Matteo Ravaioli

Liver resection for hepatocellular carcinoma on cirrhosis: univariate and multivariate analysis of risk factors for intrahepatic recurrence.

ObjectiveTo evaluate prognostic factors that could affect disease-free survival and recurrence after liver resection for hepatocellular carcinoma (HCC) on cirrhosis. Summary Background DataTumor recurrence is the main cause of poor survival after liver resection for HCC on cirrhosis. MethodsTwo hundred twenty-four liver resections for HCC on cirrhosis were retrospectively reviewed. Univariate and multivariate analyses were performed on several clinicopathologic variables to analyze factors affecting long-term outcome and intrahepatic recurrence. The relation between preoperative aminotransferase level and recurrence rate was evaluated in the overall group, and separately in HCV-positive and in HBsAg-positive patients. Median follow-up was 35.6 months. ResultsThe 1-, 3-, and 5-year overall survival rates were 83%, 62.8%, and 42.5%, respectively. The 1-, 3-, and 5-year disease-free survival rates were 70.3%, 43%, and 27.4%, respectively. The 1-, 3-, and 5-year recurrence rates were 20.8%, 38.6%, and 54.4% respectively. Tumor recurrence appeared in 93 patients (41.5%) and was the main cause of death in 51 patients (56%). Number of nodules, tumor capsule, microvascular portal vein thrombosis, and preoperative serum aspartate aminotransferase (AST) level significantly affected disease-free survival and recurrence rates. On multivariate analysis, single nodules and preoperative AST level less than twice normal (2N) were related to a better 5-year disease-free survival and lower tumor recurrence. In particular, among HCV-positive patients the recurrence rate was strongly affected by the preoperative AST level. ConclusionsChild A patients with single nodules are the best candidates for liver resection. Tumor recurrence is strictly linked to the status of the underlying liver disease, and a preoperative AST level equal to 2N seems to be a sensitive cutoff among patients with different risks of recurrence. HCV-positive patients with AST levels above 2N have the highest risk for intrahepatic recurrence and should be monitored carefully or offered alternative treatments.

Impact of model for end‐stage liver disease (MELD) score on prognosis after hepatectomy for hepatocellular carcinoma on cirrhosis

The objective of this study was to predict postoperative liver failure and morbidity after hepatectomy for hepatocellular carcinoma (HCC) with cirrhosis. The model for end‐stage liver disease (MELD) score is currently accepted as a disease severity index of cirrhotic patients awaiting liver transplantation; however, its impact on prognosis after resection of HCC on cirrhosis has never been investigated. One hundred fifty‐four cirrhotic patients resected in a tertiary care setting for HCC were retrospectively analyzed. For each patient, the MELD score was calculated and related to postoperative liver failure and complications (morbidity). Hospital stay and 1‐year survival was also investigated. MELD accuracy in predicting postoperative liver failure and morbidity of cirrhotic patients was assessed using receiver operating characteristic (ROC) analysis. Eleven patients (7.1%) experienced postoperative liver failure leading to death or transplantation. ROC analysis identified cirrhotic patients with a MELD score equal to or above 11 at high risk for postoperative liver failure (area under the curve [AUC] = 0.92, 95% confidence interval [CI] = 0.87‐0.96; sensitivity = 82%; specificity = 89%). Forty‐six patients (29.9%) developed at least 1 postoperative complication: ROC analysis identified patients with a MELD score equal to or above 9 at major risk for postoperative complications (AUC = 0.85, 95% CI = 0.78‐0.89; sensitivity = 87%; specificity = 63%). Cirrhotic patients with MELD score below 9 had no postoperative liver failure and low morbidity (8.1%). In conclusion, the MELD score can accurately predict postoperative liver failure and morbidity of cirrhotic patients referred for resection of HCC and should be used to select the best candidates for hepatectomy. Liver Transpl 12:966‐971, 2006.

