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The Cochrane Database of Systematic... Jun 2021It remains unclear whether people with non-muscle invasive bladder cancer (NMIBC) benefit from intravesical gemcitabine compared to other agents in the primary or... (Meta-Analysis)
Meta-Analysis
BACKGROUND
It remains unclear whether people with non-muscle invasive bladder cancer (NMIBC) benefit from intravesical gemcitabine compared to other agents in the primary or recurrent setting following transurethral resection of a bladder tumor. This is an update of a Cochrane Review first published in 2012. Since that time, several randomized controlled trials (RCTs) have been reported, making this update relevant. OBJECTIVES: To assess the comparative effectiveness and toxicity of intravesical gemcitabine instillation for NMIBC.
SEARCH METHODS
We performed a comprehensive literature search of the Cochrane Library, MEDLINE, Embase, four other databases, trial registries, and conference proceedings to 11 September 2020, with no restrictions on the language or status of publication.
SELECTION CRITERIA
We included RCTs in which participants received intravesical gemcitabine for primary or recurrent NMIBC.
DATA COLLECTION AND ANALYSIS
Two review authors independently assessed the included studies and extracted data for the primary outcomes: time to recurrence, time to progression, grade III to V adverse events determined by the Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v5.0), and the secondary outcomes: time to death from bladder cancer, time to death from any cause, grade I or II adverse events determined by the CTCAE v5.0 and disease-specific quality of life. We performed statistical analyses using a random-effects model and rated the certainty of the evidence using GRADE.
MAIN RESULTS
We included seven studies with 1222 participants with NMIBC across five comparisons. This abstract focuses on the primary outcomes of the three most clinically relevant comparisons. 1. Gemcitabine versus saline: based on two years' to four years' follow-up, gemcitabine may reduce the risk of recurrence over time compared to saline (39% versus 47% recurrence rate, hazard ratio [HR] 0.77, 95% confidence interval [CI] 0.54 to 1.09; studies = 2, participants = 734; I = 49%; low-certainty evidence), but the CI included the possibility of no effect. Gemcitabine may result in little to no difference in the risk of progression over time compared to saline (4.6% versus 4.8% progression rate, HR 0.96, 95% CI 0.19 to 4.71; studies = 2, participants = 654; I = 53%; low-certainty evidence). Gemcitabine may result in little to no difference in the CTCAE grade III to V adverse events compared to saline (5.9% versus 4.7% adverse events rate, risk ratio [RR] 1.26, 95% CI 0.58 to 2.75; studies = 2, participants = 668; I = 24%; low-certainty evidence). 2. Gemcitabine versus mitomycin: based on three years' follow-up (studies = 1, participants = 109), gemcitabine may reduce the risk of recurrence over time compared to mitomycin (17% versus 40% recurrence rate, HR 0.36, 95% CI 0.19 to 0.69; low-certainty evidence). Gemcitabine may reduce the risk of progression over time compared to mitomycin (11% versus 18% progression rate, HR 0.57, 95% CI 0.32 to 1.01; low-certainty evidence), but the CI included the possibility of no effect. We are very uncertain about the effect of gemcitabine on the CTCAE grade III to V adverse events compared to mitomycin (RR 0.51, 95% CI 0.13 to 1.93; very low-certainty evidence). The analysis was only based on recurrent NMIBC. 3. Gemcitabine versus Bacillus Calmette-Guérin (BCG) for recurrent (one-course BCG failure) high-risk NMIBC: based on 6 months' to 22 months' follow-up (studies = 1, participants = 80), gemcitabine may reduce the risk of recurrence compared to BCG (41% versus 97% recurrence rate, HR 0.15, 95% CI 0.09 to 0.26; low-certainty evidence) and progression over time (16% versus 33% progression rate, HR 0.45, 95% CI 0.27 to 0.76; low-certainty evidence). We are very uncertain about the effect of gemcitabine on the CTCAE grade III to V adverse events compared to BCG (RR 1.00, 95% CI 0.21 to 4.66; very low-certainty evidence). In addition, the review provides information on the comparison of gemcitabine versus BCG and gemcitabine versus one-third dose BCG. AUTHORS' CONCLUSIONS: Based on findings of this review, gemcitabine may have a more favorable impact on recurrence and progression-free survival than mitomycin but we are very uncertain as to how major adverse events compare. The same is true when comparing gemcitabine to BCG in individuals with high risk disease who have previously failed BCG. The underlying low- to very low-certainty evidence indicates that our confidence in these results is limited; the true effects may be substantially different from these findings; therefore, better quality studies are needed.
