Julian W. Mall

Laparoscopic aortofemoral bypass grafting: Human cadaveric and initial clinical experiences

PURPOSE Postoperative complications are mainly related to the surgical trauma derived from the extensive abdominal incision and dissection after a conventional aortofemoral bypass grafting procedure. In an attempt to reduce postoperative complications, a concept of video-endoscopic vascular surgery on the infrarenal aortoiliac artery has been developed. On the basis of our experience with the practicability of video-endoscopic vascular surgery in the pelvic region in an animal study and in a pilot study of human cadavers, the purpose of this report was to describe three different methods that we evaluated on human cadavers and that we partly applied to patients. METHODS In this experimental study, three different approaches were used to perform video-endoscopic aortofemoral bypass grafting. We performed an observational trial on human corpses (n = 24) with the transabdominal-retroperitoneal approach (TARA), the extraperitoneal approach (EPA), and the transabdominal left paracolic approach (TAPA). The EPA also was applied to patients with aortoiliac occlusive diseases. RESULTS The TARA on cadavers (n = 4) soon was abandoned because it caused a burdensome sliding of the intestine into the operative field adjacent to the renal vessels, particularly in cases with obese subjects. In comparison, the TAPA (n = 6) with right-sided positioning of the patient retained the intestine in the right upper abdomen throughout the procedure. Until a surgeon actually is acquainted with the anatomic landmarks and the laparoscopic preparation technique, the EPA (n = 14) is a challenging procedure that necessitates thorough training. As with the TAPA, the EPA represents a procedure that reveals constant exposure of the operating field, even in cases with obese subjects. In the clinical observational study (n = 7), aortobifemoral bypass grafting was achieved totally laparoscopically with the EPA. The mean operating time was 6.5 hours and ranged from 3 to 10 hours. Blood transfusions were necessary after surgery in three patients (range, 1 to 3 red packed blood cells). One patient, who had had occlusion of the inferior mesenteric artery, died of ischemic colitis at postoperative day 10. The other patients had uneventful postoperative courses with minor wound discomfort. CONCLUSION Laparoscopic vascular surgery seems to be a promising procedure to minimize postoperative complications. On the basis of our experience, we do not favor the TARA. Because it necessitates steep Trendelenburg positioning to displace intra-abdominal organs, the TARA is not an appropriate approach, particularly in obese and cardiopulmonary frail cases. Contrarily, the TAPA and the EPA deliver potentially better results in terms of exposing the operative field and thus reducing operating time and perioperative morbidity rates. A prospective cadaveric and clinical trial may be justified to further evaluate the use of these surgical techniques.

The ubiquitin- and proteasome-dependent degradation of COX-2 is regulated by the COP9 signalosome and differentially influenced by coxibs

The cyclooxygenase-2 (COX-2) enzyme is induced upon inflammation and in neoplastic tissues. It produces prostaglandins that stimulate tumor angiogenesis and tumor growth. Therefore, destruction and/or specific inhibition of COX-2 should be an important aspect of future tumor therapy. Recently, clinical application of specific COX-2 inhibitors called coxibs became doubtfully because they produce serious renal and cardiovascular complications under long term application. The exact underlying mechanisms are poorly understood and the different effects of diverse coxibs are not explained. It has been demonstrated before that COX-2 is degraded by the ubiquitin (Ub) proteasome system (UPS). However, how ubiquitination is accomplished and regulated was unclear. An important regulator of the UPS is the COP9 signalosome (CSN), which controls the stability of many proteins. Here we show that the proteasome-dependent degradation of COX-2 in HeLa cell lysate and in HeLa cells was stimulated by curcumin, an inhibitor of CSN-associated kinases. These data suggest a function of the CSN in the degradation of COX-2. In addition, proteolysis of COX-2 was significantly accelerated by parecoxib, but not by celecoxib or rofecoxib. By density gradient centrifugation and immunoprecipitation we demonstrate that COX-2 physically interacts with the CSN. Moreover, COX-2 is associated with large complexes consisting of the CSN, cullin-RING Ub ligases and the 26S proteasome. Pulldown experiments with Flag-COX-2 revealed cullin 1 and cullin 4 as components of the large super-complexes. Cullin 1 and 4 are scaffolding proteins of Ub ligases that presumably ubiquitinate COX-2. Treatment of HeLa cells with parecoxib results in an accelerated degradation of endogenous COX-2 accompanied by an increase of COX-2-Ub conjugates. In HeLa cells parecoxib is converted to the selective COX-2 inhibitor valdecoxib. Addition of valdecoxib also stimulates COX-2 degradation in HeLa cells. We therefore conclude that valdecoxib specifically interacts with COX-2 and induces a conformation accessible for ubiquitination and degradation.

