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Schizophrenia Research Sep 2018The use of clozapine requires monitoring the absolute neutrophil count because of the risk of agranulocytosis, but other potentially fatal adverse events associated with...
The use of clozapine requires monitoring the absolute neutrophil count because of the risk of agranulocytosis, but other potentially fatal adverse events associated with clozapine (specifically, myocarditis and cardiomyopathy) do not have mandatory procedures. We performed a systematic review of English-language articles to synthesize an evidence-based approach for myocarditis and cardiomyopathy monitoring. Articles published from January 1988 through February 2017 were identified through a search of Ovid MEDLINE, Ovid Embase, Ovid Cochrane Database of Systematic Reviews, Web of Science, Scopus, and Google Scholar. Selected articles were required to relate to myocarditis or cardiomyopathy in humans from exposure to clozapine. A total of 144 articles were included. Recommendations varied widely. Some authors recommended baseline laboratory monitoring, with or without follow-up testing, for C-reactive protein, creatine kinase MB, and troponin. Electrocardiography was commonly recommended, and echocardiography was less commonly recommended. The expense of monitoring was a consideration. A unanimous recommendation was to stop the use of clozapine and seek a cardiovascular consultation if myocarditis or cardiomyopathy is suspected. Although there is general agreement on which tests to perform for confirming myocarditis and cardiomyopathy, preemptive screening for these clozapine-induced conditions is controversial, and cost and barriers for the use of clozapine are concerns. For asymptomatic patients receiving clozapine, testing could include baseline electrocardiography, echocardiography as part of a cardiac consultation if patients have cardiac disease or risk factors, and monitoring of C-reactive protein and troponin as indicated.
Topics: Antipsychotic Agents; Cardiomyopathies; Clozapine; Humans; Monitoring, Physiologic; Myocarditis; Schizophrenia
PubMed: 29548760
DOI: 10.1016/j.schres.2018.03.006 -
The Oncologist Sep 2017Three-weekly high-dose cisplatin (100 mg/m) is considered the standard systemic regimen given concurrently with postoperative or definitive radiotherapy in locally... (Comparative Study)
Comparative Study Meta-Analysis Review
Weekly Low-Dose Versus Three-Weekly High-Dose Cisplatin for Concurrent Chemoradiation in Locoregionally Advanced Non-Nasopharyngeal Head and Neck Cancer: A Systematic Review and Meta-Analysis of Aggregate Data.
BACKGROUND
Three-weekly high-dose cisplatin (100 mg/m) is considered the standard systemic regimen given concurrently with postoperative or definitive radiotherapy in locally advanced squamous cell carcinoma of the head and neck (LA-SCCHN). However, due to unsatisfactory patient tolerance, various weekly low-dose schedules have been increasingly used in clinical practice. The aim of this meta-analysis was to compare the efficacy, safety, and compliance between these two approaches.
MATERIALS AND METHODS
We systematically searched literature for prospective trials of patients with LA-SCCHN who received postoperative or definitive conventionally fractionated concurrent chemoradiation. Radiation doses were usually 60-66 gray (Gy) in the postoperative setting and 66-70 Gy in the definitive setting. Standard, three-weekly high-dose cisplatin (100 mg/m, 3 doses) was compared with the weekly low-dose protocol (≤50 mg/m, ≥6 doses). The primary endpoint was overall survival. Secondary outcomes comprised response rate, acute and late adverse events, and treatment compliance.
RESULTS
Fifty-two studies with 4,209 patients were included in two separate meta-analyses according to the two clinical settings. There was no difference in treatment efficacy as measured by overall survival or response rate between the chemoradiation settings with low-dose weekly and high-dose three-weekly cisplatin regimens. In the definitive treatment setting, the weekly regimen was more compliant and significantly less toxic with respect to severe (grade 3-4) myelosuppression (leukopenia = .0083; neutropenia = .0024), severe nausea and/or vomiting ( < .0001), and severe nephrotoxicity ( = .0099). Although in the postoperative setting the two approaches were more equal in compliance and with clearly less differences in the cisplatin-induced toxicities, the weekly approach induced more grade 3-4 dysphagia ( = .0026) and weight loss ( < .0001).