Topics: Adjuvants, Immunologic; Administration, Intravesical; Antibiotics, Antineoplastic; Antimetabolites, Antineoplastic; BCG Vaccine; Bias; Cause of Death; Confidence Intervals; Deoxycytidine; Disease Progression; Drug Administration Schedule; Humans; Mitomycin; Neoplasm Recurrence, Local; Randomized Controlled Trials as Topic; Saline Solution; Urinary Bladder Neoplasms; Gemcitabine
PubMed: 34125951
DOI: 10.1002/14651858.CD009294.pub3 -
Current Oncology (Toronto, Ont.) May 2023Colorectal cancer is the most prevalent gastrointestinal neoplasm. When metastatic, the disease has limited systemic treatment options. Novel targeted therapies have... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Colorectal cancer is the most prevalent gastrointestinal neoplasm. When metastatic, the disease has limited systemic treatment options. Novel targeted therapies have expanded these options for subsets with specific molecular alterations, such as microsatellite instability (MSI)-high cancers, but additional treatments and combinations are in urgent need to improve outcomes and improve survival of this incurable disease. The fluoropyrimidine-derivative trifluridine, in combination with tipiracil, has been introduced as a third-line treatment, and more recently, it was studied in combination with bevacizumab. This meta-analysis reports on studies with this combination in clinical practice outside clinical trials.
METHODS
A literature search in the Medline/PubMed and Embase databases was executed for finding series of trifluridine/tipiracil with bevacizumab in metastatic colorectal cancer. Criteria for inclusion in the meta-analysis were English or French language of the report, inclusion of twenty or more patients with metastatic colorectal cancer treated with trifluridine/tipiracil in combination with bevacizumab outside of a trial and containing information regarding response rates, progression-free survival (PFS), and overall survival (OS). Information on the demographics of the patients and on adverse effects of treatment was also collected.
RESULTS
Eight series with a total of 437 patients were eligible for the meta-analysis. The performed meta-analysis discovered a summary response rate (RR) of 2.71% (95% confidence interval (CI): 1.11-4.32%) and a disease control rate (DCR) of 59.63% (95% CI: 52.06-67.21%). Summary PFS was 4.56 months (95% CI: 3.57-5.55 months), and summary OS was 11.17 months (95% CI: 10.15-12.19 months). Common adverse effects identified mirrored the adverse-effect profile of the two components of the combination.
CONCLUSION
The current systematic review and meta-analysis reports the efficacy of trifluridine/tipiracil with bevacizumab in advanced lines of therapy for metastatic colorectal cancer in the setting of clinical practice outside clinical trials. Discovery of predictive biomarkers of response to trifluridine/tipiracil with bevacizumab will promote the tailoring of this treatment to individual patients to maximize clinical benefit.
