Günter Tusch

Surgical treatment in proximal bile duct cancer. A single-center experience.

OBJECTIVES The authors evaluated the experience and results of a single center in surgical treatment of proximal bile duct carcinoma. SUMMARY BACKGROUND DATA Whenever feasible, surgery is the appropriate treatment in proximal bile duct carcinoma. To improve survival rates and with special regard to liver transplantation, the extent of surgical radicalness remains an open issue. PATIENTS AND METHODS Retrospective analysis of 249 patients who underwent surgery for proximal bile duct carcinoma via the following procedures: resection (n = 125), liver transplantation (n = 25), and exploratory laparotomy (n = 99). Survival rates were calculated according to the Kaplan-Meier method, uni- and multivariate analysis of prognostic factors, and log rank test (p < 0.05). RESULTS Survival rates after resection and liver transplantation are correlated with international Union Against Cancer (UICC) tumor stage (resection: overall 5-year, 27.1%; stage I and II, 41.9%; stage IV, 20.7%; liver transplantation: overall 5-year, 17.1%; stage I and II, 37.8%; stage IV, 5.8%). Significant univariate prognostic factors for survival after liver resection were lymph node involvement (N category), tumor stage, tumor-free margins, and vascular invasion; for transplantation, they were local tumor extent, N category, tumor stage, and infiltration of liver parenchyma. For resection and transplantation, a multivariate analysis showed prognostic significance of tumor stage and tumor-free margins. CONCLUSION Resection remains the treatment of choice in proximal bile duct carcinoma. Whenever possible, decisions about resectability should be made during laparotomy. With regard to the observation of long-term survivors, liver transplantation still can be justified in selected patients with stage II carcinoma. It is unknown whether more radical procedures, such as liver transplantation combined with multivisceral resections, will lead to better outcome in advanced stages. With regard to palliation, surgical drainage of the biliary system performed as hepatojejunostomy can be recommended.

Replacement of calcineurin inhibitors with mycophenolate mofetil in liver-transplant patients with renal dysfunction: a randomised controlled study

BACKGROUND Renal dysfunction is a major complication of long-term immunosuppressive therapy with calcineurin inhibitors (CNI) in liver-transplant recipients. We undertook a randomised study to assess the safety and efficacy of CNI withdrawal and replacement by mycophenolate mofetil. METHODS 28 people who had had renal dysfunction attributable to suspected CNI toxicity after liver transplantation participated in the study. We replaced CNI with mycophenolate mofetil in a stepwise pattern in half the group (study patients); the other half (controls) stayed on CNI immunosuppression. Renal function, blood pressure, uric acid, and blood lipids were measured before and 6 months after study entry. Side-effects of medication and graft function were recorded throughout the study. FINDINGS At the end of the study, mean (SD) serum creatinine had fallen by 44.4 (48.7) micromol/L in study patients compared with 3.1 (14.3) micromol/L in controls; a mean difference of 41.3 micromol/L (95% CI 12.4-70.2). Moreover, systolic and diastolic blood pressure, and serum uric acid decreased significantly in the study group but not in the control group (mean [95% CI] between group differences 10.8 mm Hg [3.0-18.6], 5.0 mm Hg [0.9-9.2], and 83.1 micromol/L [12.7-153.6], respectively). There were no changes in cholesterol or triglyceride concentrations in either group. Side-effects were reported by eight of the study patients. Three reversible episodes of acute graft rejection occurred in study patients during mycophenolate mofetil monotherapy, whereas none occurred in the control group. INTERPRETATION Substitution of CNI by mycophenolate mofetil can improve renal function, blood pressure, and uric acid concentration of liver-transplant patients, but there is an increased rejection risk with mycophenolate mofetil monotherapy.

Benign Liver Tumors: Differential Diagnosis and Indications for Surgery

Abstract. The differential diagnosis for hemangioma, focal nodular hyperplasia (FNH), and hepatocellular adenoma may be difficult. Reliable diagnosis is mandatory for the decision of whether to apply surgery or observation. Experience with long-term observation in nonoperated patients with hemangioma and FNH is limited. A group of 437 patients from a single institution were analyzed with regard to a diagnostic algorithm, the indications for surgery, and observation. There were 238 hemangiomas, 150 cases of FNH, 44 adenomas, and 5 mixed tumors. Of the 437 patients, 173 underwent surgery; 103 with hemangioma and 54 with FNH were observed at our own institution, whereas 117 patients underwent follow-up elsewhere or were lost. Among the operated patients with confirmed histology, a good diagnostic yield was found for a combination of ultrasonography (US), contrast (bolus)-enhanced computed tomography (CT), and labeled red blood cell (RBC) scanning: sensitivity 85.7%, specificity 100%, positive predictive value (PPV) 100%, negative predictive value (NPV) 81.8%, and accuracy 91.3%. For FNH the combination of US and CT plus cholescintigraphy showed a sensitivity 82.1%, specificity 97.1%, PPV 95.8%, NPV 84.6%, and accuracy 90.3%. Surgical mortality was 0.6%. Observation of patients with hemangioma and FNH for a median of 32 months revealed no increase in tumor size in 80% and a decrease in fewer than 7%. There was no tumor rupture and no evidence of malignant transformation. We concluded that liver hemangioma and FNH can be differentiated from adenoma with high sensitivity, specificity, and accuracy by labeled RBC scanning and cholescintigraphy in combination with US and contrast-enhanced CT. In the case of symptoms or an equivocal diagnosis with respect to adenoma or hepatocellular carcinoma, surgery can be performed with very low risk. Because in asymptomatic patients with observed hemangioma or FNH no increase of tumor size can be expected for many years, the indications for surgery must be carefully evaluated.

