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Familial Pancreatic Cancer

Between 5 to 10% of pancreatic cancer are believed to be caused by inherited genetic factors. The remainder are 'sporadic' (non-inherited). There are a number of genetic cancer syndromes that increase risk of pancreatic cancer. These syndromes tend to cause other types of cancer primarily, but also with increased risk of pancreatic cancer.

Molecular Biology of Pancreatic Cancer
Familial Pancreatic Cancer
Latest Research Publications

Familial Pancreatic Cancer (7 links)

Latest Research Publications

This list of publications is regularly updated (Source: PubMed).

Ngamruengphong S, Canto MI
Screening for Pancreatic Cancer.
Surg Clin North Am. 2016; 96(6):1223-1233 [PubMed] Related Publications
Pancreatic cancer (PC) is a highly fatal disease that can only be cured by complete surgical resection. However, most patients with PC have unresectable disease at the time of diagnosis, highlighting the need to detect PC and its precursor lesions earlier in asymptomatic patients. Screening is not cost-effective for population-based screening of PC. Individuals with genetic risk factors for PC based on family history or known PC-associated genetic syndromes, however, can be a potential target for PC screening programs. This article provides an overview of the epidemiology and genetic background of familial PC and discusses diagnostic and management approaches.

Kumar A, Singh B, Mahajan G, et al.
A novel colchicine-based microtubule inhibitor exhibits potent antitumor activity by inducing mitochondrial mediated apoptosis in MIA PaCa-2 pancreatic cancer cells.
Tumour Biol. 2016; 37(10):13121-13136 [PubMed] Related Publications
Colchicine, an antimitotic alkaloid isolated from Colchicum autumnale, is a classical drug for treatment of gout and familial Mediterranean fever. It causes antiproliferative effects through the inhibition of microtubule formation, which leads to mitotic arrest and cell death by apoptosis. Here, we report that a novel colchicine analog, 4o (N-[(7S)-1,2,3-trimethoxy-9-oxo-10-[3-(trifluoromethyl)-4-chlorophenylamino]-5,6,7,9-tetrahydrobenzo[a]heptalen-7-yl]acetamide), which exhibited potent anticancer activities both in vitro and in vivo. In this study, 4o with excellent pharmacokinetic profile and no P-gp induction liability displayed strong inhibition of proliferation against various human cancer cell lines. However, pancreatic cancer cell line MIA PaCa-2 was found to be more sensitive towards 4o and showed strong inhibition in concentration and time-dependent manner. By increasing intracellular reactive oxygen species (ROS) levels, 4o induced endoplasmic reticular stress and mitochondrial dysfunction in MIA PaCa-2 cells. Blockage of ROS production reversed 4o-induced endoplasmic reticulum (ER) stress, calcium release, and cell death. More importantly, it revealed that increased ROS generation might be an effective strategy in treating human pancreatic cancer. Further 4o treatment induced mitotic arrest, altered the expression of cell cycle-associated proteins, and disrupted the microtubules in MIA PaCa-2 cells. 4o treatment caused loss of mitochondrial membrane potential, cytochrome c release, upregulation of Bax, downregulation of Bcl-2, and cleavage of caspase-3, thereby showing activation of mitochondrial mediated apoptosis. The in vivo anticancer activity of the compound was studied using sarcoma-180 (ascitic) and leukemia (P388 lymphocytic and L1210 lymphoid) models in mice and showed promising antitumor activity with the least toxicity unlike colchicine. Such studies have hitherto not been reported. Taken together, these findings highlighted that 4o, a potent derivative of colchicine, causes tumor regression with reduced toxicity and provides a novel anticancer candidate for the therapeutic use.

Kwon EB, Jeong HR, Shim YS, et al.
Multiple Endocrine Neoplasia Type 1 Presenting as Hypoglycemia due to Insulinoma.
J Korean Med Sci. 2016; 31(6):1003-6 [PubMed] Free Access to Full Article Related Publications
Multiple endocrine neoplasia (MEN) mutation is an autosomal dominant disorder characterized by the occurrence of parathyroid, pancreatic islet, and anterior pituitary tumors. The incidence of insulinoma in MEN is relatively uncommon, and there have been a few cases of MEN manifested with insulinoma as the first symptom in children. We experienced a 9-year-old girl having a familial MEN1 mutation. She complained of dizziness, occasional palpitation, weakness, hunger, sweating, and generalized tonic-clonic seizure that lasted for 5 minutes early in the morning. At first, she was only diagnosed with insulinoma by abdominal magnetic resonance images of a 1.3 x 1.5 cm mass in the pancreas and high insulin levels in blood of the hepatic vein, but after her father was diagnosed with MEN1. We found she had familial MEN1 mutation, and she recovered hyperinsulinemic hypoglycemia after enucleation of the mass. Therefore, the early genetic identification of MEN1 mutation is considerable for children with at least one manifestation.

