Chen Mao

Comparative Effectiveness and Safety of Oral Phosphodiesterase Type 5 Inhibitors for Erectile Dysfunction: A Systematic Review and Network Meta-analysis

CONTEXT Phosphodiesterase type 5 inhibitors (PDE5-Is) are currently the first-line therapy for erectile dysfunction (ED), but available studies investigating the comparative effects of different PDE5-Is are limited. OBJECTIVE To compare the efficacy and safety of different classes of oral PDE5-Is for ED. EVIDENCE ACQUISITION A systematic search was performed in PubMed, Cochrane Library, and Embase to identify randomized controlled trials that compared different PDE5-Is or PDE5-Is with a placebo for ED. The methodological quality of included studies was appraised with the Cochrane Collaboration bias appraisal tool, and the quality of evidence was evaluated using the Grading of Recommendations, Assessment, Development, and Evaluation system. EVIDENCE SYNTHESIS A total of 118 trials (31 195 individuals) were included. There was no major difference in the results between the traditional meta-analysis and the network meta-analysis. Network meta-analysis demonstrated that PDE5-Is were superior to placebo to improve erectile function. Compared with tadalafil (relative risk [RR]: 0.61; 95% confidence interval [CI], 0.33-0.90) and vardenafil (RR: 0.63; 95% CI, 0.35-0.92), avanafil was less effective on Global Assessment Questionnaire question 1. Tadalafil was more effective than vardenafil (mean difference [MD]: 1.49; 95% CI, 0.50-2.50) and udenafil (MD: -1.84; 95% CI, -3.31 to -0.33) as measured by the erectile function domain of the International Index of Erectile Function. For all efficacy outcomes, the absolute effects and the rank tests indicated that tadalafil and vardenafil were the most effective agents. After adjusting for dosage, the conclusion remained the same. Safety analysis showed there was no major difference among different agents. CONCLUSIONS In recommended doses, oral PDE5-Is are more effective than placebo for ED, and tadalafil seems to be the most effective agent, followed by vardenafil. PDE5-Is are generally safe and well tolerated, and there is no major difference on the safety profile.

KRAS p.G13D mutation and codon 12 mutations are not created equal in predicting clinical outcomes of cetuximab in metastatic colorectal cancer

The authors conducted a systematic review and meta‐analysis to examine whether patients who had metastatic colorectal cancer (mCRC) with the v‐Ki‐ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) p.G13D mutation (an amino acid substitution at position 13 in KRAS from a glycine to an aspartic acid) and received cetuximab treatment had better clinical outcomes than patients who had mCRC tumors with KRAS codon 12 mutations.

Promising biomarkers for predicting the outcomes of patients with KRAS wild-type metastatic colorectal cancer treated with anti-epidermal growth factor receptor monoclonal antibodies: A systematic review with meta-analysis

KRAS mutations have been established as a major predictive biomarker for resistance to the treatment of metastatic colorectal cancer (mCRC) with anti‐epidermal growth factor receptor monoclonal antibodies (anti‐EGFR MoAbs). However, many patients with KRAS wild‐type tumors still do not respond to the treatment. We conducted a systematic review with meta‐analysis to assess whether BRAF mutations, PIK3CA mutations and PTEN loss can predict the outcomes of patients with KRAS wild‐type mCRC treated with anti‐EGFR MoAbs. Studies that explored the association of one or more of the three biomarkers with progression‐free survival (PFS), overall survival (OS) and/or objective response rate (ORR) were identified through August 2012. Summary hazard ratios (HRs) and rate differences (RDs) and corresponding 95% confidence intervals (CIs) were calculated by using the random‐effects model. BRAF mutations, PIK3CA exon 20 mutations and PTEN loss were all associated with shorter PFS (HR = 2.59, 95% CI 1.67–4.03; HR = 2.52, 95% CI 1.33–4.78 and HR = 1.75, 95% CI 1.19–2.56, respectively), shorter OS (HR = 2.74, 95% CI 1.79–4.19; HR = 3.29, 95% CI 1.60–6.75 and HR = 1.85, 95% CI 1.30–2.64, respectively) and lower ORR (RD = −36%, 95% CI −44 to −28%; RD = −38%, 95% CI −51 to −24% and RD = −41%, 95% CI −68 to −14%, respectively). PIK3CA exon 9 mutations were associated with none of the outcomes. Studies with relevant data consistently demonstrated a stronger predictive power of combined multiple biomarkers as compared to one alteration alone. These results suggest that BRAF mutations, PIK3CA exon 20 mutations and PTEN loss are predictive of better outcomes in KRAS wild‐type mCRC treated with anti‐EGFR MoAbs. However, the quality of included studies varied, and some of the meta‐analyses were limited by significant between‐study heterogeneity. In the future, well‐designed large randomized controlled trials conducted in KRAS wild‐type mCRC patients with subgroup analysis according to BRAF, PIK3CA exon 20 and PTEN status are essential to fully assess the clinical relevance of these biomarkers.

