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

Introduction Although the new classification of premature ejaculation (PE) has been proposed by Waldinger et al., there have been few studies investigating the four PE syndromes in China. Aims We investigated the prevalence and factors associated with the complaint of PE and the four PE syndromes in Anhui province, China. Methods Between September 2011 and September 2012, subjects were selected from five cities in Anhui province, China. They participated in this survey by completing a detailed verbal questionnaire regarding their demographic data and medical and sexual history. Men with PE complaint were diagnosed as lifelong PE (LPE), acquired PE (APE), natural variable PE (NVPE), or premature-like ejaculatory dysfunction (PLED). Main Outcome Measures PE complaint was divided into four PE syndromes. Anxiety, depression, and erectile dysfunction were independently assessed by the self-rating anxiety/depression scale and the international index of erectile function-5, respectively. Results Of the 3,016 men evaluated, 25.80% complained of PE. The distribution of the four PE syndromes in men with PE complaint was in the order of NVPE (44.09%), PLPE (24.81%), APE (18.77%), and LPE (12.34%). Patients with PE complaint were older and more likely to smoke, had more comorbidities, and a higher body mass index (BMI) than patients without the complaint (P < 0.001 for all). Similar findings were also observed in patients with APE compared with other PE patients (depression P = 0.012, cardiovascular P = 0.003, others P < 0.001). In addition, the rates of counseling by a doctor in men with LPE and APE were higher than those in men with NVPE and PLED (P < 0.001). Conclusion The prevalence of PE complaint in male population of Anhui province, China, was 25.80%, with the highest PE syndromes being NVPE and PLPE. Patients with PE complaint or APE were older and more likely to smoke, had more comorbidities, and a higher BMI.

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.

Introduction Although infertility is known to be associated with psychological and sexual problems, the relationship between these two aspects in infertile men has not been well investigated. Aim To investigate the incidence of sexual dysfunction and psychological burden, and their possible associations in infertile men. Methods From June 2009 to June 2012, a total of 1,468 infertile men and 942 fertile men were evaluated. Premature ejaculation (PE) and erectile dysfunction (ED) were measured by the PE diagnostic tool (PEDT), the intravaginal ejaculatory latency time (IELT) and the international index of erectile function (IIEF)-5. Anxiety and depression, which reflect the degree of psychological burden, were measured by the self-rating anxiety scale (SAS) and self-rating depression scale (SDS), respectively. Main Outcome Measures PE and ED were measured by the PEDT, IELT, and IIEF-5. Anxiety and depression were measured by the SAS and SDS, respectively. Results The incidences of PE and ED in the infertile group were significantly higher than those in the fertile group (PE: 19.01% vs.10.93%, P < 0.001; ED: 18.05% vs. 8.28%, P < 0.001). In addition, anxiety and depression were more prevalent in infertile than fertile men (Anxiety: 38.01% vs. 26.65%, P < 0.001; Depression: 15.74% vs. 10.08%, P < 0.001). Furthermore, after adjusting for age in the infertile group, the PEDT score was positively associated with anxiety (adjusted r = 0.57; P < 0.001) and depression (adjusted r = 0.54; P < 0.001). Moreover, the IELT were negatively associated with anxiety (adjusted r = −0.40; P < 0.001) and depression (adjusted r = −0.52; P < 0.001). Similar negative relationships were also observed between the IIEF-5 score and anxiety (adjusted r = −0.49; P < 0.001) or depression (adjusted r = −0.50; P < 0.001). Conclusion This is the first study to systematically evaluate the incidence of sexual dysfunction and psychological burden, and their possible associations in infertile men in China. Further in-depth studies are needed to confirm and extend these results.