Pancreaticoduodenectomy is curative in the majority of patients with node-negative ampullary cancer.
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Ampulla of Vater↗
Biomedical subjects
John L Cameron
Publications and source records attributed to John L Cameron.
Resection of the celiac axis for invasive pancreatic cancer.
Pancreatic cancer arising in the neck or body of the gland frequently presents at a more advanced stage compared with tumors arising in the pancreatic head. Vascular invasion into the celiac axis is a common contraindication to surgical resection. We report an en bloc pancreatectomy, splenectomy, and total gastrectomy with resection of the celiac axis for a pancreatic body adenocarcinoma invading the celiac axis and posterior stomach. Collateral blood flow to the liver via the gastroduodenal artery was initially identified on preoperative computed tomography (CT) imaging and confirmed intraoperatively with vascular testing before resection. One of 14 regional lymph nodes was positive for malignancy, and surgical margins were free of tumor. The patient's postoperative course was unremarkable. En bloc resection of the celiac axis and hepatic artery may be safely performed in select patients with localized pancreatic cancer invading these vessels.
Adenocarcinoma↗
Pancreaticoduodenectomy with or without distal gastrectomy and extended retroperitoneal lymphadenectomy for periampullary adenocarcinoma--part 3: update on 5-year survival.
The study objective was to update the survival analysis at the 5-year mark of patients undergoing standard versus radical (extended) pancreaticoduodenectomy (PD) for periampullary adenocarcinoma (cancers of the pancreas, ampulla, common bile duct, and duodenum). A prospective randomized trial was performed (April 1996 through June 2001) comparing survival after pylorus-preserving PD resection (standard) to survival after PD with distal gastrectomy and retroperitoneal lymphadenectomy (radical). An interim report (Ann Surg 1999;229:613) and report after closing the trial (Ann Surg 2002;236:355) showed no differences in survival between the standard and radical groups. Two hundred ninety-nine patients were randomized to either the standard or radical group. Five patients were excluded from final analysis because final pathology failed to reveal adenocarcinoma. The 5-year survival of the two groups was evaluated. The median live patient follow-up is now 64 months (5.33 years). For all periampullary cancer patients, those undergoing standard resection had 1- and 5-year survival rates of 78% and 25%, respectively, compared with 76% and 31% (P = 0.57) for those patients in the radical group. For pancreatic adenocarcinoma patients, the 1- and 5-year survival rates in the standard group were 75% and 13%, respectively, compared with 73% and 29% in the radical group (P = 0.13). The increased morbidity rate, longer operative time, and similar survival for radical PD led us to conclude that pylorus-preserving PD without retroperitoneal lymphadenectomy should be the procedure of choice for most patients with resectable periampullary adenocarcinoma. While there is an intriguing trend toward improved survival in patients with pancreatic adenocarcinoma in the radical group, this trend may be largely accounted for by the higher incidence of microscopically margin positive resections in the standard resection group (21%) compared with a 5% incidence in the radical group (P = 0.002).
Adenocarcinoma↗
Surgical management of bile duct injuries sustained during laparoscopic cholecystectomy: perioperative results in 200 patients.