Concordant analysis of KRAS, BRAF, PIK3CA mutations, and PTEN expression between primary colorectal cancer and matched metastases

Current data on the concordance of KRAS, BRAF, PIK3CA mutation status or PTEN expression status between primary tumors and metastases in colorectal cancer (CRC) are conflicting. We conducted a systematic review and meta-analysis to examine concordance and discordance of the status of these four biomarkers between primary tumors and corresponding metastases in CRC patients. The biomarker status in primary tumors was used as the reference standard. Concordance data for KRAS, BRAF, PIK3CA and PTEN were provided by 43, 16, 9 and 7 studies, respectively. The pooled concordance rate was 92.0% (95% CI: 89.7%–93.9%) for KRAS, 96.8% (95% CI: 94.8%–98.0%) for BRAF, 93.9% (95% CI: 89.7%–96.5%) for PIK3CA and 71.7% (95% CI: 57.6%–82.5%) for PTEN. The pooled false positive and false negative rates for KRAS were 9.0% (95% CI: 6.5%–12.4%) and 11.3% (95% CI: 8.0%–15.8%), respectively. KRAS, BRAF and PIK3CA mutations are highly concordant between primary tumors and corresponding metastases in CRC, but PTEN loss is not. Nine percent of patients with wild-type KRAS in primary tumors who received anti-EGFR treatment had mutant KRAS in metastases, while 11.3% patients with mutant KRAS primary tumors had wild-type KRAS in the metastases. These 11.3% patients currently do not receive potentially beneficial anti-EGFR treatment.

Gemcitabine plus erlotinib for advanced pancreatic cancer: a systematic review with meta-analysis.

Background This study aims to comprehensively summarize the currently available evidences on the efficacy and safety of gemcitabine plus erlotinib for treating advanced pancreatic cancer. Methodology/Principal Findings PubMed, EMBASE, The Cochrane Library and abstracts of recent major conferences were systematically searched to identify relevant publications. Studies that were conducted in advanced pancreatic cancer patients treated with gemcitabine plus erlotinib (with or without comparison with gemcitabine alone) and reporting objective response rate, disease control rate, progression-free survival, time-to-progression, overall survival, 1-year survival rate and/or adverse events were included. Data on objective response rate, disease control rate, 1-year survival rate and adverse events rate, respectively, were combined mainly by using Meta-Analyst software with a random-effects model. Data on progression-free survival, time-to-progression and overall survival were summarized descriptively. Sixteen studies containing 1,308 advanced pancreatic cancer patients treated with gemcitabine plus erlotinib were included. The reported median progression-free survival (or time-to-progression), median overall survival, 1-year survival rates, objective response rates and disease control rates were 2–9.6 months, 5–12.5 months, 20%–51%, 0%–28.6% and 25.0%–83.3%, respectively. The weighted 1-year survival rate, objective response rate and disease control rate based on studies reporting robust results were 27.9%, 9.1% and 57.0%, respectively. According to the studies with relevant data, the incidences of total and severe adverse events were 96.3% and 62.9%, respectively. The most frequently reported adverse events were leucopenia, rash, diarrhea, vomitting, neutropenia, thrombocytopenia, anaemia, stomatitis, drug-induced liver injury, fatigue and fever. Compared with gemcitabine alone, the progression-free survival and overall survival with gemcitabine plus erlotinib were significantly longer, but there were also more deaths and interstitial lung disease-like syndrome related to this treatment. Conclusions/Significance Gemcitabine plus erlotinib represent a new option for the treatment of advanced pancreatic cancer, with mild but clinically meaningful additive efficacy compared with gemcitabine alone. Its safety profile is generally acceptable, although careful management is needed for some specific adverse events.

Ambient air pollution and years of life lost in Ningbo, China.

