Albrecht Encke

Randomized trial of surgery versus surgery followed by adjuvant hepatic arterial infusion with 5-fluorouracil and folinic acid for liver metastases of colorectal cancer

OBJECTIVE To determine the impact of adjuvant hepatic arterial infusion (HAI) on survival relative to resection alone in patients with radical resection of colorectal liver metastases. SUMMARY BACKGROUND DATA Nearly 40% to 50% of all patients with colorectal carcinoma develop liver metastases. Curative resection results in a 5-year survival rate of 25% to 30%. Intrahepatic recurrence occurs after a median of 9 to 12 months in up to 60% of patients. The authors hypothesized that adjuvant intraarterial infusion of 5-fluorouracil (5-FU) might decrease the rate of intrahepatic recurrence and improve survival in patients with radical resection of colorectal liver metastases. METHODS Between April 5, 1991, and December 31, 1996, patients with colorectal liver metastases from 26 hospitals were stratified by the number of metastases and the site of the primary tumor and randomized to resection of the liver metastases followed by adjuvant HAI of 5-FU (1000 mg/m2 per day for 5 days as a continuous 24-hour infusion) plus folinic acid (200 mg/m2 per day for 5 days as a short infusion), or liver resection only. RESULTS The first planned intention-to-treat interim analysis after inclusion of 226 patients and 91 events (deaths) showed a median survival of 34.5 months for patients with adjuvant therapy versus 40.8 months for control patients. The median time to progression was 14.2 months for the chemotherapy group versus 13.7 months for the control group. Grade 3 and 4 toxicities (World Health Organization), mainly stomatitis (57.6%) and nausea (55.4%), occurred in 25.6% of cycles and 62.9% of patients. CONCLUSION According to this planned interim analysis, adjuvant HAI, when used in this dose and schedule in patients with resection of colorectal liver metastases, reduced the risk of death at best by 15%, but at worst the risk of death was doubled. Thus, the chance of detecting an expected 50% improvement in survival by the use of HAI was only 5%. Patient accrual was therefore terminated.

Second Liver Resections Are Safe and Effective Treatment for Recurrent Hepatic Metastases from Colorectal Cancer: A Bi-institutional Analysis

ObjectiveTo determine the value of repeat liver resection for recurrent colorectal metastases to the liver. Summary Background DataLiver resection represents the best and a potentially curative treatment for metastatic colorectal cancer to the liver. After resection, however, most patients develop recurrent disease, often isolated to the liver. MethodsThis study reports the combined experience of repeat liver resection for recurrent liver metastases at an American and a European surgical oncology center. Patients were identified from prospective databases and records were retrospectively reviewed. A total of 126 patients (American n = 96, 1986–2001; European n = 30, 1985–1999) underwent repeat liver resection. Patient characteristics were similar in the two institutions. Median follow-up from first liver resection was 88 and 105 months, respectively. ResultsOperations performed included 90 minor resections and 36 resections of a lobe or more. The 1-, 3-, and 5-year survival rates were 86%, 51%, and 34%. There were 19 actual 5-year survivors to date. By multivariate regression analysis (proportional hazard model), more than one lesion and tumor size larger than 5 cm were independent prognostic indicators of reduced survival. The interval between the first and second liver resection was not predictive of outcome. ConclusionsRepeat liver resection for colorectal liver metastases is safe. Patients with a low tumor load are the best candidates for a repeat resection. In well-selected patients, further resection of the liver can provide prolonged survival after recurrence of colorectal liver metastases.

Evaluation of perioperative fatal pulmonary embolism and death in cancer surgical patients: the MC-4 cancer substudy

