Risk Of Developing Pancreatic Cancer Research Articles

Meta-analysis: Risk of pancreatic cancer in patients with inflammatory bowel disease.

Studies exploring the association between inflammatory bowel disease (IBD) and pancreatic cancer have reported inconsistent results. To provide a comprehensive overview of the risk of pancreatic cancer development in patients with IBD. We searched Embase, PubMed, Scopus and ProQuest from inception to 31 October 2023. We included population-based cohort studies examining the risk of incident pancreatic cancer in adult patients with IBD compared to the non-IBD population. We also retrieved Mendelian randomisation (MR) studies investigating the relationship of IBD with pancreatic cancer risk. We conducted random-effects meta-analyses and provided pooled relative risks (RRs) with 95% confidence intervals (CIs). We included 13 studies. Among 11 cohort studies, the risk of developing pancreatic cancer increased by 79% in patients with IBD (RR = 1.79 [95% CI: 1.16-2.75]; I2 = 95.7%). Patients either with Crohn's disease (RR = 1.42 [95% CI: 1.24-1.63]) or ulcerative colitis (RR = 1.50 [95% CI: 1.17-1.92]) had increased risk (p for interaction = 0.72). The annual incidence of pancreatic cancer potentially attributable to IBD increased by 55 cases (95% CI: 17-103) per million. Two MR studies demonstrated that genetic liability to IBD was associated with an increased risk of pancreatic cancer. Our results suggest a moderate increase in the risk of pancreatic cancer in patients with IBD, which may be further heightened by genetic predisposition to IBD. The increased risk of pancreatic cancer is probably similar in Crohn's disease and ulcerative colitis.

Familial pancreatic cancer: a case study and review of the psychosocial effects of diagnoses on families

BackgroundFamilial pancreatic cancer touches families through a genetic susceptibility to developing this neoplasia. Genetic susceptibility is assessed via family history, genetic testing, or both. Individuals with two or more first-degree relatives or three or more relatives of any degree diagnosed with pancreatic cancer are considered at elevated risk. Following a diagnosis of familial pancreatic cancer, patients and families face uncertainty and anxiety about the future. Psychosocial effects of a pancreatic cancer diagnosis on families include fear, concerns about personal health, and how lifestyle may impact the risk of developing pancreatic cancer.Case presentationA 66-year-old male was diagnosed with pancreatic ductal adenocarcinoma stage IIB, T3, N1, M0. A genetic referral was made due to a history of multiple cases of pancreatic cancer within the patient’s family. Genetic testing revealed the patient had a pathogenic variant in the ATM gene that is associated with an increased risk for pancreatic cancer development. The patient’s one adult child was offered testing due to the autosomal dominant pattern of inheritance for this variant. The adult child was found to have the same pathogenic variant. She expressed fear for her future and her child’s future health and longevity. Discussing a case study allows us to capture the multi-faceted relationship between the disease, the affected individuals, and their families. Examining the psychosocial stresses and concerns when there is a pancreatic cancer diagnosis in the family is essential to provide holistic care to patients and families.ConclusionsThe psychosocial effects of FPC may be overwhelming for patients and families. Healthcare providers can offer education, support, and referrals to appropriate services to help families cope through stages of evaluation, diagnosis, and treatment of FPC.

The Link between Diabetes, Pancreatic Tumors, and miRNAs-New Players for Diagnosis and Therapy?

Despite significant progress in medicine, pancreatic cancer is one of the most tardily diagnosed cancer and is consequently associated with a poor prognosis and a low survival rate. The asymptomatic clinical picture and the lack of relevant diagnostic markers for the early stages of pancreatic cancer are believed to be the major constraints behind an accurate diagnosis of this disease. Furthermore, underlying mechanisms of pancreatic cancer development are still poorly recognized. It is well accepted that diabetes increases the risk of pancreatic cancer development, however the precise mechanisms are weakly investigated. Recent studies are focused on microRNAs as a causative factor of pancreatic cancer. This review aims to provide an overview of the current knowledge of pancreatic cancer and diabetes-associated microRNAs, and their potential in diagnosis and therapy. miR-96, miR-124, miR-21, and miR-10a were identified as promising biomarkers for early pancreatic cancer prediction. miR-26a, miR-101, and miR-200b carry therapeutic potential, as they not only regulate significant biological pathways, including the TGF-β and PI3K/AKT, but their re-expression contributes to the improvement of the prognosis by reducing invasiveness or chemoresistance. In diabetes, there are also changes in the expression of microRNAs, such as in miR-145, miR-29c, and miR-143. These microRNAs are involved, among others, in insulin signaling, including IRS-1 and AKT (miR-145), glucose homeostasis (hsa-miR-21), and glucose reuptake and gluconeogenesis (miR-29c). Although, changes in the expression of the same microRNAs are observed in both pancreatic cancer and diabetes, they exert different molecular effects. For example, miR-181a is upregulated in both pancreatic cancer and diabetes mellitus, but in diabetes it contributes to insulin resistance, whereas in pancreatic cancer it promotes tumor cell migration, respectively. To conclude, dysregulated microRNAs in diabetes affect crucial cellular processes that are involved in pancreatic cancer development and progression.

