Serine Protease Inhibitor Kazal Type 1 (SPINK1) c.194+2T > C Mutation May Predict Long-term Outcome of Endoscopic Treatments in Idiopathic Chronic Pancreatitis.

Endoscopic interventional is a commonly used treatment method for idiopathic chronic pancreatitis. Serine protease inhibitor Kazal type 1 (SPINK1) 194+2T>C mutation is most frequently observed in Chinese pancreatitis patients and influences the clinical course of idiopathic chronic pancreatitis patients. We conducted this study to determine the impacts of this mutation on the outcome of endoscopic treatments.In this study, we enrolled 423 patients. Among them, 101 idiopathic chronic pancreatitis patients without other relevant mutations had a successful endoscopic procedure and completed follow-up. Clinical characteristics including Izbicki pain score, exocrine and endocrine function, were evaluated. Genetic sequencing was conducted to detect SPINK1 194+2T>C mutations.The c.194+2T>C mutation was found in 58 (57.43%) patients. Factors relevant to pain relief are c.194+2T>C mutation (P = 0.011), severe pain before treatment (P = 0.005), and necessary subsequent endoscopic treatments (P < 0.001). More patients with the intronic mutation had deteriorated endocrine function (P = 0.001) relative to those patients without the mutation.Patients carrying the c.194+2T>C mutation were less likely to achieve pain relief through endoscopic treatments. They also have a higher risk of endocrine function deterioration. SPINK1 c.194+2T>C mutation may be applied as a pretreatment predictor in idiopathic chronic pancreatitis patients.

A comparative analysis of K-ras mutation and carcinoembryonic antigen in pancreatic cyst fluid.

BACKGROUND/AIMS: Analysis of cystic fluid may be useful in distinguishing between benign and malignant cysts which has significant impact on their management. The aim of our study was to assess the diagnostic utility of carcinoembryonic antigen (CEA) and K-ras gene mutation in pancreatic cysts fluid. METHODS: The study included 56 patients with pancreatic cystic fluid collected for analysis. The cysts were classified as benign (simple cysts, pseudocysts, serous cystadenoma) - 39 patients or premalignant/malignant (mucinous cystadenoma, IPMN, cystadenocarcinoma) - 17 patients. The patients history, CEA fluid concentrations and presence of K-ras mutation were analyzed. RESULTS: CEA were higher in patients with malignant cysts (mean levels 238 ± 12.5 ng/ml; range 32.8-4985 ng/ml) compared to benign lesions (mean levels 34.5 ± 3.7 ng/ml; range 3.9-693 ng/ml; p < 0.001). K-ras mutation correctly classified 11 of 17 patients with premalignant/malignant lesions. It was also detected in 1 patient with final diagnosis of benign cyst (the sensitivity 64.7% and the specificity 97.4%; p < 0.01). If CEA and molecular analysis were combined in that cysts with either CEA level>45 ng/ml or presence of K-ras mutation, than 16 of 17 premalignant/malignant cysts were correctly identified (94.1%). CONCLUSION: Molecular analysis of pancreatic cyst fluid adds diagnostic value to the preoperative diagnosis and should be considered when cyst cytologic examination is negative for malignancy.

Commercial molecular panels are of limited utility in the classification of pancreatic cystic lesions.

The PathfinderTG biomarker panel is useful in the evaluation of pancreatic cysts that have clinical features suspicious for malignancy, but its utility in classifying fine-needle aspiration biopsies from small pancreatic cystic lesions is yet to be proven. We used morphology to classify 20 pancreatic cyst cytology aspirates, all of which met radiographic criteria for close observation. Cases were cytologically classified as consistent with pseudocyst, serous cystadenoma, or mucinous neoplasm with low-grade, intermediate-grade, or high-grade dysplasia and analyzed for carcinoembryonic antigen. Redpath Integrated Pathology Inc. rendered diagnoses of nonmucinous (reactive/indolent or serous) or mucinous (low-risk or at risk) cyst on the basis of results of the PathfinderTG panel (KRAS mutations, DNA content, and loss of heterozygosity at microsatellites linked to tumor suppressor genes). Cytologic and commercial laboratory diagnoses were concordant in only 7 (35%) cases. Seven cysts classified as mucinous with low-grade dysplasia by cytology were interpreted as nonmucinous on the basis of the PathfinderTG panel, 2 of which were resected mucinous cysts. Two pancreatitis-related pseudocysts were misdiagnosed as low-risk mucinous cysts; 1 mucinous cyst with low-grade dysplasia was considered at risk for neoplastic progression using the PathfinderTG panel. Only 1 cyst misclassified as pseudocyst by cytology, but low-risk mucinous cyst by molecular analysis, proved to be a mucinous cystic neoplasm with low-grade dysplasia after surgical resection. We conclude that the PathfinderTG panel may aid the classification of pancreatic lesions, but is often inaccurate and should not replace cytologic evaluation of these lesions.