OBJECTIVE: A single institution retrospective analysis of 200 patients with major bile duct injuries was completed. Three patients died without surgery due to uncontrolled sepsis. One hundred seventy-five patients underwent surgical repair, with a 1.7% postoperative mortality and a complication rate of 42.9%. SUMMARY BACKGROUND DATA: The widespread application of laparoscopic cholecystectomy (LC) has led to a rise in the incidence of major bile duct injuries (BDI). Despite the frequency of these injuries and their complex management, the published literature contains few substantial reports regarding the perioperative management of BDI. METHODS: From January 1990 to April 2003, a prospective database of all patients with a BDI following LC was maintained. Patients' charts were retrospectively reviewed to analyze perioperative surgical management. RESULTS: Over 13 years, 200 patients were treated for a major BDI following LC. Patient demographics were notable for 150 women (75%) with a mean age of 45.5 years (median 44 years). One hundred eighty-eight sustained their BDI at an outside hospital. The mean interval from the time of BDI to referral was 29.1 weeks (median 3 weeks). One hundred nine patients (58%) were referred within 1 month of their injury for acute complications including bile leak, biloma, or jaundice. Twenty-five patients did not undergo a surgical repair at our institution. Three patients (1.5%) died after delayed referral before an attempt at repair due to uncontrolled sepsis. Twenty-two patients, having intact biliary-enteric continuity, underwent successful balloon dilatation of an anastomotic stricture. A total of 175 patients underwent definitive biliary reconstruction, including 172 hepaticojejunostomies (98%) and 3 end-to-end repairs. There were 3 deaths in the postoperative period (1.7%). Seventy-five patients (42.9%) sustained at least 1 postoperative complication. The most common complications were wound infection (8%), cholangitis (5.7%), and intraabdominal abscess/biloma (2.9%). Minor biliary stent complications occurred in 5.7% of patients. Early postoperative cholangiography revealed an anastomotic leak in 4.6% of patients and extravasation at the liver dome-stent exit site in 10.3% of patients. Postoperative interventions included percutaneous abscess drainage in 9 patients (5.1%) and new percutaneous transhepatic cholangiography and stent placement in 4 patients (2.3%). No patient required reoperation in the postoperative period. The mean postoperative length of stay was 9.5 days (median 9 days). The timing of operation (early, intermediate, delayed), presenting symptoms, and history of prior repair did not affect the incidence of the most common perioperative complications or length of postoperative hospital stay. CONCLUSIONS: This series represents the largest single institution experience reporting the perioperative management of BDI following LC. Although perioperative complications are frequent, nearly all can be managed nonoperatively. Early referral to a tertiary care center with experienced hepatobiliary surgeons and skilled interventional radiologists would appear to be necessary to assure optimal results.
Adult↗
Pancreatic adenocarcinoma: Clinical Practice Guidelines in Oncology.
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Adenocarcinoma↗
Differentially expressed genes in pancreatic ductal adenocarcinomas identified through serial analysis of gene expression.
Serial analysis of gene expression (SAGE) is a powerful tool for the discovery of novel tumor markers. The publicly available online SAGE libraries of normal and neoplastic tissues (http://www.ncbi.nlm.nih.gov/SAGE/) have recently been expanded; in addition, a more complete annotation of the human genome and better biocomputational techniques have substantially improved the assignment of differentially expressed SAGE "tags" to human genes. These improvements have provided us with an opportunity to re-evaluate global gene expression in pancreatic cancer using existing SAGE libraries. SAGE libraries generated from six pancreatic cancers were compared to SAGE libraries generated from 11 non-neoplastic tissues. Compared to normal tissue libraries, we identified 453 SAGE tags as differentially expressed in pancreatic cancer, including 395 that mapped to known genes and 58 "uncharacterized" tags. Of the 395 SAGE tags assigned to known genes, 223 were overexpressed in pancreatic cancer, and 172 were underexpressed. In order to map the 58 uncharacterized differentially expressed SAGE tags to genes, we used a newly developed resource called TAGmapper (http://tagmapper.ibioinformatics.org), to identify 16 additional differentially expressed genes. The differential expression of seven genes, involved in multiple cellular processes such as signal transduction (MIC-1), differentiation (DMBT1 and Neugrin), immune response (CD74), inflammation (CXCL2), cell cycle (CEB1) and enzymatic activity (Kallikrein 6), was confirmed by either immunohistochemical labeling of tissue microarrays (Kallikrein 6, CD74 and DMBT1) or by RT-PCR (CEB1, Neugrin, MIC1 and CXCL2). Of note, Neugrin was one of the genes whose previously uncharacterized SAGE tag was correctly assigned using TAGmapper, validating the utility of this program. Novel differentially expressed genes in a cancer type can be identified by revisiting updated and expanded SAGE databases. TAGmapper should prove to be a powerful tool for the discovery of novel tumor markers through assignment of uncharacterized SAGE tags.
Adenocarcinoma↗
Identification of novel highly expressed genes in pancreatic ductal adenocarcinomas through a bioinformatics analysis of expressed sequence tags.
