Association between pre-diagnostic circulating lipid metabolites and colorectal cancer risk: a nested case-control study in the European Prospective Investigation into Cancer and Nutrition (EPIC).

BACKGROUND: Altered lipid metabolism is a hallmark of cancer development. However, the role of specific lipid metabolites in colorectal cancer development is uncertain. METHODS: In a case-control study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC), we examined associations between pre-diagnostic circulating concentrations of 97 lipid metabolites (acylcarnitines, glycerophospholipids and sphingolipids) and colorectal cancer risk. Circulating lipids were measured using targeted mass spectrometry in 1591 incident colorectal cancer cases (55% women) and 1591 matched controls. Multivariable conditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for associations between concentrations of individual lipid metabolites and metabolite patterns with colorectal cancer risk. FINDINGS: Of the 97 assayed lipids, 24 were inversely associated (nominally p < 0.05) with colorectal cancer risk. Hydroxysphingomyelin (SM (OH)) C22:2 (ORper doubling 0.60, 95% CI 0.47-0.77) and acylakyl-phosphatidylcholine (PC ae) C34:3 (ORper doubling 0.71, 95% CI 0.59-0.87) remained associated after multiple comparisons correction. These associations were unaltered after excluding the first 5 years of follow-up after blood collection and were consistent according to sex, age at diagnosis, BMI, and colorectal subsite. Two lipid patterns, one including 26 phosphatidylcholines and all sphingolipids, and another 30 phosphatidylcholines, were weakly inversely associated with colorectal cancer. INTERPRETATION: Elevated pre-diagnostic circulating levels of SM (OH) C22:2 and PC ae C34:3 and lipid patterns including phosphatidylcholines and sphingolipids were associated with lower colorectal cancer risk. This study may provide insight into potential links between specific lipids and colorectal cancer development. Additional prospective studies are needed to validate the observed associations. FUNDING: World Cancer Research Fund (reference: 2013/1002); European Commission (FP7: BBMRI-LPC; reference: 313010).

Relationships Among Physical Activity, Sleep, and Cancer-related Fatigue: Results From the International ColoCare Study.

BACKGROUND: Risk factors for cancer-related fatigue are understudied in colorectal cancer. PURPOSE: This study aimed to address this critical gap in the literature by (a) describing changes in colorectal cancer-related fatigue and health behavior (physical activity, sleep problems) and (b) examining if physical activity and sleep problems predict fatigue trajectories from baseline (approximately at the time of diagnosis), to 6- and 12 months after enrollment. METHODS: Patients participating in the international ColoCare Study completed self-report measures at baseline (approximately time of diagnosis), 6-, and 12 months assessing physical activity using the International Physical Activity Questionnaire (IPAQ) and fatigue and sleep using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-C30). Mixed-effect models examined changes in physical activity, sleep problems, and fatigue. Cross-lagged panel models examined bidirectional relationships between physical activity or sleep and fatigue across time. RESULTS: Colorectal cancer patients (n = 649) had a mean age of 61 ± 13 years. Most were male (59%), non-Hispanic White (91%), diagnosed with Stages III-IV (56%) colon cancer (58%), and treated with surgery (98%). Within-person cross-lagged models indicated higher physical activity at Month 6 was associated with higher fatigue at Month 12 (ß = 0.26, p = .016). When stratified by cancer stage (I-II vs. III-IV), the relationship between physical activity at Month 6 and fatigue at Month 12 existed only for patients with advanced cancer (Stages III and IV, ß = 0.43, p = .035). Cross-lagged associations for sleep and fatigue from baseline to Month 6 were only observed in patients with Stages III or IV cancer, however, there was a clear cross-sectional association between sleep problems and fatigue at baseline and Month 6. CONCLUSIONS: Within-person and cross-lagged association models suggest fatiguability may become increasingly problematic for patients with advanced colorectal cancer the first year after diagnosis. In addition, sleep problems were consistently associated with higher fatigue in the first year, regardless of cancer stage. TRIAL REGISTRATION: The international ColoCare Study was registered on clinicaltrials.gov, NCT02328677, in December 2014.

Within-person and cross-lagged association models suggest fatiguability may become increasingly problematic for patients with advanced (Stages III and IV) colorectal cancer the first year after diagnosis.

A metabolomic investigation of serum perfluorooctane sulfonate and perfluorooctanoate.