CONCLUSION
In LA-SCCHN, current evidence is insufficient to demonstrate a meaningful survival difference between the two dosing regimens. Prior to its adoption into routine clinical practice, the low-dose weekly approach needs to be prospectively compared with the standard three-weekly high-dose schedule.
IMPLICATIONS FOR PRACTICE
Given concurrently with conventional radiotherapy in locally advanced head and neck cancer, high-dose three-weekly cisplatin has often been replaced with weekly low-dose infusions to increase compliance and decrease toxicity. The present meta-analysis suggests that both approaches might be equal in efficacy, both in the definitive and postoperative settings, but differ in toxicity. However, some toxicity data can be influenced by unbalanced representation, and the conclusions are not based on adequately sized prospective randomized studies. Therefore, low-dose weekly cisplatin should not be used outside clinical trials but first prospectively studied in adequately sized phase III trials versus the high-dose three-weekly approach.
Topics: Carcinoma, Squamous Cell; Chemoradiotherapy; Cisplatin; Clinical Trials as Topic; Dose Fractionation, Radiation; Dose-Response Relationship, Drug; Drug Administration Schedule; Head and Neck Neoplasms; Humans; Leukopenia; Nausea; Neutropenia; Patient Compliance; Radiation Dosage; Squamous Cell Carcinoma of Head and Neck; Treatment Outcome; Vomiting
PubMed: 28533474
DOI: 10.1634/theoncologist.2017-0015 -
Health Technology Assessment... Jun 2016Sepsis can lead to multiple organ failure and death. Timely and appropriate treatment can reduce in-hospital mortality and morbidity. (Review)
Review
Sepsis: the LightCycler SeptiFast Test MGRADE®, SepsiTest™ and IRIDICA BAC BSI assay for rapidly identifying bloodstream bacteria and fungi - a systematic review and economic evaluation.
BACKGROUND
Sepsis can lead to multiple organ failure and death. Timely and appropriate treatment can reduce in-hospital mortality and morbidity.
OBJECTIVES
To determine the clinical effectiveness and cost-effectiveness of three tests [LightCycler SeptiFast Test MGRADE(®) (Roche Diagnostics, Risch-Rotkreuz, Switzerland); SepsiTest(TM) (Molzym Molecular Diagnostics, Bremen, Germany); and the IRIDICA BAC BSI assay (Abbott Diagnostics, Lake Forest, IL, USA)] for the rapid identification of bloodstream bacteria and fungi in patients with suspected sepsis compared with standard practice (blood culture with or without matrix-absorbed laser desorption/ionisation time-of-flight mass spectrometry).
DATA SOURCES
Thirteen electronic databases (including MEDLINE, EMBASE and The Cochrane Library) were searched from January 2006 to May 2015 and supplemented by hand-searching relevant articles.
REVIEW METHODS
A systematic review and meta-analysis of effectiveness studies were conducted. A review of published economic analyses was undertaken and a de novo health economic model was constructed. A decision tree was used to estimate the costs and quality-adjusted life-years (QALYs) associated with each test; all other parameters were estimated from published sources. The model was populated with evidence from the systematic review or individual studies, if this was considered more appropriate (base case 1). In a secondary analysis, estimates (based on experience and opinion) from seven clinicians regarding the benefits of earlier test results were sought (base case 2). A NHS and Personal Social Services perspective was taken, and costs and benefits were discounted at 3.5% per annum. Scenario analyses were used to assess uncertainty.
RESULTS
For the review of diagnostic test accuracy, 62 studies of varying methodological quality were included. A meta-analysis of 54 studies comparing SeptiFast with blood culture found that SeptiFast had an estimated summary specificity of 0.86 [95% credible interval (CrI) 0.84 to 0.89] and sensitivity of 0.65 (95% CrI 0.60 to 0.71). Four studies comparing SepsiTest with blood culture found that SepsiTest had an estimated summary specificity of 0.86 (95% CrI 0.78 to 0.92) and sensitivity of 0.48 (95% CrI 0.21 to 0.74), and four studies comparing IRIDICA with blood culture found that IRIDICA had an estimated summary specificity of 0.84 (95% CrI 0.71 to 0.92) and sensitivity of 0.81 (95% CrI 0.69 to 0.90). Owing to the deficiencies in study quality for all interventions, diagnostic accuracy data should be treated with caution. No randomised clinical trial evidence was identified that indicated that any of the tests significantly improved key patient outcomes, such as mortality or duration in an intensive care unit or hospital. Base case 1 estimated that none of the three tests provided a benefit to patients compared with standard practice and thus all tests were dominated. In contrast, in base case 2 it was estimated that all cost per QALY-gained values were below £20,000; the IRIDICA BAC BSI assay had the highest estimated incremental net benefit, but results from base case 2 should be treated with caution as these are not evidence based.