In most microarray experiments, a significant fraction of the differentially expressed mRNAs identified correspond to expressed sequence tags (ESTs) and are generally discarded from further analyses. We used careful bioinformatics analyses to characterize those ESTs that were found to be highly overexpressed in a series of pancreatic adenocarcinomas. cDNA was prepared from 60 non-neoplastic samples (normal pancreas [n = 20], normal colon [n = 10], or normal duodenal mucosal [n = 30]) and from 64 pancreatic cancers (resected cancers [n = 50] or cancer cell lines [n = 14]) and hybridized to the complete Affymetrix Human Genome U133 GeneChip(R) set (arrays U133A and B) for simultaneous analysis of 45,000 fragments corresponding to 33,000 known genes and 6,000 ESTs. The GeneExpress(R) software system Fold Change Analysis Tool was used and 60 ESTs were identified that were expressed at levels at least 3-fold greater in the pancreatic cancers as compared to normal tissues. Searches against the human genomic sequence and comparative genomic analysis of human and mouse genomes was carried out using basic local alignment search tools (BLAST), BLASTN, and BLASTX, for identifying protein coding genes corresponding to the ESTs. Subsequently, in order to pick the most relevant candidate genes for a more detailed analysis, we looked for domains/motifs in the open reading frames using SMART and Pfam programs. We were able to definitively map 43 of the 60 ESTs to known or novel genes, and 15 of the ESTs could be localized in close proximity to a gene in the human genome although we were unable to establish that the EST was indeed derived from those genes. The differential expression of a subset of genes was confirmed at the protein level by immunohistochemical labeling of tissue microarrays (inhibin beta A [INHBA] and CD29) and/or at the transcript level by RT-PCR (INHBA, AKAP12, ELK3, FOXQ1, EIF5A2, and EFNA5). We conclude that bioinformatics tools can be used to characterize differentially overexpressed ESTs, and that some of these ESTs may represent diagnostically and therapeutically useful targets that might be missed using data solely from currently annotated databases.
Adenocarcinoma↗
Gene expression profiling identifies markers of ampullary adenocarcinoma.
Ampullary adenocarcinoma is an aggressive cancer with a poor prognosis. Without surgical resection, ampullary adenocarcinomas can be difficult to distinguish from ampullary adenomas. The aim of this study was to identify differentially expressed genes in ampullary adenocarcinoma in order to identify candidate markers of the disease. The Affymetrix Human Genome U133 GeneChip set (HG-U133A and HG-U133B) was used to obtain gene expression profiles of 5 ampullary adenocarcinomas and 10 normal duodenal samples. Using fold change analysis we identified 235 fragments expressed at least fivefold higher in ampullary cancers than in normal duodenum. The expression profiles of eight candidate overexpressed genes (osteopontin, mesothelin, tissue inhibitor of metalloproteinases 1, mucin-1, mucin-5, fascin, heat shock protein 47, fibronectin 1) were confirmed by immunohistochemistry or in situ hybridization on tissue microarrays (TMA) containing 54 ampullary adenocarcinomas. One of these genes, osteopontin, was expressed 27-fold higher levels in ampullary adenocarcinomas compared to normal duodenum by genechip analysis. We therefore determined serum osteopontin levels in patients with ampullary neoplasms, patients with other periampullary diseases and in normal controls. Mean preoperative serum osteopontin levels as measured by competitive ELISA were 906 +/- 268 ng/ml in patients with ampullary cancer, 867 +/- 160 ng/ml in patients with an ampullary adenoma, 327.1 +/- 195.6 ng/ml in patients with nonmalignant periampullary diseases and 204 +/- 65 ng/ml in age-matched healthy controls (p < 0.001). Measurement of markers of ampullary cancer such as osteopontin may aid in the early detection and differential diagnosis of patients with periampullary lesions.
Adenocarcinoma↗
Prospective risk of pancreatic cancer in familial pancreatic cancer kindreds.