Molecular analysis of cyst fluid aspiration in the diagnosis and risk assessment of cystic lesions of the pancreas.

Pancreatic cyst detection is increasing largely due to increasing use of cross-sectional imaging. The management of pancreatic cysts differs for true cysts, pseudocysts, mucinous cysts, nonmucinous cysts, and malignant lesions. Depending on the setting, diagnostic tests, such as cross-sectional imaging, endoscopic ultrasound, cyst fluid chemistry, and cytology, have moderate accuracy in characterizing the cyst subtype. Molecular analysis of cyst fluid aspirates has shown promise in preliminary studies and may require smaller fluid volumes than is needed for carcinoembryonic antigen level and cytology. This article reviews published studies in which molecular analysis was performed in the evaluation of pancreatic cysts. The molecular studies are compared with the conventional tests. Most studies have had moderate sample sizes (16-124) and have characterized a high proportion of patients with malignant cysts. Evaluation of molecular analysis as a diagnostic tool merits larger prospective trials with long-term follow-up of patients who are not sent to surgery. Larger cysts may meet size criteria for resection, and it is the smaller cysts for which molecular analysis may be of benefit if additional molecular testing results in a change in management.

Mucin expression pattern in pancreatic diseases: findings from EUS-guided fine-needle aspiration biopsies.

OBJECTIVES: Alterations in mucin (MUC) glycosylation and expression have been described in cancer. Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) can provide material for molecular biology analysis. This study assessed the feasibility of evaluating MUC expression from material obtained by EUS-FNA and studied the profile of MUC expression in benign and malignant pancreatic lesions. METHODS: A total of 90 patients with solid or cystic pancreatic lesions underwent FNA. The aspirated material was used for cytological analysis and RNA extraction to assess the expression pattern of MUCs by reverse transcription-PCR with primers specific for the MUC1, MUC2, MUC3, MUC4, MUC5A, MUC5B, MUC6, and MUC7 genes. RESULTS: RNA extraction was successful in 81% of the biopsies. The prevalences of MUC1, MUC2, MUC4, and MUC7 in ductal adenocarcinoma were 57.7, 51.4, 18.9, and 73.0%, respectively. Fifty percent of benign lesions and neuroendocrine tumors (NETs), and 63% of intraductal papillary mucinous neoplasms (IPMNs) were positive for MUC1. Twenty-five percent of benign lesions, 86% of NETs, and 47% of IPMNs were positive for MUC2. Of NETs, 50% were positive for MUC1, and 14% were positive for MUC7. None of the benign lesions or NETs expressed MUC4. MUC7 expression was highly significant for adenocarcinoma (P=0.007) and borderline for IPMN (P=0.05). MUC7 was expressed in 37.5% of chronic pancreatitis cases. CONCLUSIONS: RNA can be extracted from samples obtained under EUS-FNA. MUC7 could serve as a potential biological marker to identify malignant lesions, especially pancreatic adenocarcinoma.

Chronic pancreatitis with pancreaticolithiasis and pseudocyst in a 5-year-old boy with homozygous SPINK1 mutation.

We report a 5-year-old boy with a 5-month history of symptoms owing to chronic pancreatitis. Abdominal imaging revealed a large pseudocyst in the pancreatic tail and concretions in the main pancreatic duct. Successful endoscopic papillotomy and stent implantation were performed. Genetic testing showed homozygous SPINK1-N34S mutation, which is an established risk factor for chronic pancreatitis.