Bye A, Wesseltoft-Rao N, Iversen PO, et al.
Alterations in inflammatory biomarkers and energy intake in cancer cachexia: a prospective study in patients with inoperable pancreatic cancer.
Med Oncol. 2016; 33(6):54 [PubMed] Related Publications
Chronic systemic inflammatory response is proposed as an underlying mechanism for development of cancer cachexia. We conducted a prospective study to examine changes in inflammatory biomarkers during the disease course and the relationship between inflammatory biomarkers and cachexia in patients with inoperable pancreatic cancer. Twenty patients, median (range) age 67.5 (35-79) years, 5 females, were followed for median 5.5 (1-12) months. Cachexia was diagnosed according to the 2011 consensus-based classification system (weight loss >5 % past six months, BMI < 20 kg/m(2) and weight loss >2 %, or sarcopenia) and the modified Glasgow Prognostic score (mGPS) that combines CRP and albumin levels. Inflammatory biomarkers were measured by enzyme immunoassays. The patients had increased levels of most inflammatory biomarkers, albeit not all statistically significant, both at study entry and close to death, indicating ongoing inflammation. According to the consensus-based classification system, eleven (55 %) patients were classified as cachectic upon inclusion. They did not differ from non-cachectic patients with regard to inflammatory biomarkers or energy intake. According to the mGPS, seven (35 %) were defined as cachectic and had a higher IL-6 (p < 0.001) than the non-cachectic patients. They also had a slightly, but insignificantly longer survival than non-cachectic patients (p = 0.08). The mGPS should be considered as an additional framework for identification of cancer cachexia.

Borecka M, Zemankova P, Vocka M, et al.
Mutation analysis of the PALB2 gene in unselected pancreatic cancer patients in the Czech Republic.
Cancer Genet. 2016; 209(5):199-204 [PubMed] Related Publications
Pancreatic ductal adenocarcinoma (PDAC) has the worst prognosis among common solid cancer diagnoses. It has been shown that up to 10% of PDAC cases have a familial component. Characterization of PDAC-susceptibility genes could reveal high-risk individuals and patients that may benefit from tailored therapy. Hereditary mutations in PALB2 (Partner and Localizer of BRCA2) gene has been shown to predispose, namely to PDAC and breast cancers; however, frequencies of mutations vary among distinct geographical populations. Using the combination of sequencing, high-resolution melting and multiplex ligation-dependent probe amplification analyses, we screened the entire PALB2 gene in 152 unselected Czech PDAC patients. Truncating mutations were identified in three (2.0%) patients. Genotyping of found PALB2 variants in 1226 control samples revealed one carrier of PALB2 truncating variant (0.08%; P = 0.005). The mean age at PDAC diagnosis was significantly lower among PALB2 mutation carriers (51 years) than in non-carriers (63 years; P = 0.016). Only one patient carrying germline PALB2 mutation had a positive family breast cancer history. Our results indicate that hereditary PALB2 mutation represents clinically considerable genetic factor increasing PDAC susceptibility in our population and that analysis of PALB2 should be considered not only in PDAC patients with familial history of breast or pancreatic cancers but also in younger PDAC patients without family cancer history.

Humphris JL, Biankin AV
Diagnosis and Management of Hereditary Pancreatic Cancer.
Recent Results Cancer Res. 2016; 205:61-83 [PubMed] Related Publications
Hereditary pancreatic cancer can be diagnosed through family history and/or a personal history of pancreatitis or clinical features suggesting one of the known pancreatic cancer predisposition syndromes. This chapter describes the currently known hereditary pancreatic cancer predisposition syndromes, including Peutz-Jeghers syndrome, familial atypical multiple mole melanoma, hereditary breast and ovarian cancer, Li-Fraumeni syndrome, hereditary non-polyposis colon cancer and familial adenomatous polyposis. Strategies for genetic testing for hereditary pancreatic cancer and the appropriate options for surveillance and cancer risk reduction are discussed. Finally, ongoing research and future directions in the diagnosis and management of hereditary pancreatic cancer will be considered.

Grover S, Jajoo K
Screening for Pancreatic Cancer in High-risk Populations.
Gastroenterol Clin North Am. 2016; 45(1):117-27 [PubMed] Related Publications
Pancreatic adenocarcinoma is a leading cause of cancer death. Few patients are candidates for curative resection due to the late stage at diagnosis. While most pancreatic adenocarcinomas are sporadic, approximately 10% have an underlying hereditary basis. Known genetic syndromes account for only 20% of the familial clustering of pancreatic cancer cases. The majority are due to non-syndromic aggregation of pancreatic cancer cases or familial pancreatic cancer. Screening aims to identify high-risk lesions amenable to surgical resection. However, the optimal interval for screening and the management of pancreatic cancer precursor lesions detected on imaging are controversial.

Mughetti M, Calculli L, Chiesa AM, et al.
Implications and issues related to familial pancreatic cancer: a cohort study of hospitalized patients.
BMC Gastroenterol. 2016; 16:6 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The surveillance of subjects at risk of pancreatic cancer is restricted to clinical research; the incidence of familial pancreatic cancer needs to be better established. Thus, we aimed to evaluate the frequency of familial pancreatic cancer in a population of hospitalized patients with pancreatic cancer.
METHODS: A retrospective study based on the hospital charts of patients discharged with a diagnosis of pancreatic cancer. One hundred and eighty-seven patients or their relatives were called for a phone interview.
RESULTS: There were 97 males (51.9 %) and 90 (48.1 %) females. The overall mean ± SD age was 67.3 ± 11.8 years; the age of males was similar to that of females (P = 0140). The mean size of the tumors found was 36.3 ± 17.4 mm (range of 5-110 mm); it was related to gender but was not related to the site of the tumor or the age of the patient. Regarding genetic diseases, three females (1.6 %) had familial adenomatous polyposis; three patients (1 male and two females) (1.6 %) had at least one relative with pancreatic cancer whereas only one 80-year old male patient (0.5 %) had two relatives affected by pancreatic cancer (the mother had died at the 65 years of age and the brother had died at 75 years of age).
CONCLUSIONS: The frequency of familial pancreatic ductal adenocarcinoma is small, but its importance, from the point of view of early diagnosis, is not negligible and patients with a risk of familial cancer merit an appropriate clinical follow-up.

