H. Lippert

Role of cathepsin B in intracellular trypsinogen activation and the onset of acute pancreatitis

Autodigestion of the pancreas by its own prematurely activated digestive proteases is thought to be an important event in the onset of acute pancreatitis. The mechanism responsible for the intrapancreatic activation of digestive zymogens is unknown, but a recent hypothesis predicts that a redistribution of lysosomal cathepsin B (CTSB) into a zymogen-containing subcellular compartment triggers this event. To test this hypothesis, we used CTSB-deficient mice in which the ctsb gene had been deleted by targeted disruption. After induction of experimental secretagogue-induced pancreatitis, the trypsin activity in the pancreas of ctsb(-/-) animals was more than 80% lower than in ctsb(+/+) animals. Pancreatic damage as indicated by serum activities of amylase and lipase, or by the extent of acinar tissue necrosis, was 50% lower in ctsb(-/-) animals. These experiments provide the first conclusive evidence to our knowledge that cathepsin B plays a role in intrapancreatic trypsinogen activation and the onset of acute pancreatitis.

Comparison of 17,641 Patients With Right- and Left-Sided Colon Cancer: Differences in Epidemiology, Perioperative Course, Histology, and Survival

PURPOSE: There is a growing amount of data suggesting that carcinomas of the right and left colon should be considered as different tumor entities. Using the data and analysis compiled in the German multicentered study “Colon/Rectum Cancer,” we aimed to clarify whether the existing differences influence clinical and histological parameters, the perioperative course, and the survival of patients with right- vs left-sided colon cancer. METHODS: During a 3-year period data on all patients with colon cancer were evaluated. Right- and left-sided cancers were compared regarding the following parameters: demographic factors, comorbidities, and histology. For patients who underwent elective surgery with curative intent, the perioperative course and survival were also analyzed. RESULTS: A total of 17,641 patients with colon carcinomas were included; 12,719 underwent curative surgery. Patients with right-sided colon cancer were significantly older, and predominantly women with a higher rate of comorbidities. Mortality was significantly higher for this group. Final pathology revealed a higher percentage of poorly differentiated and locally advanced tumors. Rate of synchronous distant metastases was comparable. However, hepatic and pulmonary metastases were more frequently found in left-sided, peritoneal carcinomatosis in right-sided carcinomas. Survival was significantly worse in patients with right-sided carcinomas on an adjusted multivariate model (odds ratio, 1.12). CONCLUSIONS: We found that right- and left-sided colon cancers are significantly different regarding epidemiological, clinical, and histological parameters. Patients with right-sided colon cancers have a worse prognosis. These discrepancies may be caused by genetic differences that account for distinct carcinogenesis and biological behavior. The impact of these findings on screening and therapy remains to be defined.

Protective defunctioning stoma in low anterior resection for rectal carcinoma

Anastomotic leak is a serious complication of resection for low rectal carcinoma.

Endoscopic treatment of thoracic esophageal anastomotic leaks by using silicone-covered, self-expanding polyester stents

BACKGROUND Surgery, as well as conservative treatment, in patients with clinically apparent intrathoracic esophageal anastomotic leaks often is associated with poor results and carries a high morbidity and mortality. The successful treatment of esophageal anastomotic insufficiencies and perforations when using covered, self-expanding metallic stents is described. METHODS The feasibility and the outcome of endoscopic treatment of intrathoracic anastomotic leakages when using silicone-covered self-expanding polyester stents were investigated. Twelve consecutive patients presented with clinically apparent intrathoracic esophageal anastomotic leak caused by resection of an epiphrenic diverticulum (n = 1), esophagectomy for esophageal cancer (n = 9), or gastrectomy for gastric cancer (n = 2), were endoscopically treated in our department. The extent of the dehiscences ranged from about 20% to 70% of the anastomotic circumference. After endoscopic lavage and debridement of the leakage at 2-day intervals (mean duration, 8.6 days), a large-diameter polyester stent (Polyflex; proximal/distal diameters 25/21 mm) was placed to seal the leakage. Simultaneously, the periesophageal mediastinum was drained by chest drains. OBSERVATIONS All 12 patients were successfully treated endoscopically without the need for reoperation. A complete closure of the leakage was obtained in 11 of 12 patients after stent removal (median time to stent retrieval, 4 weeks, range 2-8 weeks). In one patient, a persistent leak was sealed endoscopically after stent removal by using 3 clips. Distal stent migration was obtained in two patients. CONCLUSIONS The placement of silicone-covered self-expanding polyester stents seems to be a successful minimally invasive treatment option for clinically apparent intrathoracic esophageal anastomotic leaks.

