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John L Cameron

Publications and source records attributed to John L Cameron.

At least 55 records · Page 3Linked to original sources
PubMed2003

Exploration of global gene expression patterns in pancreatic adenocarcinoma using cDNA microarrays.

Pancreatic cancer is the fifth leading cause of cancer death in the United States. We used cDNA microarrays to analyze global gene expression patterns in 14 pancreatic cancer cell lines, 17 resected infiltrating pancreatic cancer tissues, and 5 samples of normal pancreas to identify genes that are differentially expressed in pancreatic cancer. We found more than 400 cDNAs corresponding to genes that were differentially expressed in the pancreatic cancer tissues and cell lines as compared to normal pancreas. These genes that tended to be expressed at higher levels in pancreatic cancers were associated with a variety of processes, including cell-cell and cell-matrix interactions, cytoskeletal remodeling, proteolytic activity, and Ca(++) homeostasis. Two prominent clusters of genes were related to the high rates of cellular proliferation in pancreatic cancer cell lines and the host desmoplastic response in the resected pancreatic cancer tissues. Of 149 genes identified as more highly expressed in the pancreatic cancers compared with normal pancreas, 103 genes have not been previously reported in association with pancreatic cancer. The expression patterns of 14 of these highly expressed genes were validated by either immunohistochemistry or reverse transcriptase-polymerase chain reaction as being expressed in pancreatic cancer. The overexpression of one gene in particular, 14-3-3 sigma, was found to be associated with aberrant hypomethylation in the majority of pancreatic cancers analyzed. The genes and expressed sequence tags presented in this study provide clues to the pathobiology of pancreatic cancer and implicate a large number of potentially new molecular markers for the detection and treatment of pancreatic cancer.

Adenocarcinoma↗
PubMed2003

Prognostic value of hMLH1 methylation and microsatellite instability in pancreatic endocrine neoplasms.

BACKGROUND: The aberrant promoter methylation of the mismatch repair gene, hMLH1, is associated with microsatellite instability (MSI) in cancer cells and often is associated with a favorable prognosis. METHODS: Pancreatic endocrine neoplasms (PENs) were obtained from 48 patients who underwent surgical resection. Methylation-specific polymerase chain reaction was used to detect methylation in the hMLH1 promoter. Tumor MSI at loci BAT26, BAT25, D2S123, D5S346, and D17S250 was determined with microsatellite polymerase chain reaction. RESULTS: Hypermethylation of the hMLH1 promoter was present in 11 of 48 PENs (23%). Five of the 11 hMLH1-methylated PENs were found to be microsatellite unstable, and MSI was restricted to PENs with hMLH1 hypermethylation. Tumor recurrence at 2 years after surgical resection was significantly less common among the hMLH1-methylated PENs (11%), compared with the unmethylated PENs (35%; P=.038). Patients with hMLH1-methylated PENs experienced improved 5-year survival (100%) compared with patients with unmethylated tumors (56%; P=.010). Likewise, MSI-positive PENs were associated with improved survival compared with MSI-negative tumors (100% vs 59%; P=.017) at 5 years. CONCLUSION: As in hereditary nonpolyposis colorectal cancer in which MSI is associated with improved survival, methylation of hMLH1 leads to MSI in PENs and affords a favorable prognosis.

Adaptor Proteins, Signal Transducing↗
PubMed2003

Standard vs. radical pancreaticoduodenectomy for periampullary adenocarcinoma: a prospective, randomized trial evaluating quality of life in pancreaticoduodenectomy survivors.

