L. Belli

Predictors of Long-Term Survival After Liver Transplantation for Hepatocellular Carcinoma

AIMS:The aim of this study was to identify predictors of both survival and tumor-free survival of a cohort of 155 patients, with hepatocellular carcinoma (HCC) and cirrhosis, who were treated by orthotopic liver transplantation (OLT).METHODS:From January 1989 to December 2002, 603 OLTs were performed in 549 patients. HCC was diagnosed in 116 patients before OLT and in 39 at histological examination of the explanted livers. Eighty-four percent of the patients met “Milan” criteria at histology. Ninety-four patients received anticancer therapies preoperatively.RESULTS:The median follow-up was 49 months (range, 0–178). Overall, 1-, 3-, 5-, and 10-yr survival were 84%, 75%, 72%, and 62%, respectively. Survival was not affected by the patients age or sex, etiology of liver disease, Child score at transplantation, rejection episodes, tumor number, total tumor burden, bilobar tumor, and pathologic Tumor, Nodes, Metastasis (pTNM) stages. There was no statistically significant difference in survival when patients were grouped according to the recently proposed simplified pTNM staging (5-yr survival, 80% in stage I, 69% in stage II, 50% in stage III, p = 0.3) or the United Network for Organ Sharing (UNOS) staging system for HCC. Encapsulation of the tumor and α-fetoprotein levels significantly affect patient survival. Five-year survival of patients with poorly differentiated (G3) HCC was significantly worse than that of patients with moderately (G2) or well-differentiated (G1) HCC (respectively, G3 44%, G2 67%, and G1 97%, p = 0.0015). Patients with micro- or macro-vascular invasion had a worse 5-yr survival than patients without vascular invasion (49% vs 77%, p = 0.04). Multivariate analysis showed that histological grade of differentiation and macroscopic vascular invasion are independent predictors of survival (HR 2.4, 95% CI 1.4–4.1, p = 0.0009 and HR 2.8, 95% CI 1.2–6.8, p = 0.022).CONCLUSION:Histological grade of differentiation and macroscopic vascular invasion, as assessed on the explanted livers, are strong predictors of both survival and tumor recurrence in patients with cirrhosis who received transplants for HCC.

Liver transplantation for HCV cirrhosis: Improved survival in recent years and increased severity of recurrent disease in female recipients: Results of a long term retrospective study

In recent years, a worsening outcome of hepatitis C virus (HCV)‐positive recipients and a faster progression of recurrent disease to overt cirrhosis has been reported. Our aims were to 1) assess patient survival and development of severe recurrent disease (Ishak fibrosis score > 3) in different transplant years; and 2) model the effects of pre‐ and post‐liver transplantation (LT) variables on the severity of recurrent disease. A multicenter retrospective analysis was conducted on 502 consecutive HCV‐positive transplant recipients between January 1990 and December 2002. Protocol liver biopsies were obtained at 1, 3, 5, 7, and 10 yr post‐LT in almost 90% of the patients. All 502 patients were included in the overall survival analysis, while only the 354 patients with a follow‐up longer than 1 yr were considered for the analysis of predictors of disease progression. The overall Kaplan–Meier survival rates were 78.7%, 66.3%, and 58.6%, at 12, 60, and 120 months, respectively, and a trend for a better patient survival over the years emerged from all 3 centers. The cumulative probability of developing HCV‐related recurrent severe fibrosis (Ishak score 4‐6) in the cohort of 354 patients who survived at least 1 yr remained unchanged over the years. Multivariate analysis indicated that older donors (P = 0.0001) and female gender of recipient (P = 0.02) were the 2 major risk factors for the development of severe recurrent disease, while the adoption of antilymphocytic preparations was associated with a less aggressive course (P = 0.03). Two of these prognostic factors, donor age and recipient gender, are easily available before LT and their combination showed an important synergy, such that a female recipient not only had a much higher probability of severe recurrent disease than a male recipient but her risk increased with the increasing age of the donor, reaching almost 100% when the age of the donor was 60 or older. In conclusion, a trend for a better patient survival was observed in more recent years but the cumulative probability of developing severe recurrent disease remained unchanged. The combination of a female recipient receiving an older graft emerged as a strong risk factor for a severe recurrence. Liver Transpl, 2007.

