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The field of pancreatic stellate cell (PSC) biology is very young, as the essential in-vitro tools to study these cells (ie, methods to isolate and culture PSC) were only developed as recently as in 1998. Nonetheless, there has been an exponential increase in research output in this field over the past decade, with numerous research groups around the world focusing their energies into elucidating the biology and function of these cells. It is now well established that PSC are responsible for producing the stromal reaction (fibrosis) of two major diseases of the pancreas—chronic pancreatitis and pancreatic cancer. Despite exponentially increasing data, the methods for studying PSC remain variable. Although within individual laboratories methods are consistent, different methodologies used by various research groups make it difficult to compare results and conclusions. This article is not a review article on the functions of PSC. Instead, members of the Pancreatic Star Alliance (http://www.pancreaticstaralliance.com) discuss here and consolidate current knowledge, to outline and delineate areas of consensus or otherwise (eg, with regard to methodological approaches) and, more importantly, to identify essential directions for future research. Hepatic stellate cells (HSC) were first described by Karl von Kupffer in 1876; however, similar cells in the pancreas were first observed in the 1980s.1–3 In 1998, Apte et al 4 and Bachem et al 5 isolated and cultured PSC.4 5 In the normal pancreas, PSC are located in close proximity to the basal aspect of pancreatic acinar cells. In sections immunostained for the marker desmin (a cytoskeletal protein), quiescent PSC can be seen as cells with a central cell body and long cytoplasmic projections extending along the base of adjacent acinar cells similar to that of pericytes in the mammary gland. …

The cyclic adenosine monophosphate-inducible basic helix-loop-helix (bHLH) domain containing class-B2 transcriptional factor BHLHB2 is differentially expressed in a number of human malignancies. In the present study, the expression, regulation, functions and prognostic impact of BHLHB2 in pancreatic cancer were investigated.Expression analyses were carried out in tissues of the normal pancreas (n=10) and pancreatic ductal adenocarcinoma (n=77) as well as in eight pancreatic cancer cell lines using quantitative RT-PCR, semiquantitative immunohistochemistry, and immunoblot analyses. In vitro functional experiments were conducted using siRNA transfection, hypoxia, serum starvation, apoptosis induction with gemcitabine and actinomycin-D, and invasion assays. Survival analysis was performed using the Kaplan-Meier method. Prognostic factors were determined in a multivariable analysis using a Cox proportional hazards model.BHLHB2 mRNA and protein expressions were strongly induced by hypoxia and by serum starvation in pancreatic cancer cell lines. BHLHB2 silencing with RNAi had no significant effects on growth and invasion but increased apoptosis resistance against gemcitabine by reducing caspace-3 cleavage. In BHLHB2 silenced cells the ED50 of gemcitabine increased from 13.95 ± 1.353 to 38.70 ± 5.262 nM (p0.05). Ex vivo, the weak/absent nuclear staining in normal pancreatic ducts and acinar cells was replaced by moderate to strong nuclear/cytoplasmic staining in PanIN lesions and pancreatic cancer cells. Patients with weak/absent nuclear BHLHB2 staining had significantly worse median survival compared to those with strong staining (13 months vs. 27 months, p=0.03). In a multivariable analysis, BHLHB2 staining was an independent prognostic factor (Hazard-Ratio=2.348, 95% CI=1.250-4.411, p=0.008).Hypoxia-inducible BHLHB2 expression is a novel independent prognostic marker in pancreatic cancer patients and indicates increased chemosensitivity towards gemcitabine.

