International consensus guidelines for surgery and the timing of intervention in chronic pancreatitis.

BACKGROUND/OBJECTIVES: Chronic pancreatitis (CP) is a complex inflammatory disease with pain as the predominant symptom. Pain relief can be achieved using invasive interventions such as endoscopy and surgery. This paper is part of the international consensus guidelines on CP and presents the consensus guideline for surgery and timing of intervention in CP. METHODS: An international working group with 15 experts on CP surgery from the major pancreas societies (IAP, APA, JPS, and EPC) evaluated 20 statements generated from evidence on 5 questions deemed to be the most clinically relevant in CP. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach was used to evaluate the level of evidence available for each statement. To determine the level of agreement, the working group voted on the 20 statements for strength of agreement, using a nine-point Likert scale in order to calculate Cronbach's alpha reliability coefficient. RESULTS: Strong consensus was obtained for the following statements: Surgery in CP is indicated as treatment of intractable pain and local complications of adjacent organs, and in case of suspicion of malignant (cystic) lesion; Early surgery is favored over surgery in a more advanced stage of disease to achieve optimal long-term pain relief; In patients with an enlarged pancreatic head, a combined drainage and resection procedure, such as the Frey, Beger, and Berne procedure, may be the treatment of choice; Pancreaticoduodenectomy is the most suitable surgical option for patients with groove pancreatitis; The risk of pancreatic carcinoma in patients with CP is too low (2% in 10 year) to recommend active screening or prophylactic surgery; Patients with hereditary CP have such a high risk of pancreatic cancer that prophylactic resection can be considered (lifetime risk of 40-55%). Weak agreement for procedure choice in patients with dilated duct and normal size pancreatic head: both the extended lateral pancreaticojejunostomy and Frey procedure seems to provide equivalent pain control in patients. CONCLUSIONS: This international expert consensus guideline provides evidenced-based statements concerning key aspects in surgery and timing of intervention in CP. It is meant to guide clinical practitioners and surgeons in the treatment of patients with CP.

Differentiation of Autoimmune Pancreatitis from Pancreatic Cancer Remains Challenging.

BACKGROUND: Autoimmune pancreatitis (AIP) is an uncommon form of chronic pancreatitis. Whilst being corticosteroid responsive, AIP often masquerades radiologically as pancreatic neoplasia. Our aim is to appraise demographic, radiological and histological features in our cohort in order to differentiate AIP from pancreatic malignancy. METHODS: Clinical, biochemical, histological and radiological details of all AIP patients 1997-2016 were analysed. The initial imaging was re-reviewed according to international guidelines by three blinded independent radiologists to evaluate features associated with autoimmune pancreatitis and pancreatic cancer. RESULTS: There were a total of 45 patients: 25 in type 1 (55.5%), 14 type 2 (31.1%) and 6 AIP otherwise not specified (13.3%). The median (IQR) age was 57 (51-70) years. Thirty patients (66.6%) were male. Twenty-six patients (57.8%) had resection for suspected malignancy and one for symptomatic chronic pancreatitis. Three had histologically proven malignancy with concurrent AIP. Two patients died from recurrent pancreatic cancer following resection. Multidisciplinary team review based on radiology and clinical history dictated management. Resected patients (vs. non-resected group) were older (64 vs. 53, p = 0.003) and more frequently had co-existing autoimmune pathologies (22.2 vs. 55.6%, p = 0.022). Resected patients also presented with less classical radiological features of AIP, which are halo sign (0/25 vs. 3/17, p = 0.029) and loss of pancreatic clefts (18/25 vs. 17/17, p = 0.017). There were no differences in demographic features other than age. CONCLUSION: Despite international guidelines for diagnosing AIP, differentiation from pancreatic cancer remains challenging. Resection remains an important treatment option in suspected cancer or where conservative treatment fails.

