Prognostic Value of Excision Repair Cross-Complementing Gene 1, Dihydropyrimidine Dehydrogenase, and Human Equilibrative Nucleotide Transporter 1 Expression and Their Implications for Adjuvant Treatment in Patients With Ampullary Carcinoma.

OBJECTIVES: The purpose of this study was to characterize the intratumoral expression profiles of excision repair cross-complementing gene 1 (ERCC1), dihydropyrimidine dehydrogenase (DPD), and human equilibrative nucleotide transporter 1 (hENT1) in ampullary carcinomas (ACs) to evaluate their prognostic values and better tailor adjuvant chemotherapy for individual patients with AC after surgery. METHODS: This study included 49 patients with AC who underwent a curative pancreaticoduodenectomy. Various clinicopathological factors, including ERCC1, DPD, and hENT1, were analyzed in relation to postoperative disease recurrence and the patients' survival. RESULTS: The median recurrence-free survival and overall survival were 24.5 months and 32.4 months, respectively. Multivariate Cox regression analysis of recurrence-free survival identified a DPD expression (hazard ratio [HR], 8.18; 95% confidence interval [CI], 2.00-34.8; P = 0.003) and combined ERCC1/DPD expression (HR, 134.8; 95% CI, 11.8-1920; P < 0.001) as independent predictors of disease recurrence. Multivariate Cox regression analysis of overall survival also identified a DPD expression (HR, 8.48; 95% CI, 1.71-46.3; P = 0.008) and combined ERCC1/ DPD expression (HR, 135.6; 95% CI, 11.8-1940; P < 0.001) as independent predictors of survival. CONCLUSIONS: The DPD and ERCC1 expression profile could potentially serve as a useful prognostic biomarker and therapeutic target for surgically resected patients with AC.

Expression and prognostic significance of thymidylate synthase (TS) in pancreatic head and periampullary cancer.

BACKGROUND: Pancreatic cancer has a dismal prognosis. Attempts have been made to improve outcome by several 5-FU based adjuvant treatment regimens. However, the results are conflicting. There seems to be a continental divide with respect to the use of 5-FU based chemoradiotherapy (CRT). Furthermore, evidence has been presented showing a different response of pancreatic head and periampullary cancer to 5-FU based CRT. Expression of thymidylate synthase (TS) has been associated with improved outcome following 5-FU based adjuvant treatment in gastrointestinal cancer. This prompted us to determine the differential expression and prognostic value of TS in pancreatic head and periampullary cancer. PATIENTS AND METHODS: TS protein expression was studied by immunohistochemistry on original paraffin embedded tissue from 212 patients following microscopic radical resection (R0) of pancreatic head (n = 98) or periampullary cancer (n = 114). Expression was investigated for associations with recurrence free (RFS), cancer specific (CSS) and overall survival (OS), and conventional prognostic factors. RESULTS: High cytosolic TS expression was present in 26% of pancreatic head tumours and 37% of periampullary tumours (p = .11). Furthermore, TS was an independent factor predicting favourable outcome following curative resection of pancreatic head cancer (p = .003, .001 and .001 for RFS, CSS and OS, respectively). In contrast, in periampullary cancer, TS was not associated with outcome (all p > .10). CONCLUSION: TS, was found to be poorly expressed in both pancreatic head and periampullary cancer and identified as an independent prognostic factor following curative resection of pancreatic head cancer.

Prognostic significance of telomerase activity and human telomerase reverse transcriptase expression in ampullary carcinoma.

