Endocrine-Exocrine Signaling Drives Obesity-Associated Pancreatic Ductal Adenocarcinoma.

Obesity is a major modifiable risk factor for pancreatic ductal adenocarcinoma (PDAC), yet how and when obesity contributes to PDAC progression is not well understood. Leveraging an autochthonous mouse model, we demonstrate a causal and reversible role for obesity in early PDAC progression, showing that obesity markedly enhances tumorigenesis, while genetic or dietary induction of weight loss intercepts cancer development. Molecular analyses of human and murine samples define microenvironmental consequences of obesity that foster tumorigenesis rather than new driver gene mutations, including significant pancreatic islet cell adaptation in obesity-associated tumors. Specifically, we identify aberrant beta cell expression of the peptide hormone cholecystokinin (Cck) in response to obesity and show that islet Cck promotes oncogenic Kras-driven pancreatic ductal tumorigenesis. Our studies argue that PDAC progression is driven by local obesity-associated changes in the tumor microenvironment and implicate endocrine-exocrine signaling beyond insulin in PDAC development.

Protein biomarkers and alternatively methylated cell-free DNA detect early stage pancreatic cancer.

OBJECTIVE: Pancreatic ductal adenocarcinoma (PDAC) is commonly diagnosed at an advanced stage. Liquid biopsy approaches may facilitate detection of early stage PDAC when curative treatments can be employed. DESIGN: To assess circulating marker discrimination in training, testing and validation patient cohorts (total n=426 patients), plasma markers were measured among PDAC cases and patients with chronic pancreatitis, colorectal cancer (CRC), and healthy controls. Using CA19-9 as an anchor marker, measurements were made of two protein markers (TIMP1, LRG1) and cell-free DNA (cfDNA) pancreas-specific methylation at 9 loci encompassing 61 CpG sites. RESULTS: Comparative methylome analysis identified nine loci that were differentially methylated in exocrine pancreas DNA. In the training set (n=124 patients), cfDNA methylation markers distinguished PDAC from healthy and CRC controls. In the testing set of 86 early stage PDAC and 86 matched healthy controls, CA19-9 had an area under the receiver operating characteristic curve (AUC) of 0.88 (95% CI 0.83 to 0.94), which was increased by adding TIMP1 (AUC 0.92; 95% CI 0.88 to 0.96; p=0.06), LRG1 (AUC 0.92; 95% CI 0.88 to 0.96; p=0.02) or exocrine pancreas-specific cfDNA methylation markers at nine loci (AUC 0.92; 95% CI 0.88 to 0.96; p=0.02). In the validation set of 40 early stage PDAC and 40 matched healthy controls, a combined panel including CA19-9, TIMP1 and a 9-loci cfDNA methylation panel had greater discrimination (AUC 0.86, 95% CI 0.77 to 0.95) than CA19-9 alone (AUC 0.82; 95% CI 0.72 to 0.92). CONCLUSION: A combined panel of circulating markers including proteins and methylated cfDNA increased discrimination compared with CA19-9 alone for early stage PDAC.

Associations between common contraceptive use and circulating inflammatory biomarkers.

Ovarian cancer incidence has declined in recent decades, due in part to oral contraceptive (OC) use and tubal ligation. However, intrauterine device (IUD) use has increasingly replaced OC use. As ovarian cancer is an inflammation-related disease, we examined the association of OC use, IUD use, and tubal ligation with plasma levels of C-reactive protein (CRP), interleukin 6 (IL-6), and soluble tumor necrosis factor α receptor 2 (sTNFR2), in the Nurses' Health Study (NHS) and NHSII. After adjusting for reproductive, hormonal, and lifestyle factors, and mutual adjustment for other methods of contraception, there were no differences in inflammatory markers between ever and never use of each method. However, CRP levels decreased from an average 30.4% (-53.6, 4.4) with every 5 years since initial IUD use (P-trend=0.03), while CRP increased an average 9.9% (95% CI: 5.7, 14.3) with every 5 years of use of OC (P-trend<0.0001) as well as differences by BMI and menopausal status. Our results suggest IUD use and tubal ligation are not associated with higher circulating inflammatory markers long term, although long duration of OC use may increase generalized inflammation, which may in part explain why its protective effect wanes over time.

