V. Mazzaferro

Prevention of hepatocellular carcinoma recurrence with alpha‐interferon after liver resection in HCV cirrhosis

Tumor recurrence after resection of hepatocellular carcinoma (HCC) can occur early (<2 years) or late (>2 years) as metastases or de novo tumors. Interferon (IFN) has the potential for chemoprevention against hepatitis C virus (HCV)‐related cirrhosis. A predetermined group of 150 HCV RNA–positive patients undergoing resection of early‐ to intermediate‐stage HCC was stratified into 80 HCV‐pure (hepatitis B anticore antibody [anti‐HBc]–negative) and 70 mixed HCV+hepatitis B virus (HBV) (anti‐HBc–positive) groups, then randomized to IFN‐α (3 million units 3 times every week for 48 weeks [n = 76]) versus control (n = 74). The primary end point was recurrence‐free survival (RFS); secondary end points were disease‐specific and overall survival. Intention‐to‐treat and subgroup analysis on adherent patients were conducted. Treatment effects on early/late recurrences were assessed using multiple Cox regression analysis. No patient experienced life‐threatening adverse events. There were 28 adherent patients (37%). After 45 months of median follow‐up, overall survival was 58.5%, and no significant difference in RFS was detectable between the two study arms (24.3% vs. 5.8%; P = .49). HCC recurred in 100 patients (48 IFN‐treated, 52 controls), with a 50% reduction in late recurrence rate in the treatment arm. HCC multiplicity and vascular invasion were significantly related to recurrence (P = .01 and .0003). After viral status stratification, while no treatment effect was apparent in the mixed HCV+HBV population and on early recurrences (72 events), there was a significant benefit on late recurrences (28 events) in HCV‐pure patients adherent to treatment (HR: 0.3; 95% CI: 0.09–0.9; P = .04). In conclusion, IFN does not affect overall prevention of HCC recurrence after resection, but it may reduce late recurrence in HCV‐pure patients receiving effective treatment. (HEPATOLOGY 2006;44:1543–1554.)

Human Tumor-Derived Heat Shock Protein 96 Mediates In Vitro Activation and In Vivo Expansion of Melanoma- and Colon Carcinoma-Specific T Cells

Heat shock proteins (hsp) 96 play an essential role in protein metabolism and exert stimulatory activities on innate and adaptive immunity. Vaccination with tumor-derived hsp96 induces CD8+ T cell-mediated tumor regressions in different animal models. In this study, we show that hsp96 purified from human melanoma or colon carcinoma activate tumor- and Ag-specific T cells in vitro and expand them in vivo. HLA-A*0201-restricted CD8+ T cells recognizing Ags expressed in human melanoma (melanoma Ag recognized by T cell-1 (MART-1)/melanoma Ag A (Melan-A)) or colon carcinoma (carcinoembryonic Ag (CEA)/epithelial cell adhesion molecule (EpCAM)) were triggered to release IFN-γ and to mediate cytotoxic activity by HLA-A*0201-matched APCs pulsed with hsp96 purified from tumor cells expressing the relevant Ag. Such activation occurred in class I HLA-restricted fashion and appeared to be significantly higher than that achieved by direct peptide loading. Immunization with autologous tumor-derived hsp96 induced a significant increase in the recognition of MART-1/Melan-A27–35 in three of five HLA-A*0201 melanoma patients, and of CEA571–579 and EpCAM263–271 in two of five HLA-A*0201 colon carcinoma patients, respectively, as detected by ELISPOT and HLA/tetramer staining. These increments in Ag-specific T cell responses were associated with a favorable disease course after hsp96 vaccination. Altogether, these data provide evidence that hsp96 derived from human tumors can present antigenic peptides to CD8+ T cells and activate them both in vitro and in vivo, thus representing an important tool for vaccination in cancer patients.

Liver transplantation in patients with previous portasystemic shunt

Over a 9-year period, 58 patients who had previous portasystemic shunt procedures underwent orthotopic liver transplantation (OLTx) under a cyclosporine-steroid immunosuppressive regimen. The types of shunt used were distal splenorenal (18 patients), mesocaval (17 patients), end-to-side portacaval (11 patients), side-to-side portacaval (5 patients) and proximal splenorenal (7 patients). The mean interval between shunt and transplantation was 6 years. There was no statistical difference in survival between patients with previous shunts and the entire population of patients with primary liver transplantation performed during the same period of time. Age, sex, shunt patency, status of portal vein, and use of vein or artery graft did not affect survival. Childs classification had a significant influence on graft survival, even though no difference was subsequently observed in patient survival. A progressively improved intraoperative strategy and the use of veno-venous bypass and University of Wisconsin preservation solution had a significant impact on blood loss, length of operation, length of stay in intensive care unit, and ultimately, on survival. Distal splenorenal and mesocaval shunts with no or minimal hilum dissection are safer shunts if subsequent transplantation is planned; in fact, their 9-year survival was 87%, whereas all other shunts were associated with a survival no better than 52% (p less than 0.006).