Individuals with a family history of pancreatic cancer have an increased risk of developing pancreatic cancer. Quantification of this risk provides a rational basis for cancer risk counseling and for screening for early pancreatic cancer. In a prospective registry-based study, we estimated the risk of pancreatic cancer in individuals with a family history of pancreatic cancer. Standardized incidence ratios were calculated by comparing the number of incident pancreatic cancers observed with those expected using Surveillance, Epidemiology and End Results (SEER) rates. Familial pancreatic cancer (FPC) kindreds were defined as kindreds having at least one pair of first-degree relatives with pancreatic cancer, and sporadic pancreatic cancer (SPC) kindreds as families without such an affected pair. Nineteen incident pancreatic cancers developed among 5,179 individuals from 838 kindreds (at baseline, 370 FPC kindreds and 468 SPC kindreds). Of these 5,179 individuals, 3,957 had at least one first-degree relative with pancreatic cancer and contributed 10,538 person-years of follow-up. In this group, the observed-to-expected rate of pancreatic cancer was significantly elevated in members of FPC kindreds [9.0; 95% confidence interval (CI), 4.5-16.1], but not in the SPC kindreds (1.8; 95% CI., 0.22-6.4). This risk in FPC kindreds was elevated in individuals with three (32.0; 95% CI, 10.2-74.7), two (6.4; CI, 1.8-16.4), or one (4.6; CI, 0.5-16.4) first-degree relative(s) with pancreatic cancer. Risk was not increased among 369 spouses and other genetically unrelated relatives. Risk was higher in smokers than in nonsmokers. Individuals with a strong family history of pancreatic cancer have a significantly increased risk of developing pancreatic cancer.
Adult↗
Does fibrin glue sealant decrease the rate of pancreatic fistula after pancreaticoduodenectomy? Results of a prospective randomized trial.
Despite substantial improvements in perioperative mortality, complications, and specifically the development of a pancreatic fistula, remain a common occurrence after pancreaticoduodenectomy. It was the objective of this study to evaluate the role of fibrin glue sealant as an adjunct to decrease the rate of pancreatic fistula after pancreaticoduodenectomy. One hundred twenty-five patients were randomized after pancreaticoduodenal resection only if, in the opinion of the surgeon, the pancreaticojejunal anastomosis was at high risk for development of a pancreatic anastomotic leak. After completion of the pancreaticojejunal anastomosis, the patients were randomized to topical application of fibrin glue sealant to the surface of the anastomosis or no such application. The primary postoperative end points in this study were pancreatic fistula, total complications, death, and length of hospital stay. A total of 59 patients were randomized to the fibrin glue arm, whereas 66 patients were randomized to the control arm and did not receive fibrin glue application. The pancreatic fistula rate in the fibrin glue arm of the study was 26% vs. 30% in the control group (p = not significant [NS]). The mean length of postoperative stay for all patients randomized was similar (fibrin glue = 12.2 days, control = 13.6 days) and the mean length of stay for patients in whom pancreatic fistula developed was also not different (fibrin glue = 18.9 days, control = 21.7 days). There were no differences with respect to total complications or specific complications such as postoperative bleeding, infection, or delayed gastric emptying. These data demonstrate that the topical application of fibrin glue sealant to the surface of the pancreatic anastomosis in this patient population undergoing high-risk pancreaticojejunal anastomosis did not reduce the incidence of pancreatic fistula or total complications after pancreaticodudodenectomy. There seems to be no benefit regarding the use of this substance in this setting.
Administration, Topical↗
Risk factors and outcomes in postpancreaticoduodenectomy pancreaticocutaneous fistula.
A significant fraction of patients undergoing pancreaticoduodenectomy develop a postoperative pancreaticocutaneous fistula. To identify risk factors for this complication and to delineate its impact on patient outcomes, we conducted a retrospective review of 1891 patients undergoing pancreaticoduodenectomy between 1981 and 2002. Overall, 216 patients (11.4%) developed a postoperative pancreaticocutaneous fistula. In univariate analysis, gender, coronary disease, diabetes mellitus, operative times, blood loss, radical lymphadenectomy, gland texture, and specimen pathology correlated with fistula rates. In a multivariate model, however, only gland texture and coronary disease were statistically predictive. A soft gland was associated with a 22.6% fistula rate, a 20.4-fold increase in fistula risk over those patients with a medium or firm gland (95% confidence interval, 4.7-90.9). No patient with a firm gland developed a fistula. Although 30-day postoperative mortality was not different between those patients with and those without fistula (1.4% versus 1.5%), the mean length of stay was longer (26.0 days versus 13.2 days) and the rates of certain complications were increased in those patients with fistula. In this single-institution experience, pancreaticocutaneous fistula was most strongly predicted by pancreatic texture. Choice of anastomotic technique did not correlate with fistula rates. Pancreaticocutaneous fistula increases postoperative length of stay and morbidity but was not directly associated with increased postoperative mortality.