Altered exocrine function can drive adipose wasting in early pancreatic cancer.

Malignancy is accompanied by changes in the metabolism of both cells and the organism1,2. Pancreatic ductal adenocarcinoma (PDAC) is associated with wasting of peripheral tissues, a metabolic syndrome that lowers quality of life and has been proposed to decrease survival of patients with cancer3,4. Tissue wasting is a multifactorial disease and targeting specific circulating factors to reverse this syndrome has been mostly ineffective in the clinic5,6. Here we show that loss of both adipose and muscle tissue occurs early in the development of pancreatic cancer. Using mouse models of PDAC, we show that tumour growth in the pancreas but not in other sites leads to adipose tissue wasting, suggesting that tumour growth within the pancreatic environment contributes to this wasting phenotype. We find that decreased exocrine pancreatic function is a driver of adipose tissue loss and that replacement of pancreatic enzymes attenuates PDAC-associated wasting of peripheral tissues. Paradoxically, reversal of adipose tissue loss impairs survival in mice with PDAC. When analysing patients with PDAC, we find that depletion of adipose and skeletal muscle tissues at the time of diagnosis is common, but is not associated with worse survival. Taken together, these results provide an explanation for wasting of adipose tissue in early PDAC and suggest that early loss of peripheral tissue associated with pancreatic cancer may not impair survival.

Cancer Diagnoses After Recent Weight Loss.

Importance: Weight loss is common in primary care. Among individuals with recent weight loss, the rates of cancer during the subsequent 12 months are unclear compared with those without recent weight loss. Objective: To determine the rates of subsequent cancer diagnoses over 12 months among health professionals with weight loss during the prior 2 years compared with those without recent weight loss. Design, Setting, and Participants: Prospective cohort analysis of females aged 40 years or older from the Nurses' Health Study who were followed up from June 1978 until June 30, 2016, and males aged 40 years or older from the Health Professionals Follow-Up Study who were followed up from January 1988 until January 31, 2016. Exposure: Recent weight change was calculated from the participant weights that were reported biennially. The intentionality of weight loss was categorized as high if both physical activity and diet quality increased, medium if only 1 increased, and low if neither increased. Main Outcome and Measures: Rates of cancer diagnosis during the 12 months after weight loss. Results: Among 157 474 participants (median age, 62 years [IQR, 54-70 years]; 111 912 were female [71.1%]; there were 2631 participants [1.7%] who self-identified as Asian, Native American, or Native Hawaiian; 2678 Black participants [1.7%]; and 149 903 White participants [95.2%]) and during 1.64 million person-years of follow-up, 15 809 incident cancer cases were identified (incident rate, 964 cases/100 000 person-years). During the 12 months after reported weight change, there were 1362 cancer cases/100 000 person-years among all participants with recent weight loss of greater than 10.0% of body weight compared with 869 cancer cases/100 000 person-years among those without recent weight loss (between-group difference, 493 cases/100 000 person-years [95% CI, 391-594 cases/100 000 person-years]; P < .001). Among participants categorized with low intentionality for weight loss, there were 2687 cancer cases/100 000 person-years for those with weight loss of greater than 10.0% of body weight compared with 1220 cancer cases/100 000 person-years for those without recent weight loss (between-group difference, 1467 cases/100 000 person-years [95% CI, 799-2135 cases/100 000 person-years]; P < .001). Cancer of the upper gastrointestinal tract (cancer of the esophagus, stomach, liver, biliary tract, or pancreas) was particularly common among participants with recent weight loss; there were 173 cancer cases/100 000 person-years for those with weight loss of greater than 10.0% of body weight compared with 36 cancer cases/100 000 person-years for those without recent weight loss (between-group difference, 137 cases/100 000 person-years [95% CI, 101-172 cases/100 000 person-years]; P < .001). Conclusions and Relevance: Health professionals with weight loss within the prior 2 years had a significantly higher risk of cancer during the subsequent 12 months compared with those without recent weight loss. Cancer of the upper gastrointestinal tract was particularly common among participants with recent weight loss compared with those without recent weight loss.

Being Breastfed in Infancy and Risk of Colorectal Cancer and Precursor Lesions.