This study was designed to assess the health-related quality of life (QOL) of patients who had been randomly assigned to either standard or radical pancreaticoduodenectomy for periampullary adenocarcinoma. Pancreaticoduodenectomy has been performed in increasing numbers for periampullary adenocarcinoma. The appropriate extent of resection (standard vs. radical [extended]) remains controversial, particularly as concerns survival benefit. Past reports comparing standard vs. radical resection have suggested that the more extensive resection is attended by negative functional outcomes (diarrhea and weight loss) and poorer QOL, diminishing the impact of any possible survival advantage of the radical resection. A prospective, randomized single-institution trial comparing standard pancreaticoduodenectomy (pylorus preservation preferred) to radical pancreaticoduodenectomy (including distal gastrectomy and retroperitoneal lymphadenectomy) evaluated 299 patients with periampullary adenocarcinoma between April 1996 and June 2001. A standard Functional Assessment of Cancer Therapy-Hepatobiliary (FACT-Hep) QOL survey designed for hepatobiliary cancer was sent to 150 of these patients surviving pancreaticoduodenectomy. QOL and functional status were assessed via a series of subscale scores for physical, social, emotional, and functional well-being. A total of 105 QOL surveys (70%) were returned and analyzed, with 55 of the patients having been randomized to the standard group and 50 to the radical group. The patients were evaluated at a mean of 2.2 years after pancreaticoduodenectomy. The two groups were statistically similar with regard to multiple parameters including age at operation (64.6 years), race, intraoperative blood transfusions, pathologic diagnosis and staging, and perioperative complications. The radical group had a significantly higher percentage of men (66% vs. 44%; P = 0.02), a longer operative time (369 minutes vs. 327 minutes; P < 0.001), and a longer postoperative length of hospital stay (13.6 days vs. 10.1 days; P < 0.01). The FACT-Hep total QOL scores were similar between the standard and radical groups: 143.5 vs. 147.3, respectively. Additionally, the individual FACT-G subscale scores evaluating physical (22.1 vs. 23.3), social (24.5 vs. 24.4), emotional (19.2 vs. 19.6), and functional well-being (20.6 vs. 22.4) were comparable between the standard and radical groups. Subgroup analyses based on pathologic diagnosis (pancreatic, ampullary, distal bile duct, etc.) failed to reveal any differences in QOL assessment between the standard and radical pancreaticoduodenectomy groups. Finally, QOL measures were similar when comparing time since operation (<2 years' follow-up vs. >2 years' follow-up) and age (< or =65 years vs. >65 years). This is the largest report comparing QOL assessment in survivors of pancreaticoduodenectomy randomized between standard and radical resection. These data demonstrate no differences in long-term QOL between standard and radical resection. These results imply that no negative long-term QOL measures are associated with radical pancreaticoduodenectomy (as performed in this study) for periampullary adenocarcinoma.

Adenocarcinoma↗
PubMed2003

Pancreaticoduodenectomy: role of interventional radiologists in managing patients and complications.

Although the mortality rate after pancreaticoduodenectomy has decreased, the morbidity rate remains high. Major morbidity is often managed with the aid of interventional radiologists. The objective of this study was to evaluate the cooperative roles of interventional radiologists and pancreatic surgeons in complex pancreatic surgery, specifically pancreaticoduodenectomy. Our pancreaticoduodenectomy database was reviewed for all patients undergoing pancreaticoduodenectomy between January 1, 1995 and December 31, 2000. The interventional radiologic procedures for each patient were evaluated. A total of 1061 patients underwent pancreaticoduodenectomy. The overall mortality and morbidity rates were 2.3% and 35%, respectively. Five hundred ninety patients (56%) had no interventional radiologic procedures, whereas 471 patients (44%) had interventional radiologic procedures. Of those, 342 (32%) had preoperative biliary drainage (PBD) and 129 (12%) required postoperative interventional radiologic procedures. Percutaneous aspiration/catheter drainage was required in 84 patients for intra-abdominal abscess, biloma, or lymphocele, with 24 requiring two or more abscess drains. Thirty-nine patients underwent postoperative PBD for bile leaks due to anastomotic disruption, undrained biliary segments, or T-tube/bile stent dislodgment. Eighteen patients had hemobilia/gastrointestinal bleeding treated by angiography with embolization. The reoperation rate for the entire cohort of 1061 patients was 4.1% (n = 43). Nineteen of the 129 patients (15%) requiring postoperative radiologic intervention required reoperation. Although 4 of 18 patients who required embolization for bleeding subsequently required surgical intervention for the same reason, only 4 of 84 patients undergoing abscess drainage later required operation for anastomotic disruption or unsuccessful percutaneous drainage. As would be expected, the patients who required postoperative radiologic intervention (n = 129) had a higher incidence of postoperative complications including pancreatic fistula (20% vs. 6%, P < 0.01), bile leakage (22% vs. 1%, P < 0.01), and wound infection (16% vs. 8%, P < 0.01). With the complications in these 129 patients, the postoperative mortality rate was only 6.2% compared to 1.7% in patients who did not require radiologic intervention (n = 932, P < 0.01). The median postoperative length of stay was 15 days in those patients requiring postoperative radiologic intervention, 10 days in those not requiring intervention (P < 0.01; postoperative interventional radiology vs. no postoperative interventional radiology), and 29.5 days for patients needing reoperation. Interventional radiologists play a critical role in the management of some patients undergoing pancreaticoduodenectomy. Although complications such as anastomotic leaks, abscess formation, and bleeding can result in increased mortality and a longer hospital stay, the skills of the interventional radiology team provide expert management of some life-threatening complications, thus avoiding reoperation, speeding recovery times, and minimizing morbidity.