Recurrence Patterns of Hepatocellular and Fibrolamellar Carcinoma After Liver Transplantation

PURPOSE Tumor recurrence is the major limitation of long-term survival after liver transplantation for hepatocellular carcinoma (HCC) or fibrolamellar carcinoma (FLC). Understanding tumor-biologic characteristics is important for selection of patients and for development of adjuvant therapeutic strategies. PATIENTS AND METHODS The study included 69 patients who underwent potentially curative liver transplantation for HCC/FLC and survived for more than 150 days; minimum follow-up was 33 months. Frequency, localization, and timing of recurrence were analyzed and compared with primary tumor and patient characteristics. RESULTS Tumor recurrence was observed in 39 patients at 67 locations. Hematogenous spread was the major route of tumor recurrence (87%), and the most frequent sites were the liver (62%), lung (56%), and bone (18%). Parameters associated with recurrence were absence of cirrhosis, tumor size greater than 5 cm, more than five nodules, vascular infiltration, and International Union Against Cancer (UICC) stage IVA. Selective intrahepatic recurrence was found in nine patients (23%); it was associated with highly differentiated tumors, lack of vascular infiltration, and male sex. Recurrence at multiple sites was found predominantly in young patients (< or = 40 years) and for multicentric (> 5) primary tumors. Recurrences were observed within a wide time range after transplantation (43 to 3,204 days; median, 441 days); late recurrences (> 1,000 days, n = 8) were associated with highly differentiated or fibrolamellar tumors and low UICC stages. Surgical treatment was the only therapeutic option associated with prolonged survival after recurrence. CONCLUSION In transplant recipients, hepatocellular carcinomas vary considerably in their pattern and kinetics of metastases. Tumor cells may persist in a dormant state for long time periods before giving rise to clinical metastases. Surgical treatment of recurrence should be considered whenever possible.

Liver transplantation in HBs antigen (HBsAg) carriers. Prevention of hepatitis B virus (HBV) recurrence by passive immunization.

Liver transplantation in HBs-antigen (HBsAg) positive allograft recipients is associated with a high risk of HBV recurrence some time after surgery. So far, results of measures to prevent recurrent HBV-infection by means of treatment with interferon, hepatitis B vaccination and short-term passive immunization with hepatitis B immunoglobulin (HBIg) or monoclonal antibody to HBsAg (anti-HBs) have been disappointing. In the present study the results of long-term, anti-HBs monitored passive immunization with HBIg is reported. In 23 HBsAg-positive liver transplant recipients an anti-HBs level of greater than or equal to 100 IU/l was maintained for 6 or 12 months, respectively. The rate of recurrent infection was found to be less than 20% under HBIg substitution, whereas 11 graft recipients with no or only short-term HBIg prophylaxis were reinfected by month 15 after transplantation. HBV recurrence was associated with chronic liver disease and recurrent cirrhosis in the allograft.

Influence of arginine, omega-3 fatty acids and nucleotide-supplemented enteral support on systemic inflammatory response syndrome and multiple organ failure in patients after severe trauma

This study investigated the influence of an enteral diet supplemented with arginine, omega-3 fatty acids, and nucleotides (Impact, Sandoz Nutrition, Berne, Switzerland) on the incidence of systemic inflammatory response syndrome (SIRS) and multiple organ failure (MOF) in patients after severe trauma. Thirty-two patients with an injury-severity score > 20 were included in this prospective, randomized, double-blind, controlled study. Primary endpoints were the incidence of SIRS and MOF. Secondary endpoints were parameters of acute phase and immune response as well as infection rate, mortality, and hospital stay. For statistical analysis 29 patients (test group n = 16, control n = 13) were eligible. In the test group, significantly fewer SIRS days per patient were found during 28 d. The difference was highly significant between d 8-14 (P < 0.001). MOF score was significantly lower in the test group on d 3 and d 8-11 (P < 0.05). Acute phase parameters showed lower C-reactive protein serum levels (significant on D day 4) and fibrinogen plasma levels (significant on d 12 and 14; P < 0.05). HLA-DR expression on monocytes showed significantly higher fluorescence activity on d 7. No significant difference was found for T-lymphocyte CD4/CD8 ratio, interleukin-2 receptor expression, infection rate, mortality (2/16 vs. 4/13), and hospital stay. The results of the study provide further support for beneficial effects of arginine, omega-3-fatty acids and nucleotide-supplemented enteral diet in critically ill patients.

