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Prospective data are limited regarding dynamic adulthood weight changes and hepatocellular carcinoma (HCC) risk. We included 77,238 women (1980–2012) and 48,026 men (1986–2012), who recalled young-adult weight [age 18 years (women); 21 years (men)], and provided biennially updated information regarding weight, body mass index (BMI), and comorbidities. Overall adulthood weight change was defined as the difference in weight (kilograms) between young-adulthood and present. Using Cox proportional hazards models, we calculated multivariable adjusted HRs (aHR) and 95% confidence intervals (CI). Over 3,676,549 person-years, we documented 158 incident HCC cases. Elevated HCC risk was observed with higher BMI in both young-adulthood and later-adulthood [continuous aHRs per each 1 unit = 1.05; 95% CI = 1.02–1.09 (Ptrend = 0.019), and 1.08; 95% CI = 1.06–1.10 (Ptrend = 0.004), respectively]. Moreover, overall adulthood weight gain was also significantly associated with increased HCC risk (aHR per each 1-kg increase = 1.03; 95% CI = 1.01–1.08; Ptrend = 0.010), including after further adjusting for young-adult BMI (Ptrend = 0.010) and later-adult BMI (Ptrend = 0.008). Compared with adults with stable weight (±5 kg), the multivariable-aHRs with weight gain of 5– Prevention Relevance: Our data suggest that maintaining a stable weight during adulthood, specifically by preventing weight gain, could represent an important public health strategy for the prevention of hepatocellular carcinoma.

Obesity is known to be associated with primary liver cancer (PLC), but the separate effects of excess abdominal and gluteofemoral size are unclear. Thus, we examined the association between waist and hip circumference with risk of PLC overall and by histologic type-hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). The Liver Cancer Pooling Project is a consortium of prospective cohort studies that include data from 1,167,244 individuals (PLC n = 2,208, HCC n = 1,154, ICC n = 335). Multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CI) were estimated using proportional hazards regression. Waist circumference, per 5 cm increase, was associated with an 11% increased PLC risk (HR = 1.11, 95%CI: 1.09-1.14), including when adjusted for hip circumference (HR = 1.12, 95%CI: 1.08-1.17) and also when restricted to individuals in a normal body mass index (BMI) range (18.5 to

Background Intrahepatic cholangiocarcinoma (ICC) arises from cholangiocytes in the intrahepatic bile duct and is the second most common type of liver cancer. Cholangiocytes express both oestrogen receptor-α and -β, and oestrogens positively modulate cholangiocyte proliferation. Studies in women and men have reported higher circulating oestradiol is associated with increased ICC risk, further supporting a hormonal aetiology. However, no observational studies have examined the associations between exogenous hormone use and reproductive factors, as proxies of endogenous hormone levels, and risk of ICC. Methods We harmonised data from 1,107,498 women who enroled in 12 North American-based cohort studies (in the Liver Cancer Pooling Project, LCPP) and the UK Biobank between 1980–1998 and 2006–2010, respectively. Cox proportional hazards regression models were used to generate hazard ratios (HR) and 95% confidence internals (CI). Then, meta-analytic techniques were used to combine the estimates from the LCPP (n = 180 cases) and the UK Biobank (n = 57 cases). Results Hysterectomy was associated with a doubling of ICC risk (HR = 1.98, 95% CI: 1.27–3.09), compared to women aged 50–54 at natural menopause. Long-term oral contraceptive use (9+ years) was associated with a 62% increased ICC risk (HR = 1.62, 95% CI: 1.03–2.55). There was no association between ICC risk and other exogenous hormone use or reproductive factors. Conclusions This study suggests that hysterectomy and long-term oral contraceptive use may be associated with an increased ICC risk.

A family history of colorectal cancer (CRC) in first‐degree relatives (FDRs) increases the risk of CRC. However, the influence of family history on survival among CRC patients remains unclear. We conducted a pooled analysis of survival in 5010 incident CRC cases. Cox proportional hazards models were used to estimate the association of family history with overall survival (OS) and CRC‐specific survival (CSS). We also assessed the impact of the number of affected FDRs and age at CRC diagnosis in the affected FDRs on survival. Among CRC cases, 819 (16%) patients reported a family history of CRC. There were 1580 total deaths over a median follow‐up of 4.6 years, of which 1046 (66%) deaths were due to CRC. Having a family history of CRC was not associated with OS [hazard ratio (HR), 1.03; 95% confidence interval (CI), 0.89–1.19] or CSS (HR, 1.13; 95% CI, 0.95–1.36)]. There were no associations between the number of affected relatives or age at CRC diagnosis of the affected relative with survival (all P trend > 0.05). However, a family history of CRC did confer worse CSS in patients diagnosed with distal colon cancer (HR, 1.45, 95% CI, 1.03–2.04). A family history of CRC was generally not associated with survival after CRC diagnosis. However, having a family history of CRC was associated with worse CRC prognosis in individuals with distal colon cancer, suggesting a possible genetic predisposition with distinct pathogenic mechanism that may lead to worse survival in this group.