Adenocarcinoma↗
PubMed2003

Pancreaticoduodenectomy (Whipple resections) in patients without malignancy: are they all 'chronic pancreatitis'?

Pancreaticoduodenectomy (Whipple resection) has evolved into a safe procedure in major high-volume medical centers for the treatment of pancreatic adenocarcinoma and refractory chronic pancreatitis. However, some Whipple resections performed for a clinical suspicion of malignancy reveal only benign disease on pathologic examination. We evaluated the frequency of such Whipple resections without tumor in a large series of pancreaticoduodenectomies and classified the diverse pancreatic and biliary tract diseases present in these specimens. Of 442 Whipple resections performed during 1999-2001, 47 (10.6%) were negative for neoplastic disease and, in 40 cases, had been performed for a clinical suspicion of malignancy. Most Whipple resections revealed benign pancreatic disease, including 8 (17%) alcohol-associated chronic pancreatitis, 4 (8.5%) gallstone-associated pancreatitis, 1 (2.1%) pancreas divisum, 6 (12.8%) "ordinary" chronic pancreatitis of unknown etiology, and 11 (23.4%) lymphoplasmacytic sclerosing pancreatitis. In particular, patients with lymphoplasmacytic sclerosing pancreatitis were all thought to harbor malignancy, whereas only 13 of 19 (68.4%) of Whipple resections showing histologically "ordinary" forms of chronic pancreatitis were performed for a clinical suspicion of malignancy. Benign biliary tract disease, including three cases of primary sclerosing cholangitis, two cases of choledocholithiasis-associated chronic biliary tract disease, and four fibroinflammatory strictures isolated to the intrapancreatic common bile duct, was a common etiology for clinically suspicious Whipple resections (22.5% of cases). Pancreatic intraepithelial neoplasia (PanIN) was a common finding among all pancreata, whether involved by pancreatitis or histologically normal. Overall, PanIN 1A/1B was present in 68.1%, PanIN 2 in 40.4%, and PanIN 3 in just 2.1%. These findings indicate that "benign but clinically suspicious" Whipple resections are relatively common in high-volume centers (9.2%) and reveal a diverse group of clinicopathologically distinctive pancreatic and biliary tract disease.

Adult↗
PubMed2003

Eosinophilic pancreatitis and increased eosinophils in the pancreas.

Prominent eosinophilic infiltrates are an unusual finding in the pancreas. Eosinophilic pancreatitis is one rare etiology of pancreatic eosinophilia, but other described causes of eosinophilic infiltrates have also included pancreatic allograft rejection, pancreatic pseudocyst, lymphoplasmacytic sclerosing pancreatitis (LPSP), inflammatory myofibroblastic tumor, and histiocytosis X. In this study we describe the clinicopathologic features of three new cases of eosinophilic pancreatitis and conduct a retrospective 18-year institutional review of the myriad disease processes associated with pancreatic eosinophilia. In the files of the Johns Hopkins Hospital, <1% of all pancreatic specimens had been noted to show increased numbers of eosinophils. Eosinophilic pancreatitis itself was a rare etiology for pancreatic eosinophilia, with only one in-house case over the 18-year study period and two additional referral cases. Other disease processes associated with prominent eosinophilic infiltrates were more common and included pancreatic allograft rejection (14 cases), LPSP (5 of 24 total LPSP cases evaluated), inflammatory myofibroblastic tumor (4 cases), and systemic mastocytosis (1 case). Patients with eosinophilic pancreatitis showed two distinct histologic patterns: 1) a diffuse periductal, acinar, and septal eosinophilic infiltrate with eosinophilic phlebitis and arteritis; and 2) localized intense eosinophilic infiltrates associated with pseudocyst formation. All three patients with eosinophilic pancreatitis had peripheral eosinophilia, and all had multiorgan involvement. One patient with LPSP also had marked peripheral eosinophilia, and 5 of 24 LPSP cases demonstrated prominent eosinophilic infiltrates in the gallbladder, biliary tree, and/or duodenum. Notably, not all of these patients with LPSP with prominent eosinophils in other organs had increased eosinophils in the pancreas itself. These results emphasize the infrequent nature of pancreatic eosinophilia and its multiple potential disease associations. True eosinophilic pancreatitis, although a fascinating clinicopathologic entity, is one of the rarest causes of pancreatic eosinophilia.