The functional angiotensin converting enzyme gene I/D polymorphism does not alter susceptibility to chronic pancreatitis.

CONTEXT: Alterations of the renin-angiotensin system have been implicated in the pathogenesis of various diseases. The angiotensin converting enzyme is a key enzyme in the renin-angiotensin system. A deletion polymorphism of a 287-bp fragment of intron 16 of the angiotensin converting enzyme gene allele results in higher levels of circulating enzyme. ACE deletion genotype has been linked to heart diseases, sarcoidosis and liver fibrosis. The pancreatic renin-angiotensin system plays a role in the development of pancreatic fibrosis and ACE inhibitors decrease pancreatic fibrosis in experimental models. OBJECTIVES: We investigated the frequency of the ACE gene insertion/deletion polymorphism in chronic pancreatitis patients and controls. PATIENTS: Subjects with familial pancreatitis (n=51), sporadic chronic pancreatitis (n=104), and healthy controls (n=163) were evaluated. MAIN OUTCOME MEASURE: The presence of ACE insertion/deletion polymorphism. RESULTS: The frequency of the ACE gene deletion allele was similar in familial pancreatitis (49.0%) sporadic pancreatitis (51.0%) and controls (55.8%). Furthermore, there was no significant difference in clinical features between patients with ACE-insertion or insertion/deletion genotypes vs. patients with ACE-deletion genotype. CONCLUSION: We conclude that the ACE deletion genotype does not make a significant contribution to the pathogenesis and the progression of chronic pancreatitis.

Three truncated forms of serum albumin associated with pancreatic pseudocyst.

Plasma from a patient with chronic pancreatic pseudocyst showed an additional more negative albumin band (18%) on agarose gel electrophoresis. Both components bound (63)Ni(2+), indicating intact N-terminals; however, electrospray ionisation analysis of the intact proteins showed the mass of more negative albumin was 1254 Da less than the control and that the apparently normal band was 112 Da less. Reverse phase mapping and mass analysis of CNBr peptides showed three proteolytically modified forms of the C-terminal peptide indicating that some 81% of the albumin molecules lacked the C-terminal Leu residue, that 18% lacked the C-terminal KKLVAASQAALGL and that approximately 1% lacked the QAALGL sequence. These findings were further verified by tryptic mapping of the aberrant CNBr peptides. The truncations probably result from exposure of the albumin to 'leaking' pancreatic endo and exoproteases. During less acute phases of the disease, the 13 and 6 residue truncated forms together decreased to less than 1%, while the des-Leu(585) form made up the balance; no normal albumin was detected. This suggested that the des-Leu(585) form might be present at low levels in the plasma of normal individuals and CNBr mapping confirmed that it constituted 4-15% of the albumin from normal plasma.

[Clinicopathological features and diagnostic points of uncommon pancreatic tumors].

Clinicopathological features of uncommon pancreatic tumors including solid cystic tumor (SCT), acinar cell carcinoma and pancreatoblastoma are described, based upon a literature survey and own experiences. They are often discovered by US and CT as asymptomatic pseudocystic tumor. SCTs almost always occur in young female and Pancreatoblastoma, in children less than five years old. The prognosis is very favorable in SCT, and relatively good in acinar cell carcinoma and pancreatoblastoma. Pancreatoblastoma is often associated with the elevation of serum AFP levels. Characteristic histological features and immunocytochemical features are also described, all of which are very different from those of usual pancreatic ductal carcinoma. Molecular biological features including the results of k-ras and p53 point mutation are also discussed. In addition to the clinicopathological features, these uncommon tumors are very different from usual ductal carcinoma in the molecular biological features.

Massive bleeding into the upper gastro-intestinal tract in hereditary chronic calcifying pancreatitis in the child.

This report deals with a young girl affected with chronic hereditary calcifying pancreatitis, which gave rise to acute life-threatening arterial bleeding into the upper gastro-intestinal tract. A pancreatic pseudocyst forming in the chronically affected pancreas spontaneously perforated into the stomach, thereby eroding a gastric wall artery. We think it is conceivable that in the future this type of complication in children with pancreatitis and pseudocyst formation might occur more frequently.