Preemptive analgesia reduces pain after radical axillary lymph node dissection.

BACKGROUND Analyzing prospective data of our melanoma patients, we registered a suboptimal pain score under mobilization after radical axillary lymph node dissection (RALND). We performed a randomized, double blinded clinical trial to investigate the effects of a preemptive Parecoxib analgesic during the perioperative course. MATERIALS AND METHODS Between October 2006 and December 2007, 32 patients with stage III/IV melanoma underwent therapeutic RALND and were randomized into two groups. Patients received intravenously 40 mg Parecoxib or 0.9% normal saline solution 2 h before RALND. The postoperative treatment and analgetic regime was defined in the study protocol. Main outcome criterion was the pain under mobilization at the first postoperative morning registered via a visual analogue score. Minor criteria were the postoperative complications, fatigue, amount of analgesics, and the day of discharge. RESULTS Patients receiving a preemptive analgesic had a better outcome after RALND. The pain after mobilization was significantly decreased at the first postoperative morning (P = 0.04). Patients had less fatigue as well (P = 0.05) and the amount of pain medication in the treatment group was reduced (P = 0.04). CONCLUSIONS Preemptive application of Parecoxib enhances outcome after RALND. A preemptive analgesic with Parecoxib in the perioperative management after RALND of melanoma patients can be recommended.

Leflunomid reduziert den Angiogenesescore und das Tumorwachstum subkutan implantierter Kolonkarzinomzellen im Mausmodell

ZusammenfassungHintergrund. Die Inhibition der Tumorangiogenese könnte einen wichtigen Beitrag in der additiven Therapie von soliden Tumoren darstellen. Leflunomid, ein in Deutschland zur Therapie der rheumatoiden Arthritis zugelassenes Medikament, hemmt in vitro die Wirkung verschiedener Wachstumsfaktoren. Ziel der Untersuchung war die Wirkung des Medikaments auf die Tumorangiogenese im Nacktmausmodell. Material und Methoden. Es wurden 40 Nacktmäusen humane Kolonkarzinomzellen subkutan injiziert. Nach Randomisierung in 4 Gruppen à 10 Tiere erfolgte ab dem 5. Tag die tägliche Therapie der 1. Gruppe mit 35 mg Leflunomid/kg KG gelöst in 1,5% Carboxymethylzellulose (CMZ) oral über einen Zeitraum von 23 Tagen. Gruppe 2 diente als Kontrollgruppe und erhielt 1 ml CMZ oral. Die Tiere der 3. Gruppe erhielten täglich 35 mg Leflunomid/kg KG oral sowie 500 mg Uridin/kg KG gelöst in 1 ml Nacl 0,9% intraperitoneal. Die 4. Gruppe diente ebenfalls als Kontrollgruppe und wurde nur mit 500 mg Uridin/kg KG intraperitoneal therapiert. Hauptzielkriterium der Studie war der Angiogenesescore (AS), Nebenzielkriterien das Tumorvolumen und das Tumorgewicht. Der AS wurde immunhistochemisch durch Färbung von Paraffinschnitten mit Antikörpern gegen FVIII assoziiertes Antigen ermittelt. Ergebnisse. Alle Tiere tolerierten die Therapie gut. Sowohl in der nur mit Leflunomid behandelten als auch in der mit Leflunomid/Uridin behandelten Gruppe waren der Angiogenesescore (p<0,01), das Tumorvolumen (p<0,01) und das Tumorgewicht (p<0,01) im Vergleich zur jeweiligen Kontrollgruppe vermindert. Schlussfolgerung. Die Therapie subkutan implantierter Kolonkarzinomzellen mit Leflunomid führt im Kleintiermodell zu einer signifikanten Reduktion der Tumorgröße und des Tumorgewichts. Dies könnte auf die Reduktion der Tumorangiogenese durch Leflunomid zurückzuführen sein. Nach weiteren experimentellen und klinischen Untersuchungen könnte Leflunomid eine Rolle in der additiven Therapie von Kolonkarzinomen spielen.AbstractBackground. The inhibition of tumorangiogenesis may be of importance in the additive treatment of various cancers. Leflunomide, a drug which has been approved in Germany for the therapy of rheumatoid arthritis, inhibits the activity of several growth factors in vitro. The aim of this study was to investigate the effects of the drug on tumor angiogenesis in a nude mouse model. Materials and methods. A total of 40 nude mice were injected with human colon carcinoma cells. Following randomization in 4 groups, therapy started on day five. Group 1 was treated daily with orally administered Leflunomide (35 mg/kg) dissolved in 1.5% Carboxymethylcellulose (CMC). Group 2 served as a control group and received 1 ml CMC orally per day. The animals of group 3 were treated daily with 35 mg Leflunomide/kg KG and 500 mg Uridine/kg dissolved in 1 ml Nacl 0.9% intraperitoneally. The 4th group again served as a control group and received only 500 mg Uridine/kg intraperitoneally each day. The main outcome criterion was the angiogenesis score (AS). In addition, the tumor volume and tumor weight were also assessed. The AS was determined by immunohistochemistry using an antibody against factor VIII related antigen. Results. All animals tolerated the procedure well. In the Leflunomide and the Leflunomide/Uridine group the angiogenesis score (p<0,01), the tumor volume (p<0,01) and the tumor weight (p<0,01) were lower compared to the respective control groups. Conclusion. The administration of Leflunomide leads to a significant reduction of tumor weight and tumor volume following subcutaneous injection of human colon carcinoma cells in a nude mouse model. This could be due to the reduction of tumor angiogenesis. Following further experimental and clinical studies, Leflunomide may come to play a role in the additive treatment of colonic carcinoma.