Catts ZA, Baig MK, Milewski B, et al.
Statewide Retrospective Review of Familial Pancreatic Cancer in Delaware, and Frequency of Genetic Mutations in Pancreatic Cancer Kindreds.
Ann Surg Oncol. 2016; 23(5):1729-35 [PubMed] Related Publications
BACKGROUND: Considering the typical rapid progression and high mortality of pancreatic cancer (PC), early detection may lead to an improved outcome. To date, there is no safe, sensitive, and cost-effective screening strategy to detect PC. Currently, screening is focused on individuals at the highest risk of developing PC based on family history. A high-risk individual is defined as having two or more first-degree relatives with PC, or one first- or second-degree relative with PC with a confirmed mutation in a gene associated with PC. The BRCA2 gene is one of the most common genes linked to pancreatic-only cancer families; however, other hereditary cancer syndromes have also been associated with an increased risk for PC.
METHODS: We conducted a retrospective review of pedigrees of families with a pancreatic adenocarcinoma cancer diagnosis held in the statewide Ruth Ann Minner High Risk Family Cancer Registry at the Helen F. Graham Cancer Center and Research Institute, Christiana Care Health System, Newark, DE, USA, from 2002 to 2013. The registry was queried based on how many first-, second-, or third-degree relatives of the proband were affected with PC, genetic testing status, and (if applicable) the results. These data were then categorized into families that meet familial PC (FPC) criteria, defined as two first-degree relatives with PC (FPC families), families that did not meet the FPC definition but had one first-degree relative affected with PC (first-degree families), and probands with PC (probands). Each family was counted only once in the analysis, even if multiple family members were tested.
RESULTS: Our analysis revealed that 175 of 597 families fitting any of the above criteria completed genetic testing. Of this cohort, 52 had pathogenic alterations with nine different genes implicated. Overall, 164 of the 175 families that fitted into any of the three categories previously identified had BRCA1 or BRCA2 testing, either by DNA sequencing or next-generation sequencing via a panel test that included BRCA1/2. BRCA1 pathogenic alterations were noted in 17/164 (10.4 %) and BRCA2 pathogenic alterations were noted in 23/164 (14.0 %). FPC families (n = 46) 42/46 of the FPC families underwent BRCA1/2 testing, and 11/42 (26 % [95 % CI 12.89-39.49]) had pathogenic alterations. Specifically, 4/42 = BRCA1 (9.5 %) and 7/42 = BRCA2 (16.7 %). Additionally, 16/46 of the FPC families underwent exclusively Lynch syndrome (LS) testing, and pathogenic mutations in a mismatch repair protein were identified in 2/16. Specifically, 1/16 = MLH1 (6.3 %) and 1/16 = MSH2 (3.6 %). Overall, a genetic mutation within any gene associated with an increased PC risk was found in 28 % of FPC families. First-degree families (n = 106) 99/106 of the families with one first-degree relative underwent BRCA1/2 testing, and 21/99 (21.2 % [95 % CI 13.16-29.27]) had pathogenic alterations. Specifically, 11/99 = BRCA1 (11.1 %) and 10/99 = BRCA2 (10.1 %). 32/99 first-degree families underwent exclusively LS testing, and pathogenic mutations were identified in 4/32. Specifically, 3/32 = MLH1 (9 %) and 1/32 = MSH6 (3 %). 25/99 of the families pursued panel testing, and pathogenic alterations in any gene were identified in 3/25. Specifically, the mutations were found in 1/25 = ATM (4 %), 1/25 = CHEK2 (4 %), and 1/25 = RAD51D (4 %). Affected probands (n = 23) Lastly, all 23 probands affected with PC pursued genetic testing. Of these, 11/23 were found to have pathogenic alterations. All 23 underwent BRCA1/2 testing, and pathogenic alterations were identified in 8/23 (35 % [95 % CI 15.32-54.25]), specifically 2/23 = BRCA1 (9 %), and 6/23 = BRCA2 (26 %). 10/23 patients underwent panel testing and pathogenic alterations were found in 3/10 (30 %) patients, of whom 1/10 = MSH6 (10 %), 1/10 = ATM (10 %), and 1/10 = TP53 (10 %).
CONCLUSIONS: This study demonstrates that a statewide high-risk family cancer registry is an important instrument in studying the risk of PC in families. Our analysis revealed 14 mutations associated with FPC, among which hereditary breast and ovarian cancer and LS were most prevalent. BRCA1 was found to have the same association with PC as BRCA2, which appears unique to our population. We plan to use our knowledge of these mutations in developing a PC screening program.

Roberts NJ, Norris AL, Petersen GM, et al.
Whole Genome Sequencing Defines the Genetic Heterogeneity of Familial Pancreatic Cancer.
Cancer Discov. 2016; 6(2):166-75 [PubMed] Free Access to Full Article Related Publications
UNLABELLED: Pancreatic cancer is projected to become the second leading cause of cancer-related death in the United States by 2020. A familial aggregation of pancreatic cancer has been established, but the cause of this aggregation in most families is unknown. To determine the genetic basis of susceptibility in these families, we sequenced the germline genomes of 638 patients with familial pancreatic cancer and the tumor exomes of 39 familial pancreatic adenocarcinomas. Our analyses support the role of previously identified familial pancreatic cancer susceptibility genes such as BRCA2, CDKN2A, and ATM, and identify novel candidate genes harboring rare, deleterious germline variants for further characterization. We also show how somatic point mutations that occur during hematopoiesis can affect the interpretation of genome-wide studies of hereditary traits. Our observations have important implications for the etiology of pancreatic cancer and for the identification of susceptibility genes in other common cancer types.
SIGNIFICANCE: The genetic basis of disease susceptibility in the majority of patients with familial pancreatic cancer is unknown. We whole genome sequenced 638 patients with familial pancreatic cancer and demonstrate that the genetic underpinning of inherited pancreatic cancer is highly heterogeneous. This has significant implications for the management of patients with familial pancreatic cancer.

