J. Ordemann

Inhibition of peritoneal tumor cell growth and implantation in laparoscopic surgery in a rat model

BACKGROUND The pathogenesis of portsite recurrences after laparoscopic surgery is still unknown, and a generally accepted approach to prevent tumor implantation does not exist. METHODS The effect of taurolidine and heparin on growth of colon adenocarcinoma DHD/K12/TRb was measured in vitro and in vivo. After incubation of the cells with heparin or taurolidine or both substances, cell kinetics were determined. In a rat model (n = 60), tumor cells were administered intraperitoneally, and pneumoperitoneum was established over 30 minutes. Rats received tumor cells, tumor cells + heparin, tumor cells + taurolidine, or tumor cells + taurolidine + heparin. RESULTS In vitro, tumor cell growth decreased after incubation with taurolidine and taurolidine/heparin. In vivo, intraperitoneal tumor weight was lower in rats receiving heparin (298 +/- 155 mg) and taurolidine (149 +/- 247 mg) compared with the control group (596 +/- 278 mg) but even less when both substances were combined (21.5 +/- 36 mg). CONCLUSION Heparin inhibits intraperitoneal tumor growth in vivo slightly, while taurolidine causes significant decrease of tumor cell growth in vitro as well as tumor take and intraperitoneal tumor growth in vivo.

New Therapeutic Strategies to Avoid Intra- and Extraperitoneal Metastases during Laparoscopy: Results of a Tumor Model in the Rat

Background: Therapeutic strategies to prevent port site recurrences in laparoscopy surgery of malignancies have not been investigated until now. Methods: The effects of taurolidine, heparin, and povidone iodine on the growth of rat and human colon adenocarcinoma as well as gallbladder carcinoma were investigated in vitro. Furthermore, cytokine release of growth-stimulating IL-1β by peritoneal macrophages was measured after incubation with carbon dioxide and additional incubation with the different agents. In the third experiment, prevention of intra- and extraperitoneal metastases by intraperitoneal instillation of the different agents during laparoscopy was investigated in a colon carcinoma model in the rat. Tumor cells were administered intraperitoneally in 100 rats, and pneumoperitoneum (8 mm Hg) was established over 30 min with carbon dioxide. Rats received either tumor cells, cells + heparin, cells + povidone iodine, cells + taurolidine, or cells + taurolidine + heparin. Results: In vitro, tumor cell growth decreased after incubation with taurolidine, taurolidine/heparin, and povidone iodine. Cytokine release was stimulated by incubation with carbon dioxide and could only be suppressed by incubation with taurolidine in vitro. In vivo, intraperitoneal tumor weight was lower in rats receiving heparin (251 ± 153 mg) and povidone iodine (134 ± 117 mg) compared to the control group (541 ± 291 mg), but even less when taurolidine (79 ± 82 mg) or taurolidine/heparin (18.3 ± 30 mg) were instilled. Conclusion: Heparin slightly inhibits intraperitoneal tumor growth in vivo, while povidone iodine and taurolidine cause a significant decrease in tumor cell growth in vitro as well as intraperitoneal tumor growth in vivo. Cytokine release of peritoneal macrophages is only suppressed by taurolidine. Total tumor take and trocar metastases are only suppressed by taurolidine and taurolidine/heparin.

The Impact of Laparoscopy with Carbon Dioxide versus Helium on Immunologic Function and Tumor Growth in a Rat Model

Background: The pathogenesis of port site recurrences after laparoscopic surgery for malignant disease is still unknown. Whether different gases used to establish pneumoperitoneum have an influence on immunologic function and therefore on promotion of tumor growth has not yet been investigated. Methods: Tumor growth of colon adenocarcinoma DHD/K12/TRb was evaluated in a rat model after insufflation either with CO2 (n = 25) or helium (n = 25) and in a control group (n = 25). Tumor growth was measured subcutaneously and intraperitoneally 5 weeks after insufflation. Beside tumor growth, immunologic changes (peripheral leukocyte subpopulations, plasma levels of TNFα and IL-10) were evaluated during the perioperative course in all animals. Results: Subcutaneous tumor growth was promoted by the CO2 (99 ± 55 mg; p < 0.01) compared to the helium (40 ± 41 mg) and control groups (36 ± 33 mg). Total intraperitoneal tumor weight was 718 ± 690 mg in the CO2 group compared to the helium (549 ± 233 mg) and control groups (521 ± 221 mg). While peripheral leukocyte subpopulations only differed between the laparoscopic groups and the control group during the perioperative course, TNFα plasma levels were significantly decreased and IL-10 plasma levels significantly increased in the CO2 group compared to the helium and control groups in the postoperative course. Conclusion: The insufflation of CO2 promotes tumor growth compared to the helium and control groups in a rat model. In addition, increased tumor growth was associated with a significant increase in IL-10 and a decrease in TNFα plasma levels.

