Christian Ducerf

Small nodule detection in cirrhotic livers : Evaluation with US, spiral CT, and MRI and correlation with Pathologic examination of explanted liver

Purpose The purpose of this work was to evaluate the detection and characterization of nodules ≥8 mm and small hepatocellular carcinomas (HCCs) in liver cirrhosis. Method Pathologic examination and results of US, helical CT, and dynamic MRI with gadolinium were compared after orthotopic liver transplantation (OLT) of 43 cirrhotic patients. Nodules were classified as macroregenerative nodules (MRNs), borderline nodules (BNs), and HCC. Results Pathologic examination classified 69 nodules: 50 MRNs, 6 BNs, and 13 HCCs. Sensitivities of MRN, BN, and HCC detection were, respectively, for US imaging 2% (1/50), 33.3% (2/6), and 46.2% (6/13); for helical CT 2% (1/50), 50% (3/6), and 53.8% (7/13); and for MRI 42% (21/50), 50% (3/6), and 76.9% (10/13). MRI detected 21 MRNs. They presented on T1/T2-weighted images as hyperintense/hypointense (n = 8), hyperintense/isointense (n = 7), hypointense/hypointense (n = 4), hypointense/isointense (n = 1), and hypointense depicted only on echo planar imaging (n = 1). The three detected BNs were hyperintense/hypointense nodules. The 10 detected HCCs appeared hyperintense/isointense (n = 7), hyperintense/hypointense (n = 2), and hypointense/isointense (n = 1). None of the MRNs but eight HCCs and one BN were enhanced after gadolinium injection. Conclusion Contrast-enhanced MRI is the most sensitive technique for detecting liver nodules. No MR signal intensity pattern characteristic of small HCCs enables differentiation from benign nodules, however. Gadolinium enhancement is the most sensitive and specific characteristic of HCC.

Impact of pretransplantation transarterial chemoembolization on survival and recurrence after liver transplantation for hepatocellular carcinoma.

The actual impact of transarterial chemoembolization before liver transplantation (LT) for hepatocellular carcinoma (HCC) on patient survival and HCC recurrence is not known. Between 1985 and 1998, 479 patients with HCC in 14 French centers were evaluated for LT. Among these 479 patients, this case‐control study included 100 patients who received transarterial chemoembolization before LT (TACE group) and 100 control patients who did not receive chemoembolization (no‐TACE group). Patients and controls were matched for the pre‐LT tumor characteristics, the period of transplantation, the time spent on the waiting list, and pre‐ and posttransplantation treatments. Kaplan‐Meier estimates were calculated 5 years after LT and were compared with the log‐rank test. The mean waiting time before LT was 4.2 ± 3.2 months in the TACE group and 4.3 ± 4.4 months in the no‐TACE group. The median number of TACE procedures was 1 (range: 1‐12). Demographic data, median alpha‐fetoprotein level (21.6 ng/mL and 22.0 ng/mL, respectively), and pre‐ and post‐LT morphologic characteristics of the tumors did not differ in the TACE and no‐TACE groups. Overall 5‐year survival was 59.4% with TACE and 59.3% without TACE (ns). Survival rates did not differ significantly between the two groups with respect to the time on the waiting list, the tumor diameter, or the type of TACE (selective or nonselective). In the TACE group, 30 patients had tumor necrosis ≥80% on the liver explant with a 5‐year survival rate of 63.2%, compared with 54.2% among their matched controls (P = 0.9). In conclusion, with a mean waiting period of 4.2 months and 1 TACE procedure, pre‐LT TACE does not influence post‐LT overall survival and disease‐free survival. (Liver Transpl 2005;11:767–775.)

Long term histological improvement and clearance of intrahepatic hepatitis C virus RNA following sustained response to interferon-ribavirin combination therapy in liver transplanted patients with hepatitis C virus recurrence.