Influence of surgical complications on the level of pain after radical inguinal/iliacal lymph node dissection.

Abstract Background: We collected the data of 288 patients with malignant skin tumours. We analysed the postoperative pain assessed by a visual analogue scale (VAS) to evaluate the quality of our standard peri-operative pain therapy after a radical inguinal and iliacal lymph node dissection (RILND) as well as the influence of postoperative surgical complications on the level of pain. Materials and method: The postoperative level of pain of 85 patients with malignant skin tumours who underwent a RILND between August 2003 and December 2007 was recorded prospectively. Patients received a standardised perioperative pain therapy according to level I or II of the World Health Organisation (WHO) ladder of pain. The efficiency of our pain therapy was registered via VAS in the morning of the first three postoperative days. Results: Using our standard pain therapy, we determined a VAS < 30 in rest during the first three postoperative days, but significantly more pain (VAS median 50–30) (p < 0.001) under stress. Patients with surgical complications in the postoperative period (n = 71) had significantly more pain in the postoperative period compared to patients with a regular postoperative course (p = 0.047). Conclusions: Immediately after a RILND, an analgesic therapy according to level I or II of the WHO pain ladder does not seem to be effective enough. Postoperative surgical complications lead to a higher VAS level of pain in the postoperative period.

Quantity-guided drain management reduces seroma formation and wound infections after radical lymph node dissection: results of a comparative observational study of 374 melanoma patients

Abstract Background: Lymphatic fistulas are common complications after lymph node dissections in melanoma patients. We investigated whether drain management could improve the patient’s outcome. Methods: Patients who underwent axillary or inguinal lymph node dissection (RALND or RILND) for malignant melanoma were recorded in a prospective database. Two different methods of drain management were compared. Either the drain was removed no later than the eighth postoperative day (period I, 2003–2007) or it was left in place until fluid flow was below 50 ml in 24 h for two consecutive days (period II, 2008–2011). The main outcome criterion was the incidence of seroma punctures after drain removal. Results: 374 patients were analysed. The incidence of seroma punctures significantly decreased in period II. The number of patients with elevated lymphatic secretions rose by 41.3% (RALND) and 38.1% (RILND). With the exception of lymphatic fistulas, we observed significantly more local complications with need for treatment in period I (n = 104, 52%) than in period II (n = 31, 18%). In period II, the hospital stays after both procedures were significantly reduced. Conclusions: We conclude that quantity-guided drain management leads to a prolonged interval of drainage but is associated with a lower incidence of seroma formation and shorter hospital stay.