Risk of antiangiogenic adverse events in metastatic colorectal cancer patients receiving aflibercept in combination with chemotherapy: A meta-analysis.

BACKGROUND: Aflibercept has been approved for the treatment of metastatic colorectal cancer for more than a decade, but its antiangiogenesis adverse effect profile during treatment remains unclear. This study is conducted to systematically review the risk of antiangiogenic adverse events in patients with metastatic colorectal cancer receiving aflibercept plus chemotherapy. METHODS: We searched databases, including PubMed, Embase and the Cochrane Library up to September 9, 2021. Relevant randomized controlled trials (RCTs) and single-arm studies were included in the review. Statistical analyses were performed using R to calculate the summary incidence rate of antiangiogenic-related adverse events, odds ratios and 95% CIs. Heterogeneity among the included studies was assessed by subgroup analysis. Publication bias analysis and sensitivity analysis were performed to confirm the reliability of the results. RESULTS: A total of 2889 patients from 10 studies met the inclusion criteria. The quality of the included studies was evaluated as qualified for further quantitative synthesis. In part of single-arm studies, the occurrence rates were 44.2% (95%CI, 39.7-48.7%) for hypertension, 31.3% (95% CI, 19.3-43.3%) for proteinuria, 27.3% (95%CI, 21.2-33.4%) for epistaxis, 22.5% (95%CI, 7.8-37.3%) for hemorrhage events, 8.0% (95%CI, 2.0-14 .0%) for venous thromboembolic event in all grades and 22.6% (95%CI, 19.1-26.2%) for grade III/IV hypertension, 7.4% (95%CI, 6.2-8.5%) for grade III/IV proteinuria. In part of RCT, compared to its counterpart, aflibercept containing arm was associated with the increased incidence rate in hypertension (OR:6.30, 95%CI: 3.49-11.36), proteinuria (OR:4.12, 95%CI: 1.25-13.61), epistaxis (OR:3.71, 95%CI: 2.84-4.85), III/IV hypertension (OR:7.20, 95%CI: 5.23-9.92), III/IV proteinuria (OR:5.13, 95%CI: 3.13-8.41). The funnel plot, Begg test and Egger test were carried out on the primary endpoints, III/IV hypertension rate and III/IV proteinuria rate, the result of which detected no obvious publication bias. No significant difference was observed in subgroup analysis in the primary endpoint between the subgroups stratified by treatment line (firstline or non-firstline), chemotherapy regime (FOLFIRI or others) and study design (RCTs or single-arm trials). CONCLUSION: The available evidence suggests that using aflibercept is associated with an increased risk of antiangiogenic adverse events compared with controls. Further studies are needed to investigate this association. In the appropriate clinical scenario, the use of aflibercept in its approved indications remains justified. However, the results of this study should be interpreted with caution, as some of the evidence comes from single-arm clinical trials.

Effect of Physiotherapy Interventions on Motor Symptoms in People With Parkinson's Disease: A Systematic Review and Meta-Analysis.

OBJECTIVE: To evaluate the effectiveness of different types of physiotherapy interventions in people with Parkinson's disease (PD). DESIGN: Systematic review and meta-analysis of randomized controlled trials (RCTs). METHODS: Five databases (PubMed, Embase, Cochrane Library, CINAHL and Web of Science Core Collection) were searched for relevant RCTs published from database inception to July 14, 2022. Reviewers independently screened the literature, extracted data, and assessed the literature quality according to the Cochrane Collaboration Risk of Bias Tool and PEDro Scale. This meta-analysis was conducted using RevMan 5.4.1 and reported in compliance with the PRISMA statement. RESULTS: Forty-two RCTs with 2,530 participants were included. Across all types of physiotherapy, strength training, mind-body exercise, aerobic exercise, and non-invasive brain stimulation (NiBS) were effective in improving motor symptoms as measured by the (Movement Disorders Society-) Unified PD Scale, whereas balance and gait training (BGT) and acupuncture were not. The pooled results showed that the change in mind-body exercise (MD = -5.36, 95% CI [-7.97 to -2.74], p < .01, I2 = 68%) and NiBS (MD = -4.59, 95% CI [-8.59 to -0.59], p = .02, I2 = 78%) reached clinical threshold, indicating clinically meaningful improvements. Considering the effectiveness of the interventions on motor symptoms, balance, gait and functional mobility, mind-body exercise was recommended the most. CONCLUSIONS: Exercise appears to be a better form of physiotherapy than NiBS and acupuncture for improving motor function. Mind-body exercise showed beneficial effects on motor symptoms, balance, gait and functional mobility in people with PD, and is worthy of being promoted.