A systems approach identifies time-dependent associations of multimorbidities with pancreatic cancer risk.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is usually diagnosed in late adulthood; therefore, many patients suffer or have suffered from other diseases. Identifying disease patterns associated with PDAC risk may enable a better characterization of high-risk patients. METHODS: Multimorbidity patterns (MPs) were assessed from 17 self-reported conditions using hierarchical clustering, principal component, and factor analyses in 1705 PDAC cases and 1084 controls from a European population. Their association with PDAC was evaluated using adjusted logistic regression models. Time since diagnosis of morbidities to PDAC diagnosis/recruitment was stratified into recent (<3 years) and long term (≥3 years). The MPs and PDAC genetic networks were explored with DisGeNET bioinformatics-tool which focuses on gene-diseases associations available in curated databases. RESULTS: Three MPs were observed: gastric (heartburn, acid regurgitation, Helicobacter pylori infection, and ulcer), metabolic syndrome (obesity, type-2 diabetes, hypercholesterolemia, and hypertension), and atopic (nasal allergies, skin allergies, and asthma). Strong associations with PDAC were observed for ≥2 recently diagnosed gastric conditions [odds ratio (OR), 6.13; 95% confidence interval CI 3.01-12.5)] and for ≥3 recently diagnosed metabolic syndrome conditions (OR, 1.61; 95% CI 1.11-2.35). Atopic conditions were negatively associated with PDAC (high adherence score OR for tertile III, 0.45; 95% CI, 0.36-0.55). Combining type-2 diabetes with gastric MP resulted in higher PDAC risk for recent (OR, 7.89; 95% CI 3.9-16.1) and long-term diagnosed conditions (OR, 1.86; 95% CI 1.29-2.67). A common genetic basis between MPs and PDAC was observed in the bioinformatics analysis. CONCLUSIONS: Specific multimorbidities aggregate and associate with PDAC in a time-dependent manner. A better characterization of a high-risk population for PDAC may help in the early diagnosis of this cancer. The common genetic basis between MP and PDAC points to a mechanistic link between these conditions.

Effect of preoperative biliary drainage on bacterial flora in bile of patients with periampullary cancer.

BACKGROUND: Patients with obstructive jaundice due to periampullary tumours may undergo preoperative biliary drainage (PBD). The effect of PBD on the microbiome of the biliary system and on postoperative outcome remains unclear. METHODS: A single-centre retrospective study of patients with obstructive jaundice due to periampullary cancer, treated between July 2007 and July 2015, was undertaken. Intraoperative bile samples were obtained for microbiological analysis after transection of the common bile duct. Postoperative complications were registered. RESULTS: Of 290 patients treated, intraoperative bile samples were present for 172 patients (59·3 per cent) who had PBD and 118 (40·7 per cent) who did not. Contamination of bile was increased significantly in patients who underwent stenting (97·1 per cent versus 18·6 per cent in those without stenting; P < 0·001). PBD resulted in a shift in the biliary microbiome from Escherichia coli in non-stented patients (45 per cent versus 19·2 per cent in stented patients; P = 0·009) towards increased contamination with Enterococcus faecalis (9 versus 37·7 per cent respectively; P = 0·008) and Enterobacter cloacae (0 versus 20·4 per cent; P = 0·033). This shift was associated with a high incidence of bacterial resistance against ampicillin-sulbactam (63·6 per cent versus 18 per cent in patients with no PBD; P < 0·001), piperacillin-tazobactam (30·1 versus 0 per cent respectively; P = 0·003), ciprofloxacin (28·5 versus 5 per cent; P = 0·047) and imipenem (26·6 versus 0 per cent; P = 0·011). The rate of wound infection was higher in patients with a positive bile culture (21·0 per cent versus 6 per cent in patients with sterile bile; P = 0·002). Regression analysis revealed the presence of Enterococcus faecium (odds ratio 2·83, 95 per cent c.i. 1·17 to 6·84; P = 0·021) and Citrobacter species (odds ratio 5·09, 1·65 to 15·71; P = 0·005) as independent risk factors for postoperative wound infection. CONCLUSION: There are fundamental differences in the biliary microbiome of patients with periampullary cancer who undergo PBD and those who do not. PBD induces a shift of the biliary microbiome towards a more aggressive and resistant spectrum, which requires a differentiated perioperative antibiotic treatment strategy.