Background While tobacco and alcohol are established risk factors for hepatocellular carcinoma (HCC), the most common type of primary liver cancer, it is unknown whether they also increase the risk of intrahepatic cholangiocarcinoma (ICC). Thus, we examined the association between tobacco and alcohol use by primary liver cancer type. Methods The Liver Cancer Pooling Project is a consortium of 14 US-based prospective cohort studies that includes data from 1,518,741 individuals (HCC n = 1423, ICC n = 410). Multivariable-adjusted hazards ratios (HRs) and 95% confidence intervals (CI) were estimated using proportional hazards regression. Results Current smokers at baseline had an increased risk of HCC (hazard ratio (HR) = 1.86, 95% confidence interval (CI): 1.57–2.20) and ICC (HR = 1.47, 95% CI: 1.07–2.02). Among individuals who quit smoking >30 years ago, HCC risk was almost equivalent to never smokers (HR = 1.09, 95% CI: 0.74–1.61). Compared to non-drinkers, heavy alcohol consumption was associated with an 87% increased HCC risk (HR≥7 drinks/day = 1.87, 95% CI: 1.41–2.47) and a 68% increased ICC risk (HR≥5 drinks/day = 1.68, 95% CI: 0.99–2.86). However, light-to-moderate alcohol consumption of 0–0.5–

BACKGROUND & AIMS: Obesity in adulthood has been associated with increased risk of liver-related mortality. Whether higher levels of physical activity counteract the excess risk conferred by obesity remains unknown. We simultaneously evaluated the long-term impact of physical activity and adiposity on liver-related mortality, within two nationwide populations. METHODS: We conducted a prospective cohort study of 77,238 women and 48,026 men, with detailed, validated assessments of weekly physical activity (metabolic equivalent task [MET]-hours]), adiposity (body mass index [BMI], waist circumference), and diet, alcohol use and clinical comorbidities, biennially from 1986 through 2012. Using Cox proportional hazards regression models, we calculated multivariable adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) for liver-related mortality, including death from hepatocellular carcinoma (HCC) and other cirrhosis complications. RESULTS: Over 1,856,226 person-years, we recorded 295 liver-related deaths (108 HCC; 187 cirrhosis). Risk of liver-related mortality increased monotonically with higher BMI during adulthood (P(trend)3 hours/week could have prevented 25% of liver-related deaths (95%CI=0.12-0.38). CONCLUSIONS: In two prospective, nationwide cohorts, both excess adiposity and reduced PA were significant predictors of liver-related mortality. Achieving higher PA levels counteracted the excess liver-related risks associated with obesity.

Although increasing dairy product intake has been associated with risk of several cancers, epidemiological studies on hepatocellular carcinoma are sparse and have yielded inconsistent results. We prospectively assessed the associations of dairy products (total, milk, butter, cheese and yogurt) and their major components (calcium, vitamin D, fats and protein) with the risk of hepatocellular carcinoma development among 51,418 men and 93,427 women in the Health Professionals Follow-Up Study and the Nurses' Health Study. Diets were collected at baseline and updated every 4 years using validated food frequency questionnaires. Multivariable hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using Cox proportional hazards regression model. During up to 32 years of follow-up, a total of 164 hepatocellular carcinoma cases were documented. After adjustment for most known hepatocellular carcinoma risk factors, higher total dairy product intake was associated with an increased risk of hepatocellular carcinoma (highest vs. lowest tertile, HR = 1.85, 95% CI: 1.19-2.88; ptrend = 0.009). For the same comparison, we observed significant positive associations of high-fat dairy (HR = 1.81, 95% CI: 1.19-2.76; ptrend = 0.008) and butter (HR = 1.58, 95% CI: 1.06-2.36; ptrend = 0.04) with hepatocellular carcinoma risk. There was a nonsignificant inverse association between yogurt intake and hepatocellular carcinoma risk (HR = 0.72, 95% CI: 0.49-1.05; ptrend = 0.26). Our data suggest that higher intake of high-fat dairy foods was associated with higher, whereas higher yogurt consumption might be associated with lower risk of developing hepatocellular carcinoma among U.S. men and women.