Resection versus transplantation for liver metastases from neuroendocrine tumors.

LIVER metastases from neuroendocrine tumors (NET) is the main cause of death for patient with neuroendocrine tumors originating from the intestine and pancreas. In about 90% of patients, the distribution of liver metastases is multifocal and bilateral so that curative liver resection is feasible in no more than 20% of the referred cases. Large liver metastases often cause hormone-related symptoms (carcinoid syndrome) with severe consequences on patient quality of life. Both surgical and medical treatments have been proposed for patients with liver metastases from NET (systemic and intraarterial chemotherapy, somatostatin analogues, interferon therapy) with cumulative patient survival not exceeding 25 to 35% at five years. Resective surgery with curative intent has been associated with an improved 5 year survival in nearly 50% of cases, but the number of eligible patients is low. Total hepatectomy and liver transplantation (OLT) has been advocated for patients with bilateral unresectable symptomatic liver metastases from NET although a clear consensus on stage of disease, pathological subtypes, and patient conditions amenable of transplant candidacy are still lacking. In this report, we describe our experience with 29 patients affected by liver metastases from NET who were treated with either hepatic resections or liver transplantation. Pre-transplantation selection criteria currently applied in our centre are also proposed.

Balancing Donor and Recipient Risk Factors in Liver Transplantation: The Value of D‐MELD With Particular Reference to HCV Recipients

Donor–recipient match is a matter of debate in liver transplantation. D‐MELD (donor age × recipient biochemical model for end‐stage liver disease [MELD]) and other factors were analyzed on a national Italian database recording 5946 liver transplants. Primary endpoint was to determine factors predictive of 3‐year patient survival. D‐MELD cutoff predictive of 5‐year patient survival <50% (5yrsPS<50%) was investigated. A prognosis calculator was implemented (http://www.D‐MELD.com). Differences among D‐MELD deciles allowed their regrouping into three D‐MELD classes (A < 338, B 338–1628, C >1628). At 3 years, the odds ratio (OR) for death was 2.03 (95% confidence interval [CI], 1.44–2.85) in D‐MELD class C versus B. The OR was 0.40 (95% CI, 0.24–0.66) in class A versus class B. Other predictors were hepatitis C virus (HCV; OR = 1.42; 95% CI, 1.11–1.81), hepatitis B virus (HBV; OR = 0.69; 95% CI, 0.51–0.93), retransplant (OR = 1.82; 95% CI, 1.16–2.87) and low‐volume center (OR = 1.48; 95% CI, 1.11–1.99). Cox regressions up to 90 months confirmed results. The hazard ratio was 1.97 (95% CI, 1.59–2.43) for D‐MELD class C versus class B and 0.42 (95% CI, 0.29–0.60) for D‐MELD class A versus class B. Recipient age, HCV, HBV and retransplant were also significant. The 5yrsPS<50% cutoff was identified only in HCV patients (D‐MELD ≥ 1750). The innovative approach offered by D‐MELD and covariates is helpful in predicting outcome after liver transplantation, especially in HCV recipients.

Heat shock proteins and their use as anticancer vaccines

Despite the improvement in the outcome of anticancer therapy achieved during the last few years, several metastatic tumors remain resistant to therapy. This is particularly true for metastatic melanoma, renal and lung carcinoma, and, although to a lesser extent, for colorectal carcinoma. For these

Metabolic effects of liver transplantation in cirrhotic patients.

