61 research outputs found
International cancer of the pancreas screening (CAPS) consortium summit on the management of patients with increased risk for familial pancreatic cancer
Background Screening individuals at increased risk for
pancreatic cancer (PC) detects early, potentially curable,
pancreatic neoplasia.
Objective To develop consortium statements on
screening, surveillance and management of high-risk
individuals with an inherited predisposition to PC.
Methods A 49-expert multidisciplinary international
consortium met to discuss pancreatic screening and vote
on statements. Consensus was considered reached if
≥75% agreed or disagreed.
Results There was excellent agreement that, to be
successful, a screening programme should detect and
treat T1N0M0 margin-negative PC and high-grade
dysplastic precursor lesions (pancreatic intraepithelial
neoplasia and intraductal papillary mucinous neoplasm). It
was agreed that the following were candidates for
screening: first-degree relatives (FDRs) of patients with
PC from a familial PC kindred with at least two affected
FDRs; patients with Peutz–Jeghers syndrome; and p16,
BRCA2 and hereditary non-polyposis colorectal cancer
(HNPCC) mutation carriers with ≥1 affected FDR.
Consensus was not reached for the age to initiate
screening or stop surveillance. It was agreed that initial
screening should include endoscopic ultrasonography
(EUS) and/or MRI/magnetic resonance
cholangiopancreatography not CT or endoscopic
retrograde cholangiopancreatography. There was no
consensus on the need for EUS fine-needle aspiration to
evaluate cysts. There was disagreement on optimal
screening modalities and intervals for follow-up imaging.
When surgery is recommended it should be performed at
a high-volume centre. There was great disagreement as
to which screeni
Surveillance for pancreatic cancer in high-risk individuals
Background: Surveillance of individuals at high risk of pancreatic ductal adenocarcinoma (PDAC) and its
precursors might lead to better outcomes. The aim of this study was to determine the prevalence
and outcomes of PDAC and high-risk neoplastic precursor lesions among such patients participating
in surveillance programmes.
Methods: A multicentre study was conducted through the International CAncer of the Pancreas Screening (CAPS) Consortium Registry to identify high-risk individuals who had undergone pancreatic resection or progressed to advanced PDAC while under surveillance. High-risk neoplastic precursor lesions
were defined as: pancreatic intraepithelial neoplasia (PanIN) 3, intraductal papillary mucinous neoplasia
(IPMN) with high-grade dysplasia, and pancreatic neuroendocrine tumours at least 2 cm in diameter.
Results: Of 76 high-risk individuals identified in 11 surveillance programmes, 71 had undergone surgery
and five had been diagnosed with inoperable PDAC. Of the 71 patients who underwent resection, 32
(45 per cent) had PDAC or a high-risk precursor (19 PDAC, 4 main-duct IPMN, 4 branch-duct IPMN,
5 PanIN-3); the other 39 patients had lesions thought to be associated with a lower risk of neoplastic
progression. Age at least 65 years, female sex, carriage of a gene mutation and location of a lesion in the
head/uncinate region were associated with high-risk precursor lesions or PDAC. The survival of high-risk
individuals with low-risk neoplastic lesions did not differ from that in those with high-risk precursor
lesions. Survival was worse among patients with PDAC. There was no surgery-related mortality.
