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The prevalence of obesity, defined as the body mass index (BMI) ≥ 30 kg/m2, has reached epidemic levels. Obesity is associated with an increased risk of various cancers, including gastrointestinal ones. Recent evidence has suggested that obesity disproportionately impacts males and females with cancer, resulting in varied transcriptional and metabolic dysregulation. This study aimed to elucidate the differences in the metabolic milieu of adenocarcinomas of the gastrointestinal (GI) tract both related and unrelated to sex in obesity. To demonstrate these obesity and sex-related effects, we utilized three primary data sources: serum metabolomics from obese and non-obese patients assessed via the Biocrates MxP Quant 500 mass spectrometry-based kit, the ORIEN tumor RNA-sequencing data for all adenocarcinoma cases to assess the impacts of obesity, and publicly available TCGA transcriptional analysis to assess GI cancers and sex-related differences in GI cancers specifically. We applied and integrated our unique transcriptional metabolic pipeline in combination with our metabolomics data to reveal how obesity and sex can dictate differential metabolism in patients. Differentially expressed genes (DEG) analysis of ORIEN obese adenocarcinoma as compared to normal-weight adenocarcinoma patients resulted in large-scale transcriptional reprogramming (4029 DEGs, adj. p < 0.05 and |logFC| > 0.58). Gene Set Enrichment and metabolic pipeline analysis showed genes enriched for pathways relating to immunity (inflammation, and CD40 signaling, among others) and metabolism. Specifically, we found alterations to steroid metabolism and tryptophan/kynurenine metabolism in obese patients, both of which are highly associated with disease severity and immune cell dysfunction. These findings were further confirmed using the TCGA colorectal adenocarcinoma (CRC) and esophageal adenocarcinoma (ESCA) data, which showed similar patterns of increased tryptophan catabolism for kynurenine production in obese patients. These patients further showed disparate alterations between males and females when comparing obese to non-obese patient populations. Alterations to immune and metabolic pathways were validated in six patients (two obese and four normal weight) via CD8+/CD4+ peripheral blood mononuclear cell RNA-sequencing and paired serum metabolomics, which showed differential kynurenine and lipid metabolism, which corresponded with altered T-cell transcriptome in obese populations. Overall, obesity is associated with differential transcriptional and metabolic programs in various disease sites. Further, these alterations, such as kynurenine and tryptophan metabolism, which impact both metabolism and immune phenotype, vary with sex and obesity together. This study warrants further in-depth investigation into obesity and sex-related alterations in cancers that may better define biomarkers of response to immunotherapy.

In spring 2021, Nepal underwent a record wildfire season in which active fires were detected at a rate 10 times greater than the 2002–2020 average. Prior to these major wildfire events, the country experienced a prolonged precipitation deficit and extreme drought during the post-monsoon period (starting in October 2020). An analysis using observational, reanalysis, and climate model ensemble data indicates that both climate variability and climate change-induced severe drought conditions were at play. Further analysis of climate model outputs suggests the likely reoccurrence of drought conditions, thus favoring active wildfire seasons in Nepal throughout the twenty-first century. While the inter-model uncertainty is large and direct modeling of wildfire spread and suppression has not been completed, the demonstrated relationship between a drought index (the standardized precipitation and evapotranspiration index) and subsequent fire activity may offer actionable opportunities for forest managers to employ the monitoring and projection of climate anomalies at sub-seasonal to decadal timescales to inform their management strategies for Nepal’s wildlands.

IntroductionThe incidence of obesity, a condition characterized by systemic chronic inflammation, has reached pandemic proportions and is a poor prognostic factor in many pathologic states. However, its role on immune parameters has been diverse and at times contradictory. We have previously demonstrated that obesity can result in what has been called the "obesity paradox" which results in increased T cell exhaustion, but also greater efficacy of immune checkpoint blockade in cancer treatment.MethodsThe role of obesity, particularly in the context of aging, has not been robustly explored using preclinical models. We therefore evaluated how age impacts the immune environment on T cell development and function using diet-induced obese (DIO) mice.ResultsWe observed that DIO mice initially displayed greater thymopoiesis but then developed greater thymic involution over time compared to their lean counterparts. Both aging and obesity resulted in increased T cell memory conversion combined with increased expression of T cell exhaustion markers and Treg expansion. This increased T cell immunosuppression with age then resulted in a loss of anti-tumor efficacy by immune checkpoint inhibitors (ICIs) in older DIO mice compared to the younger DIO counterparts.DiscussionThese results suggest that both aging and obesity contribute to T cell dysfunction resulting in increased thymic involution. This combined with increased T cell exhaustion and immunosuppressive parameters affects immunotherapy efficacy reducing the advantage of obesity in cancer immunotherapy responses.

