Medullary thyroid carcinoma (MTC) occurs sporadically (sMTC) or as part of the inherited cancer syndrome, multiple endocrine neoplasia type 2 (MEN 2). While the occurence of the MEN 2 syndrome is associated with mutations in the RET protooncogene, the reason for carcinogenesis in sMTC still remains unclear. Ras is a frequently mutated oncogene in a broad spectrum of human tumors and has been found in about 50% of follicular, papillary or anaplastic thyroid carcinomas. The purpose of this study was to determine, whether mutations in the ras oncogene could play a possible role in the carcinogenesis of sMTC. In this study we analyzed 15 sMTC for mutations in the hotspots codon 12, 13 and 61 of the H- and K-ras oncogene. We used the direct sequencing technique. In none of the examined tumors we were able to detect a mutation in the codon 12, 13 and 61 of the H-ras and K-ras oncogene. Based upon these results, we conclude that H- and K-ras do not play an important role in the carcinogenesis of sMTC.

INTRODUCTION:Complex bile duct injury (BDI) is a serious condition requiring hepatectomy in some instances. The present study was to analyse the factors that led to hepatectomy for patients with BDI after laparoscopic cholecystectomy (LC).METHODS:The medical records of patients referred to our department from April 1998 to September 2007 for management of BDI following LC were reviewed, and patients who underwent hepatectomy were identified. The type of BDI, indication for liver resection, interval between LC and liver surgery, histology of the liver specimen, postoperative morbidity and long-term results were analysed.RESULTS:Hepatectomy was performed in 10 of 76 patients (13.2%), with BDI either as isolated damage or in combination with vascular injury (VI). Proximal BDI (defined as disruption of the biliary confluence) and injury to the right hepatic artery were found to be independent risk factors of hepatectomy, with odds ratios of 16 and 45, respectively. Five patients required early liver resection (within 5 weeks post-LC) to control sepsis caused by confluent liver necrosis or bile duct necrosis. In five patients, hepatectomy was indicated during long-term follow-up (over 4 months post-LC) to effectively manage recurrent cholangitis and liver atrophy. Despite of high postoperative morbidity (60%) and even mortality (10%), the long-term results (median follow-up of 34 months) were satisfactory, with either no or only transitory symptoms in 67% of the patients.CONCLUSION:Hepatectomy may inevitably be necessary to manage early or late complications after LC. Proximal BDI and VI were the two independent risk factors of hepatectomy in this series.

The passage through the hilar plate during right graft live donor liver transplantation (LDLT) can have dangerous consequences for both donors and recipients. The purpose of our study was to delineate hilar transection and biliary reconstruction strategies in right graft LDLT, with special consideration of central and peripheral hilar anatomical variants. A total of 71 consecutive donors underwent preoperative three-dimensional (3D) CT reconstructions and virtual 3D hepatectomies. A three-modal hilar passage strategy was applied, and its impact on operative strategy analyzed. In 68.4% of cases, type I and II anatomical configurations allowed for an en block hilar transection with simple anastomotic reconstructions. In 23.6% of cases, donors had "difficult" type II and types III/IV hilar bile duct anatomy that required stepwise hilar transections and complex graft biliary reconstructions. Morbidity rates for our early (A) and recent (B) experience periods were 67% and 39%, respectively. (1) Our two-level classification and 3D imaging technique allowed for donor-individualized transhilar passage. (2) A stepwise transhilar passage was favored in types III and IV inside the right-sided hilar corridor. (3) Reconstruction techniques showed no ameliorating effect on early/late biliary morbidity rates.

Purpose: The aim of this study was to elucidate the role of hypoxia-inducible factor 1 alpha HIF1A expression in hepatocellular carcinoma (HCC) and the corresponding non-malignant liver tissue and to correlate it with the clinical outcome of HCC patients after curative liver resection. Methods: HIF1A expression was determined by quantitative RT-PCR in HCC and corresponding non-malignant liver tissue of 53 patients surgically treated for HCC. High-density gene expression analysis and pathway analysis was performed on a selected subset of patients with high and low HIF1A expression in the non-malignant liver tissue. Results: HIF1A over-expression in the apparently non-malignant liver tissue was a predictor of tumor recurrence and survival. The estimated 1-year and 5-year disease-free survival was significantly better in patients with low HIF1A expression in the non-malignant liver tissue when compared to those patients with high HIF1 expression (88.9 % vs. 67.9 % and 61.0 % vs. 22.6 %, respectively, p = 0.008). Based on molecular pathway analysis utilizing high-density geneexpression profiling, HIF1A related molecular networks were identified that contained genes involved in cell migration, cell homing and cell-cell interaction. Conclusion: Our study identified a potential novel mechanism contributing to prognosis of HCC. The deregulation of HIF1A and its related pathways in the apparently non-malignant liver tissue provides for a modulated environment that potentially enhances or allows for HCC recurrence after curative resection.