Cutaneous Fistula↗
Analysis of novel tumor markers in pancreatic and biliary carcinomas using tissue microarrays.
Using global gene expression analyses, multiple novel tumor markers overexpressed in infiltrating ductal adenocarcinomas of the pancreas have recently been identified. However, the expression of these markers in morphologically similar adenocarcinomas of the biliary tree has not been investigated. The purpose of the present study was 3-fold. First, we used 8 markers that have been shown to be overexpressed in whole tissue sections of pancreatic adenocarcinomas to validate tissue microarrays (TMAs) created from a series of pancreatic adenocarcinomas (n=68). The labeling patterns of 6 epithelial markers (fascin, mucin 4, 14-3-3sigma, prostate stem cell antigen, topoisomerase IIalpha, and cdc2/p34) were concordant with previously published studies on whole tissue sections, yet required far fewer slides and reagents. Mesothelin, an epithelial marker, and heat shock protein 47, a marker of peritumoral desmoplasia, showed lower levels of expression in the TMAs when compared with whole tissue sections. Second, we examined the previously unknown expression of the same 8 novel tumor proteins in cancers of the biliary tree by using TMAs created from a series of intrahepatic cholangiocarcinomas, gallbladder adenocarcinomas, and adenocarcinomas of the distal common bile duct (n=38). Each of the 8 markers was overexpressed in the biliary cancers, ranging from 14% demonstrating at least focal labeling with prostate stem cell antigen to 100% labeling with cdc2/p34. Most of the markers showed lower frequencies of expression in the biliary tract carcinomas in comparison to the pancreatic adenocarcinomas. In addition, expression patterns varied with location in the biliary system (intrahepatic versus gallbladder versus distal common bile duct). These differences were statistically significant (P<0.05) for mesothelin, mucin 4, and heat shock protein 47. Finally, the expression of selected markers in neoplastic progression of gallbladder cancer was examined. Two markers, fascin and mesothelin, showed up-regulation of expression with transition from carcinoma in situ to invasive adenocarcinoma, implicating a role for these markers in neoplastic progression. The results of this study indicate that TMA technology provides valid and cost-effective means to screen large numbers of novel tumor markers, even in tumors such as pancreatic and biliary adenocarcinomas that characteristically have abundant desmoplastic stroma. In addition, novel tumor markers of pancreatic adenocarcinomas show similar, yet not identical, expression patterns in biliary carcinomas. Therefore, these markers are potentially useful in developing diagnostic tests and treatment paradigms for tumors involving the biliary system.
Adenocarcinoma↗
Percutaneous management of bile duct strictures and injuries associated with laparoscopic cholecystectomy: a decade of experience.
BACKGROUND: The 1990s were associated with a dramatic increase in bile duct injuries with the widespread use of laparoscopic cholecystectomy (LC). Interventional radiology has an integral role in diagnosing and managing these injuries. Definitive percutaneous management with balloon dilatation might be possible in select patients with intact biliary-enteric continuity, but longterm data are limited. STUDY DESIGN: Data were collected prospectively on 51 consecutive patients with major bile duct stricture or injury associated with LC, treated with percutaneous management, January 1, 1990, to December 31, 1999. Percutaneous transhepatic cholangiography and biliary catheter placement were followed by balloon dilatation and stenting. Outcomes were assessed with direct patient contact or hospital records. RESULTS: All patients completed treatment, and 50 (98%) were stent free at mean followup of 76 months. The success rate of percutaneous management was 58.8%, without need for subsequent intervention. Presenting symptoms, level of injury, and number of stents or dilatations did not predict outcomes. Percutaneous treatment was more likely to fail in patients stented for less than 4 months (p < 0.001). Operative repair at Hopkins before percutaneous management was predictive of a successful outcome (p < 0.05). Including subsequent operations or percutaneous management, successful outcomes were achieved in 98% of patients. CONCLUSIONS: Major bile duct injuries after LC remain a clinical challenge. Although surgical reconstruction is the treatment cornerstone, selected patients with biliary-enteric continuity can achieve successful long-term results with definitive percutaneous management. The combination of percutaneous management and surgical reconstruction results in successful outcomes in virtually all patients.