Topics: Humans; Bevacizumab; Uracil; Colorectal Neoplasms; Trifluridine; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Rectal Neoplasms
PubMed: 37366880
DOI: 10.3390/curroncol30060397 -
Archives of Toxicology Nov 2022Studies suggest that chronic lead (Pb) exposure may induce deoxyribonucleic acid (DNA) damage. However, there is no synthesised evidence in this regard. We... (Meta-Analysis)
Meta-Analysis Review
Studies suggest that chronic lead (Pb) exposure may induce deoxyribonucleic acid (DNA) damage. However, there is no synthesised evidence in this regard. We systematically reviewed existing literature and synthesised evidence on the association between chronic Pb exposure and markers of genotoxicity. Observational studies reporting biomarkers of DNA damage among occupationally Pb-exposed and unexposed controls were systematically searched from PubMed, Scopus and Embase databases from inception to January 2022. The markers included were micronucleus frequency (MN), chromosomal aberrations, comet assay, and 8-hydroxy-deoxyguanosine. During the execution of this review, we followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Mean differences in the biological markers of DNA damage between Pb-exposed and control groups were pooled using the random-effects model. The heterogeneity was assessed using the Cochran-Q test and I statistic. The review included forty-five studies comparing markers of DNA damage between Pb-exposed and unexposed. The primary studies utilised buccal and/or peripheral leukocytes for evaluating the DNA damage. The pooled quantitative results revealed significantly higher DNA damage characterised by increased levels of MN and SCE frequency, chromosomal aberrations, and oxidative DNA damage (comet assay and 8-OHdG) among Pb-exposed than the unexposed. However, studies included in the review exhibited high levels of heterogeneity among the studies. Chronic Pb exposure is associated with DNA damage. However, high-quality, multicentred studies are required to strengthen present observations and further understand the Pb's role in inducing DNA damage. CRD42022286810.
Topics: 8-Hydroxy-2'-Deoxyguanosine; Biomarkers; Chromosome Aberrations; Comet Assay; DNA; DNA Damage; Humans; Lead; Micronucleus Tests; Occupational Exposure
PubMed: 35930012
DOI: 10.1007/s00204-022-03352-9 -
The Journal of Antimicrobial... Dec 2014The efficacy of abacavir/lamivudine has been reported to be inferior to tenofovir/emtricitabine. Several randomized clinical trials (RCTs) investigated the effectiveness... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVES
The efficacy of abacavir/lamivudine has been reported to be inferior to tenofovir/emtricitabine. Several randomized clinical trials (RCTs) investigated the effectiveness and safety of abacavir/lamivudine and tenofovir/emtricitabine combined antiretroviral treatment (cART) and we have reviewed the available evidence.
DESIGN
Systematic review and meta-analysis of RCTs using standard Cochrane Collaboration methodologies.
METHODS
We calculated risk ratios (RRs) with 95% CIs. The primary outcome was the rate of patients with viral load (VL) below the pre-defined cut-off at 48 weeks and/or at 96 weeks. Where available, results were analysed according to VL screening levels (<100,000 or >100,000 copies/mL) with conventional meta-analytical pooling by subgroups and meta-regression.
RESULTS
Meta-analytical pooling of RCTs with a direct comparison of abacavir/lamivudine and tenofovir/emtricitabine according to baseline VL at 48 weeks (six trials, 4118 patients) showed that the proportions of subjects with VL <50 copies/mL were similar in the overall comparison (RR 0.98; 95% CI 0.94-1.03), in the low baseline VL strata (RR 1.01; 95% CI 0.99-1.03) and in the high baseline VL strata (RR 0.96; 95% CI 0.90-1.03). Meta-regression analysis at 48 weeks confirms the results of subgroup analysis. Similar virological results were found at 96 weeks (four trials, 2003 patients). Differences in the occurrence of adverse events requiring discontinuation of treatment favoured tenofovir recipients (RR 1.26; 95% CI 0.99-1.61), but this difference, mostly related to suspected abacavir hypersensitivity reaction, was not statistically significant.
CONCLUSIONS
Our cumulative, cross-sectional data suggest a similar virological efficacy of abacavir/lamivudine and tenofovir/emtricitabine regardless of the baseline VL.
Topics: Adenine; Anti-HIV Agents; Deoxycytidine; Dideoxynucleosides; Emtricitabine; HIV Infections; Humans; Lamivudine; Organophosphonates; Randomized Controlled Trials as Topic; Tenofovir; Treatment Outcome
PubMed: 25074854
DOI: 10.1093/jac/dku279 -
Journal of the International AIDS... Feb 2023Tenofovir alafenamide (TAF) is approved for paediatric use in fixed-dose combination tablets, but efficacy and safety data in children are limited. We conducted a... (Review)
Review
INTRODUCTION
Tenofovir alafenamide (TAF) is approved for paediatric use in fixed-dose combination tablets, but efficacy and safety data in children are limited. We conducted a systematic review on the efficacy/effectiveness and safety of TAF in infants, children and adolescents living with HIV.