The role of immune checkpoint inhibitors for patients with gastroesophageal cancer with liver metastasis remains unclear. Our objective was to investigate whether immune checkpoint inhibitors are beneficial in patients with gastroesophageal cancer with liver metastasis. We searched PubMed, Embase, European Society for Medical Oncology, and American Society of Clinical Oncology meeting abstracts for phase 3 randomized clinical trials testing immune checkpoint inhibitors in metastatic/advanced gastroesophageal cancer from 2017 to 2023. Seven studies were included. Overall survival was similar among all patients (hazard ratio [HR] = 0.72 [95% confidence interval (CI) = 0.67 to 0.77], P  < .001), in patients without liver metastases (HR = 0.73 [95% CI = 0.67 to 0.81], P  < .001, I 2 = 0.0%), and in patients with liver metastases (HR = 0.74 [95% CI = 0.67 to 0.81], P  < .001, I 2 = 0.0%). Progression-free survival was also similar among all patients (HR = 0.63 [95% CI = 0.57 to 0.70], P  < .001), in patients without liver metastases (HR = 0.62 [95% CI = 0.51 to 0.76], P  < .001), and in patients with liver metastases (HR = 0.66 [95% CI = 0.57 to 0.76], P  < .001). Immune checkpoint inhibitors showed no difference in benefit in patients with gastroesophageal cancer, regardless of liver metastasis. Future studies could focus on deciphering the tumor microenvironment of liver metastasis as an area of translational research. [ABSTRACT FROM AUTHOR]

The recent successes of immunotherapy have shifted the paradigm in cancer treatment, but because only a percentage of patients are responsive to immunotherapy, it is imperative to identify factors impacting outcome. Obesity is reaching pandemic proportions and is a major risk factor for certain malignancies, but the impact of obesity on immune responses, in general and in cancer immunotherapy, is poorly understood. Here, we demonstrate, across multiple species and tumor models, that obesity results in increased immune aging, tumor progression and PD-1-mediated T cell dysfunction which is driven, at least in part, by leptin. However, obesity is also associated with increased efficacy of PD-1/PD-L1 blockade in both tumor-bearing mice and clinical cancer patients. These findings advance our understanding of obesity-induced immune dysfunction and its consequences in cancer and highlight obesity as a biomarker for some cancer immunotherapies. These data indicate a paradoxical impact of obesity on cancer. There is heightened immune dysfunction and tumor progression but also greater anti-tumor efficacy and survival after checkpoint blockade which directly targets some of the pathways activated in obesity.

Background/Objectives: Recent epidemiological studies have revealed an upward trend in young-onset colorectal cancer (YOCRC) overall, whereas specific data on young-onset colorectal neuroendocrine neoplasms (YONEN) remain limited. This study investigated the demographic characteristics and survival trends in YONEN and compared these with those of young-onset colorectal adenocarcinoma (YOADC), the most common histologic subtype of YOCRC. Methods: A retrospective analysis was conducted from 2000 to 2019 using the Surveillance, Epidemiology, and End Results (SEER) database. Survival outcomes were assessed using univariate and multivariable Cox proportional models, with demographic differences evaluated via Wilcoxon rank sum and Chi-square tests. Results: Out of 61,705 patients aged 20–49 with colorectal cancer, 8% had NEN, and 92% had adenocarcinoma. The YONEN cohort had a higher proportion of Black patients and a lower proportion of White patients than the YOADC cohort (21% vs. 13% and 44% vs. 57%, respectively). NEN was more commonly found in the rectum (79%), and adenocarcinoma was mostly colonic (57%) in origin. YONEN patients had better survival than YOADC patients. Multivariate analysis in YONEN patients revealed that Hispanic patients had better overall survival compared to White patients (HR 0.67, 95% CI 0.47–0.95, p = 0.024). Conclusions: Racial disparities should be investigated further to aid in policymaking and targeted interventions. [ABSTRACT FROM AUTHOR]