BACKGROUND: Telomerase activity and human telomerase reverse transcriptase (TERT) have been reported as markers of tumor aggressiveness and poor prognosis in several digestive cancers. In the present study, we examined telomerase activity and TERT expression in ampullary carcinoma to determine whether these parameters could be used as indicators of aggressiveness and prognosis. METHODS: Telomerase activity was analyzed by using the telomeric repeat amplification protocol assay, and TERT was examined by immunohistochemistry in ampullary carcinoma tissue samples resected from 46 patients. RESULTS: Telomerase activity was detected in 42 (91.3%) ampullary carcinomas and 27 (58.7%) showed high activity, whereas TERT expression was detected in 35 (76.1%), including 21 with weak expression and 14 with strong expression. Univariate analysis revealed that histological grade (P = 0.029), tumor depth (P < 0.001), nodal status (P = 0.013), UICC stage (P = 0.009), perineural invasion (P < 0.001), and telomerase activity (P = 0.031) were significantly associated with disease-specific survival. In multivariate analysis, only telomerase activity remained an independent predictor of prognosis (P = 0.043). There was no statistical significance for survival among the three grades of TERT expression (P = 0.054); however, in subgroup analysis, patients with strong TERT expression showed significantly poorer prognosis than those without TERT expression (P = 0.013). CONCLUSIONS: Our results suggest that high telomerase activity and strong TERT expression may serve as new prognostic markers for evaluating the prognosis of patients with resected ampullary carcinoma.

Mutational profiling of kinases in human tumours of pancreatic origin identifies candidate cancer genes in ductal and ampulla of vater carcinomas.

BACKGROUND: Protein kinases are key regulators of cellular processes (such as proliferation, apoptosis and invasion) that are often deregulated in human cancers. Accordingly, kinase genes have been the first to be systematically analyzed in human tumors leading to the discovery that many oncogenes correspond to mutated kinases. In most cases the genetic alterations translate in constitutively active kinase proteins, which are amenable of therapeutic targeting. Tumours of the pancreas are aggressive neoplasms for which no effective therapeutic strategy is currently available. METHODOLOGY/PRINCIPAL FINDINGS: We conducted a DNA-sequence analysis of a selected set of 35 kinase genes in a panel of 52 pancreatic exocrine neoplasms, including 36 pancreatic ductal adenocarcinoma, and 16 ampulla of Vater cancer. Among other changes we found somatic mutations in ATM, EGFR, EPHA3, EPHB2, and KIT, none of which was previously described in cancers. CONCLUSIONS/SIGNIFICANCE: Although the alterations identified require further experimental evaluation, the localization within defined protein domains indicates functional relevance for most of them. Some of the mutated genes, including the tyrosine kinases EPHA3 and EPHB2, are clearly amenable to pharmacological intervention and could represent novel therapeutic targets for these incurable cancers.

COX-2 expression of ampullary carcinoma: correlation with different histotypes and clinicopathological parameters.

Epidemiological studies suggest that regular intake of nonsteroidal anti-inflammatory drugs (NSAIDs) are associated with reduced incidence of gastrointestinal cancer. Several lines of evidence indicate that the antineoplastic effect of NSAIDs is attributable to COX-2 inhibition. The aim of our study was to assess COX-2 expression in a series of primary untreated ampullary carcinomas and its possible correlation with clinicopathological parameters. In the present study, 45 surgical specimens of invasive ampullary carcinomas were histologically classified into pancreaticobiliary, intestinal, and unusual types. COX-2 expression by immunohistochemical method was analyzed. High COX-2 expression was detected in 35 (77.8%) ampullary carcinomas. Among these, 20/21 (95.2%) were classified as intestinal, 9/18 (50%) pancreaticobiliary, and 6/6 (100%) unusual type. A significant statistical difference in terms of COX-2 expression was found between pancreaticobiliary vs intestinal type (P=0.002). Furthermore, a negative significant statistical correlation was found between T factor and COX-2 expression (P=0.047). The different COX-2 expression among histopathological types supports the concept of histogenetical difference of ampullary carcinomas. Furthermore, the high rate of COX-2 expression in the intestinal subtype of ampullary carcinoma may represent the rational for a histotype-tailored therapy targeting COX-2.

COX-2 expression in ampullary carcinoma: correlation with angiogenesis process and clinicopathological variables.