Hanada K, Okazaki A, Hirano N, et al.
Effective screening for early diagnosis of pancreatic cancer.
Best Pract Res Clin Gastroenterol. 2015; 29(6):929-39 [PubMed] Related Publications
Diagnosis of pancreatic cancer (PC) at an early stage with curative surgery should improve long-term patient outcome. At present, improving survival should lie in identifying those cases with high-risk factors or precursor lesions through an effective screening including ultrasonography, some biological markers, or national familial pancreatic cancer registration. Recently, cases with PC < 10 mm with a favorable prognosis have been reported. For the diagnoses of cases with PC < 10 mm, the rate of tumor detection was higher on endoscopic ultrasonography (EUS) than on CT or other modalities, and EUS-guided fine needle aspiration was helpful in confirming the histologic diagnosis. Additionally, for the diagnosis of cases with PC in situ, EUS and magnetic resonance cholangiopancreatography (MRCP) may play important roles in detecting the local irregular stenosis of the pancreatic duct. Cytodiagnosis of pancreatic juice using endoscopic nasopancreatic drainage multiple times may be useful in the final diagnosis.

Yellu MR, Olowokure O
Simultaneous presentation of pancreatic cancer in a genetically unrelated couple.
BMJ Case Rep. 2015; 2015 [PubMed] Related Publications
Patients with pancreatic cancer tend to have a poor prognosis despite aggressive treatment, and their 5-year overall survival rate remains dismal. Several risk factors could potentially trigger the development of pancreatic cancer but many of them identified so far have been only weakly linked. Occurrence of pancreatic cancer in a husband and wife around the same time in the same household even when exposed to similar environmental factors is rare. Although familial pancreatic cancer is a known entity, pancreatic cancer in genetically unrelated married couples has not been studied. Here we present such a scenario involving one couple. In this case report, we discuss the chronological events leading to pancreatic cancer in a genetically unrelated married couple and the risk factors that may have led to cancer, in addition to exploring the possible links.

Smith AL, Alirezaie N, Connor A, et al.
Candidate DNA repair susceptibility genes identified by exome sequencing in high-risk pancreatic cancer.
Cancer Lett. 2016; 370(2):302-12 [PubMed] Related Publications
The genetic basis underlying the majority of hereditary pancreatic adenocarcinoma (PC) is unknown. Since DNA repair genes are widely implicated in gastrointestinal malignancies, including PC, we hypothesized that there are novel DNA repair PC susceptibility genes. As germline DNA repair gene mutations may lead to PC subtypes with selective therapeutic responses, we also hypothesized that there is an overall survival (OS) difference in mutation carriers versus non-carriers. We therefore interrogated the germline exomes of 109 high-risk PC cases for rare protein-truncating variants (PTVs) in 513 putative DNA repair genes. We identified PTVs in 41 novel genes among 36 kindred. Additional genetic evidence for causality was obtained for 17 genes, with FAN1, NEK1 and RHNO1 emerging as the strongest candidates. An OS difference was observed for carriers versus non-carriers of PTVs with early stage (≤IIB) disease. This adverse survival trend in carriers with early stage disease was also observed in an independent series of 130 PC cases. We identified candidate DNA repair PC susceptibility genes and suggest that carriers of a germline PTV in a DNA repair gene with early stage disease have worse survival.

Connor AA, Gallinger S
Hereditary Pancreatic Cancer Syndromes.
Surg Oncol Clin N Am. 2015; 24(4):733-64 [PubMed] Related Publications
Despite decades of scientific and clinical research, pancreatic ductal adenocarcinoma (PDAC) remains a lethal malignancy. The clinical and pathologic features of PDAC, specifically the known environmental and genetic risk factors, are reviewed here with special emphasis on the hereditary pancreatic cancer (HPC) syndromes. For these latter conditions, strategies are described for their identification, for primary and secondary prevention in unaffected carriers, and for disease management in affected carriers. Nascent steps have been made toward personalized medicine based on the rational use of screening, tumor subtyping, and targeted therapies; these have been guided by growing knowledge of HPC syndromes in PDAC.

Goral V
Pancreatic Cancer: Pathogenesis and Diagnosis.
Asian Pac J Cancer Prev. 2015; 16(14):5619-24 [PubMed] Related Publications
Pancreatic cancer is a fatal malignancies which is predominantly seen in men and at advanced age (40-85 years) and has an aggressive course. Its frequency is gradually increasing over the past years. It accounts for 2% of all cancers and 5% of cancer-related deaths. Pancreatic cancer takes the first place among asymptomatic cancers. Ninety percent of cases are adenocarcinomas. Ten percent of the patients have a familial disposition. The disease is very difficult to detect as it has no early signs and spreads rapidly to surrounding organs is one of the most deadly types of cancer. Pancreatic cancer may result from hereditary germline or somatic acquired mutations in cancer-related genes and mutations also cause cancer progression and metastasis.