BACKGROUND: Exposures to perfluorooctane sulfonate (PFOS) and perfluorooctanoate (PFOA), environmentally persistent chemicals detectable in the blood of most Americans, have been associated with several health outcomes. To offer insight into their possible biologic effects, we evaluated the metabolomic correlates of circulating PFOS and PFOA among 3,647 participants in eight nested case-control serum metabolomic profiling studies from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. METHODS: Metabolomic profiling was conducted by Metabolon Inc., using ultra high-performance liquid chromatography/tandem accurate mass spectrometry. We conducted study-specific multivariable linear regression analyses estimating the associations of metabolite levels with levels of PFOS or PFOA. For metabolites measured in at least 3 of 8 nested case-control studies, random effects meta-analysis was used to summarize study-specific results (1,038 metabolites in PFOS analyses and 1,100 in PFOA analyses). RESULTS: The meta-analysis identified 51 and 38 metabolites associated with PFOS and PFOA, respectively, at a Bonferroni-corrected significance level (4.8x10-5 and 4.6x10-5, respectively). For both PFOS and PFOA, the most common types of associated metabolites were lipids (sphingolipids, fatty acid metabolites) and xenobiotics (xanthine metabolites, chemicals). Positive associations were commonly observed with lipid metabolites sphingomyelin (d18:1/18:0) (P = 2.0x10-10 and 2.0x10-8, respectively), 3-carboxy-4-methyl-5-pentyl-2-furanpropionate (P = 2.7x10-15, 1.1x10-17), and lignoceroylcarnitine (C24) (P = 2.6x10-8, 6.2x10-6). The strongest positive associations were observed for chemicals 3,5-dichloro-2,6-dihydroxybenzoic acid (P = 3.0x10-112 and 6.8x10-13, respectively) and 3-bromo-5-chloro-2,6-dihydroxybenzoic acid (P = 1.6x10-14, 2.3x10-6). Other metabolites positively associated with PFOS included D-glucose (carbohydrate), carotene diol (vitamin A metabolism), and L-alpha-aminobutyric acid (glutathione metabolism), while uric acid (purine metabolite) was positively associated with PFOA. PFOS associations were consistent even after adjusting for PFOA as a covariate, while PFOA associations were greatly attenuated with PFOS adjustment. CONCLUSIONS: In this large metabolomic study, we observed robust positive associations with PFOS for several molecules. Further investigation of these metabolites may offer insight into PFOS-related biologic effects.

Trajectories and risk factors of fatigue following colorectal cancer diagnosis.

AIM: This study sought to identify groups of colorectal cancer patients based upon trajectories of fatigue and examine how demographic, clinical and behavioural risk factors differentiate these groups. METHOD: Patients were from six cancer centres in the United States and Germany. Fatigue was measured using the fatigue subscale of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) at five time points (baseline/enrolment and 3, 6, 12 and 24 months after diagnosis). Piecewise growth mixture models identified latent trajectories of fatigue. Logistic regression models examined differences in demographic, clinical and behavioural characteristics between fatigue trajectory groups. RESULTS: Among 1615 participants (57% men, 86% non-Hispanic White, mean age 61 ± 13 years at diagnosis), three distinct groups were identified. In the high fatigue group (36%), fatigue significantly increased in the first 6 months after diagnosis and then showed statistically and clinically significant improvement from 6 to 24 months (P values < 0.01). Throughout the study period, average fatigue met or exceeded cutoffs for clinical significance. In the moderate (34%) and low (30%) fatigue groups, fatigue levels remained below or near population norms across the study period. Patients who were diagnosed with Stage II-IV disease and/or current smokers were more likely to be in the high fatigue than in the moderate fatigue group (P values < 0.05). CONCLUSION: A large proportion of colorectal cancer patients experienced sustained fatigue after initiation of cancer treatment. Patients with high fatigue at the time of diagnosis may benefit from early supportive care.

Long-term cancer outcomes after bariatric surgery.