Hepatocellular carcinoma: comparison between liver transplantation, resective surgery, ethanol injection, and chemoembolization

Abstract Between January 1989 and June 1997, 533 patients (423 male, 110 female, mean age 61 years, range 22–89 years) with hepatocellular carcinoma (HCC) were observed at our center. We report on 419 patients retrospectively compared for different treatments: liver transplantation (LT; 55 patients), resective surgery (RS; 41 patients), transarterial chemoembolization (TACE; 171 patients) and percutaneous ethanol injection (PEI; 152 patients). The 3‐ and 5‐year actuarial survival rates were, respectively, 72% and 68% for LT, 64 and 44% for RS, 54 and 36% for PEI, and 32 and 22% for TACE. Survival curves were compared for sex, age, tumor characteristics, alphafetoprotein level, Child class, and etiology of cirrhosis. All patient‐related characteristics examined (sex, age) are not significantly related to patient survival. Tumor‐related variables and associated liver disease variables significantly conditioned survival in relation to different treatments. LT seems to be the treatment of choice for monofocal HCC less then 5 cm in diameter and in selected cases of plurifocal HCC.

Lamivudine treatment for acute hepatitis B after liver transplantation

BACKGROUND/AIMS Acute hepatitis caused by recurrent or de novo hepatitis B virus (HBV) infection after liver transplantation frequently induces aggressive disease leading to liver failure. The aim of this study was to determine the efficacy and safety of lamivudine treatment in post-transplant acute hepatitis B. METHOD Twelve patients with acute hepatitis B were started on lamivudine 100 mg p.o. daily within 8 weeks of the appearance of HBsAg. One patient was excluded after 1 month because of hepatocellular carcinoma recurrence. Patients were followed for an average of 68.6 weeks (range 32-108), and were clinically and biochemically evaluated on a monthly basis. They had a histological assessment at baseline, after at least 6 months, and whenever clinically indicated. RESULTS Basal HBV-DNA ranged between 13 and 1288 pg/ml and serum alanine aminotransferase between 97 and 1036 U/l. HBV-DNA became undetectable within 8 weeks and transaminases normalized within 24 weeks in all cases. At the last visit, eight patients (73%) remained HBV-DNA negative by liquid hybridization and had normal or close to normal alanine aminotransferase. Five patients (45%) were also HBsAg negative and HBV-DNA negative by polymerase chain reaction. HBV-DNA and transaminase breakthrough occurred in three patients (27%). Histology after 6-9 months showed chronic hepatitis in seven patients. Lamivudine was well tolerated without serious adverse reactions. CONCLUSIONS These results indicate that lamivudine treatment induces sustained inhibition of viral replication and normalization of transaminases in the majority of post-transplant patients with acute hepatitis B. HBsAg loss may be achieved in a considerable number of cases. Although viral resistance is relatively frequent, early initiation of lamivudine appears to be effective and safe.

The role of spontaneous portosystemic shunts in the course of orthotopic liver transplantation

Abstract. Spontaneous portosystemic shunts are commonly found in cirrhotic patients. Not yet established is their role after orthotopic liver transplantation (OLTx), especially when an increase in portal pressure develops, as during early acute rejection. In this study, 34 cirrhotic patients in a series of 70 OLTx are considered. Each patient had preoperative angiographic assessment, and, in 21 (62 %), large spontaneous portosystemic shunts were evident. In 12 cases the shunts were not affected by the surgical procedure and were present during the postoperative period; in 9 the hepatectomy itself involved interruption of the shunts. The patient population was divided into two groups: patients with postoperative shunts (n = 12) and those without (n= 22). The two groups were similar in age, sex. Childs stage, transplantation variables, and number and grade of rejection episodes. However, mean transaminases (AST) values in the first 2 weeks were significantly higher levels in shunt versus nonshunt patients (421 ± 335 vs 183 ± 126; P < 0.025), and this was even more evident when rejection occurred (626 + 375 vs 195 ±129; P < 0.001). Furthermore, during an acute rejection reaction, three cases showed a true “steal phenomenon” through the large reopened shunts with ischemic damage to the grafts. The data indicate a possible detrimental effect of the spontaneous shunts on graft perfusion and suggest the prophylactic surgical interruption of the residual shunts during the transplantation.

