Immune checkpoint inhibitors for patients with microsatellite instability-high colorectal cancer: protocol of a pooled analysis of clinical trials

IntroductionColorectal cancer (CRC) is the third most common cause of cancer and the second leading cause of cancer-related deaths worldwide. Microsatellite instability-high (MSI-H) is a distinct molecular subtype of CRC that occurs in approximately 15% of all cases. Recently, immune checkpoint inhibitors (ICIs) have emerged as a promising therapeutic approach for patients with MSI-H colorectal cancer, exhibiting higher response rates than standard chemotherapies. To assess the effectiveness and safety of ICIs for the treatment of patients with MSI-H CRC, we propose a comprehensive pooled analysis of clinical trial data.Methods and analysisA systematic search of multiple electronic databases, including PubMed, EMBASE, Cochrane Library, and Clinicaltrials.gov, will be conducted from their inception until September, 2023 to identify eligible randomized controlled trials (RCTs) and non-randomized studies. Inclusion criteria comprise studies of adult patients with histologically confirmed MSI-H CRC treated with immune checkpoint inhibitors, with a comparison to a control group receiving conventional therapies. Outcomes of interest will be overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and incidence of treatment-related adverse events (AEs). The Cochrane Risk of Bias tool and the Risk of Bias in Non-randomized Studies of Interventions (ROBINS-I) tool will be employed to evaluate the methodological quality of included studies. A random-effects model using the DerSimonian and Laird method will be applied for pooling the effect estimates, calculating hazard ratios (HRs) or risk ratios (RRs) with their corresponding 95% confidence intervals (CIs). Heterogeneity will be assessed using I² statistics, and subgroup analysis and meta-regression will be performed to explore potential effect modifiers in case of substantial heterogeneity. Publication bias will be evaluated with funnel plots and Egger’s test. Sensitivity analysis will be conducted to assess the robustness of the results.DiscussionThis meta-analysis will synthesize available evidence from clinical trials on immune checkpoint inhibitors in treating MSI-H colorectal cancer. The findings will offer valuable information about the effectiveness and safety of ICIs in this patient population, contributing to the refinement of clinical guidelines and enhancing the decision-making process for healthcare providers, policy-makers, and patients. The comprehensive analysis of subgroups and sensitivity allows for an in-depth understanding of potential effect modification, providing essential directions for future research.Ethics and disseminationThis study will involve the use of published data; hence, ethical approval is not required. The results of the study will be disseminated through publications in peer-reviewed journals and presentations at relevant conferences. The findings will potentially impact clinical decision-making and contribute to the development of evidence-based treatment recommendations for patients with MSI-H colorectal cancer.Clinical trial registrationOpen Science Framework identifier, 10.17605/OSF.IO/ZHJ8

Pendelluft as a predictor of weaning in critically ill patients: An observational cohort study

Objective: Weaning failure is associated with adverse clinical outcomes. This study aimed to evaluate the accuracy of pendelluft during the spontaneous breathing trials (SBT) as a predictor of weaning outcome of patients with mechanical ventilation.Methods: An observational cohort study included 60 critically ill patients who were eligible for extubation. Pendelluft and electrical activity of the diaphragm (Edi) were monitored at baseline and every 10 minutes for the first 30 min of SBT denoted as T0, T1, T2, and T3. The pendelluft was measured using electrical impedance tomography (EIT), and Edi parameters were collected by Edi catheter. Patients were followed up after extubation and were divided into success group and failure group. Pendelluft, Edi parameters, respiratory parameters, and clinical outcomes such as intensive care units (ICU) stay, mortality, and 28-day ventilator-free days were compared between the two groups. Receiver operating characteristic (ROC) curves were constructed to evaluate the ability of pendelluft to predict weaning outcome.Results: Fifty patients (50/60) were successfully weaned from the machine and 10 (10/60) failed, with weaning failure rate of 16.7%. Respiratory parameters such as rapid shallow breathing index (RSBI), respiratory rate (RR) and Edi parameters such as maximum value of Edi (Edimax), Edi variation between a maximum and minimum(ΔEdi) in the failure group were higher than those in the success group. The ICU stay and the 28-day ventilator-free days in the failure group were significantly longer than those in the success group. The 28-day mortality rate was higher in the failure group. The pendelluft mainly occurred in the early stage of SBT. Ventral pendelluft and total pendelluft in the failure group were higher than those in the success group at T1. Edimax and ΔEdi were positively correlated with pendelluft. The area under ROC curve (AUC) showed moderate predictive ability for ventral pendelluft in predicting weaning failure at T1 (AUC 0.76, 95% CI 0.58–0.94, cut-off value > 3% global tidal variation).Conclusion: Pendelluft is one of the factors leading to weaning failure, which may be related to diaphragm function. Measuring pendelluft volume maybe helpful to predict weaning

