Perioperative immune checkpoint inhibitors combined with chemotherapy versus chemotherapy for locally advanced, resectable gastric or gastroesophageal junction adenocarcinoma: A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Immunotherapy in combination with chemotherapy has been approved as an initial treatment strategy for unresectable advanced gastric cancer (GC). However, the efficacy of adding immunotherapy to perioperative chemotherapy in locally advanced resectable gastric or gastroesophageal junction adenocarcinoma (GC/GEJC) remains uncertain. Therefore, a meta-analysis of randomized controlled trials (RCTs) was performed to compare the effectiveness of perioperative immune checkpoint inhibitors (ICIs) plus chemotherapy versus chemotherapy alone in patients with locally advanced resectable GC/GEJC. METHODS: A comprehensive search of online databases was conducted to identify RCTs published until November 30, 2023. Odds ratios (ORs) with 95% confidence interval (CI) were calculated for primary outcomes, including R0 resection rate, D2 lymphadenectomy, pathologic complete response (pCR), and treatment-related adverse events (TRAEs). RESULTS: A total of 2718 patients from five RCTs (six reports) were included in the analysis. The pooled ORs of R0 resection rate and D2 lymphadenectomy demonstrated that combination therapy with ICIs showed no significant difference compared to chemotherapy alone. However, the addition of ICIs significantly improved pCR rates (OR = 3.43, 95 % CI 2.61-4.50, p < 0.0001). There were no significant differences observed in the incidence of any grade TRAEs and grade 3-4 TRAEs. However, ICIs combination therapy was associated with significantly higher incidences of any grade irAEs (OR = 4.03, 95 % CI: 2.70-6.00, p < 0.0001), as well as grade 3-4 irAEs (OR = 4.51, 95 % CI: 2.27-8.97, p < 0.0001). CONCLUSIONS: This study represents the first meta-analysis to demonstrate that perioperative combination therapy with ICIs yields superior pCR rates for patients with locally advanced GC/GEJC compared to chemotherapy.

Efficacy and safety of VEGF/VEGFR inhibitors for platinum-resistant ovarian cancer: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Almost all patients with ovarian cancer will experience relapse and eventually develop platinum-resistant. The poor prognosis and limited treatment options have prompted the search for novel approaches in managing platinum-resistant ovarian cancer (PROC). Therefore, a meta-analysis was conducted to evaluate the efficacy and safety of combination therapy with vascular endothelial growth factor (VEGF) /VEGF receptor (VEGFR) inhibitors for PROC. METHODS: A comprehensive search of online databases was conducted to identify randomized clinical trials published until December 31, 2022. Pooled hazard ratios (HR) was calculated for overall survival (OS) and progression-free survival (PFS), while pooled odds ratio (OR) was calculated for objective response rate (ORR) and treatment-related adverse events (TRAEs). Subgroup analysis was further performed to investigate the source of heterogeneity. RESULTS: In total, 1097 patients from eight randomized clinical trials were included in this meta-analysis. The pooled HRs of OS (HR = 0.72; 95% CI: 0.62-0.84, p < 0.0001) and PFS (HR = 0.52; 95% CI: 0.45-0.59, p < 0.0001) demonstrated a significant prolongation in the combination group compared to chemotherapy alone for PROC. In addition, combination therapy demonstrated a superior ORR compared to monotherapy (OR = 2.34; 95%CI: 1.27-4.32, p < 0.0001). Subgroup analysis indicated that the combination treatment of VEGF/VEGFR inhibitors and chemotherapy was significantly more effective than monochemotherapy in terms of OS (HR = 0.71; 95% CI: 0.61-0.84, p < 0.0001), PFS (HR = 0.49; 95% CI: 0.42-0.57, p < 0.0001), and ORR (OR = 2.97; 95% CI: 1.89-4.67, p < 0.0001). Although the combination therapy was associated with higher incidences of hypertension, mucositis, proteinuria, diarrhea, and hand-foot syndrome compared to monochemotherapy, these toxicities were manageable and well-tolerated. CONCLUSIONS: The meta-analysis demonstrated that combination therapy with VEGF/VEGFR inhibitors yielded better clinical outcomes for patients with PROC compared to monochemotherapy, especially when combined with chemotherapy. This analysis provides more treatment options for patients with PROC. SYSTEMATIC REVIEW REGISTRATION: [ https://www.crd.york.ac.uk/PROSPERO ], Prospective Register of Systematic Reviews (PROSPERO), identifier: CRD42023402050.

