia effect during the study, while 2 subjects experienced deterioration of akathisia and mood symptoms. The psychiatric symptoms of schizophrenia showed a trend of improvement during the study, but there was no improvement in depressive mood.\n\n\n\nA low dose of pramipexole can significantly relieve antipsychotic-induced parkinsonism, but not akathisia. Improvements in psychiatric symptoms of schizophrenia were found, but the results of this study need to be validated in a larger sample. No improvement of mood disorder was detected.",
"affiliations": "Department of Psychiatry, Shanghai Mental Health Center, Shanghai Jiao Tong University of Medicine, Shanghai, People's Republic of China.;Department of Psychiatry, Shanghai Mental Health Center, Shanghai Jiao Tong University of Medicine, Shanghai, People's Republic of China.;Department of Anesthesiology, Renji Hospital, Shanghai Jiao Tong University of Medicine, Shanghai, People's Republic of China.;Department of Psychiatry, Shanghai Mental Health Center, Shanghai Jiao Tong University of Medicine, Shanghai, People's Republic of China.;Department of Psychiatry, Shanghai Mental Health Center, Shanghai Jiao Tong University of Medicine, Shanghai, People's Republic of China.;Department of Psychiatry, Shanghai Mental Health Center, Shanghai Jiao Tong University of Medicine, Shanghai, People's Republic of China.;Department of Psychiatry, Shanghai Mental Health Center, Shanghai Jiao Tong University of Medicine, Shanghai, People's Republic of China.;Department of Psychiatry, Shanghai Mental Health Center, Shanghai Jiao Tong University of Medicine, Shanghai, People's Republic of China.",
"authors": "Weng|Jia Jun|JJ|;Wang|Li Hua|LH|;Zhu|Hao|H|;Xu|Wen Rong|WR|;Wei|Yu Mei|YM|;Wang|Zhi Yang|ZY|;Yu|Wen Juan|WJ|;Li|Hua Fang|HF|",
"chemical_list": null,
"country": "New Zealand",
"delete": false,
"doi": "10.2147/NDT.S205933",
"fulltext": "\n==== Front\nNeuropsychiatr Dis TreatNeuropsychiatr Dis TreatNDTneurodistNeuropsychiatric Disease and Treatment1176-63281178-2021Dove 3149670220593310.2147/NDT.S205933Clinical Trial ReportEfficacy of low-dose D2/D3 partial agonist pramipexole on neuroleptic-induced extrapyramidal symptoms and symptoms of schizophrenia: a stage-1 open-label pilot study Weng et alWeng et alWeng Jia Jun 1Wang Li Hua 1Zhu Hao 2Xu Wen Rong 1Wei Yu Mei 1Wang Zhi Yang 1Yu Wen Juan 1Li Hua Fang 134\n1 \nDepartment of Psychiatry, Shanghai Mental Health Center, Shanghai Jiao Tong University of Medicine, Shanghai, People’s Republic of China\n2 \nDepartment of Anesthesiology, Renji Hospital, Shanghai Jiao Tong University of Medicine, Shanghai, People’s Republic of China\n3 \nShanghai Key Laboratory of Psychotic Disorders\n, Shanghai, People’s Republic of China\n4 \nClinical Research Center, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China\nCorrespondence: Wen Juan Yu; Hua Fang LiDrug Clinical Trial Institution, Wan Ping Nan Road No. 600, Shanghai Mental Health Center, Shanghai 200300, People’s Republic of ChinaTel +86 21-34773122; +86 21-34773128 Email wenjuanyu2004@163.com; lhlh_5@163.com* These authors contributed equally to this work\n\n07 8 2019 2019 15 2195 2203 21 2 2019 03 7 2019 © 2019 Weng et al.2019Weng 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).Objective\nSome lines of evidence show that D2/D3 receptor partial agonist pramipexole may be effective in the treatment of extrapyramidal symptoms (EPS) and psychiatric symptoms of schizophrenia. Therefore, we analyzed whether a low dose of pramipexole (0.375–0.75 mg/day) has efficacy on EPS and symptoms of schizophrenia while maintaining tolerability.\n\nMethods\nTen subjects with EPS [including drug-induced parkinsonism (DIP) and akathisia] were recruited in a stage-1, open-label pilot study. All the subjects were treated with a low dose of pramipexole. The evaluations were performed at baseline, day 3, week 1, week 2, week 4, week 6, and week 8. The ratings of SAS, BARS, PANSS, CDSS, and CGI-S and adverse effects (AE) were recorded in every visit.\n\nResults\nSAS total scores decreased significantly during the study in patients with DIP (P<0.001), and mild AEs were detected. Treatments with pramipexole did not show an anti-akathisia effect during the study, while 2 subjects experienced deterioration of akathisia and mood symptoms. The psychiatric symptoms of schizophrenia showed a trend of improvement during the study, but there was no improvement in depressive mood.\n\nConclusion\nA low dose of pramipexole can significantly relieve antipsychotic-induced parkinsonism, but not akathisia. Improvements in psychiatric symptoms of schizophrenia were found, but the results of this study need to be validated in a larger sample. No improvement of mood disorder was detected.\n\nKeywords\nextrapyramidal symptomsantipsychoticspramipexoleclinical trial\n==== Body\nIntroduction\nDrug-induced extrapyramidal symptoms (EPS) is a neurological adverse effect (AE) caused by the over-blockade of D2 receptor in the substantia nigra-striatum pathway by antipsychotics.1 Various factors including drug overdose, long-term use of antipsychotics, use of first-generation antipsychotics, age, and gender are correlated with the incidence of EPS.2,3 Schizophrenia patients with EPS often have more severe psychiatric symptoms and poorer social functions.4,5 The treatment and prevention of EPS is of great importance in the treatment outcome of patients with schizophrenia.\n\nThe current treatment of EPS in China contains anticholinergics including benzoyl.6,7 However, the side effects of anticholinergics can deteriorate the physical condition and cognition of patients with schizophrenia, especially elderly patients, which strongly restrict its clinical application.8,9 Finding a safer and better-tolerated treatment of EPS is therefore warranted.\n\nPramipexole is a novel, highly active, partial dopamine (DA) receptor agonist that acts on the D2 receptor family with a preferential affinity for the D3 receptor. Pramipexole is widely used in the treatment of DA-related neurological disorder including Parkinson disease, restless leg syndrome, and EPS. The antiparkinson effect of pramipexole is correlated with its stimulation effect of the postsynaptic D2 receptor.10 The incidence of EPS is significantly correlated with the D2 receptor occupancy in the substantia nigra and striatum areas.11 Approximately, 75–80% blockade of D2 receptors by antipsychotics could lead to the induction of EPS.12 The partial D2 receptor agonist effect of pramipexole may reverse the over-blockade of D2 receptor in the substantia nigra and striatum areas and therefore reverse the symptoms of EPS.\n\nStudies have found pramipexole can also relieve mood disorders and anhedonia symptoms of Parkinson disease, which may be related to its partial agonist effect on the D3 receptors.13,14 Moreover, pramipexole may be effective in the treatment of schizophrenia considering its modulation effect on DA transmission through partial agonist effect of D2 and D3 receptors.15 Last but not least, pramipexole’s efficacy on negative symptoms also deserves to be investigated, depending on the facts antipsychotics with D2/D3 partial agonist effect, such as cariprazine, have better treatment outcome than other atypical antipsychotics.16 Therefore, symptoms of schizophrenia, especially negative symptoms that are difficult to relieve depending on the current treatment of atypical antipsychotics, might benefit from the use of the D2/D3 receptor partial agonist pramipexole.\n\nThe primary outcome of this study is to investigate whether the D2/D3 receptor partial agonist pramipexole could relieve EPS, and the secondary outcome is to evaluate the effect of low-dose pramipexole for the psychiatric and mood symptoms of schizophrenia. We hypothesized that a low dose of pramipexole may be effective in the treatment of EPS and schizophrenia.\n\nPatients and methods\nPatients\nThis study is a stage-1 pilot study of a two-stage clinical trial. In the stage-1 study, 10 subjects were recruited to preliminarily explore the efficacy and safety of pramipexole. All subjects were recruited in Shanghai Mental health center. The inclusion criteria were as follows: 1) 18–65 years of age; 2) met the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria for drug-induced parkinsonian and akathisia17; and 3) a 6-item Simpson–Angus Scale (SAS) total score above 2 or a score of 2 (mild) or above on the global subscale of the Barnes Akathisia Rating Scale (BARS). If any of the following events occurred, the subject was withdrawn from the study: 1) a serious AE (ie, death, rehospitalization, physical disability, etc.) 2) poor compliance, obvious protocol violation, or those who did not take the drugs continuously for 4 days; and 3) scored (mild) on at least two Abnormal Involuntary Movement Scale items or three (moderate) on one of the items that are considered to be tardive dyskinesia. All the subjects did not receive any treatment of EPS before entering the study.\n\nAmong the 10 subjects included in this study, 7 of them were diagnosed with schizophrenic disorder according to the DSM-IV; 1 subject was diagnosed with obsessive-compulsive disorder, 1 subject was diagnosed with major depressive disorder (MDD); and 1 was diagnosed with mental retardation. Seven subjects were diagnosed with drug-induced parkinsonism (DIP); 2 subjects were diagnosed with akathisia, and 1 subject fitted both the criteria. Most of the subjects were taking antipsychotic polytherapy. Four subjects were treated with risperidone (mean, 4.3±0.5 mg; range, 4–5 mg); four subjects were treated with aripiprazole (mean, 11.3±6.3; range, 5–20 mg); and three subjects were treated with quetiapine (mean, 366.7±251.7; range, 100–600) and clozapine (mean, 166.7±57.8; range 100–200 mg). Amisulpride (1000 mg), Olanzapine (20 mg), and Fluphenazine injection (25 mg qw) were used in one subject. The demographics and mean scale ratings are shown in Table 1, and clinical variables and drug characteristics of each subject are shown in Table 2. The drug dose of pramipexole and change in antipsychotics of each subject during the trial are shown in Table 3.\nTable 1 Demographics and baseline scale ratings of all subjects\n\nDemographics\t\t\nAge (years)\t51.4 (14.7)\t\nGender, men\t8 (80%)\t\nIllness duration (years)\t20.6 (14.6)\t\nNumber of hospitalization\t3.1 (3.2)\t\nRating scores\t\t\nSAS\t4.8 (3.6)\t\nBRAS\t0.7 (0.9)\t\nPANSS positive\t16.1(1.6)\t\nPANSS negative\t27.4(3.1)\t\nPANSS general psychopathology\t42.9(3.0)\t\nPANSS total\t86.4(6.9)\t\nCDSS\t3.7 (1.8)\t\nCGI-S\t5.0 (0.3)\t\nAbbreviations: SAS, Simpson-Angus Scale; BARS, Barnes Akathisia Rating Scale; AIMS, Abnormal Involuntary Movement Scale; CDSS, Calgary Depression Scale for Schizophrenia; CGI-S, Clinical Global Impression Scale. \n\n\nTable 2 Clinical and drug characteristics of each subject\n\nSubject\tGender/Age\tDiagnosis\tAntipsychotics\tAdditional medicine\t\n1\tM/57\tSCH/PRA\tRisperidone 5 mg\nQuetiapine 600 mg\t\t\n2\tM/58\tSCH/AKA\tAmisapride1000 mg\nClozapine 200 mg\t\t\n3\tM/60\tSCH/AKA\tRisperidone 4 mg\nClozapine 200 mg\t\t\n4\tM/60\tSCH/PRA\tRisperidone 4 mg\nOlanzapine 20 mg\tSertraline 100 mg\t\n5\tM/49\tMT/PRA\tAripiprazole 10 mg\nQuetiapine 100 mg\t\t\n6\tM/56\tSCH/PRA\tRisperidone 4 mg\nClozapine 100 mg\t\t\n7\tF/24\tSCH/PRA/AKA\tAripiprazole 20 mg\t\t\n8\tM/62\tSCH/PRA\tFluphenazine Decanoate Injection 25 mg qw\t\t\n9\tF/63\tMDD/PRA\tAripiprazole 5 mg\tVenlafaxine 300 mg\t\n10\tM/25\tOCD/BD/PRA\tAripiprazole 10mg\nQuetiapine 400 mg\tFluvoxamine 300 mg\nlithium carbonate 500 mg\t\nAbbreviations: SCH, schizophrenia; MR, mental retardation; MDD, major depressive disorder; OCD, obsessive–compulsive disorder; BD, bipolar disorder; PRA, drug-induced parkinsonism; AKA, akathisia.\n\n\nTable 3 Drug dose of pramipexole and change in antipsychotics of subjects during the trial\n\nSubject\tPramipexole\ndosage\tWhether there is a change of antipsychotics\tChange of antipsychotics\tTime of the change of antipsychotics\tThe reason for the change of antipsychotics\t\n1\tBaseline: 0.375 mg/day\nV4: 0.75mg/day\tN\t\t\t\t\n2\tBaseline: 0.375 mg/day\nV4: 0.75mg/day\tN\t\t\t\t\n3\t0.375 mg/day\tY\tRisperidone:\nIncreased from 4 to 5 mg/day\t1W\tDeterioration of psychiatric symptoms and mood symptoms\t\n4\t0.375 mg/day\tN\t\t\t\t\n5\t0.375 mg/day\tN\t\t\t\t\n6\t0.375 mg/day\tY\tAdditional Aripiprazole 10 mg/day were prescribed\t6W\tManage side effect of hyperprolactinemia\t\n7\t0.375 mg/day\tY\tAripiprazole decreased from 20 to 5 mg/day\nAdditional Quetiapine 600 mg/day were prescribed\t2W\tDeterioration of psychiatric symptoms and mood symptoms\t\n8\t0.375 mg/day\tY\tChanged from\nFluphenazine Decanoate Injection 25 mg/qw to Amisapride 600 mg/day\t4W\tLack of efficacy\t\n9\t0.375 mg/day\tN\t\t\t\t\n10\tBaseline: 0.375 mg/day\nV4: 0.75mg/day\tN\t\t\t\t\n\n\n\nTreatment protocol\nConsidering that pramipexole was being used for the first time in Chinese patients with schizophrenia, low dose of pramipexole was used for safety considerations (0.375–0.75 mg/day). Subjects took 0.375 mg/day of pramipexole (0.135 mg thrice per day) on week 1, and the dose was increased to 0.75 mg/day (0.25 mg thrice per day) after week 1 depending on the researchers’ decision. Treatment protocol was based on the treatment of Parkinson disease by pramipexole.17\n\nThe evaluations of SAS and BARS were used to assess the severity of EPS. SAS is a 10-item rating scale that is frequently used to assess DIP and muscle rigidity in clinical practice.18 One item measure gait, 6 items measure stiffness, and 3 items measure tremor, salivation, and palpebral reflex (each item ranging from 0 to 4). BARS is a scale used to assess akathisia, and it consists of 4 items, including objective symptoms, subjective symptoms, subjective distress, and global evaluations items (the score of each item ranges from 0 to 4).19 Positive and Negative Syndrome Scale (PANSS) is a 30-item rating scale designed to assess dimensions of schizophrenia symptoms. Its items were originally grouped into scales for Positive Symptoms (7 items), Negative Symptoms (7 items), and General Psychopathology (16 items). Calgary Depression Scale for Schizophrenia (CDSS) is a 9-item rated scale specifically designed to assess depression in patients with schizophrenia with high sensitivity rate and high specificity rate.20,21 The CGI-S scale is a valid, reliable instrument to evaluate severity and treatment response in schizophrenia, and its score ranges from 0 (no illness) to 7 (severe illness).22 PANSS, CDSS, and Clinical Global Impression Scale (CGI-S) were used to access the psychiatry symptoms and mood symptoms of schizophrenia. Assessments were conducted at baseline, day 3, week 1, week 2, month 1, week 6, and month 2. The laboratory measurements, vital signs, and electrocardiogram were recorded at baseline and endpoint of the study to see whether pramipexole can deteriorate the physical status of the subjects.\n\nEthics approval and informed consent\nAll subjects and their guardians signed a written informed consent, and all the assessment was conducted by trained psychiatrists who have underwent scale consistency training before the first subjects were enrolled. This study was approved by the Shanghai Mental Health Center ethics committees (No. 2017-40), and this trial has been registered in the Clinical Trial website (NCT03430596). This study was conducted in accordance with the Declaration of Helsinki.\n\nStatistical analysis\nAll statistical analyses were performed using SPSS 23.0 (SPSS Inc., Chicago, IL, USA). All data are expressed as mean ± SEM. ANOVA tests with post hoc analyses were used to examine differences in EPS, psychiatric symptoms, and mood symptoms of schizophrenia among the different visits. The Bonferroni correction was used to perform post hoc analysis for the chi-square tests, and statistical significance was set at P<0.007 (0.05/number of comparisons=0.007).\n\nResults\nPrimary outcome\nThe ratings of SAS decreased significantly during the visit [5.9±3.2 vs 1.1±0.6, respectively, F(6,7)=9.46, P<0.007] among subjects with DIP. The ratings of the BARS global subscale [2.3±0.3 vs 2.0±0.7, respectively, F(6,3)=0.12, P=0.99], objective subscale [1.3±1.3 vs 0.7±0.7, respectively, F(6,3)=0.16, P=0.98], subjective subscale [1.7±0.3 vs 1.3±0.9, respectively, F(6,3)=0.18, P=0.98], and distress subscale [1.3±0.3 vs 1.3±0.9, respectively, F(6,3) =0.09, P=099] did not significant change during the visit. The changes in the SAS and BARS scores are shown in Table 4.Table 4 The change in rating score in subjects with drug-induced parkinsonian and akathisia\n\n\tSAS#\tBARS\nobjective\tBARS subjective\tBARS distress\tBARS global\t\nBaseline\t5.9(3.2)\t1.3(0.3)\t1.7(0.3)\t1.3(0.3)\t2.3(0.3)\t\n3D\t3.8(1.8)\t0.7(0.7)\t2.0(0.6)\t2.0(1.0)\t2.7(0.3)\t\n1W\t2.1(0.6)\t0.7(0.7)\t2.0(0.6)\t1.7(0,7)\t2.7(0.7)\t\n2W\t1.5(1.4)\t0.7(0.7)\t1.7(0,7)\t1.7(1.2)\t2.3(0.9)\t\n4W\t1.5(0.9)\t0.7(0.7)\t1.3(0.9)\t1.3(0.9)\t2.0(1.2)\t\n6W\t1.4(1.0)\t0.7(0.7)\t1.3(0.9)\t1.3(0.9)\t2.0(1.2)\t\n8W\t1.1(0.6)\t0.7(0.7)\t1.3(0.9)\t1.3(0.9)\t2.0(1.2)\t\nNote:\n#P<0.007.\n\nAbbreviations: SAS, Simpson Angus Scale; BARS, Barnes Akathisia Rating Scale.\n\n\n\n\nSecondary outcome\nThe PANSS negative subscale [27.4±3.1 vs 24.3±3.5, respectively, F(6,7)=0.26, P=0.95], PANSS positive subscale [16.1±1.6 vs 13.7±1.6, respectively, F(6,7)=1.03,P=0.49], PANSS general psychopathological subscale [42.9±3.0 vs 41.6±5.6, respectively, (F6,7)=0.24, P=0.96], PANSS total score [86.4±6.9 vs 79.4±10.1, respectively, F(6,7)=0.38, P=0.89], CDSS [3.7±1.8 vs 5.0±1.6, respectively, F(6,7) =0.08, P=0.99], CGI-S [5.0±0.3 vs 4.9±0.6, respectively, F(6,7)=0.44, P=0.85] did not significant change during the study. The changes in psychiatric rating scales of schizophrenia during the study are shown in Figure 1.Figure 1 Changes in (A) PANSS positive score, (B) PANSS negative score, (C) PANSS general psychopathological score, (D) PANSS total score, (E) CDSS total score and (F) CGI-S. Abbreviations: PANSS, Positive and Negative Sydrome Scale; CDSS, Calgary Depression Scale for Schizophrenia; CGI-S, Clinical Global Impression Scale. \n\n\n\nAdverse effect\nThe main AEs of pramipexole in this study include depressed mood (2 subjects), suicidal ideation (2 subjects), drowsiness (1 subject), and nausea (1 subject). Depressed mood occurred in two subjects with akathisia. Both of them showed the deterioration of psychiatric symptoms and mood symptoms. One of them withdrew from the study, and in other patient, drug switch and MECT were performed to manage AEs. Drowsiness and nausea occurred in two subjects with DIP. Two other subjects withdrew from the study: one subject discontinued the drug intake because of nausea, and the other one withdrew the consent. All the side effects were relieved after the measurements. The adverse events that occurred during the study are shown in Table 5. The laboratory measurements, vital signs, and electrocardiogram did not change significantly during the trial.\nTable 5 Adverse effects\n\nSubject no.\tAdverse effects\tWithdrawn from the study due to AE\tSwitch to other medication or MECT due to AE\tAE recovered hereafter\t\n3\tDepressed mood/suicidal ideation\tY\tY\tY\t\n6\tDrowsiness\tN\tN\tY\t\n7\tSymptoms deterioration/depressed mood\tN\tY\tY\t\n9\tNausea\tY\tN\tY\t\nNotes: Y means yes and the event occurred; N means no and the event did not occur.\n\nAbbreviations: MECT, Modified Electra convulsive Therapy; AE, adverse effect. \n\n\n\n\nDiscussion\nOur study has shown that low doses of D2 and D3 receptor partial agonists, ranging from 0.375 to 0.75 mg/day, may be beneficial in the treatment of DIP. SAS score decreased over 80% during the visit, without worsening of psychiatric symptoms and with low dropout rate (14.2%, 1 of 7). Pramipexole was well tolerated among subjects with DIP, and side effects, primarily drowsiness and nausea, were reported. A previous study showed that the D3/D2 receptor partial agonist rotigotine in low doses is safe and effective in patients with EPS including antipsychotic-induced parkinsonism and akathisia.23 Rotigotine significantly decreased the ratings of Unified Parkinson’s Disease Rating Scale total (a scale used to evaluate the symptoms of Parkinson disease), SAS total score, and BARS global subscale. One study showed that pramipexole can relieve haloperidol-induced catalepsy and tremor in mice.24 Haloperidol-induced catalepsy is used as an animal model of extrapyramidal side effects. This relief of catalepsy by pramipexole confirmed that it may be beneficial in symptoms of antipsychotic-induced parkinsonism including dystonia, akinesia, and slowness of movement.\n\nThe mechanisms underlying the antiparkinson effect of pramipexole are complicated. Despite its partial agonistic effect on the postsynaptic D2 receptor, pramipexole can also reduce DA uptake and increase DA neurotransmission through its long-term interaction of the presynaptic D3 autoreceptor.25 The agonism of the postsynaptic D2 receptor and increase in the DA neurotransmission may reverse the phenomenon of “dopamine-acetylcholine” imbalance caused by the blockade of D2 receptor which is the key phenomenon of DIP.26 Furthermore, the neuroprotective and antioxidant effects of pramipexole can also explain its efficacy.27,28 Overall, the mechanisms of pramipexole in its treatment effect of DIP merit further investigation.\n\nTreatments with pramipexole did not show an anti-akathisia effect during the study, regardless of subjective pain, distress, or objective observation symptoms of akathisia. Nevertheless, two subjects (four subjects with akathisia in total) experienced an AE during the study. One subject (No. 3) had a depressed mood and suicidal ideation, with a deterioration of the akathisia syndrome. Another subject (No. 7) experienced a recurrence of her psychiatric symptoms, consisting of auditory hallucination and delusional thoughts. After the MECT treatment, No. 3 patients’ symptoms were immediately relieved. After a slow exchange of antipsychotics from Aripiprazole 20 mg/day to Quetiapine 600 mg/day combined with aripiprazole 5 mg/day polytherapy, symptoms of No.7’s psychiatri syndromes are stabilized and akathisia syndromes disappeared. In general, pramipexole did not show efficacy and safety in subjects with akathisia in the step 1 trial.\n\nThe immediate deterioration of akathisia and mood symptoms indicates that the partial agonist effect of the DA receptor does no good in treating the symptoms of akathisia. A previous study showed that antipsychotics with a partial DA receptor agonistic effect (ie, aripiprazole, brexpiprazole, and cariprazine) and high D2 receptor antagonist effect (ie, risperidone and haloperidol) are more risky for inducing akathisia than antipsychotics (ie, olanzapine and quetiapine).29 The relation between the partial DA receptor agonist effect and akathisia is complicated and remains unknown, especially considering the relatively high D2 receptor binding ability and both partial agonist and antagonist effect on the D2 receptor of this kind of antipsychotics.30,31 Besides, the short-term administration of pramipexole can spontaneously decrease the synaptic release of DA and firing rate of DA and norepinephrine (NE) neurons.32 The decrease of the firing rate of DA, NE neurons, and DA release may account for the spontaneous deterioration of mood symptoms and akathisia. Nevertheless, considering the relatively small sample of subjects with akathisia in step 1, this phenomenon will be observed, monitored, and validated in the step 2 study.\n\nAll the psychiatric rating scales including PANSS, CDSS, and CGI-S did not change significantly during the trial. All the psychiatric rating scales showed an increasing trend on day 3 and at 1 week, which is due to the immediate deterioration of the symptoms in two subjects with akathisia. After one subjects’ withdrawal and management of another subjects’ AE, the PANSS positive score, PANSS negative score, PANSS general psychopathology score, PANSS total score, and CGI-S all showed a trend of improvement during the remaining follow-up. The mild improvement of positive symptoms, negative symptoms, and general psychopathology symptoms of patients proved that pramipexole may be beneficial to the psychiatric symptoms of schizophrenia. The results of our trial are consistent with those of a previous study, with a higher dose range and higher rating improvement of the PANSS rating scale.15,33 Unexpectedly, we did not see improvement of mood symptoms of patients with schizophrenia in this trial. After the management of akathisia symptoms, the CDSS total score slowly decreased but remained higher than the baseline score until the endpoint. Pramipexole has shown efficacy on mood symptoms of MDD, bipolar disorder, and Parkinson disease.34–36 But the dose of pramipexole in these studies is relatively higher, ranging from 1.0 to 3.0 mg/day. The lack of efficacy on depression mood may be due to low drug dose and relatively mild depression mood of our subjects. Considering the complicated mechanism of depression mood of schizophrenia patients, whether a low dose of pramipexole can be effective in mood symptoms will be further validated in the step 2 study.\n\nLimitations and further study\nThe limitations of the study are small sample size (n=10), wide age range (18–65 years), and the open-label design. Depending on the preliminary results of the current study, we will enlarge the sample size and make a single-blind study design in Phase II study, which will further validate pramipexole’ s efficacy on EPS and symptoms of schizophrenia.\n\nConclusion\nIn conclusion, a low dose of pramipexole is efficacious in the treatment of antipsychotic-induced parkinsonism, but it did not show efficacy on akathisia. Our study also demonstrated that co-medication with pramipexole may be effective on psychiatric symptoms of schizophrenia, although the improvements are not very significant probably due to the low dose. The symptoms of mood are not improved after combining with the treatment of pramipexole. In general, the findings of this study suggest that the usage of the D2/D3 partial agonist pramipexole could be beneficial in the treatment of neuroleptic-induced EPS, especially DIP, and show a trend of improvement of schizophrenia symptoms. The results of this study need to be validated in a larger sample.\n\nAcknowledgments\nThe authors thank the staff of Drug Clinical Trial Institution of Shanghai Mental Health Center and Dr Lu WH, Dr ZLP, Dr SY, and Dr CY for their contribution to the recruitment of subjects and valuable suggestions. This study is supported by Shanghai Collaborative Innovation Center for Translational Medicine and National Science (Grant No. TM201624), Technology Major Project for Investigational New Drug (Grant No. 2018ZX09734-005), Multi-center Clinical Study of Shanghai Jiao Tong University School of Medicine (Grant No. DLY201620) and Shanghai Committee of Science and Technology Research Project (Grant No. 17411970300).\n\nAuthor contributions\nAll authors contributed to data analysis, drafting or revising the article, gave final approval of the version to be published, and agree to be accountable for all aspects of the work.\n\nDisclosure\nThe authors report no conflicts of interest in this work.\n==== Refs\nReferences\n1. Divac \nN , Prostran \nM , Jakovcevski \nI , Cerovac \nN . Second-generation antipsychotics and extrapyramidal adverse effects . Biomed Res Int . 2014 ;2014 :656370 . doi:10.1155/2014/656370 24995318 \n2. Mehta \nSH , Morgan \nJC , Sethi \nKD . A positron emission tomography study of quetiapine in schizophrenia: a preliminary finding of an antipsychotic effect with only transiently high dopamine D2 receptor occupancy . Neurol Clin . 2015 ;33 (1 ):153 –174 . doi:10.1016/j.ncl.2014.09.011 25432728 \n3. Miller \nDD , McEvoy \nJP , Davis \nSM , et al. Clinical correlates of tardive dyskinesia in schizophrenia: baseline data from the CATIE schizophrenia trial . Schizophr Res . 2005 ;80 (1 ):33 –43 . doi:10.1016/j.schres.2005.07.034 16171976 \n4. Mentzel \nTQ , Lieverse \nR , Bloemen \nO , Viechtbauer \nW , van Harten \nPN , Incidence \nH . Prevalence of drug-related movement disorders in young patients with psychotic disorders . J Clin Psychopharmacol . 2017 ;37 (2 ):231 –238 . doi:10.1097/JCP.0000000000000666 28141621 \n5. Park \nIJ , Jung \nDC , Hwang \nSS , et al. The longitudinal trends in the relationship between drug-induced extrapyramidal symptoms and personal and social performance in a population of the patients with schizophrenia: A latent growth model . Psychiatry Res . 2016 ;238 :33 –39 . doi:10.1016/j.psychres.2016.01.069 27086208 \n6. Su \nYA , Yan \nF , Li \nQ , et al. Anticholinergic use trends in 14,013 patients with schizophrenia from three national surveys on the use of psychotropic medications in China (2002–2012) . Psychiatry Res . 2017 ;257 :132 –136 . doi:10.1016/j.psychres.2017.07.038 28755603 \n7. Pristed \nSG , Correll \nCU , Nielsen \nJ . Frequency and correlates of anticholinergic use among patients with schizophrenia in Denmark: a nation-wide pharmacoepidemiological study . Psychiatry Res . 2017 ;255 :198 –203 . doi:10.1016/j.psychres.2017.05.033 28578178 \n8. Vinogradov \nS , Fisher \nM , Warm \nH , Holland \nC , Kirshner \nMA , Pollock \nBG . The cognitive cost of anticholinergic burden: decreased response to cognitive training in schizophrenia . Am J Psychiatry . 2009 ;166 (9 ):1055 –1062 . doi:10.1176/appi.ajp.2009.09010017 19570929 \n9. Kreyenbuhl \nJ , Buchanan \nRW , Dickerson \nFB , Dixon \nLB . The Schizophrenia Patient Outcomes Research Team (PORT): updated treatment recommendations 2009 . Schizophr Bull . 2010 ;36 (1 ):94 –103 . doi:10.1093/schbul/sbp130 19955388 \n10. Oertel \nW , Schulz \nJB . Current and experimental treatments of Parkinson disease: A guide for neuroscientists . J Neurochem . 2016 ;139 (Suppl 1 ):325 –337 . doi:10.1111/jnc.13750 27577098 \n11. Mehta \nSH , Morgan \nJC , Sethi \nKD . Drug-induced movement disorders . Neurol Clin . 2015 ;33 (1 ):153 –174 . doi:10.1016/j.ncl.2014.09.011 25432728 \n12. Kapur \nS , Zipursky \nR , Jones \nC , Shammi \nCS , Remington \nG , Seeman \nP . A positron emission tomography study of quetiapine in schizophrenia: a preliminary finding of an antipsychotic effect with only transiently high dopamine D2 receptor occupancy . Arch Gen Psychiatry . 2000 ;57 (6 ):553 –559 .10839333 \n13. Barone \nP , Poewe \nW , Albrecht \nS , et al. Pramipexole for the treatment of depressive symptoms in patients with Parkinson’s disease: a randomised, double-blind, placebo-controlled trial . Lancet Neurol . 2010 ;9 (6 ):573 –580 . doi:10.1016/S1474-4422(10)70106-X 20452823 \n14. Berghauzen-Maciejewska \nK , Kuter \nK , Kolasiewicz \nW , et al. Pramipexole but not imipramine or fluoxetine reverses the “depressive-like” behaviour in a rat model of preclinical stages of Parkinson’s disease . Behav Brain Res.\n2014 ;271(1):343-353 doi: 10.1016/j.bbr.2014.06.029.\n15. Kasper \nS , Barnas \nC , Heiden \nA , et al. Pramipexole as adjunct to haloperidol in schizophrenia. Safety and efficacy . Eur Neuropsychopharmacol . 1997 ;7 (1 ):65 –70 .9088887 \n16. Nemeth \nG , Laszlovszky \nI , Czobor \nP , et al. Cariprazine versus risperidone monotherapy for treatment of predominant negative symptoms in patients with schizophrenia: a randomised, double-blind, controlled trial . Lancet (London, England) . 2017 ;389 (10074 ):1103 –1113 . doi:10.1016/S0140-6736(17)30060-0 \n17. American Psychiatric Association . Diagnostic and Statistical Manual of Mental Disorders . 4th ed. Washington, DC : American Psychiatric Association ; 2011 .\n18. Clarke \nCE , Guttman \nM . Dopamine agonist monotherapy in Parkinson’s disease . Lancet (London, England) . 2002 ;360 (9347 ):1767 –1769 . doi:10.1016/s0140-6736(02)11668-0 \n19. Simpson \nGM , Angus \nJW . A rating scale for extrapyramidal side effects . Acta Psychiatrica Scandinavica Supplementum . 1970 ;212 :11 –19 .4917967 \n20. Barnes \nTR . A rating scale for drug-induced akathisia . Br J Psychiatry . 1989 ;154 :672 –676 . doi:10.1192/bjp.154.5.672 2574607 \n21. Addington \nD , Addington \nJ , Schissel \nB . A depression rating scale for schizophrenics . Schizophr Res . 1990 ;3 (4 ):247 –251 .2278986 \n22. Addington \nD , Addington \nJ , Maticka-Tyndale \nE , Joyce \nJ . Reliability and validity of a depression rating scale for schizophrenics . Schizophr Res . 1992 ;6 (3 ):201 –208 .1571313 \n23. Haro \nJM , Kamath \nSA , Ochoa \nS , et al.The Clinical Global Impression-Schizophrenia scale: a simple instrument to measure the diversity of symptoms present in schizophrenia . Acta Psychiatr ScandSuppl . 2003 ;(416 ):16 –23 . doi:10.1034/j.1600-0447.107.s416.5.x \n24. Di Fabio \nR , De Filippis \nS , Cafariello \nC , et al. Low doses of rotigotine in patients with antipsychotic-induced parkinsonism . Clin Neuropharmacol . 2013 ;36 (5 ):162 –165 . doi:10.1097/WNF.0b013e3182a2ce3f 24045607 \n25. Ferger \nB , Buck \nK , Shimasaki \nM , Koros \nE , Voehringer \nP , Buerger \nE . Continuous dopaminergic stimulation by pramipexole is effective to treat early morning akinesia in animal models of Parkinson’s disease: a pharmacokinetic-pharmacodynamic study using in vivo microdialysis in rats . Synapse (New York, NY) . 2010 ;64 (7 ):533 –541 . doi:10.1002/syn.v64:7 \n26. Castro-Hernandez \nJ , Afonso-Oramas \nD , Cruz-Muros \nI , et al. Prolonged treatment with pramipexole promotes physical interaction of striatal dopamine D3 autoreceptors with dopamine transporters to reduce dopamine uptake . Neurobiol Dis . 2015 ;74 (2 ):325 –335 . doi:10.1016/j.nbd.2014.12.007 25511804 \n27. Kharkwal \nG , Brami-Cherrier \nK , Lizardi-Ortiz \nJE , et al. Parkinsonism driven by antipsychotics originates from dopaminergic control of striatal cholinergic interneurons . Neuron . 2016 ;91 (1 ):67 –78 . doi:10.1016/j.neuron.2016.06.014 27387649 \n28. Wang \nY , Yu \nX , Zhang \nP , et al. Neuroprotective effects of pramipexole transdermal patch in the MPTP-induced mouse model of Parkinson’s disease . J Pharmacol Sci . 2018 ;138 (1 ):31 –37 . doi:10.1016/j.jphs.2018.08.008 30241783 \n29. Shibagaki \nK , Okamoto \nK , Katsuta \nO , Nakamura \nM . Beneficial protective effect of pramipexole on light-induced retinal damage in mice . Exp Eye Res . 2015 ;139 :64 –72 . doi:10.1016/j.exer.2015.07.007 26213307 \n30. Juncal-Ruiz \nM , Ramirez-Bonilla \nM , Gomez-Arnau \nJ , et al. Incidence and risk factors of acute akathisia in 493 individuals with first episode non-affective psychosis: a 6-week randomised study of antipsychotic treatment . Psychopharmacology . 2017 ;234 (17 ):2563 –2570 . doi:10.1007/s00213-017-4646-1 28567698 \n31. Brust \nTF , Hayes \nMP , Roman \nDL , Watts \nVJ . New functional activity of aripiprazole revealed: robust antagonism of D2 dopamine receptor-stimulated Gbetagamma signaling . Biochem Pharmacol . 2015 ;93 (1 ):85 –91 . doi:10.1016/j.bcp.2014.10.014 25449598 \n32. Stahl \nSM . Mechanism of action of cariprazine . CNS Spectr . 2016 ;21 (2 ):123 –127 . doi:10.1017/S1092852916000043 26956157 \n33. Chernoloz \nO , El Mansari \nM , Blier \nP . Sustained administration of pramipexole modifies the spontaneous firing of dopamine, norepinephrine, and serotonin neurons in the rat brain . Neuropsychopharmacology . 2009 ;34 (3 ):651 –661 . doi:10.1038/npp.2008.114 18688211 \n34. Kelleher \nJP , Centorrino \nF , Huxley \nNA , et al. Pilot randomized, controlled trial of pramipexole to augment antipsychotic treatment . Eur Neuropsychopharmacol . 2012 ;22 (6 ):415 –418 . doi:10.1016/j.euroneuro.2011.10.002 22153972 \n35. Cusin \nC , Iovieno \nN , Iosifescu \nDV , et al. A randomized, double-blind, placebo-controlled trial of pramipexole augmentation in treatment-resistant major depressive disorder . J Clin Psychiatry . 2013 ;74 (7 ):e636 –e641 . doi:10.4088/JCP.12m08093 23945458 \n36. Zarate \nCA \nJr., Payne \nJL , Singh \nJ , et al. Pramipexole for bipolar II depression: a placebo-controlled proof of concept study . Biol Psychiatry . 2004 ;56 (1 ):54 –60 . doi:10.1016/j.biopsych.2004.03.013 15219473\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1176-6328",
"issue": "15()",
"journal": "Neuropsychiatric disease and treatment",
"keywords": "antipsychotics; clinical trial; extrapyramidal symptoms; pramipexole",
"medline_ta": "Neuropsychiatr Dis Treat",
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"nlm_unique_id": "101240304",
"other_id": null,
"pages": "2195-2203",
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"pmid": "31496702",
"pubdate": "2019",
"publication_types": "D016428:Journal Article",
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"title": "Efficacy of low-dose D2/D3 partial agonist pramipexole on neuroleptic-induced extrapyramidal symptoms and symptoms of schizophrenia: a stage-1 open-label pilot study.",
"title_normalized": "efficacy of low dose d2 d3 partial agonist pramipexole on neuroleptic induced extrapyramidal symptoms and symptoms of schizophrenia a stage 1 open label pilot study"
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"abstract": "Heterozygous familial hypercholesterolemia (HeFH) is characterized by a twofold elevation in low-density lipoprotein cholesterol. Severe elevations in triglycerides are an uncommon manifestation. In this case report, we discuss an atypical presentation of the chylomicronemia syndrome in a patient with HeFH. Genetic analyses of the low-density lipoprotein receptor mutation and single nucleotide polymorphisms that elevate triglycerides provide confirmation for this atypical presentation of HeFH.",
"affiliations": "Cardiometabolics Unit, Mount Sinai Heart, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Electronic address: robert.rosenson@mssm.edu.;Cardiometabolics Unit, Mount Sinai Heart, Icahn School of Medicine at Mount Sinai, New York, NY, USA.;Department of Medicine and Robarts Research Institute, Schulich School of Medicine, Western University, London, ON, Canada.",
"authors": "Rosenson|Robert S|RS|;Najera|Sherwin D|SD|;Hegele|Robert A|RA|",
"chemical_list": "D014280:Triglycerides",
"country": "United States",
"delete": false,
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"issue": "11(1)",
"journal": "Journal of clinical lipidology",
"keywords": "Chylomicronemia syndrome; Genetics; Heterozygous familial hypercholesterolemia; PCSK9 inhibitors; Triglyceride rich lipoproteins",
"medline_ta": "J Clin Lipidol",
"mesh_terms": "D000328:Adult; D006579:Heterozygote; D006801:Humans; D008072:Hyperlipoproteinemia Type I; D006938:Hyperlipoproteinemia Type II; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D014280:Triglycerides",
"nlm_unique_id": "101300157",
"other_id": null,
"pages": "294-296",
"pmc": null,
"pmid": "28391899",
"pubdate": "2017",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Heterozygous familial hypercholesterolemia presenting as chylomicronemia syndrome.",
"title_normalized": "heterozygous familial hypercholesterolemia presenting as chylomicronemia syndrome"
} | [
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"abstract": "OBJECTIVE\nA case of severe macroglossia and angioedema in a child with Burkitt lymphoma who was treated with two dihydropyridine calcium-channel blockers is reported.\n\n\nCONCLUSIONS\nAn eight-year-old white boy arrived at the pediatric emergency department with complaints of abdominal pain and distention after an episode of mild abdominal trauma. Physical examination results were significant for diffuse abdominal tenderness and distention, with a large palpable mass in the right quadrants. Computed tomography revealed a large abdominal mass, and a biopsy confirmed a diagnosis of Burkitt lymphoma. Before initiation of chemotherapy, the child developed tumor lysis syndrome, with subsequent renal failure and cardiorespiratory compromise. Once the patient was stabilized and sedated on mechanical ventilation, tumor-directed chemotherapy was initiated, and rapid tumor regression ensued. To control episodes of hypertension, nicardipine was initiated and titrated to achieve the blood pressure goals. Three days after initiation of nicardipine therapy, the child developed facial swelling and significant, protruding macroglossia. Eight days after nicardipine initiation, a tracheotomy was required due to upper airway obstruction; at that time, the patient was converted to amlodipine administered via nasogastric tube for continued blood pressure control. The boy's macroglossia persisted for another 18 days, until a multi-disciplinary drug therapy review resulted in the discontinuation of amlodipine. Within one week of the withdrawal of amlodipine, the child's macroglossia was completely resolved.\n\n\nCONCLUSIONS\nAn eight-year-old boy with Burkitt lymphoma developed severe macroglossia and angioedema when treated with nicardipine. The reaction persisted throughout treatment with amlodipine and resolved quickly after amlodipine was withdrawn.",
"affiliations": "Department of Pharmacy, Medical University of South Carolina,Charleston, USA.",
"authors": "Pierce|Wesly A|WA|;Hederman|April D|AD|;Gordon|Catherine J|CJ|;Ostrenga|Andrew R|AR|;Herrington|Betty|B|",
"chemical_list": "D002121:Calcium Channel Blockers; D017311:Amlodipine; D009529:Nicardipine",
"country": "England",
"delete": false,
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"issn_linking": "1079-2082",
"issue": "68(5)",
"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": "D017311:Amlodipine; D000799:Angioedema; D002051:Burkitt Lymphoma; D002121:Calcium Channel Blockers; D002648:Child; D006801:Humans; D006973:Hypertension; D008260:Macroglossia; D008297:Male; D009529:Nicardipine; D012720:Severity of Illness Index; D015275:Tumor Lysis Syndrome",
"nlm_unique_id": "9503023",
"other_id": null,
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"pmid": "21330681",
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"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Angioedema associated with dihydropyridine calcium-channel blockers in a child with Burkitt lymphoma.",
"title_normalized": "angioedema associated with dihydropyridine calcium channel blockers in a child with burkitt lymphoma"
} | [
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"companynumb": "US-EPIC PHARMA LLC-2020EPC00019",
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"activesubstancename": "RASBURICASE"
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"abstract": "A 26-year-old man was treated with piperacillin-tazobactam because of suspected cholangitis and a 77-year-old man was given ciprofloxacin because of an infected knee-prosthesis. They both developed symptoms of an interstitial nephritis: malaise and laboratory deviations. The symptoms disappeared after the antibiotics were withdrawn. No other explanation for the renal function disorders could be found in either patient. Piperacillin-tazobactam and ciprofloxacin are considered to be relatively safe and serious adverse effects are rare. Acute interstitial nephritis may, however, occur and its clinical presentation may not be very informative. Withdrawal of the culprit usually leads to recovery.",
"affiliations": "TweeSteden Ziekenhuis, Dr.Deelenlaan 5, 5042 AD, Tilburg.",
"authors": "Mannaerts|L|L|;Van der Wurff|A A|AA|;Wolfhagen|F H J|FH|",
"chemical_list": "D000890:Anti-Infective Agents; D000077725:Piperacillin, Tazobactam Drug Combination; D002939:Ciprofloxacin; D010397:Penicillanic Acid; D010878:Piperacillin",
"country": "Netherlands",
"delete": false,
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"issue": "150(14)",
"journal": "Nederlands tijdschrift voor geneeskunde",
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"medline_ta": "Ned Tijdschr Geneeskd",
"mesh_terms": "D000328:Adult; D000368:Aged; D000890:Anti-Infective Agents; D002939:Ciprofloxacin; D006801:Humans; D008297:Male; D009395:Nephritis, Interstitial; D010397:Penicillanic Acid; D010878:Piperacillin; D000077725:Piperacillin, Tazobactam Drug Combination",
"nlm_unique_id": "0400770",
"other_id": null,
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"pmid": "16649401",
"pubdate": "2006-04-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Interstitial nephritis attributed to treatment with piperacillin-tazobactam and with ciprofloxacin.",
"title_normalized": "interstitial nephritis attributed to treatment with piperacillin tazobactam and with ciprofloxacin"
} | [
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"companynumb": null,
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DEXAMETHASONE"
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"drugadditional": "3",
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{
"abstract": "Granulomatosis polyangiitis (GPA) is an ANCA-related vasculitis (AAV) whose clinical manifestations mainly concern the respiratory tract (upper and lower) and the kidney. The treatment of GPA (as well as other AAV) includes the use of immunosuppressive drugs with numerous side effects; the most frequent complications are infectious and neoplastic. GPA frequently relapses. Epstein Barr Virus (EBV) is a ubiquitous virus; it is estimated that about 90% of the world’s population has BEEN EXPOSED TO with this pathogen and has subsequently developed a latent infection. Under certain conditions including immunosuppression EBV may reactivate. We report the clinical case of a 67-year-old woman who presented with GPA involving the upper respiratory tract and renal failure with the need for hemodialysis treatment. The fourth month of induction therapy with cyclophosphamide and methylprednisone she presented with dyspnea and respiratory failure. After excluding pulmonary embolism and heart failure, a series of investigations including high resolution tomography and fibroscopy with broncoalveolar lavage (BAL) were performed which excluded recurrence of pulmonary vasculitis including alveolar haemorrhage A BAL demonstrated EBV-DNA. On this basis EBV pneumonia was diagnosed, and antiviral therapy with acyclovir was begun, followed by clinical and radiological improvement. In patients with GPA treated with immunosuppressive drugs pulmonary involvement may not only be due to the underlying vasculitis, but also to opportunistic agents, which must always be considered.",
"affiliations": "SC Nefrologia e Dialisi-ASUITs, Azienda Sanitaria Universitaria Integrata di Trieste.;SC Nefrologia e Dialisi-ASUITs, Azienda Sanitaria Universitaria Integrata di Trieste.;SC Nefrologia e Dialisi-ASUITs, Azienda Sanitaria Universitaria Integrata di Trieste.;SC Nefrologia e Dialisi-ASUITs, Azienda Sanitaria Universitaria Integrata di Trieste.;SC Nefrologia e Dialisi-ASUITs, Azienda Sanitaria Universitaria Integrata di Trieste.;SC Nefrologia e Dialisi-ASUITs, Azienda Sanitaria Universitaria Integrata di Trieste.;SC Nefrologia e Dialisi-ASUITs, Azienda Sanitaria Universitaria Integrata di Trieste.;SC Nefrologia e Dialisi-ASUITs, Azienda Sanitaria Universitaria Integrata di Trieste.;SC Nefrologia e Dialisi-ASUITs, Azienda Sanitaria Universitaria Integrata di Trieste.",
"authors": "Mongera|Nicola|N|;Di Maso|Vittorio|V|;Ermacora|Elisabetta|E|;Carraro|Michele|M|;Bregant|Cristina|C|;Pian|Martina|M|;Savi|Umberto|U|;Lorenzon|Eric|E|;Boscutti|Giuliano|G|",
"chemical_list": "D000998:Antiviral Agents; D007166:Immunosuppressive Agents; D003520:Cyclophosphamide; D011241:Prednisone; D000212:Acyclovir",
"country": "Italy",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0393-5590",
"issue": "35(3)",
"journal": "Giornale italiano di nefrologia : organo ufficiale della Societa italiana di nefrologia",
"keywords": "EBV-associated pneumonia; granulomatosis with polyangiitis; acyclovir",
"medline_ta": "G Ital Nefrol",
"mesh_terms": "D000212:Acyclovir; D000368:Aged; D000998:Antiviral Agents; D003520:Cyclophosphamide; D004198:Disease Susceptibility; D004417:Dyspnea; D020031:Epstein-Barr Virus Infections; D005260:Female; D014890:Granulomatosis with Polyangiitis; D004854:Herpesvirus 4, Human; D006801:Humans; D016867:Immunocompromised Host; D007166:Immunosuppressive Agents; D007676:Kidney Failure, Chronic; D011024:Pneumonia, Viral; D011241:Prednisone; D006435:Renal Dialysis; D012131:Respiratory Insufficiency",
"nlm_unique_id": "9426434",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "29786186",
"pubdate": "2018-05",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "EBV-ASSOCIATED PNEUMONIA IN PATIENT WITH GRANULOMATOSIS WITH POLYANGIITIS (GPA) IN IMMUNOSOPPRESSIVE THERAPY TREATED WITH ACICLOVIR.",
"title_normalized": "ebv associated pneumonia in patient with granulomatosis with polyangiitis gpa in immunosoppressive therapy treated with aciclovir"
} | [
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"companynumb": "IT-SUN PHARMACEUTICAL INDUSTRIES LTD-2019R1-213820",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CYCLOPHOSPHAMIDE"
},
... |
{
"abstract": "BACKGROUND\nPortal and mesenteric vein thrombosis are relatively uncommon surgical complications, with difficult diagnosis and potentially severe consequences due to higher risk of bowel infarction. The purpose of this study was to present a series of patients who developed postoperative portal vein thrombosis after laparoscopic sleeve gastrectomy.\n\n\nMETHODS\nThis is a retrospective analysis of patients who underwent sleeve gastrectomy between June 2005 and June 2011 who developed portal vein thrombosis. Demographic data, personal risk factors, family history of thrombosis, and postoperative results of thrombophilia study were analyzed in this study.\n\n\nRESULTS\nA total of 1,713 laparoscopic sleeve gastrectomies were performed. Seventeen patients (1 %) developed portal vein thrombosis after surgery. Of the 17 patients, 16 were women, 8 had a history of smoking, 7 used oral contraceptives, and 2 had a family history of deep vein thrombosis of the lower limbs. All patients were discharged on the third day of surgery with no immediate complications. Symptoms presented at a median of 15 (range, 8-43) days after surgery with abdominal pain in most cases. One case required emergency laparotomy and splenectomy because of an active bleeding hematoma with massive portomesenteric vein thrombosis. In 11 cases, a thrombosis of the main portal vein was identified, in 15 the right portal branch was compromised, and in 10 the left portal branch. Eleven patients presented thrombosis of the superior mesenteric vein, and ten patients presented a concomitant thrombosis of the splenic vein. A massive PMVT was presented in six cases. Seven patients had a positive thrombophilia study.\n\n\nCONCLUSIONS\nPortal vein thrombosis and/or mesenteric thrombosis are relatively uncommon complications in patients undergoing bariatric surgery. In this series, the portomesenteric vein thrombosis was the most common complication after LSG in a high-volume center.",
"affiliations": "Surgery Division, Department of Digestive Surgery, Faculty of Medicine, Pontificia Universidad Católica de Chile, Marcoleta 350, Santiago, Chile.",
"authors": "Salinas|José|J|;Barros|Diego|D|;Salgado|Napoleón|N|;Viscido|Germán|G|;Funke|Ricardo|R|;Pérez|Gustavo|G|;Pimentel|Fernando|F|;Boza|Camilo|C|",
"chemical_list": null,
"country": "Germany",
"delete": false,
"doi": "10.1007/s00464-013-3055-8",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0930-2794",
"issue": "28(4)",
"journal": "Surgical endoscopy",
"keywords": null,
"medline_ta": "Surg Endosc",
"mesh_terms": "D000328:Adult; D050110:Bariatric Surgery; D005260:Female; D005500:Follow-Up Studies; D005743:Gastrectomy; D006801:Humans; D010535:Laparoscopy; D008297:Male; D008642:Mesenteric Veins; D008875:Middle Aged; D009765:Obesity; D011169:Portal Vein; D011183:Postoperative Complications; D011379:Prognosis; D012189:Retrospective Studies; D014057:Tomography, X-Ray Computed; D020246:Venous Thrombosis; D055815:Young Adult",
"nlm_unique_id": "8806653",
"other_id": null,
"pages": "1083-9",
"pmc": null,
"pmid": "24570009",
"pubdate": "2014-04",
"publication_types": "D016428:Journal Article",
"references": "16417768;11668324;11030868;1998400;16359257;15650628;14738671;10493318;16354529;15978165;12488196;12624633;17217642;17356932;17339177;12682554;10867463;15119663;19796994;15072666;8211621;9617964;16610067;15644039;10830225;16545171;16925296;10718950;9569363;8831536;21940219;17339187;17894158;12448396;9479726;16989696;11112234;10845677;12856849;10757900",
"title": "Portomesenteric vein thrombosis after laparoscopic sleeve gastrectomy.",
"title_normalized": "portomesenteric vein thrombosis after laparoscopic sleeve gastrectomy"
} | [
{
"companynumb": "TR-SAKK-2018SA396252AA",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ENOXAPARIN SODIUM"
},
"drugadditional": "3",
... |
{
"abstract": "A 53-year-old woman presented with an extensively metastatic and rapidly growing breast adenocarcinoma, markedly elevated lactate dehydrogenase, and mildly elevated blood urea nitrogen. She received 5-fluorouracil, doxorubicin, and cyclophosphamide. Eighteen hours after chemotherapy she was noted to have hyperuricemia, hyperkalemia, hyperphosphatemia, hypocalcemia, and acute renal failure. She experienced cardiac arrest and died 72 hours after receiving chemotherapy. A postmortem liver biopsy revealed adenocarcinoma undergoing necrosis. This case represented the acute tumor lysis syndrome that occurred after chemotherapy of breast carcinoma. Patients with metastatic breast carcinoma and similar presentations should be considered for prophylactic therapy with allopurinol and hydration before chemotherapy.",
"affiliations": null,
"authors": "Stark|M E|ME|;Dyer|M C|MC|;Coonley|C J|CJ|",
"chemical_list": "D004317:Doxorubicin; D003520:Cyclophosphamide; D005472:Fluorouracil",
"country": "United States",
"delete": false,
"doi": "10.1002/1097-0142(19870815)60:4<762::aid-cncr2820600409>3.0.co;2-p",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0008-543X",
"issue": "60(4)",
"journal": "Cancer",
"keywords": null,
"medline_ta": "Cancer",
"mesh_terms": "D000230:Adenocarcinoma; D000971:Antineoplastic Combined Chemotherapy Protocols; D001344:Autopsy; D001943:Breast Neoplasms; D003520:Cyclophosphamide; D004317:Doxorubicin; D005260:Female; D005472:Fluorouracil; D006801:Humans; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009364:Neoplasm Recurrence, Local",
"nlm_unique_id": "0374236",
"other_id": null,
"pages": "762-4",
"pmc": null,
"pmid": "3594399",
"pubdate": "1987-08-15",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Fatal acute tumor lysis syndrome with metastatic breast carcinoma.",
"title_normalized": "fatal acute tumor lysis syndrome with metastatic breast carcinoma"
} | [
{
"companynumb": "US-PFIZER INC-2021486751",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CYCLOPHOSPHAMIDE"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nRecent advances in respiratory management have improved survival for patients with Fukuyama congenital muscular dystrophy (FCMD), characterized by congenital muscular dystrophy and brain malformation. Previous studies reported that more than half of patients exhibit seizures in childhood. However, little is known about epilepsy after childhood.\n\n\nMETHODS\nTo elucidate the long-term clinical course of epilepsy, we retrospectively reviewed all medical records in nine patients (6 males, mean age 20.7 years) with FCMD diagnosed between 1981 and 2019.\n\n\nRESULTS\nThe follow-up periods ranged from 6 to 30 years (mean 18.4 years). A total of 75 EEG recordings were available from nine patients. In some patients, EEGs were normal during early childhood but tended to show paroxysmal discharges with age. Overall, epileptic seizures were observed in six patients. Except for one presenting with afebrile seizure at one year of age, the remaining five patients developed epilepsy between 13 and 22 years of age. The most common seizure type was focal impaired awareness seizure. After adolescence, four patients exhibited status epilepticus. Their convulsive movements of the seizures became less prominent with progression of the disease. At the last evaluation, most patients (5/6) had uncontrolled seizures.\n\n\nCONCLUSIONS\nDespite presence of distinct brain malformation, epileptic seizures may develop after childhood in FCMD patients. Our experience suggests that clinicians should be careful not to overlook epileptic seizures, especially in advanced-stage patients who had profound muscle weakness.",
"affiliations": "Department of Pediatric Neurology, Osaka Women's and Children's Hospital, Japan; Department of Pediatrics, Graduate School of Medicine, Osaka University, Japan.;Department of Pediatric Neurology, Osaka Women's and Children's Hospital, Japan. Electronic address: yasuzuki@wch.opho.jp.;Department of Radiology, Osaka Women's and Children's Hospital, Japan.;Department of Pediatric Neurology, Osaka Women's and Children's Hospital, Japan.;Department of Pediatric Neurology, Osaka Women's and Children's Hospital, Japan.;Department of Pediatric Neurology, Osaka Women's and Children's Hospital, Japan.;Department of Pediatric Neurology, Osaka Women's and Children's Hospital, Japan.;Department of Pediatric Neurology, Osaka Women's and Children's Hospital, Japan.",
"authors": "Kuwayama|Ryoko|R|;Suzuki|Yasuhiro|Y|;Nishikawa|Masanori|M|;Kimizu|Tomokazu|T|;Nakajima|Ken|K|;Ikeda|Tae|T|;Mogami|Yukiko|Y|;Yanagihara|Keiko|K|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.braindev.2020.06.017",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0387-7604",
"issue": "43(1)",
"journal": "Brain & development",
"keywords": "Adolescence; Adulthood; Epilepsy; Fukuyama congenital muscular dystrophy; Status epilepticus",
"medline_ta": "Brain Dev",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D004569:Electroencephalography; D004828:Epilepsies, Partial; D004827:Epilepsy; D005260:Female; D006801:Humans; D007564:Japan; D008137:Longitudinal Studies; D008297:Male; D009136:Muscular Dystrophies; D009421:Nervous System Malformations; D012189:Retrospective Studies; D012640:Seizures; D058494:Walker-Warburg Syndrome; D055815:Young Adult",
"nlm_unique_id": "7909235",
"other_id": null,
"pages": "106-110",
"pmc": null,
"pmid": "32723526",
"pubdate": "2021-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Epilepsy in patients with advanced Fukuyama congenital muscular dystrophy.",
"title_normalized": "epilepsy in patients with advanced fukuyama congenital muscular dystrophy"
} | [
{
"companynumb": "JP-SUN PHARMACEUTICAL INDUSTRIES LTD-2021RR-302138",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TOPIRAMATE"
},
"drug... |
{
"abstract": "BACKGROUND\nFacioscapulohumeral muscular dystrophy (FSHD) is a patchy and slowly progressive disease of skeletal muscle. MRI short tau inversion recovery (STIR) sequences of patient muscles often show increased hyperintensity that is hypothesized to be associated with inflammation. This is supported by the presence of inflammatory changes on biopsies of STIR-positive muscles. We hypothesized that the STIR positivity would normalize with targeted immunosuppressive therapy.\n\n\nMETHODS\n45-year-old male with FSHD type 1 was treated with 12 weeks of immunosuppressive therapy, tacrolimus and prednisone. Tacrolimus was treated to a goal serum trough of > 5 ng/mL and prednisone was tapered every month. Quantitative strength exam, functional outcome measures, and muscle MRI were performed at baseline, week 6, and week 12. The patient reported subjective worsening as reflected in quantitative strength exam. The MRI STIR signal was slightly increased from 0.02 to 0.03 of total muscle; while the T1 fat fraction was stable. Functional outcome measures also were stable.\n\n\nCONCLUSIONS\nImmunosuppressive therapy in refractive autoimmune myopathy in other contexts has been shown to reverse STIR signal hyperintensity, however this treatment did not reverse STIR signal in this patient with FSHD. In fact, STIR signal slightly increased throughout the treatment period. This is the first study of using MRI STIR and T1 fat fraction to follow treatment effect in FSHD. We find that STIR might not be a dynamic marker for suppressing inflammation in FSHD.",
"affiliations": "Department of Neurology, University of Washington, Seattle, Washington, USA. leowang@uw.edu.;Department of Rehabilitative Medicine, University of Washington, Seattle, Washington, USA.;Radiology Clinical Research Imaging Core/Neurology, Seattle Children's Hospital, Seattle, Washington, USA.;Human Biology Division, Fred Hutchinson Research Center, Seattle, Washington, USA.;Radiology Clinical Research Imaging Core/Improvement and Innovation, Seattle Children's Hospital, Seattle, Washington, USA.",
"authors": "Wang|Leo H|LH|http://orcid.org/0000-0002-5079-1416;Johnstone|Laura M|LM|;Bindschadler|Michael|M|;Tapscott|Stephen J|SJ|;Friedman|Seth D|SD|",
"chemical_list": "D011241:Prednisone; D016559:Tacrolimus",
"country": "England",
"delete": false,
"doi": "10.1186/s12891-020-03910-1",
"fulltext": "\n==== Front\nBMC Musculoskelet Disord\nBMC Musculoskelet Disord\nBMC Musculoskeletal Disorders\n1471-2474 BioMed Central London \n\n3910\n10.1186/s12891-020-03910-1\nCase Report\nAdapting MRI as a clinical outcome measure for a facioscapulohumeral muscular dystrophy trial of prednisone and tacrolimus: case report\nhttp://orcid.org/0000-0002-5079-1416Wang Leo H. leowang@uw.edu 12 Johnstone Laura M. 3 Bindschadler Michael michael.bindschadler@seattlechildrens.org 4 Tapscott Stephen J. stapscot@fredhutch.org 5 Friedman Seth D. seth.friedman@seattlechildrens.org 6 1 grid.34477.330000000122986657Department of Neurology, University of Washington, Seattle, Washington USA \n2 grid.412623.00000 0000 8535 6057University of Washington Medical Center, Box 356465, 1959 NE Pacific Street, Seattle, WA USA \n3 grid.34477.330000000122986657Department of Rehabilitative Medicine, University of Washington, Seattle, Washington USA \n4 grid.240741.40000 0000 9026 4165Radiology Clinical Research Imaging Core/Neurology, Seattle Children’s Hospital, Seattle, Washington USA \n5 Human Biology Division, Fred Hutchinson Research Center, Seattle, Washington USA \n6 grid.240741.40000 0000 9026 4165Radiology Clinical Research Imaging Core/Improvement and Innovation, Seattle Children’s Hospital, Seattle, Washington USA \n9 1 2021 \n9 1 2021 \n2021 \n22 5622 7 2020 23 12 2020 © The Author(s) 2021Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.Background\nFacioscapulohumeral muscular dystrophy (FSHD) is a patchy and slowly progressive disease of skeletal muscle. MRI short tau inversion recovery (STIR) sequences of patient muscles often show increased hyperintensity that is hypothesized to be associated with inflammation. This is supported by the presence of inflammatory changes on biopsies of STIR-positive muscles. We hypothesized that the STIR positivity would normalize with targeted immunosuppressive therapy.\n\nCase presentation\n45-year-old male with FSHD type 1 was treated with 12 weeks of immunosuppressive therapy, tacrolimus and prednisone. Tacrolimus was treated to a goal serum trough of > 5 ng/mL and prednisone was tapered every month. Quantitative strength exam, functional outcome measures, and muscle MRI were performed at baseline, week 6, and week 12. The patient reported subjective worsening as reflected in quantitative strength exam. The MRI STIR signal was slightly increased from 0.02 to 0.03 of total muscle; while the T1 fat fraction was stable. Functional outcome measures also were stable.\n\nConclusions\nImmunosuppressive therapy in refractive autoimmune myopathy in other contexts has been shown to reverse STIR signal hyperintensity, however this treatment did not reverse STIR signal in this patient with FSHD. In fact, STIR signal slightly increased throughout the treatment period. This is the first study of using MRI STIR and T1 fat fraction to follow treatment effect in FSHD. We find that STIR might not be a dynamic marker for suppressing inflammation in FSHD.\n\nKeywords\nAll neuromuscular diseaseMuscle diseaseFacioscapulohumeral muscular dystrophy (FSHD)Outcome measuresCase reporthttp://dx.doi.org/10.13039/100012644Friends of FSH Researchissue-copyright-statement© The Author(s) 2021\n==== Body\nBackground\nFacioscapulohumeral muscular dystrophy (FSHD) is a patchy and slowly progressive disease of skeletal muscle [1]. It is one of the most common muscular dystrophies that is the result of a toxic gain-of-function from de-repression of the DUX4 gene that is not normally expressed in skeletal muscle. The muscle histopathology underlying the disease is also variable, reflecting the patchy clinical involvement. Inflammation may be present in a subset of biopsies [2–4]. Given the intensity of the inflammation in some biopsies, pathologists have at times interpreted the histopathology as representing an immune-mediated disease such as polymyositis [2]. The inflammatory cells are endomysial, surrounding intact fibers, and often perivascular.\n\nMultiple studies have assessed muscle MRI in patients with FSHD focusing on determining muscles to follow in a clinical trial either by imaging or muscle biopsy (looking for DUX4-downstream signature markers) [5–10]. MRI STIR sequences null the fat signal and highlight elevated free water signal. STIR hyperintensities indicate muscle edema, a feature associated with acute changes such as inflammation, trauma, metabolic derangements, or infection [11]. Two studies, Frisullo et al. and Tasca et al., performed biopsies on muscles with STIR hyperintensities and found 5/5 biopsies with endomysial CD8+ cells, perivascular CD4+ T-cells and CD68+ cells [12, 13]. Frisullo et al. found increased percentage of circulating CD8+pSTAT1+, CD8+T-bet+, and CD14+pSTAT1+ cells in 14/25 peripheral blood samples of FSHD patients with STIR hyperintensities, a significant increase when compared to FSHD patients without STIR hyperintensities and healthy controls. In the Seattle Wellstone FSHD study of 36 patients with MRI-guided biopsies, we found that MRI STIR positivity was associated with inflammation or active myopathy in ~ 70% of the muscle biopsies versus 25% of the STIR negative muscles [10]. A most recent paper by Dahlqvist et al. found that STIR-positive muscles indicating muscle inflammation were associated with faster muscle degradation [14]. Therefore, our hypothesis was that if STIR hyperintensities represent active inflammation, these abnormalities would normalize with targeted therapy.\n\nWe chose a combination of prednisone because of its fast onset and effect on both B and T cells; and tacrolimus for its effects on T cells. This multi-agent approach was selected given that a prior, open-label, 12-week trial of immunosuppression with prednisone (1.5 mg/kg/day) in eight FSHD patients failed to show improvement in muscle strength as assessed by manual muscle testing or maximum voluntary isometric contraction testing [15]. What was not evaluated in that study was MRI imaging which could certainly be more sensitive and specific than strength.\n\nIn refractory inflammatory myopathies, the use of a calcineurin inhibitor offers effective treatment [16]. STIR signal has been reported to be reversed in small case series of patients with inflammatory myositis [17] also in a case of TNF receptor-associated periodic syndrome [18]. We selected a three-month treatment duration similar to the duration of treatment trials for inflammatory myopathies to test our hypothesis.\n\nCase presentation\nThe subject was a 45-year-old male with history of diabetes mellitus type 2 and FSHD type 1 (with clinical severity score of 2 and nine D4Z4 repeats) who first noticed symptoms at age 19, when he did 200 pull-ups as part of the Air Force Academy and thereafter lost the ability to do further pull ups. He also noticed lordosis while walking and attributed that to injury on an obstacle course. At the age 35, he realized that he could no longer set as a semi-pro volleyball player. At the age 39, after prolonged biking for a triathlon, he could no longer walk downstairs as he had problems stopping his forward progress. He then noticed that his arms got worse. He denied facial weakness but stated that his face gets tired and has been told that he never smiles. He denied problems with sucking on a straw or whistling. On exam, he demonstrated strong eyelid and lip closure, and cheek puff. Tongue and sternocleidomastoids were strong. His appendicular strength was intact, with the patient able to do deep knee bend but having a hard time walking on toes and heels. As part of the Seattle Wellstone study, an MRI showed STIR positivity in his left medial gastrocnemius and a biopsy of that muscle showed a chronic myopathy with severe myofiber size variability, necrosis, and increased endomysial inflammation (Fig. 1a); also present was perivascular inflammation (Fig. 1b-c).\nFig. 1 Muscle histopathology of left medial gastrocnemius. Muscle histopathology showed a chronic myopathy with severe myofiber size variability, necrosis, and increased endomysial inflammation (a); also present was perivascular inflammation (b-c). Courtesy of Dr. Rabi Tawil\n\n\n\nAfter informed consent was obtained, the patient was treated for 3 months with an immunosuppressive regimen of tacrolimus (2.5–3 mg twice per day for goal trough 4 ng/dL) and prednisone (40 mg per day for the first month, 20 mg per day for the second month, and then 10 mg per day for the third month). Quantitative strength exam, functional outcome measures, and muscle MRI were performed at baseline, week 6, and week 12.\n\nAll MRI examinations were performed on a 3 T Philips Ingenia scanner. Sequences were acquired using flexible array coils to cover the pelvis down to the ankles in multiple stations (more to cover anatomy with thinner slices) with the following parameters in the axial acquisition plane: T1-weighted DIXON (Fast Field Echo [FFE] readout, four anatomical blocks [stations]: TE=1.35/2.58 ms, TR=shortest [example 4.12 ms], field-of-view [FOV] phase=300, FOV read=max, matrix=448 × 272, in-plane resolution=1.6 × 1.6 mm [thigh], 1.1 × 1.1 mm [calf], slice thickness=3 mm), STIR (three stations: TE=42 ms, TR=5277 ms, FOV phase=410, FOV read=max, matrix=448 × 260, in-plane resolution=1.1 × 1.1 mm, slice thickness=9 mm, IR delay=220 ms), and T2-weighted DIXON (three stations: TE=97/97 ms [phase difference], TR=5570 ms, FOV phase=410, FOV read=max, matrix=448 × 272, in-plane resolution=1.1 × 1.1 mm, slice thickness=9 mm). Total exam time was approximately 40 min equating to ~ 4 min per sequence (four stations T1 and three for STIR and T2 DIXON).\n\nMRI data were imported into Slicer (http://www.slicer.org/, [19]) for processing. The algorithm developed creates a registered image set across the different image types. When you select a pixel within a region, for example a fatty replaced muscle compartment, across the registered images you get back a vector of voxel values, one value for each registered image at that spatial location. Since voxel values depend on the tissue type and on the MRI signal sequence, voxels with similar value vectors are likely to represent the same tissue type. The steps to select model classes and generate hard classified images is described in more detail below. Images underwent preprocessing steps: 1) stitching to join the separate series into a contiguous volume, 2) interpolation of all series to the highest resolution data (T1 DIXON), and 3) separate series intensity normalization and inhomogeneity correction. Next, data were exported for segmentation in MATLAB (Mathworks, Natick MA), with the time-points concatenated into a common block and then seeds were selected in the sum exams for the four primary classes of interest (fat, muscle, STIR+, bone). From these samples, gold-standard voxel value vectors were generated and the images classified by voxel vector similarity (least squared vector difference). To ensure that bone and sub-cutaneous fat were not included in volume measurements, both classes were expanded (digital dilation) by 5 and 4 pixels respectively. This has the practical result of removing the subcutaneous fat ring and ensuring that the bone mask is liberal enough to ensure that it is not being incorporated into muscle measures. As a last step, since bladder and vasculature appear as STIR bright features, these were removed the final segmentations by a rater blinded to time-point. This vector classification approach yielded excellent overlap between the multi-modality images for major tissue classes of interest (fat, muscle [normal-appearing], and STIR+ regions) as can be seen in Fig. 2. Summary volumes were computed for evaluating change with treatment.\nFig. 2 Vector Classification Example: From top, fat (T1 DIXON), water (T1 DIXON), water (T2 DIXON), and STIR images are shown from the same anatomical locations. Note the overlap between T2-weighted water measures and STIR+ signal. The vector segmentation overlaid on the STIR images follows, demonstrating the close correspondence between classes of air and subcutaneous tissue (green), bone (blue), muscle (red), fat (yellow), and STIR+ signal (pink). In the raw segmentation without overlay (bottom), black pixels are edited large vessels\n\n\n\nThere was no reversal of the abnormal STIR signal elevations seen at baseline by visual evaluation or by the volumes derived. Numerically, there was a slight increase in the fraction of muscle with STIR positivity from 0.02 at baseline to 0.03 at week 12 (Table 1). Data were expressed STIR/total at each time-point to account for weight changes. The stability of this biomarker and its potential to increase over the time-course can be seen in Fig. 3, with arrows demarcating areas of STIR+ features seen across the thigh and calf. Fat fraction assessed in bilateral legs showed no increase between baseline and at the end of the treatment period (12 weeks) with fat fraction at 0.27.\nTable 1 MRI characteristics over 12 weeks of treatment\n\n\tBaseline\t6 weeks\t12 weeks\t\nSTIR hyperintensity/muscle + STIR positivity\t0.02\t0.03\t0.03\t\nFat fraction\t0.27\t0.28\t0.27\t\nFig. 3 STIR and T1 MRI of lower extremity over the treatment period (6 and 12 weeks). The fat and water images derived from the T1 DIXON scan are shown at top and middle throughout the leg volumes across the study interval. In the bottom panel, regions with STIR+ signal are shown with arrows. The STIR+ signal persists at the two treatment time-points\n\n\n\nQuantitative strength examination of the lower extremity by quantitative myometry showed mild decrease in bilateral knee flexion and ankle dorsiflexion strength (Table 2). Functional outcome measures showed no clinically significant changes (Table 2).\nTable 2 Quantitative myometry (in Newtons) and functional outcome measures\n\n\tBaseline\t6 weeks\t12 weeks\t\nKnee flexion (right, N.)\t22\t13\t13\t\nKnee flexion (left)\t62\t40\t36\t\nKnee extension (right)\t209\t182\t200\t\nKnee extension (left)\t227\t218\t209\t\nAnkle dorsiflexion (right)\t76\t62\t58\t\nAnkle dorsiflexion (left)\t89\t62\t36\t\n6-min walk test (m)\t600\t580\t596\t\nTime up and go (sec)\t5\t5\t5\t\nSelf-selected gait speed (sec)\t4\t3\t3\t\nGo 30 ft (sec)\t4\t4\t4\t\nAscending stairs (sec)\t2\t2\t2\t\nDescending stairs (sec)\t2\t2\t2\t\nSit to stand (sec)\t1\t1\t1\t\n\n\nThe patient lost 9 kg during the study from a baseline weight of 104 kg. He reported no significant side-effect of the medications. Labs showed persistent hyperglycemia with hemoglobin A1c 6.6% at baseline and 8.8% at week 12. Tacrolimus trough levels were consistently therapeutic between 7.8 and 10.7 ng/mL. Renal function, potassium, magnesium, and phosphate levels were unaffected throughout the study.\n\nDiscussion and conclusions\nDespite literature data (Tasca, Frisullo, Dahlqvist, our prior work [10, 12–14]) suggesting that STIR+ features may be primarily related to inflammation, we saw no change in signal intensity during a 12-week treatment trial with tacrolimus and prednisone. If we assume that STIR-positivity is primarily related to inflammation, then there may be a chance that the inflammation was not reversed with our regimen and that a more stringent regimen was required; however, we were using therapeutic doses of tacrolimus recommended for the treatment of inflammatory myopathies [16]; and therefore this is unlikely. Notable is a study [18] where complete resolution in STIR elevations did occur with equivalent immunosuppressive agents and time-course in a different muscle disease. However, this must be interpreted cautiously in our study, as while the patient clearly had inflammation on muscle biopsy prior to the study, we do not have a follow-up muscle biopsy to prove that our immunosuppressive regimen reduced the inflammation.\n\nIf we assume that our immunosuppressive regimen was therapeutic, then our findings support the idea that the STIR hyperintensity does not exclusively depend on active inflammation. This is a conclusion that we favor. While it could be envisioned that small inflammatory components would be modulated by our immunosuppressive regimen, the bulk of the abnormality remained stable and this perhaps reflects other pathological features such as edema, vasculature changes, fibrosis, and macroscopic features of cell death and reorganization. Such inflammatory mimicry in STIR signal is found in a broad range of diseases [20].\n\nWhile we can debate the significance of the STIR signal, the immunosuppressive regimen of tacrolimus and prednisone did not improve strength as our patient subjectively reported worsened strength. This was borne out in the quantitative myometry. While it was unclear whether the changes in quantitative myometry were clinically significant, within error of measurement, or reflective of a volitional component, the patient’s strength measurements reflected his subjective experience during the study. There were other measurements that were stable throughout the study, such as distance walked in 6 min and the time in the time-up-and-go tests. Furthermore, his total T1 fat fraction of the leg muscles measured was unchanged suggesting that there was no progression in fatty replacement of muscle—a measure associated with increasing functional disability.\n\nThe inability of tacrolimus and prednisone to reverse the significant STIR hyperintensities on this patient’s muscle MRI, suggest that this regimen most likely will not succeed in reversing the STIR-positive signal in a larger study. We can also conclude that the short course of the immunosuppressive regimen of tacrolimus and prednisone did not improve the strength manifestations of FSHD. While it could always be argued that larger samples and/or longer studies are needed to generalize a single-subject result, the regimen and study design employed is not without risk. Our study shows the importance of objective outcome measures such as T1 fat fraction, representative of fibrofatty replacement, and functional outcome measure, as useful indices to infer the ever-hopeful treatment response.\n\nAbbreviations\nFSHDFacioscapulohumeral muscular dystrophy\n\nMRIMagnetic resonance imaging\n\nSTIRshort tau inversion recovery\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAcknowledgements\nThe authors thank the Friends of FSH Research and Dr. Rabi Tawil for the histopathology slides.\n\nAuthors’ contributions\nLHW, SJT, and SDF designed the study; edited and wrote the paper. LHW, SDF, and MB analyzed the data. LHW, SDF, and LMJ collected the data. All authors read and approve the manuscript.\n\nFunding\nFriends of FSH Research for funding the MRI, lab, outcome measure requisition, and the medications.\n\nStudy sponsorship: This work is supported by research grant from Friends of FSH Research.\n\nAvailability of data and materials\nThe datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.\n\nEthics approval and consent to participate\nThe study was approved by the Human Subjects Committee at the University of Washington, with written informed consent obtained.\n\nAn independent Safety Monitoring Committee consisting of one neurologist, a rheumatologist experienced in use of immunosuppressive medication, and a pharmacist reviewed safety data every 3 months throughout the trial.\n\nConsent for publication\nWritten informed consent was obtained from the patient for publication of this Case Report. A copy of the written consent is available for review by the Editor of this journal.\n\nCompeting interests\nDrs. Wang reports consultancy for Biogen. Drs. Friedman and Tapscott report consultancy for Fulcrum Therapeutics.\n==== Refs\nReferences\n1. Wang LH Tawil R Facioscapulohumeral dystrophy Curr Neurol Neurosci Rep 2016 16 7 66 10.1007/s11910-016-0667-0 27215221 \n2. DeVere R Bradley WG Polymyositis: its presentation, morbidity and mortality Brain. 1975 98 4 637 666 10.1093/brain/98.4.637 1218371 \n3. Dubowitz V Brooke MH Muscle biopsy; a modern approach 1973 London Saunders \n4. Statland JM Shah B Henderson D Van Der Maarel S Tapscott SJ Tawil R Muscle pathology grade for facioscapulohumeral muscular dystrophy biopsies Muscle Nerve 2015 52 4 521 526 10.1002/mus.24621 25704033 \n5. Andersen G Dahlqvist JR Vissing CR Heje K Thomsen C Vissing J MRI as outcome measure in facioscapulohumeral muscular dystrophy: 1-year follow-up of 45 patients J Neurol 2017 264 3 438 447 10.1007/s00415-016-8361-3 28000006 \n6. Dahlqvist JR Andersen G Khawajazada T Vissing C Thomsen C Vissing J Relationship between muscle inflammation and fat replacement assessed by MRI in facioscapulohumeral muscular dystrophy J Neurol 2019 266 5 1127 1135 10.1007/s00415-019-09242-y 30778707 \n7. Fatehi F Salort-Campana E Le Troter A Lareau-Trudel E Bydder M Foure A Long-term follow-up of MRI changes in thigh muscles of patients with Facioscapulohumeral dystrophy: a quantitative study PLoS One 2017 12 8 e0183825 10.1371/journal.pone.0183825 28841698 \n8. Ferguson MR Poliachik SL Budech CB Gove NE Carter GT Wang LH MRI change metrics of facioscapulohumeral muscular dystrophy: Stir and T1 Muscle Nerve 2018 57 6 905 912 10.1002/mus.26038 29236297 \n9. Janssen BH Voet NB Nabuurs CI Kan HE de Rooy JW Geurts AC Distinct disease phases in muscles of facioscapulohumeral dystrophy patients identified by MR detected fat infiltration PLoS One 2014 9 1 e85416 10.1371/journal.pone.0085416 24454861 \n10. Wang LH Friedman SD Shaw D Snider L Wong CJ Budech CB MRI-informed muscle biopsies correlate MRI with pathology and DUX4 target gene expression in FSHD Hum Mol Genet 2019 28 3 476 486 10.1093/hmg/ddy364 30312408 \n11. May DA Disler DG Jones EA Balkissoon AA Manaster BJ Abnormal signal intensity in skeletal muscle at MR imaging: patterns, pearls, and pitfalls Radiographics 2000 20 S295 S315 10.1148/radiographics.20.suppl_1.g00oc18s295 11046180 \n12. Frisullo G Frusciante R Nociti V Tasca G Renna R Iorio R CD8(+) T cells in facioscapulohumeral muscular dystrophy patients with inflammatory features at muscle MRI J Clin Immunol 2011 31 2 155 166 10.1007/s10875-010-9474-6 21063901 \n13. Tasca G Pescatori M Monforte M Mirabella M Iannaccone E Frusciante R Different molecular signatures in magnetic resonance imaging-staged facioscapulohumeral muscular dystrophy muscles PLoS One 2012 7 6 e38779 10.1371/journal.pone.0038779 22719944 \n14. Dahlqvist JR Poulsen NS Ostergaard ST Fornander F de Stricker Borch J Danielsen ER Evaluation of inflammatory lesions over 2 years in facioscapulohumeral muscular dystrophy Neurology. 2020 95 9 e1211 10.1212/WNL.0000000000010155 32611642 \n15. Tawil R McDermott MP Pandya S King W Kissel J Mendell JR A pilot trial of prednisone in facioscapulohumeral muscular dystrophy. FSH-DY group Neurology. 1997 48 1 46 49 10.1212/WNL.48.1.46 9008492 \n16. Castro C Gourley M Diagnosis and treatment of inflammatory myopathy: issues and management Ther Adv Musculoskelet Dis 2012 4 2 111 120 10.1177/1759720X11425092 22870499 \n17. Yao L Yip AL Shrader JA Mesdaghinia S Volochayev R Jansen AV Magnetic resonance measurement of muscle T2, fat-corrected T2 and fat fraction in the assessment of idiopathic inflammatory myopathies Rheumatology (Oxford) 2016 55 3 441 449 10.1093/rheumatology/kev344 26412808 \n18. Ida H Aramaki T Arima K Origuchi T Kawakami A Eguchi K Successful treatment using tacrolimus (FK506) in a patient with TNF receptor-associated periodic syndrome (TRAPS) complicated by monocytic fasciitis Rheumatology (Oxford) 2006 45 9 1171 1173 10.1093/rheumatology/kel178 16801330 \n19. Fedorov A Beichel R Kalpathy-Cramer J Finet J Fillion-Robin JC Pujol S 3D slicer as an image computing platform for the quantitative imaging network Magn Reson Imaging 2012 30 9 1323 1341 10.1016/j.mri.2012.05.001 22770690 \n20. Schulze M Kotter I Ernemann U Fenchel M Tzaribatchev N Claussen CD MRI findings in inflammatory muscle diseases and their noninflammatory mimics AJR Am J Roentgenol 2009 192 6 1708 1716 10.2214/AJR.08.1764 19457839\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1471-2474",
"issue": "22(1)",
"journal": "BMC musculoskeletal disorders",
"keywords": "All neuromuscular disease; Case report; Facioscapulohumeral muscular dystrophy (FSHD); Muscle disease; Outcome measures",
"medline_ta": "BMC Musculoskelet Disord",
"mesh_terms": "D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D018482:Muscle, Skeletal; D020391:Muscular Dystrophy, Facioscapulohumeral; D017063:Outcome Assessment, Health Care; D011241:Prednisone; D016559:Tacrolimus",
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"title": "Adapting MRI as a clinical outcome measure for a facioscapulohumeral muscular dystrophy trial of prednisone and tacrolimus: case report.",
"title_normalized": "adapting mri as a clinical outcome measure for a facioscapulohumeral muscular dystrophy trial of prednisone and tacrolimus case report"
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"abstract": "We describe a 52-year-old man with hypertrophic pachymeningitis (HP) who was both seropositive for antineutrophil cytoplasmatic antibodies (ANCA) against myeloperoxidase, and had an immunoglobulin G4 (IgG4) positive fibroinflammatory response in meningeal biopsy. HP is a chronic inflammatory thickening of the dura mater which typically presents with headache, cranial nerve dysfunction and other neurological deficits. While first-line treatment with corticosteroids is recommended, many patients relapse and need additional immunosuppression. One recently described etiology is IgG4-related disease and in a subgroup of idiopathic patients, evidence suggests a crucial role of ANCA. To our knowledge, the simultaneous occurrence of IgG4-related disease and ANCA has not been reported so far. This man suffered life-threatening disease progression despite the administration of high dose steroids, cyclophosphamide and azathioprine. Treatment with rituximab was initiated which led to disappearance of clinical symptoms and decrease of dural thickening within weeks. This patient presents a possible disease overlap of IgG4-related and ANCA-associated HP and illustrates the effectiveness of rituximab in refractory IgG4-related HP.",
"affiliations": "Department of Neurology, Ruhr University Bochum, University Hospital Knappschaftskrankenhaus Bochum, In der Schornau 23-25, Bochum 44892, Germany. Electronic address: popkirov@gmail.com.;Department of Neurology, Ruhr University Bochum, University Hospital Knappschaftskrankenhaus Bochum, In der Schornau 23-25, Bochum 44892, Germany.;Department of Neurology, Ruhr University Bochum, University Hospital Knappschaftskrankenhaus Bochum, In der Schornau 23-25, Bochum 44892, Germany.;Department of Neurology, Ruhr University Bochum, University Hospital Knappschaftskrankenhaus Bochum, In der Schornau 23-25, Bochum 44892, Germany.",
"authors": "Popkirov|Stoyan|S|;Kowalski|Thomas|T|;Schlegel|Uwe|U|;Skodda|Sabine|S|",
"chemical_list": "D019268:Antibodies, Antineutrophil Cytoplasmic; D007074:Immunoglobulin G; D000069283:Rituximab",
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"journal": "Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia",
"keywords": "Antineutrophil cytoplasmic antibodies; IgG4-related disease; Pachymeningitis; Rituximab",
"medline_ta": "J Clin Neurosci",
"mesh_terms": "D019268:Antibodies, Antineutrophil Cytoplasmic; D001327:Autoimmune Diseases; D006801:Humans; D006984:Hypertrophy; D007074:Immunoglobulin G; D008297:Male; D008581:Meningitis; D008875:Middle Aged; D000069283:Rituximab",
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"title": "Immunoglobulin-G4-related hypertrophic pachymeningitis with antineutrophil cytoplasmatic antibodies effectively treated with rituximab.",
"title_normalized": "immunoglobulin g4 related hypertrophic pachymeningitis with antineutrophil cytoplasmatic antibodies effectively treated with rituximab"
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"abstract": "Treatment options for advanced stage cutaneous T-cell lymphoma (CTCL) are limited by the their efficacy and side-effects profile. Gemcitabine, a pyrimidine analogue, has been reported to be efficacious in CTCL. Most of the studies published used gemcitabine as a single agent in treating advanced CTCL. Our small case series demonstrated that a combination of gemcitabine and vinorelbine induced partial remission in all four patients with refractory or advanced CTCL, although the effects were not sustained for a long duration (2-6 months). Two patients had neutropenia and one had acute hepatitis, requiring discontinuation of treatment.",
"affiliations": "Department of Dermatology, Hospital Kuala Lumpur, Kuala Lumpur, Malaysia.;Department of Dermatology, Westmead Hospital, Sydney, New South Wales, Australia.;Department of Dermatology, Westmead Hospital, Sydney, New South Wales, Australia.;Department of Haematology, Westmead Hospital, Sydney, New South Wales, Australia.;Department of Dermatology, Westmead Hospital, Sydney, New South Wales, Australia.",
"authors": "Affandi|Azura Mohd|AM|;Blumetti|Tatiana Pinto|TP|;Wells|Jillian|J|;Hertzberg|Mark|M|;Fernandez-Peñas|Pablo|P|http://orcid.org/0000-0003-4882-1564",
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"keywords": "cutaneous lymphoma; gemcitabine; vinorelbine",
"medline_ta": "Australas J Dermatol",
"mesh_terms": "D000368:Aged; D000970:Antineoplastic Agents; D000971:Antineoplastic Combined Chemotherapy Protocols; D003841:Deoxycytidine; D005260:Female; D006801:Humans; D016410:Lymphoma, T-Cell, Cutaneous; D008297:Male; D019233:Retreatment; D012878:Skin Neoplasms; D016896:Treatment Outcome; D014747:Vinblastine; D000077235:Vinorelbine",
"nlm_unique_id": "0135232",
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"title": "Gemcitabine and vinorelbine treatment in cutaneous T-cell lymphoma in four patients.",
"title_normalized": "gemcitabine and vinorelbine treatment in cutaneous t cell lymphoma in four patients"
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"abstract": "We aim to describe the clinicohaematological profile of an elderly male with plasmablastic multiple myeloma (MM) (IgG λ, International System Stage II) with an unfavourable outcome following chemotherapy. The serum interleukin-6 level was found to be markedly elevated (2464 pg/mL, reference; <50 pg/mL). Thirty-six months prior to MM diagnosis, he underwent left radical nephrectomy for a stage III (pT3N0M0) clear cell renal cell carcinoma (RCC, Fuhrman grade 2). The unique MM-RCC association, shared risk factors, myeloma pathobiology and clinical implications are discussed with a brief literature review.",
"affiliations": "Department of Pathology, Pondicherry Institute of Medical Sciences, Pondicherry, India.;Department of General Medicine, Pondicherry Institute of Medical Sciences, Pondicherry, India.;Department of Pathology, Pondicherry Institute of Medical Sciences, Pondicherry, India.;Department of Nephrology, Pondicherry Institute of Medical Sciences, Pondicherry, India.",
"authors": "Padhi|Somanath|S|;Mokkappan|Sudhagar|S|;Varghese|Renu G' Boy|RG|;Veerappan|Ilangovan|I|",
"chemical_list": "D015850:Interleukin-6",
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"mesh_terms": "D002292:Carcinoma, Renal Cell; D006801:Humans; D015850:Interleukin-6; D007668:Kidney; D007680:Kidney Neoplasms; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma; D009392:Nephrectomy; D010950:Plasma Cells; D011183:Postoperative Complications; D012307:Risk Factors",
"nlm_unique_id": "101526291",
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"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "24604959;18650185;19810147;21091979;19187270;17970789;17701606;2041555;16536756;8287765;21410373",
"title": "Plasmablastic multiple myeloma following clear cell renal cell carcinoma.",
"title_normalized": "plasmablastic multiple myeloma following clear cell renal cell carcinoma"
} | [
{
"companynumb": "IN-CELGENE-IND-2014104479",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
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"activesubstancename": "LENALIDOMIDE"
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"abstract": "BACKGROUND\nTreatment with nab-paclitaxel plus gemcitabine increases survival in patients with metastatic pancreatic cancer. However, the assessment of treatment efficacy and safety in non-selected patients in a real-life setting may provide useful information to support decision-making processes in routine practice.\n\n\nMETHODS\nRetrospective, multicenter study including patients with metastatic pancreatic cancer, who started first-line treatment with nab-paclitaxel plus gemcitabine between December 2013 and June 2015 according to routine clinical practice. In addition to describing the treatment pattern, overall survival (OS) and progression-free survival (PFS) were assessed for the total sample and the exploratory subgroups based on the treatment and patients' clinical characteristics.\n\n\nRESULTS\nAll 210 eligible patients had a median age of 65.0 years (range 37-81). Metastatic pancreatic adenocarcinoma was recurrent in 46 (21.9%) patients and de novo in 164 (78.1%); 38 (18%) patients had a biliary stent. At baseline, 33 (18.1%) patients had an ECOG performance status ≥2. Patients received a median of four cycles of treatment (range 1-21), with a median duration of 3.5 months; 137 (65.2%) patients had a dose reduction of nab-paclitaxel and/or gemcitabine during treatment, and 33 (17.2%) discontinued treatment due to toxicity. Relative dose intensity (RDI) for nab-paclitaxel, gemcitabine, and the combined treatment was 66.7%. Median OS was 7.2 months (95% CI 6.0-8.5), and median PFS was 5.0 months (95% CI 4.3-5.9); 50 patients achieved either a partial or complete response (ORR 24.6%). OS was influenced by baseline ECOG PS, NLR and CA 19.9, but not by age ≥ 70 years and/or the presence of hepatobiliary stent or RDI < 85%. All included variables, computed as dichotomous, showed a significant contribution to the Cox regression model to build a nomogram for predicting survival in these patients: baseline ECOG 0-1 vs. 2-3 (p = 0.030), baseline NLR > 3 vs. ≤ 3 (p = 0.043), and baseline CA 19.9 > 37 U/mL vs. ≤37 U/mL (p = 0.004).\n\n\nCONCLUSIONS\nNab-Paclitaxel plus gemcitabine remain effective in a real-life setting, despite the high burden of dose reductions and poorer performance of these patients. A nomogram to predict survival using baseline ECOG performance status, NLR and CA 19.9 is proposed.",
"affiliations": "Complejo Hospitalario Universitario Ourense, Calle Ramon Puga Noguerol, 54, 32005, Ourense, Spain. ana.fernandez.montes@sergas.es.;Complejo Universitario Ourense, Ourense, Spain.;Institut Català d'Oncologia (ICO) Hospital Dr. Trueta, Girona, Spain.;Hospital Clínic de Barcelona, Barcelona, Spain.;Complejo Hospitalario de Navarra, Navarra, Spain.;Hospital 12 de Octubre, Madrid, Spain.;Hospital Universitario Central de Asturias, Asturias, Spain.;Hospital Lucus Agustí, Lugo, Spain.;Hospital de Elda, Alicante, Spain.;Hospital Público Lluis Alcanyis de Xátiva, Xátiva, Spain.;Hospital Virgen de la Salud, Toledo, Spain.;Hospital Gregorio Marañón, Madrid, Spain.;Hospital Puerta del Mar, Cadiz, Spain.;Hospital Universitario de Vigo, Vigo, Spain.;Hospital Marqués de Valdecilla, Santander, Spain.;Hospital A Coruña Teresa Herrera, A Coruña, Spain.;Hospital de Pontevedra, Pontevedra, Spain.;Hospital Morales Meseguer, Murcia, Spain.;Hospital de Elche, Elche, Spain.;Hospital Ramón y Cajal, Madrid, Spain.;Hospital Provincial Castellón, Castellón de la Plana, Spain.;Complejo Hospitalario de Jaén, Jaén, Spain.;Hospital del Ferrol, Ferrol, Spain.;Hospital Regional Universitario, Málaga, Spain.;Hospital Miguel Servet, Zaragoza, Spain.;Hospital Morales Meseguer, Murcia, Spain.",
"authors": "Fernández|Ana|A|;Salgado|Mercedes|M|;García|Adelaida|A|;Buxò|Elvira|E|;Vera|Ruth|R|;Adeva|Jorge|J|;Jiménez-Fonseca|Paula|P|;Quintero|Guillermo|G|;Llorca|Cristina|C|;Cañabate|Mamen|M|;López|Luis Jesús|LJ|;Muñoz|Andrés|A|;Ramírez|Patricia|P|;González|Paula|P|;López|Carlos|C|;Reboredo|Margarita|M|;Gallardo|Elena|E|;Sanchez-Cánovas|Manuel|M|;Gallego|Javier|J|;Guillén|Carmen|C|;Ruiz-Miravet|Nuria|N|;Navarro-Pérez|Víctor|V|;De la Cámara|Juan|J|;Alés-Díaz|Inmaculada|I|;Pazo-Cid|Roberto Antonio|RA|;Carmona-Bayonas|Alberto|A|",
"chemical_list": "C520255:130-nm albumin-bound paclitaxel; D000418:Albumins; D003841:Deoxycytidine; C056507:gemcitabine; D017239:Paclitaxel",
"country": "England",
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"doi": "10.1186/s12885-018-5101-3",
"fulltext": "\n==== Front\nBMC CancerBMC CancerBMC Cancer1471-2407BioMed Central London 510110.1186/s12885-018-5101-3Research ArticlePrognostic factors for survival with nab-paclitaxel plus gemcitabine in metastatic pancreatic cancer in real-life practice: the ANICE-PaC study Fernández Ana +34 988 38 55 00ana.fernandez.montes@sergas.es 1Salgado Mercedes mercedes.salgado.fernandez@sergas.es 2García Adelaida agarcia2@iconcologia.net 3Buxò Elvira EBUXO@clinic.cat 4Vera Ruth rveragar@cfnavarra.es 5Adeva Jorge drcofi@hotmail.com 6Jiménez-Fonseca Paula palucaji@hotmail.com 7Quintero Guillermo gquinteroaldana@gmail.com 8Llorca Cristina cllorcaf@yahoo.es 9Cañabate Mamen m.canabate.arias@gmail.com 10López Luis Jesús luisl@sescam.jccm.es 11Muñoz Andrés andresmunmar@hotmail.com 12Ramírez Patricia daffos@yahoo.com 13González Paula paula.gonzalez.villarroel@sergas.es 14López Carlos clopez@humv.es 15Reboredo Margarita margareboredo@hotmail.com 16Gallardo Elena Maria.Elena.Gallardo.Martin@sergas.es 17Sanchez-Cánovas Manuel manuelsanchezcanovas@gmail.com 18Gallego Javier j.gallegoplazas@gmail.com 19Guillén Carmen carmenguillenponce@gmail.com 20Ruiz-Miravet Nuria nuriaruizm@hotmail.com 21Navarro-Pérez Víctor vnavarr1@hotmail.com 22De la Cámara Juan jcamarakq@gmail.com 23Alés-Díaz Inmaculada inales@hotmail.com 24Pazo-Cid Roberto Antonio rpazo@salud.aragon.es 25Carmona-Bayonas Alberto alberto.carmonabayonas@gmail.com 181 Complejo Hospitalario Universitario Ourense, Calle Ramon Puga Noguerol, 54, 32005 Ourense, Spain 2 Complejo Universitario Ourense, Ourense, Spain 3 Institut Català d’Oncologia (ICO) Hospital Dr. Trueta, Girona, Spain 4 0000 0000 9635 9413grid.410458.cHospital Clínic de Barcelona, Barcelona, Spain 5 grid.497559.3Complejo Hospitalario de Navarra, Navarra, Spain 6 0000 0001 1945 5329grid.144756.5Hospital 12 de Octubre, Madrid, Spain 7 0000 0001 2176 9028grid.411052.3Hospital Universitario Central de Asturias, Asturias, Spain 8 Hospital Lucus Agustí, Lugo, Spain 9 Hospital de Elda, Alicante, Spain 10 Hospital Público Lluis Alcanyis de Xátiva, Xátiva, Spain 11 0000 0004 1795 0563grid.413514.6Hospital Virgen de la Salud, Toledo, Spain 12 0000 0001 0277 7938grid.410526.4Hospital Gregorio Marañón, Madrid, Spain 13 0000 0004 1771 1175grid.411342.1Hospital Puerta del Mar, Cadiz, Spain 14 0000 0001 2097 6738grid.6312.6Hospital Universitario de Vigo, Vigo, Spain 15 0000 0001 0627 4262grid.411325.0Hospital Marqués de Valdecilla, Santander, Spain 16 Hospital A Coruña Teresa Herrera, A Coruña, Spain 17 Hospital de Pontevedra, Pontevedra, Spain 18 0000 0004 1765 5898grid.411101.4Hospital Morales Meseguer, Murcia, Spain 19 Hospital de Elche, Elche, Spain 20 0000 0000 9248 5770grid.411347.4Hospital Ramón y Cajal, Madrid, Spain 21 0000 0004 1770 9948grid.452472.2Hospital Provincial Castellón, Castellón de la Plana, Spain 22 0000 0004 1771 208Xgrid.418878.aComplejo Hospitalario de Jaén, Jaén, Spain 23 Hospital del Ferrol, Ferrol, Spain 24 grid.411457.2Hospital Regional Universitario, Málaga, Spain 25 0000 0000 9854 2756grid.411106.3Hospital Miguel Servet, Zaragoza, Spain 29 11 2018 29 11 2018 2018 18 118520 9 2018 16 11 2018 © The Author(s). 2018Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nTreatment with nab-paclitaxel plus gemcitabine increases survival in patients with metastatic pancreatic cancer. However, the assessment of treatment efficacy and safety in non-selected patients in a real-life setting may provide useful information to support decision-making processes in routine practice.\n\nMethods\nRetrospective, multicenter study including patients with metastatic pancreatic cancer, who started first-line treatment with nab-paclitaxel plus gemcitabine between December 2013 and June 2015 according to routine clinical practice. In addition to describing the treatment pattern, overall survival (OS) and progression-free survival (PFS) were assessed for the total sample and the exploratory subgroups based on the treatment and patients’ clinical characteristics.\n\nResults\nAll 210 eligible patients had a median age of 65.0 years (range 37–81). Metastatic pancreatic adenocarcinoma was recurrent in 46 (21.9%) patients and de novo in 164 (78.1%); 38 (18%) patients had a biliary stent. At baseline, 33 (18.1%) patients had an ECOG performance status ≥2. Patients received a median of four cycles of treatment (range 1–21), with a median duration of 3.5 months; 137 (65.2%) patients had a dose reduction of nab-paclitaxel and/or gemcitabine during treatment, and 33 (17.2%) discontinued treatment due to toxicity. Relative dose intensity (RDI) for nab-paclitaxel, gemcitabine, and the combined treatment was 66.7%. Median OS was 7.2 months (95% CI 6.0–8.5), and median PFS was 5.0 months (95% CI 4.3–5.9); 50 patients achieved either a partial or complete response (ORR 24.6%). OS was influenced by baseline ECOG PS, NLR and CA 19.9, but not by age ≥ 70 years and/or the presence of hepatobiliary stent or RDI < 85%. All included variables, computed as dichotomous, showed a significant contribution to the Cox regression model to build a nomogram for predicting survival in these patients: baseline ECOG 0–1 vs. 2–3 (p = 0.030), baseline NLR > 3 vs. ≤ 3 (p = 0.043), and baseline CA 19.9 > 37 U/mL vs. ≤37 U/mL (p = 0.004).\n\nConclusions\nNab-Paclitaxel plus gemcitabine remain effective in a real-life setting, despite the high burden of dose reductions and poorer performance of these patients. A nomogram to predict survival using baseline ECOG performance status, NLR and CA 19.9 is proposed.\n\nKeywords\nMetastatic pancreatic adenocarcinomaGemcitabineNab-paclitaxelReal-lifeFirst-line chemotherapySurvivalGalician Group for Research on Gastrointestinal Tumors (GITuD)http://dx.doi.org/10.13039/100006436Celgeneissue-copyright-statement© The Author(s) 2018\n==== Body\nBackground\nPancreatic adenocarcinoma, the most common form of pancreatic cancer, is currently the fourth cause of cancer-related mortality in Europe and the United States, with a 5-year survival rate in the range of 6–10% [1–4]. This has been attributed, among other causes, to the premature vascular, lymphatic and perineural spread of these tumors, which makes that 85% of patients present disseminated disease at diagnosis. Only between 15 and 20% of tumors are resectable and, within these, 50 to 86% will experience local failure despite curative resection, with a resulting 5-year survival rate of 10–20% [5].\n\nGemcitabine has been the standard first-line treatment for advanced pancreatic cancer for 15 years, and it is associated with median overall survivals (OS) ranging from 5.6 to 6.8 months [6]. Its combination with a wide range of other agents such as capecitabine, oxaliplatin, cisplatin, irinotecan, and erlotinib has unfortunately shown little impact on survival in this population [6, 7]. Nonetheless, two combination regimens, FOLFIRINOX (folinic acid, fluorouracil, irinotecan, oxaliplatin) and more recently, nab-paclitaxel plus gemcitabine, have been associated with a median OS of 11.1 months and 8.5 months in the ACCORD4/PRODIGE11 and MPACT phase III clinical trials, respectively [8, 9]. These encouraging results have set a new standard and international guidelines now recommend FOLFIRINOX and nab-paclitaxel plus gemcitabine as first-line treatments in patients with metastatic pancreatic cancer [10, 11].\n\nA questionnaire-based study showed that clinicians are likely to adhere to the selection criteria of these trials, being the patient’s performance status one of the most influential factors in the decision-making process in the real-life setting [12]. As randomized trials have strict selection criteria, particularly regarding performance status and age [8, 9], reported data might not capture the scenario faced in the real-life setting, with non-selected patients. A prospective registry-based study showed that fewer than half of the patients treated in routine clinical practice would have been eligible for the PRODIGE or MPACT trials and that meeting the eligibility criteria for either trial is associated with longer survival [13].\n\nClinicians are increasingly interested in obtaining real-life data from daily practice, which completes the clinical picture of randomized trials. As such, observational trials can provide useful information for clinicians to support decision-making processes in their routine practice, especially when treating patient groups underrepresented in clinical trials, as are elderly patients and those with poorer performance status [14, 15]. In line with this unmet need, Ellenrieder et al. highlighted the importance of real-life data regarding first-line regimens in metastatic pancreatic cancer to select the most suitable treatment for each patient [7]. The aim of the ANICE study was to assess the effectiveness and tolerability of gemcitabine and nab-paclitaxel as first-line therapy for metastatic pancreatic cancer in a real-life setting.\n\nMethods\nStudy design and patients\nThe ANICE trial was an observational, retrospective, multicenter study focused on patients with metastatic pancreatic adenocarcinoma (recurrent or de novo) treated according to routine clinical practice at 20 Spanish hospitals between December 2013 and June 2015. All adult patients (≥ 18 years) with measurable metastatic disease at baseline in at least one dimension (per Response Evaluation Criteria in Solid Tumors [RECIST], version 1.1, [16]) who received at least one dose of nab-paclitaxel (Abraxane®, Celgene Europe Limited) plus gemcitabine as first-line chemotherapy were included. Data were obtained from clinical medical records with a cut-off date of 16 March 2017. All patients provided written informed consent. The study protocol was approved by the local independent ethics committee, and was conducted in accordance with the Spanish personal data protection law (LOPD 15/1999).\n\nVariables and endpoints\nVariables collected from the patient’s medical records included demographic data (sex and age), clinical data, characteristics of the metastatic disease and treatment. Among the registered clinical and disease characteristics were performance status (PS) (ECOG and Karnofsky scales), relevant comorbidities, initial diagnosis, number and localization of metastases, time between diagnosis of the primary tumor and recurrence, presence of a hepatobiliary stent, serum bilirubin, neutrophil/lymphocyte ratio (NLR), and CA 19.9 antigen levels. Treatment characteristics included concomitant treatments, relative dose intensity (RDI) for nab-paclitaxel plus gemcitabine (i.e., per the summary of product characteristics), treatment duration, cause of treatment discontinuation, number of cycles, and dose reductions and interruptions. Decisions regarding the initial dose and subsequent dose reductions were made at physicians’ discretion, based on patient’s PS and toxicity, and following the routine practice of each participating sit.\n\nThe primary objective was to describe the treatment pattern in terms of extent of exposure and reductions of treatment with nab-paclitaxel plus gemcitabine in real-life clinical practice. Secondary objectives included objective response rate (ORR), progression-free survival (PFS) defined as the time from the start of treatment to disease progression or all-cause death, overall survival (OS) defined as the time from the start of treatment to death from any cause, and the 12-month survival rate defined as the percentage of patients alive at 12 months after starting treatment. Safety was assessed in terms of adverse events (AE), coded according to the preferred term of the Medical Dictionary for Regulatory Activities (MedDRA), and graded according to the National Cancer Institute-Common Toxicity Criteria (version 4.0) [17].\n\nStatistical analyses\nGiven the descriptive nature of the statistical analyses, the sample size was calculated based on the confidence interval (CI) of the 12-month survival rate. Considering the 12-month survival rate previously reported by Goldstein et al. [18], and assuming that nearly 20% of patients present with recurrent metastatic cancer, a sample of 225 patients was deemed necessary to estimate a 12-month survival rate of 30% with a ± 6% precision and a 95% CI.\n\nCategorical variables were summarized as frequencies and percentages, and quantitative variables as the mean and standard deviation (SD) and/or median and interquartile range (IQR). The quantitative variables NLR and CA 19.9 were transformed into dichotomous variables with the cut-offs values of 3 and 37 U/mL, respectively. Categorical values were compared using the Fisher’s exact test or the chi-square test when the requirements for a Fisher’s exact test could not be assumed. Quantitative values were compared using the T-test, ANOVA test, and their non-parametric counterparts, the Wilcoxon and Kruskal-Wallis tests. OS and PFS curves were plotted using the Kaplan-Meier estimate, and compared according to selected parameters using the Log-rank test and the Cox regression model. The significance threshold for all bivariate analyses was set at a two-sided α = 0.05. All factors showing a significant influence on OS in the bivariate analysis were included in a Cox regression model as dichotomous variables to build a nomogram for predicting OS in real-life practice. The obtained hazard ratios (HR) were used to associate each variable with a survival score. In addition to the predicted survival, a probability for 3-, 6-, 12, and 18-month survival was estimated. Based on the range of final scores resulting from the possible combinations of variables, low-, medium-, and high-risk groups were defined. All analyses were performed using the statistical package SAS system for Windows version 9.4.\n\nResults\nPatient characteristics\nOf the 216 patients recruited, 6 were excluded for one or more of the following reasons: not initiating combined treatment with gemcitabine plus nab-paclitaxel (n = 4), absence of measurable disease at baseline per RECIST (n = 2), and being enrolled in a clinical trial (n = 1). Table 1 summarizes the demographic and clinical characteristics of study patients. The 210 eligible patients had a median age of 65.0 years (range 37–81). Metastatic pancreatic adenocarcinoma was recurrent in 46 (21.9%) patients and de novo in 164 (78.1%). For patients with recurrent metastatic disease, the primary tumor was resectable in 38 cases (82.6%), borderline in 3 (6.5%), and locally advanced unresectable in 5 (10.9%), and median time to recurrence was 11.0 months. Assessment of eligibility for the MPACT and ACCORD4/PRODIGE11 trials could be assessed in 78 (37.1%) and 172 (81.9%) patients, respectively, with 37 meeting the criteria for entering the MPACT trial and 109 the ACCORD4/PRODIGE11 trial.Table 1 Demographic and clinical characteristics of study patients\n\n\tNumbera\tOverall\tRecurrent\tDe novo\t\nDemographic characteristics\t\n Age, n (%)\t210\t\t\t\t\n < 65 years\t\t99 (47.1%)\t22 (47.8%)\t77 (47.0%)\t\n 65–69 years\t\t58 (27.6%)\t8 (17.4%)\t50 (30.5%)\t\n ≥ 70 years\t\t53 (25.2%)\t16 (34.8%)\t37 (22.6%)\t\n Sex, n (%)\t210\t\t\t\t\n Males\t\t127 (60.5)\t33 (71.7)\t94 (57.3)\t\n Females\t\t83 (39.5)\t13 (28.3)\t70 (42.7)\t\nClinical characteristics\t\n Weight loss > 10%, n (%)\t208\t81 (38.9)\t9 (20.5)\t72 (43.9)\t\n ECOG PS, n (%)\t182\t\t\t\t\n 0–1\t\t149 (81.9)\t28 (77.8)\t121 (82.9)\t\n 2–3\t\t33 (18.1)\t8 (22.2)\t25 (17.1)\t\n Karnofsky PS, n (%)\t55\t\t\t\t\n < 70\t\t3 (5.5)\t–\t3 (6.8)\t\n 70–80\t\t33 (60.0)\t7 (63.6%)\t26 (59.1%)\t\n 90–100\t\t19 (34.5)\t4 (36.4%)\t15 (34.1%)\t\n Common comorbidities, n (%)\t210\t\t\t\t\n Hypertension\t\t56 (26.7)\t8 (17.4)\t48 (29.3)\t\n Diabetes\t\t26 (12.4)\t4 (8.7)\t22 (13.4)\t\n Dyslipemia\t\t29 (13.8)\t6 (13.0)\t22 (13.4)\t\n Hepatobiliary stent, n (%)\t209\t38 (18.2)\t3 (6.5)\t35 (21.5)\t\n Platelet count, median (IR)\t178\t231.0 (172.0, 318.0)\t207.0 (170.0, 303.0)\t237.0 (181.0, 318.0)\t\n Bilirubin (mg/dL), median (IR)\t175\t0.70 (0.50, 1.00)\t0.57 (0.50, 0.80)\t0.79 (0.50, 1.10)\t\n NLR, n (%)\t170\t\t\t\t\n > 3\t\t91 (53.5)\t18 (52.9)\t73 (53.7)\t\n ≤ 3\t\t79 (46.5)\t16 (47.1)\t63 (46.3)\t\n CA 19.9, n (%)\t173\t\t\t\t\n > 37 U/mL\t\t142 (82.1)\t32 (82.1)\t110 (82.1)\t\n ≤ 37 U/mL\t\t31 (17.9)\t7 (17.9)\t24 (17.9)\t\n Number of metastatic sites, n (%)\t210\t\t\t\t\n 1–3\t\t205 (97.6)\t46 (100.0)\t159 (97.0)\t\n > 3\t\t5 (2.4)\t\t5 (3.0)\t\n Concommitant treatment, n (%)\t210\t\t\t\t\n Analgesics\t\t76 (36.2)\t12 (26.1)\t63 (38.4)\t\n Corticosteroids\t\t25 (11.9)\t4 (8.7)\t20 (12.2)\t\nIR Interquartile range (percentile 25, percentile 75)\n\nanumber of evaluable patients (no-missing)\n\n\n\nTreatment characteristics and outcome\nTable 2 summarizes treatment characteristics. Median time from diagnosis to treatment start was 28 days. Patients received a median of 4 cycles (range 1–21) of treatment, with a median treatment duration of 3.5 months. Sixty-eight patients (32%) started treatment with dose reduction for either nab-paclitaxel, gemcitabine or both drugs. Table 3 summarizes the baseline characteristics of the 68 patients with dose reduction and treatment start. The median RDIs were 66.7% for nab-paclitaxel, gemcitabine, and the combined treatment. Overall, 137 patients (65.2%) had a dose reduction in nab-paclitaxel and/or gemcitabine during treatment. Thirty-four (17%) patients received ≤30 days of treatment, mainly due to toxicity (n = 11) or disease progression (n = 10). There were no significant differences between patients receiving ≤30 days of treatment and those receiving > 30 days in terms of baseline clinical characteristics including performance status, the presence of a hepatobiliary stent, NLR, CA 19.9 and bilirubin levels, or weight loss of more than 10%.Table 2 Treatment characteristics\n\n\tNo. (%)\t\nStarted treatment with dose reduction, n (%)\t\n Only gemcitabine\t1 (0.5)\t\n Only nab-Paclitaxel\t41 (19.5)\t\n Both\t26 (12.4)\t\nDose reduction during treatment, n (%)\t\n Nab-Paclitaxel\t91 (43.3)\t\n Gemcitabine\t75 (35.7)\t\n Either of the two drugs\t96 (45.7)\t\nReceived ≤30 days of treatment, n (%)\t34 (16.5)\t\nReasons for treatment discontinuationa, n (%)\t\n Progression\t134 (69.8)\t\n Toxicity\t33 (17.2)\t\n Death\t24 (12.5)\t\n Patient’s request\t7 (3.6)\t\naA patient could have more than one reason for treatment discontinuation\n\nTable 3 Demographic and clinical characteristics of patients who started treatment with dose reduction\n\nDemographic characteristics\t\n Age, n (%)\t(n = 68)\t\t\n < 65 years\t\t33 (48.5%)\t\n 65–79 years\t\t14 (20.6%)\t\n ≥ 70 years\t\t21 (30.9%)\t\n Sex, n (%)\t(n = 68)\t\t\n Males\t\t41 (60.3%)\t\n Females\t\t27 (39.7%)\t\nClinical characteristics\t\n Weight loss > 10%, n (%)\t(n = 66)\t18 (27.3%)\t\n ECOG PS, n (%)\t(n = 62)\t\t\n 0–1\t\t46 (74.2%)\t\n 2-Mar\t\t16 (25.8%)\t\n Karnofsky PS, n (%)\t(n = 23)\t\t\n < 70\t\t–\t\n 70–80\t\t13 (56.5%)\t\n 90–100\t\t10 (43.5%)\t\n Common comorbidities, n (%)\t(n = 68)\t\t\n Hypertension\t\t15 (22.1%)\t\n Diabetes\t\t8 (11.8%)\t\n Dyslipemia\t\t4 (5.9%)\t\n Hepatobiliary stent, n (%)\t(n = 68)\t10 (14.7%)\t\n Platelet count, median (IR)\t(n = 57)\t252.0 (172.0, 339.0)\t\n Bilirubin (mg/dL), median (IR)\t(n = 58)\t0.70 (0.51, 1.10)\t\n NLR, n (%)\t(n = 55)\t\t\n > 3\t\t29 (52.7%)\t\n ≤ 3\t\t26 (47.3%)\t\n CA 19.9, n (%)\t(n = 62)\t\t\n > 35\t\t52 (83.9%)\t\n ≤ 35\t\t10 (16.1%)\t\n Number of metastatic sites, n (%)\t(n = 68)\t\t\n 1–3\t\t67 (98.5%)\t\n > 3\t\t1 (1.5%)\t\n Concommitant treatment, n (%)\t(n = 68)\t\t\n Analgesics\t\t22 (32.4%)\t\n Corticosteroids\t\t9 (13.2%)\t\nIR Interquartile range (percentile 25, percentile 75)\n\nanumber of evaluable patients (no-missing)\n\n\n\nAt the time of data collection, median follow-up was 7.2 months (IQR 3.5–13.3). A total of 193 patients (91.9%) had died, with a 12-month survival rate of 30.1%. Median OS was 7.2 months (95% CI 6.0–8.5), and median PFS 5.0 months (95%CI 4.3–5.9). Among 203 patients eligible for response, 50 patients achieved either a partial or complete response (ORR 24.6%), and 72 patients (35.5%) a stable disease. Ninety-seven patients (46.9%) received further treatment lines, most of whom (n = 63, 64.9%) had one or two lines of treatment (n = 25, 25.8%).