Cancer patients undergoing surgery are at a high risk of venous thromboembolism, but few studies have described the rate of autopsy-confirmed fatal pulmonary embolism after heparin thromboprophylaxis. In a post hoc analysis of a randomized study (MC-4), which compared the efficacy and safety of certoparin (3000 anti-Xa IU, subcutaneously, once-daily) with unfractionated heparin (5000 IU, subcutaneously, three-times daily) in 23078 patients undergoing surgery lasting more than 30 min, the incidence of autopsy-confirmed fatal pulmonary embolism, death and bleeding in the cancer patients (n=6124) was compared with non-cancer patients (n=16954). Fatal pulmonary embolism was significantly more frequent in cancer patients (0.33% [20/6124]) than in non-cancer patients (0.09% [15/16954], relative risk (RR), 3.7 [95% confidence intervals (CI), 1.80, 7.77], p=0.0001) at 14 days post-prophylaxis. Perioperative mortality was also significantly higher in cancer patients than in noncancer patients (3.14% [192/6124] vs. 0.71% [120/16954], RR, 4.54 [95% CI, 3.59, 5.76], p=0.0001), as were blood loss (p<0.0001), and transfusion requirements (p<0.0001). Prevention of venous thromboembolism in cancer surgical patients remains a clinical challenge.

State-of-the-Art Review: Anticoagulation: The Present and Future

Thrombin is a central bioregulator of coagulation and is therefore a key target in the therapeutic prevention and treatment of thromboembolic disorders, including deep vein thrombosis and pulmonary embolism. The current mainstays of anticoagulation treatment are heparins, which are indirect hrombin inhibitors, and coumarins, such as warfarin, which modutate the synthesis of vitamin K-dependent proteins. Although efficacious and widely used, heparins and coumarins have limitations because their pharmacokinetics and anticoagulant effects are unpredictable, with the risk of bleeding and other complications resulting in the need for close monitoring with their use. Low-molecular-weight heparins (LMWHs) provide a more predictable anticoagulant response, but their use is limited by the need for subcutaneous administration. In addition, discontinuation of heparin treatment can result in a thrombotic rebound due to the inability of these compounds to inhibit clot-bound thrombin. Direct thrombin inhibitors (DTI) are able to target both free and clot-bound thrombin. The first to be used was hirudin, but DTIs with lower molecular weights, such as DuP 714, PPACK, and efegatran, have subsequently been developed, and these agents are better able to inhibit clot-bound thrombin and the thrombotic processes that take place at sites of arterial damage. Such compounds inhibit thrombin by covalently binding to it, but this can result in toxicity and nonspecific binding. The development of reversible noncovalent DTIs, such as inogatran and melagairan, has resulted in safer, more specific and predictable anticoagulant treatment. Oral DTIs, such as ximelagatran, are set to provide a further breakthrough in the prophylaxis and treatment of thrombosis.

Cytomegalovirus- and interferon-related effects on human endothelial cells : cytomegalovirus infection reduces upregulation of HLA class II antigen expression after treatment with interferon-γ

Cultured human umbilical vein endothelial cells (HUVEs) were infected with human cytomegalovirus (HCMV) strain AD169. Up to 50% HUVEs proved to be positive for HCMV early nuclear antigens 24 hours after inoculation with virus. Following infection kinetics of surface expression of HLA class I and II, intercellular adhesion molecule (ICAM-1) and endothelial lymphocyte adhesion molecule (ELAM-1) on HUVEs were investigated by means of flow cytometry. A slight increase in HLA class I expression was observed, whereas expression of HLA class II (DR, DP, DQ) antigens was not induced by infection with HCMV. Furthermore, when compared with uninfected cells treated with interferon-gamma (IFN-gamma), reduced enhancement of HLA-DR expression was conspicuous in HCMV-infected cells treated with IFN-gamma. There is evidence that only a portion of HUVE is affected in its ability to upregulate HLA class II antigens. While expression of ICAM-1 was found to be enhanced between 8 and 20 hours after infection with a maximum at 12 hours after infection, no modulation of ELAM-1 was seen.

Prevention of fatal pulmonary embolism and mortality in surgical patients - A randomized double-blind comparison of LMWH with unfractionated heparin