Percutaneous ablation procedures in cirrhotic patients with hepatocellular carcinoma submitted to liver transplantation: Assessment of efficacy at explant analysis and of safety for tumor recurrence

Aims of this retrospective study were to analyze the efficacy and safety of percutaneous ethanol injection (PEI) and radiofrequency ablation (RFA) in cirrhotic patients with hepatocellular carcinoma (HCC) submitted to orthotopic liver transplantation (OLT). We studied 40 patients undergoing OLT in whom 46 HCC nodules had been treated with PEI (13 nodules), RFA (30 nodules), or PEI+RFA (3 nodules). Child‐Turcotte‐Pugh class was A in 18 cases, B in 18, and C in 4. The mean waiting time for OLT was 9.5 months. The effectiveness of ablation techniques was evaluated by histological examination of the explanted livers. Complete necrosis was found in 19 nodules (41.3%), partial or absent necrosis in 27 nodules (58.7%). Among the 30 nodules treated by RFA, 14 were completely necrotic (46.7%) and 16 demonstrated partial necrosis (53.3%). Considering the 13 neoplasms undergoing PEI, 3 nodules showed complete necrosis (23.1%), 6 partial necrosis (46.1%), and 4 absent necrosis (30.8%). The rate of complete necrosis was 53.1% for nodules smaller than 3 cm and 14.3% for larger lesions (P = 0.033) but increased to 61.9% when considering only the lesions smaller than 3 cm treated by RFA. During the follow up, HCC recurred in 3 patients treated by PEI. No cases of HCC recurrence at the abdominal wall level were recorded. Percutaneous ablation procedures are effective treatments in cirrhotic patients with HCC submitted to OLT and are not associated to an increased risk of tumor recurrence. RFA provides complete necrosis in most nodules smaller than 3 cm, and appears to be the best treatment option in these cases. (Liver Transpl 2005;11:1117–1126.)

Is Portal Hypertension a Contraindication to Hepatic Resection

Background and Aims:The outcome of hepatic resection in cirrhotic patients has improved remarkably in recent years with improved surgical techniques and perioperative care; however, the role of portal hypertension is still uncertain. The aim of this study was to elucidate surgical outcomes of hepatectomy in patients with portal hypertension. Methods:Data from 241 cirrhotic patients who underwent resection for hepatocellular carcinoma were retrospectively collected and analyzed: patients were divided into 2 groups according to the presence (n = 89) or absence (n = 152) of portal hypertension at the time of surgery. To overcome biases owing to the different distribution of covariates throughout the 2 groups, a one-to-one match was created using propensity score analysis: after match, intraoperative, and postoperative course and survival rates were analyzed. Results:Patients with portal hypertension experienced worse preoperative liver function (mean model for end-stage liver disease [MELD] score, 9.5 ± 7.8 vs. 8.4 ± 1.3; P = 0.001) and survival rates (P = 0.008) in comparison to those without portal hypertension: after one-to-one matching, patients with (n = 78) and without portal hypertension (n = 78) had the same preoperative characteristics and showed the same intraoperative course, postoperative occurrence of liver failure, morbidity, length of in-hospital stay and survival rates (P = ns in all cases). The only predictors of postoperative liver failure were MELD score (P = 0.001) and extent of hepatectomy (P = 0.005). Conclusions:Faced with the same MELD score and extent of hepatectomy planning, presence of portal hypertension should not be considered as a contraindication for hepatic resection in cirrhotic patients.

Trends in perioperative outcome after hepatic resection: analysis of 1500 consecutive unselected cases over 20 years.

Objective:To estimate risk factors affecting the early outcome after hepatic resection in a high volume center specialized in hepatobiliary surgery and to analyze the changing of results during 3 different periods of treatment. Design:Retrospective review. Patients:A series of 1500 consecutive patients who underwent hepatic resection. Methods:Postoperative morbidity and mortality were analyzed in relation to indications for surgery, period of operation, patient characteristics, and intraoperative variables. Patients were classified into 4 groups, according to the indication for surgery: primary liver tumors with cirrhosis (group 1, G1); other liver malignancies (group 2, G2); biliary malignancies (group 3, G3); and benign diseases (group 4, G4). Patients were also divided into 3 groups, according to the year of operation (period 1: June 1985 to October 1993; period 2: November 1993 to September 1999; period 3: October 1999 to September 2007). Results:Overall mortality and morbidity were 3% and 22.5%, respectively. Multivariate analysis revealed that blood transfusions, G1, and additional procedures were associated with an increased risk of postoperative complications, whereas blood transfusions, G1, G3, and extended hepatectomy were associated with an increased risk of postoperative mortality. G1 decreased, whereas G3, extended hepatectomies and additional procedures significantly increased between periods 2 and 3 (P < 0.05). The complication rate was significantly lower in period 2 (18.8%) compared with period 1 (23.8%) and period 3 (24.8%). Similarly, there was a significantly lower mortality rate in period 2 (1.6%) compared with period 1 (3.4%) and period 3 (4%). Conclusions:Slightly worse short-term outcomes in liver surgery were observed in recent years, with a concomitant increase of the aggressiveness of operative strategies. Nevertheless, the present results still justify an aggressive approach in liver resections.

