Efficacy and safety of epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) monotherapy for advanced EGFR-mutated non-small cell lung cancer: systematic review and meta-analysis.

OBJECTIVE: It is controversial whether there is efficacy or safety benefit of epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) in advanced EGFR-mutated non-small cell lung cancer (NSCLC) compared to standard chemotherapy. We aim to assess the efficacy and safety of EGFR-TKIs compared to other chemotherapeutics in EGFR-mutated NSCLC. MATERIALS AND METHODS: Up to April 27th, 2020, PubMed, Embase, Medline, Scopus, Cochrane library, and ClinicalTrials.gov were searched for articles or trials meeting the inclusion criteria. After filtering, 230 eligible studies were initially identified. Data extraction followed PRISMA and included outcomes were progression-free survival (PFS), overall survival (OS), and severe adverse events (SAEs). Direct and indirect meta-analyses were generated in the context of log-linear mixed-effects models, with fixed effects for each relative comparison and random effects for each study. RESULTS: The results showed that EGFR-TKI therapy had improved PFS with a hazard ratio (HR) of 0.40 (95% CI: 0.36-0.44, p<0.001) compared to standard chemotherapy. Nevertheless, the EGFR-TKIs showed no benefit on OS (HR: 0.96, 95% CI: 0.83-1.10, p=0.556). In the analysis of adverse events, EGFR-TKIs had fewer SAEs than standard chemotherapy (HR: 0.29, 95% CI: 0.26-0.33, p<0.001). CONCLUSIONS: Our systemic review indicates that EGFR-TKI therapy has improved PFS, and reduced SAEs compared to standard chemotherapy in advanced EGFR-mutated NSCLC.

Common European Mitochondrial Haplogroups in the Risk for Radiation-induced Subcutaneous Fibrosis in Breast Cancer Patients.

AIMS: The contribution of mitochondrial DNA (mtDNA) variations to clinical radiosensitivity is largely unknown. In the present study, we evaluated the association between mtDNA haplogroups and the risk of radiation-induced subcutaneous fibrosis after postoperative radiotherapy in breast cancer patients. MATERIALS AND METHODS: Subcutaneous fibrosis was scored according to the Late Effects of Normal Tissue-Subjective Objective Management Analytical (LENT-SOMA) scale in 286 Italian breast cancer patients who received radiotherapy after breast-conserving surgery. Eight mtDNA single nucleotide polymorphisms that define the nine major haplogroups in the European population were determined by polymerase chain reaction restriction fragment length polymorphism analysis on genomic DNA extracted from peripheral blood. RESULTS: In a Kaplan-Meier analysis evaluated by the Log-rank test, carriers of haplogroup H were found to be at lower risk of grade ≥2 subcutaneous fibrosis (P = 0.018) compared with all other haplotypes combined. In the multivariate Cox regression analysis adjusted for clinical factors (body mass index, breast diameter, adjuvant treatment, dose per fraction, radiation type and acute skin toxicity), haplogroup H emerged as a protective factor for moderate to severe radiation-induced fibrosis at a nominal significance level (hazard ratio: 0.50, 95% confidence interval 0.27-0.92, P = 0.027), which did not survive correction for multiple testing. CONCLUSIONS: Our results suggest a protective effect of the mitochondrial haplogroup H in the development of radiation-induced fibrosis in breast cancer patients. However, the loss of statistical significance after correction for multiple comparisons and the lack of an independent validation cohort make our findings preliminary, requiring further confirmation in large-scale prospective studies.

BDNF Val66Met and clinical response to antipsychotic drugs: A systematic review and meta-analysis.

BACKGROUND: The polymorphic brain-derived neurotrophic factor (BDNF) gene has been postulated to be involved in inter-individual variability response to antipsychotic drugs. PURPOSE: To perform a qualitative and quantitative synthesis of studies evaluating the influence of BDNF genetic variation on clinical response to antipsychotics. METHODS: The review protocol was published in the PROSPERO database (Reg. n(o) CRD42015024614). A comprehensive search was performed through PubMed, Web of Knowledge and Cochrane databases up to July 2015. The methodological quality of identified studies was assessed using the MINORS criteria. Publication bias was estimated and potential sources of heterogeneity were investigated via meta-regression, subgroup and sensitivity analyses. RESULTS: Nine studies including a total of 2461 antipsychotic-treated patients fulfilled inclusion criteria for meta-analysis of BDNF Val66Met. Using the random-effects model, the pooled results showed no significant association with antipsychotic response for the dominant (Met carriers vs Val/Val, OR: 0.93, 95% CI: 0.72-1.19, P=0.55), codominant (Met/Met vs Val/Val, OR: 0.82, 95% CI: 0.59-1.15, P=0.25), recessive (Met/Met vs Val carriers, OR: 0.81, 95% CI 0.60-1.10, P=0.18) or the allelic contrast (Met vs Val, OR: 0.92, 95% CI 0.76-1.10, P=0.34). Visual inspection of funnel plots and further evaluation with Egger's test did not suggest evidence of publication bias. Despite lack of significant heterogeneity in most comparisons, no evidence of association also emerged in the subgroup and sensitivity analyses conducted. CONCLUSION: The present meta-analysis excludes a clinically relevant effect of BDNF Val66Met on antipsychotic drug response per se. Nevertheless, further investigation is still needed to clarify in well-designed, large sample-based studies, the impact of BDNF haplotypes containing the Val66Met polymorphism.

Functional polymorphisms in COMT and SLC6A4 genes influence the prognosis of patients with medication overuse headache after withdrawal therapy.

BACKGROUND AND PURPOSE: It is currently unknown if common genetic variants influence the prognosis of patients with medication overuse headache (MOH). Here the role of two common single nucleotide polymorphisms in the COMT gene (rs4680 and rs6269), as well as the STin2 variable number tandem repeat (VNTR) polymorphism in the SLC6A4 gene, were evaluated as predictors for long-term outcomes of MOH patients after withdrawal therapy. METHODS: Genotyping was conducted by polymerase chain reaction (PCR), PCR restriction fragment length polymorphism analysis or real-time PCR allelic discrimination assay on genomic DNA extracted from peripheral blood. Gene variants association was evaluated by logistic regression analysis adjusted for clinical confounding factors, and the threshold of statistical significance for multiple testing was set at P < 0.012. RESULTS: Sixty-five MOH patients with unsuccessful detoxification and 83 MOH patients with effective drug withdrawal therapy were available for the analysis. rs4680G allele carriers or the COMT rs6269G-rs4680G haplotype were found to be associated with a lower risk of relapse within the first year after successful detoxification therapy, in comparison with homozygous rs4680A allele carriers [odds ratio (OR) 0.17, 95% confidence interval (CI) 0.05-0.61, P = 0.007] or with the COMT rs6269A-rs4680A haplotype (OR 0.19, 95% CI 0.06-0.54, P = 0.003), respectively. In addition, carriers of the STin2 VNTR short allele were found at higher odds for the composite poor outcome including unsuccessful withdrawal therapy and relapse within 12 months of follow-up after successful detoxification (OR 2.81, 95%CI 1.26-6.25, P = 0.009). CONCLUSIONS: Our results indicate that genotyping for COMT rs4680 and SLC6A4 STin2 VNTR could be useful for the identification of MOH patients at higher risk of poor prognosis after drug withdrawal.