Background and objective: A proportion of liver transplanted patients with recurrent chronic hepatitis have a sustained virological response to combination therapy with interferon plus ribavirin. However, the long term benefit of antiviral therapy with regard to hepatitis C virus (HCV) RNA clearance remains unknown in patients with HCV recurrence. This study examined the long term biochemical, virological, and histological outcome in transplanted patients with recurrent chronic hepatitis who had a sustained virological response to antiviral therapy. Patients and methods: Fifty four patients with recurrent hepatitis C were treated with antiviral therapy involving induction by combination therapy (interferon (IFN) plus ribavirin) for six months and maintenance ribavirin therapy for 12 months. Fourteen patients who had recurrent chronic hepatitis and sustained virological response to antiviral therapy were followed for three years after the end of antiviral therapy. Serum alanine aminotransferases were assessed every three months during the observation period. Serum hepatitis C RNA detected by polymerase chain reaction was evaluated every six months during follow up, and protocol biopsy procedures were performed routinely every year. Semiquantitative histopathological assessment of allograft hepatitis was performed using the Knodell score and HCV was also detected by polymerase chain reaction on frozen graft tissue samples. Results: At the end of antiviral therapy, the sustained response rate was 26%. A complete response (normal serum alanine aminotransferase level and undetectable serum HCV RNA) was achieved in 13/14 (93%) patients three years after the end of treatment. A comparison of liver histology findings before and after a mean of three years after antiviral therapy showed a clear improvement in 12/14 (86%) patients. In 5/14 (36%) patients, the last biopsy showed normal or near normal histological findings. After three years of follow up, the total Knodell score was 3.2 (range 1–8) versus 8.3 (range 5–12) before treatment (p=0.001). Graft HCV RNA was detectable before treatment in all 14 patients and was undetectable at the end of follow up in 13/14 (93%) patients tested. Conclusion: In patients with biochemical and virological responses induced by ribavirin and interferon, a complete response was sustained in 93% for at least three years after cessation of therapy. This long term response was associated with absence of detectable intrahepatic hepatitis C RNA and marked histological improvement.

Impact of UCSF criteria according to pre‐ and post‐OLT tumor features: Analysis of 479 patients listed for HCC with a short waiting time

Orthotopic liver transplantation (OLT) indication for hepatocellular carcinoma (HCC) is currently based on the Milan criteria. The University of California, San Francisco (UCSF) recently proposed an expansion of the selection criteria according to tumors characteristics on the explanted liver. This study: 1) assessed the validity of these criteria in an independent large series and 2) tested for the usefulness of these criteria when applied to pre‐OLT tumor evaluation. Between 1985 and 1998, 479 patients were listed for liver transplantation (LT) for HCC and 467 were transplanted. According to pre‐OLT (imaging at date of listing) or post‐OLT (explanted liver) tumor characteristics, patients were retrospectively classified according to both the Milan and UCSF criteria. The 5‐yr survival statistics were assessed by the Kaplan‐Meier method and compared by the log‐rank test. Pre‐OLT UCSF criteria were analyzed according to an intention‐to‐treat principle. Based on the pre‐OLT evaluation, 279 patients were Milan+, 44 patients were UCSF+ but Milan− (subgroup of patients that might benefit from the expansion), and 145 patients were UCSF− and Milan−. With a short median waiting time of 4 months, 5‐yr survival was 60.1 ± 3.0%, 45.6 ± 7.8%, and 34.7 ± 4.0%, respectively (P < 0.001). The 5‐yr survival was arithmetically lower in UCSF+ Milan− patients compared to Milan+ but this difference was not significant (P = 0.10). Based on pathological features of the explanted liver, 5‐yr survival was 70.4 ± 3.4%, 63.6 ± 7.8%, and 34.1 ± 3.1%, in Milan+ patients (n = 184), UCSF+ Milan− patients (n = 39), and UCSF− Milan− patients (n = 238), respectively (P < 0.001). However, the 5‐yr survival did not differ between Milan+ and UCSF+ Milan− patients (P = 0.33). In conclusion, these results show that when applied to pre‐OLT evaluation, the UCSF criteria are associated with a 5‐yr survival below 50%. Their applicability is therefore limited, despite similar survival rates compared to the Milan criteria, when the explanted liver is taken into account. Liver Transpl 12:1761‐1769, 2006.