Radtke, A.; Klein, C.; Sotiropoulos, G. C.; Beckebaum, S.; Walz, R. E.; Cicinnati, V. R.; Broering, D.; Broelsch, C.; Schroeder, T.; Malagó, M. Author Information

Radtke, A.; Sotiropoulos, G. C.; Klein, C.; Beckebaum, S.; Walz, R. E.; Schroeder, T.; Cicinnati, V. R.; Broering, D.; Broelsch, C.; Malagó, M. Author Information

BACKGROUND: The aim of this study was to delineate an algorithm for donor and recipient criteria and middle hepatic vein (MHV) management in right-graft live-donor liver transplantation (LDLT) on the basis of computerized 3-dimensional computed tomographic image analysis.METHODS: Data on 94 consecutive right-graft LDLTs were prospectively collected. Graft and remnant data for the first 23 cases were retrospectively evaluated by means of 3-dimensional computed tomographic reconstructions, and on the basis of that preliminary series, a graft selection algorithm using 3 parameters-hepatic vein dominance classification, graft and remnant graft volume/body weight ratios, and congestion volumes was created. It was subsequently applied to the next 71 right-graft LDLTs.RESULTS: Fifty-nine right grafts contained the MHV. Four of the 12 grafts with no MHVs required MHV reconstructions. In 18 cases, small liver grafts were used. The postoperative function of liver grafts and remnants with versus without MHVs was not statistically different.CONCLUSIONS: The proposed algorithm favored the inclusion of the MHV with the right grafts. It also allowed for the procurement of grafts that were potentially small for size without compromising donor or recipient safety. (C) 2010 Published by Elsevier Inc.

A 63-year-old woman underwent living donor liver transplantation for hepatic metastases of an extragastrointestinal stromal tumor (EGIST) originating from the rectovaginal space. Due to a multifocal extrahepatic tumor recurrence, treatment with imatinib mesylate was started after extensive pharmacokinetic studies to rule out possible interactions with immunosuppressives. We performed several re- resections for EGIST recurrence thereafter. At the last follow-up, 17 years after primary tumor resection and 10 years after living donor liver transplantation, the patient is symptom-free under immunosuppressive and imatinib mesylate treatments with a 2-cm stable recurrent pararectal EGIST. To our knowledge, this is the only report published on a patient who underwent transplantation for hepatic EGIST metastases with a posttransplantation follow-up of 10 years and the first report on living donor liver transplantation for metastasized EGIST. This is the first description of pharmacokinetics of imatinib and its main active metabolite CGP74588 in a liver transplant recipient.

Radtke, A.; Klein, C.; Sotiropoulos, G. C.; Cicinnati, V. R.; Schroeder, T.; Beckebaum, S.; Walz, R. E.; Broering, D.; Broelsch, C.; Malagó, M. Author Information

Background: Goal of our study was to evaluate the outcome of patients who underwent hepatic resection as part of a multimodality-treatment. Methods: 38 female patients with a median age of 55.2 years underwent hepatic resection with curative intent from 1998-2006. The liver was the only site of metastatic disease. Results: 15 patients underwent major (>3segments), 11 patients minor hepatic resections, and 12 were only explored. Median hospital stay was 14.6 days, with a postoperative morbidity of 7%, and a 30-day mortality of 7%. One-, 3-, and 5-year survival among resected patients was 88%, 53% and 44%, respectively. The corresponding disease free survival was 48%, 8%, and 8%. There was no association between treatment- or patient-specific variables and survival. Conclusions: Resection seems to benefit a cohort of patients with breast cancer International Journal of Hepatology Vol.1(3) 2010 pp.39-43