Pancreatogastrostomy Versus Pancreatojejunostomy for RECOnstruction After PANCreatoduodenectomy (RECOPANC, DRKS 00000767): Perioperative and Long-term Results of a Multicenter Randomized Controlled Trial.

OBJECTIVES: To assess pancreatic fistula rate and secondary endpoints after pancreatogastrostomy (PG) versus pancreatojejunostomy (PJ) for reconstruction in pancreatoduodenectomy in the setting of a multicenter randomized controlled trial. BACKGROUND: PJ and PG are established methods for reconstruction in pancreatoduodenectomy. Recent prospective trials suggest superiority of the PG regarding perioperative complications. METHODS: A multicenter prospective randomized controlled trial comparing PG with PJ was conducted involving 14 German high-volume academic centers for pancreatic surgery. The primary endpoint was clinically relevant postoperative pancreatic fistula. Secondary endpoints comprised perioperative outcome and pancreatic function and quality of life measured at 6 and 12 months of follow-up. RESULTS: From May 2011 to December 2012, 440 patients were randomized, and 320 were included in the intention-to-treat analysis. There was no significant difference in the rate of grade B/C fistula after PG versus PJ (20% vs 22%, P = 0.617). The overall incidence of grade B/C fistula was 21%, and the in-hospital mortality was 6%. Multivariate analysis of the primary endpoint disclosed soft pancreatic texture (odds ratio: 2.1, P = 0.016) as the only independent risk factor. Compared with PJ, PG was associated with an increased rate of grade A/B bleeding events, perioperative stroke, less enzyme supplementation at 6 months, and improved results in some quality of life parameters. CONCLUSIONS: The rate of grade B/C fistula after PG versus PJ was not different. There were more postoperative bleeding events with PG. Perioperative morbidity and mortality of pancreatoduodenectomy seem to be underestimated, even in the high-volume center setting.

Strategies to improve the outcome in locally advanced pancreatic cancer.

Pancreatic cancer is associated with the worst prognosis of all gastrointestinal malignancies. The major reasons for the dismal outcome are late diagnosis due to unspecific symptoms and aggressive tumor biology. Although highly effective chemotherapeutic options have emerged within the last decade, radical resection offers the only chance of cure. Only 10-20% of patients are resectable at presentation, and 30-40% present with borderline resectable or locally advanced/unresectable tumors. Even if resectable, the 5-year-survival rate after complete resections remains unsatisfactory, with less than 25%. This article gives an overview on current therapy standards as well as on new approaches especially for locally advanced tumors and outlines the importance of ongoing research to improve prognosis.

Could hyponatremia be a marker of anastomotic leakage after colorectal surgery? A single center analysis of 1,106 patients over 5 years.