To evaluate the burden of air pollution on years of life lost (YLL) in addition to mortality, we conducted a time series analysis based on the data on air pollution, meteorological conditions and 163,704 non-accidental deaths of Ningbo, China, 2009–2013. The mean concentrations of particulate matter with aerodynamic diameter <10 μm, particulate matter with aerodynamic diameter <2.5 μm, sulfur dioxide and nitrogen dioxide were 84.0 μg/m3, 60.1 μg/m3, 25.1 μg/m3 and 41.7 μg/m3, respectively. An increase of 10-μg/m3 in particulate matter with aerodynamic diameter <10 μm, particulate matter with aerodynamic diameter <2.5 μm, sulfur dioxide and nitrogen dioxide was associated with 4.27 (95% confidence interval [CI] 1.17–7.38), 2.97 (95% CI −2.01–7.95), 29.98 (95% CI 19.21–40.76) and 16.58 (95% CI 8.19–24.97) YLL, respectively, and 0.53% (95% CI 0.29–0.76%), 0.57% (95% CI 0.20–0.95%), 2.89% (95% CI 2.04–3.76%), and 1.65% (95% CI 1.01–2.30%) increase of daily death counts, respectively. The impact of air pollution lasted for four days (lag 0–3), and were more significant in the elderly than in the young population for both outcomes. These findings clarify the burden of air pollution on YLL and highlight the importance and urgency of air pollution control in China.

EGFR gene copy number as a predictive biomarker for the treatment of metastatic colorectal cancer with anti-EGFR monoclonal antibodies: a meta-analysis.

BackgroundEpidermal growth factor receptor gene copy number (EGFR GCN) has been heavily investigated as a potential predictive biomarker for the treatment of metastatic colorectal cancer (mCRC) with anti-EGFR monoclonal antibodies (MAbs). The objective of this study was to systematically review current evidences on this issue.MethodsPubMed, EMBASE, The Cochrane Library, Chinese Biomedical Literature Database, Wanfang Data, and the conference abstracts of American Society of Clinical Oncology and European Society of Medical Oncology were comprehensively searched. Studies that reported the objective response rate (ORR), progression-free survival, and/or overall survival of mCRC patients treated with anti-EGFR MAbs, stratified by EGFR GCN status, were included. The effect measures for binary outcome (response) and time-to-event outcomes (progression-free survival and overall survival) were risk difference and hazard ratio, respectively. Statistical heterogeneity among the studies was assessed by the Cochran’s Q-test and the I2 statistic. If appropriate, a quantitative synthesis of data from different studies would be conducted with a random-effects model.ResultsNineteen eligible studies were identified. The criteria for increased EGFR GCN (GCN+) were highly inconsistent across different studies. The prevalence of GCN + ranged from 6.9% to 88.9%, and the difference in ORR between patients with GCN + and those with non-increased EGFR GCN (GCN-) varied from −28% to 84%. Because of the significant heterogeneity, no quantitative synthesis of data was performed. There was a general trend towards higher ORR in patients with GCN+. The difference in ORRs between patients with GCN + and those with GCN- was even greater in KRAS wild-type patients, while in KRAS mutated patients the difference often did not exist. Almost all patients with EGFR amplification responded to the treatment. However, the prevalence of EGFR amplification was generally low. Incomplete data on progression-free survival and overall survival seemingly supported the findings on ORR.ConclusionsAlthough increased EGFR GCN is generally associated with a better outcome of anti-EGFR MAbs treatment, especially among patients with wild-type KRAS, the clinical utility of this biomarker for selecting recipients of anti-EGFR MAbs would be severely limited by the heterogeneous scoring system and the poor reproducibility of EGFR GCN enumeration due to technical reasons.

The efficacy and safety of alpha-1 blockers for benign prostatic hyperplasia: an overview of 15 systematic reviews

Abstract Objective: A great number of clinical trials and systematic reviews have evaluated the efficacy and safety of α1 blockers for benign prostatic hyperplasia (BPH). We carried out an overview of reviews to provide an up-to-date summary of evidence regarding the efficacy and safety between different α1 blockers for BPH. Research design and methods: PubMed, EMBASE, the Cochrane Library, China National Knowledge Infrastructure, Chinese BioMedical Literature Database and VIP were searched for eligible studies. Direct evidence was analyzed narratively. We used a random-effects model within a Bayesian framework to calculate indirect estimates if no direct evidence existed. The GRADE approach was used in summarizing conclusions. Results: A total of 15 systematic reviews involving five α1 blockers met the inclusion criteria. Direct evidence demonstrated that α1 blockers were superior to placebo in reducing urinary symptom scores and improving peak urinary flow PUF. Doxazosin could significantly reduce urinary symptom scores compared with tamsulosin mean difference (MD −1.60, 95% CI −1.80 to −1.40) and alfuzosin (MD1.7, 95% CI 0.76–1.64). Indirect evidence suggested that the urinary symptom score and PUF at endpoint in men treated with naftopidil were similar to those treated with other α1 blockers. α1 Blockers generally lead to more adverse effects compared with placebo, and those caused by terazosin were more frequent than others. Conclusions: α1 Blockers are more effective than placebo for BPH, doxazosin and tamsulosin seem to be more effective than other α1 blockers. The adverse effects caused by α1 blockers are generally mild and well-tolerated.