DNA damage response-related immune activation signature predicts the response to immune checkpoint inhibitors: from gastrointestinal cancer analysis to pan-cancer validation.

OBJECTIVE: DNA damage response (DDR) deficiency has emerged as a prominent determinant of tumor immunogenicity. This study aimed to construct a DDR-related immune activation (DRIA) signature and evaluate the predictive accuracy of the DRIA signature for response to immune checkpoint inhibitor (ICI) therapy in gastrointestinal (GI) cancer. METHODS: A DRIA signature was established based on two previously reported DNA damage immune response assays. Clinical and gene expression data from two published GI cancer cohorts were used to assess and validate the association between the DRIA score and response to ICI therapy. The predictive accuracy of the DRIA score was validated based on one ICI-treated melanoma and three pan-cancer published cohorts. RESULTS: The DRIA signature includes three genes (CXCL10, IDO1, and IFI44L). In the discovery cancer cohort, DRIA-high patients with gastric cancer achieved a higher response rate to ICI therapy than DRIA-low patients (81.8% vs. 8.8%; P < 0.001), and the predictive accuracy of the DRIA score [area under the receiver operating characteristic curve (AUC) = 0.845] was superior to the predictive accuracy of PD-L1 expression, tumor mutational burden, microsatellite instability, and Epstein-Barr virus status. The validation cohort demonstrated that the DRIA score identified responders with microsatellite-stable colorectal and pancreatic adenocarcinoma who received dual PD-1 and CTLA-4 blockade with radiation therapy. Furthermore, the predictive performance of the DRIA score was shown to be robust through an extended validation in melanoma, urothelial cancer, and pan-cancer. CONCLUSIONS: The DRIA signature has superior and robust predictive accuracy for the efficacy of ICI therapy in GI cancer and pan-cancer, indicating that the DRIA signature may serve as a powerful biomarker for guiding ICI therapy decisions.

Efficacy of psychotherapy in subthreshold depression patients: A protocol for an overview of systematic reviews and meta-analyses.

Background: Subthreshold depression is a risk factor for major depression. Psychotherapy is a kind of intervention for subthreshold depression. There have been many systematic reviews synthesized the evidence for its effectiveness toward subthreshold depression. However, there is currently no overview of these systematic reviews. Objective: To undertake an overview of meta-analyses and systematic reviews to identify the efficacy of psychotherapy in subthreshold depression patients. Methods: We will search several databases such as PubMed, Embase, the Cochrane Library, Web of Science, PsycINFO, CNKI, WanFang and VIP database, for systematic reviews and meta-analyses on psychotherapy in subthreshold depression patients. The search timeline will be from inception up to August 2022. Two researchers will screen related studies back-to-back. We will include studies that evaluate the efficacy of psychotherapy in subthreshold depression patients. We will evaluate the methodological quality, the reporting quality and the quality of evidence for outcomes by AMSTAR-2, the PRISMA 2020 checklist and the GRADE grading system. We will present the results of the overview in alignment with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. The anticipated start and completion dates for this overview are 1 August 2022 and 30 December 2022, respectively. Results: From this study, we will evaluate the methodological quality and the level of evidence of the included systematic reviews and meta-analyses, and evaluate the efficacy of psychotherapy in patients with subthreshold depression. Implications: We will ascertain the efficacy of psychotherapy in subthreshold depression patients, to provide evidence to guide the treatment of subthreshold depression in the future. Registration number: Our research protocol has been registered with PROSPERO. The registration number of the protocol is CRD42021278871.