Table_1_Efficacy and safety of taxanes combined with chemotherapy drugs in advanced triple negative breast cancer: A meta-analysis of 26 randomized controlled trials.docx

BackgroundResearchers have demonstrated that the combined use of taxanes and chemotherapy drugs, especially paclitaxel-based treatment, appeared to clinically benefit on advanced triple negative breast cancer (TNBC). This meta-analysis aims to obtain the existent evidence on efficacy and safety for taxanes-based combination therapy to treat advanced TNBC.MethodsFrom 1991 to June 2022, seven databases (PubMed, Web of Science, Cochrane Library, Embase VIP, Wanfang, and CNKI databases) were comprehensively searched with no restricted language and region. The included randomized controlled trials (RCTs) compared taxanes-based combination therapy versus taxanes or other chemotherapy drugs. Statistical analysis was conducted using random-effect model, and the quality of RCTs was assessed using the tool of Cochrane Collaboration risk of bias.ResultsTwenty-six RCTs with a total of 8,236 advanced TNBC patients were included. Compared with taxanes monotherapy, taxanes-based combination therapy significantly prolonged progression-free survival (HR=0.79, 95%CI=0.74–0.83, I2= 0.0%, p=0.000) and overall survival (HR=0.88, 95%CI=0.82–0.94, I2= 9.3%, p=0.000) and increased the risk of vomiting (RR=1.26, 95%CI=1.07–1.48) and diarrhea (RR=1.82, 95%CI=1.22–2.70, I2= 90.3%, p=0.003). No statistical differences were observed in complete response rate (CRR), objective response rate (ORR), disease control rate (DCR), and progressive disease (PD) indexes (CRR: RR=1.38, 95%CI=0.96–1.99; ORR: RR=1.20, 95%CI=0.73–1.98; DCR: RR=1.09, 95%CI=1.00–1.19; PD: RR=0.70, 95%CI=0.47–1.04). Compared with other chemotherapy drugs, taxanes plus other chemotherapy drugs significantly reduced the incidence of vomiting (RR=0.60, 95%CI=0.44–0.84, I2= 12.3%, p=0.002) and neutropenia (RR=0.58, 95%CI=0.35–0.96, I2= 73.0%, p=0.036) during the treatment period.ConclusionsTaxanes-based combination therapy is evidently effective and well-tolerated in advanced TNBC, indicating that it might be a recommended option for treating advanced TNBC patients to some extent.Systematic Review Registrationhttps://www.crd.york.ac.uk/PROSPERO/, identifier CRD42022337802.</p

Table_2_Efficacy and safety of taxanes combined with chemotherapy drugs in advanced triple negative breast cancer: A meta-analysis of 26 randomized controlled trials.docx