Wada K, Takaori K, Traverso LW
Screening for Pancreatic Cancer.
Surg Clin North Am. 2015; 95(5):1041-52 [PubMed] Related Publications
Neither extended surgery nor extended indication for surgery has improved survival in patients with pancreatic cancer. According to autopsy studies, presumably 90% are metastatic. The only cure is complete removal of the tumor at an early stage before it becomes a systemic disease or becomes invasive. Early detection and screening of individuals at risk is currently under way. This article reviews the evidence and methods for screening, either familial or sporadic. Indication for early-stage surgery and precursors are discussed. Surgeons should be familiar with screening because it may provide patients with a chance for cure by surgical resection.

Whitcomb DC, Shelton CA, Brand RE
Genetics and Genetic Testing in Pancreatic Cancer.
Gastroenterology. 2015; 149(5):1252-1264.e4 [PubMed] Related Publications
Genetic testing of germline DNA is used in patients suspected of being at risk of pancreatic ductal adenocarcinoma (PDAC) to better define the individual's risk and to determine the mechanism of risk. A high genetic risk increases the pretest probability that a biomarker of early cancer is a true positive and warrants further investigation. The highest PDAC risk is generally associated with a hereditary predisposition. However, the majority of PDAC results from complex, progressive gene-environment interactions that currently fall outside the traditional risk models. Over many years, the combination of inflammation, exposure to DNA-damaging toxins, and failed DNA repair promote the accumulation of somatic mutations in pancreatic cells; PDAC risk is further increased by already present oncogenic germline mutations. Predictive models and new technologies are needed to classify patients into more accurate and mechanistic PDAC risk categories that can be linked to improved surveillance and preventative strategies.

Lu C, Xu CF, Wan XY, et al.
Screening for pancreatic cancer in familial high-risk individuals: A systematic review.
World J Gastroenterol. 2015; 21(28):8678-86 [PubMed] Free Access to Full Article Related Publications
AIM: To analyze the benefits and harms of pancreatic cancer screening in familial high-risk individuals (HRIs).
METHODS: Studies were identified by searching PubMed, EBSCO, ClinicalTrials.gov and the Cochrane database from database inception to June 2014. We also obtained papers from the reference lists of pertinent studies and systematic reviews. English-language trials and observational studies were searched. The key words used as search terms were "screening" and "surveillance". Cost-effectiveness, diagnostic rate, survival rate, mortality and adverse events were the outcomes of interest. Age, sex, lifestyle and other confounding factors were also considered. However, anticipating only a few of these studies, we also included observational studies with or without control groups. We also included studies concerning the anxiety associated with pancreatic cancer risk and other psychological changes in familial HRIs. We extracted details on study design, objectives, population characteristics, inclusion criteria, year of enrollment, method of screening, adjusted and unadjusted mortality, cost-effectiveness and adverse events from the included studies. Studies were assessed using the Reporting of Observational studies in Epidemiology (STROBE) checklist.
RESULTS: Sixteen studies on pancreatic cancer screening were included. Five studies included control groups, nine were observational studies without control groups, and the other two studies investigated the worry associated with pancreatic cancer risk. We found that pancreatic cancer screening resulted in a high curative resection rate (60% vs 25%, P = 0.011), longer median survival time (14.5 mo vs 4 mo, P < 0.001), and higher 3-year survival rate (20% vs 15.0%, P = 0.624). We also found that familial HRIs had a higher diagnostic rate of pancreatic tumors than controls (34% vs 7.2%, P < 0.001). In patients who underwent regular physical examinations, more stage I pancreatic cancers were observed (19% vs 2.6%, P = 0.001). In addition, endoscopic ultrasonography, which was the main means of detection, diagnosed 64.3% of pancreatic cancers. In comparison, endoscopic retrograde cannulation of the pancreas, magnetic resonance imaging, and computed tomography diagnosed 28.6%, 42.9%, and 21.4%, respectively. For mass lesions, instant surgery was recommended because of the beneficial effects of post-operative chemotherapy. However, in patients with intraductal papillary mucinous neoplasms, we did not find a significant difference in outcome between surgery and follow-up without treatment. Moreover, pancreatic cancer screening in familial HRIs had a greater perceived risk of pancreatic cancer (P < 0.0001), higher levels of anxiety regarding pancreatic cancer (P < 0.0001), and increased economic burden.
CONCLUSION: Pancreatic cancer screening in familial HRIs is associated with a higher detection rate and longer survival, although screening may influence psychological function and increase the economic burden.

Petersen GM
Familial Pancreatic Adenocarcinoma.
Hematol Oncol Clin North Am. 2015; 29(4):641-53 [PubMed] Free Access to Full Article Related Publications
Familial pancreatic cancer (FPC) kindreds have at least 2 first-degree relatives with pancreatic ductal adenocarcinoma. Studies of FPC have focused on the discovery of genetic cause and on the management of those at genetically high risk. Research reveals that a half dozen known hereditary syndromes or genes are associated with increased risk of developing pancreatic cancer, the most prominent of which are BRCA2 and CDKN2A. Genetic risk assessment and testing is already available. Owing to limited experience worldwide, guidance is often based on expert opinion, although all agree that research is needed to improve the shaping of options.

