The efficacy and safety of combined immune checkpoint inhibitors (nivolumab plus ipilimumab): a systematic review and meta-analysis.

BACKGROUND: Currently, nivolumab and ipilimumab are the most widely used immune checkpoint inhibitors. We performed a meta-analysis to evaluate the efficacy and treatment-related adverse events (TRAEs) of nivolumab plus ipilimumab therapy in cancer treatment. METHODS: We examined data from PubMed, Web of Science, EBSCO, and Cochrane Library. Eleven articles fulfilled our criteria, which we divided into 3 groups: nivolumab plus ipilimumab versus nivolumab (the dose used for monotherapy is 3 mg/kg), nivolumab plus ipilimumab versus ipilimumab (the dose used for monotherapy is 3 mg/kg), and nivolumab 1 mg/kg plus ipilimumab 3 mg/kg (N1I3) versus nivolumab 3 mg/kg plus ipilimumab 1 mg/kg (N3I1). We measured the complete response (CR), partial response (PR), objective response rate (ORR), and TRAEs in any grade and grade 3 or higher. RESULTS: The overall effect estimate favored the combined immunotherapy group in terms of the ORR (RR: 1.40, p < 0.001) and PR (RR: 1.50, p < 0.001) than nivolumab alone. Compared with ipilimumab alone, the combined immunotherapy group had better CR (RR: 4.89, p < 0.001), PR (RR: 2.75, p < 0.001), and ORR (RR: 3.31, p < 0.001). Finally, N1I3 showed better PR (RR: 1.35, p = 0.006) and ORR (RR: 1.21, p = 0.03) than N3I1. The incidence of any TRAEs was similar between both groups (RR: 1.05, p = 0.06). However, the incidence of serious adverse events (grade 3 or higher) was lower in group N3I1 than group N1I3 (RR: 1.51, p < 0.001). CONCLUSION: This meta-analysis showed that the curative effect of nivolumab plus ipilimumab was better than that of nivolumab or ipilimumab monotherapy. In the combined immunotherapy group, N1I3 was more effective than N3I1. Although the side effects were slightly increased in N1I3 group, overall safety was acceptable.

Risk Factors for Duodenal Stump Leakage after Laparoscopic Gastrectomy for Gastric Cancer.

PURPOSE: Duodenal stump leakage (DSL) is a potentially fatal complication that can occur after gastrectomy, but its underlying risk factors are unclear. This study aimed to investigate the risk factors and management of DSL after laparoscopic radical gastrectomy for gastric cancer (GC). MATERIALS AND METHODS: Relevant data were collected from several prospective databases to retrospectively analyze the data of GC patients who underwent Billroth II (B-II) or Roux-en-Y (R-Y) reconstruction after laparoscopic gastrectomy from 2 institutions (Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, and HwaMei Hospital, University of Chinese Academy of Sciences). The DSL risk factors were analyzed using univariate and multivariate analysis regression. RESULTS: A total of 810 patients were eligible for our analysis (426 with R-Y, 384 with B-II with Braun). Eleven patients had DSL (1.36%). Body mass index (BMI), elevated preoperative C-reactive protein (CRP) level, and unreinforced duodenal stump were the independent risk factors for DSL. DSL was diagnosed in 2-12 days, with a median of 8 days. Seven patients received conservative treatment, 3 patients received puncture treatment, and only 1 patient required reoperation. All patients recovered successfully after treatment. CONCLUSIONS: The risk factors of DSL were BMI ≥24 kg/m2, elevated preoperative CRP level, and unreinforced duodenal stump. Nonsurgical treatments for DSL are preferred.

In Terms of Nutrition, the Most Suitable Method for Bariatric Surgery: Laparoscopic Sleeve Gastrectomy or Roux-en-Y Gastric Bypass? A Systematic Review and Meta-analysis.

This study assesses the differences in postoperative nutritional status between laparoscopic sleeve gastrectomy (LSG) and laparoscopic Roux-en-Y gastric bypass (LRYGB). We searched the literature from PubMed, Web of Science, Embase, and the Cochrane Library database. Twenty-nine articles were included, with a total of 5437 obese patients. After bariatric surgery, the LSG group had less anemia and iron deficiency anemia than the LRYGB group. The serum iron, ferritin deficiency, and vitamin B12 rates after LSG were lower than patients receiving LRYGB. And PTH and serum phosphorus concentration of patients after LSG were both lower than those after LRYGB. The postoperative results of LSG were better than that of LRYGB. Therefore, we recommend LSG for a better postoperative nutrition, but only for reference.

Magnitude of benefit of the addition of poly ADP-ribose polymerase (PARP) inhibitors to therapy for malignant tumor: A meta-analysis.