Liver resection of transplantation for hepatocellular carcinoma?: Restrospective analysis of 215 patients with cirrhosis

BACKGROUND/AIMS Currently, surgical treatment of hepatocellular carcinoma in patients with cirrhosis is not clearly defined. The objective of this study was, in patients with cirrhosis with hepatocellular carcinoma, to compare liver resection to transplantation assessed by patient survival and to determine whether the tumor recurrence might be influenced by prognostic factors. METHODS We have gathered all the available data from six French Medical Universities, for 215 patients with cirrhosis with hepatocellular carcinoma surgically treated either by liver resection (102) or by transplantation (113). RESULTS The overall 5-year survival rate was similar in the transplantation group and in the resection group (32% vs. 31%, p=0.7). However, the 5-year survival rate without recurrence was higher in the transplantation group than in the resection group (60% vs. 14%, p<0.001). Three independent prognostic factors influenced significantly the survival without recurrence: the surgical treatment by transplantation (p<0.001), the number of tumors (p<0.01) and the tumor size (p<0.001). With these factors we defined a prognostic index (Ip) which allowed assessment of the probability of survival without recurrence: Ip= (Xie. x 1.41)+(Nbr T. x 0.19)+(Size TV. x 0.16); Xie=surgical treatment (Xie=0 if transplantation, Xie=1 if resection), Nbr.T. and Size TV.=number of tumors and size of the most voluminous tumor, respectively, according to the histologic study. CONCLUSIONS These results and this prognostic index are encouraging for liver transplantation as treatment of hepatocellular carcinoma in selected patients with cirrhosis.

Corticosteroid‐free immunosuppression with tacrolimus following induction with daclizumab: A large randomized clinical study

This open, randomized (1 : 1), multicenter, 3‐month study compared a dual tacrolimus plus steroids (Tac / steroids) regimen with a steroid‐free immunosuppressive regimen of tacrolimus following daclizumab induction therapy (Tac / Dac) in adult liver transplant recipients. The full analysis set comprised 347 patients in the Tac / steroids group and 351 in the Tac / Dac group. Mean tacrolimus dose during month 3 was 0.11 mg/kg/day in both groups; mean whole‐blood trough levels during month 3 were 10.9 ng/mL (Tac / steroids) and 10.6 ng/mL (Tac / Dac). The incidence of biopsy‐confirmed acute rejection that required treatment was similar in both groups: 26.5% in the Tac / steroids group and 25.4% in the Tac / Dac group (P = .727). However, the incidence of biopsy‐confirmed corticosteroid‐resistant acute rejection was higher in the Tac / steroids group than in the Tac / Dac group (6.3 vs. 2.8%; P = .027). Kaplan‐Meier estimates of graft survival (92.2 vs. 90.5%) and patient survival (94.5 vs. 93.7%) were similar in both groups. While also the overall adverse event profiles were similar, the incidences of diabetes mellitus (15.3 vs. 5.7%, respectively; P < .001) and cytomegalovirus infection (11.5 vs. 5.1%, respectively; P = .002) were higher in the Tac / steroids group compared with the Tac / Dac group. Mean cholesterol levels increased by 16% in the Tac / steroids group, but were unchanged in the Tac / Dac group during the study. In conclusion, tacrolimus monotherapy following daclizumab induction is an effective and safe regimen, with an advantage over concomitant steroid‐maintenance therapy in terms of a lower incidence of diabetes and viral infection, and a lower incidence of steroid‐resistant acute rejection. (Liver Transpl 2005;11:61–67.)

Benefit of sustained virological response to combination therapy on graft survival of liver transplanted patients with recurrent chronic hepatitis C.

Recurrent hepatitis C infection is an important cause of progressive fibrosis, cirrhosis and graft loss after liver transplantation. Treatment for post‐transplant recurrence results in sustained virological response (SVR) in up to 30% of cases. The aim of this study was to evaluate the impact of SVR on patients and graft survival. Thirty‐four patients with an SVR to IFN‐ribavirin were included. Forty‐six nonresponders to the combination formed the control group. Follow‐up data were recorded every 6 months and included HCV RNA, and the occurrence of clinical problems (cirrhosis, decompensation, hepatocellular carcinoma, death). A graft biopsy was performed every year. The mean follow‐up duration was 52 months in responders and 57 months in nonresponders. Two patients died in each group of patients. Two patients with SVR developed late virological relapse. Fibrosis decreased in 38% of patients with SVR, remained stable in 44% and worsened in 18%. In contrast, fibrosis increased in the majority of nonresponder patients (74%, p < 0.001). At the end of follow‐up, no patient without cirrhosis at inclusion developed cirrhosis of the graft versus 9 among nonresponder patients (p = 0.009). No difference in patient survival was observed in the two groups. In conclusion, this study shows that HCV eradication has a positive impact on graft survival.