The predictive value of tumor mutation burden on survival of gastric cancer patients treated with immune checkpoint inhibitors: A systematic review and meta-analysis.

BACKGROUND: Tumor mutation burden (TMB) is a complement to traditional biomarkers related to the efficacy of immune checkpoint inhibitors (ICIs). The relationship between TMB and the efficacy of ICIs in gastric cancer was controversial. The systematic review and meta-analysis were conducted to investigate the predictive value of TMB on survival of gastric cancer patients treated with ICIs. METHODS: We searched the databases PubMed, Embase, and Web of Science for articles, then screened eligible articles according to inclusion criteria. The effective data were extracted to calculate the pooled effects of hazard ratio (HR) for overall survival (OS) and progression-free survival (PFS), then perform publication bias, sensitivity analysis, and subgroup analysis by STATA 16.0. RESULTS: The high TMB patients showed significantly longer survival than the low TMB patients (OS: HR 0.65,95% CI 0.55, 0.77, p < 0.001; PFS: HR 0.51, 95% CI 0.33, 0.77, p = 0.001). In the Asian subgroup, patients with high TMB exhibited better prognosis compared to low TMB (OS: HR 0.56, 95% CI 0.43, 0.72, p < 0.001; PFS: HR 0.45, 95% CI 0.28, 0.72, p = 0.001). In the non-Asian subgroup, the survival benefit was observed to be skewed toward patients with high TMB, but it was not statistically significant (OS:HR 0.61, 95% CI 0.32, 1.16, p = 0.133; PFS:HR 0.68, 95% CI 0.31, 1.48, p = 0.322). CONCLUSIONS: This meta-analysis demonstrated that gastric cancer patients with high TMB showed significant benefits from ICIs compared to those with low TMB patients, particularly in Asian populations.

Efficacy and safety of PD-1/PD-L1 inhibitors combined with anti-angiogenic therapy for the unresectable hepatocellular carcinoma and the benefit for hepatitis B virus etiology subgroup: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death, worldwide. The predominant causative factor for HCC is hepatitis B virus (HBV) infection. We conducted a meta-analysis to estimate the efficacy and safety of PD-1/PD-L1 inhibitors combined with anti-angiogenic therapy for the first-line treatment of the unresectable HCC and to evaluate the benefits of different geographic regions and etiology stratifications. METHODS: Randomized clinical trials published up to 12th November 2022 were searched by online databases. Moreover, effects of hazard ratio (HR) for overall survival (OS) and progression-free survival (PFS) were extracted from included studies. Pooled odds ratio (OR) and 95% CI for objective response rate (ORR), disease control rate (DCR), and treatment-related adverse events (TRAEs) were calculated. RESULTS: A total of 3057 patients from five phase III randomized clinical trials were collected and reviewed for this meta-analysis. The pooled HR of OS (HR = 0.71; 95% CI: 0.60-0.85) and PFS (HR = 0.64; 95% CI: 0.53-0.77) demonstrated significantly better benefit in PD-1/PD-L1 inhibitors combination group than targeted monotherapy to treat unresectable HCC. In addition, combination therapy showed better ORR and DCR, with ORs of 3.29 (95% CI: 1.92-5.62) and 1.88 (95% CI: 1.35-2.61), respectively. The subgroup analysis indicated that PD-1/PD-L1 inhibitors combination therapy was significantly superior to anti-angiogenic monotherapy for HBV-related HCC in terms of OS (HR = 0.64; 95% CI: 0.55-0.74) and PFS (HR = 0.53; 95% CI:0.47-0.59), while there was no significant difference in patients with HCV (OS, HR = 0.81, p = 0.1) or non-viral (OS, HR = 0.91, p = 0.37; PFS, HR = 0.77, p = 0.05). CONCLUSIONS: Meta-analysis revealed for the first-time that PD-1/PD-L1 inhibitors combination therapy for unresectable HCC was associated with better clinical outcomes than anti-angiogenic monotherapy, especially for HBV infection and Asian population.