The incidences of fatal pulmonary embolism and death in surgical patients receiving low-molecular-weight heparin thromboprophylaxis have not been previously determined in large, adequately designed clinical trials and information on the relative efficacy and safety of unfractionated and low-molecular-weight heparin in preventing these clinical endpoints is not available. In a double-blind study, 23078 surgical patients randomly received the low-molecular-weight heparin, certoparin (3000 anti Xa IU) subcutaneously once-daily, or unfractionated heparin (5000 IU) subcutaneously three-times daily, for a minimum of 5 days. The primary outcome measure, autopsy-proven fatal pulmonary embolism recorded up to 14 days after the end of prophylaxis, occurred in 0.152% (95% confidence interval (CI) 0.10, 0.20%; 35 of 23078 patients) of cases, with no significant difference between the certoparin-treated patients (0.147% (95% CI 0.077, 0.217%; 17 of 11542 patients) and patients treated with unfractionated heparin (0.156% (95% CI 0.084, 0.228%; 18 of 11,536 patients, P=0.868). The autopsy rate was 70.2%. Comparing mortality, there was no significant difference between the groups (1 .44% [166 of 11542 certoparin patients] versus 1.27% [146 of 11536 unfractionated heparin patients]; P=0.279). The safety profiles of both treatment groups were similar. Once-daily certoparin and three-times daily unfractionated heparin are equally effective and safe in reducing fatal pulmonary embolism and death to low levels in surgical patients and mirror the findings of comparative efficacy studies using surrogate endpoints.

Inhibition of endothelial receptor expression and of T-cell ligand activity by mycophenolate mofetil

The novel immunosuppressive drug mycophenolate mofetil (CellCept, MMF) blocks DNA-synthesis by the inhibition of the enzyme inosine monophosphate dehydrogenase (IMDH). IMDH is also involved in the synthesis of adhesion receptors which are known to play an important role in the regulation of cell-cell contacts. Therefore, application of MMF might lead to a reduction of cellular infiltrates in the course of transplant rejection. To evaluate the therapeutic value of MMF, we investigated to what extent MMF blocks T-lymphocyte infiltration in vitro with regard to (a) adhesion to endothelial cells, (b) horizontal migration along these cells and (c) penetration through the endothelial cells. The results demonstrated a strong inhibition of both CD4+ and CD8+ T-cell adhesion and penetration by MMF. The ID50 value for CD4+ T-cell adhesion was calculated to be 0.03 microM and the ID50 value for CD4+ T-cell penetration 1.21 microM. MMF did not significantly influence the horizontal migration of T-lymphocytes along the human vascular endothelial cell (HUVEC) borders. FACS-analysis revealed a diminished E-selectin and P-selectin expression on endothelial cell membranes in the presence of MMF. Although MMF did not interfere with the synthesis of T-cell adhesion ligands, the binding activity of lymphocytic leucocyte function associated antigen 1 (LFA-1), very late antigen 4 (VLA-4) and PSGL-1 (P-selectin glycoprotein ligand 1) to immobilized intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1) and P-selectin was impaired. Moreover, MMF prevented VLA-4 and PSGL-1 receptor accumulation on the membranes of T-cell pseudopodia. It can be concluded that MMF possesses potent infiltration blocking properties. MMF evoked down-regulation of specific endothelial membrane molecules and the loss of protein localization in the lymphocyte protrusions might be predominantly responsible for the observed blockade of cell adhesion and penetration.

Experiences with Percutaneous Endoscopic Gastrostomy

Abstract. Today the procedure of choice for long-term enteral tube feeding in patients with prolonged swallowing difficulties or inabilities is percutaneous endoscopic gastrostomy (PEG). The primary indications are head and neck cancers, neurologic dysphagia, cancer cachexia, and obstruction of the esophagus and pharynx with enough space for an endoscopic procedure. This technique requires no general anesthesia and is possible in patients with contraindications to surgical gastrostomy. Between September 1994 and April 1995 a total of 115 patients underwent PEG placement attempts. We employed the pull-technique with 15-Freka PEG tubes. The average procedure time, including esophagogastroduodenoscopy, was 17 minutes. In nine cases PEG insertion was impossible owing to severe obstruction of the esophagus. In 46 (40%) patients local abdominal pains started on the first or second postoperative day; 7 of these patients required surgical consultation, and no further intervention was needed. In only one patient was there a serious complication that required surgical intervention: a presumed perforation that turned out to have no correlate upon review. All patients received single-shot antibiotic prophylaxis; and only in those patients with abdominal symptoms do we recommend a prolonged antibiosis. The abdominal symptoms reported were due to a slight leak of gastric fluid causing a topical peritonitis, which required no further treatment. In our experience PEG is a useful alternative to surgical gastrostomy. The simplicity of this procedure leads to low complication rates, short hospitalization, and is possible on an outpatient basis. It is cost-efficient and has a much better psychological tolerance than nasogastric tubes.