Efficacy of selective transarterial chemoembolization in inducing tumor necrosis in small (<5 cm) hepatocellular carcinomas

Transarterial chemoembolization (TACE) is commonly used as a bridge therapy for patients awaiting liver transplantation (LT) and for downstaging patients initially not meeting the Milan criteria. The primary aim of this study was to analyze whether a difference exists between selective/superselective and lobar TACE in determining tumor necrosis by a pathological analysis of the whole lesion at the time of LT. The secondary aim was to investigate the relationship between the tumor size and the capacity of TACE to induce necrosis. Data were extracted from a prospective database of 67 consecutive patients who underwent LT for hepatocellular carcinoma and cirrhosis from 2003 to 2009 and were treated exclusively with TACE as a bridging (n = 53) or downstaging therapy (n = 14). We identified 122 nodules; 53.3% were treated with selective/superselective TACE. The mean histological necrosis level was 64.7%; complete tumor necrosis was obtained in 42.6% of the nodules. In comparison with lobar TACE, selective/superselective TACE led to significantly higher mean levels of necrosis (75.1% versus 52.8%, P = 0.002) and a higher rate of complete necrosis (53.8% versus 29.8%, P = 0.013). A significant direct relationship was observed between the tumor diameter and the mean tumor necrosis level (59.6% for lesions < 2 cm, 68.4% for lesions of 2.1‐3 cm, and 76.2% for lesions > 3 cm). Histological necrosis was maximal for tumors > 3 cm: 91.8% after selective/superselective TACE and 66.5% after lobar procedures. Independent predictors of complete tumor necrosis were selective/superselective TACE (P = 0.049) and the treatment of single nodules (P = 0.008). Repeat sessions were more frequently needed for nodules treated with lobar TACE (31.6% versus 59.3%, P = 0.049). Conclusion: Selective/superselective TACE was more successful than lobar procedures in achieving complete histological necrosis, and TACE was more effective in 3‐ to 5‐cm tumors than in smaller ones. (Hepatology 2011;)

The Role of Liver Resections for Noncolorectal, Nonneuroendocrine Metastases: Experience With 142 Observed Cases

BackgroundTo evaluate the role of liver resection for noncolorectal, nonneuroendocrine metastases, indications and results were retrospectively reviewed in 142 observed patients.MethodsA curative liver resection was performed in 83 cases (58.5%), and the remaining 59 patients received palliative treatments. The primary tumor site was gastrointestinal in 18, breast in 21, genitourinary in 15, leiomyosarcoma in 10, and other in 19. The mean number of metastases was 1.4. The mean diameter of the nodules was 5.7 cm. Liver metastases were synchronous in 11 (13.3%) cases and metachronous in the remaining 72 (86.7%).ResultsThere was no operative mortality. Postoperative morbidity was 20.5%. The median postoperative stay was 9.5 days. The 3- and 5-year actuarial survival rate was 49.5% and 34.3% in resected cases, respectively, whereas there were almost no survivors 3 years after diagnosis in unresected cases (P < .05). The 3- and 5-year disease-free survival was 41.4% and 23.8%, respectively. Among the 83 resected cases, the 3- and 5-year actuarial survival was 17.3% and 8.6% for metastases from gastrointestinal tumors, 53.9% and 24.6% from breast cancer, 63.7% and 36.4% from leiomyosarcoma, 50.4% and 37.8% from genitourinary neoplasms, and 55.6% and 42.4% from other sites, respectively. Fifteen patients (18.1%) survived longer than 5 years.ConclusionsLiver resection is an effective treatment for noncolorectal, nonneuroendocrine metastases; it allows satisfactory long-term survival with an acceptable operative risk in selected patients. Hepatic metastases from gastrointestinal carcinoma have the worst prognosis; those from genitourinary tumors show a better outcome. Patient selection is the key to achieving encouraging results.