Background: Immune checkpoint inhibitors (ICIs) have revolutionized cancer care, with increasing data demonstrating improved survival outcomes using ICIs among patients with advanced gastroesophageal cancer (GEC). ICIs are also associated with a lower incidence of grade ≥ 3 adverse events (AEs) compared to chemotherapy, suggesting that ICIs may have favorable effects on health-related quality of life (HRQoL). This meta-analysis sought to evaluate the effects of ICIs on the HRQoL of patients with advanced GEC. Methods: We conducted an online bibliographic search on Medline via PubMed using MeSH-based terms to retrieve randomized controlled trials (RCTs) that evaluated the effects of ICIs on HRQoL in patients with advanced GEC (we searched for all studies between 2018 and 2021). We included RCTs that incorporated ICIs as part of the intervention arm either as monotherapy (first or second line) or as a combination therapy (first-line) with another ICI or chemotherapy. We combined the HRQoL measures into a meta-analysis using standard random effects models, from which estimates of the average mean difference (MD) were obtained with 95% confidence intervals. We assessed the heterogeneity of the study outcomes using the Q and I2 statistics. Results: We identified 11 phase 3 RCTs that met the inclusion criteria, with a mean enrollment of 820 patients. Eight RCTs used an ICI plus chemotherapy combination in the intervention arm, three had ICIs as monotherapy, and one had doublet ICI therapy in the intervention arm. All RCTs used chemotherapy for the control arm. Collectively, the trials reported 37 HRQoL measures using five different HRQoL tools. The pooled analysis favored the intervention over the control arm in terms of the Functional Assessment of Cancer Therapy-Esophageal (FACT-E) scores [MD 2.7 (95% CI 0.1 to 5.3), p < 0.041]. In a subgroup analysis of eight RCTs comparing combination therapy with ICIs plus chemotherapy versus chemotherapy alone, the effect estimates favored the ICI arm regarding the FACT-E [MD 2.7 (95% CI 0.1 to 5.3), p < 0.041] and the EORTC QLQ-OES18 pain scale [MD −2.2 (95% CI −4.3 to −0.2), p < 0.030]. Likewise, the effect estimates favored the ICI monotherapy arm over the chemotherapy arm regarding the QLQ-STO22 hair loss subscale [MD −23.2 (95% CI −29.7 to −16.7), p < 0.001], QLQ-STO22 dysphagia subscale [MD 6.7 (95% CI 1.7 to 11.7), p = 0.009], EQ-5D pain scale [MD 6.9 (95% CI 2.9 to 10.9), p < 0.001], and QLQ-OES18 saliva subscale [MD 5.8 (95% CI 0.1 to 11.6), p = 0.046]. Conclusions: In this meta-analysis, we found that the inclusion of ICIs as a first-line treatment for advanced GEC yielded better HRQoL outcomes than chemotherapy alone. Further research on the impact of ICIs on HRQoL is needed, with increasing evidence that ICIs improve the survival outcomes in patients with advanced GEC. [ABSTRACT FROM AUTHOR]

