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Abstract 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

Abstract Background We have identified syndecan-2 as a protein potentially involved in perineural invasion of pancreatic adenocarcinoma (PDAC) cells. Methods Syndecan-2 (SDC-2) expression was analyzed in human normal pancreas, chronic pancreatitis and PDAC tissues. Functional in vitro assays were carried out to determine its role in invasion, migration and signaling. Results SDC-2 was expressed in the majority of the tested pancreatic cancer cell lines while it was upregulated in nerve-invasive PDAC cell clones. There were 2 distinct expression patterns of SDC-2 in PDAC tissue samples: SDC-2 positivity in the cancer cell cytoplasm and a peritumoral expression. Though SDC-2 silencing (using specific siRNA oligonucleotides) did not affect anchorage-dependent growth, it significantly reduced cell motility and invasiveness in the pancreatic cancer cell lines T3M4 and Su8686. On the transcriptional level, migration-and invasion-associated genes were down-regulated following SDC-2 RNAi. Furthermore, SDC-2 silencing reduced K-ras activity, phosphorylation of Src and - further downstream - phosphorylation of ERK2 while levels of the putative SDC-2 signal transducer p120GAP remained unaltered. Conclusion SDC-2 is a novel (perineural) invasion-associated gene in PDAC which cooperates with K-ras to induce a more invasive phenotype.

Abstract 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.

Abstract Background Tissue fibrosis is an integral component of chronic inflammatory (liver and pancreas) diseases and pancreatic cancer. Activated pancreatic- (PSC) and hepatic- (HSC) stellate cells play a key role in fibrogenesis. To identify organ- and disease-specific stellate cell transcriptional fingerprints, we employed genome-wide transcriptional analysis of primary human PSC and HSC isolated from patients with chronic inflammation or cancer. Methods Stellate cells were isolated from patients with pancreatic ductal adenocarcinoma (n = 5), chronic pancreatitis (n = 6), liver cirrhosis (n = 5) and liver metastasis of pancreatic ductal adenocarcinoma (n = 6). Genome-wide transcriptional profiles of stellate cells were generated using our 51K human cDNA microarray platform. The identified organ- and disease specific genes were validated by quantitative RT-PCR, immunoblot, ELISA, immunocytochemistry and immunohistochemistry. Results Expression profiling identified 160 organ- and 89 disease- specific stellate cell transcripts. Collagen type 11a1 (COL11A1) was discovered as a novel PSC specific marker with up to 65-fold higher expression levels in PSC compared to HSC (p < 0.0001). Likewise, the expression of the cytokine CCL2 and the cell adhesion molecule VCAM1 were confined to HSC. PBX1 expression levels tend to be increased in inflammatory- vs. tumor- stellate cells. Intriguingly, tyrosine kinase JAK2 and a member of cell contact-mediated communication CELSR3 were found to be selectively up-regulated in tumor stellate cells. Conclusions We identified and validated HSC and PSC specific markers. Moreover, novel target genes of tumor- and inflammation associated stellate cells were discovered. Our data may be instrumental in developing new tailored organ- or disease-specific targeted therapies and stellate cell biomarkers.

Abstract Background Costimulatory signaling has been implicated as a potential regulator of antitumor immunity in various human cancers. In contrast to the negative prognostic value of aberrant B7-H1 expression by pancreatic cancer cells, the role of B7-H3 is still unknown. Therefore, we investigated the expression pattern and clinical significance of B7-H3 expression in human pancreatic cancer. Methods B7-H3 expression was evaluated by immunohistochemistry in 68 patients with pancreatic cancer who underwent surgical tumor resection. Expression data was correlated with clinicopathologic features and with the number of tumor-infiltrating T cells. Results B7-H3 expression was significantly upregulated in pancreatic cancer compared to normal pancreas (p < 0.05). In 60 of 68 examined tumors B7-H3 protein was detectable in pancreatic cancer cells. Patients with high tumor B7-H3 levels had a significantly better postoperative prognosis than patients with low tumor B7-H3 levels (p = 0.0067). Furthermore, tumor B7-H3 expression significantly correlated with the number of tumor-infiltrating CD8+ T cells (p = 0.018). Conclusion We demonstrate for the first time that B7-H3 is abundantly expressed in pancreatic cancer and that tumor-associated B7-H3 expression significantly correlates with prolonged postoperative survival. Our findings suggest that B7-H3 might play an important role as a potential stimulator of antitumor immune response in pancreatic cancer.