BACKGROUND & AIMS: Emerging evidence implicates the importance of perinatal and early-life exposures in colorectal cancer (CRC) development. However, it remains unclear whether being breastfed in infancy is associated with CRC risk in adult life, particularly early adulthood. METHODS: We prospectively investigated the association between history of being breastfed and risk of CRC and its precursor lesions among 66,634 women 46-93 years of age from the Nurses' Health Study and 92,062 women 27-68 years of age from the Nurses' Health Study II. Cox regression and logistic regression for clustered data were used to estimate hazard ratios for CRC and odds ratios for CRC precursors, respectively. RESULTS: During 3.5 million person-years of follow-up, we identified 1490 incident cases of CRC in 2 cohorts. Having been breastfed was associated with a 23% (95% confidence interval [CI], 10% to 38%) increased risk of CRC. The risk of CRC increased with duration of being breastfed (Ptrend < .001). These findings were validated using breastfeeding information from the mothers of a subset of participants. Among younger participants from the Nurses' Health Study II, a significant association was observed between being breastfed and increased risk of high-risk adenomas under 50 years of age (odds ratio, 1.46; 95% CI, 1.16 to 1.83). Consistently, having been breastfed was associated with increased risk of CRC among participants ≤55 years of age (hazard ratio, 1.38; 95% CI, 1.06 to 1.80). CONCLUSIONS: Being breastfed in infancy was associated with increased risk of CRC in adulthood, including among younger adults. However, further research is needed to understand the underlying biological mechanisms, as this association does not establish causation.

Utility of Normalized Body Composition Areas, Derived From Outpatient Abdominal CT Using a Fully Automated Deep Learning Method, for Predicting Subsequent Cardiovascular Events.

BACKGROUND. CT-based body composition (BC) measurements have historically been too resource intensive to analyze for widespread use and have lacked robust comparison with traditional weight metrics for predicting cardiovascular risk. OBJECTIVE. The aim of this study was to determine whether BC measurements obtained from routine CT scans by use of a fully automated deep learning algorithm could predict subsequent cardiovascular events independently from weight, BMI, and additional cardiovascular risk factors. METHODS. This retrospective study included 9752 outpatients (5519 women and 4233 men; mean age, 53.2 years; 890 patients self-reported their race as Black and 8862 self-reported their race as White) who underwent routine abdominal CT at a single health system from January 2012 through December 2012 and who were given no major cardiovascular or oncologic diagnosis within 3 months of undergoing CT. Using publicly available code, fully automated deep learning BC analysis was performed at the L3 vertebral body level to determine three BC areas (skeletal muscle area [SMA], visceral fat area [VFA], and subcutaneous fat area [SFA]). Age-, sex-, and race-normalized reference curves were used to generate z scores for the three BC areas. Subsequent myocardial infarction (MI) or stroke was determined from the electronic medical record. Multivariable-adjusted Cox proportional hazards models were used to determine hazard ratios (HRs) for MI or stroke within 5 years after CT for the three BC area z scores, with adjustment for normalized weight, normalized BMI, and additional cardiovascular risk factors (smoking status, diabetes diagnosis, and systolic blood pressure). RESULTS. In multivariable models, age-, race-, and sex-normalized VFA was associated with subsequent MI risk (HR of highest quartile compared with lowest quartile, 1.31 [95% CI, 1.03-1.67], p = .04 for overall effect) and stroke risk (HR of highest compared with lowest quartile, 1.46 [95% CI, 1.07-2.00], p = .04 for overall effect). In multivariable models, normalized SMA, SFA, weight, and BMI were not associated with subsequent MI or stroke risk. CONCLUSION. VFA derived from fully automated and normalized analysis of abdominal CT examinations predicts subsequent MI or stroke in Black and White patients, independent of traditional weight metrics, and should be considered an adjunct to BMI in risk models. CLINICAL IMPACT. Fully automated and normalized BC analysis of abdominal CT has promise to augment traditional cardiovascular risk prediction models.

Lead-Time Trajectory of CA19-9 as an Anchor Marker for Pancreatic Cancer Early Detection.

