Background and aimThe International Cancer of the Pancreas Screening Consortium met in 2018 to update its consensus recommendations for the management of individuals with increased risk of pancreatic cancer based on family history or germline mutation status (high-risk individuals).MethodsA modified Delphi approach was employed to reach consensus among a multidisciplinary group of experts who voted on consensus statements. Consensus was considered reached if ≥75% agreed or disagreed.ResultsConsensus was reached on 55 statements. The main goals of surveillance (to identify high-grade dysplastic precursor lesions and T1N0M0 pancreatic cancer) remained unchanged. Experts agreed that for those with familial risk, surveillance should start no earlier than age 50 or 10 years earlier than the youngest relative with pancreatic cancer, but were split on whether to start at age 50 or 55. Germline ATM mutation carriers with one affected first-degree relative are now considered eligible for surveillance. Experts agreed that preferred surveillance tests are endoscopic ultrasound and MRI/magnetic retrograde cholangiopancreatography, but no consensus was reached on how to alternate these modalities. Annual surveillance is recommended in the absence of concerning lesions. Main areas of disagreement included if and how surveillance should be performed for hereditary pancreatitis, and the management of indeterminate lesions.ConclusionsPancreatic surveillance is recommended for selected high-risk individuals to detect early pancreatic cancer and its high-grade precursors, but should be performed in a research setting by multidisciplinary teams in centres with appropriate expertise. Until more evidence supporting these recommendations is available, the benefits, risks and costs of surveillance of pancreatic surveillance need additional evaluation.
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.
To identify factors that regulate gut microbiota density and the impact of varied microbiota density on health, we assayed this fundamental ecosystem property in fecal samples across mammals, human disease, and therapeutic interventions. Physiologic features of the host (carrying capacity) and the fitness of the gut microbiota shape microbiota density. Therapeutic manipulation of microbiota density in mice altered host metabolic and immune homeostasis. In humans, gut microbiota density was reduced in Crohn’s disease, ulcerative colitis, and ileal pouch-anal anastomosis. The gut microbiota in recurrent Clostridium difficile infection had lower density and reduced fitness that were restored by fecal microbiota transplantation. Understanding the interplay between microbiota and disease in terms of microbiota density, host carrying capacity, and microbiota fitness provide new insights into microbiome structure and microbiome targeted therapeutics.Editorial note: This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that all the issues have been addressed (see decision letter).
OBJECTIVES Pancreatic ductal adenocarcinoma (PDAC) remains a highly lethal disease. Diabetes mellitus (DM) is both a risk factor for and a sequela of PDAC. Metformin is a commonly prescribed biguanide oral hypoglycemic used for the treatment of type II DM. We investigated whether metformin use before PDAC diagnosis affected survival of patients with DM, controlling confounders such as diabetic severity. METHODS We used the Surveillance, Epidemiology, and End Results registry (SEER)-Medicare linked database to identify patients with PDAC diagnosed between 2007 and 2011. The diabetic comorbidity severity index (DCSI) controlled for DM severity. Inverse propensity weighted Cox Proportional-Hazard Models assessed the association between metformin use and overall survival adjusting for relevant confounders. RESULTS We identified 1,916 patients with PDAC and pre-existing DM on hypoglycemic medications at least 1 year before cancer diagnosis. Of these, 1,098 (57.3%) were treated with metformin and 818 (42.7%) with other DM medications. Mean survival for those on metformin was 5.5 months compared with 4.2 months for those not on metformin (P<0.01). After adjusting for confounders including DCSI, Charlson score, and chronic kidney disease (CKD), patients on metformin had a 12% decreased risk of mortality compared with patients on other medications (hazard ratio (HR): 0.88, 95% confidence interval (CI): 0.81–0.96, P<0.01). In stratified analysis, differences persisted regardless of the Charlson score, the DCSI score, the presence of kidney disease, or the use of insulin/other hypoglycemic medications (P<0.01 for all). CONCLUSIONS Metformin is associated with increased survival among diabetics with PDAC. If confirmed in a prospective study, then these results suggest a possible role for metformin as an adjunct to chemotherapy among diabetics with PDAC.
Pancreatic ductal adenocarcinoma (PDAC) is the 4(th) deadliest cancer in the United States, due to its aggressive nature, late detection, and resistance to chemotherapy. The majority of PDAC develops from 3 precursor lesions, pancreatic intraepithelial lesions (PanIN), intraductual papillary mucinous neoplasm (IPMN), and mucinous cystic neoplasm. Early detection and surgical resection can increase PDAC 5-year survival rate from 6% for Stage IV to 50% for Stage I. To date, there are no reliable biomarkers that can detect PDAC. MicroRNAs (miRNA) are small noncoding RNAs (18-25 nucleotides) that regulate gene expression by affecting translation of messenger RNA (mRNA). A large body of evidence suggests that miRNAs are dysregulated in various types of cancers. MiRNA has been profiled as a potential biomarker in pancreatic tumor tissue, blood, cyst fluid, stool, and saliva. Four miRNA biomarkers (miR-21, miR-155, miR-196, and miR-210) have been consistently dysregulated in PDAC. MiR-21, miR-155, and miR-196 have also been dysregulated in IPMN and PanIN lesions suggesting their use as early biomarkers of this disease. In this review, we explore current knowledge of miRNA sampling, miRNA dysregulation in PDAC and its precursor lesions, and advances that have been made in using miRNA as a biomarker for PDAC and its precursor lesions.