METHODS
We searched MEDLINE, Embase, the Cochrane Library, clinical trial registries, reference lists and relevant conferences to identify literature published January 2009-March 2021. We included clinical trials and observational studies assessing the efficacy/effectiveness or safety of TAF through ≥6 months of treatment in participants aged 0-19 years.
RESULTS AND DISCUSSION
Overall 3626 abstracts and 371 full papers were screened. Four single-arm, innovator-funded trials (341 participants) and a pooled analysis of those trials were identified. All four trials included treatment-experienced and virally suppressed children or adolescents. One trial also included treatment-naïve adolescents with baseline viral load >1000 copies/ml. The risk of bias was rated as low in one study and unclear in the other three owing to missing data on study design (all conference presentations). At 48 weeks, 92% (46/50) of treatment-naïve participants were virally suppressed (one trial). Among treatment-experienced participants with viral load at 48 weeks, 214 of 224 participants were virally suppressed. Across the studies, one grade 3/4 adverse event was considered drug-related (intermediate uveitis). There were three discontinuations for adverse events (grade 2 anxiety and insomnia, grade 1 iridocyclitis [drug-related] and grade 1 pulmonary tuberculosis [unrelated to treatment]). One accidental death occurred across the four studies. In the pooled analysis of 223 participants, the median change in bone mineral density z-score (height- and age-adjusted) from baseline to 48 weeks was -0.12 (interquartile range [IQR] -0.46, 0.17) to 0.05 (IQR not reported) for spine, and -0.09 (IQR -0.33, 0.07) to 0.09 (IQR not reported) for total body less head. Weight-for-age z-scores increased by 0.25 from baseline to 48 weeks.
CONCLUSIONS
Four single-arm trials were identified in this systematic review, with initial evidence suggesting good viral suppression and no obvious safety concerns in children and adolescents on TAF-containing regimens over 24-48 weeks. However, further comparative and longer-term safety data are needed in children and adolescents, including on weight and metabolic changes.
Topics: Infant; Humans; Child; Adolescent; Tenofovir; HIV Infections; Anti-HIV Agents; HIV-1; Adenine; Emtricitabine
PubMed: 36823283
DOI: 10.1002/jia2.26037 -
Current Atherosclerosis Reports Nov 2014Oxidative stress due to an excess of reactive oxygen species (ROS) may play a role in the development and progression of cardiovascular disease (CVD).... (Review)
Review
Oxidative stress due to an excess of reactive oxygen species (ROS) may play a role in the development and progression of cardiovascular disease (CVD). 8-hydroxy-2'-deoxyguanosine (8-OHdG) is a marker of oxidative DNA damage caused by ROS. This review aimed to assess the association between 8-OHdG and CVD by reviewing the literature. Studies in human subjects using either plasma or urine to determine 8-OHdG concentrations were surveyed. Eighteen relevant studies were found, of which 13 were case-control studies and five had a prospective design. Without exception, the case-control studies showed significant positive associations between 8-OHdG and CVD. In agreement, two prospective studies showed a significant association of 8-OHdG and heart failure. Furthermore, two prospective studies found a significant association between 8-OHdG and stroke, and finally, one prospective study showed a borderline significant (p = 0.08) association between coronary artery disease (CAD) patients developing a cardiac event and 8-OHdG concentrations. In conclusion, high levels of 8-OHdG in blood and urine are associated with atherosclerosis and heart failure, but further large prospective studies are needed to investigate 8-OHdG as a predictor for cardiovascular diseases.
