Jennifer A. Wargo, Nadim J. Ajami, and Carrie R. Daniel-MacDougall.

Dr. Jennifer A. Wargo, Dr. Nadim J. Ajami, and Dr. Carrie R. Daniel-MacDougall describe their academic and clinical work on the role of the microbiome to determine response to immunotherapies and discuss current challenges and potential needs to integrate their findings into clinical practice.

The Gut Microbiome as a Biomarker and Therapeutic Target in Hepatocellular Carcinoma.

The microbiome is pivotal in maintaining health and influencing disease by modulating essential inflammatory and immune responses. Hepatocellular carcinoma (HCC), ranking as the third most common cause of cancer-related fatalities globally, is influenced by the gut microbiome through bidirectional interactions between the gut and liver, as evidenced in both mouse models and human studies. Consequently, biomarkers based on gut microbiota represent promising non-invasive tools for the early detection of HCC. There is a growing body of evidence suggesting that the composition of the gut microbiota may play a role in the efficacy of immunotherapy in different types of cancer; thus, it could be used as a predictive biomarker. In this review, we will dissect the gut microbiome's role as a potential predictive and diagnostic marker in HCC and evaluate the latest progress in leveraging the gut microbiome as a novel therapeutic avenue for HCC patients, with a special emphasis on immunotherapy.

Incidence and Risk Factors for Pneumonitis Associated With Checkpoint Inhibitors in Advanced Non-Small Cell Lung Cancer: A Single Center Experience.

INTRODUCTION: Immune checkpoint inhibitor (ICI) pneumonitis causes substantial morbidity and mortality. Estimates of real-world incidence and reported risk factors vary substantially. METHODS: We conducted a retrospective review of 419 patients with advanced non-small cell lung cancer (NSCLC) who were treated with anti-PD-(L)1 with or without anti-CTLA-4 therapy. Clinical, imaging, and microbiological data were evaluated by multidisciplinary adjudication teams. The primary outcome of interest was grade ≥2 (CTCAEv5) pneumonitis. Clinicopathologic variables, tobacco use, cancer therapies, and preexisting lung disease were assessed for univariate effects using Cox proportional hazards models. We created multivariate Cox proportional hazards models to assess risk factors for pneumonitis and mortality. Pneumonitis, pneumonia, and progression were modeled as time-dependent variables in mortality models. RESULTS: We evaluated 419 patients between 2013 and 2021. The cumulative incidence of pneumonitis was 9.5% (40/419). In a multivariate model, pneumonitis increased the risk for mortality (HR 1.6, 95% CI, 1.0-2.5), after adjustment for disease progression (HR 1.6, 95% CI, 1.4-1.8) and baseline shortness of breath (HR 1.5, 95% CI, 1.2-2.0). Incomplete resolution was more common with more severe pneumonitis. Interstitial lung disease was associated with higher risk for pneumonitis (HR 5.4, 95% CI, 1.1-26.6), particularly in never smokers (HR 26.9, 95% CI, 2.8-259.0). CONCLUSION: Pneumonitis occurred at a high rate and significantly increased mortality. Interstitial lung disease, particularly in never smokers, increased the risk for pneumonitis.

Diet-derived metabolites and mucus link the gut microbiome to fever after cytotoxic cancer treatment.

Not all patients with cancer and severe neutropenia develop fever, and the fecal microbiome may play a role. In a single-center study of patients undergoing hematopoietic cell transplant (n = 119), the fecal microbiome was characterized at onset of severe neutropenia. A total of 63 patients (53%) developed a subsequent fever, and their fecal microbiome displayed increased relative abundances of Akkermansia muciniphila, a species of mucin-degrading bacteria (P = 0.006, corrected for multiple comparisons). Two therapies that induce neutropenia, irradiation and melphalan, similarly expanded A. muciniphila and additionally thinned the colonic mucus layer in mice. Caloric restriction of unirradiated mice also expanded A. muciniphila and thinned the colonic mucus layer. Antibiotic treatment to eradicate A. muciniphila before caloric restriction preserved colonic mucus, whereas A. muciniphila reintroduction restored mucus thinning. Caloric restriction of unirradiated mice raised colonic luminal pH and reduced acetate, propionate, and butyrate. Culturing A. muciniphila in vitro with propionate reduced utilization of mucin as well as of fucose. Treating irradiated mice with an antibiotic targeting A. muciniphila or propionate preserved the mucus layer, suppressed translocation of flagellin, reduced inflammatory cytokines in the colon, and improved thermoregulation. These results suggest that diet, metabolites, and colonic mucus link the microbiome to neutropenic fever and may guide future microbiome-based preventive strategies.

Association of dietary fat intake and hepatocellular carcinoma among US adults.