BACKGROUND & AIMS: There is substantial interest in liquid biopsy approaches for cancer early detection among subjects at risk, using multi-marker panels. CA19-9 is an established circulating biomarker for pancreatic cancer; however, its relevance for pancreatic cancer early detection or for monitoring subjects at risk has not been established. METHODS: CA19-9 levels were assessed in blinded sera from 175 subjects collected up to 5 years before diagnosis of pancreatic cancer and from 875 matched controls from the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. For comparison of performance, CA19-9 was assayed in blinded independent sets of samples collected at diagnosis from 129 subjects with resectable pancreatic cancer and 275 controls (100 healthy subjects; 50 with chronic pancreatitis; and 125 with noncancerous pancreatic cysts). The complementary value of 2 additional protein markers, TIMP1 and LRG1, was determined. RESULTS: In the PLCO cohort, levels of CA19-9 increased exponentially starting at 2 years before diagnosis with sensitivities reaching 60% at 99% specificity within 0 to 6 months before diagnosis for all cases and 50% at 99% specificity for cases diagnosed with early-stage disease. Performance was comparable for distinguishing newly diagnosed cases with resectable pancreatic cancer from healthy controls (64% sensitivity at 99% specificity). Comparison of resectable pancreatic cancer cases to subjects with chronic pancreatitis yielded 46% sensitivity at 99% specificity and for subjects with noncancerous cysts, 30% sensitivity at 99% specificity. For prediagnostic cases below cutoff value for CA19-9, the combination with LRG1 and TIMP1 yielded an increment of 13.2% in sensitivity at 99% specificity (P = .031) in identifying cases diagnosed within 1 year of blood collection. CONCLUSION: CA19-9 can serve as an anchor marker for pancreatic cancer early detection applications.

Intrauterine device use and risk of ovarian cancer: Results from the New England Case-Control study and Nurses' Health Studies.

Results of studies assessing intrauterine device (IUD) use and ovarian cancer risk are inconsistent. We examined the association between IUD use, including duration, type and timing of use, and ovarian cancer risk using three population-based studies. Data from the New England Case-Control Study (NEC) and two prospective cohort studies, the Nurses' Health Studies (NHS/NHSII), were included in the analysis. Information on IUD use was collected by in-person interview in NEC and by biennial questionnaire in NHS/NHSII. We used unconditional logistic regression to calculate odds ratios (OR) and 95% confidence intervals (CI) in NEC and Cox regression to calculate hazard ratios (HR) and 95% CI in NHS/NHSII. We used meta-analysis to combine the NEC and the pooled NHS/NHSII results. Overall, IUD use was not associated with epithelial ovarian cancer risk (OR = 0.96, 95% CI: 0.81-1.14 in NEC; HR = 0.89, 95% CI: 0.69-1.15 in NHS/NHSII; combined RR = 0.94, 95% CI: 0.81-1.08). Among IUD users, older age at first use was associated with increased ovarian cancer risk (P-trend = .03). We did not observe significant associations by IUD type or duration of use. In conclusion, IUD use was not associated with ovarian cancer risk in our study.

Population-Scale CT-based Body Composition Analysis of a Large Outpatient Population Using Deep Learning to Derive Age-, Sex-, and Race-specific Reference Curves.

Background Although CT-based body composition (BC) metrics may inform disease risk and outcomes, obtaining these metrics has been too resource intensive for large-scale use. Thus, population-wide distributions of BC remain uncertain. Purpose To demonstrate the validity of fully automated, deep learning BC analysis from abdominal CT examinations, to define demographically adjusted BC reference curves, and to illustrate the advantage of use of these curves compared with standard methods, along with their biologic significance in predicting survival. Materials and Methods After external validation and equivalency testing with manual segmentation, a fully automated deep learning BC analysis pipeline was applied to a cross-sectional population cohort that included any outpatient without a cardiovascular disease or cancer who underwent abdominal CT examination at one of three hospitals in 2012. Demographically adjusted population reference curves were generated for each BC area. The z scores derived from these curves were compared with sex-specific thresholds for sarcopenia by using χ2 tests and used to predict 2-year survival in multivariable Cox proportional hazards models that included weight and body mass index (BMI). Results External validation showed excellent correlation (R = 0.99) and equivalency (P < .001) of the fully automated deep learning BC analysis method with manual segmentation. With use of the fully automated BC data from 12 128 outpatients (mean age, 52 years; 6936 [57%] women), age-, race-, and sex-normalized BC reference curves were generated. All BC areas varied significantly with these variables (P < .001 except for subcutaneous fat area vs age [P = .003]). Sex-specific thresholds for sarcopenia demonstrated that age and race bias were not present if z scores derived from the reference curves were used (P < .001). Skeletal muscle area z scores were significantly predictive of 2-year survival (P = .04) in combined models that included BMI. Conclusion Fully automated body composition (BC) metrics vary significantly by age, race, and sex. The z scores derived from reference curves for BC parameters better capture the demographic distribution of BC compared with standard methods and can help predict survival. © RSNA, 2020 Online supplemental material is available for this article. See also the editorial by Summers in this issue.