Topics: 8-Hydroxy-2'-Deoxyguanosine; Cardiovascular Diseases; Clinical Trials as Topic; DNA Damage; Deoxyguanosine; Humans; Oxidative Stress; Reactive Oxygen Species
PubMed: 25252787
DOI: 10.1007/s11883-014-0452-y -
Multiple Sclerosis and Related Disorders Mar 2023The optimal treatment strategy of multiple sclerosis (MS) is a matter of debate. The classical approach is the escalating (ESC) strategy, which consists of starting with... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
The optimal treatment strategy of multiple sclerosis (MS) is a matter of debate. The classical approach is the escalating (ESC) strategy, which consists of starting with low- to moderate-efficacy disease-modifying drugs (DMDs) and upscale to high-efficacy DMDs when noting some evidence of active disease. Another approach, the early intensive (EIT) strategy, is starting with high-efficiency DMDs as first-line therapy. Our goal was to compare effectiveness, safety, and cost of ESC and EIT strategies.
METHODS
We searched MEDLINE, EMBASE and SCOPUS until September 2022, for studies comparing EIT and ESC strategies in adult participants with relapsing-remitting MS and a minimum follow-up of 5 years. We examined the Expanded Disability Severity Scale (EDSS), the proportion of severe adverse events, and cost in a 5-year period. Random-effects meta-analysis summarized the efficacy and safety and an EDSS-based Markov model estimated the cost.
RESULTS
Seven studies with 3,467 participants showed a 30% reduction in EDSS worsening in 5 years (RR 0.7; [0.59-0.83]; p < 0.001) in the EIT group vs in the ESC group. Two studies with 1,118 participants suggested a similar safety profile for these strategies (RR 1.92; [0.38-9.72]; p = 0.4324). EIT with natalizumab in extended interval dosing, rituximab, alemtuzumab, and cladribine demonstrated cost-effectiveness in our model.
DISCUSSION
EIT presents higher efficacy in preventing disability progression, a similar safety profile, and can be cost-effective within a 5-year timeline.
Topics: Adult; Humans; Multiple Sclerosis; Immunosuppressive Agents; Multiple Sclerosis, Relapsing-Remitting; Natalizumab; Cladribine
PubMed: 36848839
DOI: 10.1016/j.msard.2023.104581 -
Nutrition, Metabolism, and... Mar 2017The generation of reactive oxygen species (ROS) plays an important role in the etiology of several pathological conditions. High levels of 8-hydroxy-2-deoxyguanosine... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND AND AIMS
The generation of reactive oxygen species (ROS) plays an important role in the etiology of several pathological conditions. High levels of 8-hydroxy-2-deoxyguanosine (8-OHdG), a biomarker of oxidative damage of DNA, have been found in patients with heart failure (HF). We performed a meta-analysis of the literature to investigate the association between 8-OHdG levels and HF.
METHODS AND RESULTS
A systematic search was performed in the PubMed, Web of Science, Scopus, EMBASE databases and studies evaluating 8-OHdG levels in HF patients and controls were included. Differences between cases and controls were expressed as standard mean difference (SMD) or mean difference (MD) with pertinent 95% confidence intervals (95%CI). Impact of clinical and demographic features on effect size was assessed by meta-regression. Six studies (446 HF patients and 140 controls) were included in the analysis. We found that HF patients showed higher 8-OHdG levels than controls (SMD:0.89, 95%CI: 0.68, 1.10). The difference was confirmed both in studies in which 8-OHdG levels were assessed in urine (MD:6.28 ng/mg creatinine, 95%CI: 4.01, 8.56) and in blood samples (MD:0.36 ng/ml, 95%CI: 0.04, 0.69). Interestingly, 8-OHdG levels progressively increased for increasing New York Heart Association (NYHA) class. Meta-regression models showed that none of clinical and demographic variables impacted on the difference in 8-OHdG levels among HF patients and controls.
CONCLUSIONS
8-OHdG levels are higher in HF patients HF than in controls, with a progressive increase for increasing NYHA class. However, larger prospective studies are needed to test 8-OHdG as a biomarker of HF severity and progression.