Adult↗
Gene expression profiling identifies genes associated with invasive intraductal papillary mucinous neoplasms of the pancreas.
The molecular pathology of intraductal papillary mucinous neoplasms (IPMNs) of the pancreas has not been well characterized, and there are no reliable markers to predict the presence of an associated invasive carcinoma in IPMNs. Using oligonucleotide microarrays, we performed a large-scale gene expression profiling of 12 IPMNs with or without an associated invasive carcinoma. A subset of genes identified was validated for the gene expression patterns in a large panel of IPMNs by reverse-transcription polymerase chain reaction and/or immunohistochemistry. A total of 673 transcripts were identified as expressed at significantly higher levels (P < 0.05 and at fivefold or greater) in IPMNs relative to normal pancreatic ductal epithelial samples. Of interest, many of the genes identified as overexpressed in IPMNs have also been previously reported to be highly expressed in infiltrating ductal adenocarcinoma of the pancreas. By analyzing genes overexpressed selectively in IPMNs with an associated invasive carcinoma (n = 7), we also identified a panel of genes potentially associated with the invasive phenotype of the neoplasms. Immunohistochemical validation revealed that claudin 4, CXCR4, S100A4, and mesothelin were expressed at significantly high frequency in invasive IPMNs than in noninvasive IPMNs. Notably, the expression of at least two of the four proteins was observed in 73% of 22 invasive IPMNs but in none of 16 noninvasive IPMNs (P < 0.0001). Our findings suggest that preoperative assessment of gene expression profiles may be able to differentiate invasive from noninvasive IPMNs.
Adenocarcinoma, Mucinous↗
Intraductal papillary mucinous neoplasms of the pancreas: an updated experience.
OBJECTIVE: To update the authors' experience with intraductal papillary mucinous neoplasms (IPMNs) of the pancreas. BACKGROUND DATA: IPMNs are intraductal mucin-producing cystic neoplasms of the pancreas with clear malignant potential. Since the authors' 2001 report, the number of IPMNs resected at our institution has more than doubled, providing an opportunity to define the clinical features of this distinct neoplasm. METHODS: All patients undergoing pancreatic resection for an IPMN at the Johns Hopkins Hospital between January 1987 and March 2003 were evaluated. Noninvasive IPMNs were classified as "adenoma," "borderline," or "carcinoma-in situ" (CIS) depending on the degree of dysplasia within the specimen. Invasive cancers were classified as tubular, colloid, mixed, or anaplastic types. Pathology was retrospectively reviewed to identify main-duct or branch-duct origin of the tumors. Long-term overall survival for patients having IPMNs with invasive cancer was compared with those patients having IPMNs without an invasive component. RESULTS: Between January 1987 and March 2003, inclusive, 136 pancreatic resections were performed for patients with IPMNs, with 78 resections performed since January 2001. The mean age of the patients was 66.8 +/- 1.1 years, with 57% being male and 89% white. Pancreaticoduodenectomy was performed in 71% of patients, total pancreatectomy in 15%, distal pancreatectomy in 12%, and central pancreatic resection in 2%. IPMNs without evidence of invasive cancer were identified in 62% (n = 84) of patients (17% adenoma, 28% borderline, or 55% CIS). The remaining 38% (n = 52) of patients had IPMNs with associated invasive cancer (60% tubular, 27% colloid, 7% mixed, and 6% anaplastic). The mean age of patients with IPMN adenoma was 63.2 years, 66.7 years for those with borderline/CIS IPMNs, and 68.1 years for those with invasive cancer (P = 0.08, adenomas vs. invasive cancer). In those patients with invasive cancers, 15% had invasive cancer at the final surgical margin, 23% had IPMN without invasive cancer at the margin, and 54% had lymph node metastases. Residual IPMN was identified at the neck or uncinate margin in 24% of patients with noninvasive IPMNs. The overall 5-year survival for patients having IPMNs without invasive cancer was 77% (several deaths secondary to metachronous invasive cancer), compared with 43% in those patients with an invasive component (P < 0.0001). There were no differences in survival when comparing adenomas, borderline neoplasms, and CIS. Similarly, there were no statistically significant differences in