Incidence rates for liver cancer have increased 3-fold since the mid-1970s in the United States in parallel with increasing trends for obesity and type II diabetes mellitus. We conducted an analysis of baseline body mass index (BMI), waist circumference (WC), and type II diabetes mellitus with risk of liver cancer. The Liver Cancer Pooling Project maintains harmonized data from 1.57 million adults enrolled in 14 U.S.-based prospective studies. Cox regression estimated HRs and 95% confidence intervals (CI) adjusted for age, sex, study center, alcohol, smoking, race, and BMI (for WC and type II diabetes mellitus). Stratified analyses assessed whether the BMI–liver cancer associations differed by hepatitis sera-positivity in nested analyses for a subset of cases (n = 220) and controls (n = 547). After enrollment, 2,162 incident liver cancer diagnoses were identified. BMI, per 5 kg/m2, was associated with higher risks of liver cancer, more so for men (HR = 1.38; 95% CI, 1.30–1.46) than women (HR = 1.25; 95% CI, 1.17–1.35; Pinteraction = 0.02). WC, per 5 cm, was associated with higher risks of liver cancer, approximately equally by sex (overall, HR = 1.08; 95% CI, 1.04–1.13). Type II diabetes mellitus was associated with higher risk of liver cancer (HR = 2.61; 95% CI, 2.34–2.91). In stratified analyses, there was a null association between BMI and liver cancer risk for participants who were sera-positive for hepatitis. This study suggests that high BMI, high WC, and type II diabetes mellitus are associated with higher risks of liver cancer and that the association may differ by status of viral hepatitis infection. Cancer Res; 76(20); 6076–83. ©2016 AACR.

Higher body mass index (BMI) is a well-established risk factor for colorectal cancer (CRC), but is inconsistently associated with CRC survival. In 6 prospective studies participating in the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), 2,249 non-Hispanic white CRC cases were followed for a median 4.5 years after diagnosis, during which 777 died, 554 from CRC-related causes. Associations between prediagnosis BMI and survival (overall and CRC-specific) were evaluated using Cox regression models adjusted for age at diagnosis, sex, study and smoking status (current/former/never). The association between BMI category and CRC survival varied by cancer stage at diagnosis (I-IV) for both all-cause (p-interaction = 0.03) and CRC-specific mortality (p-interaction = 0.04). Compared to normal BMI (18.5-24.9 kg/m(2) ), overweight (BMI 25.0-29.9) was associated with increased mortality among those with Stage I disease, and decreased mortality among those with Stages II-IV disease. Similarly, obesity (BMI ≥30) was associated with increased mortality among those with Stages I-II disease, and decreased mortality among those with Stages III-IV disease. These results suggest the relationship between BMI and survival after CRC diagnosis differs by stage at diagnosis, and may emphasize the importance of adequate metabolic reserves for colorectal cancer survival in patients with late-stage disease.

Importance Prospective data on the risk of hepatocellular carcinoma (HCC) according to dose and duration of aspirin therapy are limited. Objective To examine the potential benefits of aspirin use for primary HCC prevention at a range of doses and durations of use within 2 prospective, nationwide populations. Design, Setting, and Participants Pooled analysis of 2 prospective US cohort studies: the Nurses’ Health Study and the Health Professionals Follow-up Study. Data were accessed from November 1, 2017, through March 7, 2018. A total of 133 371 health care professionals who reported data on aspirin use, frequency, dosage, and duration of use biennially since 1980 in women and 1986 in men were included. Individuals with a cancer diagnosis at baseline (except nonmelanoma skin cancer) were excluded. Main Outcomes and Measures Cox proportional hazards regression models were used to calculate multivariable adjusted hazard ratios (HRs) and 95% CIs for HCC. Results Of the 133 371 participants, 87 507 were women and 45 864 were men; in 1996, the median time of follow-up, the mean (SD) age was 62 (8) years for women and 64 (8) years for men. Over more than 26 years of follow-up encompassing 4 232 188 person-years, 108 incident HCC cases (65 women, 43 men) were documented. Compared with nonregular use, regular aspirin use (≥2 standard-dose [325-mg] tablets per week) was associated with reduced HCC risk (adjusted HR, 0.51; 95% CI, 0.34-0.77). This benefit appeared to be dose related: compared with nonuse, the multivariable-adjusted HR for HCC was 0.87 (95% CI, 0.51-1.48) for up to 1.5 standard-dose tablets per week, 0.51 (95% CI, 0.30-0.86) for more than 1.5 to 5 tablets per week, and 0.49 (95% CI, 0.28-0.96) for more than 5 tablets per week ( P for trend = .006). Significantly lower HCC risk was observed with increasing duration ( P for trend = .03); this decrease was apparent with use of 1.5 or more standard-dose aspirin tablets per week for 5 or more years (adjusted HR, 0.41; 95% CI, 0.21-0.77). In contrast, use of nonaspirin nonsteroidal anti-inflammatory drugs was not significantly associated with HCC risk (adjusted HR, 1.09; 95% CI, 0.78-1.51). Conclusions and Relevance This study suggests that regular, long-term aspirin use is associated with a dose-dependent reduction in HCC risk, which is apparent after 5 or more years of use. Similar associations were not found with nonaspirin NSAIDs. Further research appears to be needed to clarify whether aspirin use represents a feasible strategy for primary prevention against HCC.

