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Background: Colorectal cancer is common cancer with a high mortality rate. Low-carbohydrate diet (LCD) score holistically evaluates the LCD pattern from carbohydrate, protein, and fat intake. Epidemiologic data of LCD–colorectal cancer association are sparse. Methods: We evaluated the associations between LCD (i.e., total, animal- and plant-based) and colorectal cancer risk in the Singapore Chinese Health Study, a population-based prospective cohort study including 61,321 Chinese in Singapore who were 45 to 74 years old at baseline. Cox proportional hazard regression model was used to determine the HRs and respective 95% confidence intervals (CI) for colorectal cancer associated with LCD after adjusting for potential confounders, including age, sex, BMI, physical activity, family history of colorectal cancer, etc. Results: After an average of 19.5 years of follow-up, 2,520 participants developed colorectal cancer (1,608 colon cancer and 912 rectal cancer). Overall, the association between total or plant-based LCD scores with the risk of colorectal, colon, or rectal cancer was null (all Ptrend ≥ 0.28). The animal-based LCD was modestly associated with colon cancer risk (Ptrend = 0.02), but not with rectal cancer. Compared with the lowest quartile, HRs (95% CIs) of colon cancer for quartiles 2, 3, and 4 of animal-based LCD were 1.12 (0.98–1.29), 1.27 (1.10–1.46), and 1.14 (0.99–1.31), respectively. Conclusions: A low-level carbohydrate diet with a high level of animal protein and fat was associated with a moderate increase in the risk of colon cancer among Chinese Singaporeans. Impact: High consumption of animal protein/fat and low consumption of carbohydrates may increase colon cancer risk.

Blood neutrophil to lymphocyte ratio (NLR) or lymphocyte count may be important markers for immune function. Previous work has shown higher NLR was associated with higher risk of hepatitis B-related hepatocellular carcinoma (HCC). However, studies in non-alcoholic fatty liver disease (NAFLD) patients are lacking.Utilizing the University of Pittsburgh Medical Center (UPMC) electronic health records, we created a retrospective cohort of 27,834 patients diagnosed with NAFLD from 2004 to 2018 with complete NLR data. After an average 5.5 years of follow-up, 203 patients developed HCC. Cox proportional hazard regression was used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) of HCC incidence associated with different levels of NLR and lymphocyte count.Compared with the lowest tertile of NLR (1.97), the highest tertile of NLR (≥3.09) was statistically significantly associated with a 43% higher risk of HCC incidence (HR = 1.43, 95% CI: 1.01-2.03, pHigher NLR and lower lymphocyte count are associated with significantly higher risk of HCC among NAFLD patients. These findings warrant further investigation of immune response and surveillance in association with HCC development in NAFLD patients.

Background Minimally invasive breast biopsy (MIBB) is the standard of care for the diagnosis of breast cancer, with consensus guidelines suggesting MIBB goals of 90% of total biopsies. In a previous study of patients in the rural state of Vermont, USA (population size of 640,000), rural breast cancer patients had open biopsies 42% of the time compared to 29% of urban breast cancer patients. The aim of this study was to assess overall population‐based biopsy trends in Vermont. Methods The Vermont Breast Cancer Surveillance System (VBCSS) was used to identify women receiving MIBB and excisional breast biopsies in Vermont. Patient zip code at the time of initial biopsy was used to determine the patient residence rurality by rural–urban commuting area codes (RUCA 2.0™). Results There were 9122 diagnostic episodes from 1999 to 2018. MIBB was the initial biopsy method in 7524 (82.5%) cases, while surgical excision was the initial biopsy method in 1598 (17.5%) cases. A linear trend fit estimated an increase of 1.3% per year (p, Minimally invasive needle biopsy has been the standard of care for breast cancer diagnosis since the early 2000’s. However, a number of studies through 2010, including our prior report from Vermont, showed persistently high rates of open surgical biopsies in rural populations. In this manuscript, we report updated results from a state‐wide retrospective study of breast biopsies, stratified by rurality of patient residence; we evaluated the trend of minimally invasive breast biopsies from 1999 to 2018 and show for the first time that the state as a whole has reached the standard of care of over 90% breast biopsies performed as minimally invasive.