Background & Aims Pancreatic cancer is a leading cause of cancer mortality and mortality has not decreased in recent years. We sought to determine global trends in pancreatic cancer mortality. Methods We derived data on deaths from pancreatic cancer from the World Health Organization database for 59 countries, from 1980 through 2013. Age-standardized mortalities were computed for persons of all ages and for persons 35–64 years old; for selected countries, they were computed for persons 25–49 years old. Joinpoint regression models were used to identify significant changes in mortality. For selected larger countries, we predicted numbers of deaths and mortality for 2017. Results Between 1980 and 2013, overall pancreatic cancer mortality in men increased in the European Union (EU), as well as in southern and eastern Europe, Brazil, Japan, and Republic of Korea. Overall pancreatic cancer mortality decreased in most northern European countries, Australia, Canada, Mexico, and the United States (US). In women, mortality increased in the EU, Brazil, US, Japan, and Republic of Korea but decreased in Canada and Mexico. In 2012, Eastern Europe and Japan had the highest pancreatic cancer mortality, for both sexes. In men 25–49 years old, mortality decreased in the EU, US, Japan, and most large European countries. Based on our data, we predict overall pancreatic cancer mortality in 2017 to level off in men in the EU and US, but increase in Japan. In women, mortality will continue to increase in most countries except the US; the greatest increase is predicted to occur in Japan. Conclusions Mortality from pancreatic cancer has not decreased as it has for other cancers in recent years. A notable exception is a decrease in mortality in men 25–49 years old, which could indicate a reversal in the current increasing global trends.
Purpose Pancreatic ductal adenocarcinoma (PDAC) is associated with the breast ovarian cancer syndrome (BRCA1/BRCA2) mutations. It is unknown if this association is causal. Experimental Design This is a single-site study of patients who underwent surgical pancreatic tumor resection and self-identified as Ashkenazi Jewish. DNA from normal pancreatic tissue was genotyped for the three Ashkenazi Jewish BRCA1/2 founder mutations BRCA1 185delAG, BRCA1 5382insC, and BRCA2 6174delT, and loss of heterozygosity (LOH) was determined by sequencing DNA from microdissected tumor. When additional tumor tissue was available, p53 immunohistochemistry (IHC) was conducted. Results Thirty-seven patients underwent surgery for PDAC, seven for intraductal papillary mucinous neoplasm (IPMN), and 19 for other diseases. A high prevalence of BRCA1/2 mutations was found in the surgical cohort (12/63; 19.0%; P < 0.001), PDAC cohort (8/37; 21.6%; P < 0.001), and IPMN cohort (2/7; 28.6%; P =.01) compared with published control mutation frequency. A high prevalence of BRCA1 185delAG (8.1%; P < 0.001) and BRCA2 6174delT (10.8%; P < 0.001) in Ashkenazi Jewish patients with PDAC was shown. BRCA1/2 LOH was found in 2 of 4 BRCA1-associated PDACs and 3 of 4 BRCA2-associated PDACs. Positive p53 IHC was found in 5 of 8 BRCA1/2 PDACs. Conclusions We show a high prevalence of BRCA1/2 mutations with LOH in an Ashkenazi Jewish cohort of surgically resected PDAC and neoplastic lesions, suggesting that these germline mutations are causal in selected individuals.
Background Ten percent of pancreatic ductal adenocarcinoma (PDAC) is due to genetic predisposition, including the breast and ovarian cancer syndrome germline mutations BRCA1 and BRCA2. Knowledge of specific genetic mutations predisposing to PDAC may enable risk stratification, early detection and development of effective screening and surveillance programs. We aimed to determine the diagnostic yield of testing for BRCA1/2 germline mutations in a PDAC screening cohort and a PDAC cohort referred for genetic testing. Methods Patients in a high-risk PDAC prevention and genetics program or with a personal history of PDAC referred for genetic evaluation underwent testing for BRCA1/2 germline mutations. Clinical BRCA1/2 genetic testing included testing for the 3 Ashkenazi Jewish founder mutations or BRCA1/2 comprehensive testing. Results 37 patients without PDAC underwent BRCA1/2 testing at our institution. Genetic testing identified 7 patients who were BRCA1/2 carriers for a yield of 18.9%. Six carried Ashkenazi Jewish founder mutations (3 BRCA1, 3 BRCA2), and 1 had a BRCA2 mutation on comprehensive testing. 32 patients with PDAC underwent BRCA1/2 genetic testing. Five had Ashkenazi Jewish founder mutations (two BRCA1, three BRCA2), and 2 had BRCA2 mutations on comprehensive testing. The diagnostic yield was 7/32 (21.8%). Conclusions BRCA1/2 testing is useful in PDAC risk stratification and alters risk assignment and screening recommendations for mutation positive patients and their families. Clinical BRCA1/2 testing should be considered in patients of Ashkenazi Jewish descent, with a personal history or family history of PDAC, even in the absence of a family history of breast and ovarian cancer.
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