Meta-analysis of delayed gastric emptying after pylorus-preserving versus pylorus-resecting pancreatoduodenectomy.

BACKGROUND: Delayed gastric emptying (DGE) is a frequent complication after pylorus-preserving pancreatoduodenectomy. Recent studies have suggested that resection of the pylorus is associated with decreased rates of DGE. However, superiority of pylorus-resecting pancreatoduodenectomy was not shown in a recent RCT. This meta-analysis summarized evidence of the effectiveness and safety of pylorus-preserving compared with pylorus-resecting pancreatoduodenectomy. METHODS: RCTs and non-randomized studies comparing outcomes of pylorus-preserving and pylorus-resecting pancreatoduodenectomy were searched systematically in MEDLINE, Web of Science and CENTRAL. Random-effects meta-analyses were performed and the results presented as weighted odds ratios (ORs) or mean differences with their corresponding 95 per cent confidence intervals. Subgroup analyses were performed to account for interstudy heterogeneity between RCTs and non-randomized studies. RESULTS: Three RCTs and eight non-randomized studies with a total of 992 patients were included. Quantitative synthesis across all studies showed superiority for pylorus-resecting pancreatoduodenectomy regarding DGE (OR 2·71, 95 per cent c.i. 1·48 to 4·96; P = 0·001) and length of hospital stay (mean difference 3·26 (95 per cent c.i. -1·04 to 5·48) days; P = 0·004). Subgroup analyses including only RCTs showed no significant statistical differences between the two procedures regarding DGE, and for all other effectiveness and safety measures. CONCLUSION: Pylorus-resecting pancreatoduodenectomy is not superior to pylorus-preserving pancreatoduodenectomy for reducing DGE or other relevant complications.

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.

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.

iTRAQ reveals candidate pancreatic cancer serum biomarkers: influence of obstructive jaundice on their performance.

BACKGROUND: The aims of our study were to identify serum biomarkers that distinguish pancreatic cancer (pancreatic ductal adenocarcinoma, PDAC) patients from benign pancreatic disease patients and healthy subjects, and to assess the effects of jaundice on biomarker performance. METHODS: Isobaric tags for relative and absolute quantification were used to compare pooled serum and pancreatic juice samples from a test set of 59 and 25 subjects, respectively. Validation was undertaken in 113 independent subjects. RESULTS: Candidate proteins Complement C5, inter-α-trypsin inhibitor heavy chain H3, α1-ß glycoprotein and polymeric immunoglobulin receptor were elevated in cancer, as were the reference markers CA19-9 and Reg3A. Biliary obstruction had a significant effect on the performance of the markers, in particular within the PDAC group where the presence of jaundice was associated with a significant increase in the levels of all six proteins (P<0.01). Consequently, in the absence of jaundice, proteins showed reduced sensitivity for PDAC patients over benign subjects and healthy controls (HCs). Similarly, in the presence of jaundice, markers showed reduced specificity for PDAC patients over benign subjects with jaundice. Combining markers enabled improved sensitivity for non-jaundiced PDAC patients over HCs and improved specificity for jaundiced PDAC patients over jaundiced benign disease subjects. CONCLUSIONS: The presence-absence of jaundice in the clinical scenario severely impacts the performance of biomarkers for PDAC diagnosis and has implications for their clinical translation.

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.

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.

Predictive performance of factors associated with malignancy in intraductal papillary mucinous neoplasia of the pancreas.

BACKGROUND: Estimation of the risk of malignancy in intraductal papillary mucinous neoplasia (IPMN) of the pancreas is a clinical challenge. Several routinely used clinical factors form the basis of the current consensus guidelines. This study aimed to determine the predictive values of the most commonly assessed risk factors. METHODS: A meta-analysis of individual risk factors of malignancy in IPMN was performed. Contingency tables were derived from these data, and sensitivity, specificity, negative and positive predictive values, and diagnostic odds ratios (DOR) were determined. Hierarchical summary receiver operating characteristic (HSROC) curves for each factor were calculated and the respective area under the curve (AUC) was assessed. RESULTS: A total of 3443 studies were screened initially. Analysis of recent literature revealed 60 studies with 13 relevant risk factors including clinical, serological and radiological parameters. The largest area under the HSROC curve was found for weight loss (0·84) and jaundice/raised bilirubin level (0·80), followed by increased carcinoembryonic antigen (CEA) (0·79) or carbohydrate antigen (CA) 19-9 (0·78) levels. The most sensitive factors were patient age (71 per cent) and mural nodules (65 per cent), and jaundice/raised bilirubin level (97 per cent) and increased CEA level (95 per cent) were most specific. None of the analysed factors reached a positive or negative level of prediction beyond 90 per cent. CONCLUSION: None of the established criteria safely distinguishes malignant from non-malignant lesions.

