R. Pichlmayr

Transplantation einer Spenderleber auf zwei Empfänger (Splitting-Transplantation) - Eine neue Methode in der Weiterentwicklung der Lebersegmenttransplantation

Tumor surgery in this field is no longer such a high risk as previously. Prolonged survival can be achieved by resection of hepatocellular carcinomas in non-cirrhotic livers (3-year survival 58%, n = 54 patients) and for colorectal liver metastases (3-year survival 44%, n = 124 patients). But surgery is rarely successful for the most frequent type of liver malignancy, the hepatocellular carcinoma in cirrhosis. Central bile duct carcinomas are now resected more frequently than in the past. Liver grafting seems indicated in special cases of liver and bile duct tumors. The future developments of operating on the in situ-perfused liver was discussed and the first operation on an ex situ-liver was demonstrated.SummaryA donor liver was divided in such a way that the left part (segment 11 and III without caval vein) could be transplanted into a child, the right part (segment I, IV, V to VIII) into an adult successfully. Common bile duct and common hepatic artery remained with the left part of the liver, portal vein with the right one. In the recipient of the left part of the liver the own caval vein was preserved and anastomosed with the left hepatic vein; the other anastomoses were carried out in the typical way. In the recipient of the right part of the liver the right hepatic artery of the graft was anastomosed with the recipients common hepatic artery using a saphenous interponate. Two separate intrahepatic bile ducts were anastomosed with a Roux-en-Y loop of the jejunum. The other anastomoses were carried out in the typical way. Thus the possibility of using one donor liver for two recipients (splitting transplantation) has been demonstrated.ZusammenfassungEin Spenderleberorgan wurde so getrennt, daß der linke Teil (Segment II und III ohne Vena cava) auf ein Kind, der rechte Teil (Segment 1, IV, V bis VIII) auf einen Erwachsenen erfolgreich transplantiert werden konnte. Choledochus und Arteria hepatica communis bzw. propria blieben beim linken Leberteil, Vena portae beim rechten. Beim Empfänger der linken Seite blieb die eigene Vena cava erhalten; in sie wurde die linke Vena hepatica anastomosiert; die übrigen Anastomosen wurden in üblicher Weise durchgeführt. Beim Empfänger des rechten Leberteiles wurde die spenderseitige Arteria hepatica dextra mit einem Saphenainterponat verlängert und mit der Arteria hepatica communis des Empfängers anastomosiert; zwei getrennte Hepaticusäste wurden mit einer Jejunumschlinge anastomosiert. Die übrigen Anastomosen wurden in typischer Weise ausgeführt. Die Möglichkeit der Verwendung einer Spenderleber für zwei Empfänger (Splitting-Transplantation) ist damit gezeigt.

The role of liver transplantation in hepatobiliary malignancy. A retrospective analysis of 95 patients with particular regard to tumor stage and recurrence.

The role of hepatic transplantation in patients with nonresectable liver or bile duct cancer remains a controversial issue. An analysis of 95 consecutive cases was undertaken to evaluate retrospectively the pathological tumor stage in accordance with the TNM systematic and outcome after transplantation. Included were patients with the following diagnoses: hepatocellular carcinoma (n = 52), cholangiocellular carcinoma (n = 10), hepatoblastoma (n = 2), hemangiosarcoma (n = 2), bile duct carcinoma (n = 20), and liver metastases from different primary tumors (n = 9).The overall actuarial survival rate at 5 years was 20.4%. Median survival improved significantly within the last 4 years as compared to the preceding era (18.06 vs. 4.0 months). Currently 27 patients are alive, with the longest follow-up more than 12 years. The incidences of residual or recurrent tumor were 27 and 28, respectively. Particularly in patients who underwent transplantation for hepatocellular or bile duct carcinoma without extra-hepatic tumor spread, the results were significantly better; median survival time achieved for these two groups were 120 (p < 0.01) and 35 months (p < 0.05). Prolonged survival without tumor recurrence was not seen in patients with cholangiocellular carcinoma or liver metastases. These results demonstrate clearly that liver transplantation for hepatobiliary malignancy is still justified on the premises of careful patient selection by adequate tumor staging.