BACKGROUND: There is evidence that the anti-neoplastic effect of non-steroidal anti-inflammatory drugs is attributable to cyclooxygenase-2 (COX-2) inhibition, but the exact mechanisms whereby COX-2 can promote tumour cell growth remain unclear. One hypothesis is the stimulation of tumour angiogenesis by the products of COX-2 activity. To data, there have been few clinicopathological studies on COX-2 expression in human ampullary carcinoma and no data have been reported about its relation with tumour angiogenesis. OBJECTIVE: To investigate by immunohistochemistry the expression of COX-2 and the angiogenesis process in a series of primary untreated ampullary carcinomas. METHODS: Tissue samples from 40 archival ampullary carcinomas were analysed for COX-2, vascular endothelial growth factor (VEGF), and an endothelial cell marker von Willebrand factor (vWF) by immunohistochemistry, using specific antibodies. RESULTS: COX-2 expression was detected in 39 tissue samples (97.5%), of which two (5%) were graded as weak, 26 (65%) as moderate, and 11 (27.5%) as strong. Only one lesion (2.5%) was negative for COX-2 expression. VEGF expression was detected in 36 tissue samples (90%). A significant positive correlation was found between COX-2 and VEGF expression. No statistic correlation was found between COX-2 expression and microvessel density. CONCLUSIONS: COX-2 is highly expressed in ampullary carcinomas. This suggests an involvement of the COX-2 pathway in ampullary tumour associated angiogenesis, providing a rationale for targeting COX-2 in the treatment of ampullary cancer.

Expression of cyclooxygenase-2 and its correlation with clinicopathologic factors of ampulla of vater cancer.

There has been no report for the expression of cyclooxygenase-2 (COX-2) and its clinicopathologic and biologic significance in ampulla of Vater cancer. This study was aimed for the clarification of COX-2 expression and its biologic roles in ampulla of Vater cancer. Fourty-six patients with ampulla of Vater cancer were enrolled and their COX-2 expression and clinicopathologic features were analyzed. The median age of patients was 60 yr and the mean duration of follow-up was 35 months (range: 14-82 months). Immunohistochemical stainings for COX-2, Ki-67, CD34 and TUNEL staining were performed. The immunoreactive COX-2 expression was present in 24 (52.2%) patients of ampulla of Vater cancer and mainly localized in cytosolic and perinuclear region. There was no significant difference in the length of survival between COX-2 postive and negative group (p=0.9420 by Log Rank test). Also, there were no significant differences of proliferation index (p=0.326), apoptotic index (p=0.764) and microvessel density (p=0.135) between COX-2 positive and negative group. Initial pTNM stage (p=0.0028 by Log Rank test) and blood transfusion over 4 pints during operation (p=0.0254 by Log Rank test) were independent prognostic factor in patients with ampulla of Vater cancer. It is suggested that immunoreactivity of COX-2 is not correlated with clinicopathologic and biologic features of ampulla of Vater cancer.

Expression of Cyclooxygenase-2 and Its Correlation with Clinicopathologic Factors of Ampulla of Vater Cancer

There has been no report for the expression of cyclooxygenase-2 (COX-2) and its clinicopathologic and biologic significance in ampulla of Vater cancer. This study was aimed for the clarification of COX-2 expression and its biologic roles in ampulla of Vater cancer. Fourty-six patients with ampulla of Vater cancer were enrolled and their COX-2 expression and clinicopathologic features were analyzed. The median age of patients was 60 yr and the mean duration of follow-up was 35 months (range: 14-82 months). Immunohistochemical stainings for COX-2, Ki-67, CD34 and TUNEL staining were performed. The immunoreactive COX-2 expression was present in 24 (52.2%) patients of ampulla of Vater cancer and mainly localized in cytosolic and perinuclear region. There was no significant difference in the length of survival between COX-2 postive and negative group (p=0.9420 by Log Rank test). Also, there were no significant differences of proliferation index (p=0.326), apoptotic index (p=0.764) and microvessel density (p=0.135) between COX-2 positive and negative group. Initial pTNM stage (p=0.0028 by Log Rank test) and blood transfusion over 4 pints during operation (p=0.0254 by Log Rank test) were independent prognostic factor in patients with ampulla of Vater cancer. It is suggested that immunoreactivity of COX-2 is not correlated with clinicopathologic and biologic features of ampulla of Vater cancer.