Acid-suppressive medications and risk of colorectal cancer: results from three large prospective cohort studies.

BACKGROUND: Despite several plausible biological mechanisms linking proton pump inhibitors (PPIs) and H2 receptor antagonists (H2RAs) with colorectal tumorigenesis, their association with risk of colorectal cancer (CRC) has not been adequately assessed in prospective epidemiological studies. METHODS: We evaluated the association of acid-suppressive medication use with CRC risk among 175,871 (PPI) and 208,831 (H2RA) participants from three large prospective cohort studies. Medication use was assessed at baseline and updated biennially. The association was evaluated using multivariate Cox proportional hazards regression models. RESULTS: There was no significant association between baseline PPI use (hazard ratio (HR) = 0.89, 95% confidence interval (CI), 0.71-1.12) or PPI use after a lag of 8-10 years (HR = 1.12, 95% CI, 0.78-1.59) with CRC risk. We observed no significant association between H2RA use after a lag of 8-10 years and CRC risk (HR = 1.02, 95% CI, 0.81-1.28), while risk was lower for participants with baseline H2RA use (HR = 0.76, 95% CI, 0.60-0.95). Duration of PPI use or H2RA use was not associated with CRC risk (P-trend = 0.21 and 0.95, respectively). CONCLUSIONS: Among participants from three large prospective cohorts, use of PPI or H2RA was not associated with higher risk of colorectal cancer.

Family history of cancer, Ashkenazi Jewish ancestry, and pancreatic cancer risk.

BACKGROUND: Individuals with a family history of cancer may be at increased risk of pancreatic cancer. Ashkenazi Jewish (AJ) individuals carry increased risk for pancreatic cancer and other cancer types. METHODS: We examined the association between family history of cancer, AJ heritage, and incident pancreatic cancer in 49 410 male participants of the prospective Health Professionals Follow-up Study. Hazard ratios (HRs) were estimated using multivariable-adjusted Cox proportional hazards models. RESULTS: During 1.1 million person-years (1986-2016), 452 participants developed pancreatic cancer. Increased risk of pancreatic cancer was observed in individuals with a family history of pancreatic (HR, 2.79; 95% confidence interval [CI], 1.28-6.07) or breast cancer (HR, 1.40; 95% CI, 1.01-1.94). There was a trend towards higher risk of pancreatic cancer in relation to a family history of colorectal cancer (HR, 1.21; 95% CI, 0.95-1.55) or AJ heritage (HR, 1.29; 95% CI, 0.94-1.77). The risk was highly elevated among AJ men with a family history of breast or colorectal cancer (HR, 2.61 [95% CI, 1.41-4.82] and 1.92 [95% CI, 1.05-3.49], respectively). CONCLUSION: Family history of pancreatic cancer was associated with increased risk of this malignancy. Family history of breast or colorectal cancer was associated with the increased risk among AJ men.

Regular Use of Aspirin or Non-Aspirin Nonsteroidal Anti-Inflammatory Drugs Is Not Associated With Risk of Incident Pancreatic Cancer in Two Large Cohort Studies.