Blood as a Substitute for Tumor Tissue in Detecting EGFR Mutations for Guiding EGFR TKIs Treatment of Nonsmall Cell Lung Cancer: A Systematic Review and Meta-Analysis.

AbstractTumor tissues are often absent or insufficient for testing epidermal growth factor receptor (EGFR) mutations to guide EGFR tyrosine kinase inhibitors (TKIs) treatment of patients with nonsmall cell lung cancer (NSCLC).We conducted this systematic review and meta-analysis to assess whether blood can be used as a substitute for tumor tissue in detecting EGFR mutations.MEDLINE, EMBASE, and the Cochrane Library were searched for studies that provided data to estimate the accuracy of blood testing against tissue testing in NSCLC patients and/or those directly compared the efficacy of EGFR TKIs in EGFR mutant and wild-type patients according to sources of specimens.Sensitivity, specificity, and concordance rate were used as measures of the accuracy. Risk ratio (RR) for objective response and hazard ratio (HR) for progression-free survival (PFS) and overall survival (OS) were used as measures for treatment efficacy. We combined the effects by using the fixed-effects model unless there was evidence of heterogeneity, in which case a random-effects mode was used.This systematic review included 25 studies with 2605 patients. The pooled overall sensitivity, specificity, and concordance rate were 0.61, 0.90, and 0.79, respectively. Serum showed lower sensitivity (0.56 vs 0.65) but higher specificity (0.95 vs 0.85) and higher concordance (0.86 vs 0.74) than plasma. EGFR mutations (exon 19 or 21) in blood were significantly associated with objective response (RR: 4.08; 95% confidence interval [CI] 2.48–6.70), PFS (HR: 0.72; 95% CI 0.64–0.80), and OS (HR: 0.71; 95% CI 0.50–0.99). Importantly, the association of the mutations with the 3 clinical outcomes for serum was similar to that for tumor tissue and higher than that for plasma.Blood, in particular serum, is a good substitute when tumor tissue is absent or insufficient for testing EGFR mutations to guide EGFR TKIs treatment in patients with NSCLC. EGFR mutation positivity in blood could be used to recommend EGFR TKIs treatment, but the absence of blood positivity should not necessarily be construed with confirmed negativity.

Systematic review and meta-analysis of application of fibrin sealant after liver resection

Abstract Background: Fibrin sealant (FS) has been increasingly used on the raw surface after liver resection but its clinical value has not been established to date. The aim of this study was to evaluate the efficacy and safety of the employment of FS after liver resection. Methods: PubMed, Cochrane Library, Embase, CNKI, CBM and VIP were searched for randomized trials comparing the effect of FS with no FS or any other intervention for patients undergoing liver resection. Primary outcomes included time to hemostasis, hemostatic success, amount of drainage and drainage duration. Results: Eleven randomized controlled trials were included. Meta-analysis suggested that the amount of drainage (standard mean difference −0.30; 95% confidence interval [CI] −0.82 to 0.23) and drainage duration (mean difference [MD] −0.46, 95% CI −0.61 to −1.53) were similar between FS group and no FS group. Compared with topical hemostatic agents, FS could significantly reduce time to hemostasis (MD −208.46, 95% CI −228.22 to −188.70) and increase hemostasis success rate (relative risk 1.35, 95% CI 1.17 to 1.57). Two trials compared FS with argon beam coagulation (ABC), which both suggested that FS could significantly decrease the time to hemostasis. Conclusions: This study demonstrated a modest benefit of FS over no FS, topical hemostatic agents and ABC in controlling intraoperative bleeding from the raw liver surface after liver resection. But there is no evidence that FS is beneficial to patients in reducing amount of drainage and drainage duration.