The purpose of this study is to determine the value of diffusion-weighted MR imaging (DWI) in the detection of liver metastases in patients with pancreatic tumors when compared to multidetector-row CT (MDCT).DWI and MDCT were performed in 31 consecutive patients with newly diagnosed, potentially resectable pancreatic tumors. CT images were obtained in the arterial and the portal venous phase. For DWI, a respiratory-triggered single-shot echo-planar imaging sequence (b values: 0, 300, and 600 s/mm(2)) was acquired. Images were analyzed in consensus by two radiologists blinded to the clinical data. Imaging results were correlated with intraoperative surgical and ultrasound findings as well as with results of histopathologic analysis and imaging follow-up.Sensitivity and specificity in detecting liver metastases were 53.3% and 77.8% for MDCT and 86.7% and 97.5% for DWI, respectively. In our study population DWI would have changed the therapeutic management in 4 out of 31 patients (12.9%) when compared to MDCT.In the present pilot study, DWI performed significantly better than MDCT in the detection of liver metastases in patients with pancreatic tumors. Therefore, DWI may help to optimize therapeutic management in those patients in the future.

Background and Aims Pancreatic ductal adenocarcinoma (PDAC) is a highly desmoplastic tumor with an innate resistance to therapy. Pancreatic stellate cells (PSCs) produce this excessively desmoplastic microenvironment. The impact of PSC activity on PDAC behavior in vivo is analyzed. Methods 233 patients who underwent surgery for PDAC were evaluated by immunohistochemistry using antibodies against α-smooth muscle actin as a marker of PSC activity. Aniline was used to stain collagen deposition. The ratio of α-smooth muscle actin–stained area to collagen-stained area was defined as the activated stroma index (ASI). Survival analysis was performed using the Kaplan–Meier method. Prognostic factors were determined in a multivariable analysis using a Cox proportional hazards model. Results Four major patterns of collagen deposition were defined with regard to PSC activity. The combination of high stromal activity and low collagen deposition was associated with a worse prognosis, whereas the combination of high collagen deposition and low stromal activity indicated a better prognosis. Patients with the lowest ASI had the best median survival rate (25.7 mo). The highest ASI was found in patients with the worst median survival rate (16.1 mo; P = .007; lowest vs highest ASI: hazard ratio, 1.61; 95% confidence interval, 1.014–2.562). ASI was an independent prognostic marker in multivariable survival analysis comparable with the nodal status of cancer. Conclusions The activated stroma index is a novel independent prognostic marker in PDAC in cases undergoing surgery. This finding highlights the impact of the microenvironment in cancer progression and on patient survival.

Although centralization of complex surgical procedures such as pancreaticoduodenectomies is associated with a reduction in morbidity and mortality rates, it is unclear whether such surgeries are adequately represented in the German disease-related group (DRG) system.Out of all patients who underwent pancreatic resections (n = 450) at our institution between January 2008 and November 2011, 76 patients who underwent a pylorus-preserving pancreatic head resection due to pancreatic head adenocarcinoma were selected for analysis. The revenues generated by these surgical procedures were compared with those of 144 patients who had undergone elective laparoscopic cholecystectomies for symptomatic gallstone disease between January 2009 and September 2010 in our hospital.In patients undergoing pylorus-preserving pancreaticoduodenectomy, revenues per case were 1,585.55 Euros, with an average length of hospital stay (ALOS) of 19.9 days (range 7-55 days) and an average postoperative hospital stay of 16 days; however, if the ALOS was exceeded, expenditures increasingly exceeded returns. Analysis of the cohort of patients with pylorus-preserving pancreaticoduodenectomies demonstrated average revenues per day of 79.27 Euros. In contrast, for laparoscopic cholecystectomy, which was treated with high surgical standardization and stringent case management, the ALOS was only 2.8 days, producing average revenues of 288.80 Euros per day and total revenues of 817.53 Euros per case.At university hospitals, cost-effective realization of major pancreatic surgery is difficult, while highly standardized surgeries such as laparoscopic cholecystectomies can be performed at a favorable balance. This may be due to, firstly, an underrepresentation of university hospitals in the German DRG calculation basis and, secondly, to a relatively long preoperative hospital stay as a result of extensive diagnostic measures. We consider this kind of preoperative assessment paramount for an academic pancreatic center and thus argue for an increased reimbursement for these procedures.