BACKGROUND & AIMS: Use of aspirin and/or non-aspirin nonsteroidal anti-inflammatory drugs (NSAIDs) reduces the risk of several cancers, but it is not clear if use of these drugs is associated with risk of pancreatic cancer. METHODS: We evaluated aspirin and non-aspirin NSAID use and risk of pancreatic adenocarcinoma in 141,940 participants from the Health Professionals Follow-up Study and Nurses' Health Study using multivariable-adjusted Cox proportional hazards regression. We considered several exposure classifications to model differing lag times between NSAID exposure and cancer development. We also conducted a nested case-control study of participants from 3 prospective cohorts using conditional logistic regression to evaluate pre-diagnosis levels of plasma salicylurate, a major metabolite of aspirin, in 396 pancreatic cancer cases and 784 matched individuals without pancreatic cancer (controls). RESULTS: In the prospective cohort study, 1122 participants developed pancreatic adenocarcinoma over 4.2 million person-years. Use of aspirin or non-aspirin NSAIDs was not associated with pancreatic cancer risk, even after considering several latency exposure classifications. In a pre-planned subgroup analysis, regular aspirin use was associated with reduced pancreatic cancer risk among participants with diabetes (relative risk, 0.71; 95% CI, 0.54-0.94). In the nested case-control study, pre-diagnosis levels of salicylurate were not associated with pancreatic cancer risk (odds ratio, 1.08; 95% CI, 0.72-1.61; Ptrend 0.81; comparing participants in the highest quintile with those in the lowest quintile of plasma salicylurate). CONCLUSIONS: Regular aspirin or non-aspirin NSAID use was not associated with future risk of pancreatic cancer in participants from several large prospective cohort studies. A possible reduction in risk for pancreatic cancer among people with diabetes who regularly use aspirin should be further examined in preclinical and human studies.

Menstrual pain and risk of epithelial ovarian cancer: Results from the Ovarian Cancer Association Consortium.

Menstrual pain, a common gynecological condition, has been associated with increased risk of ovarian cancer in some, but not all studies. Furthermore, potential variations in the association between menstrual pain and ovarian cancer by histologic subtype have not been adequately evaluated due to lack of power. We assessed menstrual pain using either direct questions about having experienced menstrual pain, or indirect questions about menstrual pain as indication for use of hormones or medications. We used multivariate logistic regression to calculate the odds ratio (OR) for the association between severe menstrual pain and ovarian cancer, adjusting for potential confounders and multinomial logistic regression to calculate ORs for specific histologic subtypes. We observed no association between ovarian cancer and menstrual pain assessed by indirect questions. Among studies using direct question, severe pain was associated with a small but significant increase in overall risk of ovarian cancer (OR = 1.07, 95% CI: 1.01-1.13), after adjusting for endometriosis and other potential confounders. The association appeared to be more relevant for clear cell (OR = 1.48, 95% CI: 1.10-1.99) and serous borderline (OR = 1.31, 95% CI: 1.05-1.63) subtypes. In this large international pooled analysis of case-control studies, we observed a small increase in risk of ovarian cancer for women reporting severe menstrual pain. While we observed an increased ovarian cancer risk with severe menstrual pain, the possibility of recall bias and undiagnosed endometriosis cannot be excluded. Future validation in prospective studies with detailed information on endometriosis is needed.

Prediagnosis Use of Statins Associates With Increased Survival Times of Patients With Pancreatic Cancer.

BACKGROUND & AIMS: Statin medications, most commonly prescribed to reduce lipid levels and prevent cardiovascular disease, may be associated with longer survival times of patients with cancer. However, the association of statins with outcomes of patients with pancreatic adenocarcinoma is not clear. METHODS: We analyzed the association of statin use before a diagnosis of pancreatic cancer with survival times of 648 participants in the Nurses' Health Study and Health Professionals Follow-up Study who were diagnosed with pancreatic adenocarcinoma from 2000 through 2013. We estimated hazard ratios (HRs) for overall mortality using Cox proportional hazards models with adjustment for potential confounders. We assessed the temporal association between prediagnosis statin use and cancer survival by 2-year lag periods to account for a possible latency period between statin use and cancer survival. RESULTS: Regular statin use before diagnosis of pancreatic cancer was associated with modestly prolonged survival compared with nonregular use (adjusted HR, 0.82; 95% CI, 0.69-0.97; P = .02). A 1-month longer median survival was observed in regular statin users compared with nonregular users. Regular statin use within the 2 years prior to cancer diagnosis was most strongly associated with longer survival. We observed no statistically significant effect modification by smoking status, body mass index, diabetes, or cancer stage (all Pinteraction > .53). Regular statin use before diagnosis was similarly associated with survival in the Nurses' Health Study (HR, 0.79; 95% CI, 0.64-0.97) and Health Professionals Follow-up Study (HR, 0.86; 95% CI, 0.63-1.15). CONCLUSIONS: Regular statin use before diagnosis of pancreatic cancer was associated with modest increases in survival times in 2 large prospective cohort studies.