Colorectal cancer (CRC) is a major contributor to cancer death globally. Several studies showed some protections by certain individual dietary antioxidants against CRC development. Epidemiologic data on the composite dietary antioxidant index (CDAI) in relation to CRC risk are sparse. Using the Singapore Chinese Health Study, an ongoing prospective cohort consisting of 61,321 cancer-free participants aged 45–74 years at baseline, a food-based CDAI was calculated according to a previously established and validated method that included six food-sourced antioxidants including vitamins A, C, and E, manganese, selenium, and zinc. Cox proportional hazard regression method was used to estimate the hazard ratios (HRs) and their 95% confidence intervals (CIs) for CRC associated with various levels of CDAI with adjustment for multiple potential confounders. After an average of 17.5 years of follow-up, 2,140 participants developed CRC. HRs (95% CIs) of CRC for quartiles 2, 3 and 4 of CDAI were 0.94 (0.83–1.07), 0.86 (0.75–1.00) and 0.80 (0.66–0.98), respectively, compared with the lowest quartile (P(trend)=0.02). This inverse association between CDAI and CRC risk was more apparent in women or those without a history of diabetes, without family history of CRC, never smokers or overweight/obese individuals. However, none of the heterogeneity tests for the CDAI-CRC risk association reached statistical significance. Our findings suggest that food-based antioxidants may be beneficial for reducing the risk of CRC in the general population.

Background: Nonalcoholic fatty liver disease (NAFLD) has become a major contributor to the rising incidence of hepatocellular carcinoma (HCC) in the United States and other developed countries. Iron, an essential metal primarily stored in hepatocytes, may play a role in the development of NAFLD-related HCC. Epidemiologic data on iron overload without hemochromatosis in relation to HCC are sparse. This study aimed to examine the associations between serum biomarkers of iron and the risk of HCC in patients with NAFLD. Methods: We identified 18,569 patients with NAFLD using the University of Pittsburgh Medical Center electronic health records from 2004 through 2018. After an average 4.34 years of follow-up, 244 patients developed HCC. Cox proportional hazard regression was used to calculate hazard ratios (HR) and 95% confidence intervals (CI) of HCC incidence associated with elevated levels of iron biomarkers with adjustment for age, sex, race, body mass index, history of diabetes, and tobacco smoking. Results: The HRs (95% CIs) of HCC for clinically defined elevation of serum iron and transferrin saturation were 2.91 (1.34–6.30) and 2.02 (1.22–3.32), respectively, compared with their respective normal range. No statistically significant association was observed for total iron-binding capacity or serum ferritin with HCC risk. Conclusions: Elevated levels of serum iron and transferrin saturation were significantly associated with increased risk of HCC among patients with NAFLD without hemochromatosis or other major underlying causes of chronic liver diseases. Impact: Clinical surveillance of serum iron level may be a potential strategy to identify patients with NAFLD who are at high risk for HCC.

Background. Colorectal cancer (CRC) is a commonly diagnosed cancer. Glucose intake enhances the secretion of insulin, may contribute to cell growth and proliferation, leading to CRC development. Epidemiologic studies have shown that individuals with diabetes history are at increased risk of CRC. A low-carbohydrate diet, represented by a low-carbohydrate diet (LCD) score, may reduce the risk of diabetes. Yet, little is known about the association between LCD scores and the risk of CRC. Methods. We evaluated the associations between LCD and CRC risk in the Singapore Chinese Health Study, a population-based prospective cohort study that includes 61,321 Chinese men and women in Singapore who were 45-74 years old at enrollment. Food and dietary supplement consumption were assessed by a validated semi-quantitative food frequency questionnaire. Participants were assigned a score from 0 to 10 according to their rankings by daily intake of calories from carbohydrates, fat and protein, respectively. A score of 0 was assigned to a subject ranked in the highest one-eleventh of calorie intake from carbohydrates or in the lowest one-eleventh of calories from fat or protein, respectively. In contrast, a score of 10 was given to each subject in the lowest one-eleventh of carbohydrate intake or the highest one-eleventh of fat or protein intake. The LCD score for each subject was the sum of the 3 individual ranking scores. The highest possible value was 30, which represented the lowest carbohydrate intake and the highest fat and protein. In addition, animal-based and plant-based LCDs were similarly created from the daily consumption of calories from animal or plant protein and fat, respectively, as well as carbohydrates. Cox proportional hazard regression models were used to estimate hazard ratios (HRs) and their 95% confidence intervals (CIs) for CRC according to higher quartiles of LCD scores with adjustment for potential confounders. Results. After an average of 17.5 years of follow-up, 2,140 participants developed CRC. Overall, there was a null association between total LCD and CRC risk. A moderate positive association was found for animal-based LCD with CRC risk. The multivariable-adjusted HRs(95%CIs) for CRC in quartiles 2, 3, and 4 of animal-based LCD were 1.12(0.99-1.26), 1.18(1.04-1.33), and 1.11(0.98-1.25)(Ptrend=0.06) compared with the lowest quartile. There were no statistically significant differences in the animal-based LCD and CRC risk in subgroups stratified by sex, body mass index, smoking status, and history of type 2 diabetes. Conclusions. This large population-based prospective cohort study shows that a high animal-based LCD score, which represented low intake of carbohydrates and high intake of animal protein and fat, was associated with ~10% increased risk of CRC. Our findings suggest that replacing low-carbohydrate food with animal-based food may increase the risk of developing CRC. Citation Format: Yi-Chuan Yu, Pedram Paragomi, Aizhen Jin, Renwei Wang, Robert E. Schoen, Woon-Puay Koh, Jian-Min Yuan, Hung N. Luu. Low-carbohydrate diet score and the risk of colorectal cancer: Findings from a prospective cohort study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 735.