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.

Surgical treatment of pancreatic cancer: the role of adjuvant and multimodal therapies.

Surgical treatment in specialized referral centers has improved the prognosis of resectable pancreatic cancer considerably despite the generally aggressive behavior of this malignancy. At the same time, adjuvant therapy for pancreatic cancer has been shown to be effective in providing a survival benefit. However, some controversy remains over whether to use chemotherapy alone or combined chemoradiation. Few prospective randomized controlled clinical trials (RCTs) on the use of adjuvant chemotherapy and chemoradiation have demonstrated a distinct survival advantage of systemic chemotherapy (5-FU/FA or gemcitabine) following surgical resection. The most notable published trial is the European Study Group for Pancreatic Cancer (ESPAC)-1 trial. In addition, there are several retrospective analyses and two randomized studies on adjuvant radiation and chemoradiation. Some of these suggested increased survival rates using chemoradiation, which was subsequently widely introduced in clinical routine, especially in the United States. RCTs and a recent meta-analysis of these RCTs confirm, however, the superiority of chemotherapy over chemoradiation, except for a subgroup of patients with positive resection margins. Thus, curative surgery followed by adjuvant systemic chemotherapy should be the standard treatment for patients with resectable, locally confined pancreatic cancer. Further RCTs may clarify potential benefits of chemoradiation in the adjuvant treatment setting. Moreover, the best chemotherapy, or a combination thereof, remains to be determined in large-scale randomized trials.

[Closure of pancreas stump after distal and segmental resection : Suture, stapler, coverage or anastomosis?] / Verschluss des Pankreasstumpfes bei Links- und Segmentresektion : Naht, Stapler, Deckung oder Anastomose?

Postoperative pancreatic fistulas represent the most frequent complication after distal and segmental pancreatectomy and occur with a frequency of up to 50 %. There are many technical variations of pancreatic stump treatment for reduction of fistula rates after distal resection. Most of these techniques have only been analyzed in retrospective studies and the evidence for or against a specific technique is low. Several retrospective trials have been conducted with good results to compare suturing with stapled closure of the remnant and to assess the effect of a vascularized falciform ligament patch in reducing postoperative pancreatic fistula; however, in a recently published randomized trial, which analyzed closure of the remnant with a pancreaticojejunostomy compared to standard closure, these results could not be confirmed. Because stapler resection and closure is the most commonly used technique in laparoscopic distal pancreatectomy, there are a large number of studies which assessed various novel methods of improving stapling. Extended stapler compression time and mesh augmentation of the stapler line can be valid methods to reduce fistula rates. Central pancreatectomy is a relatively rarely used procedure where the right-sided pancreatic remnant is closed in the same fashion as during distal pancreatectomy and the left-sided remnant is connected to the intestines with a pancreaticojejunostomy or pancreaticogastrostomy. In conclusion, postoperative pancreatic fistula rates are still a relevant clinical problem after distal pancreatectomy and further studies on potentially improved novel techniques are required.

Radical surgery of oligometastatic pancreatic cancer.

BACKGROUND: In metastatic disease (M1), chemotherapy (expected survival: 6-10 months) is considered the only treatment option. The aim of this study was to evaluate the outcome of curative M1 PDAC resections. METHODS: Prospective data of all patients undergoing primary tumour and metastasis resection for stage IV PDAC during a 12-year period was analysed regarding localisation (liver or distant interaortocaval lymph nodes; ILN), morbidity and survival. Patients were stratified with regard to syn- or metachronous metastases resection. RESULTS: Patients (n = 128) undergoing PDAC and metastases resection (intention-to-treat, oligometastatic stage; liver n = 85; ILN n = 43) were included. Surgical morbidity and 30-day mortality after synchronous resection of M1 tumours were 45% and 2.9%, respectively. Overall median survival after M1 resection was 12.3 months in both groups. Long-term outcome showed a 5-year survival of 8.1% after surgery for both liver metastases and 10.1% following ILN resection. CONCLUSIONS: The present collective is the largest series of resected metastatic PDAC and shows that resection of liver or ILN metastases can be done safely and should be considered as it may be superior to palliative treatment, and it is associated with long-term survival of 10% in selected patients. Further studies to stratify patients for these procedures are warranted.