Mocci E, Guillen-Ponce C, Earl J, et al.
PanGen-Fam: Spanish registry of hereditary pancreatic cancer.
Eur J Cancer. 2015; 51(14):1911-7 [PubMed] Related Publications
PURPOSE: To describe the organisation of the registry and the preliminary results in terms of characteristics of high-risk pancreatic ductal adenocarcinoma (PDAC) families recruited to date and findings of the screening programme. To compare early onset sporadic cases (⩽50 years), sporadic cases (>50 years) and cases with family history of cancer, for PDAC possible risk factors.
METHODS/PATIENTS: Families with hereditary cancer syndromes predisposing to PDAC were recruited from two main sources: Spanish hospitals participating in PanGenEU, a pan-European multicentre case-control study, and their genetic counseling unit. Individuals at high-risk of PDAC were enrolled into a screening programme, consisting of Endoscopic ultrasound, computerised tomography, magnetic resonance imaging. Genetic testing of candidate genes was offered according to each patient's risk.
RESULTS: Among 577 consecutive PDAC cases, recruited via PanGenEU, 36 (6%) had ⩾2 first-degree relative with PDAC: Familial pancreatic cancer (FPC). So far PanGen-Fam has recruited 42 high-risk PDAC families; 25 (60%) had FPC. Five index cases with cancer were positive for BRCA2 and one for BRCA1 germline mutations. In the second year of prospective PDAC screening, one neuroendocrine tumour and a high-grade dysplasia lesion suspicious of carcinoma were diagnosed among 41 high-risk individuals. Furthermore EUS detected chronic-pancreatitis-like parenchymal changes in 15 patients.
CONCLUDING STATEMENT: The identification and recruitment of PDAC high-risk families into the PanGen-Fam registry provides an opportunity to detect early onset cancer and precursor pancreatic cancer lesions at a potentially curative stage and to increase the knowledge of the natural history of the disease.

Yates CJ, Newey PJ, Thakker RV
Challenges and controversies in management of pancreatic neuroendocrine tumours in patients with MEN1.
Lancet Diabetes Endocrinol. 2015; 3(11):895-905 [PubMed] Related Publications
Multiple endocrine neoplasia type 1 (MEN1), an autosomal dominant disorder, is characterised by the occurrence of pancreatic neuroendocrine tumours (P-NETs) in association with parathyroid and pituitary tumours. P-NETs, which include gastrinomas, insulinomas, and non-functioning tumours, occur in more than 80% of MEN1 patients and account for 50% of disease-specific deaths. However, there is no consensus about the optimal methods for detecting and treating P-NETs in MEN1 patients, and extrapolations from approaches used in patients with non-familial (sporadic) P-NETs require caution because of differences, such as the younger age of onset, multi-focality of P-NETs, and concomitant presence of other tumours in MEN1 patients. Thus, the early detection of P-NETs by circulating biomarkers and imaging modalities, and their appropriate treatments by surgical approaches and/or radionuclide therapy, chemotherapy, and biotherapy pose challenges and controversies. These challenges and controversies will be reviewed and possible approaches proposed.

Chapman JS, Asthana S, Cade L, et al.
Clinical Sequencing Contributes to a BRCA-Associated Cancer Rediagnosis That Guides an Effective Therapeutic Course.
J Natl Compr Canc Netw. 2015; 13(7):835-45 [PubMed] Related Publications
Cancer is currently classified and treated using an approach based on tissue of origin. Ambiguous or incorrect diagnoses, however, are common and often go unnoticed. Clinical cancer sequencing can provide diagnostic precision, therapeutic direction, and hereditary cancer risk assessment. This report presents a patient with an initial diagnosis of metastatic pancreatic adenocarcinoma (PDA), a disease with a dismal prognosis. Tumor sequencing revealed genomic abnormalities inconsistent with PDA, instead suggesting serous ovarian cancer. This molecular rediagnosis was further refined by the identification of a BRCA2 truncating mutation in the tumor, subsequently confirmed to be a germline event. These findings prompted the initiation of platinum-based chemotherapy, which produced a life-altering response, and referral to genetic counseling for her offspring. These results suggest that clinical tumor sequencing can simultaneously clarify diagnoses, guide therapy, and inform familial risk, even in patients with end-stage metastatic disease, making the case for the development of specific strategies to deploy sequencing coupled with big data in oncology to improve clinical cancer management.

Jung JG, Lee KT, Woo YS, et al.
Behavior of Small, Asymptomatic, Nonfunctioning Pancreatic Neuroendocrine Tumors (NF-PNETs).
Medicine (Baltimore). 2015; 94(26):e983 [PubMed] Free Access to Full Article Related Publications
Small nonfunctioning pancreatic neuroendocrine tumors (NF-PNETs) usually exhibit minimal or no growth over many years. However, there is a controversy regarding the optimal management of incidentally discovered, small NF-PNETs. This study aimed to gain insights into tumor behavior and potential strategies for clinical management.We retrospectively reviewed a total of 202 patients with a suspected PNET (size 2 cm or smaller) at Samsung Medical Center from January 1, 1995 to April 30, 2012. Among these patients, 72 patients were excluded and 145 patients were enrolled in our study. Patients were included if the size of the tumor was ≤2 cm without familial syndrome, radiographic evidence of local invasion or metastases.Among the 145 patients, 76 patients (52.4%) had pathologically confirmed PNETs. Eleven (14.5%) and 3 (3.9%) of these 76 patients were diagnosed with NET G2 and G3, respectively. PNETs measuring 1.5 cm or more in size had a higher probability of being classified as NET G2 or G3 compared with PNETs measuring <1.5 cm (P = 0.03). Older age (≥55 years) and a meaningful tumor growth (≥20% or ≥5 mm) were significantly associated with NET G2 or G3 (P < 0.05).Older age (≥55 years), larger tumor size (≥1.5 cm), and a meaningful tumor growth (≥20% or ≥5 mm) were associated with NET G2 or G3. Intensive follow-up could be an acceptable approach in small (especially <1.5 cm), asymptomatic, NF-PNETs.

