Guido Schumacher

Survival advantage for irinotecan versus best supportive care as second-line chemotherapy in gastric cancer – A randomised phase III study of the Arbeitsgemeinschaft Internistische Onkologie (AIO)

BACKGROUND The value of second-line therapy for metastatic gastric cancer is unclear. So far there are no randomised phase III data comparing second-line chemotherapy to best supportive care (BSC). In this prospective, multicenter, open label, randomised phase III study we compared irinotecan to BSC to evaluate the impact on survival of second-line chemotherapy. METHODS Eligible patients (pts) had metastatic or locally advanced gastro-oesophageal junction or gastric adenocarcinoma, objective tumour progression during or within 6months after first-line chemotherapy and ECOG performance status 0-2. Stratification for time of progression after first-line therapy, ECOG PS and pretreatment secured even distribution of important prognostic factors. TREATMENT Arm A: Irinotecan 250mg/m(2)q3w (first cycle) to be increased to 350mg/m(2), depending on toxicity. Arm B: BSC. FINDINGS Between 10/2002 and 12/2006 40 pts were randomised. The study was closed prematurely due to poor accrual. Responsefor arm A (19 pts evaluable): No objective responses, SD 53%, PD 47%. Improvement of tumour related symptoms: Arm A 50% of pts, arm B 7%. Overall Survival: (all events in 40 pts have occurred): The hazard ratio for death was reduced to 0.48 (95%CI 0.25-0.92) in the irinotecan-arm (p=0.012). Median survival arm A: 4.0months (95% CI 3.6-7.5), arm B: 2.4months (95% CI 1.7-4.9). INTERPRETATION Irinotecan as second-line chemotherapy significantly prolongs overall survival compared to BSC in the studied pts. Second-line chemotherapy can now be considered as a proven treatment option for metastatic or locally advanced gastric cancer. FUNDING The study was supported by a research grant from Aventis and Pfizer.

Methylprednisolone therapy in deceased donors reduces inflammation in the donor liver and improves outcome after liver transplantation: a prospective randomized controlled trial.

Objective:To investigate potential beneficial effects of donor treatment with methylprednisolone on organ function and outcome after liver transplantation. Summary Background Data:It is proven experimentally and clinically that the brain death of the donor leads to increased levels of inflammatory cytokines and is followed by an intensified ischemia/reperfusion injury after organ transplantation. In experiments, donor treatment with steroids successfully diminished these effects and led to better organ function after transplantation. Methods:To investigate whether methylprednisolone treatment of the deceased donor is applicable to attenuate brain death-associated damage in clinical liver transplantation we conducted a prospective randomized treatment-versus-control study in 100 deceased donors. Donor treatment (n = 50) consisted of 250 mg methylprednisolone at the time of consent for organ donation and a subsequent infusion of 100 mg/h until recovery of organs. A liver biopsy was taken immediately after laparotomy and blood samples were obtained after brain death diagnosis and before organ recovery. Cytokines were assessed by real-time reverse transcriptase-polymerase chain reaction. Soluble serum cytokines were measured by cytometric bead array system. Results:After methylprednisolone treatment, steroid plasma levels were significantly higher (P < 0.05), and a significant decrease in soluble interleukins, monocyte chemotactic protein-1, interleukin-2, interleukin-6, tumor necrosis factor-&agr;, and inducible protein-10 was observed. Methylprednisolone treatment resulted in a significant downregulation of intercellular adhesion molecule-1, tumor necrosis factor-&agr;, major histocompatibility complex class II, Fas-ligand, inducible protein-10, and CD68 intragraft mRNA expression. Significantly ameliorated ischemia/reperfusion injury in the posttransplant course was accompanied by a decreased incidence of acute rejection. Conclusions:Our present study verifies the protective effect of methylprednisolone treatment in deceased donor liver transplantation, suggesting it as a potential therapeutical approach.

The physiological estrogen metabolite 2-methoxyestradiol reduces tumor growth and induces apoptosis in human solid tumors.

Abstract 2-Methoxyestradiol (2-ME) is a physiological metabolite of estrogen, which is excreted with the urine. In contrast to most estrogens, tumor growth-inhibiting effects were observed. Further studies have revealed that it may be an effective anticancer compound for many tumor types. Several different mechanisms have been attributed to 2-ME. Besides a strong antiangiogenic effect on endothelial cells and tumors, there is a tubulin-inhibiting mechanism, causing cells to arrest in the G2/M phase of the cell cycle. In other tumors, p53-dependent and p53-independent mechanisms with induction of apoptosis have been shown. The number of different tumors examined for a growth-inhibiting effect is increasing, and new mechanisms are continuously described. In vivo studies in mice, rats, and dogs show no or very little toxicity, even at high doses. Here, we discuss the antitumor activity and their mechanisms. 2-ME appears to be a new anti-tumor compound with strong potential for clinical application.

Biliary reconstruction using a side-to-side choledochocholedochostomy with or without T-tube in deceased donor liver transplantation: a prospective randomized trial.