LIMITATIONS
Robust data to accurately assess the clinical effectiveness and cost-effectiveness of the interventions are currently unavailable.
CONCLUSIONS
The clinical effectiveness and cost-effectiveness of the interventions cannot be reliably determined with the current evidence base. Appropriate studies, which allow information from the tests to be implemented in clinical practice, are required.
STUDY REGISTRATION
This study is registered as PROSPERO CRD42015016724.
FUNDING
The National Institute for Health Research Health Technology Assessment programme.
Topics: Age Factors; Anti-Bacterial Agents; Bacteremia; Cost-Benefit Analysis; Cross Infection; Febrile Neutropenia; Fungemia; Germany; Hospital Mortality; Humans; Models, Econometric; Models, Economic; Polymerase Chain Reaction; Quality-Adjusted Life Years; Sensitivity and Specificity; Sepsis; Technology Assessment, Biomedical; United Kingdom
PubMed: 27355222
DOI: 10.3310/hta20460 -
Journal of Diabetes and Its... Jan 2017Conduct a systematic review with meta-analysis to determine the association between incident chemotherapy-induced neutropenia (CIN) and either diabetes mellitus (DM) or... (Meta-Analysis)
Meta-Analysis Review
AIM
Conduct a systematic review with meta-analysis to determine the association between incident chemotherapy-induced neutropenia (CIN) and either diabetes mellitus (DM) or hyperglycemia in patients with cancer.
METHODS
Observational studies in cancer patients of any age receiving chemotherapy and having diabetes or hyperglycemia either during or before chemotherapy induction were included. Studies were retrieved by searching four databases (PubMed, EBSCO, ProQuest, and Cochrane) and cross-referencing. The metric for combining studies was the odds ratio (OR). Results were pooled using a random-effects model, while heterogeneity and inconsistency were assessed using the Q and I statistic, respectively. Potential small-study effects were assessed using the funnel plot.
RESULTS
Ten studies met the criteria for inclusion. Overall, the odds of having CIN were 32% higher among cancer patients with either DM or hyperglycemia compared with those without DM or hyperglycemia (OR=1.32, 95% CI, 1.06-1.64). Statistically significant heterogeneity and inconsistency were found (Q=33.15, p<0.05, I=72.9%). Funnel plot asymmetry reflecting potential small-study effects was observed.
CONCLUSIONS
Diabetes mellitus and hyperglycemia may be associated with an increased risk for CIN among cancer patients. However, additional well-designed studies are needed before any final and definitive recommendations can be made.
Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Diabetes Complications; Humans; Hyperglycemia; Neoplasms; Neutropenia; Reproducibility of Results; Risk
PubMed: 27751709
DOI: 10.1016/j.jdiacomp.2016.09.006 -
Current Medical Research and Opinion Jan 2014Mammalian target of rapamycin (mTOR) inhibitors, temsirolimus and everolimus, are currently approved for the treatment of several malignancies. Hematological toxicities... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Mammalian target of rapamycin (mTOR) inhibitors, temsirolimus and everolimus, are currently approved for the treatment of several malignancies. Hematological toxicities have been reported with these drugs, but overall incidence and relative risk remains undefined. We perform an up-to-date meta-analysis to determine the incidence and risk of hematologic toxicities associated with mTOR inhibitors.
METHODS
Several databases were searched, including PubMed, Embase and Cochrane databases. Eligible studies included prospective phase II and III trials of temsirolimus and everolimus with adequate safety data profile reporting anemia, leucopenia, neutropenia or thrombocytopenia. Overall incidence rates, relative risk (RR), and 95% confidence intervals (CI) were calculated by using either random effects or fixed effects models according to the heterogeneity of included studies.