Abstract Background Interactions between mononuclear cells and activated pancreatic myofibroblasts (pancreatic stellate cells; PSC) may contribute to inflammation and fibrosis in chronic pancreatitis (CP). Methods Markers of fibrosis and inflammation were concomitantly analysed by immunohistochemistry in chronic pancreatitis tissues. In vitro, PSC were stimulated with TNFalpha and LPS. Primary human blood mononuclear cells (PBMC) and PSC were cocultured, followed by analysis of cytokines and extracellular matrix (ECM) proteins. PBMC were derived from healthy donors and CP and septic shock patients. Results In areas of mononuclear cell infiltration in chronic pancreatitis tissues, there was decreased immunoreactivity for collagen1 and fibronectin, in contrast to areas with sparse mononuclear cells, although PSC were detectable in both areas. LPS and TNFalpha induced collagen1 and fibronectin levels as well as the matrix degradation enzyme MMP-1. Coculture experiments with PSC and PBMC revealed increased fibronectin secretion induced by PBMC. In addition, donor and CP PBMC significantly induced an increase in IL-6, MCP-1 and TGFbeta levels under coculture conditions. Determination of the source of cytokines and ECM proteins by mRNA expression analysis confirmed PSC as major contributors of ECM production. The increase in cytokine expression was PBMC- and also PSC-derived. Conclusion Mononuclear cells modulate the activity of pancreatic stellate cells, which may in turn promote fibrosis and inflammation.

Abstract Background Bone gamma-carboxyglutamate protein (BGLAP; osteocalcin) is a small, highly conserved molecule first identified in the mineralized matrix of bone. It has been implicated in the pathophysiology of various malignancies. In this study, we analyzed the expression and role of BGLAP in the normal human pancreas, chronic pancreatitis (CP), and pancreatic ductal adenocarcinoma (PDAC) using quantitative RT-PCR, immunohistochemistry, immunocytochemistry and enzyme immunoassays, as well as cell proliferation and invasion assays. Gene silencing was carried out using specific siRNA molecules. Results Compared to the normal pancreas, BGLAP mRNA and protein levels were not significantly different in CP and PDAC tissues. BGLAP was faintly present in the cytoplasm of normal acinar cells but was strongly expressed in the cytoplasm and nuclei of tubular complexes and PanIN lesions of CP and PDAC tissues. Furthermore, BGLAP expression was found in the cancer cells in PDAC tissues as well as in 4 cultured pancreatic cancer cell lines. TNFalpha reduced BGLAP mRNA and protein expression levels in pancreatic cancer cell lines. In addition, BGLAP silencing led to reduction of both cell growth and invasion in those cells. Conclusion BGLAP is expressed in pancreatic cancer cells, where it potentially increases pancreatic cancer cell growth and invasion through autocrine and/or paracrine mechanisms.

Abstract Background Anti-angiogenic treatment is believed to have at least cystostatic effects in highly vascularized tumours like pancreatic cancer. In this study, the treatment effects of the angiogenesis inhibitor Cilengitide and gemcitabine were compared with gemcitabine alone in patients with advanced unresectable pancreatic cancer. Methods A multi-national, open-label, controlled, randomized, parallel-group, phase II pilot study was conducted in 20 centers in 7 countries. Cilengitide was administered at 600 mg/m2 twice weekly for 4 weeks per cycle and gemcitabine at 1000 mg/m2 for 3 weeks followed by a week of rest per cycle. The planned treatment period was 6 four-week cycles. The primary endpoint of the study was overall survival and the secondary endpoints were progression-free survival (PFS), response rate, quality of life (QoL), effects on biological markers of disease (CA 19.9) and angiogenesis (vascular endothelial growth factor and basic fibroblast growth factor), and safety. An ancillary study investigated the pharmacokinetics of both drugs in a subset of patients. Results Eighty-nine patients were randomized. The median overall survival was 6.7 months for Cilengitide and gemcitabine and 7.7 months for gemcitabine alone. The median PFS times were 3.6 months and 3.8 months, respectively. The overall response rates were 17% and 14%, and the tumor growth control rates were 54% and 56%, respectively. Changes in the levels of CA 19.9 went in line with the clinical course of the disease, but no apparent relationships were seen with the biological markers of angiogenesis. QoL and safety evaluations were comparable between treatment groups. Pharmacokinetic studies showed no influence of gemcitabine on the pharmacokinetic parameters of Cilengitide and vice versa. Conclusion There were no clinically important differences observed regarding efficacy, safety and QoL between the groups. The observations lay in the range of other clinical studies in this setting. The combination regimen was well tolerated with no adverse effects on the safety, tolerability and pharmacokinetics of either agent.

Abstract Background The proteolysis-inducing factor (PIF) was identified as a tumour product in various gastrointestinal cancers. A previous study in pancreatic cancer patients suggested PIF expression as a tumour marker, which is not related to tumour size. We hypothesized that PIF could be a useful marker to exclude benign pancreatic tumors, as chronic pancreatitis with a pancreatic mass. Methods Urine of patients with a pancreatic mass of uncertain malignancy was investigated for PIF expression by Western blot. Sufficient urine protein for analysis was available in 59 patients. The diagnosis was established by histology in 54 patients and by follow up in five patients with chronic pancreatitis. In addition, serum CA19-9 was measured. Results The sensitivity (specifity) for the detection of a malignant pancreatic tumour was 90% (75%) and 54% (71%) for CA19-9 and PIF, respectively. The sensitivity (specifity) for the distinction of pancreatic cancer from chronic pancreatitis was 89% (80%) and 57% (63%) for CA19-9 and PIF, respectively. Conclusion Evaluation of PIF in urine is of no diagnostic value in patients with a pancreatic mass of unknown malignancy.