PURPOSE: The aim of this study is to define the significance of hyponatremia as a marker of anastomotic leakage after colorectal surgery. METHODS: All anastomoses in colorectal surgery performed at a single institution between July 2007 and July 2012 (n = 1,106) were retrospectively identified. Serum sodium levels and leukocyte values measured when an anastomotic leak was diagnosed by CT scan and/or surgical reintervention (n = 81) were compared to the values preferably on postoperative day 5 in the absence of an anastomotic leak (n = 1,025). RESULTS: The leak rate in anastomoses of the rectum was 9.0 %, while the leak rate of the other anastomoses was 5.4 %. Mean serum sodium level was 138.8 mmol/l in the group with an anastomotic leak and 140.5 mmol/l in the group without. Hyponatremia (<136 mmol/l) was present in 23 % of patients in the group with an anastomotic leak and in 15 % in the group without (p < 0.001). In multivariate analysis, leukocytes and serum sodium level remained as significant markers of an anastomotic leak. As a marker of an anastomotic leak, hyponatremia had a specificity of 93 % and a sensitivity of 23 %, while the presence of either leukocytosis or hyponatremia had a sensitivity of 68 %, a specificity of 75 %, a positive predictive value of 18 %, and a negative predictive value of 97 %. CONCLUSIONS: Hyponatremia could be a specific and relevant marker of anastomotic leakage after colorectal surgery. If hyponatremia and leukocytosis are present after colorectal surgery, anastomotic leakage should be suspected and a CT scan with rectal contrast dye is recommended.

Comparison of 3'-deoxy-3'-[¹8F]fluorothymidine positron emission tomography (FLT PET) and FDG PET/CT for the detection and characterization of pancreatic tumours.

PURPOSE: Despite recent advances in clinical imaging modalities, differentiation of pancreatic masses remains difficult. Here, we tested the diagnostic accuracy of molecular-based imaging including 3'-deoxy-3'-[(18)F]fluorothymidine (FLT) positron emission tomography (PET) and [(18)F]fluorodeoxyglucose (FDG) PET/CT in patients with suspected pancreatic masses scheduled to undergo surgery. METHODS: A total of 46 patients with pancreatic tumours suspicious for malignancy and scheduled for resective surgery were recruited prospectively. In 41 patients, FLT PET and FDG PET/CT scans were performed. A diagnostic CT performed on a routine basis was available in 31 patients. FLT PET and FDG PET/CT emission images were acquired according to standard protocols. Tracer uptake in the tumour [FDG and FLT standardized uptake value (SUV)] was quantified by the region of interest (ROI) technique. For FDG PET/CT analysis, correct ROI placement was ensured via side-by-side reading of corresponding CT images. RESULTS: Of 41 patients, 33 had malignancy, whereas 8 patients had benign disease. Visual analysis of FDG and FLT PET resulted in sensitivity values of 91% (30/33) and 70% (23/33), respectively. Corresponding specificities were 50% (4/8) for FDG PET and 75% (6/8) for FLT PET. In the subgroup of patients with contrast-enhanced CT (n = 31), sensitivities were 96% (PET/CT), 88% (CT alone), 92% (FDG PET) and 72% (FLT PET), respectively. Mean FLT uptake in all malignant tumours was 3.0 (range SUV(max) 1.1-6.5; mean FDG SUV(max) 7.9, range 3.3-17.8; p < 0.001). CONCLUSION: For differentiation of pancreatic tumours, FDG PET and FDG PET/CT showed a higher sensitivity but lower specificity than FLT PET. Interestingly, visual analysis of FLT PET led to two false-positive findings by misinterpreting physiological bowel uptake as pathological FLT uptake in the pancreas. Due to the limited number of patients, the clinical value of adding FLT PET to the diagnostic workup of pancreatic tumours remains to be determined.

Expression of HOXC8 is inversely related to the progression and metastasis of pancreatic ductal adenocarcinoma.