RESULTS
A total of 5436 patients with a variety of solid tumors from 26 clinical trials were included for the meta-analysis. The overall incidences of mTOR inhibitor associated all-grade and high-grade hematologic toxicities were, respectively: anemia--38.8% and 7.5%; leucopenia--19.6% and 1.8%; neutropenia--14.9% and 5.6%; thrombocytopenia--33.1% and 3.6%. Compared to placebo/control arms, mTOR inhibitors were associated with a significantly increased risk of all-grade (RR 2.05, 95% CI: 1.52-2.77; p < 0.001) and high-grade anemia (RR 1.57, 95% CI: 1.20-2.05; p = 0.001), all-grade (RR 6.03, 95% CI: 2.76-13.14; p < 0.001) and high-grade thrombocytopenia (RR 2.73, 95% CI: 1.87-3.99; p < 0.001). Additionally, a non-significantly increased risk of all-grade leucopenia (RR 1.46, 95% CI: 0.66-3.23; p = 0.34) and neutropenia (RR 1.77, 95% CI: 0.80-3.93; p = 0.16) was observed in the mTOR inhibitor group, while the risk of high-grade leucopenia (RR 0.53, 95% CI: 0.31-0.90, p = 0.019) and neutropenia (RR 0.96, 95% CI: 0.62-1.51; p = 0.87) did not increase. Similar results were also observed in sub-group analysis according to mTOR inhibitor based regimens.
CONCLUSIONS
The use of mTOR inhibitors is associated with a significant increase in the risk of developing all-grade and high-grade anemia and thrombocytopenia compared with placebo/control arms.
Topics: Anemia; Antineoplastic Agents; Everolimus; Humans; Immunosuppressive Agents; Incidence; Neoplasms; Neutropenia; Protein Kinase Inhibitors; Risk; Sirolimus; TOR Serine-Threonine Kinases; Thrombocytopenia
PubMed: 24028709
DOI: 10.1185/03007995.2013.844116 -
BMC Medicine Jan 2012Febrile neutropenia is a frequently occurring and occasionally life-threatening complication of treatment for childhood cancer. Many biomarkers have been proposed as... (Meta-Analysis)
Meta-Analysis Review
Systematic review and meta-analysis of the value of initial biomarkers in predicting adverse outcome in febrile neutropenic episodes in children and young people with cancer.
BACKGROUND
Febrile neutropenia is a frequently occurring and occasionally life-threatening complication of treatment for childhood cancer. Many biomarkers have been proposed as predictors of adverse events. We aimed to undertake a systematic review and meta-analysis to summarize evidence on the discriminatory ability of initial serum biomarkers of febrile neutropenic episodes in children and young people.
METHODS
This review was conducted in accordance with the Center for Reviews and Dissemination Methods, using three random effects models to undertake meta-analysis. It was registered with the HTA Registry of systematic reviews, CRD32009100485.
RESULTS
We found that 25 studies exploring 14 different biomarkers were assessed in 3,585 episodes of febrile neutropenia. C-reactive protein (CRP), pro-calcitonin (PCT), and interleukin-6 (IL6) were subject to quantitative meta-analysis, and revealed huge inconsistencies and heterogeneity in the studies included in this review. Only CRP has been evaluated in assessing its value over the predictive value of simple clinical decision rules.
CONCLUSIONS
The limited data available describing the predictive value of biomarkers in the setting of pediatric febrile neutropenia mean firm conclusions cannot yet be reached, although the use of IL6, IL8 and procalcitonin warrant further study.
Topics: Adolescent; Biomarkers, Tumor; C-Reactive Protein; Child; Fever; Humans; Neoplasms; Neutropenia; ROC Curve; Treatment Outcome
PubMed: 22257704
DOI: 10.1186/1741-7015-10-6 -
Pharmacogenomics Jul 2016Chemotherapeutic agents have been shown to increase lung patient survival, however their use may be limited by their serious adverse effects. We aimed to assess int... (Meta-Analysis)
Meta-Analysis Review
AIM
Chemotherapeutic agents have been shown to increase lung patient survival, however their use may be limited by their serious adverse effects. We aimed to assess int impact of pharmacogenetic variation of influx transporters on inter-individual patient variation in adverse drug reactions.