survival when comparing branch-duct, main-duct, and combined variants; however, the branch-duct variants were more often noninvasive. For those patients with invasive IPMNs, 2-year survival was 40% when margins were positive for invasive cancer or for IPMN without invasive cancer, and 60% when margins were tumor-free (P = 0.15). Those patients with colloid carcinomas (n = 14) had improved survival compared with those with tubular carcinomas (n = 31), with 5-year survival rates of 83% and 24%, respectively. IPMN recurrences and deaths from cancer occurred in patients with both invasive and noninvasive IPMNs at initial resection. CONCLUSIONS: IPMNs continue to be recognized with increasing frequency. Five-year survival for those patients following resection of IPMNs with invasive cancer (43%) is improved compared with those patients with resected pancreatic ductal adenocarcinoma in the absence of IPMN (averages 15%-25%). Survival following resection of IPMNs without invasive cancer (regardless of degree of dyplasia) is good, but recurrent disease in the residual pancreas suggests that long-term surveillance is critical. Based on the age at resection data, there appears to be a 5-year lag time from IPMN adenoma (63.2 years) to invasive cancer (68.1 years).
Adenocarcinoma, Mucinous↗
Highly expressed genes in pancreatic ductal adenocarcinomas: a comprehensive characterization and comparison of the transcription profiles obtained from three major technologies.
When using gene expression profiling to understand human tumors, one is often confronted with long lists of genes that need to be further categorized into meaningful data. We performed a comprehensive evaluation and comparison of gene expression profiles obtained from pancreatic cancers to determine those genes most differentially expressed and thus with the most promise for translation into clinically useful targets. cDNA was prepared from 50 samples of normal pancreas or duodenal mucosal tissues, 7 samples of chronic pancreatitis, and 39 samples of pancreas cancer tissues or cancer cell lines and hybridized to the complete Affymetrix Human Genome U133 GeneChip set (arrays U133A and U133B) for simultaneous analysis of 45,000 fragments corresponding to 33,000 known genes and 6,000 expressed sequence tags. Genes expressed at levels at least 3-fold greater in the pancreatic cancers as compared with nonneoplastic tissues were identified. Three hundred seventy-seven Affymetrix fragments were identified as having > or = 3-fold expression levels in pancreas cancer specimens as compared with nonneoplastic tissues, corresponding to 234 known genes. Serial analysis of gene expression libraries (http://www.ncbi.nlm.nih.gov/SAGE/) of two normal pancreatic ductal cell cultures (HX and H126) were used to exclude 17 genes with high expression levels in the normal duct epithelium (more than five tags/library). Of the remaining 217 known genes, 75 have been previously reported as highly expressed in pancreatic cancers, while the remaining 142 genes are novel. We used principal components analysis (PCA) to identify the genes among these 217 identified as the most differentially expressed and specific to pancreatic cancer tissues or cell lines. Among the most differentially expressed genes identified by PCA were Mesothelin, Muc4, Muc5A/C, Kallikrein 10, Transglutaminase 2, Fascin, TMPRSS3 and stratifin. The differential expression identified by PCA for these genes indicates they are among the more attractive targets for novel therapeutic targets, tumor markers, or as a means of screening pancreatic cancer samples for information regarding tumor classification or potential therapeutic responses. Our findings were also compared in detail to the previously reported findings of highly expressed genes in other studies of global gene expression in pancreatic cancers. We found that robust changes in gene expression were most often identified by more than one gene expression platform. Forty genes were identified by more than one method (U133 oligonucleotide arrays, cDNA arrays or serial analysis of gene expression), and 6 of these genes were identified by all three methods. Our findings identify a novel set of genes as highly expressed in pancreatic cancer, validate the differential expression of previously reported genes, and provide additional support for those genes most differentially expressed to be translated into clinically useful targets.
