Oral CPSI-2364 Treatment Prevents Postoperative Ileus in Swine without Impairment of Anastomotic Healing

Background: Postoperative ileus (POI) is an iatrogenic complication of abdominal surgery, mediated by a severe inflammation of the muscularis externa (ME). We demonstrated that orally applicated CPSI-2364 prevents POI in rodents by blockade of p38 MAPK pathway and abrogation of NO production in macrophages. In the present experimental swine study we compared the effect of orally and intravenously administered CPSI-2364 on POI and examined CPSI-2364 effect on anastomotic healing. Methods: CPSI-2364 was administered preoperatively via oral or intravenous route. POI was induced by intestinal manipulation of the small bowel. ME specimens were examined by quantitative PCR for CCL2 chemokine gene expression and myeloperoxidase activity. Functional analyzes included measurement of ileal smooth-muscle ex vivo contractility, in vivo intestinal and colonic transit. Furthermore, anastomotic healing of a rectorectostomy after CPSI-2364 treatment was assessed by perianastomotic hydroxyproline concentration, a histochemically evaluated healing score and anastomotic bursting pressure (ABP). Results: CPSI-2364 abolished inflammation of the ME and improved postoperative smooth muscle contractility and intestinal transit independently of its application route. Hydroxyproline concentration and ABP measurement revealed no wound healing disturbances after oral or intravenous CPSI-2364 treatment whereas histological scoring demonstrated delayed anastomotic healing after intravenous treatment. Conclusion: CPSI-2364 effectively prevents POI in swine independently of its application route. Impairment of anastomotic healing could be observed after intravenous but not oral preoperative CPSI-2364 treatment. Subsumed, an oral preoperative administration of CPSI-2364 appears to be a safe and efficient strategy for prophylaxis of POI

Clinical Performance of CEA, CA19-9, CA15-3, CA125 and AFP in Gastrointestinal Cancer Using LOCI (TM)-based Assays

Background/Aim: Few data are available regarding the clinical performance of LOCI (TM)-based tumor marker assays. We investigated the diagnostic power of carcinogenic antigen, carbohydrate antigen 19-9, carbohydrate antigen 15-3, carbohydrate antigen 125 and alpha-fetoprotein for detection of gastrointestinal (GI) cancer. Patients and Methods: We analyzed sera from 204 patients (107 with GI cancer, 73 with benign GI diseases and 24 healthy controls) using the Dimension (TM) Vista1500 analyzer. Results: Levels of biomarkers in healthy controls were in the expected ranges and were only slightly higher in benign GI controls. Established tumor-type-associated markers were elevated in specific cancer types and discriminated well between cancer and benign controls. Best performance was found for CEA in colorectal cancer (area under the curve=0.84, sensitivity=51.7% at 95% specificity vs. benign), CA19-9 in gallbladder/pancreatic cancer (AUC=0.85, sensitivity=60.6%) and AFP in liver cancer (AUC=0.87, sensitivity=68.4%). Conclusion: Our study demonstrated the high diagnostic power of well-known biomarkers. LOCI (TM)-based tumor marker assays give reliable results in routine diagnostics

Non-invasive transcutaneous auricular vagus nerve stimulation prevents postoperative ileus and endotoxemia in mice

Background: The cholinergic anti-inflammatory pathway comprises the perception of peripheral inflammation by afferent sensory neurons and reflex activation of efferent vagus nerve activity to regulate inflammation. Activation of this pathway was shown to reduce the inflammatory response and improve outcome of postoperative ileus (POI) and sepsis in rodents. Herein, we tested if a non-invasive auricular electrical transcutaneous vagus nerve stimulation (tVNS) affects inflammation in models of POI or endotoxemia. Methods: Mice underwent tVNS or sham stimulation before and after induction of either POI by intestinal manipulation (IM) or endotoxemia by lipopolysaccharide administration. Some animals underwent a preoperative right cervical vagotomy. Neuronal activation of the solitary tract nucleus (NTS) and the dorsal motor nucleus of the vagus nerve (DMV) were analyzed by immunohistological detection of c-fos+ cells. Gene and protein expression of IL-6, MCP-1, IL-1β as well as leukocyte infiltration and gastrointestinal transit were analyzed at different time points after IM. IL-6, TNFα, and IL-1β serum levels were analyzed 3 hours after lipopolysaccharide administration. Results: tVNS activated the NTS and DMV and reduced intestinal cytokine expression, reduced leukocyte recruitment to the manipulated intestine segment, and improved gastrointestinal transit after IM. Endotoxemia-induced IL-6 and TNF-α release was also reduced by tVNS. The protective effects of tVNS on POI and endotoxemia were abrogated by vagotomy. Conclusion: tVNS prevents intestinal and systemic inflammation. Activation of the DMV indicates an afferent to efferent central circuitry of the tVNS stimulation and the beneficial effects of tVNS depend on an intact vagus nerve. tVNS may become a non-invasive approach for treatment of POI