PATIENTS & METHODS
We conducted a meta-analysis and systemic review and identified 16 publications, totaling 1510 patients, to be eligible for review.
RESULTS
Meta-analysis showed east-Asian patients expressing SLCO1B1 521T>C or 1118G>A to have a two- to fourfold increased risk of irinotecan-induced neutropenia but not diarrhea. American patients, expressing SLC19A1 IVS2(4935) G>A, were further associated with pemetrexed/gemcitabine-induced grade 3+ leukopenia.
CONCLUSION
Future studies should look to robust validation of SLCO1B1 and SLC19A1 as prognostic markers in the management of lung cancer patients.
Topics: Antineoplastic Agents; Biomarkers, Tumor; Case-Control Studies; Humans; Liver-Specific Organic Anion Transporter 1; Neutropenia; Pharmacogenomic Testing; Pharmacogenomic Variants; Predictive Value of Tests; Reduced Folate Carrier Protein
PubMed: 27380948
DOI: 10.2217/pgs-2015-0005 -
The Journal of Antimicrobial... Mar 2017Carbapenem-resistant Gram-negative bacteria are recognized as a cause of difficult-to-treat infections associated with high mortality. (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Carbapenem-resistant Gram-negative bacteria are recognized as a cause of difficult-to-treat infections associated with high mortality.
OBJECTIVES
To perform a systematic review of currently available data on distribution, characteristics and outcome associated with carbapenem-resistant bloodstream infections in adult neutropenic patients.
METHODS
Included studies were identified through Medline, Embase and Cochrane databases between January 1995 and April 2016. Random effect meta-analysis was used to quantify the association between carbapenem resistance and mortality and between carbapenem exposure and resistance.
RESULTS
A total of 30 studies from 21 countries were included. Overall carbapenem resistance varied from 2% to 53% (median 9%) among studies. Infections due to carbapenem-resistant Pseudomonas spp . were reported in 18 (60%) studies showing high median resistance rates (44% of all carbapenem-resistant Gram-negatives and 19% of Pseudomonas isolates). Resistance of Enterobacteriaceae was less commonly reported and bloodstream infections due to carbapenem-resistant Klebsiella spp. were mainly documented from endemic areas (Greece, Italy, Israel). Carbapenem resistance in Acinetobacter spp. was reported in 9 (30%) studies (median resistance 58% of Acinetobacter isolates). Mortality rates ranged from 33% to 71% (median 50%) in patients with carbapenem-resistant infections. Carbapenem resistance appeared to correlate with mortality (OR 4.89, 95% CI 3.30-7.26) and previous exposure to carbapenems (OR 4.63, 95% CI 3.08-6.96).
CONCLUSIONS
Carbapenem resistance represents a threat to neutropenic patients. In this group, resistance is likely promoted by previous carbapenem use and leads to high mortality rates. The knowledge of resistance patterns is crucial and can direct clinicians in the use of alternatives to carbapenem-based regimens.
Topics: Acinetobacter; Adult; Anti-Bacterial Agents; Bacteremia; Carbapenems; Drug Resistance, Bacterial; Female; Global Health; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Greece; Humans; Israel; Italy; Klebsiella; Klebsiella Infections; Male; Middle Aged; Neutropenia; Prevalence; Pseudomonas; beta-Lactam Resistance
PubMed: 27999023
DOI: 10.1093/jac/dkw459 -
PloS One 2022We systematically assessed benefits and harms of tocilizumab (TCZ), which is an antibody blocking IL-6 receptors, in hospitalized COVID-19 patients. (Meta-Analysis)
Meta-Analysis
INTRODUCTION
We systematically assessed benefits and harms of tocilizumab (TCZ), which is an antibody blocking IL-6 receptors, in hospitalized COVID-19 patients.
METHODS
Five electronic databases and two preprint webpages were searched until March 4, 2021. Randomized controlled trials (RCTs) and inverse probability treatment weighting (IPTW) cohorts assessing TCZ effects in hospitalized, COVID-19 adult patients were included. Primary outcomes were all-cause mortality, clinical worsening, clinical improvement, need for mechanical ventilation, and adverse events (AE). Inverse variance random-effects meta-analyses were performed with quality of evidence (QoE) evaluated using GRADE methodology.