Immunoprophylaxis with a monoclonal anti-IL-2 receptor antibody in liver transplant patients.

The immunosuppressive effect of a monoclonal antibody (moAb), BT563, directed to the alpha-chain of the IL-2R (CD25), was analyzed in a prospective nonrandomized trial and a prospective randomized trial. Primary objectives were evaluation of the incidence of acute rejections and infections; secondary objectives were safety and tolerability of the moAb. A total of 28 patients were enrolled (phase II) to receive 10 mg/day of BT563 (12 days) as immunoprophylaxis in combination with cyclosporine, azathioprine, and low-dose steroids. Subsequently 32 patients were randomly assigned (phase III) to receive BT563 (10 mg/day) for 12 days or ATG (5 mg/kg/day) for 7 days in addition to cyclosporine and low-dose steroids. No side effects of the BT563 treatment were noted. The actuarial survival was 82% at 12 months in the phase II trial and 92% at 12 months in both arms of the phase III trial. There was one acute rejection in the phase II trial. No acute rejections were noted in the BT arm of the phase III trial and 5 acute rejections were treated in the ATG arm. In the phase II trial 7 infectious episodes were observed, while one infection was seen in the BT arm and 7 in the ATG arm of the triple immunosuppression phase III trial. In all patients circulation of coated CD25+ lymphocytes was observed during BT563 treatment; there was no evidence of depletion or modulation of CD25+ cells. Mean serum levels of BT563 ranged from 1.6 to 7.6 microgram/ml throughout the therapy. An antimurine response was seen in 82% (phase II) and 100% (phase III) of the patients. Antirabbit antibodies were found in 56% of the patients treated with ATG. Analysis of the antimurine response specificity revealed in 56% blocking anti-isotypic antibodies and only in 3% of the patients an anti-idiotypic response. The data of the study presented suggest that therapy with an anti IL-2R moAb is at least equal to ATG application according to the incidence of acute rejections and infections.

HLA compatibility and different features of liver allograft rejection

The influence of human leukocyte antigen (HLA) on acute liver allograft rejection was investigated in 48 adult patients. The diagnosis of rejection was always based on the full triad of histological findings, clinical signs, and the required antirejection treatment. Sixty-two percent of the patients closely observed for 6 months postoperatively revealed acute rejection within the first 3 weeks, mostly on days 7–11. HLA compatibility was not observed to have any significant influence on the incidence of acute rejection. However, different histological and clinical features were revealed in conjunction with DR compatibility. Patients without DR compatibility showed a type of rejection with fever and increase of bilirubin, frequently associated with cholestasis and cholangitis, which sometimes persisted for weeks. Patients with 1 DR compatibility showed a predominant increase of transaminases, which was never associated with cholangitis. The conjunction of different DR compatibilities and various clinical signs may indicate possible pathways from immunological assault to the clinical appearance of acute rejection. A knowledge of a patients individual compatibility and an expectation of certain rejection patterns may lead to earlier and more reliable diagnosis and treatment.

Knowledge Acquisition Using Syntactic Time Patterns

For knowledge acquisition based on time oriented data we describe a tool to be used for clinical research in the intensive care setting of liver transplantation. The tool incorporates a time model derived from Allen’s concepts [1]. Interactive definition and refinement of concepts can immediately tested on the data. The resulting output covers not only time intervals of the knowledge based classification process but also rule and frame based definitions of concepts. The first evaluation results are very encouraging. This knowledge acquisition tool is seen as one additional tool complementing classical ones as statistical packages, for example.

Case Description and Case Retrieval on Time Oriented Patient Data

Symptome und klinische Zeichen eines Patienten innerhalb eines Behandlungsverlaufs haben eine zeitliche Dimension. Sie bleiben phasenweise gleich oder andern sich. Ihr zeitliches Verhalten, gegebenenfalls unter dem Einflus therapeutischer Aktionen, ist wesentlich fur die klinische Urteilsfindung. Ausgehend von der klinischen Problemstellung, wahrend der postoperativen Versorgung lebertransplantierter Patienten ahnliche Verlaufskonstellationen zu fruheren Patienten zu erkennen, haben wir ein operationales Modell entwickelt, um zeitlich ausgedehnte Ereignisse formal zu beschreiben und auf zeitorientierten Daten wiederzufinden. Das Modell ist angelehnt an aus der AI bekannte Zeitlogiken. Wahrend jedoch die Intention des ‘temporal reasoning’ dort das Ableiten von Fakten aus Aussagen mit zeitlichen Komponenten ist, richtet sich unser Interesse auf die Generierung zeitlich ausgedehnter Ereignisse aus diskreten Daten. Das Modell wurde implementiert und auf das LTX-Register, eine systematische perioperative Verlaufsdokumentation auf dem Gebiet der Lebertransplantation,angewandt. Es erlaubt die komplexe Fallsuche zur explorativen Datenanalyse und in klinischen Problemsituationen.