Fecal, Duodenal and Tumor Microbiota Composition of Esophageal Carcinoma Patients, a Longitudinal Prospective Cohort.

BACKGROUND: The microbiome has been associated with chemotherapy and immune checkpoint inhibitor (ICI) efficacy. How this pertains to resectable esophageal carcinoma (EC) is unknown. Our aim was to identify microbial signatures in resectable EC associated with response to neoadjuvant chemoradiotherapy (nCRT) with or without ICI. METHODS: From two prospectively collected EC cohorts (n = 172 in total) treated with nCRT alone (n = 132) or a combination of nCRT and ICI (n = 40), fecal samples were available at baseline, during treatment, and pre-surgery. Additionally, in the ICI treated patients, tumor and duodenal snap frozen biopsies were collected over time. Fecal, tumor and duodenal DNA were extracted for 16S rRNA sequencing. Associations were investigated between microbiome composition pathological complete response (pCR) and progression-free survival (PFS). RESULTS: There was a significant shift in the microbiota profile of the fecal, tumor and duodenal microbiota over time. In the total cohort, patients with a pCR had a stable fecal alpha diversity, while the diversity of poor responders decreased during treatment, p = 0.036. Pre-surgery, lower alpha diversity (<4.12) was related to worse PFS, log-rank p = 0.025. Baseline tumor biopsies of patients with short PFS had more Fusobacterium. A low baseline duodenal alpha diversity (<3.96) was associated with worse PFS, log-rank p = 0.012. CONCLUSIONS: Lower intestinal alpha diversity was associated with worse response and survival of EC patients. In tumor biopsies Fusobacterium was more abundant in patients with poor PFS. After further mechanistic validation, these findings may aid in response prediction and the design of novel microbiome modulating treatments for EC patients.

Phenotypic immune characterization of gastric and esophageal adenocarcinomas reveals profound immune suppression in esophageal tumor locations.

Background: Tumors in the distal esophagus (EAC), gastro-esophageal junction including cardia (GEJAC), and stomach (GAC) develop in close proximity and show strong similarities on a molecular and cellular level. However, recent clinical data showed that the effectiveness of chemo-immunotherapy is limited to a subset of GEAC patients and that EACs and GEJACs generally benefit less from checkpoint inhibition compared to GACs. As the composition of the tumor immune microenvironment drives response to (immuno)therapy we here performed a detailed immune analysis of a large series of GEACs to facilitate the development of a more individualized immunomodulatory strategy. Methods: Extensive immunophenotyping was performed by 14-color flow cytometry in a prospective study to detail the immune composition of untreated gastro-esophageal cancers (n=104) using fresh tumor biopsies of 35 EACs, 38 GEJACs and 31 GACs. The immune cell composition of GEACs was characterized and correlated with clinicopathologic features such as tumor location, MSI and HER2 status. The spatial immune architecture of a subset of tumors (n=30) was evaluated using multiplex immunohistochemistry (mIHC) which allowed us to determine the tumor infiltration status of CD3+, CD8+, FoxP3+, CD163+ and Ki67+ cells. Results: Immunophenotyping revealed that the tumor immune microenvironment of GEACs is heterogeneous and that immune suppressive cell populations such as monocytic myeloid-derived suppressor cells (mMDSC) are more abundant in EACs compared to GACs (p<0.001). In contrast, GACs indicated a proinflammatory microenvironment with elevated frequencies of proliferating (Ki67+) CD4 Th cells (p<0.001), Ki67+ CD8 T cells (p=0.002), and CD8 effector memory-T cells (p=0.024). Differences between EACs and GACs were confirmed by mIHC analyses showing lower densities of tumor- and stroma-infiltrating Ki67+ CD8 T cells in EAC compared to GAC (both p=0.021). Discussions: This comprehensive immune phenotype study of a large series of untreated GEACs, identified that tumors with an esophageal tumor location have more immune suppressive features compared to tumors in the gastro-esophageal junction or stomach which might explain the location-specific responses to checkpoint inhibitors in this disease. These findings provide an important rationale for stratification according to tumor location in clinical studies and the development of location-dependent immunomodulatory treatment approaches.

The impact of the COVID-19 pandemic on the diagnosis, stage, and treatment of esophagogastric cancer.

