We report on a comprehensive analysis of the gut microbiomes of patients with gastrointestinal (GI) cancer receiving anti–PD-1/PD-L1 treatment. The human gut microbiota has been associated with clinical responses to anti–PD-1/PD-L1 immunotherapy in melanoma, non–small cell lung cancer, and renal cell carcinoma. We aimed to investigate this association in GI cancers. We also identified bacterial taxa with patient stratification potential. We recruited 74 patients with advanced-stage GI cancer receiving anti–PD-1/PD-L1 treatment and collected their fecal samples prior to and during immunotherapy, along with clinical evaluations. Our 16S rRNA taxonomy survey on the fecal samples revealed an elevation of the Prevotella/Bacteroides ratio in patients, with a preferred response to anti–PD-1/PD-L1 treatment, and a particular subgroup of responders harboring a significantly higher abundance of Prevotella, Ruminococcaceae, and Lachnospiraceae. The shotgun metagenomes of the same samples showed that patients exhibiting different responses had differential abundance of pathways related to nucleoside and nucleotide biosynthesis, lipid biosynthesis, sugar metabolism, and fermentation to short-chain fatty acids (SCFA). Gut bacteria that were capable of SCFA production, including Eubacterium, Lactobacillus, and Streptococcus, were positively associated with anti–PD-1/PD-L1 response across different GI cancer types. We further demonstrated that the identified bacterial taxa were predictive of patient stratification in both our cohort and melanoma patients from two previously published studies. Our results thus highlight the impact of gut microbiomes on anti–PD-1/PD-L1 outcomes, at least in a subset of patients with GI cancer, and suggest the potential of the microbiome as a marker for immune-checkpoint blockade responses. See articles by Tomita et al., p. 1236, and Hakozaki et al., p. 1243

Despite success in hematologic malignancies, the treatment landscape of chimeric antigen receptor (CAR) T cell therapy for solid tumors remains limited. Claudin18.2 (CLDN18.2)-redirected CAR T cells showed promising efficacy against gastric cancer (GC) in a preclinical study. Here we report the interim analysis results of an ongoing, open-label, single-arm, phase 1 clinical trial of CLDN18.2-targeted CAR T cells (CT041) in patients with previously treated, CLDN18.2-positive digestive system cancers (NCT03874897). The primary objective was safety after CT041 infusion; secondary objectives included CT041 efficacy, pharmacokinetics and immunogenicity. We treated 37 patients with one of three CT041 doses: 2.5 × 108, 3.75 × 108 or 5.0 × 108 cells. All patients experienced a grade 3 or higher hematologic toxicity. Grade 1 or 2 cytokine release syndrome (CRS) occurred in 94.6% of patients. No grade 3 or higher CRS or neurotoxicities, treatment-related deaths or dose-limiting toxicities were reported. The overall response rate (ORR) and disease control rate (DCR) reached 48.6% and 73.0%, respectively. The 6-month duration of response rate was 44.8%. In patients with GC, the ORR and DCR reached 57.1% and 75.0%, respectively, and the 6-month overall survival rate was 81.2%. These initial results suggest that CT041 has promising efficacy with an acceptable safety profile in patients with heavily pretreated, CLDN18.2-positive digestive system cancers, particularly in those with GC.

ObjectivesHepatoid adenocarcinoma of the stomach (HAS) is characterized by histological resemblance to hepatocellular carcinoma and a poor prognosis. The aim of this study is to elucidate the clinicopathological and molecular characteristics of HAS.MethodsForty-two patients with HAS who received gastrectomy were enrolled in this study. Based on a panel of 483 cancer-related genes, targeted sequencing of 24 HAS and 22 clinical parameter-matched common gastric cancer (CGC) samples was performed. Prognostic factors for overall survival (OS) and disease-free survival (DFS) were analysed with the Kaplan–Meier method.ResultsThe most frequently mutated gene in both HAS and CGC was TP53, with a mutation rate of 30%. Additionally, CEBPA, RPTOR, WISP3, MARK1, and CD3EAP were identified as genes with high-frequency mutations in HAS (10–20%). Copy number gains (CNGs) at 20q11.21-13.12 occurred frequently in HAS, nearly 50% of HAS tumours harboured at least one gene with a CNG at 20q11.21-13.12. This CNG tended to be related to more adverse biobehaviour, including poorer differentiation, greater vascular and nerve invasion, and greater liver metastasis. Pathway enrichment analysis revealed that the HIF-1 signalling pathway and signalling pathways regulating stem cell pluripotency were specifically enriched in HAS. The survival analysis showed that a preoperative serum AFP level ≥ 500 ng/ml was significantly associated with poorer OS (p = 0.007) and tended to be associated with poorer DFS (p = 0.05).ConclusionCNGs at 20q11.21-13.12 happened frequently in HAS and tended to be related to more adverse biobehaviour. The preoperative serum AFP level was a sensitive prognostic biomarker for DFS and OS.Electronic supplementary materialThe online version of this article (10.1007/s10120-019-00965-5) contains supplementary material, which is available to authorized users.

Background and AimsMET, the hepatocyte growth factor receptor, is a receptor tyrosine kinase overexpressed and activated in a subset of gastric cancer. Several studies investigated the relationship between MET amplification and expression with the clinical outcome in patients with gastric cancer, but yielded conflicting results. We performed a systematic review and meta-analysis to determine the influence of MET amplification and expression on prognosis in gastric cancer.MethodsMEDLINE and EMBASE were searched for studies that explored the association between MET amplification and expression with survival in patients with gastric cancer up to 1 April, 2013. Data of individual hazard ratios (HRs) and 95% confidence intervals (CIs) for meta-analyses were extracted from the publications and combined in pooled HRs.ResultsFourteen studies involving 2,258 patients with gastric cancer were included. It was suggested that MET overexpression had an unfavorable impact on survival of patients with gastric cancer, with HRs (95% CIs) of 2.57 (95% CI: 1.97–3.35) overall, 2.82 (95% CI: 1.86–4.27) among studies using amplification for measure scale of MET and 2.42 (95% CI: 1.66–3.54) for expression. The magnitude of association was reduced whereas remained statistically significant in high quality studies or in larger sample size studies and corresponding HRs were 2.18(1.76, 2.70) and 2.35(1.93, 2.87), respectively, without significant heterogeneity.ConclusionThe findings from present study indicated that higher MET gene amplification and expression in gastric cancer was an indicator of poor prognosis.

The cytokine, macrophage migration inhibitory factor (MIF), is encoded in a functionally polymorphic locus and subjects with high-expression MIF alleles are at an increased risk of inflammatory disease. Severe sepsis is the leading cause of death in intensive care units, and the prevailing hypothesis is that an excessive innate response contributes to its pathogenesis. To assess if MIF alleles influence the clinical course of infection, we conducted a case-control study to assess susceptibility and a parallel inception cohort study of community-acquired pneumonia (CAP) to assess risk of severe sepsis and 90-d mortality. Two distinct polymorphisms in the MIF promoter were analyzed: a G/C transition at -173 and a CATT repeat at -794. The frequency of both polymorphisms was similar in the CAP cohort (n=1739) and controls (n=639); however, the 90-d mortality was lower for the high-expression C allele (P=0.003). This association remained significant after adjusting for demographics, comorbid conditions, and disease severity score [hazard ratio=0.64 (0.44-0.91), P=0.01]. The hazard ratio was similar in different geographic subcohorts, and the association remained significant after adjusting for false discovery. These data indicate that polymorphisms associated with higher MIF expression may have a beneficial effect in community-acquired pneumonia.