Background: Type 2 diabetes (T2D) is a risk factor for hepatocellular carcinoma (HCC). However, it is unknown whether T2D duration or additional metabolic comorbidities further contribute to HCC risk. Methods: From the Nurses' Health Study (NHS), 120,826 women were enrolled in 1980, and from the Health Professionals Follow-up Study (HPFS), 50,284 men were enrolled in 1986, and followed through 2012. Physician-diagnosed T2D was ascertained at baseline and updated biennially. Cox proportional hazards regression models were used to calculate age- and multivariable adjusted hazard ratios (HRs) and 95% confidence intervals (CI) for incident HCC. Results: Over 32 years of follow-up (4,488,410 person-years), we documented 112 cases of HCC (69 women, 43 men). T2D was associated with an increased HCC risk (multivariable HR 4.59, 95% CI 2.98-7.07), as was an increasing T2D duration (Ptrend

OBJECTIVE: Obesity and diabetes are associated with an increased liver cancer risk. However, most studies have examined all primary liver cancers or hepatocellular carcinoma, with few studies evaluating intrahepatic cholangiocarcinoma (ICC), the second most common type of liver cancer. Thus, we examined the association between obesity and diabetes and ICC risk in a pooled analysis and conducted a systematic review/meta-analysis of the literature. DESIGN: For the pooled analysis, we utilized the Liver Cancer Pooling Project, a consortium of 13 US-based, prospective cohort studies with data from 1,541,143 individuals (ICC cases n=414). In our systematic review, we identified 14 additional studies. We then conducted a meta-analysis, combining the results from LCPP with results from the 5 prospective studies identified through September 2017. RESULTS: In the LCPP, obesity and diabetes were associated with a 62% [Hazard Ratio (HR)=1.62, 95% Confidence Interval (CI): 1.24–2.12] and an 81% (HR=1.81, 95%CI: 1.33–2.46) increased ICC risk, respectively. In the meta-analysis of prospectively ascertained cohorts and nested case-control studies, obesity was associated with a 49% increased ICC risk [Relative Risk (RR)=1.49, 95%CI: 1.32–1.70; n=4 studies; I(2)=0%]. Diabetes was associated with a 53% increased ICC risk (RR=1.53, 95%CI: 1.31–1.78; n=6 studies). While we noted heterogeneity between studies (I(2)=67%) for diabetes, results were consistent in subgroup analyses. Results from hospital-based case-control studies (n=9) were mostly consistent, but these studies are potentially subject to reverse causation. CONCLUSIONS: These findings suggest that obesity and diabetes are associated with increased ICC risk, highlighting similar etiologies of hepatocellular carcinoma and intrahepatic cholangiocarcinoma. However, additional prospective studies are needed to verify these associations.

This is a pre-print of an article published in European Journal of Epidemiology. The final authenticated version is available online at: https://doi.org/10.1007/s10654-017-0262-y. Higher levels of circulating adiponectin have been related to lower risk of colorectal cancer in several prospective cohort studies, but it remains unclear whether this association may be causal. We aimed to improve causal inference in a Mendelian Randomization meta-analysis using nested case–control studies of the European Prospective Investigation into Cancer and Nutrition (EPIC, 623 cases, 623 matched controls), the Health Professionals Follow-up Study (HPFS, 231 cases, 230 controls) and the Nurses’ Health Study (NHS, 399 cases, 774 controls) with available data on pre-diagnostic adiponectin concentrations and selected single nucleotide polymorphisms in the ADIPOQ gene. We created an ADIPOQ allele score that explained approximately 3% of the interindividual variation in adiponectin concentrations. The ADIPOQ allele score was not associated with risk of colorectal cancer in logistic regression analyses (pooled OR per score-unit unit 0.97, 95% CI 0.91, 1.04). Genetically determined twofold higher adiponectin was not significantly associated with risk of colorectal cancer using the ADIPOQ allele score as instrumental variable (pooled OR 0.73, 95% CI 0.40, 1.34). In a summary instrumental variable analysis (based on previously published data) with higher statistical power, no association between genetically determined twofold higher adiponectin and risk of colorectal cancer was observed (0.99, 95% CI 0.93, 1.06 in women and 0.94, 95% CI 0.88, 1.01 in men). Thus, our study does not support a causal effect of circulating adiponectin on colorectal cancer risk. Due to the limited genetic determination of adiponectin, larger Mendelian Randomization studies are necessary to clarify whether adiponectin is causally related to lower risk of colorectal cancer.