\n\nSafety\nGrade ≥ 3 treatment-related AEs were reported in 78 patients (37.1%), the most common being neutropenia, thrombocytopenia, and fatigue (Table 4). One treatment-related event of paralytic ileus led to treatment interruption and death.Table 4 Common treatment-related adverse events (> 1% of patients overall) of grade 3. No. (%)\n\n\tOverall\n(n = 210)\t< 70 years\n(n = 157)\t≥ 70 years\n(n = 53)\t\nHematological toxicities\t\n Neutropenia\t38 (18.1)\t33 (21.0)\t5 (9.4)\t\n Thrombocytopenia\t13 (6.2)\t9 (5.7)\t4 (7.5)\t\n Anemia\t7 (3.3)\t2 (1.3)\t5 (9.4)\t\n Febrile neutropenia\t4 (1.9)\t2 (1.3)\t2 (3.8)\t\nNon-hematological toxicities\t\n Fatigue\t13 (6.2)\t10 (6.4)\t3 (5.7)\t\n Vomiting\t3 (1.4)\t1 (0.6)\t2 (3.8)\t\n Colangitis\t3 (1.4)\t3 (1.9)\t–\t\n Neurotoxicity\t3 (1.4)\t1 (0.6)\t2 (3.8)\t\n Peripheral neuropathy\t5 (2.4)\t3 (1.9)\t2 (3.8)\t\n Alopecia\t9 (4.3)\t6 (3.8)\t3 (5.7)\t\n\n\nPatients aged < 70 years received a median of 5 cycles of combined treatment and patients aged ≥70 years received a median of 3. Of 53 elderly patients (i.e., aged ≥70 years), 38 (71.7%) experienced at least one treatment-related AE, compared to 78.1% in the overall population, with similar profile of grade ≥ 3 events (Table 4). No significant differences were found in the frequency of treatment-related AEs of grade 3 or higher between patients aged ≥70 years and < 70 (39.6% vs. 36.3%; p = 0.789).\n\nPrognostic factors\nAnalysis of the influence of baseline characteristics on survival showed that only ECOG, NLR, and CA 19.9 significantly influenced OS, PFS (Fig. 1), and/or 12-month survival. Baseline CA 19.9 had a significant influence on the three analyzed outcomes: patients with CA 19.9 ≤ 37 U/mL had longer OS (p = 0.004) (Fig. 1e), PFS (p = 0.011) (Fig. 1f), and a higher 12-month survival rate (45.2% vs. 24.8%; p = 0.030). On the other hand, patients with baseline NLR ≤ 3 had longer OS (p = 0.024) (Fig. 1c) and a higher 12-month survival rate than those with NLR > 3 (38% vs. 23.3%; p = 0.045) but showed similar PFS (Fig. 1d). Patients with a baseline ECOG PS of 0 or 1 had longer OS than those with an ECOG PS of 2 or 3 (p = 0.018) (Fig. 1a), although this trend was not observed in PFS (Fig. 1b). Likewise, the 12-month survival for patients with ECOG PS 0 or 1 and 2 or 3 was 31.1 and 21.2%, respectively (p = 0.297). Patients with stable ECOG (n = 68) or ECOG improvement (n = 22) during the first three treatment cycles had longer OS than those with a worsening ECOG (n = 19), with a median OS of 12.9 months (95% CI 6.7–15.4), 10.6 months (95% CI 8.1–13.3), and 7.1 months (95% CI 4.7–9.2) for ECOG improvement, stable, and worsening, respectively (p = 0.020).Fig. 1 Overall survival (a, c and e) and progression-free survival (b, d and f) depending on baseline ECOG (a and b), NLR (c and d) and CA 19.9 (e and f). Survival is presented as median (95% CI); p-values correspond to the Log-rank test for inter-curve differences\n\n\n\nNeither age ≥ 70 years, the presence of an hepatobiliary stent, nor an RDI of gemcitabine plus nab-paclitaxel < 85% showed a significant influence on median PFS and OS at 12 months (Fig. 2). The 12-month survival rate was 28.3 and 30.8% for patients aged ≥70 and < 70 years, respectively (p = 0.863); 36.8 and 28.8% for patients with and without hepatobiliary stent, respectively (p = 0.335); and 28.0 and 31.5% for patients with RDI of the combined treatment ≥85 and < 85%, respectively (p = 0.645).Fig. 2 Overall survival (a, c and e) and progression-free survival (b, d and f) depending on baseline age (a and b), presence of hepatobiliary stent (c and d), and relative dose intensity (RDI) (e and f). Survival is presented as median (95% CI); p-values correspond to the Log-rank test for inter-curve differences\n\n\n\nFactors significantly influencing OS (ECOG PS, NLR, and CA 19.9) were used to build a nomogram to predict survival of patients with pancreatic adenocarcinoma treated in the real-life setting (Fig. 3a). All included variables, computed as dichotomous, showed a significant contribution to the Cox regression model: baseline ECOG PS 0 or 1 vs 2 or 3 (p = 0.030), baseline NLR > 3 vs ≤ 3 (p = 0.043), and baseline CA 19.9 > 37 U/mL vs ≤ 37 U/mL (p = 0.004) (Fig. 3a). Based on the scale obtained with the nomogram, three risk groups were defined: low-risk group (n = 21, 15.1%), medium-risk group (n = 93, 66.9%), and high-risk group (n = 25, 18.0%). Figure 3b shows the survival curves (Kaplan-Meier estimates for these groups).Fig. 3 Survival estimate of patients with metastatic pancreatic cancer starting combined treatment with nab-paclitaxel plus gemcitabine in real-life practice. a Nomogram for predicting overall survival and the probability of 3-month, 6-month, 12-month in real-life practice. b Survival (Kaplan Meier estimate) for low-, medium-, and high-risk groups\n\n\n\nDiscussion\nIn this observational retrospective study including all the patients with metastatic pancreatic cancer treated at the participating centers with first-line nab-paclitaxel plus gemcitabine in a real-life setting, 25% of patients were aged 70 years or more and 18% had a baseline ECOG score of 2 or 3. Furthermore, 32% of patients started combined treatment with a dose reduction of nab-paclitaxel, and 17% of patients discontinued treatment within 30 days of treatment, 33% of them due toxicity. Despite the poor baseline characteristics in our cohort, median OS and PFS were of 7.2 months (95% CI 6.0, 8.5) and 5.0 months (4.3, 5.9), respectively, indicating that this combination is effective in the real-life setting. OS was influenced by the baseline ECOG PS, NLR, and CA 19.9, but not by age ≥ 70 years, the presence of hepatobiliary stent or RDI < 85%.\n\nRandomized controlled trials investigating therapies for metastatic pancreatic cancer have restrictive selection criteria, particularly regarding the patient’s age and performance status [8, 9]. In the case of the pivotal study of the combined treatment (MPACT trial), a Karnofsky index of 70 or more was required [9]. In Spain the preferred scale to assess the performance status in most centers is the ECOG score, thus, in our study, the Karnofsky index could only be assessed in a limited number of patients. However, although the Karnofsky index and the ECOG score lack a linear relationship for direct comparisons between study populations, the fact that 18% of patients had ECOG ≥2 (roughly ≥70 in the Karnofsky index) indicates a trend towards a poorer average performance status in our study population than those in the pivotal MPACT trial. In the case of the ACCORD4/PRODIGE11 study, recruitment was limited to patients under 76 years with ECOG performance status ≤1; [8] based on these criteria alone, nearly 40% of our study patients would have been excluded. In addition to the patients’ baseline characteristics, treatment patterns in real-life practice often differ from those used in pivotal trials. In our study, 66.2% of patients had a dose reduction in either nab-paclitaxel and/or gemcitabine. Overall, the median RDI was 67% for both nab-paclitaxel and gemcitabine, which is well below those reported in the MPACT trial (81 and 75% for nab-paclitaxel and gemcitabine, respectively). Thus, the demographic, clinical and treatment characteristics of this large cohort of real-life patients underscore fundamental differences between RCTs and routine practice settings.\n\nDespite the inclusion of elderly patients, the trend towards a poorer performance status, and adjusted treatment schedule in our study, our results confirmed the effectiveness of combined treatment with gemcitabine plus nab-paclitaxel in the real-life setting. The estimated median OS (7.2 months) was slightly lower than that observed in the MPACT trial (8.5 months) and those reported by Giordano et al. (11 months), Lo Re et al. (9.2 months), and De Vita et al. (10 months) in three series of 118, 37, and 41 real-life patients, respectively [19–21]. Likewise, the median PFS of our cohort (5.0 months) was comparable to that reported in the MPACT trial (5.5 months), but lower than that reported by Giordano et al. (7 months), Lo Re et al. (6.2 months), and of notably Da Vitta et al. (9.2 months). Of note, patients of our cohort had poorer PS than that reported in these studies.\n\nAs reported in previous studies, neutropenia was the most common treatment-related adverse event of grade 3 or higher, however its 18% incidence was substantially below that reported in the MPACT trial (38%) [9] and slightly lower than in previous series of real-life patients (20 to 24%) [14, 19, 20]. Remarkably, being aged over 70 years was not associated with a worse toxicity profile in our study, consistent with the trend reported by Giordano et al. in a retrospective study addressing the safety of this treatment in the elderly [14].\n\nIn addition to assessing the safety and effectiveness of first-line nab-paclitaxel plus gemcitabine in real-life patients, we also analyzed prognostic factors and their influence on survival in this setting. The influence of the patient’s performance status has been consistently reported by various authors. [18, 19, 21, 22] As in previous analyses of real-life patients, [19, 21] stratifying patients according to the baseline ECOG score of 0–1 or > 1, shows an influence of ECOG on OS. Similarly, the inflammation-based NLR score, identified as a prognostic factor for OS and PFS in patients receiving nab-paclitaxel plus gemcitabine in pivotal studies [18] and real-life practice [20, 21, 23], influenced OS in our patients but did not reach the significance threshold in the PFS analysis. In both localized and metastatic pancreatic adenocarcinoma, a proinflammatory status of the tumor results in worse prognosis, and therefore, influences treatment response and consequently, survival. Finally, the antigen CA 19.9 significantly influenced both OS and PFS with a cut-off of 37 U/mL. Other factors, such as age, the presence of a hepatobiliary stent, and the RDI did not significantly influence either OS or PFS. This finding is particularly controversial for age, which has been identified as a major prognostic factor for all patients with metastatic pancreatic cancer [22], and was subsequently confirmed for patients treated specifically with gemcitabine plus nab-paclitaxel [18]. It is worth noting that the cut-off age considered as a prognostic factor is not homogeneous across studies, and while risk analyses were traditionally based on patients over 60 or 65 years [18, 22], there is increasing interest in investigating patients over 70 years as a risk group in real-life practice [14, 24].\n\nThe prognostic factors identified in our cohort (i.e., ECOG PF, NLR, and CA 19.9) allowed us to develop a nomogram for predicting survival of real-life patients treated with first-line nab-paclitaxel plus gemcitabine. A similar tool for predicting survival in real-life patients receiving gemcitabine-based chemotherapy was presented by Hamada et al., and included age, sex, PS, tumor size, and the presence of nodal or distant metastases [25]. As in their analysis, PS carried a notable weight in our nomogram, with patients having an ECOG score of 2 or more dramatically reducing the predicted survival. On the other hand, variables not routinely assessed in standard practice, such as tumor size were not considered. In addition to the nomogram by Hamada et al., Goldstein et al. presented a similar tool based on the cohort of the MPACT trial [26]. The nomogram by Goldstein et al. was similar to ours in terms of the inclusion of performance status and NLR, but included other variables such as albumin, tumor size, and the presence of liver metastasis. Future studies shall validate the proposed nomogram as a tool for predicting survival in real-life patients.\n\nOur results should be interpreted in the context of the intrinsic limitations of retrospective studies. Thus, in addition to the risk of reporting bias associated with observational designs, missing data in the medical records could not be considered for the analysis, leading uneven sample sizes across analyses. The retrospective design also precluded the inclusion of variables not recorded in routine clinical practice in Spain, notably the Karnofsky index, which was reported in very few patients and prevented a direct comparison with the study sample of the pivotal trial MPACT. Another limitation of the retrospective design was the lack of pre-defined criteria for dose reductions, which were established at physician’s discretion, according to the routine practice in each center. Finally, the reduced size of some patient subgroups in the comparative analyses limited the investigation of baseline factors with potential influence on patient survival.\n\nConclusions\nOur results, obtained from the largest published series of real-world patients with metastatic pancreatic cancer, show that nab-paclitaxel plus gemcitabine remains effective in this setting, despite the high burden of dose reductions and the poorer performance of these patients. Based on the exploratory analysis of prognostic factors, a nomogram was developed to predict survival of patients starting treatment with the combination. It was based on three variables routinely assessed in real-life practice, ECOG performance status, NLR, and CA 19.9.\n\nAbbreviations\nAEAdverse events\n\nCIConfidence interval\n\nHRHazard ratio\n\nIQRInterquartile range\n\nNLRNeutrophil lymphocyte rate\n\nORRObjective response rate\n\nOSOverall survival\n\nPFSProgression-free survival\n\nPSPerformance status\n\nRDIRelative dose intensity\n\nRECISTResponse Evaluation Criteria in Solid Tumors\n\nAcknowledgements\nThe authors would like to thank the Galician Group for Research on Gastrointestinal Tumors (GITuD), as well as all study patients and their relatives. Statistical and medical writing support were provided by Josep Puig and Gerard Carot-Sans (PhD) on behalf of BioClever S.L.\n\nFunding\nThe study coordination, data analysis, and medical writing assistance were supported by the non-profit Galician Group for Research on Gastrointestinal Tumors (GITuD) with funding from Celgene Corporation. The funding body was not directly involved in the study design, data analysis, and manuscript writing, which were performed by either the authors or the contract research organization BioClever, S.L. as stated in the acknowledgements section.\n\nAvailability of data and materials\nThe datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.\n\nAuthors’ contributions\nAF and MS significantly contributed to the study design. AF, AG, EB, RV, JA, PJ, GQ, CLl, MC, LJL, AM, PR, PG, CLó, MR, EG, MSC, AC, JG, CG, NR, VN, JC, IA, RAP, and AC contributed to data collection, and AF, AG, PJ, and AC analyzed and interpreted the results. The manuscript was drafted by AF, AG, JA, PJ, and AC. AF, MS, AG, EB, RV, JA, PJ, GQ, CLl, MC, LJL, AM, PR, PG, CLó, MR, EG, MSC, JG, CG, NR, VN, JC, IA, RAP, and AC revised the manuscript drafts critically and approved the final version of the manuscript.\n\nEthics approval and consent to participate\nThe study was approved by the ethics committee of the autonomous community of Galicia (SERGAS) (Spain). All patients provided written informed consent before data collection.\n\nConsent for publication\nNot applicable.\n\nCompeting interests\nAG has received a grant for attending an international oncology congress and fees as scientific consultant from Celgene. AM has received research support grants and fees as consultant from Celgene, and fees as speaker from Shire. CL2 has received fees as speaker and consultant from Celgene. AF, MS, EB, RV, JA, PJ, GQ, CL1, LJL, PR, PG, MR, EG, MSC, AC, JG, CG, NR, VN, JC, IA, RAP declare that they have no conflicts of interest regarding the content of this manuscript.\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. Siegel RL Miller KD Jemal A Cancer statistics, 2015 CA Cancer J Clin 2015 65 1 5 29 10.3322/caac.21254 25559415 \n2. De Angelis R Sant M Coleman MP Francisci S Baili P Pierannunzio D Cancer survival in Europe 1999–2007 by country and age: results of EUROCARE-5—a population-based study Lancet Oncol 2014 15 1 23 34 10.1016/S1470-2045(13)70546-1 24314615 \n3. Bouvier Anne-Marie Bossard Nadine Colonna Marc Garcia-Velasco Adelaida Carulla Maria Manfredi Sylvain Trends in net survival from pancreatic cancer in six European Latin countries European Journal of Cancer Prevention 2017 26 S63 S69 10.1097/CEJ.0000000000000303 28005607 \n4. Malvezzi M Carioli G Bertuccio P Boffetta P Levi F La Vecchia C European cancer mortality predictions for the year 2018 with focus on colorectal cancer Ann Oncol Off J Eur Soc Med Oncol 2018 29 4 1016 1022 10.1093/annonc/mdy033 \n5. De Felice F Musio D Raffetto N Tombolini V Neoadjuvant strategy as initial treatment in resectable pancreatic cancer: concrete evidence of benefit Anticancer Res 2014 34 9 4673 4676 25202043 \n6. Conroy T Bachet J-BB Ayav A Huguet F Lambert A Caramella C Current standards and new innovative approaches for treatment of pancreatic cancer Eur J Cancer 2016 57 10 22 10.1016/j.ejca.2015.12.026 26851397 \n7. Ellenrieder V König A Seufferlein T Konig A Seufferlein T Current standard and future perspectives in first- and second-line treatment of metastatic pancreatic adenocarcinoma Digestion 2016 94 1 44 49 10.1159/000447739 27438590 \n8. Conroy T Desseigne F Ychou M Bouché O Guimbaud R Bécouarn Y FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer N Engl J Med 2011 364 19 1817 1825 10.1056/NEJMoa1011923 21561347 \n9. Von Hoff DD Ervin T Arena FP Chiorean EG Infante J Moore M Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine N Engl J Med 2013 369 18 1691 1703 10.1056/NEJMoa1304369 24131140 \n10. Sohal DPS Mangu PB Khorana AA Shah MA Philip PA O’Reilly EM Metastatic pancreatic cancer: american society of clinical oncology clinical practice guideline J Clin Oncol 2016 34 23 2784 2796 10.1200/JCO.2016.67.1412 27247222 \n11. Ducreux M Cuhna AS Caramella C Hollebecque A Burtin P Goere D Cancer of the pancreas: ESMO clinical practice guidelines for diagnosis, treatment and follow-up Ann Oncol 2015 26 Suppl 5 v56 v68 10.1093/annonc/mdv295 26314780 \n12. Le N Vinci A Schober M Krug S Javed MA Kohlmann T Real-world clinical practice of intensified chemotherapies for metastatic pancreatic cancer: results from a pan-european questionnaire study Digestion 2017 94 4 222 229 10.1159/000453257 \n13. Peixoto RD Ho M Renouf DJ Lim HJ Gill S Ruan JY Eligibility of metastatic pancreatic cancer patients for first-line palliative intent nab-paclitaxel plus gemcitabine versus FOLFIRINOX Am J Clin Oncol Cancer Clin Trials 2017 40 5 507 511 10.1097/COC.0000000000000193 \n14. Giordano G Vaccaro V Lucchini E Musettini G Bertocchi P Bergamo F Nab-paclitaxel (Nab-P) and gemcitabine (G) as first-line chemotherapy (CT) in advanced pancreatic cancer (APDAC) elderly patients (pts): a “real-life” study J Clin Oncol 2015 33 3_suppl 424 10.1200/jco.2015.33.3_suppl.424 \n15. Ghosn M Ibrahim T Assi T El Rassy E Kourie HR Kattan J Dilemma of first line regimens in metastatic pancreatic adenocarcinoma World J Gastroenterol 2016 22 46 10124 10130 10.3748/wjg.v22.i46.10124 28028360 \n16. Therasse P Arbuck SG Eisenhauer EA Wanders J Kaplan RS Rubinstein L New guidelines to evaluate the response to treatment in solid tumors J Natl Cancer Inst 2000 92 3 205 216 10.1093/jnci/92.3.205 10655437 \n17. National Cancer Institute CTCAE v4.0 Archive. Common Terminology Criteria for Adverse Events (CTCAE) 2009 \n18. Goldstein D El-Maraghi RH Hammel P Heinemann V Kunzmann V Sastre J Nab-paclitaxel plus gemcitabine for metastatic pancreatic cancer: long-term survival from a phase III trial J Natl Cancer Inst 2015 107 2 dju413 10.1093/jnci/dju413 25638248 \n19. Lo Re G Santeufemia DA Foltran L Bidoli E Basso SMM Lumachi F Prognostic factors of survival in patients treated with nab- paclitaxel plus gemcitabine regimen for advanced or metastatic pancreatic cancer: a single institutional experience Oncotarget 2015 6 10 8255 8260 25779664 \n20. De Vita F Ventriglia J Febbraro A Laterza MM Fabozzi A Savastano B NAB-paclitaxel and gemcitabine in metastatic pancreatic ductal adenocarcinoma (PDAC): from clinical trials to clinical practice BMC Cancer 2016 16 1 1 8 10.1186/s12885-016-2671-9 \n21. Giordano G Vaccaro V Lucchini E Bertocchi P Bergamo F Musettini G Analysis of prognostic factors in advanced pancreatic cancer (APDAC) patients (pts) undergoing to first-line nab-paclitaxel (Nab-P) and gemcitabine (G) treatment J Clin Oncol 2015 33 3_suppl 412 10.1200/jco.2015.33.3_suppl.412 \n22. Tas F Sen F Keskin S Kilic L Yildiz I Prognostic factors in metastatic pancreatic cancer: older patients are associated with reduced overall survival Mol Clin Oncol 2013 1 4 788 792 10.3892/mco.2013.131 24649248 \n23. Montes A Villarroel P Ayerbes M la Gómez JC Aldana G Tuñas L Prognostic and predictive markers of response to treatment in patients with locally advanced unresectable and metastatic pancreatic adenocarcinoma treated with gemcitabine/nab-paclitaxel: results of a retrospective analysis J Cancer Res Ther 2017 13 2 240 10.4103/0973-1482.181181 28643741 \n24. Huang L, Jansen L, Balavarca Y, Molina-Montes E, Babaei M, van der Geest L, et al. Resection of pancreatic cancer in Europe and USA: an international large-scale study highlighting large variations. Gut. 2017. 10.1136/gutjnl-2017-314828.\n25. Hamada T Nakai Y Yasunaga H Isayama H Matsui H Takahara N Prognostic nomogram for nonresectable pancreatic cancer treated with gemcitabine-based chemotherapy Br J Cancer 2014 110 8 1943 1949 10.1038/bjc.2014.131 24642625 \n26. Goldstein David Von Hoff Daniel D. Chiorean E. Gabriela Reni Michele Tabernero Josep Ramanathan Ramesh K. Aly Abdalla Botteman Marc Wilkersen Julia Margunato-Debay Sandra Lu Brian Louis Chrystal Ursula Renschler Markus Frederic McGovern Desmond Micahel Thomas Lee Chee Khoon Nomogram for predicting overall survival (OS) in patients (pts) treated with nab-paclitaxel (nab-P) plus gemcitabine (Gem) or Gem alone for metastatic pancreatic cancer (MPC) Journal of Clinical Oncology 2017 35 15_suppl 4109 4109 10.1200/JCO.2017.35.15_suppl.4109\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1471-2407",
"issue": "18(1)",
"journal": "BMC cancer",
"keywords": "First-line chemotherapy; Gemcitabine; Metastatic pancreatic adenocarcinoma; Nab-paclitaxel; Real-life; Survival",
"medline_ta": "BMC Cancer",
"mesh_terms": "D000328:Adult; D000368:Aged; D000418:Albumins; D000971:Antineoplastic Combined Chemotherapy Protocols; D015897:Comorbidity; D003841:Deoxycytidine; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D017239:Paclitaxel; D010190:Pancreatic Neoplasms; D011379:Prognosis; D012189:Retrospective Studies; D016019:Survival Analysis; D016896:Treatment Outcome",
"nlm_unique_id": "100967800",
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"pmc": null,
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"pubdate": "2018-11-29",
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"references": "27247222;25844823;28030863;25202043;21561347;10655437;25638248;24131140;29562308;24314615;24649248;29158237;24642625;25779664;27590845;25559415;28028360;26851397;28643741;27438590;28005607;26314780",
"title": "Prognostic factors for survival with nab-paclitaxel plus gemcitabine in metastatic pancreatic cancer in real-life practice: the ANICE-PaC study.",
"title_normalized": "prognostic factors for survival with nab paclitaxel plus gemcitabine in metastatic pancreatic cancer in real life practice the anice pac study"
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"abstract": "OBJECTIVE\nTwo patients with chronic kidney disease presented with severe anemia and iron deficiency. Because of their religious beliefs, red blood cell transfusions were not possible, and an aggressive therapeutic regimen of iron replenishment was instituted.\n\n\nMETHODS\nThe regimen included epoetin, folic acid and high-dose intravenous iron sucrose infusions over multiple successive days (total dosages of 2 and 3.5 g).\n\n\nRESULTS\nThe patients' iron stores were replenished and an erythropoietic response ensued subsequent to this aggressive and unique therapeutic regimen. There were no side effects observed which could be attributed to iron sucrose, and both patients stabilized and were discharged after 3 - 4 weeks.\n\n\nCONCLUSIONS\nIn patients with chronic kidney disease who are severely anemic and iron-deficient and where transfusions are not possible, an aggressive regimen of multiple high-dose iron sucrose infusions may be both safe and effective.",
"affiliations": "Division of Nephrology and Hypertension, The New York Hospital Medical Center of Queens, Flushing, NY, USA. mhschwen@nyp.org",
"authors": "Schwenk|M H|MH|;Blaustein|D A|DA|",
"chemical_list": "D005290:Ferric Compounds; D000077605:Ferric Oxide, Saccharated; D005937:Glucaric Acid",
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"issn_linking": "0301-0430",
"issue": "62(2)",
"journal": "Clinical nephrology",
"keywords": null,
"medline_ta": "Clin Nephrol",
"mesh_terms": "D000368:Aged; D000740:Anemia; D002908:Chronic Disease; D005260:Female; D005290:Ferric Compounds; D000077605:Ferric Oxide, Saccharated; D005937:Glucaric Acid; D006801:Humans; D007262:Infusions, Intravenous; D000090463:Iron Deficiencies; D033221:Jehovah's Witnesses; D007674:Kidney Diseases; D008875:Middle Aged; D012720:Severity of Illness Index; D013997:Time Factors",
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"pmid": "15356968",
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"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Rapid, high-dose intravenous iron sucrose therapy in 2 Jehovah's Witness patients with severe anemia, iron deficiency and chronic kidney disease.",
"title_normalized": "rapid high dose intravenous iron sucrose therapy in 2 jehovah s witness patients with severe anemia iron deficiency and chronic kidney disease"
} | [
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"companynumb": "US-AMGEN-USASP2020182887",
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"abstract": "BACKGROUND\nThere is no standard chemotherapy regimen that is universally accepted for the treatment of advanced gastric cancer. Trastuzumab added to chemotherapy improves survival in patients with metastatic human epidermal growth factor receptor-2 (Her2/neu)-overexpressing gastric cancer. Data are lacking for the combination of trastuzumab with other chemotherapy regimens, apart from the cisplatin/fluorouracil backbone used in the pivotal TOGA trial.\n\n\nMETHODS\nIn this retrospective analysis, we included patients with gastric cancer with HER2 overexpression who received trastuzumab in addition to their first-line chemotherapy, with or without trastuzumab maintenance therapy. The end-points were response and tolerance to treatment.\n\n\nRESULTS\nWe identified seven patients who met the search criteria; six had metastatic disease and one had locally advanced unresectable disease. Four patients received epirubicin/oxaliplatin/capecitabine/trastuzumab, and the others had non-anthracycline-based chemotherapy with trastuzumab. All patients had radiological responses to treatment - one had a complete response and six had partial responses. Among the four patients who received anthracycline-based chemotherapy with trastuzumab, there was a transient decline in cardiac ejection fraction in three, but all resolved without sequelae. All patients received a period of chemotherapy induction followed by trastuzumab monotherapy for maintenance. The median progression-free survival was 14.6 months and median overall survival was 16.4 months.\n\n\nCONCLUSIONS\nTrastuzumab is an important agent for the treatment of HER2-overexpressing gastric cancer. We recorded an acceptable safety and efficacy profile in this small cohort treated with anthracycline-based chemotherapy with trastuzumab followed by trastuzumab maintenance.",
"affiliations": "1475 NW 12th Avenue. Suite 3400, Miami, 33136, FL, U.S.A. phosein@med.miami.edu.",
"authors": "Palacio|Sofia|S|;Loaiza-Bonilla|Arturo|A|;Kittaneh|Muaiad|M|;Kyriakopoulos|Christos|C|;Ochoa|Roberto E|RE|;Escobar|Mauricio|M|;Arango|Belisario|B|;Restrepo|Maria H|MH|;Merchan|Jaime R|JR|;Rocha Lima|Caio M S R|CM|;Hosein|Peter J|PJ|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D003841:Deoxycytidine; D015251:Epirubicin; D000069287:Capecitabine; C508053:ERBB2 protein, human; D018719:Receptor, ErbB-2; D000068878:Trastuzumab; D005472:Fluorouracil",
"country": "Greece",
"delete": false,
"doi": null,
"fulltext": null,
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"issn_linking": "0250-7005",
"issue": "34(1)",
"journal": "Anticancer research",
"keywords": "Gastric cancer; chemotherapy; trastuzumab",
"medline_ta": "Anticancer Res",
"mesh_terms": "D000328:Adult; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols; D000069287:Capecitabine; D003841:Deoxycytidine; D015251:Epirubicin; D005260:Female; D005472:Fluorouracil; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D011379:Prognosis; D018719:Receptor, ErbB-2; D012189:Retrospective Studies; D013274:Stomach Neoplasms; D000068878:Trastuzumab",
"nlm_unique_id": "8102988",
"other_id": null,
"pages": "301-6",
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"pubdate": "2014-01",
"publication_types": "D002363:Case Reports; D003160:Comparative Study; D016428:Journal Article",
"references": null,
"title": "Successful use of Trastuzumab with anthracycline-based chemotherapy followed by trastuzumab maintenance in patients with advanced HER2-positive gastric cancer.",
"title_normalized": "successful use of trastuzumab with anthracycline based chemotherapy followed by trastuzumab maintenance in patients with advanced her2 positive gastric cancer"
} | [
{
"companynumb": "US-CIPLA LTD.-2015US01103",
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"activesubstancename": "EPIRUBICIN"
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{
"abstract": "Chorioangioma or chorangioma is a benign placental tumour which occurs in 1% of the pregnancies. Large lesions of more than 4-5 cm in size, also known as giant chorangiomas, are rare with the incidence of 1:3500 and 1:9000 birth. Unlike small tumours, the giant chorangiomas are highly associated with pregnancy complications. We report a case of multiple large chorangiomas resulting in an extremely preterm delivery. A 24-year-old primigravida presented at 25 weeks of gestation for threatened preterm labour. Transabdominal ultrasound revealed an echogenic mass on the placenta measuring 8.7 × 4.4 cm. Following a successful tocolysis and administration of a course of antenatal corticosteroids, she was discharged home. At 27 weeks of gestation, she developed a second episode of preterm contractions. Besides, the foetus was found to be small for gestational age. In the second episode of preterm contractions, intravenous magnesium sulfate infusion was commenced for foetal neuroprotection. Tocolysis was commenced for severe prematurity. She went into spontaneous preterm labour. Placenta examination revealed multiple solid masses with fleshy and congested dark red surface. A histopathological examination of the placenta confirmed the diagnosis of chorangiomas. The baby was discharged in good condition at 5 months of age. Placental chorangiomas, notably when they are multiple and large in size, are associated with adverse pregnancy outcomes. Therefore, close antenatal surveillance is necessary to allow timely recognition and intervention of pregnancy complications. Our case portrays an unexpected favourable neonatal outcome associated with a giant chorangiomas.",
"affiliations": "Department of Obstetrics and Gynaecology, Sibu Hospital, Batu ½, Jalan Ulu Oya, 96000 Sibu, Sarawak, Malaysia, Phone: +60135025175.;Department of Obstetrics and Gynaecology, Sibu Hospital, Ministry of Health Malaysia, Sibu, Sarawak, Malaysia.;Department of Pathology, Sarawak General Hospital, Ministry of Health Malaysia, Sibu, Sarawak, Malaysia.;Department of Obstetrics and Gynaecology, Sibu Hospital, Ministry of Health Malaysia, Sibu, Sarawak, Malaysia.",
"authors": "Ting|Evelyn Lee Pian|ELP|;Yong|Soon Leong|SL|https://orcid.org/0000-0003-2836-0756;Suhashini|Ganapaty|G|;Kang|Marcus|M|",
"chemical_list": null,
"country": "Germany",
"delete": false,
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"issn_linking": "1868-1883",
"issue": "40(2)",
"journal": "Hormone molecular biology and clinical investigation",
"keywords": "giant chorangioma; placenta mass; prematurity",
"medline_ta": "Horm Mol Biol Clin Investig",
"mesh_terms": "D000328:Adult; D005260:Female; D020073:Gravidity; D006391:Hemangioma; D006801:Humans; D007231:Infant, Newborn; D007752:Obstetric Labor, Premature; D010920:Placenta; D011247:Pregnancy; D011252:Pregnancy Complications, Neoplastic; D055815:Young Adult",
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"abstract": "BACKGROUND\nThis article reports a case diagnosis of a 44-year-old female who presented with intractable hiccups and vomit complicated with an acute onset of paraplegia. Transverse myelitis was evident on MRI and serological studies were consistent with Neuromyelitis Optica (NMO) based on NMO-IgG sero-positivity. Further studies revealed positive ANA, anti-RNA polymerase III autoantibodies, and Scl-70, leading to a concurrent diagnosis of systemic sclerosis (SSc). The coexistence of these two disease processes and their underlying clinical manifestations and therapeutic interventions are seldom reported in literature and are worth reporting.\n\n\nMETHODS\nThe patient was treated with high dose steroids, and subsequently developed malignant hypertension and acute renal failure, later identified on biopsy as steroids-induced scleroderma renal crisis. Although Neuromyelitis Optica spectrum disorder (NMOSD) has often been associated with various collagen and autoimmune diseases, the coexistence of NMOSD and SSc presented a challenge where the patient underwent aggressive physical therapy and necessitated an intervention with Rituximab to achieve an appropriate clinical response. We have received a written consent forms from the participant in our study, and we have them on file in case they are requested. We have also received the patient's written consent for the data and images presented in this article.\n\n\nCONCLUSIONS\nThis article expands on NMOSD associated autoimmune diseases. Systemic Sclerosis is an insidious disease that is often diagnosed late as not all patients often report skin manifestation. The finding suggests that patients presenting with acute neurological manifestations get tested for NMO-IgG/AQP-4 antibodies and other immunological studies based on clinical findings.",
"affiliations": "Miller School of Medicine, Internal Medicine Residency, University of Miami, 5301 S Congress Aven, Atlantis, FL, 33426, USA. kdeeb@med.miami.edu.;Miller School of Medicine, Palm Beach Regional Campus, University of Miami, Atlantis, FL, USA.;Department of Neurology, JFK Medical Center, Atlantis, FL, USA.",
"authors": "Deeb|Khaled|K|;Eby|Jessika|J|;Labault-Santiago|Jose|J|",
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"fulltext": "\n==== Front\nBMC NeurolBMC NeurolBMC Neurology1471-2377BioMed Central London 147210.1186/s12883-019-1472-6Case ReportDemyelinating syndrome in systemic sclerosis and neuromyelitis optica Deeb Khaled 954-483-3381kdeeb@med.miami.edu 1Eby Jessika jdold@umiami.edu 2Labault-Santiago Jose jrl188@miami.edu 31 0000 0004 1936 8606grid.26790.3aMiller School of Medicine, Internal Medicine Residency, University of Miami, 5301 S Congress Aven, Atlantis, FL 33426 USA 2 0000 0004 1936 8606grid.26790.3aMiller School of Medicine, Palm Beach Regional Campus, University of Miami, Atlantis, FL USA 3 0000 0004 0433 5895grid.414998.9Department of Neurology, JFK Medical Center, Atlantis, FL USA 14 10 2019 14 10 2019 2019 19 23420 2 2019 20 9 2019 © The Author(s). 2019Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nThis article reports a case diagnosis of a 44-year-old female who presented with intractable hiccups and vomit complicated with an acute onset of paraplegia. Transverse myelitis was evident on MRI and serological studies were consistent with Neuromyelitis Optica (NMO) based on NMO-IgG sero-positivity. Further studies revealed positive ANA, anti-RNA polymerase III autoantibodies, and Scl-70, leading to a concurrent diagnosis of systemic sclerosis (SSc). The coexistence of these two disease processes and their underlying clinical manifestations and therapeutic interventions are seldom reported in literature and are worth reporting.\n\nCase presentation\nThe patient was treated with high dose steroids, and subsequently developed malignant hypertension and acute renal failure, later identified on biopsy as steroids-induced scleroderma renal crisis. Although Neuromyelitis Optica spectrum disorder (NMOSD) has often been associated with various collagen and autoimmune diseases, the coexistence of NMOSD and SSc presented a challenge where the patient underwent aggressive physical therapy and necessitated an intervention with Rituximab to achieve an appropriate clinical response.\n\nWe have received a written consent forms from the participant in our study, and we have them on file in case they are requested. We have also received the patient’s written consent for the data and images presented in this article.\n\nConclusion\nThis article expands on NMOSD associated autoimmune diseases. Systemic Sclerosis is an insidious disease that is often diagnosed late as not all patients often report skin manifestation. The finding suggests that patients presenting with acute neurological manifestations get tested for NMO-IgG/AQP-4 antibodies and other immunological studies based on clinical findings.\n\nKeywords\nNeuromyelitis opticaSystemic sclerosisDemyelinating syndromeSystemic lupus erythematousissue-copyright-statement© The Author(s) 2019\n==== Body\nBackground\nNeuromyelitis optica (formerly known as Devic’s disease) is an inflammatory disorder of the CNS affecting predominantly the spinal cord, brainstem, and optic nerves. Typical presentation includes acute optic neuritis (leading to vision loss), transverse myelitis (leading to limb weakness, sensory loss), or brainstem syndromes (intractable hiccups, nausea, vomiting). Intractable hiccups and nausea are rare and unique symptoms in NMO, and they are believed to be due to involvement of area postrema and nucleus tractus solitarius in the dorsomedial medulla and ventrolateral respiratory center [1, 2].\n\nNeuromyelitis optica spectrum disorders are rare, constituting less than 1% of demyelinating disease with a significantly higher number of female than male patients. The incidence and prevalence are based on population-based studies conducted in Europe, South East and Southern Asia, the Caribbean, and Cuba ranged from 0.05 to 0.4 and 0.52 to 4.4 per 100,000, respectively [3]. It was previously believed to be a variant of multiple sclerosis (MS), as it shares both clinical and radiologic features [2, 4]. However, it is now considered a separate entity after the discovery of disease-specific NMO-IgG antibody that selectively binds aquaporin-4 (AQP4). It is thus crucial to differentiate between MS and NMO because Immunosuppressive drugs (eg, azathioprine and corticosteroids) are regarded as the best treatment for NMO, whereas immunomodulatory treatments (eg, interferon beta and glatiramer acetate) are presently recommended for early treatment of MS. Our case of NMO diagnosis is based on the revised consensus criteria in 2015 [5], with the presence of six clinical features, in conjunction with antibody seropositivity and additional MRI findings, as shown in Table 1.\nTable 1 Titers and lab values\n\nTest name\tTiters\tReference ranges\t\n\tNeuromyelitis Optica... 7.7 A\tNegative 0.0–3.0;Indeterminate 3.1–5.0;Positive > 5.1\t\nANA Positive\t\t\nANTI-DNA < 1.0\tNegative: <=4.9 IU/mL;Indeterminate: 5–9.9 IU/mL;Positive: > = 10 IU/mL\t\nSmooth Muscles\tSM AB < 0.2\tNegative: < 1.0;Positive: > = 1.0\t\nNeutrophil Cytoplasmic Ab\tC-ANCA < 0.2, P-ANCA < 0.2\tNegative: < 1.0;Positive: > = 1.0\t\nScleroderma 70 Ab\tSCLERODERM... 4.5 H\tNegative: < 1.0;Positive: > = 1.0\t\nJO-1 ANTIB... < 0.2\tNegative: < 1.0;Positive: > = 1.0\t\nCENTROMERE AB... < 0.2\tNegative: < 1.0;Positive: > = 1.0\t\nSjorgen\tANTI-SSA... < 0.2, ANTI-SSB... < 0.2\tNegative: < 1.0;Positive: > = 1.0\t\nRNP AB < 0.2\tNegative: < 1.0;Positive: > = 1.0\t\nCHROMATIN ... < 0.2\tNegative: < 1.0;Positive: > = 1.0\t\nRA Negative\t\t\nHBsAg Scre... NEGATIVE\t\t\nHEP B SURF... NEGATIVE\t\t\nRNA Polymerase III IgG Abs 40 Units/mL\tNegative: < 20;Weak Positive: 20–39;Moderate Positive: > 40–80;Strong Positive: > 80a\t\nC3 131\t\t\nC4 40\t\t\nHIV By By RT-PCR\tHIV RNA... Target Not Detected\t\t\nToxoplasma Igg\tTOXOPLASMA... 27.0 H,\t\t\nTOXOPLASMA... 0.24\t< 0.9 Negative;0.9–0.99 Equivocal;> 1.00 Positive\t\nMYELIN BASIC PROTEIN... 6.3 A\t\t\nEBV EARLY ... < 0.20, EBV NUCLEA... > 8.00 H,\t\t\nEBV VCA IG... > 8.0 H, EBV VCA IG... < 0.2\t< OR = 0.8 AI: NEGATIVE;0.9–1.0 AI: EQUIVOCAL;> OR = 1.1 AI: POSITIVE\t\nVARICELLA IgG … .3.3\t< OR = 0.8 AI: NEGATIVE;0.9–1.0 AI: EQUIVOCAL;> OR = 1.1 AI: POSITIVE\t\nHTLV I/II ... TNP\t\t\nEpst Barr Virus DNA\tEpst Barr ... Negative\t\t\nVaricella Zoster Ab Pcr (Csf)\tVARICELLA ... Negative\t\t\nCrypto.Ag,Csf\tCRYPTO.AG,... Negative\t\t\nHerpes Virus Dna By Pcr\tHSV1 DNA P... Negative, HSV2 DNA P... Negative\t\t\nLyme Disease Ab (Csf)\tB.burgd Ig... < 0.08, B.burgd Ig... < 0.06\tNegative: < or = 0.09;Positive: > 0.09B.\t\nEnterovirus... Negative\t\t\nCSF VDRL Nonreactive\t\t\nIGG 1500\t\t\nCoccidioides Abs, CSF (CF) < 1:2 < 1:2\t\t\nCoccidioides Ab, IgG 0.1 IV < =0.9\t\t\nToxo IgG C... < 3.0\t\t\nOligoclonal\tOLIGOCLONAL ab negative\t\t\nGLUCOSE, C... 99 H; PROT.,CSF 55.6 H\t\t\nImmunofix/Pep Csf Profile\tPROTEIN (C... 36.9, PREALBUMIN 2.9,\t\t\nALBUMIN 54.5 A, ALPHA-1-GL... 4.1, ALPHA-2-GL... 6.4,\t\t\nBETA GLOBU... 17.8, GAMMA GLOB... 14.4 A\t\t\nLymph/Leuk Body Fluid\tplasma cells are not identified\tT cells with an increased CD4/CD8 ratio are detected. b\t\nANGIOTENSIN ENZYM < 15\t\t\nRenin Activity... 13.774 A\t\t\nD-DIMER 476 H\t\t\nCORTISOL 34.66\t\t\nTSH 0.910\t\t\nESR 86 H\t\t\nCRP-HIGH S... 1.910 H\t\t\naRNA Polymerase III is strongly associated with diffuse cutaneous scleroderma and with an increases risk of acute renal crisis. A positive result supports a possible diagnosis of systemic sclerosis while a negative result does not rule out the possibility of systemic sclerosis, as the sensitivity for detection of RNA Polymerase III is between 11 and 23%\n\nbFlow cytometric analysis identifies a population of lymphocytes (91.1% of all analyzed events) that consists of a mixture of minute B-cell population (2.7% of cells in this gate), T cells with an increased CD4/CD8 ratio of 7.8 and mild down-regulation of CD7 expression (91.6% of cells in this gate), and NK-cells (2.0% of cells in this gate). An increased CD4/CD8 ratio is a non-specific finding that may be seen in reactive / inflammatory processes and autoimmune disease; less likely, it may represent an atypical population. The B-cells show minimal lambda excess, the significance of which is uncertain\n\n\n\nNeuromyelitis optica is known to coexist with other connective tissue and autoimmune disorders (e.g., SLE, Sjögren); however, it has no prior conjunction with Systemic Sclerosis (SSc). One may confirm the positivity of NMO by having NMO-IgG/AQP-4 antibodies. Serum detection of specific autoantibodies, such as anti-dsDNA, is the hallmark of SLE, and anti-topoisomerase antibodies (SCL-70) are the most specific test for SSc, as they may help in the differential diagnosis of the first demyelinating episode. Demyelinating syndromes could be life threatening and may lead to disability and even death. The estimated prevalence of SLE is 1.3% and incidence rate of 1.5 case per 1000 patients [6]. It was found that IFNs play an important role in the pathogenesis of connective tissue diseases where it was noted that serum IFN-α/β activity is elevated in SLE as well as NMO, which is no surprise due to the similarities in pathophysiology [7]. It was also found that the higher the IFN activity, the more severe is the SLE disease [8]. Furthermore, Patients with gray matter dysfunction had higher levels of SLE activity, whereas patients with white matter dysfunction were more likely to meet criteria for NMO [9]. On the other hand, SSc is another form of autoimmune rheumatic disease described by having excess collagen deposition in the skin and viscera, along with vascular abnormalities including vasospasm and microvascular occlusion [10]. While uncommon, neurological complications of SSc has been reported with manifestations of peripheral neuropathy with sensitive-motor forms [11–14].\n\nCase presentation\nThis case presents a 44-year-old Hispanic female, with no known past medical history, complaining of an acute onset of intractable hiccups, vomiting, and dysphagia. Physical examination was notable for a thin female appearing much younger than stated age. Cardiac and pulmonary examinations were unremarkable. Skin thickening of the fingers extending proximal to the metacarpophalangeal joints was noted bilaterally. Review of systems was positive for Reynaud’s phenomenon, however negative for finger ulceration, nail pitting, dry eyes or mucus membranes, or skin rash. Vital signs on admission were stable. Laboratory studies were unremarkable except for hyponatremia and hypokalemia, which were replaced appropriately. Patient received supportive IV fluids and anti-emetics. The following day, the patient developed new onset of blurry vision, motor weakness and paresthesias of the bilateral lower limbs. Lower extremities were notable for hypertonia and paroxysmal tonic spasms. Motor strength of lower extremities was 0/5 with intact bilateral upper extremity strength. Upper extremity reflexes were 2+, and knee and ankle reflexes were 4+ bilaterally. Babinski’s sign was present bilaterally. Loss of pinprick and vibratory sensation up to bilateral anterior superior iliac spine was noted. Visual acuity diminished bilaterally with no visual field defects, and extra ocular movement was intact. Other cranial nerves were intact. Brain MRI with and without gadolinium enhancement showed multiple scattered hyper-intense T2 flair foci in the bilateral periventricular white matter. MRI spine revealed multiple enhancing lesions in the spinal cord at the levels of C2–C6, consistent with transverse myelitis.\n\nExtensive laboratory evaluation, which included thyroid function, vitamin B12 level, and folic acid was normal. Serologies and PCRs for common neurotropic viruses (HSV1, HSV2, CMV, EBV, HBV, HCV, VZV, HTLV 1/2, Toxoplasma, and HIV) were negative in blood and in cerebrospinal fluid analysis (CSF). Specifically, CSF analysis revealed lymphocytic pleocytosis but no oligoclonal bands. Immunological tests for anti-dsDNA, anti-cardiolipin, anti-β2GPI, ANCA, and cryoglobulins were negative. However, ANA, anti-RNA polymerase III autoantibodies, Scl-70, and NMO-IgG were all positive. Repeat NMO-IgG was positive. Effectively, preliminary diagnosis of NMO was made based on seropositivity and clinical features consistent with transverse myelitis and area postrema syndrome (see Table 1). Our case of NMO diagnosis is based on the revised consensus criteria in 2015, shown in Table 2.\nTable 2 Neuromyelitis optica spectrum disorders diagnostic criteria for adult patients\n\nDiagnostic criteria for NMOSD with AQP4IgG\t\n 1. At least one core clinical characteristic\t\n 2. Positive test for AQP4IgG using best available detection method (cell-based assay strongly recommended)\t\n 3. Exclusion of alternative diagnoses\t\nDiagnostic criteria for NMOSD without AQP4IgG or NMOSD with unknown AQP4IgG status\t\n 1. At least two core clinical characteristics occurring as a result of one or more clinical attacks and meeting all of the following requirements:\t\n a. At least one core clinical characteristic must be optic neuritis, acute myelitis with LETM, or area postrema syndrome\t\n b. Dissemination in space (two or more different core clinical characteristics)\t\n c. Fulfillment of additional MRI requirements, as applicable\t\n 2. Negative tests for AQP4IgG using best available detection method, or testing unavailable\t\n 3. Exclusion of alternative diagnoses\t\nCore clinical characteristics\t\n 1. Optic neuritis\t\n 2. Acute myelitis\t\n 3. Area postrema syndrome: Episode of otherwise unexplained hiccups or nausea and vomiting\t\n 4. Acute brainstem syndrome\t\n 5. Symptomatic narcolepsy or acute diencephalic clinical syndrome with NMOSD typical diencephalic MRI lesions\t\n 6. Symptomatic cerebral syndrome with NMOSD typical brain lesions\t\nAdditional MRI requirements for NMOSD without AQP4IgG and NMOSD with unknown AQP4IgG status\t\n 1. Acute optic neuritis: Requires brain MRI showing (a) normal findings or only nonspecific white matter lesions, or (b) optic nerve MRI with T2 hyperintense lesion or T1weighted gadolinium enhancing lesion extending over more than one half the optic nerve length or involving optic chiasm\t\n 2. Acute myelitis: Requires associated intramedullary MRI lesion extending over ≥3 contiguous segments (LETM) or ≥ 3 contiguous segments of focal spinal cord atrophy in patients with history compatible with acute myelitis\t\nAQP4 aquaporin4, IgG immunoglobulin G, LETM longitudinally extensive transverse myelitis lesions, NMOSD neuromyelitis optica spectrum disorders\n\n\n\nThe patient was started on high-dose intravenous methylprednisolone (1 g daily for five consecutive days) on day. Resolution of visual symptoms occurred within 2 days. Nonetheless, the patient showed marginal improvement in motor symptoms. On day 5 of hospitalization, patient developed abrupt onset of malignant hypertension, as well as acute onset of renal failure with non-nephrotic range proteinuria, requiring urgent hemodialysis. Renal biopsy showed obliteration of the vascular lumen, with concentric fibrinoid necrosis and “onion-skin” hypertrophy, most consistent with diagnosis of steroid induced scleroderma renal crisis. Steroids were discontinued and patient was started on an ACE inhibitor with resultant normalization of blood pressure and slow recovery of renal function. Patient was started on Azathioprine with improvement of motor symptoms; however, it was discontinued due to hepatotoxity. Effectively, it was changed to Rituximab 1000 mg × 2 doses 14 days apart, with gradual improvement in motor functions.\n\nIn sum, our patient was diagnosed with both NMO and Systemic Sclerosis based on her history, clinical presentation, MRI findings as shown in Fig. 1, anti-Scl-70 antibodies, and the presence of serum NMO-IgG antibody. She had a subacute onset of lower extremity paraparesis, dysesthesia, and hyperreflexia, with gradual improvement in motor function over the course of a year. In the interim, she had multiple readmissions for painful paroxysmal tonic spasms which responded to Gabapentin, Baclofen and Carbamazepine.\nFig. 1 a T1-weighted sagittal MRI (left) of the cervical spinal and upper thoracic cord showing transverse myelitis related. Also noted extensive multiple areas of increased T2 signal abnormality within the thoracic spinal cord with patchy areas of post-contrast enhancement. b T2-weighted sequence MRI of the brain (right) show scattered bright foci of FLAIR demyelinating process in the bilateral deep periventricular and cerebral white matter and in the dorsum of medulla oblongata\n\n\n\nDiscussion and conclusions\nNeuromyelitis optica (NMO) and neuromyelitis optica spectrum disorders (NMOSD) are rare demyelinating disorders of the central nervous system that predominantly affects the spinal cord, brainstem and optic nerves [4]. While the cause of NMO is unknown, it has been hypothesized that an autoimmune-mediated inflammatory cascade leads to demyelination and axonal injury. Characteristics findings include optic neuritis, and episodic transverse myelitis. Association with other autoimmune disorders has been widely recognized, including systemic lupus erythematosus (SLE), sjögren syndrome (SS), rheumatoid arthritis (RA), and organ-specific autoimmune diseases (e.g., thyroid diseases, myasthenia gravis, ulcerative colitis) [15]. However, SSc-associated NMO is rarely reported in the literature. Systemic sclerosis is a systemic autoimmune disease characterized by excess collagen deposition in the skin and internal organs. Given that the etiology of NMOSD is not clearly understood, it is uncertain if SSc is an etiological factor in NMO.\n\nThis case highlights the need for proper diagnosis and treatment of coexisting autoimmune conditions, as well as the recognition of possible life-threatening side effects of conventional first line steroid therapy. Proper recognition also ensures prompt initiation of immunotherapy for motor and sensory recovery, as well as the need for comprehensive care of these patients in rehabilitation centers.\n\nAlthough there have been several reports of NMO and SLE overlap syndrome responding to glucocorticoid therapy, treatment with steroid therapy in SSc should be avoided given the increased risk of scleroderma renal crisis. Alternatively, Rituximab was found effective for the prevention of attacks in one NMO case, resistant to cyclosporine therapy [9]. Immunoablative dose cyclosporine has also been successful in SLE-associated NMO in patients unresponsive to high-dose oral and intravenous corticosteroids, intravenous immunoglobulin, mycophenolate mofetil, tacrolimus, and rituximab [16]. Another case reported late onset of NMOSD after a long-standing SSc, where CSF studies showed positivity of anti-Smith antibodies and anti-Slc-70 antibodies. Disease modifying treatment was given with an infusion of rituximab [3].\n\nWe report a case of NMO overlapping with SSc without other organ involvement (e.g., GI, pulmonary, cardiac) except for steroid induced scleroderma hypertensive renal crisis and skin manifestation. Our patient fulfilled the criteria for both NMO and SSc given NMO-IgG and anti Scl-70 positivity in conjunction with typical physical findings and clinical presentation. Per guidelines, our patient was started on first-line immunosuppressive therapies (prednisolone and rituximab) and plasmapheresis. Although initially responding to plasmapheresis and rituximab therapy with improvement in motor function, she continued to experience disease relapses, including paraplegia and severe spastic muscle crisis. Muscle spasticity was improved with initiation of tizanidine and carbamazepine. Our patient had vigilant monitoring with timely intervention to address organ-based complications, namely arterial hypertension and scleroderma renal crisis.\n\nAbbreviations\nMSMultiple sclerosis\n\nNMONeuromyelitis optica\n\nNMOSDOptica spectrum disorder\n\nRARheumatoid arthritis\n\nSLESystemic lupus erythematosus\n\nSSSjögren syndrome\n\nSScSystemic sclerosis\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAcknowledgements\nNot Applicable\n\nAuthors’ contributions\nKD: Design and conceptualized study; analyzed the data; Data collection and analysis; drafted the revised manuscript for intellectual content. JE: Design and conceptualized study; Data collection and analysis, drafting and manuscript. JLS: Review and edit the manuscript. Share knowledge. All authors have read and approved the manuscript.\n\nFunding\nStudy is not funded.\n\nAvailability of data and materials\nThe datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.\n\nEthics approval and consent to participate\nNot Applicable\n\nConsent for publication\nThe patient provided written informed consent for the publication of clinical details.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n==== Refs\nReferences\n1. Misu T Fujihara K Nakashima I Sato S Itoyama Y Intractable hiccup and nausea with periaqueductal lesions in neuromyelitis optic-a Neurology 2005 65 9 1479 10.1212/01.wnl.0000183151.19351.82 16275842 \n2. Takahashi T Miyazawa I Misu T Takano R Nakashima I Fujihara K Intractable hiccup and nausea in neuromyelitis optica with anti-aquaporin-4 antibody: a herald of acute exacerbations J Neurol Neurosurg Psychiatry 2008 79 9 1075 10.1136/jnnp.2008.145391 18420727 \n3. Pandit L Asgari N Apiwattanakul M Palace J Paul F Leite MI Demographic and clinical features of neuromyelitis optica: a review Mult Scler J 2015 21 7 845 853 10.1177/1352458515572406 \n4. Wingerchuk DM Lennon VA Lucchinetti CF Pittock SJ Weinshenker BG The spectrum of neuromyelitis optica Lancet Neurol 2007 6 9 805 815 10.1016/S1474-4422(07)70216-8 17706564 \n5. Wingerchuk DM Banwell B Bennett JL Cabre P Carroll W Chitnis T International consensus diagnostic criteria for neuromyelitis optica spectrum disorders Neurology 2015 85 2 177 189 10.1212/WNL.0000000000001729 26092914 \n6. Piga M Chessa E Peltz MT Floris A Mathieu A Cauli A Demyelinating syndrome in SLE encompasses different subtypes: do we need new classification criteria? Pooled results from systematic literature review and monocentric cohort analysis Autoimmun Rev 2017 16 3 244 252 10.1016/j.autrev.2017.01.011 28159705 \n7. Feng X Reder NP Yanamandala M Hill A Franek BS Niewold TB Type I interferon signature is high in lupus and neuromyelitis optica but low in multiple sclerosis J Neurol Sci 2012 313 1 48 53 10.1016/j.jns.2011.09.032 22036215 \n8. Sá MJ Acute transverse myelitis: a practical reappraisal Autoimmun Rev 2009 9 2 128 131 10.1016/j.autrev.2009.04.005 19389491 \n9. Birnbaum J Kerr D Optic neuritis and recurrent myelitis in a woman with systemic lupus erythematosus Nat Clin Pract Rheumatol 2008 4 381 10.1038/ncprheum0818 18493269 \n10. Joseph A Brasington R Kahl L Ranganathan P Cheng TP Atkinson J Immunologic rheumatic disorders J Allergy Clin Immunol 2010 125 2 S204 S215 10.1016/j.jaci.2009.10.067 20176259 \n11. Averbuch-Heller L Steiner I Abramsky O Neurologic manifestations of progressive systemic sclerosis Arch Neurol 1992 49 12 1292 1295 10.1001/archneur.1992.00530360094024 1333182 \n12. Berth-Jones J Coates PAA Graham-Brown RAC Burns DA Neurological complications of systemic sclerosis-a report of three cases and review of the literature Clin Exp Dermatol 1990 15 2 91 94 10.1111/j.1365-2230.1990.tb02039 2161303 \n13. Brown Jeffrey J Murphy MJ Transverse myelopathy in progressive systemic sclerosis Ann Neurol 1985 17 6 615 617 10.1002/ana.410170617 \n14. Torabi AM Patel RK Wolfe GI Hughes CS Mendelsohn DB Trivedi JR Transverse myelitis in systemic sclerosis Arch Neurol 2004 61 1 126 128 10.1001/archneur.61.1.126 14732630 \n15. Freitas E Guimarães J Neuromyelitis optica spectrum disorders associated with other autoimmune diseases Rheumatol Int 2015 35 2 243 253 10.1007/s00296-014-3066-3 24952418 \n16. Mok CC To CH Mak A Poon WL Immunoablative cyclophosphamide for refractory lupus-related neuromyelitis optica J Rheumatol 2008 35 1 172 174 18176991\n\n",
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"issn_linking": "1471-2377",
"issue": "19(1)",
"journal": "BMC neurology",
"keywords": "Demyelinating syndrome; Neuromyelitis optica; Systemic lupus erythematous; Systemic sclerosis",
"medline_ta": "BMC Neurol",
"mesh_terms": "D000328:Adult; D001323:Autoantibodies; D005260:Female; D006801:Humans; D007155:Immunologic Factors; D008279:Magnetic Resonance Imaging; D009188:Myelitis, Transverse; D009471:Neuromyelitis Optica; D000069283:Rituximab; D012595:Scleroderma, Systemic; D013577:Syndrome",
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"pubdate": "2019-10-14",
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"references": "16275842;19389491;4026234;26092914;18176991;24952418;18493269;28159705;14732630;1333182;17706564;18420727;20176259;2161303;22036215;25921037",
"title": "Demyelinating syndrome in systemic sclerosis and neuromyelitis optica.",
"title_normalized": "demyelinating syndrome in systemic sclerosis and neuromyelitis optica"
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"abstract": "We herein describe an 82-year-old patient who presented with proteinuria and systemic edema. He was diagnosed with minimal change disease (MCD) and was found to have stage III pancreatic cancer. He could not undergo surgical resection due to invasion to the celiac artery and he was thus treated with chemotherapy. After a month of chemotherapy, his proteinuria improved to a normal level. After two months of chemotherapy, computed tomography indicated a partial response to the therapy. MCD can occur as paraneoplastic syndrome in patients with malignant disease, and chemotherapy can be effective for MCD associated with paraneoplastic syndrome.",
"affiliations": "Department of Gastroenterology Medicine Center, Shonan Kamakura General Hospital, Japan.;Department of Gastroenterology Medicine Center, Shonan Kamakura General Hospital, Japan.;Department of Nephrology, Shonan Kamakura General Hospital, Japan.;Department of Gastroenterology Medicine Center, Shonan Kamakura General Hospital, Japan.;Department of Gastroenterology, Internal Medicine, Kitasato University School of Medicine, Japan.;Department of Gastroenterology Medicine Center, Shonan Kamakura General Hospital, Japan.;Department of Gastroenterology Medicine Center, Shonan Kamakura General Hospital, Japan.;Department of Gastroenterology Medicine Center, Shonan Kamakura General Hospital, Japan.;Department of Gastroenterology Medicine Center, Shonan Kamakura General Hospital, Japan.;Department of Gastroenterology Medicine Center, Shonan Kamakura General Hospital, Japan.;Department of Gastroenterology Medicine Center, Shonan Kamakura General Hospital, Japan.;Department of Nephrology, Shonan Kamakura General Hospital, Japan.;Department of Pathology, Shonan Kamakura General Hospital, Japan.",
"authors": "Masuda|Sakue|S|;Koizumi|Kazuya|K|;Moriya|Hidekazu|H|;Nishino|Takashi|T|;Uojima|Haruki|H|;Tazawa|Tomohiko|T|;Kimura|Karen|K|;Tasaki|Junichi|J|;Ichita|Chikamasa|C|;Sasaki|Akiko|A|;Kako|Makoto|M|;Hidaka|Sumi|S|;Kudo|Madoka|M|",
"chemical_list": "D000418:Albumins; D003841:Deoxycytidine; D017239:Paclitaxel",
"country": "Japan",
"delete": false,
"doi": "10.2169/internalmedicine.5499-20",
"fulltext": "\n==== Front\nIntern Med\nIntern Med\nInternal Medicine\n0918-2918 1349-7235 The Japanese Society of Internal Medicine \n\n32963158\n10.2169/internalmedicine.5499-20\nCase Report\nSecondary Minimal Change Disease Due to Pancreatic Cancer Improved by Chemotherapy\nMasuda Sakue 1 Koizumi Kazuya 1 Moriya Hidekazu 2 Nishino Takashi 1 Uojima Haruki 3 Tazawa Tomohiko 1 Kimura Karen 1 Tasaki Junichi 1 Ichita Chikamasa 1 Sasaki Akiko 1 Kako Makoto 1 Hidaka Sumi 2 Kudo Madoka 4 \n1 Department of Gastroenterology Medicine Center, Shonan Kamakura General Hospital, Japan\n\n2 Department of Nephrology, Shonan Kamakura General Hospital, Japan\n\n3 Department of Gastroenterology, Internal Medicine, Kitasato University School of Medicine, Japan\n\n4 Department of Pathology, Shonan Kamakura General Hospital, Japan\nCorrespondence to Dr. Sakue Masuda, sakue.masuda@tokushukai.jp\n\n\n19 9 2020 \n15 1 2021 \n60 2 251 257\n5 6 2020 29 7 2020 Copyright © 2021 by The Japanese Society of Internal MedicineThe Internal Medicine is an Open Access journal distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view the details of this license, please visit (https://creativecommons.org/licenses/by-nc-nd/4.0/).We herein describe an 82-year-old patient who presented with proteinuria and systemic edema. He was diagnosed with minimal change disease (MCD) and was found to have stage III pancreatic cancer. He could not undergo surgical resection due to invasion to the celiac artery and he was thus treated with chemotherapy. After a month of chemotherapy, his proteinuria improved to a normal level. After two months of chemotherapy, computed tomography indicated a partial response to the therapy. MCD can occur as paraneoplastic syndrome in patients with malignant disease, and chemotherapy can be effective for MCD associated with paraneoplastic syndrome. \n\nminimal change diseaseproteinuriapancreatic cancernab-Paclitaxelchemoradiotherapy\n==== Body\nIntroduction\nIn adults, minimal change disease (MCD) represents approximately 10-15% of patients with idiopathic nephrotic syndrome (1, 2). Secondary MCD is associated with neoplasia, drug use (e.g., non-steroidal anti-inflammatory drugs), infections, and atopy superimposed on another renal diseases. However, MCD is an uncommon occurrence associated with malignant tumors (3). Lymphoma are among the most frequently reported neoplastic processes associated with MCD (3), and a few solid tumors with MCD have been reported, especially with thymoma, renal cell carcinoma, colorectal carcinoma, and lung carcinoma (4). However, only two cases of pancreatic cancer (PC) associated with MCD have been previously reported (5, 6).\n\nThe complications of nephrotic syndrome include increased susceptibility to infections due to urinary loss of immunoglobulins, an increased frequency of thromboembolic events due to urinary loss of antithrombotic factors, and increased frequency of acute kidney injury (7-11). The prognosis for secondary MCD is generally favorable because the remission rate for prednisolone in MCD is high and the relapse rate is low (10, 12). However, when MCD is secondary to paraneoplastic syndrome, the relapse rate for prednisolone in MCD is high (13). The relationship between the treatment of the malignant lesion and the prognosis of MCD has been reported; for example, Hodgkin's disease associated with MCD that is refractory to chemotherapy has very adverse prognoses (3), and mesotheliomas with MCD are associated with a poor prognoses (14). Therefore, aggressive therapy for cancer is preferable in patients with cancer-associated MCD. However, there have beenfew reports about the treatment for MCD associated with PC. We herein report a rare case of MCD associated with PC that was effectively treated with chemotherapy for both PC and MCD.\n\nCase Report\nAn 82-year-old man presented with a 2-month history of upper abdominal pain and a 2-week history of bilateral lower limb edema. He had a history of hyperuricemia, and he had received allopurinol treatment. He had no history of smoking. Computed tomography (CT) revealed a pancreatic tumor measuring 3 cm in diameter which had invaded the celiac artery (Fig. 1a, b). Among the serum tumor markers, carbohydrate antigen 19-9, Duke pancreatic monoclonal antigen type 2 (DUPAN-2), and s-pancreas antigen-1 (SPan-1) were elevated to 772 U/mL (normal range: <37 U/mL), 1,600 or more U/mL (normal range: <150 U/mL) and 824 U/mL (normal range: <30 U/mL), respectively; carcinoembryonic antigen was within the normal limits. Tests for hepatitis B virus surface antigens and for antibodies to hepatitis C virus were negative. The following laboratory tests were normal level: Immunoglobulins IgG, IgA, and IgM; complement proteins C3 and C4; antinuclear antibody; rheumatoid factor; and antineutrophil cytoplasmic antibodies. Serum protein electrophoresis was normal. Serum creatinine was 1.05 mg/dL. A urine protein-to-creatinine ratio was high: 6.94 g/gCr (per gram of creatinine) and a 24-hour urine specimen contained 7.46 g of protein. The urine protein selectivity index was low (0.08). He was found to have a reduced serum albumin level of 2.9 g/dL and total protein level of 5.7 g/dL. The total cholesterol level was normal. Renal ultrasonography showed no abnormal findings. (Table 1)\n\nFigure 1. CT findings on admission. (a, b) Computed tomography on admission revealed a pancreatic tumor (red arrow) which invaded the celiac and common hepatic arteries.\n\nTable 1. Blood Test and Urinalysis.\n\nWBC\t4,700\t/μL\t\nHb\t13.0\tg/dL\t\nHt\t37.6\t%\t\nMCV\t91.0\tfL\t\nPLT\t162,000\t/μL\t\nPT-INR\t1.00\t\t\nAPTT\t30.2\ts\t\nT-BIL\t0.3\tmg/dL\t\nAST\t28\tU/L\t\nALT\t15\tU/L\t\nLDH\t211\tU/L\t\nγGTP\t15\tU/L\t\nALP\t2.9\tU/L\t\nTP\t5.7\tg/dL\t\nALB\t2.9\tg/dL\t\nT-chol\t196\tmg/dL\t\nHbA1c\t5.8\t%\t\nBUN\t16.2\tmg/dL\t\nCRE\t1.05\tmg/dL\t\nNa\t139\tmEq/L\t\nK\t4.3\tmEq/L\t\nCl\t105\tmEq/L\t\nCa\t8.5\tmg/dL\t\nCRP\t0.023\tmg/dL\t\nCA19-9\t772\tU/mL\t\nDUPAN-2\t>1,600\tU/mL\t\nSPan-1\t824\tU/mL\t\nCEA\t4.5\tng/mL\t\nHBs antigens\t(-)\t\t\nHBs antibody\t(-)\t\t\nHCV antibody\t(-)\t\t\nIgG\t656\tmg/dL\t\nIgA\t242\tmg/dL\t\nIgM\t56\tmg/dL\t\nC3\t95\tmg/dL\t\nC4\t25\tmg/dL\t\nRF\t2.69\tU/mL\t\nPR3-ANCA\t0.1\tU/mL\t\nMPO-ANCA\t0.1\tU/mL\t\nSerum protein electrophoresis\tNormal\t\t\n \t\t\t\nA urine protein-to-creatinine ratio\t6.94\tg/gCr\t\na 24-hour urine specimen\t7.46\tg\t\nThe urine protein selectivity index\t0.08\t\t\nT-chol: total cholesterol, DUPAN-2: Duke pancreatic monoclonal antigen type 2, SPan-1: s-pancreas antigen-1, CA19-9: carbohydrate antigen 19-9, CEA: carcinoembryonic antigen, HBs antigens: tests for hepatitis B virus surface antigens, HCV antibodies: antibodies to hepatitis C virus, Ig: immunoglobulins, C3 and C4: complement proteins C3 and C4, RF: rheumatoid factor, ANCA: antineutrophil cytoplasmic antibodies\n\nWe performed a renal biopsy and endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) for a pancreatic tumor (Fig. 2). The specimen obtained by EUS-FNA revealed a well-differentiated adenocarcinoma (Fig. 3). Renal biopsy specimens showed minor glomerular abnormalities on light microscopy (Fig. 4a, b) and negative staining on immunofluorescence microscopy against IgG, IgA, IgM, and carbohydrate antigen 19-9. Electron microscopy showed diffuse foot process effacement without electron-dense deposits (Fig. 4c). Therefore, he was diagnosed with pancreatic cancer and nephrotic syndrome due to MCD. The patient was classified as stage III (T4N0M0) in accordance with the Union for International Cancer Control 7th edition.\n\nFigure 2. Endoscopic ultrasound. (a, b) A pancreatic tumor (red arrowhead) is observed to have invaded the superior mesenteric vein (yellow arrowhead) and common hepatic artery (orange arrowhead). (c) Endoscopic ultrasound-guided fine needle aspiration with aspiration needle via the gastric wall (green arrowhead).\n\nFigure 3. Pathology of pancreatic cancer (×400). Normal pancreatic duct cells (blue arrow), Adenocarcinoma cells (red arrow).\n\nFigure 4. Pathology of the renal biopsy. (a) PAS staining (b) PAM staining (×400). A renal biopsy shows a minor glomerular abnormality on light microscopy. (c) Electron microscopy (×5,000) shows diffuse foot process effacement without any electron dense deposits (red arrow). PAM: periodic acid-methenamine silver, PAS: periodic acid-Schiff\n\nHe was started on angiotensin receptor blocker (ARB); however, ARB treatment was interrupted after one month due to a low blood pressure and totter. In the ARB period, proteinuria remained at a high level with the urine protein-to-creatinine ratio fluctuating from 6.94 to 2.02 to 8.94 to 3.89 g/gCr. After a second opinion, he was started on definitive treatment with chemotherapy (gemcitabine+nab-paclitaxel: GnP) (gemcitabine 1,800 mg; nab-paclitaxel 226 mg). Just before the start of GnP treatment, the serum creatinine was 1.89 mg/dL, serum albumin was 1.7 g/dL, and the urine protein-to-creatinine ratio was 3.89 g/gCr. He was not administered steroids, except for the small amount of dexamethasone (6.6 mg per dose, three times per month) included in the GnP regimen, or any other immunosuppressive agents. His proteinuria improved to the normal level one month after the start of chemotherapy. Because of grade 3 neutropenia based on the common terminology criteria for adverse events version 4.0 (CTCAE ver. 4.0), he required a dose reduction of the GnP therapy (gemcitabine 1,400 mg; nab-paclitaxel 174 mg) during cycles 2 to 5. Because of exertional dyspnea and peripheral neuropathy, he required a two-dose reduction of the GnP therapy (gemcitabine 1,100 mg; nab-paclitaxel 135 mg) during cycles 6 and 7. A follow-up CT performed 2 months after the start of GnP therapy showed a partial response. A follow-up CT performed 6 months after the start of GnP therapy (Fig. 5) showed no further change. The serum level of carbohydrate antigen 19-9 decreased to near-normal levels by 5 months (Fig. 6). However, due to advanced general fatigue, we changed the GnP therapy to chemoradiotherapy [tegafur/gimeracil/oteracil (S-1) + radiation at 50.4 Gy in 28 fractions] (S-1 120 mg). A follow-up CT performed after the completion of chemoradiotherapy showed stable disease (Fig. 7). He was then started on S-1 monotherapy with a two-dose reduction (S-1 80 mg) due to general fatigue and appetite loss. A follow-up CT performed 6 months after the start of S-1 monotherapy showed stable disease (Fig. 8). At 20 months after the start of GnP therapy, the patient was in complete remission for MCD.\n\nFigure 5. Computed tomography 6 months after the start of GnP. (a, b) pancreatic cancer (red arrowhead). GnP: gemcitabine+nab-paclitaxel\n\nFigure 6. Changes in proteinuria and CA19-9. The yellow line shows the proteinuria level. ARB was not effective. However, it normalized one month after GnP. The red line shows the CA19-9 level. It decreased accompanied by proteinuria. ARB: angiotensin receptor blocker, CA19-9: carbohydrate antigen 19-9, GnP: gemcitabine+nab-paclitaxel, S-1: tegafur/gimeracil/oteracil\n\nFigure 7. Computed tomography 2 months after switch of S-1+radiation therapy. (a, b) pancreatic cancer (red arrowhead). S-1: tegafur/gimeracil/oteracil\n\nFigure 8. Computed tomography 6 months after switch of S-1. (a, b) pancreatic cancer (red arrowhead). S-1: tegafur/gimeracil/oteracil\n\nDiscussion\nGlomerular disease in malignancies has been recognized for decades. Membranous nephropathy is the most common glomerular pathology. MCD has been associated with Hodgkin's lymphoma as well as other hematological malignancies; however, in two large studies on 1,700 Hodgkin's disease patients, only 0.4% of them had MCD (15, 16). MCD has rarely been associated with carcinomas such as thymoma, renal cell carcinoma, colorectal carcinoma, and lung carcinoma (3, 4). We searched for case reports of minimal change nephrotic syndrome patients with malignancy through PubMed using “minimal change nephrotic syndrome,” “pancreatic adenocarcinoma,” or “pancreatic cancer” as queries; only two cases were found (5, 6). The main characteristics of these patients and our case are shown in Table 2. The ages of the patients ranged from 67-82 years. The proteinuria level was in the nephrotic range in all patients (>3.5 g/day or urine test 4+). The creatinine level was high in our patient, but the other cases had no records. Although our patient received chemotherapy, others received no treatment for the malignant tumor. One case was administered a corticosteroid for MCD (5). Although the prognoses of pancreatic cancer with MCD were unclear in the previous reports, a long-term survival was obtained in our case using chemotherapy and chemoradiotherapy.\n\nTable 2. The Characteristics of the Patients with Minimal Change Disease (MCD) Associated with Pancreatic Cancer.\n\nReference\tAge/sex\tCreatinine level (mg/dL)\tProteinuria (g/day)\tmalignat tumor\tTherapy for MCD\tTherapy for malignant tumor\tEvaluate the response to treatment for tumor\tProteinuria after treatment (g/day)\tcourse of MCD\tPrognosis (from MCD diagnosis)\tadverse event\t\nour case\t82/M\t1.89\t6.94\tPancreatic carcinoma\t×\tchemotherapy\teffective\t0.01\tno recurrent\tsurvived (24 mo)\t\t\n[5]\t67/M\tNR\t>3.5\tPancreatic carcinoma\tPrednizolone\t×\tNR\t<0.15\tNR\tdied (8 mo)\tinfection (pneumonia, liver abscess)\t\n[6]\t68/M\tNR\tNR (urine test 4+)\tPancreatic carcinoma, Thymoma\t×\t×\tNR\tNR\tNR\tdied (3 days)\t\t\nNR: no record, M: man, mo: month\n\nAcute renal failure in the setting of MCD has been well described. In one study, it occurred in 25% of adult MCD patients and 4% of cases that required dialysis (10). In our case, the serum creatinine level was elevated at 1.89 mg/dL before the start of the GnP treatment, and it normalized during the therapy for the malignant tumor.\n\nNakayama et al. suggested the possible role of the inflammatory cytokines such as tumor necrosis factor-α in MCD preceding Hodgkin lymphoma (17). Inflammatory responses induced by Th2-related cytokines such as interleukin-13 might be important for development of MCD in patients with Hodgkin lymphoma (18). Although the cause of MCD with solid tumors has not yet been identified, cytokines, chemokines, other related factors produced by tumor cells, and general inflammation caused by tumors may be implicated (14).\n\nA diagnosis of paraneoplastic nephrotic syndrome can be considered if the following criteria are present: 1) no evidence of any other etiology, 2) nephrotic syndrome develops 6 months before or after a cancer diagnosis, 3) cancer treatment is associated with a decrease in proteinuria, and 4) cancer relapse is associated with an increase in proteinuria (19). Since the first three criteria were fulfilled in our patient, we considered that the MCD was therefore related to PC.\n\nThe currently accepted treatment of MCD in adults is prednisolone at 1 mg/kg per day for 16 weeks (10). The remission rate is 80-90%, and immunosuppressive agents such as cyclophosphamide, cyclosporine, or tacrolimus are rarely necessary (12). However, when MCD is secondary to a paraneoplastic syndrome, the treatment of neoplasia should be considered (20). Kofman et al. reported that 18 of 13,992 cases of non-Hodgkin lymphoma showed MCD, and that relapse of MCD occurred more frequently in patients treated only by steroids (77.8%) than those receiving combined therapy with steroids and other chemotherapeutic agents (25%) (13). Just before GnP, the urine protein-to-creatinine ratio was 3.89 g/gCr in our case. The prognosis of MCD associated with neoplasia was poor. Moreover, for the remission of MCD with steroid treatment without chemotherapy, the relapse rate is high (3, 14). Thus, it was considered that the complete remission of MCD was difficult, regardless of chemotherapy. Since the effects of steroids may be insufficient (13), we considered that chemotherapy was more important than steroid therapy for MCD associated with a malignant tumor. Moreover, diuretics improved the bilateral lower limb edema in our case. Thus, chemotherapy was administered first, but steroids were planned to be introduced if the improvement of nephrotic syndrome was poor. In our case, since the GnP was effective for nephrotic syndrome, steroids were therefore not administered.\n\nThe criteria considered as remission are as follows: resolution of edema, normalization of serum albumin (≥3.5 g/dL), and marked reduction in proteinuria. In adults, a complete remission is less than 0.3 g/day proteinuria, and a partial remission is less than 3.5 g/day proteinuria and a 50% reduction (21). To achieve proteinuria reduction normally requires several months of treatment in adults. In idiopathic MCD, the probability of remission is approximately 30% after 4 weeks and 80% after 16 weeks of steroid therapy (10, 22, 23). The criterion considered as relapse in adults is the recurrence of massive proteinuria (≥3.5 g/day) (21). In our case, a partial remission was achieved after 2 weeks of GnP therapy, and a complete remission was achieved after 5 weeks. Although the GnP regimen included a small amount of dexamethasone, it was very low compared to an MCD therapeutic dose. In addition, even though relapse of MCD occurred in 77.8% in patients with malignant diseases treated only by steroid (13), there was no relapse of MCD after switching to the TS-1 regimen in which steroids were not included in our case. Therefore, we considered that the GnP therapy was effective for both the pancreatic cancer and for the MCD.\n\nIn summary, we herein presented a rare case of MCD associated with pancreatic cancer treated with GnP therapy. Since the prognosis of MCD associated with a malignant tumor is a poor outcome in cases in which the therapy for the malignant tumor is not effective, it is considered that aggressive therapy for the malignant tumor is preferable in patients with malignancy-associated MCD.\n\n\nThe patient gave her informed consent for inclusion in the study.\n\n\nThe authors state that they have no Conflict of Interest (COI).\n==== Refs\n1. Nachman PH , Jennette JC , Falk RJ \nPrimary glomerular disease\n. In: The Kidney . 8th ed \nBrenner \nBM , Ed. Saunders Elsevier , Philadelphia , 2008 : 987 -1066\n.\n2. Cameron JS \nThe nephrotic syndrome and its complications\n. Am J Kidney Dis \n10 : 157 -171\n, 1987 .3307394 \n3. Glassock RJ \nSecondary minimal change disease\n. Nephrol Dial Transplant \n18 : vi52 -vi58\n, 2003 .12953043 \n4. Jhaveri KD , Shah HH , Calderon K , Campenot ES , Radhakrishnan J \nGlomerular diseases seen with cancer and chemotherapy: a narrative review\n. Kidney Int \n84 : 34 -44\n, 2013 .23364518 \n5. Whelan TV , Hirszel P \nMinimal-change nephropathy associated with pancreatic carcinoma\n. Arch Intern Med \n148 : 975 -976\n, 1988 .3355313 \n6. Hirokawa M , Moriya T , Manabe T \nMinimal change renal disease associated with thymoma and pancreatic carcinoma\n. Acta Pathol \n36 : 1075 -1081\n, 1986 .\n7. Avner ED , Harmon WE , Niaudet P , Yoshikawa N , Emma F , Goldstein SL \nIdiopathic nephrotic syndrome in children: clinical aspects\n. In: Pediatric Nephrology . 7th ed \nSpringer , Berlin , 2016 : 2730 .\n8. Lewis JB . Neilson EG \nGlomerular diseases\n. In: Harrison's Online [Internet]. 18th ed. Longo DL, Fauci AS, Kasper DL, et al., Eds. McGraw-Hill, New York, 2012. Available from: https://www.sohailuniversity.edu.pk/wp-content/uploads/2018/12/Harrisons-Manual-of-Medicine-18th-Edition.pdf\n9. Shalhoub RJ \nPathogenesis of lipid nephrosis: a disorder of T-cell function\n. Lancet \n2 : 556 -560\n, 1974 .4140273 \n10. Waldman M , Crew RJ , Valeri A , et al \nAdult minimal-change disease: clinical characteristics, treatment, and outcomes\n. Clin J Am Soc Nephrol \n2 : 445 -453\n, 2007 .17699450 \n11. Kerlin BA , Ayoob R , Smoyer WE \nEpidemiology and pathophysiology of nephrotic syndrome-associated thromboembolic disease\n. Clin J Am Soc Nephrol \n7 : 513 -520\n, 2012 .22344511 \n12. Hogan J , Radhakrishman J \nThe treatment of minimal change disease in adults\n. J Am Soc Nephrol \n24 : 702 -711\n, 2013 .23431071 \n13. Kofman T , Zhang SY , Copie-Bergman C , et al \nMinimal change nephrotic syndrome associated with non-Hodgkin lymphoid disorders: a retrospective study of 18 cases\n. Medicine (Baltimore) \n93 : 350 -358\n, 2014 .25500704 \n14. Li JY , Yong TY , Kuss BJ , Klebe S , Kotasek D , Barbara JA \nMalignant pleural mesothelioma with associated minimal change disease and acute renal failure\n. Renal Failure \n32 : 1012 -1115\n, 2010 .20722572 \n15. Plager J , Stutzman L \nAcute nephrotic syndrome as a manifestation of active Hodgkin's disease\n. Am J Med \n50 : 56 -66\n, 1971 .5539577 \n16. Kramer P , Sizoo W , Twiss EE \nNephrotic syndrome in Hodgkin's disease\n. Neth J Med \n24 : 114 -119\n, 1981 .7254442 \n17. Nakayama S , Yokote T , Kobayashi K , et al \nMinimal-change nephrotic syndrome preceding Hodgkin lymphoma by 5 years with expression of tumor necrosis factor alpha in Hodgkin-Reed-Sternberg cells\n. Hum Pathol \n41 : 1196 -1199\n, 2010 .20624522 \n18. Audard V , Larousserie F , Grimbert P , et al \nMinimal change nephrotic syndrome and classical Hodgkin's lymphoma: report of 21 cases and review of the literature\n. Kidney Int \n69 : 2251 -2260\n, 2006 .16672913 \n19. Burstein DM , Korbet SM , Schwartz MM \nMembranous glomerulonephritis and malignancy\n. Am J Kidney Dis \n9 : 23 -26\n, 1993 .\n20. Yildiz H , Andreea SI , Hoton D , Yombi JC \nMinimal change disease associated with malignant pleural mesothelioma: case report and review of literature\n. BMJ Case Rep \n2016 : bcr2016217958 , 2016 .\n21. Vivarelli M , Massella L , Ruggiero B , Emma F \nMinimal change disease\n. Clin J Am Soc Nephrol \n12 : 332 -345\n, 2017 .27940460 \n22. Vivarelli M , Moscaritolo E , Tsalkidis A , Massella L , Emma F \nTime for initial response to steroids is a major prognostic factor in idiopathic nephrotic syndrome\n. J Pediatr \n156 : 965 -971\n, 2010 .20223477 \n23. Chen CL , Fang HC , Chou KJ , et al \nIncreased endothelin 1 expression in adult-onset minimal change nephropathy with acute renal failure\n. Am J Kidney Dis \n45 : 818 -825\n, 2005 .15861346\n\n",
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"issn_linking": "0918-2918",
"issue": "60(2)",
"journal": "Internal medicine (Tokyo, Japan)",
"keywords": "chemoradiotherapy; minimal change disease; nab-Paclitaxel; pancreatic cancer; proteinuria",
"medline_ta": "Intern Med",
"mesh_terms": "D000369:Aged, 80 and over; D000418:Albumins; D000971:Antineoplastic Combined Chemotherapy Protocols; D003841:Deoxycytidine; D006801:Humans; D008297:Male; D009402:Nephrosis, Lipoid; D017239:Paclitaxel; D010190:Pancreatic Neoplasms",
"nlm_unique_id": "9204241",
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"pages": "251-257",
"pmc": null,
"pmid": "32963158",
"pubdate": "2021-01-15",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "17699450;27993826;20223477;16672913;3751567;20624522;20722572;3355313;15861346;23364518;4140273;8322793;3307394;27940460;7254442;12953043;22344511;5539577;25500704;23431071",
"title": "Secondary Minimal Change Disease Due to Pancreatic Cancer Improved by Chemotherapy.",
"title_normalized": "secondary minimal change disease due to pancreatic cancer improved by chemotherapy"
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"companynumb": "JP-ACCORD-203945",
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"patient": {
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"activesubstancename": "GEMCITABINE\\GEMCITABINE HYDROCHLORIDE"
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"abstract": "We report on a 16-year-old female who developed hypothermia as a result of a drug-drug interaction that produced supratherapeutic serum concentrations of clobazam. Although clobazam and its active metabolite (N-desmethylclobazam) are metabolized by cytochrome 2C19 (CYP2C19), literature suggests that clobazam-associated drug interactions involving this isoenzyme are not clinically relevant because of its wide therapeutic index. This report describes clobazam-associated hypothermia due to supratherapeutic serum concentrations of clobazam that resulted from the combination of 2 CYP2C19 inhibitors.",
"affiliations": null,
"authors": "Parman|Malinda G|MG|;Holmes|Amy P|AP|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.5863/1551-6776-24.2.156",
"fulltext": null,
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"issn_linking": "1551-6776",
"issue": "24(2)",
"journal": "The journal of pediatric pharmacology and therapeutics : JPPT : the official journal of PPAG",
"keywords": "CYP2C19; clobazam; drug interaction; hypothermia; omeprazole; oxcarbazepine; pediatric",
"medline_ta": "J Pediatr Pharmacol Ther",
"mesh_terms": null,
"nlm_unique_id": "101089851",
"other_id": null,
"pages": "156-159",
"pmc": null,
"pmid": "31019409",
"pubdate": "2019",
"publication_types": "D002363:Case Reports",
"references": "15483195;22293514;22422635;23112237;23318278;26870662;7249508;8807034",
"title": "Hypothermia in an Adolescent Due to Probable Drug-Drug Interaction Involving Clobazam.",
"title_normalized": "hypothermia in an adolescent due to probable drug drug interaction involving clobazam"
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"companynumb": "US-LUNDBECK-DKLU2071635",
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"activesubstancename": "CLOBAZAM"
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"... |
{
"abstract": "Ibrutinib, a potent and irreversible small-molecule inhibitor of both Bruton's tyrosine kinase and interleukin-2 inducible kinase (ITK), has been used to treat relapsed/refractory chronic lymphocytic leukemia (CLL) with prolongation of progression-free and overall survival. Here, we present 27 patients with relapsed CLL following allogeneic hematopoietic cell transplant (HCT) who subsequently received ibrutinib salvage therapy. Sixteen of these patients were part of multi-institutional clinical trials and achieved an overall response rate of 87.5%. An additional 11 patients were treated at Stanford University following US Food and Drug Administration approval of ibrutinib; 7 (64%) achieved a complete response, and 3 (27%) achieved a partial response. Of the 9 patients treated at Stanford who had mixed chimerism-associated CLL relapse, 4 (44%) converted to full donor chimerism following ibrutinib initiation, in association with disease response. Four of 11 (36%) patients evaluated by ClonoSeq achieved minimal residual disease negativity with CLL <1/10 000 white blood cells, which persisted even after ibrutinib was discontinued, in 1 case even after 26 months. None of the 27 patients developed graft-versus-host-disease (GVHD) following ibrutinib initiation. We postulate that ibrutinib augments the graft-versus-leukemia (GVL) benefit through a T-cell-mediated effect, most likely due to ITK inhibition. To investigate the immune modulatory effects of ibrutinib, we completed comprehensive immune phenotype characterization of peripheral B and T cells from treated patients. Our results show that ibrutinib selectively targets pre-germinal B cells and depletes Th2 helper cells. Furthermore, these effects persisted after drug discontinuation. In total, our results provide evidence that ibrutinib effectively augments GVL without causing GVHD.",
"affiliations": "Stanford Cancer Center, Stanford University School of Medicine, Stanford, CA.;Stanford Cancer Center, Stanford University School of Medicine, Stanford, CA.;Helen Diller Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA.;Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX.;The Ohio State University Medical Center, Columbus, OH.;St. James Institute of Oncology, The Leeds Teaching Hospitals, West Yorkshire, United Kingdom.;Division of Hematologic Malignancies, Dana-Farber Cancer Institute, Boston, MA.;Ernest and Helen Scott Haematological Research Institute, University of Leicester, Leicester, United Kingdom.;Center for CLL, University of Pennsylvania, Philadelphia, PA.;Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX.;The Ohio State University Medical Center, Columbus, OH.;Pharmacyclics LLC, an AbbVie Company, Sunnyvale, CA.;Stanford Cancer Center, Stanford University School of Medicine, Stanford, CA.;Pharmacyclics LLC, an AbbVie Company, Sunnyvale, CA.;Stanford Cancer Center, Stanford University School of Medicine, Stanford, CA.;Stanford Cancer Center, Stanford University School of Medicine, Stanford, CA.",
"authors": "Ryan|Christine E|CE|;Sahaf|Bita|B|;Logan|Aaron C|AC|;O'Brien|Susan|S|;Byrd|John C|JC|;Hillmen|Peter|P|;Brown|Jennifer R|JR|;Dyer|Martin J S|MJ|;Mato|Anthony R|AR|;Keating|Michael J|MJ|;Jaglowski|Samantha|S|;Clow|Fong|F|;Rezvani|Andrew R|AR|;Styles|Lori|L|;Coutre|Steven E|SE|;Miklos|David B|DB|",
"chemical_list": "D010880:Piperidines; D011720:Pyrazoles; D011743:Pyrimidines; C551803:ibrutinib; D000225:Adenine",
"country": "United States",
"delete": false,
"doi": "10.1182/blood-2016-06-715284",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0006-4971",
"issue": "128(25)",
"journal": "Blood",
"keywords": null,
"medline_ta": "Blood",
"mesh_terms": "D000225:Adenine; D000328:Adult; D000368:Aged; D001402:B-Lymphocytes; D046528:Chimerism; D015331:Cohort Studies; D005260:Female; D018858:Germinal Center; D006086:Graft vs Host Disease; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D056747:Immunomodulation; D015451:Leukemia, Lymphocytic, Chronic, B-Cell; D008198:Lymph Nodes; D008212:Lymphocyte Depletion; D008297:Male; D008875:Middle Aged; D018365:Neoplasm, Residual; D010880:Piperidines; D011720:Pyrazoles; D011743:Pyrimidines; D012008:Recurrence; D018418:Th2 Cells; D014019:Tissue Donors; D014184:Transplantation, Homologous; D016896:Treatment Outcome; D028761:Withholding Treatment",
"nlm_unique_id": "7603509",
"other_id": null,
"pages": "2899-2908",
"pmc": null,
"pmid": "27802969",
"pubdate": "2016-12-22",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article; D016448:Multicenter Study",
"references": "25150798;26813675;26847060;24113792;18182662;19168788;26819453;15613541;22547582;23940282;20615965;23782158;18551193;18216293;23419792;25662332;25766725;26944544;23382226;19290923;25730880;18364393;25700432;25271622;23247726;24332241;26752141;26660519;20528878;22160699;21232624;24881631;25847930;26422743;21422473;24829205;19423725;23886836;26991435;26576865;21314428;25573991",
"title": "Ibrutinib efficacy and tolerability in patients with relapsed chronic lymphocytic leukemia following allogeneic HCT.",
"title_normalized": "ibrutinib efficacy and tolerability in patients with relapsed chronic lymphocytic leukemia following allogeneic hct"
} | [
{
"companynumb": "US-JNJFOC-20170108586",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "IBRUTINIB"
},
"drugadditional": "3",
"d... |
{
"abstract": "The optimal treatment for medically refractory epilepsy in Aicardi syndrome (AS) is still unclear. Palliative surgical treatment, including vagus nerve stimulation and corpus callosotomy, has therefore been used. There is limited data on the role of resective epilepsy surgery as a treatment choice in patients with AS. Here, we describe the seizures, anatomo-pathological findings, and neurodevelopmental outcome of palliative epilepsy surgery in two children with AS who had resective epilepsy surgery at the Cleveland Clinic. The related literature is also reviewed. Case 1 had a left functional hemispherectomy and was free of seizures and hypsarrhythmia for six months after surgery. Her gross motor skills improved after surgery. Outcome at 43 months was 1-3 isolated spasms per day. Case 2 had a right fronto-parietal lobectomy. Her seizures improved in frequency and severity, but remained daily after epilepsy surgery. Neurodevelopment changes included improved alertness and recognition of caregivers. This patient died 21 months after epilepsy surgery of unclear causes. Surgical pathology in both cases showed focal cortical dysplasia associated with other findings, such as nodular heterotopia and polymicrogyria. Epilepsy surgery could be an alternative palliative treatment choice in selective cases of AS, but studies on a larger patient cohort are needed to identify the possible role of surgery in children with AS. The complexity of the pathological findings may offer an explanation for the severity of seizures in AS.",
"affiliations": "Epilepsy Center, Neurological Institute.;Epilepsy Center, Neurological Institute.;Epilepsy Center, Neurological Institute.;Epilepsy Center, Neurological Institute.;Epilepsy Center, Neurological Institute.;Anatomic Pathology, Cleveland Clinic, Cleveland, Ohio, USA.;Epilepsy Center, Neurological Institute.",
"authors": "Podkorytova|Irina|I|;Gupta|Ajay|A|;Wyllie|Elaine|E|;Moosa|Ahsan|A|;Bingaman|William|W|;Prayson|Richard|R|;Knight|Elia M Pestana|EM|",
"chemical_list": null,
"country": "France",
"delete": false,
"doi": "10.1684/epd.2016.0872",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1294-9361",
"issue": "18(4)",
"journal": "Epileptic disorders : international epilepsy journal with videotape",
"keywords": "Aicardi syndrome; focal cortical dysplasia; palliative treatment; polymicrogyria; resective epilepsy surgery; surgical pathology",
"medline_ta": "Epileptic Disord",
"mesh_terms": "D058540:Aicardi Syndrome; D002648:Child; D005260:Female; D006801:Humans; D010166:Palliative Care; D012640:Seizures",
"nlm_unique_id": "100891853",
"other_id": null,
"pages": "431-439",
"pmc": null,
"pmid": "27818366",
"pubdate": "2016-12-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Aicardi syndrome: epilepsy surgery as a palliative treatment option for selected patients and pathological findings.",
"title_normalized": "aicardi syndrome epilepsy surgery as a palliative treatment option for selected patients and pathological findings"
} | [
{
"companynumb": "US-UCBSA-2017007856",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "LACOSAMIDE"
},
"drugadditional": null,
"d... |
{
"abstract": "We present three fatal intoxications of methylone, a cathinone derivative. Blood was analyzed with a routine alkaline liquid-liquid extraction and analyzed by gas chromatography coupled with a mass spectrometer (GC-MS). Methylone was identified by a full scan mass spectral comparison to an analytical standard of methylone. For a definitive and conclusive confirmation and quantitation, methylone was also derivatized with heptafluorobutyric anhydride and analyzed by GC-MS. In all three fatalities, the deceased exhibited seizure-like activity and elevated body temperatures (103.9, 105.9 and 107°F) before death. Two of the three cases also exhibited metabolic acidosis. One of the three cases had prolonged treatment and hospitalization before death with symptoms similar to sympathomimetic toxicity, including metabolic acidosis, rhabdomyolysis, acute renal failure and disseminated intravascular coagulation. The laboratory results for this patient over the 24 h period of hospitalization were significant for increased lactate, liver transaminases, creatinine, myoglobin, creatine kinase and clotting times, and decreased pH, glucose and calcium. Peripheral blood methylone concentrations in the three fatal cases were 0.84, 3.3 and 0.56 mg/L. In conlusion, peripheral blood methylone concentrations in excess of 0.5 mg/L may result in death due to its toxic properties, which can include elevated body temperature and other sympathomimetic-like symptoms.",
"affiliations": "Hillsborough County Medical Examiner Department, Tampa, FL, USA. pearsonjm@hillsboroughcounty.org",
"authors": "Pearson|Julia M|JM|;Hargraves|Tiffanie L|TL|;Hair|Laura S|LS|;Massucci|Charles J|CJ|;Frazee|C Clinton|CC|;Garg|Uttam|U|;Pietak|B Robert|BR|",
"chemical_list": "D000697:Central Nervous System Stimulants; D013287:Illicit Drugs; D008694:Methamphetamine; C400939:methylone",
"country": "England",
"delete": false,
"doi": "10.1093/jat/bks043",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0146-4760",
"issue": "36(6)",
"journal": "Journal of analytical toxicology",
"keywords": null,
"medline_ta": "J Anal Toxicol",
"mesh_terms": "D000138:Acidosis; D000328:Adult; D000697:Central Nervous System Stimulants; D017809:Fatal Outcome; D005260:Female; D005334:Fever; D006801:Humans; D013287:Illicit Drugs; D008297:Male; D008694:Methamphetamine; D011605:Psychoses, Substance-Induced; D012640:Seizures; D055815:Young Adult",
"nlm_unique_id": "7705085",
"other_id": null,
"pages": "444-51",
"pmc": null,
"pmid": "22589523",
"pubdate": "2012-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Three fatal intoxications due to methylone.",
"title_normalized": "three fatal intoxications due to methylone"
} | [
{
"companynumb": "US-TARO-2021TAR00787",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "LAMOTRIGINE"
},
"drugadditional": null,
... |
{
"abstract": "Although Nexplanon is one of the most effective and most utilized long-acting reversible contraceptives in Ghana. We report a rare event of Nexplanon failure in a woman with human immunodeficiency virus (HIV) infection in rural Ghana.",
"affiliations": "Ghana Health Service Nabdam District Health Directorate Nangodi Ghana.;Ghana Health Service Talensi District Hospital Tongo Ghana.;Ghana Health Service Nabdam District Health Directorate Nangodi Ghana.",
"authors": "Kumbeni|Maxwell Tii|MT|https://orcid.org/0000-0001-5525-4022;Apanga|Paschal Awingura|PA|;Ayamga|Emmanuel Awine|EA|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1002/ccr3.3156",
"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/ccr3.3156\nCCR33156\nCase Report\nCase Reports\nNexplanon failure in a woman with HIV infection in rural Ghana: A case report\nKUMBENI et al.Kumbeni Maxwell Tii https://orcid.org/0000-0001-5525-4022\n1\ntiimax2@gmail.com Apanga Paschal Awingura \n2\n Ayamga Emmanuel Awine \n1\n \n1 \nGhana Health Service\nNabdam District Health Directorate\nNangodi\nGhana\n\n\n2 \nGhana Health Service\nTalensi District Hospital\nTongo\nGhana\n\n* Correspondence\n\nMaxwell Tii Kumbeni, Ghana Health Service, Nabdam District Health Directorate, Nangodi, Ghana.\n\nEmail: tiimax2@gmail.com\n\n16 7 2020 \n12 2020 \n8 12 10.1002/ccr3.v8.122369 2372\n15 5 2020 06 6 2020 30 6 2020 © 2020 The Authors. Clinical Case Reports published by John Wiley & Sons LtdThis 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\nAlthough Nexplanon is one of the most effective and most utilized long‐acting reversible contraceptives in Ghana. We report a rare event of Nexplanon failure in a woman with human immunodeficiency virus (HIV) infection in rural Ghana.\n\nAlthough Nexplanon is one of the most effective and most utilized long‐acting reversible contraceptives in Ghana. We report a rare event of Nexplanon failure in a woman with human immunodeficiency virus (HIV) infection in rural Ghana.\n\n\nefavirenzGhanaNexplanonunplanned pregnancy source-schema-version-number2.0cover-dateDecember 2020details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:5.9.6 mode:remove_FC converted:21.12.2020\n\n\nKumbeni \nMT \n, \nApanga \nPA \n, \nAyamga \nEA \n. Nexplanon failure in a woman with HIV infection in rural Ghana: A case report\n. Clin Case Rep . 2020 ;8 :2369 –2372\n. 10.1002/ccr3.3156\n==== Body\n1 INTRODUCTION\nFamily planning is considered globally as an important intervention toward attaining the sustainable development goals (SDG) target 3.7, which is focused on preventing unplanned pregnancy and reducing teenage childbirth through universal access to sexual and reproductive health services.\n1\n The United Nations (UN) has lauded the rise on contraceptive use, particularly the use of long‐acting or permanent contraceptive methods among married couples.\n2\n The UN reported that more than one‐third of married women globally are on contraceptive methods such as subdermal implants, intrauterine devices (IUD), and sterilization.\n2\n The use of long‐acting reversible contraceptives (LARCs) has led to significant lower rates of unplanned pregnancies as compared to short‐acting reversible contraceptives (SARCs).\n3\n, \n4\n LARCs also have higher satisfaction and adherence rates compared to SARCs.\n5\n The use of LARCs have also been effective in preventing unplanned pregnancies during postpartum or postabortion.\n6\n, \n7\n\n\n\nThe use of subdermal implants to prevent unplanned pregnancies has increasingly become prevalent globally including Ghana.\n2\n Nexplanon is a long‐acting reversible subdermal contraceptive implant which has been proven as a highly efficacious contraceptive device.\n8\n, \n9\n It is cost effective, convenient to use, and highly efficacious compared to other contraceptive methods.\n10\n, \n11\n Return to fertility is also quick with Nexplanon and can safely be used by breastfeeding mothers.\n10\n, \n12\n It can also be used by women who are not tolerant to estrogen.\n12\n Despite its benefits, clients on Nexplanon have reported adverse effects, discontinued its use, and have reported contraceptive failure.\n9\n, \n13\n, \n14\n Most of these “failures” are associated with faulty insertion technique, client already pregnant, insertion at the wrong time during the menstrual cycle, expulsion of the implant, and drug interactions.\n15\n, \n16\n\n\n\nWe present a rare case of Nexplanon failure in a woman with HIV infection in rural Ghana. There are limited studies on the failure of subdermal contraceptive implants such Nexplanon in clients with HIV infection.\n13\n To the best of our knowledge, Nexplanon failure has also not been reported in a woman with HIV infection in rural Ghana.\n\n2 CASE PRESENTATION\nThe client is a 37‐year‐old widow with weigh of 68kg and was diagnosed of HIV infection in 2014 and has been on the following antiretrovirals: Tenofovir (300 mg); Lamivudine (300 mg); and Efavirenz (600 mg). Diagnosis of HIV infection was made using first response rapid diagnostic HIV test kits and confirmed with OraQuick test. The diagnosis of HIV infection and regimen of treatment in this woman was based on local protocols. Her parity is six with four children alive with two infant deaths. All six gestations were carried to term, uneventful with spontaneous vaginal deliveries. She has a regular menstrual cycle of 28 days. She has no history of other chronic diseases such as diabetes, hypertension, and epilepsy. She has no history of contraceptive failure including Nexplanon. She is not on any other medications except the antiretrovirals. She also has no history of smoking or alcohol consumption.\n\nThe client presented to the family planning clinic of a health facility in rural Ghana on the 6th of December 2017 and requested for Nexplanon (68 mg Etonogestrel) after informed counseling on all available contraceptive methods. Her last menstrual period was on 30th November 2017, and a urine pregnancy test was also done to rule out pregnancy. The client was eligible for Nexplanon based on the WHO Medical Eligibility Criteria for contraceptive use.\n17\n An experienced trained community health nurse on LARCs inserted the Nexplanon into her upper nondominant arm (left arm) under aseptic conditions on the same day. The client returned for review in a month's later without any complains. The expiry date of the Nexplanon inserted was December 2020.\n\nOn the 13th of February 2020, the client reported to the health facility with the complains of amenorrhea for six weeks, feeling of breast heaviness and dizziness. Client tested positive for pregnancy at the health facility. An obstetric ultrasound scan confirmed a single viable intrauterine gestation at six weeks and three days with no visible fetal pole yet (Figure 1). This was an unplanned pregnancy, and client requested for termination of pregnancy after counseling. On examination of the left upper arm, the Nexplanon rod was well positioned and rod was removed. Client's pregnancy was terminated via manual vacuum aspiration after obtaining informed consent. After the termination of the pregnancy, client against medical advice refused to be put on any form of contraception. However, the client returned to the family planning clinic of the health facility on the 22nd February 2020. She chose Jadelle, and this was inserted for her after informed counseling was done.\n\nFigure 1 Obstetric ultrasound scan taken on 14th February 2020. Gestational sac (GS) was 2.12 cm, and gestational age (GA) was 6 weeks and 3 days according to the scan. Expected date of delivery was 6th October 2020\n\n3 DISCUSSION\nDrug interactions with LARCs can reduce the efficacy of contraceptives.\n18\n The cytochrome P450 (CYP) enzyme system in the liver plays a crucial role in drug metabolism, and drugs that induce these enzymes are capable of causing increased elimination of hormonal contraceptives, leading to reduced efficacy and exposing the client to a high risk of unplanned pregnancies.\n19\n Some common enzyme inducers include antiepileptic drugs (phenytoin, phenobarbital, oxcarbazepine, topiramate, and carbamazepine) \n20\n; antitubercular drugs (rifampicin and isoniazid); and non‐nucleoside reverse transcriptase inhibitors (efavirenz and nevirapine).\n21\n, \n22\n These drugs induce the CYP450 system which enhances the metabolism of estrogen and progestin and thereby reducing the serum concentration of progestin.\n20\n Such drugs have led to sporadic cases of subdermal implant failure which have resulted into intrauterine or ectopic pregnancies.\n3\n, \n13\n, \n14\n\n\n\nThis client was treated with an Efavirenz (EFV)‐based antiretroviral while on Nexplanon. Etonogestrel is metabolized by cytochrome P450 3A4 (CYP 3A4), and EFV enhances the systemic clearance of coadministered drugs that are cytochrome CYP 3A4 substrates.\n23\n Thus, EFV might have led to reduced serum levels of etonogestrel in our client leading to her unplanned pregnancy. This is a possible as recent studies have suggested that women on Nexplanon contraception and EFV‐based antiretrovirals have a lower serum concentration of etonogestrel plasma concentration as compared with women who are not on antiretrovirals.\n24\n, \n25\n, \n26\n EFV‐based antiretrovirals are known to reduce the etonogestrel serum concentration threshold for ovulation suppression which reported as 90 pg/mL.\n24\n, \n26\n This increases the risk of ovulation among clients that combine the use of EFV‐based antiretrovirals and Nexplanon.\n\nStudies have reported Nexplanon failure in patients on EFV.\n27\n, \n28\n The failure of implants due to its interaction with EFV has the potential to result in many unwanted pregnancies.\n27\n It can also undermine the confidence women have on implants. To avoid unwanted pregnancies, it has been suggested by Shelton to replace EFV with another ARV that does not significantly reduce progestin blood levels.\n27\n\n\n\nAlthough Nevirapine and EFV are inducers of CYP 3A4, these drugs are part of the recommended first‐line regimen for treatment of people living with HIV including women of reproductive age according to the WHO.\n29\n Women of reproductive age living with HIV and on EFV‐based antiretrovirals are also eligible to receive Nexplanon.\n17\n Though our client's treatment of HIV infection and use of Nexplanon were consistent with the WHO guidelines on antiretrovirals and contraceptive use, clients on EFV‐based antiretrovirals may not be suitable candidates for Nexplanon use due to the interactions between EFV/ Nevirapine and etonogestrel.\n\n4 CONCLUSION\nThis case report emphasizes the possibility of unplanned pregnancy with the concurrent use of Nexplanon and EFV‐based antiretrovirals although the WHO medical eligibility criteria permit the use of Nexplanon in women who are on EFV‐based antiretrovirals. However, further studies are needed to establish whether a causal relationship exists between EFV‐based antiretrovirals and Nexplanon failure.\n\nCONFLICT OF INTEREST\nNone declared.\n\nAUTHOR CONTRIBUTIONS\nMTK and EAA: involved in care of the patient. MTK and PAA: prepared the manuscript. EAA: edited the manuscript. All authors: read and approved the final manuscript.\n\nCONSENT FOR PUBLICATION\nWritten informed consent was obtained from the patient for publication of this case report and its accompanying image. A copy of the written consent is available for review by the Editor‐in‐Chief of this journal.\n\nACKNOWLEDGMENTS\nPublished with written consent of the patient.\n==== Refs\nREFERENCES\n1 \nUnited Nations General Assembly \n. Transforming our world: the 2030 agenda for sustainable development\n. 2015. https://www.un.org/development/desa/dspd/2015/08/transforming‐our‐world‐the‐2030‐agenda‐for‐sustainable‐development/. Accessed March 16, 2020.\n2 \n\nScoggins \nS \n, \nBremner \nJ \n.FP2020 Momentum at the Midpoint 2015–2016 Progress report\n. 2016. http://2015‐2016progress.familyplanning2020.org/uploads/05/15/FP2020_DIGITAL_Spreads_LoRes.pdf. Accessed March 10, 2020.\n3 \n\nHubacher \nD \n, \nSpector \nH \n, \nMonteith \nC \n, \nChen \nPL \n, \nHart \nC \n. Long‐acting reversible contraceptive acceptability and unintended pregnancy among women presenting for short‐acting methods: a randomized patient preference trial\n. Am J Obstet Gynecol . 2017 ;216 (2 ):101 ‐109\n.27662799 \n4 \n\nTibaijuka \nL \n, \nOdongo \nR \n, \nWelikhe \nE \n, et al. Factors influencing use of long‐acting versus short‐acting contraceptive methods among reproductive‐age women in a resource‐limited setting\n. BMC Womens Health . 2017 ;17 (1 ):25 .28376779 \n5 \n\nCasey \nSE \n, \nCannon \nA \n, \nMushagalusa Balikubirhi \nB \n, \nMuyisa \nJB \n, \nAmsalu \nR \n, \nTsolka \nM \n. Twelve‐month contraceptive continuation among women initiating short‐ and long‐acting reversible contraceptives in North Kivu, Democratic Republic of the Congo\n. PLoS One . 2017 ;12 (9 ):e0182744.28886016 \n6 \n\nMoniz \nMH \n, \nSpector‐Bagdady \nK \n, \nHeisler \nM \n, \nHarris \nLH \n. Inpatient postpartum long‐acting reversible contraception: care that promotes reproductive justice\n. Obstet Gynecol . 2017 ;130 (4 ):783 ‐787\n.28885401 \n7 \n\nLuo \nZ \n, \nGao \nL \n, \nAnguzu \nR \n, \nZhao \nJ \n. Long‐acting reversible contraceptive use in the post‐abortion period among women seeking abortion in mainland China: intentions and barriers\n. Reprod Health . 2018 ;15 (1 ):85 .29793501 \n8 \n\nRoberts \nA \n, \nMorhason‐Bello \nI \n, \nOkunlola \nM \n. Profile of Implanon acceptors and pattern of side effects\n. J Reprod Contracept . 2015 ;26 :46 ‐52\n.\n9 \n\nMitchell \nD \n, \nAndrew \nM \n, \nPhilip \nD \n, \nHampton \nT \n, \nGordon \nK \n, \nRekers \nH \n. The US etonogestrel implant mandatory clinical training and active monitoring programs: 6‐year experience\n. Contraception . 2017 ;95 :205 ‐210\n.27452317 \n10 \n\nAli \nM \n, \nBahamondes \nL \n, \nBent \nLS \n. Extended effectiveness of the etonogestrel‐releasing contraceptive implant and the 20 µg levonorgestrel‐releasing intrauterine system for 2 years beyond U.S. Food and Drug Administration product labeling\n. Glob Health Sci Pract . 2017 ;5 (4 ):534 ‐539\n.29263025 \n11 \n\nMerck \nS \n, \nDohme \nB \n. IMPLANON® (etonogestrel implant) FDA approved labelling\n. 2016 .\n12 \n\nChen \nM \n, \nHsia \nJ \n, \nCreinin \nM \n. Etonogestrel implant use in women primarily choosing a combined oral contraceptive pill: a proof‐of‐concept trial\n. Contraception . 2018 ;97 (6 ):533 ‐537\n.29496473 \n13 \n\nPatel \nRC \n, \nOnono \nM \n, \nGandhi \nM \n, et al. Pregnancy rates in HIV‐positive women using contraceptives and efavirenz‐based or nevirapine‐based antiretroviral therapy in Kenya: a retrospective cohort study\n. Lancet HIV . 2015 ;2 :474 ‐482\n.\n14 \n\nRamdhan \nRC \n, \nSimonds \nE \n, \nWilson \nC \n, \nLoukas \nM \n, \nOskouian \nRJ \n, \nTubbs \nRS \n. Complications of subcutaneous contraception: a review\n. Cureus . 2018 ;10 (1 ):e2132.29610715 \n15 \n\nChoi \nJH \n, \nKim \nHY \n, \nLee \nSS \n, \nCho \nS \n. Migration of a contraceptive subdermal device into the lung\n. Obstet Gynecol Sci . 2017 ;60 (3 ):314 ‐317\n.28534019 \n16 \n\nAli \nM \n, \nAkin \nA \n, \nBahamondes \nL \n, et al. Extended use up to 5 years of the etonogestrel‐releasing subdermal contraceptive implant: comparison to levonorgestrel‐releasing subdermal implant\n. Hum Reprod . 2016 ;31 (11 ):2491 ‐2498\n.27671673 \n17 \nWorld Health Organization \n. Medical eligibility criteria for contraceptive use , 5th edn. Geneva, Switzerland : WHO \n2015 :82 ‐92\n.\n18 \n\nScarsi \nKK \n, \nDarin \nKM \n, \nChappell \nCA \n, \nNitz \nSM \n, \nLamorde \nM \n. Drug‐drug interactions, effectiveness, and safety of hormonal contraceptives in women living with HIV\n. Drug Saf . 2016 ;39 (11 ):1053 ‐1072\n.27562873 \n19 \n\nZhang \nN \n, \nShon \nJ \n, \nKim \nMJ \n, et al. Role of CYP3A in oral contraceptives clearance\n. Clin Transl Sci . 2018 ;11 (3 ):251 ‐260\n.28986954 \n20 \n\nHole \nK \n, \nWollmann \nBM \n, \nNguyen \nC \n, \nHaslemo \nT \n, \nMolden \nE \n. Comparison of CYP3A4‐inducing capacity of enzyme‐inducing antiepileptic drugs using 4β‐hydroxycholesterol as biomarker\n. Ther Drug Monit . 2018 ;40 (4 ):463 ‐468\n.29649093 \n21 \n\nStolbach \nA \n, \nPaziana \nK \n, \nHeverling \nH \n, \nPham \nP \n. A review of the toxicity of HIV medications II: interactions with drugs and complementary and alternative medicine products\n. J Med Toxicol . 2015 ;11 (3 ):326 ‐341\n.26036354 \n22 \n\nGufford \nBT \n, \nRobarge \nJD \n, \nEadon \nMT \n, et al. Rifampin modulation of xeno‐ and endobiotic conjugating enzyme mRNA expression and associated microRNAs in human hepatocytes\n. Pharmacol Res Perspect . 2018 ;6 (2 ):e00386.29610665 \n23 \n\nNanda \nK \n, \nStuart \nGS \n, \nRobinson \nJ \n, \nGray \nAL \n, \nTepper \nNK \n, \nGaffield \nME \n. Drug interactions between hormonal contraceptives and antiretrovirals\n. AIDS . 2017 ;31 (7 ):917 ‐952\n.28060009 \n24 \n\nChappell \nCA \n, \nLamorde \nM \n, \nNakalema \nS \n, et al. Efavirenz decreases etonogestrel exposure : a pharmacokinetic evaluation of implantable contraception with antiretroviral therapy\n. AIDS . 2017 ;31 :1965 ‐1972\n.28692531 \n25 \n\nScarsi \nKK \n, \nDarin \nKM \n, \nNakalema \nS \n, et al. Unintended pregnancies observed with combined use of the levonorgestrel contraceptive implant and efavirenz‐based antiretroviral therapy: a three‐arm pharmacokinetic evaluation over 48 weeks\n. Clin Infect Dis . 2016 ;62 (6 ):675 ‐682\n.26646680 \n26 \n\nBishop \nIJ \n, \nGertz \nAM \n, \nSimon \nB \n, et al. Etonogestrel concentrations among contraceptive implant users in Botswana using and not using dolutegravir‐based antiretroviral therapy\n. Contraception . 2020 ;S0010–7824 (20 ):30134 ‐30137\n.\n27 \n\nShelton \nJD \n. Reduced effectiveness of contraceptive implants for women taking the antiretroviral efavirenz (EFV): still good enough and for how long?\n\nGlob Health Sci Pract . 2015 ;3 (4 ):528 ‐531\n.26681700 \n28 \n\nPatel \nRC \n, \nMorroni \nC \n, \nScarsi \nKK \n, \nSripipatana \nT \n, \nKiarie \nJ \n, \nCohen \nCR \n. Concomitant contraceptive implant and efavirenz use in women living with HIV: perspectives on current evidence and policy implications for family planning and HIV treatment guidelines\n. J Int AIDS Soc . 2017 ;20 (1 ):21396 .28530033 \n29 \n\nDimala \nCA \n, \nBechem \nNN \n, \nAroke \nD \n, \nKadia \nBM \n. Motives for change of first‐line antiretroviral therapy regimens in an unselected cohort of HIV/AIDS patients at a major referral centre in South‐west Cameroon\n. BMC Res Notes . 2017 ;10 (1 ):623 .29183354\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2050-0904",