Adult↗
PubMed2003

p16 Inactivation in pancreatic intraepithelial neoplasias (PanINs) arising in patients with chronic pancreatitis.

Patients with long-standing chronic pancreatitis are thought to be at increased risk of developing pancreatic ductal adenocarcinoma, but the mechanism for this increased risk is unknown. Since increasing evidence supports the notion that infiltrating pancreatic ductal adenocarcinomas arise from pancreatic intraepithelial lesions (PanINs), we sought to determine if patients with chronic pancreatitis harbor PanINs with alterations in tumor suppressor genes that are associated with infiltrating pancreatic ductal adenocarcinoma. We identified 122 patients with a diagnosis of chronic pancreatitis and 29 patients with a well-differentiated pancreatic endocrine tumor that underwent pancreatic surgery at the Johns Hopkins Hospital from 1985 to 1999. PanINs from each resection specimen were identified, graded, counted, and correlated with smoking and alcohol history. The expression patterns of p16 and Smad4 were determined in a subset of PanINs by immunohistochemistry, and the pattern of labeling compared with that seen in PanINs associated with infiltrating adenocarcinoma of the pancreas as identified in prior studies, and to PanINs associated with pancreatic endocrine tumor. Duct lesions were present in 80 of the 122 pancreata with chronic pancreatitis (66%). Of 405 duct lesions identified in the chronic pancreatitis group, 7.6% were reactive changes, 65.5% were PanIN-1A, 18% were PanIN-1B, 7.4% were PanIN-2, and 1.5% were PanIN-3. Within the pancreatic endocrine tumor group, 22 PanINs were identified: 15 PanIN-1A, 4 PanIN-1B, and 3 PanIN-2. There were significantly fewer high-grade PanINs in the pancreata with chronic pancreatitis than in pancreata with pancreatic adenocarcinoma (P < 0.0001). Within the chronic pancreatitis group, the 80 patients with PanINs were significantly older than the 42 patients without PanINs (mean age 57.0 +/- 14.1 years vs. 50.9 +/- 14.7 years, P = 0.01). Smoking history was not associated with PanIN prevalence or grade, but patients who reported a history of excessive alcohol consumption had fewer PanINs (25 of 44 harbored PanINs, 57%) than those who did not (54 of 74, 73%, P = 0.07). In the chronic pancreatitis group, 0% of PanIN-1A, 11% of the PanIN-1B, 16% of the PanIN-2, and 40% of the PanIN-3 lesions showed loss of p16 expression, whereas all of the PanINs from patients with an pancreatic endocrine tumor retained p16 expression. All of the PanINs analyzed from patients with chronic pancreatitis retained normal Smad4 expression. We conclude that a significant minority of PanINs arising in patients with chronic pancreatitis show loss of p16 expression. This alteration, common to pancreatic cancer-associated PanINs, may contribute to the predisposition of patients with chronic pancreatitis to develop pancreatic ductal adenocarcinoma.

Adult↗
PubMed2003

Chronic pancreatitis. Long-term pain relief with or without surgery, cancer risk, and mortality.