Abstract Purpose: The aim of our prospective study was to assess the results of major hepatic resections for primary liver tumours in patients 75 years of age or older. Methods: From 10/1999 to 04/2006, 23 patients with non-cirrhotic livers > 75 years presented to our department to undergo curative resection for primary liver malignancies. Data were collected prospectively. Patients were assigned to two groups. Group A included those with resectable tumours, while Group B was made up of those with unresectable lesions. Results: Fourteen patients had intrahepatic cholangiocarcinoma while 9 had hepatocellular carcinoma. Comorbidities were present in every case. Morbidity and hospital mortality rates for group A patients were 25% and 8%, respectively. The corresponding rates for group B patients were 9% and 9%. The 1-, 2-, and 3-year cumulative group A survival was 71%, 51% and 26% for cholangiocarcinoma and 80%, 60% and 60% for hepatocellular carcinoma, respectively. The corresponding group B survival was 45%, 18% and 0%. Conclusion: Advanced age does not seem to negatively affect the outcome of liver resections for malignancies. Hepatic resections in patients 75 years of age or older may be carried out with relative safety as long as patients are appropriately selected.

BACKGROUND:Hepatic surgery is presumed to improve survival of patients with liver metastases (LM) from neuroendocrine tumours (NET). This study identified LM-specific variables that could be used as additional selection criteria for aggressive treatment. METHODS:A novel classification of LM from NET was established based on their localization and presentation. RESULTS:From 1992 to 2006, 119 patients underwent staging and treatment of LM. Three growth types of LM were identified radiologically: single metastasis (type I), isolated metastatic bulk accompanied by smaller deposits (type II) and disseminated metastatic spread (type III). The three groups differed significantly in terms of chronological presentation of LM, hormonal symptoms, Ki-67 index, 5-hydroxyindoleacetic acid and chromogranin A levels, lymph node involvement, presence of bone metastases and treatment options. The 3-, 5- and 10-year disease-specific survival rates for the entire cohort were 76.4, 63.9 and 46.5 per cent respectively. There were significant differences in survival between the three groups: 5- and 10-year rates were both 100 per cent for type I, 84 and 75 per cent respectively for type II, and 51 and 29 per cent for type III. CONCLUSION:The localization and biological features of LM from NET defines therapeutic management and is predictive of outcome.

The purpose of this study was to evaluate the long-term results with monotherapy for hepatocellular carcinoma (HCC) in the setting of cirrhosis. We reviewed data of 14 patients who survived for at least 5 years after performance of liver resection (n = 1), transarterial chemoembolization (TACE, n = 3), or liver transplantation (OLT, n = 19). Eight patients were within the Milan criteria, whereas the remaining 6 were beyond the criteria. Tumor stages according to the UICC were I (n = 8), II (n = 5), and IIIA (n = 1). Vascular invasion was not detected in any patient. The HCCs recurred in 2 patients, at 81 and 48 months' posttransplant. Sites of recurrence were the intrathoracic lymph nodes in the first case, and lungs in the second case. Treatment of recurrence included chemotherapy in the first case and local resection in the second case. Both patients died at 98 and 64 months postoperation (ie, 17 and 16 months, respectively, after the diagnosis of the recurrence). A third patient died of nontumor-related causes at 69 months after his first TACE. Currently, 11 patients are alive with a median survival of 70 months (range, 63-144 months). The alpha-fetoprotein level was demonstrated to be prognostic of recurrence by discriminant function analysis. In conclusion, OLT provided the best long-term results as monotherapy for HCC in the setting of cirrhosis.

Over the last three decades liver transplantation has become an established therapy for patients suffering from end-stage liver disease. In 1955, Welch reported the first attempt at experimental heterotopic grafting of a liver in a dog [1]. The first known experimental orthotopic liver transplantation (OLT) was reported by Cannon in 1956 at the University of California [2]. In 1963, Starzl performed a human-to-human OLT in a 3 year old child with congenital biliary atresia who died intraoperatively [3]. The following 2 transplant recipients lived for 22 days and 1 week, respectively [3]. In 1967, Starzl succesfully transplanted several patients [4]

Yttrium-90 microspheres constitute one of the most recent treatment options for hepatocellular carcinoma (HCC) in the setting of cirrhosis. As such, their spectrum of indication is not yet fully established. Herein, we have reported the case of a patient with HCC beyond the listing criteria for liver transplantation (OLT) who was treated preoperatively with selective transarterial chemoembolization and yttrium-90 microspheres. He was subsequently transplanted with a liver from an 81-year-old donor allocated through Eurotransplant as a "rescue offer." The posttransplant course was uneventful. Pathologic examination revealed a multifocal, well-differentiated pT2 tumor with no vascular invasion. The patient is currently alive and in good condition at 14 months posttransplant, with no evidence of tumor recurrence by a current computed tomography scan. This report provided encouraging information on the potential of yttrium-90 microspheres as a bridging option before OLT for multifocal HCC.