"issue": "8(12)",
"journal": "Clinical case reports",
"keywords": "Ghana; Nexplanon; efavirenz; unplanned pregnancy",
"medline_ta": "Clin Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101620385",
"other_id": null,
"pages": "2369-2372",
"pmc": null,
"pmid": "33363743",
"pubdate": "2020-12",
"publication_types": "D002363:Case Reports",
"references": "29263025;27662799;27562873;26681700;28376779;26646680;29793501;28885401;29610665;29183354;28986954;27452317;28060009;26036354;28534019;28692531;29496473;28886016;29649093;32387328;26520927;29610715;28530033;27671673",
"title": "Nexplanon failure in a woman with HIV infection in rural Ghana: A case report.",
"title_normalized": "nexplanon failure in a woman with hiv infection in rural ghana a case report"
} | [
{
"companynumb": "GH-009507513-2008GHA000821",
"fulfillexpeditecriteria": "1",
"occurcountry": "GH",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "LAMIVUDINE"
},
"drugadditional": null,
... |
{
"abstract": "A 76-year-old man developed recurrent encephalopathy, visual disturbance, myoclonus, generalised seizures and atonic drop attacks on a background of a gastrectomy for adenocarcinoma and stable chronic lymphocytic leukaemia. He presented to three different hospitals and was admitted twice, with normal investigations. His symptoms transiently improved during each admission (and with starting levetiracetam) but recurred each time on hospital discharge. Subsequent careful inspection of his medication box identified that his community pharmacy had in error been dispensing baclofen 80 mg per day instead of his prescribed Buscopan 80 mg per day. This case highlights the importance of physically inspecting a patient's medications and emphasises the spectrum of baclofen-related toxicity; it also highlights potential deficiencies in the pharmacy dispensary process and the need for multiple checks by patients and professionals.",
"affiliations": "Clinical Neuroscience, Royal Free London NHS Foundation Trust, London, UK soontjin@gmail.com.;Clinical Neuroscience, Royal Free London NHS Foundation Trust, London, UK.;Clinical Neuroscience, Royal Free London NHS Foundation Trust, London, UK.;Clinical Neuroscience, Royal Free London NHS Foundation Trust, London, UK.",
"authors": "Lim|Soon Tjin|ST|http://orcid.org/0000-0003-1345-3079;Yates|Timothy|T|;Liang|Di|D|;Angus-Leppan|Heather|H|",
"chemical_list": "D009125:Muscle Relaxants, Central; D001418:Baclofen",
"country": "England",
"delete": false,
"doi": "10.1136/practneurol-2019-002301",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1474-7758",
"issue": "20(3)",
"journal": "Practical neurology",
"keywords": "baclofen; drug errors; encephalopathy; myoclonus; seizures",
"medline_ta": "Pract Neurol",
"mesh_terms": "D000368:Aged; D001418:Baclofen; D003221:Confusion; D006970:Disorders of Excessive Somnolence; D006801:Humans; D008297:Male; D008508:Medication Errors; D059065:Medication Reconciliation; D009125:Muscle Relaxants, Central; D014786:Vision Disorders",
"nlm_unique_id": "101130961",
"other_id": null,
"pages": "243-245",
"pmc": null,
"pmid": "32001662",
"pubdate": "2020-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Out of sight: a lesson in drug errors.",
"title_normalized": "out of sight a lesson in drug errors"
} | [
{
"companynumb": "GB-TEVA-2021-GB-1935792",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "BACLOFEN"
},
"drugadditional": "1",
"... |
{
"abstract": "Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors such as afatinib are used for non-small cell lung cancer (NSCLC) and show varying efficacy depending on EGFR gene mutation. Few studies have examined the relationship between EGFR gene mutations and the adverse events of afatinib in NSCLC. This retrospective study included 32 Japanese patients with NSCLC with EGFR gene mutation who were treated with afatinib between May 2014 and August 2018 at Kagawa University Hospital. Among the 32 Japanese patients with NSCLC treated with afatinib, 19 patients were positive for exon 19 deletion mutation (Del 19) and 13 patients were negative for Del 19. The incidence of grade ≥ 2 skin rash was slightly higher in patients positive for Del 19 (42.1% vs. 7.7%, P = 0.050). No significant differences were detected in other adverse events between the two patient groups. Patients positive for Del 19 also showed significantly longer median progression-free survival (288 vs. 84 days, P = 0.049). Our study indicates a higher incidence of skin rash associated with afatinib treatment in Japanese patients with NSCLC positive for Del 19 compared with patients without Del 19. The Del 19 positive patient group also showed better progression-free survival. J. Med. Invest. 68 : 125-128, February, 2021.",
"affiliations": "Department of Pharmacy, Kagawa University Hospital, Kagawa 761-0793, Japan.;Department of Pharmacy, Kagawa University Hospital, Kagawa 761-0793, Japan.;Department of Pharmacy, Kagawa University Hospital, Kagawa 761-0793, Japan.;Department of Pharmacy, Kagawa University Hospital, Kagawa 761-0793, Japan.;Department of Pharmacy, Kagawa University Hospital, Kagawa 761-0793, Japan.;Department of Pharmacy, Kagawa University Hospital, Kagawa 761-0793, Japan.;Department of Pharmacy, Kagawa University Hospital, Kagawa 761-0793, Japan.;Kagawa School of Pharmaceutical Sciences, Tokushima Bunri University, Kagawa 769-2193, Japan.;Department of Pharmacy, Kagawa University Hospital, Kagawa 761-0793, Japan.",
"authors": "Yamashita|Sayaka|S|;Tanaka|Hiroaki|H|;Tatsumichi|Takakiyo|T|;Yamaguchi|Kazunori|K|;Tai|Tatsuya|T|;Suzuki|Kiyo|K|;Motoki|Takahiro|T|;Houchi|Hitoshi|H|;Kosaka|Shinji|S|",
"chemical_list": "D000077716:Afatinib; D066246:ErbB Receptors",
"country": "Japan",
"delete": false,
"doi": "10.2152/jmi.68.125",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1343-1420",
"issue": "68(1.2)",
"journal": "The journal of medical investigation : JMI",
"keywords": "afatinib; non-small cell lung cancer; skin rash, exon 19 deletion mutation",
"medline_ta": "J Med Invest",
"mesh_terms": "D000077716:Afatinib; D002289:Carcinoma, Non-Small-Cell Lung; D066246:ErbB Receptors; D006801:Humans; D008175:Lung Neoplasms; D009154:Mutation; D012189:Retrospective Studies",
"nlm_unique_id": "9716841",
"other_id": null,
"pages": "125-128",
"pmc": null,
"pmid": "33994456",
"pubdate": "2021",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Relationship between Epidermal Growth Factor Receptor Mutations and Adverse Events in Non-Small Cell Lung Cancer Patients treated with Afatinib.",
"title_normalized": "relationship between epidermal growth factor receptor mutations and adverse events in non small cell lung cancer patients treated with afatinib"
} | [
{
"companynumb": "JP-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2021-BI-105217",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "AFATINIB"
},
"dr... |
{
"abstract": "OBJECTIVE\nOmbitasvir/Paritaprevir/ritonavir/Dasabuvir (OBV/PTV/r+DSV) is one of the elective direct-acting antivirals (DAAs) recommended by international guidelines and the only one covered by the National Insurance System in Romania until November 2016. Our aim was to present the first prospective Romanian cohort evaluating the effectiveness and safety in clinical practice of this 3DAA combination in patients with HCV genotype-1b Child A liver cirrhosis.\n\n\nMETHODS\n681 patients received OBV/PTV/r+DSV+RBV for 12 weeks and were assessed clinically and biologically at baseline, week 4, 8, 12 (end of treatment, EOT), and 12 weeks after therapy (sustained viral response, SVR).\n\n\nRESULTS\nPer protocol, EOT virological response was 99.8% and SVR12 rate was 99.4%. Adverse events were present in 36.4% of patients. Permanent discontinuation of 3DAA regimen due to side effects was reported in 11 patients (1.6%). In 47.6% (185/389) of patients, Transient Elastography values were >20kPa (defined as clinically significant portal hypertension, CSPH) at baseline. Independent variables associated with CSPH were: baseline cholesterol level (p=0.003), platelet count <120,000/mm³ (p=0.02), MELD score (p=0.01). Liver stiffness measurement has significantly improved between baseline (26.6+/-12.7kPa) and SVR12 (21.6+/-11.8kPa) (p<0.0001). The same was true for APRI score (2.66+/-0.15 at baseline vs 0.85+/-0.02 at SVR12, p<0.0001) and FIB4 score (5.53+/-0.28 vs 3.24+/-0.08, p<0.0001), but not for Lok score (0.57+/-0.01 vs 0.63+/-0.01, p<0.0001).\n\n\nCONCLUSIONS\nWe report a high efficacy of the 3DAA regimen in a homogeneous compensated HCV genotype-1b liver cirrhosis population, in a real-life setting. Noninvasive fibrosis scores significantly improved at SVR12.",
"affiliations": "Digestive Diseases and Liver Transplantation Center, Fundeni Clinical Institute; Carol Davila University of Medicine and Pharmacy, Bucharest, Romania.;Digestive Diseases and Liver Transplantation Center, Fundeni Clinical Institute; Carol Davila University of Medicine and Pharmacy, Bucharest, Romania. msiacob@gmail.com.;Department of Infectious Diseases, Victor Babeș University of Medicine and Pharmacy, Timisoara, Romania.;Department of Gastroenterology, University of Medicine, Oradea, Romania.;Institute of Gastroenterology and Hepatology, Gr.T. Popa University of Medicine and Pharmacy Iasi, Romania.;Carol Davila University of Medicine and Pharmacy, Bucharest;Matei Bals National Institute of Infectious Diseases, Bucharest, Romania.;Institute of Gastroenterology and Hepatology, Gr.T. Popa University of Medicine and Pharmacy Iasi, Romania.;Digestive Diseases and Liver Transplantation Center, Fundeni Clinical Institute, Bucharest, Romania.;Department of Gastroenterology and Hepatology, Victor Babeș University of Medicine and Pharmacy, Timisoara, Romania.;Digestive Diseases and Liver Transplantation Center, Fundeni Clinical Institute; Carol Davila University of Medicine and Pharmacy, Bucharest, Romania.;Digestive Diseases and Liver Transplantation Center, Fundeni Clinical Institute; Carol Davila University of Medicine and Pharmacy, Bucharest, Romania.;Carol Davila University of Medicine and Pharmacy, Bucharest; Matei Bals National Institute of Infectious Diseases, Bucharest, Romania.;Department of Gastroenterology and Hepatology, Victor Babeș University of Medicine and Pharmacy, Timisoara, Romania.;Institute of Gastroenterology and Hepatology, Gr.T. Popa University of Medicine and Pharmacy Iasi, Romania.",
"authors": "Gheorghe|Liana|L|;Iacob|Speranta|S|;Curescu|Manuela|M|;Brisc|Ciprian|C|;Cijevschi|Cristina|C|;Caruntu|Florin|F|;Stanciu|Carol|C|;Simionov|Iulia|I|;Sporea|Ioan|I|;Gheorghe|Cristian|C|;Iacob|Razvan|R|;Arama|Victoria|V|;Sirli|Roxana|R|;Trifan|Anca|A|",
"chemical_list": "D000813:Anilides; D000998:Antiviral Agents; D002219:Carbamates; D003521:Cyclopropanes; D047029:Lactams, Macrocyclic; D047028:Macrocyclic Compounds; D013449:Sulfonamides; C586094:ombitasvir; D014498:Uracil; D011392:Proline; D015081:2-Naphthylamine; C588260:dasabuvir; D014633:Valine; D019438:Ritonavir; C585405:paritaprevir",
"country": "Romania",
"delete": false,
"doi": "10.15403/jgld.2014.1121.263.iac",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1841-8724",
"issue": "26(3)",
"journal": "Journal of gastrointestinal and liver diseases : JGLD",
"keywords": null,
"medline_ta": "J Gastrointestin Liver Dis",
"mesh_terms": "D015081:2-Naphthylamine; D000368:Aged; D000813:Anilides; D000998:Antiviral Agents; D002219:Carbamates; D003521:Cyclopropanes; D004359:Drug Therapy, Combination; D054459:Elasticity Imaging Techniques; D005260:Female; D005838:Genotype; D016174:Hepacivirus; D006526:Hepatitis C; D006801:Humans; D047029:Lactams, Macrocyclic; D008103:Liver Cirrhosis; D047028:Macrocyclic Compounds; D008297:Male; D008875:Middle Aged; D011392:Proline; D011446:Prospective Studies; D019438:Ritonavir; D012383:Romania; D013449:Sulfonamides; D000072230:Sustained Virologic Response; D013997:Time Factors; D016896:Treatment Outcome; D014498:Uracil; D014633:Valine",
"nlm_unique_id": "101272825",
"other_id": null,
"pages": "275-281",
"pmc": null,
"pmid": "28922440",
"pubdate": "2017-09",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Real-Life Use of 3 Direct-Acting Antiviral Regimen in a Large Cohort of Patients with Genotype-1b HCV Compensated Cirrhosis.",
"title_normalized": "real life use of 3 direct acting antiviral regimen in a large cohort of patients with genotype 1b hcv compensated cirrhosis"
} | [
{
"companynumb": "RO-KADMON PHARMACEUTICALS, LLC-KAD201710-001124",
"fulfillexpeditecriteria": "1",
"occurcountry": "RO",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "RIBAVIRIN"
},
"drugaddi... |
{
"abstract": "Injectable opioid agonist therapy (iOAT) has previously been demonstrated to be an effective treatment option for individuals with a severe opioid use disorder (OUD) who have been unsuccessful on first line therapy (eg, buprenorphine/naloxone or methadone). Many individuals with severe OUD may also have HIV infection. Despite this, no literature currently exists examining the relationship between antiretroviral therapy (ART) initiation and adherence following iOAT initiation in the outpatient setting.\n\n\n\nRetrospective case series (n = 3) of HIV-infected individuals with a severe OUD who were refractory to oral opioid agonist treatment and were started on iOAT in a community setting in Vancouver, Canada. Outcomes of interest included: (1) iOAT induction and maintenance dosing schedules; (2) ART adherence demonstrated by change in HIV viral load.\n\n\n\nAll 3 patients initiated and successfully reached iOAT maintenance doses with significant reduction in illicit opioid use. Stable iOAT was associated with increased ART initiation and adherence, and decreased HIV viral loads. Conversely, poor retention or discontinuation of iOAT was associated with reduced adherence to ART and in 1 patient, increased HIV viral loads.\n\n\n\nThe individual cases presented suggest that among individuals with severe OUD and HIV infection, iOAT may improve HIV treatment uptake and retention in care.",
"affiliations": "British Columbia Centre on Substance Use (BCCSU), Vancouver, BC, Canada (VG, RB, CS, SN); Department of Medicine, University of British Columbia, St. Paul's Hospital, Vancouver, BC, Canada (VG, RB, CS, SN).",
"authors": "Giang|Valerie|V|;Brar|Rupinder|R|;Sutherland|Christy|C|;Nolan|Seonaid|S|",
"chemical_list": "D000701:Analgesics, Opioid",
"country": "United States",
"delete": false,
"doi": "10.1097/ADM.0000000000000609",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1932-0620",
"issue": "14(5)",
"journal": "Journal of addiction medicine",
"keywords": null,
"medline_ta": "J Addict Med",
"mesh_terms": "D000701:Analgesics, Opioid; D002170:Canada; D015658:HIV Infections; D006801:Humans; D058850:Opiate Substitution Treatment; D009293:Opioid-Related Disorders; D012189:Retrospective Studies",
"nlm_unique_id": "101306759",
"other_id": null,
"pages": "437-440",
"pmc": null,
"pmid": "32011407",
"pubdate": "2020",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "HIV Treatment Initiation and Retention Among Individuals Initiated on Injectable Opioid Agonist Therapy for Severe Opioid Use Disorder: A Case Series.",
"title_normalized": "hiv treatment initiation and retention among individuals initiated on injectable opioid agonist therapy for severe opioid use disorder a case series"
} | [
{
"companynumb": "CA-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-307300",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "METHADONE HYDROCHLORIDE"
},
... |
{
"abstract": "OBJECTIVE\nTo present the largest series reported so far of brimonidine induced granulomatous anterior uveitis.\n\n\nMETHODS\nRetrospective chart review of patients with chronic glaucoma on treatment with brimonidine presenting with anterior uveitis.\n\n\nRESULTS\n19 eyes of 12 patients with chronic glaucoma developed anterior uveitis with granulomatous keratic precipitates after being treated with brimonidine for periods of 7 days to 5 years (mean 19.7 months, +18.6 months). One patient had a gap of 1 year between onset in one eye and onset in the other. Ten eyes (52.6%) had concurrent granulomatous conjunctivitis; 16 eyes were pseudophakic. Stopping brimonidine led to complete, rapid resolution of uveitis in all patients, in most cases (11 eyes, 58%) without topical corticosteroids. No recurrences have occurred after withdrawal of brimonidine, over a follow-up period of 12-52 months (mean 27.9 months, +13.8 months).\n\n\nCONCLUSIONS\nOphthalmologists should be aware of this easily reversible uveitis syndrome that is induced by a common glaucoma medication. Familiarity with this entity is essential in making the correct diagnosis and avoiding unnecessary investigations and interventions.",
"affiliations": "a Centre For Eye Research Australia, The Royal Victorian Eye and Ear Hospital , Melbourne , Australia and.;a Centre For Eye Research Australia, The Royal Victorian Eye and Ear Hospital , Melbourne , Australia and.",
"authors": "Beltz|Jacqueline|J|;Zamir|Ehud|E|",
"chemical_list": "D058647:Adrenergic alpha-2 Receptor Agonists; D000068438:Brimonidine Tartrate",
"country": "England",
"delete": false,
"doi": "10.3109/09273948.2015.1037845",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0927-3948",
"issue": "24(2)",
"journal": "Ocular immunology and inflammation",
"keywords": "Brimonidine uveitis; drug induced uveitis",
"medline_ta": "Ocul Immunol Inflamm",
"mesh_terms": "D058647:Adrenergic alpha-2 Receptor Agonists; D000368:Aged; D000369:Aged, 80 and over; D000068438:Brimonidine Tartrate; D003231:Conjunctivitis; D005260:Female; D005902:Glaucoma, Open-Angle; D006801:Humans; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D014606:Uveitis, Anterior; D028761:Withholding Treatment",
"nlm_unique_id": "9312169",
"other_id": null,
"pages": "128-33",
"pmc": null,
"pmid": "26399160",
"pubdate": "2016",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Brimonidine Induced Anterior Uveitis.",
"title_normalized": "brimonidine induced anterior uveitis"
} | [
{
"companynumb": "AU-ALLERGAN-1520140US",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "BRIMONIDINE TARTRATE"
},
"drugadditional": "1",
... |
{
"abstract": "Bacterial keratitis can threaten vision through permanent corneal scarring and even perforation, resulting in loss of the eye. Klebsiella oxytoca is resistant to several antibiotics because it produces extended-spectrum β-lactamase encapsulated with polysaccharide. Thus, this article is aimed at reporting a rare case of Klebsiella oxytoca-induced keratitis in Jimma University Medical Centre, Jimma, Ethiopia.\nTA 25-year-old female patient presented with photophobia, redness, and purulent discharge from the right eye. She had matted cilia of the eyelid, conjunctiva injection, corneal ulcer, and deep fibrinous anterior chamber reaction. She had light perception (LP) visual acuity for the same eye and it was firm when examined digitally. The cornea-scleral repair was performed one month earlier, due to open globe injury. The patient had taken empirical fortified antibiotics before the identification of the specific pathogen. Culture and drug sensitivity test was performed in order to identify the aetiology. The result of the test revealed that the identified pathogen was multi-drug-resistant Klebsiella oxytoca. Based on this result and drug availability, high dose topical fluoroquinolones eye drops (Ciprofloxacin eye drop 0.3% and Ofloxacin 0.3%) were given. Besides, dexamethasone 0.1% eye drop was added to the aforementioned antibiotics. After four months of treatment, the visual outcome was changed from LP to hand motion.\nA rare case of multi-drug resistant Klebsiella oxytoca induced keratitis which was isolated in a biochemical test was successfully treated with a high dose of fluoroquinolones.",
"affiliations": "Department of Pharmacy, College of Medicine and Health Science, Mizan-Tepi University, Mizan-Aman, Ethiopia.;Department of Pharmacy, College of Medicine and Health Science, Mizan-Tepi University, Mizan-Aman, Ethiopia.;Department of Pharmacy, College of Medicine and Health Science, Mizan-Tepi University, Mizan-Aman, Ethiopia.;Department of Pharmacy, College of Medicine and Health Science, Mizan-Tepi University, Mizan-Aman, Ethiopia.;Department of Ophthalmology, Institute of Health Science, Jimma University, Jimma, Ethiopia.",
"authors": "Dago|Tolcha Regasa|TR|0000-0002-2921-8471;Zewudie|Ameha|A|0000-0002-2657-6089;Mamo|Yitagesu|Y|;Feyissa|Desalegn|D|0000-0002-5781-0368;Geleta|Sinbona|S|",
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"doi": "10.2147/IMCRJ.S278625",
"fulltext": "\n==== Front\nInt Med Case Rep J\nInt Med Case Rep J\nimcrj\nimcrj\nInternational Medical Case Reports Journal\n1179-142X Dove \n\n278625\n10.2147/IMCRJ.S278625\nCase Report\nMulti-Drug Resistant Post Corneal Repair Klebsiella oxytoca’s Keratitis\nDago et alDago et alhttp://orcid.org/0000-0002-2921-8471Dago Tolcha Regasa 1 http://orcid.org/0000-0002-2657-6089Zewudie Ameha 1 Mamo Yitagesu 1 http://orcid.org/0000-0002-5781-0368Feyissa Desalegn 1 Geleta Sinbona 2 1 Department of Pharmacy, College of Medicine and Health Science, Mizan-Tepi University, Mizan-Aman, Ethiopia\n2 Department of Ophthalmology, Institute of Health Science, Jimma University, Jimma, Ethiopia\nCorrespondence: Tolcha Regasa Dago Department of Pharmacy, College of Medicine and Health Science, Mizan Tepi University, Mizan-Aman, EthiopiaTel +251917233151 Email negasatolosa@gmail.com\n20 10 2020 \n2020 \n13 537 541\n28 8 2020 23 9 2020 © 2020 Dago et al.2020Dago et al.This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php).Background\nBacterial keratitis can threaten vision through permanent corneal scarring and even perforation, resulting in loss of the eye. Klebsiella oxytoca is resistant to several antibiotics because it produces extended-spectrum β-lactamase encapsulated with polysaccharide. Thus, this article is aimed at reporting a rare case of Klebsiella oxytoca-induced keratitis in Jimma University Medical Centre, Jimma, Ethiopia.\n\nCase Presentation\nTA 25-year-old female patient presented with photophobia, redness, and purulent discharge from the right eye. She had matted cilia of the eyelid, conjunctiva injection, corneal ulcer, and deep fibrinous anterior chamber reaction. She had light perception (LP) visual acuity for the same eye and it was firm when examined digitally. The cornea-scleral repair was performed one month earlier, due to open globe injury. The patient had taken empirical fortified antibiotics before the identification of the specific pathogen. Culture and drug sensitivity test was performed in order to identify the aetiology. The result of the test revealed that the identified pathogen was multi-drug-resistant Klebsiella oxytoca. Based on this result and drug availability, high dose topical fluoroquinolones eye drops (Ciprofloxacin eye drop 0.3% and Ofloxacin 0.3%) were given. Besides, dexamethasone 0.1% eye drop was added to the aforementioned antibiotics. After four months of treatment, the visual outcome was changed from LP to hand motion.\n\nConclusion\nA rare case of multi-drug resistant Klebsiella oxytoca induced keratitis which was isolated in a biochemical test was successfully treated with a high dose of fluoroquinolones.\n\nKeywords\nKlebsiella oxytocakeratitisanti-microbial resistantEthiopia\n==== Body\nIntroduction\nBacterial keratitis is a serious ocular infectious disease that can lead to severe visual disability. The severity of the corneal infection usually depends on the underlying conditions of the cornea and the pathogenicity of the infecting bacteria. The eye is hard and protected by a continuous flow of tears which contain antibacterial compounds. However, underlying conditions such as inflammation, previous surgical procedures, scarring, and immunity-compromising conditions may predispose the cornea for infection.1–3\n\nKlebsiella oxytoca is rare but it can cause severe bacterial keratitis. It is a gram-negative bacterial pathogen which is encapsulated with cylindrical polysaccharide. It is also a rod-shape, non-motile in nature, belonging to the Enterobacteriaceae family and the genus of Klebsiella.4,5\n\nBacterial keratitis can threaten vision through permanent corneal scarring and even perforation, resulting in the loss of the eye. If definitive identification and treatment are given, significant morbidity associated with severe microbial keratitis may be avoided. However, in this case complications occurred due to the misidentification of the responsible microbial organism and subsequent inadequate and/or inappropriate treatment.6,7 Isolation of the indole-positive Klebsiella species- Klebsiella oxytoca is difficult. This characteristic increases the incidence of extended-spectrum β-lactamase producing Klebsiella oxytoca. Klebsiella oxytoca is a serious problem worldwide, because of their incrimination in antibiotic resistance.8,9 Polysaccharide capsule and different mutation of Klebsiella oxytoca contributes to great resistance against the host defence mechanism. Therefore, this case reports the isolation of Klebsiella oxytoca’ without polymerase chain reaction and successful treatment of multi-drug resistant Klebsiella oxytoca- induced keratitis with fluoroquinolone eye drops (Ciprofloxacin eye drop 0.3% and Ofloxacin 0.3%).\n\nCase Presentation\nA 25-year-old female patient admitted to the Jimma University Medical Centre, Jimma, Ethiopia, Ophthalmology clinic on May 9, 2019 with the complaint of photophobia, redness, and purulent discharge from the right eye. The slit-lamp examination also showed matted cilia of the eyelid, conjunctiva injection which had eroded around the stitch, corneal ulcer of 3.5 x 3 mm, negative sidle test, hypopyon, deep fibrinous anterior chamber reaction, pupil not visible well due to stitch-site abscess, the lens was transparent and located around thestitch. She had also a light perception (LP) visual acuity for the same eye. The eye was firm when examined digitally (Figure 1).Figure 1 Klebsiella oxytoca induced keratitis showing hypopyon, redness, ulcer and stitch on cornea sclera after admission. Green arrow shows ulcer, black arrow shows redness of eye, and blue arrow shows hypopyon.\n\n\n\nShe had a traumatic globe injury of the same eye one month earlier. At that time, she had bleeding from the eye. There was also laceration of the cornea and iris. For this reason, the cornea-scleral repair was performed under aseptic technique and corneal wound repair was performed with nylon 10/0 while sclera’s wound was repaired with vicryl 5/0. Tetracycline and sub-conjunctiva vancomycin and ceftazidime were given at that time.\n\nAn abscess was debrided and 3–5 stitches were removed during admission one month after cornea-scleral repair. The corneal scraped sample was then sent to the microbiology department for culture and drug susceptibility test and an empirical fortified antibiotic was prescribed. Fortified vancomycin eye drop 50mg/mL (5%) and fortified gentamicin eye drops 14mg/mL (1.4%, tropicamide 0.3% eye drop, and acetazolamide 250mg orally were given for patient). The patient was taking the above medication until the result of the microbiology report (7days) but no improvement was seen. Ophthalmologist collected corneal scrapings with a 20 gauge sterile needle during admission. A topical anaesthetic (1% tetracaine) was used during taking of the corneal specimens. Then the scraping was inserted into a 2mL brain heart infusion broth (Oxoid, Hampshire, UK) tube. After that, it was immediately inoculated into chocolate and blood agar. A chocolate and a blood agar plate were placed into a candle jar for fastidious bacterial pathogens, which require CO2, while one blood agar plate was placed into a cold chain to maintain the viability of the bacterial pathogens during transport. This three culture plates and one tube were incubated appropriately. After incubation, subcultures were made onto sheep blood agar (5%), chocolate agar, mannitol salt agar and MacConkey agar (Oxoid, Hampshire, UK) using the standard methods. The inoculated media plates were incubated at their respective optimal temperatures. The plates were then checked for growth after 48 hours. The bacterial isolates from the corneal scrapings was identified up to species-level based on different criteria which included morpho-cultural and biochemical tests. Currently using a molecular method such as polymerase chain reaction is recommended to identify different species of Klebsiella but we used a biochemical test method (old method). Biochemical test on isolated organism showed negative methyl red, positive Voges-Proskauer reaction, positive citrate, urea and growth on sulfide-indole motility medium (indole-positive). It was also ornithine decarboxylase negative and lysine decarboxylase positive. Finally, these were all test-proven characteristics of Klebsiella oxytoca which as reported by Jimma University Medical Center Microbiology Department. In vitro antibiotic susceptibility testing of the bacterial isolates was performed by Kirby-Bauer disc diffusion method.10 The interpretation of the results was according to the Clinical and Laboratory Standards Institute methodology as susceptible, intermediate and resistant (Table 1).Table 1 Culture Result and Drug Susceptibility of Isolated Organism from Sample of Case Report\n\n\tAmpicillin\tAmpicillin-Sulbactam\tAmoxicillin-Clavulanic Acid\tTetracycline\tCefepime\tCeftriaxone\tCeftazidime\tChloramphenicol\tCiprofloxacilline\tErythromycin\tGentamicin\tMeropenem\tTobramycin\tImipenem\tPiperacillin-Tazobactum\tCotrimoxazole\t\nKlebsiella oxytoca\tR\tS\t\t\tR\t\t\tR\tI\t\tR\tI\t\t\t\t\t\nAbbreviations: R, resistant; S, susceptible; I, intermediate.\n\n\n\n\nDue to this, drug susceptibility test and local availability of eye drop fortified antibiotics were discontinued and a high dose of ciprofloxacin 0.3% eye drop was prescribed every 2 hours with dexamethasone eye drops every 6 hours. Ibuprofen 400mg as required was also given for pain relief. She had also taken cloxacillin 500mg orally every 6 hours for 7days. Pain, photophobia, and discharges were much decreased. Ulcer size also decreased to less than 1.5 x 1mm She was discharged after one month on June 8, 2019 (Figure-2). After discharge, she was kept on weekly follow-up and stayed on follow-up until September 21, 2019. At follow-up, she was taking tetracycline eye ointment, ciprofloxacin eye drops, and tropicamide eye drops. Sometimes, she took ofloxacillin eye drops in place of ciprofloxacin eye drops. At the end of follow-up, a scar was formed around the stitch and improvement of vision was seen from LP to hand motion at the end of 4 months (Figure-3).Figure 2 Photograph of Klebsiella oxytoca-induced infectious keratitis showing some improvement: significantly decreased ulcer, stitch removed around ulcer while the patient was undergoing treatment and discharged.\n\nFigure 3 Photograph of Klebsiella oxytoca-induced infectious keratitis showing formed scar from ulcer and scar around removed stitch at final follow-up.\n\n\n\nDiscussion\nThis case reported the isolation of Klebsiella oxytoca without polymerase chain reaction and successful treatment of multi-drug resistant Klebsiella oxytoca- induced keratitis with fluoroquinolones eye drops (ciprofloxacin eye drop 0.3% and ofloxacin 0.3%).\n\nKlebsiella oxytoca is a rare cause of infectious keratitis. For instance, a study conducted in British Columbia University, Canada showed that the incidences of bloodstream infection due to Klebsiella Pneumoniae and Klebsiella oxytoca were 9.1 and 2.9 per 100,000 per year, respectively. About 75% of those pathogens were healthcare-associated. The incidence case of Klebsiella oxytoca-induced keratitis is far less than those of blood steam infections.11\n\nAs far as our knowledge, there is only one case that was reported worldwide before this case.4\n\nIn this case report, the isolated Klebsiella oxytoca strain was resistant to ampicillin, cefepime, chloramphenicol, and gentamicin. However, it was susceptible to ampicillin-sulbactam and intermediate resistant for ciprofloxacin and meropenem. Since the susceptible drugs were not available in the study setting, fluoroquinolones (ciprofloxacin eye drop and ofloxacin eye drop) were prescribed for the patients. Finally, the patient’s visual acuity was improved from LP to hand motion after four month of treatment with fluoroquinolones. This is in line with the study conducted in India which revealed that the isolated Klebsiella oxytoca strains were resistant to cefepime and gentamicin. However, the finding of the above report showed out of 175 Klebsiella oxytoca isolated, 117 were fluoroquinolone-resistant.12 Similar to our report, a study conducted at Hinduja Hospital, Mumbai identified, Klebsiella oxytoca as resistant to ampicillin, cefepime, and gentamicin.12 In contrast to our report, a study conducted at Hinduja Hospital, Mumbai identified Klebsiella oxytoca resistant to ampicillin/sulbactam.13\n\nFluoroquinolones have good clinical effect against Enterobacteriaceae including Klebsiella. However, the recurrence of ciprofloxacin-resistant Klebsiella species has expanded worldwide lately.14\nKlebsiella pneumonia and Klebsiella oxytoca are the two most common pathogens causing nosocomial infections in humans, among different genus of Klebsiella. Because of this reason, they are of great concern for developing multi-drug resistance.15 The emergence of strains of Klebsiella oxytoca that are resistant to extended-spectrum β-lactam antibiotics enforced the physicians to choice of an appropriate antimicrobial agent for treating these infections.16\n\nThe risk factors for Klebsiella oxytoca-induced keratitis in our case report may include previous cornea-scleral surgery and use of dexamethasone eye drops. This is similar to studies conducted by Karp et al and Chang et al which showed that the history of corneal surgery and use of topical corticosteroids were the risk factors for Klebsiella oxytoca induced keratitis. The incidence of post-laser surgery infectious keratitis is estimated to be between 1/1000 and 1/5000.17,18 Physicians routinely order antibiotics to treat Klebsiella oxytoca-induced keratitis infection. However, some strains are resistant to most commonly used antibiotics. In such cases, specialized laboratory tests may be used in order to prescribe alternative antibiotics to treat the infections.6\n\nIn this case report, we used an old method (biochemical test) to differentiate Klebsiella oxytoca from other Klebsiella species. Molecular methods such as polymerase chain reaction have been evaluated for the rapid and accurate identification of Klebsiella in human clinical specimens.19\n\nIn conclusion, a rare case of multi-drug resistant Klebsiella oxytoca-induced keratitis was successfully treated with high dose topical fluoroquinolone eye drops (ciprofloxacin eye drop 0.3% and ofloxacin 0.3%).\n\nAcknowledgment\nWe would like to acknowledge our colleague from Jimma University Medical Centre, the Ophthalmology hospital where the patient was initially diagnosed and managed. We would also like to acknowledge the patient for her willingness in providing all the necessary information.\n\nEthics\nEthical approval was obtained from the institutional review board of Jimma University Medical Centre. The patient has provided written informed consent to have the case details published.\n\nDisclosure\nAll authors declare that they have no conflicts of interest in this work.\n==== Refs\nReferences\n1. Vajpayee \nRB , Dada \nT , Saxena \nR , et al. Study of the first contact management profile of cases of infectious keratitis: a hospital-based study\n. Cornea . 2000 ;19 (1 ):52 –56\n. doi:10.1097/00003226-200001000-00011 10632009 \n2. Miedziak \nAI , Miller \nMR , Rapuano \nCJ , Laibson \nPR , Cohen \nEJ . Risk factors in microbial keratitis leading to penetrating keratoplasty\n. Ophthalmology . 1999 ;106 (6 ):1166 –1171\n.10366087 \n3. Teweldemedhin \nM , Gebreyesus \nH , Atsbaha \nAH , Asgedom \nSW , Saravanan \nM . Bacterial profile of ocular infections: a systematic review\n. BMC Ophthalmol . 2017 ;17 (1 ):212 . doi:10.1186/s12886-017-0612-2 29178851 \n4. Chou \nTY , Adyanthaya \nR . Infectious crystalline keratopathy associated with Klebsiella oxytoca\n. J Ophthalmic Inflamm Infect . 2012 ;2 (4 ):211 . doi:10.1007/s12348-012-0071-0 22447560 \n5. Gorkiewicz \nG . Nosocomial and antibiotic-associated diarrhoea caused by organisms other than Clostridium difficile\n. Int J Antimicrob Agents . 2009 ;33 :S37 –S41\n. doi:10.1016/S0924-8579(09)70015-9 19303568 \n6. Bourcier \nT , Thomas \nF , Borderie \nV , Chaumeil \nC , Laroche \nL . Bacterial keratitis: predisposing factors, clinical and microbiological review of 300 cases\n. Br J Ophthalmol . 2003 ;87 (7 ):834 –838\n. doi:10.1136/bjo.87.7.834 12812878 \n7. Karsten \nE , Watson \nSL , Foster \nLJ . Diversity of microbial species implicated in keratitis: a review\n. Open Ophthalmol J . 2012 ;6 :110 . doi:10.2174/1874364101206010110 23248737 \n8. Mori \nM , Ohta \nM , Agata \nN , et al. Identification of species and capsular types of Klebsiella clinical isolates, with special reference to Klebsiella planticola\n. Microbiol Immunol . 1989 ;33 (11 ):887 –895\n. doi:10.1111/j.1348-0421.1989.tb00976.x 2593874 \n9. Hori \nK , Yasoshima \nH , Yamada \nA , et al. Adrenal hemorrhage associated with Klebsiella oxytoca bacteremia\n. Intern Med . 1998 ;37 (11 ):990 –994\n. doi:10.2169/internalmedicine.37.990 9868968 \n10. Cheesbrough \nM . District Laboratory Practice in Tropical Countries . 2nd ed. London : Cambridge ; 2006 :132 –135\n.\n11. Reid \nCB , Steele \nL , Pasquill \nK , Parfitt \nEC , Laupland \nKB . Occurrence and determinants of Klebsiella species bloodstream infection in the western interior of British Columbia, Canada\n. BMC Infect Dis . 2019 ;19 (1 ):1 –7\n. doi:10.1186/s12879-019-4706-8 30606108 \n12. Rath \nS , Padhy \nRN . Prevalence of two multidrug-resistant Klebsiella species in an Indian teaching hospital and adjoining community\n. J Infect Public Health . 2014 ;7 (6 ):496 –507\n.24996691 \n13. Trivedi \nMK , Branton \nA , Trivedi \nD , et al. Characterization of antimicrobial susceptibility profile of biofield treated multidrug-resistant klebsiella oxytoca\n. Appl Microbiol . 2015 ;1 (1 ). Open Access, Longdom Publishing SL .\n14. Thomson \nCJ . The global epidemiology of resistance to ciprofloxacin and the changing nature of antibiotic resistance: a 10 year perspective\n. J Antimicrob Chemother . 1999 ;43 (suppl_1 ):31 –40\n. doi:10.1093/jac/43.suppl_1.31 \n15. Chakraborty \nS , Mohsina \nK , Sarker \nPK , Alam \nMZ , Karim \nMI , Sayem \nSA . Prevalence, antibiotic susceptibility profiles and ESBL production in Klebsiella pneumoniae and Klebsiella oxytoca among hospitalized patients\n. Period Biol . 2016 ;118 (1 ):53 –58\n. doi:10.18054/pb.2016.118.1.3160 \n16. Arakawa \nY , Ohta \nM , Kido \nN , et al. Chromosomal b-lactamase of Klebsiella oxytoca, a new class A enzyme that-hydrolyzes broad-spectrum b-lactam antibiotics\n. Antimicrob Agents Chemother . 1989 ;33 :63 –70\n. doi:10.1128/AAC.33.1.63 2653216 \n17. Karp \nCL , Tuli \nSS , Yoo \nSH , et al. Infectious keratitis after LASIK\n. Ophthalmology . 2003 ;110 (3 ):503 –510\n. doi:10.1016/S0161-6420(02)01760-8 12623812 \n18. Chang \nMA , Jain \nS , Azar \nDT . Infections following laser in situ keratomileusis: an integration of the published literature\n. Surv Ophthalmol . 2004 ;49 (3 ):269 –280\n. doi:10.1016/j.survophthal.2004.02.007 15110665 \n19. Chander \nY , Ramakrishnan \nMA , Jindal \nN , Hanson \nK , Goyal \nSM . Differentiation of Klebsiella pneumoniae and K. oxytoca by multiplex polymerase chain reaction\n. Int J Appl Res Vet Med . 2011 ;9 (2 ):138 .\n\n",
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"issn_linking": "1179-142X",
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"journal": "International medical case reports journal",
"keywords": "Ethiopia; Klebsiella oxytoca; anti-microbial resistant; keratitis",
"medline_ta": "Int Med Case Rep J",
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"nlm_unique_id": "101566269",
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"pages": "537-541",
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"pmid": "33116946",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": "10632009;12812878;15110665;31856756;10225569;10366087;24996691;19303568;22447560;9868968;29178851;2593874;12623812;2653216;23248737",
"title": "Multi-Drug Resistant Post Corneal Repair Klebsiella oxytoca's Keratitis.",
"title_normalized": "multi drug resistant post corneal repair klebsiella oxytoca s keratitis"
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"abstract": "Severe pulmonary hypertension (PH) in obese patients pose a challenge to treat despite advances in medical therapeutics. Current treatment options are limited for patients who are not responding to maximal medical therapy. Here, we present a case of multifactorial PH, not responsive to ambrisentan, tadalafil, and treprostinil, even after optimization of cardiac and pulmonary function and had a poor prognosis. She demonstrated weight loss after bariatric surgery, improving her restrictive lung disease, obstructive sleep apnea and PH, and overall functionality. Bariatric surgery may offer a potential therapeutic option, in patients with morbid obesity and PH resistant to maximal medical therapy.",
"affiliations": "Divisions of Pulmonary, Critical Care and Sleep Medicine, McGovern Medical School, Houston, TX, USA.;Divisions of Pulmonary, Critical Care and Sleep Medicine, McGovern Medical School, Houston, TX, USA.;Center for Advanced Cardiopulmonary Therapies and Transplantation, McGovern Medical School, Houston, TX, USA.",
"authors": "Karna|Rahul|R|;Hussain|Rahat|R|;Jyothula|Soma S K|SSK|",
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"doi": "10.4103/lungindia.lungindia_76_21",
"fulltext": "\n==== Front\nLung India\nLung India\nLI\nLung India : Official Organ of Indian Chest Society\n0970-2113\n0974-598X\nWolters Kluwer - Medknow India\n\n34747741\nLI-38-571\n10.4103/lungindia.lungindia_76_21\nCase Report\nClinical and functional recovery in a patient with pulmonary hypertension after bariatric surgery\nKarna Rahul 1\nHussain Rahat 1\nJyothula Soma SK 2\n1 Divisions of Pulmonary, Critical Care and Sleep Medicine, McGovern Medical School, Houston, TX, USA\n2 Center for Advanced Cardiopulmonary Therapies and Transplantation, McGovern Medical School, Houston, TX, USA\nAddress for correspondence: Dr. Soma SK Jyothula, Center for Advanced Cardiopulmonary Therapies and Transplantation, McGovern Medical School, Fannin St #2550, Houston, TX 77030, USA. E-mail: Soma.s.jyothula@uth.tmc.edu\nNov-Dec 2021\n26 10 2021\n38 6 571573\n02 2 2021\n25 3 2021\n15 7 2021\nCopyright: © 2021 Indian Chest Society\n2021\nhttps://creativecommons.org/licenses/by-nc-sa/4.0/ This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.\nSevere pulmonary hypertension (PH) in obese patients pose a challenge to treat despite advances in medical therapeutics. Current treatment options are limited for patients who are not responding to maximal medical therapy. Here, we present a case of multifactorial PH, not responsive to ambrisentan, tadalafil, and treprostinil, even after optimization of cardiac and pulmonary function and had a poor prognosis. She demonstrated weight loss after bariatric surgery, improving her restrictive lung disease, obstructive sleep apnea and PH, and overall functionality. Bariatric surgery may offer a potential therapeutic option, in patients with morbid obesity and PH resistant to maximal medical therapy.\n\nKEY WORDS:\n\nBariatric surgery\nobstructive sleep apnea\npulmonary hypertension\n==== Body\npmcINTRODUCTION\n\nPulmonary hypertension (PH) is defined as pulmonary artery pressure (PAP) ≥20 mm Hg, two standard deviations above the normal (14.0 ± 3.3).[1] The management of PH preemptively requires optimization of their cardiac and pulmonary functions. Medical therapeutics are currently limited to only idiopathic pulmonary artery hypertension.[2] Patients with PH due to chronic thromboembolism need surgical intervention either mechanical thrombectomy or percutaneous transluminal pulmonary angioplasty.[3] There are no available therapeutic options for PH due to other causes and treatment is aimed at the management of underlying disease.\n\nHere, we present a case of multifactorial PH in morbidly obese patient who exhibited dramatic clinical and functional recovery after bariatric surgery.\n\nCASE REPORT\n\nA 60-year-old African American female with a history of morbid obesity (body mass index: 39.06 kg/m2), hypertension, chronic hypoxemic/hypercapnic respiratory failure, chronic obstructive pulmonary disease, PH on triple therapy of ambrisentan, tadalafil, and treprostinil for 2 years (likely Group 1, 2, and 3), heart failure with preserved ejection fraction on torsemide and spironolactone was evaluated in our clinic in 2018. Examination was significant for lower extremity edema and loud S2. She exhibited severe limitation on 6 min walk test and needed 6 L/min of oxygen supplementation for 298 m walk distance. Her ventilation-perfusion scan was consistent with mild-to-moderate chronic obstructive pulmonary disease. Her sleep study showed severe obstructive sleep apnea (OSA) with apnea-hypopnea index 7/h of sleep and total respiratory disturbance index of 40.9 obstructive events/hour of sleep. Transthoracic echocardiogram revealed abnormal left ventricular diastolic filling, left atrial index 49.3, ejection fraction 60%–65%, and moderately enlarged right ventricle. Despite attempts at weight reduction, her body mass index and mean PAP did not decrease and she continued to deteriorate further. Subsequently, despite high risk attributed to PH, gastric sleeve surgery was done to achieve long-term weight loss and subsequent improvement in OSA and PH. During the hospital course, we used continuous pump treprostinil, milrinone, and inhaled nitric oxide to stabilize mean PAP and right ventricular systolic pressures. General anesthesia was used during surgery and she was weaned off inhaled nitric oxide and milrinone within 24 h. She was discharged on postoperative day 2 on ambrisentan, tadalafil, and treprostinil.\n\nShe experienced dramatic weight loss and functional improvement over the next 6 months. During her clinic visit, she denied any lower extremity edema and was able to exercise 30 min a day without any limitations. Within 6 months, she was able to be weaned off daytime oxygen and was placed on continuous positive airway pressure of 10 cm H2O for OSA. We have compiled her pre- and post-surgery pulmonary function test and right heart catheterization data for comparison as shown in Table 1.\n\nTable 1 Comparing pulmonary function test and right heart catheterization data before and after surgery\n\n\tBefore surgery\tAfter surgery\t\nBMI (kg/m2)\t39.06\t25.2\t\nPFT (%)\t\t\t\n FEV1\t38\t40\t\n FVC\t39\t48\t\n TLC\t60\t76\t\n RV\t109\t122\t\n RV/TLC\t185\t158\t\nRHC\t\t\n RAP (mm Hg)\t22\t10\t\n RVP (mm Hg)\t110/19\t61/6\t\n PAP (mm Hg)\t106/39\t59/17\t\n PVR (woods unit)\t6.3\t3.5\t\n TPG (mm Hg)\t39\t21\t\n DPG (mm Hg)\t16\t3\t\n PCWP (mm Hg)\t23\t14\t\n CO (LPM)\t6.1\t6\t\n CI (LPM/M²)\t2.9\t3.44\t\nOxygen requirements\tAVAPS EPAP/IPAP 18/22-28 mm hg\t\t\n Sleep\t6 LPM\tCPAP 10 cm H2O\t\n 6MWT\t6 LPM\tNo additional O2\t\nFunctional capacity\tWHO IV\tWHO I\t\nBMI: Body mass index, PFT: Pulmonary function tests, RVP: Right ventricular pressure, PAP: Pulmonary artery pressure, PVR: Pulmonary vascular resistance, FEV: Forced expiratory volume, FVC: Forced vital capacity, TLC: Total lung capacity, RV: Residual volume, RHC: Right heart catheterisation, RAP: Right atrial pressure, TPG: Trans-pulmonary gradient, DPG: Diastolic pressure gradient, PCWP: Pulmonary capillary wedge pressure, CO: Cardiac output, CI: Cardiac index, 6MWT: 6-minute walk test, LPM: Liters per minute, CPAP: Continuous positive airway pressure, AVAPS: Average volume assured pressure support, EPAP: Expiratory positive airway pressure, IPAP: Inspiratory positive airway pressure\n\nDISCUSSION\n\nObese patients with PH should be advised hypocaloric diet and weight loss. Bariatric surgery is another well-established therapy for obesity, which also improves medical complications related to obesity. Conventionally, patients with PH were considered high risk for surgery. However, the improvement in medical therapy for PH now allows better hemodynamic control for such surgeries to be performed. Recently, some studies have suggested improvement in PH in obese patients after bariatric surgery.\n\nIn a study conducted among 29 morbidly obese patients who underwent bariatric surgery, Valencia-Flores et al. reported fall in systolic PAP in subgroup of patients with resolved OSA from mean of 61.4 ± 15.8 mmHg to 42.6 ± 9.2 mmHg.[4] Sheu et al. reported improvement in PAP (46.6 vs. 24.0 mm Hg; P = 0.03), reduction in pulmonary vasodilator therapy, and diuretic requirement than the control group, among 10 patients with severe PH who underwent bariatric surgery.[5] Furthermore, the test group reported decreased supplemental oxygen requirements in 75% of patients while the oxygen requirement increased in 50% of the control group.[6]\n\nHanipah et al., in a study with 61 obese patients with PH, reported improvement in right ventricular systolic pressures from 44 to 40 mm Hg (P = 0.03) after a median follow-up of 22 months.[6] Improvement in PH after bariatric surgery points toward the role of insulin resistance, lipid metabolism, and leptin in the development of PH.[7]\n\nThis is a very exciting avenue both for unraveling the role of metabolic syndrome in the pathology of PH and also for bariatric surgery as a potential therapeutic strategy for obese patients with PH. Though exciting, PH patients still present a high operative risk. In a study by Kaw et al., there was a higher morbidity rate (26% vs. 3%, P < 0.0001), longer intensive care unit stays, and 30-day readmission rate in PH group as compared to the control group.[8] Hence, large-scale prospective studies are required to evaluate bariatric surgery as a potential therapeutic tool, taking into consideration the high risks of taking these patients to surgery and risks due to perioperative morbidities.\n\nDeclaration of patient consent\n\nThe authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given her consent for her images and other clinical information to be reported in the journal. The patient understands that name and initials will not be published and due efforts will be made to conceal identity, but anonymity cannot be guaranteed.\n\nFinancial support and sponsorship\n\nNil.\n\nConflicts of interest\n\nThere are no conflicts of interest.\n==== Refs\nREFERENCES\n\n1 Simonneau G Montani D Celermajer DS Denton CP Gatzoulis MA Krowka M Haemodynamic definitions and updated clinical classification of pulmonary hypertension Eur Respir J 2019 53 1801913 30545968\n2 Maron BA Galiè N Diagnosis, treatment, and clinical management of pulmonary arterial hypertension in the contemporary era: A review JAMA Cardiol 2016 1 1056 65 27851839\n3 Mahmud E Madani MM Kim NH Poch D Ang L Behnamfar O Chronic thromboembolic pulmonary hypertension: Evolving therapeutic approaches for operable and inoperable disease J Am Coll Cardiol 2018 71 2468 86 29793636\n4 Valencia-Flores M Orea A Herrera M Santiago V Rebollar V Castaño VA Effect of bariatric surgery on obstructive sleep apnea and hypopnea syndrome, electrocardiogram, and pulmonary arterial pressure Obes Surg 2004 14 755 62 15318977\n5 Sheu EG Channick R Gee DW Improvement in severe pulmonary hypertension in obese patients after laparoscopic gastric bypass or sleeve gastrectomy Surg Endosc 2016 30 633 7 26091991\n6 Hanipah ZN Mulcahy MJ Sharma G Punchai S Steckner K Dweik R Bariatric surgery in patients with pulmonary hypertension Surg Obes Relat Dis 2018 14 1581 6 30449514\n7 Pugh ME Newman JH Williams DB Brittain E Robbins IM Hemnes AR Hemodynamic improvement of pulmonary arterial hypertension after bariatric surgery: Potential role for metabolic regulation Diabetes Care 2013 36 e32 3 23431096\n8 Kaw R Pasupuleti V Deshpande A Hamieh T Walker E Minai OA Pulmonary hypertension: An important predictor of outcomes in patients undergoing non-cardiac surgery Respir Med 2011 105 619 24 21195595\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "0970-2113",
"issue": "38(6)",
"journal": "Lung India : official organ of Indian Chest Society",
"keywords": "Bariatric surgery; obstructive sleep apnea; pulmonary hypertension",
"medline_ta": "Lung India",
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"nlm_unique_id": "8405380",
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"pages": "571-573",
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"pmid": "34747741",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Clinical and functional recovery in a patient with pulmonary hypertension after bariatric surgery.",
"title_normalized": "clinical and functional recovery in a patient with pulmonary hypertension after bariatric surgery"
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"abstract": "OBJECTIVE\nTo determine the incidence of chemotherapy-induced nausea/vomiting (CINV) and chemotherapy treatment delay and adherence among patients receiving palonosetron versus other 5-hydroxytryptamine receptor antagonist (5-HT3 RA) antiemetics.\n\n\nMETHODS\nThis retrospective claims analysis included adults with primary malignancies who initiated treatment consisting of single-day intravenous highly emetogenic chemotherapy (HEC) or moderately EC (MEC) regimens. Treatment delay was defined as a gap in treatment at least twice the National Comprehensive Cancer Network-specified cycle length, specific to each chemotherapy regimen. Treatment adherence was determined by the percentage of patients who received the regimen-specific recommended number of chemotherapy cycles within the recommended time frame.\n\n\nRESULTS\nWe identified 1,832 palonosetron and 2,387 other 5-HT3 RA (\"other\") patients who initiated HEC therapy, and 1,350 palonosetron users and 1,379 patients on other antiemetics who initiated MEC therapy. Fewer patients receiving palonosetron experienced CINV versus other (HEC, 27.5% versus 32.2%, P=0.0011; MEC, 36.1% versus 41.7%, P=0.0026), and fewer treatment delays occurred among patients receiving palonosetron versus other (HEC, 3.2% versus 6.0%, P<0.0001; MEC, 17.0% versus 26.8%, P<0.0001). Compared with the other cohort, patients receiving palonosetron were significantly more adherent to the index chemotherapy regimen with respect to the recommended time frame (HEC, 74.7% versus 69.7%, P=0.0004; MEC, 43.1% versus 37.3%, P=0.0019) and dosage (HEC, 27.3% versus 25.8%, P=0.0004; MEC, 15.0% versus 12.6%, P=0.0019).\n\n\nCONCLUSIONS\nPalonosetron more effectively reduced occurrence of CINV in patients receiving HEC or MEC compared with other agents in this real-world setting. Additionally, patients receiving palonosetron had better adherence and fewer treatment delays than patients receiving other 5-HT3 RAs.",
"affiliations": "HealthCore, Wilmington, DE, USA.;HealthCore, Wilmington, DE, USA.;HealthCore, Wilmington, DE, USA.;University of California San Francisco Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA.",
"authors": "Palli|Swetha Rao|SR|;Grabner|Michael|M|;Quimbo|Ralph A|RA|;Rugo|Hope S|HS|",
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"doi": "10.2147/CMAR.S71355",
"fulltext": "\n==== Front\nCancer Manag ResCancer Manag ResCancer Management and ResearchCancer Management and Research1179-1322Dove Medical Press 10.2147/CMAR.S71355cmar-7-175Original ResearchThe impact of 5-hydroxytryptamine-receptor antagonists on chemotherapy treatment adherence, treatment delay, and nausea and vomiting Palli Swetha Rao 1Grabner Michael 1Quimbo Ralph A 1Rugo Hope S 21 HealthCore, Wilmington, DE, USA2 University of California San Francisco Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USACorrespondence: Michael Grabner, HealthCore, 123 Justison Street, Suite 200, Wilmington, DE 19801, USA, Tel +1 302 230 2000, Fax +1 302 230 2020, Email mgrabner@healthcore.com2015 16 6 2015 7 175 188 © 2015 Palli et al. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License2015The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.Purpose\nTo determine the incidence of chemotherapy-induced nausea/vomiting (CINV) and chemotherapy treatment delay and adherence among patients receiving palonosetron versus other 5-hydroxytryptamine receptor antagonist (5-HT3 RA) antiemetics.\n\nMaterials and methods\nThis retrospective claims analysis included adults with primary malignancies who initiated treatment consisting of single-day intravenous highly emetogenic chemotherapy (HEC) or moderately EC (MEC) regimens. Treatment delay was defined as a gap in treatment at least twice the National Comprehensive Cancer Network-specified cycle length, specific to each chemotherapy regimen. Treatment adherence was determined by the percentage of patients who received the regimen-specific recommended number of chemotherapy cycles within the recommended time frame.\n\nResults\nWe identified 1,832 palonosetron and 2,387 other 5-HT3 RA (“other”) patients who initiated HEC therapy, and 1,350 palonosetron users and 1,379 patients on other antiemetics who initiated MEC therapy. Fewer patients receiving palonosetron experienced CINV versus other (HEC, 27.5% versus 32.2%, P=0.0011; MEC, 36.1% versus 41.7%, P=0.0026), and fewer treatment delays occurred among patients receiving palonosetron versus other (HEC, 3.2% versus 6.0%, P<0.0001; MEC, 17.0% versus 26.8%, P<0.0001). Compared with the other cohort, patients receiving palonosetron were significantly more adherent to the index chemotherapy regimen with respect to the recommended time frame (HEC, 74.7% versus 69.7%, P=0.0004; MEC, 43.1% versus 37.3%, P=0.0019) and dosage (HEC, 27.3% versus 25.8%, P=0.0004; MEC, 15.0% versus 12.6%, P=0.0019).\n\nConclusion\nPalonosetron more effectively reduced occurrence of CINV in patients receiving HEC or MEC compared with other agents in this real-world setting. Additionally, patients receiving palonosetron had better adherence and fewer treatment delays than patients receiving other 5-HT3 RAs.\n\nKeywords\npalonosetronadherenceCINVdelay of therapyobservationalhealth services research\n==== Body\nIntroduction\nNausea and vomiting are common chemotherapy-associated side effects ranked by patients as especially distressing.1–7 Chemotherapy-induced nausea and vomiting (CINV) can cause psychological distress, nutritional deficiencies, and reduced quality of life among patients receiving chemotherapy.5–8 Furthermore, its occurrence may potentially affect adherence to chemotherapy regimens, leading to treatment delays or receipt of fewer treatments or lower dosages than recommended.9,10 Such events may have an adverse effect on treatment efficacy, ultimately resulting in suboptimal clinical outcomes and potentially increased health care-related resource utilization and costs.3\n\nRecognizing the importance of preventing and managing CINV, leading oncology societies have issued treatment guidelines11–13,29 recommending 5-hydroxytryptamine-receptor antagonists (5-HT3 RAs) as the preferred medication class to effectively prevent CINV in patients receiving highly emetogenic chemotherapy (HEC) or moderately EC (MEC).19,20 Compared to the older agents, palonosetron – a newer 5-HT3 RA – is pharmacologically distinct, with a longer half-life and greater receptor-binding affinity, allosteric binding to serotonin receptors with positive cooperativity, and cross talk with Neurokinin-1 (NK-1) receptors.21–23 While the early 5-HT3 RA compounds were considered equally efficacious,19 palonosetron demonstrated greater efficacy than active comparators in preventing CINV in patients receiving HEC or MEC in multiple clinical trials.20,24–26 Hatoum et al compared palonosetron with other 5-HT3 RAs in a real-world setting among patients with breast/lung cancer undergoing cisplatin/carboplatin treatments.19,27 They concluded that patients who received prophylaxis with palonosetron had a significantly lower risk of CINV events than those who had received other 5-HT3 RA agents. Furthermore, those breast/lung cancer patients receiving palonosetron experienced 49.5% and 29.1% fewer CINV days, respectively.27 Their study focused on serious CINV events resulting in hospital or emergency department admissions, and did not include CINV events occurring in an outpatient context. Craver et al found that prophylactic administration of palonosetron among patients with hematologic malignancies who were receiving HEC/MEC resulted in a 20.4% decrease in CINV event rate per cycle compared with patients receiving other 5-HT3 RAs.28 However, while 5-HT3 RA agents have been proven effective in preventing CINV, little is known regarding their impact on chemotherapy treatment adherence and delay. To address these questions, a real-world study was designed comparing patients who received palonosetron with those who received other 5-HT3 RAs on incidence of acute and delayed CINV and chemotherapy treatment delay and adherence. This study also contributes to the development of methods to assess medication adherence for intravenous (IV) agents.\n\nMaterials and methods\nThis was an observational nested case–control study using data from the HealthCore Integrated Research Database (HIRDSM). The HIRD is an integrated medical and pharmacy-claims and laboratory-result database of commercially insured patients from 14 major commercial health plans across the US representing approximately 45 million patient-lives dating as far back as January 1, 2001.\n\nCohort creation\nThe index date was defined as the earliest medical or pharmacy claim date for an IV HEC or MEC between January 1, 2002 and October 31, 2010. All patients included in the study were adults (≥18 years of age as of the index date) who had one or more medical claims with a diagnosis of primary malignant breast, lung, or colorectal neoplasm during the baseline period, which was defined as the 12 months before the index date. All patients had continuous medical and pharmacy health plan eligibility for at least 12 months pre- and 12 months postindex date. Patients were excluded if they 1) had a secondary malignant neoplasm or primary neoplasms at multiple sites, 2) had preindex HEC or MEC claims, 3) initiated multiday chemotherapy, 4) received oral chemotherapy alone or in combination with an IV formulation, 5) switched from a single-day-per-cycle chemotherapy regimen to multiday chemotherapy, or 6) had medical claim(s) for pregnancy, labor, or delivery in the 6 months postindex.\n\nLastly, in order to create clean comparison cohorts, patients receiving both palonosetron and any of the “other” 5-HT3 RAs any time during the course of one or more chemotherapy treatment cycles were excluded from the analysis. The remaining patients were stratified into either the palonosetron or other 5-HT3 RA treatment cohorts. Specifically, patients in the palonosetron group received only palonosetron and no other IV 5-HT3 RA agent (ie, dolasetron, granisetron, and/or ondansetron; see Table S1) as prophylactic or rescue therapy beginning 1 day before through 5 days after the start of any chemotherapy treatment cycle; those in the other 5-HT3 RA cohort were allowed to receive any prophylactic 5-HT3 RA agent other than palonosetron.\n\nAssignment of chemotherapy regimens\nIndex HEC and MEC agents were defined as any chemotherapeutic agent classified as having a known high or moderate emetogenic potential (Table S2).29 Chemotherapy agents were identified using generic product identifier (GPI) and Healthcare Common Procedure Coding System (HCPCS) codes. Chemotherapy dose determined the HEC/MEC status of certain chemotherapy drugs (eg, cyclophosphamide and cisplatin) by calculating the index dose administered and then applying the National Comprehensive Cancer Network® (NCCN®)-recommended Guidelines available at the time of the study for classification (Table S3).29 Because only single-day administration regimens were included in the study, the average dose was equal to the average strength, as noted on medical or pharmacy claims. Body-surface area (BSA) was not available on claim forms, so published BSA estimates of cancer patients were used to determine the average dose per square meter.30 The standard estimates used were 1.91 m2 for men (95% confidence interval [CI] 1.90–1.92) and 1.71 m2 for women (95% CI 1.70–1.72).\n\nFor regimens involving a combination of chemotherapeutic agents, the agent with the highest emetic risk defined the risk of the combination (ie, one MEC agent and one HEC agent equaled an HEC regimen; one lowly EC [LEC] and one MEC equaled an MEC regimen).12,13 Two MEC agents were classified as HEC; however, two LEC agents remained a lowly emetogenic regimen (Table 1).31 Additional information on the step-by-step regimen identification can be found in the Supplementary materials.\n\nClaims for index chemotherapy agents dated 7 days or later after the beginning of the cycle were designated as the beginning of the subsequent cycle, and so on until the end of the 12-month observation period. The end of a chemotherapy cycle was determined using either the passing of the NCCN-recommended number of weeks between two cycles (Table 2), which was specific to each treatment regimen, or the start date of the subsequent treatment cycle, whichever occurred earlier.\n\nOutcome measures\nAcute CINV was identified by International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) diagnosis codes for nausea and vomiting, persistent vomiting, or volume depletion, or current procedural terminology codes for hydration, on the day of chemotherapy (Table S1). Delayed CINV was identified by the same ICD-9-CM and CPT codes for nausea and vomiting, volume depletion and hydration, as well as GPI/HCPCS codes for IV rescue medications (dexamethasone, fosaprepitant, diphenhydramine, promethazine, haloperidol, prochlorperazine, lorazepam, or metoclopramide) or 5-HT3 RAs (Table S1) between the day after chemotherapy and day 5 of the chemotherapy cycle of interest. CINV events were assessed on a patient- and cycle-level basis.\n\nEach index chemotherapy regimen was assigned a total number of chemotherapy cycles and an allowed gap between chemotherapy cycles according to the recommendations of the 2011 NCCN Clinical Practice Guidelines In Oncology (NCCN Guidelines®) (Table 2).14–18 For example, a lung cancer patient on cisplatin (index dose of 100 mg/m2) and vinorelbine would be assumed to have initiated a therapy involving four treatment cycles with an allowed rest period of 4 weeks between each cycle.\n\nTreatment delay was measured in two ways: 1) the proportion of patients who delayed their index chemotherapy based on the presence of a significant gap between two chemotherapy cycles, and 2) the mean and median time from the index date to the date of treatment delay. Delay of therapy was defined as a gap in treatment exceeding twice the NCCN-specified cycle length specific to each chemotherapy regimen (Table 2). The date of treatment delay was the date of the last chemotherapy cycle start date prior to delay plus one cycle length. For patients on combination regimens, delay of any one agent involved in the regimen constituted delay of the entire regimen. We also performed a sensitivity analysis around the permissible treatment gap, assigning a lower limit of 1.5 times the NCCN-recommended cycle length and an upper limit of three times the NCCN-recommended cycle length.\n\nTreatment adherence was measured in four related ways: the percentage of patients who received the 1) recommended number of cycles for their specific chemotherapy regimen, as determined by NCCN guidelines, 2) recommended number of chemotherapy cycles for their regimen within the recommended time frame, 3) recommended chemotherapy dose within a 10% margin, and 4) recommended number of cycles within the specified time frame at the expected dose. We used measure 2 as our primary measure of adherence. Patients on multiagent regimes were required to be adherent with each component of the regimen to be considered adherent overall.\n\nStatistical analysis\nDescriptive statistics were used to characterize the incidence of acute and delayed CINV, as well as baseline patient characteristics, such as primary cancer site and chemotherapy regimen. Means/standard deviations were used for continuous data, and counts/relative frequencies were used for categorical data. Each baseline characteristic and study outcome was compared using unadjusted statistical tests between patients receiving palonosetron and those receiving all other 5-HT3 RAs. Continuous variables were compared using Student’s t-test or Wilcoxon rank-sum test, depending on the distributional characteristics. Categorical data were compared using χ2 tests.\n\nLogistic regression models were used to estimate associations between antiemetic treatment (palonosetron versus other 5-HT3 RAs) and CINV (acute and/or delayed), delay of index chemotherapy regimen, and adherence to index chemotherapy regimen. Covariates in the multivariable regression analysis included age, sex, geographic region, health plan type, year of index date, cancer type, Deyo–Charlson Comorbidity Index (DCI) score,32 individual comorbidities, and baseline receipt of LEC, radiation, and antiemetics. All analyses were stratified by HEC and MEC regimens.\n\nResults\nPatient characteristics\nWe identified 1,832 HEC patients who received only palonosetron and no other 5-HT3 RA and 2,387 HEC patients who received other 5-HT3 RAs excluding palonosetron (Table 3). In the HEC group, the mean age was slightly higher among palonosetron users (52.0 versus 51.4 years for those receiving other 5-HT3 RAs, P=0.0345), and breast cancer was the most common malignancy (97.3% palonosetron and 96.0% other 5-HT3 RAs). The mean baseline DCI scores were 4.35 for patients receiving palonosetron and 4.56 for those receiving other 5-HT3 RAs (P=0.0211). Similarly, we identified 1,350 palonosetron users and 1,379 other 5-HT3 RA recipients who indexed on an MEC therapy. Within the MEC cohort, the mean age and DCI scores were slightly lower among palonosetron patients compared to those receiving other 5-HT3 RAs (56.8 versus 59.2 years, P<0.0001; 4.29 versus 4.55, P=0.0229; respectively). Breast (48.6%) and colon (29.3%) cancers were the most prevalent malignancies among palonosetron recipients, whereas lung (35.2%) and colon (34.0%) cancers were more common among those receiving other 5-HT3 RAs in the MEC group.\n\nIncidence of CINV\nWithin the HEC cohort, fewer palonosetron patients experienced CINV compared with those who received other 5-HT3 RAs (27.5% versus 32.2%, P=0.001; Table 4). Likewise, 19.1% and 14.8% of HEC patients receiving palonosetron experienced ≥1 acute and ≥1 delayed CINV event(s) respectively, compared to 20.5% and 20.2% of other 5-HT3 RA HEC patients. Furthermore, patients in the other 5-HT3 RA group experienced more CINV events per cycle than the palonosetron group (0.3 versus 0.2 events/cycle). In the MEC cohort, fewer palonosetron patients experienced CINV and CINV events per cycle compared with those who received other 5-HT3 RAs (36.1% versus 41.7%, P=0.003; 0.3 versus 0.4 events/cycle). MEC patients in the palonosetron cohort were significantly less likely to experience delayed CINV versus patients in the other 5-HT3 RA cohort (20.6% versus 29.5%, P<0.0001).\n\nChemotherapy treatment delay\nFewer chemotherapy treatment delays occurred among patients receiving palonosetron compared with other 5-HT3 RAs in both the HEC (3.2% versus 6.0%, P<0.0001) and MEC (17.0% versus 26.8%, P<0.0001) cohorts (Table 4). The results for delayed therapy remained consistent when using the upper and lower limits as defined earlier (see Table 4). Mean time to delay was similar across the palonosetron and other 5-HT3 RAs groups (approximately 76 days in the HEC cohort and 86 days in the MEC cohort).\n\nChemotherapy treatment adherence\nIn both the HEC and MEC cohorts, more patients receiving palonosetron were adherent to their chemotherapy regimen compared to those who received other 5-HT3 RAs for three of the four different adherence measures. In the HEC cohort, slightly more of those who received palonosetron completed the recommended number of chemotherapy cycles versus those who received other 5-HT3 RAs (87.7% versus 86.4%, respectively; P=0.2022). The difference was greater in the MEC cohort, with 65.6% of those receiving palonosetron and 59.8% of those receiving other 5-HT3 RAs completing the recommended number of chemotherapy cycles (P=0.0017). Compared with those who received other 5-HT3 RAs, significantly more patients receiving palonosetron completed the recommended number of chemotherapy cycles within the specified time frame (HEC, 74.7% versus 69.7%, respectively, P=0.0004; MEC, 43.1% versus 37.3%, respectively, P=0.0019) and at the expected doses (HEC, 27.3% versus 25.8%, respectively, P=0.0004; MEC, 15.0% versus 12.6%, respectively, P=0.0019) (Table 4). A similar proportion of patients in both the palonosetron and other 5-HT3 RA cohorts received the recommended chemotherapy doses for HEC (33.6% palonosetron and 33.4% other 5-HT3 RAs, P=0.8951) and MEC regimens (34.6% palonosetron and 37.1% other 5-HT3 RAs, P=0.1673).\n\nThese findings were supported in a multivariable analysis (Figure 1). Treatment with palonosetron was associated with a reduced likelihood of CINV occurrence in the HEC (odds ratio [OR] 0.82, 95% CI 0.71–0.95) and MEC (OR 0.77, 95% CI 0.65–0.92) cohorts. Palonosetron treatment was also associated with fewer chemotherapy treatment delays in both cohorts (HEC, OR 0.63, 95% CI, 0.45–0.87; MEC, OR 0.74, 95% CI 0.60–0.91). Although palonosetron was associated with greater chemotherapy adherence in the HEC cohort (OR 1.25, 95% CI 1.07–1.45), no association was found in the MEC cohort (OR 1.1, 95% CI 0.92–1.32).\n\nDiscussion\nIn this retrospective, observational, nested case–control study, patients who received prophylactic or rescue palonosetron had significantly fewer CINV events, fewer chemotherapy treatment delays, and higher adherence to their chemotherapy regimen compared with patients who received any other IV 5-HT3 RA medication. These findings were seen both among patients who were undergoing HEC treatment and those undergoing MEC treatment.\n\nResults from clinical trials have demonstrated the overall efficacy of palonosetron in preventing acute CINV in patients receiving HEC and in preventing acute or delayed CINV in patients receiving MEC.20,24–26 However, limited evidence is available regarding the effect of palonosetron on chemotherapy adherence and treatment delay in a real-world setting. To our knowledge, no previous study has evaluated this association. A previous administrative claims analysis evaluated the risk of serious CINV events associated with hospital or emergency department admissions among patients with breast or lung cancer undergoing MEC or HEC who received palonosetron compared with those who received any other 5-HT3 RA.19 Patients receiving palonosetron experienced a significantly reduced risk of serious CINV compared to those who received other 5-HT3 RAs, ranging from 31% to 45% among lung and breast cancer patients, respectively. Another recent study by Craver et al evaluated the risk of CINV among recipients of palonosetron versus other 5-HT3 RAs initiating HEC/MEC therapy in all medical settings,28 using a broader definition of CINV encompassing events occurring any time within 7 days of the chemotherapy cycle-start date. While both studies showed a reduction in CINV with palonosetron use as expected, an exploration of the effect of CINV risk reduction on chemotherapy adherence or delay was not conducted.\n\nThe real-world analysis in the current study demonstrated improved adherence to chemotherapy regimens among patients who received palonosetron compared with other 5-HT3 RA agents. The association between the use of antiemetics and adherence may have been underestimated: patients undergoing chemotherapy, particularly HEC, are more likely to have been prepared by their health care providers to expect nausea and vomiting; such preparedness has been shown to alleviate the reported incidence of nausea and vomiting in patients receiving chemotherapy.31 Additionally, some patients undergoing IV chemotherapy regimens will have advanced disease, and may therefore not have the option of delaying or discontinuing treatment because of nausea and vomiting.33\n\nFuture research exploring the association between reduced CINV and chemotherapy adherence would benefit from a cost analysis, which was not included in the current study. A therapy that improves chemotherapy adherence by reducing CINV events could potentially reduce costs, both direct (costs of antiemetic medications, physician visits, and hospitalizations) and indirect (lost workdays and intangibles, including lower quality of life and potential consequences of delayed or reduced chemotherapy treatment). Other chemotherapy-associated side effects, such as fatigue, insomnia, or dermatologic conditions, which cannot be easily identified through claims, may also affect treatment adherence.\n\nThe nature of the administrative claims database and the lack of granularity precluded us from identifying more than one CINV event per day or the severity of the CINV experienced. While our approach to identify CINV events from claims matches that used in clinical trials of antiemetics,19,28 others have used criteria that were either more strict (eg, nausea, vomiting, and dehydration associated with hospital admissions27) or that relied on patient diaries rather than diagnosis codes.24,25 The strategy used in the current study to define CINV did not capture patients using oral antiemetics or over-the-counter remedies, and the IV antiemetics may have been prescribed for reasons other than CINV (eg, for nausea and vomiting associated with migraine,34 surgery,35 or gastroparesis36). Nausea and vomiting occurring after day 5 of the chemotherapy cycle and before the subsequent cycle were not attributed to chemotherapy, and may have resulted in an underestimation of CINV events. Despite these limitations, the narrow time frame and broader medical setting used for identifying CINV in the current study design resulted in a conservative estimate of the impact of palonosetron and other 5-HT3 RAs on CINV in a real-world setting.\n\nAdministrative claims are designed for reimbursement rather than research, and may contain coding errors or omissions. Therefore, the claim-based algorithm developed to identify patients with early stage cancers may be susceptible to potential misidentification. Furthermore, standard definitions of adherence with IV chemotherapy regimens within an administrative claim database are lacking in the published literature. All patients were members of large commercial health plans in the US; the results may not be generalizable to patients outside the US or with other types of health insurance. While enrollment was limited to patients with single-day chemotherapy regimens, further research in patients receiving multiday regimens would be desirable. Because of concerns regarding patient selection and cohort size, the comparative analysis was limited to IV chemotherapy in general and IV 5-HT3 RAs as a class. Consistent with NCCN guideline recommendations, the analysis assumed that the non-5-HT3 RA components of the observed antiemetic regimens were similar across the palonosetron and other cohorts. NCCN guidelines were used to define chemotherapy regimens for this analysis, and did not allow for individualized treatment plans. BSA was needed to calculate the index dosage of cyclophosphamide and cisplatin; however, this information is unavailable in administrative claims. In the absence of US-based data, BSA estimates developed in a prior UK study30 were used to calculate index doses.\n\nConclusion\nIn this real-world retrospective analysis, patients receiving palonosetron were more adherent to their HEC/MEC regimens and experienced fewer treatment delays compared to patients receiving other 5-HT3 RAs. Palonosetron was also associated with a decrease in the occurrence of CINV events. These results highlight the importance of symptom control in the context of adherence to prescribed chemotherapy, which may ultimately influence treatment and disease outcomes, including costs. This study also presents an innovative approach to estimate adherence to IV chemotherapy using administrative claims data.\n\nSupplementary materials\nAssignment of index chemotherapy regimens\nIdentification of chemotherapeutic regimens involves a two-step process. Step one involves the identification of the highly emetogenic chemotherapy (HEC)/moderately EC (MEC) agents making up the regimen, which are identified within 6 days of the index date. For instance, for a breast cancer patient with a claim for cyclophosphamide on the index date (ie, the start date of the first chemotherapy cycle), medical and pharmacy claims are evaluated to determine the presence of another HEC/MEC drug (eg, doxorubicin, epirubicin, etc). If no other HEC/MEC drug is found, then the index dose is calculated by using the strength (as determined from the index medical or pharmacy claim) and the body surface-area estimate. A dose of >1,500 mg/m2 indicates receipt of HEC, while an index dose ≤1,500 mg/m2 indicates MEC. However, if doxorubicin is present, then the patient is classified as HEC as per the Hesketh algorithm.31 Step two of the chemotherapy-regimen identification involves claims for non-HEC/MEC chemotherapy agents also observed within 6 days of the index date (Table S3). In the aforementioned example, for a patient indexing on cyclophosphamide and doxorubicin, if a claim for another lowly EC or non-EC drug (eg, docetaxel, paclitaxel, etc) is found within ±6 days of the index date, then the patient’s adherence will be evaluated as per the NCCN Guidelines® recommendations for the appropriate cyclophosphamide/doxorubicin/docetaxel combination regimen. Where multiple regimen options were available for the drugs involved, additional analysis was performed to determine the specific regimen. This included determining the doses of the HEC/MEC components in order to pinpoint the specific regimen. For example, a doxorubicin dose of 50 and 60 mg/m2 would indicate a regimen involving six and four cycles, respectively (Table 2). Duration between the claims for the index HEC/MEC drugs was also used if the doses were insufficient in differentiating among the various regimen options. A combination involving cyclophosphamide/doxorubicin/paclitaxel could be assigned a regimen either 8 weeks or 12 weeks long if the gap between the first and second claim for cyclophosphamide/doxorubicin was found to be 14 or 21 days, respectively.\n\nTable S1 CINV codes and antiemetic therapies\n\nGeneric name\tGPI\tHCPCS\tICD-9-CM diagnosis\t\n5-HT3 RAs\t\nDolasetron mesylate\t50250025x\tJ1260, Q0180\t\t\nGranisetron\t50250035x\tJ1626, Q0166\t\t\nOndansetron\t50250065x\tJ2405, Q0179\t\t\nPalonosetron\t50250070x\tJ2469\t\t\nOther antiemetics\t\nDexamethasone\t22100020x\tJ1094, J1100, J7637, J7638, J7312, J8540\t\t\nFosaprepitant\t502800351021x\tJ1453\t\t\nPromethazine\t41400020101210, 414000201020x, 414000201003x, 41400020101215, 414000201029x, 414000201052x\tJ2550, J2180, Q0169, Q0170\t\t\nProchlorperazine\t59200055x\tJ0780, Q0164, Q165, S0183\t\t\nMetoclopramide\t523000201020x, 523000201003x, 523000201012x, 523000201013x, 523000201029x, 523000201072x, 5230002011x\tJ2765\t\t\nLorazepam\t571000600020x, 571000600003x, 571000600013x\tJ2060\t\t\nHaloperidol\t5910001030x, 591000102020x, 5910001010x, 591000102013x\tJ1630, J1631\t\t\nDiphenhydramine\t4120003010x, 412000303x, 60300020x, 6030990x\tJ1200, Q0163\t\t\nNausea\t\nNausea and vomiting\t22100020x\tJ1094, J1100, J7637, J7638, J7312, J8540\t787.0x\t\nPersistent vomiting\t5028002000x\tJ8501\t536.2x\t\nVolume depletion\t502800351021x\tJ1453\t276.5x\t\nHydration (nontherapeutic administration)\t\t96360, 96361, 90760, 90761, 2018F, G0345\t\t\nAbbreviations: CINV, chemotherapy-induced nausea/vomiting; HT, hydroxytryptamine; RAs, receptor antagonists; GPI, generic product identifier; HCPCS, Healthcare Common Procedure Coding System; ICD-9-CM: International Classification of Diseases, Ninth Revision, Clinical Modification.\n\n Table S2 Chemotherapy codes and emetogenic potential\n\nDescription\tGPI code\tHCPCS code\tEmetogenicity\tFormulation\t\nCarmustine\t21102010x\tJ9050, C9437\tOther\tIV\t\nCisplatin\t211000200020x\tJ9060, J9062, C9418\tOther\tIV\t\nDacarbazine\t2170002000x\tJ9130, J9140, C9423\tHEC\tIV\t\nMechlorethamine\t211010301021x\tJ9230\tHEC\tIV\t\nStreptozotocin\t21102030002105\tJ9320\tHEC\tIV\t\nAlemtuzumab\t21353010x\tJ9010\tMinimal\tIV\t\nArsenic trioxide\t21700008x\tJ9017\tMEC\tIV\t\nAzacitidine\t21300003x\tJ9025\tMEC\tIV\t\nBendamustine\t21100009x\tJ9033\tMEC\tIV\t\nCarboplatin\t21100015x\tJ9045\tMEC\tIV\t\nClofarabine\t21300008x\tJ9027, C9129\tMEC\tIV\t\nDactinomycin\t212000200021x\tJ9120\tMEC\tIV\t\nDaunorubicin\t21200030x\tJ9150–J9151, C9424\tMEC\tIV\t\nDoxorubicin\t21200040x\tJ9000–J9001, C9415\tOther\tIV\t\nEpirubicin\t21200042x\tJ9178, J9180\tOther\tIV\t\nIdarubicin\t21200045x\tJ9211, C9429\tMEC\tIV\t\nIfosfamide\t2110102500x, 219900024064x\tJ9208, C9427\tOther\tIV\t\nIrinotecan\t21550040x\tJ9206\tMEC\tIV\t\nMelphalan\t211010400021x, 211010401021x\tJ9245\tMEC\tIV\t\nOxaliplatin\t21100028x\tJ9263, C9205\tMEC\tIV\t\nTemozolomide\t211040700021x\tJ9328, C9253\tMEC\tIV\t\nAldesleukin\t21703020x\tJ9015\tOther\tIV\t\nAmifostine crystalline\t21758010x\tJ0207\tOther\tIV\t\nCyclophosphamide\t21101020002x\tJ9070–J9097, C9420, C9421\tOther\tIV\t\nCytarabine\t21300010x\tJ9098–J9110, C9422\tOther\tIV\t\nInterferon-α\t217000601x, 217000602x, 217000603x\tJ9212–J9215\tOther\tIV\t\nAltretamine\t21100005x\t\tMEC/HEC\tOral\t\nProcarbazine\t21700050x\tS0182\tMEC/HEC\tOral\t\nCyclophosphamide\t211010200003x\tJ8530\tOther\tOral\t\nImatinib\t21534035x\tS0088\tMinimal/Low\tOral\t\nTemozolomide\t211040700001x\tJ8700\tOther\tOral\t\nBusulfan\t211000100003x\tJ0594, J8510\tOther\tOral\t\nEstramustine phosphate sodium\t2140302010x\t\tMEC/HEC\tOral\t\nEtoposide\t21500010x\tJ8560\tMEC/HEC\tOral\t\nLomustine\t211020200001x\tS0178\tMEC/HEC\tOral\t\nNotes: Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Antiemesis, Version 1.2012. © National Comprehensive Cancer Network, Inc 2015. All rights reserved. Accessed August 11, 2011. To view the most recent and complete version of the guideline, go online to NCCN.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc. Other = NCCN emetogenicity rating depends on dosage.\n\nAbbreviations: GPI, generic product identifier; HCPCS, Healthcare Common Procedure Coding System; HEC, highly EC; MEC, moderately EC; EC, emetogenic chemotherapy; IV, intravenous.\n\n Table S3 HEC/MEC regimens\n\nAgent\tRegimen\tSchedule\tRegimen type\tMEC/HEC\t\nCyclophosphamide\tTC\t• Cyclophosphamide 600 mg/m2 IV day 1\nCycled every 3 weeks for four cycles\tSingle day\tDepends on dosage\t\nCyclophosphamide/doxorubicin\tTAC (with docetaxel)\t• Doxorubicin 50 mg/m2 IV day 1\tSingle day\tHEC\t\n• Cyclophosphamide 500 mg/m2 IV day 1\nCycled every 3 weeks for six cycles\t\nTAC (with docetaxel)\t• Doxorubicin 60 mg/m2 on day 1\tSingle day\tHEC\t\n• Cyclophosphamide 500 mg/m2 IV day 1\nCycled every 3 weeks for four cycles\t\nAC\t• Doxorubicin 60 mg/m2 IV day 1\tSingle day\tHEC\t\n• Cyclophosphamide 600 mg/m2 IV day 1\nCycled every 2 weeks for four cycles\t\n• Doxorubicin 60 mg/m2 IV day 1\tSingle day\tHEC\t\n• Cyclophosphamide 600 mg/m2 IV day 1\nCycled every 3 weeks for four cycles\t\n• Doxorubicin 60 mg/m2 IV day 1\tSingle day\tHEC\t\n• Cyclophosphamide 600 mg/m2 IV day 1\nCycled every 3 weeks for four cycles\t\n• Doxorubicin 60 mg/m2 IV day 1\tSingle day\tHEC\t\n• Cyclophosphamide 600 mg/m2 IV day 1\nCycled every 3 weeks for four cycles\t\nFAC/CAF (with 5-FU)\t• Doxorubicin 50 mg/m2 IV day 1\tSingle day\tHEC\t\n• Cyclophosphamide 500 mg/m2 IV day 1\nCycled every 3 weeks for six cycles\t\nCyclophosphamide/epirubicin\tFEC/CEF (with 5-FU)\t• Epirubicin 75 mg/m2 IV day 1\tSingle day\tHEC\t\n• Cyclophosphamide 500 mg/m2 day 1\nCycled every 3 weeks for four cycles\t\nEC\t• Epirubicin 100 mg/m2 IV day 1\tSingle day\tHEC\t\n• Cyclophosphamide 830 mg/m2 IV day 1\nCycled every 3 weeks for eight cycles\t\nFEC\t• Epirubicin 100 mg/m2 IV day 1\tSingle day\tHEC\t\n• Cyclophosphamide 500 mg/m2 day 1\nCycled every 3 weeks for three cycles\t\nFEC\t• Epirubicin 90 mg/m2 IV day 1\tSingle day\tHEC\t\n• Cyclophosphamide 600 mg/m2 IV day 1\nCycled every 3 weeks for four cycles\t\nCarboplatin\tTCH\t• Carboplatin AUC 6 IV day 1\nCycled every 3 weeks for six cycles\tSingle day\tMEC\t\nCH (with trastuzumab)\t• Carboplatin AUC 6 IV day 1\nCycled every 3 weeks for six cycles\tSingle day\tMEC\t\nCT (with docetaxel)\t• Carboplatin AUC 6 IV day 1\nCycled every 3 weeks for six cycles\tSingle day\tMEC\t\nCisplatin\tCV (with vinorelbine)\t• Cisplatin 100 mg/m2 day 1\nCycled every 4 weeks for four cycles\tSingle day\tHEC/depends on dosage\t\nCV (with vinorelbine)\t• Cisplatin 75–80 mg/m2 day 1\nCycled every 3 weeks for four cycles\tSingle day\tHEC/depends on dosage\t\nCG (with gemcitabine)\t• Cisplatin 75 mg/m2 day 1\nCycled every 3 weeks for four to six cycles\tSingle day\tHEC/depends on dosage\t\nCD (with docetaxel)\t• Cisplatin 75 mg/m2 day 1\nCycled every 3 weeks for four to six cycles\tSingle day\tHEC/depends on dosage\t\nCP (with pemetrexed)\t• Cisplatin 75 mg/m2 day 1\nCycled every 3 weeks for four cycles\tSingle day\tHEC/depends on dosage\t\nCarboplatin\tPC (with paclitaxel)\t• Carboplatin AUC 6 day 1\nCycled every 3 weeks for four to six cycles\tSingle day\tMEC\t\nPC (with paclitaxel)\t• Carboplatin AUC 2 (initial) and 6 (last 2) weekly\nTotal of three cycles\tSingle day\tMEC\t\nPG (with gemcitabine)\t• Carboplatin AUC 2 day 1\nCycled every 3 weeks for six cycles\tSingle day\tMEC\t\nPE (with etoposide)\t• Carboplatin AUC 2 day 1\nCycled every 4 weeks for six cycles\tSingle day\tMEC\t\nOxaliplatin\tFOLFOX\t• Oxaliplatin 85 mg/m2 day 1\nCycled every 2 weeks for 6 months\tSingle day\tMEC\t\nFOLFOX (modified)\t• Oxaliplatin 85 mg/m2 day 1\nCycled every 2 weeks for 6 months\tSingle day\tMEC\t\nXELOX\t• Oxaliplatin 130 mg/m2 day 1\nCycled every 3 weeks for eight cycles\tSingle day\tMEC\t\nNote: Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Breast Cancer V2.2011, Colon Cancer V3.2011, Rectal Cancer V4.2011, Small Cell Lung Cancer V2.2012, Non-Small Cell Lung Cancer V3.2011 [All accessed July 11, 2011], Antiemesis V1.2012 [Accessed August 11, 2011]. © National Comprehensive Cancer Network, Inc 2015. All rights reserved. To view the most recent and complete version of the guidelines, go online to NCCN.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc.\n\nAbbreviations: MEC, moderately emetogenic chemotherapy; HEC, highly EC; TC, taxotere/cyclophosphamide; IV, intravenous; TAC, Docetaxel/doxorubicin/cyclophosphomide; AC, Doxorubicin/cyclophosphomide; FAC/CAF, Flurouracil/doxorubicin/cyclophosphomide; 5-FU, 5-fluorouracil; FEC/CEF, Cyclophosphomide/Epirubicin/Flurouracil; TCH, Docetaxel/carboplatin/trastuzumab; CH, Docetaxel/carboplatin/trastuzumab; CT, Carboplatin/trastuzumab; CV, Cisplatin/vinorelbine; CG, Cisplatin/gemicitabine; CD, Cisplatin/docetaxel; CP, Cisplatin/pemetrexed; PC, Paclitaxel/Carboplatin; PG, Paclitaxel/Carboplatin/gemicitabine; PE, Paclitaxel/Carboplatin/etoposide; FOLFOX, Folinic acid/Fluorouracil/Oxaliplatin; XELOX, Capecitabine/Oxaliplatin.\n\n Acknowledgments\nThe authors acknowledge Russell Knoth of Eisai Pharmaceuticals, Inc., for his input on the study design and manuscript. The authors also acknowledge Cheryl Jones for her editorial assistance in preparing the manuscript. Funding for this study was provided by Eisai, Inc., which distributes palonosetron.\n\nDisclosure\n\nSRP was an employee of HealthCore at the time of the study, and MG and RAQ are current employees of HealthCore, an independent research organization that received funding from Eisai Pharmaceuticals for the conduct of this study. HSR is a consultant to Eisai Pharmaceuticals. SRP is now an employee of CTI Clinical Trial and Consulting Services, Cincinnati, OH, USA.\n\nFigure 1 Odds ratios and 95% confidence intervals for palonosetron versus other 5-HT3-RAs.\n\nNotes: For CINV and delayed therapy, an odds ratio <1 is associated with improved outcomes; for adherence, an odds ratio <1 is associated with improved outcomes.\n\nAbbreviations: HT, hydroxytryptamine; CINV, chemotherapy-induced nausea/vomiting; HEC, highly EC; MEC, moderately EC; EC, emetogenic chemotherapy.\n\nTable 1 Algorithm to identify HEC and MEC regimens\n\nRegimen makeup\tHEC/MEC classification of regimen\t\nAny HEC drug\tHEC\t\nTwo or more MEC drugs\tHEC\t\nOne MEC drug with or without low or minimal emetogenic chemotherapy (LEC)\tMEC\t\nMultiple LEC drugs\tLEC\t\nAbbreviations: HEC, highly emetogenic chemotherapy; MEC, moderately EC; LEC, lowly EC; EC, emetogenic chemotherapy.\n\nTable 2 Chemotherapy index regimens\n\nIndex HEC/MEC regimen (± LEC)\tEmetogenicity\tNumber of recommended cyclesa\tAllowed gap (weeks)b\tRegimen duration (weeks)\t\nBreast cancer\t\nCyclophosphamide (600 mg/m2; with or without docetaxel)\tIf index dose >1,500 mg/m2 then HECc;\nif index dose ≤1,500 mg/m2 then MECc\t4\t3\t12\t\nCyclophosphamide (600 mg/m2)/doxorubicin (60 mg/m2)\tHECc\t4\t3\t12\t\nCyclophosphamide (600 mg/m2)/doxorubicin (50 mg/m2) + docetaxel\tHECc\t6\t3\t18\t\nCyclophosphamide (600 mg/m2)/doxorubicin (60 mg/m2) + docetaxel\tHECc\t4\t3\t12\t\nCyclophosphamide (600 mg/m2)/doxorubicin (60 mg/m2) + paclitaxel (R1)\tHECc\t4\t2\t8\t\nCyclophosphamide (600 mg/m2)/doxorubicin (60 mg/m2) + paclitaxel (R2)\tHECc\t4\t3\t12\t\nCyclophosphamide (500 mg/m2)/doxorubicin (50 mg/m2) + 5-fluorouracil\tHECc\t6\t3\t18\t\nCyclophosphamide (100 mg/m2)/epirubicin (830 mg/m2)\tHECc\t8\t3\t24\t\nCyclophosphamide (500 mg/m2)/epirubicin (75 mg/m2) + 5-fluorouracil\tHECc\t4\t3\t12\t\nCyclophosphamide (500 mg/m2)/epirubicin (100 mg/m2) + docetaxel + 5-fluorouracil\tHECc\t6\t3\t18\t\nCyclophosphamide (600 mg/m2)/epirubicin (90 mg/m2) + paclitaxel + 5-fluorouracil\tHECc\t4\t3\t12\t\nCarboplatin (500–900 mg/m2; with docetaxel or trastuzumab or both)\tMECc\t6\t3\t18\t\nCarboplatin (150 mg) + paclitaxel\tMECc\t3\t1\t3\t\nCarboplatin (500 mg) + paclitaxel\tMECc\t3\t3\t9\t\nCarboplatin (150–900 mg/m2) + gemcitabine\tMECc\t6\t3\t18\t\nLung cancer\t\nCisplatin (100 mg) + vinorelbine\nCisplatin (75–80 mg) + vinorelbine\nCisplatin (75 mg/m2) + gemcitabine\nCisplatin (75 mg/m2) + docetaxel\tIf index dose ≥50 mg/m2,\nthen HECc;\nif index dose <50 mg/m2,\nthen MECc\t4\n4\n4\n4\t4\n3\n3\n3\t16\n12\n12\n12\t\nCisplatin (75 mg/m2) + etoposide\t\t4\t4\t16\t\nCisplatin (75 mg/m2) + pemetrexed\t\t4\t3\t12\t\nCarboplatin (150–900 mg/m2) + etoposide\tMECc\t6\t4\t24\t\nCarboplatin (150–900 mg/m2) + gemcitabine\tMECc\t6\t3\t18\t\nCarboplatin (500–900 mg/m2) + docetaxel\tMECc\t6\t3\t18\t\nCarboplatin (500–900 mg) + paclitaxel\tMECc\t3\t3\t9\t\nCarboplatin (150–900 mg) + paclitaxel\tMECc\t3\t1\t3\t\nColorectal cancer\t\nOxaliplatin (85 mg/m2) + 5-fluorouracil\tMECc\t12\t2\t24\t\nOxaliplatin (85 mg/m2) + 5-fluorouracil + leucovorin\tMECc\t12\t2\t24\t\nOxaliplatin (130 mg/m2) + capecitabine\tMECc\t8\t3\t24\t\nNotes:\n\na As per NCCN guidelines at the time of the study14–18 (the most recent NCCN guidelines indicate minor changes to the emetogenicity classification);\n\nb equal to the recommended cycle length as per NCCN guidelines14–18;\n\nc Hesketh rule in effect.31 Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Breast Cancer V2.2011, Colon Cancer V3.2011, Rectal Cancer V4.2011, Small Cell Lung Cancer V2.2012, Non-Small Cell Lung Cancer V3.2011. © National Comprehensive Cancer Network, Inc 2015. All rights reserved. All accessed July 11, 2011. To view the most recent and complete version of the guidelines, go online to NCCN.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc.\n\nAbbreviations: HEC, highly emetogenic chemotherapy; MEC, moderately EC; LEC, lowly EC; EC, emetogenic chemotherapy; NCCN, National Comprehensive Cancer Network.\n\nTable 3 Palonosetron versus other 5-HT3 RAs among patients initiating an HEC/MEC regimen\n\nCharacteristics\tHEC\n\tMEC\n\t\nPalonosetron groupa\nn=1,832\tOther 5-HT3 RA groupb\nn=2,387\tP-value\tPalonosetron groupa\nn=1,350\tOther 5-HT3 RA groupb\nn=1,379\tP-value\t\nFemale, n (%)\t1,805 (98.5)\t2,333 (97.7)\t0.0643\t981 (72.7)\t857 (62.2)\t<0.0001\t\nAge at index (years), mean ± SD\t52.04 (±9.52)\t51.41 (±9.6)\t0.0345\t56.82 (±10.9)\t59.21 (±11.33)\t<0.0001\t\n 18–44\t394 (21.5)\t571 (23.9)\t0.1046\t175 (13.0)\t144 (10.4)\t<0.0001\t\n 45–64\t1,276 (69.7)\t1,632 (68.4)\t\t858 (63.6)\t804 (58.3)\t\t\n ≥65\t162 (8.8)\t184 (7.7)\t\t317 (23.5)\t431 (31.3)\t\t\nGeographic region, n (%)\t\n Northeast\t288 (15.7)\t278 (11.7)\t<0.0001\t185 (13.7)\t173 (12.6)\t<0.0001\t\n South\t585 (31.9)\t736 (30.8)\t\t445 (33.0)\t480 (34.8)\t\t\n Midwest\t651 (35.5)\t488 (20.4)\t\t485 (35.9)\t406 (29.4)\t\t\n West\t232 (12.7)\t773 (32.4)\t\t172 (12.7)\t276 (20.0)\t\t\n Unknown\t76 (4.2)\t112 (4.7)\t\t63 (4.7)\t44 (3.2)\t\t\nHealth plan type, n (%)\t\n HMO\t314 (17.1)\t487 (20.4)\t0.0047\t238 (17.6)\t278 (20.2)\t0.0115\t\n POS\t99 (5.4)\t85 (3.6)\t\t49 (3.6)\t34 (2.5)\t\t\n PPO\t1,286 (70.2)\t1,661 (69.6)\t\t898 (66.5)\t879 (63.7)\t\t\n FFS\t12 (0.7)\t15 (0.6)\t\t7 (0.5)\t21 (1.5)\t\t\n Other/unknown\t121 (6.6)\t139 (5.8)\t\t158 (11.7)\t167 (12.1)\t\t\n Medicare planc\t134 (7.3)\t190 (8.0)\t0.4352\t233 (17.3)\t353 (25.6)\t<0.0001\t\nIndex year, n (%)\t\n 2002–2004\t16 (0.9)\t736 (30.8)\t<0.0001\t8 (0.6)\t105 (7.6)\t<0.0001\t\n 2005–2006\t936 (51.1)\t924 (38.7)\t\t343 (25.4)\t515 (37.4)\t\t\n 2007–2008\t854 (46.6)\t670 (28.1)\t\t963 (71.3)\t685 (49.7)\t\t\n 2009–2011\t26 (1.4)\t57 (2.4)\t\t36 (2.7)\t74 (5.4)\t\t\nBaseline medical conditions, n (%)\t\n Breast cancer\t1,782 (97.3)\t2,291 (96.0)\t0.0228\t656 (48.6)\t425 (30.8)\t<0.0001\t\n Lung cancer\t50 (2.7)\t96 (4.0)\t0.0228\t299 (22.2)\t485 (35.2)\t<0.0001\t\n Colorectal cancer\t0\t0\tNA\t395 (29.26)\t469 (34.0)\t0.0076\t\n Hypertension\t679 (37.1)\t871 (36.5)\t0.7015\t700 (51.9)\t751 (54.5)\t0.1722\t\n Cerebrovascular disease\t33 (1.8)\t47 (2.0)\t0.6922\t80 (5.9)\t101 (7.3)\t0.1422\t\n Heart failure\t26 (1.4)\t39 (1.6)\t0.5748\t49 (3.6)\t76 (5.5)\t0.0187\t\nRenal diseased\t35 (1.9)\t46 (1.9)\t0.9689\t60 (4.4)\t63 (4.6)\t0.8759\t\n Liver disease\t28 (1.5)\t34 (1.4)\t0.7808\t40 (3.0)\t36 (2.6)\t0.5759\t\n Diabetes mellitus\t174 (9.5)\t194 (8.1)\t0.1179\t216 (16)\t226 (16.4)\t0.7829\t\n Ischemic heart disease\t84 (4.6)\t107 (4.5)\t0.8738\t165 (12.2)\t238 (17.3)\t0.0002\t\n Pulmonary diseasee\t211 (11.5)\t297 (12.4)\t0.3602\t315 (23.3)\t460 (33.4)\t<0.0001\t\n Osteoporosis\t197 (10.8)\t244 (10.2)\t0.5761\t149 (11.0)\t149 (10.8)\t0.8459\t\n Mental health disorder\t441 (24.1)\t543 (22.8)\t0.3135\t352 (26.1)\t375 (27.2)\t0.5083\t\nDCI score\t\n Mean ± SD\t4.35 (±2.92)\t4.56 (±2.98)\t0.0211\t4.29 (±2.88)\t4.55 (±2.95)\t0.0229\t\n Median (Q1–Q3)\t2 (2–8)\t3 (2–8)\t0.0264\t3 (2–8)\t3 (2–8)\t0.0002\t\nBaseline therapies, n (%)\t\n LEC\t93 (5.1)\t108 (4.5)\t0.4042\t193 (14.3)\t205 (14.9)\t0.6734\t\n Radiation\t60 (3.3)\t113 (4.7)\t0.0179\t237 (17.6)\t290 (21.0)\t0.0215\t\n 5-HT3 antiemetics\t675 (36.8)\t895 (37.5)\t0.6652\t450 (33.3)\t374 (27.1)\t0.0004\t\n Non-5-HT3 antiemetics\t1,166 (63.7)\t1,359 (56.9)\t<0.0001\t828 (61.3)\t728 (52.8)\t<0.0001\t\nChemotherapeutic regimens, n (%)\t\n Cyclophosphamide\t6 (0.3)\t7 (0.3)\t\t499 (37.0)\t287 (20.8)\t\t\n Cyclophosphamide/doxorubicin\t1,656 (90.4)\t2,133 (89.4)\t\t\t\t\t\n Cyclophosphamide/epirubicin\t120 (6.6)\t151 (6.3)\t\t\t\t\t\n Cisplatin\t50 (2.7)\t96 (4.0)\t\t21 (1.6)\t13 (0.9)\t\t\n Carboplatin\t\t\t\t435 (32.2)\t610 (44.2)\t\t\n Oxaliplatin\t\t\t\t395 (29.3)\t469 (34.0)\t\t\nDuration of study follow-up, days\t\n Mean ± SD\t1,239.79 (±521.83)\t1,398.59 (±722.88)\t<0.0001\t1,036.1 (±414.11)\t1,089.16 (±517.92)\t0.0031\t\n Median (Q1–Q3)\t1,200 (835.5–1,648.5)\t1,295 (807–1,885)\t<0.0001\t994.5 (716–1,270)\t1,013 (648–1,407)\t0.1939\t\nNotes:\n\na Receipt of palonosetron and no other 5-HT3 RA during any cycle, measured from (HEC cycle-start date -1 day) until (HEC cycle-start date +5 days);\n\nb receipt of any 5-HT3 RA except palonosetron during any cycle, measured from (chemotherapy cycle-start date -1 day) until (chemotherapy cycle start date +5 days);\n\nc consisting of Medicare Advantage, supplemental, and Part D plans;\n\nd renal disease included kidney disease, nephrosis, nephritis, and renal function impairment, including dialysis;\n\ne pulmonary disease included asthma, bronchitis, pneumonia, emphysema, and COPD.\n\nAbbreviations: HT, hydroxytryptamine; RAs, receptor antagonists; HEC, highly EC; MEC, moderately EC; LEC, lowly EC; NEC, non-EC; EC, emetogenic chemotherapy; SD, standard deviation; HMO, health maintenance organization; POS, point of service; PPO, preferred provider organization; FFS, fee for service; NA, not applicable; Q, quartile; COPD, chronic obstructive pulmonary disease; DCI, Deyo–Charlson Comorbidity Index.\n\nTable 4 Outcomes among palonosetron versus other 5-HT3 RAs in patients initiating an HEC/MEC regimen\n\nOutcomes of interest\tHEC\n\tMEC\n\t\nPalonosetron group\nn=1,832\tOther 5-HT3 RA group\nn=2,387\tP-value\tPalonosetron group\nn=1,350\tOther 5-HT3 RA group\nn=1,379\tP-value\t\nCINV\t\n Patients experiencing ≥1 CINV event, n (%)\t504 (27.5)\t768 (32.2)\t0.0011\t487 (36.1)\t575 (41.7)\t0.0026\t\n Patients experiencing ≥1 acute CINV event\t350 (19.1)\t490 (20.53)\t0.2513\t361 (26.74)\t334 (24.22)\t0.1308\t\n Patients experiencing ≥1 delayed CINV event\t271 (14.79)\t482 (20.19)\t<0.0001\t278 (20.59)\t407 (29.51)\t<0.0001\t\n Total number of cycles\t7,616\t9,878\t\t7,952\t8,749\t\t\n Total number of events\t1,552\t2,685\t\t2,070\t3,686\t\t\n Acute\t769\t1,212\t\t1,193\t1,196\t\t\n Delayed\t783\t1,473\t\t877\t2,490\t\t\n Events/cycle\t0.2038\t0.2718\t\t0.2603\t0.4213\t\t\nTreatment delay\t\n Treatment delay, n (%)\t59 (3.2)\t144 (6.0)\t<0.0001\t230 (17.0)\t369 (26.8)\t<0.0001\t\n Treatment delay, lower limit, n (%)\t102 (5.6)\t199 (8.3)\t0.0005\t363 (26.9)\t536 (38.9)\t<0.0001\t\n Treatment delay, upper limit, n (%)\t19 (1.0)\t40 (1.7)\t0.08\t101 (7.5)\t163 (11.8)\t0.0001\t\nTherapy length until delay (days)\t\n Mean (± SD)\t76.28 (±22.65)\t76.32 (±22.62)\t0.9577\t87.38 (±42.45)\t85.45 (±48.18)\t0.2659\t\n Median (Q1–Q3)\t67 (64–85)\t76 (64–85)\t0.0147\t85 (62–111)\t85 (48–126)\t0.0147\t\nTreatment adherence, n(%)\t\n Receipt of\t\n 1. Recommended number of cycles\t1,607 (87.7)\t2,062 (86.4)\t0.2022\t885 (65.6)\t824 (59.8)\t0.0017\t\n 2. Recommended number of cycles within the specified time frame\t1,368 (74.7)\t1,664 (69.7)\t0.0004\t582 (43.1)\t514 (37.3)\t0.0019\t\n 3. Recommended number of cycles within the specified time frame at the expected dose\t500 (27.3)\t616 (25.8)\t0.0004\t202 (15.0)\t173 (12.6)\t0.0019\t\n 4. Recommended dose\t616 (33.6)\t798 (33.4)\t0.8951\t467 (34.6)\t512 (37.1)\t0.1673\t\nAbbreviations: HT, hydroxytryptamine; RAs, receptor antagonists; HEC, highly EC; MEC, moderately EC; EC, emetogenic chemotherapy; CINV, chemotherapy-induced nausea/vomiting; SD, standard deviation; Q, quartile.\n==== Refs\nReferences\n1 de Boer-Dennert M de Wit R Schmitz PI Patient perceptions of the side-effects of chemotherapy: the influence of 5HT3 antagonists Br J Cancer 1997 76 1055 1061 9376266 \n2 Hickok JT Roscoe JA Morrow GR King DK Atkins JN Fitch TR Nausea and emesis remain significant problems of chemotherapy despite prophylaxis with 5-hydroxytryptamine-3 antiemetics: a University of Rochester James P. Wilmot Cancer Center Community Clinical Oncology Program Study of 360 cancer patients treated in the community Cancer 2003 97 2880 2886 12767103 \n3 Ihbe-Heffinger A Ehlken B Bernard R The impact of delayed chemotherapy-induced nausea and vomiting on patients, health resource utilization and costs in German cancer centers Ann Oncol 2004 15 526 536 14998860 \n4 Shih YC Xu Y Elting LS Costs of uncontrolled chemotherapy-induced nausea and vomiting among working-age cancer patients receiving highly or moderately emetogenic chemotherapy Cancer 2007 110 678 685 17567835 \n5 Farrell C Brearley SG Pilling M Molassiotis A The impact of chemotherapy-related nausea on patients’ nutritional status, psychological distress and quality of life Support Care Cancer 2013 21 59 66 22610269 \n6 Roscoe JA Morrow GR Colagiuri B Insight in the prediction of chemotherapy-induced nausea Support Care Cancer 2010 18 869 876 19701781 \n7 Sun CC Bodurka DC Weaver CB Rankings and symptom assessments of side effects from chemotherapy: insights from experienced patients with ovarian cancer Support Care Cancer 2005 13 219 227 15538640 \n8 Bloechl-Daum B Deuson RR Mavros P Hansen M Herrstedt J Delayed nausea and vomiting continue to reduce patients’ quality of life after highly and moderately emetogenic chemotherapy despite antiemetic treatment J Clin Oncol 2006 24 4472 4478 16983116 \n9 Owusu C Buist DS Field TS Predictors of tamoxifen discontinuation among older women with estrogen receptor-positive breast cancer J Clin Oncol 2008 26 549 555 18071188 \n10 Wilcox PM Fetting JH Nettesheim KM Abeloff MD Anticipatory vomiting in women receiving cyclophosphamide, methotrexate, and 5-FU (CMF) adjuvant chemotherapy for breast cancer Cancer Treat Rep 1982 66 1601 1604 7049385 \n11 Roila F Herrstedt J Aapro M Guideline update for MASCC and ESMO in the prevention of chemotherapy- and radiotherapy-induced nausea and vomiting: results of the Perugia consensus conference Ann Oncol 2010 21 Suppl 5 v232 v243 20555089 \n12 Jordan K Sippel C Schmoll HJ Guidelines for antiemetic treatment of chemotherapy-induced nausea and vomiting: past, present, and future recommendations Oncologist 2007 12 1143 1150 17914084 \n13 Kris MG Hesketh PJ Somerfield MR American Society of Clinical Oncology guideline for antiemetics in oncology: update 2006 J Clin Oncol 2006 24 2932 2947 16717289 \n14 Carlson R NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®). Breast Cancer, Version 2 2011 © 2015 National Comprehensive Cancer Network, Inc. Available at NCCN.org Accessed: July 11, 2011 \n15 Engstrom P NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®). Colon Cancer, Version 3 2011 © 2015 National Comprehensive Cancer Network, Inc. Available at NCCN.org Accessed: July 11, 2011 \n16 Engstrom P NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®). Rectal Cancer, Version 4 2011 © 2015 National Comprehensive Cancer Network, Inc. Available at NCCN.org Accessed: July 11, 2011 \n17 Kalemkerian G NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®). Small Cell Lung Cancer, Version 2 2012 © 2015 National Comprehensive Cancer Network, Inc. Available at NCCN.org Accessed: July 11, 2011 \n18 Ettinger D NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®). Non-Small Cell Lung Cancer, Version 3 2011 © 2015 National Comprehensive Cancer Network, Inc. Available at NCCN.org Accessed: July 11, 2011 \n19 Hatoum HT Lin SJ Buchner D Cox D Comparative clinical effectiveness of various 5-HT3 RA antiemetic regimens on chemotherapy-induced nausea and vomiting associated with hospital and emergency department visits in real world practice Support Care Cancer 2012 20 941 949 21533811 \n20 Schwartzberg L Jackson J Jain G Balu S Buchner D Impact of 5-HT3 RA selection within triple antiemetic regimens on uncontrolled highly emetogenic chemotherapy-induced nausea/vomiting Expert Rev Pharmacoecon Outcomes Res 2011 11 481 488 21711119 \n21 Stoltz R Cyong JC Shah A Parisi S Pharmacokinetic and safety evaluation of palonosetron, a 5-hydroxytryptamine-3 receptor antagonist, in US and Japanese healthy subjects J Clin Pharmacol 2004 44 520 531 15102873 \n22 Rojas C Stathis M Thomas AG Palonosetron exhibits unique molecular interactions with the 5-HT3 receptor Anesth Analg 2008 207 469 478 18633025 \n23 Rojas C Slusher BS Pharmacological mechanisms of 5-HT3 and tachykinin NK1 receptor antagonism to prevent chemotherapy-induced nausea and vomiting Eur J Pharmacol 2012 684 1 7 22425650 \n24 Aapro MS Grunberg SM Manikhas GM A phase III, double-blind, randomized trial of palonosetron compared with ondansetron in preventing chemotherapy-induced nausea and vomiting following highly emetogenic chemotherapy Ann Oncol 2006 17 1441 1449 16766588 \n25 Eisenberg P Figueroa-Vadillo J Zamora R Improved prevention of moderately emetogenic chemotherapy-induced nausea and vomiting with palonosetron, a pharmacologically novel 5-HT3 receptor antagonist: results of a phase III, single-dose trial versus dolasetron Cancer 2003 98 473 482 \n26 Gralla R Lichinitser M Van der Vegt S Palonosetron improves prevention of chemotherapy-induced nausea and vomiting following moderately emetogenic chemotherapy: results of a double-blind randomized phase III trial comparing single doses of palonosetron with ondansetron Ann Oncol 2003 14 1570 1577 14504060 \n27 Lin SJ Hatoum HT Buchner D Cox D Balu S Impact of 5-HT3 receptor antagonists on chemotherapy-induced nausea and vomiting: a retrospective cohort study BMC Health Serv Res 2012 12 215 22823909 \n28 Craver C Gayle J Balu S Buchner D Palonosetron versus other 5-HT3 receptor antagonists for prevention of chemotherapy-induced nausea and vomiting in patients with hematologic malignancies treated with emetogenic chemotherapy in a hospital outpatient setting in the United States J Med Econ 2011 14 341 349 21542674 \n29 Ettinger D NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®). Antiemesis, Version 1 2012 © 2015 National Comprehensive Cancer Network, Inc. Available at NCCN.org Accessed: August 11, 2011 \n30 Sacco JJ Botten J Macbeth F Bagust A Clark P The average body surface area of adult cancer patients in the UK: a multicentre retrospective study PLoS One 2010 5 e8933 20126669 \n31 Hesketh PJ Chemotherapy-induced nausea and vomiting N Engl J Med 2008 358 2482 2494 18525044 \n32 Deyo RA Cherkin DC Ciol MA Adapting a clinical comorbidity index for use with ICD-9-CM administrative databases J Clin Epidemiol 1992 45 613 619 1607900 \n33 Taylor SE Lichtman RR Wood JV Compliance with chemotherapy among breast cancer patients Health Psychol 1984 3 553 562 6536503 \n34 Silberstein S Practice parameter: evidence-based guidelines for migraine headaches (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology Neurology 2000 55 754 762 10993991 \n35 Carlisle JB A meta-analysis of prevention of postoperative nausea and vomiting: randomised controlled trials by Fujii et al compared with other authors Anaesthesia 2012 67 1076 1090 22734848 \n36 Camilleri M Parkman HP Shafi MA Abell TL Gerson L Clinical guideline: management of gastroparesis Am J Gastroenterol 2013 108 18 37 23147521\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1179-1322",
"issue": "7()",
"journal": "Cancer management and research",
"keywords": "CINV; adherence; delay of therapy; health services research; observational; palonosetron",
"medline_ta": "Cancer Manag Res",
"mesh_terms": null,
"nlm_unique_id": "101512700",
"other_id": null,
"pages": "175-88",
"pmc": null,
"pmid": "26124681",
"pubdate": "2015",
"publication_types": "D016428:Journal Article",
"references": "14504060;15102873;10993991;9376266;22610269;16717289;16983116;17567835;14635083;19701781;16766588;20555089;14998860;22425650;18525044;7049385;15538640;18633025;21533811;18071188;23147521;1607900;21542674;22734848;12767103;20126669;21711119;17914084;6536503;22823909",
"title": "The impact of 5-hydroxytryptamine-receptor antagonists on chemotherapy treatment adherence, treatment delay, and nausea and vomiting.",
"title_normalized": "the impact of 5 hydroxytryptamine receptor antagonists on chemotherapy treatment adherence treatment delay and nausea and vomiting"
} | [
{
"companynumb": "US-JNJFOC-20150721623",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DOCETAXEL"
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"drugadditional": null,
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{