Difference of Risk of Pancreatic Cancer in New-Onset Diabetes and Long-standing Diabetes: A Population-based Cohort Study.

Considering the absence of methods to find pancreatic cancer early, surveillance of high-risk groups is needed for early diagnosis. The study aimed to investigate the effect in the incidence of pancreatic cancer and the differences between new-onset diabetes mellitus (NODM) and long-standing DM (LSDM) since NODM group is a representative high-risk group. The Korean National Health Insurance Service-National Sample Cohort between 2002 and 2013 data were used. Regarding 88 396 people with DM (case group), we conducted a 1:1 propensity score matching to select a matched non-DM population (control group). To investigate the interaction between DM and the time variable distinguishing NODM and LSDM, we performed a multivariate time-dependent Cox regression analysis. The incidence of pancreatic cancer was higher in the DM group compared to the non-DM group (0.52% vs 0.16%; P < .001). The DM group had shown different risk of pancreatic cancer development according to the duration since the DM diagnosis (NODM hazard ratio (HR): 3.81; 95% CI, 2.97-4.88; P < .001; LSDM HR: 1.53; 95% CI, 1.11-2.11; P < .001). When the NODM and the LSDM groups were compared, the risk of pancreatic cancer was higher in the NODM group than in the LSDM group (HR: 1.55; P = .020). In subgroup analysis, NODM group showed that men (HR = 4.42; 95% CI, 3.15-6.19; P < .001) and patients who were in their 50 seconds (HR = 7.54; 95% CI, 3.24-17.56; P < .001) were at a higher risk of developing pancreatic cancer than matched same sex or age control group (non-DM population), respectively. The risk of pancreatic cancer was greater in people with DM than in a non-DM population. Among people with DM, NODM showed a higher risk of pancreatic cancer than LSDM.

The Role of Type 2 Diabetes in Pancreatic Cancer.

The incidence of type 2 diabetes mellitus (T2DM) and its potential complications, such as cancers, are increasing worldwide at an astounding rate. There are many factors such as obesity, diabetes, alcohol consumption, and the adoption of sedentary lifestyles that are driving pancreatic cancer (PC) to become one of the leading causes of cancer mortality in the United States. PC is notorious for its generic symptoms and late-stage presentation with rapid metastasis. The connection between T2DM and the risk of PC development is multifaceted and complex. Some of the proposed theories reveal that chronic inflammation, insulin resistance, hyperinsulinemia, hyperglycemia, and abnormalities in the insulin and insulin-like growth factor axis (IGF) contribute to the disease association between these two conditions. This literature review aims to highlight relevant studies and explore the molecular mechanisms involved in the etiology of diabetes and its impact on PC development, as well as the role of anti-diabetic agents on PC. Despite extensive studies, the exact interaction between T2DM and PC remains obscure and will need further investigation. According to current knowledge, there is a substantial link between diabetes, obesity, and dietary patterns in the development and progression of PC. Consequently, focusing our efforts on preventive measures by reducing modifiable risk factors remains the most effective strategy to reduce the risk of PC at this time. Antidiabetic drugs can have various effects on the occurrence and prognosis of PC with metformin offering a clear benefit of inhibiting PC and insulin increasing the risk of PC. The development of future novel therapies will require a deeper knowledge of the triggering mechanisms and interplay between these two disease states.

Laparoscopic distal pancreatectomy for intraductal papillary mucinous neoplasm-associated pancreatic cancer: A case report.