To determine the natural history of chronic pancreatitis (CP), we retrospectively studied 193 consecutive patients who had at least one hospitalization for the control of pain or a complication of CP by examining the hospital records and by using a standard questionnaire. Alcohol (66%) was the major cause of CP and the cause was unknown in 21%. Pain was the presenting symptom in 93%. Pancreatic calcification was observed in 41% (alcoholic 54% vs. nonalcoholic 19%; OR = 6.7, CI = 2.7, 14.3; p < 0.0001). Diabetes (28%), malabsorption (16%), pseudocysts (21%) and pancreatic (3%) or extrapancreatic malignancy (5%) were the main complications. 43% had surgical intervention for pain relief, 10% had either endoscopic sphincterotomy or surgical sphincteroplasty and 16% had surgery for complications. Surgical or endoscopic intervention was more commonly performed in nonalcoholics compared with alcoholics (OR = 12.8, CI = 3.6, 53.9; p < 0.0001). However, if sphincterotomy and sphincteroplasty were excluded, the total number of surgical procedures for pain relief was similar in both groups. Complete follow-up information was available in 107 patients with a mean duration of follow-up of 10 years (range, 1-28 years); 27 patients died during the follow-up; 5, 10 and 15 year mortality was 14%, 18% and 20% respectively. The mortality was significantly higher in patients with alcoholic CP than in nonalcoholic CP (35% vs. 10%; OR = 1.4, 18.7; p = 0.005). Of the 80 patients who were alive and had complete long-term follow-up, pain improved in 62 patients, remained unchanged in 17 and worsened in one. Pain improved in 34 of 41 (83%) patients who had surgical intervention for pain, 7 of 9 patients (78%) who had surgery for complications, 4 of 7 (57%) who had sphincter ablation and 17 of 23 patients (74%) who had nonprocedural treatment. Long-term pain relief was similar in patients with alcoholic and nonalcoholic pancreatitis.

Chronic Disease↗
PubMed2003

Role of the DPC4 tumor suppressor gene in adenocarcinoma of the ampulla of Vater: analysis of 140 cases.

The K-ras oncogene is activated in approximately 90% of pancreatic adenocarcinomas, and the DPC4 (MADH4/SMAD4) tumor suppressor gene is inactivated in approximately 55% of pancreatic adenocarcinomas. The contributions of these genetic alterations to the development of adenocarcinoma of the ampulla of Vater have not been fully established. One hundred forty surgically resected ampullary adenocarcinomas (76 with associated adenomas with high-grade dysplasia) were immunohistochemically labeled for the DPC4 gene product, and in 85 cases the results were correlated with the status of the K-ras oncogene from previously reported data. The results were correlated with clinical outcome and with other pathologic predictors of prognosis. Complete loss of Dpc4 labeling was identified in 34% (95% confidence interval [CI]: 26%, 43%) of the invasive carcinomas and in none (upper 95% CI: 6%) of the associated adenomas. Focal loss of Dpc4 was seen in three (4%; 95% CI: 1%, 14%) of the areas of high-grade dysplasia. Complete loss of Dpc4 expression was seen in 28/77 intestinal-type tumors, in 17/46 pancreaticobiliary-type tumors, and in 0/10 colloid carcinomas. Activating point mutations in the K-ras gene were identified in 40% of the invasive cancers. There was no correlation between K-ras gene mutations and Dpc4 expression and no correlation between these variables and survival. The overall 5-year survival rate was 38%. Lymph node metastases were associated with shorter survival (P =.03). Loss of Dpc4 expression occurs in approximately one third of invasive ampullary cancers but is not seen in adenomas; thus, loss of Dpc4 expression occurs late in ampullary carcinogenesis. Although ampullary and pancreatic adenocarcinomas share histologic and molecular features, ampullary carcinomas are less likely to show loss of Dpc4 expression or K-ras gene mutations.

Adenocarcinoma↗
PubMed2003

Immunohistochemical and genetic analysis of non-small cell and small cell gallbladder carcinoma and their precursor lesions.

Gallbladder carcinomas can be highly lethal neoplasms. Relatively little is known about the genetic abnormalities that underlie these tumors, particularly with respect to their timing in neoplastic progression. The authors evaluated 5 noninvasive dysplasias and 33 invasive gallbladder carcinomas (6 small cell carcinomas, 27 non-small cell carcinomas, of which 16 were accompanied by an in situ carcinoma component) for expression of the protein products of the p16, p53, Dpc4, and pRB tumor suppressor genes by immunohistochemistry. Neoplasms were also evaluated for the presence of activating K-ras oncogene mutations. Seventy-five percent of non-small cell gallbladder carcinomas demonstrated loss of p16 expression, whereas 63% accumulated high levels of p53. Loss of Dpc4 and pRB expression was less frequent, seen in 19% and 4% of the neoplasms, respectively. Thirty percent of neoplasms harbored activating K-ras mutations. In contrast, 100% of the small cell carcinomas of the gallbladder demonstrated inactivation of the pRB/p16 pathway; 67% showed loss of pRB expression, and the other 33% lost p16 expression. Eighty-three percent of small cell carcinomas accumulated high levels of p53, whereas loss of Dpc4 expression and activating K-ras mutations were not found. Among 15 evaluable in situ components, 13 harbored the same alterations found in the invasive component. Inactivation of p16 and p53 occur in the majority of non-small cell gallbladder carcinomas. Dpc4 inactivation and K-ras mutations occur in a significant minority of cases. pRB loss is uncommon in non-small cell gallbladder carcinoma, but virtually all small cell carcinomas inactivate the p16/pRB pathway, usually by retinoblastoma protein loss. It is noteworthy that all of these alterations occur at the level of carcinoma in situ.