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.

Normalised intrinsic mortality risk in liver transplantation: European Liver Transplant Registry study

BACKGROUND No model exists for liver transplantation to estimate the mortality risk in a given patient, and no standard by which to assess performance in different centres. We investigated the intrinsic mortality risk in the absence of known mortality risk factors. METHODS We identified mortality risk factors and risk ratios quantified in data from the European Liver Transplant Registry (22,089 patients at 102 centres in 18 countries) registered from 1988 to 1997. To develop a model of the intrinsic risk and the risk ratios for specific factors, univariate and multivariate analyses were done separately for the overall population, for adults, and for children younger than 15 years, and the number of deaths were estimated. We validated the model by comparing mortality in patients without risk factors with the model-adjusted mortality in patients with risk factors. FINDINGS Overall 5-year and 8-year actuarial survival was 66% (95% CI 65-66) and 61% (60-62). 65% of deaths occurred within 6 months. Retransplantation, transplantation for cancer, acute liver failure, fewer than 20 split-liver grafts per year, and a centre workload of fewer than 25 transplants per year were the main risk factors of 12 identified factors. 1-year and 5-year death rates among adults with no risk factors were similar to model estimates (15 [13-16] vs 14% [13-15], and 22 (20-24) vs 23% [21-24]). Corresponding data for paediatric transplants were 9% (7-12) compared with 11% (9-12) and 13% (10-17) compared with 14% (11-16). The reduction of mortality risk in high-volume centres was even greater in patients without risk factors (48 vs 23%, p<0.001). INTERPRETATION The normalised intrinsic mortality risk can be combined with the relative risk ratios of known risk factors to better estimate the mortality risk of a given procedure in a given patient. Centres can assess performance by removing potential bias of donor and recipient selection.

Resectional surgery of hilar cholangiocarcinoma: a multivariate analysis of prognostic factors.

PURPOSE To define the prognostic factors after surgical resection of bile duct carcinomas at the hepatic bifurcation. PATIENTS AND METHODS The retrospective single-center experience details 151 patients after surgical resection of central bile duct carcinoma performed between 1971 and 1995. Tumor removal was accomplished by resection of the bile duct bifurcation either alone (group I, n = 33), in combination with hepatic resection (group II, n = 77), or combined with hepatic and vascular resection (group III, n = 41). Survival analysis was performed by the Kaplan-Meier method and the relationship between each of the clinicopathologic variables and survival was assessed by the log-rank test. Multivariate results were confirmed using Cox regression. RESULTS The overall hospital mortality rate was 9.9% and depended on the extent of resection (group 1, 6.1%; group II, 7.8%; group III, 17.1%). After exclusion of hospital deaths, the overall patient survival rate was 28.4% at 5 and 15.5% at 10 years, with a median survival duration of 2.05 +/- 0.23 years. Univariate survival analysis identified tumor size, lymph node metastases, residual tumor stage, and tumor grading as factors with a statistically significant prognostic impact. Survival prognosis was not influenced by the site of the tumor according to the classification of Bismuth and Corlette, extent of resection, International Union Against Cancer (UICC) stage, perineural and vascular invasion, age, or sex. In a multivariate Cox analysis, only lymph node metastases and residual tumor stage proved to be of independent prognostic significance. CONCLUSION Resection of central bile duct carcinoma is feasible in many patients and a favorable outcome after resection is mainly determined by curative resection and the absence of lymph node metastases.

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.

Adenine nucleotide metabolism and its relation to organ viability in human liver transplantation

The relationship between adenine nucleotide metabolism and ischemic damage was studied in human liver. Thirty transplanted grafts were divided into two groups assording to their functional outcome. Cellular adenine nucleotide levels were assayed by high-performance liquid chromatography. During cold ischema, the adenosine triphosphate (ATP) level was not correlated with graft function, but two grafts with low total adenine nucleotides (TAN) levels showed poor function after transplantation. After recirculation, the ATP level showed good recovery in grafts that functioned satisfactorily (n=24), 5.47±1.51 mUmol/g dry weight), but remained low in poorly functioning grafts (n=6), 3.30pL 1.68 mUmol/g dry weight) (P<0.01). Bile production, used as a parameter of initial function, was observed shortly after implantation in 17 of 24 grafts that functioned satisfactorily, but in only 1 of 6 poorly functioning grafts. It is concluded that loss of ademine nucleotides and lack of bile production during transplantation are good markers of damaged grafts in human liver transplantation.