Background. Composite Dietary Antioxidant Index (CDAI) is a summary score derived from statistical modeling that ranks an individual’s dietary intake of antioxidants in relation to the overall mean of the study population. Antioxidants may offer a beneficial effect on reducing the risk of pancreatic cancer. No prospective epidemiological study has investigated the association between food-based CDAI (fCDAI) and pancreatic cancer risk. Methods. The fCDAI score was calculated based on dietary intakes of vitamins A, C, and E, manganese, selenium, and zinc from food but not from dietary supplements, for each participant of the Singapore Chinese Health Study, a population-based prospective epidemiological cohort study consisting of 61,321 Chinese men and women in Singapore aged 45-74 years at baseline enrollment during 1993-1998. Intake of antioxidants was derived from self-reported consumption of food items using a validated semi-quantitative food frequency questionnaire and the Singapore Food Composition Table. Incident cases of cancer, including pancreatic cancer, and death were identified through the linkage analysis with the nationwide Singapore Cancer Registry and the Singapore Registry of Birth and Death, respectively. The Cox proportional hazard regression method was used to estimate hazard ratio (HR) and its 95% confidence interval (CI) of pancreatic cancer associated with higher quartiles of fCDAI relative to the lowest quartile with adjustment for multiple potential confounders, including age, sex, dialect group, level of education, smoking status, alcohol consumption, a history of diabetes, sleep duration, physical activity, year of enrollment, and total energy intake. Results. Overall, 311 participants who were free of cancer at baseline developed pancreatic cancer during an average of 17.7 years of follow-up after baseline assessment of food consumption. Compared with the lowest quartile, the multivariable-adjusted HR of pancreatic cancer for the highest quartile of fCDAI was 0.54 (95% CI: 0.31-.91, P=0.02). This inverse association between the fCDAI and pancreatic cancer risk was more apparent in overweight/obese subjects (HRQ4vsQ1=0.28, 95% CI: 0.13-0.60, Ptrend=0.02), or those without a history of diabetes (HRQ4vsQ1=0.50, 95% CI: 0.29-0.88, Ptrend=0.04). No association was observed between CDAI derived from dietary supplements and the risk of pancreatic cancer. Conclusions. The inverse association between fCDAI and pancreatic cancer risk supports the notion that overall dietary antioxidants may provide a beneficial effect against the development of pancreatic cancer, specifically overweight/obese individuals and those free of diabetes who may have a long-term persistent dietary pattern. These results highlight the importance of promoting healthy eating for the primary prevention of pancreatic cancer. Citation Format: Pedram Paragomi, Renwei Wang, Aizhen Jin, Yi-Chuan Yu, Randall E. Brand, Li-Ting Sheng, An Pan, Woon-Puay Koh, Jian-Min Yuan, Hung Luu. Composite dietary antioxidant index and the risk of pancreatic cancer: Findings from a prospective cohort study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3667.

