Rene Hennig

5-Lipoxygenase and Leukotriene B4 Receptor Are Expressed in Human Pancreatic Cancers But Not in Pancreatic Ducts in Normal Tissue

The 5-lipoxygenase (5-LOX) pathway is critical for pancreatic cancer cell growth and escape from apoptosis. Inhibition of 5-LOX blocks proliferation and induces apoptosis in human pancreatic cancer cells. However, the expression of 5-LOX and its downstream signaling pathway have not been investigated in human pancreatic adenocarcinoma. Reverse transcriptase-polymerase chain reaction revealed expression of 5-LOX mRNA in all pancreatic cancer cell lines tested including, PANC-1, AsPC-1, and MiaPaCa2 cells, but not in normal pancreatic ductal cells. The expression of 5-LOX protein in pancreatic cancer cell lines was demonstrated by Western blotting. Finally, 5-LOX up-regulation in human pancreatic cancer tissues was verified by intense positive staining in cancer cells by immunohistochemistry. Staining for the 5-LOX protein was particularly evident in the ductal components of the more differentiated tumors but not in ductal cells in normal pancreatic tissues from cadaver donors. Immunohistochemistry also revealed strong staining of cancer tissues with an antibody to the receptor of the downstream 5-LOX metabolite, leukotriene B(4). The current study demonstrated marked expression of 5-LOX and the leukotriene B(4) receptor in human pancreatic cancer tissues. These findings provide further evidence of up-regulation of this pathway in pancreatic cancer and that LOX inhibitors are likely to be valuable in the treatment of this dreadful disease.

Lipoxygenase and cyclooxygenase metabolism: new insights in treatment and chemoprevention of pancreatic cancer

The essential fatty acids, linoleic acid and arachidonic acid play an important role in pancreatic cancer development and progression. These fatty acids are metabolized to eicosanoids by cyclooxygenases and lipoxygenases. Abnormal expression and activities of both cyclooxygenases and lipoxygenases have been reported in pancreatic cancer. In this article, we aim to provide a brief summary of (1) our understanding of the roles of these enzymes in pancreatic cancer tumorigenesis and progression; and (2) the potential of using cyclooxygenase and lipoxygenase inhibitors for pancreatic cancer treatment and prevention.

5-Lipoxygenase, a Marker for Early Pancreatic Intraepithelial Neoplastic Lesions

Pancreatic cancer has an abysmal prognosis because of late diagnosis. Therefore, it is important to identify risk factors if we are to be able to prevent and detect this cancer in an early, noninvasive stage. Pancreatic intraepithelial neoplasias (PanIN) are the precursor lesions which could be an ideal target for chemoprevention. This study shows up-regulation of 5-lipoxygenase (5-LOX) in all grades of human PanINs and early lesions of pancreatic cancer in two different animal models (EL-Kras mice and N -nitrosobis(2-oxopropyl)amine–treated hamsters) by immunohistochemistry. The results were consistent in all tissues examined, including seven chronic pancreatitis patients, four pancreatic cancer patients, one multiorgan donor, nine EL-Kras mice, and three N -nitrosobis(2-oxopropyl)amine–treated hamsters, all with PanINs. Overexpression of 5-LOX in NIH3T3 cells resulted in greater sensitivity of these cells to the growth inhibitory effects of the 5-LOX inhibitor Rev5901. These findings provide evidence that 5-LOX plays a key role in the development of pancreatic cancer. Furthermore, the lipoxygenase pathway may be a target for the prevention of this devastating disease.

Effectiveness of triclosan-coated PDS Plus versus uncoated PDS II sutures for prevention of surgical site infection after abdominal wall closure: the randomised controlled PROUD trial

BACKGROUND Postoperative surgical site infections are one of the most frequent complications after open abdominal surgery, and triclosan-coated sutures were developed to reduce their occurrence. The aim of the PROUD trial was to obtain reliable data for the effectiveness of triclosan-coated PDS Plus sutures for abdominal wall closure, compared with non-coated PDS II sutures, in the prevention of surgical site infections. METHODS This multicentre, randomised controlled group-sequential superiority trial was done in 24 German hospitals. Adult patients (aged ≥18 years) who underwent elective midline abdominal laparotomy for any reason were eligible for inclusion. Exclusion criteria were impaired mental state, language problems, and participation in another intervention trial that interfered with the intervention or outcome of this trial. A central web-based randomisation tool was used to randomly assign eligible participants by permuted block randomisation with a 1:1 allocation ratio and block size 4 before mass closure to either triclosan-coated sutures (PDS Plus) or uncoated sutures (PDS II) for abdominal fascia closure. The primary endpoint was the occurrence of superficial or deep surgical site infection according to the Centers for Disease Control and Prevention criteria within 30 days after the operation. Patients, surgeons, and the outcome assessors were masked to group assignment. Interim and final analyses were by modified intention to treat. This trial is registered with the German Clinical Trials Register, number DRKS00000390. FINDINGS Between April 7, 2010, and Oct 19, 2012, 1224 patients were randomly assigned to intervention groups (607 to PDS Plus, and 617 to PDS II), of whom 1185 (587 PDS Plus and 598 PDS II) were analysed by intention to treat. The study groups were well balanced in terms of patient and procedure characteristics. The occurrence of surgical site infections did not differ between the PDS Plus group (87 [14·8%] of 587) and the PDS II group (96 [16·1%] of 598; OR 0·91, 95% CI 0·66-1·25; p=0·64). Serious adverse events also did not differ between the groups-146 of 583 (25·0%) patients treated with PDS Plus had at least one serious adverse event, compared with 138 of 602 (22·9%) patients treated with PDS II; p=0·39). INTERPRETATION Triclosan-coated PDS Plus did not reduce the occurrence of surgical site infection after elective midline laparotomy. Innovative, multifactorial strategies need to be developed and assessed in future trials to reduce surgical site infections. FUNDING Johnson & Johnson Medical Limited.