Adult↗
PubMed2003

Liver metastases arising from well-differentiated pancreatic endocrine neoplasms demonstrate increased VEGF-C expression.

Pancreatic endocrine neoplasms (PENs) are uncommon, generally well-differentiated neoplasms that demonstrate prominent endocrine differentiation. Although the majority of PENs remain localized, malignant spread may occur via lymphatic or hematogenous routes. Angiogenic growth factors, including the vascular endothelial growth factor (VEGF) family, have been implicated in new vessel growth and hematogenous metastases, although this has not been studied in PENs. We therefore examined 19 primary well-differentiated PENs and 7 liver metastases to determine the expression of VEGF-A and its family member VEGF-C by immunolabeling analysis. VEGF-A immunoreactivity was evident only in scattered cells throughout all lesions. VEGF-C, however, demonstrated low-to-moderate expression in primary PENs by semiquantitative histoscore analysis (factor of labeling intensity by percentage of positive cells), with significantly increased expression in liver metastases (mean histoscore indices: primary PEN, 4.7 versus liver metastases, 9.5; Student's t test; P =.002773). Microvascular density of primary PENs and liver metastases did not appear to linearly correlate with VEGF-C expression. Examination of the VEGF-C-specific receptors VEGFR-2/KDR/Flk-1 and VEGFR-3/Flt-4 demonstrated intense endothelial immunoreactivity for VEGFR-2, as well as VEGFR-2 and -3 expression on the majority of neoplastic cells, suggesting a possible role in autocrine/paracrine neoplastic growth regulation. We postulate that the upregulation of VEGF-C may be involved in PEN progression and metastases, although not via a direct proangiogenic mechanism.

Adult↗
PubMed2003

Multicomponent analysis of the pancreatic adenocarcinoma progression model using a pancreatic intraepithelial neoplasia tissue microarray.

A multistep model for pancreatic adenocarcinoma has been proposed recently. In this model, well-defined, noninvasive ductal lesions are recognized as precursors of invasive cancer and have been classified under the nomenclature of pancreatic intraepithelial neoplasia, or PanIN. Increasing evidence suggests that PanINs represent true neoplasms of the pancreatic ductal epithelium, accumulating histologic and genetic abnormalities in their progression toward invasive cancer. We have constructed a tissue microarray containing 55 PanIN lesions of all histologic grades in order to perform a multicomponent analysis of the pancreatic adenocarcinoma progression model. The protein products of 14 genes encompassing a variety of functional classes, such as tumor suppressor genes (p53, Smad4/Dpc4), oncogenes (beta-catenin), cell cycle antigens (p16, cyclin D1), proliferation antigens (Ki-67, topoisomerase II alpha), and epithelial apomucins (MUC1, MUC2, MUC5), as well as "novel" genes described as differentially up-regulated in invasive pancreas cancer by global microarray expression analysis (mesothelin, prostate stem cell antigen, fascin, and 14-3-3varsigma), were analyzed by immunohistochemistry on the PanIN tissue microarray. Comparison of the results from the current study with previously published data performed on routine histologic sections of PanINs demonstrates that tissue microarrays are a valid platform for molecular analysis not only of invasive cancers but of precursor lesions as well. In addition, this study demonstrates that molecular abnormalities in PanINs are not random but can usually be stratified into "early" changes (e.g., expression of MUC5 and prostate stem antigen, or loss of p16), "intermediate" changes (e.g., expression of cyclin D1), and "late" changes (e.g., expression of p53, proliferation antigens, MUC1, mesothelin, and 14-3-3varsigma, or loss of Smad4/Dpc4). Understanding the molecular pathogenesis of precursor lesions of invasive pancreatic adenocarcinomas using a high-throughput tissue microarray-based approach is a valuable adjunct to designing rational strategies for early detection of this lethal neoplasm.

Adenocarcinoma↗
PubMed2003

Results of pancreaticoduodenectomy for lymphoplasmacytic sclerosing pancreatitis.