Introduction and importanceIntraductal papillary mucinous neoplasm (IPMN) of the pancreas is often found incidentally during examination for other diseases. In addition to the risk of malignant transformation, patients with IPMN are at risk of developing pancreatic cancer. We report a case of pancreatic tail cancer that developed separately from a preexisting IPMN after minimally invasive esophagectomy for cancer of the esophagogastric junction and was resected successfully by laparoscopic distal pancreatectomy.Case presentationA 72-year-old man underwent thoracoscopic and laparoscopic esophagectomy for esophagogastric junction cancer. He had undergone surgery for ascending colon cancer 20 years ago. At that time, IPMN was confirmed in the pancreatic body by a preoperative examination. Computed tomography was regularly performed for postoperative work-up and follow-up of the IPMN, and a solid lesion with cystic components was detected in the pancreatic tail 9 months after the operation. On detailed examination, pancreatic ductal adenocarcinoma concomitant with IPMN, accompanied by a retention cyst, was considered. Laparoscopic distal pancreatectomy was successfully performed after neoadjuvant chemotherapy. Pathological diagnosis of the lesion in the pancreatic tail was of an invasive intraductal papillary mucinous carcinoma (ypT3ypN0yM0 ypStageIIA).Clinical discussionIf an IPMN is detected during preoperative examination for malignancies of other organs, careful follow-up is necessary due to the high risk of pancreatic cancer development. Furthermore, initial operation with minimally invasive surgery may reduce adhesion and facilitate subsequent surgeries.ConclusionWe have provided evidence that supports the importance of a careful follow-up of IPMNs, even if they are low risk.

A case of non-dilated pancreaticobiliary maljunction with branch-type IPMN

A woman in her 60's visited our hospital complaining abnormality in medical examination. Pancreatic cysts, adenomyomatosis, a gallbladder stone, and thickened gallbladder wall were detected using abdominal ultrasonography. Detailed investigations, including ERCP, revealed a non-dilated pancreaticobiliary maljunction, with branch-type IPMN and cholecystectomy was performed. Pathological examination revealed adenomyomatosis of the gallbladder at the bottom and cholesterosis in the gallbladder wall. Biliary carcinoma occurs in 42.4% of non-dilated bile duct-pancreatic-biliary junction abnormalities, and 88.1% of these cases are gallbladder carcinoma; therefore, prophylactic cholecystectomy is recommended. However, because this case was diagnosed in an elderly patient, surgery was performed immediately after confirming the absence of malignancy in the biliary system by using EUS and biliary cytology. In addition, the patient also has IPMN, which is considered to be a high risk for pancreatic cancer development. Frequent follow-up of the patient's pancreatic-biliary system function is required.

A comprehensive analysis of candidate genes in familial pancreatic cancer families reveals a high frequency of potentially pathogenic germline variants

BackgroundThe 5-year survival rate of patients with pancreatic ductal adenocarcinoma (PDAC) is around 5% due to the fact that the majority of patients present with advanced disease that is treatment resistant. Familial pancreatic cancer (FPC) is a rare disorder that is defined as a family with at least two affected first degree relatives, with an estimated incidence of 4%–10%. The genetic basis is unknown in the majority of families although around 10%–13% of families carry germline mutations in known genes associated with hereditary cancer and pancreatitis syndromes.MethodsPanel sequencing was performed of 35 genes associated with hereditary cancer in 43 PDAC cases from families with an apparent hereditary pancreatic cancer syndrome. Findings: Pathogenic variants were identified in 19% (5/26) of PDAC cases from pure FPC families in the genes MLH1, CDKN2A, POLQ and FANCM. Low frequency potentially pathogenic VUS were also identified in 35% (9/26) of PDAC cases from FPC families in the genes FANCC, MLH1, PMS2, CFTR, APC and MUTYH. Furthermore, an important proportion of PDAC cases harboured more than one pathogenic, likely pathogenic or potentially pathogenic VUS, highlighting the multigene phenotype of FPC.InterpretationThe genetic basis of familial or hereditary pancreatic cancer can be explained in 21% of families by previously described hereditary cancer genes. Low frequency variants in other DNA repair genes are also present in 35% of families which may contribute to the risk of pancreatic cancer development.FundingThis study was funded by the Instituto de Salud Carlos III (Plan Estatal de I + D + i 2013–2016): ISCIII (PI09/02221, PI12/01635, PI15/02101 and PI18/1034) and co-financed by the European Development Regional Fund ‘‘A way to achieve Europe’’ (ERDF), the Biomedical Research Network in Cancer: CIBERONC (CB16/12/00446), Red Temática de investigación cooperativa en cáncer: RTICC (RD12/0036/0073) and La Asociación Española contra el Cáncer: AECC (Grupos Coordinados Estables 2016).