Value of a Protective Stoma in Low Anterior Resections for Rectal Cancer

AbstractINTRODUCTION: Anastomotic leakage is a major problem in colorectal surgery and in particular in operations for low rectal cancer. The present study investigates the question whether a protective stoma can reduce the (clinical and radiologic) anastomotic leakage rate and/or the rate of leakage requiring surgery. METHODS: The investigation took the form of a prospective multicenter study involving 75 German hospitals and was performed between January 1, 1999, and December 31, 1999. A comparison was made of the postoperative results of procedures performed with and those performed without a protective stoma in patients undergoing low anterior rectal resection. In addition, logistic regression using the target criteria, overall anastomotic leakage and anastomotic leakage requiring surgery, was applied. RESULTS: Among the 3,695 operations performed for carcinoma of the rectum or colon, 482 were low anterior resections. In 334 patients (69.3 percent) no protective stoma was constructed, whereas 148 (30.7 percent) received such protection. Age, American Society of Anesthesiologists physical status, and body mass index were identical in both groups. In the group receiving a protective stoma, however, neoadjuvant radiochemotherapy was more common, the tumors were lower—and thus the total mesorectal excision rate higher, the intraoperative complication rate was higher, and the duration of the operation was longer. The differences were all significant. The major criterion (overall anastomotic leakage rate) was identical in the two groups, but the rate of leakage requiring surgery was significantly lower in patients receiving a protective stoma (P = 0.028). The logistic regression revealed that use of a protective stoma is a predictor of protection against anastomotic leakage requiring surgery. The distance of the tumor from the anal verge and the duration of the operation are further predictors. CONCLUSION: The particular benefit of a covering stoma is reduction in the rate of leaks requiring surgery and thus in the severe consequences of an anastomotic leakage.

Immunomodulation by perioperative administration of n -3 fatty acids

It has been increasingly reported that administration of n-3 fatty acids is beneficial in patients with inflammatory processes. This effect is most likely caused by different biological characteristics, including an immunomodulating effect of the products derived from n-3 fatty acids through eicosanoid metabolism. The aim of this study was to investigate the effect of perioperative administration of n-3 fatty acids on inflammatory and immune responses as well as on the postoperative course of patients with extended surgical interventions of the abdomen. In particular, the effect of n-3 fatty acids on interleukin-6 release and on granulocyte/monocyte function (HLA-DR expression) was studied. There was a downregulation of the inflammatory response, and, simultaneously, a smaller postoperative immune suppression in the n-3 fatty acid group. In addition, we observed shorter postoperative periods in the intensive care unit and on the regular medical wards as well as lower rates of severe infections. The results suggest that perioperative administration of n-3 fatty acids may have a favourable effect on outcome in patients with severe surgical interventions by lowering the magnitude of inflammatory response and by modulating the immune response.

In vivo studies comparing the biocompatibility of various polypropylene meshes and their handling properties during endoscopic total extraperitoneal (TEP) patchplasty: an experimental study in pigs

Background: Polypropylene (PP) meshes are currently being used in millions of operations for hernial repair. We tested several recently modified PP meshes to evaluate them in terms of their biocompatibility and handling characteristics during minimally invasive procedures. Methods: Four different PP meshes (a heavyweight PP, Atrium; a lightweight PP incorporating absorbable polyglactic acid, Vypro II; a lightweight PP, Parietene; and a titanium-coated lightweight PP, Ti-Mesh Extralight), all implanted using the endoscopic total extrapreperitoneal (TEP) technique, were investigated in groups comprising 11 pigs each. After 94 ± 5 days, the animals were autopsied and tissue samples were studied histologically, immunohistochemically, and electron-microscopically. Results: Whereas endoscopic handling of the Vypro II mesh proved difficult, the already good properties of the Atrium mesh were significantly improved on by Parietene and the Ti-Mesh. Clear differences were also found in the shrinkage characteristics of the implant materials. In comparison with Atrium (12%), Vypro II mesh shrinkage was significantly greater (28%), whereas Parietene (7%) and Ti-Mesh (5%) incurred less shrinkage. With regard to the chronic inflammatory reaction, the titanium-coated mesh showed a significantly lower inflammatory activity (13.1% partial volume [%PV] vs 34.1%PV and 29.0%PV) than the lightweight meshes Vypro II and Parietene, but—with the exception of the monocytic (0.2 vs 9.1, 5.1, and 7.9) and B-lymphocytic reaction (1.1 vs 18.0, 11.7, and 12.2)—no significant difference was seen in comparison with Atrium. The various mediators in the extracellular matrix (matrix metalloproteinases 1 [MMP-1 transforming growth factor beta [TGF-β], urokinase plasminogen activator [uPA], and type I collagen) tended to show the highest expression with Vypro II (13.6, 113.2, 132.7, and 139.5, respectively) and the lowest expression with Ti-Mesh (11.9, 68.5, 92.8, and 75.0, respectively). With regard to cell proliferation, Parietene and Ti-Mesh appeared to have slight advantages, but no differences were observed in the apoptotic rate. Conclusion: In our opinion, despite a reduction in material, Vipro II, on account of the inflammatory reaction, does not represent a true improvement over the meshes currently used for hernia repair. In comparison, the two lightweight PP patches are characterized by a more favorable foreign body reaction, with the titanium coating of the Ti-Mesh providing an additional advantage in terms of its biocompatibility.