In vivo functional dissection of a context-dependent role for Hif1α in pancreatic tumorigenesis.

Hypoxia-inducible factor 1α (Hif1α) is a key regulator of cellular adaptation and survival under hypoxic conditions. In pancreatic ductal adenocarcinoma (PDAC), it has been recently shown that genetic ablation of Hif1α accelerates tumour development by promoting tumour-supportive inflammation in mice, questioning its role as the key downstream target of many oncogenic signals of PDAC. Likely, Hif1α has a context-dependent role in pancreatic tumorigenesis. To further analyse this, murine PDAC cell lines with reduced Hif1α expression were generated using shRNA transfection. Cells were transplanted into wild-type mice through orthotopic or portal vein injection in order to test the in vivo function of Hif1α in two major tumour-associated biological scenarios: primary tumour growth and remote colonization/metastasis. Although Hif1α protects PDAC cells from stress-induced cell deaths in both scenarios-in line with the general function Hif1α-its depletion leads to different oncogenic consequences. Hif1α depletion results in rapid tumour growth with marked hypoxia-induced cell death, which potentially leads to a persistent tumour-sustaining inflammatory response. However, it simultaneously reduces tumour colonization and hepatic metastases by increasing the susceptibility to anoikis induced by anchorage-independent conditions. Taken together, the role of Hif1α in pancreatic tumorigenesis is context-dependent. Clinical trials of Hif1α inhibitors need to take this into account, targeting the appropriate scenario, for example palliative vs adjuvant therapy.

EU Pancreas: an integrated European platform for pancreas cancer research--from basic science to clinical and public health interventions for a rare disease.

BACKGROUND: Large-scale international collaboration is essential to decipher relevant information in the context of omics-scale interrogations in cancer research. This is even more important for rare and fatal diseases like pancreas cancer (PC). METHODS: The COST Action BM1204 is a unique platform to facilitate the collaboration of a broad range of European and international PC multidisciplinary research groups in order to: (1) integrate knowledge and experience in a multidisciplinary way 'from cell to society', (2) promote the application of uniform study tools and protocols, (3) foster their optimal use by early-stage researchers, (4) enhance the mobility and training of researchers, and (5) disseminate the results produced to the broader society. RESULTS: This Action will develop novel interdisciplinary tools for collaborative research to improve our understanding of PC and its prevention, diagnosis and treatment. It also aims to answer questions related to the etiology, early detection, evidence-based and personalized treatment, and health management for PC. Furthermore, the Action will contribute to new insights into PC personalized medicine and beyond as well as to the understanding of complex and rare diseases taking PC as a best practice example. The Action aims at attracting young scholars across a range of disciplines in collaboration with more experienced researchers and enhancing active European participation in the international scenario of PC research. CONCLUSION: The ultimate aim is to foster PC research in Europe and to coordinate this effort with other international initiatives to reduce disease mortality.

Surgical procedure as an inducer of tumor angiogenesis.

Surgical resection is the main treatment modality for the vast majority of patients with locally confined solid tumors. The healing process following surgery necessitates extensive angiogenesis which can be a clinical challenge due to its tumor-promoting effect. In line with this, plasma (serum) levels of several pro-angiogenic factors such as vascular endothelial growth factor (VEGF) and angiopoietin 2 were found to be significantly increased after surgical tumor resection. Furthermore, increased levels of these proangiogenic factors seem to correlate with the extent of surgical wounding; yet, it remains unknown whether minimal-invasive surgery is superior to open surgery in terms of avoiding the pro-angiogenesis response. Derived from various sources (e.g. endothelial cells, cancer cells, fibroblasts and/or immune cells), an increase of these pro-angiogenic factors can occur as early as day one postoperatively and they can remain persistently elevated for up to four weeks. The presence of such proteins not only supports a microenvironment favorable for tumor growth and metastasis, but also protects tumor cells from conventional chemotherapy. Therefore, initiation of anti-angiogenesis therapies has been proposed for the early postoperative period before the start of conventional chemotherapy. Because such a treatment would potentially affect wound and anastomotic healing, the long-term effects and safety issues associated with early postoperative anti-angiogenic therapy require further investigation.