Side-branch intraductal papillary mucinous neoplasms of the pancreas: outcome of MR imaging surveillance over a 10 years follow-up

PurposeTo evaluate the outcome of a MR imaging procotol in assessing the evolution of individuals with branch duct - intraductal papillary mucinous neoplasms (BD-IPMN) without worrisome features (WF) and/or high risk stigmata (HRS) at the time of the diagnosis in a follow-up period of at least 10 years. Material and methodsA retrospective revision of a prospectively collected radiological database including a total number of 600 patients who were investigated and diagnosed with “presumed” diagnosis of BD-IPMN at MRI/MRCP at our Department since 2008 was performed. Inclusion criteria were: 1) absence of worrisome features and/or high-risk stigmata at the time of diagnosis (baseline); 2) a radiological follow-up with abdominal MRI/MRCP of at least 10 years. Changes in cysts size, development of WF, HRS and pancreatic cancer, and any other modification during the follow-up were retrospectively analysed by two observers in consensus. ResultsSixty-nine patients fulfilled all the inclusion criteria. During surveillance, the cysts remained dimensionally unchanged or slightly reduced in size in 26.2% and 4.3% of cases respectively, whereas cyst enlargement was demonstrated in 69.5% of cases. Median annual growth rate was of 0.97 ± 0.87 mm/yr (range 0.13-5.0). WF and HRS developed in 10/69 (14.5%) and 3/69 (4.3%) cases, respectively. The incidence of pancreatic cancer in patients with BD-IPMN was 2.9%. ConclusionOur data confirm the low risk of pancreatic cancer development in patients with BD-IPMN, thus justifying an imaging follow-up. Worrisome features and high-risk stigmata were promptly identified during the follow-up, supporting the utility of our surveillance MR imaging protocol.

Chronic pancreatitis as a risk factor for pancreatic cancer (a clinical case)

The differential diagnosis between chronic pancreatitis (CP) and pancreatic cancer (PC) is a challenging issue in the clinical practice, taking into account common risk factors shared by these disorders (smoking, obesity, diabetes mellitus and insulin resistance), as well as a high risk of PC development against the underlying CP of 2 to 3 years' duration; this risk would be manifold in hereditary CP. The article presents a clinical case of PC in a 60-year old man at three years after he had been diagnosed with CP. The disease manifested from an acute episode of pancreatitis, which was treated in a hospital. Two years later, the patient suffered from acute destructive pancreatitis complicated by portal vein thrombosis and formation of pseudocysts. Subsequently, there was a rupture of the post-necrotic cyst with leakage into the abdominal cavity; this required surgical intervention. The differential diagnosis between CP and PC was done at all steps of the diagnostic work-up and treatment. However, after the inflammation resolved, there was a period of apparent well-being, during which the patient developed PC. This clinical case is intended to draw attention of clinicians, while making differential diagnosis, to the detailed past history assessment, use of multiaxial computed tomography with intravenous bolus contrast enhancement, and endoscopic ultrasound examination with elastography. In difficult cases, regular follow-up of at least every three months would be necessary.

Prediction model for pancreatic cancer risk in the general Japanese population.

Genome-wide association studies (GWASs) have identified many single nucleotide polymorphisms (SNPs) that are significantly associated with pancreatic cancer susceptibility. We sought to replicate the associations of 61 GWAS-identified SNPs at 42 loci with pancreatic cancer in Japanese and to develop a risk model for the identification of individuals at high risk for pancreatic cancer development in the general Japanese population. The model was based on data including directly determined or imputed SNP genotypes for 664 pancreatic cancer case and 664 age- and sex-matched control subjects. Stepwise logistic regression uncovered five GWAS-identified SNPs at five loci that also showed significant associations in our case-control cohort. These five SNPs were included in the risk model and also applied to calculation of the polygenic risk score (PRS). The area under the curve determined with the leave-one-out cross-validation method was 0.63 (95% confidence interval, 0.60–0.66) or 0.61 (0.58–0.64) for versions of the model that did or did not include cigarette smoking and family history of pancreatic cancer in addition to the five SNPs, respectively. Individuals in the lowest and highest quintiles for the PRS had odds ratios of 0.62 (0.42–0.91) and 1.98 (1.42–2.76), respectively, for pancreatic cancer development compared with those in the middle quintile. We have thus developed a risk model for pancreatic cancer that showed moderately good discriminatory ability with regard to differentiation of pancreatic cancer patients from control individuals. Our findings suggest the potential utility of a risk model that incorporates replicated GWAS-identified SNPs and established demographic or environmental factors for the identification of individuals at increased risk for pancreatic cancer development.