The influence of laparotomy and laparoscopy on tumor growth in a rat model

AbstractBackground: The effects of laparotomy and laparoscopy with different gases on subcutaneous and intraperitoneal tumor growth have not been evaluated yet. Methods: Tumor growth of colon adenocarcinoma DHD/K12/TRb was measured in rats after laparotomy, laparoscopy with CO2 or air, and in control group. Cell kinetics were determined after incubation with carbon dioxide or air in vitro and tumor growth was measured subcutaneously and intraperitoneally after surgery in vivo. Results: In vitro, tumor cell growth increased significantly after incubation with air and CO2. In vivo, intraperitoneal tumor weight was increased after laparotomy (1,203 ± 780 mg) and after laparoscopy with air (1,085 ± 891 mg) and with CO2 (718 ± 690 mg) compared to control group (521 ± 221 mg) (p < 0.05). Subcutaneous tumor growth was promoted after laparotomy (71 ± 35 mg) and even more after laparoscopy with air (82 ± 45 mg) and CO2 (99 ± 55 mg) compared to control group (36 ± 33 mg). Conclusions: Insufflation of air and CO2 promote tumor growth in vitro. In vivo, intraperitoneal tumor growth seems to be promoted primarily by intraperitoneal air and subcutaneous tumor growth by CO2.

Local and systemic chemotherapy with taurolidine and taurolidine/heparin in colon cancer-bearing rats undergoing laparotomy

Experimental studies in the therapy of malignant abdominal tumors have shown that different cytotoxic agents suppress the intraperitoneal tumor growth. Nevertheless, a general accepted approach to prevent tumor recurrences does not exist. Following subcutaneous and intraperitoneal injection of 104 colon adenocarcinoma cells (DHD/K12/TRb), the influences of both taurolidine or taurolidine/heparin on intraperitoneal and subcutaneous tumor growth was investigated in 105 rats undergoing midline laparotomy. The animals were randomized into 7 groups and operated on during 30 min. To investigate the intraperitoneal (local) influence of either taurolidine or heparin on tumor growth, the substances were applied intraperitoneally. Systemic and intraperitoneal effects were evaluated after intravenous injection of the substances. Both application forms were also combined to analyze synergistic effects. Tumor weights, as well as the incidence of abdominal wound metastases, were determined four weeks after the intervention. In order to evaluate the effects of the agents, blood was taken to determine the peripheral leukocytes counts. Intraperitoneal tumor growth in rats receiving intraperitoneal application of taurolidine (median 7.0 mg, P=0.05) and of taurolidine/heparin (median 0 mg, P=0.02) was significantly reduced when compared to the control group (median 185 mg). The simultaneous instillation of both agents also reduced the intraperitoneal tumor growth (median 4 mg, P=0.04), while the intravenous injection of the substances caused no local effect. In contrast, the subcutaneous tumor growth did not differ among all groups. In all groups, abdominal wound recurrences were rare and did not differ. Independent of the agents and the application form, the operation itself caused a slight leukopenia shortly after the operation and a leukocytosis in the following course. Intraperitoneal therapy of either taurolidine or in combination with heparin inhibits local tumor growth and abdominal wound recurrences in rats undergoing midline laparotomy. Neither the intraperitoneal nor the intravenous application or the combination of the two agents influenced the subcutaneous tumor growth. The substances did not alter the changes of peripheral leukocytes.

Peritoneale Instillation von Taurolidin und Heparin zur Verhinderung von intraperitonealem Tumorwachstum und Trokarmetastasen bei laparoskopischen Operationen im Rattenmodell