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.

Compartment-oriented microdissection of regional lymph nodes in medullary thyroid carcinoma

Lymph node metastases have been proven to be the main prognostic factor in medullary thyroid carcinoma (MTC). This retrospective study was undertaken to evaluate the efficiency of two surgical techniques of regional lymph node dissection with regard to the normalization of pentagastrin-stimulated serum calcitonin level and patient survival: selective lymphadenectomy, i.e., the excision of macroscopically or microscopically involved lymph nodes, versus a systematic lymphadenectomy performed by the new technique of a compartment-oriented microdissection. From 1970 to 1990, 82 patients with sporadic (n=57) and hereditary (n=25) MTC underwent a total of 142 operations including 63 selective lymphadenectomies and, since 1986, 35 systematic lymphadenectomies. The study revealed that in node-positive MTC the rate of interventions with a postoperative normalization of pentagastrin-stimulated serum calcitonin was higher after systematic lymphadenectomy (29.2%) than after selective lymphadenectomy (8.5%) (P<0.01). The rate of patients undergoing repeat surgery due to a recurrence of MTC was 48% after selective lymphadenectomy and 10% after systematic lymphadenectomy. Survival was significantly better for patients after systematic versus selective lymphadenectomy (P<0.005). This study thus emphasizes that systematic lymphadenectomy, using the technique of a compartment-oriented microdissection of cervicomediastinal lymph nodes, represents the preferred surgical treatment as well as the optimum technique in primary as well as secondary node-positive MTC.

Drug metabolism in hepatocyte sandwich cultures of rats and humans

Adult hepatocytes from rat and man were maintained for 2 weeks between two gel layers in a sandwich configuration to study the influence of this culture technique on the preservation of basal activities of xenobiotic-metabolizing phase I and phase II enzymes. The response of these enzyme activities to an enzyme inducer was investigated using rifampicin (RIF). Basal levels of cytochrome P-450 (CYP) isozymes were characterized by measuring ethoxyresorufin O-deethylation (EROD), ethoxycoumarin O-deethylation (ECOD), and the specific oxidation of testosterone (T). In hepatocytes from untreated rats, CYP isozyme levels, including the major form CYP 2C11, increased during the first 3 days in culture. After this period of recovery, the levels of CYP 2C11, CYP 2A1, and CYP 2B1 decreased, whereas CYP 3A1 increased. In contrast to these dynamic changes, CYP activities such as CYP 1A2 and the major isozyme CYP 3A4 were largely preserved until day 9 in cultures of human hepatocytes. In measuring phase II activities, a distinct increase in glucuronosyltransferase (UDP-GT) activity toward p-nitrophenol (PNP) was found for rat and human hepatocytes over 2 weeks in culture. Sulfotransferase (ST) activity toward PNP showed an initial increase, with a maximum at day 7 and day 9 in culture, respectively, and then decreased until day 14. Glutathione S-transferase (GST) activity decreased constantly during the time of culture. Effects of the enzyme-inducing drug rifampicin on phase I and phase II enzymes were investigated using cultured human hepatocytes. Rifampicin treatment (50 micromol/L) for 7 days resulted in a 3.7-fold induction of CYP 3A4 at day 9 in culture. ECOD activity was increased sixfold and phase II ST activity increased twofold compared to the initial value at day 3. No effect of rifampicin on CYP 3A was found in cultures of rat hepatocytes. These results demonstrate that rat and human hepatocytes preserve the major forms of CYP isozymes and phase II activities and respond to inducing drugs such as rifampicin. The novel hepatocyte sandwich culture is suitable for investigating drug metabolism, drug-drug interactions and enzyme induction.