"abstract": "OBJECTIVE\nTreatment targeting immune checkpoint with programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitors has demonstrated efficacy and tolerability in the treatment of metastatic urothelial carcinoma (mUC). We investigated the efficacy and safety of atezolizumab in mUC patients who failed platinum-based chemotherapy.\nA retrospective study using the Samsung Medical Center cancer chemotherapy registry was performed on 50 consecutive patients with mUC treated with atezolizumab, regardless of their PD-L1(SP142) status, as salvage therapy after chemotherapy failure between May 2017 and June 2018. Endpoints included overall response rate (RR), progression-free survival (PFS), and safety.\n\n\nRESULTS\nAmong 50 patients, men constituted 76% and the median age was 68 years (range, 46 to 82 years). Twenty-three patients (46%) received atezolizumab as second-line therapy. PD-L1 (SP142) status IC0/1 and IC2/3 were found in 21 (42%) and 21 (42%) of patients, respectively; in eight patients (16%), PD-L1 (SP142) expression was not available. Atezolizumab was generally well tolerated, with pruritus and fatigue being the most commonly observed toxicities. As a result, partial response was noted in 20 patients (40%), with 12 (24%) stable diseases. RRwas higherin IC2/3 (62%) than in IC0/1 patients (24%, p=0.013). The median PFS was 7.4 months (95% confidence interval, 3.4 to 11.4 months). As expected, PFS also was significantly longer in IC2/3 patients than in IC0/1 (median, 12.7 vs. 2.1 months; p=0.005). PFS was not significantly influenced by age, sex, performance status, number of previous chemotherapy, site of metastases, or any of the baseline laboratory parameters.\n\n\nCONCLUSIONS\nIn this retrospective study, atezolizumab demonstrated clinically efficacy and tolerability in unselected mUC patients who failed platinum-based chemotherapy.",
"affiliations": "Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.;Department of Medicine, Sungkyunkwan University Samsung Changwon Hospital, Changwon, Korea.;Department of Pathology, Sungkyunkwan University School of Medicine, Seoul, Korea.;Department of Urology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.;Department of Urology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.;Department of Urology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.;Department of Urology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.;Department of Urology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.;Department of Urology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.;Department of Urology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.;Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.;Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.",
"authors": "Hur|Joon Young|JY|;Kim|Youjin|Y|;Kwon|Ghee-Young|GY|;Kang|Minyong|M|;Sung|Hyun Hwan|HH|;Jeon|Hwang Gyun|HG|;Jeong|Byong Chang|BC|;Seo|Seong Il|SI|;Jeon|Seong Soo|SS|;Lee|Hyun Moo|HM|;Lee|Su Jin|SJ|;Park|Se Hoon|SH|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D000074322:Antineoplastic Agents, Immunological; D060890:B7-H1 Antigen; C423236:CD274 protein, human; C000594389:atezolizumab",
"country": "Korea (South)",
"delete": false,
"doi": "10.4143/crt.2018.604",
"fulltext": "\n==== Front\nCancer Res TreatCancer Res TreatCRTCancer Research and Treatment : Official Journal of Korean Cancer Association1598-29982005-9256Korean Cancer Association 10.4143/crt.2018.604crt-2018-604Original ArticleAtezolizumab in Patients with Pretreated Urothelial Cancer: a Korean Single-Center, Retrospective Study Hur Joon Young MD1Kim Youjin MD2Kwon Ghee-Young MDPhD3Kang Minyong MDPhD4Sung Hyun Hwan MDPhD4Jeon Hwang Gyun MDPhD4Jeong Byong Chang MDPhD4Seo Seong Il MDPhD4Jeon Seong Soo MDPhD4Lee Hyun Moo MDPhD4Lee Su Jin MDPhD1Park Se Hoon MDPhD1\n1 Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea\n2 Department of Medicine, Sungkyunkwan University Samsung Changwon Hospital, Changwon, Korea\n3 Department of Pathology, Sungkyunkwan University School of Medicine, Seoul, Korea\n4 Department of Urology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, KoreaCorrespondence: Se Hoon Park, MD, PhD Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 06351, Korea Tel: 82-2-3410-1779 Fax: 82-2-3410-1754 E-mail: hematoma@skku.edu10 2019 9 1 2019 51 4 1269 1274 6 11 2018 4 1 2019 Copyright © 2019 by the Korean Cancer Association2019This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Purpose\nTreatment targeting immune checkpoint with programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitors has demonstrated efficacy and tolerability in the treatment of metastatic urothelial carcinoma (mUC). We investigated the efficacy and safety of atezolizumab in mUC patients who failed platinum-based chemotherapy.\n\nMaterials and Methods\nA retrospective study using the Samsung Medical Center cancer chemotherapy registry was performed on 50 consecutive patients with mUC treated with atezolizumab, regardless of their PD-L1(SP142) status, as salvage therapy after chemotherapy failure between May 2017 and June 2018. Endpoints included overall response rate (RR), progression-free survival (PFS), and safety.\n\nResults\nAmong 50 patients, men constituted 76% and the median age was 68 years (range, 46 to 82 years). Twenty-three patients (46%) received atezolizumab as second-line therapy. PD-L1 (SP142) status IC0/1 and IC2/3 were found in 21 (42%) and 21 (42%) of patients, respectively; in eight patients (16%), PD-L1 (SP142) expression was not available. Atezolizumab was generally well tolerated, with pruritus and fatigue being the most commonly observed toxicities. As a result, partial response was noted in 20 patients (40%), with 12 (24%) stable diseases. RRwas higherin IC2/3 (62%) than in IC0/1 patients (24%, p=0.013). The median PFS was 7.4 months (95% confidence interval, 3.4 to 11.4 months). As expected, PFS also was significantly longer in IC2/3 patients than in IC0/1 (median, 12.7 vs. 2.1 months; p=0.005). PFS was not significantly influenced by age, sex, performance status, number of previous chemotherapy, site of metastases, or any of the baseline laboratory parameters.\n\nConclusion\nIn this retrospective study, atezolizumab demonstrated clinically efficacy and tolerability in unselected mUC patients who failed platinum-based chemotherapy.\n\nAtezolizumabSalvageUrothelial carcinomaRetrospective\n==== Body\nIntroduction\nBladder cancer, the seventh most common malignancy in Korea [1], is the most frequent among urothelial carcinoma (UC) that also include the less common UC arising from renal pelvis, ureter and urethra. Over the past two decades, there has been no significant improvement in survival of UC with 5-year survival rates for locally-advanced and metastatic disease of 33% and 5%, respectively [2]. In metastatic UC (mUC), platinum-based combination chemotherapy has been the standard-of-care with a median overall survival (OS) of approximately 15 months [3]. Recently, programmed death-1 (PD-1) and programmed death-ligand 1 (PD-L1) checkpoint inhibitors including atezolizumab and pembrolizumab received approval for the treatment of patients with mUC who have disease progression during or following platinum-based chemotherapy, regardless of PD-L1 expression level [4,5]. In Korea, although reimbursement is provided only for patients with PD-L1 positive disease since the approval in May 2017, atezolizumab has been widely administered to mUC patients pretreated with platinum-based chemotherapy.\n\nDespite promising clinical data with immune checkpoint inhibitors, not all patients with mUC who are treated with atezolizumab achieve clinical response, and even in the responders, resistance to therapy will, if not all, eventually develops. Considering most mUC patients would receive platinum-based chemotherapy in first-line setting, and in an effort to generate real-world data in Korean mUC patients, we conducted a retrospective review of a prospectively collected cancer chemotherapy registry. Herein, we report the outcomes of mUC patients who received atezolizumab following clinical failure to platinum-based chemotherapy. Although this study is limited by the retrospective nature of the analysis, the present evaluation was also done with the intent to develop improved therapeutic strategies for pretreated mUC patients and support further prospective studies to better define the full therapeutic potential of immune checkpoint inhibitors.\n\nMaterials and Methods\n1. Patients and samples\nAll patients, with histologically-proven mUC, had been treated with platinum-based combination chemotherapy for metastatic disease. With the help of Samsung Medical Center (SMC) cancer registry, we retrospectively collected and reviewed follow-up data of adult mUC patients (> 20 years) who were consecutively treated with atezolizumab as salvage therapy, between May 2017 and June 2018. Other criteria for case inclusion were as follows: (1) histologically confirmed diagnosis of UC arising from bladder and/or upper urinary tract, (2) presence of measurable metastatic disease, and (3) availability of clinical data at the beginning of therapy and follow-up. We excluded patients who were enrolled in clinical trials to ensure the study population reflected our daily clinical practice, and the choice of atezolizumab was solely at the discretion of the treating oncologists.\n\nIn all patients, archival tumor samples were evaluated with SP142 PD-L1 immunohistochemical assay (Ventana, Tucson, AZ). According to the current Korean Health Insurance policy, only patients with PD-L1 expression on 5% or more of tumor-infiltrating immune cells (IC2/3) were reimbursed for atezolizumab. For patients with PD-L1 (SP142) IC0 or IC1, as well as those with no available PD-L1 data, atezolizumab was self-paid in full. Atezolizumab 1,200 mg was administered intravenously every 3 weeks. Supportive care including the administration of blood products, palliative radiotherapy for painful bone metastases, and the use of analgesics was given if judged appropriately by the treating physicians. Before initiating the first dose of atezolizumab, patients had a complete history taken, complete blood counts and serum chemistries, chest X-rays, and computed tomography (CT) scans of all involved sites. Baseline characteristics and outcome data were collected using a uniform case report form. In order to evaluate clinical response to atezolizumab, CT scans were usually performed every 6 weeks. Response Evaluation Criteria in Solid Tumors (RECIST v1.1) and the assessment of the treating physicians were used to categorize response. Atezolizumab was continued until objective disease progression, unacceptable toxicity, or patient’s refusal.\n\nPrimary endpoint of the present study was the overall response rate (RR). Secondary endpoints included progression-free survival (PFS) and safety. Time from the first day of atezolizumab administration to the date of documented disease progression or death was used to calculate PFS. PFS was calculated using the Kaplan-Meier method. To examine the impact of baseline parameters collected on PFS, Cox proportional hazard model was used. The potential presence of interaction effects between baseline parameters was tested by defining product terms for the respective factors in a regression model. All p-values were two-sided, with p < 0.05 indicating statistical significance. All analyses were performed using the R for Windows v2.11.1 software (R Core Team, Vienna, Austria; http://www.r-project.org).\n\n2. Ethical statement\nThis retrospective study was approved by the Institutional Review Board of SMC (approval number: SMC 2018-02-016) and performed in accordance with the principles of the Declaration of Helsinki. Written informed consent was waived for this study, because of its retrospective nature.\n\nResults\nMedical records from 50 eligible patients who were consecutively treated with atezolizumab for pretreated mUC at the medical oncology department of SMC between May 2017 and June 2018 were collected for the present retrospective study. Patient characteristics are given in Table 1. As shown, men constituted 76% of the patients. All patients had previously been treated with gemcitabine plus platinum combination chemotherapy, and 46% received atezolizumab as second-line therapy. Among 42 patients whose PD-L1 expression was available, 21 (50%) had IC2/3 (i.e., 5% or higher). Approximately half of the patients had two or more metastatic disease sites, mostly involving lung, bone and lymph nodes. At the time of data collection, with a median follow-up duration of 14 months, 33 patients (66%) discontinued atezolizumab and 32 patients (64%) had experienced disease progression.\n\nPatients received atezolizumab for a total of 318 cycles (median, 5; range, 1 to 17). The most common reason for therapy discontinuation was disease progression (58%), followed by toxicity (4%) and economic burden (4%). Overall, salvage atezolizumab was generally well tolerated, with fatigue and pruritus being the most commonly observed toxicities (Table 2). Severe and persistent immune-related adverse events resulting in treatment discontinuation were observed in two patients. Three patients (6%) had an immune-related adverse event that necessitated systemic corticosteroid use. One patient died of causes whose relation to atezolizumab could not be completely ruled out (68-year-old male, who was known to have multiple lung and pleural metastases, died of respiratory failure shortly after the first dose of atezolizumab therapy). Although the extent of pleural effusions and pneumonitis was markedly increased, the possibility of drug-related mortality was not completely excluded.\n\nResponse evaluation was possible in 50 patients. In an intent-to-treat analysis, partial responses to atezolizumab were noted in 20 patients (RR, 40%; 95% confidence interval [CI], 26 to 54). Stable disease was observed in 12 patients (24%), leading to a 64% disease control rate. Except for PD-L1 status (Fig. 1), RR was not significantly influenced by age, sex, performance status, primary site, number of prior chemotherapy regimens, or number and site of metastases. We observed higher RR in patients with PD-L1 IC2/3 (62%) than in those with PD-L1 IC0/1 (62% vs. 24%, p=0.013). Of the 50 patients analyzed in the study, the median PFS was 7.4 months (95% CI, 3.4 to 11.4) (Fig. 2). The estimated PFS was significantly longer for patients with PD-L1 IC2/3 (median, 12.7 months; 95% CI, 10.5 to 14.8) compared to those with PD-L1 IC0/1/unknown (median, 2.1 months; 95% CI, 1.6 to 2.6; log-rank p=0.005). In a Cox proportional hazards model, only PD-L1 IC2/3 was associated with the lower risk for disease progression (hazard ratio, 0.26; 95% CI, 0.10 to 0.66).\n\nFor exploratory purpose, we compared PFS according to the clinical response to atezolizumab. PFS was longer (p < 0.001) in patients who achieved response (median, 12.8 months) than in non-responders (2.1 months). After atezolizumab failure, 32% of the patients received third-line therapy, mostly with taxanes (n=11) or investigational agents (n=6).\n\nDiscussion\nThis retrospective study was designed to evaluate the activity and safety of salvage atezolizumab therapy in a subset of Korean patients with mUC who had been treated with platinum-based combination chemotherapy. The 40% RR, together with an additional stable disease rate of 24%, provided an overall disease control rate of 64%. A median PFS of 7.4 months in PD-L1 unselected patients compared favorably with the results observed in the pivotal phase 2/3 studies [4,6], as well as those seen in other second-line mUC studies involving pembrolizumab [5], nivolumab [7], durvalumab [8], or avelumab [9]. PFS and overall response may be good because more IC2/3 patients (n=21, 50%) enrolls in this study than other studies.\n\nIn metastatic or advanced setting, platinum-based combination chemotherapy has been regarded as standard treatment, because it has shown remarkable RR and PFS, as well as tolerability [3]. However, most patients would develop resistance to these chemotherapy regimens after months, or even after years, of clinical benefit. In these patients, despite the lack of evidence for benefit associated with patients may benefit from second-line treatment, it is common practice to offer further chemotherapy involving taxanes, pemetrexed, or other platinum-based regimens. Since currently another immune checkpoint inhibitor pembrolizumab [5] had demonstrated activity when compared with chemotherapy, the optimal second-line therapy in patients with mUC is still undecided. While pembrolizumab was not readily available as second-line therapy when the present study was initiated, selection based on the benefits of atezolizumab versus pembrolizumab should come from randomized, direct comparison clinical trials.\n\nSurprisingly, phase 3 trials involving pembrolizumab (KEYNOTE-045) and atezolizumab (IMvigor-211) revealed different results and conclusions [5,6]. In KEYNOTE-045, where pembrolizumab was compared with chemotherapy [5], significantly longer OS (10.3 months vs. 7.4 months) and RR (21% vs. 11%) were demonstrated. It was of note that the benefit of pembrolizumab over chemotherapy was seen in both the total population and those with a PD-L1 overexpression. In IMvigor-211 [6], unfortunately, atezolizumab was not associated with longer OS than chemotherapy in total population (8.6 months vs. 8.0 months) or patients with PD-L1 IC2/3 mUC (11.1 months vs. 10.6 months). Nevertheless, although the efficacy of second-line atezolizumab was not evident in the phase 3 IMvigor-211 trial, the authors concluded that the well-tolerated and durable remissions observed with atezolizumab can be considered favorable for patients with mUC previously treated with platinum-based chemotherapy. Everyone knows that indirect comparisons of different randomized trials should be based on similarity and consistency assumptions but often lead to bias. Currently, the lesson we learned from these two trials is that immune checkpoint inhibitors targeting PD-1/PD-L1 offer clinically relevant benefit in patients with platinum-treated mUC.\n\nTherefore, the identification of prognostic or predictive factors allowing the selection of patients who are likely to benefit from PD-1/PD-L1 inhibitors is an important challenge. Our study showed that, among the total of 50 patients with mUC, 18 patients (36%) experienced a progressive disease as their best response to atezolizumab, comparable to findings in published reports [4,6]. The patients have been treated outside the clinical trials, thus accurately reflecting the current clinical practice in mUC. Although this study is retrospective in nature, it is clear that atezolizumab may not be beneficial for all mUC patients with chemotherapy failure. One of the most widely recognized predictive markers for immune checkpoint inhibitors is PD-L1 expression [10]. In the present study, the difference in RR (62% vs. 24%) and PFS (12.7 months vs. 2.1 months) between patients with PD-L1 IC0/1 and IC2/3 was distinct. However, the presence of robust responses in some patients with IC0/1, as well as the similar outcomes seen in phase 3 studies, complicates the issue of PD-L1 as an exclusionary predictive biomarker. Tumor mutation burden, which is known to be high in UC, and DNA mismatch repair deficiency (dMMR) are thought to be surrogate markers for benefit from immune checkpoint inhibitor therapy [10]. Tumor mutation burden, dMMR and PD-L1 expression are somewhat interrelated [11], as mechanistically the relationship between these biomarkers may be related to increased neoantigen load required for immune recognition of tumors. Although we found that response to atezolizumab was significantly related to the PD-L1 status, it should be noted that the present retrospective study may have a selection bias. Actually, among the immune checkpoint inhibitors approved for salvage treatment of mUC, only atezolizumab is fully reimbursed by the health insurance system in Korea. Since the reimbursement is provided only for patients with PD-L1 IC2/3 disease, and our patients received atezolizumab at the discretion of the treating medical oncologists, it may be that clinical and/or economic judgment withheld the use of atezolizumab from those with first-line chemotherapy failure. Therefore, we still do not know whether the PD-L1 indicates optimal forms of treatment for the individual patient. Needless to say, when interpreting the results, it is of note that this analysis represents only a small sample of patient, but it is possible that patients with PD-L1 IC0/1 disease may have more aggressive disease than those with IC2/3. In recent years, extensive translational and clinical researches are underway to identify biologically relevant biomarkers for PD-1/PD-L1 therapy. Since immunotherapy with intravesical bacillus Calmette-Guerin was the first effective treatment in UC [12], immune checkpoint inhibitors, alone or in combination with chemotherapy, are in development for UC in earlier stage of disease with promising results [13,14].\n\nIn conclusion, the present study demonstrates that salvage atezolizumab platinum-based combination chemotherapy provides clinically relevant efficacy and tolerability in patients with mUC. It is suggested that the magnitude of the benefit of atezolizumab in Korean patients are similar to that obtained in the phase 2/3 trials. Although not confirmed in the prospective IMvigor-211 trial, we found that patients with PD-L1 IC2/3 tumors had better clinical outcomes that those in IC0/1 tumors. It is hoped that, with better patient selection, clinical outcomes of mUC patients can be improved. Furthermore, emerging science and the knowledge of the disease may further guide us to develop individualized treatment for UC patients.\n\nConflict of interest relevant to this article was not reported.\n\nFig. 1. Percentages of best response to atezolizumab for patients with programmed death-ligand 1 (PD-L1) expression < 5% or unknown (blue line, n=29) and those with PD-L1 expression > 5% or higher (red line, n=21). IC, immune cell.\n\nFig. 2. Kaplan-Meier plots of progression-free survival (PFS) for all patients (blue line), patients programmed death-ligand 1 (PD-L1) expression < 5% or unknown (red line), and those with PD-L1 expression > 5% or higher (green line). IC, immune cell.\n\nTable 1. Patient characteristics\n\nCharacteristic\tNo. (%)\t\nAge, median (range, yr)\t68 (46-82)\t\nSex\t\t\n Male\t38 (76)\t\n Female\t12 (24)\t\nECOG performance status\t\t\n 0\t19 (38)\t\n 1\t29 (58)\t\n 2\t2 (4)\t\nPrimary site\t\t\n Bladder\t28 (56)\t\n Upper tract (renal pelvis or ureter)\t22 (44)\t\nPrior chemotherapeutic regimens\t\t\n Gemcitabine plus platinum\t50 (100)\t\n Taxanes\t24 (48)\t\n M-VAC or CMV\t5 (10)\t\n Investigational agents\t3 (6)\t\n Pemetrexed\t2 (4)\t\nLine of atezolizumab therapy\t\t\n Second-line\t23 (46)\t\n Third-line\t19 (38)\t\n Fourth-line or later\t8 (16)\t\nPD-L1 IC expression (%)\t\t\n 0\t3 (6)\t\n 1-4\t18 (36)\t\n 5 or higher\t21 (42)\t\n Unknown\t8 (16)\t\nSites of metastases\t\t\n Lymph nodes\t40 (80)\t\n Bone\t15 (30)\t\n Lung\t16 (32)\t\n Liver\t8 (16)\t\nECOG, Eastern Cooperative Oncology Group; M-VAC, methotrexate+vinblastine+doxorubicin+cisplatin; CMV, cisplatin+methotrexate+vinblastine; PD-L1, programmed death-ligand 1; IC, immune cell.\n\nTable 2. Most commonly observed adverse events per patients (n=50)\n\n\tAll grades\tGrade 3 or 4\t\nFatigue\t8 (16)\t2 (4)\t\nPruritus\t6 (12)\t0\t\nRash\t5 (10)\t0\t\nAnorexia\t5 (10)\t1 (2)\t\nDiarrhea\t4 (8)\t0\t\nConstipation\t4 (8)\t0\t\nVomiting\t4 (8)\t0\t\nStomatitis\t4 (8)\t0\t\nAminotransferase increase\t3 (6)\t0\t\nCreatinine increase\t3 (6)\t1 (2)\t\nThyroid dysfunction\t6 (12)\t0\t\nDiabetes\t5 (10)\t0\t\nPneumonitis\t1 (2)\t1 (2)\t\nInfection\t4 (8)\t0\t\nValues are presented as number (%).\n==== Refs\nReferences\n1 Roscigno M Shariat SF Freschi M Margulis V Karakiewizc P Suardi N Assessment of the minimum number of lymph nodes needed to detect lymph node invasion at radical nephroureterectomy in patients with upper tract urothelial cancer Urology 2009 74 1070 4 19883824 \n2 Siegel R Ma J Zou Z Jemal A Cancer statistics, 2014 CA Cancer J Clin 2014 64 9 29 24399786 \n3 von der Maase H Sengelov L Roberts JT Ricci S Dogliotti L Oliver T Long-term survival results of a randomized trial comparing gemcitabine plus cisplatin, with methotrexate, vinblastine, doxorubicin, plus cisplatin in patients with bladder cancer J Clin Oncol 2005 23 4602 8 16034041 \n4 Rosenberg JE Hoffman-Censits J Powles T van der Heijden MS Balar AV Necchi A Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial Lancet 2016 387 1909 20 26952546 \n5 Bellmunt J de Wit R Vaughn DJ Fradet Y Lee JL Fong L Pembrolizumab as second-line therapy for advanced urothelial carcinoma N Engl J Med 2017 376 1015 26 28212060 \n6 Powles T Duran I van der Heijden MS Loriot Y Vogelzang NJ De Giorgi U Atezolizumab versus chemotherapy in patients with platinum-treated locally advanced or metastatic urothelial carcinoma (IMvigor211): a multicentre, open-label, phase 3 randomised controlled trial Lancet 2018 391 748 57 29268948 \n7 Sharma P Retz M Siefker-Radtke A Baron A Necchi A Bedke J Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275): a multicentre, single-arm, phase 2 trial Lancet Oncol 2017 18 312 22 28131785 \n8 Powles T O'Donnell PH Massard C Arkenau HT Friedlander TW Hoimes CJ Efficacy and safety of durvalumab in locally advanced or metastatic urothelial carcinoma: updated results from a phase 1/2 open-label study JAMA Oncol 2017 3 e172411 28817753 \n9 Patel MR Ellerton J Infante JR Agrawal M Gordon M Aljumaily R Avelumab in metastatic urothelial carcinoma after platinum failure (JAVELIN Solid Tumor): pooled results from two expansion cohorts of an open-label, phase 1 trial Lancet Oncol 2018 19 51 64 29217288 \n10 Kim ST Klempner SJ Park SH Park JO Park YS Lim HY Correlating programmed death ligand 1 (PD-L1) expression, mismatch repair deficiency, and outcomes across tumor types: implications for immunotherapy Oncotarget 2017 8 77415 23 29100397 \n11 Salem ME Puccini A Grothey A Raghavan D Goldberg RM Xiu J Landscape of tumor mutation load, mismatch repair deficiency, and PD-L1 expression in a large patient cohort of gastrointestinal cancers Mol Cancer Res 2018 16 805 12 29523759 \n12 Lamm DL Thor DE Stogdill VD Radwin HM Bladder cancer immunotherapy J Urol 1982 128 931 5 6757467 \n13 Balar AV Galsky MD Rosenberg JE Powles T Petrylak DP Bellmunt J Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial Lancet 2017 389 67 76 27939400 \n14 Balar AV Castellano D O'Donnell PH Grivas P Vuky J Powles T First-line pembrolizumab in cisplatin-ineligible patients with locally advanced and unresectable or metastatic urothelial cancer (KEYNOTE-052): a multicentre, single-arm, phase 2 study Lancet Oncol 2017 18 1483 92 28967485\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1598-2998",
"issue": "51(4)",
"journal": "Cancer research and treatment",
"keywords": "Atezolizumab; Retrospective; Salvage; Urothelial carcinoma",
"medline_ta": "Cancer Res Treat",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D061067:Antibodies, Monoclonal, Humanized; D000074322:Antineoplastic Agents, Immunological; D060890:B7-H1 Antigen; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D056910:Republic of Korea; D012189:Retrospective Studies; D016879:Salvage Therapy; D016019:Survival Analysis; D016896:Treatment Outcome; D014571:Urologic Neoplasms",
"nlm_unique_id": "101155137",
"other_id": null,
"pages": "1269-1274",
"pmc": null,
"pmid": "30653744",
"pubdate": "2019-10",
"publication_types": "D016428:Journal Article",
"references": "26952546;29268948;28131785;29217288;28967485;6757467;29100397;16034041;19883824;27939400;28817753;28212060;24399786;29523759",
"title": "Atezolizumab in Patients with Pretreated Urothelial Cancer: a Korean Single-Center, Retrospective Study.",
"title_normalized": "atezolizumab in patients with pretreated urothelial cancer a korean single center retrospective study"
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"actiondrug": "5",
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"activesubstancename": "ATEZOLIZUMAB"
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{
"abstract": "Listeria monocytogenes is a common bacterium that can trigger an episode of amphixenosis from the consumption of contaminated food. It survives in the host as an intracellular parasite and can get reactivated when the host's immune system is compromised. The use of anti-tumor necrosis factor-α (TNF-α) blockers is reported to increase the risk of L. monocytogenes infections. In the field of gastroenterology, the use of TNF-α blockers is on the rise due to remarkable efficacy in select patients with inflammatory bowel diseases (IBDs) such as ulcerative colitis and Crohn's disease and the rise in the incidence and prevalence of IBDs. There are few case reports on this topic, despite the rapid development of novel TNF-α blockers. Here, we report two cases of septicemic listeriosis encountered during treatment with the more recent TNF-α blockers, namely, adalimumab and golimumab, in ulcerative colitis and review the published literature on the topic.",
"affiliations": "Department of Gastroenterology, Saiseikai Niigata Daini Hospital, Niigata, Japan.;Department of Gastroenterology, Saiseikai Niigata Daini Hospital, Niigata, Japan. pyloki-sato@med.niigata-u.ac.jp.;Department of Gastroenterology, Saiseikai Niigata Daini Hospital, Niigata, Japan.;Division of Gastroenterology and Hepatology, Niigata University Medical and Dental Hospital, Niigata, Japan.",
"authors": "Horigome|Ryoko|R|;Sato|Hiroki|H|http://orcid.org/0000-0001-7766-3724;Honma|Terasu|T|;Terai|Shuji|S|",
"chemical_list": "D000900:Anti-Bacterial Agents; D000911:Antibodies, Monoclonal; D005938:Glucocorticoids; D007166:Immunosuppressive Agents; D000079424:Tumor Necrosis Factor Inhibitors; D000667:Ampicillin; C529000:golimumab; D000068879:Adalimumab",
"country": "Japan",
"delete": false,
"doi": "10.1007/s12328-019-01005-6",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1865-7265",
"issue": "13(1)",
"journal": "Clinical journal of gastroenterology",
"keywords": "Anti-tumor necrosis factor-α blocker; Golimumab; Inflammatory bowel disease; Listeria; Ulcerative colitis",
"medline_ta": "Clin J Gastroenterol",
"mesh_terms": "D000068879:Adalimumab; D000667:Ampicillin; D000900:Anti-Bacterial Agents; D000911:Antibodies, Monoclonal; D000071997:Blood Culture; D003093:Colitis, Ulcerative; D005260:Female; D005938:Glucocorticoids; D006801:Humans; D016867:Immunocompromised Host; D007166:Immunosuppressive Agents; D008088:Listeriosis; D008875:Middle Aged; D018805:Sepsis; D000079424:Tumor Necrosis Factor Inhibitors",
"nlm_unique_id": "101477246",
"other_id": null,
"pages": "22-25",
"pmc": null,
"pmid": "31222454",
"pubdate": "2020-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": "16514404;19542009;15766516;25057381;11930099;30060938;10710107;18159561;29429045;21039077;17973302;18294633;29282389;29607962;12571839;12908351;19841597;30735257;30378141;17051484;28956537;16902896;16555939;14650115;28588016;22626505",
"title": "Septicemic listeriosis during adalimumab- and golimumab-based treatment for ulcerative colitis: case presentation and literature review.",
"title_normalized": "septicemic listeriosis during adalimumab and golimumab based treatment for ulcerative colitis case presentation and literature review"
} | [
{
"companynumb": "JP-TEVA-2020-JP-1190047",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
},
"drugadditional": "3",
... |
{
"abstract": "A case of acute poisoning with amlodipine with deep hypotension, transient oliguria and clinical signs of acute heart failure was described. A woman of 23 years swallowed intentionally 60 tablets of amlodipine (600 mg). After eleven hours of ingestion she was admitted to Warsaw Poison Control Centre. She was in severe clinical condition; tachycardia and deep hypotension were the prominent signs of poisoning. There was not CNS depression. Intensive treatment with i.v. catecholamines (dopamine, norepinephrine), crystalloids (with continuous control of central venous pressure), and i.v. calcium salts (with control of plasma calcium concentration) was started immediately. The patient did not improve but got worse. Acute heart failure developed, especially of left ventricle, so i.v. crystalloids were stopped and dubutamin, morphine, nitroglycerin and glucagon were introduced. Because of oliguria and insufficient effect of high doses of furosemide four-hours hemodiafiltration was set in. The patient's condition slowly improve after third and forth day of hospitalization. The systolic blood pressure rose, heart work was really better and on sixth day--the stabilization of diastolic blood pressure was definitely achieved. The patient was discharge in good condition with heart ejection fraction of 65% measured echocardiographically.",
"affiliations": "III Oddział Chorób Wewnetrznych, Stołeczny Ośrodek Ostrych Zatruć.",
"authors": "Feldman|R|R|;Glińska-Serwin|M|M|",
"chemical_list": "D000959:Antihypertensive Agents; D002121:Calcium Channel Blockers; D017311:Amlodipine",
"country": "Poland",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": null,
"issue": "105(6)",
"journal": "Polskie Archiwum Medycyny Wewnetrznej",
"keywords": null,
"medline_ta": "Pol Arch Med Wewn",
"mesh_terms": "D000328:Adult; D017311:Amlodipine; D000959:Antihypertensive Agents; D002121:Calcium Channel Blockers; D062787:Drug Overdose; D005260:Female; D006333:Heart Failure; D006801:Humans; D007022:Hypotension; D009846:Oliguria; D013406:Suicide, Attempted; D016896:Treatment Outcome",
"nlm_unique_id": "0401225",
"other_id": null,
"pages": "495-9",
"pmc": null,
"pmid": "11865580",
"pubdate": "2001-06",
"publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article",
"references": null,
"title": "Deep hypotension with transient oliguria and severe heart failure in course of acute intentional poisoning with amlodipine.",
"title_normalized": "deep hypotension with transient oliguria and severe heart failure in course of acute intentional poisoning with amlodipine"
} | [
{
"companynumb": "PL-LUPIN PHARMACEUTICALS INC.-2015-03711",
"fulfillexpeditecriteria": "1",
"occurcountry": "PL",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "AMLODIPINE BESYLATE"
},
"drug... |
{
"abstract": "BACKGROUND\nIn patients with autoimmune hepatitis, efficient immunosuppressive therapy is essential to avoid progression to cirrhosis. There is no established second line therapy for patients failing standard therapy with steroids and azathioprine. The aim of this study was to examine the possible role of mycophenolate mofetil (MMF) as second line treatment of autoimmune hepatitis (AIH).\n\n\nMETHODS\nWe were able to identify 37 patients (29 women, 8 men) with AIH proven according to International AIH Group criteria who failed standard therapy. One patient on MMF was excluded due to non-compliance. A total of 28 of 36 patients had experienced side effects necessitating stop of treatment. One patient stopped azathioprine due to pregnancy. A total of nine patients did not respond sufficiently to azathioprine. A total of four patients with a treatment duration of 3 months or less because of severe side effects were considered as intolerant to MMF. Remission was defined as aspartate transaminase (ASP) < twice upper normal limit (UNL).\n\n\nRESULTS\nOf 36 patients on MMF included in the analysis, 14 patients (39%) experienced remission. A total of 22 patients (61%) did not respond sufficiently to MMF. The response rate to MMF was dependent on the cause of treatment cessation of azathioprine. Of eight patients with prior nonresponse to azathioprine, six (75%) did not respond to MMF and only two (25%) reached biochemical remission. Of 28 patients with azathioprine intolerance in 16 (57%) patients, the response to MMF was insufficient and in 12 patients (43%) remission was reached. The difference did not reach statistical significance due to the relatively small numbers included.\n\n\nCONCLUSIONS\nIn the light of its good tolerability, MMF seems to be an alternative for patients who could not tolerate azathioprine previously. However, our data suggest that a majority of patients fail MMF particularly if they are switched because of an insufficient response to azathioprine.",
"affiliations": "First Department of Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.",
"authors": "Hennes|Elke M|EM|;Oo|Ye H|YH|;Schramm|Christoph|C|;Denzer|Ulrike|U|;Buggisch|Peter|P|;Wiegard|Christiane|C|;Kanzler|Stephan|S|;Schuchmann|Marcus|M|;Boecher|Wulf|W|;Galle|Peter R|PR|;Adams|David H|DH|;Lohse|Ansgar W|AW|",
"chemical_list": "D007166:Immunosuppressive Agents; D009173:Mycophenolic Acid",
"country": "United States",
"delete": false,
"doi": "10.1111/j.1572-0241.2008.02180.x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0002-9270",
"issue": "103(12)",
"journal": "The American journal of gastroenterology",
"keywords": null,
"medline_ta": "Am J Gastroenterol",
"mesh_terms": "D000328:Adult; D005260:Female; D019693:Hepatitis, Autoimmune; D006801:Humans; D007166:Immunosuppressive Agents; D008297:Male; D009173:Mycophenolic Acid; D016896:Treatment Outcome",
"nlm_unique_id": "0421030",
"other_id": null,
"pages": "3063-70",
"pmc": null,
"pmid": "18853972",
"pubdate": "2008-12",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Mycophenolate mofetil as second line therapy in autoimmune hepatitis?",
"title_normalized": "mycophenolate mofetil as second line therapy in autoimmune hepatitis"
} | [
{
"companynumb": "DE-ALKEM LABORATORIES LIMITED-DE-ALKEM-2017-01933",
"fulfillexpeditecriteria": "2",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MYCOPHENOLATE MOFETIL"
},
... |
{
"abstract": "Tyrosine kinase inhibitors (TKIs) are standard therapy for chronic myeloid leukemia (CML). However, the effects of these agents on mature B cell lymphoma are not well known. We describe a 50-year-old man who was diagnosed with CML in the chronic phase and treated with imatinib. After 3 years of imatinib therapy that achieved a complete cytogenetic response of CML, he developed Philadelphia-negative follicular lymphoma (FL). Rituximab monotherapy induced a partial response of FL, and he subsequently achieved a major molecular response (MMR) of CML. Three years later, however, the MMR was lost, followed by the progression of FL. Imatinib was switched to nilotinib for the treatment of CML, while we chose watchful waiting for FL. He achieved MMR again under treatment with nilotinib for 8 months including one month of substitutional use of dasatinib due to adverse events, but thereafter nilotinib was switched to bosutinib due to hyperbilirubinemia. With the administration of second-generation TKIs (2G-TKIs) for a total of 18 months, he achieved a complete response to FL without antilymphoma treatment. This is the first report to suggest that 2G-TKIs may have direct or indirect effects on FL.",
"affiliations": "Division of Hematology, Department of Medicine, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi, 329-0498, Japan.;Division of Hematology, Department of Medicine, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi, 329-0498, Japan.;Division of Hematology, Department of Medicine, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi, 329-0498, Japan.;Division of Hematology, Department of Medicine, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi, 329-0498, Japan.;Division of Hematology, Department of Medicine, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi, 329-0498, Japan.;Division of Hematology, Department of Medicine, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi, 329-0498, Japan.;Division of Hematology, Department of Medicine, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi, 329-0498, Japan.;Division of Hematology, Department of Medicine, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi, 329-0498, Japan.;Division of Hematology, Department of Medicine, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi, 329-0498, Japan.;Division of Hematology, Department of Medicine, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi, 329-0498, Japan.;Division of Hematology, Department of Medicine, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi, 329-0498, Japan.;Division of Hematology, Department of Medicine, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi, 329-0498, Japan.;Division of Hematology, Department of Medicine, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi, 329-0498, Japan.;Division of Hematology, Department of Medicine, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi, 329-0498, Japan.;Division of Hematology, Department of Medicine, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi, 329-0498, Japan.;Division of Hematology, Department of Medicine, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi, 329-0498, Japan.;Division of Hematology, Department of Medicine, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi, 329-0498, Japan.;Division of Hematology, Department of Medicine, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi, 329-0498, Japan.;Division of Hematology, Department of Medicine, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi, 329-0498, Japan.;Division of Hematology, Department of Medicine, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi, 329-0498, Japan.;Division of Hematology, Department of Medicine, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi, 329-0498, Japan.;Division of Hematology, Department of Medicine, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi, 329-0498, Japan.;Division of Hematology, Department of Medicine, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi, 329-0498, Japan.;Division of Hematology, Department of Medicine, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi, 329-0498, Japan. ycanda-tky@umin.ac.jp.",
"authors": "Fujiwara|Shin-Ichiro|SI|;Shirato|Yuya|Y|;Ikeda|Takashi|T|;Kawaguchi|Shin-Ichiro|SI|;Toda|Yumiko|Y|;Ito|Shoko|S|;Ochi|Shin-Ichi|SI|;Nagayama|Takashi|T|;Mashima|Kiyomi|K|;Umino|Kento|K|;Minakata|Daisuke|D|;Nakano|Hirofumi|H|;Morita|Kaoru|K|;Yamasaki|Ryoko|R|;Kawasaki|Yasufumi|Y|;Sugimoto|Miyuki|M|;Ashizawa|Masahiro|M|;Yamamoto|Chihiro|C|;Hatano|Kaoru|K|;Sato|Kazuya|K|;Oh|Iekuni|I|;Ohmine|Ken|K|;Muroi|Kazuo|K|;Kanda|Yoshinobu|Y|",
"chemical_list": "C498826:4-methyl-N-(3-(4-methylimidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-((4-pyridin-3-ylpyrimidin-2-yl)amino)benzamide; D000814:Aniline Compounds; D009570:Nitriles; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011804:Quinolines; C471992:bosutinib; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl; D000069439:Dasatinib",
"country": "Japan",
"delete": false,
"doi": "10.1007/s12185-017-2378-y",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0925-5710",
"issue": "107(6)",
"journal": "International journal of hematology",
"keywords": "CML; FL; Second-generation TKI",
"medline_ta": "Int J Hematol",
"mesh_terms": "D000814:Aniline Compounds; D000069439:Dasatinib; D057915:Drug Substitution; D016044:Fusion Proteins, bcr-abl; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive; D008224:Lymphoma, Follicular; D008297:Male; D008875:Middle Aged; D009570:Nitriles; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011804:Quinolines; D013997:Time Factors; D016896:Treatment Outcome",
"nlm_unique_id": "9111627",
"other_id": null,
"pages": "712-715",
"pmc": null,
"pmid": "29185155",
"pubdate": "2018-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "28064239;20525993;24238639;19295545;19965662;18398720;21402714;23045577;26859076;2660545;19152174;23719297;19039322;27697771;28049640;20525995;21120481;12637609;23279183",
"title": "Successful treatment of follicular lymphoma with second-generation tyrosine kinase inhibitors administered for coexisting chronic myeloid leukemia.",
"title_normalized": "successful treatment of follicular lymphoma with second generation tyrosine kinase inhibitors administered for coexisting chronic myeloid leukemia"
} | [
{
"companynumb": "DE-MYLANLABS-2018M1003842",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "IMATINIB"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nLiver transplantation is now considered a safe procedure in patients with HIV because of the advent of potent antiretroviral therapies (ART).\n\n\nOBJECTIVE\nWe aimed to describe the use of dolutegravir-based maintenance ART in patients with HIV and liver transplant regularly followed in our hospital.\n\n\nMETHODS\nWe searched the database of our Department of Infectious Diseases for liver transplant recipients receiving calcineurin inhibitor-based maintenance immunosuppression concomitantly treated with dolutegravir for at least 1 month.\n\n\nRESULTS\nTen HIV-positive liver transplant recipients were identified. At 4.6 ± 3.5 years post-transplant, all the patients were switched to dolutegravir-based therapies for treatment simplification. However, at 1 year after the switch, five of the ten patients returned to their previous ART regimens because of increased serum transaminases (n = 1), reversible increased serum creatinine (n = 4), repeated episodes of nausea/vomiting (n = 1) and variable out-of-range concentrations of tacrolimus or cyclosporine (n = 2). However, it should be recognized that these events cannot be unequivocally ascribed to dolutegravir and, in the case of increased serum creatinine, are predictable.\n\n\nCONCLUSIONS\nThe management of HIV-positive liver transplant recipients in clinical practice is a complex task, where possibility of simplifying antiretroviral regimens must be balanced with the need to guarantee optimal immunosuppression and the finest treatment tolerability. A multidisciplinary approach involving physicians and clinical pharmacologists/pharmacists could help achieve this goal.",
"affiliations": "Gestione Ambulatoriale Politerapie (GAP) Outpatient Clinic, ASST Fatebenefratelli Sacco University Hospital, Milan, Italy. dario.cattaneo@asst-fbf-sacco.it.;Department of Infectious Diseases, ASST Fatebenefratelli Sacco University Hospital, Milan, Italy.;Department of Infectious Diseases, ASST Fatebenefratelli Sacco University Hospital, Milan, Italy.;Department of Infectious Diseases, ASST Fatebenefratelli Sacco University Hospital, Milan, Italy.;Department of Infectious Diseases, ASST Fatebenefratelli Sacco University Hospital, Milan, Italy.;Unit of Clinical Pharmacology, ASST Fatebenefratelli Sacco University Hospital, Milan, Italy.;Infectious Diseases Department, San Matteo Hospital Foundation, University of Pavia, Pavia, Italy.;Gestione Ambulatoriale Politerapie (GAP) Outpatient Clinic, ASST Fatebenefratelli Sacco University Hospital, Milan, Italy.",
"authors": "Cattaneo|Dario|D|http://orcid.org/0000-0003-1512-6530;Sollima|Salvatore|S|;Meraviglia|Paola|P|;Milazzo|Laura|L|;Minisci|Davide|D|;Fusi|Marta|M|;Filice|Carlo|C|;Gervasoni|Cristina|C|",
"chemical_list": "D019380:Anti-HIV Agents; D019428:HIV Integrase Inhibitors; D006575:Heterocyclic Compounds, 3-Ring; D010078:Oxazines; D010879:Piperazines; D011728:Pyridones; C562325:dolutegravir",
"country": "New Zealand",
"delete": false,
"doi": "10.1007/s40268-020-00300-9",
"fulltext": "\n==== Front\nDrugs R D\nDrugs R D\nDrugs in R&D\n1174-5886 1179-6901 Springer International Publishing Cham \n\n300\n10.1007/s40268-020-00300-9\nShort Communication\nDolutegravir-Based Antiretroviral Regimens for HIV Liver Transplant Patients in Real-Life Settings\nhttp://orcid.org/0000-0003-1512-6530Cattaneo Dario dario.cattaneo@asst-fbf-sacco.it 12 Sollima Salvatore 3 Meraviglia Paola 3 Milazzo Laura 3 Minisci Davide 3 Fusi Marta 2 Filice Carlo 4 Gervasoni Cristina 13 1 grid.144767.70000 0004 4682 2907Gestione Ambulatoriale Politerapie (GAP) Outpatient Clinic, ASST Fatebenefratelli Sacco University Hospital, Milan, Italy \n2 grid.144767.70000 0004 4682 2907Unit of Clinical Pharmacology, ASST Fatebenefratelli Sacco University Hospital, Milan, Italy \n3 grid.144767.70000 0004 4682 2907Department of Infectious Diseases, ASST Fatebenefratelli Sacco University Hospital, Milan, Italy \n4 grid.8982.b0000 0004 1762 5736Infectious Diseases Department, San Matteo Hospital Foundation, University of Pavia, Pavia, Italy \n18 3 2020 \n18 3 2020 \n6 2020 \n20 2 155 160\n© The Author(s) 2020Open AccessThis article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License, which permits any non-commercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc/4.0/.Background and Objectives\nLiver transplantation is now considered a safe procedure in patients with HIV because of the advent of potent antiretroviral therapies (ART).\n\nObjective\nWe aimed to describe the use of dolutegravir-based maintenance ART in patients with HIV and liver transplant regularly followed in our hospital.\n\nMethods\nWe searched the database of our Department of Infectious Diseases for liver transplant recipients receiving calcineurin inhibitor-based maintenance immunosuppression concomitantly treated with dolutegravir for at least 1 month.\n\nResults\nTen HIV-positive liver transplant recipients were identified. At 4.6 ± 3.5 years post-transplant, all the patients were switched to dolutegravir-based therapies for treatment simplification. However, at 1 year after the switch, five of the ten patients returned to their previous ART regimens because of increased serum transaminases (n = 1), reversible increased serum creatinine (n = 4), repeated episodes of nausea/vomiting (n = 1) and variable out-of-range concentrations of tacrolimus or cyclosporine (n = 2). However, it should be recognized that these events cannot be unequivocally ascribed to dolutegravir and, in the case of increased serum creatinine, are predictable.\n\nConclusions\nThe management of HIV-positive liver transplant recipients in clinical practice is a complex task, where possibility of simplifying antiretroviral regimens must be balanced with the need to guarantee optimal immunosuppression and the finest treatment tolerability. A multidisciplinary approach involving physicians and clinical pharmacologists/pharmacists could help achieve this goal.\n\nissue-copyright-statement© The Author(s) 2020\n==== Body\nKey Points\n\nLiver transplantation is considered a safe procedure in selected HIV-positive patients with end-stage hepatic disease because of the advent of potent antiretroviral therapies.\t\nDolutegravir, a second-generation integrase inhibitor, may represent an attractive option for HIV-positive liver transplant recipients because of its minimal dependence on cytochrome P450 (CYP)-3A-mediated metabolism, high potency and high genetic barrier.\t\nOur findings that 50% of patients from our database who had switched to dolutegravir returned to their previous regimens indicates the complexity of therapy management in HIV-positive liver transplant recipients in real-life settings.\t\n\n\n\nBackground\nLiver transplantation is now considered a safe procedure in select HIV-positive patients with end-stage hepatic disease because of the advent of potent antiretroviral therapies (ART) [1, 2]. Moreover, potential concerns related to drug–drug interactions (DDIs) between immunosuppressive agents and ART have been overcome by the availability of booster-free, integrase inhibitor-based regimens, which are now considered first-line ART according to international guidelines [3, 4]. Indeed, raltegravir is exclusively metabolized by uridine 5′-diphospho-glucuronosyltransferase and is neither an inducer nor an inhibitor of cytochrome P450 (CYP)-3A4 and 3A5, the phase I enzymes mainly involved in the metabolism of calcineurin inhibitors. Conversely, elvitegravir requires the coadministration of cobicistat, a pharmaco-enhancer specifically designed to inhibit the CYP3A-mediated metabolism that is likely to affect the metabolism of both cyclosporine and tacrolimus and eventually increase their toxicity [3, 4]. Dolutegravir, a recent integrase inhibitor, may represent an attractive option for HIV-positive liver transplant recipients because of its minimal dependence on CYP3A-mediated metabolism, high potency and high genetic barrier [3, 4]. However, data on the use of dolutegravir in real-life transplant settings are limited and exclusively involve kidney transplant recipients [5–9]. Here, we sought to describe the use of dolutegravir-based maintenance ART in HIV-positive liver transplant patients regularly followed in our hospital.\n\nMaterials and Methods\nSubject Population\nWe searched the database of our Department of Infectious Diseases (with more than 6000 HIV-positive patients actively followed-up) for liver transplant recipients receiving calcineurin inhibitor-based maintenance immunosuppression concomitantly treated with dolutegravir for at least 1 month. Demographic and clinical information was also collected, together with data on therapeutic drug monitoring of immunosuppressive trough concentrations.\n\nStatistical Analyses\nThe frequency distribution data are expressed as percentages, and all other measures are expressed as means ± standard deviation. All statistical analyses were performed in MEDCALC, Software (Mariakerke, Belgium). A P value < 0.05 was considered statistically significant.\n\nEthics Statement\nThis retrospective study was conducted using data collected for clinical purposes, all of which had been previously made anonymous in accordance with the requirements of the Italian Personal Data Protection Code (Legislative Decree No. 196/2003) and the general authorizations issued by the Italian Data Protection Authority. Ethics committee approval was unnecessary because Italian law states it is only required for prospective clinical trials of medical products for clinical use (Arts. 6 and 9 of Legislative Decree No. 211/2003). All patients provided informed consent for the medical procedures used for routine treatment purposes.\n\nResults\nTen HIV-positive liver transplant recipients were identified (nine men, one woman, mean age 57 ± 3 years) who received a transplant 6.0 ± 3.1 years previously (see Table 1 for detailed information). Reasons for liver transplantation were hepatocellular carcinoma (n = 2), hepatitis C (n = 5) or hepatitis B/delta-virus-related end-stage liver cirrhosis (n = 3). The immunosuppressive therapy consisted of tacrolimus (n = 4) or cyclosporine (n = 6); two of the ten patients were also given everolimus. For ART, patients were receiving tenofovir disoproxil fumarate/emtricitabine (n = 7) combined with raltegravir (n = 5), dolutegravir (n = 1) or unboosted fosamprenavir (n = 1); the remaining three patients were receiving abacavir/lamivudine/raltegravir, atazanavir/ritonavir/raltegravir or darunavir/ritonavir/raltegravir, respectively.Table 1 Demographic and clinical characteristics of the ten HIV-positive liver transplant recipients\n\nPatient\tSex\tAge\tYear of tx\tImmunosuppressive therapy\tART early post-tx\tART maintenance post-tx\tPost-tx follow-up\t\n1\tM\t63\t2007\tTacrolimus\tTDF/FTC/uFPV\tTAF/FTC/DTG\tIncrement of serum transaminases (+ 100–400%), variable tacrolimus concentrations, switched to TAF/FTC/uFPV\t\n2\tM\t57\t2010\tCyclosporine\tABC/3TC/RAL\tABC/3TC/DTG\tDTG-based HAART maintained\t\n3\tM\t57\t2010\tTacrolimus/everolimus\tTDF/FTC/RAL\tTAF/FTC/DTG\tDTG-based HAART maintained\t\n4\tM\t60\t2011\tCyclosporine\tTDF/FTC/RAL\tTAF/FTC/DTG\tDTG-based HAART maintained\t\n5\tM\t52\t2012\tCyclosporine/everolimus\tTDF/FTC/RAL\tTAF/FTC/DTG\tDTG-based HAART maintained\t\n6\tM\t58\t2014\tCyclosporine\tATV/r/RAL\tATVr/DTG\tIncrement of serum creatinine (+ 38%), some cyclosporine dose adjustments, switched back to ATVr/RAL\t\n7\tF\t55\t2015\tTacrolimus\tDRVr//RAL\tDRVc/DTG\tIncrement of serum creatinine (+ 23%), nausea and vomiting, switched back to DRVr//RAL\t\n8\tM\t57\t2015\tCyclosporine\tTDF/FTC/DTG\tTAF/FTC/DTG\tDTG-based HAART maintained\t\n9\tM\t55\t2016\tCyclosporine\tTDF/FTC/RAL\tTAF/FTC/DTG\tIncrement of serum creatinine (+ 125%), variable cyclosporine concentrations, switched to TAF/FTC/RAL\t\n10\tM\t55\t2016\tTacrolimus\tTDF/FTC/RAL\tTAF/FTC/DTG\tIncrement of serum creatinine (+ 55%), switched to TAF/FTC/RAL\t\n3TC lamivudine, ABC abacavir, ART antiretroviral therapy, ATV atazanavir, c cobicistat, DRV darunavir, DTG dolutegravir, F female, FPV fosamprenavir, FTC emtricitabine, HAART highly active ART, M male, r ritonavir, RAL raltegravir, TAF tenofovir alafenamide, TDF tenofovir disoproxil fumarate, Tx transplantation, u unboosted\n\n\n\nAt 4.6 ± 3.5 years post-transplant, all the patients switched to dolutegravir-based therapies for treatment simplification. At 1 year after the switch, five of the ten patients returned to their previous ART for several reasons (Table 1). Specifically, patient 1 experienced progressive increases in serum aspartate aminotransferase (from 38 to 78 IU/L) and alanine aminotransferase (from 19 to 100 IU/L) in the first 3 months after the switch to dolutegravir that was also associated with variable and unpredictable tacrolimus trough concentrations (reaching a nadir of 1.1 ng/mL then increasing to 22.9 ng/mL as shown in Fig. 1a) despite prompt tacrolimus dose adjustments (ranging from 0.5 to 1.5 mg daily). Patient 9 experienced increased serum creatinine concentrations (from 0.8 to 1.8 mg/dL before and after conversion to dolutegravir) associated with variable and unpredictable cyclosporine trough concentrations (reaching a nadir of 59 ng/mL as shown in Fig. 1b), despite prompt cyclosporine dose adjustments (ranging from 50 to 125 mg twice daily). Patients 6 and 10 experienced increased serum creatinine concentrations (from 1.3 to 1.8 mg/dL and from 1.1 to 1.7 mg/dL, respectively, before and after conversion to dolutegravir). Moreover, patient 6 had their cyclosporine dose changed several times (ranging from 10 to 50 mg twice daily). Patient 7 experienced repeated episodes of nausea/vomiting associated with increased serum creatinine (from 1.3 to 1.6 mg/dL before and after conversion from raltegravir/darunavir/ritonavir to dolutegravir/darunavir/cobicistat). Clinical conditions and laboratory examinations improved in all five patients after returning to the initial ART. In all circumstances, the decisions to modify the ART regimens were made by the infectious disease physicians after consultation with the transplant physicians and were not guided by specific pharmacy algorithms.Fig. 1 Time course of tacrolimus (a) or cyclosporine (b) trough concentrations measured in two HIV-positive liver transplant recipients before, during and after the switch to dolutegravir-based antiretroviral therapies. All therapeutic drug monitoring assessments were done at steady state conditions (at least a week after immunosuppressant dose adjustment). Shaded areas represent therapeutic ranges of immunosuppressive trough concentrations adopted in our center\n\n\n\nDiscussion\nTo the best of our knowledge, this is the first report on the use of dolutegravir-based ART in HIV-positive liver transplant recipients on stable maintenance immunosuppression. The case of a renal transplant recipient in whom a switch from a protease inhibitor-based regimen to dolutegravir led to subtherapeutic tacrolimus concentrations and increased serum creatinine was recently published [5]. Of course, in this case, the reduction of tacrolimus concentrations was related to the discontinuation of ritonavir, which has a well-known boosting effect on tacrolimus metabolism/disposition, and not to dolutegravir. However, it does provide another example of the difficulty of managing immunosuppressive therapy in HIV-positive transplant recipients.\n\nHere, we documented that, at 1 year after the switch to dolutegravir, 50% of the liver transplant patients identified from our database returned to their previous ART for several reasons. However, it should be recognized that the safety concerns cannot be univocally ascribed to dolutegravir, except for the observed increment in serum transaminases in one liver transplant recipient, an uncommon effect already reported for dolutegravir [10]. Four additional patients experienced increased serum creatinine, which is a known “cosmetic” effect of dolutegravir [3, 4]. Indeed, dolutegravir has been shown to increase serum creatinine due to inhibition of tubular secretion of creatinine without affecting renal glomerular function [2]. Therefore, this change does not reflect renal toxicity or worsening renal function, and infectious diseases physicians who start a dolutegravir-containing regimen should expect this change and advise their patients. Conversely, increased serum creatinine concentration is also a well-known side effect of cobicistat and calcineurin inhibitors [11, 12]. This can be challenging from a clinical viewpoint in transplant patients who are receiving immunosuppressive therapy with calcineurin inhibitors, which can also often cause serum creatinine increases but as a result of nephrotoxicity [8]. Equally, the episodes of nausea/vomiting can be caused by many different DDIs or specific drug toxicities, such as dolutegravir, ritonavir or cobicistat (as in the case of patient 7). Therefore, a causal association between dolutegravir use and the reported episodes of drug-related adverse events cannot be established, and this is beyond the scope of the present investigation. This study was not intended to investigate the tolerability of dolutegravir in a liver transplant setting; we solely intended to provide evidence on the difficulty of managing therapies in patients with complex polypharmacy, such as HIV-positive liver transplant recipients, in clinical practice.\n\nSignificant fluctuations in tacrolimus and cyclosporine concentrations (despite prompt drug dose adjustments) were observed in two patients immediately after the switch to dolutegravir. This is an unexpected finding. Indeed, in vitro investigations have shown that dolutegravir has a low propensity to cause DDIs given its neutral effect on metabolic enzymes and drug transporters (with the exclusion of organic cation transporter-2 [OCT2] [3, 4]). However, some unanticipated DDIs involving dolutegravir have recently been reported and attributed to unknown mechanisms [13, 14]. These findings, together with ours, suggest that the potential for dolutegravir DDIs in real-life settings needs to be better characterized. Nevertheless, we cannot exclude that variable calcineurin inhibitor concentrations may be related to adjustments in drug dosage performed by transplant physicians based on the observed increase in serum creatinine concentrations (being unaware that this increase is caused by the inhibition of OCT2 by dolutegravir rather than being a reflection of an aggravation of renal function). Therefore, it is likely that the expected change in serum creatinine concentrations was unanticipated by transplant physicians unfamiliar with these effects. It would have been helpful to know who made the immunosuppressive dose adjustments; however, this information was not available in our database, and this is the main limitation of the present study. This lack of information is because HIV-positive transplant patients are followed in our hospital for the management of HIV treatment but the immunosuppressive therapy is managed by individual transplant centers from other hospitals (the Luigi Sacco Hospital does not have a transplant program). We can only speculate that, if the immunosuppressive doses were not changed in consultation with pharmacists, clinical pharmacologists or transplant infectious disease physicians, this could have led to inappropriate adjustments in immunosuppression, causing further problems. Finally, a potential contribution of fosamprenavir discontinuation on the observed variable tacrolimus exposure cannot be ruled out, at least in patient 1. Indeed, it has been reported that fosamprenavir, although less potent than other HIV protease inhibitors, may significantly inhibit tacrolimus clearance [15].\n\nConclusions\nBalancing the possibility of simplifying ART with the need to guarantee optimal immunosuppression and finest treatment tolerability in HIV-positive liver transplant recipients in clinical practice is a complex task. A multidisciplinary approach involving physicians and clinical pharmacologists/pharmacists could help in achieving this goal.\n\nAuthor contributions\nDC and CG supervised all the stages of the study and wrote the first draft of the manuscript. MF performed pharmacokinetic analyses and revised the draft manuscript. SS, PM, DM and LM cared for the liver transplant patients and revised the draft manuscript.\n\nFunding\nThe study was not funded or supported. DC has received honoraria and/or travel grants from Pfizer, Janssen, ViiV Healthcare and Angelini. CF contributed to study design and revised the draft manuscript. CG has received honoraria and/or travel grants from MSD, Janssen, ViiV Healthcare and Gilead.\n\nCompliance with Ethical Standards\nConflict of interest\nDario Cattaneo, Salvatore Sollima, Paola Meraviglia, Laura Milazzo, Davide Minisci, Marta Fusi, Carlo Filice and Cristina Gervasoni declare no potential conflicts of interest with respect to the research, authorship and/or publications of this article.\n\nEthical approval\nThis retrospective study was conducted using data collected for clinical purposes, all of which had been previously made anonymous in accordance with the requirements of the Italian Personal Data Protection Code (Legislative Decree No. 196/2003) and the general authorizations issued by the Italian Data Protection Authority.\n==== Refs\nReferences\n1. Joshi D Agarwal K Role of liver transplantation in human immunodeficiency virus positive patients World J Gastroenterol 2015 21 12311 12321 10.3748/wjg.v21.i43.12311 26604639 \n2. Kardashian AA Price JC Hepatitis C virus-HIV-coinfected patients and liver transplantation Curr Opin Organ Transplant 2015 20 276 285 10.1097/MOT.0000000000000199 25944240 \n3. Elliot E Chirwa M Boffito M How recent findings on the pharmacokinetics and pharmacodynamics of integrase inhibitors can inform clinical use Curr Opin Infect Dis 2017 30 58 73 27798496 \n4. Podany AT Scarsi KK Fletcher CV Comparative clinical pharmacokinetics and pharmacodynamics of HIV-1 integrase strand transfer inhibitors Clin Pharmacokinet 2017 56 25 40 10.1007/s40262-016-0424-1 27317415 \n5. Jimenez HR Natali KM Zahran AAR Drug interaction after ritonavir discontinuation: considerations for antiretroviral therapy changes in renal transplant recipients Int J STD AIDS 2019 30 710 714 10.1177/0956462419829989 30961466 \n6. Yılmaz M Gökengin D Bozbıyık O Hoşcoşkun C Uyan A Töz H Kidney transplant in a human immunodeficiency virus-positive patient: case report of drug interactions Exp Clin Transplant. 2017 10.6002/ect.2017.0013 29287582 \n7. Ambaraghassi G, Cardinal H, Corsilli D, Fortin C, Fortin MC, Martel-Laferrière V, Malaise J, Pâquet MR, Rouleau D. First Canadian case report of kidney transplantation from an HIV-positive donor to an HIV-positive recipient. Can J Kidney Health Dis. 2017;4:2054358117695792 (eCollection 2017).\n8. Lee DH Malat GE Bias TE Harhay MN Ranganna K Doyle AM Serum creatinine elevation after switch to dolutegravir in a human immunodeficiency virus-positive kidney transplant recipient Transpl Infect Dis 2016 18 625 627 10.1111/tid.12545 27159656 \n9. Han Z Kane BM Petty LA Josephson MA Sutor J Pursell KJ Cobicistat significantly increases tacrolimus serum concentrations in a renal transplant recipient with human immunodeficiency virus infection Pharmacotherapy 2016 36 e50 e53 10.1002/phar.1752 27041642 \n10. Wang B Abbott L Childs K Taylor C Agarwal K Cormack I Miquel R Suddle A Dolutegravir-induced liver injury leading to sub-acute liver failure requiring transplantation: a case report and review of literature Int J STD AIDS 2018 29 414 417 10.1177/0956462417734099 29059031 \n11. Krejcí K Tichý T Hrubý M Horák P Ciferská H Horcicka V Strebl P Al-Jabry S Bachleda P Zadrazil J Subclinical toxicity of calcineurin inhibitors in repeated protocol biopsies: an independent risk factor for chronic kidney allograft damage Transpl Int 2010 23 364 373 10.1111/j.1432-2277.2009.00995.x 19906031 \n12. Rush D The impact of calcineurin inhibitors on graft survival Transplant Rev (Orlando) 2013 27 93 95 10.1016/j.trre.2013.04.003 23743217 \n13. Palazzo A Trunfio M Pirriatore V Milesi M De Nicolò A Alcantarini C D'Avolio A Bonora S Di Perri G Calcagno A Lower dolutegravir plasma concentrations in HIV-positive patients receiving valproic acid J Antimicrob Chemother 2018 73 826 827 10.1093/jac/dkx461 29244118 \n14. Hikasa S Sawada A Seino H Shimabukuro S Hideta K Uwa N Higasa S Tokugawa T Kimura T A potential drug interaction between phenobarbital and dolutegravir: a case report J Infect Chemother 2018 24 476 478 10.1016/j.jiac.2017.12.022 29415844 \n15. Pea F Tavio M Pavan F Londero A Bresadola V Adani GL Furlanut M Viale P Drop in trough blood concentrations of tacrolimus after switching from nelfinavir to fosamprenavir in four HIV-infected liver transplant patients Antivir Ther 2008 13 739 742 18771060\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1174-5886",
"issue": "20(2)",
"journal": "Drugs in R&D",
"keywords": null,
"medline_ta": "Drugs R D",
"mesh_terms": "D019380:Anti-HIV Agents; D005260:Female; D015658:HIV Infections; D019428:HIV Integrase Inhibitors; D006575:Heterocyclic Compounds, 3-Ring; D006801:Humans; D016031:Liver Transplantation; D008297:Male; D008875:Middle Aged; D010078:Oxazines; D010879:Piperazines; D011728:Pyridones; D012189:Retrospective Studies",
"nlm_unique_id": "100883647",
"other_id": null,
"pages": "155-160",
"pmc": null,
"pmid": "32189238",
"pubdate": "2020-06",
"publication_types": "D016428:Journal Article",
"references": "27798496;26604639;23743217;27317415;27041642;29059031;28321326;27159656;28969531;19906031;30961466;25944240;29415844;18771060;29244118",
"title": "Dolutegravir-Based Antiretroviral Regimens for HIV Liver Transplant Patients in Real-Life Settings.",
"title_normalized": "dolutegravir based antiretroviral regimens for hiv liver transplant patients in real life settings"
} | [
{
"companynumb": "IT-ACCORD-177777",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional": "3",
"druga... |
{
"abstract": "Aseptic osteonecrosis has been described in many and dissimilar pathologic conditions--most frequently as the aftermath of fractures or dislocations; in falciform anemia, obesity, alcoholism; in diseases requiring constant and heavy corticosteroid therapy, and also following renal transplantation. Many of these pathologies, especially alcoholism, diabetes, uremia, and collagen vascular diseases, have a common denominator: peripheral neuropathy, which is believed to be a pathogenetic factor supporting osteonecrosis. The authors analyze 3 cases of aseptic osteonecrosis of the femoral head in cancer patients treated with vincristine and/or vinblastine. Since in these subjects severe and persistent neuropathy preceded the onset of osteonecrosis, a possible relationship is postulated between the vincristine/vinblastine treatment and the onset of femoral head osteonecrosis, through the pathogenetic mechanism of peripheral neuropathy.",
"affiliations": "Complesso Clinico Ospedaliero, Padova.",
"authors": "Meneghello|A|A|;Presacco|D|D|;Di Maggio|C|C|",
"chemical_list": "D014750:Vincristine; D014747:Vinblastine",
"country": "Italy",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0033-8362",
"issue": "77(6)",
"journal": "La Radiologia medica",
"keywords": null,
"medline_ta": "Radiol Med",
"mesh_terms": "D000328:Adult; D001177:Arthropathy, Neurogenic; D001859:Bone Neoplasms; D005260:Female; D005271:Femur Head Necrosis; D006801:Humans; D008175:Lung Neoplasms; D008223:Lymphoma; D008297:Male; D008479:Mediastinal Neoplasms; D008875:Middle Aged; D010017:Osteoma, Osteoid; D011859:Radiography; D013724:Teratoma; D014747:Vinblastine; D014750:Vincristine",
"nlm_unique_id": "0177625",
"other_id": null,
"pages": "626-30",
"pmc": null,
"pmid": "2756179",
"pubdate": "1989-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Aseptic osteonecrosis of the femoral head in cancer patients with neuropathies caused by vincristine and vinblastine.",
"title_normalized": "aseptic osteonecrosis of the femoral head in cancer patients with neuropathies caused by vincristine and vinblastine"
} | [
{
"companynumb": "IT-PFIZER INC-2016405648",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "VINCRISTINE SULFATE"
},
"drugadditional": "3",... |
{
"abstract": "BACKGROUND\nStrongyloides stercoralis is a common human parasite worldwide and has been associated with severe infection in immunosuppressed patients. High mortality rates have accompanied this severe disseminated infection. There is a scarcity of literature surrounding severe Strongyloides infection in pregnancy.\n\n\nMETHODS\nA 30-year-old primigravid Haitian woman at 25 weeks of gestation presented with acute abdominal pain and an abnormal fetal heart tracing. Mild anemia and eosinophilia were laboratory abnormalities on admission. She received corticosteroids for the fetus and subsequently developed septic shock. Sputum and stool were positive for S stercoralis larvae. Hyperinfection was diagnosed, stillbirth occurred, and the patient died.\n\n\nCONCLUSIONS\nA more global awareness and education surrounding helminth infection during pregnancy may improve response, reduce delay in diagnosis, and potentially improve outcome.",
"affiliations": "Montefiore Medical Center, Einstein College of Medicine, Department of Obstetrics & Gynecology and Women's Health, Division of Maternal-Fetal Medicine, Bronx, New York.",
"authors": "Buresch|Arin M|AM|;Judge|Nancy E|NE|;Dayal|Ashlesha K|AK|;Garry|David J|DJ|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1097/AOG.0000000000000676",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0029-7844",
"issue": "126(1)",
"journal": "Obstetrics and gynecology",
"keywords": null,
"medline_ta": "Obstet Gynecol",
"mesh_terms": "D000328:Adult; D000818:Animals; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D011247:Pregnancy; D015597:Pregnancy Complications, Parasitic; D050497:Stillbirth; D017171:Strongyloides stercoralis; D013322:Strongyloidiasis",
"nlm_unique_id": "0401101",
"other_id": null,
"pages": "87-9",
"pmc": null,
"pmid": "25774935",
"pubdate": "2015-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A Fatal Case of Strongyloidiasis in Pregnancy.",
"title_normalized": "a fatal case of strongyloidiasis in pregnancy"
} | [
{
"companynumb": "PHHY2015US089766",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MORPHINE"
},
"drugadditional": null,
"drugad... |
{
"abstract": "BACKGROUND\nAcute kidney injury (AKI) in patients receiving vancomycin has been associated with trough concentrations ≥15 mg/L and longer therapy duration. The objective of this study was to determine the incidence and factors associated with late AKI in children receiving ≥8 days of vancomycin therapy.\n\n\nMETHODS\nChildren aged 30 days to 17 years who were admitted to our institution and received intravenous vancomycin for at least 8 days during January to December of 2007 and 2010 and had a suspected or proven gram-positive infection were included. Late AKI was categorized as AKI occurring after the first 7 days of therapy and within 48 hours following vancomycin discontinuation. The primary outcome was incidence of late AKI as determined by modified pRIFLE criteria.\n\n\nRESULTS\nOne-hundred sixty-seven patients were included, with a median (interquartile range) age (years) and weight (kg) of 2 (1-7) and 12.5 (8.9-23.8). Late AKI was identified in 12.6% (21/167). A higher percentage of late AKI patients received concomitant treatment with intravenous acyclovir, amphotericin products, or piperacillin-tazobactam. Age <1 year was the only factor independently associated with late AKI development (odds ratio = 4.4; 95% confidence interval = 1.3-15.4).\n\n\nCONCLUSIONS\nLate AKI occurred in nearly 13% of children receiving ≥8 days of vancomycin therapy. This study suggests that vancomycin trough concentrations are not associated with late AKI, but that age <1 year and concomitant administration of certain nephrotoxins may be factors associated with increased risk.",
"affiliations": "Butler University, Indianapolis, IN, USA cknodere@butler.edu.;Butler University, Indianapolis, IN, USA.;Butler University, Indianapolis, IN, USA Riley Hospital for Children at Indiana University Health, Indianapolis, IN, USA Indiana University School of Medicine, Indianapolis, IN, USA.;Indiana University School of Medicine, Indianapolis, IN, USA.",
"authors": "Knoderer|Chad A|CA|;Gritzman|Allison L|AL|;Nichols|Kristen R|KR|;Wilson|Amy C|AC|",
"chemical_list": "D000900:Anti-Bacterial Agents; D014640:Vancomycin",
"country": "United States",
"delete": false,
"doi": "10.1177/1060028015594190",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1060-0280",
"issue": "49(10)",
"journal": "The Annals of pharmacotherapy",
"keywords": "nephrotoxicity; pediatrics; pharmacodynamics; pharmacokinetics; vancomycin",
"medline_ta": "Ann Pharmacother",
"mesh_terms": "D058186:Acute Kidney Injury; D000293:Adolescent; D000367:Age Factors; D000900:Anti-Bacterial Agents; D002648:Child; D002675:Child, Preschool; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D015994:Incidence; D007223:Infant; D007297:Inpatients; D008297:Male; D013997:Time Factors; D014640:Vancomycin",
"nlm_unique_id": "9203131",
"other_id": null,
"pages": "1113-9",
"pmc": null,
"pmid": "26160972",
"pubdate": "2015-10",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Late-Occurring Vancomycin-Associated Acute Kidney Injury in Children Receiving Prolonged Therapy.",
"title_normalized": "late occurring vancomycin associated acute kidney injury in children receiving prolonged therapy"
} | [
{
"companynumb": "US-STRIDES ARCOLAB LIMITED-2016SP000218",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "VANCOMYCIN"
},
"drugadditional... |
{
"abstract": "Concerns about topical steroid withdrawal are causing some patients to cease long-term topical corticosteroid therapy, however, little is known about the ensuing clinical outcomes. This qualitative case series studied 10 children whose parents stopped their chronic topical corticosteroid use and subsequently developed features typically reported in adults experiencing topical steroid withdrawal. Patients were seen in an Australian general practice between April 2014 and October 2018, with follow-up periods ranging from 18 months to 4 years. Symptoms were difficult initially for the children and their families, however, all ultimately improved. At the final review, 4 of the children had clear skin and another 4 had symptoms consistent with their original, pre-treatment atopic dermatitis. More research is required into long-term topical corticosteroid use and its discontinuation, including topical steroid withdrawal, particularly in the pediatric population.",
"affiliations": "Royal Randwick Medical Centre, 70/73-115 Belmore Road, Randwick NSW 203, Australia. belinda.sheary@ipn.com.au.",
"authors": "Sheary|Belinda|B|",
"chemical_list": "D000305:Adrenal Cortex Hormones",
"country": "Sweden",
"delete": false,
"doi": "10.2340/00015555-3144",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0001-5555",
"issue": "99(6)",
"journal": "Acta dermato-venereologica",
"keywords": "atopic dermatitis; eczema; red skin syndrome; topical corticosteroids; topical steroid withdrawal",
"medline_ta": "Acta Derm Venereol",
"mesh_terms": "D000279:Administration, Cutaneous; D000293:Adolescent; D000305:Adrenal Cortex Hormones; D002675:Child, Preschool; D003873:Dermatitis, Exfoliative; D004890:Erythema; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D010146:Pain; D011537:Pruritus; D036301:Qualitative Research; D012871:Skin Diseases; D013375:Substance Withdrawal Syndrome; D028761:Withholding Treatment",
"nlm_unique_id": "0370310",
"other_id": null,
"pages": "551-556",
"pmc": null,
"pmid": "30734047",
"pubdate": "2019-05-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Topical Steroid Withdrawal: A Case Series of 10 Children.",
"title_normalized": "topical steroid withdrawal a case series of 10 children"
} | [
{
"companynumb": "AU-BAUSCH-BL-2019-017616",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "HYDROCORTISONE"
},
"drugadditional": null,
... |
{
"abstract": "Trastuzumab-induced cardiomyopathy is a known complication of its use in breast cancer treatment, but it remains mostly asymptomatic and often reversible. Non-myopathic cardiac complications have been rarely reported with trastuzumab. These include left and right bundle branch block, arrhythmias and sinus node dysfunction. We report a case of a 52-year-old female breast cancer patient with trastuzumab-induced asymptomatic intermittent left bundle branch block recurring nearly a year after the initial diagnosis and resolution of trastuzumab-related cardiomyopathy.",
"affiliations": "Department of Cardiology, University of South Alabama, Mobile, AL, USA.;Department of Cardiology, University of South Alabama, Mobile, AL, USA.;Department of Cardiology, University of South Alabama, Mobile, AL, USA.;Department of Cardiology, University of South Alabama, Mobile, AL, USA.;Department of Cardiology, University of South Alabama, Mobile, AL, USA.;Department of Cardiology, University of South Alabama, Mobile, AL, USA.;Department of Cardiology, University of South Alabama, Mobile, AL, USA.",
"authors": "Tahir|Hassan|H|;Bardia|Nikky|N|;Bath|Kulwant|K|;Ahmed|Yasir|Y|;Rafique|Muhammad|M|;Omar|Bassam|B|;Malozzi|Christopher|C|",
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"fulltext": "\n==== Front\nCardiol ResCardiol ResElmer PressCardiology Research1923-28291923-2837Elmer Press 10.14740/cr888Case ReportTrastuzumab-Induced Cardiomyopathy and Intermittent Left Bundle Branch Block Trastuzumab-Induced CardiomyopathyTahir Hassan abBardia Nikky aBath Kulwant aAhmed Yasir aRafique Muhammad aOmar Bassam aMalozzi Christopher aa Department of Cardiology, University of South Alabama, Mobile, AL, USAb Corresponding Author: Hassan Tahir, Department of Cardiology, University of South Alabama, 10th Floor, Ste B, Mobile, AL 36617, USA. Email: htahir@health.southalabama.edu8 2019 31 7 2019 10 4 230 235 24 5 2019 7 6 2019 Copyright 2019, Tahir et al.2019This article is distributed under the terms of the Creative Commons Attribution Non-Commercial 4.0 International License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Trastuzumab-induced cardiomyopathy is a known complication of its use in breast cancer treatment, but it remains mostly asymptomatic and often reversible. Non-myopathic cardiac complications have been rarely reported with trastuzumab. These include left and right bundle branch block, arrhythmias and sinus node dysfunction. We report a case of a 52-year-old female breast cancer patient with trastuzumab-induced asymptomatic intermittent left bundle branch block recurring nearly a year after the initial diagnosis and resolution of trastuzumab-related cardiomyopathy.\n\nTrastuzumabTransient left bundle branch blockNon-myopathic cardiac complications\n==== Body\nIntroduction\nTrastuzumab is a humanized monoclonal antibody directed against human epidermal growth factor receptor 2 (HER2), which is expressed in about 20-25% of breast cancers and promotes growth of cancer cells [1]. This targeted immunotherapy is approved for the treatment of HER2-positive breast cancer [2]. Trastuzumab exhibits its anticancer attributes by binding the extracellular domain IV of HER2, and thereby directly modulating pro-survival and proliferative signaling cascades, including phosphatidylinositol 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) pathways [3, 4].\n\nBreast cancer is one of the most common cancers among American women, affecting one in eight (12%) females [5]. Clinically, trastuzumab has been shown to be highly efficacious as a single agent for the treatment of breast cancer or in conjunction with anthracyclines. However, it has been associated with numerous cardiotoxic effects. The most common cardiac complication of trastuzumab is cardiomyopathy [6]. However, more non-myopathic cardiac complications are being reported due to a significant rise in the use of trastuzumab among breast cancer patients [6]. We report a case of a 52-year-old Caucasian woman with HER2-positive breast cancer who experienced recurrent, intermittent, asymptomatic LBBB nearly a year after trastuzumab use causing reversible cardiomyopathy with systolic dysfunction.\n\nCase Report\nA 52-year-old Caucasian woman with biopsy proven stage IIB, grade 3, HER2-positive, invasive carcinoma of the left breast was referred to cardiology for evaluation of chemotherapy-related cardiotoxicity. Her neo-adjuvant chemotherapeutic regimen included dose-dense adriamycin and cyclophosphamide (DDAC) along with paclitaxel, trastuzumab and pertuzumab. She had no prior history of cardiovascular disease. Her risk factors were tobacco use and family history of coronary artery disease (CAD).\n\nThe patient’s initial multigated acquisition (MUGA) scan prior to beginning treatment showed left ventricular ejection fraction (LVEF) of 80.9%. Upon completion of neo-adjuvant therapy, she underwent left mastectomy. Radiation therapy was discussed but had not been started. Following surgery, she restarted trastuzumab. A follow-up MUGA scan showed a decline in LVEF to 30.2%. Subsequent transthoracic echocardiogram (TTE) confirmed severely reduced LVEF. No significant valvular regurgitant or stenotic lesions were noted. Electrocardiogram (ECG) obtained at the referral visit revealed normal sinus rhythm (NSR) and an LBBB with a QRS duration of 124 ms (Fig. 1). This was new compared to a prior ECG from 3 years earlier (Fig. 2). She denied symptoms of shortness of breath, orthopnea, paroxysmal nocturnal dyspnea, bendopnea or leg swelling. She reported the ability to walk briskly without limitations or symptoms. The patient was started on beta-blocker (BB) and angiotensin-converting enzyme inhibitor (ACE-I) therapy. Trastuzumab therapy was discontinued. Over the next 8 months, LVEF was reassessed with TTE and eventually returned to normal, 50-55%. The patient remained asymptomatic during this time but was not able to resume trastuzumab.\n\nFigure 1 Presenting ECG to cardiology clinic with NSR and newly recognized LBBB. ECG: electrocardiogram; NSR: normal sinus rhythm; LBBB: left bundle branch block.\n\nFigure 2 Prior ECG with NSR and normal conduction. ECG: electrocardiogram; NSR: normal sinus rhythm.\n\nA year after the patient’s first cardiology encounter and approximately 5 months after recovery of systolic function, the patient required surgical repair of a complication from her initial mastectomy. This was scheduled to be performed at a neighboring hospital. Preoperative ECG revealed an LBBB not previously documented at that facility (Fig. 3). The procedure was cancelled, and the patient referred back to cardiology for preoperative risk assessment. ECG at time of the visit revealed NSR and resolution of the LBBB noted 1 week prior (Fig. 4). However, new ST-T wave changes were present concerning for ischemia. The patient was referred for limited echocardiography and exercise stress myocardial perfusion imaging. Exercise stress testing was considered given the absence of LBBB on ECG in clinic and the concern for intermittent LBBB, possibly rate- or exercise-related. Limited echocardiogram revealed normal EF, 50-55%. During exercise, the patient developed LBBB when the heart rate (HR) reached 120 beat per minute (bpm) and resolved during rest when the HR returned to below 90 bpm (Fig. 5). The patient had persistent anterior T-wave inversions. The stress test was converted to a pharmacologic stress imaging exam. The myocardial perfusion scans revealed a small area of reversible ischemia in the anteroseptal wall vs. LBBB artifact (Fig. 6). The patient was referred to coronary angiography for definitive diagnosis of CAD. Left heart catheterization (LHC) revealed an LVEF of 60% and a right dominant system with angiographically normal arteries (Fig. 7). The patient underwent her surgical procedure without complications and continues on BB and ACE-I therapy along with cardiovascular risk factor modification.\n\nFigure 3 Preoperative ECG with recurrent LBBB. ECG: electrocardiogram; LBBB: left bundle branch block.\n\nFigure 4 ECG obtained upon patient’s return to cardiology clinic for preoperative risk assessment. This tracing shows the absence of LBBB and new T-wave inversions in multiple leads (arrows). ECG: electrocardiogram; LBBB: left bundle branch block.\n\nFigure 5 Representative ECG tracings during exercise stress revealing the development of intermittent LBBB (arrows). ECG: electrocardiogram; LBBB: left bundle branch block.\n\nFigure 6 Example images from nuclear perfusion testing suggesting anteroseptal ischemia (arrows). The top row of images are stress images and the bottom are rest images (displayed left to right: short axis apex to base (a-c), horizontal long axis (d) and vertical long axis (e)).\n\nFigure 7 Representative images from coronary angiography revealing no significant CAD: (a) left coronary system; (b) right coronary system. CAD: coronary artery disease.\n\nDiscussion\nTrastuzumab is likely the most clinically important biologic agent developed for the treatment of HER2-positive breast cancer to date. Various clinical trials have shown reduction of cancer recurrence, increased response rates, increased progression-free survival and improvement in overall survival with addition of trastuzumab to standard chemotherapy [3, 7]. Because of this evidence, in 1998, The United States Food and Drug Administration approved trastuzumab for metastatic breast cancer treatment, but in 2006, its use was expanded for treatment of adjuvant HER2-positive breast cancer as well [7]. However, left ventricular systolic dysfunction from trastuzumab is a known potential consequence of treatment. Other potential adverse cardiac side effects have been described as well. The underlying mechanism leading to cardiac problems is still unclear. Some proposed mechanisms are defective HER2 signaling, immune-mediated destruction of cardiomyocytes and inhibition of the neuregulin-ErbB system [2, 8].\n\nThe most common cardiotoxicity associated with trastuzumab is a decline in LVEF. Most patients remain asymptomatic and therefore systolic dysfunction is found on routine surveillance echocardiography done specifically to monitor for this. Clinical, symptomatic heart failure is less common. Regardless, systolic dysfunction is often reversible and responds to conventional heart failure therapy [9]. The risk of cardiac dysfunction is significantly higher when trastuzumab is used in combination with other antineoplastic agents, such as cyclophosphamide and anthracyclines [10]. It has been reported that cardiotoxicity occurs in approximately 4% of patients receiving trastuzumab monotherapy and 27% of patients receiving it along with anthracycline and cyclophosphamide [9]. This side effect has been well established, and guidelines exist regarding echocardiographic monitoring and whether trastuzumab should be continued or withheld, temporarily or permanently [11].\n\nOn the other hand, there are also less well-recognized, non-myopathic, cardiac complications that have been described. These are rarely reported and are mostly asymptomatic as well [12, 13]. Table 1 [6, 13-17] lists the non-myopathic cardiac complications of trastuzumab reported in literature. Piotrowski and colleagues followed 253 women with early HER2-positive breast cancer treated with trastuzumab [6]. A cardiac complication developed in 52 patients, out of which only one had permanent asymptomatic LBBB which occurred 3 months after starting therapy. Trastuzumab was discontinued in this particular patient; however, the conduction problem persisted. Of note, LBBB in this case was not associated with cardiomyopathy. Asymptomatic right bundle branch block (RBBB) also occurred in two patients but therapy was not discontinued [6]. There are two reported cases of new LBBB in patients who presented with chest pain mimicking acute coronary syndrome. Both patients underwent LHC and neither had significant CAD [14, 15]. LBBB was persistent in one case [14] and transient in the other [15]. Both of these cases were also associated with reduced LVEF and were treated with guideline-directed medical therapy. Right ventricular failure has also been reported with trastuzumab use [18].\n\nTable 1 Non-Myopathic Cardiac Complications Associated With Trastuzumab [6, 13-17]\nComplications\tStudy\tSymptoms\tFurther testing and results\tCardiomyopathy present\t\nAsymptomatic new LBBB\tPiotrowski et al [6]\tNo symptoms\tNo\tNo\t\nNew RBBB\tPiotrowski et al [6]\tNo Symptoms\tNo\tNo\t\nT-wave inversions in anterior leads\tOlin et al [13]\tChest pain\tLeft heart catheterization revealed normal coronaries.\tNo\t\nSinus node dysfunction\tOlin et al [13]\tSyncope\tNo\tNo\t\nSymptomatic new LBBB\tTwo studies (Tu et al [14] and Ribiero et al [15])\tChest pain and shortness of breath\tLeft heart catheterization revealed normal coronaries.\tYes\t\nVentricular tachycardia\tOliveira et al [16]\tSudden death\tAutopsy showed LV hypertrophy, myocardial lymphocytic infiltrate, pulmonary congestion.\tYes\t\nNon-sustained ventricular tachycardia\tFerguson et al [17]\tpalpitations and near-syncope\tHolter revealed NSVT\tNo\t\nLBBB: left bundle branch block; RBBB: right bundle branch block; LV: left ventricular; NSVT: non-sustained ventricular tachycardia.\n\nThis particular case is unique in that the patient exhibited two, possibly three, cardiac side effects of trastuzumab. She initially presented as newly diagnosed, asymptomatic cardiomyopathy and LBBB. Both of these effects eventually resolved with cessation of trastuzumab and routine heart failure therapy. However, despite a normal LVEF, the patient had recurrent but intermittent LBBB. When normal conduction was present, she also exhibited anterior T-wave inversion, also a previously described cardiac electrical complication [12]. CAD was excluded by LHC as a cause for all the ECG abnormalities.\n\nThis report reviews the many possible cardiac complications of trastuzumab therapy. It also highlights the less recognized potential non-myopathic cardiac effects. More importantly, the long-term follow-up in this patient emphasizes that trastuzumab cardiotoxicity can occur at any time during or after treatment and manifest itself in many different ways. Therefore, a patient exposed to trastuzumab must have diligent cardiac monitoring both during and after treatment, especially since many of these toxicities are asymptomatic. However, at this time there are no guidelines available for short-term or long-term monitoring of non-myopathic side effects as there are with surveillance for cardiomyopathy. Also, decision regarding discontinuation of trastuzumab after asymptomatic, non-myopathic cardiac complications is still a topic of debate and an opportunity for future research.\n\nConclusion\nTrastuzumab has been associated with an increased risk of asymptomatic decrease in ejection fraction, and, in a small number of patients, symptomatic congestive heart failure. In both situations, the cardiotoxicity is mostly responsive to medical management. This risk, however, is compounded when used in combination with anthracyclines as part of the chemotherapy regimen. Non-myopathic cardiac complications of trastuzumab are either rare or underreported. Increased use of this medication has led increased identification of additional cardiac side effects. The natural course of these rare complications is unknown. More research is needed to study the association of these complications with trastuzumab use and its impact on breast cancer treatment.\n\nNone.\n\nFinancial Disclosure\nNone.\n\nConflict of Interest\nNone.\n\nInformed Consent\nConsent was taken from patient.\n\nAuthor Contributions\nAll authors participated sufficiently in the intellectual content, review of literature and the analysis of data. Each author has reviewed the final version of the manuscript and approves it for publication.\n==== Refs\nReferences\n1 Toikkanen S Helin H Isola J Joensuu H Prognostic significance of HER-2 oncoprotein expression in breast cancer: a 30-year follow-up J Clin Oncol 1992 10 7 1044 1048 10.1200/JCO.1992.10.7.1044 1351537 \n2 Hudis CA Trastuzumab - mechanism of action and use in clinical practice N Engl J Med 2007 357 1 39 51 10.1056/NEJMra043186 17611206 \n3 Slamon DJ Leyland-Jones B Shak S Fuchs H Paton V Bajamonde A Fleming T et al Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2 N Engl J Med 2001 344 11 783 792 10.1056/NEJM200103153441101 11248153 \n4 Wu WJ Dokmanovic M Trastuzumab Schwab M Encyclopedia of Cancer Berlin, Heidelberg, Germany Springer Reference; Springer-Verlag 2009 3048 3049 \n5 Miller KD Siegel RL Lin CC Mariotto AB Kramer JL Rowland JH Stein KD et al Cancer treatment and survivorship statistics, 2016 CA Cancer J Clin 2016 66 4 271 289 10.3322/caac.21349 27253694 \n6 Piotrowski G Gawor R Stasiak A Gawor Z Potemski P Banach M Cardiac complications associated with trastuzumab in the setting of adjuvant chemotherapy for breast cancer overexpressing human epidermal growth factor receptor type 2 - a prospective study Arch Med Sci 2012 8 2 227 235 10.5114/aoms.2012.28549 22661994 \n7 Nabholtz JM Reese DM Lindsay MA Riva A HER2-positive breast cancer: update on Breast Cancer International Research Group trials Clin Breast Cancer 2002 3 Suppl 2 S75 79 10.3816/CBC.2002.s.016 12435291 \n8 Fedele C Riccio G Malara AE D'Alessio G De Lorenzo C Mechanisms of cardiotoxicity associated with ErbB2 inhibitors Breast Cancer Res Treat 2012 134 2 595 602 10.1007/s10549-012-2103-8 22674190 \n9 Keefe DL Trastuzumab-associated cardiotoxicity Cancer 2002 95 7 1592 1600 10.1002/cncr.10854 12237930 \n10 Seidman A Hudis C Pierri MK Shak S Paton V Ashby M Murphy M et al Cardiac dysfunction in the trastuzumab clinical trials experience J Clin Oncol 2002 20 5 1215 1221 10.1200/JCO.2002.20.5.1215 11870163 \n11 Genetech: Herceptin (trastuzumab): highlights of prescribing information, 04/2015 update. http://www.gene.com/download/pdf/hercetpin_prescribing.pdf \n12 Perez EA Romond EH Suman VJ Jeong JH Sledge G Geyer CE Jr Martino S et al Trastuzumab plus adjuvant chemotherapy for human epidermal growth factor receptor 2-positive breast cancer: planned joint analysis of overall survival from NSABP B-31 and NCCTG N9831 J Clin Oncol 2014 32 33 3744 3752 10.1200/JCO.2014.55.5730 25332249 \n13 Olin RL Desai SS Fox K Davidson R Non-myopathic cardiac events in two patients treated with trastuzumab Breast J 2007 13 2 211 212 10.1111/j.1524-4741.2007.00408.x 17319871 \n14 Tu CM Chu KM Yang SP Cheng SM Wang WB Trastuzumab (Herceptin)-associated cardiomyopathy presented as new onset of complete left bundle-branch block mimicking acute coronary syndrome: a case report and literature review Am J Emerg Med 2009 27 7 903 e901-903 10.1016/j.ajem.2008.11.012 19683138 \n15 Ribeiro KB Miranda CH Andrade JM Galli LG Tiezzi DG Oliveira HF Zola FE et al Trastuzumab-induced myocardiotoxicity mimicking acute coronary syndrome Case Rep Oncol 2012 5 1 125 133 10.1159/000337576 22666200 \n16 Oliveira M Nave M Gil N Passos-Coelho JL Sudden death during adjuvant trastuzumab therapy of breast cancer Ann Oncol 2010 21 4 901 10.1093/annonc/mdp587 20044583 \n17 Ferguson C Clarke J Herity NA Ventricular tachycardia associated with trastuzumab N Engl J Med 2006 354 6 648 649 10.1056/NEJMc052708 16467559 \n18 Bayar N Kucukseymen S Goktas S Arslan S Right ventricle failure associated with trastuzumab Ther Adv Drug Saf 2015 6 3 98 102 10.1177/2042098615582162 26240743\n\n",
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"title": "Trastuzumab-Induced Cardiomyopathy and Intermittent Left Bundle Branch Block.",
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"abstract": "A 78-year-old man with angle closure glaucoma and on treatment with oral anticoagulants, underwent phacoemulsification. An early acute suprachoroidal hemorrhage (SCH) occurred and the surgical wound was rapidly sutured without complete soft lens matter removal, nor insertion of intraocular lens. The SCH was managed conservatively and it resolved in 5 weeks; the intraocular pressure was 35 mm Hg despite maximal medical treatment. Secondary soft lens matter removal followed by intraocular lens implantation combined with XEN45 was then performed. After 7 days the patient developed a potentially \"kissing\" choroidal touch due to significant delayed SCH. This was treated with surgical drainage. Significant suprachoroidal bleeding can occur after minimally invasive glaucoma procedures. Patients on anticoagulant therapy may require careful monitoring while planning glaucoma surgery.",
"affiliations": "Royal Blackburn and Burnley General Teaching Hospitals, East Lancashire Hospitals NHS Trust, Lancashire, United Kingdom.",
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"title": "Managing Delayed Suprachoroidal Hemorrhage After Insertion of XEN45 Glaucoma Device.",
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"abstract": "We report a case of colchicine-induced rhabdomyolysis in a heart/lung-transplanted man treated with cyclosporin. A treatment was to resolve an acute gouty arthritis and was started with 3 mg of colchicine the first day, then 2 mg the second and the third day, and finally 1 mg/d during 6 days. Eight days later, the patient developed multiple organ failure and rhabdomyolysis. The concentration of colchicine analyzed was greater than the standard 153 hours after his last intake. Pharmacokinetic interactions are responsible of this toxicity. Cyclosporin, pravastatin, and azithromycin are known to inhibit P-glycoprotein, which will enhance the intracellular colchicine level by acting in its bioavailability and moderating hepatic and renal excretion. Moreover, long-term treatment by cyclosporin generates chronic renal failure that will, in the same time, decrease colchicine elimination. Even short-term administration of therapeutic colchicine dose may cause colchicine-related toxicity, especially in the setting of a renal failure and/or polymedicinal treatment.",
"affiliations": "Clinical Pharmacology Department and EA 4275 Biostatistique, Recherche Clinique et Mesures Subjectives en Santé, Hospital of the University of Nantes, Nantes, France. regis.bouquie@chu-nantes.fr",
"authors": "Bouquié|Régis|R|;Deslandes|Guillaume|G|;Renaud|Christian|C|;Dailly|Eric|E|;Haloun|Alain|A|;Jolliet|Pascale|P|",
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"title": "Colchicine-induced rhabdomyolysis in a heart/lung transplant patient with concurrent use of cyclosporin, pravastatin, and azithromycin.",
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"abstract": "We describe a case of a patient on warfarin who developed an extensive haematoma after a hip hemiarthroplasty and was successfully treated with embolisation. This case highlights the importance of regular haematology input, careful consideration of a suitable surgical approach, close monitoring of postoperative wounds in patients on warfarin and the emerging role of embolisation.",
"affiliations": "Department of Trauma and Orthopaedics, St Mary's Hospital, London, UK.;Department of Trauma and Orthopaedics, St Mary's Hospital, London, UK.;Department of Trauma and Orthopaedics, St Mary's Hospital, London, UK.;Department of Trauma and Orthopaedics, St Mary's Hospital, London, UK.",
"authors": "Al-Obaidi|Bilal|B|;Field|Michael H|MH|;Al-Hadithy|Nawfal|N|;Griffiths|Dylan|D|",
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"mesh_terms": "D000369:Aged, 80 and over; D019644:Arthroplasty, Replacement, Hip; D002081:Buttocks; D004621:Embolization, Therapeutic; D005260:Female; D005265:Femoral Neck Fractures; D005593:Fracture Fixation, Internal; D006406:Hematoma; D062785:Hemiarthroplasty; D006615:Hip; D006620:Hip Fractures; D006621:Hip Joint; D006622:Hip Prosthesis; D006801:Humans; D007083:Iliac Artery; D011183:Postoperative Complications; D014859:Warfarin",
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"title": "Extensive gluteal haematoma after an intracapsular hip fracture in a patient on warfarin.",
"title_normalized": "extensive gluteal haematoma after an intracapsular hip fracture in a patient on warfarin"
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{
"abstract": "Three patients with a medical history of breast carcinoma and metastatic carcinomatous liver disease associated with severe portal hypertension and refractory ascites are presented. Transjugular intrahepatic portosystemic shunt creation was considered as a palliative treatment option and a valuable alternative to regular paracenteses in these patients. In 2 of the 3 patients, the refractory ascites was controlled for several months without need for paracentesis, and subsequently transjugular intrahepatic portosystemic shunt may provide valuable palliation and ascites control in patients with refractory ascites due to breast cancer-induced pseudocirrhosis.",
"affiliations": "Department of Radiology, University Hospitals Leuven, Herestraat 49, B-3000 Leuven, Belgium.;Department of Pathology, University Hospitals Leuven, Herestraat 49, B-3000 Leuven, Belgium.;Department of Radiology, University Hospitals Leuven, Herestraat 49, B-3000 Leuven, Belgium.;Department of General Medical Oncology, University Hospitals Leuven, Herestraat 49, B-3000 Leuven, Belgium.;Department of Gastroenterology and Hepatology, University Hospitals Leuven, Herestraat 49, B-3000 Leuven, Belgium.;Department of Radiology, University Hospitals Leuven, Herestraat 49, B-3000 Leuven, Belgium. Electronic address: geert.maleux@uzleuven.be.",
"authors": "Geeroms|Barbara|B|;De Hertogh|Gert|G|;Vanslembrouck|Ragna|R|;Wildiers|Hans|H|;Nevens|Frederik|F|;Maleux|Geert|G|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.jvir.2018.08.007",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1051-0443",
"issue": "29(12)",
"journal": "Journal of vascular and interventional radiology : JVIR",
"keywords": null,
"medline_ta": "J Vasc Interv Radiol",
"mesh_terms": "D000368:Aged; D001201:Ascites; D001706:Biopsy; D001943:Breast Neoplasms; D018270:Carcinoma, Ductal, Breast; D005260:Female; D006801:Humans; D006975:Hypertension, Portal; D008113:Liver Neoplasms; D008875:Middle Aged; D017082:Portal Pressure; D019168:Portasystemic Shunt, Transjugular Intrahepatic; D012720:Severity of Illness Index; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome",
"nlm_unique_id": "9203369",
"other_id": null,
"pages": "1713-1716",
"pmc": null,
"pmid": "30392802",
"pubdate": "2018-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Transjugular Intrahepatic Portosystemic Shunt for the Treatment of Portal Hypertension-Induced Refractory Ascites Due to Metastatic Carcinomatous Liver Disease.",
"title_normalized": "transjugular intrahepatic portosystemic shunt for the treatment of portal hypertension induced refractory ascites due to metastatic carcinomatous liver disease"
} | [
{
"companynumb": "BE-PFM-2018-14901",
"fulfillexpeditecriteria": "1",
"occurcountry": "BE",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "VINORELBINE\\VINORELBINE TARTRATE"
},
"drugadditiona... |
{
"abstract": "A 53-year-old woman attended for a routine outpatient appointment for follow-up of antineutrophil cytoplasmic antibody-positive vasculitis. Her disease had relapsed despite appropriate medical management with mycophenolate mofetil (MMF), as evidenced by rising acute phase response and antimyeloperoxidase titre with ongoing symptoms. On further questioning, she had been taking oral charcoal as part of a detoxification diet, which we postulate was causing significantly impaired MMF absorption. This case report summarises the presentation and highlights the importance of a thorough drug history, and should prompt the reader to keep an open mind with regard to drug interactions and treatment regimen adherence when treatment is, unexpectedly, seemingly failing.",
"affiliations": "Department of Rheumatology, London North West Hospitals NHS Trust, Harrow, UK.;Department of Rheumatology, London North West Hospitals NHS Trust, Harrow, UK.",
"authors": "Glanville|James Robert William|JR|;Penn|Henry|H|",
"chemical_list": "D019268:Antibodies, Antineutrophil Cytoplasmic; D000931:Antidotes; D007166:Immunosuppressive Agents; D002606:Charcoal; D011239:Prednisolone; D009173:Mycophenolic Acid",
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2016()",
"journal": "BMJ case reports",
"keywords": null,
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D065966:Absorption, Physicochemical; D056648:Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; D019268:Antibodies, Antineutrophil Cytoplasmic; D000931:Antidotes; D002606:Charcoal; D004347:Drug Interactions; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents; D008875:Middle Aged; D009173:Mycophenolic Acid; D011239:Prednisolone; D012008:Recurrence",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "26746838",
"pubdate": "2016-01-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "12089393;20596502;21060104;3285126",
"title": "Unusual cause of flare in antineutrophil cytoplasmic antibody-associated vasculitis.",
"title_normalized": "unusual cause of flare in antineutrophil cytoplasmic antibody associated vasculitis"
} | [
{
"companynumb": "GB-ACCORD-037139",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CALCIUM CARBONATE\\CHOLECALCIFEROL"
},
"drugadditiona... |
{
"abstract": "Generalized pustular psoriasis (GPP) is a severe, life-threatening disease that represents a major therapeutic challenge. There is a lack of randomized controlled trials assessing the efficacy of various treatment options for GPP. TNFα inhibitors have proven to be effective and are increasingly used in this indication. In the current paper, we present two patients with GPP treated with infliximab (Ifx) and a literature review appraising currently available data on the use of Ifx in GPP. Case 1 was a 73-year-old woman with GPP who exhibited lack of treatment response or primary intolerance to standard therapeutic options (high-dose acitretin, methotrexate, cyclosporine A, and methylprednisolone). However, Ifx therapy combined with low-dose acitretin resulted in rapid and sustained resolution of skin lesions. Case 2 was a 60-year-old man with GPP and numerous comorbidities who was initially treated with Ifx in combination with methotrexate, with good treatment response for 9 months. Following an infection-induced flare of GPP at week 38, methotrexate was discontinued in favor of low-dose acitretin and Ifx continued. This regimen again resulted in rapid resolution of pustules. We present these cases to highlight the advantage of long-term Ifx therapy with low-dose acitretin in GPP.",
"affiliations": "Department of Dermatology, Institute of Medical Sciences, Medical College of Rzeszów University, Rzeszów, Poland.;Department of Dermatology, Institute of Medical Sciences, Medical College of Rzeszów University, Rzeszów, Poland.;Department of Dermatology, Institute of Medical Sciences, Medical College of Rzeszów University, Rzeszów, Poland.",
"authors": "Kołt-Kamińska|Marta|M|;Żychowska|Magdalena|M|0000-0001-8268-0529;Reich|Adam|A|0000-0002-5573-1754",
"chemical_list": null,
"country": "New Zealand",
"delete": false,
"doi": "10.2147/BTT.S323239",