Environmental cadmium and the risk of pancreatic cancer development

Etiology of human pancreatic cancer (PC) is still rather scant. Exposure to environmental cadmium (Cd), a ubiquitous metal with well-established toxic and carcinogenic properties, has been hypothesized to be one of putative cause of PC. The aim of this case-control prospective study was to determined Cd levels in pancreatic tissue. The cases were a consecutive series of pancreatic tissue excised from 31 patients with PC, while controls pancreatic-tissue samples were taken during routine postmortem examinations from subjects who died from a nonmalignant illness. Tissue samples were wet digested and Cd content was assessed using graphite furnace atomic absorption spectrometry. Higher concentrations of Cd were found in cancerous tissue when compared to control levels. Cadmium content in cancerous tissue was also higher than in surrounding non-cancerous tissue. The association between pancreatic cancer risk and Cd levels in pancreatic tissue is indicated by the ORs and ORs were 2.79 (95% CL 0.91–8.50) and 3.44 (95% CL 1.19–9.95) in the third and fourth quartiles of the distribution of Cd concentrations in the study population, respectively. The chances to develop cancer if not exposed to Cd are between 35%-37.5% while in persons exposed to Cd these chances are higher 56.8%-65.6% depending on chosen quartile cutoffs used to determine the level of Cd exposure. Results of this study indicated a significant association between PC development and Cd tissue levels. However, further investigations are needed to confirm or infirm the environmental Cd involvement in PC development.

Abstract 2273: Serum choline, methionine, betaine, dimethylglycine, and trimethylamine-N-oxide in relation to pancreatic cancer risk in two nested case-control studies in Asian populations

Abstract Background: Choline, methionine, and betaine are methyl group donors associated with DNA methylation. Diets deficient in choline and methionine have been shown to promote pancreatic carcinogenesis in experimental animals. We have previously reported an inverse association between dietary intake of choline and pancreatic cancer risk in a prospective cohort of Singapore Chinese. In the present study biomarkers of dietary choline and other methyl donor nutrients were evaluated in relation to pancreatic cancer risk. Method: Two case-control studies were nested within the Shanghai Cohort Study (129 cases and 258 matched controls) and the Singapore Chinese Health Study (58 cases and 104 matched controls). Concentrations of choline, methionine, betaine, dimethylglycine (DMG), and trimethylamine-N-oxide (TMAO) were measured by LC-MS/MS in pre-diagnostic serum samples. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using conditional logistic regression method with adjustment for potential confounders. Results: Choline, methionine, and betaine were moderately associated with each other (spearman correlation coefficient: 0.28 ~0.43). In the pooled analysis, serum choline, betaine, and methionine were inversely associated with risk of pancreatic cancer, while TMAO, an oxidative metabolite of choline produced by gut microbiota, was positively associated with risk of pancreatic cancer. Compared with the lowest quartile, ORs (95%CIs) of pancreatic cancer for the highest quartiles of choline, methionine, betaine, and TMAO were 0.37 (0.17-0.80), 0.39 (0.22-0.69), 0.49 (0.28-0.85), and 1.60 (0.94-2.74), respectively (all Ps for trend &amp;lt; 0.05). DMG was not associated with pancreatic cancer risk. Conclusion: The novel inverse associations of serum choline, methionine, and betaine with risk of pancreatic cancer support the notion that methyl groups related to DNA methylation may modulate the risk of pancreatic cancer development. The positive association between TMAO and pancreatic cancer risk suggested gut microbiota may play an important role in pancreatic carcinogenesis. Citation Format: Joyce Huang, Lesley Butler, Øivind Midttun, Renwei Wang, Aizhen Jin, Yu-Tang Gao, Per Ueland, Woon-Puay Koh, Jian-Min Yuan. Serum choline, methionine, betaine, dimethylglycine, and trimethylamine-N-oxide in relation to pancreatic cancer risk in two nested case-control studies in Asian populations [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 2273. doi:10.1158/1538-7445.AM2017-2273

Necroptosis DAMPens anti-tumor immunity.

Necroptosis DAMPens anti-tumor immunity.