Inoue T, Nishi Y, Okumura F, et al.
Solid pseudopapillary neoplasm of the pancreas associated with familial adenomatous polyposis.
Intern Med. 2015; 54(11):1349-55 [PubMed] Related Publications
A man in his thirties visited our hospital for an evaluation of a 12×10-mm pancreatic solid tumor that was accidentally detected on computed tomography performed for follow-up of familial adenomatous polyposis (FAP). We diagnosed the patient with a solid pseudopapillary neoplasm (SPN) based on endoscopic ultrasound-guided fine-needle aspiration, and he underwent pancreaticoduodenectomy. Small SPN tumors appear as solid tumors, without typical features of SPN, making the definitive diagnosis more difficult. The genetic background of FAP patients can predispose them to SPN, and imaging of the pancreas should be performed at prescribed intervals in FAP patients.

Bruenderman E, Martin RC
A cost analysis of a pancreatic cancer screening protocol in high-risk populations.
Am J Surg. 2015; 210(3):409-16 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Pancreatic cancer is the 4th leading cause of cancer death in the United States. A screening protocol is needed to catch early-stage, resectable disease. This study suggests a protocol for high-risk individuals and assesses the cost in the context of the Affordable Care Act.
METHODS: Medicare and national average pricing were used for cost analysis of a protocol using magnetic resonance imaging/MRCP biannually in high-risk groups.
RESULTS: Costs per year of life added" based on Medicare and national average costs, respectively, are as follows: $638.62 and $2,542.37 for Peutz-Jeghers syndrome, $945.33 and $3,763.44 for hereditary pancreatitis, $1,141.77 and $4,545.45 for familial pancreatic cancer and "p16-Leiden" mutations, and $356.42 and $1,418.92 for new-onset diabetes over age 50 with weight loss or smoking.
CONCLUSIONS: A screening program using magnetic resonance imaging/MRCP is affordable in high-risk populations. The United States Preventive Services Task Force must re-evaluate its pancreatic cancer screening guidelines to make screening more cost-effective for the individual.

Singhi AD, Ishida H, Ali SZ, et al.
A histomorphologic comparison of familial and sporadic pancreatic cancers.
Pancreatology. 2015 Jul-Aug; 15(4):387-91 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: It is estimated that approximately 10% of pancreatic cancers have a familial component. Many inheritable genetic syndromes are associated with increased risk of pancreatic cancer, such as Peutz-Jeghers syndrome, hereditary breast-ovarian cancer and familial atypical multiple mole melanoma, but these conditions account for only a minority of familial pancreatic cancers. Previous studies have identified an increased prevalence of noninvasive precursor lesions, including pancreatic intraepithelial neoplasia, in the pancreata of patients with a strong family history of pancreatic cancer. A detailed investigation of the histopathology of invasive familial pancreatic cancer could provide insights into the mechanisms responsible for familial pancreatic cancer, as well as aid early detection and treatment strategies.
METHODS: We have conducted a blinded review of the pathology of 519 familial and 651 sporadic pancreatic cancers within the National Familial Pancreas Tumor Registry. Patients with familial pancreatic cancer were defined as individuals from families in which at least a pair of first-degree relatives have been diagnosed with pancreatic cancer.
RESULTS: Overall, there were no statistically significant differences in histologic subtypes between familial and sporadic pancreatic cancers (p > 0.05). In addition, among surgical resection specimens within the study cohort, no statistically significant differences in mean tumor size, location, perineural invasion, angiolymphatic invasion, lymph node metastasis and pathologic stage were identified (p > 0.05).
CONCLUSIONS: Similar to sporadic pancreatic cancer, familial pancreatic cancer is morphologically and prognostically a heterogeneous disease.

Słowik-Moczydłowska Ż, Rogulski R, Piotrowska A, et al.
Desmoid tumor of the pancreas: a case report.
J Med Case Rep. 2015; 9:104 [PubMed] Free Access to Full Article Related Publications
INTRODUCTION: Desmoid tumor is a rare, benign, usually asymptomatic fibromatous lesion. The etiology is unknown and the diagnosis is based on histopathological examination. The treatment is complete resection of the tumor. Pancreatic desmoid tumor is extremely rare. In the literature there have been only 11 cases described, most of them as solid or solid-cystic masses. We report the case of a patient with an isolated cystic pancreatic desmoid tumor that is, to the best of our knowledge, the second reported case.
CASE PRESENTATION: A 13-year old Caucasian boy presented with recurrent pain of two months' duration in the left hypochondrium of his abdomen. An ultrasound examination and computed tomography scan revealed the presence of a cystic mass located in his splenic hilum, tightly adjacent to the pancreatic tail. A splenic cyst was suspected. Operative findings showed a 10 x 10 cm cystic mass tightly connected to the pancreatic tail and left colonic flexure, adherent to the spleen, splenic vein and artery. Distal splenopancreatectomy with en bloc resection of the left colonic flexure was performed. Histological analysis confirmed that the resection was complete. The mass had infiltrated the pancreatic parenchyma. All tumor cells were positive for anti-beta-catenin staining characteristic for desmoid tumor. No abnormalities in the spleen and colon were found.
CONCLUSIONS: Isolated sporadic pancreatic desmoid tumor with cyst formation is extremely rare and its diagnosis can be difficult, especially because of uncharacteristic symptoms and radiological findings, as in our patient. This case report should be of interest not only to surgeons, as the treatment of choice is radical resection, but also gastroenterologists, considering it is in close relation with familial adenomatous polyposis, and oncologists as the reason for differentiation with other pancreatic tumors.

