Gerd Nestler

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.

Low-molecular-weight heparin (reviparin) diminishes tumor cell adhesion and invasion in vitro, and decreases intraperitoneal growth of colonadeno-carcinoma cells in rats after laparoscopy

BACKGROUND Metastases, adhesion and invasion of tumor cells involve a cascade of complex phenomena, which potentially can be affected by glycosaminoglycans. We studied the influence of a low-molecular-weight heparin, reviparin, on the intraabdominal tumor growth in rats undergoing laparoscopy. We also studied cytotoxicity, anti-adhesive, and anti-invasive effects of reviparin in vitro using adenocarcinoma cells CC531. METHODS In vitro assays: Adhesion of 1 x 10(5) CC531 adenocarcinoma cells onto microtiter plates coated with 10 microg/ml collagen type I or 10 microg/ml Matrigel was studied in the presence of 0.55; 1.10 and 2.76 mg/ml reviparin, and compared to saline. The cytotoxicity of 1 x 10(4) adenocarcinoma cells was studied in a similar assay. Transwell dual chambers with polycarbonate filters coated with 100 microg/cm2 Matrigel were used to investigate the effect of 0.55; 1.10 and 2.76 mg/ml reviparin on the invasion of 1 x 10(5) adenocarcinoma cells/ml. In vivo experiments: CC531 adenocarcinoma cells (5 x 10(6) cells/ml) were intraperitoneally applied to Wistar Albino Glaxo rats (n=150, Harlan, Germany) with a median weight of 278 g. The rats were divided into 15 groups with 10 animals in each group, underwent laparoscopy, and 1 ml saline containing 0, 0.5, 2.0, 4.0, and 10 mg reviparin per kg b.w. was introduced for intraperitoneal lavage or s.c. After 21 days the animals underwent an autopsy, and the tumor weight was determined. RESULTS In vitro experiments: We found a highly significant inhibition of tumor cell adhesion and invasion (p<0.001) by all reviparin concentrations used in the assays. There was no effect of reviparin on the viability of cells in the cytoxicity assay. In vivo experiments: We found that application of 4.0 and 10.0 mg/kg b.w., but not 0.5 or 2.0 mg/kg b.w. significantly (p<0.01) decreased the tumor mass compared to controls, receiving only saline. This effect was most pronounced after the combined i.p. and s.c. application, whereas after a sole i.p. application, only the highest dose of 10 mg/kg b.w. caused a significant inhibition of tumor growth. CONCLUSION Low-molecular-weight heparin, reviparin, given in combination of i.p. lavage and s.c. injections, significantly diminishes intraabdominal tumor growth of CC531 adenocarcinoma cells in rats undergoing laparoscopy. This may offer additional therapeutic options for patients undergoing laparoscopic cancer surgery.

[Hartmann's procedure indication in colorectal carcinoma].

ZusammenfassungAnhand der Daten einer prospektiven Multizenterstudie zur operativen Therapie des kolorektalen Karzinoms wird der aktuelle Stellenwert der Diskontinuitätsresektion nach Hartmann im Vergleich zu anderen Operationsverfahren in der Elektiv- und Notfallsituation bei Rektumkarzinomen (n=10.355) und bei Karzinomen am Linkskolon (n=8.825) untersucht. Nur in 3,4% (n=353) der Rektumkarzinome wurde in kurativer Intention eine Hartmann-Operation durchgeführt. Als primäres Operationsverfahren ist es nur für die seltenen Notfälle und für elektive Einzelindikationen (sog. „tiefer Hartmann“ bei „High-risk-Patienten“) zu empfehlen. Im Gegensatz dazu hat die Hartmann-Operation im Rahmen von Obstruktionen und Perforationen am Linkskolon weiterhin eine große Bedeutung, zumal hier die niedrigste Letalitätsrate (7,5%) der radikalen Verfahren festgestellt wurde. In der palliativen Situation wurde bei 449 Rektumkarzinomen (4,3%) primär ein Anus praeter angelegt. Dagegen war am Linkskolon die palliative Segmentkontinuitätsresektion der Elektiveingriff mit der niedrigsten Letalität (6,1%) und Morbidität (33,9%), während im Notfall wiederum die Hartmann-Operation bevorzugt wurde.AbstractBased on data obtained in a prospective, multicenter trial investigating the surgical treatment of colorectal carcinomas, the aim of this study was to investigate the value and relevance of Hartmann’s procedure compared with alternative surgical approaches in elective interventions and emergency situations in carcinoma of the rectum (n=10,355) and the left hemicolon (n=8,825). Only in 3.4% (n=353) of patients with rectal carcinoma was the Hartmann’s procedure executed with curative intention, indicating that this approach is recommendable only in (1) rare emergency situations (1.66%, n=172), (2) selected cases with elective intervention such as high-risk patients or subjects with poor prognosis, and (3) individuals with rectal carcinoma of the lower third who require deep resection (2+3, 1.75%, n=181). However, Hartmann’s procedure resulted in the lowest mortality (7.5%) of the various procedures aiming for radical resection in the case of luminal obstruction or perforation at the left hemicolon. With palliative intention, 4.3% of patients with rectal carcinoma (n=449) received primary colostomies. At the left hemicolon, palliative segmental colon resection with primary anastomosis maintaining intestinal passage showed the lowest mortality (6.1%) and perioperative morbidity (33.9%) under elective circumstances, whereas Hartmann’s procedure was preferred in emergency situations.