OBJECTIVE: Obesity is associated with increased cancer risk. Because of the substantial and sustained weight loss following bariatric surgery, postsurgical patients are ideal to study the association of weight loss and cancer. METHODS: Retrospectively (1982-2019), 21,837 bariatric surgery patients (surgery, 1982-2018) were matched 1:1 by age, sex, and BMI with a nonsurgical comparison group. Procedures included gastric bypass, gastric banding, sleeve gastrectomy, and duodenal switch. Primary outcomes included cancer incidence and mortality, stratified by obesity- and non-obesity-related cancers, sex, cancer stage, and procedure. RESULTS: Bariatric surgery patients had a 25% lower risk of developing any cancers compared with a nonsurgical comparison group (hazard ratio [HR] 0.75; 95% CI 0.69-0.81; p < 0.001). Cancer incidence was lower among female (HR 0.67; 95% CI 0.62-0.74; p < 0.001) but not male surgery patients, with the HR lower for females than for males (p < 0.001). Female surgery patients had a 41% lower risk for obesity-related cancers (i.e., breast, ovarian, uterine, and colon) compared with nonsurgical females (HR 0.59; 95% CI 0.52-0.66; p < 0.001). Cancer mortality was significantly lower after surgery in females (HR 0.53; 95% CI 0.44-0.64; p < 0.001). CONCLUSIONS: Bariatric surgery was associated with lower all-cancer and obesity-related cancer incidence among female patients. Cancer mortality was significantly lower among females in the surgical group versus the nonsurgical group.

New-Onset Diabetes after an Obesity-Related Cancer Diagnosis and Survival Outcomes in the Women's Health Initiative.

BACKGROUND: Individuals diagnosed with an obesity-related cancer (ORC survivors) are at an elevated risk of incident diabetes compared with cancer-free individuals, but whether this confers survival disadvantage is unknown. METHODS: We assessed the rate of incident diabetes in ORC survivors and evaluated the association of incident diabetes with all-cause and cancer-specific mortality among females with ORC in the Women's Health Initiative cohort (N = 14,651). Cox proportional hazards regression models stratified by exposure-risk periods (0-1, >1-3, >3-5, >5-7, and >7-10 years) from ORC diagnosis and time-varying exposure (diabetes) analyses were performed. RESULTS: Among the ORC survivors, a total of 1.3% developed diabetes within ≤1 year of follow-up and 2.5%, 2.3%, 2.3%, and 3.6% at 1-3, 3-5, 5-7, and 7-10 years of follow-up, respectively, after an ORC diagnosis. The median survival for those diagnosed with diabetes within 1-year of cancer diagnosis and those with no diabetes diagnosis in that time frame was 8.8 [95% confidence interval (CI), 7.0-14.5) years and 16.6 (95% CI, 16.1-17.0) years, respectively. New-onset compared with no diabetes as a time-varying exposure was associated with higher risk of all-cause (HR, 1.27; 95% CI, 1.16-1.40) and cancer-specific (HR, 1.17; 95% CI, 0.99-1.38) mortality. When stratified by exposure-risk periods, incident diabetes in ≤1 year of follow-up was associated with higher all-cause (HR, 1.76; 95% CI, 1.40-2.20) and cancer-specific (HR0-1, 1.82; 95% CI, 1.28-2.57) mortality, compared with no diabetes diagnosis. CONCLUSIONS: Incident diabetes was associated with worse cancer-specific and all-cause survival, particularly in the year after cancer diagnosis. IMPACT: These findings draw attention to the importance of diabetes prevention efforts among cancer survivors to improve survival outcomes.

Trends in Diet and Cancer Research: A Bibliometric and Visualization Analysis.

Diet plays a critical role for patients across the cancer continuum. The World Cancer Research Fund International and the American Cancer Society have published evidence supporting the role of nutrition in cancer prevention. We conducted an analysis of the literature on dietary nutrients and cancer to uncover opportunities for future research. The objective of the bibliometric analysis was to describe trends in peer-reviewed publications on dietary components and cancer and to highlight research gaps. PubMed was queried for manuscripts with diet- and cancer-related keywords and Medical Subject Headings (MeSH) terms. Metadata covering 99,784 publications from 6469 journals were analyzed to identify trends since 1970 on diet topics across 19 tumor types. Publications focused largely on breast, colorectal, and liver cancer, with fewer papers linking diet with other cancers such as brain, gallbladder, or ovarian. With respect to "unhealthy" diets, many publications focused on high-fat diets and alcohol consumption. The largest numbers of publications related to "healthy" diets examined the Mediterranean diet and the consumption of fruits and vegetables. These findings highlight the need for additional research focused on under-investigated cancers and dietary components, as well as dietary studies during cancer therapy and post-therapy, which may help to prolong survivorship.