Around 95% of patients diagnosed with pancreatic cancer will die of their disease within 5 years, three quarters within a year. The major hurdle in improving prognosis is the lack of a therapeutic time window. Early cancerous lesions are far beneath our threshold of detection. Therefore, at the time of diagnosis even early (T1) tumors can be metastatic and resistant to conventional treatments. Several therapies targeting epithelial tumor cells-all showing impressive results in vitro and in animal experiments-have failed to show relevant effects in clinical trials. This discrepancy between experimental data and clinical reality results mostly from the inefficiency of our current experimental setups in recreating the tumor microenvironment. Forming more than 80% of the tumor mass, the fibrotic stroma of pancreatic ductal adenocarcinoma is not a passive scaffold for the malignant cells but an active player in carcinogenesis. This component is mostly missing in the xeno-/allograft- mouse models. Although tumors are bigger if stellate cells are co-implanted, due to the disproportionate cancer/stromal cell ratio and -possibly- too rapid tumor growth, the stromal reaction is much smaller than in human pancreatic cancer. One the other hand, desmoplasia is present only in some of the genetically engineered mouse models. Clinically, stromal activity of the pancreatic ductal adenocarcinoma has as great an impact on patient prognosis as the lymph node status of the tumor. The exact molecular mechanisms behind this observation remain obscure. However, one possible fundamental biologic explanation could be that selective pressure applied by the stroma leads to the evolution of cancer cells. Consequently, somatic evolution of invasive cancer could be viewed as a sequence of phenotypical adaptations to this barrier, highlighting the importance of the fibrotic tumor microenvironment in the behavior of pancreatic cancer. In this review, the interaction of the epithelial tumor cells with the stroma in humans and in various animal models is scrutinized, and novel therapeutic options for uncoupling cancer-stroma interactions are discussed.

Pigment epithelium-derived factor (PEDF) is a noninhibitory member of the serine protease inhibitor gene family with neuroprotective, neuroproliferative, and anti-angiogenic functions. Its role in pancreatic fibrosis and neuropathy is unknown.The expression and localization of PEDF were assessed by quantitative real-time (RT)-PCR, immunohistochemistry, and quantitative image analysis and correlated with neural and microvessel densities (MVDs) in the normal pancreas (n=20) and pancreatic cancer (n=55). Primary human pancreatic stellate cells (PSCs), mouse neuroblastoma, and human Schwann cells were used for functional experiments. The effect of hypoxia on PEDF production in cancer cell lines and immortalized pancreatic ductal epithelial cells was assessed by quantitative RT-PCR and enzyme-linked immunosorbent assay. The effect of recombinant PEDF on PSCs was assessed by immunoblot analysis.PEDF expression was homogeneous in epithelial cells of the normal pancreas where some acinar cells consistently displayed stronger staining. A higher expression was found in tubular complexes, PanIN lesions, and inflammatory cells in pancreatic cancer. Cancer cells expressed various levels of PEDF. In cancer cell lines and in human immortalized pancreatic ductal epithelial cells, hypoxia increased PEDF mRNA up to 132-fold. Higher expression of PEDF in cancer cells was significantly correlated with better patient survival (median survival 21.5 months vs. 17.5 months, P=0.043), increased neuropathy (P=0.0251), increased PSC activity, and extracellular matrix protein production.PEDF increases PSC activity, thereby contributing to the desmoplasia of pancreatic cancer. PSC overactivation likely leads to periacinar fibrosis and degeneration of fine acinar innervation. Increased focal PEDF expression in cancer cells correlates with neuropathic changes and better patient survival.

Background Colonic intussusception is a rare congenital abnormality, mostly manifesting before the age of two with abdominal pain and acute intestinal obstruction with or without bleeding. In adults it may occur idiopathically or due to an intraluminal tumor mass. Case presentation A 25-year-old man presented with an acute abdomen and severe crampy abdominal pain. The clinical picture mimicked acute appendicitis. Transabdominal ultrasound examination revealed a 5 cm circular mass in the right upper abdomen. The ensuing computed tomography suggested an intussusception in the ascending colon. Intraoperatively, no full thickness invagination was detected. Due to a hard, intraluminal tumor a standard right hemicolectomy with ileotransversostomy was performed. The histopathological analysis revealed a cystic colon duplication leading to mucosal invagination and obstruction. Conclusions In adults, colon intussusception is a rare event causing approximately 1% of all acute intestinal obstructions. Unlike its preferentially nonsurgical management in children, a bowel intussusception in adults should be operated because an organic, often malignant lesion is present in most cases.