Background Higher intake of whole grain and dietary fiber has been associated with lower risk of insulin resistance, hyperinsulinemia, and inflammation, which are known predisposing factors for hepatocellular carcinoma (HCC). To our knowledge, no epidemiological study has yet examined the association between whole grain intake and HCC risk. Therefore, we hypothesized that long-term intake of whole grain and dietary fiber may be associated with lower risk of developing HCC. Methods We tested this hypothesis by utilizing data from two large U.S. prospective cohorts, the Nurses’ Health Study and Health Professionals Follow-up Study. Intake of whole grain and its subcomponents (bran and germ), and dietary fiber (cereal, fruit, and vegetable) were collected and updated almost every 4 years using validated food frequency questionnaires. Time-varying Cox proportional hazards regression model was utilized to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of of HCC by tertiles of energy-adjusted whole grain and fiber, after adjusting for sex, race, age, body mass index, alcohol drinking, smoking, physical activity, regular aspirin use, and type 2 diabetes. Results During up to 32 years of follow-up, we identified a total of 141 incident HCC cases. Higher whole grain intake was significantly associated with lower risk of HCC (the highest versus lowest tertile intake, HR=0.63, 95% CI: 0.41-0.96, Ptrend=0.04). A suggestive inverse HCC association was found for total bran (HR=0.70, 95% CI: 0.46-1.07, Ptrend=0.11), but not for germ. After mutual adjustment for bran and germ, the inverse association between total bran and HCC persisted (HR=0.66, 95% CI: 0.41-1.07, Ptrend=0.13). Increasing intake of cereal fiber (HR=0.68, 95% CI: 0.45-1.03, Ptrend=0.07), but not fruit or vegetable fiber, was also suggestively associated with reduced risk of HCC. In sensitivity analyses, the results did not materially change after excluding HCC cases with hepatitis B or C virus infections. In addition, we observed similar inverse associations for whole grain, bran and germ, or dietary fiber with risk of HCC subtypes by history of cirrhosis (i.e., cirrhotic versus non-cirrhotic HCC). Conclusions Intake of whole grains, cereal fiber, and bran could be associated with reduced risk of HCC among U.S. adults. Future studies that carefully consider hepatitis B and C virus infections are needed to replicate our findings, to examine these associations in other racial or high-risk populations, and to elucidate the underlying mechanisms. Citation Format: Wanshui Yang, Yanan Ma, Yue Liu, Smith-Warner Stephanie, Tracey G. Simon, Dawn Chong, Jeffrey A. Meyerhardt, Edward L. Giovannucci, Andrew T. Chan, Xuehong Zhang. Intake of whole grain and dietary fiber and risk of hepatocellular carcinoma among U.S. adults [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2680.

Worldwide, hepatocellular carcinoma (HCC) is the fifth most common cancer and the second-leading cause of cancer-related death worldwide. In the U.S., the incidence rate of HCC has tripled since 1975. Although preliminary evidence suggesting a biological impact of diet on multiple inflammatory pathways implicated in hepatocarcinogenesis, the most comprehensive review by the WCRF/AICR concluded that the relationship between diet and HCC remains largely unknown. HCC is an inflammation-related cancer but few studies have investigated diet quality based on its inflammatory potential in relation to HCC risk. The empirical dietary inflammatory pattern scores (EDIP) score were calculated from validated food frequency questionnaires. It characterized dietary inflammatory potential based on circulating levels of inflammatory bio-markers. We prospectively followed 49,674 men in the Health Professionals Follow-up Study (1986-2012), and 74,139 women in the Nurses' Health Study (1984-2012). Cox regression analyses were used to calculate hazards ratios (HR) for HCC risk adjusting for body mass index, smoking, history of diabetes, race, physical activity, and regular aspirin use. We documented a total of 89 incident HCC cases (44 in women and 45 in men) over 28 years, encompassing 1,522,972 person-years of follow-up. Compared to the lowest tertile, the highest tertile of the EDIP score was associated with a multivariable HR for HCC of 2.86 (95%CI, 1.20-6.81) among women (P-trend=0.01) and of 0.68 (95%CI, 0.31-1.50) among men (P-trend=0.35). Future study is warranted to confirm this finding and elucidate the potential biological basis. Key words: inflammation, dietary patterns, HCC A. T. C. and X. Z contributed equally to this work. Citation Format: Yanan Ma, Tracey G. Simon, Fred K Tabung, Lindsay Y. King, Dawn Q. Chong, Long Nguyen, Trang VoPham, Charles S. Fuchs, Jeffrey A. Meyerhardt, Kathleen E. Corey, Hamed Khalili, Stephanie Smith-Warner, Raymond T. Chung, Edward L. Giovannucci, Andrew T. Chan, Xuehong Zhang. A prospective study of inflammatory diet potential and risk of hepatocellular carcinoma (HCC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5256.