Conclusion: A high proportion of high-risk individuals who had surgical resection for screening- or
surveillance-detected pancreatic lesions had a high-risk neoplastic precursor lesion or PDAC
Clinical applications of detecting dysfunctional p53 tumor suppressor protein
The p53 gene encodes for a protein, p53,
which plays a critical role in controlling the cell cycle, in
DNA repair and in programed cell death (apoptosis). p53
is one of the most frequently mutated genes in human
neoplasms and a variety of techniques have been
developed to detect these mutations. These range from
advanced molecular-genetic analyses to immunohistochemical
staining for the p53 protein. This review
will summarize our current understanding of the
function of p53 as well as current methods to detect
dysfunctional p53 and the clinical value of such
analyses
BITC Sensitizes Pancreatic Adenocarcinomas to TRAIL-induced Apoptosis
Pancreatic adenocarcinoma is an aggressive cancer with a greater than 95% mortality rate and short survival after diagnosis. Chemotherapeutic resistance hinders successful treatment. This resistance is often associated with mutations in codon 12 of the K-Ras gene (K-Ras 12), which is present in over 90% of all pancreatic adenocarcinomas. Codon 12 mutations maintain Ras in a constitutively active state leading to continuous cellular proliferation. Our study determined if TRAIL resistance in pancreatic adenocarcinomas with K-Ras 12 mutations could be overcome by first sensitizing the cells with Benzyl isothiocyanate (BITC). BITC is a component of cruciferous vegetables and a cell cycle inhibitor. BxPC3, MiaPaCa2 and Panc-1 human pancreatic adenocarcinoma cell lines were examined for TRAIL resistance. Our studies show BITC induced TRAIL sensitization by dual activation of both the extrinsic and intrinsic apoptotic pathways
Preferential Expression of MUC6 in Oncocytic and Pancreatobiliary Types of Intraductal Papillary Neoplasms Highlights a Pyloropancreatic Pathway, Distinct From the Intestinal Pathway, in Pancreatic Carcinogenesis
The expression of different MUC glycoproteins has helped define cellular lineage in variety of pancreatic neoplasms, and has helped identify distinct carcinogenic pathways such as the intestinal pathway characterized by diffuse/strong MUC2/CDX2 expression in intestinal-type intraductal papillary mucinous neoplasms (IPMNs) and their associated colloid carcinomas (CCs). In this study, the expression profile of MUC6, a pyloric-type mucin, was investigated in both preinvasive and invasive pancreatic neoplasia.Florid papillary ("in-situ") components of 9 intraductal oncocytic papillary neoplasms (IOPNs), 24 IPMNs, and 7 mucinous cystic neoplasms (MCNs), were analyzed immunohistochemically for MUC6 expression, as were 15 PanINs, 112 usual invasive ductal adenocarcinomas (DAs), and 14 CCs.In PanINs, MUC6 expression was limited to the very early areas of PanIN-1A that typically have pyloric features. Expression was lost in later stages. Similarly, in IOPNs or IPMNs or MCNs, MUC6 expression was detectable in the cystic or flat areas that have pyloric-like histology. However, in the more advanced (papillary) components of these neoplasms, MUC6 expression was mostly limited to the "cuboidal-cell" but was not seen in the "columnar-cell" phenotype: there was diffuse or strong expression in 8/9 IOPN and, relatively weaker but consistent expression in all 6/6 pancreatobiliary-type IPMNs; whereas virtually no expression in villous or intestinal-type IPMNs. The 7/8 gastric or foveolar-type IPMNs were also negative; in the single case with positivity, the labeling was limited to high-grade dysplastic areas. Interestingly, the papillae in MCNs were also mostly negative. Among invasive carcinomas, 39/112 DAs and only 1/14 CC expressed MUC6. In DA, the expression did not correlate with survival (P=0.94), or any of the markers of aggressiveness: more than 2-cm tumor size (P=0.76), positive surgical margins (P=0.27), lymph node metastasis (P =0.82), or high grade (P=0.08).In conclusion: (1) The expression of MUC6 in oncocytic and pancreatobiliary-type neoplasms but not in villous or intestinal-type neoplasms supports the presence of a pyloropancreatic pathway distinct from the MUC2/CDX2 expressing intestinal pathway in intraductal papillary neoplasia. (2) MUC6 expression is present in the earliest (nonpapillary) form of any type of preinvasive neoplasia regardless of whether it is PanIN or IOPN or IPMN or MCN suggesting that these entities may share some characteristics early on, but evolve along divergent pathways as they progress
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