"fulltext": "\n==== Front\nBiologics\nBiologics\nbtt\nbtt\nBiologics : Targets & Therapy\n1177-5475\n1177-5491\nDove\n\n323239\n10.2147/BTT.S323239\nCase Series\nInfliximab in Combination with Low-Dose Acitretin in Generalized Pustular Psoriasis: A Report of Two Cases and Review of the Literature\nKołt-Kamińska et al\nKołt-Kamińska et al\nKołt-Kamińska Marta 1\nhttp://orcid.org/0000-0001-8268-0529\nŻychowska Magdalena 1\nhttp://orcid.org/0000-0002-5573-1754\nReich Adam 1\n1 Department of Dermatology, Institute of Medical Sciences, Medical College of Rzeszów University, Rzeszów, Poland\nCorrespondence: Magdalena Żychowska Department of Dermatology, Institute of Medical Sciences, Medical College of Rzeszów University, Reszów, PolandTel +48 66-942-2237Fax +48 17 86 66 294 Email magda.zychowska@gmail.com\n07 8 2021\n2021\n15 317327\n03 6 2021\n13 7 2021\n© 2021 Kołt-Kamińska et al.\n2021\nKołt-Kamińska et al.\nhttps://creativecommons.org/licenses/by-nc/3.0/ 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).\nAbstract\n\nGeneralized pustular psoriasis (GPP) is a severe, life-threatening disease that represents a major therapeutic challenge. There is a lack of randomized controlled trials assessing the efficacy of various treatment options for GPP. TNFα inhibitors have proven to be effective and are increasingly used in this indication. In the current paper, we present two patients with GPP treated with infliximab (Ifx) and a literature review appraising currently available data on the use of Ifx in GPP. Case 1 was a 73-year-old woman with GPP who exhibited lack of treatment response or primary intolerance to standard therapeutic options (high-dose acitretin, methotrexate, cyclosporine A, and methylprednisolone). However, Ifx therapy combined with low-dose acitretin resulted in rapid and sustained resolution of skin lesions. Case 2 was a 60-year-old man with GPP and numerous comorbidities who was initially treated with Ifx in combination with methotrexate, with good treatment response for 9 months. Following an infection-induced flare of GPP at week 38, methotrexate was discontinued in favor of low-dose acitretin and Ifx continued. This regimen again resulted in rapid resolution of pustules. We present these cases to highlight the advantage of long-term Ifx therapy with low-dose acitretin in GPP.\n\nKeywords\n\ninfliximab\nanti-TNFα\ngeneralized pustular psoriasis\nacitretin\n==== Body\nIntroduction\n\nGeneralized pustular psoriasis (GPP), also called von Zumbusch psoriasis, is characterized by the presence of widespread sterile pustules on erythematous skin, usually of rapid onset and accompanied by systemic symptoms, including fever, malaise, nausea, and arthralgia.1–4 Prompt management is required, as the condition may lead to life-threatening complications.5,6 Classical therapies, including acitretin, cyclosporine A (CsA), or methotrexate (Mtx), are usually used as first-line options, but their onset of action may be delayed and their application associated with significant systemic toxicity. The National Psoriasis Foundation recommends infliximab (Ifx) as the first-line biologic for severe GPP in adults. It should also be considered as a second-line therapeutic option for juvenile GPP and first-line therapy for GPP (or impetigo herpetiformis) developing during pregnancy (category B).5 However, due to the rarity of GPP, these recommendations are mainly based on case reports and expert opinions. Therefore, in the current paper, we present two patients with GPP treated with Ifx. We also review the existing literature on the treatment of GPP in adults with Ifx and discuss management options for pustular flares during long-term Ifx therapy.\n\nCase Reports\n\nCase 1\n\nA 73-year-old woman with several months’ history of recalcitrant GPP was admitted to the Department of Dermatology in Rzeszów due to severe exacerbation of her skin condition. Her personal and family history of psoriasis was negative. Prior treatment included acitretin (initially at 0.8 mg/kg and gradually tapered down due to side effects, including massive hair loss, epistaxis, and severe skin hypersensitivity, and eventually discontinued due to lack of efficacy at lower doses in monotherapy), CsA 300–400 mg/day (discontinued due to nephrotoxicity), oral Mtx 15 mg/week (discontinued due to primary lack of efficacy), and oral methylprednisolone 16 mg/day (discontinued due to lack of efficacy). On admission, she presented with widespread painful erythematous plaques with coalescing pustules (Figure 1A and B), accompanied by systemic symptoms (fever, malaise, and chills). Laboratory results showed anemia (hemoglobin 9.9 g/dL, red blood–cell count 3.32×106/uL), accelerated ESR (28 mm), and elevated CRP (5.6 mg/dL). Treatment with acitretin was reintroduced at 50 mg/day (0.8 mg/kg);, though with only minimal improvement. Therefore, after 3 weeks, Ifx (5 mg/kg intravenously) was initiated with concurrent tapering down of acitretin. Rapid improvement of the skin was observed after the first infusion of Ifx. The second dose was administered 2 weeks later, as per the standard dosing schedule. At this point, the patient exhibited widespread postinflammatory hyperpigmentation with residual erythema and exfoliation on the distal parts of the upper limbs (Figure 1C and D). The third infusion of Ifx, initially scheduled for week 6, had to be postponed until week 10 due to segmental herpes zoster. The fourth infusion of Ifx was administered at week 18. At that time, only minimal residual erythema was present on the dorsa of the hands, with complete resolution of the rest of her skin (Figure 1E and F). Acitretin was given at a slowly tapered dose until week 18, when it was discontinued. However, the patient experienced severe exacerbation of GPP just before the fifth Ifx infusion. Ifx was administered according to schedule (week 26), and acitretin was restarted at 20 mg/day (0.3 mg/kg), with rapid resolution of pustules. No further pustules have developed in the meantime. The patient has thus far received nine infusions of Ifx combined with acitretin (currently 20 mg/day). No significant side effects, with the exception of herpes zoster at week 6, have been noted during the entire period of treatment.Figure 1 Case 1 (A and, B) widespread erythematous plaques and coalescing pustules on day 0; (C and, D) widespread postinflammatory hyperpigmentation with residual erythema and exfoliation on the distal parts of the upper limbs at week 2; (E and, F) almost-clear skin with discrete residual erythema on the dorsa of the hands at week 18.\n\nCase 2\n\nA 60-year-old man with a 40-year history of plaque psoriasis was admitted to the Department of Dermatology in Rzeszów due to GPP triggered by upper respiratory tract infection. He had multiple comorbidities, including obesity, hypertension, thoracic aortic aneurysm, coronary artery disease, pulmonary fibrosis, fatty liver, and previous HBV infection. He had already suffered several erythrodermic exacerbations, and treatment modalities already attempted at that point included acitretin, Mtx, and psoralen and –ultraviolet A. On admission, the patient presented with widespread pustules on a background of erythema with psoriatic plaques on the extensor surfaces of the elbows and knees, accompanied by arthralgia and general malaise (Figure 2A and B). Laboratory investigations revealed leukocytosis (12.95×109 cells/L) with neutrophilia (10.16×109 cells/L), accelerated ESR (46 mm) and elevated CRP (19.8 mg/dL). Taking into consideration the severity of the GPP and his comorbidities, therapy with Ifx (5 mg/kg) in combination with Mtx (7.5 mg/week) was initiated. Significant improvement was observed after the first Ifx infusion. Residual erythema was present on the trunk, lower legs, and forearms at week 2 (Figure 2C and D). Treatment with Ifx was continued according to the standard regimen (weeks 0, 2, and 6 and 8-weekly thereafter). At week 30, the skin was clear, apart from residual plaques on the elbows (Figure 2E and F). Mtx 7.5 mg/week was continued throughout the treatment with Ifx. No adverse effects were detected. Nine months after initiation of Ifx therapy (prior to the seventh infusion), the patient once again experienced a severe exacerbation of GPP following an upper respiratory tract infection. Mtx was discontinued, and acitretin at a dose of 35 mg/day (0.35 mg/kg) was initiated. The seventh dose of Ifx was administered according to schedule. Again, rapid improvement of GPP was achieved. Since then, only persistent psoriatic plaques on the extensor surfaces of his elbows and knees and in the sacral region have been observed. He remains on a combination regimen of Ifx and acitretin (4 months following the last flare), without significant adverse events. No pustular flares have been observed since the introduction of acitretin.Figure 2 Case 2 (A and, B) widespread erythematous plaques with coalescing pustules on day 0; (C and, D) significant improvement with residual erythema on the trunk and upper limbs at week 2; (E and, F) erythema on the trunk and limbs and residual psoriatic plaques on the elbows at week 30.\n\nThis study was exempt from institutional review board approval. Written informed consent was obtained from both patients for publication of their photographs and this report.\n\nDiscussion\n\nIfx is a chimeric anti-TNFα monoclonal antibody that is used for the treatment of psoriasis and psoriatic arthritis.6 As mentioned in the Introduction, Ifx is also recommended in GPP, despite the lack of reliable clinical studies.5 Therefore, we performed a comprehensive search of three medical databases (PubMed, Scopus, and Web of Science) using the search terms “infliximab” and “generalized pustular psoriasis” to identify all reported cases of GPP treated with Ifx. Reports of impetigo herpetiformis in pregnant women were not included in the analysis. Cases of GPP in adults treated with Ifx are summarized in Table 1. Data from the literature, based predominantly on single case reports and case series, highlight high efficacy and rapid onset of action of Ifx in GPP.1–4,6–20 However, we found a large variety of therapeutic strategies undertaken. Cases of single-dose Ifx,8–10,15,17,20,23 and longer therapy (up to 3 years)1–4,6–9,12–14,16–19,21 were among those reported. In cases of prolonged treatment, the standard dosing regimen used in plaque psoriasis (infusions of 5 mg/kg Ifx at weeks 0, 2, and 6 and subsequently every 8 weeks) was most commonly utilized.6,7,9,13,17,19,21 However, irregular dosing, only in the event of pustular flares, was also used in some cases.14 Despite the fact that Ifx induces rapid resolution of pustules within 1–8 days, monotherapy was frequently insufficient to provide long-term disease control. Pustular flares during Ifx treatment2–4,6,8,11,12,14,16,18,19,23 and secondary loss of efficacy3,4,6,8,12 were observed in a majority of reports. Various strategies were undertaken in such cases, including the addition of Mtx14,15,19 or acitretin14,18,22,23 or switching to adalimumab,4,6,8 etanercept,3,8 or ustekinumab.3,4 Ifx survival calculated on the basis of reports available in the literature and current cases indicates that nearly 70% of patients with GPP are treated with Ifx for at least 1 year and 40% of patients for about 3 years (Figure 3).Table 1 Summary of cases of GPP in adults treated with infliximab\n\n\tSex/age (years)\tPrior treatment\tIfx dose\tResponse to Ifx\tConcomitant treatment\tDuration of Ifx treatment (weeks)\tGPP flare during treatment\tAction taken during flare\tReason for Ifx discontinuation\tFollow-up after Ifx treatment (weeks)\tLoss of efficacy\t\nSegawa et al1\tF/28\tsGCS\tNA\tYes\tNo\t144\tNo\tNA\tAE\tNA\tNo\t\nGeorgakopoulos et al2\tM/68\tCsA\t5 mg/kg\tYes\tApremilast\t24\tYes\tApremilast (2×30 mg) added\tNA\tNA\tNo\t\nRodriguez-Lomba et al3\tM/28\tsGCS + acitretin, CsA + acitretin\tNo data\tYes\tNo\t96\tYes\tSwitched to ustekinumab, then etanercept\tSecondary loss of efficacy\tNA\tYes\t\nMatsumoto et al4\tF/70\tCsA, etretinate\t5 mg/kg\tYes\tNo\t96\tYes\tSwitched to ustekinumab, then adalimumab\tSecondary loss of efficacy\t44\tYes\t\nF/36\tNone\t5 mg/kg\tYes\tNo\t36\tYes\tSwitched to adalimumab\tSecondary loss of efficacy\tNA\tYes\t\nM/56\tMtx, CsA, etretinate\t5 mg/kg, 10 mg/kg\tYes\tNo\t132\tYes\tDose increased to 10 mg/kg, then switched to adalimumab\tSecondary loss of efficacy\tNA\tYes\t\nM/43\tMtx, CsA, NB-UVB\t5 mg/kg, 6.6 mg/kg\tYes\tEtretinate 20 mg/day\t112\tNo\tNA\tSecondary loss of efficacy\tNA\tYes\t\nKawakami et al6\tM/43\tCsA, Mtx, bath PUVA, Ifx\t5 mg/kg\tPartial\tNo\t6\tYes\tSwitched to adalimumab\tSecondary loss of efficacy\t101\tYes\t\nF/30\tCsA, Mtx\t5 mg/kg\tYes\tNo\t22\tYes\tSwitched to adalimumab\tSecondary loss of efficacy\t64\tYes\t\nSugiura et al7\tF/39\tCsA\t5 mg/kg\tYes\tNo\t144\tNo\tNA\tNA\tNA\tNo\t\nM/29\tCsA\t5 mg/kg\tYes\tNo\t144\tNo\tNA\tNA\tNA\tNo\t\nF/65\tCsA\t5 mg/kg\tYes\tNo\t144\tNo\tNA\tNA\tNA\tNo\t\nKim et al9\tF/41\tMtx, sulfasalazine, CsA\t3 mg/kg\tYes\tNo\t48\tNo\tNA\tNA\tNA\tNo\t\nF/39\tNone\t3 mg/kg\tYes\tAcitretin 30–20 mg/day\tSingle dose\tNo\tNA\tNA\tNA\tNo\t\nSmith et al10\tM/33\tMtx\t5 mg/kg\tYes\tMtx\tSingle dose\tNo\tNA\tNA\t0.7\tNo\t\nFurusawa et al11\tF/42\tCsA\t5 mg/kg\tNo\tNo\tNA\tYes\tGranulocyte–monocyte adsorption apheresis\tPrimary lack of efficacy\tNA\tNA\t\nTang et al22\tM/72\tNone\t5 mg/kg\tYes\tAcitretin 35 mg/day (0.5 mg/kg)\t2\tNo\tMaintenance treatment with acitretin\tNA\t96\tNo\t\nViguier et al8\tF/NA\tNA\tNA\tYes\tNA\tSingle dose\tNA\tNA\tComplete remission\tNA\tNo\t\nM/NA\tNA\tNA\tYes\tNA\t48\tNA\tNA\tAE\tNA\tNo\t\nF/NA\tNA\tNA\tYes\tNA\t88\tNo\tNA\tAE\tNA\tNo\t\nM/NA\tNA\tNA\tYes\tNA\t24\tNo\tNA\tUncontrolled psoriasis vulgaris\tNA\tNo\t\nF/NA\tNA\tNA\tNo\tNA\t12\tNA\tSwitched to adalimumab, then etanercept\tPrimary lack of efficacy\tNA\tNA\t\nF/NA\tNA\tNA\tYes\tNA\t2\tNA\tNA\tAE\tNA\tNo\t\nF/NA\tNA\tNA\tYes\tNA\t21\tYes\tSwitched to etanercept\tSecondary loss of efficacy\tNA\tYes\t\nF/NA\tNA\tNA\tYes\tNA\tSingle dose\tNA\tNA\tComplete remission\tNA\tNo\t\nF/NA\tNA\tNA\tYes\tNA\t6\tNA\tNA\tAE\tNA\tNo\t\nF/NA\tNA\tNA\tYes\tNA\tSingle dose\tNA\tNA\tPatient preference\tNA\tNo\t\nTorii et al12\tF 5, M 2,/mean 41.7\tCsA (n=4), etretinate (n=1)\t5 mg/kg\tYes\tsGCS (n=2)\t19 (n=1), 30 (n=2), 50 (n=4)\tYes (n=5), no (n=2)\tNA\tSecondary loss of efficacy (n=1), AEs, (n=2)\tNA\tYes (n=1), no (n=6)\t\nChandran et al23\tF/NA\tPrednisolone, Mtx, acitretin, PUVA\t5 mg/kg\tYes\tAcitretin 40 mg/day (0.8 mg/kg)\tSingle dose\tYes\tMaintenance treatment with acitretin\tNA\t28\tNo\t\nVieira-,Serrão et al13\tM/NA\tAcitretin, Mtx, sGCS\tNo data\tYes\tNo\t32\tNo\tNA\tNA\tNA\tNo\t\nRouthouska et al14\tF/77\tAcitretin, Mtx, CsA, 6-thioguanine\t5 mg/kg\tYes\tMtx\t144\tYes\tMtx 10 mg/week added\tNA\tNA\tNo\t\nF/72\tEtretinate, isotretinoin, dapsone, CsA with PUVA\t5 mg/kg\tYes\tMtx, acitretin 25 mg/day\t60\tYes\tAcitretin 25 mg/day and Mtx 15 mg/week added\tInsurance issues\tNA\tNo\t\nF/22\tCsA, etanercept\t5 mg/kg\tYes\tMtx\t12\tYes\tMtx 25 mg/week added\tInfusion reaction\t>24\tNo\t\nWeishaupt et al15\tNot reported/24\tsGCS, retinoids, fumaric acid esters, PUVA\t4 mg/kg\tYes\tPrednisolone\tSingle dose\tYes\tTopical treatment\tNA\t24\tNo\t\nNot reported/16\tNone\t5 mg/kg\tYes\tNo\tSingle dose\tYes\tSwitched to Mtx\tNA\tNA\tYes\t\nSchmick et al16\tF/82\tAcitretin, Mtx, CsA, dapsone\t5 mg/kg\tYes\tNo\t12\tYes\tTopical treatment\tNA\t12\tNo\t\nTrent et al17\tF/17\tMycophenolate mofetil\t5 mg/kg\tYes\tNo\t>14\tNo\tNA\tNA\tNA\tNo\t\nF/46\tMycophenolate mofetil, etanercept\t5 mg/kg\tYes\tMtx, prednisone\t>14\tNo\tNA\tNA\tNA\tNo\t\nF/52\tEtanercept\t5 mg/kg\tYes\tNo\tSingle dose\tNo\tNA\tNA\tNA\tNo\t\nBenoit et al18\tM/61\tAcitretin, Mtx\t5 mg/kg\tYes\tMtx, acitretin 0.5–1 mg/kg\t27\tYes\tAcitretin 0.5 mg/kg added\tNA\t12\tNo\t\nLisby et al19\tF/59\tMtx, CsA, prednisone\t3 mg/kg\tYes\tMtx\t6\tYes\tMtx 15 mg/week added\tNA\t4\tNo\t\nNewland et al20\tF/44\tUVB, Mtx, acitretin, bexarotene, PUVA, dapsone, isotretinoin, CsA, etretinate\t5 mg/kg\tYes\tNo\tSingle dose\tNA\tNA\tNA\t0.3\tNo\t\nElewski et al21\tM/39\tMtx, acitretin, prednisone\t5 mg/kg\tYes\tMtx, acitretin, prednisone\t6\tNo\tNA\tNA\t>10\tNo\t\nCurrent cases\tK/73\tAcitretin, CsA, Mtx, methyloprednisolone\t5 mg/kg\tYes\tAcitretin\t54\tYes\tAcitretin 0.3 mg/kg reintroduced\tIfx ongoing\tNA\tNo\t\nM/60\tNone\t5 mg/kg\tYes\tMtx\t54\tYes\tMtx replaced by acitretin 0.35 mg/kg\tIfx ongoing\tNA\tNo\t\nAbbreviations: GPP, generalized pustular psoriasis; AE, adverse event; Mtx, methotrexate; CsA, cyclosporine A; Ifx, infliximab; F, female; M, male; sGCS, systemic glucocorticosteroids; NB-UVB, narrowband ultraviolet B; NA, not available.\n\nFigure 3 Infliximab (Ifx) survival in GPP calculated on the basis of cases available in the literature.\n\nIfx is commonly used in combination with Mtx not only to improve therapeutic response but also to avoid formation of anti–Ifx neutralizing antibodies.14,17–19,21 Combined use of Ifx and acitretin is less documented in the literature.9,14,18,22,23 In one report of severe GPP in a patient with neutrophilic cholangitis, acitretin 0.8 mg/kg was introduced as concurrent systemic treatment on day 6 after a single dose of Ifx, and the patient remained pustule-free during a 7-month follow-up.23 In another report, Tang et al22 administered Ifx in combination with acitretin (0.5 mg/kg), which resulted in rapid amelioration of GPP within 48 hours. In total, two infusions of Ifx were given and acitretin was tapered down to 10 mg/day, which enabled satisfactory control of the disease over a 24-month follow-up. In our patients, the combination of Ifx and acitretin (0.3–0.35 mg/kg) was associated with good therapeutic effects. In addition, the therapy was well tolerated and no adverse events, usually common with doses above 0.5 mg/kg, were noted.\n\nConclusion\n\nIfx is a safe and highly effective treatment option for GPP. Rapid amelioration of the condition may be observed after a single Ifx dose, which makes Ifx a suitable option for “rescue treatment” in the most severe cases. Ifx may be also safely combined with low-dose acitretin in the treatment of GPP to achieve long-term control of the disease. Nevertheless, larger randomized studies are needed to compare the efficacy of monotherapy with Ifx versus combination therapy of Ifx with low-dose acitretin in GPP.\n\nDisclosure\n\nMarta Kołt-Kamińska and Magdalena Żychowska declare no conflicts of interest for this work. Adam Reich reports personal fees from AbbVie, Novartis, Chema Rzeszów, Galderma, Pfizer, Eli Lilly, Trevi Therapeutics, Dermira, Janssen, BMS, and GlaxoSmithKline outside the submitted work, and has been a consultant or speaker for AbbVie, Bioderma, Celgene, Chema Elektromet, Eli Lilly, Galderma, Janssen, Leo Pharma, Medac, Menlo Therapeutics, Novartis, Pierre-Fabre, Sandoz, and Trevi and principal investigator or subinvestigator in clinical trials sponsored by AbbVie, Drug Delivery Solutions, Galderma, Genentech, Janssen, Kymab Limited, Leo Pharma, Menlo Therapeutics, MetrioPharm, MSD, Novartis, Pfizer, and Trevi. He reports no other potential conflicts of interest for this work.\n==== Refs\nReferences\n\n1. SegawaY, IshidaR, KanehisaF, et al. IgA nephropathy in a patient receiving infliximab for generalized pustular psoriasis. BMC Nephrol. 2020;21 :366. doi:10.1186/s12882-020-02015-0 32842976\n2. GeorgakopoulosJR, IghaniA, YeungJ. Short- and long-term management of an acute pustular psoriasis flare: a case report. J Cutan Med Surg. 2017;21 :452–456. doi:10.1177/1203475417712499 28535721\n3. Rodríguez-LombaE, BaniandrésO, CanoN, Suárez-FernándezR. Generalized pustular psoriasis and neutrophilic cholangitis: an infrequently reported association with excellent response to tumour necrosis factor inhibitors. Australas J Dermatol. 2017;58 :70–71. doi:10.1111/ajd.12471 28195322\n4. MatsumotoA, KomineM, KarakawaM, KishimotoM, OhtsukiM. Adalimumab administration after infliximab therapy is a successful treatment strategy for generalized pustular psoriasis. J Dermatol. 2017;44 :202–204. doi:10.1111/1346-8138.13632 27743397\n5. RobinsonA, Van VoorheesAS, HsuS, et al. Treatment of pustular psoriasis: from the Medical Board of the National Psoriasis Foundation. J Am Acad Dermatol. 2012;67 (2 ):279–288. doi:10.1016/j.jaad.2011.01.032 22609220\n6. KawakamiH, MaedaT, AbeN, et al. Efficacy of adalimumab and methotrexate combination therapy on generalized pustular psoriasis patients unresponsive to infliximab monotherapy due to anti-infliximab antibody development. J Dermatol. 2015;42 :94–95. doi:10.1111/1346-8138.12704 25425479\n7. SugiuraK, EndoK, AkasakaT, AkiyamaM. Successful treatment with infliximab of sibling cases with generalized pustular psoriasis caused by deficiency of interleukin-36 receptor antagonist. J Eur Acad Dermatol Venereol. 2015;29 :2054–2056. doi:10.1111/jdv.12590 24910924\n8. ViguierM, AubinF, DelaporteE, et al. Efficacy and safety of tumor necrosis factor inhibitors in acute generalized pustular psoriasis. Arch Dermatol. 2012;148 :1423–1425. doi:10.1001/2013.jamadermatol.80 23247492\n9. KimHS, YouHS, ChoHH, et al. Two cases of generalized pustular psoriasis: successful treatment with infliximab. Ann Dermatol. 2014;26 :787–788. doi:10.5021/ad.2014.26.6.787 25473247\n10. SmithN, HarmsKL, HinesAC, et al. Acute treatment of generalized pustular psoriasis of von Zumbusch with single-dose infliximab. J Am Acad Dermatol. 2013;68 :e187–9. doi:10.1016/j.jaad.2012.11.017 23680215\n11. FurusawaK, HasegawaT, IkedaS. Immunosuppressant and infliximab-resistant generalized pustular psoriasis successfully treated with granulocyte and monocyte adsorption apheresis. Ther Apher Dial. 2012;16 :379–380. doi:10.1111/j.1744-9987.2012.01067.x 22817129\n12. ToriiH, NakagawaH; Japanese Infliximab Study Investigators. Long-term study of infliximab in Japanese patients with plaque psoriasis, psoriatic arthritis, pustular psoriasis and psoriatic erythroderma. J Dermatol. 2011;38 :321–334. doi:10.1111/j.1346-8138.2010.00971.x 21544940\n13. Vieira-SerrãoV, MartinsA, Paiva LopesMJ. Infliximab in recalcitrant generalized pustular arthropathic psoriasis. Eur J Dermatol. 2008;18 :71–73.18086593\n14. RouthouskaSB, ShethPB, KormanNJ. Long-term management of generalized pustular psoriasis with infliximab: case series. J Cutan Med Surg. 2008;12 :184–188. doi:10.2310/7750.2008.07036 18627699\n15. WeishauptC, MetzeD, LugerTA, StänderS. Treatment of pustular psoriasis with infliximab. J Dtsch Dermatol Ges. 2007;5 :397–399. doi:10.1111/j.1610-0387.2007.06296.x 17451384\n16. SchmickK, GrabbeJ. Recalcitrant, generalized pustular psoriasis: rapid and lasting therapeutic response to antitumour necrosis factor-alpha antibody (infliximab). Br J Dermatol. 2004;150 (2 ):367. doi:10.1111/j.1365-2133.2004.05719.x\n17. TrentJT, KerdelFA. Successful treatment of Von Zumbusch pustular psoriasis with infliximab. J Cutan Med Surg. 2004;8 :224–228. doi:10.1177/120347540400800404 16091999\n18. BenoitS, ToksoyA, BröckerEB, GillitzerR, GoebelerM. Treatment of recalcitrant pustular psoriasis with infliximab: effective reduction of chemokine expression. Br J Dermatol. 2004;150 :1009–1012. doi:10.1111/j.1365-2133.2004.05960.x 15149518\n19. LisbyS, GniadeckiR. Infliximab (Remicade) for acute, severe pustular and erythrodermic psoriasis. Acta Derm Venereol. 2004;84 :247–248.15202853\n20. NewlandMR, WiensteinA, KerdelF. Rapid response to infliximab in severe pustular psoriasis, von Zumbusch type. Int J Dermatol. 2002;41 :449–452. doi:10.1046/j.1365-4362.2002.01543.x 12121565\n21. ElewskiBE. Infliximab for the treatment of severe pustular psoriasis. J Am Acad Dermatol. 2002;47 :796–797. doi:10.1067/mjd.2002.128382 12399781\n22. TangMM, SpanouZ, TangH, et al. Rapid downregulation of innate immune cells, interleukin-12 and interleukin-23 in generalized pustular psoriasis with infliximab in combination with acitretin. Dermatology. 2012;225 (4 ):338–343. doi:10.1159/000346243 23343611\n23. ChandranNS, ChongWS. A dramatic response to a single dose of infliximab as rescue therapy in acute generalized pustular psoriasis of von Zumbusch with a neutrophilic cholangitis. Australas J Dermatol. 2010;51 (1 ):29–31. doi:10.1111/j.1440-0960.2009.00588.x 20148838\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1177-5475",
"issue": "15()",
"journal": "Biologics : targets & therapy",
"keywords": "acitretin; anti-TNFα; generalized pustular psoriasis; infliximab",
"medline_ta": "Biologics",
"mesh_terms": null,
"nlm_unique_id": "101321511",
"other_id": null,
"pages": "317-327",
"pmc": null,
"pmid": "34393480",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": "17451384;25473247;23247492;18627699;23680215;28535721;18086593;12399781;21544940;28195322;32842976;14996114;24910924;27743397;12121565;25425479;15202853;22817129;16091999;23343611;22609220;15149518;20148838",
"title": "Infliximab in Combination with Low-Dose Acitretin in Generalized Pustular Psoriasis: A Report of Two Cases and Review of the Literature.",
"title_normalized": "infliximab in combination with low dose acitretin in generalized pustular psoriasis a report of two cases and review of the literature"
} | [
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"companynumb": "PL-CELLTRION INC.-2021PL013901",
"fulfillexpeditecriteria": "1",
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"actiondrug": "4",
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"activesubstancename": "INFLIXIMAB"
},
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... |
{
"abstract": "OBJECTIVE\nTo evaluate the occurrence of megaloblastic anemia induced by the infusion of therapeutic or prophylactic methotrexate in patients with acute leukemia.\n\n\nMETHODS\nData on 3 patients with acute leukemia receiving intrathecal methotrexate were prospectively analyzed.\n\n\nMETHODS\nLarge tertiary-care center.\n\n\nRESULTS\nAll 3 patients with acute leukemia developed megaloblastic anemia confirmed by examination of the bone marrow aspirate and biopsy. Two of the 3 patients had low folic acid levels, while all patients had normal serum B(12) levels. All patients responded favorably to a therapeutic trial of folic acid. The median time for recovery of the hematologic parameters in these patients was 7 days.\n\n\nCONCLUSIONS\nIntrathecally administered methotrexate may result in megaloblastic changes in the bone marrow of leukemic patients. The morphologic clues suggestive of folate deficiency in patients with acute leukemia may be masked by coexisting factors, such as the effects of cytotoxic treatment, prior transfusions, or persistent changes from the leukemic clone itself. Caution should be exercised to avoid attributing these changes to the neoplastic process, since the prognosis and treatment for the conditions involved are totally different. Repeat examination of the bone marrow, obtaining folic acid and vitamin B(12) levels, and a therapeutic trial of folic acid may help identify and reverse these changes.",
"affiliations": "Department of Medicine, Division of Hematology/Oncology, East Carolina University, School of Medicine, Greenville, NC, USA.",
"authors": "Sallah|S|S|;Hanrahan|L R|LR|;Phillips|D L|DL|",
"chemical_list": "D000964:Antimetabolites, Antineoplastic; D005492:Folic Acid; D008727:Methotrexate",
"country": "United States",
"delete": false,
"doi": "10.5858/1999-123-0774-IMIMAI",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0003-9985",
"issue": "123(9)",
"journal": "Archives of pathology & laboratory medicine",
"keywords": null,
"medline_ta": "Arch Pathol Lab Med",
"mesh_terms": "D000328:Adult; D000749:Anemia, Megaloblastic; D000964:Antimetabolites, Antineoplastic; D005260:Female; D005492:Folic Acid; D006801:Humans; D007278:Injections, Spinal; D015479:Leukemia, Myelomonocytic, Acute; D008297:Male; D008727:Methotrexate; D008875:Middle Aged; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma; D011446:Prospective Studies",
"nlm_unique_id": "7607091",
"other_id": null,
"pages": "774-7",
"pmc": null,
"pmid": "10458822",
"pubdate": "1999-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Intrathecal methotrexate-induced megaloblastic anemia in patients with acute leukemia.",
"title_normalized": "intrathecal methotrexate induced megaloblastic anemia in patients with acute leukemia"
} | [
{
"companynumb": "US-PFIZER INC-2020015488",
"fulfillexpeditecriteria": "1",
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"patient": {
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{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHOTREXATE SODIUM"
},
"drugadditional": "3",... |
{
"abstract": "Acid suppressive therapy (AST)-namely, proton pump inhibitors (PPIs) and histamine-2 receptor antagonists (H2RAs)-is routinely prescribed to hospitalized patients for stress ulcer prophylaxis (SUP).\n\n\n\nTo identify the incidence of and indications for AST use in the hematology/oncology population as well as to identify the occurrence of the following PPI-associated adverse events: pneumonia and Clostridium difficile-associated diarrhea (CDAD).\n\n\n\nA retrospective chart review was conducted on adult hematology/oncology patients admitted to any oncology service for ≥48 hours from October 1, 2014, to December 31, 2014.\n\n\n\nOf the 298 patients who met the inclusion criteria, 73% (n = 218) received an AST during admission. The most common indication for an AST was SUP (63%). The incidence of hospital-acquired pneumonia (HAP) was 10%, 0%, and 4% in patients who received a PPI, H2RA, and no AST, respectively (14/142 vs 0/70 vs 3/80; odds ratio [OR] for PPI vs no AST = 2.68; 95% CI = 0.75-9.63). The incidence of CDAD was 3%, 1.3%, and 1.2% in patients who received a PPI, H2RA, and no AST, respectively (4/142 vs 1/70 vs 1/80; OR for PPI vs H2RA = 1.92; 95% CI = 0.21-17.47).\n\n\n\nThis is the first study to describe the incidence of and indications for AST use in the hospitalized hematology/oncology population. There was a high occurrence of AST use, particularly PPIs, in these patients at our institution. Additionally, there was a trend toward an increased risk of HAP and CDAD in patients who received AST during admission.",
"affiliations": "University of Arkansas for Medical Sciences College of Pharmacy, Little Rock, AR, USA Georgia Regents Medical Center, Augusta, GA, USA University of Georgia College of Pharmacy, Augusta, GA, USA.;Georgia Regents Medical Center, Augusta, GA, USA University of Georgia College of Pharmacy, Augusta, GA, USA ARGANDHI@gru.edu.;Georgia Regents Medical Center, Augusta, GA, USA.;Georgia Regents Medical Center, Augusta, GA, USA University of Georgia College of Pharmacy, Augusta, GA, USA.",
"authors": "McCaleb|Rachael V|RV|;Gandhi|Arpita S|AS|;Clark|Stephen Michael|SM|;Clemmons|Amber B|AB|",
"chemical_list": "D006635:Histamine H2 Antagonists; D054328:Proton Pump Inhibitors",
"country": "United States",
"delete": false,
"doi": "10.1177/1060028016644469",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1060-0280",
"issue": "50(7)",
"journal": "The Annals of pharmacotherapy",
"keywords": "cancer; drug-related problems; hematology; histamine-2 receptor antagonist; oncology; proton pump inhibitor",
"medline_ta": "Ann Pharmacother",
"mesh_terms": "D000046:Academic Medical Centers; D000328:Adult; D016360:Clostridioides difficile; D003428:Cross Infection; D003967:Diarrhea; D017723:Drug Utilization Review; D005260:Female; D006402:Hematologic Diseases; D006635:Histamine H2 Antagonists; D006760:Hospitalization; D006801:Humans; D015994:Incidence; D008297:Male; D008499:Medical Records; D008875:Middle Aged; D009369:Neoplasms; D016017:Odds Ratio; D010437:Peptic Ulcer; D011014:Pneumonia; D054328:Proton Pump Inhibitors; D012189:Retrospective Studies; D012307:Risk Factors",
"nlm_unique_id": "9203131",
"other_id": null,
"pages": "541-7",
"pmc": null,
"pmid": "27091869",
"pubdate": "2016-07",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Clinical Outcomes of Acid Suppressive Therapy Use in Hematology/Oncology Patients at an Academic Medical Center.",
"title_normalized": "clinical outcomes of acid suppressive therapy use in hematology oncology patients at an academic medical center"
} | [
{
"companynumb": "US-JNJFOC-20170600880",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FAMOTIDINE"
},
"drugadditional": "3",
"... |
{
"abstract": "Romosozumab, which binds sclerostin, rebuilds the skeletal foundation before transitioning to antiresorptive treatment. This subgroup analysis of an international, randomized, double-blind study in postmenopausal women with osteoporosis showed efficacy and safety outcomes for romosozumab followed by denosumab in Japanese women were generally consistent with those for the overall population.\n\n\n\nIn the international, randomized, double-blind, phase 3 FRActure study, in postmenopausal woMen with ostEoporosis (FRAME; NCT01575834), romosozumab followed by denosumab significantly improved bone mineral density (BMD) and reduced fracture risk. This report evaluates Japanese women in FRAME.\n\n\n\nPostmenopausal women with osteoporosis (T-score - 3.5 to - 2.5 at total hip or femoral neck) received romosozumab 210 mg or placebo subcutaneously monthly for 12 months, then each group received denosumab 60 mg subcutaneously every 6 months for 24 months. The key endpoint for Japanese women was BMD change. Other endpoints included new vertebral, clinical, and nonvertebral fracture; the subgroup analysis did not have adequate power to demonstrate statistically significant reductions.\n\n\n\nOf 7180 enrolled subjects, 492 (6.9%) were Japanese (247 romosozumab, 245 placebo). BMD increases from baseline were greater (P < 0.001) for romosozumab-to-denosumab than placebo-to-denosumab at the lumbar spine (36 months, 12.7%), total hip (4.2%), and femoral neck (4.1%). Fracture risk was lower through 36 months for romosozumab-to-denosumab vs placebo-to-denosumab for new vertebral (1.7% vs 4.5%; relative risk reduction (RRR) 63%, P = 0.070), clinical (3.2% vs 7.3%; RRR 53%, P = 0.072), nonvertebral (2.8% vs 6.1%; RRR 50%, P = 0.12), and all other fracture types evaluated. Rates of adverse events and positively adjudicated serious cardiovascular events were generally balanced between groups.\n\n\n\nEfficacy and safety for romosozumab-to-denosumab were similar between Japanese women and the overall population. The sequence of romosozumab to rebuild the skeletal foundation before transitioning to antiresorptive treatment with denosumab is a promising regimen for Japanese postmenopausal women with osteoporosis at high risk of fracture.",
"affiliations": "Miyauchi Medical Center, Osaka, Japan. akimiyauchi0129@gmail.com.;Amgen Inc., Thousand Oaks, CA, USA.;Amgen Inc., Thousand Oaks, CA, USA.;Amgen Inc., Thousand Oaks, CA, USA.;Amgen Inc., Thousand Oaks, CA, USA.;Amgen Astellas BioPharma K.K., Tokyo, Japan.;Amgen Astellas BioPharma K.K., Tokyo, Japan.;UCB Pharma, Brussels, Belgium.;Amgen Inc., Thousand Oaks, CA, USA.;Amgen Astellas BioPharma K.K., Tokyo, Japan.",
"authors": "Miyauchi|Akimitsu|A|;Dinavahi|Rajani V|RV|;Crittenden|Daria B|DB|;Yang|Wenjing|W|;Maddox|Judy C|JC|;Hamaya|Etsuro|E|;Nakamura|Yoichi|Y|;Libanati|Cesar|C|;Grauer|Andreas|A|;Shimauchi|Junichiro|J|",
"chemical_list": "D000911:Antibodies, Monoclonal; D050071:Bone Density Conservation Agents; C557282:romosozumab; D000069448:Denosumab",
"country": "England",
"delete": false,
"doi": "10.1007/s11657-019-0608-z",
"fulltext": "\n==== Front\nArch Osteoporos\nArch Osteoporos\nArchives of Osteoporosis\n1862-3522 1862-3514 Springer London London \n\n31168657\n608\n10.1007/s11657-019-0608-z\nOriginal Article\nIncreased bone mineral density for 1 year of romosozumab, vs placebo, followed by 2 years of denosumab in the Japanese subgroup of the pivotal FRAME trial and extension\nMiyauchi Akimitsu +81 72 686 3330akimiyauchi0129@gmail.com 1 Dinavahi Rajani V. 2 Crittenden Daria B. 2 Yang Wenjing 2 Maddox Judy C. 2 Hamaya Etsuro 3 Nakamura Yoichi 3 Libanati Cesar 4 Grauer Andreas 2 Shimauchi Junichiro 3 1 Miyauchi Medical Center, Osaka, Japan \n2 0000 0001 0657 5612grid.417886.4Amgen Inc., Thousand Oaks, CA USA \n3 Amgen Astellas BioPharma K.K., Tokyo, Japan \n4 0000 0004 0605 7243grid.421932.fUCB Pharma, Brussels, Belgium \n5 6 2019 \n5 6 2019 \n2019 \n14 1 591 3 2019 18 5 2019 © The Author(s) 2019Open Access This 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.Summary\nRomosozumab, which binds sclerostin, rebuilds the skeletal foundation before transitioning to antiresorptive treatment. This subgroup analysis of an international, randomized, double-blind study in postmenopausal women with osteoporosis showed efficacy and safety outcomes for romosozumab followed by denosumab in Japanese women were generally consistent with those for the overall population.\n\nPurpose\nIn the international, randomized, double-blind, phase 3 FRActure study, in postmenopausal woMen with ostEoporosis (FRAME; NCT01575834), romosozumab followed by denosumab significantly improved bone mineral density (BMD) and reduced fracture risk. This report evaluates Japanese women in FRAME.\n\nMethods\nPostmenopausal women with osteoporosis (T-score − 3.5 to − 2.5 at total hip or femoral neck) received romosozumab 210 mg or placebo subcutaneously monthly for 12 months, then each group received denosumab 60 mg subcutaneously every 6 months for 24 months. The key endpoint for Japanese women was BMD change. Other endpoints included new vertebral, clinical, and nonvertebral fracture; the subgroup analysis did not have adequate power to demonstrate statistically significant reductions.\n\nResults\nOf 7180 enrolled subjects, 492 (6.9%) were Japanese (247 romosozumab, 245 placebo). BMD increases from baseline were greater (P < 0.001) for romosozumab-to-denosumab than placebo-to-denosumab at the lumbar spine (36 months, 12.7%), total hip (4.2%), and femoral neck (4.1%). Fracture risk was lower through 36 months for romosozumab-to-denosumab vs placebo-to-denosumab for new vertebral (1.7% vs 4.5%; relative risk reduction (RRR) 63%, P = 0.070), clinical (3.2% vs 7.3%; RRR 53%, P = 0.072), nonvertebral (2.8% vs 6.1%; RRR 50%, P = 0.12), and all other fracture types evaluated. Rates of adverse events and positively adjudicated serious cardiovascular events were generally balanced between groups.\n\nConclusions\nEfficacy and safety for romosozumab-to-denosumab were similar between Japanese women and the overall population. The sequence of romosozumab to rebuild the skeletal foundation before transitioning to antiresorptive treatment with denosumab is a promising regimen for Japanese postmenopausal women with osteoporosis at high risk of fracture.\n\nElectronic supplementary material\nThe online version of this article (10.1007/s11657-019-0608-z) contains supplementary material, which is available to authorized users.\n\nKeywords\nRomosozumabDenosumabJapaneseBone mineral densityFractureissue-copyright-statement© International Osteoporosis Foundation and National Osteoporosis Foundation 2019\n==== Body\nIntroduction\nAmong postmenopausal women with osteoporosis, fractures are associated with substantial clinical and economic burden [1, 2]. A recent report estimated that although the incidence of hip fracture in Japan was decreasing, the prevalence was increasing as the number of elderly patients increased [3]. Key risk factors for fracture in postmenopausal women include low bone mineral density (BMD) and older age [4–14]. Fracture risk is particularly high in women with a prior history of fracture [15], yet globally, only about 20% of patients receive treatment to prevent recurrent fractures [16–18]. A study in Japan showed consistent findings, with only 19% of patients receiving pharmacologic medication in the year following a hip fracture [19].\n\nIn Japan, osteoporosis is a major public health problem, consistent with global trends. Approximately 13 million Japanese women have osteoporosis, 40% of whom are 70 years of age or older [20]. A threshold for intervention in Japanese guidelines for prevention and treatment of osteoporosis [21] is a 10-year probability of major osteoporotic fracture that is 15% or greater, based on the Fracture Risk Assessment Tool (FRAX) [22]. In 2010, an estimated 29.7 million women (46% of the total female population) in Japan were over the age of 50 years, and 9.3 million (31.5%) of those women exceeded the 15% threshold for intervention [23]. According to population growth estimation, the number of women aged 50 years or older above this threshold is projected to rise from 9.3 million to 12.7 million (38% of women over the age of 50 years) by the year 2035.\n\nThe most commonly prescribed initial therapy for the treatment of osteoporosis in Japan is an antiresorptive agent (oral bisphosphonate, selective estrogen receptor modulator, eldecalcitol, or denosumab) [24]. In Japan, two forms of teriparatide treatment are available: a subcutaneous injection of teriparatide acetate at 56.5 μg/week [25] and a subcutaneous injection of recombinant human teriparatide at 20 μg/day [13, 24]. A possible alternative for the treatment of osteoporosis is the bone-forming agent romosozumab, a monoclonal antibody that binds sclerostin, leading to the dual effect of increasing bone formation and decreasing bone resorption [26, 27]. In the FRActure study in postmenopausal woMen with ostEoporosis (FRAME; NCT01575834), a pivotal, international, double-blind, phase 3 study of postmenopausal women, 12 months of treatment with romosozumab once monthly, significantly improved BMD and reduced fracture risk vs placebo [28]. At 12 months, women in each treatment group transitioned to open-label treatment with the antiresorptive agent denosumab, administered every 6 months for an additional 24 months, including an open-label period (months 12–24) and an extension period (months 24–36). Significant improvements in BMD and fracture risk in the romosozumab-to-denosumab group persisted through 36 months in FRAME, supporting the benefit of rebuilding the skeletal foundation with romosozumab before transitioning to antiresorptive treatment with denosumab [29]. This subgroup analysis of FRAME examined cumulative results for BMD and fracture risk through 36 months among Japanese postmenopausal women with osteoporosis.\n\nMethods\nThe full methods for FRAME were reported previously [28]. Methods pertaining to the subgroup analysis are described here.\n\nStudy participants\nFRAME was an international study at 222 centers across 25 countries in North America, Europe, Central/South America, and Asia-Pacific (including 54 in Japan). Key inclusion criteria were postmenopausal women, age 55–90 years, and osteoporosis (BMD T-score − 3.5 to − 2.5 at total hip or femoral neck). Subjects had to have at least two vertebrae in the L1 through L4 region and at least one hip that could be evaluated by means of dual-energy x-ray absorptiometry (DXA). Due to the placebo-controlled study design, women were excluded from the study if they presented with a history of hip fracture, severe vertebral fracture, or more than two moderate vertebral fractures. Women with recent or repeated use of the following osteoporosis therapies were excluded from the study: strontium ranelate, fluoride, bisphosphonates, denosumab, any cathepsin K inhibitor, teriparatide, any parathyroid hormone analog, estrogen, hormonal ablation therapy, tibolone, cinacalcet, or calcitonin. Women with recent and prolonged use of systemic glucocorticoids were excluded from the study. Other key exclusion criteria were a history of metabolic bone disease or conditions affecting bone metabolism, osteonecrosis of the jaw, a 25-hydroxyvitamin D [25(OH)D] level of less than 20 ng/mL, and current hypercalcemia or hypocalcemia.\n\nStudy design\nDuring the 12-month double-blind period, subjects were randomized 1:1 to receive treatment with romosozumab 210 mg or placebo, administered subcutaneously once monthly (Online Resource 1). At 12 months, subjects in each treatment group transitioned to open-label treatment with denosumab 60 mg subcutaneously every 6 months for 24 months. Randomization was stratified by age (< 75 or ≥ 75 years) and prevalent vertebral fracture (yes or no). The original treatment assignment to romosozumab or placebo remained blinded throughout the study. All subjects received at minimum daily calcium (500–1000 mg) and vitamin D (600–800 IU) supplementation. If serum 25(OH)D was 20–40 ng/mL at baseline, then the subject could receive a vitamin D loading dose of 50,000–60,000 IU.\n\nAssessments\nDXA scans of the lumbar spine and proximal femur were scheduled for all subjects at screening and at 12, 24, and 36 months. Lateral spine radiographs (thoracic and lumbar spine) were taken at screening and at 6, 12, 24, and 36 months, or when a subject experienced back pain suggestive of vertebral fracture. When a nonvertebral or clinical vertebral fracture was suspected, additional radiographs were obtained for confirmation. A central imaging vendor (BioClinica, Newark, CA, USA), blinded to the initial treatment assignment, assessed and graded vertebral radiographs (using the Genant semiquantitative criteria [30]) and nonvertebral radiographs. Only those fractures confirmed by the central imaging vendor were included for the analyses.\n\nStatistical analyses\nFor this report, most efficacy analyses were conducted in the Japanese full analysis set, defined as the subgroup of subjects at study centers in Japan who were randomized to treatment with romosozumab-to-denosumab or placebo-to-denosumab. The analysis set for new vertebral fractures at each visit included all randomized subjects who had a baseline and at least one postbaseline evaluation of vertebral fracture. The Japanese safety analysis set included all randomized subjects who received ≥ 1 dose of romosozumab or placebo in the 12-month double-blind period. Subject incidences of adverse events for the 36-month study period included all events that occurred in the double-blind period (among all subjects in the Japanese safety analysis set), as well as those in the open-label or extension periods (among those subjects who received ≥ 1 dose of denosumab).\n\nBaseline demographics and clinical characteristics were summarized descriptively. The baseline 10-year probability of a major osteoporotic fracture was calculated with the FRAX algorithm including femoral neck BMD [22, 23]. Baseline BMD for each location was also expressed as the percentage of young adult mean. Diagnostic criteria for osteoporosis in Japan recommend calculation of the BMD as a percentage of the young adult mean value for adults 20–44 years of age (for lumbar spine) or 20–29 years of age (for the proximal femur) [31]. BMD values below 70% of the young adult mean in Japan correspond to approximately − 2.5 SD.\n\nIn FRAME, the primary efficacy endpoints were the incidence of new vertebral fracture through 12 and 24 months, and exploratory endpoints for the final analysis at 36 months included the incidences of new vertebral fracture and other fracture types, as well as the percentage change from baseline in BMD at the lumbar spine, total hip, and femoral neck. This subgroup analysis analyzed the same endpoints within the Japanese full analysis set. The key endpoint for this subgroup was percentage change from baseline of lumbar spine BMD. Fractures, including vertebral, clinical, and nonvertebral fractures, were also exploratory endpoints, but the subgroup analysis did not have adequate power to detect significant differences in endpoints. No multiplicity adjustment was applied. All P values were nominal.\n\nAnalyses of BMD used analysis of covariance models to determine the least squares mean percentage change from baseline, with adjustment for baseline BMD, machine type, and interaction between baseline BMD and machine type. A responder analysis assessed the percentage of subjects with a percentage change from baseline in BMD by DXA of varying magnitudes (i.e., ≥ 3%, ≥ 6%, and ≥ 10%, chosen empirically, with ≥ 3% representing the approximate least significant change) at the lumbar spine and total hip at 12 months, as well as subjects who had BMD decreases from baseline. The responder analysis used logistic regression models adjusting for treatment, age, and prevalent vertebral fracture stratification variables, baseline value, machine type, and baseline value-by-machine type interaction. Analyses of shifts in BMD T-score from ≤ − 2.5 at baseline to > − 2.5 at 12, 24, and 36 months at the lumbar spine and total hip used logistic regression models adjusting for treatment, age, prevalent vertebral fracture stratification variables, and baseline BMD T-score.\n\nFor new vertebral fracture, risk ratios were calculated by the Mantel-Haenszel method in the analysis set for new vertebral fractures, and P values were determined by logistic regression models that were stratified by age (< 75 or ≥ 75 years) and prevalent vertebral fracture (yes or no) at baseline. For other fracture types, hazard ratios and P values were determined by Cox proportional-hazards models that were also stratified by age and prevalent vertebral fracture. Nonvertebral fractures excluded fractures of the skull, facial bones, metacarpals, fingers, and toes; pathologic fractures; and fractures associated with high trauma. Major nonvertebral fractures included fractures of the pelvis, distal femur, proximal tibia, ribs, proximal humerus, forearm, and hip. Major osteoporotic fractures included clinical vertebral, hip, forearm, and humerus fractures, excluding pathologic fractures.\n\nResults\nSubject disposition\nJapanese subjects were included in this subgroup analysis. The 7180 women who were randomized in FRAME were from the following regions: Central/Latin America (43.0%); Central and Eastern Europe (29.2%), Western Europe, Australia, or New Zealand (13.6%); Asia-Pacific (11.5%); and North America (2.7%). Of the 829 women from the Asia-Pacific region, most (59.3%) were from Japan (247 romosozumab, 245 placebo), followed by Hong Kong (27.9%) and India (12.8%). Overall, 81.1% (399/492) of Japanese women (190/247 romosozumab-to-denosumab vs 209/245 placebo-to-denosumab) completed the 36-month study period. The most common reason for early study discontinuation was consent withdrawn (33 (13.4%) romosozumab-to-denosumab vs 20 (8.2%) placebo-to-denosumab); other reasons such as adverse event (12 (4.9%) vs 11 (4.5%)), administrative decision (3 (1.2%) vs 1 (0.4%)), death (2 (0.8%) vs 1 (0.4%)), and lost to follow-up (2 (0.8%) vs 1 (0.4%)) had similar incidences in both treatment groups (Fig. 1).Fig. 1 Subject disposition flowchart. QM once monthly, Q6M every 6 months\n\n\n\nBaseline characteristics\nWomen in the romosozumab group were more likely than those in the placebo group to have at least one prevalent vertebral fracture (23.9% vs 18.8% of Japanese subjects), and these fractures were more likely to be moderate or severe (13.0% vs 6.9% of subjects; Table 1). Other baseline characteristics were similar between the romosozumab and placebo groups at baseline, including age, body mass index, BMD T-score (lumbar spine, total hip, and femoral neck), percentage of young adult mean, the incidence of nonvertebral fracture at age ≥ 45 years, and 25(OH)D. Median baseline FRAX scores for the 10-year probability of major osteoporotic fracture were also similar between the romosozumab and placebo groups, but the median baseline FRAX score overall in Japanese subjects was nearly double that in non-Japanese subjects.Table 1 Baseline demographics and clinical characteristics\n\nCharacteristic\tPlacebo-to-denosumab (N = 245)\tRomosozumab-to-denosumab (N = 247)\t\nAge\t\n Years, mean (SD)\t70.4 (6.6)\t71.3 (6.8)\t\n ≥ 75 years, n (%)\t68 (27.8)\t86 (34.8)\t\n Japanese, n (%)\t245 (100.0)\t247 (100.0)\t\n Body mass index, kg/m2, mean (SD)\t21.4 (2.8)\t21.1 (2.9)\t\nT-score,a mean (SD)\t\n Lumbar spine\t− 2.45 (0.82)\t− 2.41 (0.90)\t\n Total hip\t− 2.44 (0.47)\t− 2.44 (0.48)\t\n Femoral neck\t− 2.82 (0.30)\t− 2.84 (0.30)\t\nBMD % young adult mean, mean (SD)\t\n Lumbar spine\t69.7 (9.9)\t70.2 (10.9)\t\n Total hip\t68.0 (5.9)\t68.0 (6.0)\t\n Femoral neck\t60.6 (4.0)\t60.2 (4.1)\t\nPrevalent vertebral fracture, n (%)\t\n 0\t193 (78.8)\t186 (75.3)\t\n 1\t35 (14.3)\t47 (19.0)\t\n ≥2\t11 (4.5)\t12 (4.9)\t\n Not readable/missing\t6 (2.4)\t2 (0.8)\t\nGrade of most severe vertebral fracture,b\nn (%)\t\n Mild\t29 (11.8)\t27 (10.9)\t\n Moderate/severe\t17 (6.9)\t32 (13.0)\t\n Nonvertebral fracture at ≥45 years of age, n (%)\t60 (24.5)\t53 (21.5)\t\n FRAX 10-year probability of major osteoporotic fracture, median (IQR)\t20.6 (14.8–27.9)\t21.6 (15.5–26.8)\t\n 25-hydroxyvitamin D, ng/mL, median (IQR)\t28.6 (23.8–33.8)\t29.6 (24.0–35.2)\t\nBMD bone mineral density, FRAX Fracture Risk Assessment Tool [22], IQR interquartile range, N number of subjects randomized, SD standard deviation\n\naDerived from Japanese reference ranges\n\nbThe most severe vertebral fracture was assessed with the use of the Genant semiquantitative grading scale\n\n\n\nBone mineral density\nAfter 12 months of romosozumab treatment, the mean increase in BMD from baseline was 15.2% at the lumbar spine (Fig. 2a), 5.3% at the total hip (Fig. 2b), and 5.4% at the femoral neck (Fig. 2c). Each of these increases was significantly different (P < 0.001) from the mean changes that occurred at 12 months in the placebo group (lumbar spine, 0.3%; total hip, 0.5%; and femoral neck, 0.8%). Even after subjects transitioned to denosumab, the percentage increases in BMD from baseline continued to favor the romosozumab-to-denosumab group over the placebo-to-denosumab group through 24 and 36 months. The mean increases in BMD at 36 months in the romosozumab-to-denosumab vs placebo-to-denosumab groups, respectively, were lumbar spine, 22.1% vs 9.5% (difference, 12.7%; P < 0.001); total hip, 8.7% vs 4.5% (difference, 4.2%; P < 0.001); and femoral neck, 8.6% vs 4.4% (difference, 4.1%; P < 0.001).Fig. 2 Percentage change from baseline in bone mineral density (BMD): effect of romosozumab (Romo) treatment for 12 months followed by denosumab (Dmab) treatment for 24 months. Least squares mean percentage changes at a lumbar spine, b total hip, and c femoral neck. n number of subjects with evaluable data at the time point, N number of subjects randomized, Pla placebo, QM once monthly, Q6M every 6 months. *Nominal P < 0.001 between treatment groups based on analysis of covariance model adjusting for treatment, age, prevalent vertebral fracture stratification variables, baseline value, machine type, and baseline value-by-machine type interaction\n\n\n\nIn the responder analysis after 12 months of treatment, lumbar spine BMD gains of ≥ 3%, ≥ 6%, and ≥ 10% from baseline, respectively, were achieved by 96.3%, 94.4%, and 80.6% of subjects in the romosozumab group and by 19.6%, 3.5%, and < 0.1% of subjects in the placebo group (Fig. 3a). Total hip BMD gains of ≥ 3%, ≥ 6%, and ≥ 10%, respectively, were achieved by 68.5%, 41.4%, and 9.1% of subjects in the romosozumab group and by 19.9%, 4.1%, and 0.4% of subjects in the placebo group (Fig. 3b). Each of the response rates for BMD was significantly greater in the romosozumab group than in the placebo group (P < 0.001).Fig. 3 Responder analysis of percentage change from baseline to 12 months in bone mineral density (BMD) for individual subjects. a Lumbar spine. b Total hip. The x axis represents each individual subject. Horizontal lines reflect 3%, 6%, and 10% responses relative to baseline. Arrowheads and values represent the percentage of subjects with the indicated percentage changes in BMD. N number of subjects with a baseline BMD assessment and at least one postbaseline BMD assessment at or before 12 months\n\n\n\nOf the subjects with a lumbar spine T-score of ≤ − 2.5 at baseline, a T-score of > − 2.5 at 12, 24, and 36 months, respectively, was observed for 67.3%, 85.7%, and 89.9% of subjects in the romosozumab-to-denosumab group and for 10.3%, 34.6%, and 43.4% of subjects in the placebo-to-denosumab group. Of the subjects with a total hip T-score of ≤ − 2.5 at baseline, a T-score of > − 2.5 at 12, 24, and 36 months, respectively, was observed for 42.7%, 58.5%, and 65.3% of subjects in the romosozumab-to-denosumab group and for 16.4%, 36.4%, and 44.9% of subjects in the placebo-to-denosumab group. At each assessment, the percentage of subjects with a positive shift in T-score was significantly greater in the romosozumab-to-denosumab group than in the placebo-to-denosumab group (P < 0.001).\n\nFracture risk\nRomosozumab treatment for 12 months was associated with a 55% lower risk of new vertebral fracture compared with placebo (P = 0.15; Fig. 4a). After all subjects transitioned to open-label denosumab treatment, romosozumab-to-denosumab had a lower risk of new vertebral fracture by 63% at both 24 and 36 months compared with placebo-to-denosumab (P = 0.070). The cumulative subject incidences of new vertebral fracture were 1.7% (4/237) at each time point in the romosozumab-to-denosumab group and 3.7% (9/243), 4.5% (11/243), and 4.5% (11/243) at 12, 24, and 36 months, respectively, in the placebo-to-denosumab group.Fig. 4 Fracture risk in Japanese postmenopausal women: effect of romosozumab or placebo for 12 months, followed by denosumab treatment in all subjects for 24 months. a Subject incidence and relative risk reduction (RRR), based on relative risks, for new vertebral fracture by study visit in the analysis set for vertebral fractures. b Subject incidence and RRR, based on hazard ratios, for key fracture endpoints in the full analysis set through 36 months. The last observation was carried forward for missing data. n number of subjects with fracture, N number of subjects analyzed, NE not evaluable\n\n\n\nThe risk for fracture by 36 months was lower in the romosozumab-to-denosumab group compared with the placebo-to-denosumab group by 30–78% for each fracture type examined (clinical (P = 0.072), nonvertebral (P = 0.12), major nonvertebral (P = 0.48), major osteoporotic (P = 0.53), and clinical new or worsening vertebral (P = 0.13); Fig. 4b). The risk for hip fracture was lower as well (0.8 vs 0.0%), but as no subject in the romosozumab-to-denosumab group had a hip fracture, no risk reduction or P value could be calculated. The subject incidence of fracture through 36 months was numerically lower in the romosozumab-to-denosumab group than in the placebo-to-denosumab group for all fracture types examined.\n\nIn the Kaplan-Meier time-to-event analyses for clinical fractures and nonvertebral fractures, cumulative fracture rates were lower through follow-up in the romosozumab-to-denosumab group than in the placebo-to-denosumab group (Online Resource 2). For each of these fracture types, separation of the curves for fracture incidence appeared within the first few months and the separation of the curves increased over time, even after all subjects had transitioned to denosumab treatment.\n\nSafety\nThe Japan safety analysis set included all 489 subjects in Japan (245 romosozumab, 244 placebo) who received at least one dose of study treatment. The incidences of adverse events through 36 months were overall balanced between the romosozumab-to-denosumab and placebo-to-denosumab groups (87.8% vs 89.8%; Table 2). The most commonly reported adverse events, which occurred with similar incidences in each group, were nasopharyngitis, back pain, fall, osteoarthritis, contusion, and constipation. Adverse events led to study drug discontinuation for 4.5% of subjects in the romosozumab-to-denosumab group and 4.9% of subjects in the placebo-to-denosumab group.Table 2 Subject incidence of treatment-emergent adverse events through 36 months\n\n\tPlacebo-to-denosumab (N = 244)\tRomosozumab-to-denosumab (N = 245)\t\nAny adverse event\t219 (89.8)\t215 (87.8)\t\nMost frequent adverse eventsa\t\n Nasopharyngitis\t91 (37.3)\t103 (42.0)\t\n Back pain\t31 (12.7)\t35 (14.3)\t\n Fall\t32 (13.1)\t30 (12.2)\t\n Osteoarthritis\t30 (12.3)\t29 (11.8)\t\n Contusion\t26 (10.7)\t29 (11.8)\t\n Constipation\t24 (9.8)\t28 (11.4)\t\n Any serious adverse event\t37 (15.2)\t39 (15.9)\t\n Any serious cardiovascular adverse eventb\t2 (0.8)\t3 (1.2)\t\n Death\t1 (0.4)\t2 (0.8)\t\n Cardiovascular deathb\t1 (0.4)\t2 (0.8)\t\n Leading to study drug discontinuation\t12 (4.9)\t11 (4.5)\t\n Leading to study discontinuation\t11 (4.5)\t12 (4.9)\t\nEvents of interestc\t\n Hypersensitivityd\t54 (22.1)\t46 (18.8)\t\n Osteoarthritis\t47 (19.3)\t51 (20.8)\t\n Hyperostosis\t10 (4.1)\t18 (7.3)\t\n Malignancy\t4 (1.6)\t9 (3.7)\t\n Injection-site reaction\t3 (1.2)\t8 (3.3)\t\n Osteonecrosis of the jawb\t0 (0.0)\t1 (0.4)\t\n Atypical femoral fractureb\t0 (0.0)\t0 (0.0)\t\n Hypocalcemia\t0 (0.0)\t0 (0.0)\t\nN number of subjects who were randomized and received at least one dose of the study drug in the 12-month double-blind study period. The subject incidence rates include all events that occurred in the 12-month double-blind period and, in addition, all events that occurred in the open-label and extension periods for those subjects who received at least one dose of denosumab\n\naMost frequent adverse events occurring in ≥ 10% of subjects in either treatment group\n\nbIncludes adverse events adjudicated positive by an independent adjudication committee. For cardiovascular deaths, includes fatal events adjudicated as cardiovascular-related or undetermined (presumed cardiac-related)\n\ncIdentified by prespecified Medical Dictionary for Regulatory Activities (MedDRA) search strategies using MedDRA version 19.1. Hypocalcemia, injection-site reaction, osteoarthritis, and hyperostosis include only treatment-emergent adverse events as a result of Amgen-defined MedDRA search strategies. Hypersensitivity and malignancy include only treatment-emergent adverse events as a result of a narrow search/scope in standardized MedDRA queries\n\ndSerious adverse events of hypersensitivity were reported in 1 subject who received romosozumab followed by denosumab occurring in the first 12 months and in 0 subjects who received placebo followed by denosumab\n\n\n\nThe subject incidence of any serious adverse event was 15.9% for romosozumab-to-denosumab and 15.2% for placebo-to-denosumab. Positively adjudicated cardiovascular death was reported for 2 (0.8%) subjects in the romosozumab-to-denosumab group (1 with congestive cardiomyopathy during the double-blind period and 1 with multiple organ dysfunction syndrome after the transition to denosumab) and 1 (0.4%) subject in the placebo-to-denosumab group (acute cardiac failure after the transition to denosumab). Investigators did not consider any of the fatal events to be related to study treatment. No other deaths were reported. Positively adjudicated nonfatal cardiovascular events were reported for 2 (0.8%) subjects in the romosozumab-to-denosumab group (1 with acute myocardial infarction during the double-blind period and 1 with cerebral hemorrhage after the transition to denosumab (this subject also had the fatal multiple organ dysfunction syndrome)) and 1 (0.4%) subject in the placebo-to-denosumab group (cerebral infarction during the double-blind period).\n\nThe subject incidences for adverse events of interest in the romosozumab-to-denosumab and placebo-to-denosumab groups were as follows: hypersensitivity (18.8% vs 22.1%), osteoarthritis (20.8% vs 19.3%), hyperostosis (7.3% vs 4.1%), malignancy (3.7% vs 1.6%), and injection-site reaction (3.3% vs 1.2%). Positively adjudicated osteonecrosis of the jaw occurred in 1 (0.4%) subject in the romosozumab-to-denosumab group and no subjects in the placebo-to-denosumab group. This case occurred after 12 months of romosozumab treatment and one dose of denosumab, following a tooth extraction and subsequent osteomyelitis of the jaw. No subject had a positively adjudicated atypical femoral fracture or hypocalcemia. Adverse events of hypersensitivity and injection-site reaction were mostly mild in severity, and none led to discontinuation of treatment in the romosozumab-to-denosumab group.\n\nBinding antibodies to romosozumab were observed at any time for 58 (23.7%) subjects in the romosozumab-to-denosumab group. Neutralizing antibodies to romosozumab developed at any time for 2 (0.8%) subjects in the romosozumab-to-denosumab group. Antibodies to romosozumab had no detectable effect on efficacy or safety.\n\nDiscussion\nIn this subgroup analysis of Japanese postmenopausal women with osteoporosis in the phase 3 FRAME trial, the outcomes for BMD, fracture risk, and safety through 36 months were consistent with those for the overall FRAME population [28, 29]. In both populations, subjects in the romosozumab-to-denosumab group showed significantly higher increases in BMD at the spine, total hip, and femoral neck at 12, 24, and 36 months than the subjects in the placebo-to-denosumab group, and the romosozumab-to-denosumab group had consistently lower fracture incidences for all fracture types evaluated. Compared with the overall population of FRAME, Japanese women had lower mean body mass index, higher prevalence of previous nonvertebral fracture at ≥ 45 years of age, and nearly double the median baseline FRAX 10-year probability of major osteoporotic fracture. Baseline T-scores and percentage changes from baseline for BMD at 12, 24, and 36 months at the total hip and femoral neck were similar between Japanese subjects and the overall FRAME population. Reference values for peak bone mass or young adult mean are lower in Japanese women than in Caucasian women, so the same T-score corresponds to a lower baseline BMD in Japanese women.\n\nBMD responder analyses and T-score shift analyses provided further evidence of the consistent bone-forming effect of romosozumab among Japanese postmenopausal women with osteoporosis. By 12 months, a meaningful gain of ≥ 3% for BMD at the lumbar spine was achieved by almost every woman in the romosozumab group and less than 20% of women in the placebo group; this included substantial gains of ≥ 10% in BMD at the lumbar spine for > 80% of women in the romosozumab group and < 1% of women in the placebo group. A working group from the American Society for Bone and Mineral Research and the United States National Osteoporosis Foundation developed principles of goal-directed treatment for osteoporosis that included freedom from fracture and a T-score > −2.5 [32]. In this study, romosozumab was associated with positive shifts at the lumbar spine from a T-score of ≤ − 2.5 at baseline to > − 2.5 at 12 months for more than 2 in 3 women, compared with approximately 1 in 10 women in the placebo group. Thus, as a result of the observed increases in BMD during romosozumab treatment, only one-third of Japanese subjects in the romosozumab group (vs 90% of subjects in the placebo group) still met the lumbar spine T-score criterion for osteoporosis at 12 months, when they transitioned to denosumab. Progressively, more women in each treatment group who started the study with a T-score of ≤ − 2.5 at baseline shifted to a T-score of > − 2.5 at 24 and 36 months. These findings suggest that romosozumab followed by denosumab is a promising treatment regimen to achieve treatment goals in Japanese postmenopausal women with osteoporosis.\n\nAs was observed in the overall population [28, 29], Japanese women in FRAME who received romosozumab during the first 12 months of the study had a lower risk of new vertebral fracture compared with women who received placebo during the first 12 months, but the subgroup analysis did not have adequate power to demonstrate statistically significant reductions in fracture risk. The relative risk reduction for this endpoint in the romosozumab-to-denosumab group compared with the placebo-to-denosumab group was 73% overall and 55% in Japanese women, reflecting similar trends. In both populations, the benefits for vertebral fractures persisted at 24 and 36 months, after all subjects from each treatment group transitioned to open-label antiresorptive treatment with denosumab. In each analysis, the romosozumab-to-denosumab group had lower subject incidences than the placebo-to-denosumab group at 36 months for all other fracture types examined. This study evaluated clinical fractures (including nonvertebral fractures and clinical vertebral fractures, defined as radiographically confirmed new or worsening vertebral fractures associated with back pain), nonvertebral fractures, and other fracture types (including major nonvertebral, major osteoporotic, clinical new or worsening vertebral, and multiple new or worsening vertebral fractures). In the overall FRAME population, risk reductions for fractures at 36 months favored the romosozumab-to-denosumab group over the placebo-to-denosumab group. Among Japanese women, the risk for nonvertebral fractures was 50% lower in the romosozumab-to-denosumab group, which did not achieve statistical significance.\n\nIn Japanese women, adverse events were generally similar between the treatment groups and were consistent with those of the overall FRAME population [28], including subject incidences of all adverse events, serious adverse events, adjudicated cardiovascular events, deaths, adjudicated cardiovascular deaths, events leading to study discontinuation, the most commonly reported events, and events of interest, which include hypocalcemia, hypersensitivity, injection-site reactions, malignancy, osteoarthritis, hyperostosis, atypical femoral fracture, and osteonecrosis of the jaw. Incidences of positively adjudicated cardiovascular events, deaths, and positively adjudicated cardiovascular deaths were low and similar between the romosozumab-to-denosumab and placebo-to-denosumab groups in Japanese subjects, as they were in the overall FRAME population. One case of osteonecrosis of the jaw was reported in a Japanese woman after romosozumab treatment and the first dose of denosumab, following a tooth extraction and subsequent osteomyelitis of the jaw. Antibodies to romosozumab had no detectable effect on efficacy or safety among Japanese women.\n\nThe main limitation of this analysis was the examination of a subgroup of subjects from an international study that was neither designed nor powered to demonstrate the safety and efficacy of the study treatment in this subgroup.\n\nWhile a majority of Japanese postmenopausal women with osteoporosis receive an antiresorptive agent as their initial treatment [24], the available evidence from global clinical research supports rebuilding the skeletal foundation with romosozumab, followed by antiresorptive therapy with denosumab. This treatment sequence offers patients rapid BMD increases and fracture reduction benefits that are sustained over time [7, 33]. In conclusion, outcomes for romosozumab-to-denosumab through 36 months in Japanese subjects were consistent with those in the overall FRAME population. Romosozumab, as a foundational bone-forming treatment, followed by denosumab, is a promising regimen for Japanese postmenopausal women with osteoporosis at high risk of fracture.\n\nElectronic Supplementary Material\n\nESM 1 (DOCX 183 kb)\n\n \n\n\nPublisher’s note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAmgen Inc. and UCB Pharma provided assistance with the preparation of the manuscript and funded all costs associated with the development of the manuscript. Jessica Ma (Amgen Inc.) and Jonathan Latham (PharmaScribe, LLC, on behalf of Amgen Inc.) provided medical writing assistance. We thank the subjects and investigators who were part of this study.\n\nFunding\nAmgen Inc., Astellas, and UCB Pharma sponsored this study (NCT01575834).\n\nData availability\nQualified researchers may request data from Amgen clinical studies. Complete details are available at the following: https://wwwext.amgen.com/science/clinical-trials/clinical-data-transparency-practices/.\n\nCompliance with ethical standards\nConflict of interest\nA Miyauchi received a research grant from Amgen Inc.; R Dinavahi, W Yang, and J Maddox are employees and shareholders of Amgen Inc.; DB Crittenden and A Grauer were employees and shareholders of Amgen Inc. at the time this study was conducted; E Hamaya is an employee of Amgen Astellas Biopharma KK and a shareholder of Amgen Inc.; Y Nakamura is an employee of Amgen Astellas Biopharma K.K. and shareholder of Astellas Pharma Inc.; J Shimauchi is an employee of Amgen Astellas Biopharma KK; and C Libanati is an employee and shareholder of UCB Pharma.\n\nEthical approval\nAll procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. An independent ethics committee or institutional review board approved the study design for each center.\n\nInformed consent\nInformed consent was obtained from each subject.\n==== Refs\nReferences\n1. Burge R Dawson-Hughes B Solomon DH Wong JB King A Tosteson A Incidence and economic burden of osteoporosis-related fractures in the United States, 2005-2025 J Bone Miner Res 2007 22 465 475 10.1359/jbmr.061113 17144789 \n2. Tajeu GS Delzell E Smith W Arora T Curtis JR Saag KG Morrisey MA Yun H Kilgore ML Death, debility, and destitution following hip fracture J Gerontol A Biol Sci Med Sci 2014 69 346 353 10.1093/gerona/glt105 23873945 \n3. Orimo H Yaegashi Y Hosoi T Fukushima Y Onoda T Hashimoto T Sakata K Hip fracture incidence in Japan: estimates of new patients in 2012 and 25-year trends Osteoporos Int 2016 27 1777 1784 10.1007/s00198-015-3464-8 26733376 \n4. Lyles KW Colon-Emeric CS Magaziner JS Adachi JD Pieper CF Mautalen C Hyldstrup L Recknor C Nordsletten L Moore KA Lavecchia C Zhang J Mesenbrink P Hodgson PK Abrams K Orloff JJ Horowitz Z Eriksen EF Boonen S Trial HRF Zoledronic acid and clinical fractures and mortality after hip fracture N Engl J Med 2007 357 1799 1809 10.1056/NEJMoa074941 17878149 \n5. Ryg J Rejnmark L Overgaard S Brixen K Vestergaard P Hip fracture patients at risk of second hip fracture: a nationwide population-based cohort study of 169,145 cases during 1977-2001 J Bone Miner Res 2009 24 1299 1307 10.1359/jbmr.090207 19257816 \n6. van Helden S Cals J Kessels F Brink P Dinant GJ Geusens P Risk of new clinical fractures within 2 years following a fracture Osteoporos Int 2006 17 348 354 10.1007/s00198-005-2026-x 16378167 \n7. Cosman F Nieves JW Dempster DW Treatment sequence matters: anabolic and antiresorptive therapy for osteoporosis J Bone Miner Res 2017 32 198 202 10.1002/jbmr.3051 27925287 \n8. Geusens P Marin F Kendler DL Russo LA Zerbini CA Minisola S Body JJ Lespessailles E Greenspan SL Bagur A Stepan JJ Lakatos P Casado E Moericke R Lopez-Romero P Fahrleitner-Pammer A Effects of teriparatide compared with risedronate on the risk of fractures in subgroups of postmenopausal women with severe osteoporosis: the VERO trial J Bone Miner Res 2018 33 783 794 10.1002/jbmr.3384 29329484 \n9. Johansson H Siggeirsdottir K Harvey NC Oden A Gudnason V McCloskey E Sigurdsson G Kanis JA Imminent risk of fracture after fracture Osteoporos Int 2017 28 775 780 10.1007/s00198-016-3868-0 28028554 \n10. Johnell O Kanis JA Oden A Sernbo I Redlund-Johnell I Petterson C De Laet C Jonsson B Fracture risk following an osteoporotic fracture Osteoporos Int 2004 15 175 179 10.1007/s00198-003-1514-0 14691617 \n11. Roux C Briot K Imminent fracture risk Osteoporos Int 2017 28 1765 1769 10.1007/s00198-017-3976-5 28236126 \n12. van Dort MJ Geusens P Driessen JH Romme EA Smeenk FW Wouters EF van den Bergh JP High imminent vertebral fracture risk in subjects with COPD with a prevalent or incident vertebral fracture J Bone Miner Res 2018 33 1233 1241 10.1002/jbmr.3429 29572955 \n13. Miyauchi A Matsumoto T Sugimoto T Tsujimoto M Warner MR Nakamura T Effects of teriparatide on bone mineral density and bone turnover markers in Japanese subjects with osteoporosis at high risk of fracture in a 24-month clinical study: 12-month, randomized, placebo-controlled, double-blind and 12-month open-label phases Bone 2010 47 493 502 10.1016/j.bone.2010.05.022 20580870 \n14. Reginster JY Sarlet N The treatment of severe postmenopausal osteoporosis : a review of current and emerging therapeutic options Treat Endocrinol 2006 5 15 23 10.2165/00024677-200605010-00003 16396515 \n15. van Geel TA van Helden S Geusens PP Winkens B Dinant GJ Clinical subsequent fractures cluster in time after first fractures Ann Rheum Dis 2009 68 99 102 10.1136/ard.2008.092775 18677009 \n16. Harrington JT Broy SB Derosa AM Licata AA Shewmon DA Hip fracture patients are not treated for osteoporosis: a call to action Arthritis Rheum 2002 47 651 654 10.1002/art.10787 12522840 \n17. Panneman MJ Lips P Sen SS Herings RM Undertreatment with anti-osteoporotic drugs after hospitalization for fracture Osteoporos Int 2004 15 120 124 10.1007/s00198-003-1544-7 14618302 \n18. Wilk A Sajjan S Modi A Fan CP Mavros P Post-fracture pharmacotherapy for women with osteoporotic fracture: analysis of a managed care population in the USA Osteoporos Int 2014 25 2777 2786 10.1007/s00198-014-2827-x 25112720 \n19. Hagino H Sawaguchi T Endo N Ito Y Nakano T Watanabe Y The risk of a second hip fracture in patients after their first hip fracture Calcif Tissue Int 2012 90 14 21 10.1007/s00223-011-9545-6 22076525 \n20. Yoshimura N Nakamura K Epidemiology of locomotive organ disorders and symptoms: an estimation using the population-based cohorts in Japan Clin Rev Bone Miner Metab 2016 14 68 73 10.1007/s12018-016-9211-7 27375371 \n21. Orimo H Nakamura T Hosoi T Iki M Uenishi K Endo N Ohta H Shiraki M Sugimoto T Suzuki T Soen S Nishizawa Y Hagino H Fukunaga M Fujiwara S Japanese 2011 guidelines for prevention and treatment of osteoporosis--executive summary Arch Osteoporos 2012 7 3 20 10.1007/s11657-012-0109-9 23203733 \n22. Kanis JA Johnell O Oden A Johansson H McCloskey E FRAX and the assessment of fracture probability in men and women from the UK Osteoporos Int 2008 19 385 397 10.1007/s00198-007-0543-5 18292978 \n23. Kanis JA Johansson H Oden A McCloskey EV The distribution of FRAX((R))-based probabilities in women from Japan J Bone Miner Metab 2012 30 700 705 10.1007/s00774-012-0371-3 22911378 \n24. Fujiwara S Miyauchi A Hamaya E Nicholls RJ Weston A Baidya S Pinto L Barron R Takada J Treatment patterns in patients with osteoporosis at high risk of fracture in Japan: retrospective chart review Arch Osteoporos 2018 13 34 10.1007/s11657-018-0443-7 29564555 \n25. Nakamura T Sugimoto T Nakano T Kishimoto H Ito M Fukunaga M Hagino H Sone T Yoshikawa H Nishizawa Y Fujita T Shiraki M Randomized Teriparatide [human parathyroid hormone (PTH) 1-34] Once-Weekly Efficacy Research (TOWER) trial for examining the reduction in new vertebral fractures in subjects with primary osteoporosis and high fracture risk J Clin Endocrinol Metab 2012 97 3097 3106 10.1210/jc.2011-3479 22723322 \n26. Padhi D Jang G Stouch B Fang L Posvar E Single-dose, placebo-controlled, randomized study of AMG 785, a sclerostin monoclonal antibody J Bone Miner Res 2011 26 19 26 10.1002/jbmr.173 20593411 \n27. McClung MR Grauer A Boonen S Bolognese MA Brown JP Diez-Perez A Langdahl BL Reginster JY Zanchetta JR Wasserman SM Katz L Maddox J Yang YC Libanati C Bone HG Romosozumab in postmenopausal women with low bone mineral density N Engl J Med 2014 370 412 420 10.1056/NEJMoa1305224 24382002 \n28. Cosman F Crittenden DB Adachi JD Binkley N Czerwinski E Ferrari S Hofbauer LC Lau E Lewiecki EM Miyauchi A Zerbini CA Milmont CE Chen L Maddox J Meisner PD Libanati C Grauer A Romosozumab treatment in postmenopausal women with osteoporosis N Engl J Med 2016 375 1532 1543 10.1056/NEJMoa1607948 27641143 \n29. Lewiecki EM Dinavahi RV Lazaretti-Castro M Ebeling PR Adachi JD Miyauchi A Gielen E Milmont CE Libanati C Grauer A One year of romosozumab followed by two years of denosumab maintains fracture risk reductions: results of the frame extension study J Bone Miner Res 2018 34 419 428 10.1002/jbmr.3622 30508316 \n30. Genant HK Wu CY van Kuijk C Nevitt MC Vertebral fracture assessment using a semiquantitative technique J Bone Miner Res 1993 8 1137 1148 10.1002/jbmr.5650080915 8237484 \n31. Soen S Fukunaga M Sugimoto T Sone T Fujiwara S Endo N Gorai I Shiraki M Hagino H Hosoi T Ohta H Yoneda T Tomomitsu T Diagnostic criteria for primary osteoporosis: year 2012 revision J Bone Miner Metab 2013 31 247 257 10.1007/s00774-013-0447-8 23553500 \n32. Cummings SR Cosman F Lewiecki EM Schousboe JT Bauer DC Black DM Brown TD Cheung AM Cody K Cooper C Diez-Perez A Eastell R Hadji P Hosoi T Jan De Beur S Kagan R Kiel DP Reid IR Solomon DH Randall S Goal-directed treatment for osteoporosis: a progress report from the ASBMR-NOF working group on goal-directed treatment for osteoporosis J Bone Miner Res 2017 32 3 10 10.1002/jbmr.3039 27864889 \n33. Cosman F Crittenden DB Ferrari S Khan A Lane NE Lippuner K Matsumoto T Milmont CE Libanati C Grauer A FRAME study: the foundation effect of building bone with 1 year of romosozumab leads to continued lower fracture risk after transition to denosumab J Bone Miner Res 2018 33 1219 1226 10.1002/jbmr.3427 29573473\n\n",
"fulltext_license": "CC BY",
"issn_linking": null,
"issue": "14(1)",
"journal": "Archives of osteoporosis",
"keywords": "Bone mineral density; Denosumab; Fracture; Japanese; Romosozumab",
"medline_ta": "Arch Osteoporos",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal; D015519:Bone Density; D050071:Bone Density Conservation Agents; D000069448:Denosumab; D004311:Double-Blind Method; D005260:Female; D005272:Femur Neck; D050723:Fractures, Bone; D006801:Humans; D007564:Japan; D008159:Lumbar Vertebrae; D008875:Middle Aged; D010024:Osteoporosis; D015663:Osteoporosis, Postmenopausal; D012306:Risk; D040242:Risk Reduction Behavior",
"nlm_unique_id": "101318988",
"other_id": null,
"pages": "59",
"pmc": null,
"pmid": "31168657",
"pubdate": "2019-06-05",
"publication_types": "D017428:Clinical Trial, Phase III; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial",
"references": "30508316;16378167;27864889;28236126;14618302;17144789;29564555;20593411;17878149;29329484;29573473;18677009;25112720;27641143;28028554;20580870;22723322;12522840;27925287;24382002;8237484;23203733;23553500;16396515;22911378;23873945;29572955;26733376;14691617;27375371;19257816;22076525;18292978",
"title": "Increased bone mineral density for 1 year of romosozumab, vs placebo, followed by 2 years of denosumab in the Japanese subgroup of the pivotal FRAME trial and extension.",
"title_normalized": "increased bone mineral density for 1 year of romosozumab vs placebo followed by 2 years of denosumab in the japanese subgroup of the pivotal frame trial and extension"
} | [
{
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"activesubstancename": "DENOSUMAB"
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... |
{
"abstract": "Cerebral venous sinus thrombosis (CVST) is an uncommon condition accounting for 0.5-1% of all strokes. It occurs more commonly in women, particularly in the age group of 20-40 years of age due to pregnancy and oral contraceptive use. Systemic anticoagulation is recommended as first line treatment but 10-20% of patients deteriorate despite medical treatment and require surgical or endovascular interventions. We summarize a 41-year-old female with a past medical history of acute disseminated encephalomyelitis who presented with headaches and worsening mental status. Further workup confirmed inferior sagittal sinus thrombus with intraventricular hemorrhage for which she was initiated on heparin continuous infusion. Due to worsening of clot burden and cerebral edema, a right frontal external ventricular drain was placed in addition to medical management of elevated ICP. Intravenous heparin infusion was stopped intermittently for such procedures. However, even when heparin was continued, sub-therapeutic and supra-therapeutic ranges were commonly observed, making anticoagulation management challenging. A new left-sided EVD had to be placed after increased IVH and worsening of hydrocephalus due to clotting. Due to patient's clinical worsening, a microcatheter was placed in the straight sinus and continuous alteplase via intra-sinus catheter was initiated at a rate of 1 mg/hour. This was continued for 72 hours in addition to the continuous heparin infusion. Additionally, she received intraventricular alteplase 1 mg x 3 doses for IVH. Unfortunately, she continued to deteriorate despite maximal medical therapy. She was made comfort care and expired.",
"affiliations": "Critical Care and Surgery Pharmacy, 1501Johns Hopkins Hospital, Baltimore MD, USA.;Division of Neuroscience Critical Care, Departments of Neurology, Neurosurgery, and Anesthesia and Critical Care Medicine, USA.;Critical Care and Surgery Pharmacy, 1501Johns Hopkins Hospital, Baltimore MD, USA.",
"authors": "Sullinger|Danine P|DP|https://orcid.org/0000-0002-5945-8935;Cho|Sung-Min|SM|https://orcid.org/0000-0002-5132-0958;Farrokh|Salia|S|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1177/0897190020958260",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0897-1900",
"issue": null,
"journal": "Journal of pharmacy practice",
"keywords": "alteplase; cerebral edema; cerebral venous sinus thrombosis (CVST); heparin; intraventricular hemorrhage (IVH)",
"medline_ta": "J Pharm Pract",
"mesh_terms": null,
"nlm_unique_id": "8900945",
"other_id": null,
"pages": "897190020958260",
"pmc": null,
"pmid": "32924755",
"pubdate": "2020-09-14",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Prolonged Intra-Sinus Alteplase Infusion in Severe Case of CVST.",
"title_normalized": "prolonged intra sinus alteplase infusion in severe case of cvst"
} | [
{
"companynumb": "US-MYLANLABS-2020M1086452",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
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{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "HEPARIN SODIUM"
},
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... |
{
"abstract": "An 11-year-old boy presented with an antimuscarinic toxidrome due to benztropine and risperidone ingestion. His delirium was prolonged and difficult to treat with benzodiazepines. Multiple doses of physostigmine successfully treated it. Benztropine is a potent antimuscarinic agent, whereas risperidone has not been reported to cause antimuscarinic toxicity. The use of physostigmine to treat benztropine intoxication in a pediatric patient has not previously been described. In this case, multiple doses were used and were well tolerated.",
"affiliations": "From the *Poison Control Center, University of Kansas Hospital, Kansas City, KS; †Department of Medicine/Pediatrics, and ‡Division of Medical Toxicology, Department of Emergency Medicine, University of California San Diego, San Diego, CA.",
"authors": "Thornton|Stephen L|SL|;Farnaes|Lauge|L|;Minns|Alicia|A|",
"chemical_list": "D002800:Cholinesterase Inhibitors; D018727:Muscarinic Antagonists; D001590:Benztropine; D010830:Physostigmine",
"country": "United States",
"delete": false,
"doi": "10.1097/PEC.0000000000000503",
"fulltext": null,
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"issn_linking": "0749-5161",
"issue": "32(4)",
"journal": "Pediatric emergency care",
"keywords": null,
"medline_ta": "Pediatr Emerg Care",
"mesh_terms": "D001590:Benztropine; D002648:Child; D002800:Cholinesterase Inhibitors; D003693:Delirium; D006801:Humans; D008297:Male; D018727:Muscarinic Antagonists; D010830:Physostigmine",
"nlm_unique_id": "8507560",
"other_id": null,
"pages": "243-5",
"pmc": null,
"pmid": "26383155",
"pubdate": "2016-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Prolonged Antimuscarinic Delirium in a Child Due to Benztropine Exposure Treated With Multiple Doses of Physostigmine.",
"title_normalized": "prolonged antimuscarinic delirium in a child due to benztropine exposure treated with multiple doses of physostigmine"
} | [
{
"companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2016US-116710",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BENZTROPINE"
},
"dru... |
{
"abstract": "To evaluate whether patients with external sphincter invasion have a better prognosis than patients with invasion of other organs.\n\n\n\nPatients with cT4b adenocarcinoma of the rectum were treated with a tri-modality approach, including neo-adjuvant chemoradiotherapy (CRT), surgery and adjuvant chemotherapy. Patients with external sphincter invasion were classified as cT4b1, whereas patients with invasion of other organs as cT4b2. Survival curves were compared for cT4b sub-stage.\n\n\n\nBetween January 2008 and December 2014, a total of 21 consecutive patients with cT4b disease (14 with cT4b1 and seven with cT4b2) were treated with CRT, followed by surgery and adjuvant chemotherapy. In total, the overall survival rate at 5 years was 57.4%, whereas 5-year disease-free survival was 52%. The 5-year overall survival rates were 65.3% and 44.4% for patients with cT4b1 and cT4b2 disease, respectively.\n\n\n\nExternal sphincter invasion seems to be associated with a better prognosis when compared to primary lesion with extension to other organs.",
"affiliations": "Department of Radiotherapy, Policlinico Umberto I Sapienza University of Rome, Rome, Italy fradefelice@hotmail.it.;Department of Radiotherapy, Policlinico Umberto I Sapienza University of Rome, Rome, Italy.;Department of Radiotherapy, Policlinico Umberto I Sapienza University of Rome, Rome, Italy.;Department of Radiotherapy, Policlinico Umberto I Sapienza University of Rome, Rome, Italy.;Department of Radiotherapy, Policlinico Umberto I Sapienza University of Rome, Rome, Italy.;Department of Radiotherapy, Policlinico Umberto I Sapienza University of Rome, Rome, Italy.;Department of Radiotherapy, Policlinico Umberto I Sapienza University of Rome, Rome, Italy.",
"authors": "DE Felice|Francesca|F|;Musio|Daniela|D|;Benevento|Ilaria|I|;Magnante|Annalisa|A|;Bulzonetti|Nadia|N|;Rossella|Caiazzo|C|;Tombolini|Vincenzo|V|",
"chemical_list": null,
"country": "Greece",
"delete": false,
"doi": "10.21873/anticanres.11123",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0250-7005",
"issue": "36(10)",
"journal": "Anticancer research",
"keywords": "Rectal cancer; cT4; organ invasion; prognosis; radiotherapy; sphincter",
"medline_ta": "Anticancer Res",
"mesh_terms": "D000368:Aged; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D012004:Rectal Neoplasms; D012189:Retrospective Studies; D015996:Survival Rate; D016896:Treatment Outcome",
"nlm_unique_id": "8102988",
"other_id": null,
"pages": "5443-5447",
"pmc": null,
"pmid": "27798913",
"pubdate": "2016-10",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Influence of Organ Invasion in Clinical Outcomes for Locally Advanced Rectal Cancer.",
"title_normalized": "influence of organ invasion in clinical outcomes for locally advanced rectal cancer"
} | [
{
"companynumb": "IT-ACCORD-047136",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "OXALIPLATIN"
},
"drugadditional": "3",
"drug... |
{
"abstract": "Statistical screening of Vigibase, the global database of individual case safety reports, highlighted an association between the MedDRA Preferred Term (PT) \"colitis\" and nintedanib. Nintedanib is a protein kinase inhibitor authorized in accelerated regulatory procedures for the treatment of idiopathic pulmonary fibrosis (IPF). The aim of this report is to describe the integration of two types of real-world evidence, spontaneous reports of adverse drug reactions (ADR), and observational health data (OHD) in the assessment of a post-authorization safety signal of ischemic colitis.\n\n\n\nAssessment of the statistical signal of \"nintedanib - colitis\" was undertaken using data from VigiBase, OHD from the Observational Heath Data Sciences and Informatics (OHDSI) collaborative, published literature, and openly available regulatory documents. Evidence synthesis was performed to support Bradford Hill criteria in causality assessment.\n\n\n\nEvidence for strength of association, specificity, consistency, and analogy was found upon review of the case series. OHD was used to calculate incidence rates of colitis in new users of nintedanib across multiple populations, supportive of consistency, and further evidence for strength of association. Literature review identified support for biological plausibility and analogy. Signal assessment was supplemented with characterization of real-world users and exploration of potential risk factors using OHD.\n\n\n\nAn integrated approach using two forms of real-world data, spontaneous reports of ADRs and data from observational databases allowed a comprehensive and efficient signal assessment of nintedanib and colitis. Further exploration of the complementary use of real-time OHD in signal assessment could inform more efficient approaches to current signal management practices.",
"affiliations": "Uppsala Monitoring Centre, Uppsala, Sweden.",
"authors": "Chandler|Rebecca E|RE|0000-0002-9334-9046",
"chemical_list": "D007211:Indoles; D047428:Protein Kinase Inhibitors; C530716:nintedanib",
"country": "England",
"delete": false,
"doi": "10.1002/pds.5022",
"fulltext": "\n==== Front\nPharmacoepidemiol Drug Saf\nPharmacoepidemiol Drug Saf\n10.1002/(ISSN)1099-1557\nPDS\nPharmacoepidemiology and Drug Safety\n1053-8569 1099-1557 John Wiley & Sons, Inc. Chichester, UK \n\n10.1002/pds.5022\nPDS5022\nBrief Report\nBrief Reports\nNintedanib and ischemic colitis: Signal assessment with the integrated use of two types of real‐world evidence, spontaneous reports of suspected adverse drug reactions, and observational data from large health‐care databases\nChandlerChandler Rebecca E. https://orcid.org/0000-0002-9334-9046\n1\nrebecca.chandler@who-umc.org \n1 \nUppsala Monitoring Centre\nUppsala\nSweden\n\n* Correspondence\n\nRebecca E. Chandler, Uppsala Monitoring Centre, Uppsala, Sweden.\n\nEmail: rebecca.chandler@who-umc.org\n\n12 5 2020 \n8 2020 \n29 8 10.1002/pds.v29.8951 957\n31 3 2020 20 4 2020 © 2020 Uppsala Monitoring Centre. Pharmacoepidemiology and Drug Safety 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\nPurpose\nStatistical screening of Vigibase, the global database of individual case safety reports, highlighted an association between the MedDRA Preferred Term (PT) “colitis” and nintedanib. Nintedanib is a protein kinase inhibitor authorized in accelerated regulatory procedures for the treatment of idiopathic pulmonary fibrosis (IPF). The aim of this report is to describe the integration of two types of real‐world evidence, spontaneous reports of adverse drug reactions (ADR), and observational health data (OHD) in the assessment of a post‐authorization safety signal of ischemic colitis.\n\nMethods\nAssessment of the statistical signal of “nintedanib – colitis” was undertaken using data from VigiBase, OHD from the Observational Heath Data Sciences and Informatics (OHDSI) collaborative, published literature, and openly available regulatory documents. Evidence synthesis was performed to support Bradford Hill criteria in causality assessment.\n\nResults\nEvidence for strength of association, specificity, consistency, and analogy was found upon review of the case series. OHD was used to calculate incidence rates of colitis in new users of nintedanib across multiple populations, supportive of consistency, and further evidence for strength of association. Literature review identified support for biological plausibility and analogy. Signal assessment was supplemented with characterization of real‐world users and exploration of potential risk factors using OHD.\n\nConclusions\nAn integrated approach using two forms of real‐world data, spontaneous reports of ADRs and data from observational databases allowed a comprehensive and efficient signal assessment of nintedanib and colitis. Further exploration of the complementary use of real‐time OHD in signal assessment could inform more efficient approaches to current signal management practices.\n\npharmacoepidemiologypharmacovigilancereal‐world evidencesignal detection source-schema-version-number2.0cover-dateAugust 2020details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:5.9.0 mode:remove_FC converted:11.09.2020\n\n\nChandler \nRE \n. Nintedanib and ischemic colitis: Signal assessment with the integrated use of two types of real‐world evidence, spontaneous reports of suspected adverse drug reactions, and observational data from large health‐care databases\n. Pharmacoepidemiol Drug Saf . 2020 ;29 :951 –957\n. 10.1002/pds.5022 \n32399991\n==== Body\n1 KEY POINTS\n\nA causal relationship between ischemic colitis and nintedanib is hypothesized\n\nComplementary use of two types of real‐world evidence, spontaneous reports of ADR, and claims data from observational databases can be used in signal assessment\n\n“Real‐time evidence synthesis” has the potential to increase the efficiency in the system to act on post‐marketing safety signals.\n\n\n\n\n2 INTRODUCTION\nNintedanib is a small molecule receptor tyrosine kinase inhibitor (TKI) blocking vascular endothelial growth factor receptors (VEGFR 1‐3), fibroblast growth factor receptors (FGFR 1‐3), and platelet‐derived growth factor receptors (PDGFR) α and β kinase activity. It received marketing approval from the European Medicines Agency (EMA) and the United States Food and Drug Administration (USFDA) in 2014 for the treatment of IPF, a rare disease characterized by an excess of fibroblasts, leading to progressive fibrosis of the lung. Marketing approval was granted by the EMA after an accelerated assessment and the USFDA after a priority review; less than 1000 patients received nintedanib in pivotal trials that provided the basis for licensure. 1, 2\n\n\nIschemic colitis is a condition caused by insufficient blood flow to the large intestine, which results in mucosal ulceration, inflammation, and hemorrhage. Causes are physiological (hypotension, secondary to embolus/thrombosis) or iatrogenic (secondary to medicines, surgery). Ischemic colitis manifests with diarrhea, colicky abdominal pain, and rectal bleeding. Patients with ischemic colitis should be recognized quickly, as colonoscopic evaluation is recommended within 48 hours of symptom onset. Colonoscopy can distinguish those cases that may be treated with conservative management from those that require emergency resection. The complications arising from ischemic colitis include obstruction, necrosis, and perforation.\n3\n\n\n\nThe aim of this report is to describe the assessment of a signal of colitis and nintedanib with the complementary use of spontaneous reports of ADRs and OHD.\n\n3 METHODS\nStatistical screening in VigiBase using the VigiRank algorithm\n4\n was performed in December 2019 and highlighted the drug‐adverse event (AE) combination of “nintedanib – colitis” for review. The drug‐AE pair was assessed for the potential for a causal relationship using the Bradford Hill criteria.\n5\n Additional analyses within VigiBase and several observational databases (insurance claims databases from the US) available via the Observational Heath Data Sciences and Informatics (OHDSI) collaborative,\n6\n as well as reviews of the licensure application and published medical literature, were performed to explore the potential for a causal relationship between nintedanib and colitis.\n\n4 RESULTS\nClinical review of the 25 individual case safety reports (ICSRs) for the drug‐AE pair revealed different types of colitis, such as ischemic or inflammatory, or was further unspecified. Given that nintedanib acts upon the VEGF receptor, the association between nintedanib and the more specific clinical concept of “ischemic colitis” was explored.\n\nOne case from the original “colitis” case series had information sufficient to be considered as “ischemic colitis” (colonoscopy results were provided). Subsequent exploration within VigiBase used the MedDRA SMQ, ischemic colitis (narrow); nine additional cases were identified. The final case series of ischemic colitis included a total of 10 cases coded to different MedDRA PT: five cases of “colitis ischemic,” two of “intestinal ischemia,” one reporting both “colitis ischemic” and “intestinal ischemia,” one of “intestinal infarction,” and one of “colitis.”\n\nWithin these 10 reports, seven reports described males and three described females (Table 1). Ages ranged between 53 and 78; age was not included in one report. Reports originated from five countries (one country in the Americas, three countries in Europe, and one country in Asia). Time to onset was from 3 days to 5 months. In seven cases, the indication for nintedanib was IPF; in the three other cases, non‐small cell lung cancer, bronchial carcinoma, and glioblastoma. Diagnostic results were reported in three cases (6, 8, and 10). Fatal outcomes were reported in four cases. Limited additional information was available in most cases given that narratives had not been shared into Vigibase. Potential confounding/risk factors for ischemic colitis were advanced age, concomitant use of corticosteroids in two cases (1 and 5) and medical history of hyperlipidemia in two cases (2 and 5).\n\nTABLE 1 Individual case safety reports included in the relevant case series identified from Vigibase\n\nCase\tAge/sex\tDrugs\tIndication\tADR\tDosage\tTTO\tOutcome\tNotes\t\n1\t78y/M\t\nNintedanib (S)\n\n\nPrednisolone (S)\n\n\nAcetylcysteine (C)\n\n\nDimemorfan (C)\n\n\nDrug not accepted in WHODrug (C)\n\n\n\tIdiopathic pulmonary fibrosis\tIschemic enterocolitis\t300 mg qd × 2 months, 200 mg qd × + months\t15 days\tRecovered\t\n55 kg, 159 cm\n\n\nReport from study\n\n\n\t\n2\t74y/M\t\nNintedanib (S)\n\n\nVonoprazan (C)\n\n\nIrbesartan; Trichlormethiazide (C)\n\n\nAtorvastatin (C)\n\n\nAcetylsalicylic acid (C)\n\n\n\tIdiopathic pulmonary fibrosis\t\nColitis ischemic\n\n\nPneumonia bacterial\n\n\n\t\n300 mg qd × 11 months\n\n\n200 mg × qd × 2 months\n\n\n\t3 days\tRecovered\t\n62.9 kg, 165 cm\n\n\nReport from study\n\n\n\t\n3\t65y/F\t\nNintedanib (S)\n\n\nAlfacalcidol (C)\n\n\nLevothyroxine (C)\n\n\nAscorbic acid; pantothenic acid (C)\n\n\nMinodronic acid (C)\n\n\nDrug not accepted in WHODrug (C)\n\n\n\tIdiopathic pulmonary fibrosis\tColitis ischemic\t300 mg qd × 10 months\t4 months\tNot recovered\t\n50.5 kg, 161 cm\n\n\nReport from study\n\n\n\t\n4\t77y/M\t\nNintedanib (S)\n\n\nInsulin (C)\n\n\n\tIdiopathic pulmonary fibrosis\t\nColitis ischemic\n\n\nAbnormal loss of weight\n\n\nSeptic shock\n\n\nDecreased appetite\n\n\nVomiting\n\n\nNausea\n\n\nDiarrhea\n\n\n\t150 mg 2 per day\t\tDied\t\t\n5\t78y/F\t\nNintedanib (S)\n\n\nTacrolimus (C)\n\n\nPrednisolone (C)\n\n\nTrimethoprim/sulfamethaxazole (C)\n\n\nWarfarin (C)\n\n\nAlfacalcidiol (C)\n\n\nRabeprazole (C)\n\n\nLoperamide (C)\n\n\nDrug not accepted in WHODrug (C)\n\n\nDrug not accepted in WHODrug (C)\n\n\nDrug not accepted in WHODrug (C)\n\n\nDrug not accepted in WHODrug (C)\n\n\n\tIdiopathic pulmonary fibrosis\tIschemic enterocolitis\t200 mg qd × 5 months\t5 months\tDied secondary to ischemic entercolitis and lower gastrointestinal perforation\t\n36 kg/153 cm\n\n\nReport from study.\n\n\nHistory of hyperlipidemia, osteoporosis, gastroesophageal reflux disease, venous thrombosis, constipation, insomnia, chronic gastritis, and breast cancer\n\n\n\t\n6\t53y/M\tNintedanib (S)\tGlioblastoma\t\nMesenteric ischemia\n\n\nColitis ischemic\n\n\nObstipation\n\n\nStomach pain\n\n\nThromboembolic event Ischemia peripheral\n\n\nWound healing delayed\n\n\nWound infection\n\n\n\t400 mg per day\t27 days\tDied\t\n185 cm\n\n\nReport from study.\n\n\nPatient presented with abdominal pain 27 days after initiation on nintedanib. Admitted to hospital, diagnosed with ischemic colitis (grade 2), and treated with mesalazin. Five days later, the patient experienced obstipation. Ten days later, the patient had stomach pain (grade 3), acute mesenteric ischemia (grade 4), thromboembolic event (grade 4), and peripheral ischemia (grade 3). Had thromobectomy of arteria mesenterica superior, explorative laparotomy, and small intestinal segment resection. Hospitalization complicated by wound healing disorder, which led to cardiovascular failure, sepsis, and death.\n\n\n\t\n7\t‐/M\t\nNintedanib (S)\n\n\nOmeprazole (S)\n\n\nIndacaterol (C)\n\n\nOlmesartan (C)\n\n\nSalbutamol (C)\n\n\nLercanidipine (C)\n\n\n\tFibrosis lung\t\nBowel ischemia\n\n\nVein thrombosis mesenteric\n\n\n\t2 DF per day\t\tRecovering\t\t\n8\t56y/F\t\nNintedanib (S)\n\n\nDocetaxel (S)\n\n\nZoledronic acid (C)\n\n\nLevothyroxine (C)\n\n\n\tBronchial carcinoma\t\nIntestinal ischemia\n\n\nBowel ischemia\n\n\nGastrointestinal necrosis\n\n\nNecrosis bowel\n\n\n\t400 mg per day\t20 days\tUnknown\t\nSurgery preparation of colon descendens, sigmoideum, and upper rectum with intense and distinct ischemic necrosis of gut wall, inclusion of max.\n\n\n2.3 cm polyp, without evidence of vital mucosa. Beside a 0.9 cm in sano resected tubular adenoma with slight intraepithelial neoplasia (low‐grade adenoma following WHO‐classification). Transmural hemorrhagic necrosis (reaching out up to the resection area) of gut wall without inflammation, as appropriate for ischemia.\n\n\n\t\n9\t74y/M\t\nNintedanib (S)\n\n\nLansoprazole (C)\n\n\n\tIdiopathic pulmonary fibrosis\tIntestinal infarction\t\t\tDied\t69 kg\t\n10\t57 y/M\t\nNintedanib (S)\n\n\nIpratropium (C)\n\n\nAcetylsalicyclic acid (C)\n\n\nGlyceryl trinitrate (C)\n\n\nFluvastatin (C)\n\n\nTorasemide (C)\n\n\nLormetazepam (C)\n\n\nMetamizole (C)\n\n\nOmeprazole (C)\n\n\n\tNon‐small cell lung cancer\t\nColitis\n\n\nDiarrhea\n\n\nNausea\n\n\nMucositis\n\n\nAnorexia\n\n\nRespiratory failure\n\n\n\t\t9 days\t\t\nSerious. Clinical trial patient. Died, cause of death “respiratory failure”\n\n\nMedical history:\n\n\nIdiopathic cardiomyopathy\n\n\nBronchial disorder\n\n\nInsomnia\n\n\nPain\n\n\nSmoker\n\n\nAlcohol abuse\n\n\nPatient experienced diarrhea and vomiting which required hospitalization 10 days after initiation of drug. CT scan of abdomen on day of admission with probably stenosis lesion of the sigmoid colon and proximal colonic dilation and loops of small bowel. Colonoscopy 11 days after discontinuation of drug revealed ischemic colitis. Repeat CT 16 days after discontinuation revealed no evidence of obstruction.\n\n\nInvestigator considered that there is a causal relationship between the drug and GI symptoms and signs.\n\n\n\t\n(C), drug concomitantly administered with suspected drug. (S), drug suspected to be associated with reported adverse drug reaction (ADR).\n\nObservational data were used to explore “real‐world use” of nintedanib after marketing approval. Use of nintedanib started in 2014 with most users in the 70‐ to 80‐year age range and in more males than females. New users of nintedanib had no prior history of colitis and did not significantly differ from users of the alternative therapy for IPF, pirfenidone.\n\nFurther signal assessment included synthesis of data from ICSRs and the ODH as well as published literature in the consideration of the Bradford Hill criteria. The biologic plausibility is supported by the inhibitory action of nintedanib on the VEGF receptor. VEGF is a protein that mediates multiple functions within the vascular system, including endothelial cell proliferation as well as vascular permeability and vasodilation.\n7\n A mouse model has shown that inhibition of VEGF signaling resulted in regression of capillaries of intestinal villi,\n8\n and VEGF inhibition could contribute to perforation by inducing regression of normal blood vessels in the gastrointestinal tract\n9\n (presumptively via an intermediate step of ischemia). Specificity was explored in the spontaneous database using the MedDRA SMQ “ischemic colitis”; evidence of disproportionality was found for multiple PTs within this SMQ, including “colitis ischemic” (IC025 0.32), “large intestine perforation” (IC025 1.67), and “large intestinal hemorrhage” (IC025 0.39). Evidence for strength of association is found in the disproportionality in Vigibase and measures of incidence from observational data (eg, 56.74 cases per 1000 person‐years from one insurance system). Consistency is found in both ICSRs (reports from numerous countries) and OHD (increased incidence observed in multiple insurance systems). A consideration of analogy is feasible given the availability of other antiangiogenic agents which antagonize VEGF (aflibercept and bevacizumab) or inhibit the VEGF receptor (regorafenib and sorafenib). Literature review reveals case reports of ischemic colitis with aflibercept\n10\n and bevacuzimab,\n11\n both administered intravitreally. Data mining within Vigibase reveals disproportional reporting of MedDRA PT within the “ischemic colitis” SMQ for a number of other analogous agents: (bevacizumab: intestinal ischemia 2.23; colitis ischemic 2.18; aflibercept: colitis ischemic 0.66; midostaurin: intestinal ischemia 0.42; ranibizumab: intestinal ischemia 0.38; sunitinib: intestinal ischemia 0.23; and sorafenib: colitis ischemic 0.18).\n\nAdditionally, OHD could allow for a preliminary estimation of the incidence risk ratio from a self‐controlled “pre‐exposure” comparative cohort.\n\n5 DISCUSSION\nComplementary use of two types of real‐world evidence, ICSRs and ODH, supports the hypothesis of a causal relationship between nintedanib and ischemic colitis. Integration of evidence from the case series and explorations of observational data in “real‐time” allowed for a comprehensive and efficient review of the points to consider in signal assessment, such as a characterization of real‐world users, exploration of potential confounders, and evidence in support Bradford Hill causality criteria. Communication of this signal is considered warranted as early identification of ischemia may prevent progression to the serious, life‐threatening event of gastrointestinal perforation. Given that the most commonly occurring gastrointestinal adverse reaction for nintedanib is diarrhea, which can be a symptom of ischemic colitis, it could be important to inform health‐care providers to rule out ischemia prior to the recommended symptomatic treatment of diarrhea with loperamide.\n\nAn important limitation in this pilot study was the differences in the amounts of data and medical terminology between the different data sources. For example, further specification of “colitis” was not possible in the OHD due to the relatively small number of patients taking nintedanib. Furthermore, clinical reasoning is required to translate signals identified in MedDRA terminology into explorations of databases using ICD coding.\n\nSeveral publications have explored different approaches to the use of observational data in signal detection. A large European initiative, the EU‐ADR project, has explored the use of real‐world healthcare data in signal detection; the findings revealed that potential for signal detection within real‐world data was found to be dependent on frequency of the event and utilization of drugs in the general population.\n12\n Other proposals have included a signal detection strategy that requires signaling from both an adverse event reporting system and electronic health records\n13\n and the use of electronic medical records for placing signals, which have been highlighted by individual case safety reports, within clinical context. \n14\n\n\n\nAs noted in a piece by Trifuro et al, “To harness the potential of big data in pharmacovigilance, it is important to use complementary methods and data sources that play on their respective strengths.”\n15\n This signal assessment is intended as a proof‐of‐concept example of how an analysis of individual cases and observational data can be synthesized into evidence to support a causal hypothesis. Further exploration of the complementary use of observational data in signal assessment should be performed to inform more efficient approaches to current signal management practices.\n\nCONFLICTS OF INTEREST\nThe opinions expressed in this piece are not necessarily those of the national pharmacovigilance centers of the WHO Program for International Drug Monitoring or of the WHO. The author has no conflicts of interest that are directly relevant to the content of this piece.\n\nACKNOWLEDGEMENTS\nThe author wishes to thank Patrick Ryan of the Observational Health Data Sciences and Informatics for his collaboration in our signal detection exercise and his genuine enthusiasm in the strength of spontaneous data and the knowledge we can share from the UMC. The author also wishes to thank Niklas Norén and Pia Caduff‐Janosa for their help in the preparation of the manuscript as well as the national pharmacovigilance centers participating in the WHO Program for International Drug Monitoring.\n==== Refs\nREFERENCES\n1 \nEuropean Medicines Agency \n. Ofev. Assessment report. Procedure No. EMEA/H/C/003821/0000. Available at: https://www.ema.europa.eu/en/documents/assessment-report/ofev-epar-public-assessment-report_en.pdf. Accessed January 16, 2020.\n2 \nFDA \n. Highlights of Prescribing Information. Ofev. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/205832s012lbl.pdf. Accessed January 16, 2020.\n3 \n\nTrotter \nJM \n, \nPeter \nMB \n. Ischaemic colitis\n. BMJ . 2016 ;355 :i6600.28007701 \n4 \n\nCaster \nO \n, \nJuhlin \nK \n, \nWatson \nS \n, \nNorén \nGN \n. Improved statistical signal detection in pharmacovigilance by combining multiple strength‐of‐evidence aspects in VigiRank\n. Drug Saf . 2014 ;37 (8 ):617 ‐628\n.25052742 \n5 \n\nPerrio \nM \n, \nVoss \nS \n, \nShakir \nSA \n. Application of the Bradford Hill criteria to assess the causality of cisapride‐induced arrhythmia: a model for assessing causal association in pharmacovigilance\n. Drug Saf . 2007 ;30 (4 ):333 ‐346\n.17408310 \n6 \n\nHripcsak \nG \n, \nDuke \nJD \n, \nShah \nNH \n, et al. Observational health data sciences and informatics (OHDSI): opportunities for observational researchers\n. Stud Health Technol Inform . 2015 ;216 :574 ‐578\n.26262116 \n7 \n\nEllis \nLM \n, \nHicklin \nDL \n. VEGF‐targeted therapy: mechanisms of anti‐tumour activity\n. Nat Rev Cancer . 2008 ;8 :579 ‐591\n.18596824 \n8 \n\nKamba \nT \n, \nTam \nBY \n, \nHashizume \nH \n, et al. VEGF‐dependent plasticity of fenestrated capillaries in the normal adult microvasculature\n. Am J Physiol . 2006 ;290 (2 ):H560 ‐H5766\n.\n9 \n\nSaif \nMW \n, \nElfiky \nA \n, \nSalem \nRR \n. Gastrointestinal perforation due to bevacizumab in colorectal cancer\n. Ann Surg Oncol . 2007 ;14 :1860 ‐1869\n.17356952 \n10 \n\nBatteux \nB \n, \nGras \nV \n, \nMahboud \nY \n, et al. Ischemic colitis associated with intravitreal administration of aflibercept: a first case report\n. Br J Clin Pharmacol . 2019 ;4 :845 –848\n.\n11 \n\nOnoda \nY \n, \nShiba \nT \n, \nHori \nY \n, \nMaeno \nT \n, \nTakahashi \nM \n. Two cases of acute abdomen after an intravitreal injection of bevacizumab\n. Case Rep Ophthalmol . 2015 ;6 (1 ):110 ‐114\n.25960733 \n12 \n\nPatadia \nVK \n, \nColoma \nP \n, \nSchuemie \nMJ \n, et al. Using real‐world healthcare data for pharmacovigilance signal detection ‐ the experience of the EU‐ADR project\n. Expert Rev Clin Pharmacol . 2015 ;8 (1 ):95 ‐102\n.25487079 \n13 \n\nHarpaz \nR \n, \nVilar \nS \n, \nDumouchel \nW \n, et al. Combing signals from spontaneous reports and electronic health records for detection of adverse drug reactions\n. J Am Med Inform Assoc . 2018 ;20 :413–419.\n14 \n\nStar \nK \n, \nWatson \nS \n, \nSandberg \nL \n, \nJohansson \nJ \n, \nEdwards \nIR \n. Longitudinal medical records as a complement to routine drug safety signal analysis\n. Pharmacoepidemiol Drug Saf . 2015 ;24 (5 ):486 ‐494\n.25623045 \n15 \n\nTrifirò \nG \n, \nSultana \nJ \n, \nBate \nA \n. From big data to smart data for pharmacovigilance: the role of healthcare databases and other emerging sources\n. Drug Saf . 2018 ;41 (2 ):143 ‐149\n.28840504\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1053-8569",
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"journal": "Pharmacoepidemiology and drug safety",
"keywords": "pharmacoepidemiology; pharmacovigilance; real-world evidence; signal detection",
"medline_ta": "Pharmacoepidemiol Drug Saf",
"mesh_terms": "D000368:Aged; D001208:Asia; D017091:Colitis, Ischemic; D016208:Databases, Factual; D064420:Drug-Related Side Effects and Adverse Reactions; D005060:Europe; D005260:Female; D006801:Humans; D007211:Indoles; D008297:Male; D008875:Middle Aged; D064887:Observational Studies as Topic; D060735:Pharmacovigilance; D047428:Protein Kinase Inhibitors; D014481:United States",
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"title": "Nintedanib and ischemic colitis: Signal assessment with the integrated use of two types of real-world evidence, spontaneous reports of suspected adverse drug reactions, and observational data from large health-care databases.",
"title_normalized": "nintedanib and ischemic colitis signal assessment with the integrated use of two types of real world evidence spontaneous reports of suspected adverse drug reactions and observational data from large health care databases"
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"abstract": "Gemcitabine is a commonly used antineoplastic agent used to treat a variety of cancers with rarely reported cardiac side effects. We describe a case of a 67-year-old woman with follicular lymphoma who experienced a rarely reported side effect of gemcitabine: cardiomyopathy. This case highlights a multiple hit mechanism of myocyte damage that may occur following the use of multiple cardio-toxic agents despite their administration in doses not associated with cardiotoxicity.",
"affiliations": "Department of Internal Medicine Beth Israel Deaconess Medical Center Boston MA USA.;Department of Internal Medicine, Division of Cardiology Beth Israel Deaconess Medical Center Boston MA USA.;Program in Cardio-oncology, Department of Internal Medicine, Division of Cardiology, Beth Israel Deaconess Medical Center Harvard Medical School Boston MA USA.",
"authors": "Mohebali|Donya|D|;Matos|Jason|J|;Chang|James Ducksoon|JD|",