Background. Conflicting data exist regarding the prognostic impact of the isocitrate dehydrogenase (IDH) mutation in intrahepatic cholangiocarcinoma (ICC), and limited data exist in patients with advanced-stage disease. Similarly, the clinical phenotype of patients with advanced IDH mutant (IDHm) ICC has not been characterized. In this study, we report the correlation of IDH mutation status with prognosis and clinicopathologic features in patients with advanced ICC. Methods. Patients with histologically confirmed advanced ICC who underwent tumor mutational profiling as a routine part of their care between 2009 and 2014 were evaluated. Clinical and pathological data were collected by retrospective chart review for patients with IDHm versus IDH wild-type (IDHwt) ICC. Pretreatment tumor volume was calculated on computed tomography or magnetic resonance imaging. Results. Of the 104 patients with ICC who were evaluated, 30 (28.8%) had an IDH mutation (25.0% IDH1, 3.8% IDH2). The median overall survival did not differ significantly between IDHm and IDHwt patients (15.0 vs. 20.1 months, respectively; p = .17). The pretreatment serum carbohydrate antigen 19-9 (CA19-9) level in IDHm and IDHwt patients was 34.5 and 118.0 U/mL, respectively (p = .04). Age at diagnosis, sex, histologic grade, and pattern of metastasis did not differ significantly by IDH mutation status. Conclusion. The IDH mutation was not associated with prognosis in patients with advanced ICC. The clinical phenotypes of advanced IDHm and IDHwt ICC were similar, but patients with IDHm ICC had a lower median serum CA19-9 level at presentation. Implications for Practice: Previous studies assessing the prognostic impact of the isocitrate dehydrogenase (IDH) gene mutation in intrahepatic cholangiocarcinoma (ICC) mainly focused on patients with early-stage disease who have undergone resection. These studies offer conflicting results. The target population for clinical trials of IDH inhibitors is patients with unresectable or metastatic disease, and the current study is the first to focus on the prognosis and clinical phenotype of this population and reports on the largest cohort of patients with advanced IDH mutant ICC to date. The finding that the IDH mutation lacks prognostic significance in advanced ICC is preliminary and needs to be confirmed prospectively in a larger study.

Circulating adiponectin is inversely related to the risk of colorectal cancer. However, its influence on colorectal cancer survival is unclear. We conducted a prospective study to evaluate the association between prediagnostic plasma levels of adiponectin and mortality in patients with colorectal cancer. We identified 621 incident colorectal cancer cases who provided blood specimens prior to diagnosis within the Nurses' Health Study (NHS) and Health Professionals Follow-up Study (HPFS). Cox proportional hazards models were used to calculate HRs and 95% confidence intervals (CI). After a median follow-up of 9 years, there were 269 (43%) total deaths, of which 181 (67%) were due to colorectal cancer. Compared with participants in the lowest quartile of adiponectin, those in the highest quartile had multivariate HRs of 1.89 (95% CI, 1.21–2.97; Ptrend = 0.01) for colorectal cancer–specific mortality and 1.66 (95% CI, 1.15–2.39; Ptrend = 0.009) for overall mortality. The apparent increased risk in colorectal cancer–specific mortality was more pronounced in patients with metastatic disease (HR, 3.02: 95% CI, 1.50–6.08). Among patients with colorectal cancer, prediagnostic plasma adiponectin is associated with an increased risk of colorectal cancer–specific and overall mortality and is more apparent in patients with metastatic disease. Adiponectin may be a marker for cancers which develop through specific pathways that may be associated with worsened prognosis. Further studies are needed to validate these findings. Cancer Prev Res; 8(12); 1138–45. ©2015 AACR.