Abstract A36: Recreational physical activity and the risk of pancreatic cancer in the California Teachers Study

Abstract Background: Pancreatic cancer is highly fatal; thus, preventive strategies are needed. Besides cessation of cigarette smoking, physical activity may reduce pancreatic cancer risk by improving insulin sensitivity and glucose tolerance. However, the existing data lack consistency and generally, physical activity has been measured only at one time point. We examined recreational physical activity during different periods of life as well as a cumulative, long-term physical activity measure in relation to the risk of pancreatic cancer in California Teachers Study (CTS). Methods: 120,921 women aged 22-84 years participating in the CTS with no history of pancreatic cancer were followed from 1995 through 2011. The self-administered baseline (1995-1996) questionnaire captured information on demographics, moderate and strenuous recreational physical activity during high school, between ages 18 and 24, 25 and 34, 35 and 44, and 45 and 54 years, and in the three years before baseline, and potential risk factors for pancreatic cancer such as body mass index (BMI), diabetes, alcohol consumption, cigarette smoking, and dietary fat intake. Incident diagnoses of invasive pancreatic cancer were identified through annual linkages with the California Cancer Registry. We calculated average number of hours per week for recreational physical activity during different periods of life and combined them into a long-term physical activity measure. We fit Cox proportional hazards models to data to estimate the hazard ratios (HR) of pancreatic cancer risk and their corresponding 95% confidence intervals (CI) associated with moderate and strenuous physical activity in each age/time period and over the “long-term.” For each analysis, the least active group (≤0.5 hours/week) served as the reference group. Multivariable models were stratified by age at baseline (in single years) and were adjusted for race, total pack-years of cigarette smoking, alcohol consumption and total dietary fat intake in the year before baseline, diabetes, and BMI at baseline. Furthermore, we tested for a linear trend in risk by fitting the median value of physical activity within each category; we also examined whether BMI, smoking status, and alcohol intake modified any physical activity association. Results: During 1,715,690 person-years of follow-up, 429 women were diagnosed with invasive pancreatic cancer. The average age at diagnosis of pancreatic cancer was 74 years. In the multivariable model, women with higher levels of long-term moderate/strenuous physical activity had lower risk of pancreatic cancer than the least active women (≤0.5 hours/week) although the 95% CI included one (2.51-5.5 hours/week: HR=0.76; 95% CI=0.56-1.02, &amp;gt;5.5 hours/week: HR=0.85; 95% CI=0.63-1.15) and no linear trend in pancreatic cancer risk was observed (Ptrend=0.35). In the analysis of physical activity during different periods of life, we observed a marginally significant decreasing trend in risk with increasing physical activity during ages 18-24 years (Ptrend=0.05). The stratified analysis indicated a decreasing trend in pancreatic cancer risk with increasing physical activity during ages 18-24 years among women who were overweight or obese at baseline (Ptrend=0.006), who never smoked cigarettes (Ptrend=0.02), and who consumed &amp;lt;10 grams of alcohol per day in the year before baseline (Ptrend=0.02). No significant effect modifications were observed. Conclusions: The CTS data suggest that a higher level of recreational physical activity in early adulthood modestly reduces the risk of pancreatic cancer development in subgroups of women. However, we lacked sufficient statistical power to demonstrate effect modification. Larger studies are needed to understand whether the effect of physical activity on pancreatic cancer varies by age at activity, BMI, smoking status, or alcohol intake. Citation Format: Kayo Togawa, Huiyan Ma, Jane Sullivan-Halley, Jessica Clague, Susan Neuhausen, Eunjung Lee, Dennis Deapen, Leslie Bernstein. Recreational physical activity and the risk of pancreatic cancer in the California Teachers Study. [abstract]. In: Proceedings of the Thirteenth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2014 Sep 27-Oct 1; New Orleans, LA. Philadelphia (PA): AACR; Can Prev Res 2015;8(10 Suppl): Abstract nr A36.

Abstract 539: Usefulness of genetic markers in pancreatic juice for the diagnosis of pancreatic cancer distinguishing from chronic inflammation: A meta-analysis