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"fulltext": "\n==== Front\nESC Heart FailESC Heart Fail10.1002/(ISSN)2055-5822EHF2ESC Heart Failure2055-5822John Wiley and Sons Inc. Hoboken 2821731510.1002/ehf2.12113EHF212113ESCHF-16-00017Case ReportCase ReportsGemcitabine induced cardiomyopathy: a case of multiple hit cardiotoxicity A case of multiple hit cardiotoxicityD. Mohebali et al.Mohebali Donya \n1\nMatos Jason \n2\nChang James Ducksoon jchang@bidmc.harvard.edu \n3\n\n1 \nDepartment of Internal Medicine\nBeth Israel Deaconess Medical Center\nBoston\nMA\nUSA\n\n2 \nDepartment of Internal Medicine, Division of Cardiology\nBeth Israel Deaconess Medical Center\nBoston\nMA\nUSA\n\n3 \nProgram in Cardio‐oncology, Department of Internal Medicine, Division of Cardiology, Beth Israel Deaconess Medical Center\nHarvard Medical School\nBoston\nMA\nUSA\n* \nCorrespondence to: James Ducksoon Chang, Advanced Heart Failure Center, The Cardiovascular Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, MA 02215, USA. Tel: +1 617 632 7752; Fax: +1 617 632 7760.\n\nEmail: jchang@bidmc.harvard.edu\n21 9 2016 2 2017 4 1 10.1002/ehf2.v4.171 74 25 2 2016 28 6 2016 08 8 2016 © 2016 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology.This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.Abstract\nGemcitabine is a commonly used antineoplastic agent used to treat a variety of cancers with rarely reported cardiac side effects. We describe a case of a 67‐year‐old woman with follicular lymphoma who experienced a rarely reported side effect of gemcitabine: cardiomyopathy. This case highlights a multiple hit mechanism of myocyte damage that may occur following the use of multiple cardio‐toxic agents despite their administration in doses not associated with cardiotoxicity.\n\nCardiomyopathyCardio‐oncologyChemotherapy source-schema-version-number2.0component-idehf212113cover-dateFebruary 2017details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:5.2.8 mode:remove_FC converted:29.12.2017\n\n\nMohebali , D. \n, \nMatos , J. \n, and \nChang , J. D. \n (2017 ) Gemcitabine induced cardiomyopathy: a case of multiple hit cardiotoxicity . ESC Heart Failure , 4 : 71 –74 . doi: 10.1002/ehf2.12113.28217315\n==== Body\nIntroduction\nGemcitabine is a commonly used antineoplastic agent that is a nucleoside analog and pyrimidine antimetabolite that inhibits RNA synthesis.1 It is most commonly used in solid organ malignancies such as non‐small cell lung cancer, and breast, ovarian, and pancreatic cancer, although is also used in diffuse large B‐cell lymphoma in relapsed or refractory elderly patients.2 It has rare cardiac side effects including acute myocardial infarction, but is not well known to cause cardiomyopathy.\n\nCase report\nA 67‐year‐old woman with past medical history significant for follicular lymphoma with transformation to diffuse large B cell lymphoma status post multiple cycles of chemotherapy complicated by transient left ventricular systolic dysfunction presented with sensation of throat closing and difficulty breathing upon completion of Cycle 2 of Rituximab plus Gemcitabine and Oxaliplatin (R‐GemOx).\n\nHer follicular lymphoma was initially diagnosed in 2007 and treated with Rituximab, Cyclophosphamide, Doxorubicin, and Vincristine (R‐CHOP). Prior to initiation of chemotherapy, her left ventricular ejection fraction (LVEF) was normal. Three years following treatment with doxorubicin, her LVEF remained normal. Her only risk factor for cardiovascular disease was hyperlipidemia (total cholesterol 248 mg/dL, LDL 171 mg/dL); with no known hypertension, diabetes, or family history of coronary disease, and a normal exercise nuclear stress test.\n\nIn 2010, her cancer transformed to diffuse large B cell lymphoma (DLBCL) requiring autologous stem cell transplant. She was then treated with Rituximab, Ifosfamide, Carboplatin, and Etoposide (R‐ICE). Her disease remained in remission until 2013. At that time, a left groin biopsy revealed recurrent DLBCL. She was placed on Bretuximab/Rituximab, but once her disease progressed on this regimen, she was transitioned to Rituximab, Dexamethasone, Cytarabine, and platinol (R‐DHAP). One month into treatment with R‐DHAP, the patient's echocardiogram showed severely depressed LVEF (25–30%) with global hypokinesis. R‐DHAP was discontinued, and a repeat echocardiogram 3 months later showed an improved LVEF to 35–40% (Figure\n1, Table\n1). All ejection fractions were determined by visual estimation.\n\nFigure 1 Ejection fraction over time.\n\nTable 1 Chemotherapy agent by year, drug class, and frequency of cardiac adverse event\n\nDate\tChemotherapy/treatment regimen\tDrug class/name\tCardiac adverse event\tFrequency of adverse effect\t\n2003\tNone\t\t\t\t\n2007\tR‐CHOPa\n\tAnthracycline/donarubicin\tCHF/LV dysfunction\t+++\t\n2010\tAutologous stem cell transplant (cytoxan‐cardiotoxic)\tAlkylating agent/cytoxan (cyclophosphamide)\t\nPericarditis/myocarditis\n\nCHF\t\n+\n\n++\t\n05/2011\tR‐ICEb\n\tBiologic agent/rituximab\tArrhythmias\t++\t\n11/2013\tBretuximab/rituximab\tBiologic agent/rituximab\tArrhythmias\t++\t\n05/2014\tR‐DHAPc (04/2014)\tAlkylating agents/cisplatin\t\nIschemia\n\nHypertension\n\nCHF\t\n++\n\n++++\n\n+++\t\n07/2014\tNone\t\t\t\t\n11/2014\tR‐GemOxa\n\tPyrimidine analog/gemcitabine\t\nSupraventricular\n\nTachycardia\n\nIschemia cardiomyopathy\t\n++\n\n++\n\n+\t\n05/2015\tNone\t\t\t\t\na Rituximab, gemcitabine, oxaliplatin.\n\nb Rituximab, ifosfamide, carboplatin, and etoposide.\n\nc Rituximab, cyclophosphamide, doxorubicin, and vincristine.\n\nIn October 2014, Rituximab, Gemcitabine, and Oxaliplatin (R‐Gem‐Ox) were started. One month later, the patient presented to the hospital with sensation of throat closing and difficulty breathing. She was admitted with suspicion of laryngospasm from Oxaliplatin. Upon further questioning, since initiation of R‐GemOx, the patient noted exertional dyspnea and fatigue. She was previously able to walk three to four laps around her local shopping mall although now endorsed dyspnea upon ambulation to the nearby bathroom.\n\nOn examination, she was found to have a new oxygen requirement and a 7 pound weight gain. Her jugular venous pressure was elevated with diminished bibasilar lung sounds and 2+ pitting edema of the lower extremities. Cardiac auscultation revealed an S3 gallop and III/VI holosystolic murmur. Chest X‐ray showed bilateral pleural effusions. NT pro‐BNP was noted to be 40 000 with a lactate of 4.2. EKG demonstrated no acute ST or T wave changes. Transthoracic echocardiogram revealed an LVEF of 20% with global free wall hypokinesis and severe mitral regurgitation. The patient was treated with intravenous furosemide. Her renal function subsequently improved and lactate normalized. Home dosing of lisinopril and beta‐blocker were reintroduced. Given the concern for gemcitabine‐induced cardiomyopathy, this agent was discontinued. Repeat echocardiogram 6 months later showed an improved LVEF of 40% and mild mitral regurgitation.\n\nDiscussion\nOur patient was exposed to multiple chemotherapy agents with known cardio‐toxicity, and her ejection fraction therefore fluctuated throughout the course of her treatment. Cardiomyocytes, as well as other cell types comprising the heart, have a limited capacity for repair after sustaining injury from one agent or another. Perhaps, the most cogent example of the multiple hit hypothesis is found in cardiotoxicity occurring after chemotherapy for HER‐2/neu‐amplified breast cancer. When administered alone, the anti‐HER‐2/neu monoclonal antibody trastuzumab is associated with a low incidence of subsequent left ventricular contractile dysfunction, in the range of 4–6%.3 However, when administered after an anthracycline‐based adjuvant regimen, the incidence of left ventricular systolic dysfunction is as high as 28%.3 The most plausible explanation for this finding is that when anthracycline‐induced cardiomyocyte injury occurs, the limited ability of cardiomyocytes to repair this damage is abrogated by the subsequent administration of trastuzumab, which, by inhibiting HER‐2/neu‐dependent signalling (including phoshoinositide 3‐kinase/Akt) in the cardiomyocyte, inactivates cell survival pathways.\n\nOur patient was initially exposed to doxorubicin at a total cumulative dose of 450 mg/m2. The mechanism of cardio‐toxicity here involves disruption of topoisomerase‐II‐mediated DNA repair and generation of oxygen‐derived free radicals.4, 5, 6, 7 Serial echocardiograms during several years after doxorubicin administration showed stable LVEF. The fact that her LVEF fluctuated, rather than displaying a secular downtrend, in her later course is more consistent with acute cardiomyocyte injury following administration of individual agents, and not with chronic anthracycline‐induced left ventricular systolic dysfunction which is irreversible.\n\nThree years after treatment with doxorubicin, the patient was exposed to cyclophosphamide at the time of her stem cell transplant. Cyclophosphamide can cause endothelial and myocyte injury mediated through its toxic metabolic phosphoramide mustard that leads to DNA crosslinking and subsequent apoptosis.4 The patient was then exposed to R‐DHAP, of which, cisplatin has been shown to cause congestive heart failure, particularly in the elderly. Its mode of toxicity involves crosslinking with purine bases on the DNA and thus interfering with DNA repair mechanisms, causing DNA damage and cell apoptosis.4, 6\n\n\nFollowing cessation of R‐DHAP, and prior to initiation of GemOx, our patient's LVEF improved to 35–40%. After two cycles of R‐GemOx, her LVEF became severely depressed to 20–25%. Oxaliplatin, although commonly known for many side effects including laryngospasm (for which the patient was likely initially referred for hospitalization), peripheral neuropathy, and ototoxicity, is not associated with cardiomyopathy. The co‐administration of this agent with intravenous fluids may have contributed to volume overload. However, this alone would not explain the abrupt development of acute kidney injury, lactic acidosis, and pronounced drop in ejection fraction. The more likely culprit for this was gemcitabine. Acute kidney injury and lactic acidosis resolved with intravenous diuresis. Upon cessation of gemcitabine, the patient's LVEF improved to 40%, near her baseline prior to initiation of all chemotherapy agents.\n\nCardiotoxicity secondary to gemcitabine has rarely been reported in the literature.\n\nA handful of case reports describe arrhythmias as a side effect of gemcitabine use. Most of these report supraventricular tachycardias including atrial fibrillation.8, 9 Atrial fibrillation is typically seen 18–24 h of infusion. This side effect is likely because of a gemcitabine metabolite, 2′,2′‐difluorodeoxyuridine (diFdU), which has a an equivalent half‐life of approximately 18–24 h similar to the time of onset of atrial fibrillation.8, 9 Several case reports have demonstrated acute myocardial infarction acutely post‐gemcitabine infection secondary to drug‐induced vascular injury or endothelial damage.10, 11, 12\n\n\nOf all the possible cardiac toxicities, cardiomyopathy appears to be the least reported. In phase I clinical trials of gemcitabine use, significant reduction in LVEF occurred in 0.2% of patient, whereas 0.4–1.7% of patients developed cardiac arrhythmias.13 Review of the literature of phase II clinical trials of approximately 979 patients revealed 0.2% arrhythmias, 0.4% cardiomyopathies, and 0.2% with exudative pericarditis.14 In these trials, patients who developed cardiomyopathies had underlying coronary artery disease, whereas our patient had no history of coronary disease. Outside of clinical trials, gemcitabine‐induced cardiomyopathy has been reported only once in the literature.2 The patient described was similar to ours. He did not have prior coronary artery disease or risk factors. As with our described case, the patient presented with signs and symptoms of congestive heart failure after the second cycle of gemcitabine for pancreatic cancer. The patient's LVEF at the time of presentation with symptoms of exertional dyspnea was noted to be 15–20% with findings of global hypokinesis in addition to functional mitral regurgitation. Gemcitabine was discontinued, and two months later an echocardiogram showed recovery of LVEF to 40% and resolution of mitral regurgitation.\n\nWe propose a multiple hit mechanism that ultimately led to a severely depressed LVEF in our patient. The delayed toxicity of doxorubicin, in combination with the direct cytotoxic effects and apoptosis seen with cyclophosphamide, led to her initial drop in LVEF.4, 15 Subsequent exposure to cisplatin in May 2014 further damaged DNA repair mechanisms and quickly depressed our patient's LVEF to 25%. Upon discontinuation of cisplatin, her LVEF rapidly improved to 35–40%. It was not until the administration of gemcitabine in November 2014 that her LVEF once again decreased to 25%.\n\nThe primary message of our report is that the administration of multiple cytotoxic cancer treatments, each with a different mechanism of action, can result in major cardiotoxicity despite being given in doses that for each individual agent may not be cardiotoxic. In the era of combination chemotherapy employing multiple chemotherapeutic drugs, it is important to recognize that an interaction may exist between the effects of individual agents resulting in cardiac dysfunction that is either unexpected or more severe than expected.\n\nConclusions\nThis case highlights a multiple hit mechanism of cardiomyocyte damage that may occur when employing multiple cardio‐toxic agents in doses that, individually, may not be associated with cardiotoxicity.\n\nConflicts of interest\nNone declared.\n==== Refs\nReferences\n1 \n\nPlunkett \nW \n, \nHuang \nP \n, \nXu \nYZ \n, \nHeinemann \nV \n, \nGrunewald \nR \n, \nGandhi \nV \n. Gemcitabine: metabolism, mechanisms of action, and self‐potentiation . Semin Oncol \n1995 ; 22 : 3 –10 .\n2 \n\nKhan \nM \n, \nGottesman \nS \n, \nBoyella \nR \n, \nJuneman \nE \n. Gemcitabine‐induced cardiomyopathy: a case report and review of the literature . J Med Case Rep \n2014 ; 8 : 220 previously.24957905 \n3 \n\nEwe \nMS \n, \nEwer \nSM \n. Cardiotoxicity of anticancer treatments: what the cardiologist needs to know . Nat Rev Cardiol \n2010 ; 7 : 564 –575 .20842180 \n4 \n\nYeh \nE \n. Cardiovascular complications of cancer therapy: diagnosis, pathogenesis, and management . Circulation \n2004 ; 109 : 3122 –3131 .15226229 \n5 \n\nThorn \nC \n, \nOshiro \nC \n, \nMarsh \nS \n, \nHernandez‐Boussard \nT \n, \nMcLeod \nH \n, \nKlein \nT \n. Doxorubicin pathways . Pharmacogenetics and Genomics \n2011 ; 21 : 440 –446 .21048526 \n6 \n\nShakir \nD \n. Chemotherapy induced cardiomyopathy: pathogenesis, monitoring and management . J Clin Med Res \n2009 ; 1 : 8 –12 .22505958 \n7 \n\nKremer \nC \n. Anthracycline‐induced clinical heart failure in a cohort of 607 children: long‐term follow‐up study . Journal of Clinical Oncology. \n2001 ; 19 : 191 –196 .11134212 \n8 \n\nFerrari \nD \n, \nCarbone \nC \n, \nCodeca \nC \n, \nFumagalli \nL \n, \nGilardi \nL \n, \nMarussi \nD \n, \nTartaro \nT \n, \nOldani \nS \n, \nZannier \nF \n, \nFoa \nP \n. Gemcitabine and atrial fibrillation: a rare manifestation of chemotherapy toxicity . Anti‐Cancer Drugs \n2006 ; 17 : 359 –361 .16520666 \n9 \n\nSantini \nD \n, \nTonini \nG \n, \nAbbate \nA \n, \nDi Cosimo \nS \n, \nGravante \nG \n, \nVincenzi \nB \n. Gemcitabine‐induced atrial fibrillation: a hitherto unreported manifestation of drug toxicity . Ann Oncol. \n2000 ; 11 : 479 –481 .10847470 \n10 \n\nBdair \nF \n, \nGraham \nS \n, \nSmith \nP \n, \nJavle \nM \n. Gemcitabine and acute myocardial infarction: a case report . Angiology \n2006 ; 57 : 367 –371 .16703198 \n11 \n\nKalapura \nT \n, \nKrishnamurthy \nM \n, \nReddy \nC \n, \nReddy \nC \n. Acute myocardial infarction following gemcitabine therapy: a case report . Angiology \n1999 ; 50 : 1021 –1025 .10609769 \n12 \n\nDasanu \nC \n. Gemcitabine: vascular toxicity and prothrombotic potential . Expert Opin Drug Saf \n2008 ; 7 : 703 –716 .18983217 \n13 \n\nStorniolo \nA \n, \nAllerheiligen \nS \n, \nPearce \nH \n. Preclinical, pharmacologic, and phase I studies of gemcitabine . Semin Oncol \n1997 ; 24 : 2 –7 .\n14 \n\nDuvic \nM \n, \nTalpur \nR \n, \nWen \nS \n, \nKurzrock \nR \n, \nDavid \nC \n, \nApisarnthanarax \nN \n. Phase II evaluation of gemcitabine monotherapy for cutaneous T‐cell lymphoma . Clinical Lymphoma and Myeloma \n2006 ; 7 : 51 –58 .16879770 \n15 \n\nAtalay \nF \n, \nGulmez \nO \n, \nOzsancak \nA \n. Cardiotoxicity following cyclophosphamide therapy: a case report . Journal of Medical Case Reports \n2014 ; 8 : 252 .25023062\n\n",
"fulltext_license": "CC BY-NC-ND",
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"issue": "4(1)",
"journal": "ESC heart failure",
"keywords": "Cardiomyopathy; Cardio‐oncology; Chemotherapy",
"medline_ta": "ESC Heart Fail",
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"pages": "71-74",
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"pubdate": "2017-02",
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"title": "Gemcitabine induced cardiomyopathy: a case of multiple hit cardiotoxicity.",
"title_normalized": "gemcitabine induced cardiomyopathy a case of multiple hit cardiotoxicity"
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"abstract": "A conditioning regimen with fludarabine and myeloablative dose of busulfan (FLU/BU4) has been commonly used in allogeneic hematopoietic cell transplantation (allo-HCT). However, there are two major problems with this regimen: insufficient anti-leukemic effect, especially in advanced cases, and slow time to complete donor-type chimerism, especially T-cell chimerism. To overcome these issues, we designed a combination regimen with FLU (150 mg/m2), intravenous BU (12.8 mg/kg), and melphalan (100 mg/m2) (FLU/BU4/MEL) and conducted retrospective analyses of treatment outcomes at our institute. Forty-two patients with myeloid malignancies received allogeneic bone-marrow transplantation or peripheral blood stem-cell transplantation (allo-BMT/PBSCT) with FLU/BU4/MEL regimen. The median age of patients was 46.5 years (20-63 years). Thirteen patients (31%) did not achieve complete hematological remission at transplantation. All patients examined achieved complete whole and T-cell chimerism within 1 month after allo-HCT. The 4-year overall survival and disease-free survival rates were 66.0% [95% confidence interval (CI) 49.4-78.3%] and 59.5% (95% CI 43.2-72.6%) in all patients, and 49.4% (95% CI 19.7-73.6%) and 38.5% (95% CI 14.1-62.8%) in patients who were not in remission. In conclusion, FLU/BU4/MEL showed curative potential, even in patients with advanced myeloid malignancies, accompanied by achievement of rapid complete chimerism after allo-BMT/PBSCT.",
"affiliations": "Department of Hematology and Oncology, Osaka University Graduate School of Medicine, 2-2 Yamada-Oka, Suita, 565-0871, Japan. uedat@bldon.med.osaka-u.ac.jp.;Department of Hematology and Oncology, Osaka University Graduate School of Medicine, 2-2 Yamada-Oka, Suita, 565-0871, Japan.;Department of Hematology and Oncology, Osaka University Graduate School of Medicine, 2-2 Yamada-Oka, Suita, 565-0871, Japan.;Department of Hematology and Oncology, Osaka University Graduate School of Medicine, 2-2 Yamada-Oka, Suita, 565-0871, Japan.;Department of Hematology and Oncology, Osaka University Graduate School of Medicine, 2-2 Yamada-Oka, Suita, 565-0871, Japan.;Department of Hematology and Oncology, Osaka University Graduate School of Medicine, 2-2 Yamada-Oka, Suita, 565-0871, Japan.;Department of Hematology and Oncology, Osaka University Graduate School of Medicine, 2-2 Yamada-Oka, Suita, 565-0871, Japan.;Department of Blood Transfusion, Osaka University Hospital, Suita, Japan.;Department of Hematology and Oncology, Osaka University Graduate School of Medicine, 2-2 Yamada-Oka, Suita, 565-0871, Japan.",
"authors": "Ueda|Tomoaki|T|;Maeda|Tetsuo|T|;Kusakabe|Shinsuke|S|;Fujita|Jiro|J|;Fukushima|Kentaro|K|;Yokota|Takafumi|T|;Shibayama|Hirohiko|H|;Tomiyama|Yoshiaki|Y|;Kanakura|Yuzuru|Y|",
"chemical_list": "D019653:Myeloablative Agonists; D014740:Vidarabine; D002066:Busulfan; C024352:fludarabine; D008558:Melphalan",
"country": "Japan",
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"doi": "10.1007/s12185-018-2562-8",
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"issue": "109(2)",
"journal": "International journal of hematology",
"keywords": "Allogeneic bone-marrow transplantation/peripheral blood stem-cell transplantation; Conditioning regimen; Intravenous busulfan; Melphalan; Myeloid malignancy",
"medline_ta": "Int J Hematol",
"mesh_terms": "D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D016026:Bone Marrow Transplantation; D002066:Busulfan; D046528:Chimerism; D005260:Female; D006801:Humans; D007951:Leukemia, Myeloid; D008297:Male; D008558:Melphalan; D008875:Middle Aged; D019653:Myeloablative Agonists; D036102:Peripheral Blood Stem Cell Transplantation; D012189:Retrospective Studies; D023981:Sarcoma, Myeloid; D016019:Survival Analysis; D014184:Transplantation, Homologous; D016896:Treatment Outcome; D014740:Vidarabine; D055815:Young Adult",
"nlm_unique_id": "9111627",
"other_id": null,
"pages": "197-205",
"pmc": null,
"pmid": "30448938",
"pubdate": "2019-02",
"publication_types": "D016428:Journal Article",
"references": "11535508;15073038;16109776;16338616;16384925;17606460;18264144;18804045;19349956;20147978;21338705;21423123;22331955;22592321;22911907;23208313;23394705;23871781;24744269;24907627;24978140;25175796;25424330;25545836;26429297;26457908;26612281;27345142;27686673;27943166;30135184",
"title": "Addition of melphalan to fludarabine/busulfan (FLU/BU4/MEL) provides survival benefit for patients with myeloid malignancy following allogeneic bone-marrow transplantation/peripheral blood stem-cell transplantation.",
"title_normalized": "addition of melphalan to fludarabine busulfan flu bu4 mel provides survival benefit for patients with myeloid malignancy following allogeneic bone marrow transplantation peripheral blood stem cell transplantation"
} | [
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"companynumb": "JP-OTSUKA-2019_007066",
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"activesubstancename": "FLUDARABINE PHOSPHATE"
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"abstract": "BACKGROUND\nTopiramate is a drug which emerged from its anticonvulsant properties and now over the years is used for a wider range of indications, including migraine prophylaxis. We described a very rare case of topiramate induced acute onset myopia during use for migraine. It is the first reported case of its kind from Sri Lanka with only a handful of reported cases in world literature.\n\n\nMETHODS\nA 35-year-old Sri Lankan female presented with long standing history of intermittent headache with recent worsening. A diagnosis of migraine was made and due to poor response to other medication was initiated on topiramate. Two weeks later patient developed visual impairment which was finally attributed to topiramate. Following discontinuation of the drug, within 3 days the symptoms started to improve with full recovery in 10 days.\n\n\nCONCLUSIONS\nAll clinicians should be aware of the potential ocular side effects of topiramate. Although relatively rare, prompt recognition is key to appropriate management.",
"affiliations": "Teaching hospital, Peradeniya, Sri Lanka. rajithaasa55@gmail.com.",
"authors": "Medagama|Arjuna|A|;Senaratne|Tissa|T|;Bandara|Jayasuriya Mudiyanselage Ruwanthi Panchali|JM|;Abeysekera|Rajitha Asanga|RA|;Imbulpitiya|Imbulpitiya Vidanalage Buddhini|IV|",
"chemical_list": "D000077236:Topiramate; D005632:Fructose",
"country": "England",
"delete": false,
"doi": "10.1186/1756-0500-7-665",
"fulltext": "\n==== Front\nBMC Res NotesBMC Res NotesBMC Research Notes1756-0500BioMed Central London 25240257318610.1186/1756-0500-7-665Case ReportTopiramate-induced acute onset myopia: a case report Medagama Arjuna arjuna.medagama@gmail.com Senaratne Tissa tissa.senaratne@yahoo.com Bandara Jayasuriya Mudiyanselage Ruwanthi Panchali ruwanthibandara@yahoo.com Abeysekera Rajitha Asanga rajithaasa55@gmail.com Imbulpitiya Imbulpitiya Vidanalage Buddhini dhin_im@yahoo.com Department of Medicine, Faculty of Medicine, University of Peradeniya, Peradeniya, Sri lanka General Hospital, Kandy, Sri lanka Teaching hospital, Peradeniya, Sri Lanka 21 9 2014 21 9 2014 2014 7 66510 3 2014 16 9 2014 © Medagama et al.; licensee BioMed Central Ltd. 2014This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nTopiramate is a drug which emerged from its anticonvulsant properties and now over the years is used for a wider range of indications, including migraine prophylaxis. We described a very rare case of topiramate induced acute onset myopia during use for migraine. It is the first reported case of its kind from Sri Lanka with only a handful of reported cases in world literature.\n\nCase presentation\nA 35-year-old Sri Lankan female presented with long standing history of intermittent headache with recent worsening. A diagnosis of migraine was made and due to poor response to other medication was initiated on topiramate. Two weeks later patient developed visual impairment which was finally attributed to topiramate. Following discontinuation of the drug, within 3 days the symptoms started to improve with full recovery in 10 days.\n\nConclusion\nAll clinicians should be aware of the potential ocular side effects of topiramate. Although relatively rare, prompt recognition is key to appropriate management.\n\nKeywords\nTopiramateAcute myopiaCiliochoroidal effusion syndromeissue-copyright-statement© The Author(s) 2014\n==== Body\nBackground\nTopiramate (TPM) emerged from its anticonvulsant properties and now is recommended as a first line medication in some seizure disorders. Over the years its use has significantly increased and is used for a wide spectrum of other indications including migraine prophylaxis.\n\nTopiramate is a sulfa-derivative monosaccharide with several mechanisms of action, mainly including blockage of voltage-gated sodium channels, hyperpolarization and enhancement of postsynaptic gamma-aminobutyric acid receptor activity [1]. It is a drug with numerous side effects, in particular ophthalmologic side effects [2]. Due to increased use it is prudent that the clinician is fully aware of these potential side effects. We describe here a rare case of topiramate induced acute onset myopia. The author feels it is the first reported case of its kind from Sri Lanka despite having reported cases in world literature [3].\n\nCase presentation\nA 35-year-old Sri Lankan female with long standing intermittent headaches presented with recent worsening of headache. Clinical examination performed by the physician revealed normal neurological examination and vision with a visual acuity of 6/6 without any correction. A provisional diagnosis of migraine has been made on a previous occasion and she had been commenced on multiple medications over a period of time including propranolol and flunarazine. This had helped initially, but not in the long term.\n\nThe patient was reassured and asked to continue flunarazine. She presented one month later with no relief from her headaches. Examination was unremarkable. Flunarazine was discontinued and she was commenced on topiramate 25 mg at night.\n\n2 weeks later she complained of acute onset blurring of vision. There were no other neurological symptoms. An ophthalmological consultation revealed no significant visual finding except for a bilateral refractive error of – 0.5 diopters. Her visual symptoms persisted to the next day, but did not worsen. Suspecting topiramate induced myopia the drug was discontinued and the patient was referred back to the ophthalmologist who noted a visual acuity of 6/6, normal intraocular pressure and a worsening of refractive error to −3.5 diopters bilaterally. On the 3rd day following discontinuation of topiramate her visual symptoms started to improve and at the end of 10 days her vision was back to normal with no evidence of a refractive error (0 diopters).\n\nA diagnosis of topiramate induced acute myopia was made. An ophthalmologist review 2 weeks later was normal.\n\nDiscussion\nThis patient had no other previous medical illness or visual disorders prior to the commencement of topiramate. The symptom onset was very acute in nature following commencement of topiramate and improved spontaneously on discontinuation of the drug.\n\nThe exact mechanism by which TPM and other sulfa derivatives initially triggers myopia is not completely understood. However, to date, a number of mechanisms have been suggested as possible triggers.\n\nOne of the earliest hypotheses was proposed by Sen et al. [4]. They suggested that the entry of TPM into the lens alters its osmotic status, causing it to swell and, consequently, resulting in angle closure glaucoma (ACG) and myopia. Another hypothesis by Ikeda et al.\n[5] in 2002 led to the origin of the clinical entity “Ciliochoroidal effusion syndrome” which can be defined as a spectrum of clinical manifestations ranging from transient topiramate induced myopia to severe bilateral ACG . These complications were attributed to ciliochoroidal effusion and swelling of the ciliary body, which can potentially result in anterior rotation of the ciliary processes, causing narrowing of the ciliary sulcus and forward displacement of the iris and lens.\n\nAnother theory is that Ciliochoroidal effusion syndrome is due to an idiosyncratic reaction. This complication occurring in a small proportion and some studies showing no correlation between TPM dosage with the level of intra ocular pressure or myopia supports this.\n\nPatients with topiramate induced myopia often complain of sudden blurred vision. The symptoms are documented to occur within the first 2 weeks after drug initiation. As the mean plasma elimination half life of the drug is about 21 hours, rapid visual recovery usually occurs although in some cases it can take several weeks. In the management of topiramate induced myopia, the most important measure is to discontinue TPM and seek urgent ophthalmology opinion. In the long term an alternative agent should be used.\n\nConclusion\nOcular examination before starting topiramate cannot identify eyes at risk. Patients commencing topiramate should therefore be advised to immediately report any symptoms of eye pain or blurred vision especially in the first few weeks of treatment.\n\nAll clinicians involved in the management of the patient including the physician, neurologist and ophthalmologists need to be aware of the potential ocular side effects of topiramate. Although relatively rare, prompt recognition is key so appropriate management can be instituted and visual outcomes minimized.\n\nConsent\nWritten informed consent was obtained from the patient for publication of this Case Report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nAbbreviations\nTPMTopiramate\n\nACGAngle closure glaucoma.\n\nCompeting interests\n\nThe authors declare that they have no competing interests. There was no funding available for any of the authors in this article.\n\nAuthors’ contributions\n\nAM, TS conceived the idea. AM, TS, JMRPB, RAA and IVB recorded clinical data. AM, RAA, JMRPB and IVB drafted the manuscript. All the authors read and approved the final version of the script.\n==== Refs\nReferences\n1. Perucca E A pharmacological and clinical review on topiramate, a new antiepileptic drug Pharmacol Res 1997 35 4 241 256 10.1006/phrs.1997.0124 9264038 \n2. Panday VA Rhee DJ Review of sulfonamide-induced acute myopia and acute bilateral angle- closure glaucoma Compr Ophthalmol Update 2007 8 5 271 276 18201514 \n3. Bhattacharyya KB Basu S Acute myopia induced by topiramate: report of a case and review of the literature Neurol India 2005 53 1 108 109 10.4103/0028-3886.15074 15805668 \n4. Sen HA O’Halloran HS Lee WB Case reports and small case series: topiramate-induced acute myopia and retinal striae Arch Ophthalmol 2001 119 775 777 11346412 \n5. Ikeda N Ikeda T Nagata M Mimura O Ciliochoroidal effusion syndrome induced by sulfa derivatives Arch Ophthalmol 2002 120 12 1775 10.1001/archopht.120.12.1775 12470170\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1756-0500",
"issue": "7()",
"journal": "BMC research notes",
"keywords": null,
"medline_ta": "BMC Res Notes",
"mesh_terms": "D000208:Acute Disease; D000328:Adult; D005260:Female; D005632:Fructose; D006801:Humans; D008881:Migraine Disorders; D009216:Myopia; D020127:Recovery of Function; D012307:Risk Factors; D013997:Time Factors; D000077236:Topiramate; D014785:Vision, Ocular",
"nlm_unique_id": "101462768",
"other_id": null,
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"pmid": "25240257",
"pubdate": "2014-09-21",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "9264038;18201514;11346412;12470170;15805668",
"title": "Topiramate-induced acute onset myopia: a case report.",
"title_normalized": "topiramate induced acute onset myopia a case report"
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"companynumb": "LK-LUPIN PHARMACEUTICALS INC.-2015-02092",
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"abstract": "Pediatric kidney donors remain underutilized due to the high risk of postoperative thrombosis. To address this problem, we developed a novel en bloc kidney transplantation technique using donor thoracic aorta and the distal abdominal aorta as inflow and outflow tracts, respectively. Briefly, eight kidneys from deceased infant donors under five months old and with low body weight (1.9-4.9 kg) were transplanted en bloc into four pediatric and four adult patients. The donor's common iliac artery or external iliac artery was anastomosed to the recipient's distal external iliac artery or inferior epigastric artery, respectively, as an outflow tract. Recipients received basiliximab or antithymocyte globulin as induction therapy followed by tacrolimus, mycophenolate mofetil, and prednisone but without prophylactic anticoagulation. Delayed graft function was observed in one patient but was reversed at 90 days posttransplant. Two patients had urine leakage, which was cured by conservative treatment. Two recipients developed lung infections that eventually cleared. No patients experienced posttransplant vascular thrombosis. After 1-1.5 years of follow-up, all patients are well and have normal serum creatinine levels. In conclusion, this novel en bloc kidney transplantation technique using a modified arterial inflow and outflow tract can prevent vascular thrombosis and provide adequate graft function.",
"affiliations": "Department of Urological Organ Transplantation, Center of Organ Transplantation, The Second Xiangya Hospital of Central South University, Changsha, China.;Department of Urological Organ Transplantation, Center of Organ Transplantation, The Second Xiangya Hospital of Central South University, Changsha, China.;Department of Urological Organ Transplantation, Center of Organ Transplantation, The Second Xiangya Hospital of Central South University, Changsha, China.;Department of Urological Organ Transplantation, Center of Organ Transplantation, The Second Xiangya Hospital of Central South University, Changsha, China.;Department of Urological Organ Transplantation, Center of Organ Transplantation, The Second Xiangya Hospital of Central South University, Changsha, China.;Department of Urological Organ Transplantation, Center of Organ Transplantation, The Second Xiangya Hospital of Central South University, Changsha, China.;Department of Urological Organ Transplantation, Center of Organ Transplantation, The Second Xiangya Hospital of Central South University, Changsha, China.;Department of Urological Organ Transplantation, Center of Organ Transplantation, The Second Xiangya Hospital of Central South University, Changsha, China.;Department of Urological Organ Transplantation, Center of Organ Transplantation, The Second Xiangya Hospital of Central South University, Changsha, China.;Department of Urological Organ Transplantation, Center of Organ Transplantation, The Second Xiangya Hospital of Central South University, Changsha, China.;Department of Urological Organ Transplantation, Center of Organ Transplantation, The Second Xiangya Hospital of Central South University, Changsha, China.;Department of Urological Organ Transplantation, Center of Organ Transplantation, The Second Xiangya Hospital of Central South University, Changsha, China.;Department of Urological Organ Transplantation, Center of Organ Transplantation, The Second Xiangya Hospital of Central South University, Changsha, China.",
"authors": "Dai|Helong|H|;Peng|Longkai|L|;Peng|Fenghua|F|;Lan|Gongbin|G|;Wang|Yu|Y|;Chen|Jingjing|J|;Liu|Lei|L|;Gao|Chen|C|;Guo|Yong|Y|;Fang|Chunhua|C|;Nie|Manhua|M|;Long|Wang|W|;Yu|Shaojie|S|",
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"journal": "American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons",
"keywords": "clinical research/practice; complication: surgical/technical; donors and donation: donation after circulatory death (DCD); kidney (allograft) function/dysfunction; kidney transplantation/nephrology; organ procurement; paediatrics",
"medline_ta": "Am J Transplant",
"mesh_terms": "D000328:Adult; D001012:Aorta, Abdominal; D001835:Body Weight; D002648:Child; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007676:Kidney Failure, Chronic; D016030:Kidney Transplantation; D008297:Male; D011379:Prognosis; D013927:Thrombosis; D014019:Tissue Donors; D009927:Tissue and Organ Procurement",
"nlm_unique_id": "100968638",
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"pubdate": "2018-09",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "A novel technique for en bloc kidney transplantation from infant donors with extremely low body weight by using the distal abdominal aorta as an outflow tract.",
"title_normalized": "a novel technique for en bloc kidney transplantation from infant donors with extremely low body weight by using the distal abdominal aorta as an outflow tract"
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"abstract": "BACKGROUND\nEwing sarcoma is the second most common bone tumor, occurring mainly in children and young adults. It shows a typical primitive, small round cell morphology and a characteristic fusion oncogene involving EWSR1 and members of the ETS family in most of the cases. Neuronal maturation after chemotherapy is a rare phenomenon and we herein describe such an exceptional case.\n\n\nMETHODS\nAn 8-year old boy was diagnosed with a Ewing sarcoma in the left femur. On biopsy the morphology was typical and there was an EWSR1-FLI1 gene fusion. He underwent neo-adjuvant chemotherapy and resection of the tumor. On microscopic evaluation, part of the tumor showed ganglioneuroblastoma-like differentiation with expression of neuronal markers. The continued presence of EWSR1 rearrangement in both the blue round cell component and the ganglioneuroblastoma-like component was shown by FISH analysis.\n\n\nCONCLUSIONS\nIn conclusion, this case describes the possibility of a Ewing sarcoma to differentiate into a ganglioneuroblastoma-like lesion after neo-adjuvant chemotherapy treatment; the prognostic value of this phenomenon remains questionable.",
"affiliations": "Department of Pathology, Radboud University Medical Center, P.O. Box 9101, Nijmegen, 6500 HB, The Netherlands. Myrthe.Salet@radboudumc.nl.;Department of Pathology, Radboud University Medical Center, P.O. Box 9101, Nijmegen, 6500 HB, The Netherlands.;Department of Pediatric Oncology, Radboud University center, P.O. Box 9101, Nijmegen, 6500 HB, The Netherlands.;Department of Orthopedics, Radboud University Center, P.O. Box 9101, Nijmegen, 6500 HB, The Netherlands.;Department of Pathology, Radboud University Medical Center, P.O. Box 9101, Nijmegen, 6500 HB, The Netherlands.",
"authors": "Salet|Maria Carolina Wilhelmina|MC|;Vogels|Rob|R|;Brons|Paul|P|;Schreuder|Bart|B|;Flucke|Uta|U|",
"chemical_list": "D002148:Calmodulin-Binding Proteins; C500986:EWSR1 protein, human; C576197:EWSR1-FLI1 fusion protein, human; D015514:Oncogene Proteins, Fusion; D034802:RNA-Binding Protein EWS; D016601:RNA-Binding Proteins; D014750:Vincristine; D005047:Etoposide; D004317:Doxorubicin; D007069:Ifosfamide",
"country": "England",
"delete": false,
"doi": "10.1186/s13000-016-0516-0",
"fulltext": "\n==== Front\nDiagn PatholDiagn PatholDiagnostic Pathology1746-1596BioMed Central London 51610.1186/s13000-016-0516-0Case ReportMaturation toward neuronal tissue in a Ewing sarcoma of bone after chemotherapy Salet Maria Carolina Wilhelmina Myrthe.Salet@radboudumc.nl 1Vogels Rob Rob.Vogels@radboudumc.nl 1Brons Paul Paul.Brons@radboudumc.nl 2Schreuder Bart Bart.Schreuder@radboudumc.nl 3Flucke Uta Uta.Flucke@radboudumc.nl 11 Department of Pathology, Radboud University Medical Center, P.O. Box 9101, Nijmegen, 6500 HB The Netherlands 2 Department of Pediatric Oncology, Radboud University center, P.O. Box 9101, Nijmegen, 6500 HB The Netherlands 3 Department of Orthopedics, Radboud University Center, P.O. Box 9101, Nijmegen, 6500 HB The Netherlands 9 8 2016 9 8 2016 2016 11 7423 1 2016 19 7 2016 © The Author(s). 2016\nOpen AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nEwing sarcoma is the second most common bone tumor, occurring mainly in children and young adults. It shows a typical primitive, small round cell morphology and a characteristic fusion oncogene involving EWSR1 and members of the ETS family in most of the cases. Neuronal maturation after chemotherapy is a rare phenomenon and we herein describe such an exceptional case.\n\nCase presentation\nAn 8-year old boy was diagnosed with a Ewing sarcoma in the left femur. On biopsy the morphology was typical and there was an EWSR1-FLI1 gene fusion. He underwent neo-adjuvant chemotherapy and resection of the tumor. On microscopic evaluation, part of the tumor showed ganglioneuroblastoma-like differentiation with expression of neuronal markers. The continued presence of EWSR1 rearrangement in both the blue round cell component and the ganglioneuroblastoma-like component was shown by FISH analysis.\n\nConclusions\nIn conclusion, this case describes the possibility of a Ewing sarcoma to differentiate into a ganglioneuroblastoma-like lesion after neo-adjuvant chemotherapy treatment; the prognostic value of this phenomenon remains questionable.\n\nElectronic supplementary material\nThe online version of this article (doi:10.1186/s13000-016-0516-0) contains supplementary material, which is available to authorized users.\n\nKeywords\nEwing sarcomaPathologyMaturationDifferentiationNeuralissue-copyright-statement© The Author(s) 2016\n==== Body\nBackground\nEwing sarcoma, first described by James Ewing in 1921, is the second most common malignant bone tumor after osteosarcoma. Occurring mainly in children and young adults; it accounts for 3 % of childhood malignancies. During the last decades, the 5 year overall survival has improved up to 85 % for patients with localized disease but is still only 30 % for patients with metastatic disease [1, 2]. Ewing sarcomas are primitive small blue round cell tumors of bone and soft tissue, characterized by the expression of EWS-ETS fusion genes as a driver mutation [3, 4].\n\nNeural differentiation in Ewing sarcoma is a rare phenomenon and has been described before in a few cases [3, 5]. Here we present a case in which an Ewing sarcoma shows ganglioneuroblastoma-like differentiation after chemotherapeutic treatment.\n\nCase presentation\nAn 8-year old boy with no previous relevant medical history, presented with pain and a palpable mass in the left upper thigh. MRI showed a ca. 10 cm large lesion in the femur with soft tissue extension. There were no signs of metastasis elsewhere. The patient received neo-adjuvant chemotherapy by the Ewing 2008 protocol. After 4 cycles of VIDE (vincristine, ifosfamide, doxorubicin and etoposide) chemotherapy, a staging FDG-PET/CT-scan was performed, showing tumor regression, however no normalization of metabolic activity at the primary tumor site. After 6 cycles of VIDE, resection of the femur diaphysis was performed with reconstruction with a vascularised fibula transplant. An optimal recovery has been seen so far, with no sign of recurrence or metastatic disease at 21 months after surgery.\n\nHistology\nBiopsy\nThe pretreatment biopsy (routinely formalin-fixed, paraffin-embedded, decalcified and hematoxylin-eosin-stained) revealed microscopically a small blue round cell tumor with necrosis. A panel of antibodies was applied according to standard protocol (antibodies used can be seen in Additional file 1). There was positive membranous staining for CD99 and CD56, consistent with the diagnosis of Ewing sarcoma. By RT-PCR, the presence of the EWSR1-FLI1 fusion gene confirmed this diagnosis.\n\nResection specimen\nMacroscopically, a 15 cm measuring femur bone and surrounding soft tissue specimen, showed on the cut surface a 10.5 cm large tumor with soft tissue extension. Necrosis, cystic and myxoid changes as well as areas of hemorrhage were present. Microscopy of the tumor showed, beside the usual small blue round cell population, maturated neuroblastoma-like cells and ganglion-like cells against a fibrillary (neuropil-like) background (Fig. 1). It was estimated that of the surviving tumor load about 70 % showed neural differentiation. Again, there was a membrane reactivity for CD99 in the primitive population, whereas the ganglioneuroblastoma-like component showed expression of neural markers, including NF, Neu-N and GFAP. There was no S100 expression (Fig. 2). To confirm the continued presence of the fusion gene FISH analysis was performed showing rearrangement of EWSR1 in both the small blue round cell component and the ganglioneuroblastoma-like component.Fig. 1 Resection specimen showing ganglioneuroblastoma-like differentiation. a: Overview (2.5x) (b): 10x (c): 20x (d): 40x\n\nFig. 2 Immunohistochemistry on resection specimen (40x) (a) HE showing a part of the tumor with both differentiated (neuronal and ganglion-like cell) and small groups of primitive (typical Ewing) tumor cells (b) NF Highlights part of the differentiated tumor cells and the neuropil. The primitive tumor cells are mainly negative (c) CD99 labels the primitive tumor cells, whereas the differentiated component is negative. d Neu-N shows strong reactivity of the differentiated tumor cells and is negative in the primitive tumor cells\n\n\n\nDiscussion\nThe cellular origin of Ewing sarcomas remains both elusive and controversial. However, the immature neural phenotype of many tumors, formerly known as PNET [5, 6], along with their gene expression signatures and their disposition to neural differentiation in experimental models implicate a neural crest stem cell genetic program as integral feature of pathogenesis of Ewing sarcoma [7]. Therefore, it is not surprising that patient material, at least in some cases, show (ganglio) neuroblastoma-like morphology.\n\nDelattre et al. and Burchill et al. described neuroblastoma-like features in a few untreated Ewing sarcoma cases with genetic confirmation [8, 9], which could be a diagnostic pitfall.\n\nOn the other hand, our case and the reported cases by Maeda et al. and Collini et al. show ganglioneuroblastoma-like maturation after chemotherapy probably as treatment effect (3,5).\n\nWhereas Maeda et al. confirmed their diagnosis molecularly only on biopsy material (5), Collini et al. demonstrated the presence of the EWSR1-FLI1 fusion gene in both pre- and post-treatment specimens, as we did in our case [3].\n\nHowever, such cases are very rare, we didn’t find another one when reviewing 26 cases from our archives. This is in line with the results of Delattre et al. investigating a series of more than 90 cases with two neuroblastoma-like instances [8].\n\nMaturation during chemotherapeutic treatment is a more common finding in other primitive pediatric tumors such as rhabdomyosarcoma and neuroblastoma [10–13]. Since neural maturation is very rare in Ewing sarcoma, the prognostic value remains unclear in comparison to e.g., embryonal rhabdomyosarcoma where it is associated with favorable outcome [10, 14]. At least the case by Maeda et al. had a unfavorable outcome with metastatic disease showing typical small blue round cell morphology of Ewing sarcoma in contrast to our case with no signs of recurrence or metastases at 21 month after surgery [5].\n\nConclusions\nIn conclusion, this case describes the possibility of a Ewing sarcoma to differentiate into neural tissue after neo-adjuvant chemotherapy treatment, the prognostic value of this phenomenon remains questionable.\n\nAbbreviations\nCT, computed tomography; FDG, fluordeoxyglucose; GFAP, glial fibrillary acidic protein; HE, hematoxylin-eosin; MRI, magnetic resonance imaging; Neu-N, neuronal nuclei; NF, neurofilament; PET/CT, positron emission tomography–computed tomography; PNET, primitive neuroectodermal tumor\n\nAdditional file\nAdditional file 1: The used antibodies. (XLSX 10kb)\n\n\n\nAcknowledgements\nNot applicable.\n\nFunding\nNo funding was received.\n\nAvailability of data and materials\nThe dataset supporting the conclusions of this article is included within the article.\n\nAuthors’ contributions\nMS wrote the manuscript. PB and BS were involved in the treatment of the patient. UF and RV revised the manuscript. All authors read and approved the final manuscript.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nConsent for publication\nWritten informed consent was obtained from the guardian of the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nEthics approval and consent to participate\nNot applicable.\n==== Refs\nReferences\n1. Hamilton SN et al. Long-term Outcomes and Complications in Pediatric Ewing Sarcoma. Am J Clin Oncol. 2015.\n2. Rodriguez-Galindo C Analysis of prognostic factors in ewing sarcoma family of tumors: review of St. Jude Children’s Research Hospital studies Cancer 2007 110 2 375 84 10.1002/cncr.22821 17569105 \n3. Collini P Evidence of neural differentiation in a case of post-therapy primitive neuroectodermal tumor/Ewing sarcoma of bone Am J Surg Pathol 2003 27 8 1161 6 10.1097/00000478-200308000-00016 12883251 \n4. Arvand A Denny CT Biology of EWS/ETS fusions in Ewing’s family tumors Oncogene 2001 20 40 5747 54 10.1038/sj.onc.1204598 11607824 \n5. Maeda G Ganglion cells in Ewing’s sarcoma following chemotherapy: a case report Pathol Int 1998 48 6 475 80 10.1111/j.1440-1827.1998.tb03936.x 9702862 \n6. Jaffe R The neuroectodermal tumor of bone Am J Surg Pathol 1984 8 12 885 98 10.1097/00000478-198412000-00001 6083729 \n7. von Levetzow C Modeling initiation of Ewing sarcoma in human neural crest cells PLoS One 2011 6 4 e19305 10.1371/journal.pone.0019305 21559395 \n8. Delattre O The Ewing Family of Tumors - a Subgroup of Small-Round-Cell Tumors Defined by Specific Chimeric Transcripts N Engl J Med 1994 331 5 294 9 10.1056/NEJM199408043310503 8022439 \n9. Burchill SA EWS-FLI1 fusion transcripts identified in patients with typical neuroblastoma Eur J Cancer 1997 33 2 239 43 10.1016/S0959-8049(96)00463-7 9135495 \n10. Coffin CM Pathologic features of rhabdomyosarcoma before and after treatment: a clinicopathologic and immunohistochemical analysis Mod Pathol 1997 10 12 1175 87 9436961 \n11. Smith LM Anderson JR Coffin CM Cytodifferentiation and clinical outcome after chemotherapy and radiation therapy for rhabdomyosarcoma (RMS) Med Pediatr Oncol 2002 38 6 398 404 10.1002/mpo.10060 11984800 \n12. Lowichik A Therapy associated changes in childhood tumors Adv Anat Pathol 2000 7 6 341 59 10.1097/00125480-200007060-00002 11078058 \n13. Molenaar WM Oosterhuis JW Kamps WA Cytologic “differentiation” in childhood rhabdomyosarcomas following polychemotherapy Hum Pathol 1984 15 10 973 9 10.1016/S0046-8177(84)80127-6 6479975 \n14. Arndt CA Significance of persistent mature rhabdomyoblasts in bladder/prostate rhabdomyosarcoma: Results from IRS IV J Pediatr Hematol Oncol 2006 28 9 563 7 10.1097/01.mph.0000212978.21372.97 17006261\n\n",
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"issue": "11(1)",
"journal": "Diagnostic pathology",
"keywords": "Differentiation; Ewing sarcoma; Maturation; Neural; Pathology",
"medline_ta": "Diagn Pathol",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D002148:Calmodulin-Binding Proteins; D002454:Cell Differentiation; D017024:Chemotherapy, Adjuvant; D002648:Child; D004317:Doxorubicin; D005047:Etoposide; D005266:Femoral Neoplasms; D005269:Femur; D018305:Ganglioneuroblastoma; D015321:Gene Rearrangement; D006801:Humans; D007069:Ifosfamide; D008297:Male; D020360:Neoadjuvant Therapy; D015514:Oncogene Proteins, Fusion; D011379:Prognosis; D034802:RNA-Binding Protein EWS; D016601:RNA-Binding Proteins; D012512:Sarcoma, Ewing; D016896:Treatment Outcome; D014750:Vincristine",
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"other_id": null,
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"pmid": "27506465",
"pubdate": "2016-08-09",
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"references": "17006261;11607824;11984800;21559395;9135495;9702862;6479975;25599318;11078058;8022439;6083729;9436961;12883251;17569105",
"title": "Maturation toward neuronal tissue in a Ewing sarcoma of bone after chemotherapy.",
"title_normalized": "maturation toward neuronal tissue in a ewing sarcoma of bone after chemotherapy"
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"abstract": "OBJECTIVE\nTo study the prevalence and incidence of seizures in patients prescribed clozapine.\n\n\nMETHODS\nThe treatment records of 222 patients commenced on clozapine were retrospectively reviewed during the period of January 2007 to June 2014 to evaluate the prevalence of seizures before and after starting clozapine.\n\n\nRESULTS\nThe majority of patients commenced on clozapine were male (65%), single (65%), and unemployed (57%). The mean (± standard deviation) dose of clozapine was 277.9 ± 102.5 mg/day. A history of seizure was present in 6 patients who were also prescribed antiepileptic medication; of these 6 patients, only 1 case had recurrence of seizure while taking clozapine due to poor compliance with ongoing antiepileptic medication. The incidence rate of new-onset seizure with clozapine was 6% (12/216). Most patients who developed seizures were male, aged between 24 and 41 years, and had a long duration of illness (≥ 10 years). The risk of seizure was associated with the dose of clozapine used: 3% (5/159) with dose up to 300 mg/day, 8% (4/49) with 325 to 500 mg/day, and 38% (3/8) in those receiving > 500 mg/day. More than half of the patients (7/12) who developed seizures while prescribed clozapine were managed with reduction in the dose of clozapine. In one-third of cases (4/12) an antiepileptic medication was added and in 1 case, clozapine was stopped. All patients who continued on clozapine remained seizure-free at follow-up that ranged from 6 months to 4 years.\n\n\nCONCLUSIONS\nThe incidence of seizures with clozapine was 6% and the risk of seizures increased with higher doses.",
"affiliations": "Department of Psychiatry, Postgraduate Institute of Medical Education and Research, Chandigarh 160012, India.;Department of Psychiatry, Postgraduate Institute of Medical Education and Research, Chandigarh 160012, India.;Department of Psychiatry, Postgraduate Institute of Medical Education and Research, Chandigarh 160012, India.;Department of Psychiatry, Postgraduate Institute of Medical Education and Research, Chandigarh 160012, India.",
"authors": "Grover|S|S|;Hazari|N|N|;Chakrabarti|S|S|;Avasthi|A|A|",
"chemical_list": "D000927:Anticonvulsants; D014150:Antipsychotic Agents; D003024:Clozapine",
"country": "China",
"delete": false,
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"issue": "25(2)",
"journal": "East Asian archives of psychiatry : official journal of the Hong Kong College of Psychiatrists = Dong Ya jing shen ke xue zhi : Xianggang jing shen ke yi xue yuan qi kan",
"keywords": "Clozapine; Drug-related side effects and adverse reactions; Seizures",
"medline_ta": "East Asian Arch Psychiatry",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000927:Anticonvulsants; D014150:Antipsychotic Agents; D003024:Clozapine; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D015994:Incidence; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D012307:Risk Factors; D012559:Schizophrenia; D012640:Seizures; D055815:Young Adult",
"nlm_unique_id": "101536416",
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"pages": "73-8",
"pmc": null,
"pmid": "26118746",
"pubdate": "2015-06",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Association of Clozapine with Seizures: A Brief Report Involving 222 Patients Prescribed Clozapine.",
"title_normalized": "association of clozapine with seizures a brief report involving 222 patients prescribed clozapine"
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"abstract": "Natalizumab is a disease-modifying drug that has proved greatly effective and well-tolerated in highly-active Multiple Sclerosis (MS). However, it may increase the risk for opportunistic infections, such as viral ones. We describe a 37-year-old woman treated with Natalizumab for Relapsing-Remitting Multiple Sclerosis (RR-MS) who presented to our clinic with malaise, arthromyalgias, rash, and fever. She later developed diarrhea and severe abdominal pain. A diagnosis of parvovirus B19 (B19V) infection and acute acalculous cholecystitis (AAC) was eventually made. To our knowledge, this is the first reported case of AAC possibly related to Natalizumab therapy and B19V infection.",
"affiliations": "Department of Neurology, Hospital Universitario Miguel Servet, Paseo Isabel la Católica 1-3, 50009, Zaragoza, Spain.;Department of Internal Medicine, Hospital Universitario Miguel Servet, Paseo Isabel la Católica 1-3, 50009, Zaragoza, Spain.;Department of Neurology, Hospital Universitario Miguel Servet, Paseo Isabel la Católica 1-3, 50009, Zaragoza, Spain.;Department of Neurology, Hospital Universitario Miguel Servet, Paseo Isabel la Católica 1-3, 50009, Zaragoza, Spain.;Department of Internal Medicine, Hospital Universitario Miguel Servet, Paseo Isabel la Católica 1-3, 50009, Zaragoza, Spain.;Department of Neurology, Hospital Universitario Miguel Servet, Paseo Isabel la Católica 1-3, 50009, Zaragoza, Spain.",
"authors": "Lambea-Gil|Alvaro|A|;Fumanal-Idocin|Luis|L|;Sebastián-Torres|Berta|B|;Saldaña-Inda|Ignacio|I|;Huici-Polo|Patxi|P|;Alarcia-José-Ramon-Ramon Ara-Callizo|Raquel|R|",
"chemical_list": "D000069442:Natalizumab",
"country": "India",
"delete": false,
"doi": "10.4103/0028-3886.314544",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0028-3886",
"issue": "69(2)",
"journal": "Neurology India",
"keywords": "Acalculous cholecystitis; immunosuppression; multiple sclerosis; natalizumab; parvovirus B19",
"medline_ta": "Neurol India",
"mesh_terms": "D042101:Acalculous Cholecystitis; D000328:Adult; D041881:Cholecystitis, Acute; D005260:Female; D006801:Humans; D009103:Multiple Sclerosis; D020529:Multiple Sclerosis, Relapsing-Remitting; D000069442:Natalizumab",
"nlm_unique_id": "0042005",
"other_id": null,
"pages": "495-496",
"pmc": null,
"pmid": "33904486",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Acute Acalculous Cholecystitis in a Multiple Sclerosis Patient Treated with Natalizumab.",
"title_normalized": "acute acalculous cholecystitis in a multiple sclerosis patient treated with natalizumab"
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"abstract": "A 22-year-old woman presented with symptoms and signs consistent with acute severe asthma. After significant doses of beta-agonist, she developed a significant lactic acidosis. Significant issues arose in this patient's history with regards to purchase of medications, compliance and follow-up with respiratory service. Beta-adrenergic receptors when stimulated have been hypothesised to increase lipolysis, producing free fatty acids, which inhibit the conversion of pyruvate to coenzyme A within the Krebs cycle. Additional pyruvate is generated through stimulation of glycolysis and glycogenolysis through simultaneous catecholamine surge. This increased pyruvate load is shunted through anaerobic glycolysis, producing increased lactate. Steroid use during an asthma attack enhances the beta-2 receptor sensitivity, further potentiating lactate production. The hyperadrenergic state in this young asthmatic likely resulted in pyruvate and therefore lactate rise and thus metabolic acidosis as mentioned before. This piece highlights a physiological phenomenon that may occur in the context of iatrogenic hyperadrenergism.",
"affiliations": "Irish Higher Specialist Trainee, Royal College of Physicians of Ireland, Dublin, Ireland.;Our Lady's Hospital Navan, Navan, Ireland.",
"authors": "Sharif|Zain|Z|http://orcid.org/0000-0003-4635-5862;Al-Alawi|Mazen|M|",
"chemical_list": "D058666:Adrenergic beta-2 Receptor Agonists; D000420:Albuterol",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2017-224090",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2018()",
"journal": "BMJ case reports",
"keywords": "Asthma; Respiratory System",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000140:Acidosis, Lactic; D000208:Acute Disease; D000280:Administration, Inhalation; D058666:Adrenergic beta-2 Receptor Agonists; D000420:Albuterol; D001249:Asthma; D001784:Blood Gas Analysis; D017281:Cost of Illness; D005260:Female; D006801:Humans; D007049:Iatrogenic Disease; D010349:Patient Compliance; D055815:Young Adult",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "29914901",
"pubdate": "2018-06-17",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "23331938;15911945;1353501;21802882;11153575;2118447;23245609;11348975;12534556;21722560;11398069;24000245;7913243",
"title": "Beware of beta! A case of salbutamol-induced lactic acidosis in severe asthma.",
"title_normalized": "beware of beta a case of salbutamol induced lactic acidosis in severe asthma"
} | [
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"companynumb": "IE-TEVA-2018-IE-929557",
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{
"abstract": "OBJECTIVE\nTo report a case of late iatrogenic bleb formation and hypotony maculopathy after pterygium surgery applying Mitomycin C (MMC).\n\n\nMETHODS\nA 66-year-old man presented with an elevated, bleb-like, fluid-filled, cystic lesion on the nasal sclera of the right eye. The patient had undergone pterygium surgery with a combination of conjunctival autograft and adjuvant intraoperative MMC 0.02% four years before. The sclera seemed fistulized at the site of surgery and a thin layer of conjunctiva completely covered the lesion. A scleral patch graft was secured over the fistula with sutures, followed by excision of the thinned, avascular conjunctiva and advancement of the healthy adjacent conjunctiva to cover the patch graft. One month later, a small bleb re-appeared adjacent to the scleral patch graft and IOP was 2 mmHg. Argon-laser treatment of the bleb was tried to induce scarring and reduction of bleb size, and was highly effective. After one week, IOP was increased to 8 mmHg. The clinical features remained stable four months after initial presentation.\n\n\nCONCLUSIONS\nPterygium surgery using adjuvant MMC may result in late iatrogenic bleb formation and hypotony maculopathy. This complication can be successfully corrected surgically using a scleral patch graft combined with argon laser treatment over the inadvertent bleb.",
"affiliations": "Eye Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.;Eye Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; Glaucoma Division, Jules Stein Eye Institute, Doris Stein Eye Research Center, CA, USA.;Eye Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.",
"authors": "Shokouhi-Rad|Saeed|S|;Alizadeh|Reza|R|;Daneshvar|Ramin|R|",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": "10.4103/2008-322X.170341",
"fulltext": "\n==== Front\nJ Ophthalmic Vis ResJ Ophthalmic Vis ResJOVRJournal of Ophthalmic & Vision Research2008-20102008-322XMedknow Publications & Media Pvt Ltd India JOVR-10-34510.4103/2008-322X.170341Case ReportIatrogenic Bleb Formation and Hypotony Maculopathy Following Pterygium Surgery with Mitomycin-C Shokouhi-Rad Saeed MD1Alizadeh Reza MD12Daneshvar Ramin MD11 Eye Research Center, Mashhad University of Medical Sciences, Mashhad, Iran2 Glaucoma Division, Jules Stein Eye Institute, Doris Stein Eye Research Center, CA, USACorrespondence to: Reza Alizadeh. Glaucoma Division, Jules Stein Eye Institute, Doris Stein Eye Research Center, 200 Stein Plaza, Los Angeles, CA 90095-7000, USA. E-mail: alizadehr881@mums.ac.irJul-Sep 2015 10 3 345 347 10 7 2013 20 5 2014 Copyright: © 2015 Journal of Ophthalmic and Vision Research2015This 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.Purpose:\nTo report a case of late iatrogenic bleb formation and hypotony maculopathy after pterygium surgery applying Mitomycin C (MMC).\n\nCase Report:\nA 66-year-old man presented with an elevated, bleb-like, fluid-filled, cystic lesion on the nasal sclera of the right eye. The patient had undergone pterygium surgery with a combination of conjunctival autograft and adjuvant intraoperative MMC 0.02% four years before. The sclera seemed fistulized at the site of surgery and a thin layer of conjunctiva completely covered the lesion. A scleral patch graft was secured over the fistula with sutures, followed by excision of the thinned, avascular conjunctiva and advancement of the healthy adjacent conjunctiva to cover the patch graft. One month later, a small bleb re-appeared adjacent to the scleral patch graft and IOP was 2 mmHg. Argon-laser treatment of the bleb was tried to induce scarring and reduction of bleb size, and was highly effective. After one week, IOP was increased to 8 mmHg. The clinical features remained stable four months after initial presentation.\n\nConclusion:\nPterygium surgery using adjuvant MMC may result in late iatrogenic bleb formation and hypotony maculopathy. This complication can be successfully corrected surgically using a scleral patch graft combined with argon laser treatment over the inadvertent bleb.\n\nIatrogenic Bleb FormationHypotony MaculopathyPterygium Surgery\n==== Body\nINTRODUCTION\nIn this interventional case report, we describe a unique case of iatrogenic bleb formation following pterygium surgery with adjunctive intraoperative Mitomycin C (MMC). To our knowledge this is the first report of late iatrogenic bleb formation with hypotony maculopathy after pterygium surgery in the literature.\n\nCASE REPORT\nA 66-year-old Turkmen man was referred due to gradual and painless decreased vision following an initially uncomplicated course of recovery after pterygium surgery 4 years before, at another center. According to the surgical records, pterygium removal was performed using a combination of conjunctival autograft and adjuvant intraoperative MMC 0.02%. The patient was in good general health with no remarkable medical or ocular history, except for pterygium surgery.\n\nOn examination, uncorrected distance visual acuity (UCDVA) were 1.5 and 0.8 LogMAR (20/630 and 20/125, Snellen acuity) in the right and left eyes, respectively. With a refraction of +6.00-0.75 @ 130° and −1.50-0.75 @ 135°, best spectacle corrected distance visual acuity was 0.5 and 0.2 LogMAR (20/63 and 20/32, Snellen acuity) in the right and left eyes, respectively. There was no afferent pupillary defect, nor pupillary abnormality. Slit lamp biomicroscopy of the left eye was unremarkable, while in the right eye, an elevated, bleb-like, fluid-filled, cystic lesion was noticeable in the nasal sclera (over the presumed site of previous surgery). The sclera seemed fistulized at the surgical site (approximately for 1 × 1 mm2) and a thin layer of conjunctiva completely covered the lesion [Figure 1]. Seidel's test was negative. The anterior chamber had normal depth comparable to the opposite side and was quiet. There was neither a significant cataract nor synechiae. Goldmann applanation tonometry readings were 6 and 10 mmHg in the right and left eyes, respectively. On dilated fundus examination at the slit lamp, the optic disc had no significant cupping in either eye; however, in the right eye the disc margin was slightly blurred and marked choroidal folds were present in the macular region [Figure 2]. Optical coherence tomography (OCT) further documented the clinical findings [Figure 3].\n\nFigure 1 Slit lamp photography at presentation. There is a bleb like elevation, filled with fluid on the nasal side, at the site of previous pterygium surgery.\n\nFigure 2 Fundus photograph at presentation, note the choroidal folds and macular folds due to hypotony.\n\nFigure 3 Optical coherence tomography image at presentation shows retinal folds and macular edema due to hypotony.\n\nWith a diagnosis of iatrogenic bleb formation, complicated by hypotony maculopathy, surgical closure of the fistula was planned. A precisely sized, donor scleral patch graft was secured water-tightly over the fistula with multiple 10-0 nylon sutures, followed by excision of the thinned avascular conjunctiva and advancement of the healthy adjacent conjunctiva to cover the patch graft. One day following surgery, the graft was in good condition [Figure 4], intraocular pressure (IOP) was 16 mmHg, and UCDVA was improved to 0.5 Log MAR (20/63 Snellen acuity). Choroidal folds were markedly reduced.\n\nFigure 4 Slit lamp photograph, one day after scleral patch grafting. The donor sclera's white hue is visible beyond the advanced conjunctiva.\n\nOne month later, a small bleb re-appeared adjacent to the scleral patch graft and UCDVA dropped to 1.2 Log MAR (20/320 Snellen acuity). IOP was 2 mmHg; however, Seidel's test demonstrated no leakage over the bleb. Faint wrinkling was obvious on fundus examination. Regarding the good condition of the overlying conjunctiva and low-lying nature of the bleb, argon laser was applied to induce scarring and reduction of bleb size. The procedure was highly effective [Figure 5] and after one week IOP was increased to 8 mmHg, UCDVA improved to 0.3 LogMAR (20/40, Snellen acuity), and choroidal folds were reduced markedly. Repeat OCT evaluation confirmed the reduction in macular thickness [Figure 6]. The clinical features remained stable through all other visits until final follow-up, 4 months after initial presentation.\n\nFigure 5 Slit lamp photograph one day after argon laser therapy.\n\nFigure 6 Last follow-up optical coherence tomography image (one week after argon-laser therapy) shows reduction of macular folds and edemaable.\n\nDISCUSSION\nWe believe that in the patient presented herein, the leading cause of scleral melting, subconjunctival leakage, bleb formation and hypotony was excessive use of MMC 0.02% intraoperatively;[12] however, details of the previous surgical procedure were not available.\n\nAs there were no other cases comparable to the present case, scleral patch grafting was performed to reinforce the site of inadvertent scleral fistulization.[3] However, this procedure failed to completely resolve the situation due to the large size of the iatrogenic bleb. Thus we complemented treatment with argon laser treatment,[4567] and this combination therapy[89] succeeded in managing the condition.\n\nFinancial Support and Sponsorship\nNil.\n\nConflicts of Interest\nThere are no conflicts of interest.\n==== Refs\nREFERENCES\n1 Shi WY Wang FH Mitomycin C related complications shouldn’t be neglected in the pterygium surgery Zhonghua Yan Ke Za Zhi 2013 49 869 872 24433686 \n2 Doshi RR Harocopos GJ Schwab IR Cunningham ET Jr The spectrum of postoperative scleral necrosis Surv Ophthalmol 2013 58 620 633 23410842 \n3 Harizman N Ben-Cnaan R Goldenfeld M Levkovitch-Verbin H Melamed S Donor scleral patch for treating hypotony due to leaking and/or overfiltering blebs J Glaucoma 2005 14 492 496 16276283 \n4 Akova YA Dursun D Aydin P Akbatur H Duman S Management of hypotony maculopathy and a large filtering bleb after trabeculectomy with mitomycin C: Success with argon laser therapy Ophthalmic Surg Lasers 2000 31 491 494 11095128 \n5 Amini H Razeghinejad MR Ghaffary E Abdollahi A Effect of diode laser application with G-probe on ocular hypotony after trabeculectomy with mitomycin-C Photomed Laser Surg 2006 24 741 744 17199475 \n6 Fink AJ Boys-Smith JW Brear R Management of large filtering blebs with the argon laser Am J Ophthalmol 1986 101 695 699 3717254 \n7 Kahook MY Schuman JS Noecker RJ Trypan blue-assisted neodymium: YAG laser treatment for overfiltering bleb J Cataract Refract Surg 2006 32 1089 1090 16857492 \n8 Haynes WL Alward WL Combination of autologous blood injection and bleb compression sutures to treat hypotony maculopathy J Glaucoma 1999 8 384 387 10604298 \n9 Hyung SM Choi MY Kang SW Management of chronic hypotony following trabeculectomy with mitomycin C Korean J Ophthalmol 1997 11 15 24 9283150\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "2008-322X",
"issue": "10(3)",
"journal": "Journal of ophthalmic & vision research",
"keywords": "Hypotony Maculopathy; Iatrogenic Bleb Formation; Pterygium Surgery",
"medline_ta": "J Ophthalmic Vis Res",
"mesh_terms": null,
"nlm_unique_id": "101497643",
"other_id": null,
"pages": "345-7",
"pmc": null,
"pmid": "26730324",
"pubdate": "2015",
"publication_types": "D002363:Case Reports",
"references": "23410842;17199475;16857492;10604298;3717254;16276283;24433686;9283150;11095128",
"title": "Iatrogenic Bleb Formation and Hypotony Maculopathy Following Pterygium Surgery with Mitomycin-C.",
"title_normalized": "iatrogenic bleb formation and hypotony maculopathy following pterygium surgery with mitomycin c"
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{
"abstract": "BACKGROUND\nPatients with lymphoma are at risk for developing pulmonary opportunistic infections due to immunocompromise. However, clinical reports of concurrent lymphoma and opportunistic infection at presentation are rare and often confined to single cases. A delayed diagnosis of either opportunistic infection or lymphoma usually occurs in this complex situation. Here, we report such a case and analyse 18 similar cases searched in the PubMed database to deepen clinicians' understanding.\n\n\nMETHODS\nA 48-year-old man presented with a 3-month history of fever, cough and emaciation. High-resolution computed tomography revealed bilateral cavitating lesions of different sizes. Aspergillus fumigatus complex was identified from a bronchoalveolar lavage fluid culture. However, antifungal treatment combined with multiple rounds of antibacterial therapy was unsuccessful, and the patient's lung lesions continued to deteriorate. Multiple puncture biopsies finally confirmed the coexistence of diffuse large B-cell lymphoma. Despite the initiation of combination chemotherapy, the patient died of progressive respiratory failure.\n\n\nCONCLUSIONS\nSynchronous pulmonary lymphoma and simultaneous opportunistic infection is rare and usually lacks specific clinical and imaging manifestations. Lymphoma should be considered as part of the differential diagnosis of patients with an opportunistic infection when treatment fails or other symptoms are present that could be considered \"atypical\" for the condition. Tissue biopsy is the gold standard, and multiple biopsies are essential for making the final diagnosis and should be performed upon early suspicion.",
"affiliations": "Division of Pulmonary Medicine, Key Laboratory of Heart and Lung, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China.;Division of Pulmonary Medicine, Integrated Chinese and Western Medicine Hospital of Wenzhou, Wenzhou, Zhejiang, 325000, China.;Division of Pulmonary Medicine, Key Laboratory of Heart and Lung, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China.;Division of Pulmonary Medicine, Key Laboratory of Heart and Lung, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China.;Division of Pulmonary Medicine, Key Laboratory of Heart and Lung, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China. 38805@163.com.;Division of Pulmonary Medicine, Key Laboratory of Heart and Lung, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China. zjwzhxy@126.com.",
"authors": "Shao|Lianyou|L|;Jiang|Longxiang|L|;Wu|Siyao|S|;Yu|Lihua|L|;Wang|Liangxing|L|;Huang|Xiaoying|X|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1186/s12885-019-6471-x",
"fulltext": "\n==== Front\nBMC CancerBMC CancerBMC Cancer1471-2407BioMed Central London 647110.1186/s12885-019-6471-xCase ReportSimultaneous occurrence of invasive pulmonary aspergillosis and diffuse large B-cell lymphoma: case report and literature review Shao Lianyou slyou1994@163.com 1Jiang Longxiang 1099963887@qq.com 2Wu Siyao 418235317@qq.com 1Yu Lihua 554850340@qq.com 1Wang Liangxing 38805@163.com 1Huang Xiaoying zjwzhxy@126.com 11 0000 0004 1808 0918grid.414906.eDivision of Pulmonary Medicine, Key Laboratory of Heart and Lung, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325000 China 2 Division of Pulmonary Medicine, Integrated Chinese and Western Medicine Hospital of Wenzhou, Wenzhou, Zhejiang, 325000 China 6 1 2020 6 1 2020 2020 20 1513 5 2019 17 12 2019 © The Author(s). 2020Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nPatients with lymphoma are at risk for developing pulmonary opportunistic infections due to immunocompromise. However, clinical reports of concurrent lymphoma and opportunistic infection at presentation are rare and often confined to single cases. A delayed diagnosis of either opportunistic infection or lymphoma usually occurs in this complex situation. Here, we report such a case and analyse 18 similar cases searched in the PubMed database to deepen clinicians’ understanding.\n\nCase presentation\nA 48-year-old man presented with a 3-month history of fever, cough and emaciation. High-resolution computed tomography revealed bilateral cavitating lesions of different sizes. Aspergillus fumigatus complex was identified from a bronchoalveolar lavage fluid culture. However, antifungal treatment combined with multiple rounds of antibacterial therapy was unsuccessful, and the patient’s lung lesions continued to deteriorate. Multiple puncture biopsies finally confirmed the coexistence of diffuse large B-cell lymphoma. Despite the initiation of combination chemotherapy, the patient died of progressive respiratory failure.\n\nConclusions\nSynchronous pulmonary lymphoma and simultaneous opportunistic infection is rare and usually lacks specific clinical and imaging manifestations. Lymphoma should be considered as part of the differential diagnosis of patients with an opportunistic infection when treatment fails or other symptoms are present that could be considered “atypical” for the condition. Tissue biopsy is the gold standard, and multiple biopsies are essential for making the final diagnosis and should be performed upon early suspicion.\n\nKeywords\nLymphomaOpportunistic infectionConcurrent infectionBiopsyissue-copyright-statement© The Author(s) 2020\n==== Body\nBackground\nLymphomas are a diverse group of clonal neoplasms arising from B and T lymphocytes and natural killer cells. Manipulation and silencing of the host’s immune system by methods ranging from changes in the cellular microenvironment composition to changes in distinct signalling pathways is an important feature of various lymphomas [1, 2]. Chemotherapeutic treatment of these diseases can also cause prolonged and profound neutropenia and immunosuppression. Therefore, individuals with lymphoma are at high risk for developing opportunistic infections. The incidence of tuberculosis (TB) has been reported to range from 0.9 to 13.2%, and that of miliary TB has been reported to be 35 times higher than in the general population [3, 4]. A retrospective study revealed that the incidence of invasive fungal infection (IFI) was 1.1% in Hodgkin’s lymphoma (HL) patients and 0.3% in non-Hodgkin’s lymphoma (NHL) patients [5]. Aspergillus was the most frequent causative pathogen, and most cases appeared during intensive therapy for tumours using chemotherapy, immunosuppressive agents or haematopoietic stem cell transplantation [5, 6]. However, a rare clinical scenario remains in which lymphoma and opportunistic infection exist simultaneously at presentation. The exact incidence is unknown, and it is often confined to single cases. The presence of one disease may eclipse another and thereby provide a challenge to clinicians. Here, we present the case of a patient with synchronous pulmonary aspergillosis and diffuse large B-cell lymphoma at presentation to improve our understanding of this condition.\n\nCase presentation\nA 48-year-old male was referred to the clinic for recurrent fever, cough and 5-kg weight loss during past 3 months. He denied breathing difficulties, chest pain, night sweats, wheezing and other uncomfortable symptoms. He was a smoker of 30 pack-years and had no history of travel or TB. There were no significant findings in his prior medical or family history.\n\nAt the time of the initial evaluation, the patient showed an auricular temperature of 39.2 °C, a blood pressure of 108/70 mmHg, a pulse of 108, and a respiratory rate of 20. He had diminished breath sounds on both sides, and no enlarged lymph nodes were noted. Examinations of the heart, abdomen, extremities and nervous system were normal.\n\nLaboratory data showed that the patient’s white blood cell count, haemoglobin level and platelet count were normal. C-reactive protein and lactate dehydrogenase (LDH) levels were elevated at 151.00 mg/L (normal range: 0~8 mg/L) and 395.00 U/L (0~247 U/L). Tumour markers, such as CEA, NSE, SCCA, ProGRP and CYFRA21-1, were all in the normal range. HIV serology was also negative. Computed tomography (CT) of the chest showed bilateral cavitating lesions with mediastinal enlarged lymph nodes (Fig. 1, A-C). The patient was started on empiric antibiotic treatment with cefoperazone-sulbactam. After 3 days of therapy, his temperature was still above 38.5 °C. A CT-guided biopsy of the pulmonary cavity was performed on the 4th day after admission. Pathology revealed mild atypical alveolar epithelioid cells and chronic interstitial fibrous tissue proliferation with necrosis. The tissue was negative on smear and culture for acid-fast bacilli. Periodic Acid-Schiff (PAS) stain was also negative. The patient’s antibiotics were changed to imipenem-cilastin sodium and metronidazole. However, the second combination of antibiotics was ineffective. The patient was still febrile, and further blood cultures remained negative. On the fifth day, he underwent bronchoscopy and bronchoalveolar lavage, which were negative for any masses, abscesses or areas of bleeding. However, the patient tested positive for galactomannan antigenemia in bronchoalveolar lavage fluid (BALF) and blood. Aspergillus fumigatus complex was identified from the BALF culture on the 10th day. Due to the new microbiological findings, the patient was treated with voriconazole. In addition, the patient was still treated with linezolid, moxifloxacin and imipenem-cilastin sodium combined with metronidazole successively during the third round of antibiotic use. He was persistently febrile and developed breathing difficulties. We recommended the patient undergo positron emission tomography/computed tomography (PET-CT) to assess the possibility of haematological malignancies. It was refused because of the financial burden. We performed bone marrow aspiration on the 20th day. No abnormal cells were observed in the bone marrow examination. A CT scan performed 23rd day revealed further expanding consolidation and bilateral pleural effusion (Fig. 1, D-F). Thoracentesis was performed on the 24th day. Pleural fluid analysis revealed a red blood cell count of 16,320 cells/μL and a nucleated cell count of 1280 cells/μL (31% lymphocytes and 54% segmented cells), and the Rivalta test was negative. LDH and adenosine deaminase (ADA) levels were 381.00 U/L (0~247 U/L) and 15.00 U/L, respectively. There were no malignant cells in the pleural effusion. Considering the possibility of opportunistic pathogens, additional drugs were added to cover nocardia and pneumocystic infections. However, his temperature still increased to 40 °C. A second CT-guided biopsy was performed on 27th day to find the cause of repeated fever, and the pathological examination of the specimen revealed polygonal atypical lymphoid cell proliferation with necrosis. The second PAS staining and tissue culture were also negative. Immunohistochemical staining on 35th day showed positive markers for CD20, EBER, BCL-2, PAX5, MUM-1 and a Ki-67 rate of 70% (Fig. 2), which was consistent with a diagnosis of diffuse large B-cell lymphoma (DLBCL). He also had a serum IgM test for Epstein–Barr virus (EBV) and other viruses, including influenza and toxoplasma, rubella virus, cytomegalovirus, herpes virus (TORCH), which were all negative. The EBV load was less than 5*103 (< 5*103). He was therefore diagnosed with synchronous pulmonary aspergillosis and DLBCL. Despite the combined R-COPE chemotherapy (rituximab 600 mg d 0 + cyclophosphamide 0.4 g d1–2 + vindesine 4 mg d1 + dexamethasone 20 mg d1–4 + VP-16 0.1 g d1–2) starting 38th days after hospitalization, the patient’s situation continued to deteriorate. He developed cervical, axillary and inguinal lymph node enlargement, which were unremarkable on admission. His LDH increased to 1627 U/L. The following CT scan (Fig. 1, G-I) showed bilateral pleural effusion, atelectasis and consolidations of all right lung lobes with air bronchograms. Then, the patient died of progressive respiratory failure on the 52nd day.\nFig. 1 Chest CT findings during hospitalization. a-c: A CT scan of the chest (on admission) showing multiple nodules (thick arrows) and thick-walled cavities (black triangle) in lung fields as well as enlarged mediastinal lymph nodes. d-f: Subsequent chest CT (23rd day) showing new emerging round opacities (thick arrows), expending lung abscess and cavities (black stars), bilateral pleural effusion (thin arrows). g-i: Subsequent chest CT (49th day) showing increased pleural effusion, atelectasis and consolidations on both sides with air bronchograms (white star)\n\n\nFig. 2 Pathological staining and immunohistochemical results. a-b: Coagulative necrosis and polygonal atypical lymphoid cell proliferation. Immunohistochemical staining shows positive markers for EBER (c, 400×) and CD20 (d, 400×) with a Ki-67 rate of 70% (e, 400×)\n\n\n\nDiscussion and conclusion\nLymphoma represents a spectrum of malignant neoplasms arising from the lymphoid system with an incidence of approximately 8% of all malignancies. 25 to 40% of HL/NHL tumours arise at extranodal sites. The most common sites are the gastrointestinal tract, tonsils, skin and connective tissues. Lymphomas originating from the lung may account for 3.6% of cases [7–9]. Pulmonary lymphoma may represent primary or secondary involvement of the lungs. Primary pulmonary lymphoma (PPL) has been defined as a clonal lymphoid proliferation affecting one or both lungs (parenchyma and/or bronchi) in a patient with no clinical, pathological, or radiographic evidence of lymphoma elsewhere, either in the past or at present or for 3 months after presentation [10]. Secondary pulmonary lymphoma is more common than PPL. It refers to a secondary involvement of the lung from a known extrapulmonary lymphoma or dominant pulmonary lesion, with indolent primary extrapulmonary lesions observed within 3 months [11, 12]. Lymphoma of the lung is asymptomatic or have nonspecific respiratory symptoms, such as fever, cough, dyspnoea, chest pain, and haemoptysis. Radiological manifestations of lymphoma involving the lung are also variable. The vast majority of cases present as multiple nodules, consolidation, solitary masses or cavities with or without enlarged lymph nodes. A rare subtype of lymphoma can also present with diffuse ground-glass shadows or pleural effusion on a chest CT scan [13]. Therefore, the differential diagnosis includes TB, fungal infections, interstitial lung disease, neoplastic disease and metastatic spread from solid malignancies.\n\nOpportunistic infection frequently develops in people with reduced immunity, such as individuals with advanced age, diabetes mellitus, HIV infection, or a history of drug abuse, organ transplantation or immunosuppresive therapy. The presentation of an opportunistic infection is related to host immunity and physiological conditions. The lung is the classical site of opportunistic infection. Disseminated infections caused by Mycobacterium tuberculosis and pathogenic fungi can also manifest as multifocal infiltration and lymph node masses in the image. Therefore, significant overlaps exist among opportunistic infections and lymphoma.\n\nThe patient we reported first presented with a high fever and multiple pulmonary cavities on a CT scan. Based on the findings of microbiology, the initial diagnosis was pulmonary aspergillosis, which was consistent with the imaging. However, neither antifungal therapy nor multiple rounds of antibiotic therapy were effective. The patient’s lung lesions showed rapid progression, and he developed superficial lymph node enlargement during hospitalization. A repeat biopsy of the same lesion confirmed malignant lymphoma.\n\nThe coexistence of lymphoma and opportunistic infection at the initial time of diagnosis is rare in the literature. We chose “lymphoma”, “Hodgkin’s lymphoma”, “opportunistic infection”, “fungal infection”, “tuberculosis” etc. as keywords and searched cases from 1960 to present in the PubMed database through different combinations of keywords.\n\nOnly a few publications have reported this condition (Table 1) [14–30] (see Table 1. Reported cases of synchronous opportunistic infection and lymphoma). In all 18 cases, both diseases coexisted at initial presentation, with 12 cases of concomitant TB, 2 cases of pulmonary Aspergillus infection, 2 cases of pulmonary cryptococcosis, 1 case of Legionella pneumophila pneumonia, and 1 case of pulmonary cytomegalovirus (CMV) infection (Table 2).\nTable 1 Reported cases of synchronous opportunistic infection and lymphoma\n\nNO.\tAge ranges\tDiagnosis\tAuthor\tTitle\tYear\tReference\t\n1\t55–60\tNHL + Pulmonary cryptococcosis\tRobert, K. et al.\tNon-Hodgkin’s Lymphoma with Lung Lesion\t1977\t[14]\t\n2\t35–40\tLymphoma+Pulmonary cryptococcosis\tOka, M. et al.\tA case of pulmonary cryptococcosis with diffuse pulmonary involvement of malignant lymphoma\t1985\t[15]\t\n3\t70–75\tLymphoma + Legionella pneumophila pneumonia\tMiyara, T. et al.\tRapidly expanding lung abscess caused by Legionella pneumophila in immunocompromised patients: a report of two cases\t2002\t[16]\t\n4\t40–45\tHL + TB\tCosta, L.J. et al.\tSimultaneous occurrence of Hodgkin disease and tuberculosis: report of three cases\t2004\t[17]\t\n5\t40–45\tHL + TB\tCosta, L.J. et al.\tSimultaneous occurrence of Hodgkin disease and tuberculosis: report of three cases\t2004\t[17]\t\n6\t10–15\tHL + TB\tCodrich, D. et al.\tPrimary pulmonary Hodgkin’s disease and tuberculosis in an 11-year-old boy: case report and review of the literature\t2006\t[18]\t\n7\t60–65\tDLBCL+TB\tSachdev, R. et al.\tCoexistent Nodal Diffuse Large B-Cell Lymphoma With Extrapulmonary Tuberculosis: A Rare Case\t2016\t[19]\t\n8\t60–65\tNHL + TB\tDres, M. et al.\tTuberculosis hiding a non-Hodgkin lymphoma “there may be more to this than meets the eye”\t2012\t[20]\t\n9\t65–70\tT-cell lymphoma+Pseudomembranous tracheitis\tMalhotra, P. et al.\tPseudomembranous tracheitis caused by Aspergillus fumigatus in the setting of high grade T-cell lymphoma\t2017\t[21]\t\n10\t55–60\tT cell lymphoma+TB\tHashmi, H.R.T. et al.\tAn Unusual Triad of Hemophagocytic Syndrome, Lymphoma and Tuberculosis in a Non-HIV Patient\t2017\t[22]\t\n11\t25–30\tHL + TB\tReddy, R. C. et al.\tA case of concomitant Hodgkin’s lymphoma with tuberculosis\t2014\t[23]\t\n12\t15–20\tHL + TB\tEnteria. et al.\tA Rare Case of Anterior Mediastinal and Right Lateral Neck Mass: TB With Hodgkin’s Lymphoma\t2017\t[24]\t\n13\t10–15\tALCL+TB\tBaka, M. et al.\tSuccessful treatment in a child with anaplastic large cell lymphoma and coexistence of pulmonary tuberculosis\t2013\t[25]\t\n14\t65–70\tBALT lymphoma+TB\tKlein, T.O. et al.\tBronchus-associated lymphoid tissue lymphoma and Mycobacterium tuberculosis infection: an unusual case and a review of the literature\t2007\t[26]\t\n15\t65–70\tBALT lymphoma+Mycobacterium avium Infection\tGaur,S. et al.\tBronchus-Associated Lymphoid Tissue Lymphoma Arising in a Patient With Bronchiectasis and Chronic Mycobacterium avium Infection\t2004\t[27]\t\n16\t70–75\tBALT lymphoma+TB\tYukinori Inadome, et al.\tMalignant lymphoma of bro nchus-associated lymphoid tissue (BALT) coexistent with pulmonary tuberculosis\t2001\t[28]\t\n17\t80–85\tNHL + pulmonary aspergillosis\tMiguel G.G. et al.\tInvasive pulmonary aspergillosis: a rare presentation of non-Hodgkin’s lymphoma\t1994\t[29]\t\n18\t65–70\tNHL + CMV infection\tAnnunziata M. et al.\tCMV infection and pneumonia in hematological malignancies\t2003\t[30]\t\nNHL non-Hodgkin’s lymphoma, HL Hodgkin’s lymphoma, TB tuberculosis, DLBCL diffuse large B cell lymphoma, ALCL anaplastic large cell lymphoma, BALT lymphoma bronchus-associated lymphoid tissue lymphoma, CMV cytomegalovirus\n\n\nTable 2 Analysis of information about synchronous opportunistic infection and lymphoma\n\nGender\t\n Men\t12\t\n Women\t6\t\nAge\t\n ≤ 20\t3\t\n 20–60\t6\t\n ≥ 60\t9\t\nLymphoma coexisting with\t\n Tuberculosis\t12\t\n Pulmonary Aspergillus infection\t2\t\n Pulmonary cryptococcosis\t2\t\n CMV infection\t1\t\n Legionella pneumophila infection\t1\t\nClinical presentation\t\n Fever\t9\t\n Cough/haemoptysis\t7\t\n Superficial lymphadenopathy\t5\t\n Weight loss\t4\t\n Dyspnoea\t4\t\n Dizzy\t2\t\n Chest pain\t2\t\nOutcome\t\n Remission\t10\t\n Died\t7\t\n UK\t1\t\nCMV cytomegalovirus, UK unknown\n\n\n\nThis condition can happen to individuals of any age or either gender. And it seems to be more frequent in males, with a ratio of approximately 2 to 1. Only one (no. 14) of the patients had an explicit history of diabetes mellitus, and one patient had urothelial cancer (status postresection, no. 9), and the other patients had no immunocompromised statuses previously. The three most prevalent clinical presentations among such patients are fever (50.0%), cough (38.9%) and superficial lymph node enlargement (27.8%). Most chest images indicate mediastinal or hilar lymph node enlargement, solitary or multiple pulmonary nodules and cavitating lesions. Other presentations include consolidation and hydrothorax on thorax CT scans (Table 3) (see Table 3 Clinical presentations and imaging features of the chest).\nTable 3 Clinical presentations and imaging features of the chest\n\nNo.\tAge ranges\tClinical presentations\tImaging features of the chest\t\nFever\tSuperficial lymphadenopathy\tCough/hemoptysis\tWeight loss\tDyspnea\tDizzy\tChest pain\tUK\t\n1\t55–60\t\t√\t\t\t\t\t\t\tA nodule in the right lung.\t\n2\t35–40\t\t\t√\t\t√\t\t\t\tConsolidations in both lungs and enlarged left hilar lymph node.\t\n3\t70–75\t√\t\t\t\t\t\t\t\tThe first time: not remarkable.\t\n\t\t\t\t\t\t\t\t\t\tThe second time: a nodule in the left lung.\t\n\t\t\t\t\t\t\t\t\t\tThe third time: cavitation in consolidation.\t\n4\t40–45\t\t√\t\t\t\t\t\t\tA cavitated lesion in the right lobe.\t\n5\t40–45\t√\t\t\t\t\t\t\t\tEnlarged mediastinal lymph node.\t\n6\t10–15\t√\t\t√\t√\t\t\t\t\tLeft lower lobe atelectasis.\t\n7\t60–65\t√\t\t\t√\t\t\t\t\tEnlarged mediastinal lymph node and pleural effusion.\t\n8\t60–65\t√\t\t√\t√\t\t√\t\t\tEnlarged mediastinal lymph nodes.\t\n9\t65–70\t√\t\t\t√\t\t\t\t\tEnlarged mediastinal, hilar and subcarinal lymph nodes.\t\n10\t55–60\t√\t\t\t\t\t√\t\t\tBilateral nodules and ground-glass opacification.\t\n11\t25–30\t\t\t√\t\t√\t\t√\t\tEnlarged mediastinal and hilar lymph nodes.\t\n12\t15–20\t\t√\t\t\t\t\t√\t\tMediastinal mass.\t\n13\t10–15\t\t√\t\t\t\t\t\t\tThe first time: a nodule in the left lung and enlarged mediastinal lymph node.\t\n\t\t\t\t\t\t\t\t\t\tThe second time: two new nodules in the lung.\t\n14\t65–70\t\t\t\t\t\t\t\t√\tThe first time: miliary pattern and consolidation in the lung.\t\n\t\t\t\t\t\t\t\t\t\tThe second time: multiple masses and small cavities in the lung.\t\n15\t65–70\t\t\t√\t\t\t\t\t\tThe first time: bronchiectatic change and parenchymal infiltrates in the right upper and lower lobes.\t\n\t\t\t\t\t\t\t\t\t\tThe second time: persistent bronchiectatic change and parenchymal infiltrates with a new consolidation in the right middle lobe.\t\n16\t70–75\t\t\t\t\t\t\t\t√\tA nodular lesion with pleural thickening and several satellite lesions involving a peripheral small bronchus.\t\n17\t80–85\t√\t\t√\t\t√\t\t\t\tBilateral interstitial pattern.\t\n18\t65–70\t√\t√\t√\t\t√\t\t\t\tA bilateral diffuse interstitial pattern without pleural effusion.\t\nUK unknown;\n\n\n\nDuring the diagnostic process, the persistent clinical symptoms and new lesions are the main reasons prompting clinicians to take another cause into consideration. The diagnostic approach almost always involves various types of invasive methods, such as superficial lymph node biopsy (61.1%), bronchoscopy or BAL (38.9%), bone marrow aspiration (38.9%), transbronchial biopsy (33.3%), needle aspiration biopsy of lung lesions (27.8%), surgical operations (22.2%), mediastinoscopy (11.1%) and thoracoscopy (11.1%) (Table 4) (see Table 4 Multiple biopsy methods involved in diagnostic processes). Eighty percent of patients undergo more than one biopsy in the same or different lesions during the diagnostic process because of negative pathology results or a lack of satisfactory biopsy specimens. In only two cases (no. 7, 13), the same tissue specimen revealed Mycobacterium tuberculosis infection coexisting with lymphoma. Three cases (no. 2, 3,17) were diagnosed only by postmortem analysis. The time from initial onset to definite diagnosis ranged from 3 days to 14 months (Table 5).\nTable 4 Multiple biopsy methods involved in diagnostic processes\n\nNo.\tAge ranges\tBiopsy methods\t\nNeedle aspiration or excision biopsy of lymph node\tNeedle aspiration biopsy of lung lesion\tBronchoscopy or BAL\tTBLB or TBNA\tThoracocentesis\tBone marrow aspiration\tLumbar puncture\tMediastinoscopy\tThoracoscopy\tSurgical Operation\tPostmortem\t\n1\t55–60\t√\t√\t√\t\t\t√\t\t\t\t\t\t\n2\t35–40\t\t\t\t√\t\t\t\t\t\t\t√\t\n3\t70–75\t√\t\t√\t√\t\t√\t\t\t\t\t√\t\n4\t40–45\t√\t\t\t\t\t\t\t\t√\t\t\t\n5\t40–45\t√\t\t\t\t\t\t\t√\t\t\t\t\n6\t10–15\t\t\t√√\t\t\t√\t\t\t\t√\t\t\n7\t60–65\t√\t\t\t\t√\t\t\t\t\t\t\t\n8\t60–65\t\t\t√\t\t\t\t\t\t\t√\t\t\n9\t65–70\t√\t\t√\t√\t\t√√\t\t\t\t\t\t\n10\t55–60\t√\t\t\t√\t\t√\t\t\t\t\t\t\n11\t25–30\t√\t\t\t√\t\t\t\t√\t\t\t\t\n12\t15–20\t√\t√\t\t\t\t\t\t\t\t\t\t\n13\t10–15\t√\t√\t\t\t\t√\t√\t\t\t\t\t\n14\t65–70\t\t√\t√\t\t\t\t\t\t\t\t\t\n15\t65–70\t\t√\t√\t\t\t√√\t\t\t\t√\t\t\n16\t70–75\t\t\t\t√\t\t\t\t\t√\t√\t\t\n17\t80–85\t\t\t\t\t\t\t\t\t\t\t√\t\n18\t65–70\t√\t\t\t\t\t\t\t\t\t\t\t\n\nTable 5 The delayed time and prognosis of each case\n\nNo.\tAge ranges\tDiagnosis 1\tDelayed time (days)\tDiagnosis 2\tOutcome\t\n1\t55–60\tNHL\tUK\tPulmonary cryptococcosis\tRemission\t\n2\t35–40\tPulmonary cryptococcosis\t139\tLymphoma\tDied (respiratory failure)\t\n3\t70–75\tpneumonia\t29\tLymphoma + Legionella pneumophila pneumonia\tDied (cardiac arrhythmia)\t\n4\t40–45\tTB\tUK\tHL\tRemission\t\n5\t40–45\tTB\t60\tHL\tRemission\t\n6\t10–15\tTB\tUK\tHL\tRemission\t\n7\t60–65\tDLBCL\tUK\tTB\tRemission\t\n8\t60–65\tTB\t14\tNHL\tDied (septic shock)\t\n9\t65–70\tT-cell lymphoma\tUK\tPseudomembranous tracheitis\tDied (respiratory failure)\t\n10\t55–60\tT-cell lymphoma\t20\tTB\tDied (multiple organ failure)\t\n11\t25–30\tTB\t120\tHL\tRemission\t\n12\t15–20\tTB\tUK\tHL\tUK\t\n13\t10–15\tALCL\t135\tTB\tRemission\t\n14\t65–70\tTB\t330\tBALT lymphoma\tRemission\t\n15\t65–70\tMycobacterium avium infection\t420\tBALT lymphoma\tRemission\t\n16\t70–75\tBALT lymphoma+TB\t–\t–\tRemission\t\n17\t80–85\tpneumonia\t3\tNHL + pulmonary aspergillosis\tDied (respiratory failure)\t\n18\t65–70\tNHL + CMV infection\t–\t–\tDied (respiratory failure)\t\nNHL non-Hodgkin’s lymphoma, UK unknown, TB tuberculosis, HL Hodgkin’s lymphoma, DLBCL diffuse large B-cell lymphoma, ALCL anaplastic large cell lymphoma, BALT lymphoma bronchus-associated lymphoid tissue lymphoma, CMV cytomegalovirus\n\n\n\nThe concurrence of lymphoma and TB is more common than concomitant fungal infection. The cellular immunodeficiency that usually accompanies lymphoma is believed to be a predisposing factor for opportunistic infection. But an aetiological role cannot be completely excluded. It has been reported that the risk of NHL is significantly increased in individuals with a history of TB, which is related to the DNA damage and apoptosis inhibition caused by M. tuberculosis [31–33]. It is not clear whether aspergillosis plays a similar role.\n\nThe concurrence of pulmonary lymphoma and opportunistic infection poses a management dilemma for physicians. A delayed diagnosis of either opportunistic infection or lymphoma usually occurs in this clinical scenario. The reasons can be summarized as follows: (1) Common symptoms and radiographic findings are shared by both disorders. When lymphoma and opportunistic infection exist simultaneously, it is difficult to judge whether the multifocal lesions and lymphadenopathy are lymphoma infiltrations or associated with infection. It makes the selection of the biopsy site challenging. (2) Tissue biopsy is the gold standard for the diagnosis and typing of lymphoma. While needle biopsy is inclusive, the majority of the tumour is constituted by reactive or inflammatory cells in varying compositions, especially HL. In HL, the neoplastic Hodgkin and Reed-Sternberg cells represent only a minority of the cellular infiltrate, with a frequency ranging from 0.1–10% [34]. Therefore, a single needle aspiration biopsy cannot ensure diagnostic yield.\n\nThe dilemma of lymphoma complicated with opportunistic infection is also reflected in treatment. Immediate application of chemotherapy may induce potential infection and aggravate the severity of the primary infection, especially for a particularly weak patient. Thus, it is necessary to identify whether evidence of infection exists in pathological specimens by specimen culture or special stains in addition to immunohistochemical staining. If anti-infectious treatments are given first, clinicians must notice that continuous antibiotic treatment for chronic infection may result in suppression of lymphoma and then create an illusion of clinical remission [27]. Therefore, when the treatment is less effective than expected or the clinical manifestations are not consistent with the infection, clinicians should look for other potential causes as soon as possible. If both diseases are treated at the same time, the risk of drug toxicity may be increased. So, choosing appropriate treatment timing is very important for these patients. Additional clinical data about the therapeutic plan for this condition should be collected to improve the prognosis.\n\nIn conclusion, simultaneous lymphoma and opportunistic infection in a primary presentation is a challenging condition. The diagnostic process should involve maintaining a high index of suspicion based upon an understanding of the clinical and imaging manifestations, of the therapeutic effect, and of the limitations of diagnostic methods. Different and various invasive diagnostic methods, including needle aspiration or excision biopsy of lymph nodes, CT-guided transthoracic needle aspiration, transbronchial biopsy and bone marrow puncture, should be performed to reach an early diagnosis.\n\nAbbreviations\nADAAdenosine deaminase\n\nALCLAnaplastic large cell lymphoma\n\nBALFBronchoalveolar lavage fluid\n\nBALT lymphomaBronchus-associated lymphoid tissue lymphoma\n\nCMVCytomegalovirus\n\nDLBCLDiffuse large B-cell lymphoma\n\nHLHodgkin’s lymphoma\n\nHRCTHigh-resolution computed tomography\n\nIFIInvasive fungal infection\n\nLDHLactate dehydrogenase\n\nNHLNon-Hodgkin’s lymphoma\n\nPASPeriodic Acid-Schiff stain\n\nPET-CTPositron emission tomography/computed tomography\n\nPPLPrimary pulmonary lymphoma\n\nTBTuberculosis\n\nTORCHToxoplasma, others, rubella virus, cytomegalovirus, herpes virus\n\nUKUnknown\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAcknowledgements\nWe thanks all the authors and those who helped in the preparation of the study and Mayun Chen for revising the figures and tables.\n\nAuthors’ contributions\nLYS wrote the manuscript, and all authors carefully revised the manuscript. LYS and LXJ performed a literature review and data collection to present. LHY cared for and followed up the patient. LHY and SYW assisted with the presentation of findings, figures and assisted with drafting and revising the manuscript. XYH and LXW contributed to the conception of the study. XYH and LXW verified all data, figures, materials and helped perform the analysis with constructive discussions. All authors read and approved the final version of this manuscript.\n\nFunding\nNot applicable.\n\nAvailability of data and materials\nThe datasets used and/or analysed during the current study are available from the corresponding author upon reasonable request.\n\nEthics approval and consent to participate\nEthical approval for this investigation was obtained from the Research Ethics Committee of the First Affiliated Hospital of Wenzhou Medical University.\n\nConsent for publication\nWritten informed consent was obtained from the patient’s son for publication of the case report.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n==== Refs\nReferences\n1. Menter T Tzankov A Mechanisms of immune evasion and immune modulation by lymphoma cells Front Oncol 2018 8 54 64 10.3389/fonc.2018.00054 29564225 \n2. Kumar D Xu ML Microenvironment cell contribution to lymphoma immunity Front Oncol 2018 8 288 298 10.3389/fonc.2018.00288 30101129 \n3. 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Malhotra Prashant Singh Karan Gill Paul Sahni Sonu Makaryus Mina Talwar Arunabh Pseudomembranous tracheitis caused by Aspergillus fumigatus in the setting of high grade T-cell lymphoma Respiratory Medicine Case Reports 2017 21 42 45 10.1016/j.rmcr.2017.03.016 28393004 \n22. Hashmi Hafiz Rizwan Talib Mishra Rashmi Niazi Masooma Venkatram Sindhaghatta Diaz-Fuentes Gilda An Unusual Triad of Hemophagocytic Syndrome, Lymphoma and Tuberculosis in a Non-HIV Patient American Journal of Case Reports 2017 18 739 745 10.12659/AJCR.903990 28669977 \n23. Narasimhan R Reddy RamanjulaC Mathew Meghena Parameswaran Ashok A case of concomitant Hodgkin′s lymphoma with tuberculosis Lung India 2014 31 1 59 10.4103/0970-2113.125985 24669086 \n24. Enteria Mary Ann A Rare Case of Anterior Mediastinal and Right Lateral Neck Mass: TB With Hodgkin's Lymphoma Chest 2017 152 4 A689 A690 10.1016/j.chest.2017.08.718 \n25. Baka Margarita Doganis Dimitrios Pourtsidis Apostolos Tsolia Maria Bouhoutsou Despina Varvoutsi Maria Strantzia Katerina Kosmidis Helen Successful Treatment in a Child with Anaplastic Large Cell Lymphoma and Coexistence of Pulmonary Tuberculosis Case Reports in Pediatrics 2013 2013 1 5 10.1155/2013/928701 \n26. Klein TO, Soll BA, Issel BF, et al. Bronchus-associated lymphoid tissue lymphoma and Mycobacterium tuberculosis infection: an unusual case and a review of the literature. Respir Care. 2007;52:755–8.\n27. Gaur S. Trayner E. Aish L. Weinstein R. Bronchus-associated lymphoid tissue lymphoma arising in a patient with bronchiectasis and chronicMycobacterium avium infection American Journal of Hematology 2004 77 1 22 25 10.1002/ajh.20136 15307101 \n28. Inadome Yukinori Ikezawa Tsuyoshi Oyasu Ryoichi Noguchi Masayuki Malignant lymphoma of bronchus-associated lymphoid tissue (BALT) coexistent with pulmonary tuberculosis Pathology International 2001 51 10 807 811 10.1046/j.1440-1827.2001.01272.x 11881735 \n29. Garcia-Gonzalez M. Sanroman A. L. Arribas R. Torres G. Cuesta C. Moreira V. F. Invasive pulmonary aspergillosis: a rare presentation of non-Hodgkin's lymphoma Postgraduate Medical Journal 1994 70 824 459 460 10.1136/pgmj.70.824.459 8029172 \n30. Manna Annunziata Pronzato Paolo Cordani Stefano Canessa Pieraldo CMV infection and pneumonia in hematological malignancies Journal of Infection and Chemotherapy 2003 9 3 265 267 10.1007/s10156-003-0251-9 14513398 \n31. Kumar P. Nucleoside diphosphate kinase from Mycobacterium tuberculosis cleaves single strand DNA within the human c-myc promoter in an enzyme-catalyzed reaction Nucleic Acids Research 2005 33 8 2707 2714 10.1093/nar/gki568 15888727 \n32. Tavani A Vecchia C La Franceschi S Serraino D Carbone A Medical history and risk of Hodgkinʼs and non-Hodgkinʼs lymphomas European Journal of Cancer Prevention 2000 9 1 59 64 10.1097/00008469-200002000-00008 10777011 \n33. Brooks P. C. Dawson L. F. Rand L. Davis E. O. The Mycobacterium-Specific Gene Rv2719c Is DNA Damage Inducible Independently of RecA Journal of Bacteriology 2006 188 16 6034 6038 10.1128/JB.00340-06 16885473 \n34. Swerdlow Steven H. Campo Elias Pileri Stefano A. Harris Nancy Lee Stein Harald Siebert Reiner Advani Ranjana Ghielmini Michele Salles Gilles A. Zelenetz Andrew D. Jaffe Elaine S. The 2016 revision of the World Health Organization classification of lymphoid neoplasms Blood 2016 127 20 2375 2390 10.1182/blood-2016-01-643569 26980727\n\n",
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"mesh_terms": "D001232:Aspergillus fumigatus; D001706:Biopsy; D003937:Diagnosis, Differential; D006801:Humans; D055744:Invasive Pulmonary Aspergillosis; D008168:Lung; D016403:Lymphoma, Large B-Cell, Diffuse; D008297:Male; D008875:Middle Aged; D009894:Opportunistic Infections; D014057:Tomography, X-Ray Computed",
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"title": "Simultaneous occurrence of invasive pulmonary aspergillosis and diffuse large B-cell lymphoma: case report and literature review.",
"title_normalized": "simultaneous occurrence of invasive pulmonary aspergillosis and diffuse large b cell lymphoma case report and literature review"
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"abstract": "Fluconazole for fungal infections and amiodarone for arrhythmia are commonly prescribed medications, and coadministration of such medications is sometimes inevitable in clinical practice. However, both medications have been associated with prolonged QTc intervals and subsequent arrhythmias, which are sometimes fatal. We present the case of a 75-year-old man with sudden cardiac arrest triggered by coadministration of fluconazole and amiodarone, which raises the need for caution regarding coadministration of these medications. To our knowledge, this case has not been previously described.",
"affiliations": "Department of Respiratory Medicine, The First Affiliated Hospital of Soochow University, Suzhou, China.",
"authors": "Wang|Jiajia|J|;Chen|Yanbin|Y|;Lei|Wei|W|;Chen|Cheng|C|;Zhu|Yehan|Y|;Su|Nan|N|;Zhang|Chuankai|C|;Huang|Jian-An|JA|",
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"title": "Sudden Cardiac Arrest Triggered by Coadministration of Fluconazole and Amiodarone.",
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"abstract": "Paraneoplastic cerebellar degeneration and Lambert-Eaton myasthenic syndrome (PCD-LEMS) are usually associated with small-cell lung carcinoma (SCLC). PCD-LEMS with extrapulmonary non-SCLC tumors; however, has not been previously reported. A 78-year-old man presented with dysarthria, dysphagia, staggering gait, and lower extremity muscle fatigue. He was diagnosed with PCD-LEMS associated with neuroendocrine carcinoma of the oropharynx, based on the histological findings of the biopsy, the existence of antibodies against P/Q-type voltage-gated calcium channels, and an incremental response of the compound muscle action potentials during repetitive nerve stimulation tests. Thus, PCD-LEMS should be included in the differential diagnosis of neurological dysfunction, even in extrapulmonary non-SCLC patients.",
"affiliations": "Department of Neurology, Osaka University Graduate School of Medicine, Japan.;Department of Neurology, Osaka University Graduate School of Medicine, Japan.;Department of Neurology, Osaka University Graduate School of Medicine, Japan.;Department of Otorhinolaryngology-Head and Neck Surgery, Osaka University Graduate School of Medicine, Japan.;Department of Otorhinolaryngology-Head and Neck Surgery, Osaka University Graduate School of Medicine, Japan.;Department of Otorhinolaryngology-Head and Neck Surgery, Osaka University Graduate School of Medicine, Japan.;Department of Pathology, Osaka University Graduate School of Medicine, Japan.;Department of Pathology, Osaka University Graduate School of Medicine, Japan.;Department of Electrical and Electronics Engineering, Faculty of Engineering, Nagasaki Institute of Applied Science, Japan.;Department of Neurology, Osaka University Graduate School of Medicine, Japan.;Department of Neurology, Osaka University Graduate School of Medicine, Japan.;Department of Neurology, Osaka University Graduate School of Medicine, Japan.",
"authors": "Takasugi|Junji|J|;Shimamura|Munehisa|M|;Koda|Toru|T|;Kishikawa|Toshihiro|T|;Hanamoto|Atsushi|A|;Inohara|Hidenori|H|;Sato|Kazuaki|K|;Morii|Eiichi|E|;Motomura|Masakatsu|M|;Sakaguchi|Manabu|M|;Nakatsuji|Yuji|Y|;Mochizuki|Hideki|H|",