Chronic inflammation plays a pivotal role in the pathogenesis of hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC), the two most common types of liver cancer. A number of prior experimental studies have suggested that nonsteroidal anti-inflammatory drugs (NSAIDs), including aspirin and ibuprofen, may potentially protect against liver cancer. However, no observational study has examined the association between aspirin duration and dose or other over-the-counter non-aspirin NSAIDs, such as ibuprofen, and liver cancer incidence. Furthermore, the association between NSAID use and risk of ICC is unclear. As part of the Liver Cancer Pooling Project, we harmonized data on 1,084,133 individuals (HCC = 679, ICC = 225) from 10 U.S.-based prospective cohort studies. Cox proportional hazards regression models were used to evaluate multivariable-adjusted HRs and 95% confidence intervals (CI). Current aspirin use, versus nonuse, was inversely associated with HCC (HR, 0.68; 95% CI, 0.57–0.81), which persisted when restricted to individuals not using non-aspirin NSAIDs and in a 5- and 10-year lag analysis. The association between aspirin use and HCC risk was stronger for users who reported daily use, longer duration use, and lower dosage. Ibuprofen use was not associated with HCC risk. Aspirin use was associated with a reduced ICC risk in men (HR, 0.64; 95% CI, 0.42–0.98) but not women (HR, 1.34; 95% CI, 0.89–2.01; Pinteraction = 0.01). The observed inverse association between aspirin use and liver cancer in our study, together with previous data, suggests the merit of future intervention studies of aspirin and other agents that affect chronic inflammatory pathways for HCC and possibly ICC. Cancer Prev Res; 8(12); 1156–62. ©2015 AACR.

Background: Coffee consumption has been reported to be inversely associated with hepatocellular carcinoma (HCC), the most common type of liver cancer. Caffeine has chemopreventive properties, but whether caffeine is responsible for the coffee–HCC association is not well studied. In addition, few studies have examined the relationship by sex, and no studies have examined whether there is an association between coffee and intrahepatic cholangiocarcinoma (ICC), the second most common type of liver cancer. Methods: In the Liver Cancer Pooling Project, a consortium of U.S.-based cohort studies, data from 1,212,893 individuals (HCC, n = 860; ICC, n = 260) in nine cohorts were pooled. Multivariable-adjusted hazard ratios (HR) and 95% confidence intervals (CI) were estimated using proportional hazards regression. Results: Higher coffee consumption was associated with lower risk of HCC (HR>3 cups/day vs. non-drinker, 0.73; 95% CI, 0.53–0.99; Ptrend cups/day = 3 cups/day vs. non-drinker, 0.71; 95% CI, 0.50–1.01) than decaffeinated coffee (HR, 0.92; 95% CI, 0.55–1.54). There was no association between coffee consumption and ICC. Conclusions: These findings suggest that, in a U.S. population, coffee consumption is associated with reduced risk of HCC. Impact: Further research into specific coffee compounds and mechanisms that may account for these associations is needed. Cancer Epidemiol Biomarkers Prev; 24(9); 1398–406. ©2015 AACR.

Background & Aims Patients with colorectal cancer (CRC) have high circulating levels of macrophage inhibitory cytokine-1 (MIC1 or growth differentiation factor 15), a marker of inflammation that might be involved in carcinogenesis. We analyzed blood samples collected from individuals before they were diagnosed with CRC to determine whether levels of MIC1 were associated with mortality. Methods We collected data on survival of 618 participants diagnosed with CRC who provided prediagnosis blood specimens in 1990 (Nurses' Health Study) and 1994 (Health Professionals' Follow-up Study) and were followed through 2010. Levels of MIC1 were measured by enzyme-linked immunosorbent assay and then were categorized into quartiles based on the known distribution of MIC1 levels among previously matched individuals without CRC (controls) within each cohort. We then examined the association of MIC1 levels with overall and CRC-specific mortality using Cox proportional hazards models, with adjustments for mortality-associated risk factors and other plasma markers of inflammation. We also assessed the relationship between levels of MIC1 and levels of prostaglandin-endoperoxide synthase 2 expression (PTGS2 or cyclooxygenase-2), measured in 245 tumor samples by immunohistochemistry. Results Compared with participants in the lowest quartile for plasma level of MIC1, the multivariate hazard ratio for CRC-specific death for participants in the highest quartile of MIC1 level was 2.40 (95% confidence interval: 1.33−4.34; P for linear trend = .009). The association of MIC1 with survival varied with level of PTGS2 expression in tumor samples ( P interaction = .04). For individuals with PTGS2-positive tumors, the hazard ratio for CRC-specific death among those with high levels of MIC1 (equal to or greater than the median) was 2.13 (95% confidence interval: 0.99−4.58) compared with participants with low levels of MIC1 (below the median). In individuals with PTGS2-negative CRC, a high level of MIC1 was not associated with an increased risk of CRC-specific death (multivariate hazard ratio = 0.61; 95% confidence interval: 0.13−2.93). Conclusions Based on an analysis of blood and colorectal tumor samples from 2 large studies, high plasma levels of MIC1 (growth differentiation factor 15) before diagnosis of CRC are associated with greater CRC-specific mortality, particularly in individuals with PTGS2-positive tumors.