Abstract Background: Although port-site metastases occur after laparoscopic surgery, there is no generally accepted approach to prevent tumor implantation so far. Methods: In order to prevent tumor metastases, the effect of taurolidine and heparin on the growth of colon adenocarcinoma DHD/K12/TRb was measured in vitro and in a rat model. After incubation of the cells with heparin, taurolidine or both substances, the cell kinetics were determined. In a second experiment, tumor cells were administered intraperitoneally in rats (n = 60) and pneumoperitoneum was established over 30 min. Rats were randomized into four groups (I: tumor cells; II: cells + heparin; III: cells + taurolidine; IV: cells + taurolidine + heparin). Results: While tumor cell growth was not influenced by heparin in vitro, growth decreased significantly after incubation with taurolidine and taurolidine/heparin. In vivo, intraperitoneal tumor weight was lower in rats receiving heparin (298 ± 155 mg) and taurolidine (149 ± 247 mg) than in the control group (596 ± 278 mg). When the two substances were combined, tumor growth was even less (21.5 ± 36 mg). Trocar metastases were only lower in rats receiving taurolidine or the combination of taurolidine and heparin. Conclusion: In vivo, heparin inhibits intraperitoneal tumor growth only slightly, while taurolidine causes a significant decrease in tumor cell growth in vitro as well as intraperitoneal tumor growth and trocar metastases in vivo.Zusammenfassung Hintergrund: Zur Zeit existiert keine einheitlich akzeptierte Therapie zur Verhinderung von Trokarmetastasen bei laparoskopischen Operationen von malignen Tumoren. Methode: Um ein intraperitoneales Tumorwachstum und Trokarmetastasen bei laparoskopischen Operationen zu verhindern, wurden die Effekte von Taurolidin und Heparin auf das Wachstum von Kolonkarzinomzellen (DHD/K12/TRb) in vitro sowie im Rattenmodell untersucht. In vitro erfolgte zunächst nach Inkubation der Zellen mit Heparin, Taurolidin oder beiden Substanzen die Bestimmung der Wachstumskinetiken der Zellen. In einem 2. Experiment erfolgte dann bei Ratten (n = 60) die intraperitoneale Applikation der Tumorzellen und anschließend der Aufbau eines Pneumoperitoneums für 30 min. Die Ratten wurden in 4 Gruppen randomisiert (I: Tumorzellen; II: Tumorzellen und Heparin; III: Tumorzellen und Taurolidin; IV: Tumorzellen und Taurolidin + Heparin). Ergebnisse: Während das Tumorzellwachstum in vitro durch Heparin nicht beeinflußt wurde, konnte durch Taurolidin und Taurolidin/Heparin eine signifikante Supprimierung des Wachstums erreicht werden. In vivo hingegen war das intraperitoneale Tumorgewicht gegenüber der Kontrollgruppe (596 ± 278 mg) sowohl bei der Instillation von Heparin (298 ± 155 mg) als auch von Taurolidin (149 ± 247 mg) vermindert. Die Kombination beider Substanzen verursachte eine weitere Verminderung des Tumorgewichts auf durchschnittlich (21,5 ± 36 mg). Die Entwicklung von Trokarmetastasen konnte hingegen nur durch die Instillation von Taurolidin oder die Kombination von Taurolidin und Heparin signifikant supprimiert werden. Schlußfolgerung: Während durch Heparin das intraperitoneale Tumorwachstum nur geringgradig beeinflußt wurde, konnten durch die Instillation von Taurolidin und Taurolidin/Heparin sowohl das intraperitoneale Tumorwachstum als auch die Entwicklung von Trokarmetastasen fast vollständig verhindert werden.

Einfluss des Pneumoperitoneum auf strukturelle Veränderungen des Peritoneum. Eine rasterelektronenmikroskopische Studie an der Ratte

The mechanism of potential tumor cell spread during laparoscopy is poorly understood. It is speculated that the increased intraabdominal pressure and the use of carbon dioxide during laparoscopy change the structure of the peritoneum and enhance adhesion of tumor cells.

Einfluß der intraoperativen intravenösen und intraperitonealen Gabe von Taurolidinoder Taurolidin/Heparin in der laparoskopischen Chirurgie auf das intra- und extraperitoneale Tumorwachstum

Hintergrund: Eine einheitlich akzeptierte Therapie zur Verhinderung von Trokarmetastasen bei laparoskopischen Resektionen von Malignomen existiert nicht.

Kann durch die präoperative Immunfunktion die postoperative Morbidität abgeschätzt werden? Eine prospektive Analyse bei Patienten mit einem Magenkarzinom

In einer prospektiven Studie wurde die praoperative Immunfunktion von Magenkarzinompatienten (n=47) analysiert und deren Korrelation mit den postoperativen Komplikationen ermittelt. Folgende Parameter wurden erfast: Expression von CD3, CD4 und CD8 auf Lymphozyten, HLA-DR und CD14 auf Monozyten sowie die Plasmaspiegel der Zytokine IL-6 und IL-10. Unabhangig von der Operationsdauer oder dem Resektionsverfahren bestand ein negativer Zusammenhang zwischen den CD3+ Lymphozyten und CD4+ T-Zellen sowie der Inzidenz lokaler Wundinfektionen (n=10) (p<0,05), hingegen korrelierten die IL-10 Spiegel positiv mit dem Auftreten pulmonaler und septischer Komplikationen (p<0,05). Eine praoperative Wiederherstellung der Immunfunktion bei Magenkarzinompatienten sollte angestrebt werden, um die postoperative Morbiditat zu senken.

PERIOPERATIVES IMMUNMONITORING BEIM MAGENKARZINOM : SINNVOLLE DIAGNOSTISCHE ERGANZUNG ZUR ERKENNUNG KOMPLIKATIONSGEFAHRDETER PATIENTEN?

Durch ein gezieltes perioperatives Monitoring scheint es moglich, Komplikationen fruhzeitig zu erkennen bevor klinische Zeichen existieren. Ein Anstieg des antiinflammatorischen IL-10 im Plasma zeigte hierbei bereits 4 Stunden postoperativ bei Patienten mit Anastomoseinsuffizienz signifikant erhohte Werte.