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"fulltext": "\n==== Front\nIntern MedIntern. MedInternal Medicine0918-29181349-7235The Japanese Society of Internal Medicine 2909341510.2169/internalmedicine.9333-17Case ReportParaneoplastic Cerebellar Degeneration and Lambert-Eaton Myasthenic Syndrome Associated with Neuroendocrine Carcinoma of the Oropharynx Takasugi Junji 1Shimamura Munehisa 1Koda Toru 1Kishikawa Toshihiro 2Hanamoto Atsushi 2Inohara Hidenori 2Sato Kazuaki 3Morii Eiichi 3Motomura Masakatsu 4Sakaguchi Manabu 1Nakatsuji Yuji 1Mochizuki Hideki 1\n1 Department of Neurology, Osaka University Graduate School of Medicine, Japan\n2 Department of Otorhinolaryngology-Head and Neck Surgery, Osaka University Graduate School of Medicine, Japan\n3 Department of Pathology, Osaka University Graduate School of Medicine, Japan\n4 Department of Electrical and Electronics Engineering, Faculty of Engineering, Nagasaki Institute of Applied Science, JapanCorrespondence to Dr. Hideki Mochizuki, hmochizuki@neurol.med.osaka-u.ac.jp\n\n1 11 2017 15 2 2018 57 4 587 590 9 4 2017 4 6 2017 Copyright © 2018 by The Japanese Society of Internal Medicine2018The Internal Medicine is an Open Access article distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view the details of this license, please visit (https://creativecommons.org/licenses/by-nc-nd/4.0/).Paraneoplastic cerebellar degeneration and Lambert-Eaton myasthenic syndrome (PCD-LEMS) are usually associated with small-cell lung carcinoma (SCLC). PCD-LEMS with extrapulmonary non-SCLC tumors; however, has not been previously reported. A 78-year-old man presented with dysarthria, dysphagia, staggering gait, and lower extremity muscle fatigue. He was diagnosed with PCD-LEMS associated with neuroendocrine carcinoma of the oropharynx, based on the histological findings of the biopsy, the existence of antibodies against P/Q-type voltage-gated calcium channels, and an incremental response of the compound muscle action potentials during repetitive nerve stimulation tests. Thus, PCD-LEMS should be included in the differential diagnosis of neurological dysfunction, even in extrapulmonary non-SCLC patients. \n\nLambert-Eaton myasthenic syndrome (LEMS)paraneoplastic cerebellar degeneration (PCD)antibodies against P/Q-type voltage-gated calcium channels (VGCC)neuroendocrine carcinomaoropharyngeal cancer\n==== Body\nIntroduction\nLambert-Eaton myasthenic syndrome (LEMS) is a rare autoimmune disorder of neuromuscular junction transmission, which often presents with clinical features of proximal muscle weakness, diminished deep tendon reflexes, and autonomic dysfunction. Since more than half of patients have them, LEMS is often associated with tumors (1,2), especially small-cell lung carcinoma (SCLC). Antibodies to P/Q-type voltage-gated calcium channels (VGCC), which have been detected in 85-95% of patients with LEMS, play a significant role in its pathogenesis (3-5). The antibodies inhibit the release of acetylcholine at the neuromuscular junction, which results in muscle weakness.\n\nThese antibodies are also associated with paraneoplastic cerebellar degeneration (PCD), regardless of whether PCD-related autoantibodies, such as anti-Yo, Hu, or Ri antibodies, are present in the serum (6). Although the precise mechanism by which PCD is caused in LEMS remains controversial, Fukuda et al. (6) reported that antibodies directed against P/Q-type VGCCs reduced the number of these channels in the molecular layer of the cerebellum. Importantly, a cohort of Japanese patients with PCD and LEMS (PCD-LEMS) reportedly had SCLC and high titers of P/Q-type VGCC antibodies (4). However, PCD-LEMS has not been reported in patients with extrapulmonary non-SCLC tumors.\n\nWe herein report a unique case of PCD-LEMS associated with a neuroendocrine carcinoma (NEC) of the oropharynx, in a patient who showed no recurrence of NEC in 16 months of follow-up.\n\nCase Report\nThe patient was a 78-year-old man with a 60-pack-per-year smoking history and no history of alcohol consumption, whose gait gradually became unsteady. In the following months, he also suffered from dysarthria, dysphagia, and lower extremity muscle fatigue during walking. At five months after the onset of symptoms, he consulted an otolaryngologist for a tumor on the left side of the base of tongue and swelling of the cervical lymph nodes. Magnetic resonance T2-weighted “iterative decomposition of water and fat with echo asymmetry and least squares estimation” (IDEAL) water imaging revealed a 3.8×1.8 cm tumor of the left side of the base of the tongue (Fig. 1). Positron emission tomography-computed tomography (PET-CT) showed multiple swollen lymph nodes in the neck and mediastinum. There were no other distant metastases. The histological examination of an oropharynx biopsy specimen showed that the cells were arranged in clusters or sheets, which mostly consisted of atypical cells, with a high nuclear-cytoplasmic ratio (Fig. 2A), which were consistent with the features of small-cell type cancer. Immunohistochemically, the tumor cells were positive for cytokeratin AE1/AE3, synaptophysin (Fig. 2B), p16 and neural cell adhesion molecule (CD56, Fig. 2C), and negative for cytokeratin 5/6, p63, p40, and chromogranin A. The Ki-67 labeling index was approximately 70% (Fig. 2D). Thus, the patient was diagnosed with small-cell neuroendocrine carcinoma (G3) of the oropharynx (cT2N2bM0, clinical stage IVA). The levels of the serum tumor markers were within the normal limits.\n\nFigure 1. Magnetic resonance T2-weighted “iterative decomposition of water and fat with echo asymmetry and least squares estimation” (IDEAL) water imaging showed a 3.8×1.8 cm tumor on the left side of the base of the tongue (arrow).\n\nFigure 2. Histological and immunohistochemical findings of the oropharynx tumor. Hematoxylin and Eosin staining revealed atypical cells, with a high nuclear-cytoplasmic ratio, which were arranged in clusters or sheets (A). Immunohistochemical staining showed tumor cells that were positive for synaptophysin (B) and neural cell adhesion molecules (C). The Ki-67 labeling index was approximately 70% (D). The original magnification was ×400. Scale bar=100 μm.\n\nHe was admitted to our hospital to undergo chemoradiotherapy seven months after the onset of symptoms. During hospitalization, his staggering gait and lower extremity muscle fatigue remained. A neurological examination revealed proximal muscle weakness of all limbs (grade 4 on the Medical Research Council scale) and the absence of deep tendon reflexes. He exhibited saccadic eye movements, nystagmus, hypernasal speech, hypermetria of all limbs, staggering gait, and truncal ataxia. When assessed with the scale for the assessment and rating of ataxia (SARA) (7), his score was 13.5. He also had dry mouth, constipation, and orthostatic hypotension. His cranial nerve, sensory examinations, and cognitive functions were normal, except for dysarthria due to oropharynx carcinoma.\n\nNerve conduction studies demonstrated generalized low amplitude compound muscle action potentials, which increased by more than 200% after 10 seconds of maximal voluntary exercise. High frequency (30 Hz) repetitive nerve stimulation of ulnar nerve showed an increment of over 200% of the compound muscle action potential (CMAP) amplitude. The serum titer of anti-P/Q-type VGCC antibodies was elevated (44.0 pmol/L). The serum was negative for anti-acetylcholine receptor, anti-Yo, Hu, and Ri antibodies. Magnetic resonance imaging of the head revealed no cerebellar abnormality. Based on these findings, he was diagnosed as having PCD-LEMS. He underwent combination chemotherapy with cisplatin (60 mg/m2) and etoposide (75 mg/m2), and intensity-modulated radiation therapy to the left tonsil, neck, and mediastinum (70 Gy in 35 fractions). Initially one cycle of chemotherapy was performed, due to adverse events, which included neutropenia and pneumonia, this was followed by another cycle 6 months later. Pyridostigmine (120 mg) was administered orally to relieve the patient's neurological symptoms. Since 3,4-diaminopyridine is not covered by health insurance in Japan, it was not administered to the patient. The patient's proximal muscle weakness gradually improved and returned to almost normal at the end of chemoradiotherapy. His cerebellar ataxia also improved (SARA score: 6.5). Follow-up PET-CT at 3 months revealed the disappearance of the oropharyngeal tumor and a reduction in the size of the swollen neck and mediastinal lymph nodes, without metastases. The oropharynx biopsy showed no sign of malignancy, indicating that a complete response had been achieved. He remained alive, without recurrence of NEC or a worsening of his neurological symptoms, after 16 months of follow-up.\n\nDiscussion \nWe herein describe a case of PCD-LEMS associated with small-cell NEC of the oropharynx. Since NECs usually arise from lungs and gastrointestinal tract, NEC originating in the oropharynx, such as in the present case, is uncommon (8). Histologically, NECs can be mainly classified into small cell type, large cell type, and mixed type (9). Among these various subtypes, small-cell NECs have been reported to have the potential to cause LEMS, because of their morphological and immunohistochemical similarity with SCLC (9). This hypothesis is supported by a few reports on LEMS with extrapulmonary small-cell NECs of the seminal vesicles (10) or mediastinum (11). No cases of PCD-LEMS with small-cell NECs have previously been reported.\n\nIn the treatment of LEMS associated with cancer, anti-tumor therapy plays a significant role in achieving remission from LEMS symptoms, such as muscle weakness (12). On the other hand, the responsiveness of PCD to anti-tumor and immunosuppressive therapy is controversial. For example, a previous report described two patients with PCD-LEMS who responded to anti-tumor therapy and plasma exchange (13), but another study revealed that three patients with PCD-LEMS who received immunotherapy showed no apparent improvement of their cerebellar symptoms (14). In the present case, chemoradiotherapy and pyridostigmine improved the patient's cerebellar ataxia, as well as his proximal muscle weakness, which is in line with the former report. One possibility is that the improvement of the patient's cerebellar symptoms might have been dependent on the degree of downregulation of the P/Q-type VGCCs in the cerebellar molecular layer. If anti-tumor therapy is administered early, the degree of downregulation might not be as severe and might recover.\n\nExtrapulmonary NECs are known to have a poor prognosis, despite combination therapy. The median survival ranges from 4-16 months (9). In particular, small-cell NECs of the head and neck are highly aggressive and tend to develop early regional or distant metastasis (8). Interestingly, our patient with oropharynx NEC was alive with no sign of recurrence after 16 months of follow-up. This long survival without a recurrence of NEC is similar to that described in a previous study on SCLC-LEMS, which was associated with anti-P/Q-type VGCC antibodies (15). The authors suggested that the autoimmune response with anti-P/Q-type VGCC antibodies might play a role in retarding tumor growth (15). Thus, the present case highlighted that the diagnosis of LEMS would be helpful for predicting the prognosis of patients with small-cell NEC, as well as those with SCLC.\n\nIn conclusion, PCD-LEMS could be associated with extrapulmonary small-cell NECs; and cerebellar ataxia in this condition might respond to anti-tumor therapy. PCD-LEMS should be considered, even in cases with extrapulmonary small-cell NECs, in the differential diagnosis of muscular weakness and cerebellar ataxia.\n\n\nThe authors state that they have no Conflict of Interest (COI).\n==== Refs\n1. \nO'Neill JH , Murray NM , Newsom-Davis J \nThe Lambert-Eaton myasthenic syndrome. A review of 50 cases . Brain \n111 : 577 -596 , 1988 .2838124 \n2. \nTitulaer MJ , Maddison P , Sont JK , et al \nClinical Dutch-English Lambert-Eaton myasthenic syndrome (LEMS) tumor association prediction score accurately predicts small-cell lung cancer in the LEMS . J Clin Oncol \n29 : 902 -908 , 2011 .21245427 \n3. \nLennon VA , Kryzer TJ , Griesmann GE , et al \nCalcium-channel antibodies in the Lambert-Eaton syndrome and other paraneoplastic syndromes . N Engl J Med \n332 : 1467 -1474 , 1995 .7739683 \n4. \nNakao YK , Motomura M , Fukudome T , et al \nSeronegative Lambert-Eaton myasthenic syndrome: study of 110 Japanese patients . Neurology \n59 : 1773 -1775 , 2002 .12473768 \n5. \nMotomura M , Lang B , Johnston I , Palace J , Vincent A , Newsom-Davis J \nIncidence of serum anti-P/O-type and anti-N-type calcium channel autoantibodies in the Lambert-Eaton myasthenic syndrome . J Neurol Sci \n147 : 35 -42 , 1997 .9094058 \n6. \nFukuda T , Motomura M , Nakao Y , et al \nReduction of P/Q-type calcium channels in the postmortem cerebellum of paraneoplastic cerebellar degeneration with Lambert-Eaton myasthenic syndrome . Ann Neurol \n53 : 21 -28 , 2003 .12509844 \n7. \nSchmitz-Hübsch T , du Montcel ST , Baliko L , et al \nScale for the assessment and rating of ataxia: development of a new clinical scale . Neurology \n66 : 1717 -1720 , 2006 .16769946 \n8. \nWang HY , Zou J , Zhou GY , Yan JQ , Liu SX \nPrimary small cell neuroendocrine carcinoma of the tonsil: a case report and review of the literature . Int J Clin Exp Pathol \n7 : 2678 -2682 , 2014 .24966986 \n9. \nSmith J , Reidy-Lagunes D \nThe management of extrapulmonary poorly differentiated (high-grade) neuroendocrine carcinomas . Semin Oncol \n40 : 100 -108 , 2013 .23391117 \n10. \nKreiner B , Denzinger S , Ganzer R , et al \nNeuroendocrine carcinoma of the seminal vesicles presenting with Lambert Eaton syndrome: a case report . J Med Case Rep \n4 : 320 , 2010 .20939874 \n11. \nZhang K , Liu W , Li Y , Zhang K , Gao X , Wang J \nMediastinal small cell cancer associated with Lambert-Eaton myasthenic syndrome: a case report . Exp Ther Med \n10 : 117 -120 , 2015 .26170921 \n12. \nTitulaer MJ , Lang B , Verschuuren JJ \nLambert-Eaton myasthenic syndrome: from clinical characteristics to therapeutic strategies . Lancet Neurol \n10 : 1098 -1107 , 2011 .22094130 \n13. \nMason WP , Graus F , Lang B , et al \nSmall-cell lung cancer, paraneoplastic cerebellar degeneration and the Lambert-Eaton myasthenic syndrome . Brain \n120 : 1279 -1300 , 1997 .9278623 \n14. \nGraus F , Lang B , Pozo-Rosich P , Saiz A , Casamitjana R , Vincent A \nP/Q type calcium-channel antibodies in paraneoplastic cerebellar degeneration with lung cancer . Neurology \n59 : 764 -766 , 2002 .12221175 \n15. \nMaddison P , Newsom-Davis J , Mills KR , Souhami RL \nFavourable prognosis in Lambert-Eaton myasthenic syndrome and small-cell lung carcinoma . Lancet \n353 : 117 -118 , 1999 .\n\n",
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"issue": "57(4)",
"journal": "Internal medicine (Tokyo, Japan)",
"keywords": "Lambert-Eaton myasthenic syndrome (LEMS); antibodies against P/Q-type voltage-gated calcium channels (VGCC); neuroendocrine carcinoma; oropharyngeal cancer; paraneoplastic cerebellar degeneration (PCD)",
"medline_ta": "Intern Med",
"mesh_terms": "D000368:Aged; D018278:Carcinoma, Neuroendocrine; D006801:Humans; D015624:Lambert-Eaton Myasthenic Syndrome; D008297:Male; D009959:Oropharyngeal Neoplasms; D020362:Paraneoplastic Cerebellar Degeneration",
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"title": "Paraneoplastic Cerebellar Degeneration and Lambert-Eaton Myasthenic Syndrome Associated with Neuroendocrine Carcinoma of the Oropharynx.",
"title_normalized": "paraneoplastic cerebellar degeneration and lambert eaton myasthenic syndrome associated with neuroendocrine carcinoma of the oropharynx"
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"abstract": "Metastatic cancers during pregnancy have historically been associated with dismal outcomes, with greater rates of tumor progression in part because of diminished treatment alternatives. Immunotherapy with T-cell checkpoint inhibitors has significantly impacted the survival of several metastatic tumors. However, given their mechanism of action, immune-related adverse events can occur, especially with combined immunotherapy treatments. During pregnancy, checkpoint pathways have a major role, providing immune tolerance to the fetal allograft. Furthermore, evidence suggests that inhibition of this pathway may be associated with an increased risk of miscarriage. We describe, to our knowledge, the first case reported in the literature of a patient 7 weeks pregnant, diagnosed with metastatic melanoma and treated with nivolumab plus ipilimumab. We also present the associated immune-related side effects and their treatment, as well as the oncologic results that lead to favorable pregnancy outcome.",
"affiliations": "Medical Oncology Service, Clínica Alemana de Santiago, Santiago, Chile. Electronic address: mburotto@alemana.cl.;Medical Oncology Service, Clínica Alemana de Santiago, Santiago, Chile.;Medical Oncology Service, Clínica Alemana de Santiago, Santiago, Chile.;Department of Anesthesia, Hospital clínico Universidad de Chile, Santiago, Chile.;Medical Oncology Service, Clínica Alemana de Santiago, Santiago, Chile.;Medical Oncology Service, Clínica Alemana de Santiago, Santiago, Chile.;Medical Oncology Service, Clínica Alemana de Santiago, Santiago, Chile.;Departamento de Ginecología y Obstetricia, Clínica Las Condes, Santiago Chile.",
"authors": "Burotto|Mauricio|M|;Gormaz|Juan G|JG|;Samtani|Suraj|S|;Valls|Nicolas|N|;Silva|Ricardo|R|;Rojas|Carlos|C|;Portiño|Sergio|S|;de la Jara|Carlos|C|",
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"mesh_terms": "D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D000074324:Ipilimumab; D008545:Melanoma; D009362:Neoplasm Metastasis; D000077594:Nivolumab; D011247:Pregnancy; D011252:Pregnancy Complications, Neoplastic; D011256:Pregnancy Outcome; D012878:Skin Neoplasms; D016896:Treatment Outcome",
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"references": null,
"title": "Viable Pregnancy in a patient with metastatic melanoma treated with double checkpoint immunotherapy.",
"title_normalized": "viable pregnancy in a patient with metastatic melanoma treated with double checkpoint immunotherapy"
} | [
{
"companynumb": "CL-ALLERGAN-1857703US",
"fulfillexpeditecriteria": "1",
"occurcountry": "CL",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "IPILIMUMAB"
},
"drugadditional": null,
... |
{
"abstract": "Interactions of imatinib with other drugs have been scarcely reported. We report a previously unknown effect of imatinib on levothyroxine therapy. Eleven patients (1 with gastrointestinal stromal tumor and 10 with medullary thyroid carcinoma) received imatinib. Eight had undergone thyroidectomy and used levothyroxine, and 3 had the thyroid in situ. Thyroid function was measured before, during, and within 2 weeks after any change in either imatinib or levothyroxine dosage. We observed symptoms of hypothyroidism in all patients who had undergone thyroidectomy, whereas patients with the thyroid in situ remained clinically and biochemically euthyroid. On average, thyrotropin (INN, thyrotrophin) levels increased to 384% +/- 228% of the upper limit in patients after thyroidectomy, whereas free thyroxine (fT4) and free tri-iodothyronine (fT3) values remained within the reference range (59% +/- 17% of the upper limit for fT4 and 63% +/- 4% of the upper limit for fT3). Clinicians should be aware that hypothyroid subjects receiving imatinib have a high likelihood for increased levothyroxine replacement and should be closely monitored for elevations in thyrotropin indicating worsening hypothyroidism.",
"affiliations": "Department of Endocrinology, University Medical Centre Groningen, Groningen, and Department of Medical Oncology, University Medical Centre Utrecht, Utrecht, The Netherlands.",
"authors": "de Groot|Jan Willem B|JW|;Zonnenberg|Bernard A|BA|;Plukker|John T M|JT|;van Der Graaf|Winette T A|WT|;Links|Thera P|TP|",
"chemical_list": "D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D014284:Triiodothyronine; D000068877:Imatinib Mesylate; D013972:Thyrotropin; D013974:Thyroxine",
"country": "United States",
"delete": false,
"doi": "10.1016/j.clpt.2005.06.010",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0009-9236",
"issue": "78(4)",
"journal": "Clinical pharmacology and therapeutics",
"keywords": null,
"medline_ta": "Clin Pharmacol Ther",
"mesh_terms": "D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents; D001549:Benzamides; D018276:Carcinoma, Medullary; D004357:Drug Synergism; D005260:Female; D046152:Gastrointestinal Stromal Tumors; D006801:Humans; D007037:Hypothyroidism; D000068877:Imatinib Mesylate; D008297:Male; D008875:Middle Aged; D010879:Piperazines; D011743:Pyrimidines; D013964:Thyroid Neoplasms; D013965:Thyroidectomy; D013972:Thyrotropin; D013974:Thyroxine; D014284:Triiodothyronine",
"nlm_unique_id": "0372741",
"other_id": null,
"pages": "433-8",
"pmc": null,
"pmid": "16198662",
"pubdate": "2005-10",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "Imatinib induces hypothyroidism in patients receiving levothyroxine.",
"title_normalized": "imatinib induces hypothyroidism in patients receiving levothyroxine"
} | [
{
"companynumb": "PHBS2005NL15146",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ALENDRONIC ACID"
},
"drugadditional": "3",
"d... |
{
"abstract": "BACKGROUND\nThe aim of this study was to assess the rate of response to long-term low-dose levetiracetam (LEV) treatment and the clinical factors associated with response.\n\n\nMETHODS\nThe response to low-dose LEV of 43 patients with epilepsy (22 male, 21 female; age range, 5-39 years; median age, 13 years) was retrospectively assessed. Patients aged <15 years received <20 mg/kg/day LEV, whereas those aged ≥15 years received <1000 mg/day LEV. Clinical features were compared between responders to low-dose LEV, responders to the recommended dose, and non-responders.\n\n\nRESULTS\nOf the 43 patients who received low-dose LEV, 13 (30%) showed improvement, defined as seizure cessation or >75% seizure reduction over 6 months for patients with monthly, weekly, and daily seizures; and over 1 year for patients with yearly seizures. Efficacy was maintained for >1 year in 10 (77%) of the 13 patients. Long-term response to low-dose LEV was significantly associated with older age at onset and fewer previous treatments with ineffective anti-epileptic drugs. All patients showing long-term response to low-dose LEV developed only focal seizures.\n\n\nCONCLUSIONS\nTitration of LEV starting from a low dose may be effective in selected patients. Once patients respond to low-dose treatment, maintenance of the effective dosage may prolong response.",
"affiliations": "Department of Pediatrics, Osaka Rosai Hospital, Osaka, Japan.;Department of Pediatrics, Osaka Medical College, Osaka, Japan.;Department of Pediatrics, Osaka Medical College, Osaka, Japan.;Department of Pediatrics, Osaka Medical College, Osaka, Japan.;Department of Pediatric Neurology, Tanabe Children's Clinic, Osaka, Japan.;Department of Pediatrics, Osaka Medical College, Osaka, Japan.",
"authors": "Yoshikawa|Sosuke|S|;Shimakawa|Shuichi|S|;Fukui|Miho|M|;Nomura|Shohei|S|;Tanabe|Takuya|T|;Tamai|Hiroshi|H|",
"chemical_list": "D000927:Anticonvulsants; D000077287:Levetiracetam; D010889:Piracetam",
"country": "Australia",
"delete": false,
"doi": "10.1111/ped.12753",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1328-8067",
"issue": "58(1)",
"journal": "Pediatrics international : official journal of the Japan Pediatric Society",
"keywords": "epilepsy; levetiracetam; long-term treatment; low-dose treatment; titration",
"medline_ta": "Pediatr Int",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000927:Anticonvulsants; D002648:Child; D002675:Child, Preschool; D004305:Dose-Response Relationship, Drug; D004827:Epilepsy; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D000077287:Levetiracetam; D008297:Male; D010889:Piracetam; D012189:Retrospective Studies; D013997:Time Factors; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "100886002",
"other_id": null,
"pages": "40-4",
"pmc": null,
"pmid": "26189956",
"pubdate": "2016-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Clinical features of long-term low-dose levetiracetam treatment for epilepsy.",
"title_normalized": "clinical features of long term low dose levetiracetam treatment for epilepsy"
} | [
{
"companynumb": "JP-LUPIN PHARMACEUTICALS INC.-2016-01356",
"fulfillexpeditecriteria": "2",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "LEVETIRACETAM"
},
"drugadditi... |
{
"abstract": "A 44-year-old female, with a background of cerebral palsy, epilepsy and learning disabilities, presented with multiple seizures and a persistently reduced consciousness level secondary to valproate-induced hyperammonaemic encephalopathy (plasma levels >50 µg/dl). Withdrawal of valproate and subsequent infusion of L-carnitine led to full recovery. Nonhepatic hyperammonaemia has been shown to be effectively treated by intravenous L-carnitine therapy by a series of case reports. To date, no randomised controlled trials have demonstrated this. Hyperammonaemic encephalopathy is possibly a more common presentation than expected that is currently underdiagnosed and exacerbated by valproate.",
"affiliations": "Harefield Hospital, Hill End Road, Harefield, Uxbridge UB9 6JH, UK, alex.khakwani@nhs.net.;Colchester Hospital, Colchester, UK.",
"authors": "Khakwani|Alex|A|;Gannon|David|D|",
"chemical_list": "D000927:Anticonvulsants; D014635:Valproic Acid; D002331:Carnitine",
"country": "Scotland",
"delete": false,
"doi": "10.4997/JRCPE.2019.410",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1478-2715",
"issue": "49(4)",
"journal": "The journal of the Royal College of Physicians of Edinburgh",
"keywords": "carnitine; encephalopathy; hyperammonaemia; valproate; valproic acid",
"medline_ta": "J R Coll Physicians Edinb",
"mesh_terms": "D000328:Adult; D000927:Anticonvulsants; D001774:Blood Chemical Analysis; D002331:Carnitine; D002547:Cerebral Palsy; D019587:Dietary Supplements; D004827:Epilepsy; D005260:Female; D005500:Follow-Up Studies; D015600:Glasgow Coma Scale; D006801:Humans; D022124:Hyperammonemia; D020258:Neurotoxicity Syndromes; D018570:Risk Assessment; D016896:Treatment Outcome; D014635:Valproic Acid",
"nlm_unique_id": "101144324",
"other_id": null,
"pages": "301-303",
"pmc": null,
"pmid": "31808457",
"pubdate": "2019-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "L-carnitine supplementation as a potential therapy for suspected hyperammonaemic encephalopathy.",
"title_normalized": "l carnitine supplementation as a potential therapy for suspected hyperammonaemic encephalopathy"
} | [
{
"companynumb": "GB-UNICHEM PHARMACEUTICALS (USA) INC-UCM201912-000925",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "DIVALPROEX SODIUM"
},
... |
{
"abstract": "Coronavirus disease 2019 (COVID-19), caused by the late 2019 outbreak of Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), causes a respiratory disease which could put myasthenia gravis patients at a greater risk of developing severe disease course. This paper presents a single-institution case series of hospitalized myasthenia gravis patients with COVID 19. We identified eight patients previously diagnosed with myasthenia gravis, four of whom presented with clear signs of myasthenia gravis symptom worsening on admission. No form of respiratory support was needed during the complete duration of stay for three patients, oxygen therapy was administered to two patients, while the remaining three patients required mechanical ventilation. Treatment was successful for seven patients, six of whom were discharged without any myasthenia gravis symptoms. One patient died after eleven days of intensive care unit treatment. Although treatment of patients with myasthenia gravis and COVID-19 patients is challenging, case series of myasthenia gravis patients with COVID-19 treated in our institution demonstrates relatively favorable treatment outcome. Our data seem to support the notion that immunosuppressive medication does not seem to result in worse outcomes. Our data also support the notion that intravenous immunoglobulin treatment is safe and should be administered to patients with myasthenia gravis and COVID-19 in case of myasthenia gravis worsening since benefits seem to greatly outweigh the risks.",
"affiliations": "Department of Neurology, Clinical Hospital Dubrava, Avenija Gojka Šuška 6, 10000, Zagreb, Republic of Croatia. szupanic1@kbd.hr.;Department of Neurology, Clinical Hospital Dubrava, Avenija Gojka Šuška 6, 10000, Zagreb, Republic of Croatia.;Department of Neurology, Clinical Hospital Dubrava, Avenija Gojka Šuška 6, 10000, Zagreb, Republic of Croatia.;Department of Neurology, Clinical Hospital Dubrava, Avenija Gojka Šuška 6, 10000, Zagreb, Republic of Croatia.;Department of Neurology and Neurosurgery, Faculty of Dental Medicine and Health, Josip Juraj Strossmayer University of Osijek, Osijek, Republic of Croatia.;Department of Neurology, Clinical Hospital Dubrava, Avenija Gojka Šuška 6, 10000, Zagreb, Republic of Croatia.",
"authors": "Županić|Sven|S|http://orcid.org/0000-0002-7053-5460;Perić Šitum|Martina|M|;Majdak|Maja|M|;Karakaš|Mirna|M|;Bašić|Silvio|S|;Sporiš|Davor|D|",
"chemical_list": "D016756:Immunoglobulins, Intravenous",
"country": "Italy",
"delete": false,
"doi": "10.1007/s13760-021-01662-w",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0300-9009",
"issue": "121(4)",
"journal": "Acta neurologica Belgica",
"keywords": "COVID-19; Immunosuppression; Myasthenia gravis; Neuromuscular disorders; SARS-CoV-2",
"medline_ta": "Acta Neurol Belg",
"mesh_terms": "D000086382:COVID-19; D017523:Croatia; D005260:Female; D006801:Humans; D016756:Immunoglobulins, Intravenous; D008297:Male; D008875:Middle Aged; D009157:Myasthenia Gravis; D000086402:SARS-CoV-2",
"nlm_unique_id": "0247035",
"other_id": null,
"pages": "1039-1044",
"pmc": null,
"pmid": "33797054",
"pubdate": "2021-08",
"publication_types": "D016428:Journal Article",
"references": "32052466;32166607;32651248;33013676;32247193;32658332;32776781;32850160;32731059;32392389;32634699;33217262;32416330;33317589;32788101;15970713;16965420;32773098;32283154;32696108;33227024",
"title": "Case series of COVID-19 in patients with myasthenia gravis: a single institution experience.",
"title_normalized": "case series of covid 19 in patients with myasthenia gravis a single institution experience"
} | [
{
"companynumb": "HR-TAKEDA-2021TUS054422",
"fulfillexpeditecriteria": "1",
"occurcountry": "HR",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "PYRIDOSTIGMINE"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nMalignant external otitis is an aggressive and potentially life-threatening infection. This rare disorder is typically caused by Pseudomonas aeruginosa and affects almost exclusively elderly diabetic patients. However, fungal malignant external otitis have been identified, especially in immunocompromised hosts.\n\n\nMETHODS\nWe report a rare case of invasive malignant external otitis caused by Aspergillus flavus in a diabetic patient without other underlying immunosuppression. A review of Aspergillus spp. malignant external otitis since voriconazole became the first line for invasive aspergillosis was performed.\n\n\nRESULTS\nA 72-year-old man with diabetes mellitus developed invasive malignant external otitis with a vascular involvement. The patient was treated with empiric courses of antibiotics until a fungal infection was diagnosed. Proven Apsergillus infection was based on histopathological examination and isolation of A. flavus from culture of osteo-meningeal biopsies. Despite optimal antimicrobial therapy with voriconazole, the patient presented with cerebral infarction in the setting of an angioinvasive fungal infection leading to a fatal outcome. From a review of the literature, we found 39 previously published cases of proven Aspergillus spp. malignant external otitis treated with new triazoles.\n\n\nCONCLUSIONS\nGiven our experience and the literature review, a fungal etiology should be considered early in the course of malignant external otitis unresponsive to a conventional broad spectrum antibiotic therapy, with the need for a tissue biopsy to confirm the diagnosis.",
"affiliations": "Service de Maladies Infectieuses Et Tropicales, APHP, Hôpital Bichat-Claude Bernard, 46, rue Henri Huchard, 75018, Paris, France. maud.pichon@free.fr.;Service de Maladies Infectieuses Et Tropicales, APHP, Hôpital Bichat-Claude Bernard, 46, rue Henri Huchard, 75018, Paris, France.;Laboratoire de Parasitologie-Mycologie, APHP, Hôpital Bichat-Claude Bernard, 46, rue Henri Huchard, 75018, Paris, France.;Laboratoire de Parasitologie-Mycologie, APHP, Hôpital Bichat-Claude Bernard, 46, rue Henri Huchard, 75018, Paris, France.;Laboratoire de Mycologie, APHP, Hôpital Saint Louis, 1 avenue Claude Vellefaux, 75010, Paris, France.;Laboratoire de Mycologie, APHP, Hôpital Saint Louis, 1 avenue Claude Vellefaux, 75010, Paris, France.;Laboratoire de Pathologie, APHP, Hôpital Lariboisière, 2, rue Ambroise Paré, 75010, Paris, France.;Service D'Oto-Rhino-Laryngologie, APHP, Hôpital Lariboisière, 2, rue Ambroise Paré, 75010, Paris, France.;Service de Maladies Infectieuses Et Tropicales, APHP, Hôpital Bichat-Claude Bernard, 46, rue Henri Huchard, 75018, Paris, France.",
"authors": "Pichon|Maud|M|http://orcid.org/0000-0001-8227-3704;Joly|Véronique|V|;Argy|Nicolas|N|;Houze|Sandrine|S|;Bretagne|Stéphane|S|;Alanio|Alexandre|A|;Wassef|Michel|M|;Verillaud|Benjamin|B|;Yazdanpanah|Yazdan|Y|",
"chemical_list": "D000900:Anti-Bacterial Agents; D000935:Antifungal Agents; D001393:Azoles",
"country": "Germany",
"delete": false,
"doi": "10.1007/s15010-020-01394-8",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0300-8126",
"issue": "48(2)",
"journal": "Infection",
"keywords": "Angioinvasive aspergillosis; Aspergillus; Diabetes mellitus; Malignant external otitis; Voriconazole",
"medline_ta": "Infection",
"mesh_terms": "D000368:Aged; D000900:Anti-Bacterial Agents; D000935:Antifungal Agents; D001228:Aspergillosis; D001231:Aspergillus flavus; D001393:Azoles; D048909:Diabetes Complications; D017809:Fatal Outcome; D006801:Humans; D008297:Male; D010032:Otitis Externa; D013997:Time Factors",
"nlm_unique_id": "0365307",
"other_id": null,
"pages": "193-203",
"pmc": null,
"pmid": "32036556",
"pubdate": "2020-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": "24649388;10503576",
"title": "Aspergillus flavus malignant external otitis in a diabetic patient: case report and literature review.",
"title_normalized": "aspergillus flavus malignant external otitis in a diabetic patient case report and literature review"
} | [
{
"companynumb": "FR-AUROBINDO-AUR-APL-2020-020615",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "VORICONAZOLE"
},
"drugadditional": nul... |
{
"abstract": "With the current widespread use of dolutegravir in low-income countries, the understanding of the impact of nucleoside reverse transcriptase inhibitor (NRTI-) associated mutations on the efficacy of dolutegravir-containing antiretroviral therapy (ART) is of utmost importance. We describe a rare case of a patient with pre-existing M184V/I mutation and virological failure on a dolutegravir/lamivudine/abacavir regimen with the emergence of integrase strand transfer inhibitor resistance mutations. Additional risk factors, which may have triggered the virological failure, included suboptimal adherence and low nadir CD4+ cell count. This case illustrates that dolutegravir-containing triple-therapy should be prescribed with caution to patients with pre-existing M184V/I mutation and poor efficacy of the reverse transcriptase inhibitor backbone. In addition, this case highlights the need for viral load monitoring in patients on dolutegravir-containing regimens in settings with a high prevalence of the M184V/I mutation such as in low-income countries.",
"affiliations": "Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, University of Zurich, 8091 Zurich, Switzerland.;Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, University of Zurich, 8091 Zurich, Switzerland.;Private Practice, 8008 Zurich, Switzerland.;Center for Infectious Diseases, 8038 Zurich, Switzerland.;Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, University of Zurich, 8091 Zurich, Switzerland.;Institute of Medical Virology, University of Zurich, 8057 Zurich, Switzerland.;Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, University of Zurich, 8091 Zurich, Switzerland.",
"authors": "Braun|Dominique L|DL|0000-0003-4036-1030;Scheier|Thomas|T|;Ledermann|Ulrich|U|;Flepp|Markus|M|;Metzner|Karin J|KJ|0000-0003-4862-1503;Böni|Jürg|J|;Günthard|Huldrych F|HF|",
"chemical_list": "D019428:HIV Integrase Inhibitors; D006575:Heterocyclic Compounds, 3-Ring; D010078:Oxazines; D010879:Piperazines; D011728:Pyridones; C562325:dolutegravir",
"country": "Switzerland",
"delete": false,
"doi": "10.3390/v12111330",
"fulltext": "\n==== Front\nViruses\nViruses\nviruses\nViruses\n1999-4915 MDPI \n\n33228206\n10.3390/v12111330\nviruses-12-01330\nBrief Report\nEmergence of Resistance to Integrase Strand Transfer Inhibitors during Dolutegravir Containing Triple-Therapy in a Treatment-Experienced Patient with Pre-Existing M184V/I Mutation\nhttps://orcid.org/0000-0003-4036-1030Braun Dominique L. 12* Scheier Thomas 1 Ledermann Ulrich 3 Flepp Markus 4 https://orcid.org/0000-0003-4862-1503Metzner Karin J. 12 Böni Jürg 2 Günthard Huldrych F. 12 1 Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, University of Zurich, 8091 Zurich, Switzerland; thomas.scheier@usz.ch (T.S.); karin.metzner@usz.ch (K.J.M.); huldrych.guenthard@usz.ch (H.F.G.)\n2 Institute of Medical Virology, University of Zurich, 8057 Zurich, Switzerland; boeni.juerg@virology.uzh.ch\n3 Private Practice, 8008 Zurich, Switzerland; ulrich.ledermann@hin.ch\n4 Center for Infectious Diseases, 8038 Zurich, Switzerland; markus.flepp@hin.ch\n* Correspondence: dominique.braun@usz.ch\n19 11 2020 \n11 2020 \n12 11 133008 10 2020 18 11 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/).With the current widespread use of dolutegravir in low-income countries, the understanding of the impact of nucleoside reverse transcriptase inhibitor (NRTI-) associated mutations on the efficacy of dolutegravir-containing antiretroviral therapy (ART) is of utmost importance. We describe a rare case of a patient with pre-existing M184V/I mutation and virological failure on a dolutegravir/lamivudine/abacavir regimen with the emergence of integrase strand transfer inhibitor resistance mutations. Additional risk factors, which may have triggered the virological failure, included suboptimal adherence and low nadir CD4+ cell count. This case illustrates that dolutegravir-containing triple-therapy should be prescribed with caution to patients with pre-existing M184V/I mutation and poor efficacy of the reverse transcriptase inhibitor backbone. In addition, this case highlights the need for viral load monitoring in patients on dolutegravir-containing regimens in settings with a high prevalence of the M184V/I mutation such as in low-income countries.\n\nHIV-1antiretroviral therapydolutegravirvirological failuredrug resistanceM184V/I mutationintegrase strand transfer inhibitor\n==== Body\n1. Introduction\nInfection with the human immunodeficiency virus type 1 (HIV-1) can be very efficiently treated with combination antiretroviral therapy (cART), however, this success can be jeopardized by the emergence of HIV-1 drug resistance. Dolutegravir (DTG) is a second-generation integrase strand transfer inhibitor (INSTI) often used as a component of preferred cART due to its favorable properties, including a high genetic barrier to resistance, good tolerability and safety profile, and low potential for drug-drug interactions [1]. In clinical trials at 96 and 148 weeks, no emergence of resistance to INSTI has been reported among patients failing on first-line DTG-containing triple-therapy. However, real-life data from treatment-naïve and treatment-experienced patients on DTG-containing triple-therapy describe a few cases of virologic failure with the emergence of HIV-1 resistance to INSTIs [2,3,4,5,6].\n\nWith the current widespread use of DTG in low-income countries, the understanding of the impact of nucleoside reverse transcriptase inhibitor (NRTI-) associated mutations on the efficacy of dolutegravir-containing ART is of utmost importance [7]. The M184V/I mutation is one of the most common NRTI-associated mutations in HIV-1 infected patients and typically selected in patients failing on lamivudine (3TC) or emtricitabine (FTC) containing regimen. The presence of M184V/I reduces the susceptibility to these drugs by more than 100-fold and additionally causes an impaired efficacy to abacavir (ABC). In contrast, it enhances the susceptibility to tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide fumarate (TAF). Recently, a prospective study using data from five large HIV cohorts in four European countries assessed the efficacy of the ABC/3TC/DTG regimen in virologically suppressed, treatment-experienced patients and found no evidence for an impact of previously acquired M184V/I mutation on the incidence of virological failure [8]. Furthermore, no new mutations were observed in reverse transcriptase or integrase after virological failure in any of the patients in whom genotyping was successfully performed. However, due to the short observation time and the low number of virological failure events, the study concluded that additional analyses are required to demonstrate whether these findings remain robust during an extended observation period.\n\nHere we describe a rare case of a patient with a pre-existing M184V/I mutation who failed on the ABC/3TC/DTG regimen with the emergence of resistance to all currently licensed INSTIs including the second-generation INSTIs DTG and bictegravir (BIC).\n\n2. Case Description and Results\nA 45-year-old man who has sex with men was diagnosed with HIV-1 infection in March 1997. The CD4+ cell count at the time of diagnosis revealed 325 cells per microliter (µL) blood with an HIV-1 viral load of 94,267 copies (cp) per milliliter (mL) plasma. His medical history was remarkable for chronic depression and intermittent illicit drug use. ART consisting of nelfinavir (NFV), 3TC, and stavudine (d4T) was initiated and virus suppression below the limit of quantification of 50 cp/mL plasma was achieved six months later (Figure 1). According to the autovaccination hypothesis that re-exposure to HIV-1 during treatment interruptions may stimulate the HIV-1 specific immune response and lead to low viremia after the withdrawal of ART, the patients were enrolled into the Swiss-Spanish Intermittent Treatment Trial (SSITT) in October 1999 [9]. In brief, in this trial ART was interrupted for 2 weeks, restarted, and continued for 8 weeks. After four such cycles, treatment was indefinitely suspended. During the indefinite treatment interruption period, the viral load increased to a maximum of 25,558 cp/mL and decreased to a minimum of zero copies/mL as measured with a single copy assay when treatment with NFV, 3TC, and d4T was re-initiated. Longitudinal blood samples were analyzed using an in-house allele-specific-PCR (AS-PCR) to determine the frequency of M184V and L90M drug-resistant variants [10]. The M184V mutation was not detectable in the second structured treatment interruption cycle. In the fifth cycle, six time-points were measured, and one of them was positive for the M184V mutation at a low frequency of 0.9% (Figure 1). The amplification of samples at the other short structured treatment interruption cycles and additional time points during the fifth cycle was unsuccessful.\n\nFollowing the SSITT trial, the patient remained off ART until October 2008. At that time, the CD4+ cell count had decreased to a nadir of 167 cells/µL blood with a viral load of 114,000 cp/mL plasma and the patient had developed candida esophagitis. Prior to developing symptoms, he did not want to reinitiate treatment although this was recommended according to treatment guidelines at that time [11]. In October 2007, a genotypic HIV resistance test using Sanger technology was performed from a blood repository sample taken before the patient started his first ART in 1997. This resistance test revealed infection with HIV-1 subtype B and the presence of the accessory mutations M36I, I62V, and V77I not causing any clinically relevant resistance to antiretroviral drugs. The M184V mutation, which was identified during the SSITT trial, was not present in 1997, suggesting a selection of the M184V mutation during the structured treatment interruption cycles (Figure 1). In October 2008, ART with ritonavir (RTV) boosted lopinavir (LPV) and tenofovir disoproxil fumarate (TDF)/FTC was started. However, the treatment was switched to ritonavir-boosted fosamprenavir (FAPV) with the continuation of TDF/FTC some days later because of severe LPV/RTV-associated diarrhea. With this ART the viral load remained <50 copies/mL plasma. In May 2011, the patient experienced virological failure with an increased viral load of 3390 copies/mL plasma, most likely caused by suboptimal adherence as self-reported by the patient. The genotypic resistance test using Sanger technology revealed the M184I mutation causing high- and low-level resistance to 3TC/FTC and ABC, respectively. In addition, the accessory protease mutations K20R, L10I, I13V, and G16E were detected. ART was switched to RTV-boosted darunavir (DRV) and raltegravir (RGV) with the continuation of TDF/FTC. With this salvage therapy, the viral load was fully suppressed one month later and ART was continued with DRV/TDF/FTC. Within the following 4 years, the viral load remained always below the limit of quantification of <20 cp/mL plasma, but viral RNA was detectable at most time points. In June 2015, the patient demanded to switch to a single-tablet regimen (STR), because of the pill burden of his ART. Hence, ART was switched to the STR DTG/3TC/ABC. Afterward, intermittent low-level viremia up to 383 cp/mL occurred, most likely associated with periods of poor ART adherence. Indeed, the patient reported to miss his ART regularly for several consecutive days, often related to concomitant illicit drug use. During periods of good adherence, however, the viral load decreased to levels <20 cp/mL plasma. In October 2019, when the viral load increased from 45 cp/mL to 183 cp/mL plasma, a genotypic resistance test was performed. This resistance test newly revealed the E138K, Q148R, and R263K INSTI mutations at frequencies of 100% by means of next-generation sequencing (NGS), causing high-level resistance to RAL, EVG, DTG, and BIC. In addition, the prior M184V mutation—but no other NRTI mutations—was detected at a frequency of 100%. The patient’s ART was switched to a salvage regimen consisting of twice-daily RTV-boosted DRV, twice-daily etravirine (ETR), and tenofovir alafenamide fumarate (TAF)/FTC (Figure 1). With this salvage regimen, the viral load returned to levels <20 cp/mL plasma and remained suppressed until present in January 2020.\n\n3. Discussion\nThis is a rare case of a patient with pre-existing M184V/I mutation and virological failure on a DTG/3TC/ABC regimen with the emergence of INSTI resistance mutations. Most likely, the virological failure was triggered by suboptimal adherence and a low nadir CD4+ cell count.\n\nVirological failure with the emergence of resistance to INSTIs on a DTG-based triple-therapy is a rare event with only a few cases published so far [2,3,4,5,6]. Our patient exhibited several features that might have increased his risk for a virological failure: Firstly, the patient re-started his ART following a structured treatment interruption with a low CD4+ cell count of 167 cells/µl blood. Indeed, a CD4+ cell count below 200 cells/µL blood is associated with less favorable virological, immunological, and clinical outcomes in many studies [12]. Secondly, the patient reported suboptimal adherence during several years with detectable low-level viremia and viral blips. Thirdly, the patient harbored the M184V/I mutation, which causes reduced susceptibility to two (3TC, ABC) out of the three components of the DTG/3TC/ABC regimen. A recent European observational study assessed the impact of the M184V/I mutation on the virological failure rate on the DTG/3TC/ABC regimen [8]. Of the 1626 patients included, 137 (8.4%) harbored the genotypically documented M184V/I mutation. Patients with the M184V/I mutation had a lower CD4 nadir and a long history of antiviral treatment. Overall, the study observed a very low virological failure rate (1.3%) after the switch to ABC/3TC/DTG, with no statistically significant difference in the virological failure incidence among patients with or without M184V/I. However, the generalization of the results is limited due to the small sample size and the short observational period (median follow-up 288 days). Furthermore, an indication bias may have occurred as physicians tended to prescribe a single-pill regimen in patients with documented resistance mutations only if they were confident about patients’ adherence [8]. It is convincing that in our case the combination of poor adherence with low-level replication and pre-existing M184V/I mutation, first observed as a low-abundant variant in the SSITT study, led to virological failure and consecutively emergence of INSTI resistance.\n\nThe learning points of this case are manifold: Firstly, this case illustrates that patients with a low CD4+ cell count nadir, pre-existing NRTI-associated mutations, and poor adherence are not candidates for a DTG-containing regimen with limited efficacy of the NRTI-backbone, at least not without close monitoring of the viral load. Other INSTIs with a lower resistance barrier than DTG, such as elvitegravir (EVG) in the co-formulation EVG/cobicistat/FTC/TAF, showed to be effective in maintaining viral suppression despite archived M184V/I mutations at week 24 in a prospective open-label study. However, in this study-population the median nadir CD4+ cell count was high (724 cells/µL blood), the sample size was small, and the observational period was rather short [13]. Furthermore, TAF exhibits still full efficacy in the presence of the M184V/I mutation in contrast to ABC. Secondly, our case and others indicate that DTG might have a lower resistance barrier than previously postulated, in particular when given with a not fully active backbone. This finding may have important consequences in light of the current widespread use of DTG in low-income countries. In this setting, pre-existing NRTI-associated mutations—including the M184V/I mutation—are highly prevalent and there is no possibility of close viral load monitoring. In addition, the cut-off of a viral load >1000 cp/mL plasma recommended by the World Health Organization (WHO) for the definition of virological failure will lead to delayed action when a patient fails on a DTG-containing regimen with an increased risk for the emergence of resistance to INSTIs and the loss of future treatment options [7]. Given that TDF/TAF still exhibits full efficacy in the presence of the M184V/I mutation, this backbone component should be preferred in combination with DTG in low—and middle-income countries.\n\nOur case has several limitations. Firstly, DTG drug levels were not measured at the time of virological failure and therefore suboptimal adherence as an important co-factor for the virological failure cannot be proven. However, self-reported adherence of missed doses of ART—as systematically collected in these patients within the Swiss HIV Cohort Study—is a good predictor for poor adherence and associated with an increased risk of both viral failure and death [14]. Hence, monitoring adherence helps to identify patients at risk for negative clinical outcomes and offers opportunities for intervention. Another limitation is that we didn’t sequence the integrase gene at baseline when the patient started his first cART, thus, we cannot rule out pre-existing INSTI-associated mutations. However, a recent large study within the SHCS clearly indicated that resistance-associated mutations to INSTIs were almost absent in Switzerland in drug naïve patients [15]. Finally, we were unable to perform next-generation sequencing of the virus from different time points because there was no plasma left for extraction. Therefore, we cannot exclude that the M184I mutation detected at different time points may potentially be linked to different viral quasispecies. However, while this discrimination is interesting from a viral evolution point of view, such information most likely would not have had any impact on the clinical management of the patient.\n\n4. Conclusions\nIn conclusion, we describe a rare case of a virological failure on the DTG/3TC/ABC regimen with the emergence of resistance to all INSTIs in a patient with pre-existing M184V/I mutation. Other risk factors, which may have triggered the virological failure, included suboptimal adherence and a low nadir CD4+ cell count. This case illustrates that DTG/3TC/ABC should be prescribed with caution to patients with pre-existing M184V/I mutation, a low CD4 cell count, and/or poor adherence. Even more caution in this patient population is probably indicated when DTG/3TC containing dual regimens are planned. In addition, this case questions the current understanding of DTG as a drug with high resistance barrier similar to contemporary boosted PIs and highlights the need for close viral load monitoring in countries with a high prevalence of NRTI-mutations.\n\nPublisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAuthor Contributions\nD.L.B. wrote the first draft of the manuscript. T.S. created the figure and reviewed the manuscript. U.L., M.F., K.J.M., J.B. reviewed the manuscript. H.F.G. conceptualized and reviewed the manuscript. All authors have read and agreed to the published version of the manuscript.\n\nFunding\nSNF grant 324730B_179571 (to H.F.G) and the Yvonne Jacob Foundation (to H.F.G) supported this work. The funders had no role in preparing, writing, or interpreting the manuscript.\n\nConflicts of Interest\nD.L.B. reports travel grants and honoraria from ViiV, MSD, and Gilead Sciences outside the submitted work. K.J.M. reports grants travel grants and honoraria from ViiV and Gilead Sciences outside the submitted work; the University of Zurich received an unrestricted research grant from Gilead Science for studies that Metzner serves as principal investigator, unrelated to the submitted work. H.F.G. has received unrestricted research grants from Gilead Sciences; fees for data and safety monitoring board or consulting/advisory board membership from Merck Gilead Sciences, ViiV, Sandoz, and Mepha.\n\nFigure 1 Virological evolution and emergence of resistance-associated mutations (arrows pointing downwards) of our patient since initiation of antiretroviral treatment. Abbreviations: ART: antiretroviral treatment, 3TC: lamivudine, D4T: stavudine, NFV: nelfinavir, SSITT: Swiss Spanish Intermittent Treatment Trial, FAPV/r: fosamprenavir/ritonavir, TDF: tenofovir disoproxil-fumarate, FTC: emtricitabine, (*) add-on raltegravir for one month, DRV/r: darunavir/ritonavir, ETV: etravirine, TAF: tenofovir alafenamide, LOQ: level of quantification. The persisting M184V/I mutation is highlighted in bold.\n==== Refs\nReferences\n1. Saag M.S. Benson C.A. Gandhi R.T. Hoy J.F. Landovitz R.J. Mugavero M.J. Sax P.E. Smith D.M. Thompson M.A. Buchbinder S.P. Antiretroviral drugs for treatment and prevention of HIV Infection in Adults: 2018 recommendations of the international antiviral society-USA panel JAMA 2018 320 379 396 10.1001/jama.2018.8431 30043070 \n2. Pena M.J. Chueca N. D’Avolio A. Zarzalejos J.M. Garcia F. Virological failure in HIV to triple therapy with dolutegravir-based firstline treatment: Rare but possible Open Forum Infect. Dis. 2019 6 ofy332 10.1093/ofid/ofy332 30631792 \n3. Cardoso M. Baptista T. Diogo I. Aleixo M.J. Marques N. Mansinho K. Gomes P. Two cases of dolutegravir failure with R263K mutation AIDS 2018 32 2639 2640 10.1097/QAD.0000000000001978 30379690 \n4. Lubke N. Jensen B. Huttig F. Feldt T. Walker A. Thielen A. Daumer M. Obermeier M. Kaiser R. Knops E. Failure of dolutegravir first-line ART with selection of virus carrying R263K and G118R N. Engl. J. Med. 2019 381 887 889 10.1056/NEJMc1806554 31461601 \n5. Fulcher J.A. Du Y. Zhang T.H. Sun R. Landovitz R.J. Emergence of integrase resistance mutations during initial therapy containing dolutegravir Clin. Infect. Dis. 2018 67 791 794 10.1093/cid/ciy228 29933437 \n6. Lepik K.J. Harrigan P.R. Yip B. Wang L. Robbins M.A. Zhang W.W. Toy J. Akagi L. Lima V.D. Guillemi S. Emergent drug resistance with integrase strand transfer inhibitor-based regimens AIDS 2017 31 1425 1434 10.1097/QAD.0000000000001494 28375875 \n7. Dorward J. Lessells R. Drain P.K. Naidoo K. de Oliveira T. Pillay Y. Abdool Karim S.S. Garrett N. Dolutegravir for first-line antiretroviral therapy in low-income and middle-income countries: Uncertainties and opportunities for implementation and research Lancet HIV 2018 5 e400 e404 10.1016/S2352-3018(18)30093-6 29884404 \n8. Olearo F. Nguyen H. Bonnet F. Yerly S. Wandeler G. Stoeckle M. Cavassini M. Scherrer A. Costagiola D. Schmid P. Impact of the M184V/I mutation on the efficacy of abacavir/lamivudine/dolutegravir therapy in HIV Treatment-experienced patients Open Forum Infect. Dis. 2019 6 ofz330 10.1093/ofid/ofz330 31660328 \n9. Fagard C. Oxenius A. Gunthard H. Garcia F. Le Braz M. Mestre G. Battegay M. Furrer H. Vernazza P. Bernasconi E. A prospective trial of structured treatment interruptions in human immunodeficiency virus infection Arch. Intern. Med. 2003 163 1220 1226 10.1001/archinte.163.10.1220 12767960 \n10. Metzner K.J. Bonhoeffer S. Fischer M. Karanicolas R. Allers K. Joos B. Weber R. Hirschel B. Kostrikis L.G. Gunthard H.F. Emergence of minor populations of human immunodeficiency virus type 1 carrying the M184V and L90M mutations in subjects undergoing structured treatment interruptions J. Infect. Dis. 2003 188 1433 1443 10.1086/379215 14624368 \n11. Hammer S.M. Saag M.S. Schechter M. Montaner J.S. Schooley R.T. Jacobsen D.M. Thompson M.A. Carpenter C.C. Fischl M.A. Gazzard B.G. Treatment for adult HIV infection: 2006 recommendations of the International AIDS Society-USA panel JAMA 2006 296 827 843 10.1001/jama.296.7.827 16905788 \n12. Miller V. Mocroft A. Reiss P. Katlama C. Papadopoulos A.I. Katzenstein T. van Lunzen J. Antunes F. Phillips A.N. Lundgren J.D. Relations among CD4 lymphocyte count nadir, antiretroviral therapy, and HIV-1 disease progression: Results from the EuroSIDA study Ann. Intern. Med. 1999 130 570 577 10.7326/0003-4819-130-7-199904060-00005 10189326 \n13. Perez-Valero I. Llibre J.M. Lazzarin A. di Perri G. Pulido F. Molina J.M. Esser S. McNicholl I.R. Lorgeoux R.P. Margot N. A Phase 3b open-label pilot study to evaluate switching to Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide (E/C/F/TAF) single-tablet regimen in virologically-suppressed HIV-1 infected adults harboring the NRTI resistance mutation M184V and/or M184I (GS-US-292-1824): Week 24 Results Proceedings of the 22nd International AIDS Conference Amsterdam, The Netherlands 23–27 July 2018 \n14. Glass T.R. Sterne J.A. Schneider M.P. De Geest S. Nicca D. Furrer H. Gunthard H.F. Bernasconi E. Calmy A. Rickenbach M. Self-reported nonadherence to antiretroviral therapy as a predictor of viral failure and mortality AIDS 2015 29 2195 2200 10.1097/QAD.0000000000000782 26544582 \n15. Scherrer A.U. Yang W.L. Kouyos R.D. Boni J. Yerly S. Klimkait T. Aubert V. Cavassini M. Battegay M. Hauser C. Successful prevention of transmission of integrase resistance in the Swiss HIV cohort study J. Infect. Dis. 2016 214 399 402 10.1093/infdis/jiw165 27130429\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1999-4915",
"issue": "12(11)",
"journal": "Viruses",
"keywords": "HIV-1; M184V/I mutation; antiretroviral therapy; dolutegravir; drug resistance; integrase strand transfer inhibitor; virological failure",
"medline_ta": "Viruses",
"mesh_terms": "D024882:Drug Resistance, Viral; D015658:HIV Infections; D019428:HIV Integrase Inhibitors; D015497:HIV-1; D006575:Heterocyclic Compounds, 3-Ring; D018451:Homosexuality, Male; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010078:Oxazines; D010879:Piperazines; D011728:Pyridones; D012307:Risk Factors; D017211:Treatment Failure; D019562:Viral Load",
"nlm_unique_id": "101509722",
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"pmc": null,
"pmid": "33228206",
"pubdate": "2020-11-19",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "30043070;12767960;29884404;27130429;16905788;10189326;30379690;14624368;31660328;30631792;31461601;28375875;29933437;26544582",
"title": "Emergence of Resistance to Integrase Strand Transfer Inhibitors during Dolutegravir Containing Triple-Therapy in a Treatment-Experienced Patient with Pre-Existing M184V/I Mutation.",
"title_normalized": "emergence of resistance to integrase strand transfer inhibitors during dolutegravir containing triple therapy in a treatment experienced patient with pre existing m184v i mutation"
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"abstract": "OBJECTIVE\nThis case report describes a rare and potentially fatal condition associated with anesthesia administration. Our aim was to discuss the causes of sudden cardiac arrest during the perioperative period in apparently healthy patients and the pathophysiology of anomalous origin of the coronary arteries as a cause of sudden cardiac arrest.\n\n\nMETHODS\nFemale patient, 44 years old, with no previous symptoms of heart disease or arrhythmias, had a sudden cardiac arrest during general anesthesia in two different situations. In the first episode, the patient presented signs of acute abdomen, but remained hemodynamically stable. Following induction of anesthesia, the patient exhibited bradycardia and hypotension refractory to volume replacement and vasopressors. The condition progressed to asystole. The patient was successfully resuscitated and discharged from the hospital in good condition. In the second episode, one year after the first, the patient was in good clinical condition to undergo an elective surgery. After induction of anesthesia, the patient developed ventricular tachycardia followed by asystole, which was promptly reversed. After extensive investigation, an anomalous origin of the left coronary artery was identified.\n\n\nCONCLUSIONS\nOur report is illustrative as it emphasizes that a thorough diagnostic investigation should be done in cases of sudden cardiac arrest during the perioperative period, even in patients that appear to be healthy.",
"affiliations": "Anesthesiology Department, Hospital Universitário de Brasília, Universidade de Brasília (UnB), Brazil. mdagomes@gmail.com",
"authors": "Daher|Maurício|M|;Zanatta|André Rodrigues|AR|;Henz|Benhur David|BD|;da Silva|Marcelo Carneiro|MC|;dos Santos|Simone Nascimento|SN|;Leite|Luiz Roberto|LR|",
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"issue": "62(6)",
"journal": "Revista brasileira de anestesiologia",
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"medline_ta": "Rev Bras Anestesiol",
"mesh_terms": "D000328:Adult; D000768:Anesthesia, General; D003330:Coronary Vessel Anomalies; D016757:Death, Sudden, Cardiac; D005260:Female; D006801:Humans",
"nlm_unique_id": "0401316",
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"pages": "878-84",
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"pubdate": "2012",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Sudden cardiac arrest in general anesthesia as the first manifestation of anomalous origin of the left coronary artery.",
"title_normalized": "sudden cardiac arrest in general anesthesia as the first manifestation of anomalous origin of the left coronary artery"
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"companynumb": "BR-PFIZER INC-2012316856",
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"abstract": "Glatiramer acetate (GA) is a drug that commonly is used for the treatment of relapsing-remitting multiple sclerosis (RRMS). Although it typically is known as a safe and effective therapy, a number of adverse effects associated with GA have been reported in the literature. Local injection-site reactions (LISRs) and mild systemic symptoms are among the most commonly described adverse effects. A review of the literature revealed limited reports of panniculitis as an adverse effect of GA injection and even fewer describing associated skin necrosis. We report a case of GA-induced panniculitis and skin necrosis and discuss the occurrence of panniculitis, necrosis, and lipoatrophy following GA injections.",
"affiliations": "Quillen College of Medicine, East Tennessee State University, PO Box 70580, Johnson City, TN 37614, USA. watkince@goldmail.etsu.edu.",
"authors": "Watkins|Casey E|CE|;Litchfield|John|J|;Youngberg|George|G|;Leicht|Stuart S|SS|;Krishnaswamy|Guha|G|",
"chemical_list": "D000068717:Glatiramer Acetate",
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"issue": "95(3)",
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"mesh_terms": "D000328:Adult; D005260:Female; D000068717:Glatiramer Acetate; D006801:Humans; D020529:Multiple Sclerosis, Relapsing-Remitting; D009336:Necrosis; D015434:Panniculitis; D012867:Skin",
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"title": "Glatiramer acetate-induced lobular panniculitis and skin necrosis.",
"title_normalized": "glatiramer acetate induced lobular panniculitis and skin necrosis"
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{
"abstract": "Hypomagnesemia can be caused by a wide range of diseases (e.g. gastrointestinal disorders, kidney diseases or endocrine disorders), but it can also be a side effect of several drugs. It can be asymptomatic or cause many different clinical symptoms, and the clinical manifestations mainly depend on the rate of development rather than the actual serum magnesium concentration. We here present a 40-year-old female patient with Torsade de pointes ventricular tachycardia and cardiac arrest caused by severe hypomagnesemia as an adverse effect of the proton pump inhibitor omeprazole.",
"affiliations": "Section for Endocrinology , Department of Medicine , Haukeland University Hospital , Bergen , Norway.;Section for Endocrinology , Department of Clinical Science , University of Bergen , Bergen, Norway.",
"authors": "Hansen|Bent-Are|BA|;Bruserud|Øyvind|Ø|",
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"doi": "10.1093/omcr/omw062",
"fulltext": "\n==== Front\nOxf Med Case ReportsOxf Med Case ReportsomcromcrOxford Medical Case Reports2053-8855Oxford University Press 10.1093/omcr/omw062omw062Case ReportHypomagnesemia as a potentially life-threatening adverse effect of omeprazole Hansen Bent-Are 1†Bruserud Øyvind 2*†1 Section for Endocrinology, Department of Medicine, Haukeland University Hospital, Bergen, Norway2 Section for Endocrinology, Department of Clinical Science, University of Bergen, Bergen, Norway* Correspondence address. Department of Clinical Science, University of Bergen, N-5021 Bergen, Norway. Tel: +47 98425331; Fax: +47 55975000; E-mail: oyvind.bruserud@uib.no† These authors contributed equally to this paper.\n\n7 2016 27 7 2016 2016 7 147 149 9 5 2015 3 6 2016 19 6 2016 © The Author 2016. Published by Oxford University Press.2016This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.comHypomagnesemia can be caused by a wide range of diseases (e.g. gastrointestinal disorders, kidney diseases or endocrine disorders), but it can also be a side effect of several drugs. It can be asymptomatic or cause many different clinical symptoms, and the clinical manifestations mainly depend on the rate of development rather than the actual serum magnesium concentration. We here present a 40-year-old female patient with Torsade de pointes ventricular tachycardia and cardiac arrest caused by severe hypomagnesemia as an adverse effect of the proton pump inhibitor omeprazole.\n==== Body\nINTRODUCTION\nHypomagnesemia can result from a variety of different causes including gastrointestinal diseases, kidney diseases and as a side effect of drugs in medical treatments. The symptoms depend on the rate of development as well as the actual serum concentration of magnesium. Furthermore, symptoms may be diverse because of the various biochemical and physical effects of magnesium, and similar to other electrolyte disturbances symptoms may be diffuse and/or atypical. In the following case report, we present a 40-year-old female patient with Torsade de pointes arrhythmia and cardiac arrest caused by severe hypomagnesemia as an adverse effect of proton pump inhibitor (PPI) treatment.\n\nCASE REPORT\nA 40-year-old female presented with nausea, fatigue and diarrhea at the emergency department. She also described palpitations but denied other cardiovascular symptoms, and no neuromuscular symptoms were reported. She had not been able to eat or drink properly for the last weeks, and her symptoms had progressed during the last days before admittance to the hospital. Medical history was significant only for familial hypercholesterolemia and gastric esophageal reflux disease. Especially, no chronic endocrine diseases were present. She used 20–40 mg omeprazole and 20 mg atorvastatin on a daily basis and she had smoked for the last 20 years. She denied using narcotics or alcohol and also to have taken any nephrotoxic drugs.\n\nThe patient was in acute stress at admittance. The blood pressure was 103/80 mmHg, heart rate was regular with 125 beats per minute and the respiratory rate was 24 per minute. On the physical examination she presented clinical signs of dehydration, otherwise the physical examination showed no abnormalities. The laboratory tests showed hemoglobin 18.6 g/dL (references: 11.7–15.3 g/dL), leukocyte count 27.8 * 109/L (references: 3.5–11.0 * 109/L), thrombocyte count 468 (references: 165–387 * 109/L), creatinine 349 µmol/L (references: 45–90 µmol/L), urea 8.6 mmol/L (references: 2.6–6.4 mmol/L), sodium 150 mmol/L (references: 137–145 mmol/L), potassium 3.6 mmol/L (references: 3.4–4.8 mmol/L), estimated glomerular filtration rate (GFR) 13 mL/min/1.73 m2 (references: >30 mL/min/1.73 m2), troponin I 925 ng/L (references: <15 ng/L), calcium 2.18 mmol/L (references: 2.17–2.52 mmol/L), albumin 53 g/L (references: 36–45 g/L), PTH 22.1 pmol/L (references: 1.6–6.9 pmol/L). A urine test strip was positive on proteins (2+) and microscopy of the urine showed a few hyaline casts. An electrocardiogram (ECG) revealed sinus tachykardi with frequency 125 beats per minute and diffuse changes in the ST-segments of lateral and anterior leads (aVL, II, III, V1, V2, V4, V5, V6). The corrected QT-interval was 388 ms. Ultrasound of the kidneys and transthoracic echocardiography were both normal.\n\nThe patient was then admitted to the department of internal medicine with the diagnosis acute renal failure probably secondary to dehydration, and she received intravenous Ringer's acetate infusion. Her urine production was sparse during the first hours of admittance, about 20 mL/hour.\n\nFive hours after admittance the patient became critically ill presenting convulsions, cyanosis and loss of consciousness. Resuscitation was started immediately and the ECG showed Torsade de pointes ventricular tachycardia. A bolus injection of intravenous magnesium (20 mmol) converted her arrhythmia to sinus rhythm and she woke up. Severe hypomagnesemia was diagnosed with magnesium <0.27 mmol/L (references: 0.71–0.94 mmol/L). Magnetic resonance imaging of the cerebrum and cerebral angiography were both normal. Further treatment with intravenous Ringer's acetate and 5% glucose solution supplemented with MgSo4 caused normalization of the serum level and she also showed gradual clinical improvement. Careful examination could not detect any gastrointestinal or renal cause of hypomagnesemia. Although, her diarrhea present at admittance probably contributed to her severe hypomagnesemia causing the arrhythmia.\n\nShe was discharged home after 14 days in hospital with daily oral supplements of magnesium. However, 3 months later she was again admitted to hospital with hypomagnesemia despite the daily supplementation. The laboratory tests showed magnesium 0.28 mmol/L (references: 0.71–0.94 mmol/L), creatinine 106 µmol/L (references: 45–90 µmol), sodium 144 mmol/L (references: 137–145 mmol/L), potassium 3.2 mmol/L (references: 3.4–4.8 mmol/L), estimated GFR 57 mL/min/1.73 m2 (references: >30 mL/min/1.73 m2), calcium 2.42 mmol/L (references: 2.17–2.52 mmol/L), PTH 4.8 pmol/L (references: 1.6–6.9 pmol/L). Her kidney function had improved and her renal failure at the first admittance was probably secondary to the severe dehydration. After a thorough examination, it was concluded that the hypomagnesemia was a side effect of the PPI omeprazole. She had taken PPI for the last 13 years and her serum magnesium was within the normal range at the last control 7 years before the first admittance. Her PPI treatment was stopped and she is now under surveillance in the outpatient clinic with stable normal serum magnesium levels for 5 months after last discharge.\n\nDISCUSSION\nSymptoms of hypomagnesemia typically begin to be manifested at serum levels <0.66 mmol/L (1.6 mg/dl) [1]. The magnesium balance is maintained by renal regulation of magnesium reabsorption and hypomagnesemia can result from a variety of causes. However, it usually occurs secondary to other disease processes or drugs, and features of the primary disease process may complicate or mask magnesium deficiency. Magnesium plays an important role in several biochemical and physiological processes, and is the fourth most abundant cation in the body. Hypomagnesemia therefore tends to cause symptoms from different tissues including the neuromuscular, central nervous system and the cardiovascular system [2]. The classic symptoms of severe hypomagnesemia include tetany, convulsions, bradycardia, hypotension and in worst case death. The prevalence of hypomagnesemia in hospitalized patients varies (7–11%) and is even more frequent in patients with other coexisting electrolyte abnormalities [3–5]. Hypomagnesemia in critical ill patients is associated with increased mortality [6]. Unfortunately, there are no readily and easy methods to assess magnesium status, although serum magnesium and the magnesium tolerance test are the most widely used [2].\n\nPPIs are extremely widely used, and during the last decades PPI-induced hypomagnesemia has become a well-established phenomenon [7–9]. Growing evidence suggest that PPI impair the intestinal magnesium absorption through molecular mechanism of magnesium transporters; probably influenced by a complicated interplay of molecular biology, pharmacology and genetic predisposition [10]. Our patient in the case report presented severe hypomagnesemia resulting in Torsade de pointe and cardiac arrest. She was successfully treated and widely investigated, searching for the cause of her hypomagnesemia which was found to be an adverse effect of PPI. Her PPI was stopped and she then presented stable serum concentration of magnesium within the normal range in the following surveillance.\n\nCONCLUSION\nSevere hypomagnesemia can cause life-threatening ventricular arrhythmias. Hypomagnesemia can be caused by many different conditions, e.g. be a side effect of the widely used drug PPI. Serum concentration of magnesium should be analyzed in hospitalized patients especially when the patient presents with other electrolyte disturbances or when conditions affecting magnesium metabolism are present.\n\nACKNOWLEDGEMENT\nWe would like to thank Dr Øystein Bruserud for his valuable contributions.\n\nCONFLICT OF INTEREST STATEMENT\nNone declared.\n\nETHICAL APPROVAL\nNo approval is required.\n\nCONSENT\nThe patient gave written consent for publication of this case report.\n\nGUARANTOR\nØyvind Bruserud and Bent-Are Hansen.\n==== Refs\nREFERENCES\n1 Pham PC , Pham PA , Pham SV , Pham PT , Pham PM , Pham PT. \nHypomagnesemia: a clinical perspective . Int J Nephrol Renovasc Dis \n2014 ;7 :219 –30 .24966690 \n2 Swaminathan R. \nMagnesium metabolism and its disorders . Clin Biochem Rev \n2003 ;24 :47 –66 .18568054 \n3 Whang R , Oei TO , Aikawa JK , Watanabe A , Vannatta J , Fryer A , et al \nPredictors of clinical hypomagnesemia. Hypokalemia, hypophosphatemia, hyponatremia, and hypocalcemia . Arch Intern Med \n1984 ;144 :1794 –6 .6476998 \n4 Wong ET , Rude RK , Singer FR , Shaw ST Jr \nA high prevalence of hypomagnesemia and hypermagnesemia in hospitalized patients . Am J Clin Pathol \n1983 ;79 :348 –52 .6829504 \n5 Hayes JP , Ryan MF , Brazil N , Riordan TO , Walsh JB , Coakley D. \nSerum hypomagnesaemia in an elderly day-hospital population . Ir Med J \n1989 ;82 :117 –9 .2599834 \n6 Rubeiz GJ , Thill-Baharozian M , Hardie D , Carlson RW. \nAssociation of hypomagnesemia and mortality in acutely ill medical patients . Crit Care Med \n1993 ;21 :203 –9 .8428470 \n7 Corleto VD , Festa S , Di Giulio E , Annibale B. \nProton pump inhibitor therapy and potential long-term harm . Curr Opin Endocrinol Diabetes Obes \n2014 ;21 :3 –8 .24310148 \n8 Janett S , Camozzi P , Peeters GG , Lava SA , Simonetti GD , Goeggel Simonetti B , et al \nHypomagnesemia induced by long-term treatment with proton-pump inhibitors . Gastroenterol Res Pract \n2015 ;2015 :951768 .26064102 \n9 William JH , Danziger J. \nMagnesium deficiency and proton-pump inhibitor use: a clinical review . J Clin Pharmacol \n2015 ; doi:10.1002/jcph.672 .\n10 William JH , Danzinger J. \nProton-pump inhibitor-induced hypomagnesemia: current research and proposed mechanisms . World J Nephrol \n2016 ;5 :152 –7 .26981439\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2053-8855",
"issue": "2016(7)",
"journal": "Oxford medical case reports",
"keywords": null,
"medline_ta": "Oxf Med Case Reports",
"mesh_terms": null,
"nlm_unique_id": "101642070",
"other_id": null,
"pages": "147-9",
"pmc": null,
"pmid": "27471598",
"pubdate": "2016-07",
"publication_types": "D002363:Case Reports",
"references": "6476998;8428470;2599834;6829504;26582556;26064102;18568054;26981439;24310148;24966690",
"title": "Hypomagnesemia as a potentially life-threatening adverse effect of omeprazole.",
"title_normalized": "hypomagnesemia as a potentially life threatening adverse effect of omeprazole"
} | [
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"companynumb": "NO-MYLANLABS-2016M1034302",
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"activesubstancename": "ATORVASTATIN"
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{
"abstract": "Lymphocytic colitis is a subtype of microscopic colitis characterized by normal colonoscopy findings and microscopic evidence of lymphocytic infiltration of colonic epithelial cells. The concomitant diagnosis of lymphocytic colitis and ulcerative colitis has been rarely reported. We present a 68-year-old man with a 40-year history of ulcerative colitis who was referred to our hospital for 3-4 weeks of non-bloody diarrhea with subsequent colonoscopy and biopsies confirming lymphocytic colitis.",
"affiliations": "Department of Internal Medicine, University of Arizona, Tucson, AZ.;Department of Pathology, University of Arizona, Tucson, AZ.;Division of Gastroenterology and Hepatology, Department of Medicine, University of Arizona, Tucson, AZ.",
"authors": "Stavrakis|Dimitris|D|;Meiklejohn|Karleen M|KM|;Taleban|Sasha|S|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.14309/crj.2018.82",
"fulltext": "\n==== Front\nACG Case Rep JACG Case Rep JcrjACG Case Reports Journal2326-3253American College of Gastroenterology crj.2018.8210.14309/crj.2018.82Case ReportInflammatory Bowel DiseaseLymphocytic Colitis Diagnosis 40 Years after Onset of Ulcerative Colitis Stavrakis et alLymphocytic Colitis in Patient with Ulcerative ColitisStavrakis Dimitris MD1Meiklejohn Karleen M. MD2Taleban Sasha MD31 Department of Internal Medicine, University of Arizona, Tucson, AZ2 Department of Pathology, University of Arizona, Tucson, AZ3 Division of Gastroenterology and Hepatology, Department of Medicine, University of Arizona, Tucson, AZCorrespondence: Sasha Taleban, MD, University of Arizona College of Medicine, Tucson, AZ 85718 (staleban@email.arizona.edu).2018 28 11 2018 5 e8217 2 2018 6 8 2018 Copyright © Stavrakis et al.2018This is an open-access article. This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/4.0/Lymphocytic colitis is a subtype of microscopic colitis characterized by normal colonoscopy findings and microscopic evidence of lymphocytic infiltration of colonic epithelial cells. The concomitant diagnosis of lymphocytic colitis and ulcerative colitis has been rarely reported. We present a 68-year-old man with a 40-year history of ulcerative colitis who was referred to our hospital for 3–4 weeks of non-bloody diarrhea with subsequent colonoscopy and biopsies confirming lymphocytic colitis.\n==== Body\nIntroduction\nMicroscopic colitis (MC) is an inflammatory disease of the colon characterized by chronic non-bloody diarrhea, fecal urgency, and abdominal pain, and it has two subtypes: lymphocytic colitis (LC) and collagenous colitis (CC).1-6 The etiology of MC and its association with inflammatory bowel disease (IBD) is uncertain; however, recent reports indicate a possible common pathophysiology between MC and IBD and suggest that MC may be part of a spectrum of IBD.1,3-5,7 Albeit rare, previous case reports have documented the diagnosis of LC up to 30 years after a diagnosis of ulcerative colitis (UC).1,3-5,8\n\nCase Report\nA 68-year-old man with a history of ankylosing spondylitis (AS) and UC presented for an outpatient colonoscopy in 1975 after an acute presentation of bloody diarrhea. Proctoscopy showed active inflammation, and he was diagnosed with UC, which improved with cortisone treatment without maintenance therapy. In the late 1970s, he was diagnosed with AS and was started on sulfasalazine. Approximately 10 years later, the patient had an acute episode of bloody diarrhea, with colonoscopy indicating diffuse colonic inflammation (Montreal Classification E3). Stool studies were negative. He was treated with prednisone and mesalamine; symptoms resolved, and he stopped mesalamine after a few months. The patient was started on methotrexate at this time for his AS. In 2009, he started adalimumab for his AS but switched to infliximab in 2014 for insurance reasons. The patient lost clinical response to infliximab in 2017 and was transitioned back to adalimumab and methotrexate. The patient denied any gastrointestinal (GI) symptoms from the 1980s up until 2017, and routine surveillance colonoscopies over that time revealed no active inflammation or dysplasia.\n\nIn May 2017, the patient was referred for colonoscopy due to 3–4 weeks of non-bloody diarrhea. He denied fecal urgency, nighttime symptoms, weight loss, or any other symptoms. GI pathogen analysis including stool culture, Clostridium difficile toxin, ova, and parasites was negative. The colonoscopy revealed no endoscopic evidence of active and chronic small or large bowel inflammation with a Ulcerative Colitis Endoscopic Index of Severity (UCEIS) of [0,0,0] and a Mayo endoscopic score of 0. Dysplasia surveillance biopsies throughout the colon revealed mild active colitis at 10 cm (Figure 1). Biopsies at 30 cm and 70 cm showed LC (considered an active colitis) with chronicity, lymphocytes, and plasma cells; the presence of lymphocytes and plasma cells indicated chronic inflammation (Figure 2). During this time, he was also on aspirin and simvastatin for coronary artery disease and hyperlipidemia. At IBD clinic 4 months later, the patient reported that his diarrhea had resolved 3–4 weeks after the colonoscopy without further intervention from his regimen of adalimumab and methotrexate for AS. Patient has been asymptomatic from UC and LC at 14 months of follow-up since his diagnosis of LC.\n\nFigure 1 Hematoxylin and eosin (H&E) stain of a 10-cm colon biopsy (20×) showing mild active colitis with occasional intraepithelial neutrophils in a background of intraepithelial lymphocytosis (arrows) and chronic interstitial inflammation.\n\nFigure 2 (A and B) H&E stain of a 70-cm colon biopsy (20×) showing lymphocytic colitis with surface epithelial injury associated with lymphocytic infiltration (arrows), loss of mucin, and scattered eosinophils. There is no thickened subepithelial collagen, which distinguishes lymphocytic colitis from collagenous colitis. (C) H&E stain of a 30-cm colon biopsy (20×) showing lymphocytic colitis with abundant subepithelial plasma cells. Arrows indicate intraepithelial lymphocytes.\n\nDiscussion\nLC is characterized by unremarkable endoscopic findings with histologic analysis indicating >20 intraepithelial lymphocytes per 100 surface epithelial cells on colonic biopsies.2-4,7 The rare occurrence of LC in patients with UC in remission has been previously documented; however, the epidemiology of this concordance is not well described.1,4,5,9 A 2017 case-control study reports an increased frequency of UC history in LC patients (7% vs 1% in controls), and a 2016 cohort study reports that <2% of patients diagnosed with LC had a history of UC.1,9\n\nA review of the scientific literature indicates 58 confirmed cases in the past 30 years of MC diagnosed in patients before or after a diagnosis of IBD.4,5,13 Of these cases, only 11 were of patients diagnosed with LC and UC.4,5,13 One case series identified 4 patients with UC in remission who subsequently developed LC, while another case series reported 2 patients initially diagnosed with LC who later developed UC.4,5,13 A 2018 retrospective observational study and review reports 5 cases of LC in women previously diagnosed with UC; 4 of the 5 patients were diagnosed with extensive colitis.13 The time between diagnosis of LC and UC ranged from 1 to 30 years.\n\nThe etiologies of MC and IBD are still not fully elucidated and require further research.1,4,5 Smoking has been associated with the development of MC and Crohn’s disease, but is protective against UC.1,2,5,10 Non-steroidal anti-inflammatory drugs (NSAIDs), proton pump inhibitors, and statins have also been implicated in the development of MC; however, further research is required to prove causation.2,3,5-7,10\n\nPrevious records indicate an increased prevalence of autoimmune disorders in patients diagnosed with MC (e.g., type 1 diabetes, thyroiditis, celiac disease), all of which (including MC) share the HLA-DQ2 allele.1-5,7,11 Furthermore, antecedent reports indicate that patients with MC and IBD may share similar genetics and that MC may share a common pathophysiology with IBD, namely a dysregulated immune response to the gut microbiome in genetically susceptible individuals.1-5,12 Finally, a recent review suggests patients originally diagnosed with extensive UC may be more prone to developing LC compared to patients with limited left-sided and proctosigmoid involvement of UC.13\n\nOur patient developed LC despite being treated with adalimumab and methotrexate for his AS, both of which have been used to treat MC.2,3 His exposure to NSAIDs and statin medications, in addition to the extent of his UC, may all have predisposed him to developing LC.2,3,5-7,13 However, a common genetic etiology between MC and IBD is unlikely in our case because there was a long interval (40 years) between the 2 diagnoses, which, to our knowledge, is the longest documented time period between the development of LC and UC. In addition, although nonspecific colonic lymphocytic infiltration may be seen in patients with AS, no definitive correlation has been established between LC and AS.14 In conclusion, identification of risk factors such as medications and the extent of disease in UC patients may help predict development of LC in the future.\n\nDisclosures\nAuthor contributions: D. Stavrakis and S. Taleban wrote the manuscript, and K.M. Meiklejohn provided pathology slides. S. Taleban is article guarantor.\n\nFinancial disclosure: None to report.\n\nInformed consent was obtained for this case report.\n==== Refs\nReferences\n1. Wickbom A , Nyhlin N , Montgomery SM , Bohr J , Tysk C \nFamily history, comorbidity, smoking and other risk factors in microscopic colitis: A case-control study . Eur J Gastroenterol Hepatol . 2017 ;29 :587 –94 .28350750 \n2. Gentile N , Yen EF \nPrevalence, pathogenesis, diagnosis, and management of microscopic colitis . Gut Liver . 2017 ;12 (6 ):227 –35 .\n3. Pardi DS \nDiagnosis and management of microscopic colitis . Am J Gastroenterol . 2017 ;112 :78 –85 .27897155 \n4. Jegadeesan R , Liu X , Pagadala MR , et al \nMicroscopic colitis: Is it a spectrum of inflammatory bowel disease? . World J Gastroenterol . 2013 ;19 (26 ):4252 –6 .23864791 \n5. Osman H , Watson R , Fan R , Nalbantoglu I , Lin J \nIntermittent inflammatory bowel disease and microscopic colitis: variant or epiphenomenon? \nGastroenterol Hepatol . 2015 ;2 (1 ):1 –7 .\n6. Pascua MF , Kedia P , Weiner MG , et al \nMicroscopic colitis and medication use . Clin Med Insights Gastroenterol . 2010 ;(3 ):11 –9 .20640056 \n7. Brown WR , Tayal S \nMicroscopic colitis. A review . J Dig Dis . 2013 ;14 :277 –81 .23419063 \n8. Saad RE , Shobar RM , Jakate S , Mutlu EA \nDevelopment of collagenous colitis in inflammatory bowel disease: Two case reports and a review of the literature . Gastroenterol Rep . 2017 \n10.1093/gastro/gox026 \n9. Mellander MR , Ekbom A , Hultcrantz R , et al \nMicroscopic colitis: A descriptive clinical cohort study of 795 patients with collagenous and lymphocytic colitis . Scand J Gastroenterol . 2016 ;5 :556 –62 .\n10. Pardi DS , Ramnath VR , Loftus EV , Tremaine WJ , Sandborn WJ \nLymphocytic colitis: Clinical features, treatment, and outcomes . Am J Gastroenterol . 2002 ;97 (11 ):2829 –33 .12425555 \n11. Oleson M , Eriksson S , Bohr J , Jarnerot G , Tysk C \nLymphocytic colitis: A retrospective clinical study of 199 Swedish patients . Gut . 2004 ;53 :536 –41 .15016748 \n12. Knights D , Lassen KG , Xavier RJ \nAdvances in inflammatory bowel disease pathogenesis: Linking host genetics and the microbiome . Gut . 2013 ;62 :1505 –10 .24037875 \n13. Wickbom A , Bohr J , Nyhlin N , et al \nMicroscopic colitis in patients with ulcerative colitis or crohn's disease: A retrospective observational study and review of the literature . Scand J Gastroenterol . 2018 ;53 :410 –6 .29546806 \n14. Ciccia F , Rizzo A , Triolo G \nSubclinical gut inflammation in ankylosing spondylitis . Curr Opin Rheumatol . 2016 ;28 :89 –96 .26599385\n\n",
"fulltext_license": "CC BY-NC-ND",
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"journal": "ACG case reports journal",
"keywords": null,
"medline_ta": "ACG Case Rep J",
"mesh_terms": null,
"nlm_unique_id": "101638398",
"other_id": null,
"pages": "e82",
"pmc": null,
"pmid": "30568970",
"pubdate": "2018",
"publication_types": "D002363:Case Reports",
"references": "12425555;15016748;20640056;23419063;23864791;24037875;26599385;26679722;27897155;28350750;28669150;29546806",
"title": "Lymphocytic Colitis Diagnosis 40 Years after Onset of Ulcerative Colitis.",
"title_normalized": "lymphocytic colitis diagnosis 40 years after onset of ulcerative colitis"
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"companynumb": "US-MICRO LABS LIMITED-ML2019-00066",
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"activesubstancename": "METHOTREXATE"
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"abstract": "A 66-year-old man presented with chest pain and a 1-year history of generalised weakness, accompanied with generalised aches and pains. Symptoms worsened when he was initiated on statins. Investigations yielded high creatine kinase, high HMG-coenzymeA reductase (HMGCR) antibody titre, myopathic features on electromyography and muscle biopsy, and muscle atrophy on MRI. These results were in keeping with anti-HMGCR antibody myopathy. The patient responded well to immunosuppressive therapy.",
"affiliations": "Neuroscience, Mater Dei Hospital, Msida, Malta.;Neuroscience, Mater Dei Hospital, Msida, Malta.;Neuroscience, Mater Dei Hospital, Msida, Malta.",
"authors": "Abdilla|Ylenia|Y|;Chircop|Charmaine|C|;Vella|Norbert|N|",
"chemical_list": "D001323:Autoantibodies; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2018-226302",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2018()",
"journal": "BMJ case reports",
"keywords": "muscle disease; neuro genetics; unwanted effects/adverse reactions",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000368:Aged; D001323:Autoantibodies; D001706:Biopsy; D004576:Electromyography; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007165:Immunosuppression Therapy; D008279:Magnetic Resonance Imaging; D008297:Male; D018908:Muscle Weakness; D018482:Muscle, Skeletal; D009336:Necrosis",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "30420560",
"pubdate": "2018-11-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "26090508;22933019;29720800;26886523;24797170;26492593;21360500;27491568;25866831;22154355;23995277;21972203",
"title": "Anti-HMGCR antibody-associated necrotising myopathy and its association with statin use.",
"title_normalized": "anti hmgcr antibody associated necrotising myopathy and its association with statin use"
} | [
{
"companynumb": "MT-PFIZER INC-2019040578",
"fulfillexpeditecriteria": "1",
"occurcountry": "MT",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "SIMVASTATIN"
},
"drugadditional": "1",
... |
{
"abstract": "BACKGROUND\nImatinib is generally well tolerated by patients. The most common ophthalmic side effects are eyelid edema and periorbital edema. Other side effects which occur at rates of <1% include blepharitis, blurred vision, conjunctival hemorrhage, conjunctivitis, retinal hemorrhage, etc. An uncommon case is here reported of a 51-year-old male with chronic myeloid leukemia who developed vitreous hemorrhage due to imatinib after 9 months of treatment.\n\n\nMETHODS\nA 51-year-old male with leukocytosis detected in the blood test examination was referred to the Hematology Department. The bone marrow biopsy result was compatible with chronic myeloid leukemia. Imatinib treatment (400 mg/day) was started. In the ninth month of imatinib treatment, the patient complained of a sudden decrease in vision. Vitreous hemorrhage was detected in the left eye and the patient underwent surgery. Vitreous hemorrhage recurred 1 month after the operation. On the fourth day after the discontinuation of imatinib treatment, the patient's ophthalmic complaints improved significantly. The Naranjo algorithm was applied and a score of 9 was detected. The vitreous hemorrhage of the patient was attributed to imatinib, and so the treatment of the patient was switched to bosutinib.\n\n\nCONCLUSIONS\nImatinib is an oral signal inhibitor that targets tyrosine kinase for BCR/ABL, platelet-derived growth factor, stem cell factor, and c-kit (CD117). The conjunctiva and sclera have a large amount of c-kit positive mast cells which are inhibited by imatinib. The inhibition of c-kit positive mast cells by imatinib may be responsible for further exposure of the conjunctival mucosa to injuries.",
"affiliations": "University of Health Sciences, 146992Diskapi Yildirim Beyazit Training and Research Hospital, Department of Hematology, Ankara, Turkey.;University of Health Sciences, 146992Diskapi Yildirim Beyazit Training and Research Hospital, Department of Hematology, Ankara, Turkey.;University of Health Sciences, 146992Diskapi Yildirim Beyazit Training and Research Hospital, Department of Hematology, Ankara, Turkey.;University of Health Sciences, 146992Diskapi Yildirim Beyazit Training and Research Hospital, Department of Hematology, Ankara, Turkey.;University of Health Sciences, 146992Diskapi Yildirim Beyazit Training and Research Hospital, Department of Hematology, Ankara, Turkey.;University of Health Sciences, 146992Diskapi Yildirim Beyazit Training and Research Hospital, Department of Hematology, Ankara, Turkey.;University of Health Sciences, 146992Diskapi Yildirim Beyazit Training and Research Hospital, Department of Hematology, Ankara, Turkey.;University of Health Sciences, 146992Diskapi Yildirim Beyazit Training and Research Hospital, Department of Hematology, Ankara, Turkey.",
"authors": "Yılmaz|Fatma|F|https://orcid.org/0000-0001-6112-3950;Albayrak|Murat|M|;Tığlıoğlu|Pınar|P|;Tığlıoğlu|Mesut|M|https://orcid.org/0000-0002-4111-2004;Sağlam|Buğra|B|https://orcid.org/0000-0001-8342-990X;Reis Aras|Merih|M|https://orcid.org/0000-0002-9161-5582;Maral|Senem|S|https://orcid.org/0000-0003-4766-1861;Afacan Öztürk|Hacer Berna|HB|https://orcid.org/0000-0001-9386-7604",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1177/10781552211060730",
"fulltext": null,
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"issn_linking": "1078-1552",
"issue": null,
"journal": "Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners",
"keywords": "Imatinib; chronic myeloid leukemia; vitreous hemorrhage",
"medline_ta": "J Oncol Pharm Pract",
"mesh_terms": null,
"nlm_unique_id": "9511372",
"other_id": null,
"pages": "10781552211060730",
"pmc": null,
"pmid": "34775854",
"pubdate": "2021-11-13",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Vitreous hemorrhage: A rare ophthalmic adverse effect due to imatinib treatment.",
"title_normalized": "vitreous hemorrhage a rare ophthalmic adverse effect due to imatinib treatment"
} | [
{
"companynumb": "TR-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-318816",
"fulfillexpeditecriteria": "1",
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{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "IMATINIB"
},
"drugad... |
{
"abstract": "The current coronavirus disease 2019 (COVID-19) pandemic requires extra attention for immunocompromised patients, including solid organ transplant recipients. We report on a case of a 35-year-old renal transplant recipient who suffered from a severe COVID-19 pneumonia. The clinical course was complicated by extreme overexposure to the mammalian target of rapamycin inhibitor everolimus, following coadministration of chloroquine and lopinavir/ritonavir therapy. The case is illustrative for dilemmas that transplant professionals may face in the absence of evidence-based COVID-19 therapy and concurrent pressure for exploration of experimental pharmacological treatment options. However, the risk-benefit balance of experimental or off-label therapy may be weighed differently in organ transplant recipients than in otherwise healthy COVID-19 patients, owing to their immunocompromised status and potential drug interactions with immunosuppressive therapy. With this case report, we aimed to achieve increased awareness and improved management of drug-drug interactions associated with the various treatment options for COVID-19 in renal transplant patients.",
"affiliations": "Department of Internal Medicine, Division of Nephrology, Leiden University Medical Center, Leiden, The Netherlands.;Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, The Netherlands.;Department of Internal Medicine, Division of Nephrology, Amphia Hospital, Breda, The Netherlands.;Department of Intensive Care, Leiden University Medical Center, Leiden, The Netherlands.;Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, The Netherlands.;LUMC Transplant Center, Leiden University Medical Center, Leiden, The Netherlands.;Department of Internal Medicine, Division of Nephrology, Leiden University Medical Center, Leiden, The Netherlands.;Department of Internal Medicine, Division of Nephrology, Leiden University Medical Center, Leiden, The Netherlands.;Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, The Netherlands.;Department of Internal Medicine, Division of Nephrology, Leiden University Medical Center, Leiden, The Netherlands.",
"authors": "Meziyerh|Soufian|S|https://orcid.org/0000-0001-7694-8381;Zwart|Tom C|TC|https://orcid.org/0000-0003-3692-0901;van Etten|Ronald W|RW|;Janson|Jeroen A|JA|;van Gelder|Teun|T|https://orcid.org/0000-0001-5980-6947;Alwayn|Ian P J|IPJ|;de Fijter|Johan W|JW|;Reinders|Marlies E J|MEJ|https://orcid.org/0000-0001-9543-567X;Moes|Dirk J A R|DJAR|;de Vries|Aiko P J|APJ|https://orcid.org/0000-0002-9284-3595",
"chemical_list": "D000998:Antiviral Agents; D004338:Drug Combinations; D007166:Immunosuppressive Agents; C558899:lopinavir-ritonavir drug combination; D061466:Lopinavir; D002738:Chloroquine; D000068338:Everolimus; D019438:Ritonavir",
"country": "United States",
"delete": false,
"doi": "10.1111/ajt.15943",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1600-6135",
"issue": "20(7)",
"journal": "American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons",
"keywords": "clinical decision-making; clinical research/practice; drug interaction; immunosuppressive regimens; infection and infectious agents - viral; infectious disease; kidney transplantation/nephrology; pharmacokinetics/pharmacodynamics; pharmacology",
"medline_ta": "Am J Transplant",
"mesh_terms": "D000328:Adult; D000998:Antiviral Agents; D000073640:Betacoronavirus; D000086382:COVID-19; D002738:Chloroquine; D018352:Coronavirus Infections; D004338:Drug Combinations; D004347:Drug Interactions; D000068338:Everolimus; D006801:Humans; D016867:Immunocompromised Host; D007166:Immunosuppressive Agents; D007676:Kidney Failure, Chronic; D016030:Kidney Transplantation; D061466:Lopinavir; D008297:Male; D009426:Netherlands; D058873:Pandemics; D011024:Pneumonia, Viral; D013902:Radiography, Thoracic; D019438:Ritonavir; D000086402:SARS-CoV-2; D066027:Transplant Recipients; D016896:Treatment Outcome",
"nlm_unique_id": "100968638",
"other_id": null,
"pages": "1896-1901",
"pmc": null,
"pmid": "32337790",
"pubdate": "2020-07",
"publication_types": "D002363:Case Reports",
"references": "17201457;32187464;17458776;32179140;16968120;17646028;32227760;32181990;32204907;32196933;21752960;23025916;27097824;24841269;8247209;23018468;32198834;32337790;1436274",
"title": "Severe COVID-19 in a renal transplant recipient: A focus on pharmacokinetics.",
"title_normalized": "severe covid 19 in a renal transplant recipient a focus on pharmacokinetics"
} | [
{
"companynumb": "NL-TEVA-2020-NL-1805884",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CHLOROQUINE"
},
"drugadditional": null,
... |
{
"abstract": "Familial Mediterranean fever is characterized by self-limited attacks of serositis and arthritis. However, substantial number of patients suffer from chronic complications of this disease, primarily involving musculoskeletal system. Treatment for these complications is challenging due to limited evidence. Interleukin-1 (IL-1) antagonists, tocilizumab and anti-tumor necrosis factor (anti-TNF) agents are off-label treatment options for the management of chronic manifestations of FMF, such as secondary (AA) amyloidosis, chronic arthritis and sacroiliitis. This paper presents a case series of four FMF patients who are refractory to IL-1 antagonists, anti-TNF agents and tocilizumab, who responded well to tofacitinib. The authors also conducted a comprehensive literature search for studies investigating tofacitinib use in FMF patients. Although still limited, current data suggest that tofacitinib could be a useful treatment option for FMF patients with associated inflammatory comorbid conditions and chronic manifestations of disease.",
"affiliations": "Division of Rheumatology, Department of Internal Medicine, Gazi University Faculty of Medicine, 06100, Ankara, Turkey. drhazankaradeniz@hotmail.com.;Division of Rheumatology, Department of Internal Medicine, Gazi University Faculty of Medicine, 06100, Ankara, Turkey.;Division of Rheumatology, Department of Internal Medicine, Gazi University Faculty of Medicine, 06100, Ankara, Turkey.;Division of Rheumatology, Department of Internal Medicine, Gazi University Faculty of Medicine, 06100, Ankara, Turkey.;Division of Rheumatology, Department of Internal Medicine, Gazi University Faculty of Medicine, 06100, Ankara, Turkey.;Division of Rheumatology, Department of Internal Medicine, Gazi University Faculty of Medicine, 06100, Ankara, Turkey.;Division of Rheumatology, Department of Internal Medicine, Gazi University Faculty of Medicine, 06100, Ankara, Turkey.",
"authors": "Karadeniz|Hazan|H|http://orcid.org/0000-0003-4665-3421;Güler|Aslıhan Avanoğlu|AA|http://orcid.org/0000-0001-9866-9797;Atas|Nuh|N|http://orcid.org/0000-0001-5880-4974;Satış|Hasan|H|http://orcid.org/0000-0002-7605-1301;Salman|Reyhan Bilici|RB|http://orcid.org/0000-0002-0783-1072;Babaoglu|Hakan|H|http://orcid.org/0000-0002-3728-0259;Tufan|Abdurrahman|A|http://orcid.org/0000-0001-6244-9362",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D018501:Antirheumatic Agents; D053590:Interleukin 1 Receptor Antagonist Protein; D000075242:Janus Kinase Inhibitors; D010880:Piperidines; D011743:Pyrimidines; D050257:Tubulin Modulators; D000079424:Tumor Necrosis Factor Inhibitors; C479163:tofacitinib; C502936:tocilizumab; D003078:Colchicine",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00296-019-04490-7",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0172-8172",
"issue": "40(1)",
"journal": "Rheumatology international",
"keywords": "Auto-inflammatory disease; Familial Mediterranean fever; Janus kinase (JAK) inhibitor; Spondylarthritis; Tofacitinib",
"medline_ta": "Rheumatol Int",
"mesh_terms": "D000328:Adult; D061067:Antibodies, Monoclonal, Humanized; D018501:Antirheumatic Agents; D003078:Colchicine; D004351:Drug Resistance; D010505:Familial Mediterranean Fever; D005260:Female; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein; D000075242:Janus Kinase Inhibitors; D008297:Male; D008875:Middle Aged; D010880:Piperidines; D011743:Pyrimidines; D017211:Treatment Failure; D016896:Treatment Outcome; D050257:Tubulin Modulators; D000079424:Tumor Necrosis Factor Inhibitors",
"nlm_unique_id": "8206885",
"other_id": null,
"pages": "169-173",
"pmc": null,
"pmid": "31813060",
"pubdate": "2020-01",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": "28371574;31392498;22147632;27100444;29618084;23356447;30535114;23070486;20701804;9844766;12371636",
"title": "Tofacitinib for the treatment for colchicine-resistant familial Mediterranean fever: case-based review.",
"title_normalized": "tofacitinib for the treatment for colchicine resistant familial mediterranean fever case based review"
} | [
{
"companynumb": "TR-AMGEN-TURSP2020010984",
"fulfillexpeditecriteria": "2",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "SULFASALAZINE"
},
"drugadditional": null,
... |
{
"abstract": "This review-with tables summarizing opioid options, dosing considerations, and recommendations for tapering-will help you provide rigorous Tx for noncancer pain while ensuring patient safety.",
"affiliations": "University of Wyoming School of Pharmacy, Laramie, USA.;University of Wyoming School of Pharmacy, Laramie, USA. Email: tbaher@uwyo.edu.;Fort Collins Family Medicine Residency/Poudre Valley Hospital, CO, USA.;University of Wyoming School of Pharmacy, Laramie, USA.;University of Wyoming School of Pharmacy, Laramie, USA.;University of Wyoming School of Pharmacy, Laramie, USA.",
"authors": "Linn|Becky S|BS|;Mahvan|Tracy|T|;Smith|Benjamin Elliot Yelnosky|BEY|;Oung|Alvin B|AB|;Aschenbrenner|Heidi|H|;Berg|Justin M|JM|",
"chemical_list": "D000701:Analgesics, Opioid; D009270:Naloxone",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0094-3509",
"issue": "69(6)",
"journal": "The Journal of family practice",
"keywords": null,
"medline_ta": "J Fam Pract",
"mesh_terms": "D000701:Analgesics, Opioid; D059350:Chronic Pain; D006801:Humans; D007407:Interviews as Topic; D008297:Male; D008403:Mass Screening; D008875:Middle Aged; D009270:Naloxone; D010147:Pain Measurement; D061214:Patient Safety; D010818:Practice Patterns, Physicians'",
"nlm_unique_id": "7502590",
"other_id": null,
"pages": "280-292",
"pmc": null,
"pmid": "32724906",
"pubdate": "2020",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Tips and tools for safe opioid prescribing.",
"title_normalized": "tips and tools for safe opioid prescribing"
} | [
{
"companynumb": "US-MLMSERVICE-20210920-3113508-1",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "OXYCODONE"
},
"drugadditional": "4",
... |
{
"abstract": "BACKGROUND\nAnticoagulants and antiplatelet agents are well-known risk factors for post-operative bleeding. The aim of this prospective, randomized pilot study was to evaluate the effectiveness of a topical haemostatic agent, namely TachoSil, for the prevention of postoperative bleeding in patients on antithrombotic therapy undergoing thyroidectomy. Perioperative management and some distinctive aspects of cervical haematomas were also discussed.\n\n\nMETHODS\nBetween January 2012 and May 2014, all patients taking vitamin K antagonists (VKAs) or acetyl salicylic acid (ASA) scheduled for total thyroidectomy were enrolled and randomly allocated to group 1 (standard haemostasis) and group 2 (standard haemostasis + TachoSil). Antithrombotic drugs were always suspended prior to surgery and, when indicated, replaced by bridging anticoagulation with low-molecular-weight heparin. The primary endpoint was the incidence of postoperative cervical haematomas.\n\n\nRESULTS\nA total of 70 patients were included in the study, representing 8.5% (70/820) of all patients who underwent thyroidectomies in the same period. The overall rate of post-operative cervical haematoma was 7.1% (5/70) and reached 14.8% (4/27) in patients on VKA therapy. All but one occurred more than 24 h after surgery (32nd hour, 8th, 10th, and 13th days). Group 1 (37 patients) and group 2 (33 patients) were well-matched according to clinical and demographic features. Postoperative haematoma was observed in 2/37 patients (5.4%) recruited in the Group 1 and 3/33 patients (9.1%) recruited in the Group 2 (P = 0.661).\n\n\nCONCLUSIONS\nPatients taking antithrombotic drugs represent a major problem in thyroid surgery. The incidence of bleeding after thyroidectomy is significantly high and the use of TachoSil do not seem effective in preventing its occurrence. However, larger multicenter study is needed to confirm these results.",
"affiliations": "Chirurgia Generale A, Policlinico Universitario di Monserrato, AOU di Cagliari, Italy. Electronic address: enricoerdas@medicina.unica.it.;Chirurgia Generale A, Policlinico Universitario di Monserrato, AOU di Cagliari, Italy.;Chirurgia Generale A, Policlinico Universitario di Monserrato, AOU di Cagliari, Italy.;Chirurgia Generale A, Policlinico Universitario di Monserrato, AOU di Cagliari, Italy.;Chirurgia Generale A, Policlinico Universitario di Monserrato, AOU di Cagliari, Italy.;Chirurgia Generale A, Policlinico Universitario di Monserrato, AOU di Cagliari, Italy.;Chirurgia Generale A, Policlinico Universitario di Monserrato, AOU di Cagliari, Italy.",
"authors": "Erdas|Enrico|E|;Medas|Fabio|F|;Podda|Francesco|F|;Furcas|Silvia|S|;Pisano|Giuseppe|G|;Nicolosi|Angelo|A|;Calò|Pietro Giorgio|PG|",
"chemical_list": "D001688:Biological Products; D004338:Drug Combinations; D005343:Fibrinolytic Agents; D006490:Hemostatics; D006495:Heparin, Low-Molecular-Weight; C518955:TachoSil; D014812:Vitamin K; D005340:Fibrinogen; D013917:Thrombin; D001241:Aspirin",
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1743-9159",
"issue": "20()",
"journal": "International journal of surgery (London, England)",
"keywords": "Antithrombotic drugs; Postoperative bleeding; Thyroid surgery; Topical haemostatic agents",
"medline_ta": "Int J Surg",
"mesh_terms": "D000287:Administration, Topical; D000368:Aged; D001241:Aspirin; D001688:Biological Products; D004338:Drug Combinations; D005260:Female; D005340:Fibrinogen; D005343:Fibrinolytic Agents; D006490:Hemostatics; D006495:Heparin, Low-Molecular-Weight; D006801:Humans; D008297:Male; D008875:Middle Aged; D010865:Pilot Projects; D019106:Postoperative Hemorrhage; D011446:Prospective Studies; D013917:Thrombin; D013961:Thyroid Gland; D013965:Thyroidectomy; D014812:Vitamin K",
"nlm_unique_id": "101228232",
"other_id": null,
"pages": "95-100",
"pmc": null,
"pmid": "26079499",
"pubdate": "2015-08",
"publication_types": "D016428:Journal Article; D016449:Randomized Controlled Trial",
"references": null,
"title": "The use of a biologic topical haemostatic agent (TachoSil(®)) for the prevention of postoperative bleeding in patients on antithrombotic therapy undergoing thyroid surgery: A randomised controlled pilot trial.",
"title_normalized": "the use of a biologic topical haemostatic agent tachosil for the prevention of postoperative bleeding in patients on antithrombotic therapy undergoing thyroid surgery a randomised controlled pilot trial"
} | [
{
"companynumb": "IT-TAKEDA-2016TEU002186",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "FIBRINOGEN HUMAN\\THROMBIN HUMAN"
},
"drugaddi... |
{
"abstract": "We observed individuals affected by spinal cord dysfunction (SCD) after coronavirus disease 2019 (COVID-19). The aim of our report is to provide our initial experience with individuals experiencing SCD after COVID-19 in a referral center in Northern Italy, from February 21 to July 15, 2020.\n\n\n\nWe report on three men with SCD after COVID-19. Case 1, aged 69 years, experienced T10 AIS B paraplegia upon awakening due to spinal cord ischemia from T8 to conus medullaris, besides diffuse thromboses, 27 days after the onset of COVID-19 symptoms. Case 2, aged 56 years, reported progressive cervicalgia 29 days after COVID-19 onset associated with C3 AIS C tetraplegia. Magnetic resonance imaging (MRI) revealed a C4-C6 spinal epidural abscess (SEA) requiring a C3-C4 left hemilaminectomy. Case 3, aged 48 years, reported backache together with lower limb muscle weakness on day 16 after being diagnosed with COVID-19. Exam revealed T2 AIS A paraplegia and an MRI showed a T1-T7 SEA. He underwent a T3-T4 laminectomy. Prior to SCD, all three individuals suffered from respiratory failure due to COVID-19, required mechanical ventilation, had cardiovascular risk factors, experienced lymphopenia, and received tocilizumab (TCZ).\n\n\n\nTo our knowledge, this is the first report of SCD after COVID-19. Based on our experience, we did not observe a direct viral infection, but there were two different etiologies. In Case 1, the individual developed spinal cord ischemia, whereas in Cases 2 and 3 SEAs were likely related to the use of TCZ used to treat COVID-19.",
"affiliations": "Unipolar Spinal Unit and Neurourology Service, ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy.;Unipolar Spinal Unit and Neurourology Service, ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy.;Unipolar Spinal Unit and Neurourology Service, ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy.;Unipolar Spinal Unit and Neurourology Service, ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy.;Unipolar Spinal Unit and Neurourology Service, ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy.;Unit of Urology, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy.;Unipolar Spinal Unit and Neurourology Service, ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy. michele.spinelli@ospedaleniguarda.it.",
"authors": "Sampogna|Gianluca|G|;Tessitore|Noemi|N|;Bianconi|Tatiana|T|;Leo|Alessandra|A|;Zarbo|Michele|M|;Montanari|Emanuele|E|;Spinelli|Michele|M|http://orcid.org/0000-0002-6245-0205",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1038/s41394-020-00341-x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2058-6124",
"issue": "6(1)",
"journal": "Spinal cord series and cases",
"keywords": null,
"medline_ta": "Spinal Cord Ser Cases",
"mesh_terms": "D000368:Aged; D000073640:Betacoronavirus; D000086382:COVID-19; D018352:Coronavirus Infections; D006801:Humans; D007796:Laminectomy; D008297:Male; D008875:Middle Aged; D058873:Pandemics; D011024:Pneumonia, Viral; D000086402:SARS-CoV-2; D013116:Spinal Cord; D013118:Spinal Cord Diseases",
"nlm_unique_id": "101680856",
"other_id": null,
"pages": "92",
"pmc": null,
"pmid": "32999271",
"pubdate": "2020-09-30",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "32719526;32307905",
"title": "Spinal cord dysfunction after COVID-19 infection.",
"title_normalized": "spinal cord dysfunction after covid 19 infection"
} | [
{
"companynumb": "IT-SUN PHARMACEUTICAL INDUSTRIES LTD-2020R1-268284",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TOCILIZUMAB"
},
"dru... |
{
"abstract": "The antimetabolite fluorouracil (5-FU) is frequently administered for chemotherapy of various malignant neoplasms. The drug is well known for its adverse effects involving bone marrow, skin, mucous membranes, intestinal tract and central nervous system, whereas its cardiotoxicity is less familiar to clinicians. The pathophysiology of fluorouracil-associated cardiac adverse events is controversial and conclusions are based on clinical studies and case reports more than on solid experimental evidence. While clinical and electrocardiographic features suggest myocardial ischaemia as a main aetiological factor, possibly induced by coronary vasospasm, histomorphological and biochemical studies indicate a more direct drug-mediated cytotoxic action. Estimates of the overall incidence of fluorouracil cardiotoxicity have varied widely from 1.2 to 18% of patients. Patients may present with angina-like chest pain, cardiac arrhythmias or myocardial infarction. There is no unequivocally effective prophylaxis or treatment in this syndrome. Once fluorouracil administration is discontinued symptoms are usually reversible, although fatal events have been described. The overall mortality rate has been estimated to be between 2.2 and 13.3%. There is a high risk of relapse when patients are re-exposed to this drug following previous cardiac incidents. From the present data it is concluded that cardiotoxicity is a relevant but underestimated problem in fluorouracil treatment. Since the mechanisms of fluorouracil-associated cardiotoxicity are not yet fully understood, all patients undergoing this chemotherapy have to be carefully evaluated and monitored for cardiac risk factors and complaints. After cardiotoxic events, fluorouracil should definitely be withdrawn and replaced by an alternative antiproliferative regimen.",
"affiliations": "Department of Internal Medicine and Gastroenterology, Hospital Florence Nightingale, Diakoniewerk Kaiserswerth, Düsseldorf, Germany.",
"authors": "Becker|K|K|;Erckenbrecht|J F|JF|;Häussinger|D|D|;Frieling|T|T|",
"chemical_list": "D000964:Antimetabolites, Antineoplastic; D006131:Growth Inhibitors; D005472:Fluorouracil",
"country": "New Zealand",
"delete": false,
"doi": "10.2165/00003495-199957040-00003",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0012-6667",
"issue": "57(4)",
"journal": "Drugs",
"keywords": null,
"medline_ta": "Drugs",
"mesh_terms": "D000964:Antimetabolites, Antineoplastic; D005472:Fluorouracil; D006131:Growth Inhibitors; D006331:Heart Diseases; D006801:Humans",
"nlm_unique_id": "7600076",
"other_id": null,
"pages": "475-84",
"pmc": null,
"pmid": "10235688",
"pubdate": "1999-04",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": "9459149;647321;7296556;8085212;1299974;1990260;3938225;2656050;5804822;8422644;6506081;3046359;1637660;8374889;3660474;3383127;1642435;2466960;3946274;3661619;1580574;1648430;1607921;3187073;8391384;8035725;8193429;9528843;2083185;3663962;4662004;386594;2741789;1606078;46502;1222391;7079856;7005788;3345535;3826112;2989687;8714749;7777242;3409458;8905032;373913;630214;3335642;2737845;4475611;6233441;3300968;2351781;7964939;5430334;9250550;8633257;3403776;9015489;4724850;1671927;7168016;2973029;8221682;7466925;2293556;3984047;9296228;7649677;6411954;3275485;7980224;9538168;2947159;13418758;3245824;3189387;1403060;2328669;3208811;8233284;7810505;2297659;7241861;7704035;3604903;2040332;8374883;7161314;7954023;8471333;8664057",
"title": "Cardiotoxicity of the antiproliferative compound fluorouracil.",
"title_normalized": "cardiotoxicity of the antiproliferative compound fluorouracil"
} | [
{
"companynumb": "DE-PFIZER INC-202101411896",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "FLUOROURACIL"
},
"drugadditional": "1",
... |
{
"abstract": "Clinicians face many challenges regarding conception and pregnancy management for women with panhypopituitarism. Fertility in women with panhypopituitarism is often reduced, and they are at risk of obstetric complications. The authors describe the case of a woman with congenital panhypopituitarism who had a successful pregnancy after ovulation induction and optimization of hormonal replacement therapy. This case report emphasizes the importance of careful adjustment of hormonal replacement therapy in managing pregnant women with panhypopituitarism.",
"affiliations": "Department of Obstetrics and Gynecology, Amphia Hospital, Breda, the Netherlands.;Department of Endocrinology, Amphia Hospital, Breda, the Netherlands.;Department of Obstetrics and Gynecology, Amphia Hospital, Breda, the Netherlands.",
"authors": "van Zundert|Sofie Karolina Maria|SKM|;Krol|Charlotte Georgette|CG|;Spaan|Julia Jeltje|JJ|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.crwh.2021.e00351",