Expression of thymidylate synthase in cancer of the ampulla of Vater.

The clinical and therapeutic significance of thymidylate synthase (TS) in cancers of the ampulla of Vater have not yet been reported. We immunohistochemically evaluated TS expression in 33 ampullary cancers using an anti-TS antibody. TS expression, clinicopathologic variables, and survival rates were examined and the correlations between these parameters were identified. Fifteen patients were found to express high levels of TS (high TS group), while 18 patients expressed low levels of TS (low TS group). No significant difference was found between TS expression and clinicopathologic factors. Univariate and multivariate analysis revealed that lymph node metastasis and pancreatic invasion are important variables for independently predicting post-operative survival. Although TS expression was not identified as an important factor for postoperative survival, recurrent cases in patients with chemotherapy existed only in the high TS group. In the present study, it was found that TS expression itself in cancers of the ampulla of Vater has no impact in predicting the prognosis of ampullary cancers, but a chemotherapeutic benefit of evaluating TS expression may exist.

Possible role of telomerase activation in the multistep tumor progression of periampullary lesions in patients with familial adenomatous polyposis.

OBJECTIVES: The role of telomerase in periampullary tumor progression in patients with familial adenomatous polyposis (FAP) was investigated. METHODS: Relative telomerase activity was measured using a telomerease amplification protocol in periampullary biopsy specimens of normal mucosa and adenoma obtained from patients with FAP, and was compared with that of periampullary normal mucosa and cancer specimens from patients without FAP. RESULTS: None of normal mucosa from the non-FAP patients showed a telomerase ladder. Telomerase was positively detected in three of seven normal mucosa (42.9%) and in five of seven adenoma from FAP patients (62.5%). In papillary cancer from the non-FAP patients, seven of nine tissue specimens (77.8%) showed positive activity. When semiquantitatively analyzed, the relative telomerase activity increased in accordance with the progression of the diseases. CONCLUSIONS: Telomerase is activated even in normal mucosa of FAP patients, and the intensities of telomerase may reflect the malignant potential of periampullary neoplasms.

[Metabolic changes in a patient in the early phase of acute pancreatitis]. / Stoffwechselveränderungen bei einer Patientin in der Frühphase der akuten Pankreatitis.

The present paper reports on the perioperative metabolic changes in a 70-year-old female patient in whom an acute (oedematous) pancreatitis occurred during the transduodenal excision of a villous adenoma of the duodenal papilla. Since blood was taken for metabolic investigations before, during and after surgery, data on the changes in the intermediary metabolism during the early phase of acute pancreatitis in humans was recorded. Raised activity of the pancreatic enzymes amylase and lipase was demonstrable just minutes after extirpation of the papillary tumour after intraoperative cholangiography had been performed via a choledochotomy. This showed occlusion of the duodenal papilla as well as imaging the pancreatic duct. The reflux of bile into the pancreatic duct is considered to be one of the causative factors of acute pancreatitis (Opie-syndrome). The following metabolic changes were registered at surgery and on the first day thereafter: reduction in the serum concentration of cholesterol ester, the triglycerides and the phospholipids by 30 to 50% of the preoperative values respectively, as well as lactacidaemia (up to 60 mg/dl). At the same time, the serum bilirubin concentration and the concentrations of the amino acids alanine and glutamate in the serum were temporarily raised. The question is, whether these metabolic changes were a direct consequence of the activity of the pancreatic enzymes of amino acid and lipid metabolism that were released into the blood, or whether reduced synthesis by the liver (lipoproteins, lecithin: cholesterol-acyl-transferase) was responsible for these changes.