PURPOSE:The purpose of this study was to review our institutional experience with re-liver transplantation (OLT) after split and full-size OLT.PATIENTS AND METHODS:We evaluated data corresponding to retransplanted patients over an 8-year period who underwent deceased donor OLT at our institution. Variables analyzed included indications for primary OLT, and re-OLT, the type of graft used during the initial versus re-OLT, the time from initial to re-OLT, and patient survival after re-OLT.RESULTS:Sixty-four of 697 first OLT (9.2%) required re-OLT. Forty-nine cases were among 637 (7.6%) full-size OLT, while 15 were among 60 (25%) split OLT (P < .001). Median time to re-OLT was 8 days (range = 1-1885 days). Main indications for re-OLT were primary nonfunction/initial poor function (44%), hepatic artery thrombosis (26%), biliary complications (11%), and hepatitis C recurrence (6%). Forty-eight percent of the re-OLTs were performed within the first posttransplant week. The overall survival for these 64 patients was 55% and 48% at 1 and 3 years after the primary OLT, and 44% at both 1 and 3 years after the re-OLT, respectively.CONCLUSIONS:The overall incidence of re-OLT remains 9%. Approximately half of all re-OLT occured within the first posttransplant week. Early retransplantation was associated with the best patient survival. Overall survival after re-OLT was about 10% to 20% lower than that after primary OLT.

BACKGROUND:The precise preoperative calculation of functional liver volumes for both donor and recipient is a crucial part of the evaluation process in adult living donor liver transplantation. The purpose of this study was to describe and validate our modus 3-D CT volumetry.PATIENTS AND METHODS:Native (unenhanced), arterial, and venous phase CT images from 62 consecutive live liver donors were subjected to 3-D CT liver volume calculations and virtual 3-D liver partitioning. Graft-volume estimates based on our modus 3-D volumetry, which subtracted intrahepatic vascular volume from the "smallest" (native) unenhanced CT phase, were subsequently compared to the intraoperative graft-weights obtained in all 62 cases. Calculated (preoperative) liver-volume-body-weight-ratios and measured (intraoperative) liver-weight-body-weight-ratios of liver grafts were analyzed.RESULTS:Preoperative calculations of graft-volume according to our modus 3-D CT volumetry did not yield statistically significant over- or under-estimations when compared to the intraoperative findings independent of their age or gender.CONCLUSION:Our modus 3-D volumetry, when based on the "smallest" (native) unenhanced CT phase, accurately accounted for intrahepatic vascular volumes and offered a precise virtual model of individualized operative conditions for each potential live liver donor.

Background. The purpose of this study was to evaluate our experience with orthotopic liver transplantation (OLT) using grafts from septuagenarians.Patients and Methods. Seventeen adult patients underwent transplantation with grafts from donors 70 years of age or older during an 8-year period.Results. The median donor age was 73 years (range, 70-83). Eleven (64.7%) donors had experienced at least I hypotensive period and received vasoactive drugs. Median cold and warm ischemia times were 7.25 hours and 35 minutes, respectively. Two recipients underwent re transplantation because of dysfunction or primary nonfunction. Morbidity rate was 47% and hospital mortality rate was 23.5%. After a median follow-up of 34.5 months (range, 3-84 months), 5 additional patients died. Median patient survival was 17 months (range, 0-84 months). One-, 3-, 5-, and 7-year cumulative survival rates were 69.7%, 57.5%, 46.2%, and 23.3%, respectively. Only graft dysfunction (P = .042) was observed to be an independent predictor of survival upon multivariate analysis.Conclusions. Although grafts from septuagenarians allow for expansion of the donor pool, long-term recipient survival is inferior to that encountered with younger donors.