Staging Laparoscopy and Its Indications in Pancreatic Cancer Patients

Background: Laparoscopy has become a popular and widespread surgical technique. An important goal in the treatment of patients with pancreatic cancer is to avoid any unnecessary procedure. Laparoscopy has been suggested as a routine tool for staging in order to prevent unnecessary laparotomies in these patients. Methods: In this article we present our experience regarding the value of laparoscopic staging and review the literature on this topic. Results and Conclusion: A direct and conclusive comparison of the controversial literature is difficult because of different study designs. Inconsistent use of high-quality CT scans significantly affects the results. However, recent studies reveal that not more than 14% of the patients benefit from diagnostic laparoscopy when a state-of-the-art CT scan has been performed previously. Therefore, we conclude that routine diagnostic laparoscopy is not justified in all patients with pancreatic cancer. Rather, selective use is appropriate, especially in patients in whom ascites is an indirect sign of peritoneal metastases, or if liver metastases cannot be surely excluded preoperatively. This approach is cost-effective and limits diagnostic laparoscopy to a subgroup of patients in whom a laparotomy can be avoided.

Delayed gastric emptying and intestinal hormones following pancreatoduodenectomy.

Background/Aims: Delayed gastric emptying (DGE) is frequently reported in patients following pancreatoduodenectomy (PD). The present study tested the hypothesis that gastrointestinal hormones known to effect gastric emptying contribute to DGE in patients after PD. Methods: Patients with (delayed, n = 9) or without clinical signs of DGE (non-delayed, n = 22) after PD were investigated. Plasma concentrations of motilin, glucagon-like peptide-1 (GLP-1), neurotensin, and peptide YY (PYY) and the gastric emptying rate (GER), assessed by the paracetamol absorption method were measured after a liquid meal on postoperative day 11. Results: Days with a nasogastric tube (p < 0.01), days until solid food was tolerated (p < 0.05), and hospital stay (p < 0.001) were increased in delayed compared to non-delayed patients. The total and incremental integrated peptide responses of motilin and GLP-1 were similar, but the responses of neurotensin and PYY were reduced, in delayed compared to non-delayed patients, whether considered on clinical grounds or by measured GER (p < 0.05–0.005). Conclusion: Neurotensin and PYY slow the rate of gastric emptying in humans. Therefore, our findings suggest that reduced hormone responses were the consequence of DGE arising from delayed delivery of nutrients to the distal intestine where the endocrine cells secrete neurotensin and PYY reside.

The Role of PPARgamma Receptors and Leukotriene B(4) Receptors in Mediating the Effects of LY293111 in Pancreatic Cancer.

Pancreatic cancer is a devastating disease in which current therapies are inadequate. Separate lines of research have identified the 5-lipoxygenase/leukotriene B4 receptor pathway and the PPARγ pathway as potential targets for prevention or treatment of this disease. LY293111 was originally designed as a potent leukotriene B4 receptor antagonist for treatment of inflammatory conditions. LY293111 was also known to have inhibitory effects on 5-lipoxygenase, which is upstream of the production of leukotrienes. LY293111 was shown to have potent anticancer effects in pancreatic cancer and several other solid malignancies, where it caused cell cycle arrest and marked apoptosis. Subsequently, it came to light that LY293111 exhibited PPARγ agonist activity in addition to its effects on the 5-lipoxygenase pathway. This raises the question of which of the two targets is of greatest importance with regard to the anticancer effects of this agent. The evidence to date is not conclusive, but suggests that the effects of LY293111 may be mediated by both LTB4 receptors and PPARγ.

Pancreatic polypeptide in pancreatitis.