Tumor microenvironment and progression of pancreatic cancer.

Pancreatic ductal adenocarcinoma is characterized by « tumor desmoplasia ¼, a remarkable increase in connective tissue that penetrates and envelopes the neoplasm. It is becoming clear that this desmoplastic microenvironment of pancreatic cancer--which is forming approximately eighty percent of the tumor mass--is not a passive scaffold for the tumor cells but an active player in carcinogenesis. Several chemotherapeutic agents and novel molecular targeted therapies against epithelial tumor cells--although showing antitumor activity in cell culture and mouse experiments--have failed to show significant effects in the clinic. Thus, targeting pancreatic tumor cells alone seems unlikely to improve the dismal prognosis of pancreatic cancer. It has recently been shown that the activated stroma of pancreatic cancer is an independent prognostic marker with an impact on patient survival as much as the lymph node status of the cancer. Several primarily benign conditions associated with expansion of stromal and inflammatory components, such as chronic pancreatitis or hereditary pancreatitis are believed to increase the risk of pancreatic cancer. Similar observations have been made in other cancer types such as chronic hepatitis-liver cancer, Barrett dyplasia-esophageal cancer, and inflammatory bowel disease-colon cancer. The common denominator of all these conditions is; chronic inflammation leads to increased incidence of cancer. In this review the impact of the activated stroma on pancreatic carcinogenesis is discussed.

AZGP1 is a tumor suppressor in pancreatic cancer inducing mesenchymal-to-epithelial transdifferentiation by inhibiting TGF-ß-mediated ERK signaling.

Epithelial-to-mesenchymal transdifferentiation (EMT) mediated by transforming growth factor-ß (TGF-ß) signaling leads to aggressive cancer progression. In this study, we identified zinc-α2-glycoprotein (AZGP1, ZAG) as a tumor suppressor in pancreatic ductal adenocarcinoma whose expression is lost due to histone deacetylation. In vitro, ZAG silencing strikingly increased invasiveness of pancreatic cancer cells accompanied by the induction of a mesenchymal phenotype. Expression analysis of a set of EMT markers showed an increase in the expression of mesenchymal markers (vimentin (VIM) and integrin-α5) and a concomitant reduction in the expression of epithelial markers (cadherin 1 (CDH1), desmoplakin and keratin-19). Blockade of endogenous TGF-ß signaling inhibited these morphological changes and the downregulation of CDH1, as elicited by ZAG silencing. In a ZAG-negative cell line, human recombinant ZAG (rZAG) specifically inhibited exogenous TGF-ß-mediated tumor cell invasion and VIM expression. Furthermore, rZAG blocked TGF-ß-mediated ERK2 phosphorylation. PCR array analysis revealed that ZAG-induced epithelial transdifferentiation was accompanied by a series of concerted cellular events including a shift in the energy metabolism and prosurvival signals. Thus, epigenetically regulated ZAG is a novel tumor suppressor essential for maintaining an epithelial phenotype.

[Middle segmental pancreatic resection: an organ-preserving option for benign lesions]. / Pankreassegmentresektion : Organerhaltende Option bei benignen Läsionen.

Benign and low malignant tumors of the middle pancreatic segment can be resected by extended pancreaticoduodenectomy or distal pancreatic resection. Both procedures involve unavoidably extensive loss of normal pancreatic parenchyma, leading to deteriorated endocrine and exocrine pancreatic function. Segmental pancreatic resection represents an organ-preserving surgical procedure. Normal pancreatic tissue can be preserved as only the tumor with a pancreatic segment is resected. Several reports confirm lower mortality and minimal risk of postoperative endocrine or exocrine insufficiency than with standard pancreatic resections. The indication should be limited exclusively to benign or low malignant pancreatic tumors, metastases from other tumors, and focal chronic pancreatitis, as this type of resection cannot be deemed oncologic. Segmental pancreatic resections are technically more demanding and therefore should be performed in experienced centers.