Objective MicroRNA-122 (miR-122) has been identified as a biomarker of liver diseases. However, the miR-122 detection accuracy in patients with hepatocellular carcinoma (HCC) associated with hepatitis C virus (HCV) is inconclusive. Methods We conducted a systematic literature search of Web of Science, Cochrane Library, PubMed, and Embase to identify studies related to the diagnostic value of miR-122 in HCV-related HCC. We analyzed the results and validated them using data from the Cancer Genome Atlas (TCGA). Results Six articles were included in this meta-analysis, comprising 354 cases and 420 controls. The pooled specificity, sensitivity, positive likelihood ratio, negative likelihood ratio, diagnostic odds ratio, and area under the curve were 0.87, 0.83, 5.1, 0.16, 32, and 0.92, respectively. Additional sub-group analyses showed that results for plasma were more sensitive than those for serum. In addition, miR-122 was better at distinguishing between HCV-associated HCC and healthy people or those with HCV than between those with HCV-associated HCC and HCV-related cirrhosis. Small samples (≤100) had better diagnostic odds ratios than larger samples (>100). Analysis of data from TCGA confirmed that miRNA-122 had a high diagnostic value. Conclusion This meta-analysis demonstrates that miR-122 may be a useful diagnostic biomarker for HCV-associated HCC.

Background: Hepatocellular carcinoma (HCC) is the 6th most commonly diagnosed cancer and the 3rd leading cause of cancer death in the US. Around 85-90% of primary liver cancer is HCC. Besides identified risk factors for HCC including chronic infection with hepatitis B and C virus (HBV and HCV), alcohol abuse, dietary aflatoxin exposure and hereditary hemochromatosis, nonalcoholic fatty liver disease (NAFLD) is as another important risk factor for HCC. NAFLD is a spectrum of liver disease that ranges from hepatic steatosis through non-alcoholic steatohepatitis (NASH) with or without fibrosis and may progress to cirrhosis or HCC. Iron is an essential metal and hepatocytes are its main storage site. Increased body iron from the intestine due to high dietary iron or hereditary or acquired hemochromatosis may result in hepatic iron overload. NAFLD is frequently associated with elevated serum iron indices when hepatic iron in the absence of hemochromatosis. Epidemiologic data on the association between serum iron markers and risk of HCC are sparse. The aim of the study was to examine the association of iron related serum markers with risk of HCC in NAFLD patients. We hypothesized that elevated serum iron levels, which reflects hepatic iron, are associated with increased risk of HCC among NAFLD patients. Methods: 48,328 patients with NAFLD were identified in the electronic health records (EHR) of the University of Pittsburgh Medical Center (UPMC) between 1/1/2004 to 12/31/2018. Among them, 19,908 had at least one measurement of serum iron, transferrin saturation, total iron binding capacity (TIBC) and serum ferritin. After an average 4.47 years of follow-up, 363 patients with NAFLD were diagnosed with HCC at least 30 days after measurement of iron markers. Cox proportional hazard regression was used to calculate hazard ratios (HRs) and the 95% confidence intervals (CIs) for HCC incidence associated with elevated levels of the four iron markers adjusted for age, sex, race, body mass index, history of diabetes and tobacco smoking. Results: Serum iron and transferrin saturation were significantly elevated in NAFLD patients who developed HCC compared to others who remained free of HCC during the study. The HR of HCC for elevated serum iron >175 mcg/dl was 3.41 (95% CI 1.48 - 7.85) compared to its normal range at 75-175 mcg/dl. Similarly, the HR for HCC associated with elevated transferrin saturation >35% was 2.56 (95% CI 1.49-4.39) relative to the normal range at 25-35%. The associations were not statistically significant for TIBC and serum ferritin with HCC risk. Conclusions: Elevated serum iron and transferrin saturation levels, but not TIBC or serum ferritin, were significantly associated with increased risk of developing HCC in NAFLD patients. These findings support future studies evaluating serum iron level in risk stratification of NAFLD patients at risk of HCC and potential links to pathogenesis of HCC. Citation Format: Yi-Chuan Yu, Renwei Wang, Jaideep Behari, Ada Youk, Nancy W. Glynn, Jian-Min Yuan. Serum iron markers in relation to hepatocellular carcinoma risk among patients with non-alcoholic fatty liver disease [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 754.