An integrated plasma and urinary metabonomic study using UHPLC-MS: intervention effects of Epimedium koreanum on 'Kidney-Yang Deficiency syndrome' rats.

A metabonomic strategy based on UHPLC-MS with principal component analysis was developed to investigate the intervention effects of Epimedium koreanum on metabolism characters of 'Kidney-Yang Deficiency syndrome' rats. The rats were injected intraperitoneally hydrocortisone once daily for 15 days to simulate 'Kidney-Yang Deficiency syndrome' and then administered orally E. koreanum extract once daily for the following 15 days. Plasma and urine samples before hydrocortisone injection, on day 15 of hydrocortisone injection and on days 3, 6, 9, 12, 15 exposed to E. koreanum extract were collected. Significant metabolic disorders were observed in 'Kidney-Yang Deficiency syndrome' rats and sixteen potential biomarkers were identified. The disturbed plasma levels of phenylalanine, tryptophan, cholic acid, lysophosphatidylcholines and urinary levels of phenylalanine, hippurate, phenylacetylglycine, N(2)-succinyl-l-ornithine, creatinine, α-ketoglutarate, citrate, phenol sulfate, indoxyl sulfate, cresol sulfate in model rats were gradually restored to normal after administration of E. koreanum extract, which indicated that E. koreanum had time-dependent recovering effects via regulating oxidant-antioxidant balance, amino acid metabolism, lipid metabolism, energy metabolism, and gut microflora. This work highlights that metabonomics is a promising tool for studying the essence of Chinese medicine's syndrome theory and the action mechanism of traditional Chinese medicine, and provides scientific and reasonable information on safety and efficacy of traditional Chinese medicine.

LC-MS/MS determination and pharmacokinetic study of four lignan components in rat plasma after oral administration of Acanthopanax sessiliflorus extract.

ETHNOPHARMACOLOGICAL RELEVANCE: Acanthopanax sessiliflorus (Rupr. et Maxim.) Seem. is a shrub mainly present in China, Japan and Korea, the root bark of which is considered as one of the sources of Wujiapi and widely used for its various pharmacological effects. AIM OF THE STUDY: A selective and sensitive UPLC-MS/MS method was developed and validated for the determination and pharmacokinetic study of asarinin, sesamin, helioxanthin and savinin in rat plasma. MATERIALS AND METHODS: Sample preparation involved a liquid-liquid extraction of the analytes with methyl tert-butyl ether (MTBE). LC separation was achieved on a UPLC C(18) column at 30°C with a mobile phase consisting of methanol-2 mM ammonium acetate (68:32, v/v). The detection was accomplished by multiple-reaction monitoring (MRM) scanning with electrospray ionization (ESI) source operating in the positive ionization mode. The optimized mass transition ion-pairs (m/z) monitored for asarinin, sesamin, helioxanthin, savinin and IS were 372.2/233.0, 372.2/233.0, 349.1/319.0, 352.9/334.9 and 180.0/109.7, respectively. RESULTS: The current LC-MS/MS assay was validated for linearity, intra-day and inter-day precisions, accuracy, extraction recovery and stability and was suitable for pharmacokinetic studies of the four lignans after oral administration of Acanthopanax sessiliflorus extract. The time to reach the maximum plasma concentration (T(max)) was 2.50±0.15 h for asarinin, 1.94±0.28 for sesamin, 2.22±0.48 h for helioxanthin and 2.83±0.29 h for savinin. The elimination half-time (t(1/2)) of asarinin, sesamin, helioxanthin and savinin was 6.08±1.10, 11.69±0.50, 7.16±0.52 and 6.26±0.57 h, respectively. CONCLUSION: This paper described a simple, sensitive and validated UPLC-MS/MS method for simultaneous determination of four lignans in rat plasma after oral administration of Acanthopanax sessiliflorus extract, and investigated on their pharmacokinetic studies as well.