Leucocyte telomere length, genetic variants at the TERT gene region and risk of pancreatic cancer.

OBJECTIVE: Telomere shortening occurs as an early event in pancreatic tumorigenesis, and genetic variants at the telomerase reverse transcriptase (TERT) gene region have been associated with pancreatic cancer risk. However, it is unknown whether prediagnostic leucocyte telomere length is associated with subsequent risk of pancreatic cancer. DESIGN: We measured prediagnostic leucocyte telomere length in 386 pancreatic cancer cases and 896 matched controls from five prospective US cohorts. ORs and 95% CIs were calculated using conditional logistic regression. Matching factors included year of birth, cohort (which also matches on sex), smoking status, fasting status and month/year of blood collection. We additionally examined single-nucleotide polymorphisms (SNPs) at the TERT region in relation to pancreatic cancer risk and leucocyte telomere length using logistic and linear regression, respectively. RESULTS: Shorter prediagnostic leucocyte telomere length was associated with higher risk of pancreatic cancer (comparing extreme quintiles of telomere length, OR 1.72; 95% CI 1.07 to 2.78; ptrend=0.048). Results remained unchanged after adjustment for diabetes, body mass index and physical activity. Three SNPs at TERT (linkage disequilibrium r2<0.25) were associated with pancreatic cancer risk, including rs401681 (per minor allele OR 1.33; 95% CI 1.12 to 1.59; p=0.002), rs2736100 (per minor allele OR 1.36; 95% CI 1.13 to 1.63; p=0.001) and rs2736098 (per minor allele OR 0.75; 95% CI 0.63 to 0.90; p=0.002). The minor allele for rs401681 was associated with shorter telomere length (p=0.023). CONCLUSIONS: Prediagnostic leucocyte telomere length and genetic variants at the TERT gene region were associated with risk of pancreatic cancer.

Periodontal disease, tooth loss and colorectal cancer risk: Results from the Nurses' Health Study.

Periodontal diseases including tooth loss might increase systemic inflammation, lead to immune dysregulation and alter gut microbiota, thereby possibly influencing colorectal carcinogenesis. Few epidemiological studies have examined the association between periodontal diseases and colorectal cancer (CRC) risk. We collected information on the periodontal disease (defined as history of periodontal bone loss) and number of natural teeth in the Nurses' Health Study. A total of 77,443 women were followed since 1992. We used Cox proportional hazard models to calculate multivariable hazard ratios (HRs) and 95% confidence intervals (95% CIs) after adjustment for smoking and other known risk factors for CRC. We documented 1,165 incident CRC through 2010. Compared to women with 25-32 teeth, the multivariable HR (95% CI) for CRC for women with <17 teeth was 1.20 (1.04-1.39). With regard to tumor site, the HRs (95% CIs) for the same comparison were 1.23 (1.01-1.51) for proximal colon cancer, 1.03 (0.76-1.38) for distal colon cancer and 1.48 (1.07-2.05) for rectal cancer. In addition, compared to those without periodontal disease, HRs for CRC were 0.91 (95% CI 0.74-1.12) for periodontal disease, and 1.22 (95% CI 0.91-1.63) when limited to moderate to severe periodontal disease. The results were not modified by smoking status, body mass index or alcohol consumption. Women with fewer teeth, possibly moderate or severe periodontal disease, might be at a modest increased risk of developing CRC, suggesting a potential role of oral health in colorectal carcinogenesis.

Lymph node metastases in resected pancreatic ductal adenocarcinoma: predictors of disease recurrence and survival.