Ceramides Increase Fatty Acid Utilization in Intestinal Progenitors to Enhance Stemness and Increase Tumor Risk.

BACKGROUND & AIMS: Cancers of the alimentary tract, including esophageal adenocarcinomas, colorectal cancers, and cancers of the gastric cardia, are common comorbidities of obesity. Prolonged, excessive delivery of macronutrients to the cells lining the gut can increase one's risk for these cancers by inducing imbalances in the rate of intestinal stem cell proliferation vs differentiation, which can produce polyps and other aberrant growths. We investigated whether ceramides, which are sphingolipids that serve as a signal of nutritional excess, alter stem cell behaviors to influence cancer risk. METHODS: We profiled sphingolipids and sphingolipid-synthesizing enzymes in human adenomas and tumors. Thereafter, we manipulated expression of sphingolipid-producing enzymes, including serine palmitoyltransferase (SPT), in intestinal progenitors of mice, cultured organoids, and Drosophila to discern whether sphingolipids altered stem cell proliferation and metabolism. RESULTS: SPT, which diverts dietary fatty acids and amino acids into the biosynthetic pathway that produces ceramides and other sphingolipids, is a critical modulator of intestinal stem cell homeostasis. SPT and other enzymes in the sphingolipid biosynthesis pathway are up-regulated in human intestinal adenomas. They produce ceramides, which serve as prostemness signals that stimulate peroxisome-proliferator activated receptor-α and induce fatty acid binding protein-1. These actions lead to increased lipid utilization and enhanced proliferation of intestinal progenitors. CONCLUSIONS: Ceramides serve as critical links between dietary macronutrients, epithelial regeneration, and cancer risk.

Dietary Oncopharmacognosy as a Crosswalk between Precision Oncology and Precision Nutrition.

While diet and nutrition are modifiable risk factors for many chronic and infectious diseases, their role in cancer prevention and control remains under investigation. The lack of clarity of some diet-cancer relationships reflects the ongoing debate about the relative contribution of genetic factors, environmental exposures, and replicative errors in stem cell division as determinate drivers of cancer risk. In addition, dietary guidance has often been based upon research assuming that the effects of diet and nutrition on carcinogenesis would be uniform across populations and for various tumor types arising in a specific organ, i.e., that one size fits all. Herein, we present a paradigm for investigating precision dietary patterns that leverages the approaches that led to successful small-molecule inhibitors in cancer treatment, namely understanding the pharmacokinetics and pharmacodynamics of small molecules for targeting carcinogenic mechanisms. We challenge the scientific community to refine the paradigm presented and to conduct proof-in-concept experiments that integrate existing knowledge (drug development, natural products, and the food metabolome) with developments in artificial intelligence to design and then test dietary patterns predicted to elicit drug-like effects on target tissues for cancer prevention and control. We refer to this precision approach as dietary oncopharmacognosy and envision it as the crosswalk between the currently defined fields of precision oncology and precision nutrition with the goal of reducing cancer deaths.

Metabolomic Analysis of Vitamin E Supplement Use in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial.

The effects of vitamin E supplementation on cancer and other chronic diseases are not clear. We compared the serum metabolomic profile of differing vitamin E dosages in order to re-examine the previously observed changes in a novel C22 lactone sulfate compound, androgenic steroids, and other metabolites. A total of 3409 women and men previously selected for metabolomics studies in the PLCO Cancer Screening Trial were included in this investigation. Serum metabolites were profiled using ultrahigh-performance liquid and gas chromatography/tandem mass spectrometry. Seventy known metabolites including C22 lactone sulfate and androgens were significantly associated with vitamin E supplementation. In the sex-stratified analysis, 10 cofactors and vitamins (e.g., alpha-CEHC sulfate and alpha-CEHC glucuronide), two carbohydrates (glyceric and oxalic acids), and one lipid (glycocholenate sulfate) were significantly associated with vitamin E dose in both males and females (FDR-adjusted p-value < 0.01). However, the inverse association between C22 lactone sulfate and daily vitamin E supplementation was evident in females only, as were two androgenic steroids, 5-androstenediol and androsterone glucuronide. Our study provides evidence of distinct steroid hormone pathway responses based on vitamin E dosages. Further studies are needed to gain biological insights into vitamin E biochemical effects relevant to cancer and other chronic diseases.