BACKGROUND: The transcription factor HOXC8 regulates many genes involved in tumour progression. This study was to investigate the role of HOXC8 in pancreatic ductal adenocarcinoma (PDAC) growth and metastasis. METHODS: The Hoxc8 expression was determined in 15 PDAC cell lines and human specimens by RT-polymerase chain reaction and/or immunohistochemistry. The effects of HOXC8 silencing by RNA interference were investigated by functional tests. RESULTS: The Hoxc8 mRNA expression in PDAC cell lines was negatively related to their growth in vivo. Except for Suit2-007 cells, only those with low Hoxc8 mRNA expression grew in nude rats. Successful down-regulation of HOXC8 expression caused increased proliferation, migration (P ≤ 0.05) and colony formation (P ≤ 0.05) in Suit2-007, Panc-1 and MIA PaCa-2 PDAC cells, respectively. The Hoxc8 mRNA levels in diseased human pancreas tissues were significantly increased over normal in PDAC and autoimmune chronic pancreatitis specimens (P<0.01, respectively), but negatively related to tumour stage (P=0.09). In primary and metastatic tumour samples, immunohistochemical staining for HOXC8 was stronger in surrounding than in neoplastic tissues. Furthermore, grading of primary carcinomas was negatively associated with HOXC8 staining (P=0.03). Liver metastases showed the lowest HOXC8 expression of all neoplastic lesions. CONCLUSION: These data indicate that HOXC8 expression is inversely related to PDAC progression and metastasis.

Gallbladder disease and pancreatic cancer risk: a multicentric case-control European study.

BACKGROUND AND AIMS: The overall evidence on the association between gallbladder conditions (GBC: gallstones and cholecystectomy) and pancreatic cancer (PC) is inconsistent. To our knowledge, no previous investigations considered the role of tumour characteristics on this association. Thus, we aimed to assess the association between self-reported GBC and PC risk, by focussing on timing to PC diagnosis and tumour features (stage, location, and resection). METHODS: Data derived from a European case-control study conducted between 2009 and 2014 including 1431 PC cases and 1090 controls. We used unconditional logistic regression models to estimate odds ratios (ORs) and corresponding 95% confidence intervals (CIs) adjusted for recognized confounders. RESULTS: Overall, 298 (20.8%) cases and 127 (11.6%) controls reported to have had GBC, corresponding to an OR of 1.70 (95% CI 1.33-2.16). The ORs were 4.84 (95% CI 2.96-7.89) for GBC diagnosed <3 years before PC and 1.06 (95% CI 0.79-1.41) for ≥3 years. The risk was slightly higher for stage I/II (OR = 1.71, 95% CI 1.15-2.55) vs. stage III/IV tumours (OR = 1.23, 95% CI 0.87-1.76); for tumours sited in the head of the pancreas (OR = 1.59, 95% CI 1.13-2.24) vs. tumours located at the body/tail (OR = 1.02, 95% CI 0.62-1.68); and for tumours surgically resected (OR = 1.69, 95% CI 1.14-2.51) vs. non-resected tumours (OR = 1.25, 95% CI 0.88-1.78). The corresponding ORs for GBC diagnosed ≥3 years prior PC were close to unity. CONCLUSION: Our study supports the association between GBC and PC. Given the time-risk pattern observed, however, this relationship may be non-causal and, partly or largely, due to diagnostic attention and/or reverse causation.

[Unresectable pancreatic cancer--palliative interventional and surgical treatment]. / Das inoperable Pankreaskarzinom--palliative interventionelle und chirurgische Therapie.

In most cases pancreatic cancer appears in a non-curatively resectable stage at time the diagnosis is made. Thus, palliative treatment concepts come to the fore in these patients. Patients without metastases, but presenting with marginally resectable or locally non-resectable tumours should not be treated in a palliative therapeutic scheme. These patients should be enrolled in neoadjuvant radiochemotherapy trials. After finishing treatment and restaging, a potentially curative resection can be achieved in approximately one-third of these patients. Within the scope of the best possible palliative care, excision of metastases together with resection of the primary cancer represents a therapeutic option to be contemplated in selected cases. For distinct locally unresectable or metastasised advanced pancreatic cancer, treatment of bile duct or duodenal obstruction is an essential part of the comprehensive palliative therapy. However, both endoscopic / percutaneous stenting procedures and surgical bypass makeshifts constitute safe and highly effective therapeutic alternatives in this context. In the case of operative drainage of the biliary tract the prophylactic creation of a gastro-intestinal bypass (double bypass) is recommended. The decision on a surgical versus an endoscopic procedure for palliation depends considerably on the tumour stage and the estimated prognosis and has to be determined interdisciplinary and individually in each case.