BACKGROUND: The purpose of this study was to analyze the efficacy of PARP inhibitor on solid tumors. METHODS: For this study, the following databases were searched for articles published from its inception until July 2019: PubMed, Web of Science, EBSCO, and Cochrane library, of which the main conclusion was the overall survival (OS) and progression-free survival (PFS). RESULTS: We conducted a meta-analysis and the results showed that PARP inhibitor increased the patients' PFS (HR: 0.51, p < 0.001), PFS with BRCA1/2 mutations (HR: 0.32, p < 0.001), OS (HR: 0.74, p < 0.001), OS with BRCA1/2 mutations (HR: 0.78, p = 0.03), complete response (CR) (RR: 1.89, p = 0.10), partial response (PR) (RR: 1.34, p = 0.01), overall response rate (ORR) (RR: 1.42, p = 0.001) respectively. The main adverse events (AEs) observed were decreased appetite. CONCLUSIONS: PARP inhibitors may prolong survival. PARP inhibitors were more favorable for BRCA1/2 mutations in ovarian cancer patients. Additionally, the overall safety factor was controllable.

A meta-analysis of the medium- and long-term effects of laparoscopic sleeve gastrectomy and laparoscopic Roux-en-Y gastric bypass.

BACKGROUND: Laparoscopic Roux-en-Y gastric bypass (LRYGB) and laparoscopic sleeve gastrectomy (LSG) are two representative bariatric surgeries. This study aimed to compare the effects of the LSG and LRYGB based on high-quality analysis and massive amount of data. METHODS: For this study databases of PubMed, Web of Science, EBSCO, Medline, and Cochrane Library were searched for articles published until January 2019 comparing the outcomes of LSG and LRYGB. RESULTS: This study included 28 articles. Overall, 9038 patients (4597, LSG group; 4441, LRYGB group) were included. The remission rate of type 2 diabetes mellitus (T2DM) in the LRYGB group was superior to that in the LSG group at the 3-years follow-up. Five-year follow-up results showed that LRYGB had an advantage over LSG for the percentage of excess weight loss and remission of T2DM, hypertension, dyslipidemia, and abnormally low-density lipoprotein. CONCLUSIONS: In terms of the long-term effects of bariatric surgery, the effect of LRYGB was better than of LSG.

Smokers or non-smokers: who benefits more from immune checkpoint inhibitors in treatment of malignancies? An up-to-date meta-analysis.

BACKGROUND: Immune checkpoint inhibitors, which are a milestone in anti-cancer therapy, have been applied in the treatment of multiple malignancies. Real-world data have suggested that smoking status may be associated with the efficacy of anti-PD-1/PD-L1 therapy. Hereby, to evaluate "smoking benefit or not", we included numerous high-quality randomized controlled clinical trials (RCTs) without any restriction on category. METHODS: A systematic search of online database was performed from July 2010 to July 2019. Eligible studies included phase II/III RCTs comparing PD-1/PD-L1 inhibitors with chemotherapy in the treatment of multiple carcinomas and contained subgroup analysis of smoking status. Then, related hazard ratios (HRs) with 95% confidence intervals (CIs) of overall survival (OS) were pooled. RESULTS: In the initial meta-analysis, compared with chemotherapy, the OS of non-smokers (HR, 0.81; 95% CI, 0.67-0.98) and smokers (HR, 0.77; 95% CI, 0.71-0.83) were significantly prolonged with PD-1/PD-L1 inhibitors. Outcomes from subgroup analysis showed that in anti-PD-1/PD-L1 monotherapy groups, non-smokers showed no significant improvement in OS (HR, 0.94; 95% CI, 0.83-1.06), while the OS of smokers was significantly prolonged (HR, 0.79; 95% CI, 0.74-0.85); in groups of PD-1/PD-L1 inhibitors combined with chemotherapy, the OS of non-smokers (HR, 0.45; 95% CI, 0.28-0.71) and smokers (HR, 0.72; 95% CI, 0.61-0.85) were significantly prolonged. Combined ipilimumab and chemotherapy showed no significance in both groups. CONCLUSION: Smokers benefit from either anti-PD-1/PD-L1 monotherapy or the combined regimen compared with chemotherapy. Considering cost-effectiveness, monotherapy was recommended to smokers. For non-smokers, only the combined regimen was feasible in non-small cell lung cancer.

A Comparison Between the Prognosis of Simultaneous and Salvage Radical Resection in Incidental Gallbladder Cancer.