Metabolic obesity phenotypes and obesity-related cancer risk in the National Health and Nutrition Examination Survey.

INTRODUCTION: Body mass index (BMI) fails to identify up to one-third of normal weight individuals with metabolic dysfunction who may be at increased risk of obesity-related cancer (ORC). Metabolic obesity phenotypes, an alternate metric to assess metabolic dysfunction with or without obesity, were evaluated for association with ORC risk. METHODS: National Health and Nutrition Examination Survey participants from 1999 to 2018 (N = 19,500) were categorized into phenotypes according to the metabolic syndrome (MetS) criteria and BMI: metabolically healthy normal weight (MHNW), metabolically unhealthy normal weight (MUNW), metabolically healthy overweight/obese (MHO) and metabolically unhealthy overweight/obese (MUO). Adjusted multivariable logistic regression models were used to evaluate associations with ORC. RESULTS: With metabolic dysfunction defined as ≥1 MetS criteria, ORC cases (n = 528) had higher proportions of MUNW (28.2% vs. 17.4%) and MUO (62.6% vs. 60.9%) phenotypes than cancer-free individuals (n = 18,972). Compared with MHNW participants, MUNW participants had a 2.2-times higher ORC risk [OR (95%CI) = 2.21 (1.27-3.85)]. MHO and MUO participants demonstrated a 43% and 56% increased ORC risk, respectively, compared to MHNW, but these did not reach statistical significance [OR (95% CI) = 1.43 (0.46-4.42), 1.56 (0.91-2.67), respectively]. Hyperglycaemia, hypertension and central obesity were all independently associated with higher ORC risk compared to MHNW. CONCLUSIONS: MUNW participants have a higher risk of ORC than other abnormal phenotypes, compared with MHNW participants. Incorporating metabolic health measures in addition to assessing BMI may improve ORC risk stratification. Further research on the relationship between metabolic dysfunction and ORC is warranted.

Metabolic and bariatric surgery and obesity pharmacotherapy for cancer prevention: current status and future possibilities.

Obesity is a chronic, relapsing, progressive disease of excess adiposity that increases the risk of developing at least 13 types of cancer. This report provides a concise review of the current state of the science regarding metabolic and bariatric surgery and obesity pharmacotherapy related to cancer risk. Meta-analyses of cohort studies report that metabolic and bariatric surgery is independently associated with a lower risk of incident cancer than nonsurgical obesity care. Less is known regarding the cancer-preventive effects of obesity pharmacotherapy. The recent approval and promising pipeline of obesity drugs will provide the opportunity to understand the potential for obesity therapy to emerge as an evidence-based cancer prevention strategy. There are myriad research opportunities to advance our understanding of how metabolic and bariatric surgery and obesity pharmacotherapy may be used for cancer prevention.

Reliability estimates for assessing meal timing derived from longitudinal repeated 24-hour dietary recalls.

BACKGROUND: Regulating meal timing may have efficacy for improving metabolic health for preventing or managing chronic disease. However, the reliability of measuring meal timing with commonly used dietary assessment tools needs characterization prior to investigating meal timing and health outcomes in epidemiologic studies. OBJECTIVES: To evaluate the reliability of estimating meal timing parameters, including overnight fasting duration, the midpoint of overnight fasting time, the number of daily eating episodes, the period with the largest percentage of daily caloric intake, and late last eating episode (> 09:00 pm) from repeated 24-h dietary recalls (24HRs). METHODS: Intraclass correlation coefficients (ICC), Light's Kappa estimates, and 95% CIs were calculated from repeated 24HR administered in 3 epidemiologic studies: The United States-based Interactive Diet and Activity Tracking in AARP (IDATA) study (n = 996, 6 24HR collected over 12-mo), German EPIC-Potsdam Validation Study (European Prospective Investigation into Cancer and Nutrition Potsdam Germany cohort) (n = 134, 12 24HR collected over 12-mo) and EPIC-Potsdam BMBF-II Study (Federal Ministry of Education and Research, "Bundesministerium für Bildung und Forschung") (n = 725, 4 24HR collected over 36 mo). RESULTS: Measurement reliability of overnight fasting duration based on a single 24HR was "poor" in all studies [ICC range: 0.27; 95% CI: 0.23, 0.32 - 0.46; 95% CI: 0.43, 0.50]. Reliability was "moderate" with 3 24HR (ICC range: 0.53; 95% CI: 0.47, 0.58 in IDATA, 0.62; 95% CI: 0.52, 0.69 in the EPIC-Potsdam Validation Study, and 0.72; 95% CI: 0.70-0.75 in the EPIC-Potsdam BMBF-II Study). Results were similar for the midpoint of overnight fasting time and the number of eating episodes. Reliability of measuring late eating was "fair" in IDATA (Light's Kappa: 0.30; 95% CI: 0.21, 0.39) and "slight" in the EPIC-Potsdam Validation study and the EPIC-Potsdam BMBF-II study (Light's Kappa: 0.19; 95% CI: 0.15, 0.25 and 0.09; 95% CI: 0.06, 0.12, respectively). Reliability estimates differed by sex, BMI, weekday, and season of 24HR administration in some studies. CONCLUSIONS: Our results show that ≥ 3 24HR over a 1-3-y period are required for reliable estimates of meal timing variables.