Systematic review and meta-analysis of prophylactic gastroenterostomy for unresectable advanced pancreatic cancer.

BACKGROUND: The value of prophylactic gastroenterostomy (usually combined with a biliary bypass) in patients with unresectable cancer of the pancreatic head is controversial. METHODS: A systematic review of retrospective and prospective studies, and a meta-analysis of prospective studies, on the use of prophylactic gastroenterostomy for unresectable pancreatic cancer were performed. RESULTS: Analysis of retrospective studies did not reveal any advantage or disadvantage of prophylactic gastroenterostomy. Three prospective studies comparing prophylactic gastroenterostomy plus biliodigestive anastomosis with no bypass or a biliodigestive anastomosis alone were identified (altogether 218 patients). For patients who had prophylactic gastroenterostomy, the chance of gastric outlet obstruction during follow-up was significantly lower (odds ratio (OR) 0.06 (95 per cent confidence interval (c.i.) 0.02 to 0.21); P < 0.001). The rates of postoperative delayed gastric emptying were similar in both groups (OR 1.93 (95 per cent c.i. 0.57 to 6.53); P = 0.290), as were morbidity and mortality. The estimated duration of hospital stay after prophylactic gastroenterostomy was 3 days longer than for patients without bypass (weighted mean difference 3.1 (95 per cent c.i. 0.7 to 5.5); P = 0.010). CONCLUSION: Prophylactic gastroenterostomy should be performed during surgical exploration of patients with unresectable pancreatic head tumours because it reduces the incidence of long-term gastroduodenal obstruction without impairing short-term outcome.

Defining new pancreatic tumour entities by molecular analysis.

Recent advances in molecular biology, biochemistry and genetics have broadened our understanding of tumourigenesis and of the maintenance and spread of pancreatic cancer far beyond traditional microscopic histopathological analysis. While the main focus of pancreatic cancer research has been on pancreatic ductal adenocarcinoma, molecular research has also led to a better understanding of rare tumours of the pancreas, as well as to the definition of previously unknown tumour entities that can only be identified through the application of molecular tools. Furthermore, molecular analysis increasingly reveals the genetic and cell biological heterogeneity of established tumour entities, making subclassification of tumours possible. Genetic and molecular approaches may, therefore, not only lead to a better understanding of the pathogenesis of pancreatic tumours, but also culminate in more precise diagnosis as well as individually tailored treatment strategies for affected patients.

[Surgery of malignant pancreatic tumors]. / Chirurgie maligner Pankreastumoren.

Ductal adenocarcinoma is the most common malignant tumor of the pancreas. Despite great efforts in basic and clinical pancreatic cancer research, the prognosis remains poor with an overall 5-year survival rate of less than 5%. Complete surgical resection represents the only curative treatment option and 5-year survival rates of 20-25% can be achieved following curative resection and adjuvant chemotherapy. Although pancreatic surgery is considered one of the most technically demanding and challenging procedures, there has been constant progress in surgical techniques and advances in perioperative care with a modern interdisciplinary approach including anesthesiology, oncology, radiology and nursing. This has reduced morbidity and especially mortality rates in high-volume centers. Among extended resection procedures multivisceral and venous resections are technically feasible and should be considered if a complete tumor resection can be achieved. Multimodal regimens have shown promising results, however, only adjuvant chemotherapy is supported by solid evidence from randomized controlled trials.

Expression of YPEL1 in pancreatic cancer cell lines and tissues.