76-year-old man with a single episode of diarrhea dis-played an increased CA 19-9 value on routine laboratoryexaminations. The patient did not complain of pain, jaundice,weight loss, diabetes mellitus, or steatorrhea. Over a period of 1year the CA 19-9 value increased continuously from 59 to 1149U/mL (normal value, 37 U/mL). Endosonography, repeated ab-dominal computerized tomography scans (Figure

BACKGROUND AND AIMS: Although both cancer and stellate cells (PSCs) secrete proangiogenic factors, pancreatic cancer is a scirrhous and hypoxic tumor. The impact of cancer-PSCs interactions on angiogenesis was analyzed. METHODS: Expression of periostin, CD31, and alpha-smooth muscle actin was assessed by immunohistochemistry. Human PSCs and cancer cells were cultivated under normoxia and hypoxia alone, or in coculture, to analyze the changes in their angiogenic and fibrogenic attributes, using enzyme-linked immunosorbent assay, immunoblot, and quantitative polymerase chain reaction analyses and growth of cultured endothelial cells in vitro. RESULTS: On the invasive front of the activated stroma, PSCs deposited a periostin-rich matrix around the capillaries in the periacinar spaces. Compared with the normal pancreas, there was a significant reduction in the microvessel density in chronic pancreatitis (five-fold, P < .001) and pancreatic cancer (four-fold, P < .01) tissues. In vitro, hypoxia increased PSCs' activity and doubled the secretion of periostin, type I collagen, fibronectin, and vascular endothelial growth factor (VEGF). Cancer cells induced VEGF secretion of PSCs (390 +/- 60%, P < .001), whereas PSCs increased the endostatin production of cancer cells (210 +/- 14%, P < .001) by matrix metalloproteinase-dependent cleavage. In vitro, PSCs increased the endothelial cell growth, whereas cancer cells alone, or their coculture with PSCs, suppressed it. CONCLUSIONS: Although PSCs are the dominant producers of VEGF and increase endothelial cell growth in vitro, in the peritumoral stroma, they contribute to the fibrotic/hypoxic milieu through abnormal extracellular matrix deposition and by amplifying endostatin production of cancer cells.

Background Postoperative surgical site infections cause substantial morbidity, prolonged hospitalization, costs and even mortality and remain one of the most frequent surgical complications. Approximately 14% to 30% of all patients undergoing elective open abdominal surgery are affected and methods to reduce surgical site infection rates warrant further investigation and evaluation in randomized controlled trials. Methods/design To investigate whether the application of a circular plastic wound protector reduces the rate of surgical site infections in general and visceral surgical patients that undergo midline or transverse laparotomy by 50%. BaFO is a randomized, controlled, patient-blinded and observer-blinded multicenter clinical trial with two parallel surgical groups. The primary outcome measure will be the rate of surgical site infections within 45 days postoperative assessed according to the definition of the Center for Disease Control. Statistical analysis of the primary endpoint will be based on the intention-to-treat population. The global level of significance is set at 5% (2 sided) and sample size (n = 258 per group) is determined to assure a power of 80% with a planned interim analysis for the primary endpoint after the inclusion of 340 patients. Discussion The BaFO trial will explore if the rate of surgical site infections can be reduced by a single, simple, inexpensive intervention in patients undergoing open elective abdominal surgery. Its pragmatic design guarantees high external validity and clinical relevance. Trial registration http://www.clinicaltrials.gov NCT01181206. Date of registration: 11 August 2010; date of first patient randomized: 8 September 2010