Is the use of marginal donors justified in liver transplantation? Analysis of results and proposal of modern criteria

Abstract  A discrepancy exists worldwide between the number of suitable liver donors and the in creasing demand for transplantation. Thus many centers have considered widening their liver donor acceptance criteria and this may in crease the incidence of primary dysfunction (PD) with negative effect on the results of transplantation. In order to reduce the incidence of PD and improve patient and graft survival it becomes important to identify those risk factors associated with its occurrence. In a retrospective univariate and multivariate analysis we evaluated several donor, preservation and recipient parameters and their correlation with PD. In our Department 282 orthotopic liver transplantations (OLT) were per formed on 256 adult patients over a 10–year period. Excluded were 15 cases with early vascular problems and 4 intraoperative deaths. A complete series of donor, recipient and procedure‐related data were ana lyzed. About 30 % of donors showed abnormal values. In 70 cases of PD (26 %) there was a 61.4 % graft failure rate compared with 15 % in the group with immediate function (P < 0.05). Univariate analysis showed donor age, steatosis, is chemia time, amines, oliguria, hy potension and ICU stay to be signif icantly associated with PD. Multi variate analysis showed steatosis, is chemia time and amine dosage to be independent risk factors for the de velopment of primary non function. In conclusion, the acceptance of marginal donors worsened the results of transplantation, but the rejection of these donors would reduce by about 30 % our transplant activity resulting in increased mortality in the waiting list. Combinations of risk factors when possible should be avoided, and ischemia time, as the only variable that can be controlled, should be kept as short as possible.

Reflex control of blood pressure and heart rate by arterial baroreceptors and by cardiopulmonary receptors in the unanaesthetized cat.

Studies in unanaesthetized animals have reported that section of the carotid sinus and aortic nerves is accompanied by an increased blood pressure variability but not by a sustained blood pressure rise, thus questioning the role of arterial baroreceptors in the long term control of mean blood pressure values. However, sino-aortic denervation (SAD) does not produce denervation of all baroreceptor areas, and it has been suggested that aortic baroreceptor fibres in the vagus and cardiopulmonary vagal afferents that restrain sympathetic vasoconstrictor tone prevent blood pressure from permanently rising. In unanaesthetized cats we recorded blood pressure intra-arterially for 8-12 h when baroreflexes were intact, 7 days after SAD and 1-2 days additional bilateral cervical vagotomy. Blood pressure signals were analysed by computer to provide means and coefficients of variation (CV, variabilities) for each recording period. In intact cats, mean blood pressure was 99 +/- 7 mmHg (average +/- s.e.) and CV 6 +/- 1%. SAD did not alter mean blood pressure but markedly increased CV (12 +/- 2%; P less than 0.01). Additional vagotomy did not alter mean blood pressure (104 +/- 6 mmHg), nor did it alter the increased CV observed after SAD alone. Vagotomy failed to affect mean blood pressure and CV even when performed in cats with intact carotid and aortic nerves. The lack of effect of vagotomy did not depend on simultaneous section of afferent and efferent fibres, because selective blockade of the latter by atropine also failed to affect mean blood pressure and CV.(ABSTRACT TRUNCATED AT 250 WORDS)

A Multistep, Consensus‐Based Approach to Organ Allocation in Liver Transplantation: Toward a “Blended Principle Model”