Abstract Background: Pancreatic ductal adenocarcinoma (PDAC) shows frequent genomic alterations in the 4 major genes, KRAS, CDKN2A/p16, TP53, and SMAD4/DPC4. Furthermore, a recent high-sensitivity mutational analysis discovered KRAS mutations in over 90% of pancreatic intraepithelial neoplasms. The genomic alterations of those genes in the pancreatic juice (PJ) have been studied for the early detection of PDAC, but the results were heterogeneous and its application was limited mainly because of the low diagnostic specificity; KRAS gene mutations have been also detected in chronic pancreatitis (CP). Therefore, for the diagnosis of early pancreatic cancer distinguishing from CP using PJ samples, more sensitive and specific method should be developed. Objective: To evaluate the diagnostic accuracy of the genetic or molecular markers in PJ samples distinguishing PDAC from CP, which is associated with a risk of pancreatic cancer development. Methods: We conducted a quantitative meta-analysis of the diagnostic studies using PJ samples, and validated the diagnostic utility of the 4 major genes, the telomerase activity, and combination assays. A systematic search of all relevant literature was performed in MEDLINE, Cochrane Database, and Web of Science. Quality assessment was conducted by adopting the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) checklist. Data are presented as forest plots and hierarchical summary receiver operating characteristic curve analysis was used to summarize the overall test performance. Results: Thirty-nine studies fulfilled the inclusion criteria, and data were pooled for the analysis. Pooled estimates for the KRAS analysis were as follows: sensitivity 0.67 (95% CI: 0.63-0.71); specificity 0.82 (95% CI: 0.79-0.85); diagnostic odds ratio (DOR) 9.24 (95% CI: 6.00-14.23). Pooled estimates for the telomerase activity analysis were: sensitivity 0.82 (95% CI: 0.76-0.87); specificity 0.96 (95% CI: 0.90-0.99); DOR 54.38 (95% CI: 21.80-135.66). All 3 tumor suppressor genes, TP53, CDKN2A/p16, and SMAD4/DPC4, demonstrated low sensitivity. The combined analysis of KRAS with telomerase activity revealed higher diagnostic sensitivity (0.94, 95% CI: 0.83-0.99) than KRAS alone. The combined assay of telomerase activity with cytology revealed more reliable diagnosis of PDAC than telomerase activity alone with respect to sensitivity (0.88, 95% CI: 0.74-0.96) and specificity (1.00, 95% CI: 0.91-1.00). Conclusion: The most reliable marker for the diagnosis of PDAC in PJ samples was telomerase activity. The assessment by each 3 major tumor suppressor was not unsatisfactory. Telomerase activity can play a central role in diagnostic analysis using PJ samples, and combination assays with KRAS mutations or cytological examination would increase diagnostic accuracy. Citation Format: Tatsuo Hata, Masaharu Ishida, Fuyuhiko Motoi, Takeshi Naitoh, Yu Katayose, Shinichi Egawa, Michiaki Unno. Usefulness of genetic markers in pancreatic juice for the diagnosis of pancreatic cancer distinguishing from chronic inflammation: A meta-analysis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 539. doi:10.1158/1538-7445.AM2015-539

Abstract B42: Metabolic changes, associated with loss of the tumor suppressor LKB1, promote tumorigenesis

Abstract The LKB1 tumor suppressor encodes a serine/threonine kinase that serves as a master regulator of energy metabolism. Germline mutations in LKB1 cause the Peutz-Jeghers polyposis and cancer syndrome and are associated with a high risk of pancreatic cancer development. Despite being the subject of extensive investigation for more than 15 years, the primary mechanisms of LKB1-mediated tumor suppression remain poorly defined. The best-characterized function of LKB1 in cell physiology is to coordinate adaptation to a drop in ATP stores, shutting down multiple biosynthetic processes and favoring catabolic pathways, thereby restoring cellular energy charge. Since LKB1 has pleiotropic effects on cell polarity, migration, and inflammation in addition to cell metabolism, it remains uncertain to what extent LKB1-mediated tumor suppression involves its roles in metabolic reprogramming. In this regard, LKB1 inactivation renders cells vulnerable to a number of metabolic stress stimuli such as glucose deprivation or reactive oxygen species (ROS), indicating that alterations in metabolic control may decrease, rather than increase, the fitness of LKB1 deficient cells. To resolve these questions, we have conducted comprehensive metabolic profiling and functional studies that revealed that LKB1 inactivation results in greatly improved efficiency of nutrient acquisition and utilization, which fuels accelerated cell growth and tumorigenesis. By using a series of primary epithelial culture systems and genetically engineered mouse models coupled with integrative metabolic profiling and flux analyses, we find that LKB1 loss potentiates glucose uptake and glycolysis, and diverts a significant amount of glycolytic intermediates toward biosynthetic processes. Most notably fatty acid and nucleotide pools are greatly expanded upon LKB1 inactivation. This extensive metabolic reprogramming results in a shift in the nutrient requirements of LKB1 mutant cells including a reduced dependence on select exogenous amino acids and greatly increased need for glutamine and glucose. Collectively, our studies uncover adaptive metabolic changes conferred by LKB1 inactivation and suggest potential targetable vulnerabilities of LKB1 mutant cancers. Citation Format: Filippos Kottakis, Brandon N. Nicolay, Nagle M. Julia, Marc Liesa, Orian S. Sirihai, Nicholas J. Dyson, Nabeel Bardeesy. Metabolic changes, associated with loss of the tumor suppressor LKB1, promote tumorigenesis. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr B42.