Pancreatitis is a disease with increasing incidence which can be divided into an acute and a chronic form. In both acute and chronic pancreatitis, changes in plasma concentration of pancreatic polypeptide (PP) and its regulation have been reported. In daily clinical work a serologic test for the precise diagnosis and staging of acute and chronic pancreatitis is still desirable. Therefore, many studies have investigated plasma concentrations of PP in acute and chronic pancreatitis as a diagnostic marker and as a therapeutic option to treat pancreatogenic diabetes mellitus. Although the study results are presently inconclusive and potentially contradictory, the findings are nevertheless encouraging, and indicate that PP might have a role in diagnosis, grading and estimation of the prognosis of pancreatitis. Further data and prospective controlled studies are needed to judge whether PP is of clinical value for diagnosing, staging and predicting long-term outcome in acute and chronic pancreatitis.

Association between gallstone-evoked pain, inflammation and proliferation of nerves in the gallbladder: A possible explanation for clinical differences

Objective. To investigate whether enhanced neuroproliferation could be involved in the pathogenesis of gallstone pain. Material and methods. Gallbladders from 117 patients with gallstones and 43 controls were examined. The gallbladder samples were immunostained against the pan-neuronal marker PGP 9.5 and the number of nerves and nerve area per tissue area estimated. Results. More nerves and an increased nerve area per tissue area were found in uncomplicated symptomatic gallstone disease. In comparison, acute cholecystitis displayed a significantly (p=0.01) decreased number of nerves and nerve area per tissue area. In both categories, the gallbladder neck contained more nerves (p=0.06 and 0.04, respectively) and an increased nerve area per tissue area (p=0.034 and 0.008, respectively) than the body. Conclusions. Uncomplicated disease showed enhanced neuroproliferation, significantly more in the gallbladder neck, whereas significantly fewer nerves were observed in acute cholecystitis. Nerve growth alteration may play a role in uncomplicated gallstone pain but the pathology may be different in inflammation.

Leukotriene B4 Rezeptor 2 (BLT2) — ein spezifischer Marker und Promoter in der Pankreaskarzinogenese?

Introduction: Pancreatic cancer has an abysmal prognosis because of its late diagnosis and lack of response to available therapeutics. Incidence almost equals mortality. Pancreatic intraepithelial neoplasias (PanINs) and intraductal papillary mucinous neoplasias (IPMNs) are precursor lesions which could be an ideal target for chemoprevention. Obesity and high fat intake are risk factors for the development of pancreatic cancer. The arachidonic acid pathway plays a key role. Overexpression of cyclooxygenase-2 (COX-2) in transgenic mice promotes the development of pancreatic cancer, a process inhibited by COX-2 inhibitors. Furthermore, 5-lipoxygenase (5-LOX) is pro-tumorigenic and overexpressed in PanINs, IPMNs and pancreatic adenocarcinoma. Leukotriene B4 (LTB4) as a product of the 5-LOX metabolism stimulates tumor cell growth and insulin secretion. The expression and role of the second LTB4 receptor (BLT2) was unknown and therefore, aim of this study. Materials and Methods: Expression of BLT2 was investigated in pancreatic cancer cell lines and human pancreatic tissues (10 normal pancreas, 10 chronic pancreatitis, 10 pancreatic adenocarcinoma and 38 IPMNs) by real time RT-PCR and immunohistochemistry. Cell proliferation was studied by cell counting and Wst-1 assay in Colo357, Panc-1 and AsPC1 cells after stable transfection with BLT2 to cause overexpression of this receptor and after treatment with siRNA, Compound A as an agonist and LY255283 as an antagonist. Results: BLT2 is expressed in all pancreatic cancer cell lines. Results from real-time RT-PCR revealed significant overexpression of BLT2 in malignant IPMNs and pancreatic adenocarcinoma. Intense staining for BLT2 was evident in infiltrating tumor cells and advanced PanINs (> PanIN-1b) in 10/10 cancer and 1/10 pancreatitis tissues but not in normal ductal cells or PanIN-1a lesions (9 pancreatitis and 10 normal tissues). BLT2 was expressed in all IPMNs. Specificity of the antibody was demonstrated by using a blocking peptide. Overexpression of BLT2 as well as stimulation of Colo357, Panc-1 and AsPC1 cells with Compound A caused a significant increase in tumor cell proliferation, an effect reversed after siRNA treatment. Blocking BLT2 with LY255283 also significantly inhibited tumor cell growth. Conclusion: This study demonstrates for the first time expression of BLT2 in the pancreas and overexpression in pancreatic cancers and malignant IPMNs in particular. Furthermore, up-regulation of BLT2 is already evident in precursor lesions (PanINs, IPMNs). Overexpressing this receptor or stimulation of BLT2 enhances proliferation of cancer cells. In contrast, the BLT2 antagonist LY255283 inhibits tumor cell growth. These findings provide evidence that BLT2 serves as a specific marker and tumor promoter in pancreatic carcinogenesis. BLT2 antagonists may be a new tool for prevention and therapy in the fight against pancreatic cancer.