Gasless laparoscopy in abdominal surgery

Pneumoperitoneum, as a necessary precondition of laparoscopic procedures, represents a restriction of the surgeons freedom of movement and can lead to rare but typical complications. We describe our first experiences with laparoscopic surgery without using pneumoperitoneum. Under direct vision and digital control a fan-formed wall retractor, which is attached to an electric lift arm, is introduced into the abdominal cavity. After raising the abdominal wall, the scope is introduced through the same access and the laparoscopic procedure can be started without the technical and physiopathological problems which may occur using a pneumoperitoneum. In this gasless laparoscopic procedure, simple valveless trocars and instruments can be used. Furthermore, an unlimited suction can be obtained without a loss of exposure. During anesthesia, neither increased ventilation nor increased ventilation pressure is necessary, and the surgeon has increased freedom of action. Not only special laparoscopic instruments, but the conventional instruments, used in open surgery, can also be employed in gasless laparoscopy. In this way we performed gasless laparoscopic surgery on 54 patients: cholecystectomy (n=37), abdominal exploration for NSAP (n=5) or tumor staging (n=4), fenestration of liver cysts (n=5), and appendectomy (n=3). We did observe three wound infections as related complications. Six times, we had to change the surgical procedure. Compared to the traditional procedure with a CO2 pneumoperitoneum, the results of the first gasless procedures demonstrate potential advantages.

Historical evolution of inguinal hernia repair

When analyzing original articles since the sixteenth century, it becomes apparent that all surgical techniques for repair of the inguinal hernial orifice can be traced back to two simple repair principles. The first is reinforcement of the anterior wall of the inguinal canal and tightening of the external inguinal ring (Stromayr 1559, Purmann 1694, Czerny 1877), and the second is reinforcement of the posterior wall of the inguinal canal and the tightening of the internal inguinal ring, either externally (Lucas-Championnière 1881, Bassini 1889, Lotheissen 1898, McVay 1942, Shouldice 1945, Lichtenstein 1987, Stoppa 1989) or via an intraabdominal approach by laparotomy (Tait 1891) or laparoscopically (Ger 1990, Velez and Klein 1990). We have tried to provide a systematic order to the diverse procedures of surgery of inguinal hernias according to their repair principles. We also point out their historical development.RésuméLorsque l’on analyse les articles originaux du 16è siècle, on se rend compte que toutes les techniques de réparation de la hernie inguinale reposent sur deux principes. Premièrement, le renforcement de la paroi antéricure du canal inguinal et fermeture de l’anneau inguinal externe (orifice profond) (techniques de Stomayr 1559, de Purmann 1694, et Czerny 1877), et deuxièmement, le renforcement de la paroi postérieure du canal inguinal et fermeture de l’anneau interne (orifice superficiel) soit par dehors (techniques de Lucas-Championnière 1881, Bassini 1889, Lotheissen 1898, McVay 1942, Shouldice 1945, Lichtenstein 1987, Stoppa 1989), soit par la cavité abdominale, soit en laparotomie (Tait 1891) or par laparoscopie (Ger 1990, Velez et Klein 1990). Nous avons essayé de donner un ordre logique dans les différents principes des procédés de réparation et de mettre en exergue leur place dans le contexte historique.ResumenAl analizar los artículos originales publicados a partir del siglo XVI, résulta aparente que todas las técnicas quirúrgicas empleadas para la reparatión del orificio de la hernia inguinal pueden ser reducidas a dos simples principios de reparatión: Primero, al refuerzo de la pared anterior del canal inguinal y la reparatión del anillo externo (Stromayr 1559, Purmann 1964, Czerny 1877) y, segundo, al refuerzo de la pared posterior del canal inguinal y la reparatión del anillo inguinal interno, bien en forma externa (Lucas-Championniere 1881, Bassini 1889, Lotheissen 1898, McVay 1942, Shouldice 1945, Lichtenstein 1987, Stoppa 1989) o bien por vía intra-abdominal, mediante laparotomía (Tait 1891) o por laparoscopia (Ger 1990, Velez and Klein 1990). Hemos tratado de dar un orden sistemático a los diversos procedimientos de la cirugía de las hernias inguinales según su principio de reparatión y señalar su desarrollo histórico.