Die Hartmann-Operation

ZusammenfassungAnhand der Daten einer prospektiven Multizenterstudie zur operativen Therapie des kolorektalen Karzinoms wird der aktuelle Stellenwert der Diskontinuitätsresektion nach Hartmann im Vergleich zu anderen Operationsverfahren in der Elektiv- und Notfallsituation bei Rektumkarzinomen (n=10.355) und bei Karzinomen am Linkskolon (n=8.825) untersucht. Nur in 3,4% (n=353) der Rektumkarzinome wurde in kurativer Intention eine Hartmann-Operation durchgeführt. Als primäres Operationsverfahren ist es nur für die seltenen Notfälle und für elektive Einzelindikationen (sog. „tiefer Hartmann“ bei „High-risk-Patienten“) zu empfehlen. Im Gegensatz dazu hat die Hartmann-Operation im Rahmen von Obstruktionen und Perforationen am Linkskolon weiterhin eine große Bedeutung, zumal hier die niedrigste Letalitätsrate (7,5%) der radikalen Verfahren festgestellt wurde. In der palliativen Situation wurde bei 449 Rektumkarzinomen (4,3%) primär ein Anus praeter angelegt. Dagegen war am Linkskolon die palliative Segmentkontinuitätsresektion der Elektiveingriff mit der niedrigsten Letalität (6,1%) und Morbidität (33,9%), während im Notfall wiederum die Hartmann-Operation bevorzugt wurde.AbstractBased on data obtained in a prospective, multicenter trial investigating the surgical treatment of colorectal carcinomas, the aim of this study was to investigate the value and relevance of Hartmann’s procedure compared with alternative surgical approaches in elective interventions and emergency situations in carcinoma of the rectum (n=10,355) and the left hemicolon (n=8,825). Only in 3.4% (n=353) of patients with rectal carcinoma was the Hartmann’s procedure executed with curative intention, indicating that this approach is recommendable only in (1) rare emergency situations (1.66%, n=172), (2) selected cases with elective intervention such as high-risk patients or subjects with poor prognosis, and (3) individuals with rectal carcinoma of the lower third who require deep resection (2+3, 1.75%, n=181). However, Hartmann’s procedure resulted in the lowest mortality (7.5%) of the various procedures aiming for radical resection in the case of luminal obstruction or perforation at the left hemicolon. With palliative intention, 4.3% of patients with rectal carcinoma (n=449) received primary colostomies. At the left hemicolon, palliative segmental colon resection with primary anastomosis maintaining intestinal passage showed the lowest mortality (6.1%) and perioperative morbidity (33.9%) under elective circumstances, whereas Hartmann’s procedure was preferred in emergency situations.

Effect of Intraperitoneal Application of an Endotoxin Inhibitor on Survival Time in a Laparoscopic Model of Peritonitis in Rats

Gram-negative sepsis due to fecal peritonitis is a hazardous disease with a high percentage having a lethal course. The inflammatory effects are induced by endotoxin release. We performed this study to evaluate the potential of direct intraperitoneal application of an endotoxin inhibitor in a laparoscopic peritonitis model in rats. The human feces specimen was prepared, and a standard fecal specimen (0.5 ml/kg b.w.) was applied via minilaparotomy. The rats were randomized to two studies. First, rats were randomized to three groups to define the survival time: (1) rats without further manipulation; (2) rats with laparoscopic lavage using NaCl; (3) rats with laparoscopic lavage using endotoxin inhibitor. Second, rats underwent the same procedure used in the first part of the study and an additional group with only NaCl lavage without peritonitis was randomized. To evaluate the immunologic or biochemical effects, animals were killed at a standard time of 20 hours until the postmortem examination was established. Interleukins 6 and 10 (IL-6, IL-10), malondialdehyde, and protein carbonyl group levels in plasma and particularly in peritoneal fluid were assayed. The first part of the experiment showed significantly increased survival after endotoxin inhibitor lavage. In the second part, administration of endotoxin inhibitor intraperitoneally caused a significant reduction of IL-6 in the peritoneal fluid, in contrast to that in the other groups. Laparoscopic application of endotoxin inhibitor intraperitoneally thus produced a beneficial effect on survival and reduction of IL-6 in peritoneal fluid. Hence, it is possible to influence the inflammation cascade by causing intraperitoneal endotoxin inhibition.

Intraperitoneale Applikation von Gefitinib inhibiert das Tumorwachstum der Kolonkarzinomzelllinie CC 531 im laparoskopischen Rattenmodell

Moglicherweise stellt die von uns gewahlte direkte Applikation eine zusatzliche Alternative im Behandlungskonzept des Kolonkarzinoms dar. Die Potenz von Tyrosinkinaseinhibitoren beim Kolonkarzinom ist unklar und sollte unbedingt weiter evaluiert werden. Ansatzpunkte sind die Prufung einer optimalen Dosierung, der Intervalle und die Kombination mit zytostatischen Substanzen.