BACKGROUND: Few studies have simultaneously assessed the prognostic value of the multiple classification systems for lymph node (LN) metastases in resected pancreatic ductal adenocarcinoma (PDAC). METHODS: In 600 patients with resected PDAC, we examined the association of LN parameters (AJCC 7th and 8th editions, LN ratio (LNR), and log odds of metastatic LN (LODDS)) with pattern of recurrence and patient survival using logistic regression and Cox proportional hazards regression, respectively. Regression models adjusted for age, sex, margin status, tumour grade, and perioperative therapy. RESULTS: Lymph node metastases classified by AJCC 7th and 8th editions, LNR, and LODDS were associated with worse disease free-survival (DFS) and overall survival (OS) (all Ptrend<0.01). American Joint Committee on Cancer 8th edition effectively predicted DFS and OS, while minimising model complexity. Lymph node metastases had weaker prognostic value in patients with positive margins and distal resections (both Pinteraction<0.03). Lymph node metastases by AJCC 7th and 8th editions did not predict the likelihood of local disease as the first site of recurrence. CONCLUSIONS: American Joint Committee on Cancer 8th edition LN classification is an effective and practical tool to predict outcomes in patients with resected PDAC. However, the prognostic value of LN metastases is attenuated in patients with positive resection margins and distal pancreatectomies.

Predictors of pretreatment CA125 at ovarian cancer diagnosis: a pooled analysis in the Ovarian Cancer Association Consortium.

PURPOSE: Cancer antigen 125 (CA125) is a glycoprotein expressed by epithelial cells of several normal tissue types and overexpressed by several epithelial cancers. Serum CA125 levels are mostly used as an aid in the diagnosis of ovarian cancer patients, to monitor response to treatment and detect cancer recurrence. Besides tumor characteristics, CA125 levels are also influenced by several epidemiologic factors, such as age, parity, and oral contraceptive use. Identifying factors that influence CA125 levels in ovarian cancer patients could aid in the interpretation of CA125 values for individuals. METHODS: We evaluated predictors of pretreatment CA125 in 13 studies participating in the Ovarian Cancer Association Consortium. This analysis included a total of 5,091 women with invasive epithelial ovarian cancer with pretreatment CA125 measurements. We used probit scores to account for variability in CA125 between studies and linear regression to estimate the association between epidemiologic factors and tumor characteristics and pretreatment CA125 levels. RESULTS: In age-adjusted models, older age, history of pregnancy, history of tubal ligation, family history of breast cancer, and family history of ovarian cancer were associated with higher CA125 levels while endometriosis was associated with lower CA125 levels. After adjusting for tumor-related characteristics (stage, histology, grade), body mass index (BMI) higher than 30 kg/m2 was associated with 10% (95% CI 2, 19%) higher CA125 levels, while race (non-white vs. white) was associated with 15% (95% CI 4, 27%) higher CA125 levels. CONCLUSION: Our results suggest that high BMI and race may influence CA125 levels independent of tumor characteristics. Validation is needed in studies that use a single assay for CA125 measurement and have a diverse study population.

Reproductive and hormonal factors in relation to survival and platinum resistance among ovarian cancer cases.

BACKGROUND: Ovarian cancer survival is poor, particularly for platinum-resistant cases. The previous literature on pre-diagnostic reproductive factors and ovarian cancer survival has been mixed. Therefore, we evaluated pre-diagnostic reproductive and hormonal factors with overall survival and, additionally, platinum-chemotherapy resistance. METHODS: We followed 1649 invasive epithelial ovarian cancer cases who were enrolled between 1992 and 2008 for overall mortality within the New England Case-Control Study and abstracted chemotherapy data on a subset (n=449). We assessed pre-diagnostic reproductive and hormonal factors during in-person interviews. We calculated hazard ratios (HRs) using Cox-proportional hazards models. RESULTS: We observed 911 all-cause deaths among 1649 ovarian cancer cases. Self-reported endometriosis and longer duration of hormone therapy use were associated with improved survival (HR: 0.72; 95% confidence interval (CI): 0.54-0.94 and HR, ⩾5 years vs never: 0.70; 95% CI: 0.55-0.90, respectively). Older age at menopause and menarche were associated with worse survival (HR, ⩽50 vs >50 years: 1.23; 95% CI: 1.03-1.46 and HR, 13 vs <13 years: 1.24; 95% CI: 1.06-1.44, respectively). We observed no association between oral contraceptive use, parity and tubal ligation, and overall survival. No significant associations were observed for any of the reproductive and hormonal factors and platinum resistance. CONCLUSIONS: These results suggest that pre-diagnostic exposures such as endometriosis and HT use may influence overall survival among ovarian cancer patients.