Background: Since 1980, liver cancer has been among the most rapidly increasing cancer types in the United States (US), with 5-year survival rates of approximately 17%. While tobacco and alcohol are known to be associated with primary liver cancer, it is unclear whether they only increase the risk of hepatocellular carcinoma (HCC), the most common type of liver cancer, or whether they also increase risk of intrahepatic cholangiocarcinoma (ICC), second most common histologic type. Additionally, it is unclear what amount of alcohol consumption is associated with an increased risk of liver cancer. As liver cancer is a rare cancer type, we conducted a study of pooled data from the National Cancer Institute Cohort Consortium to examine the associations between smoking and alcohol use and liver cancer, stratified by histologic subtype. Methods: In the Liver Cancer Pooling Project, a consortium of US-based cohort studies, we pooled data from 1,518,741 individuals (HCC n=1,423, ICC n=410) in 14 cohorts. Multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CI) were estimated using proportional hazards regression. Cubic splines were used to model the association between alcohol and liver cancer risk. Results: Compared to never smokers, both former and current smokers at study baseline had an increased risk of ICC (HR=1.32, 95% CI: 1.03-1.68 and HR=1.47, 95% CI: 1.07-2.02, respectively) and HCC (HR=1.24, 95% CI: 1.08-1.43 and HR=1.86, 95% CI: 1.57-2.20, respectively). This finding was consistent for heavier smoking intensity, longer duration of smoking, and more pack-years of smoking. Heavy alcohol consumption was associated with an 87% increased risk of HCC (HR≥7 drinks/day v. non-drinker=1.87, 95% CI: 1.41-2.47) and a non-significant 68% increased risk of ICC (HR≥5 drinks/day v. non-drinker=1.68, 95% CI: 0.99-2.86). Risk of HCC significantly increased at 4.5 alcoholic drinks per day, while risk of ICC was non-significantly increased with any amount of consumption. Conclusions: These findings suggest that, in a US population, cigarette smoking is associated with an increased risk of both histologic subtypes of primary liver cancer - HCC and ICC. In contrast, alcohol consumption was primarily associated with an increased risk of HCC. These results suggest that smoking cessation and alcohol reduction programs could be important intervention opportunities for these lethal cancer types. Citation Format: Jessica Leigh Petrick, Peter T. Campbell, Jill Koshiol, Jake E. Thistle, Gabriella Andreotti, Laura E. Beane-Freeman, Julie E. Buring, Andrew T. Chan, Dawn Q. Chong, Michele M. Doody, Susan M. Gapstur, John Michael Gaziano, Edward Giovannucci, Barry I. Graubard, I-Min Lee, Linda M. Liao, Martha S. Linet, Julie R. Palmer, Jenny N. Poynter, Mark P. Purdue, Kim Robien, Lynn Rosenberg, Catherine Schairer, Howard D. Sesso, Rashmi Sinha, Meir J. Stampfer, Marcia Stefanick, Jean Wactawski-Wende, Xuehong Zhang, Anne Zeleniuch-Jacquotte, Neal D. Freedman, Katherine A. McGlynn. Tobacco smoking, alcohol use and risk of hepatocellular carcinoma and intrahepatic cholangiocarcinoma: The Liver Cancer Pooling Project [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3007. doi:10.1158/1538-7445.AM2017-3007

Lancet Oncology, The - In Press.Proof corrected by the author Available online since mercredi 15 juillet 2015

3594Background: A family history of colorectal cancer (CRC) in first-degree relatives (FDRs) increases the risk of CRC. However, beyond rare hereditary CRC syndromes, the influence of family histor...

Background and aim: Aberrant DNA methylation plays critical roles in the development of colorectal cancers (CRCs). Laterally spreading tumors (LSTs) are generally defined as lesions greater than 10 mm in diameter with a low vertical axis that extend laterally along the luminal wall. Those flat lesions are thought to be less invasive because they are likely to be found in the adenoma stage or intramucosal CRCs. On the other hand, a subset of CRCs are known to develop from nonpolypoid lesions and the nonpolypoid submucosal invasive CRCs were smaller than did the polypoid cancers. We aimed to identify DNA methylation changes, which are associated with growth pattern and invasiveness of colorectal tumors. Methods: Methylated CpG island amplification coupled with CpG island microarray (MCAM) analysis was carried out to screen for differentially methylated genes between large (≥20 mm in diameter) noninvasive tumors (NTs) and small (