Influence of surgical margins on outcome in patients with intrahepatic cholangiocarcinoma: a multicenter study by the AFC-IHCC-2009 study group

Objective:Define the optimal surgical margin in patients undergoing surgery for intrahepatic cholangiocarcinoma (IHCC). Background Data:Surgery is the most effective treatment for IHCC. However, the influence of R1 resection on outcome is controversial and that of margin width has not been evaluated. Methods:We studied 212 patients undergoing curative resection of mass-forming–type IHCC. The respective influences on survival of resection status (R0 vs R1), surgical margin width, pTNM stage, and the latters components were evaluated. Results:Incidence of R1 resection was 24%. Overall, R1 resection was not an independent predictor of survival [odds ratio (OR) 1.2 (0.7–2.1)] in contrast to the pTNM stage [OR 2.10 (1.2–3.5)]. In the 78 pN+ patients, survival was similar after R0 and R1 resections (median: 18 vs 13 months, respectively, P = 0.1). In the 134 pN0 patients, R1 resection was an independent predictor of poor survival [OR 9.6 (4.5–20.4)], as was the presence of satellite nodules [OR 1.9 (1.1–3.2)]. In the 116 pN0 patients with R0 resections, median survival was correlated with margin width (⩽1 mm: 15 months; 2–4 mm: 36 months; 5–9 mm: 57 month; ≥10 mm: 64 month, P < 0.001) and a margin >5 mm was an independent predictor of survival [OR 2.22 (1.59–3.09)]. Conclusion:Patients undergoing surgery for IHCC are at high risk of R1 resections. In pN0 patients, R1 resection is the strongest independent predictor of poor outcome and a margin of at least 5 mm should be created. The survival benefits of resection in pN+ patients and R1 resection in general are very low.

Anatomical variations of the hepatic artery: study of 932 cases in liver transplantation

The aim of this study was to identify and to classify anatomical hepatic artery (HA) variations concerning 932 HA dissections in liver transplantation (LT). Normal HA distribution was found in 68.1%. Variations of HA were detected in 31.9% and were divided into three groups describing 48 common hepatic artery (CHA) anomalies, 236 left or right hepatic artery (RHA) anomalies and 13 rare variations including one case of RHA stemmed from the inferior mesenteric artery and one case of normal CHA passed behind the portal vein. The authors propose a modified classification for HA anomalies which are based on the origin of the hepatic arterial supply (either by the CHA as the only source of the arterial vascularization or by additional or replaced right and left arteries) in order to improve management of liver disease thus as in LT.

Hepatic outflow study after piggyback liver transplantation

BACKGROUND Hepatic vein outflow is discussed in liver transplantation after preservation of recipient retrohepatic vena cava. The aim of this study was to compare two methods of suparahepatic caval anastomosis. METHODS From January 1993 to January 1995, 81 patients received 88 liver transplants because of liver cirrhosis (n = 70), acute liver failure (n = 7), elective retransplantation after hepatic artery thrombosis (n = 2), giant hemangioma (n = 1), and combined liver-small bowel transplantation (n = 1). Seven patients underwent urgent retransplantation, 12 had preoperative transjugular intrahepatic portocaval stent, and 11 had portal vein thrombosis. Five patients required extracorporeal venous shunt. A total of 82 liver transplantations had preservation of RHVC, and 70 patients received temporary end-to-side portacaval shunt. Suprahepatic caval anastomosis was carried out in 52 patients (group 1) between the graft suprahepatic vena cava and the ostia of recipient left and median hepatic veins. Thirty patients (group 2) had associated 3 cm vertical cavotomy with partial clamping of RHVC. In the fourth postoperative month 20 patients from each group had pressure and gradient measurement made among the hepatic veins, right atria, and the RHVC. RESULTS Mean pressure gradient between hepatic veins and right atria was 0.75 +/- 0.49 mm Hg in group 1 and 2.06 +/- 0.85 mm Hg in group 2. Between the RHVC and the right atria it was 0.63 +/- 0.5 mm Hg in group 1 and 2.22 +/- 1.29 mm Hg in group 2. A pressure gradient higher than 3 mm Hg was considered hemodynamically significant. This pressure gradient was found between the hepatic veins and right atria in 10% of patients in group 1 and 40% of patients in group 2 (p = 0.03) and between the RHVC and right atria in 15% of patients in group 1 and 30% of patients in group 2 (p = 0.3). CONCLUSIONS Preservation of the recipient RHVC with recipient caval anastomosis at the ostia of the median and left hepatic veins is a reliable technique without any hepatic venous outflow alteration. Associated cavotomy is not necessary.