BACKGROUND: The COVID-19 pandemic has affected the entire global healthcare system, including oncological care. This study investigated the effects of the COVID-19 pandemic on the diagnosis, stage, and treatment of esophagogastric cancer in the Netherlands. METHODS: Patients diagnosed in 2020 were divided into 5 periods, based on the severity of the COVID-19 pandemic in the Netherlands, and compared to patients diagnosed in the same period in the years 2017-2019. Patient characteristics and treatments were evaluated for esophageal cancer (EC) and gastric cancer (GC) separately. RESULTS: The number of esophagogastric cancer diagnoses decreased prominently during the first 2 months of the COVID-19 pandemic. During this period, a significantly higher percentage of GC patients was diagnosed with incurable disease (52.5% in 2017-2019 and 67.7% in 2020, p = 0.011). We observed a significant reduction in the percentage of patients with potentially curable EC treated with resection and neoadjuvant chemoradiotherapy (from 35.0% in 2017-2019 to 27.3% in 2020, p < 0.001). Also, patients diagnosed with incurable GC were treated less frequently with a resection (from 4.6% in 2017-2019 to 1.5% in 2020, p = 0.009) in the second half of 2020. CONCLUSIONS: Compared to previous years, the number of esophagogastric cancer diagnoses decreased in the first 2 months of the COVID-19 pandemic, while an increased percentage of patients was diagnosed with incurable disease. Both in the curative and palliative setting, patients were less likely to be treated with a surgical resection.

The Relation between Hair-Cortisol Concentration and Various Welfare Assessments of Dutch Dairy Farms.

Many protocols have been developed to assess farm animal welfare. However, the validity of these protocols is still subject to debate. The present study aimed to compare nine welfare assessment protocols, namely: (1) Welfare Quality© (WQ), (2) a modified version of Welfare Quality (WQ Mod), which has a better discriminative power, (3) WelzijnsWijzer (Welfare Indicator; WW), (4) a new Welfare Monitor (WM), (5) Continue Welzijns Monitor (Continuous Welfare Monitor; CWM), (6) KoeKompas (Cow Compass; KK), (7) Cow Comfort Scoring System (CCSS), (8) Stall Standing Index (SSI) and (9) a Welfare Index (WI Tuyttens). In addition, a simple welfare estimation by veterinarians (Estimate vets, EV) was added. Rank correlation coefficients were calculated between each of the welfare assessment protocol scores and mean hair cortisol concentrations from 10 cows at 58 dairy farms spread over the Netherlands. Because it has been suggested that the hair cortisol level is related to stress, experienced over a long period of time, we expected a negative correlation between cortisol and the result of the welfare protocol scores. Only the simple welfare estimation by veterinarians (EV) (ρ = -0.28) had a poor, but significant, negative correlation with hair cortisol. This correlations, however, failed to reach significance after correction of p-values for multiple correlations. Most of the results of the different welfare assessment protocols had a poor, fair or strong positive correlation with each other, supporting the notion that they measure something similar. Additional analyses revealed that the modified Welfare Quality protocol parameters housing (ρ = -0.30), the new Welfare Monitor (WM) parameter health (ρ = -0.33), and milk yield (ρ = -0.33) showed negative correlations with cortisol. We conclude that because only five out of all the parameter scores from the welfare assessment protocols showed a negative, albeit weak, correlation with cortisol, hair cortisol levels may not provide a long term indicator for stress in dairy cattle, or alternatively, that the protocols might not yield valid indices for cow welfare.

A Systematic Review With Meta-Analysis of the Efficacy of Cannabis and Cannabinoids for Inflammatory Bowel Disease: What Can We Learn From Randomized and Nonrandomized Studies?

GOAL AND BACKGROUND: A number of studies have investigated the effectiveness of cannabis or cannabinoids for treatment of inflammatory bowel diseases (IBD). We aimed to systematically analyze their effect in in the treatment of IBD patients. STUDY: We included randomized controlled trials and nonrandomized studies analyzing IBD patients of any age using cannabi(noid)s. Two reviewers searched 3 databases until August 13, 2019. Primary outcome was clinical remission and secondary outcomes included inflammatory biomarkers, symptom improvement, quality of life (QoL) scores, and hospital outcomes. Risk of bias was assessed according to study type. The meta-analyses were performed using a random-effects model with subgroup analyses based on study type. RESULTS: The search identified 682 records of which 15 nonrandomized studies and 5 randomized controlled trials were eligible for inclusion. The meta-analysis of the primary outcome included 146 randomized participants, all 18 years of age or older. Risk of bias was moderate. Cannabi(noid)s were not effective at inducing remission (risk ratio=1.56, 95% confidence interval=0.99-2.46). No effect on inflammatory biomarkers was observed. However, clinical symptoms (abdominal pain, general well-being, nausea, diarrhea, and poor appetite) all improved with cannabi(noid)s on Likert-scales. Baseline QoL scores were lower in patients using cannabis among cohort studies but improved significantly with cannabi(noid)s. Although length of hospital stay was shorter and risk of parenteral nutrition was lower in patients using cannabis, there was no effect on other IBD complications. CONCLUSIONS: Cannabi(noid)s do not induce clinical remission or affect inflammation in IBD patients. However, cannabi(noid)s significantly improve patient-reported symptoms and QoL.