Impact of anastomotic leakage on oncological outcome after rectal cancer resection

Anastomotic leakage has a major impact on morbidity and mortality in rectal cancer surgery. Its relevance to oncological outcome is controversial. This observational study investigated the influence of anastomotic leakage on oncological outcome.

Endoscopic treatment of clinically symptomatic leaks of thoracic esophageal anastomoses

BACKGROUND The mortality of thoracic anastomotic leakage following esophageal reconstruction has been reported to be as high as 60%. Early septic fulminant suture line leaks require rethoracotomy. In addition, however, clinically symptomatic leaks may also occur 2 to 7 days after resection of the esophagus. METHODS Among 80 esophageal reconstructions performed between January 1994 and July 1998, a total of 7 (8.75%) clinically apparent leaks of thoracic anastomoses were observed. The standard treatment consisted of endoscopic lavage, drainage and subsequent closure of the defect by repeated intraluminal and submucosal applications of fibrin glue. In 2 patients a novel approach permitting rapid closure by plugging the fistula with a Vicryl-cylinder was tried. In 4 patients the effect of endoscopic treatment on the HLA-DR expression on monocytes was investigated and compared to 6 patients with intact anastomoses. RESULTS All 7 patients were successfully treated via endoscopy. The cylinder plug achieved immediate closure of the leak. The measured change in HLA-DR expression reflected the improvement in the inflammatory response and thus documented the success of endoscopic treatment. CONCLUSIONS Endoscopic management of thoracic leakages represents a safe and relatively noninvasive therapeutic option.

Thymoquinone Triggers Inactivation of the Stress Response Pathway Sensor CHEK1 and Contributes to Apoptosis in Colorectal Cancer Cells

There are few reports describing the role of p53-dependent gene repression in apoptotic cell death. To identify such apoptosis-associated p53 target genes, we used the pro-oxidant plant-derived drug thymoquinone and compared p53+/+ and p53-/- colon cancer cells HCT116. The p53 wild-type (wt) status correlated with more pronounced DNA damage and higher apoptosis after thymoquinone treatment. A significant up-regulation of the survival gene CHEK1 was observed in p53-/- cells in response to thymoquinone due to the lack of transcriptional repression of p53. In p53-/- cells, transfection with p53-wt vector and CHEK1 small interfering RNA treatment decreased CHEK1 mRNA and protein levels and restored apoptosis to the levels of the p53+/+ cells. p53-/- cells transplanted to nude mice treated with thymoquinone up-regulated CHEK1 expression and did not undergo apoptosis unlike p53+/+ cells. Immunofluorescence analysis revealed that the apoptosis resistance in p53-/- cells after thymoquinone treatment might be conveyed by shuttling of CHEK1 into the nucleus. We confirmed the in vivo existence of this CHEK1/p53 link in human colorectal cancer, showing that tumors lacking p53 had higher levels of CHEK1, which was accompanied by poorer apoptosis. CHEK1 overexpression was correlated with advanced tumor stages (P = 0.03), proximal tumor localization (P = 0.02), and worse prognosis (1.9-fold risk, univariate Cox regression; Kaplan-Meier, P = 0.04). We suggest that the inhibition of the stress response sensor CHEK1 might contribute to the antineoplastic activity of specific DNA-damaging drugs.