Objective:The biliary anastomosis is still one of the major causes for morbidity after orthotopic liver transplantation. The optimal method of reconstruction remains controversial. The aim of the study was to assess biliary complications after liver transplantation using a choledochocholedochostomy with or without a temporary T-tube. Background Data:Several reports have suggested that biliary reconstruction without T-tube is a safer method with a lower rate of biliary complications compared with T-tube insertion. Methods:A total of 194 recipients of deceased donor liver grafts were randomized. In group 1 the biliary reconstruction was performed by side-to-side choledochocholedochostomy with (n = 99) and in group 2 (n = 95) without a T-tube. The T-tube was removed after 6 weeks. Results:The overall biliary complication rate was significantly increased in group 2 (P < 0.0005). Biliary leaks occurred in 5 patients in group 1 and in 9 patients in group 2 (5.05% vs. 9.47%; P = 0.2756 ns). Anastomotic strictures of the bile duct were seen in 7 patients in group 1 and in 8 patients in group 2 (7.07% vs. 8.42%; P = 0.7923 ns). Two of the patients in group 1 and 5 patients in group 2 developed an ischemic type biliary lesion (2.02% vs. 5.26%; P = 0.2716 ns). The rate of reoperations was comparable in both groups. The rate of invasive interventions was higher in the group without T-tubes (9% vs. 18%, P = ns), as was the rate of cholangitis (5% vs. 11%. P = ns) and pancreatitis (4% vs. 14%, P = 0.0218). No complications after removal of the T-tube were observed. Conclusion:This study is a large prospective randomized trial to assess biliary complications that occur following liver transplantation, after anatomizing the bile duct with or without T-tubes. A significant increased rate of complications in the group without T-tube insertion was observed. In summary, our results indicate that the usage of T-tubes is safe and an excellent tool for the quality control of biliary anastomoses.

Improved long-term graft survival after HO-1 induction in brain-dead donors

Brain death (BD) of the donor, a risk factor uniquely relevant for organs derived from cadaver donors, influences organ quality by induction of various inflammatory events. Consequently ischemia/reperfusion injury is deteriorated and acute and chronic rejections accelerated. Donor treatment might be an approach to improve the quality of the graft. The induction of heme oxygenase 1 (HO‐1) has been shown to exert beneficial effects in living‐donor transplantation models. Therefore, we examined the impact of donor treatment with the selective inducer of HO‐1, cobalt protoporphyrin (CoPP), on organ quality and transplant outcome in a standardized BD model in a F344→LEW kidney transplant rat model. Immediately after BD induction, donor animals were administered a single dose of CoPP (5 mg/kg) and in control groups, HO‐1 activity was blocked with zinc protoporphyrin (ZnPP, 20 mg/kg). Recipients of organs from brain‐dead donors treated with CoPP survived significantly better than those from untreated brain‐dead donors (p < 0.05) and intra‐graft analysis showed improved histology (p < 0.05). Blockade of HO‐1 with ZnPP decreased the survival rates (p < 0.05) comparable to untreated brain‐dead donors. Our results demonstrate that HO‐1 induction by one single treatment of CoPP in brain‐dead donors leads to enhanced allograft survival.

Liver resection for metastatic gastric cancer

AIMS Liver resection represents a curative treatment approach in patients suffering from liver metastases from gastric cancer. However, its value in the treatment of these patients remains controversial. This study was conducted to evaluate the safety and effectiveness of liver resection in these conditions and to identify criteria for the selection of suitable patients. METHODS From January 1988 to December 2002, 24 patients underwent liver resection for metastatic gastric cancer. The outcome of these 24 patients was retrospectively reviewed using a prospective database. Patient, tumour and operative parameters were analyzed for their influence on long-term survival. RESULTS One patient died and four patients (17%) developed complications during the postoperative course. The overall one-, three- and five-year survival was 38%, 16% and 10%, respectively. After curative resection (n=17), the one-, three- and five-year survival rate was 53%, 22% and 15%, respectively, and patients with metachronous metastases restricted to the liver (n=5) had a one-, three- and five-year survival of 80%, 40% and 40%, respectively. In the univariate analysis, extrahepatic manifestation showed in tendency (p=0.069) and resection margins statistically significant (p=0.005) influence on survival. The multivariate analysis revealed only resection margins as an independent prognostic factor for survival. CONCLUSIONS Long-term survival can be achieved by liver resection in well selected patients and may be considered in the multidisciplinary treatment approach of metastatic gastric cancer. Patients with metastatic disease restricted to the liver in whom a curative resection can be achieved seem to be most suitable for liver resection.