Abstract Hsulf-1 is a newly identified enzyme, which has the ability to decrease the growth of hepatocellular, ovarian, and head and neck squamous cell carcinoma cells by interfering with heparin-binding growth factor signaling. Since pancreatic cancers over-express a number of heparin-binding growth factors and their receptors, the expression and function of this enzyme in pancreatic cancer was analyzed. Results Pancreatic cancer samples expressed significantly (22.5-fold) increased Hsulf-1 mRNA levels compared to normal controls, and Hsulf-1 mRNA was localized in the cancer cells themselves as well as in peritumoral fibroblasts. 4 out of 8 examined pancreatic cancer cell lines expressed Hsulf-1, whereas its expression was below the level of detection in the other cell lines. Stable transfection of the Hsulf-1 negative Panc-1 pancreatic cancer cell line with a full length Hsulf-1 expression vector resulted in increased sulfatase activity and decreased cell-surface heparan-sulfate proteoglycan (HSPG) sulfation. Hsulf-1 expression reduced both anchorage-dependent and -independent cell growth and decreased FGF-2 mediated cell growth and invasion in this cell line. Conclusion High expression of Hsulf-1 occurs in the stromal elements as well as in the tumor cells in pancreatic cancer and interferes with heparin-binding growth factor signaling.

Abstract Background Melanoma inhibitory activity (MIA) is a small secreted protein that interacts with extracellular matrix proteins. Its over-expression promotes the metastatic behavior of malignant melanoma, thus making it a potential prognostic marker in this disease. In the present study, the expression and functional role of MIA was analyzed in pancreatic cancer by quantitative real-time PCR (QRT-PCR), immunohistochemistry, immunoblot analysis and ELISA. To determine the effects of MIA on tumor cell growth and invasion, MTT cell growth assays and modified Boyden chamber invasion assays were used. Results The mRNA expression of MIA was 42-fold increased in pancreatic cancers in comparison to normal pancreatic tissues (p < 0.01). In contrast, MIA serum levels were not significantly different between healthy donors and pancreatic cancer patients. In pancreatic tissues, MIA was predominantly localized in malignant cells and in tubular complexes of cancer specimens, whereas normal ductal cells, acinar cells and islets were devoid of MIA immunoreactivity. MIA significantly promoted the invasiveness of cultured pancreatic cancer cells without influencing cell proliferation. Conclusion MIA is over-expressed in pancreatic cancer and has the potential of promoting the invasiveness of pancreatic cancer cells.

Abstract Background Pancreatic cancer is an aggressive malignancy characterized by low responsiveness to chemotherapy and radiotherapy. This resistance is partly due to the overexpression of several tyrosine kinase receptors and their ligands. STI571 has specific activity in inhibiting c-kit, PDGF and Abl receptor tyrosine kinases and has proven successful in the treatment of CML and GIST patients. Here, we investigated the potential role of STI571 in pancreatic cancer. Results The GI50 of STI571 as well as the effects of STI571 on growth factor actions in pancreatic cell lines were analyzed using the MTT assay. FACS analysis using Annexin and PI staining was performed to study cell cycle, apoptosis, and cell death. Western blot analysis was carried out to investigate MAP kinase and receptor tyrosine kinase phosphorylation. STI571 inhibited cell proliferation in pancreatic cancer cell lines with GI50 concentrations ranging from 17 to 31.5 microM. EGF, IGF-1, and FGF-2 but not PDGF exerted growth stimulatory effects in pancreatic cancer cell lines. STI571 only partly blocked these effects on cell growth, and did not abrogate growth factor-induced receptor and MAPK phosphorylation. Conclusion Our data demonstrate that STI571 inhibits pancreatic cancer cell growth with high GI50 concentrations through tyrosine-kinase receptor independent pathways. The clinical application of STI571 in pancreatic cancer is therefore rather doubtful.

The aim of this study was to analyse and compare the outcome of open surgery (OS) and endovascular repair (ER) for the treatment of visceral artery aneurysms (VAA). A systematic literature search was carried out. 25 comparative cohort studies with 4447 patients (2469 OS and 1978 ER) were included in the meta-analysis. Mortality (ER vs OS 1.8% vs 2.1%, OR.77, 95% CI [.51; 1.17], P =.23) and technical success rates (97% vs 98%, OR.50, 95% CI [.21; 1.16], P =.11) were comparable between both groups. Lower mortality rates for ER were observed for ruptured aneurysms (4.1% vs 31%, OR.43 95% CI [.13; 1.43], P =.17). Length of stay was shorter (mean difference −4.25 days, 95% CI [−5.52; −2.98], P <.00001) and 1-year reintervention rates were higher in the ER group (9% vs 5%, OR 1.55 95% CI [.58; 4.12], P =.38. The presented evidence suggests that ER should be considered a first-line treatment for VAAs, especially in an emergency setting, due to lower morbidity and comparable mortality and technical success. Follow-up should be offered to these patients due to the higher reintervention rates. Systematic review registration: PROSPERO ID 348699 [ABSTRACT FROM AUTHOR]