PURPOSE: Incidental gallbladder cancer (IGBC) is defined as gallbladder cancer (GBC) that is accidentally discovered during cholecystectomy to treat benign lesions. We aimed to compare the prognosis of IGBC patients who underwent simultaneous radical resection (SIR) vs salvage radical resection (SAR). PATIENTS AND METHODS: We retrospectively reviewed data for IGBC patients admitted to Sir Run Run Shaw Hospital from January 2000 to May 2016. Survival analysis was performed using Kaplan-Meier (univariate) and COX regression (multivariate) analyses. RESULTS: Eighty-four patients with IGBC underwent radical resection; 43/84 underwent SIR, and 41/84 underwent SAR. Compared with SIR, the SAR group was more likely to receive comprehensive preoperative radiographic evaluation, port-site excision, and have more lymph nodes excised (all P < 0.05). Kaplan-Meier analysis indicated that the prognosis in the SAR group was better than that in SIR (overall survival: P = 0.050, recurrence-free survival: P = 0.028). Regression analysis indicated that the type of radical resection (SIR/SAR) was not an independent prognostic factor (overall survival: P = 0.737, recurrence-free survival: P = 0.957). CONCLUSION: Patients undergoing SAR had non-inferior survival compared with SIR. It is possible that patients in SAR underwent preoperative radiographical evaluations more comprehensively and the surgical operations were more well performed.

The relationship between the number of examined lymph nodes and the efficacy of chemotherapy for gastric cancer.

BACKGROUND: The purpose of this research was to investigate the relationship between the number of examined lymph nodes (eLNs) and the prognosis. METHODS: A retrospective examination of reports and studies carried out at two institutions was conducted. According to TNM stages, the relationship between the number of eLNs and the prognosis was analyzed. RESULTS: The 5-year disease-specific survival (DSS) of all enrolled patients was 66.3%. A multivariate analysis showed the type of gastrectomy, histologic type, perineural invasion, pT stage, pN stage, chemotherapy and eLNs to be independent prognostic markers. Additionally, with the exception of patients with stage I disease, the 5-year DSS of patients who had < 25 eLNs removed had a higher risk of having a worst prognosis compared to patients who had ≥ 25 eLNs removed. Through this study, a hypothetical TNM staging system was obtained for predicting the prognosis according to the number of eLNs. Chemotherapy was able to improve the prognosis of patients with stage III and < 25 eLNs in stage II. CONCLUSIONS: Extended lymphadenectomy with a new goal of dissecting 25 LNs for the evaluation of stage II-III cancer cases is recommended. Our hypothetical TNM staging system may be able to stratify the risk more accurately compared to the current AJCC 8th system. Chemotherapy can improve the prognosis in advanced gastric cancer, but its benefit may be affected by the surgical quality.

Clinical Significance of Tumor Deposits in Gastric Cancer: a Retrospective and Propensity Score-Matched Study at Two Institutions.

BACKGROUND: Gastric cancer (GC) treatment is largely determined by tumor stage. Despite improvements in the mode of treatment of various types of advanced disease, staging is still evolving. The role of tumor deposits (TDs) in staging remains debated. The purpose of this research is to investigate the relationship between TDs and prognosis in GC. METHODS: A total of 3098 patients were considered eligible for prognostic analysis (2706 patients in the TDs-negative group and 392 patients in the TDs-positive group). A one-to-one propensity score-matching analysis was performed using a logistic regression mode and the following covariates: age, gender, tumor location, size, differentiation, perineural invasion, lymphovascular invasion, pTNM stage, type of gastrectomy, and the number of lymph nodes retrieved between TDs-negative and TDs-positive group, then 323 patients in each group were analyzed. Univariate and multivariate analyses of prognostic factors were conducted accordingly. The predictive ability of different staging system incorporating TDs was evaluated. RESULTS: TDs were present in 14.5% cases and almost all of the patients (99%) suffered from advanced GC. Multivariate analysis showed that pN stage, chemotherapy, and TDs were the independent prognostic factors. The TDs-positive group showed a lower rate of 5-year disease-free survival compared with the TDs-negative group in all patients, stage II, and stage III patients (p = 0.001, 0.029, and 0.003, respectively). The 5-year disease-free survival for patients with TDs and without TDs was 27.6% and 34.4%, respectively. CONCLUSIONS: Our research shows that TDs are closely associated with prognosis in GC. TDs should be incorporated into the TNM staging system, which could then accurately improve the staging reliability and prognostic assessment.

Genetic And Epigenetic Regulation Of E-Cadherin Signaling In Human Hepatocellular Carcinoma.