PURPOSE: Early-onset colorectal cancer (EOCRC), defined as CRC diagnosed before age 50 years, has increased significantly worldwide. The majority of EOCRCs do not appear to be driven by genetic factors and may be influenced by environmental factors. We hypothesized that sociodemographic disparities exist in EOCRC. The purpose was of the study was to examine the geographic disparities in patients with EOCRC. METHODS: We retrospectively examined the SEER database from 1976 to 2016 to examine the geographic disparities in EOCRC. A total of 73,378 patients with EOCRC were included in the analysis. We performed univariate and multivariable analyses to evaluate overall survival (OS) and disease-specific survival (DSS). Sociodemographic factors, including the location of residence (metropolitan areas [MA] or rural areas [RA]), sex, race, insurance status, and marital status, were included in the statistical analysis. RESULTS: The incidence and mortality rates were consistently higher in RA versus MA during the study period. Multivariable analysis showed that patients living in RA had worse OS (hazard ratio [HR], 1.14; P <.01) and DSS (HR, 1.15; P <.001) compared with those living in MA. Similarly, non-Hispanic Black ethnicity and uninsured patients had significantly worse survival when compared with non-Hispanic White and insured patients, respectively. Married status showed better survival outcomes. CONCLUSION: Patients with EOCRC living in RA have worse outcomes. Understanding the mechanisms behind such socioeconomic disparities is important so that future studies can reduce these disparities. We highlighted geographic disparities in YOCRC pts and found worse outcomes for YOCRC pts in rural versus urban areas. [ABSTRACT FROM AUTHOR]

Simple Summary: Recent animal studies have shown a correlation between environmental temperature and tumor growth. Based on these studies, we hypothesized that esophageal cancer and gastric cancer patients living in warmer climates have improved survival as compared to patients living in colder climates. We conducted a study using the SEER (Surveillance, Epidemiology, and End Results) database and analyzed the cancer outcomes with the county-level average annual temperature in which those patients resided. We analyzed 17,408 esophageal cancer and 20,533 gastric cancer patients. We noted for the first time that higher environmental temperatures were associated with significant improvements in survival in patients with esophageal and gastric cancers. Further confirmatory population-based studies as well as mechanistic-bench studies are needed to support our findings. Background: Cold stress suppresses antitumor response in animal models, leading to tumor growth. Recent studies have also shown a negative correlation between the average annual temperature (AAT) and cancer incidence. We hypothesized that esophageal cancer (EC) and gastric cancer (GC) patients living in warmer climates have improved survival outcomes than those living in colder climates. Methods: We conducted a retrospective analysis using the Surveillance, Epidemiology, and End Results (SEER) database from 1996 to 2015. We retrieved the National Centers for Environmental Information data to calculate the county-level AAT. Cox multivariate regression models were performed to measure the association between temperature (measured continuously at diagnosis and in 5-degree increments) and OS/DSS, adjusting for variables. All associations were compared at a significance level of 0.05. The OS and DSS were summarized using Kaplan–Meier methods. All statistics were performed using SAS version 9.4 (SAS Institute Inc., Cary, NC, USA). Results: A total of 17,408 EC patients were analyzed. The average age of the cohort was 65 years, 79% of which were males and 21% were females. Of them, 61.6% had adenocarcinoma, and 37.6% were squamous. After adjusting for covariates, patients in regions with an AAT > 53.5 °F had an 11% improvement in OS [HR 0.89 (95% CI 0.86–0.92), p < 0.0001] and 13% in DSS [HR 0.87 (95% CI 0.84–0.90), p < 0.0001]. When the temperature was analyzed in 5 °F increments, with each increment, there was a 3% improvement in OS [HR 0.97 (95% CI 0.96–0.98), p < 0.0001] and 4% in DSS [HR 0.96 (95% CI 0.95–0.97), p < 0.0001]. Subgroup analysis of squamous and adenocarcinoma showed similar results. These findings were validated in 20,553 GC patients. After adjusting for covariates, patients in regions with an AAT > 53.5 had a 13% improvement in OS [HR 0.87 (95% CI 0.85–0.90), p < 0.0001] and 14% in DSS [HR 0.86 (95% CI 0.83–0.89), p < 0.0001]. When analyzed in 5 °F increments, with each increment, there was a 4% improvement in OS [HR 0.96 (95% CI 0.952–0.971), p < 0.0001] and 4% in DSS [HR 0.96 (95% CI 0.945–0.965), p < 0.0001]. Conclusion: We showed for the first time that higher environmental temperatures are associated with significant improvements in OS and DSS in patients with gastro-esophageal cancers, notwithstanding the limitations of a retrospective database analysis. Further confirmatory and mechanistic studies are required to implement specific interventional strategies. [ABSTRACT FROM AUTHOR]