Chari ST, Kelly K, Hollingsworth MA, et al.
Early detection of sporadic pancreatic cancer: summative review.
Pancreas. 2015; 44(5):693-712 [PubMed] Free Access to Full Article Related Publications
Pancreatic cancer (PC) is estimated to become the second leading cause of cancer death in the United States by 2020. Early detection is the key to improving survival in PC. Addressing this urgent need, the Kenner Family Research Fund conducted the inaugural Early Detection of Sporadic Pancreatic Cancer Summit Conference in 2014 in conjunction with the 45th Anniversary Meeting of the American Pancreatic Association and Japan Pancreas Society. This seminal convening of international representatives from science, practice, and clinical research was designed to facilitate challenging interdisciplinary conversations to generate innovative ideas leading to the creation of a defined collaborative strategic pathway for the future of the field. An in-depth summary of current efforts in the field, analysis of gaps in specific areas of expertise, and challenges that exist in early detection is presented within distinct areas of inquiry: Case for Early Detection: Definitions, Detection, Survival, and Challenges; Biomarkers for Early Detection; Imaging; and Collaborative Studies. In addition, an overview of efforts in familial PC is presented in an addendum to this article. It is clear from the summit deliberations that only strategically designed collaboration among investigators, institutions, and funders will lead to significant progress in early detection of sporadic PC.

Shin EJ, Topazian M, Goggins MG, et al.
Linear-array EUS improves detection of pancreatic lesions in high-risk individuals: a randomized tandem study.
Gastrointest Endosc. 2015; 82(5):812-8 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Studies comparing linear and radial EUS for the detection of pancreatic lesions in an asymptomatic population with increased risk for pancreatic cancer are lacking.
OBJECTIVES: To compare pancreatic lesion detection rates between radial and linear EUS and to determine the incremental diagnostic yield of a second EUS examination.
DESIGN: Randomized controlled tandem study.
SETTING: Five academic centers in the United States.
PATIENTS: Asymptomatic high-risk individuals (HRIs) for pancreatic cancer undergoing screening EUS.
INTERVENTIONS: Linear and radial EUS performed in randomized order.
MAIN OUTCOME MEASUREMENTS: Pancreatic lesion detection rate by type of EUS, miss rate of 1 EUS examination, and incremental diagnostic yield of a second EUS examination (second-pass effect).
RESULTS: Two hundred seventy-eight HRIs were enrolled, mean age 56 years (43.2%), and 90% were familial pancreatic cancer relatives. Two hundred twenty-four HRIs underwent tandem radial and linear EUS. When we used per-patient analysis, the overall prevalence of any pancreatic lesion was 45%. Overall, 16 of 224 HRIs (7.1%) had lesions missed during the initial EUS that were detected by the second EUS examination. The per-patient lesion miss rate was significantly greater for radial followed by linear EUS (9.8%) than for linear followed by radial EUS (4.5%) (P = .03). When we used per-lesion analysis, 73 of 109 lesions (67%) were detected by radial EUS and 99 of 120 lesions (82%) were detected by linear EUS (P < .001) during the first examination. The overall miss rate for a pancreatic lesion after 1 EUS examination was 47 of 229 (25%). The miss rate was significantly lower for linear EUS compared with radial EUS (17.5% vs 33.0%, P = .007).
LIMITATIONS: Most detected pancreatic lesions were not confirmed by pathology.
CONCLUSION: Linear EUS detects more pancreatic lesions than radial EUS. There was a "second-pass effect" with additional lesions detected with a second EUS examination. This effect was significantly greater when linear EUS was used after an initial radial EUS examination.

Laitman Y, Keinan Boker L, Liphsitz I, et al.
Cancer risks in Jewish male BRCA1 and BRCA2 mutation carriers.
Breast Cancer Res Treat. 2015; 150(3):631-5 [PubMed] Related Publications
Cancer risks and tumor types in male BRCA1 and BRCA2 mutation carriers are still unsettled. Cancer risks in men who were found to harbor a BRCA1 (n = 150) or a BRCA2 (n = 88) mutation or both (n = 2) were assessed by cross referencing with data on cancer occurrence in the Israeli National Cancer Registry. Incidence rates in mutation carriers were compared with men who were counseled, genotyped, and found not to harbor the familial mutation (true negative n = 122), and with standardized incidence rates (SIRs). Of 210 cancer-free individuals at initial counseling, 11 cancers were diagnosed after a mean follow-up of 5.06 ± 4.1 years (1064 person/years) compared with 1/122 in a BRCA true-negative man. The SIR for all BRCA1/2 mutation carriers compared with the rates in the general population were elevated for pancreatic cancer [2.97 (95 % CI 1.83-4.29)] and breast cancer [16.44 (95 % CI 9.65-26.24)]. For prostate cancer these rates were 0.59 (95 % CI 0.4-0.84). Jewish BRCA1/2 mutation carriers are at an increased risk for breast and pancreatic, but not prostate cancer. These cancer risks and the consequent recommendations, if validated, should be transmitted to carriers at test result disclosure.

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