OBJECTIVE: To compare the presentation and short-term results of pancreaticoduodenectomy for lymphoplasmacytic sclerosing pancreatitis (LPSP) and pancreatic adenocarcinoma (PA) and to provide long-term follow-up on patients undergoing resection for LPSP. SUMMARY BACKGROUND DATA: LPSP is a rare form of chronic pancreatitis characterized by a mixed inflammatory infiltrate centered around pancreatic ducts and ductules, combined with obliterative phlebitis. Its presentation may mimic that of PA. METHODS: Among 1,648 patients undergoing pancreaticoduodenectomy at the authors' institution from January 1992 to May 2002, 37 with LPSP were identified. The demographics, clinical features, and short- and long-term outcomes of these patients were analyzed. Where applicable, comparisons were made to a consecutive group of 45 patients who underwent pancreaticoduodenectomy for PA from July 2001 to December 2001. RESULTS: Twenty-four percent (9/37) of the LPSP patients and none of the PA patients had a history of either atopic or autoimmune disease. The LPSP patients had a similar clinical presentation to the PA patients, but the LPSP patients were less likely to have a discrete pancreatic mass on CT and more likely to have CT findings suggesting a diffusely enlarged pancreas. The LPSP patients were also less likely to have a discrete pancreatic mass at operation, more likely to have a diffusely firm or hard gland, and more likely to have a difficult portal vein/superior mesenteric vein dissection when compared to the PA patients. Transfusion requirement, operative time, postoperative length of stay, and overall complication rate were similar between groups; however, the LPSP patients had a greater operative blood loss. The median length of follow-up for LPSP patients was 33 months. No patients had recurrent jaundice. One patient with LPSP had clinically evident recurrent pancreatitis. Among LPSP patients available for current telephone interview, 68% subjectively rated their quality of life as better, 18% reported no change, and 14% reported diminished quality of life compared to before surgery. CONCLUSION: LPSP mimics PA in clinical presentation, though CT findings of a diffusely enlarged pancreas without a discrete mass may suggest a diagnosis of LPSP. Nevertheless, differentiation from pancreatic neoplasia remains difficult. Patients undergoing pancreaticoduodenectomy for LPSP have durable relief of symptoms and a subjectively improved quality of life.

Adenocarcinoma↗
PubMed2003

Aberrant hypermethylation of tumor suppressor genes in pancreatic endocrine neoplasms.

OBJECTIVE: Because histologic features can be unreliable in determining the malignant potential of pancreatic endocrine neoplasms (PENs), we characterized the methylation patterns of PENs to develop a molecular marker system useful for clinical prognosis. SUMMARY BACKGROUND DATA: Aberrant promoter methylation of tumor suppressor genes is associated with a loss of gene function that can afford selective growth advantages to neoplastic cells. Gene hypermethylation, coupled with sporadic genetic mutations, defines the heterogeneous biology of human neoplasms. METHODS: Forty-eight well-differentiated PENs were subjected to methylation-specific polymerase chain reaction to detect aberrant methylation associated with 11 candidate tumor suppressor genes (INK4a/p16, APC, O6-MGMT, hMLH1, p73, E-cadherin, RAR-beta, p14ARF, GST-pi, TIMP3, and RASSF1A). Methylation differences among PENs, subdivided according to tumor size, lymph node status, or liver metastasis, were analyzed, and the association of gene methylation with tumor recurrence and patient survival was evaluated. RESULTS: Aberrant hypermethylation of any of the 11 tumor suppressor genes was detected in 87% of the PENs. In decreasing order of frequency, the 5 most commonly methylated genes were: RASSF1A (75%), INK4a/p16 (40%), O6-MGMT (40%), RAR-beta (25%), and hMLH1 (23%). In general, tumors larger than 5 cm and those associated with lymph node or hepatic metastases exhibited a higher frequency of methylation at each promoter site compared with PENs without malignant histologic features. The methylation of specific tumor suppressor genes was an independent predictor of early PEN recurrence and decreased 5-year survival following surgical resection. The accumulation of methylation of multiple tumor suppressor genes was associated with early tumor recurrence and reduced survival among a subpopulation of patients with lymph node-negative PENs. CONCLUSIONS: Aberrant methylation of multiple tumor suppressor genes is associated with advanced tumor stage and identifies molecularly distinct PENs with identical histologic characteristics. The methylation status of specific tumor suppressor genes is predictive of PEN behavior.