"fulltext": "\n==== Front\nCase Rep Womens Health\nCase Rep Womens Health\nCase Reports in Women's Health\n2214-9112\nElsevier\n\nS2214-9112(21)00069-2\n10.1016/j.crwh.2021.e00351\ne00351\nArticle\nManagement of panhypopituitarism during pregnancy: A case report\nvan Zundert Sofie Karolina Maria s.vanzundert@erasmusmc.nl\na⁎\nKrol Charlotte Georgette b\nSpaan Julia Jeltje a\na Department of Obstetrics and Gynecology, Amphia Hospital, Breda, the Netherlands\nb Department of Endocrinology, Amphia Hospital, Breda, the Netherlands\n⁎ Corresponding author at: PO Box 90158, Breda 4800 RK, the Netherlands. s.vanzundert@erasmusmc.nl\n19 8 2021\n10 2021\n19 8 2021\n32 e0035125 7 2021\n12 8 2021\n16 8 2021\n© 2021 The Authors\n2021\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).\nClinicians face many challenges regarding conception and pregnancy management for women with panhypopituitarism. Fertility in women with panhypopituitarism is often reduced, and they are at risk of obstetric complications. The authors describe the case of a woman with congenital panhypopituitarism who had a successful pregnancy after ovulation induction and optimization of hormonal replacement therapy. This case report emphasizes the importance of careful adjustment of hormonal replacement therapy in managing pregnant women with panhypopituitarism.\n\nHighlights\n\n• Successful pregnancy is possible in women with panhypopituitarism.\n\n• Women with panhypopituitarism are at risk of obstetric complications.\n\n• Management of panhypopituitarism during pregnancy requires a multidisciplinary approach.\n\nKeywords\n\nPanhypopituitarism\nPituitary deficiency\nPregnancy\nCase report\n==== Body\npmc1 Introduction\n\nPanhypopituitarism refers to a complete deficiency of hormones produced by the pituitary. In clinical practice it encompasses growth hormone deficiency, central adrenal insufficiency, central hypothyroidism, central hypogonadism and in some cases central diabetes insipidus and prolactin deficiency [1]. Central hypogonadism is mainly responsible for reduced fertility in women with panhypopituitarism [2]. Assisted reproductive techniques, and in particular ovulation induction, have led to improved pregnancy rates in these women [2] but there is an increased risk of an adverse pregnancy outcome [3,4]. Optimal hormonal replacement therapy is crucial to minimize this risk. To date, data on pregnancy outcome in women with panhypopituitarism is limited.\n\n2 Case Presentation\n\nA 30-year-old woman with panhypopituitarism due to aplasia of the anterior pituitary and an ectopic posterior pituitary (EPP) achieved pregnancy after the first attempt at induction of ovulation. On cycle day 2, stimulation with human menopausal gonadotropin (hMG; 150 IU/day) started and lasted 11 days. After this stimulation period, three follicles were observed and human chorionic gonadotropin (hCG; 250 μg) was administered to induce ovulation.\n\nPreconception counseling and investigations took place in advance of ovulation induction. A vaginal ultrasound scan showed inactive ovaries and a small uterus. Preconception laboratory test results were all within normal ranges (sodium 141 mmol/l, potassium 4.1 mmol/l, hemoglobin 8.8 mmol/l, hemoglobin A1c 38 mmol/mol, free thyroxine (FT4) 15.6 pmol/l, insulin-like growth factor 1 (IGF-1) 29.1 nmol/l and dehydroepiandrosterone sulfate 1.41 μmol/l) except for low levels of thyroid-stimulating hormone (TSH) (< 0.05 mU/l; normal range: 0.56–4.27 mU/l), follicle stimulating hormone (FSH) and luteinizing hormone (LH) (1.1 and 1.0 U/l; normal range: 2–8 U/l). Furthermore, she had normal blood pressure (114/75 mmHg). Investigations of the partner revealed no abnormalities.\n\nPrior to ovulation induction, the treatment regimen consisted of growth hormone (0.54 mg/day), hydrocortisone (20 mg/day), levothyroxine (100 μg/day), dehydroepiandrosterone (DHEA) (50 mg/day), estradiol/dydrogesterone (2 mg/day estradiol plus sequential dydrogesterone 10 mg/day for 14 days of each 28-day cycle), and desmopressin (0.05 mg/day). Immediately upon pregnancy diagnosis, growth hormone, DHEA and estradiol/dydrogesterone administration was stopped and vaginal progesterone (200 mg, three times a day) was administered throughout the first trimester. During pregnancy, the dose of levothyroxine was gradually increased to 200 μg/day based on FT4 levels, which were determined every four to six weeks, thereby maintaining FT4 levels in the upper half of the normal range. The dosage hydrocortisone and desmopressin remained unaltered.\n\nThe first and second trimester were uneventful. During the third trimester, she developed gestational diabetes, which was diagnosed using the one-step 75 g oral glucose tolerance test. She had a normal fasting plasma glucose (5.8 (< 7.0) mmol/l) but an abnormal plasma glucose after two hours (8.6 (< 7.8) mmol/l). However, no pharmacological intervention was required.\n\nAt 30 weeks of gestation, during a regular checkup, her blood pressure was measured and laboratory tests were performed. Her blood pressure was 124/76 mmHg and the laboratory test results did not show any abnormalities: sodium 131 mmol/l, potassium 3.9 mmol/l, hemoglobin A1c 38 mmol/mol, FT4 20.7 pmol/l and IGF-1 31.2 nmol/l. An adrenal crisis at 31 weeks of gestation was successfully treated with 30 mg hydrocortisone.\n\nAt 38 weeks of gestation, she was physically exhausted, and therefore admitted for induction of labor. Intracervical insertion of a Foley catheter and misoprostol for cervical ripening resulted in no more than 3 cm of cervical dilatation. A cesarean section was performed on maternal request. During the cesarean section, a steroid replacement protocol was followed (two intravenous boluses of 50 mg and 100 mg hydrocortisone respectively, followed by a continuous infusion of 200 mg hydrocortisone over 24 hours). The procedure was complicated by a hemorrhage of 1000 ml caused by a surgical uterine bleed. In order to prevent further hemorrhage, an intravenous bolus of 5 IU oxytocin and a continuous infusion of 10 IU oxytocin over four hours were administered.\n\nA boy weighing 3515 g was delivered in good condition. One day after the cesarean section, the continuous infusion of hydrocortisone was lowered to 100 mg over 24 hours. Thereafter, the continuous infusion of hydrocortisone was switched to oral administration (30 mg, three times a day) and the dosage was gradually lowered to 20 mg/day. Directly after the cesarean section, the dose of levothyroxine was lowered to 175 mg/day and the pre-pregnancy dosages of DHEA and growth hormone were restarted. Three days postpartum she experienced engorgement, but lactation was not initiated. She and her son were discharged from the hospital five days postpartum. The puerperium showed no abnormalities for either mother or child.\n\n3 Discussion\n\nHormonal replacement therapy in women with panhypopituitarism mimics the normal physiological production and release of pituitary hormones. Especially during the preconception period and pregnancy, the status of the hormonal replacement therapy is extremely important.\n\nPrior to ovulation induction, we recommend that blood pressure is checked and the following laboratory tests are performed (normal range in parentheses): sodium (136–145 mmol/l), potassium (3.5–5.1 mmol/l), hemoglobin (7.5–9.5 mmol/l), hemoglobin A1c (26–42 mmol/mol), FT4 (13.5–24.3) pmol/l, TSH (0.56–4.27 mU/l), IGF-1 (9.6–33.9 nmol/l), FSH and LH (both 2–8 U/l). Ovulation induction in patients with central hypogonadism involves FSH/hCG or hMG/hCG [5]. We treated our patient with the latter. Messinis [6] elaborates in more detail the different protocols of ovulation induction for patients with hypogonadotropic hypogonadism. Data on pregnancy rates in patients with congenital panhypopituitarism are scarce. However, Hall et al. [7] determined a pregnancy rate of 42% after ovulation induction in a group of women with pan- or partial hypopituitarism, and Overton et al. [3] showed that those who achieved pregnancy after ovulation induction had only a 61% chance of a live birth.\n\nAs pregnancy alters both the physiology and anatomy of the pituitary gland, hormonal replacement therapy during pregnancy is challenging [8]. We strongly recommend using the guidelines produced by Fleseriu et al. [5] as a roadmap for management of panhypopituitarism during pregnancy. Their advice is to stop growth hormone replacement, as the evidence for safety during pregnancy is controversial and the placenta also produces growth hormone [5].\n\nIncreasing the dosage of glucocorticoid replacement, preferably hydrocortisone, during pregnancy, depending on the individual course, is recommended (suggested dose: 12–15 mg/m2/day) [5]. The best means to monitor glucocorticoid replacement is clinical judgement; assessing for signs of under- or over-replacement [9]. On the one hand, glucocorticoid underexposure can cause an electrolyte imbalance, hypoglycemia and, in the worst case, an adrenal crisis [10]. On the other hand, glucocorticoid overexposure is associated with gestational diabetes, excessive weight gain, hyperglycemia, and hypertension [10]. Both are associated with low birth weight, preterm birth, and increased risks of developing cardio-metabolic disease in later life [10,11]. In order to avoid these adverse pregnancy outcomes, we recommend monitoring the weight, blood pressure and blood glucose levels (normal range glucose: 4.0–6.1 mmol/l, and hemoglobin A1c: 26–42 mmol/mol) of women with central adrenal insufficiency at least every trimester [10]. During labor and delivery, a stress dose of hydrocortisone is recommended (50 mg intravenous in the second stage of labor; 50–100 mg intravenous preoperatively and every 8 hours postoperatively for a cesarean section) [2,5].\n\nAs the response of thyrotropin receptors to hCG varies in pregnant women with panhypopituitarism [5], we advise the determination of FT4 levels every four to six weeks and adjustment of the levothyroxine dosage accordingly. In order to minimize the risks of under-replacement of thyroid hormone for the fetus, we recommend FT4 levels in the upper half of the normal range (normal range: 13.5–24.3 pmol/l) [12].\n\nVaginal progesterone improves pregnancy rates after ovulation induction with gonadotrophins as it supports the luteal phase [13]. Data on the safety and effectiveness of DHEA replacement is limited and is therefore not advised [5]. Remarkably, our patient used DHEA prior to conception.\n\nPregnant women with pre-existing diabetes insipidus are recommended to continue their treatment with desmopressin [5]. We recommend to evaluate the need for desmopressin during pregnancy clinically (polyuria-polydipsia) and biochemically (sodium levels, normal range: 136–145 mmol/l) every trimester [5].\n\nCurrently, there are no fetal gender-specific recommendations regarding hormonal replacement therapy during pregnancy. However, this might be an interesting topic for future research.\n\nPanhypopituitarism diagnosed in childhood, as in our patient, is associated with smaller ovarian and uterine size. These morphological disturbances may contribute to the reduced fertility and adverse pregnancy outcomes in this group [2]. In several prior cases, women with panhypopituitarism delivered vaginally [14]. In contrast, our patient showed no signs of active labor after induction of labor. Usually, the function of the posterior pituitary remains preserved with EPP. However, the posterior pituitary of our patient was affected as she had diabetes insipidus. Therefore, her oxytocin-releasing cells could be impaired as well.\n\nTo our surprise, the patient experienced engorgement three days after cesarean section. Even though no lactation was initiated, the fact that she experienced engorgement suggests her hypothalamic-pituitary axis regulating prolactin is partly intact.\n\nIn conclusion, this case report contributes to the evidence that successful conception and pregnancy are possible in women with panhypopituitarism, and highlights that this complex condition requires a multidisciplinary approach to reduce the risk of adverse pregnancy outcomes.\n\nContributors\n\nSofie Karolina Maria van Zundert drafted the manuscript.\n\nDr. Charlotte Georgette Krol critically revised the manuscript.\n\nDr. Julia Jeltje Spaan was involved in patient care and critically revised the manuscript.\n\nAll authors contributed to the interpretation of data and approved the final version to be submitted.\n\nConflict of interest\n\nThe authors declare that they have no conflict of interest regarding the publication of this case report.\n\nFunding\n\nThis work did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\n\nPatient consent\n\nWritten informed consent was obtained from the patient for her anonymized information to be published in this article.\n\nProvenance and peer review\n\nThis article was not commissioned and was peer reviewed.\n\nAcknowledgements\n\nThe authors gratefully acknowledge the support of Dr. Jantien Visser, a clinician who was also involved in patient care, throughout all aspects of this case report.\n==== Refs\nReferences\n\n1 Toogood A.A. Stewart P.M. Hypopituitarism: clinical features, diagnosis, and management Endocrinol. Metab. Clin. N. Am. 37 Mar 2008 235 261 x\n2 Vila G. Fleseriu M. Fertility and pregnancy in women with hypopituitarism: a systematic literature review J. Clin. Endocrinol. Metab. 105 2020\n3 Overton C.E. Davis C.J. West C. Davies M.C. Conway G.S. High risk pregnancies in hypopituitary women Hum. Reprod. 17 2002 1464 1467 12042262\n4 Kübler K. Klingmüller D. Gembruch U. Merz W.M. High-risk pregnancy management in women with hypopituitarism J. Perinatol. 29 2009 89 95 19177043\n5 Fleseriu M. Hashim I.A. Karavitaki N. Melmed S. Murad M.H. Salvatori R. Hormonal replacement in hypopituitarism in adults: an endocrine society clinical practice guideline J. Clin. Endocrinol. Metab. 101 Nov 2016 3888 3921 27736313\n6 Messinis I.E. Ovulation induction: a mini review Hum. Reprod. 20 Oct 2005 2688 2697 16006478\n7 Hall R. Manski-Nankervis J. Goni N. Davies M.C. Conway G.S. Fertility outcomes in women with hypopituitarism Clin. Endocrinol. 65 Jul 2006 71 74\n8 Karaca Z. Tanriverdi F. Unluhizarci K. Kelestimur F. Pregnancy and pituitary disorders Eur. J. Endocrinol. 162 2010 453 475 19934270\n9 Bornstein S.R. Allolio B. Arlt W. Barthel A. Don-Wauchope A. Hammer G.D. Diagnosis and treatment of primary adrenal insufficiency: an endocrine society clinical practice guideline J. Clin. Endocrinol. Metab. 101 Feb 2016 364 389 26760044\n10 Langlois F. Lim D.S.T. Fleseriu M. Update on adrenal insufficiency: diagnosis and management in pregnancy Curr. Opin. Endocrinol. Diabetes Obes. 24 Jun 2017 184 192 28288009\n11 Duthie L. Reynolds R.M. Changes in the maternal hypothalamic-pituitary-adrenal axis in pregnancy and postpartum: influences on maternal and fetal outcomes Neuroendocrinology 98 2013 106 115 23969897\n12 Persani L. Brabant G. Dattani M. Bonomi M. Feldt-Rasmussen U. Fliers E. 2018 European Thyroid Association (ETA) guidelines on the diagnosis and management of central hypothyroidism Eur. Thyroid J. 7 Oct 2018 225 237 30374425\n13 Green K.A. Zolton J.R. Schermerhorn S.M. Lewis T.D. Healy M.W. Terry N. Progesterone luteal support after ovulation induction and intrauterine insemination: an updated systematic review and meta-analysis Fertil. Steril. 107 Apr 2017 924–933 e5\n14 Shinar S. Many A. Maslovitz S. Questioning the role of pituitary oxytocin in parturition: spontaneous onset of labor in women with panhypopituitarism--a case series Eur. J. Obstet. Gynecol. Reprod. Biol. 197 Feb 2016 83 85 26708476\n\n",
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"abstract": "BACKGROUND\nUse of selective serotonin reuptake inhibitors (SSRIs) has been associated with an increased risk of intracranial hemorrhage. However, little is known about cerebrovascular risk in users of serotonin-norepinephrine reuptake inhibitors (SNRIs). Our aim was to determine the differential risk of cerebrovascular events between SSRIs and SNRIs.\n\n\nMETHODS\nA nationwide population-based cohort study was conducted in adult patients who started taking SSRIs or SNRIs during the time period 2005 through 2009. The outcome of interest was defined by the first hospitalization diagnosis for ischemic stroke (ICD-9-CM codes 433, 434, 436) or intracranial hemorrhage (ICD-9-CM codes 430, 431, 432). We used a Cox regression model with time-varying medication use and adjusted for stroke risk factors to estimate the hazard ratios (HRs) of ischemic stroke and intracranial hemorrhage associated with SNRI use, using SSRI use as a reference.\n\n\nRESULTS\nAmong 582,650 SSRI and 76,920 SNRI initiators with an average follow-up period of 3.2 years, there was a nonsignificantly increased trend toward intracranial hemorrhage (adjusted HR = 1.24 [95% CI, 0.97-1.58]) in SNRI users compared to SSRI users. The risk of ischemic stroke was comparable between the 2 treatment groups (adjusted HR = 1.01 [0.90-1.12]). Similar results were obtained in sensitivity analyses, considering a dose-response relation, allowance of a 7-day grace period between study drug discontinuation and outcome occurrence, and restriction to exclusive users, who remained on the initial treatment. In the subgroup analysis, there was an increased incidence of intracranial hemorrhages in SNRI users compared to SSRI users in patients without prior depression (adjusted HR = 1.63 [1.14-2.32]).\n\n\nCONCLUSIONS\nUse of SNRIs is not associated with an increased risk of either ischemic stroke or intracranial hemorrhage as compared to use of SSRIs in adult patients with depression or anxiety. However, SNRIs should be used cautiously in patients without depression.",
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"abstract": "ST-segment elevation in post-return of spontaneous circulation after cardiac arrest is a major concern for underlying acute coronary syndrome. This case report presents a rare case of vasopressor-induced coronary vasospasm as an underlying cause for this ST-segment elevation with complete reversal of EKG changes after reducing the vasopressor dose. (Level of Difficulty: Beginner.).",
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"authors": "Elkaryoni|Ahmed|A|;Ramakrishnan|Dushyant|D|;Abdelkarim|Islam|I|;Noman|Anas|A|;Qintar|Mohammed|M|;Baweja|Paramdeep|P|",
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"fulltext": "\n==== Front\nJACC Case Rep\nJACC Case Rep\nJACC Case Reports\n2666-0849\nElsevier\n\nS2666-0849(19)30092-0\n10.1016/j.jaccas.2019.05.023\nMini-Focus Issue: Interventional Complications and Their Management\nCase Report: Clinical Case\nVasopressor-Induced Generalized Coronary Vasospasm Presenting as Inferior ST-Segment Elevation in Post-Cardiopulmonary Resuscitation\nElkaryoni Ahmed MD Elkaryonia@UMKC.edu\n@Ahmed_Karyoo\na∗\nRamakrishnan Dushyant MD a\nAbdelkarim Islam MD a\nNoman Anas MD a\nQintar Mohammed MD ab\nBaweja Paramdeep MD ac\na Division of Internal Medicine, University of Missouri-Kansas City, Kansas City, Missouri\nb Division of Cardiovascular Disease, Saint Luke's Mid America Heart Institute, Kansas City, Missouri\nc Division of Cardiovascular Disease, Truman Medical Center, Kansas City, Missouri\n∗ Address for correspondence: Dr. Ahmed Elkaryoni, Division of Internal Medicine, University of Missouri-Kansas City, 2411 Holmes Street, Kansas City, Missouri 64108. Elkaryonia@UMKC.edu@Ahmed_Karyoo\n21 8 2019\n8 2019\n21 8 2019\n1 2 9498\n3 4 2019\n22 4 2019\n14 5 2019\n© 2019 The Authors\n2019\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).\nThis case describes a 47-year-old man with a history of malignant hypertension and end-stage renal disease who had an in-hospital cardiac arrest…\n\nST-segment elevation in post-return of spontaneous circulation after cardiac arrest is a major concern for underlying acute coronary syndrome. This case report presents a rare case of vasopressor-induced coronary vasospasm as an underlying cause for this ST-segment elevation with complete reversal of EKG changes after reducing the vasopressor dose. (Level of Difficulty: Beginner.)\n\nGraphical abstract\n\nKey Words\n\ncardiac arrest\ncoronary vasospasm\nreturn of spontaneous circulation\nST-segment elevation myocardial infarction\nvasopressor\nAbbreviations and Acronyms\n\nECG, electrocardiogram\nCA, cardiac arrest\nCC, cardiac catheterization\nROSC, return of spontaneous circulation\nLVEF, left ventricular ejection fraction\nMI, myocardial infarction\n==== Body\nThis case describes a 47-year-old man with a history of malignant hypertension and end-stage renal disease who had an in-hospital cardiac arrest (CA) (pulseless electrical activity and ventricular fibrillation). The post-resuscitative period was complicated by hypotension requiring vasopressor support with norepinephrine, epinephrine, and vasopressin. Initial electrocardiogram (ECG) post-return of spontaneous circulation (ROSC) did not show acute ischemic changes (Figure 1), but on a later repeat, it showed ST-segment elevation in the inferior leads with ST-segment depression in the aVR lead consistent with possible inferior myocardial infarction (MI) (Figure 2). Creatine kinase level was elevated to 270 U/l, and troponin-T levels trended up as well, from 0.17 ng/ml (baseline) to 0.66 ng/ml.Learning Objectives\n\n• To recognize the possibility of vasopressor use during the post–cardiac resuscitation period as a possible cause of ST-segment elevation in post-RSOC ECG.\n\n• To recognize the importance of cautious up-titration of the vasopressors, with recommended bedside titration to maintain the desirable goal and limiting side effects.\n\nFigure 1 First ECG Immediately Post-ROSC With No ST-Segment Elevation\n\nThe first electrocardiogram (ECG) was performed immediately post return of spontaneous circulation (ROSC) with no ST-segment elevation.\n\nFigure 2 Second ECG Post-ROSC With ST-Segment Elevation in Inferior Leads\n\nThe second ECG was performed post-ROSC with ST-segment elevation in the inferior leads. Abbreviations as in Figure 1.\n\nDifferential Diagnosis\n\nPost-ROSC ST-segment elevation is usually a sign of an urgent need for cardiac catheterization (CC), especially in the setting of shockable rhythm CA (1). Post-ROSC ST-segment elevation can be attributed to pericarditis, early repolarization, spontaneous subarachnoid hemorrhage, acute ST-segment elevation MI, or as a result of defibrillation electrical shock itself (2). CC is mandated in this situation to rule out acute coronary syndrome (1).\n\nInvestigations and management\n\nThe patient was taken emergently to coronary angiogram, which demonstrated severe diffuse vasospasm (Figure 3) in all 3 coronary arteries that was completely reversed with intracoronary vasodilator injection and de-escalation of vasopressors’ doses (Figure 4). No definite obstructive coronary artery disease was found. A bedside echocardiogram done after completion of the coronary angiography showed moderate global hypokinesis of the left ventricle (LV) and LV ejection fraction of <35% compared with a study done 2 days earlier that demonstrated normal LV wall motion and LV ejection fraction of 50% to 55%, likely stemming from myocardial stunning post-CA. A follow-up ECG demonstrated resolved ischemic changes (Figure 5), thus raising the question of an iatrogenic pseudo-MI due to the vasopressors.Figure 3 Coronary Angiogram Showing Diffuse Coronary Vasospasm Before Injecting Vasodilators or De-Escalating the Vasopressor Dose\n\n(A) Coronary angiogram anteroposterior-cranial view showing diffuse coronary vasospasm in proximal, mid, and distal segments of left anterior descending artery (black arrows). (B) Coronary angiogram anteroposterior-caudal view showing coronary vasospasm mid and distal segments of left anterior descending artery (white arrows), as well as mid and distal segments of left circumflex artery (black arrows). (C) Coronary angiogram left anterior oblique artery-30° view showing proximal and mid-segment vasospasm of the right coronary artery (black arrows) and posterior descending artery (white arrow).\n\nFigure 4 Coronary Angiogram After Injecting Vasodilators and De-Escalating the Vasopressors Showing Normal Coronary Arteries\n\nCoronary angiogram after injecting vasodilators or de-escalating the vasopressors showing: (A) relief of vasospasm in left anterior descending artery shown in anteroposterior-cranial view; (B) anteroposterior-caudal view with the relief of the vasospasm in both left anterior descending artery and left circumflex artery; (C) left anterior oblique artery-30° view with relieved spasm in both right coronary artery proper and pulmonary descending artery.\n\nFigure 5 ECG Post Coronary Angiogram Showing Resolved Previous ST-Segment Elevation\n\nElectrocardiogram (ECG) performed post coronary angiogram showing resolved previous ST-segment elevation.\n\nIn this case, the patient was initially started on norepinephrine, which was eventually up-titrated to 1.5 μg/kg/min, followed by vasopressin up-titrated to a maximum rate of 0.04 U/min and epinephrine up-titrated to a maximum rate of 0.5 μg/kg/min. CC was done approximately 2 h after the patient was on these maximized rates. Based on the CC findings, vasopressin and epinephrine were both discontinued and norepinephrine rate was titrated down over 1 h following CC with improvement in coronary spasm with subsequent ECG no longer showing an ST-segment elevation. Hemodynamic stability was maintained even after discontinuation of vasopressor support.\n\nDiscussion\n\nManagement of patients post-ROSC covers a wide set of parameters. Obtaining an ECG is essential in forming a differential diagnosis as to the cause of CA 1, 2. For patients in whom a cardiac cause is suspected and post-ROSC ECG shows ST-segment elevation (as it did in our patient), studies have shown that early invasive management with CC is needed with possible percutaneous coronary intervention, thus making it an integral part of the post-CA care guidelines (1). A recent study demonstrated that a culprit coronary lesion could be found in up to 81% of patients with ST-segment elevation on post-ROSC ECG (3). This is in contrast to non-ST-segment elevation MI patients in post-CA with no difference in survival with immediate versus delayed angiography (4). Transient ST-segment elevations can also be seen on post-ROSC ECG as a result of defibrillation electrical shock, with different explanations for this electrical phenomenon: direct and transient myocardial injury; electrical-induced coronary vasospasm; or sustained depolarization due to microscopic breaks in the cardiomyocyte’s membrane (5). However, this phenomenon is likely to occur in the immediate post cardiopulmonary resuscitation episode, whereas our patient had the ST-segment elevation changes show up on the ECG almost 5 h post cardiopulmonary resuscitation.\n\nAnother aspect of post-ROSC management is maintaining hemodynamic stability and volume resuscitation, which in some cases requires use of vasopressor and/or inotropic agents to combat the shock. There is no evidence demonstrating the superiority of any vasopressor or inotropic in the post-CA. Norepinephrine is an adrenergic agent that is usually the agent of choice especially in undifferentiated type of shock, with vasopressin, phenylephrine, dopamine, milrinone, or epinephrine being used as secondary agents for refractory shock (6). Although in general, studies have demonstrated improved outcomes with better control of blood pressure post-resuscitation, target goals for mean arterial pressure (MAP) and oxygen saturation have been difficult to define; however, a MAP ≥65 mm Hg and O2 saturation ≥70% are generally reasonable targets (6). In our patient, the post-ROSC shock state required support with 3 vasopressors to maintain a MAP goal of >65 mm Hg. The overall effects of adrenergic vasopressors on the coronary arteries have usually been found to be vasodilatory and hyperemic in prior studies (7). However, there have been case reports where the use of vasopressor support with adrenergic agents to correct hypotension occurring with anesthesia has been associated with coronary spasm (8). Coronary vasospasm leading to MI has also been seen to occur in a patient receiving pseudoephedrine for sinus congestion (9). However, there is no reported case showing the occurrence of coronary vasospasm and ST-segment elevation due to vasopressor use in post-resuscitative efforts.\n\nA stepwise approach is recommended in the management of post-CA hypotension. First, volume replacement is important to maintain central venous pressure of 8 to 12 mm Hg. Then inotropic and vasopressor agents should be tailored for each patient based on the possible underlying cause for the shock (e.g., cardiogenic vs. distributive) and undesirable adverse effects of medications (e.g., arrhythmia, increased afterload). Medications have to be titrated at the bedside to ensure the intended MAP goal and limiting the side effects (6).\n\nFollow-up\n\nA follow-up echocardiogram done 2 weeks post code showed a hyperdynamic LV with LV ejection fraction >70% and normal LV wall motion. The patient was discharged from the hospital in stable condition once his other major comorbidities were adequately addressed.\n\nConclusions\n\nPost-ROSC ST-segment elevation ECG changes can be attributed to vasopressor-induced coronary vasospasm without underlying obstructive coronary artery disease. Although per guidelines, it is reasonable to rapidly correct hypotension post-ROSC, it is imperative to de-escalate vasopressor use whenever and as soon as possible (6).\n\nThe question arises whether an ST-segment elevation on ECG in this setting of high vasopressor dose post-ROSC would lend credence to initially monitoring and de-escalating vasopressor support with serial monitoring of ECG to prevent unnecessary invasive interventions. However, the evidence has shown that in the majority of such cases, a culprit coronary lesion is usually found. In such situations, it may be life-threatening to wait and watch while reducing vasopressor dose, thus putting the onus on early invasive management with CC despite suspicion of vasospasm in all cases with post-ROSC ST-segment elevation as recommended in the guidelines.\n\nAmendment\n\n1. The first ECG was just after ROSC and was not yet on the 3 agents but in the process of uptitration as his mean blood pressure readings were low.\n\n2. ST-segment elevation around 15 min after being max on the 3 pressors.\n\n3. The patient did not receive propranolol.\n\nThe authors have reported that they have no relationships relevant to the contents of this paper to disclose.\n==== Refs\nReferences\n\n1 Lavonas E.J. Drennan I.R. Gabrielli A. Part 8: post–cardiac arrest care 2015 American Heart Association Guidelines update for cardiopulmonary resuscitation and emergency cardiovascular care Circulation 132 Suppl 2 2015 S315 S367 26472989\n2 Kim Y.J. Min S.Y. Lee D.H. The role of post-resuscitation electrocardiogram in patients with ST-segment changes in the immediate post-cardiac arrest period J Am Coll Cardiol Intv 10 2017 451 459\n3 Tateishi K. Abe D. Iwama T. Hamabe Y. Aonuma K. Sato A. Clinical value of ST-segment change after return of spontaneous cardiac arrest and emergent coronary angiography in patients with out-of-hospital cardiac arrest: diagnostic and therapeutic importance of vasospastic angina Eur Heart J Acute Cardiovasc Care 7 2018 405 413 28730843\n4 Lemkes J.S. Janssens G.N. van der Hoeven N.W. Coronary angiography after cardiac arrest without ST-segment elevation N Engl J Med 380 2019 1397 1407 30883057\n5 Gurevitz O. Lipchenca I. Yaacoby E. ST-segment deviation following implantable cardioverter defibrillator shocks: incidence, timing, and clinical significance Pacing Clin Electrophysiol 25 2002 1429 1432 12418739\n6 Peberdy M.A. Callaway C.W. Neumar R.W. Part 9: post-cardiac arrest care: 2010 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care Circulation 122 Suppl 3 2010 S768 S786 20956225\n7 Vargas Pelaez A.F. Gao Z. Ahmad T.A. Effect of adrenergic agonists on coronary blood flow: a laboratory study in healthy volunteers Physiol Rep 4 2016 e12806\n8 Khavandi A. Gatward J.J. Whitaker J. Walker P. Myocardial infarction associated with the administration of intravenous ephedrine and metaraminol for spinal-induced hypotension Anaesthesia 64 2009 563 566 19413828\n9 Derreza H. Fine M.D. Sadaniantz A. Acute myocardial infarction after use of pseudoephedrine for sinus congestion J Am Board Fam Pract 10 1997 436 438 9407485\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2666-0849",
"issue": "1(2)",
"journal": "JACC. Case reports",
"keywords": "CA, cardiac arrest; CC, cardiac catheterization; ECG, electrocardiogram; LVEF, left ventricular ejection fraction; MI, myocardial infarction; ROSC, return of spontaneous circulation; ST-segment elevation myocardial infarction; cardiac arrest; coronary vasospasm; return of spontaneous circulation; vasopressor",
"medline_ta": "JACC Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101757292",
"other_id": null,
"pages": "94-98",
"pmc": null,
"pmid": "34316757",
"pubdate": "2019-08",
"publication_types": "D002363:Case Reports",
"references": "30883057;12418739;27225628;19413828;20956225;28730843;26472989;9407485",
"title": "Vasopressor-Induced Generalized Coronary Vasospasm Presenting as Inferior ST-Segment Elevation in Post-Cardiopulmonary Resuscitation.",
"title_normalized": "vasopressor induced generalized coronary vasospasm presenting as inferior st segment elevation in post cardiopulmonary resuscitation"
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"abstract": "Clinical studies have shown high rates of sustained virological response (hepatitis C virus [HCV] RNA <15 IU/mL) at post-treatment week 12 (SVR12) in patients with genotype 1b infection with and without cirrhosis who received coformulated ombitasvir, paritaprevir, and ritonavir, plus dasabuvir, without ribavirin, for 12 weeks. In this study, we aimed to assess 8-week treatment with ombitasvir, paritaprevir, and ritonavir, plus dasabuvir, without ribavirin in patients infected with HCV genotype 1b without cirrhosis.\n\n\n\nWe did a multicentre, open-label, single-arm, phase 3b study (GARNET) in 20 hospitals or clinics in Australia, Canada, France, Germany, Israel, Italy, Spain, and the UK, to assess the safety and efficacy of an 8-week treatment duration of once-daily oral ombitasvir 25 mg, paritaprevir 150 mg, and ritonavir 100 mg, plus twice-daily oral dasabuvir 250 mg in previously untreated patients with chronic HCV genotype 1b infection without cirrhosis (as assessed by liver biopsy, transient elastography, or serum markers). Eligible patients were aged at least 18 years, with more than 1000 IU/mL HCV RNA, and a laboratory result at screening indicating infection with HCV genotype 1b subtype only. Patients were excluded if they had evidence of HCV genotype or subtype other than genotype 1b, if they tested positive for hepatitis B surface antigen or anti-HIV antibody at screening, or if they had previously been treated for HCV. The primary endpoint was the proportion of patients with SVR12; the primary endpoint and safety were assessed in all patients who received at least one dose of study drugs. This trial is registered with ClinicalTrials.gov, number NCT02582632.\n\n\n\nPatients were screened between Nov 24, 2015, and March 1, 2016, and 166 patients were enrolled. 163 (98%) of 166 enrolled patients had HCV genotype 1b infection, and three (2%) of 166 had other genotypes or subtypes (genotype 1a, genotype 1d, and genotype 6). All enrolled patients received at least one dose of study drugs. 162 (98% [95% CI 95·3-99·9]) of 166 patients achieved SVR12. One patient discontinued treatment on day 45 due to adverse events. Most adverse events were mild in severity, and the most common adverse events were headache (35 [21%] of 166) and fatigue (28 [17%] of 166). Two (1%) of 166 patients had serious adverse events; neither were considered related to study drug treatment.\n\n\n\nTreatment with ombitasvir, paritaprevir, and ritonavir, plus dasabuvir, without ribavirin, for 8 weeks was efficacious and well tolerated. 8-week treatment options for previously untreated patients with HCV genotype 1b infection without cirrhosis are limited; shortening the treatment duration might reduce the burden associated with medical visits and procedures, thereby improving access to care and enabling the treatment of more patients.\n\n\n\nAbbVie.",
"affiliations": "J W Goethe University, Frankfurt, Germany. Electronic address: tania.welzel@kgu.de.;Centre de Recherche sur l'Inflammation, Université Paris Diderot, AP-HP Hôpital Beaujon, Clichy, France.;AbbVie, Chicago, IL, USA.;J W Goethe University, Frankfurt, Germany.;Royal Adelaide Hospital, Adelaide, SA, Australia.;Ha'emek Medical Center, Afula, Israel.;Liver Unit, Hospital Clinic, CIBEREHD, IDIBAPS, University of Barcelona, Barcelona, Spain.;AbbVie, Chicago, IL, USA.;AbbVie, Chicago, IL, USA.;AbbVie, Chicago, IL, USA.;Toronto Centre for Liver Disease, University of Toronto, Toronto, ON, Canada.",
"authors": "Welzel|Tania M|TM|;Asselah|Tarik|T|;Dumas|Emily O|EO|;Zeuzem|Stefan|S|;Shaw|David|D|;Hazzan|Rawi|R|;Forns|Xavier|X|;Pilot-Matias|Tami|T|;Lu|Wenjing|W|;Cohen|Daniel E|DE|;Feld|Jordan J|JJ|",
"chemical_list": "D000813:Anilides; D000998:Antiviral Agents; D002219:Carbamates; D003521:Cyclopropanes; D047029:Lactams, Macrocyclic; D047028:Macrocyclic Compounds; D013449:Sulfonamides; C586094:ombitasvir; D014498:Uracil; D011392:Proline; D015081:2-Naphthylamine; C588260:dasabuvir; D014633:Valine; D019438:Ritonavir; C585405:paritaprevir",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/S2468-1253(17)30071-7",
"fulltext": null,
"fulltext_license": null,
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"issue": "2(7)",
"journal": "The lancet. Gastroenterology & hepatology",
"keywords": null,
"medline_ta": "Lancet Gastroenterol Hepatol",
"mesh_terms": "D015081:2-Naphthylamine; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000813:Anilides; D000998:Antiviral Agents; D002219:Carbamates; D003521:Cyclopropanes; D004334:Drug Administration Schedule; D024882:Drug Resistance, Viral; D004359:Drug Therapy, Combination; D005260:Female; D005838:Genotype; D016174:Hepacivirus; D019698:Hepatitis C, Chronic; D006801:Humans; D047029:Lactams, Macrocyclic; D047028:Macrocyclic Compounds; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D011392:Proline; D019438:Ritonavir; D013449:Sulfonamides; D000072230:Sustained Virologic Response; D017211:Treatment Failure; D014498:Uracil; D014633:Valine",
"nlm_unique_id": "101690683",
"other_id": null,
"pages": "494-500",
"pmc": null,
"pmid": "28416221",
"pubdate": "2017-07",
"publication_types": "D017428:Clinical Trial, Phase III; D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Ombitasvir, paritaprevir, and ritonavir plus dasabuvir for 8 weeks in previously untreated patients with hepatitis C virus genotype 1b infection without cirrhosis (GARNET): a single-arm, open-label, phase 3b trial.",
"title_normalized": "ombitasvir paritaprevir and ritonavir plus dasabuvir for 8 weeks in previously untreated patients with hepatitis c virus genotype 1b infection without cirrhosis garnet a single arm open label phase 3b trial"
} | [
{
"companynumb": "DE-CIPLA LTD.-2017DE07946",
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"activesubstancename": "RITONAVIR"
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... |
{
"abstract": "Our aim in this study was to describe the clinical, morphological, and molecular profile of gastrointestinal stromal tumor (GIST) metastatic to bone. We analyzed the morphological, phenotypic, and molecular characteristics of seven cases, and in addition reviewed 17 cases from literature. Sequence analysis of KIT and PDGFRA genes was possible for six cases. For the GIST cases with bone metastasis, the most common primaries were small intestine (29%), stomach (25%), and rectum (21%). Sites of bone metastases were vertebrae (11), pelvis (8), femur (8), ribs (6), humerus (5), skull (3), scapula (1), and mandible (1). The size ranged from 1.5 to 13 cm (median, 3.8 cm). Bone metastases without involvement of any other organ were seen in 17% of the cases and were solitary in 14 (58%). Adjacent soft tissue involvement was present in nearly half of the patients. Bone metastasis was either manifest at the time of diagnosis (28%) or occurred after a mean period of 4.7 years (3 months-20 years). Morphologically, neoplastic cells were spindle in 67%, epithelioid in 13%, and mixed epithelioid and spindle in 20%. CD117, DOG1, and CD34 were positive in 88, 86, and 85% of the cases, respectively. KIT Exon 11 mutations were the most frequent gene alteration (78%), followed by KIT Exon 13 mutations. Of 17 of the cases with available follow-up information, 7 (41%) patients developed bone metastasis under imatinib therapy. Five patients (29%) died of disease within a mean of 17 months. Bone metastases from GIST are usually found in patients with advanced disease and typically present as lytic masses with occasional soft tissue involvement. We could not identify any KIT or PDGFRA alterations predisposing to bone metastasis.",
"affiliations": "Department of Pathology, Hacettepe University School of Medicine, Ankara, Turkey. dokemal@hotmail.com.;Department of Pathology, Ankara University School of Medicine, Ankara, Turkey.;Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.;Department of Pathology, Istanbul University Cerrahpasa School of Medicine, Istanbul, Turkey.;Department of Pathology, Acıbadem University School of Medicine, Istanbul, Turkey.;Department of Pathology, Ankara University School of Medicine, Ankara, Turkey.;Hepatology Institute, Ankara University, Ankara, Turkey.;Department of Pathology, Ankara University School of Medicine, Ankara, Turkey.;, Ankara, Turkey.;Department of Pathology, Istanbul University Cerrahpasa School of Medicine, Istanbul, Turkey.;Department of Pathology, Ankara University School of Medicine, Ankara, Turkey.",
"authors": "Kosemehmetoglu|Kemal|K|http://orcid.org/0000-0002-7747-0460;Kaygusuz|Gulsah|G|;Fritchie|Karen|K|;Aydin|Ovgu|O|;Yapicier|Ozlem|O|;Coskun|Oznur|O|;Karatayli|Ersin|E|;Boyacigil|Senay|S|;Guler|Gulnur|G|;Dervisoglu|Sergulen|S|;Kuzu|Isinsu|I|",
"chemical_list": "D019009:Proto-Oncogene Proteins c-kit; D020796:Receptor, Platelet-Derived Growth Factor alpha",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00428-017-2138-7",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0945-6317",
"issue": "471(1)",
"journal": "Virchows Archiv : an international journal of pathology",
"keywords": "Bone metastasis; DOG1; Gastrointestinal stromal tumor; KIT; Mutation; PDGFRA",
"medline_ta": "Virchows Arch",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001859:Bone Neoplasms; D005260:Female; D005770:Gastrointestinal Neoplasms; D046152:Gastrointestinal Stromal Tumors; D006801:Humans; D008297:Male; D008875:Middle Aged; D019009:Proto-Oncogene Proteins c-kit; D020796:Receptor, Platelet-Derived Growth Factor alpha",
"nlm_unique_id": "9423843",
"other_id": null,
"pages": "77-90",
"pmc": null,
"pmid": "28488171",
"pubdate": "2017-07",
"publication_types": "D016428:Journal Article",
"references": "10636102;22676893;15930355;19838991;22017257;16625094;18955458;11474281;20096441;20930018;19562456;16146747;15613856;19653356;18312355;24384849;19239429;25605837;20953912;28028119;19545287;12563150;12960119;19776004;14632569;21334201;16439005;11688571;19646278;22407696;22811827;27258566;16551858;19440146;16810068;22069171;19606013;21921354;15781488;21668468;18246046;22227175;10224103;19696616;16135486;10824931;16343205;26544626;21830406;16082245;21605429;15087667;11387135;26936919;17589841;21769316;16780037;18350628;15507676;26687836",
"title": "Clinical and pathological characteristics of gastrointestinal stromal tumor (GIST) metastatic to bone.",
"title_normalized": "clinical and pathological characteristics of gastrointestinal stromal tumor gist metastatic to bone"
} | [
{
"companynumb": "TR-SUN PHARMACEUTICAL INDUSTRIES LTD-2017RR-150652",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "IMATINIB"
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"drugad... |
{
"abstract": "The suspicion of a serious condition arises if a smoker is coughing and losing weight constantly. Serology and imaging are great options for diagnosis, but what is their specificity? A 62-year-old man presented with persistent cough, weight loss and hypoxia. A chest x-ray revealed bilateral interstitial infiltrates. Treatment with several antibiotics failed. Serological results showed antineutrophil cytoplasmic antibodies (c-ANCA) positivity. However, biopsy result indicated cryptogenic organising pneumonia. This case report discloses the differential diagnosis of c-ANCA positive interstitial lung disease in detail.",
"affiliations": "Department of Internal Medicine, Creighton University Medical Center, Omaha, Nebraska, USA. kaanakturk@yahoo.com",
"authors": "Akturk|Halis Kaan|HK|;Vashisht|Priyanka|P|",
"chemical_list": "D019268:Antibodies, Antineutrophil Cytoplasmic",
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2013()",
"journal": "BMJ case reports",
"keywords": null,
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D019268:Antibodies, Antineutrophil Cytoplasmic; D001706:Biopsy; D003371:Cough; D018549:Cryptogenic Organizing Pneumonia; D003937:Diagnosis, Differential; D006801:Humans; D000860:Hypoxia; D008297:Male; D008875:Middle Aged; D013902:Radiography, Thoracic; D012680:Sensitivity and Specificity; D015431:Weight Loss",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "23456160",
"pubdate": "2013-03-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "22573292;20724743;11176728;11904336;22921790;11354560;10722773;22669754;9507222",
"title": "How far you can trust c-ANCA?",
"title_normalized": "how far you can trust c anca"
} | [
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"companynumb": "US-JNJFOC-20130511411",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
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"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PIPERACILLIN SODIUM\\TAZOBACTAM SODIUM"
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"druga... |
{
"abstract": "BACKGROUND\nIn late 2011, a shortage of IV acyclovir led to the need to empirically substitute high-dose oral valacyclovir (HDVA) to conserve IV acyclovir for patients with confirmed herpes simplex virus (HSV) meningitis or encephalitis. This report describes the management of the most recent national IV acyclovir shortage by the Antimicrobial Stewardship Program (ASP) at Northwestern Memorial Hospital (NMH), Chicago, IL, USA, and the use of HDVA. Secondarily, we assessed the safety and tolerability of HDVA as an alternate to IV acyclovir during this shortage.\n\n\nMETHODS\nWe report the step-wise management, restrictions, and guidelines implemented at NMH during a protracted IV acyclovir shortage. The assessment of HDVA was a retrospective, observational cohort study of hospitalized patients receiving HDVA between 1 January 2012 and 31 December 2013. Appropriate demographic and treatment variables were collected. The primary outcome was percentage of patients experiencing an adverse event.\n\n\nRESULTS\nThere were 15 adult patients included in the study on a median daily dose of HDVA of 3 g (IQR 2-8). There were four patients with microbiologically confirmed viral CNS infections (n = 1 HSV-1, n = 2 HSV-2, n = 1 VZV encephalitis) and eleven patients with unknown causative pathogens. Six (40%) patients experienced at least one adverse drug reaction (ADR) to HDVA (thrombocytopenia, 33.3%, n = 5; headache, 6.7%, n = 1; nausea, 6.7%, n = 1; rash, 6.7%, n = 1). One patient (6.7%) was readmitted within 30 days with a suspected non-CNS infection. There were no treatment discontinuations or symptomatic therapy necessary to treat any of the ADRs.\n\n\nCONCLUSIONS\nThe shortage of IV acyclovir was successfully managed by the ASP and HDVA appeared to be well tolerated when used as an alternative to IV acyclovir.",
"affiliations": "Northwestern Memorial Hospital, Chicago, IL, USA. milgriff@nm.org.;Northwestern Memorial Hospital, Chicago, IL, USA.;Chicago College of Pharmacy, Midwestern University, Downers Grove, IL, USA.;Northwestern Memorial Hospital, Chicago, IL, USA.",
"authors": "McLaughlin|Milena M|MM|http://orcid.org/0000-0002-8748-185X;Sutton|Sarah H|SH|;Jensen|Ashley O|AO|;Esterly|John S|JS|",
"chemical_list": null,
"country": "New Zealand",
"delete": false,
"doi": "10.1007/s40121-017-0157-y",
"fulltext": "\n==== Front\nInfect Dis Ther\nInfect Dis Ther\nInfectious Diseases and Therapy\n2193-8229\n2193-6382\nSpringer Healthcare Cheshire\n\n28417331\n157\n10.1007/s40121-017-0157-y\nBrief Report\nUse of High-Dose Oral Valacyclovir During an Intravenous Acyclovir Shortage: A Retrospective Analysis of Tolerability and Drug Shortage Management\nhttp://orcid.org/0000-0002-8748-185X\nMcLaughlin Milena M. milgriff@nm.org\n\n12\nSutton Sarah H. 13\nJensen Ashley O. 2\nEsterly John S. 1\n1 0000 0001 0491 7842 grid.416565.5 Northwestern Memorial Hospital, Chicago, IL USA\n2 grid.260024.2 Chicago College of Pharmacy, Midwestern University, Downers Grove, IL USA\n3 0000 0001 2299 3507 grid.16753.36 Northwestern University Feinberg School of Medicine, Chicago, IL USA\n17 4 2017\n17 4 2017\n6 2017\n6 2 259264\n2 3 2017\n© The Author(s) 2017\nhttps://creativecommons.org/licenses/by-nc/4.0/ This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/), which permits any noncommercial 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.\nIntroduction\n\nIn late 2011, a shortage of IV acyclovir led to the need to empirically substitute high-dose oral valacyclovir (HDVA) to conserve IV acyclovir for patients with confirmed herpes simplex virus (HSV) meningitis or encephalitis. This report describes the management of the most recent national IV acyclovir shortage by the Antimicrobial Stewardship Program (ASP) at Northwestern Memorial Hospital (NMH), Chicago, IL, USA, and the use of HDVA. Secondarily, we assessed the safety and tolerability of HDVA as an alternate to IV acyclovir during this shortage.\n\nMethods\n\nWe report the step-wise management, restrictions, and guidelines implemented at NMH during a protracted IV acyclovir shortage. The assessment of HDVA was a retrospective, observational cohort study of hospitalized patients receiving HDVA between 1 January 2012 and 31 December 2013. Appropriate demographic and treatment variables were collected. The primary outcome was percentage of patients experiencing an adverse event.\n\nResults\n\nThere were 15 adult patients included in the study on a median daily dose of HDVA of 3 g (IQR 2–8). There were four patients with microbiologically confirmed viral CNS infections (n = 1 HSV-1, n = 2 HSV-2, n = 1 VZV encephalitis) and eleven patients with unknown causative pathogens. Six (40%) patients experienced at least one adverse drug reaction (ADR) to HDVA (thrombocytopenia, 33.3%, n = 5; headache, 6.7%, n = 1; nausea, 6.7%, n = 1; rash, 6.7%, n = 1). One patient (6.7%) was readmitted within 30 days with a suspected non-CNS infection. There were no treatment discontinuations or symptomatic therapy necessary to treat any of the ADRs.\n\nConclusions\n\nThe shortage of IV acyclovir was successfully managed by the ASP and HDVA appeared to be well tolerated when used as an alternative to IV acyclovir.\n\nKeywords\n\nAcyclovir\nShortage\nValacyclovir\nViral encephalitis\nViral meningitis\nissue-copyright-statement© Springer Healthcare 2017\n==== Body\nIntroduction\n\nDrug shortages continue to be a problem in the United States, causing numerous difficulties for clinicians, health-care facilities, patients, and federal regulators [1, 2]. As a generic injectable agent, intravenous (IV) acyclovir is vulnerable to drug shortage due to a variety of reasons including manufacturing difficulties, supply and demand issues, regulatory issues, and raw material shortage [2–4]. In late 2011, a severe shortage of IV acyclovir led to the decision by the Antimicrobial Stewardship Program (ASP) to empirically substitute high-dose oral valacyclovir (HDVA) to conserve IV acyclovir for patients with confirmed herpes simplex virus (HSV) meningitis or encephalitis [5]. Pharmacokinetic data suggest similar serum concentrations to IV acyclovir doses can be achieved with HDVA [6, 7]; however, little data exist regarding the safety and tolerability of HDVA for viral central nervous system (CNS) infections. Here, we describe the management of the most recent national IV acyclovir shortage by the ASP at Northwestern Memorial Hospital (NMH), Chicago, IL, USA, and the replacement with HDVA. Secondarily, we assessed the safety and tolerability of HDVA as an alternate to IV acyclovir during this shortage.\n\nMethods\n\nIV Acyclovir Shortage Management\n\nThe restrictions on IV acyclovir were progressively intensified as supplies dwindled over the 11-month shortage. As of October 2012, ASP pharmacists performed next-day review of new medication starts to assess for appropriateness. Restrictions were added in late November 2012 due to dwindling supplies. IV acyclovir was reserved for patients with HSV disseminated disease, neurological or eye involvement, and neonatal HSV. As the shortage continued, a mandatory next-day infectious disease (ID) consult was required in mid-December 2012 for all IV acyclovir use. In February 2013, restrictions for IV acyclovir use were tightened to diseases with high morbidity and mortality: HSV or varicella zoster virus (VZV) encephalitis documented by cerebrospinal fluid (CSF) polymerase chain reaction (PCR) and neonatal HSV.\n\nIn order to implement these restrictions, the ASP partnered with the microbiology department to have the CSF PCR specimens tested on a daily basis rather than only Monday through Friday, the previous routine schedule. This collaboration highlights the importance of engagement of all parties involved in shortage management and communication. HDVA was used as an alternative to IV acyclovir if clinicians desired treatment for a suspected viral syndrome and the patient did not meet criteria for IV acyclovir use. A dose of at least 6 g of valacyclovir per day (adjusted for renal function) was targeted for CNS infections to achieve expected therapeutic CNS concentrations. These restrictions on IV acyclovir remained in place until September 2013 when an ample supply of IV acyclovir was able to be ordered from warehouses.\n\nHDVA Study Design\n\nThis was a retrospective, observational cohort study of hospitalized patients receiving HDVA between 1 January 2012 and 31 December 2013. This elongated timeline was meant to capture any patients past the date of the resolution of the shortage who may have received HDVA after restrictions had been lifted. Subjects eligible for review were male or female ≥18 years of age receiving treatment for suspected viral meningitis or encephalitis with HDVA per the patient’s medical record. HDVA was defined as any dose and length of therapy exceeding the Food and Drug Administration (FDA) recommendations (e.g., 3 g/day for regimens lasting >1 day for normal renal function). Subjects were assessed for demographics, renal function status, liver function status, steroid use, modified APACHE II score, duration of HDVA treatment, IV acyclovir use, duration of hospital stay, intensive care unit (ICU) transfer, use of symptomatic treatment, adverse drug events, whether ID consultation occurred, time from neurological symptoms to first dose, readmission within 30 days, and neurological sequelae. Patients were also assessed for results of viral microbiological tests. The primary outcome was percentage of patients experiencing an adverse event. This study was approved by the Northwestern and Midwestern University Institutional Review Boards. This article is based on previously conducted studies and does not involve any new studies of human or animal subjects performed by any of the authors. Descriptive statistics were compiled using Intercooled Stata, v.13 (Statacorp, College Station, TX, USA).\n\nResults\n\nThere were 15 patients on HDVA who were included in the study. The average patient in the study was a 45-year-old (IQR 35–60), immunocompromised (66.7%, n = 10), Caucasian (46.7%, n = 7), male (66.7%, n = 10), with a modified APACHE II score of 13.5 (IQR 8–24; Table 1). The most common presenting symptom suggestive of viral CNS disease was altered mental status (n = 13) followed by nuchal rigidity (n = 7). All patients had a lumbar puncture. There was 1 patient with microbiologically confirmed HSV-1 encephalitis, 2 patients with confirmed HSV-2 (n = 1 encephalitis, n = 1 meningitis), 1 patient with confirmed VZV encephalitis, and 11 patients with unknown causative pathogens (n = 5 meningioencephalitis, n = 3 encephalitis, n = 2 meningitis, n = 1 unknown). In total, 8 patients received at least one dose of IV acyclovir and there were 2 patients who had neurological sequelae. The average length of hospital stay per patient was 7 (IQR 4–44) days, including 6 patients (40%) transferred to the ICU (Table 2). One patient (6.7%) was readmitted within 30 days with a diagnosis of Enterococcus faecalis and Staphylococcus epidermidis blood stream infection; his symptoms included chills, somnolence, and generalized weakness.Table 1 Patient demographics\n\n\tn = 15\t\nAge, years (median, IQR)\t45 (35–60)\n\nRange: 28–73\n\n\t\nRace (n, %)\t\n Caucasian\t7 (46.7)\t\n African American\t4 (26.7)\t\n Hispanic\t3 (20)\t\n Asian\t1 (6.7)\t\nGender, male (n, %)\t10 (66.7)\t\nWeight, kg (median, IQR)\t72.9 (59.3–92)\n\nRange: 52–96.6\n\n\t\nBaseline serum creatinine, mg/dL (median, IQR)\t0.89 (0.70–1.46)\n\nRange: 0.42–8.16\n\n\t\nHighest serum creatinine, mg/dL (median, IQR)\t0.94 (0.75–1.46)\n\nRange: 0.44–10.28\n\n\t\nValacyclovir renal adjustment necessary (n, %)\t4 (26.7)\t\nImmunocompromised (n, %)\t10 (66.7)\t\nNeutropenic (n, %)\t1 (6.7)\t\nModified APACHE II, day 0 (median, IQR)\t13.5 (8–24)\n\nRange: 6–26\n\n\t\nIntravenous acyclovir given (n, %)\t8 (53.3)\t\nInfectious diseases consult obtained (n, %)\t13 (86.7)\t\nIQR interquartile range\n\nTable 2 Patient outcomes\n\n\tn = 15\t\nLength of hospital stay, days (median, IQR)\t7 (4–44)\n\nRange: 2–76\n\n\t\nTransferred to ICU (n, %)\t6 (40)\t\nICU length of stay, days, n = 6 (median, IQR)\t9.5 (4–24)\n\nRange: 4–32\n\n\t\nTime to first dose from admission, h (median, IQR)\t10 (6–53)\n\nRange: 1.75–600\n\n\t\nTime from symptoms to first dose, h (median, IQR)\t25.5 (5.5–48)\n\nRange: 0–96\n\n\t\nNeurological sequelae (n, %)\t2 (13.3)\t\nReadmission within 30 days with suspected infection (n, %)\t1 (6.7)\t\nIQR interquartile range, ICU intensive care unit\n\nThe median daily dose of HDVA given to the patients was 3 g (IQR 2–8) with median total length of therapy 11 days (IQR 4–16; Table 3). Six (40%) patients experienced at least one adverse drug reaction (ADR) to HDVA with thrombocytopenia being the most common (33.3%, n = 5) followed by headache (6.7%, n = 1), nausea (6.7%, n = 1), and rash (6.7%, n = 1). There were no treatment discontinuations or symptomatic therapy necessary to treat any of the ADRs.Table 3 Dosing characteristics and adverse effects associated with HDVA\n\n\tn = 15\t\nValacyclovir grams per day (median, IQR)\t3 (2–8)\n\nRange: 1–8\n\n\t\nHighest AST, IU/L (median, IQR)\t24 (18–49)\n\nRange: 12–326\n\n\t\nHighest ALT, IU/L (median, IQR)\t24 (13–48)\n\nRange: 6–286\n\n\t\nHighest total bilirubin, mg/dL (median, IQR)\t0.7 (0.4–1)\n\nRange: 0.3–2.3\n\n\t\nDuration of valacyclovir, days (median, IQR)\t11 (4–16)\n\nRange: 2–34\n\n\t\nAdverse reaction to valacyclovir (n, %)\t6 (40)\t\nHeadache (n, %)\t1 (6.7)\t\nNausea (n, %)\t1 (6.7)\t\nVomiting (n, %)\t0 (0)\t\nRash (n, %)\t1 (6.7)\t\nThrombocytopenia (n, %)\t5 (33.3)\t\nNephrotoxicity (n, %)\t0 (0)\t\nSymptomatic therapy needed (n, %)\t0 (0)\t\nIQR interquartile range\n\nDiscussion\n\nThrough the application of restrictions, guidelines, and expanded microbiological testing, the available inventory of IV acyclovir was adequate to sustain the institution through the shortage period. An important drug management strategy includes identifying alternative or therapeutically equivalent drugs; however, safety and efficacy data for alternatives may be limited. In this study, HDVA appeared to be well tolerated and may be an option when IV acyclovir is unavailable for viral meningitis.\n\nWhen implementing restrictions during drug shortages, ASPs should consider relevant treatment guidelines, current primary literature should be utilized to guide evidence-based decisions, and appropriate hospital committees and administration should be involved. As an example, in a review article regarding neonatal treatment for CNS or disseminated HSV infections during an acyclovir shortage, foscarnet and ganciclovir were both considered unsafe to use due to ADRs and very little safety data [8]. As such, one of the allowed indications for IV acyclovir at NMH was neonatal HSV. ASPs have also successfully managed antibiotic shortages using a prospective audit approach and without restrictions [9].\n\nOrally administered valacylovir for various CNS infections has been well tolerated in previous studies with few reported adverse events or drug-related abnormalities [10, 11]. The most common ADRs in these studies were mild headache and low back pain (n = 19 total patients; dose 1 g by mouth three times daily). The most common ADRs using HDVA in a previous study for episodic treatment of HSV cold sores were headache, nausea, and diarrhea (n = 310 patients treated with HDVA) [7]. This is similar to the current findings and supports potential use outside of FDA dose recommendations when necessary for patient care.\n\nLimitations of this study include a small sample size, retrospective review, and a limited follow-up period. However, the entire shortage period was analyzed to increase the sample size and larger studies are needed to confirm safety and provide data on the efficacy of HDVA for viral meningitis when specifically used due to a shortage of IV acyclovir. As the focus of this study was tolerability and safety, a larger cohort of a more homogenous population would be necessary to comment on the observed effects of efficacy from the use of high-dose valacyclovir. As generic injectable shortages may repeat, this is an area of interest for future study.\n\nConclusion\n\nThe shortage of IV acyclovir was successfully managed through guidelines and restrictions by the ASP. As the shortage intensified, the ASP implemented a policy of reserving IV acyclovir for PCR-confirmed HSV and VZV encephalitis and neonatal HSV disease. HDVA appeared to be well tolerated as initial and directed therapy for HSV meningitis and may be an option when IV acyclovir is unavailable.\n\nAcknowledgements\n\nNo funding or sponsorship was received for this study or publication of this article. The article processing charges were funded by the authors. All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this manuscript, take responsibility for the integrity of the work as a whole, and have given final approval for the version to be published. The authors would like to acknowledge Shadi A. Haddadin, PharmD and Michael Kassa, PharmD for their assistance with clinical data collection.\n\nJohn Esterly’s new affiliation at the time of writing is Merck Research Labs, Merck & Co., Inc., Kenilworth, NJ, USA.\n\nPortions of this research were previously presented: McLaughlin MM and Esterly JS. Safety and Tolerability of High-dose Oral Valacyclovir during a Shortage of Intravenous Acyclovir. Poster Presentation 4202. Microbe. Boston, MA 2016.\n\nDisclosures\n\nMilena McLaughlin, Sarah Sutton, Ashley O. Jensen and John Esterly have nothing to disclose.\n\nCompliance with Ethics Guidelines\n\nThis article is based on previously conducted studies and does not involve any new studies of human or animal subjects performed by any of the authors.\n\nOpen Access\n\nThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/), which permits any noncommercial 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.\n\nEnhanced content\n\nTo view enhanced content for this article go to http://www.medengine.com/Redeem/FD08F06077F449A2.\n==== Refs\nReferences\n\n1. Caulder CR Mehta B Bookstaver PB Impact of drug shortages on health system pharmacies in the southeastern united states Hosp Pharm. 2015 50 279 286 10.1310/hpj5004-279 26448658\n2. Ventola CL The drug shortage crisis in the united states: causes, impact, and management strategies P T. 2011 36 740 757 22346307\n3. ASHP Expert Panel on Drug Product ShortagesFox ER Birt A ASHP guidelines on managing drug product shortages in hospitals and health systems Am J Health Syst Pharm 2009 66 1399 1406 10.2146/ajhp090026 19635779\n4. McLaughlin MM Skoglund EW Drug shortages and patient safety: an overview of essential information for the infusion nurse J Infus Nurs. 2015 38 205 208 10.1097/NAN.0000000000000101 25871867\n5. American Society of Health-System Pharmacists. Drug Shortages: Resolved Shortages. http://www.ashp.org/menu/DrugShortages/ResolvedShortages. Accessed Feb 14, 2017.\n6. Smith JP Weller S Johnson B Pharmacokinetics of acyclovir and its metabolites in cerebrospinal fluid and systemic circulation after administration of high-dose valacyclovir in subjects with normal and impaired renal function Antimicrob Agents Chemother 2010 54 1146 1151 10.1128/AAC.00729-09 20038622\n7. Spruance SL Jones TM Blatter MM High-dose, short-duration, early valacyclovir therapy for episodic treatment of cold sores: results of two randomized, placebo-controlled, multicenter studies Antimicrob Agents Chemother 2003 47 1072 1080 10.1128/AAC.47.3.1072-1080.2003 12604544\n8. Yang C Wu L Cai W Current situation, determinants, and solutions to drug shortages in shaanxi province, china: a qualitative study PLoS ONE 2016 11 e0165183 10.1371/journal.pone.0165183 27780218\n9. Hsueh K Reyes M Krekel T Effective antibiotic conservation by emergency antimicrobial stewardship during a drug shortage Infect Control Hosp Epidemiol. 2016 38 3 356 359 10.1017/ice.2016.289 27917734\n10. Lycke J Malmestrom C Stahle L Acyclovir levels in serum and cerebrospinal fluid after oral administration of valacyclovir Antimicrob Agents Chemother 2003 47 2438 2441 10.1128/AAC.47.8.2438-2441.2003 12878501\n11. Pouplin T Pouplin JN Van Toi P Valacyclovir for herpes simplex encephalitis Antimicrob Agents Chemother 2011 55 3624 3626 10.1128/AAC.01023-10 21576427\n\n",
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"title": "Use of High-Dose Oral Valacyclovir During an Intravenous Acyclovir Shortage: A Retrospective Analysis of Tolerability and Drug Shortage Management.",
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"abstract": "Kawasaki disease (KD) is an acute self-limited systemic vasculitis of unknown etiology. Intravenous immunoglobulin (IVIG) is an effective treatment and decreases the risk of cardiac complications to less than 5%. In spite of its effectiveness, some children do not respond to this therapy and still develop coronary aneurysms (CAA). The optimal treatment for IVIG non-responsive patients remains controversial although corticoids have been suggested to be an effective treatment in some patients. For those patients still resistant to IVIG and corticoids, interleukin-1 receptor antagonists (IL-1RA) such anakinra could be an alternative.\n\n\n\nWe present a 3 year-old Caucasian patient with KD without cardiac complications but with important resistance to treatment. After becoming resistant to IVIG and corticoids, anakinra proved to be an effective treatment.\n\n\n\nTo our knowledge, this is the first report of the utility of IL-1RA in refractory KD without coronary impairment. The patient fulfilled the classical criteria for KD and, after becoming resistant to first and second line treatments, anakinra proved to be an effective treatment. Further studies are required to determine if this is an effective treatment option for other cases of resistant Kawasaki disease.",
"affiliations": "Pediatric Rheumatology Unit, Pediatrics Department, Hospital Parc Taulí Sabadell, Barcelona, Spain. jsanchez@tauli.cat.;Pediatrics Department, Hospital Parc Taulí Sabadell, Barcelona, Spain.;Pediatrics Department, Hospital Parc Taulí Sabadell, Barcelona, Spain.;Pediatric Cardiology Unit, Pediatrics Department, Hospital Parc Taulí Sabadell, Barcelona, Spain.;Pediatric Cardiology Unit, Pediatrics Department, Hospital Parc Taulí Sabadell, Barcelona, Spain.;Pharmacy Department, Hospital Parc Taulí Sabadell, Barcelona, Spain.;Pediatrics Department, Hospital Parc Taulí Sabadell, Barcelona, Spain.;Pediatric Rheumatology Unit, Pediatrics Department, Hospital Sant Joan de Déu Esplugues, Barcelona, Spain.",
"authors": "Sánchez-Manubens|J|J|;Gelman|A|A|;Franch|N|N|;Teodoro|S|S|;Palacios|J R|JR|;Rudi|N|N|;Rivera|J|J|;Antón|J|J|",
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"fulltext": "\n==== Front\nBMC PediatrBMC PediatrBMC Pediatrics1471-2431BioMed Central London 85210.1186/s12887-017-0852-6Case ReportA child with resistant Kawasaki disease successfully treated with anakinra: a case report Sánchez-Manubens J. jsanchez@tauli.cat 12Gelman A. agelman@tauli.cat 3Franch N. nfranch@tauli.cat 3Teodoro S. steodoro@tauli.cat 4Palacios J. R. jrpalacios@tauli.cat 4Rudi N. nrudi@tauli.cat 5Rivera J. privera@tauli.cat 3Antón J. janton@hsjdbcn.org 21 grid.428313.fPediatric Rheumatology Unit, Pediatrics Department, Hospital Parc Taulí Sabadell, Barcelona, Spain 2 grid.411160.3Pediatric Rheumatology Unit, Pediatrics Department, Hospital Sant Joan de Déu Esplugues, Barcelona, Spain 3 grid.428313.fPediatrics Department, Hospital Parc Taulí Sabadell, Barcelona, Spain 4 grid.428313.fPediatric Cardiology Unit, Pediatrics Department, Hospital Parc Taulí Sabadell, Barcelona, Spain 5 grid.428313.fPharmacy Department, Hospital Parc Taulí Sabadell, Barcelona, Spain 8 4 2017 8 4 2017 2017 17 10228 4 2016 29 3 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. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nKawasaki disease (KD) is an acute self-limited systemic vasculitis of unknown etiology. Intravenous immunoglobulin (IVIG) is an effective treatment and decreases the risk of cardiac complications to less than 5%. In spite of its effectiveness, some children do not respond to this therapy and still develop coronary aneurysms (CAA). The optimal treatment for IVIG non-responsive patients remains controversial although corticoids have been suggested to be an effective treatment in some patients. For those patients still resistant to IVIG and corticoids, interleukin-1 receptor antagonists (IL-1RA) such anakinra could be an alternative.\n\nCase presentation\nWe present a 3 year-old Caucasian patient with KD without cardiac complications but with important resistance to treatment. After becoming resistant to IVIG and corticoids, anakinra proved to be an effective treatment.\n\nConclusions\nTo our knowledge, this is the first report of the utility of IL-1RA in refractory KD without coronary impairment. The patient fulfilled the classical criteria for KD and, after becoming resistant to first and second line treatments, anakinra proved to be an effective treatment. Further studies are required to determine if this is an effective treatment option for other cases of resistant Kawasaki disease.\n\nKeywords\nKawasaki diseaseIVIG resistanceAnakinraIL1 blockadeCase reportNo fundingissue-copyright-statement© The Author(s) 2017\n==== Body\nBackground\nKD is an acute self-limited systemic vasculitis of unknown etiology presenting predominantly in toddlers and children under 5 years old. Diagnosis is based on clinical criteria including fever, exanthema, conjunctivitis, changes in hands and feet, erythema of oral mucosa and lips and cervical lymphadenopathy. Prognosis depends on the extent of cardiac involvement; CAA develop in 20-25% of untreated patients and these may lead to myocardial infarction and sudden death if proper treatment with IVIG is not administered within the first 10 days of illness [1, 2]. Early treatment with IVIG decreases the risk of cardiac complications to less than 5%. In spite of its effectiveness, some children do not respond to this therapy and still develop CAA. Although the optimal treatment for IVIG non-responsive patients remains controversial, adding steroids to the 2nd IVIG dose has proven to be effective to reduce the incidence of CAA and improve the prognosis of resistant KD when administered in patients fulfilling IVIG resistance criteria in the Kobayashi scoring system [3, 4]. For those who present a lack of response to this 2nd step of treatment, other approaches have been described, such as infliximab [5], plasma exchange [6] or cyclosporine [7]. In the last years some reports have suggested the role of IL-1RA in the treatment of severe or resistant cases of KD [8, 9]. We present a case of a IVIG and steroids resistant KD successfully treated with IL-1RA (anakinra).\n\nCase presentation\nWe present a previously healthy 3 year-old Caucasian girl, who was admitted with persistent fever for 5 days, generalized rash, non-purulent conjunctivitis, labial and lingual erythema and swollen feet. On admission, the girl had significant irritability. Blood tests showed normal hemoglobin, white blood cells and platelets, high C-reactive protein (CRP - 14 mg/dL) and high transaminases (AST 168 U/L, ALT 86 U/L). Fulfilling the KD classical criteria, KD was diagnosed and treatment with IVIG (2 g/kg) and aspirin (100 mg/kg) was initiated. Echocardiography two days after admission showed mild mitral and tricuspideal regurgitation but no CAA. Electrocardiogram was normal.\n\nDespite the initial IVIG treatment, fever, rash, conjunctivitis and labial and lingual erythema remained, and 2 additional IVIG doses and 2 metilprednisolone (30 mg/kg) pulses were administered in the subsequent days. Eight days after admission, fever disappeared and analytical features normalized.\n\nMaintenance treatment with oral prednisone (0.5 mg/kg/day) was initiated but, on day 11 after admission, fever recurred with important irritability, exanthema and hand and feet desquamation. An important increase on CRP (16.5 mg/dL), ESR (126 mm/h) and platelets (808000) was registered and there was a decrease in hemoglobin (7.5 g/dL) (Fig. 1). Echocardiography did not show changes. Another 2 metilprednisolone pulses were administered without response. On day 14 after admission (19 days since onset), due to conventional treatment failure and having ruled out, together with the patient’s parents, the use of other intravenous treatments such as infliximab, IL-1RA was initiated (anakinra - 2 mg/kg subcutaneous once a day for 14 days). Fever and irritability disappeared within hours and CRP, ESR, platelets and hemoglobin became normal in the subsequent blood tests (24 h and 5 days after treatment initiation).Fig. 1 Time course of C reactive protein (CRP), platelets and treatment\n\n\n\n\nSix days after anakinra was initiated the patient was discharged. Treatment was maintained for 2 weeks combined with aspirin. No relapses appeared after anakinra discontinuation and subsequent blood tests and echocardiographies at weeks 2, 8 and 16 after discharge were normal (no changes on coronary arteries sizes have been recorded over time and z-scores have maintained between 1 and 1.5 SDs). The patient did not experience any side effects or complications during or after the use of anakinra.\n\nDiscussion\nIn the last years, some studies have suggested an important role for interleukin 1 (IL-1) in the pathogenesis of KD [10]. Genome-Wide Association Studies (GWAS) have also found functional SNPs in ITPKC and CASP3 genes that are associated with an increased risk of unresponsiveness to IVIG therapy [11]. Lee et al. suggested, using a mouse model of KD, that IL-1 receptor-deficient mice were protected from induced coronary lesions. Furthermore, daily injections of the IL-1RA prevented induced coronary lesions in normal mice [12].\n\nAnother study developed in a cohort of Taiwanese children with KD, found a significant increase in IVIG resistance risk in those patients with the IL-1B −511 TT and IL-1B −31 CC genotypes and the diplotype TC/TC in the IL-1 family of genes [13]. These results suggest an important genetic association between IL-1 and failure of initial IVIG therapy and support the previous findings that IL-1 secretion is associated with IVIG treatment in KD [14, 15].\n\nAnakinra is a recombinant antagonist of the IL-1 receptor used successfully to treat systemic onset juvenile idiopathic arthritis. Regarding the clinical application of the exposed findings on the role of IL-1 in the pathogenesis of KD, two clinical trials are being held in Europe and the USA and two case reports on KD patients treated with anti-Il-1 have been reported [8, 9]. Both papers describe severe cases of KD, one of them complicated with a macrophage activation syndrome (MAS), that were resistant to multiple IVIG and prednisolone pulses and improved drastically after the administration of anakinra with analytical normalization and complete reversal of the echocardiogram changes. We present a case report in which the patient fulfilled the classical criteria for KD but had no cardiac or severe complications and, after becoming resistant to first and second line treatments, IL-1R blockade proved to be an effective treatment. Further studies are required and are being held to determine if this is an effective treatment option for all cases of resistant Kawasaki disease.\n\nConclusion\nTo our knowledge, this is the first report on the utility of IL-1RA in refractory KD without coronary impairment or MAS. The patient fulfilled the classical criteria for KD and, after becoming resistant to first and second line treatments, IL-1R blockade proved to be an effective treatment without side effects or complications. Further studies are required to determine if this is an effective treatment option for other cases of resistant Kawasaki disease.\n\nAbbreviations\nALTAlanine aminotransferase\n\nASTAspartate aminotransferase\n\nCAACoronary aneurysms\n\nCRPC-reactive protein\n\nESRErythrocyte sedimentation rate\n\nIL-1RAInterleukin-1 receptor antagonists\n\nIVIGIntravenous immunoglobulin\n\nKDKawasaki disease\n\nMASMacrophage activation syndrome\n\nWe would like to thank all the staff in the Pediatrics Department of Hospital Parc Taulí and Rheumatology Unit of Hospital Sant Joan de Déu for their help in the resolution of the case.\n\nFunding\nNo external funding has been obtained for the realization or publication of the article.\n\nAvailability of data and materials\nThe dataset supporting the conclusions of this article is included within the article.\n\nAuthors’ contributions\nAll authors have read and approved the manuscript. They have contributed to the article as follows: JSM: carried out the data collection, drafted the initial manuscript, obtained the patient consent form and approved the final manuscript as submitted. AG, NF, ST, JRP and NR: helped with the resolution of the clinical case and reviewed and revised the manuscript and approved the final manuscript as submitted. JR and JA: reviewed and revised the manuscript and approved the final manuscript as submitted.\n\nCompeting interests\nThe authors declare that they have no competing interests. The authors of the article state that they don’t have conflict of interest to disclose. They are not shareholding in a company, they have not received any grant or consultancy fee from a company whose product features in the submitted manuscript or manufactures a competing product.\n\nConsent for publication\nWritten informed consent was obtained from the parents for publication of this case report.\n\nEthics approval and consent to participate\nEthics approval and consent was no needed for the use of anakinra in the patient. It was used as an off-label medication with the parents and the Pharmacy Department consent. Written informed consent was obtained from the parents for publication of this case report.\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. Newburger JW Takahashi M Gerber MA Diagnosis, treatment, and long-term management of Kawasaki disease: a statement for health professionals from the committee on rheumatic fever, Endocarditis, and Kawasaki disease, council on cardiovascular disease in the young, American Heart Association Pediatrics 2004 114 1708 1733 10.1542/peds.2004-2182 15574639 \n2. Sánchez-Manubens J Bou R Anton J Diagnosis and classification of Kawasaki disease J Autoimmun 2014 48–49 113 117 10.1016/j.jaut.2014.01.010 24485156 \n3. Kobayashi T Kobayashi T Morikawa A Efficacy of intravenous immunoglobulin combined with prednisolone following resistance to initial intravenous immunoglobulin treatment of acute Kawasaki disease J Pediatr 2013 163 521 526 10.1016/j.jpeds.2013.01.022 23485027 \n4. Brogan P Levin M Intravenous immunoglobulin plus corticosteroids prevent coronary artery abnormalities in Kawasaki disease Evid Based Med 2013 18 217 218 10.1136/eb-2013-101264 23564929 \n5. Son MB, Gauvreau K, Burns JC, et al. Infliximab for intravenous immunoglobulin resistance in Kawasaki disease: a retrospective study. J Pediatr 2011;158:644–649. e1. doi:10.1016/j.jpeds.2010.10.012\n6. Sonoda K, Mori M, Hokosaki T, Yokota S. Infliximab plus plasma exchange rescue therapy in Kawasaki disease. J Pediatr 2014;164:1128–1132. e1. doi:10.1016/j.jpeds.2014.01.020.\n7. Tremoulet AH, Pancoast P, Franco A, et al. Calcineurin inhibitor treatment of intravenous immunoglobulin-resistant Kawasaki disease. J Pediatr 2012;161:506–512. e1. doi:10.1016/j.jpeds.2012.02.048.\n8. Cohen S Tacke CE Straver B A child with severe relapsing Kawasaki disease rescued by IL-1 receptor blockade and extracorporeal membrane oxygenation Ann Rheum Dis 2012 71 2059 2061 10.1136/annrheumdis-2012-201658 22689319 \n9. Shafferman A Birmingham JD Cron RQ High dose Anakinra for treatment of severe neonatal Kawasaki disease: a case report Pediatr Rheumatol Online J 2014 12 26 10.1186/1546-0096-12-26 25045337 \n10. Hoang LT Shimizu C Ling L Global gene expression profiling identifies new therapeutic targets in acute Kawasaki disease Genome Med 2014 6 541 10.1186/s13073-014-0102-6 25614765 \n11. Onouchi Y Suzuki Y Suzuki H ITPKC and CASP3 polymorphisms and risks for IVIG unresponsiveness and coronary artery lesion formation in Kawasaki disease Pharmacogenomics J 2013 13 52 59 10.1038/tpj.2011.45 21987091 \n12. Lee Y Schulte DJ Shimada K Interleukin-1β is crucial for the induction of coronary artery inflammation in a mouse model of Kawasaki disease Circulation 2012 125 1542 1550 10.1161/CIRCULATIONAHA.111.072769 22361326 \n13. Weng K-P Hsieh K-S Ho T-Y IL-1B polymorphism in association with initial intravenous immunoglobulin treatment failure in Taiwanese children with Kawasaki disease Circ J 2010 74 544 551 10.1253/circj.CJ-09-0664 20081319 \n14. Leung DY Cotran RS Kurt-Jones E Endothelial cell activation and high interleukin-1 secretion in the pathogenesis of acute Kawasaki disease Lancet (London, England) 1989 2 1298 1302 10.1016/S0140-6736(89)91910-7 \n15. Suzuki H Uemura S Tone S Effects of immunoglobulin and gamma-interferon on the production of tumour necrosis factor-alpha and interleukin-1 beta by peripheral blood monocytes in the acute phase of Kawasaki disease Eur J Pediatr 1996 155 291 296 10.1007/BF02002715 8777922\n\n",
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"abstract": "BACKGROUND\nAfter platinum and taxane chemotherapy, with or without bevacizumab, active regimens for advanced or recurrent cervical cancer are lacking. Our objective was to review a single institution experience in treating recurrent, refractory cervical cancer with nano-particle albumin bound (NAB) paclitaxel with or without bevacizumab.\n\n\nMETHODS\nThis retrospective case series was conducted in accordance with the regulations set forth by the Institutional Review Board at St. Joseph's Hospital and Medical center. The chemotherapy log at the outpatient infusion center at the University of Arizona Cancer Center was reviewed to identify all advanced cervical cancer patients treated with NAB-paclitaxel from November 2011 until February 2015. The following data points were extracted from patient charts: demographic information, number of cycles, progression free survival (PFS), overall survival (OS), dose reductions and dose-limiting toxicities. In addition the average number of treatment cycles and age at recurrence were calculated.\n\n\nRESULTS\nA total of 12 subjects were identified as receiving treatment with NAB-paclitaxel. Mean age at time of recurrence was 47.2 years (36-55). Nine subjects had squamous cell histology and three subjects had adenocarcinoma histology. All subjects had failed treatment with platinum and taxane, or platinum and topotecan chemotherapy. Two subjects were lost to follow up. The Median number of cycles of NAB-paclitaxel was 6.5 (2-19). The total number of cycles of NAB-paclitaxel in the study population was 65. Seven subjects were treated in combination with bevacizumab. Of these, three subjects are still alive and one subject is currently receiving active treatment with NAB-paclitaxel. The median PFS and OS for all subjects that met mortality endpoint was 4.8 months and 8.9 months (n = 7), respectively. One subject discontinued NAB-paclitaxel secondary to peripheral neuropathy, and one subject developed a vesicovaginal fistula while obtaining combination NAB-paclitaxel and bevacizumab therapy.\n\n\nCONCLUSIONS\nNAB-paclitaxel with or without bevacizumab is tolerable and potentially active in treating recurrent cervical cancer after failing platinum-taxane or topotecan chemotherapy. This small case series deserves confirmation through prospective clinical trials.",
"affiliations": "Dignity Health St. Joseph's Hospital and Medical Center, 500 West Thomas Road, Suite 660, Phoenix, AZ 85013 USA.;Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Arizona Cancer Center at Dignity Health St. Joseph's Hospital and Medical Center, 500 West Thomas Road, Suite 660, Phoenix, AZ 85013 USA.;Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Arizona Cancer Center at Dignity Health St. Joseph's Hospital and Medical Center, 500 West Thomas Road, Suite 660, Phoenix, AZ 85013 USA.;Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Arizona Cancer Center at Dignity Health St. Joseph's Hospital and Medical Center, 500 West Thomas Road, Suite 660, Phoenix, AZ 85013 USA.;Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Arizona Cancer Center at Dignity Health St. Joseph's Hospital and Medical Center, 500 West Thomas Road, Suite 660, Phoenix, AZ 85013 USA.",
"authors": "Minion|Lindsey E|LE|;Chase|Dana M|DM|;Farley|John H|JH|;Willmott|Lyndsay J|LJ|;Monk|Bradley J|BJ|",
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"fulltext": "\n==== Front\nGynecol Oncol Res PractGynecol Oncol Res PractGynecologic Oncology Research and Practice2053-6844BioMed Central London 2510.1186/s40661-016-0025-6ResearchSafety and efficacy of salvage nano-particle albumin bound paclitaxel in recurrent cervical cancer: a feasibility study Minion Lindsey E. Lindsey.Minion@mihs.org Chase Dana M. Dana.Chase@dignityhealth.org Farley John H. John.Farley@dignityhealth.org Willmott Lyndsay J. Lyndsay.Willmott@dignityhealth.org Monk Bradley J. 602-405-7730bradley.monk@dignityhealth.org Dignity Health St. Joseph’s Hospital and Medical Center, 500 West Thomas Road, Suite 660, Phoenix, AZ 85013 USA Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Arizona Cancer Center at Dignity Health St. Joseph’s Hospital and Medical Center, 500 West Thomas Road, Suite 660, Phoenix, AZ 85013 USA 14 4 2016 14 4 2016 2016 3 423 10 2015 5 4 2016 © Minion et al. 2016\nOpen AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nAfter platinum and taxane chemotherapy, with or without bevacizumab, active regimens for advanced or recurrent cervical cancer are lacking. Our objective was to review a single institution experience in treating recurrent, refractory cervical cancer with nano-particle albumin bound (NAB) paclitaxel with or without bevacizumab.\n\nMethods\nThis retrospective case series was conducted in accordance with the regulations set forth by the Institutional Review Board at St. Joseph’s Hospital and Medical center. The chemotherapy log at the outpatient infusion center at the University of Arizona Cancer Center was reviewed to identify all advanced cervical cancer patients treated with NAB-paclitaxel from November 2011 until February 2015. The following data points were extracted from patient charts: demographic information, number of cycles, progression free survival (PFS), overall survival (OS), dose reductions and dose-limiting toxicities. In addition the average number of treatment cycles and age at recurrence were calculated.\n\nResults\nA total of 12 subjects were identified as receiving treatment with NAB-paclitaxel. Mean age at time of recurrence was 47.2 years (36–55). Nine subjects had squamous cell histology and three subjects had adenocarcinoma histology. All subjects had failed treatment with platinum and taxane, or platinum and topotecan chemotherapy. Two subjects were lost to follow up. The Median number of cycles of NAB-paclitaxel was 6.5 (2–19). The total number of cycles of NAB-paclitaxel in the study population was 65. Seven subjects were treated in combination with bevacizumab. Of these, three subjects are still alive and one subject is currently receiving active treatment with NAB-paclitaxel. The median PFS and OS for all subjects that met mortality endpoint was 4.8 months and 8.9 months (n = 7), respectively. One subject discontinued NAB-paclitaxel secondary to peripheral neuropathy, and one subject developed a vesicovaginal fistula while obtaining combination NAB-paclitaxel and bevacizumab therapy.\n\nConclusions\nNAB-paclitaxel with or without bevacizumab is tolerable and potentially active in treating recurrent cervical cancer after failing platinum-taxane or topotecan chemotherapy. This small case series deserves confirmation through prospective clinical trials.\n\nKeywords\nNano-particle albumin bound paclitaxelRecurrent cervical cancerMetronomic chemotherapyissue-copyright-statement© The Author(s) 2016\n==== Body\nBackground\nHallmarks of recurrent cervical cancer continue to be poor prognosis, and limited treatment options. In this heavily pre-treated population with prior radiation, where disease is not amenable to surgical excision, there has been an evolution in cytotoxic chemotherapy regimens [1]. Gynecologic Oncology Group (GOG) protocol 204 established double therapy of cisplatin and paclitaxel as the standard of care. This combination had an overall response rate of 29.1 % [2]. Then, GOG-240 demonstrated an improvement in both PFS, and OS endpoints from this doublet with the addition of bevacizumab. By harnessing this anti-angiogenic agent, there was an addition of 3.4 months to OS [3]. However, if a GOG-240 treatment regimen fails, there are no established treatment options in recurrent cervical cancer.\n\nNano-particle albumin bound (NAB) paclitaxel is a 130-nanimeter, chremophor-free preparation of paclitaxel. This preparation eliminates the need for pre-medication, has a shorten infusion time, and increase tumor concentration as compared to standard preparation [4, 5].\n\nNAB-paclitaxel was evaluated in recurrent cervical cancer a phase II trial as a part of the GOG-127 queue. For this trial all 35 subjects were taxane naïve. Subjects were treated with 125 mg/m2 on days 1, 8 and 15 of a 28-day cycle. Results demonstrated moderate activity with a median PFS, and OS was 5.0 and 9.4 months, respectively. Ten subjects had a partial response, and additional 15 subjects had stable disease [6].\n\nTargeting angiogenesis, the phenotypic driver of cervical cancer, is central to effective therapy of this disease [7]. In addition to agents that directly inhibit vascular growth pathways, there is significant data corroborating that the administration of chemotherapy in reduced doses with a more frequent schedule produces an anti-angiogenic effect. So-called metronomic chemotherapy reduces endothelial repair time, endothelial cell proliferation, migration and circulating levels of endothelial progenitor cells [8–10].\n\nThus, based on a prior positive phase II evaluation of NAB-paclitaxel, and anti-angiogenic induced properties with metronomic administration we treated recurrent cervical cancer patient that failed prior chemotherapy with NAB-paclitaxel with or without bevacizumab.\n\nMethods\nPatients\nThis retrospective chart review was conducted in accordance with the regulations set forth by the Institutional Review Board of The Dignity Health at St. Joseph’s Hospital and Medical Center. The pharmacy chemotherapy log was review at the University of Arizona Cancer Center Chemotherapy Infusion Suite at Dignity Health at St. Joseph’s Hospital and Medical Center from to identify all patients that received nab-paclitaxel. Charts were review for patients that had the diagnoses of cervical carcinoma. All subjects were assigned a subject number, and information was de-identified during data collection. The data points collected included: demographic, tumor history, prior therapies, adverse events and treatment response.\n\nStatistical considerations\nThe primary endpoint of this series was PFS defined as initiation of nab-paclitaxel to discontinuation of treatment. Secondary endpoint included: dose reductions, completed cycles, adverse events, time to progression, time to death and indication for discontinuation of therapy. Adverse events were categorized using the Common Terminology Criteria for Adverse Events (CTCAE – version 4.0) [11]. The median number of cycles, PFS and OS were calculated.\n\nResults\nFrom November 2011 to February of 2015 time period, 12 patients with the diagnoses of recurrent cervical carcinoma received NAB-paclitaxel. Two subjects were lost to follow up; one patient relocated out-of-state. The remaining 10 patients had the average age of 43.5 (range 36–55). Seven subjects were self-identified as non-Hispanic white, 4 subjects Hispanic and one other. Table 1 displays the demographic characteristic of the study group.Table 1 Patient demographics\n\nCharacteristic\tCategory\t\nn\n\t\nAge Group\t35–40\t3\t\n41–45\t4\t\n46–50\t1\t\n51–55\t3\t\n>56\t1\t\nEthnicity\tNon-Hispanic\t7\t\nHispanic\t4\t\nOther\t1\t\nCell Type\tSquamous Cell Carcinoma\t7\t\nAdenocarcinoma\t3\t\nLines of Prior Therapy\t1\t8\t\n2\t2\t\nPrior Radiation\tYes\t9\t\nNo\t1\t\nPrior Surgery\tYes\t5\t\nNo\t5\t\nPrior Paclitaxel\tYes\t9\t\nNo\t1\t\nPrior Bevacizumab\tYes\t6\t\nNo\t4\t\n\n\nAll subjects had recurrent cervical cancer. Of note, prior to NAB-paclitaxel therapy all subjects had failed prior cytotoxic chemotherapy. Two subjects failed 2 prior lines of chemotherapy. Chemotherapy administered in conjunction with primary radiation, as a radio-sensitizer, was not counted as a systemic chemotherapy regimen. Nine subjects had prior radiation therapy. Of the prior chemotherapy, 9 subjects had prior paclitaxel, and 6 had prior bevacizumab treatment. The only subject not treated with prior paclitaxel had failed prior topotecan. The majority of the subjects had prior pelvic radiation therapy (n = 9).\n\nSubjects were treated with nab-paclitaxel with a dose of 60 mg/m2 to 100 mg/m2. There were 5 dose reductions, and 7 dose delays. Most common indication for treatment alterations was myleosuppression. Eight subjects were treated concomitantly with bevacizumab. A total of 65 cycles were completed; mean cycles completed 6.5 (range 2–19).\n\nThere were no grade 4 or 5 adverse events. The only grade 3 adverse events were anemia-requiring transfusion of packed red blood cells. One subject was diagnosed with a vesicovaginal fistula during NAB-paclitaxel therapy. For a complete list of adverse events please see Table 2.Table 2 Adverse Events\n\n\tGrade 1–2\tGrade 3–4\t\nAnemia\t4\t6\t\nThrombocytopenia\t1\t0\t\nLeukopenia\t4\t0\t\nFatigue\t7\t0\t\nInsomnia\t1\t0\t\nWeight Loss\t3\t0\t\nNeuropathy\t2\t0\t\nConstipation\t4\t0\t\nDiarrhea\t3\t0\t\nNausea & Vomiting\t5\t0\t\nHypertension\t1\t0\t\nEpistasis\t1\t0\t\nVesicovaginal Fistula\t1\t0\t\nPleural Effusion\t2\t0\t\nSmall Bowel Obstruction\t1\t0\t\nAtrial fibrillation\t1\t0\t\n\n\nThree subjects are still alive; one subject is currently receiving active treatment with NAB-paclitaxel. Median PFS and OS for all subjects that met mortality endpoint were 4.8 and 8.9 months (n = 7), respectively (Figs. 1 and 2). Median PFS and OS for the subjects treated with NAB-paclitaxel and bevacizumab that meet mortality endpoint was 6.9 and 14.02 months (n = 6), respectively. One subject discontinued NAB-paclitaxel secondary to peripheral neuropathy.Fig. 1 Progression free survival: Median PFS = 4.8 months (Range: 1.5-17.3 months)\n\nFig. 2 Overall survival. Median OS = 8.9 months (Range: 2.5-21.1 months)\n\n\n\nDiscussion\nNAB-paclitaxel has three Food and Drug Administration (FDA) approved indications: locally advanced or metastatic non-small cell lung cancer, metastatic adenocarcinoma of the pancreas, and metastatic breast cancer after failure of combination chemotherapy or relapse within 6 months of adjuvant therapy [12, 13]. There have been limited evaluations of NAB-paclitaxel in cervical cancer. Here we review our experience in treating heavily pre-treated recurrent cervical cancer patients that have failed prior cytotoxic chemotherapy.\n\nNAB-paclitaxel was previously reviewed in the 127 series. This phase II study queue was launched in the 1990’s by the GOG to evaluate recurrent squamous cell cervical cancer. Most agents studied were not effective with overall response rates ranged from 0 to 22 %. In this series, NAB-paclitaxel was the most effective agent demonstrating a partial response in 10 of 35 subjects (28.6 %). An additional 15 subjects experienced stable disease (42.9 %) [14, 15].\n\nIn comparison, within the prior phase II evaluation of NAB-paclitaxel in cervical cancer, our subjects were heavily pretreated, versus the paclitaxel naïve status of the prior study. While that data supported further investigation of NAB-paclitaxel, it is important to not disregard this significant limitation. Furthermore, data here supports the metronomic administration of this agent and this is the first report of such a dosing schedule in the setting of recurrent cervical cancer.\n\nOne subject was diagnosed with a vesicovaginal fistula during NAB-paclitaxel therapy. This subject was a 35 year old initially diagnosed with stage IIA2 adenocarcinoma. Nineteen months after her primary treatment of cisplatin and radiation, she experienced her first recurrence, and was treated with carboplatin and paclitaxel doublet therapy. Biopsy proven recurrent disease was noted during surveillance. The patient’s exam was notable for “thickened area palpable inferior to the urethra”. This subject completed 11 cycles of NAB-paclitaxel at 80 mg/m2 and bevacizumab 10 mg/kg, and after eleventh cycle the fistula was detected on exam.\n\nWhile this subject represents 10 % of our study population, the authors argue that this is more likely a representation of a pretreated-patient with extensive pelvic disease. Furthermore, the occurrence of this complication is more likely due to the administered bevacizumab with the known complication of fistula formation. This is supported by the lack of fistulas that occurred in the phase II study of NAB-paclitaxel. As this was a limited study population, future studies will need to address the incidence of fistulas during NAB-paclitaxel therapy.\n\nWhile this study provides evidence for the feasibility and tolerability of NAB-paclitaxel in the setting of recurrent cervical cancer, there are several limitations to this data including: lack of patient reported outcomes, Response Evaluation Criteria In Solid Tumors (RECIST) response, and small study population. \n\nConclusions\nIn conclusion, anti-angiogenic therapy has proven pivotal in the treatment of recurrent, metastatic and persistent cervical cancer, however if a GOG-240 treatment regimen fails, there are no established treatment options in recurrent cervical cancer. Metronomic-chemotherapy maybe another treatment option as this administration schedule produces anti-angiogenic properties by effecting endothelial repair time, endothelial cell proliferation, migration, and circulating levels of endothelial progenitor cells. NAB-paclitaxel was overall well tolerated with no grade 4 or 5 adverse events. NAB-paclitaxel with or without bevacizumab is feasible and potentially active in treating recurrent cervical cancer after failing platinum-taxane or topotecan chemotherapy. This small case series deserves confirmation through prospective clinical trials. \n\nAbbreviations\nCTCAEcommon terminology criteria for adverse events\n\nFDAFood and Drug Administration\n\nGOGGynecologic Oncology Group\n\nmg/kgmilligram per kilogram\n\nmg/m2milligram per meters-square\n\nNABnano-particle albumin bound\n\nOSoverall survival\n\nPFSprogression free survival\n\nRECISTresponse evaluation criteria in solid tumors\n\nCompeting interests\n\nLindsey E. Minion, Dana M. Chase, John H. Farley and Lyndsay J. Willmott, have nothing to disclose related to the content of this study. Bradley J. Monk’s institution has received per capita funding from Genentech/Roche for clinical trials. Bradley J. Monk has also received honoraria from Genentech/Roche for consulting and is a part of their speaker’s bureau.\n\nAuthors’ contributions\n\nBM was responsible for study conception and design. LM was responsible for data collection. All authors were involved in data interpretation, manuscript writing and figure creation. All authors gave final approval of final manuscript.\n==== Refs\nReferences\n1. Tewari K Monk B Chemotherapy for metastatic and recurrent cervical cancer Curr Oncol Rep 2005 7 419 34 10.1007/s11912-005-0007-z 16221379 \n2. Monk BJ Sill MW McMeekin DS Cohn DE Phase III trial of four cisplatin containing doublet combinations in stage IVB, recurrent, or persistent cervical carcinoma: a Gynecologic Oncology Group study J Clin Oncol 2009 27 4649 55 10.1200/JCO.2009.21.8909 19720909 \n3. Tewari KS Sill MW Long HJ III Improved survival with bevacizumab in advanced cervical cancer N Engl J Med 2014 370 734 43 10.1056/NEJMoa1309748 24552320 \n4. Gardner ER Dahut WL Scripture CD Randomized crossover pharmacokinetic study of solvent based paclitaxel and nab-paclitaxel Clin Cancer Res 2008 14 13 4200 5 10.1158/1078-0432.CCR-07-4592 18594000 \n5. Desai N Trieu V Yao Z Increased antitumor activity, intratumor paclitaxel concentration and endothelial cell transport of cremophor-free, albumin-bound paclitaxel, ABI-007, compared with cremophor-based paclitaxel Clin Cancer Res 2006 12 4 1317 24 10.1158/1078-0432.CCR-05-1634 16489089 \n6. Alberts DS Blessing JA Landrum LM Phase II trial of nab-paclitaxel in the treatment of recurrent or persistent advanced cervix cancer: A gynecologic oncology group study Gynecol Oncol 2012 127 3 451 5 10.1016/j.ygyno.2012.09.008 22986144 \n7. Willmott LJ Monk BJ Cervical cancer therapy: current, future and anti-angiogensis targeted treatment Expert Rev Anticancer Ther 2009 9 7 895 903 10.1586/era.09.58 19589029 \n8. Pasquier E Honore S Braguer D Microtubule-targeting agents in angiogensis. Where do we stand? Drug Resist Updat 2006 9 1–2 74 86 10.1016/j.drup.2006.04.003 16714139 \n9. Kerbel SK Kamen BA The anti-angiogenic basis of metronomic chemotherapy Nat Rev Cancer 2004 4 6 423 36 10.1038/nrc1369 15170445 \n10. Ng SS Figg WD Sparreboom A Taxane-mediated antiangiogenesis in vitro: influence of formulation vehicles and binding proteins Cancer Res 2004 64 3 821 4 10.1158/0008-5472.CAN-03-3391 14871806 \n11. National Cancer Institute: Common Terminology Criteria for Adverse Events v4.0. NCI, NIH, DHHS. May 29, 2009, NIH publication # 09-7473. http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf\n12. Gradishar WJ Tjudlandin S Davidson N Phase III Trial of Nanoparticle Albumin-Bound Paclitaxel Compared With Polyethylated Castor Oil–Based Paclitaxel in Women With Breast Cancer J Clin Oncol 2005 23 31 7794 803 10.1200/JCO.2005.04.937 16172456 \n13. Abraxane [package insert]. Summitt, NJ: Celgene Coporation; 2014.\n14. Tewari K Monk B Gynecologic oncology group trials of chemotherapy for metastatic and recurrent cervical cancer Curr Oncol Rep 2005 7 6 419 34 10.1007/s11912-005-0007-z 16221379 \n15. Brewer CA Blessing JA Nagourney RA McMeekin DS Lele S Zweizig SL Cisplatin plus gemcitabine in previously treated squamous cell carcinoma of the cervix: a phase II study of the Gynecologic Oncology Group Gynecol Oncol 2006 100 2 385 8 10.1016/j.ygyno.2005.09.009 16271750\n\n",
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"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Simultaneous total occlusion of two coronary arteries associated with use of drospirenone-ethinyl estradiol (oral contraceptive).",
"title_normalized": "simultaneous total occlusion of two coronary arteries associated with use of drospirenone ethinyl estradiol oral contraceptive"
} | [
{
"companynumb": "TR-JUBILANT CADISTA PHARMACEUTICALS-2020JUB00076",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DROSPIRENONE\\ETHINYL ESTRADIOL"
... |
{
"abstract": "A 57-year-old man was admitted because of pain in the right upper leg due to an osteolytic lesion of the femoral bone which was complicated by a spontaneous fracture. At first a malignancy was suspected. However, blood and bone cultures revealed the Streptococcus anginosus group. A diagnosis of acute osteomyelitis was made. In spite of extensive antibiotic and surgical treatment the patient developed severe septic shock with multiple organ failure and died. In the case of a pathological fracture, one should consider the broad differential diagnosis, including osteomyelitis, which should lead to a laboratory work-up and imaging studies. When bone biopsy for histological analysis is necessary, a microbiological culture to look for osteomyelitis should always be performed.",
"affiliations": "Department of Internal Medicine, Amphia Hospital, Breda, the Netherlands.",
"authors": "Janssen|E H C C|EHCC|;de Bree|L C J|LCJ|;Kant|K M|KM|;van Wijngaarden|P|P|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0300-2977",
"issue": "75(3)",
"journal": "The Netherlands journal of medicine",
"keywords": null,
"medline_ta": "Neth J Med",
"mesh_terms": "D000208:Acute Disease; D003937:Diagnosis, Differential; D017809:Fatal Outcome; D005264:Femoral Fractures; D005269:Femur; D005598:Fractures, Spontaneous; D006801:Humans; D008297:Male; D008875:Middle Aged; D010019:Osteomyelitis; D013290:Streptococcal Infections; D034366:Streptococcus anginosus",
"nlm_unique_id": "0356133",
"other_id": null,
"pages": "121-124",
"pmc": null,
"pmid": "28469049",
"pubdate": "2017-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Spontaneous fracture of the femur due to osteomyelitis caused by the Streptococcus anginosus group.",
"title_normalized": "spontaneous fracture of the femur due to osteomyelitis caused by the streptococcus anginosus group"
} | [
{
"companynumb": "NL-PFIZER INC-2017205941",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CLINDAMYCIN PHOSPHATE"
},
"drugadditional": nu... |
{
"abstract": "Acute gout is a common arthritis that may eventually develop into chronic tophaceous gout (CTG). CTG usually is manifested by recurrent gout attacks. The diagnosis and treatment of CTG is challenging. Although the emergence of CTG without previous gout attacks is uncommon, it is important to recognize this unusual gout presentation.\n\n\n\nHerein, we present two cases of CTG, occurring in elderly patients with chronic kidney disease (CKD) on diuretics, who presented without a prior history of acute gout attacks. We also searched PUBMED, Ovid MEDLINE, and Google scholar (1970-2017), for \"tophi as the initial manifestation of gout\" and \"chronic gout without previous attacks\", and extracted relevant data.\n\n\n\nThe search disclosed one retrospective study and several case reports and case series describing 96 patients. Clinical and laboratory data was extracted from 34 patients. We found that a specific group of patients, e.g., elderly patients, most often female patients, suffering from CKD, and treated with diuretics, are specifically reported in the English medical literature to present with CTG as their first manifestation of gout.\n\n\n\nThe two cases and our literature review try to emphasize the many faces of chronic gout, in particular, its presentation without previous gout attacks.",
"affiliations": "Rheumatic Diseases Unit, Ha'Emek Medical Center, Afula 18101, Israel. Electronic address: amir.bieber@gmail.com.;Division of Rheumatology, Department of Medicine, Rutgers, Robert Wood Johnson Medical School, New Brunswick, NJ.;Rheumatic Diseases Unit, Ha'Emek Medical Center, Afula 18101, Israel.;Rheumatic Diseases Unit, Ha'Emek Medical Center, Afula 18101, Israel; The Technicon Institute of Technology, Haifa, Israel.",
"authors": "Bieber|Amir|A|;Schlesinger|Naomi|N|;Fawaz|Abdallah|A|;Mader|Reuven|R|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.semarthrit.2017.11.006",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0049-0172",
"issue": "47(6)",
"journal": "Seminars in arthritis and rheumatism",
"keywords": "Chronic kidney disease; Chronic tophaceous gout; Diuretics; Hyperuricemia",
"medline_ta": "Semin Arthritis Rheum",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D006073:Gout; D050823:Hand Joints; D006801:Humans; D008297:Male; D051436:Renal Insufficiency, Chronic",
"nlm_unique_id": "1306053",
"other_id": null,
"pages": "843-848",
"pmc": null,
"pmid": "29275830",
"pubdate": "2018-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Chronic tophaceous gout as the first manifestation of gout in two cases and a review of the literature.",
"title_normalized": "chronic tophaceous gout as the first manifestation of gout in two cases and a review of the literature"
} | [
{
"companynumb": "IL-TEVA-2018-IL-913684",
"fulfillexpeditecriteria": "1",
"occurcountry": "IL",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CLOPIDOGREL BISULFATE"
},
"drugadditional": "3",... |
{
"abstract": "OBJECTIVE\nWe prospectively investigated the differences in pulmonary vein reconnections (PVRs) and clinical outcomes between contact force (CF)-guided and conventional circumferential PV isolation (CPVI) of atrial fibrillation (AF).\n\n\nMETHODS\nOne hundred twenty consecutive AF patients (63 ± 10 years; 88 males) undergoing an initial CPVI were randomized to ablation with a target CF of 20 g (CF group; n = 60) or that with operators blinded to the CF information (blind group; n = 60).\n\n\nRESULTS\nThe CF group had fewer PVRs (0.67 ± 0.91/patient vs. 1.16 ± 1.16/patient; P = 0.007), a lower incidence of persistent PVRs (13.2 vs. 41.2%; P < 0.001), and a shorter procedural time for the CPVI (50 vs. 56 min; P = 0.019) than the blind group. The mean CF was higher in the CF group than the blind group (18.0 vs. 16.1 g; P < 0.001), with the most significant difference observed along the posterior right-sided PVs (P-RPVs) and anterior left-sided PVs (A-LPVs). In logistic regression models, the mean CF was a negative predictor of PVRs along the P-RPVs and A-LPVs in the blind group (odds ratios, 0.728 and 0.786; P < 0.001 and 0.007), while no significant predictor was identified in the CF group or elsewhere in the blind group. In the Kaplan-Meier analysis, the arrhythmia-free survival rate at 12 months was 89.9% in the CF group and 88.2% in the blind group, respectively (P = 0.624).\n\n\nCONCLUSIONS\nCF-guided CPVI can reduce PVRs and the procedural time and be particularly beneficial along regions where a relatively low CF tends to be applied: the P-RPVs and A-LPVs. The comparable clinical outcomes may be due to the learning curve effect obtained by the CF-guided technique and repeated provocation of dormant PV conduction.",
"affiliations": "Division of Cardiology, Gunma Prefectural Cardiovascular Center, 3-12 Kameizumi-machi, Maebashi City, Gunma, 371-0004, Japan. kohkinakamura@yahoo.co.jp.;Division of Cardiology, Gunma Prefectural Cardiovascular Center, 3-12 Kameizumi-machi, Maebashi City, Gunma, 371-0004, Japan.;Division of Cardiology, Gunma Prefectural Cardiovascular Center, 3-12 Kameizumi-machi, Maebashi City, Gunma, 371-0004, Japan.;Division of Cardiology, Gunma Prefectural Cardiovascular Center, 3-12 Kameizumi-machi, Maebashi City, Gunma, 371-0004, Japan.;Division of Cardiology, Gunma Prefectural Cardiovascular Center, 3-12 Kameizumi-machi, Maebashi City, Gunma, 371-0004, Japan.;Division of Cardiology, Gunma Prefectural Cardiovascular Center, 3-12 Kameizumi-machi, Maebashi City, Gunma, 371-0004, Japan.;Division of Cardiology, Gunma Prefectural Cardiovascular Center, 3-12 Kameizumi-machi, Maebashi City, Gunma, 371-0004, Japan.;Division of Cardiology, Gunma Prefectural Cardiovascular Center, 3-12 Kameizumi-machi, Maebashi City, Gunma, 371-0004, Japan.;Division of Cardiology, Gunma Prefectural Cardiovascular Center, 3-12 Kameizumi-machi, Maebashi City, Gunma, 371-0004, Japan.;Department of Cardiovascular Science and Medicine, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba City, Chiba, 260-8670, Japan.;Division of Cardiology, Gunma Prefectural Cardiovascular Center, 3-12 Kameizumi-machi, Maebashi City, Gunma, 371-0004, Japan.",
"authors": "Nakamura|Kohki|K|;Naito|Shigeto|S|;Sasaki|Takehito|T|;Nakano|Masahiro|M|;Minami|Kentaro|K|;Nakatani|Yosuke|Y|;Ikeda|Kentaro|K|;Yamashita|Eiji|E|;Kumagai|Koji|K|;Funabashi|Nobusada|N|;Oshima|Shigeru|S|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1007/s10840-015-0056-7",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1383-875X",
"issue": "44(3)",
"journal": "Journal of interventional cardiac electrophysiology : an international journal of arrhythmias and pacing",
"keywords": "Atrial fibrillation; Contact force; Pulmonary vein isolation; Pulmonary vein reconnection; Radiofrequency catheter ablation",
"medline_ta": "J Interv Card Electrophysiol",
"mesh_terms": "D001281:Atrial Fibrillation; D018780:Body Surface Potential Mapping; D005260:Female; D006329:Heart Conduction System; D006801:Humans; D008297:Male; D008875:Middle Aged; D011667:Pulmonary Veins; D013314:Stress, Mechanical; D025321:Surgery, Computer-Assisted; D016896:Treatment Outcome",
"nlm_unique_id": "9708966",
"other_id": null,
"pages": "235-45",
"pmc": null,
"pmid": "26387117",
"pubdate": "2015-12",
"publication_types": "D016428:Journal Article; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": "17394453;17286569;21841190;15623542;22381429;23219078;25068575;24575734;19995881;25125294;20367658;22820056;20132400;25280910;25381331;22034876;21098450;16061753;23515263;24762005;24814326;24433324;24657428;14993124;22386883;15363079;22946636;19808430;24557861;21248244;19656250;19067813;12963643",
"title": "Randomized comparison of contact force-guided versus conventional circumferential pulmonary vein isolation of atrial fibrillation: prevalence, characteristics, and predictors of electrical reconnections and clinical outcomes.",
"title_normalized": "randomized comparison of contact force guided versus conventional circumferential pulmonary vein isolation of atrial fibrillation prevalence characteristics and predictors of electrical reconnections and clinical outcomes"
} | [
{
"companynumb": "JP-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2015-BI-68187BI",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DABIGATRAN ETEXILATE MESYLATE"
... |
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