To assess whether liver transplantation (LTx) can correct the metabolic alterations of chronic liver disease, 14 patients (LTx-5) were studied 5+/-1 mo after LTx, 9 patients (LTx-13) 13+/-1 mo after LTx, and 10 patients (LTx-26) 26+/-2 months after LTx. Subjects with chronic uveitis (CU) and healthy volunteers (CON) were also studied. Basal plasma leucine and branched-chain amino acids were reduced in LTx-5, LTx-13, and LTx-26 when compared with CU and CON (P < 0.01). The basal free fatty acids (FFA) were reduced in LTx-26 with respect to CON (P < 0.01). To assess protein metabolism, LTx-5, LTx-13, and LTx-26 were studied with the [1-14C]leucine turnover combined with a 40-mU/m2 per min insulin clamp. To relate changes in FFA metabolism to glucose metabolism, eight LTx-26 were studied with the [1-14C]palmitate and [3-3H]glucose turnovers combined with a two-step (8 and 40 mU/m2 per min) euglycemic insulin clamp. In the postabsorptive state, LTx-5 had lower endogenous leucine flux (ELF) (P < 0.005), lower leucine oxidation (LO) (P < 0.004), and lower non-oxidative leucine disposal (NOLD) (P < 0.03) with respect to CON (primary pool model). At 2 yr (LTx-26) both ELF (P < 0.001 vs. LTx-5) and NOLD (P < 0.01 vs. LTx-5) were normalized, but not LO (P < 0.001 vs. CON) (primary and reciprocal pool models). Suppression of ELF by insulin (delta-reduction) was impaired in LTx-5 and LTx-13 when compared with CU and CON (P < 0.01), but normalized in LTx-26 (P < 0.004 vs. LTx-5 and P = 0.3 vs. CON). The basal FFA turnover rate was decreased in LTx-26 (P < 0.01) and CU (P < 0.02) vs. CON. LTx-26 showed a lower FFA oxidation rate than CON (P < 0.02). Tissue glucose disposal was impaired in LTx-5 (P < 0.005) and LTx-13 (P < 0.03), but not in LTx-26 when compared to CON. LTx-26 had normal basal and insulin-modulated endogenous glucose production. In conclusion, LTx have impaired insulin-stimulated glucose, FFA, and protein metabolism 5 mo after surgery. Follow-up at 26 mo results in (a) normalization of insulin-dependent glucose metabolism, most likely related to the reduction of prednisone dose, and, (b) maintenance of some alterations in leucine and FFA metabolism, probably related to the functional denervation of the graft and to the immunosuppressive treatment.

Propensity score analysis of outcomes following laparoscopic or open liver resection for hepatocellular carcinoma

Liver resection is a potentially curative approach for hepatocellular carcinoma (HCC). Laparoscopic liver resections may reduce complication rates, especially in patients with cirrhosis. The aim of this study was to compare the results of laparoscopic liver resection with those of open liver resection for HCC.

Liver transplantation for “very early” intrahepatic cholangiocarcinoma: International retrospective study supporting a prospective assessment

The presence of an intrahepatic cholangiocarcinoma (iCCA) in a cirrhotic liver is a contraindication for liver transplantation in most centers worldwide. Recent investigations have shown that “very early” iCCA (single tumors ≤2 cm) may have acceptable results after liver transplantation. This study further evaluates this finding in a larger international multicenter cohort. The study group was composed of those patients who were transplanted for hepatocellular carcinoma or decompensated cirrhosis and found to have an iCCA at explant pathology. Patients were divided into those with “very early” iCCA and those with “advanced” disease (single tumor >2 cm or multifocal disease). Between January 2000 and December 2013, 81 patients were found to have an iCCA at explant; 33 had separate nodules of iCCA and hepatocellular carcinoma, and 48 had only iCCA (study group). Within the study group, 15/48 (31%) constituted the “very early” iCCA group and 33/48 (69%) the “advanced” group. There were no significant differences between groups in preoperative characteristics. At explant, the median size of the largest tumor was larger in the “advanced” group (3.1 [2.5‐4.4] versus 1.6 [1.5‐1.8]). After a median follow‐up of 35 (13.5‐76.4) months, the 1‐year, 3‐year, and 5‐year cumulative risks of recurrence were, respectively, 7%, 18%, and 18% in the very early iCCA group versus 30%, 47%, and 61% in the advanced iCCA group, P = 0.01. The 1‐year, 3‐year, and 5‐year actuarial survival rates were, respectively, 93%, 84%, and 65% in the very early iCCA group versus 79%, 50%, and 45% in the advanced iCCA group, P = 0.02. Conclusion: Patients with cirrhosis and very early iCCA may become candidates for liver transplantation; a prospective multicenter clinical trial is needed to further confirm these results. (Hepatology 2016;64:1178‐1188)

Toward a better liver graft allocation that accounts for candidates with and without hepatocellular carcinoma

In some countries where the Model for End‐Stage Liver Disease (MELD) score is used for graft allocation, selected patients with hepatocellular carcinoma (HCC) receive a fixed number of exception points at listing, and increasing priority on the list by accruing additional exception points at regular time intervals. This system originally aimed at balancing the risks of HCC patients of developing contraindications and of non‐HCC patients of dying before transplantation, is not ideal because it appears to offer an advantage to HCC patients, regardless of tumor characteristics and response to loco‐regional treatment. Scores modulated by HCC characteristics have been proposed. They are based on a more refined estimate of the risk of pretransplant drop‐out or of the posttransplant transplant benefit expressed as the life‐years gained for each graft. This review describes the newly proposed systems, and discusses their advantages and drawbacks. We believe that the current exception points allocation should be revised and that drop‐out‐equivalent or transplant benefit‐equivalent models should be studied further. As with all policy changes, these should be done under close monitoring that allows subsequent revisions.