YPEL1 is a nuclear protein that is suggested to be involved in mesenchymal to epithelial-like transition during tissue development. Recently we have identified YPEL1 as a gene whose expression is deregulation in perineural invasive pancreatic cancer cells. In this study we assessed the expression of YPEL1 in normal and diseased pancreatic tissues and pancreatic cancer cell lines. Quantitative real time polymerase chain reaction was used to analyze the expression of YPEL1 mRNA in nine cultured pancreatic cancer cell lines and pancreatic bulk tissues of the normal pancreas (n=19), chronic pancreatitis (n=19) and pancreatic adenocarcinoma tissues (n=31). Quantitative real time polymerase chain reaction analysis revealed a significant down-regulation of YPEL1 mRNA expression in pancreatic adenocarcinoma tissues compared to normal tissues (54.1+/-5.2 vs. 85.8+/-14.1 copies/10,000 copies cpb) and low expression of this gene indicated a tendency for better survival of pancreatic cancer patients (16 vs. 13 months; p=0.17). Expression of YPEL1 mRNA was present in all tested pancreatic cancer cell lines with comparably low to moderate expression levels of 4.3 - 88.0 copies/10,000 copies cpb. Reduced expression of YPEL1 in pancreatic cancer might be related to perineural invasion. and prognosis. YPEL1 might be an important factor during the development and malignant transformation of tissues. Further studies are required to better assess the role of human YPEL1 in pancreatic cancer pathogenesis.

Ex vivo chemosensitivity testing and gene expression profiling predict response towards adjuvant gemcitabine treatment in pancreatic cancer.

Efficacy of chemotherapy for pancreatic cancer may be improved by tailoring it to individual chemosensitivity profiles. Identification of nonresponders before initiation of treatment may help to avoid side effects. In this study, primary pancreatic cancer cells were isolated from 18 patients undergoing pancreaticoduodenectomy for pancreatic cancer. Eight commonly used pancreatic cancer cell lines were used as controls. Ex vivo chemosensitivity for gemcitabine, 5-fluorouracil, mitomycin-C, cisplatinum, oxaliplatinum, paclitaxel and a combination of gemcitabine with oxaliplatinum or mitomycin-C was determined using a cellular ATP-based tumour chemosensitivity assay (ATP-TCA). Quantitative real-time-polymerase chain reaction was performed to determine RNA expression levels of genes implicated in chemoresistance. Chemosensitivity towards cytotoxic agents was highly variable in primary pancreatic cancer cells and pancreatic cancer cell lines. ATP-TCA results for gemcitabine correlated to the tissue expression of human equilibrative nucleoside transporter-1 (hENT1). Time to relapse in patients with gemcitabine-sensitive tumours was significantly higher than in patients with chemoresistant pancreatic cancers (P=0.01; 71 vs 269 days). Furthermore, time to relapse in gemcitabine-treated patients was related to hENT1 expression (P=0.0067). Thus, chemosensitivity testing using ATP-TCA in pancreatic cancer is feasible and correlated with time to relapse in gemcitabine-treated patients. This suggests that ATP-TCA testing could be used as a decision-making tool in the adjuvant treatment of pancreatic cancer.

Clinical outcome and long-term survival in 118 consecutive patients with neuroendocrine tumours of the pancreas.

BACKGROUND: The aim was to assess the clinical relevance of the World Health Organization and tumour node metastasis (TNM) classifications in patients with pancreatic neuroendocrine tumours (pNETs). METHODS: Prospectively collected data from 118 consecutive patients with a pNET receiving surgical intervention were analysed. RESULTS: Forty-one patients had well differentiated neuroendocrine tumours, 64 had well differentiated neuroendocrine carcinomas and 13 had poorly differentiated neuroendocrine carcinomas. Five-year survival rates were 95, 44 and 0 per cent respectively (P < 0.001). There was no difference in survival after R0 and R1/R2 resections in patients with neuroendocrine carcinomas (P = 0.905). In those with well differentiated neuroendocrine carcinomas, any resection and having a clinically non-functional tumour significantly increased survival (P = 0.003 and P = 0.037 respectively). The TNM stage was I in 37 patients, II in 15 patients, III in 32 patients and IV in 34 patients. There were significant differences in 5-year survival between stage I and II (88 and 85 per cent respectively) and stage III and IV (31 and 42 per cent respectively) (P = 0.010). CONCLUSION: Both classifications accurately reflect the clinical outcome of patients with pNET. The resection status may not be critical for long-term survival in patients with pNET.