BACKGROUND AND AIMS: The role of dietary fat consumption in the etiology of hepatocellular carcinoma (HCC) remains unclear. We investigated the associations of total fat and fatty acids with risk of HCC among US adults in a hospital-based case-control study. METHODS: We analyzed data from 641 cases and 1034 controls recruited at MD Anderson Cancer Center during 2001-2018. Cases were new patients with a pathologically or radiologically confirmed diagnosis of HCC; controls were cancer-free spouses of patients with cancers other than gastrointestinal, lung, liver, or head and neck. Cases and controls were frequency-matched by age and sex. Dietary intake was assessed using a validated food frequency questionnaire. Odds ratios (ORs) and corresponding confidence intervals (CIs) were computed using unconditional logistic regression with adjustment for major HCC risk factors, including hepatitis B virus and hepatitis C virus infection. RESULTS: Monounsaturated fatty acid (MUFA) intake was inversely associated with HCC risk (highest vs. lowest tertile: OR, 0.49; 95% CI, 0.33-0.72). Total polyunsaturated fatty acid (PUFA) intake was directly associated with HCC risk (highest vs. lowest tertile: OR, 1.82; 95% CI, 1.23-2.70). Omega-6 PUFA was directly associated with HCC risk (highest vs. lowest tertile: OR 2.29; 95% CI, 1.52-3.44). Long-chain omega-3 PUFA (eicosapentaenoic acid and docosahexaenoic acid) intake was also inversely associated with HCC risk (highest vs. lowest tertile: OR, 0.50; 95% CI, 0.33-0.70). No association was observed for saturated fat and HCC risk. CONCLUSION: Our findings support a direct association of omega-6 PUFA intake with HCC and an inverse association of MUFA and long-chain omega-3 PUFA intake with HCC.

A systematic review of the use of dietary self-monitoring in behavioural weight loss interventions: delivery, intensity and effectiveness.

OBJECTIVE: To identify dietary self-monitoring implementation strategies in behavioural weight loss interventions. DESIGN: We conducted a systematic review of eight databases and examined fifty-nine weight loss intervention studies targeting adults with overweight/obesity that used dietary self-monitoring. SETTING: NA. PARTICIPANTS: NA. RESULTS: We identified self-monitoring implementation characteristics, effectiveness of interventions in supporting weight loss and examined weight loss outcomes among higher and lower intensity dietary self-monitoring protocols. Included studies utilised diverse self-monitoring formats (paper, website, mobile app, phone) and intensity levels (recording all intake or only certain aspects of diet). We found the majority of studies using high- and low-intensity self-monitoring strategies demonstrated statistically significant weight loss in intervention groups compared with control groups. CONCLUSIONS: Based on our findings, lower and higher intensity dietary self-monitoring may support weight loss, but variability in adherence measures and limited analysis of weight loss relative to self-monitoring usage limits our understanding of how these methods compare with each other.

Dietary Patterns and Hepatocellular Carcinoma Risk among US Adults.

The objective of this study was to assess the association between dietary patterns and risk of hepatocellular carcinoma (HCC) among US adults in a hospital-based case-control study. We analyzed data from 641 cases and 1002 controls recruited at The University of Texas MD Anderson Cancer Center during 2001-2018. Cases were patients with a pathologically or radiologically confirmed new diagnosis of HCC; controls were cancer-free spouses of patients with cancers other than gastrointestinal, lung, liver, or head and neck cancer. Cases and controls were frequency-matched by age and sex. Dietary patterns were identified by principal component analysis. Odds ratios (ORs) and corresponding confidence intervals (CIs) were computed using unconditional logistic regression with adjustment for major HCC risk factors, including hepatitis B virus and hepatitis C virus infection. A vegetable-based dietary pattern was inversely associated with HCC risk (highest compared with lowest tertile: OR 0.66, 95% CI 0.46-0.94). A Western diet pattern was directly associated with HCC risk (highest compared with lowest tertile: OR 1.79, 95% CI 1.19-2.69). These findings emphasize the potential role of dietary intake in HCC prevention and clinical management.

Plasma MicroRNA signature predicting weight gain among Mexican-American women.

OBJECTIVE: There is growing evidence that circulating microRNAs (miRNAs) play an important role in obesity. However, whether they can contribute to adult weight gain is still unclear. METHODS: In the training set with 40 nonsmoking, healthy women identified from the Mano-A-Mano Mexican American Cohort study, global circulating miRNA profiles in plasma samples were assessed. Cox proportional hazard regression was used to assess the effects of plasma miRNAs on significant weight gain during a 5-year follow-up. Plasma miRNAs associated with significant weight gain were further validated in two testing sets (N = 160 and 100, respectively). RESULTS: A total of 23 significant plasma miRNAs were identified in the training set. Among them, eight were validated in two testing sets. They were miR-142, miR-122, miR-125b, miR-15b, miR-130b, miR222, miR-519d, and miR-31. Using those eight miRNAs, a risk score for significant weight gain was created. Study participants with a high risk score had 3.01-fold increased risk of having significant weight gain in the whole study population (hazard ratio: 3.01, 95% confidence interval: 1.70-5.47). CONCLUSIONS: The findings provide evidence that circulating miRNAs play important roles in obesity and weight gain and suggest new targets for understanding the mechanisms of weight gain and developing weight loss intervention strategies.