Metabolic dysfunction and obesity-related cancer: Results from the cross-sectional National Health and Nutrition Examination Survey.

BACKGROUND: Metabolic syndrome (MetS), a group of risk factors that define metabolic dysfunction in adults, is strongly associated with obesity and is an emerging risk factor for cancer. However, the association of MetS and degree of metabolic dysfunction with obesity-related cancer is unknown. METHODS: Using National Health and Nutrition Examination Survey data from 1999 to 2018, we identified 528 obesity-related cancer cases and 18,972 cancer-free participants. MetS was defined as the presence of or treatment for ≥3 of hyperglycemia, hypertension, hypertriglyceridemia, low HDL-cholesterol, and abdominal obesity. A metabolic syndrome score (MSS) was computed as the total number of abnormal MetS parameters to determine the severity of metabolic dysfunction. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using multivariable logistic regression models, adjusting for sociodemographic and lifestyle factors. RESULTS: About 45.7% of obesity-related cancer cases were classified as having MetS compared with only 33.0% of cancer-free participants. Overall, MetS and MSS were not associated with obesity-related cancer. However, MSS was associated with higher obesity-related cancer risk among participants under 50 years of age (OR [95% CI] = 1.28 [1.08-1.52]). When evaluating MSS categorically, compared with healthy participants with no abnormal MetS parameters (MSS = 0), participants with one or two abnormal parameters had a statistically significant higher risk of obesity-related cancer (OR [95% CI] = 1.73 [1.06-2.83]). CONCLUSIONS: Metabolic dysfunction is associated with a higher risk of obesity-related cancer, particularly in young adults under 50 years of age, and among participants with one or two abnormal metabolic parameters. A more accurate indicator of metabolic dysfunction, beyond metabolic syndrome, is needed to better assist in stratifying individuals for obesity-related cancer risk.

Inflammatory and insulinemic dietary patterns and risk of endometrial cancer among US women.

BACKGROUND: Although unopposed estrogen exposure is considered a major driver of endometrial carcinogenesis, chronic inflammation and insulin resistance and hyperinsulinemia are also major endometrial cancer risk factors. However, it is unclear whether diets with inflammatory or insulinemic potential are associated with risk of endometrial cancer. METHODS: We followed 48 330 women from the Nurses' Health Study (1984-2016) and 85 426 women from the Nurses' Health Study II (1989-2017). Using food frequency questionnaires, we calculated repeated measures of empirical dietary inflammatory pattern (EDIP) and empirical dietary index for hyperinsulinemia (EDIH) scores, which characterize the potential of the whole diet to modulate circulating biomarkers of inflammation or C-peptide, respectively. We used multivariable-adjusted Cox regression to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for type I endometrial cancer risk. RESULTS: We documented 1462 type I endometrial cancer cases over 2 823 221 person-years of follow-up. In the pooled multivariable-adjusted analyses, women in the highest compared with lowest quintiles were at higher risk of type I endometrial cancer (EDIP HRQ5vsQ1 = 1.46, 95% CI = 1.24 to 1.73; Ptrend < .001; EDIH HRQ5vsQ1 = 1.58, 95% CI = 1.34 to 1.87; Ptrend < .001). Additional adjustment for body mass index attenuated the associations (EDIP HR = 1.03, 95% CI = 0.87 to 1.22; EDIH HR = 1.01, 95% CI = 0.85 to 1.21), and mediation analyses showed that body mass index may explain 60.4% (95% CI = 37.4% to 79.6%; P < .001) and 71.8% (95% CI = 41.0% to 90.4%; P < .001) of the association of endometrial cancer with EDIP and EDIH, respectively. CONCLUSIONS: In this large cohort study, higher dietary inflammatory and insulinemic potential were each associated with increased endometrial cancer incidence, and this association may be almost entirely mediated by adiposity.