BackgroundResearchers have demonstrated that the combined use of taxanes and chemotherapy drugs, especially paclitaxel-based treatment, appeared to clinically benefit on advanced triple negative breast cancer (TNBC). This meta-analysis aims to obtain the existent evidence on efficacy and safety for taxanes-based combination therapy to treat advanced TNBC.MethodsFrom 1991 to June 2022, seven databases (PubMed, Web of Science, Cochrane Library, Embase VIP, Wanfang, and CNKI databases) were comprehensively searched with no restricted language and region. The included randomized controlled trials (RCTs) compared taxanes-based combination therapy versus taxanes or other chemotherapy drugs. Statistical analysis was conducted using random-effect model, and the quality of RCTs was assessed using the tool of Cochrane Collaboration risk of bias.ResultsTwenty-six RCTs with a total of 8,236 advanced TNBC patients were included. Compared with taxanes monotherapy, taxanes-based combination therapy significantly prolonged progression-free survival (HR=0.79, 95%CI=0.74–0.83, I2= 0.0%, p=0.000) and overall survival (HR=0.88, 95%CI=0.82–0.94, I2= 9.3%, p=0.000) and increased the risk of vomiting (RR=1.26, 95%CI=1.07–1.48) and diarrhea (RR=1.82, 95%CI=1.22–2.70, I2= 90.3%, p=0.003). No statistical differences were observed in complete response rate (CRR), objective response rate (ORR), disease control rate (DCR), and progressive disease (PD) indexes (CRR: RR=1.38, 95%CI=0.96–1.99; ORR: RR=1.20, 95%CI=0.73–1.98; DCR: RR=1.09, 95%CI=1.00–1.19; PD: RR=0.70, 95%CI=0.47–1.04). Compared with other chemotherapy drugs, taxanes plus other chemotherapy drugs significantly reduced the incidence of vomiting (RR=0.60, 95%CI=0.44–0.84, I2= 12.3%, p=0.002) and neutropenia (RR=0.58, 95%CI=0.35–0.96, I2= 73.0%, p=0.036) during the treatment period.ConclusionsTaxanes-based combination therapy is evidently effective and well-tolerated in advanced TNBC, indicating that it might be a recommended option for treating advanced TNBC patients to some extent.Systematic Review Registrationhttps://www.crd.york.ac.uk/PROSPERO/, identifier CRD42022337802.</p

Factors predicting successful vaginal birth after caesarean section: protocol for evidence-based consensus recommendations using a Delphi survey

Introduction With the wide adoption of the two-child policy in China since 2016, a large percentage of women with a history of caesarean delivery plan to have a second child. Accordingly, the rate of vaginal birth after caesarean (VBAC) delivery is increasing. Women attempting repeat VBAC may experience multiple morbidities, which is also one of the leading causes of maternal and perinatal mortality. However, it remains to be addressed how we evaluate factors for successful VBAC. This study aims to use a novel approach to identify a set of potential predictive factors for successful VBAC, especially for Chinese women, to be included in prediction models which can be most applicable to pregnant women in China. We plan to assess all potential predictive factors collected through a comprehensive literature review. Then the certainty of the evidence for the identified potential predictive factors will be assessed using the Grading of Recommendations Assessment, Development and Evaluation process. Finally, a two-round international Delphi survey will be conducted to determine the level of consensus.Methods and analysis This study will apply a methodology through an evidence-based approach. A long list of potential predictive factors for successful VBAC will be extracted and identified through the following stages: First, an up-to-date systematic review of the published literature will be conducted to extract identified potential predictive factors for successful VBAC. Second, an online Delphi survey will be performed to achieve expert consensus on which factors should be included in future prediction models. The online questionnaires will be developed in the field of patient, maternal and fetal-related factors. A two-round international Delphi survey will be distributed to the expert panel in the field of perinatal medicine using Google Forms. Experts will be asked to score each factor using the 9-point Likert rating scale to establish potential predictive factors for the successful VBAC. The expert panel will determine on whether to include, potentially include or exclude predictive factors, based on a systematic review of clinical evidence and the Delphi method.Ethics and dissemination The study was approved by the Institutional Review Board of the Jiaxing Maternity and Children Healthcare Hospital (approval number: 2019–79). The results of this study will be submitted to international peer-reviewed journals or conferences in perinatal medicine or obstetrics