Topics: 8-Hydroxy-2'-Deoxyguanosine; Biomarkers; Chi-Square Distribution; DNA Damage; Deoxyguanosine; Heart Failure; Humans; Myocardium; Oxidative Stress; Predictive Value of Tests; Prognosis; Risk Factors; Severity of Illness Index; Stroke Volume; Up-Regulation; Ventricular Function, Left
PubMed: 28065503
DOI: 10.1016/j.numecd.2016.10.009 -
Clinical Pharmacology and Therapeutics Feb 2018The purpose of this guideline is to provide information for the interpretation of clinical dihydropyrimidine dehydrogenase (DPYD) genotype tests so that the results can...
The purpose of this guideline is to provide information for the interpretation of clinical dihydropyrimidine dehydrogenase (DPYD) genotype tests so that the results can be used to guide dosing of fluoropyrimidines (5-fluorouracil and capecitabine). Detailed guidelines for the use of fluoropyrimidines, their clinical pharmacology, as well as analyses of cost-effectiveness are beyond the scope of this document. The Clinical Pharmacogenetics Implementation Consortium (CPIC ) guidelines consider the situation of patients for which genotype data are already available (updates available at https://cpicpgx.org/guidelines/guideline-for-fluoropyrimidines-and-dpyd/).
Topics: Antimetabolites, Antineoplastic; Capecitabine; Clinical Decision-Making; Dihydrouracil Dehydrogenase (NADP); Drug Dosage Calculations; Fluorouracil; Genotype; Humans; Patient Selection; Pharmacogenetics; Pharmacogenomic Testing; Pharmacogenomic Variants; Phenotype; Precision Medicine; Predictive Value of Tests
PubMed: 29152729
DOI: 10.1002/cpt.911 -
HIV Clinical Trials Nov 2016Tenofovir disoproxil fumarate (TDF) is a component of many combinations of antiretroviral treatment (ART) regimens. Although potent and generally well tolerated, TDF may... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Tenofovir disoproxil fumarate (TDF) is a component of many combinations of antiretroviral treatment (ART) regimens. Although potent and generally well tolerated, TDF may cause renal and bone toxicity. The magnitude of off-target side effects is proposed to be related to tenofovir plasma concentrations, which are affected by food and drug-drug interactions with concomitant antiretrovirals.
OBJECTIVE
To perform a systematic literature review and qualitatively report on renal and bone safety outcomes associated with efavirenz (EFV), emtricitabine (FTC), and TDF (EFV+FTC+TDF) ART.
METHODS
Embase and PubMed databases were searched for randomized clinical trials and observational cohort studies reporting on HIV treatment with EFV+FTC+TDF. Relevant articles were hand-searched for renal (Grade 3-4 serum creatinine/estimated glomerular filtration rate elevations, renal adverse events [AEs], discontinuation due to renal AEs, and urinary biomarkers) and bone outcomes (bone mineral density [BMD] reductions, bone turnover markers, and fracture), and results compiled qualitatively.
RESULTS
Of 337 retrieved articles, 29 reporting renal and 11 reporting bone outcomes met the review criteria. EFV+FTC+TDF was associated with a low frequency of renal AEs and treatment discontinuations due to renal AEs. Renal AEs were more frequent when TDF was taken with protease inhibitor (PI)- or cobicistat-containing ART. EFV+FTC+TDF was associated with reduced BMD and increased bone turnover markers, but BMD reductions were less than with PI-containing ART. No treatment-related bone fractures were identified.
CONCLUSIONS
EFV+FTC+TDF appeared to have a more favorable renal safety profile than TDF administered with a PI or cobicistat. BMD decreased with EFV+FTC+TDF, but no treatment-related fractures were identified.
Topics: Alkynes; Antiretroviral Therapy, Highly Active; Benzoxazines; Bone Diseases; Clinical Trials as Topic; Cyclopropanes; Drug Interactions; Emtricitabine; HIV Infections; Humans; Incidence; Kidney Diseases; Tenofovir; Treatment Outcome
PubMed: 27809711
DOI: 10.1080/15284336.2016.1243363