Diet quality indices and changes in cognition during chemotherapy.

PURPOSE: No evidence-based prevention strategies currently exist for cancer-related cognitive decline (CRCD). Although patients are often advised to engage in healthy lifestyle activities (e.g., nutritious diet), little is known about the impact of diet on preventing CRCD. This secondary analysis evaluated the association of pre-treatment diet quality indices on change in self-reported cognition during chemotherapy. METHODS: Study participants (n = 96) completed the Block Brief Food Frequency Questionnaire (FFQ) before receiving their first infusion and the PROMIS cognitive function and cognitive abilities questionnaires before infusion and again 5 days later (i.e., when symptoms were expected to be their worst). Diet quality indices included the Dietary Approaches to Stop Hypertension (DASH), Alternate Mediterranean Diet (aMED), and a low carbohydrate diet index and their components. Descriptive statistics were generated for demographic and clinical variables and diet indices. Residualized change models were computed to examine whether diet was associated with change in cognitive function and cognitive abilities, controlling for age, sex, cancer type, treatment type, depression, and fatigue. RESULTS: Study participants had a mean age of 59 ± 10.8 years and 69% were female. Although total diet index scores did not predict change in cognitive function or cognitive abilities, higher pre-treatment ratio of aMED monounsaturated/saturated fat was associated with less decline in cognitive function and cognitive abilities at 5-day post-infusion (P ≤ .001). CONCLUSIONS: Higher pre-treatment ratio of monounsaturated/saturated fat intake was associated with less CRCD early in chemotherapy. Results suggest greater monounsaturated fat and less saturated fat intake could be protective against CRCD during chemotherapy.

Metabolic dysfunction and obesity-related cancer: Beyond obesity and metabolic syndrome.

OBJECTIVES: The metabolic dysfunction driven by obesity, including hyperglycemia and dyslipidemia, increases risk for developing at least 13 cancer types. The concept of "metabolic dysfunction" is often defined by meeting various combinations of criteria for metabolic syndrome. However, the lack of a unified definition of metabolic dysfunction makes it difficult to compare findings across studies. This review summarizes 129 studies that evaluated variable definitions of metabolic dysfunction in relation to obesity-related cancer risk and mortality after a cancer diagnosis. Strategies for metabolic dysfunction management are also discussed. METHODS: A comprehensive search of relevant publications in MEDLINE (PubMed) and Google Scholar with review of references was conducted. RESULTS: Metabolic dysfunction, defined as metabolic syndrome diagnosis or any number of metabolic syndrome criteria out of clinical range, inflammatory biomarkers, or markers of metabolic organ function, has been associated with risk for, and mortality from, colorectal, pancreatic, postmenopausal breast, and bladder cancers. Metabolic dysfunction associations with breast and colorectal cancer risk have been observed independently of BMI, with increased risk in individuals with metabolically unhealthy normal weight or overweight/obesity compared with metabolically healthy normal weight. CONCLUSION: Metabolic dysfunction is a key risk factor for obesity-related cancer, regardless of obesity status. Nonetheless, a harmonized definition of metabolic dysfunction will further clarify the magnitude of the relationship across cancer types, enable better comparisons across studies, and further guide criteria for obesity-related cancer risk stratification.

Following Roux-en-Y gastric bypass surgery, serum ceramides demarcate patients that will fail to achieve normoglycemia and diabetes remission.