Risk of pancreatic cancer associated with family history of cancer and other medical conditions by accounting for smoking among relatives.

Background: Family history (FH) of pancreatic cancer (PC) has been associated with an increased risk of PC, but little is known regarding the role of inherited/environmental factors or that of FH of other comorbidities in PC risk. We aimed to address these issues using multiple methodological approaches. Methods: Case-control study including 1431 PC cases and 1090 controls and a reconstructed-cohort study (N = 16 747) made up of their first-degree relatives (FDR). Logistic regression was used to evaluate PC risk associated with FH of cancer, diabetes, allergies, asthma, cystic fibrosis and chronic pancreatitis by relative type and number of affected relatives, by smoking status and other potential effect modifiers, and by tumour stage and location. Familial aggregation of cancer was assessed within the cohort using Cox proportional hazard regression. Results: FH of PC was associated with an increased PC risk [odds ratio (OR) = 2.68; 95% confidence interval (CI): 2.27-4.06] when compared with cancer-free FH, the risk being greater when ≥ 2 FDRs suffered PC (OR = 3.88; 95% CI: 2.96-9.73) and among current smokers (OR = 3.16; 95% CI: 2.56-5.78, interaction FHPC*smoking P-value = 0.04). PC cumulative risk by age 75 was 2.2% among FDRs of cases and 0.7% in those of controls [hazard ratio (HR) = 2.42; 95% CI: 2.16-2.71]. PC risk was significantly associated with FH of cancer (OR = 1.30; 95% CI: 1.13-1.54) and diabetes (OR = 1.24; 95% CI: 1.01-1.52), but not with FH of other diseases. Conclusions: The concordant findings using both approaches strengthen the notion that FH of cancer, PC or diabetes confers a higher PC risk. Smoking notably increases PC risk associated with FH of PC. Further evaluation of these associations should be undertaken to guide PC prevention strategies.

The cell-surface heparan sulfate proteoglycan glypican-1 regulates growth factor action in pancreatic carcinoma cells and is overexpressed in human pancreatic cancer.

Heparan sulfate proteoglycans (HSPGs) play diverse roles in cell recognition, growth, and adhesion. In vitro studies suggest that cell-surface HSPGs act as coreceptors for heparin-binding mitogenic growth factors. Here we show that the glycosylphosphatidylinositol- (GPI-) anchored HSPG glypican-1 is strongly expressed in human pancreatic cancer, both by the cancer cells and the adjacent fibroblasts, whereas expression of glypican-1 is low in the normal pancreas and in chronic pancreatitis. Treatment of two pancreatic cancer cell lines, which express glypican-1, with the enzyme phosphoinositide-specific phospholipase-C (PI-PLC) abrogated their mitogenic responses to two heparin-binding growth factors that are commonly overexpressed in pancreatic cancer: fibroblast growth factor 2 (FGF2) and heparin-binding EGF-like growth factor (HB-EGF). PI-PLC did not alter the response to the non-heparin-binding growth factors EGF and IGF-1. Stable expression of a form of glypican-1 engineered to possess a transmembrane domain instead of a GPI anchor conferred resistance to the inhibitory effects of PI-PLC on growth factor responsiveness. Furthermore, transfection of a glypican-1 antisense construct attenuated glypican-1 protein levels and the mitogenic response to FGF2 and HB-EGF. We propose that glypican-1 plays an essential role in the responses of pancreatic cancer cells to certain mitogenic stimuli, that it is relatively unique in relation to other HSPGs, and that its expression by pancreatic cancer cells may be of importance in the pathobiology of this disorder.