Obstetric and Perinatal Outcomes in Female Cancer Survivors: Protocol of a Pooled Analysis of Population-based Cohort Studies

Abstract Introduction Approximately 80% of children, adolescents and young adults (CAYA) cancer patients are expected to fully recover and survive for five years or more. The reproductive health is a particular area of their concern. Evidence demonstrates that previous therapeutic treatments for cancer and comorbidities may have harmful effects on female fertility and delivery outcomes, which will significantly affect patient quality of life. However, these reports are heterogeneous. Therefore, the purpose of this study is to provide the up-to-date evidence of associations between cancer and obstetric and perinatal outcomes. Methods and analysis This meta-analysis will be carried out and reported with adherence to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and the Cochrane Handbook. We will search online databases including PubMed, Cochrane Library, and Embase until March, 2022 to identify all relevant cohort studies examining the relationship between cancer and subsequent obstetric and perinatal outcomes. Data extraction from eligible studies will be conducted independently by two unblinded investigators using pre-tested standardized data extraction forms and crosschecked by a senior investigator. Discrepancies will be resolved via discussion until consensus is reached. Methodological quality assessment for each study will be conducted using the Newcastle–Ottawa scale (NOS) tool. We will apply the DerSimonian-Laird random-effects model to calculate the pooled estimates. Further sources of heterogeneity will be explored by performing subgroup analysis based on multiple study characteristics. Potential publication bias will be assessed by inspection of a funnel plot, Begg’s and Egger’s regression tests of funnel plot asymmetry. Ethics and dissemination Ethical approval will not be required as all data used for this pooled analysis will be obtained from published cohort studies. The results of this study will be disseminated in a peer-reviewed journal and conference presentation

A protocol for a pooled analysis of cohort studies: The association between depression and anxiety in epileptic disorders.

Background/introductionDepressive and anxiety disorders constitute major mental health challenges affecting adults of all ages globally. It has been reported that individuals with depressive or anxiety disorders face an elevated risk of developing neurological conditions, including seizures and epilepsy. Additionally, people with these disorders tend to exhibit distinct clinical outcomes compared to the general population. However, the associations between depressive or anxiety disorders and epilepsy remain contentious. Thus, this study aims to elucidate the associations between these neuropsychiatric disorders, including depressive and anxiety disorders, and epilepsy or seizures.MethodsWe will systematically search three electronic databases-PubMed, EMBASE, and the Cochrane Library-from inception through March 2023 to identify relevant cohort studies investigating the associations between depressive or anxiety disorders and epilepsy or seizures. Two independent reviewers will extract data from eligible studies using pre-designed standardized data extraction forms, and cross-check results. A third author will resolve any discrepancies. Quality assessment will be performed using the Newcastle-Ottawa Quality Assessment Scale (NOS). Pooled risk estimates (Relative risks or hazard ratios with their 95% CI) will be calculated using the DerSimonian-Laird random-effects model. If between-study heterogeneity is identified, we will conduct subgroup analyses or meta-regressions to explore the possible sources of heterogeneity (participants, exposure, outcome, and study design) stratified by various study characteristics. Potential publication bias will be detected through the inspection of funnel plot asymmetry, complemented by the Egger linear regression approach (Egger's test) and the Begg rank correlation test (Begg's test).DiscussionThis pooled analysis will evaluate the association between depressive or anxiety disorders and epilepsy or seizures, providing high-level evidence to inform early identification and prevention strategies for epilepsy or seizures.Ethics and disseminationGiven that the data utilized for analysis in this pooled analysis does not involve human subjects or medical records, no ethical approval is required for this study. We intend to present the results of this study at national or international conferences or submit the findings to a peer-reviewed journal.Osf registration numberDOI 10.17605/OSF.IO/WM2X8