E-cadherin is well known as a growth and invasion suppressor and belongs to the large cadherin family. Loss of E-cadherin is widely known as the hallmark of epithelial-to-mesenchymal transition (EMT) with the involvement of transcription factors such as Snail, Slug, Twist and Zeb1/2. Tumor cells undergoing EMT could migrate to distant sites and become metastases. Recently, numerous studies have revealed how the expression of E-cadherin is regulated by different kinds of genetic and epigenetic alteration, which are implicated in several crucial transcription factors and pathways. E-cadherin signaling plays an important role in hepatocellular carcinoma (HCC) initiation and progression considering the highly mutated frequency of CTNNB1 (27%). Combining the data from The Cancer Genome Atlas (TCGA) database and previous studies, we have summarized the roles of gene mutations, chromosome instability, DNA methylation, histone modifications and non-coding RNA in E-cadherin in HCC. In this review, we discuss the current understanding of the relationship between these modifications and HCC. Perspectives on E-cadherin-related research in HCC are provided.

Relationship Between Bariatric Surgery and Gastroesophageal Reflux Disease: a Systematic Review and Meta-analysis.

The purpose of this study was to investigate the relationship between bariatric surgery (laparoscopic sleeve gastrectomy [LSG] and laparoscopic Roux-en-Y gastric bypass [LRYGB]) and gastroesophageal reflux disease (GERD). The number of obese patients with newly onset, worsened, or improved GERD after bariatric surgery in each article were extracted. In the pooled analysis, LSG was associated with a higher risk of GERD than LRYGB (odds ratio [OR] = 5.10, 95% confidence interval [CI] 3.60-7.23, p < 0.001). Compared with LSG, LRYGB had a better effect on GERD (OR = 0.19, 95% CI 0.12-0.30, p < 0.001). LRYGB was more effective for treating GERD in obese patients than LSG and the incidence of newly onset GERD after LRYGB was lower.

The safety and tolerability of combined immune checkpoint inhibitors (anti-PD-1/PD-L1 plus anti-CTLA-4): a systematic review and meta-analysis.

BACKGROUND: The future of combined immunotherapy (a PD-1/PD-L1 plus a CTLA-4 antagonist) is very bright. However, besides improving efficacy, combined therapy increases treatment-related adverse events (TRAEs). Also, the clinical application is limited in some solid tumors. METHODS: This paper purports to investigate the TRAEs for the combined immunotherapy aiming for a more appropriate utilization of immune checkpoint inhibitors (ICIs) in clinical practice through a meta-analysis. RESULTS: A total of 17 eligible studies covering 2626 patients were selected for a meta-analysis based on specified inclusion and exclusion criteria. The incidence rates of any grade and grade 3 or higher TRAEs were 88% (95%CI, 84-92%) and 41% (95%CI, 35-47%), respectively. The overall incidence of any grade TRAEs leading to discontinuation of treatment was 20% (95%CI, 16-24%). The incidence rate of treatment related deaths was 4.3‰ (95%CI, 1.4‰-8.4‰). Analysis showed that NIVO1 + IPI3 cohort had higher incidences of grade 3 or higher TRAEs (RR = 1.77, 95%CI, 1.34-2.34, p < 0.0001) and any grade TRAEs leading to discontinuation of treatment (RR = 1.81, 95%CI, 1.08-3.04, P = 0.02), compared with NIVO3 + IPI1 regimen. CONCLUSIONS: The combined therapy had high TRAEs. The TRAEs, especially grade 3 or higher, led to discontinuation of the treatment. Furthermore, the incidence of treatment-related deaths was rare. Moreover, the NIVO3 + IPI1 regimen, regardless of efficacy, is more recommended because of better tolerance and lower adverse events.

A Risk-Scoring Model for Predicting Lymph Node Metastasis in Early Gastric Cancer Patients: a Retrospective Study and External Validation.

BACKGROUND: The possibility of lymph node metastasis (LNM) is critical to the assessment of the indication for endoscopic submucosal dissection. Thus, the aim of this study is to identify the risk factors for LNM and construct a risk-scoring model for patients with early gastric cancer to guide treatment. METHODS: A retrospective examination of reports and studies carried out January 2000 and December 2014 was conducted. A risk-scoring model for predicting LNM was developed based on the data thus collected. In addition, the model is subject to verification and validation by three institutions. RESULTS: Of the 1029 patients, 228 patients (22%) had LNM. Multivariate analysis showed that female, depressed type, undifferentiated type, submucosa, tumor size, and lymphovascular invasion were significantly associated with LNM. An 11-point risk-scoring model was used to predict LNM risk. An area under the receiver operating characteristic (AUROC) of the risk-scoring model was plotted using the development set and the AUROC of the model [0.76 (95% CI 0.73-0.80)] to predict LNM risk. After internal and external validation, the AUROC curve for predicting LNM was 0.77 (95% CI 0.68-0.86), 0.82 (95% CI 0.72-0.91), and 0.82 (95% CI 0.70-0.94), respectively. CONCLUSIONS: A risk-scoring model for predicting LNM was developed and validated. It could help with personalized care for patients with EGC.