Pancreatic ductal adenocarcinoma: risk factors, screening, and early detection.

Pancreatic cancer is the fourth most common cause of cancer-related deaths in the United States, with over 38000 deaths in 2013. The opportunity to detect pancreatic cancer while it is still curable is dependent on our ability to identify and screen high-risk populations before their symptoms arise. Risk factors for developing pancreatic cancer include multiple genetic syndromes as well as modifiable risk factors. Genetic conditions include hereditary breast and ovarian cancer syndrome, Lynch Syndrome, familial adenomatous polyposis, Peutz-Jeghers Syndrome, familial atypical multiple mole melanoma syndrome, hereditary pancreatitis, cystic fibrosis, and ataxia-telangiectasia; having a genetic predisposition can raise the risk of developing pancreatic cancer up to 132-fold over the general population. Modifiable risk factors, which include tobacco exposure, alcohol use, chronic pancreatitis, diet, obesity, diabetes mellitus, as well as certain abdominal surgeries and infections, have also been shown to increase the risk of pancreatic cancer development. Several large-volume centers have initiated such screening protocols, and consensus-based guidelines for screening high-risk groups have recently been published. The focus of this review will be both the genetic and modifiable risk factors implicated in pancreatic cancer, as well as a review of screening strategies and their diagnostic yields.

6616 POSTER Impact of Progression on Resource Utilization in the Treatment of NET

restriction fragment size was identified by horizontal electrophoresis. The survival was determined using Kaplan–Meier method, and the log-rank test was used for evaluation of differences in survival. The association between genetic factors and cancer risk were analyzed by logistic regression, and the results were expressed as odds ratios (OR) and 95% confidence intervals (CI). Statistical analyses were performed using CRAN 2.4.0 statistical software, and the decision on significance was based on p < 0.05. Results: Comparison of allele distribution between PC patients and controls demonstrated that Val/Val genotype carriers in codon 432 CYP1B1 had lower PC risk of pancreatic cancer development compared wild type carriers (OR 0.59; 95%CI 0.36–0.96; p = 0.035). Heterozygotes also had lower risk (OR 0.69; 95%CI 0.49–0.97; p = 0.033). There was an even more signficant increase of risk in patients who had histologically verified PC. Variant allele in GSTP1 codone 105 was associated with a trend of higher PC risk (OR 1.38; 95%CI 0.96–1.97, p < 0.05). Increased PC risk was also observed for GSTT1deletion (OR 1.56; 95%CI 0.93–2.61, p < 0.05). The combination of GSTT1 mutation and GSTP1 deletion was associted with significantly increased PC risk (OR 2.5; 95%CI 1.20–5.20; p < 0.05). No significant association was observed between the polymorphism of other biotransforming genes and PC risk, and none of the gene polymorphisms investigated was associated with differences in PC survival. Conclusions: Gene polymorphism of biotransforming genes may be associated with the risk of PC.

The relationship between new-onset diabetes mellitus and pancreatic cancer risk: A case–control study

Diabetes mellitus (DM) is widely considered to be associated with pancreatic cancer, however, whether DM is a cause or consequence of pancreatic cancer is controversial. In the present study, 1458 patients with pancreatic ductal adenocarcinoma (PDAC) and 1528 age-, sex- and sociodemographic variables-matched controls were recruited in two university-affiliated hospitals from 1st January 2000 to 31st December 2009. DM was defined as fasting blood glucose (FBG) level of 7.0 mmol/L or greater. An unconditional multivariable logistic regression analysis was used to estimate adjusted odds ratios (AORs) and 95% confidence interval (CI). Compared with controls, a moderate increased risk of PDAC was observed among cases with long-standing diabetes (⩾2-year duration), with an AOR (95% CI) of 2.11 (1.51–2.94). Interestingly, a significant higher risk was observed among cases with new-onset DM (<2-year duration), with an AOR of 4.43 (3.44–5.72) compared to controls without DM. In addition, we found a synergistic interaction between cigarette smoking and DM on modifying the risk of pancreatic cancer development (AOR = 6.17, 95% CI 3.82–9.94). Similarly, a synergistic interaction between new-onset DM and family history of pancreatic cancer was found for pancreatic cancer risk, with an AOR (95% CI) of 11.04 (2.51–48.53). This study suggested that DM could be both an early manifestation of pancreatic cancer and an aetiologic factor. Possible effect modification on DM by family history of pancreatic cancer and smoking status should be further explored in future aetiologic studies.