BACKGROUND: Obesity is a prevalent health threat and risk factor for type 2 diabetes. In this study, we evaluate the relationship between ceramides, which inhibit insulin secretion and sensitivity, and markers of glucose homeostasis and diabetes remission or recursion in patients who have undergone a Roux-en-Y gastric bypass (RYGB). METHODS: The Utah Obesity Study is a prospective cohort study, with targeted ceramide and dihydroceramide measurements performed on banked serum samples. The Utah Obesity Study consists of 1,156 participants in three groups: a RYGB surgery group, a non-surgery group denied insurance coverage, and severely obese population controls. Clinical examinations and ceramide assessments were performed at baseline and 2 and 12 years after RYGB surgery. FINDINGS: Surgery patients (84% female, 42.2 ± 10.6 years of age at baseline) displayed lower levels of several serum dihydroceramides and ceramides at 2 and 12 years after RYGB. By contrast, neither the control group (77% female, 48.7± 6.4 years of age at baseline) nor the non-surgery group (95% female, 43.0± 11.4 years of age at baseline) experienced significant decreases in any species. Using a linear mixed effect model, we found that multiple dihydroceramides and ceramides positively associated with the glycemic control measures HOMA-IR and HbA1c. In surgery group participants with prevalent diabetes, ceramides inversely predict diabetes remission, independent of changes in weight. CONCLUSIONS: Ceramide decreases may explain the insulin sensitization and diabetes resolution observed in most RYGB surgery patients. FUNDING: Funded by the National Institutes of health (NIH), The Juvenile Diabetes Research Foundation, and the American Heart Association.

Metabolically Defined Body Size Phenotypes and Risk of Endometrial Cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC).

BACKGROUND: Obesity is a risk factor for endometrial cancer but whether metabolic dysfunction is associated with endometrial cancer independent of body size is not known. METHODS: The association of metabolically defined body size phenotypes with endometrial cancer risk was investigated in a nested case-control study (817 cases/ 817 controls) within the European Prospective Investigation into Cancer and Nutrition (EPIC). Concentrations of C-peptide were used to define metabolically healthy (MH; <1st tertile) and metabolically unhealthy (MU; ≥1st tertile) status among the control participants. These metabolic health definitions were combined with normal weight (NW); body mass index (BMI)<25 kg/m2 or waist circumference (WC)<80 cm or waist-to-hip ratio (WHR)<0.8) and overweight (OW; BMI≥25 kg/m2 or WC≥80 cm or WHR≥0.8) status, generating four phenotype groups for each anthropometric measure: (i) MH/NW, (ii) MH/OW, (iii) MU/NW, and (iv) MU/OW. RESULTS: In a multivariable-adjusted conditional logistic regression model, compared with MH/NW individuals, endometrial cancer risk was higher among those classified as MU/NW [ORWC, 1.48; 95% confidence interval (CI), 1.05-2.10 and ORWHR, 1.68; 95% CI, 1.21-2.35] and MU/OW (ORBMI, 2.38; 95% CI, 1.73-3.27; ORWC, 2.69; 95% CI, 1.92-3.77 and ORWHR, 1.83; 95% CI, 1.32-2.54). MH/OW individuals were also at increased endometrial cancer risk compared with MH/NW individuals (ORWC, 1.94; 95% CI, 1.24-3.04). CONCLUSIONS: Women with metabolic dysfunction appear to have higher risk of endometrial cancer regardless of their body size. However, OW status raises endometrial cancer risk even among women with lower insulin levels, suggesting that obesity-related pathways are relevant for the development of this cancer beyond insulin. IMPACT: Classifying women by metabolic health may be of greater utility in identifying those at higher risk for endometrial cancer than anthropometry per se.

A New Approach to Understanding Cancer-Related Fatigue: Leveraging the 3P Model to Facilitate Risk Prediction and Clinical Care.

A major gap impeding development of new treatments for cancer-related fatigue is an inadequate understanding of the complex biological, clinical, demographic, and lifestyle mechanisms underlying fatigue. In this paper, we describe a new application of a comprehensive model for cancer-related fatigue: the predisposing, precipitating, and perpetuating (3P) factors model. This model framework outlined herein, which incorporates the emerging field of metabolomics, may help to frame a more in-depth analysis of the etiology of cancer-related fatigue as well as a broader and more personalized set of approaches to the clinical treatment of fatigue in oncology care. Included within this review paper is an in-depth description of the proposed biological mechanisms of cancer-related fatigue, as well as a presentation of the 3P model's application to this phenomenon. We conclude that a clinical focus on organization risk stratification and treatment around the 3P model may be warranted, and future research may benefit from expanding the 3P model to understand fatigue not only in oncology, but also across a variety of chronic conditions.