Since Italian liver allocation policy was last revised (in 2012), relevant critical issues and conceptual advances have emerged, calling for significant improvements. We report the results of a national consensus conference process, promoted by the Italian College of Liver Transplant Surgeons (for the Italian Society for Organ Transplantation) and the Italian Association for the Study of the Liver, to review the best indicators for orienting organ allocation policies based on principles of urgency, utility, and transplant benefit in the light of current scientific evidence. MELD exceptions and hepatocellular carcinoma were analyzed to construct a transplantation priority algorithm, given the inequity of a purely MELD‐based system for governing organ allocation. Working groups of transplant surgeons and hepatologists prepared a list of statements for each topic, scoring their quality of evidence and strength of recommendation using the Centers for Disease Control grading system. A jury of Italian transplant surgeons, hepatologists, intensivists, infectious disease specialists, epidemiologists, representatives of patients’ associations and organ‐sharing organizations, transplant coordinators, and ethicists voted on and validated the proposed statements. After carefully reviewing the statements, a critical proposal for revising Italys current liver allocation policy was prepared jointly by transplant surgeons and hepatologists.

Liver transplantation for hepatocellular carcinoma: prognostic factors associated long-term survival

Abstract  Between December 1985 and February 1995, 260 orthotopic liver transplantations (OLTX) were performed on 238 patients at Niguarda Hospital. Sixty‐three patients had hepatocellular carcinoma (HCC); in 13 of the patients HCC was incidental. All patients had negative lymph nodes. According to the Child classification, 13 patients were Child A, 30 Child B, and 18 Child C. According to the TNM classification, 11 patients were stage I, 22 stage II, 15 stage III, and 15 stage IVa. Pre‐OLTX chemoem‐bolization was performed on 25 patients. The perioperative mortality rate was 27 % (17 patients). Overall survival and disease‐free actuarial survival rates at 1, 3, and 5 years were 94 %, 76 %, 76 %, and 83 %, 75 %, 75 %, respectively. Survival curves were compared for 16 different variables. No difference was observed for all parameters analyzed except tumor site, TNM stage, pre‐OLTX AFP levels and vascular infiltration. These results seem to demonstrate that the OLTX for un‐resectable HCC can be considered in specifically selected cases as the treatment of choice. An adequate tumor staging is also necessary for a better patient selection in order to increase survival.

Is the risk of neoplastic recurrence increased after prescribing direct-acting antivirals for HCV patients whose HCC was previously cured?

Variable Total cohort (n = 31) (%) Antitumoral treatment Resection 13 (42%) Resection and percutaneous ablation 1 (3%) Resection and TACE and percutaneous ablation 1 (3%) Resection and TACE 3 (10%) Percutaneous ablation and TACE 3 (10%) Percutaneous ablation 6 (19%) TACE 4 (13%) Worst BCLC stage prior to DAA therapy BCLC-0 8 (26%) BCLC-A1 4 (13%) BCLC-A2 9 (29%) BCLC-A3 2 (6%) BCLC-A4 3 (10%) BCLC-B 4 (13%) BCLC-C 1 (3%) Bilirubin (mean ± SD) 1.1 ± 0.7 Albumin (mean ± SD) 3.7 ± 0.5 Prothrombin time (INR) (mean ± SD) 1.1 ± 0.1 Alanine aminotransferase (mean ± SD) 71 ± 30 Pre-DAA HCV RNA levels (Log10), (median, range) (IU/ml) 5.6 (3.8-7.5) Pre-DAA serum AFP levels (median, range) (ng/ml) 10 (2-278) Treatment regimens SOF/LDV ± RBV for 12 or 24 weeks 15 (48%) SIM/SOF for 12 weeks 6 (19%) SOF/DCV ± RBV for 24 weeks 2 (6%) PrOD or the 3D regimen ± RBV for 12 or 24 weeks 3 (9.6%) SOF/RBV for 24 weeks 3 (9.6%) End of treatment response 31 (100%) Post-DAA serum AFP levels (median, range) (ng/ml) 6 (1-44) Interval between start of DAA therapy and last radiological assessment (months) (median, percentile 25-75) 8 (5-10.9)