RESULTS
Nine RCTs (n = 7,021) and nine IPTW cohorts (n = 7,796) were included. TCZ significantly reduced all-cause mortality in RCTs (RR 0.89, 95%CI 0.81-0.98, p = 0.03; moderate QoE) and non-significantly in cohorts (RR 0.67, 95%CI 0.44-1.02, p = 0.08; very low QoE) vs. control (standard of care [SOC] or placebo). TCZ significantly reduced the need for mechanical ventilation (RR 0.80, 95%CI 0.71-0.90, p = 0.001; moderate QoE) and length of stay (MD -1.92 days, 95%CI -3.46 to -0.38, p = 0.01; low QoE) vs. control in RCTs. There was no significant difference in clinical improvement or worsening between treatments. AEs, severe AEs, bleeding and thrombotic events were similar between arms in RCTs, but there was higher neutropenia risk with TCZ (very low QoE). Subgroup analyses by disease severity or risk of bias (RoB) were consistent with main analyses. Quality of evidence was moderate to very low in both RCTs and cohorts.
CONCLUSIONS
In comparison to SOC or placebo, TCZ reduced all-cause mortality in all studies and reduced mechanical ventilation and length of stay in RCTs in hospitalized COVID-19 patients. Other clinical outcomes were not significantly impacted. TCZ did not have effect on AEs, except a significant increased neutropenia risk in RCTs. TCZ has a potential role in the treatment of hospitalized COVID-19 patients.
Topics: Adult; Antibodies, Monoclonal, Humanized; Humans; Neutropenia; Randomized Controlled Trials as Topic; COVID-19 Drug Treatment
PubMed: 35657993
DOI: 10.1371/journal.pone.0269368 -
International Journal of Colorectal... Jul 2022Sunitinib offers a significant survival benefit to patients with imatinib-resistant gastrointestinal stromal tumors (GIST). However, the incidence and risk of... (Meta-Analysis)
Meta-Analysis Review
PURPOSE
Sunitinib offers a significant survival benefit to patients with imatinib-resistant gastrointestinal stromal tumors (GIST). However, the incidence and risk of sunitinib-induced hematologic toxicities in such a population are often overlooked and have not been well characterized. This meta-analysis was performed to assess the summary incidence and risk of hematologic toxicities secondary to sunitinib in patients with GIST.
METHODS
Searches were performed in PubMed, Embase, Cochrane Library, and Web of Science as well as ClinicalTrials.gov to identify relevant studies up to April 2022. Studies with adequate safety profile, including anemia, neutropenia, and thrombocytopenia, were included to calculate the pooled incidence, relative risk (RR), and corresponding 95% confidence intervals (CIs). This study was registered with PROSPERO under number CRD42022328202.
RESULTS
A total of 2593 patients from 13 studies were included in the present meta-analysis. For patients with GIST assigned to sunitinib, the overall incidences of all-grade anemia, neutropenia, and thrombocytopenia were 26.2% (95% CI, 14.9-39.4%), 41.8% (95% CI, 29.0-55.1%), and 36.4% (95% CI, 22.8-51.1%), respectively. Regarding high-grade (grades 3 and 4) events, there were 4.7% (95% CI, 3.8-5.6%) for anemia, 9.3% (95% CI, 5.6-13.7%) for neutropenia and 5.0% (95% CI, 2.9-7.3%) for thrombocytopenia. Compared to placebo arms, sunitinib was related to an increased risk of high-grade neutropenia with an RR of 10.39 (95% CI, 1.53-70.72; p = 0.017).
CONCLUSIONS
Sunitinib carries a relatively high incidence of hematologic toxicities and a substantial increased risk of high-grade neutropenia in patients with GIST. Appropriate prevention and management seem to be inevitable.
Topics: Anemia; Antineoplastic Agents; Gastrointestinal Stromal Tumors; Humans; Neutropenia; Pyrroles; Sunitinib; Thrombocytopenia
PubMed: 35780257
DOI: 10.1007/s00384-022-04214-7