Carcinoma, Pancreatic Ductal↗
Discovery of novel targets for aberrant methylation in pancreatic carcinoma using high-throughput microarrays.
To identify potential targets for aberrant methylation in pancreatic cancer, we analyzed global changes in gene expression profiles of four pancreatic cancer cell lines after treatment with the demethylating agent 5-aza-2'-deoxycytidine (5Aza-dC) and/or the histone deacetylase inhibitor trichostatin A. A substantial number of genes were induced 5-fold or greater by 5Aza-dC alone (631 transcripts), trichostatin A alone (1196 transcripts), and by treatment with both agents (857 transcripts). Four hundred and seventy-five genes were markedly (>5-fold) induced after 5Aza-dC treatment in pancreatic cancer cell lines but not in a nonneoplastic pancreatic epithelial cell line. The methylation status of 11 of these 475 genes was examined in a panel of 42 pancreatic cancers, and all 11 of these genes were aberrantly methylated in pancreatic cancer but rarely, if any, methylated in 10 normal pancreatic ductal epithelia. These genes include UCHL1 (methylated in 100% of 42 pancreatic cancers), NPTX2 (98%), SARP2 (95%), CLDN5 (93%), reprimo (86%), LHX1 (76%), WNT7A (71%), FOXE1 (69%), TJP2 (64%), CDH3 (19%), and ST14 (10%). Three of these 11 genes (NPTX2, SARP2, and CLDN5) were selected for further analysis in a larger panel of specimens, and aberrant methylation of at least one of these three genes was detectable in 100% of 43 primary pancreatic cancers and in 18 of 24 (75%) pancreatic juice samples obtained from patients with pancreatic cancer. Thus, a substantial number of genes are induced by 5Aza-dC treatment of pancreatic cancer cells, and many of them may represent novel targets for aberrant methylation in pancreatic carcinoma.
Adult↗
Tumor suppressor gene hypermethylation as a predictor of gastric stromal tumor behavior.
The growing understanding of the epigenetic changes associated with cancer, including aberrant promoter methylation of tumor suppressor genes that afford selective growth advantages to human neoplasms, suggests that the characterization of gene methylation patterns among gastrointestinal stromal tumors (GISTs) may be useful for predicting tumor behavior. Thirty-eight c-kit-positive gastric stromal tumors were subjected to methylation-specific polymerase chain reaction (MSP) to detect promoter methylation associated with 11 candidate tumor suppressor genes (p16/INK4a, APC, MGMT, hMLH1, p73, E-cadherin, RAR-beta, RASSF1A, RB, ER, and DAPK), established to have a role in tumorigenesis of several solid human organs. Aberrant methylation of any of the 11 candidate tumor suppressor genes was detected in 84% of all GISTs. In decreasing order of frequency, the six most commonly methylated genes were: MGMT (47%), p16 (45%), RASSF1A (40%), E-cadherin (37%), hMLH1 (34%), and APC (31%). For all of the GISTs, promoter methylation was less reliable than tumor mitotic rate in predicting 5-year tumor-free survival for the GISTs; however, E-cadherin methylation was a multivariate prognostic factor for early recurrence of GISTs (50% at 2 years; P=0.030). Among the mitotically active (>5 per 50 high-power field), histologically indistinguishable GISTs, E-cadherin methylation was an independent predictor of tumor-related mortality: 5-year disease-free survival was worse for the E-cadherin methylated GISTs (19%) compared to the E-cadherin unmethylated tumors (71%; P=0.010). Detection of methylation within selected genes may afford a reliable and accurate molecular marker system for predicting neoplastic behavior among GISTs. This study supports the methylation status of E-cadherin as a prognostic marker for early GIST recurrence and survival.
Adult↗