Carcinoma, Islet Cell↗
PubMed2003

Loss of p27 nuclear expression in a prognostically favorable subset of well-differentiated pancreatic endocrine neoplasms.

Decreased expression of p27 occurs in aggressive colon, breast, and prostate neoplasms; p27 loss often correlates with worsened prognosis. Paradoxical overexpression has been described in benign and malignant pancreatic endocrine neoplasms (PENs). To investigate prognostic usefulness of p27 expression in PENs, we immunolabeled 42 primary PENs, with or without metastases, for p27 and separated lesions using a nuclear labeling index (NLI) of 10%. Of the 42 lesions, 26 demonstrated a 10% or higher NLI and 16 an NLI less than 10%. Comparison of lymph node status revealed that 50% of primary PENs with a 10% or higher NLI (13/26) demonstrated lymph node metastases, whereas only 6% of lesions with an NLI of less than 10% (1/16) demonstrated lymph node metastases (P = .0067). We next examined 11 liver and 7 lymph node metastases for p27 immunolabeling to determine whether p27 also is paradoxically retained in lesions that have metastasized. All 18 lesions demonstrated an NLI of 10% or higher for p27. Expression of p27 protein therefore appears to be lost in a subset of well-differentiated PENs with indolent features but paradoxically retained in PENs associated with metastatic disease.

Cell Cycle Proteins↗
PubMed2002

Identification of hepatocarcinoma-intestine-pancreas/pancreatitis-associated protein I as a biomarker for pancreatic ductal adenocarcinoma by protein biochip technology.

New biomarkers of pancreatic adenocarcinoma are needed to improve the early detection of this deadly disease. We performed surface enhanced laser desorption ionization (SELDI) mass spectrometry using ProteinChip technology (Ciphergen Biosystems, Fremont, CA) to screen for differentially expressed proteins in pancreatic juice. Pancreatic juice samples obtained from patients undergoing pancreatectomy for pancreatic adenocarcinoma were compared with juice samples from patients with other pancreatic diseases. We identified a peak approximately 16,570 daltons present in the pancreatic juice from 10/15 (67%) of the patients with pancreatic adenocarcinoma and in the pancreatic juice from 1/7 (17%) of the patients with other pancreatic diseases. Using a ProteinChip immunoassay, we identified this differentially expressed protein as hepatocarcinoma-intestine-pancreas/pancreatitis-associated-protein I (HIP/PAP-I), a protein released from pancreatic acini during acute pancreatitis and overexpressed in hepatocellular carcinoma. We then quantified by ELISA the pancreatic juice HIP/PAP-I levels in 43 patients (28 with pancreatic adenocarcinoma, 15 with other pancreatic diseases) and the serum HIP/PAP-I levels in 98 patients (53 with pancreatic adenocarcinoma, 45 with other pancreatic diseases or healthy individuals). HIP/PAP-I levels were significantly higher in both the pancreatic juice (P < 0.001) and in the serum (P < 0.001) of patients with pancreatic adenocarcinoma compared with the control group. HIP/PAP-I levels were approximately 1000-fold higher in pancreatic juice compared with serum and the magnitude of the difference between the pancreatic adenocarcinoma group and the control group was greater in the pancreatic juice samples (143.75 +/- 235.52 microg/ml versus 6.04 +/- 7.59 microg/ml) than in the serum samples (99.96 +/- 140.66 ng/ml versus 35.25 +/- 28.44 ng/ml). In our study, patients with pancreatic juice HIP/PAP-I levels > or= 20 microg/ml were 21.9 times (95% confidence interval, 3.5-136.5; P < 0.001) more likely to have pancreatic adenocarcinoma than patients with levels <20 microg/ml. Immunolabeling of tissue sections revealed that the HIP/PAP-I protein was strongly expressed in acini adjacent to the invasive adenocarcinoma, but it was only rarely (1/30; 3%) expressed in the neoplastic epithelium, which suggests that the main source of HIP/PAP-I release in the pancreatic juice is acini. This low level of HIP/PAP-I expression in pancreatic adenocarcinoma was confirmed by reverse transcription-PCR: only 1 (5%) of 19 pancreatic cancer cell lines expressed HIP/PAP-I transcripts. Taken together, these data suggest that pancreatic juice measurement of HIP/PAP-I may help to identify patients with pancreatic adenocarcinoma.

Adult↗