Symptomatic lymphoceles after kidney transplantation – multivariate analysis of risk factors and outcome after laparoscopic fenestration

Ulrich F, Niedzwiecki S, Fikatas P, Nebrig M, Schmidt SC, Kohler S, Weiss S, Schumacher G, Pascher A, Reinke P, Tullius SG, Pratschke J. Symptomatic lymphoceles after kidney transplantation – multivariate analysis of risk factors and outcome after laparoscopic fenestration.
Clin Transplant 2009 DOI: 10.1111/j.1399‐0012.2009.01073.x
© 2009 John Wiley & Sons A/S.

Living donor liver transplantation of the right lobe for hepatocellular carcinoma in cirrhosis in a European center

Living donor liver transplantation of the right lobe might offer the possibility to extend the eligibility criteria of patients with hepatocellular carcinoma (HCC) in cirrhosis without penalizing patients who are waiting for a graft from a deceased donor. From 1988 to 2005, surgical treatment of HCC was performed in 580 patients (187 transplantation, 393 resection) in a European center. In the transplantation group, 21 patients with HCC in cirrhosis underwent LDLT (11% of all transplantations for HCC; 22% of 96 LDLT). Solitary HCC were accepted irrespective of their diameter unless vascular invasion was detectable. Multiple HCC nodes were considered acceptable up to a diameter of the largest node of 6 cm and a total tumor diameter of 15 cm. The median follow‐up period was 26 months (range, 1‐65 months). Vascular invasion had occurred in 12 patients (57%). One patient (4.8%) died within 60 days after transplantation from sepsis. Rates of 3‐year survival and 3‐year recurrence‐free survival were 68% and 64%, respectively. Overall 3‐year survival rates in patients with HCC in cirrhosis not meeting the Milan criteria (n = 13) or the San Francisco criteria (n = 8) were 62% and 53%, respectively. LDLT is a safe procedure. However, small sample sizes do not yet permit a definitive comparison to be made between the former results obtained after cadaveric donation. So far, the outcome of the patients is in favor of a careful extension of the selection criteria for HCC in cirrhosis. Liver Transpl 13:896–903, 2007.

De novo esophageal neoplasia after liver transplantation.

The purpose of the study was to determine the incidence, risk factors, treatment, and influence on survival of patients with de novo esophageal cancer after liver transplantation (LT). From 1988 to 2006, 1,926 patients underwent LT in our institution. A total of 9 patients (0.5%) developed a de novo esophageal cancer and 1 patient a cancer of the cardia (0.05%). A retrospective analysis was performed to reveal underlying diseases, timeframes between LT and appearance of cancer, predisposing factors, cancer therapy, complications, immunosuppressive regimens, and survival. Of our 10 patients, 7 (70%) suffered from esophageal squamous cell carcinoma (SCC) and 3 patients (30%) developed an adenocarcinoma, including the patient with cancer of the cardia. A total of 9 patients were transplanted due to alcoholic cirrhosis; 1 patient suffered from hepatocellular carcinoma in nonA‐nonB hepatitis‐related cirrhosis. Median time to tumor diagnosis was 51 months after transplantation. A total of 5 patients were treated conservatively with combined radiochemotherapy and 5 underwent surgical resection. Patients with radiochemotherapy showed a mean survival of 14.8 months vs. 24.8 months for the patients of the surgery group. No major postoperative complication has been observed. A total of 2 patients of the surgery group are still alive after a follow‐up of 15 and 89 months. In conclusion, de novo esophageal and cancer of the cardia after LT is a rare event. In spite of immunosuppression, no increased complication rate has been observed. Patients may have a survival benefit from surgical resection. Liver Transpl 13:443–450, 2007.

Radiofrequency Ablation of Liver Tumors Using a Novel Bipolar Device

PURPOSE Radiofrequency ablation (RFA) is now an established tool for treating unresectable liver tumors. Monopolar RFA is currently the accepted standard. However, the variability of the ablation shape and size impedes their further advancement. For this study, we were interested in the evaluation of a new bipolar device for technical feasibility. PATIENTS AND METHODS We have treated 6 patients [5 with hepatocellular carcinoma (HCC) one with metastatic disease] with a total of 7 tumors (6 HCCs, a solitary metastasis), using a new bipolar RFA device consisting of two separate needles, each with deployable electrodes. The treatment approaches included two percutaneous, three laparoscopic, and one open surgical. Average tumor size was 2.5 cm. Follow-up examinations were performed at intervals of 3 months and included computed tomography, (18)fluorodeoxyglucose positron emission tomography, magnetic resonance imaging and B-mode ultrasound. RESULTS All tumors could be ablated successfully. Electrode placement was accurate and visualization in transabdominal, laparoscopic, or intraoperative ultrasound was excellent. Because of the requirement of positioning two needles simultaneously, particularly in the laparoscopic RFA, the procedures were more time-consuming (average, 104 minutes) than placing a single needle. Local tumor control after a follow-up of 6 months was 100%. No major complication occurred. CONCLUSIONS Successful ablation of liver tumors, using the new bipolar device, is feasible and without complications. The procedure is technically demanding; however, local tumor control seems to be superior, as compared to other RFA devices. The long-term success of the procedure has yet to be evaluated.