Liver Transplantation for Recurrent Hepatocellular Carcinoma on Cirrhosis After Liver Resection : University of Bologna Experience

Liver resection (LR) for patients with small hepatocellular carcinoma (HCC) with preserved liver function, employing liver transplantation (LT) as a salvage procedure (SLT) in the event of HCC recurrence, is a debated strategy.

Liver transplantation for hepatocellular carcinoma under calcineurin inhibitors: reassessment of risk factors for tumor recurrence.

Objective:We assessed the effect of tacrolimus on recurrence of hepatocellular carcinoma (HCC) after liver transplantation (LT) and compared it with that of the other calcineurin inhibitor, cyclosporine. Introduction:HCC recurrence after LT can be favored by overexposure to cyclosporine. Tacrolimus is now the most widely used main immunosuppressant after LT; its possible effect on HCC recurrence has never been investigated. Materials and Methods:One hundred and thirty nine HCC patients who had LT were reviewed; 60 of them were administered tacrolimus, and 79, cyclosporine. The exposure to the drugs was calculated with the trapezoidal rule in each patient, using blood levels measured after transplantation and compared with HCC recurrence together with several clinical and pathologic risk factors. Results:HCC recurred in 12 of the 60 (20%) patients under tacrolimus in comparison with that in 9 of the 79 (11.4%) patients under cyclosporine; however, the proportion of poorly differentiated and more advanced tumors was significantly higher in the tacrolimus group than in the cyclosporine group. Exposure to tacrolimus was 11.6 ± 1.5 ng/mL in patients with recurrence and 8.6 ± 1.7 ng/mL in those without recurrence (P < 0.001). The optimal cut-off values of exposure identified with receiver operating characteristics analysis to categorize the risk of recurrence were 10 ng/mL for tacrolimus (area under the curve (AUC) = 0.913) and 220 ng/mL for cyclosporine (AUC = 0.752). In the tacrolimus group, high drug exposure independently predicted recurrence (P = 0.005). Multivariate analysis, including all patients (tacrolimus + cyclosporine) characterized higher exposure to immunosuppression (P = 0.01), alpha-fetoprotein levels (P = 0.001), tumor grading (P = 0.009), and microvascular invasion (P = 0.04) as independent predictors of HCC recurrence. Conclusions:Just as it is with cyclosporine, overexposure to tacrolimus increases the risk of HCC recurrence after LT. Careful management of calcineurin inhibitors is recommended in HCC patients.

In hepatocellular carcinoma miR-519d is up-regulated by p53 and DNA hypomethylation and targets CDKN1A/p21, PTEN, AKT3 and TIMP2.

MiR‐519d belongs to the chromosome 19 miRNA cluster (C19MC), the largest human miRNA cluster. One of its members, miR‐519d, is over‐expressed in hepatocellular carcinoma (HCC) and we characterized its contribution to hepatocarcinogenesis. In HCC cells, the over‐expression of miR‐519d promotes cell proliferation, invasion and impairs apoptosis following anticancer treatments. These functions are, at least in part, exerted through the direct targeting of CDKN1A/p21, PTEN, AKT3 and TIMP2. The mechanisms underlying miR‐519d aberrant expression in HCC were assayed by genomic DNA amplification, methylation analysis and ChIP assay. The aberrant hypomethylation of C19MC and TP53 were respectively identified as an epigenetic change allowing the aberrant expression of miR‐519d and one of the factors able to activate its transcription. In conclusion, we assessed the oncogenic role of miR‐519d in HCC by characterizing its biological functions, including the modulation of response to anticancer treatments and by identifying CDKN1A/p21, PTEN, AKT3 and TIMP2 among its targets. Copyright