Massimo Del Gaudio

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.

Improved Results of Liver Resection for Hepatocellular Carcinoma on Cirrhosis Give the Procedure Added Value

ObjectiveTo review a single-center experience to update the performance indexes of liver resection (LR). Summary Background DataSeveral therapies have been proposed in the treatment of hepatocellular carcinoma (HCC) on cirrhosis, although LR was the first to be widely applied. MethodsOf 408 patients with cirrhosis admitted for HCC in the period 1983 to 1998, 264 had a LR. Patient selection, surgical technique, 30-day deaths, long-term survival, recurrence rate, and recurrence treatment were reviewed after stratifying patients according to the year of surgery. Mean follow-up was 34.5 ± 29.1 months. ResultsThe number of Child A patients who underwent surgery after the discovery of the tumor at routine evaluation increased significantly from 64.5% to 87.9% during the study period. Procedures carried out without blood transfusions increased from 31.4% to 76.9%. The overall operative death rate was 4.9%. Actuarial survival rates were 63.1% and 41.1% after 3 and 5 years, respectively; actuarial tumor-free survival rates were 49.3% and 27.9% at the same intervals. After 1992, surgical deaths decreased from 9.3% to 1.3%. Actuarial survival rates increased from 52.9% and 32.3% to 71.7% and 49.4% after 3 and 5 years, respectively. There was no difference in the actuarial recurrence rate between the two periods, but the chance to treat recurrence increased over time from 22.4% to 53.7% with a concomitant, significant improvement in survival. ConclusionsLR represents a well-established therapy for HCC on cirrhosis. It remains one of the fundamentals in the multidisciplinary approach to this tumor and should be considered as the first option for patients with preserved hepatic function and limited disease. Today, LR should offer a surgical death rate of less than 1.5%, a 5-year survival rate of approximately 50%, and a 5-year tumor-free survival rate of 28% when performed in specialized centers.

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.

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 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.

Effects of 10 Minutes of Ischemic Preconditioning of the Cadaveric Liver on the Graft's Preservation and Function: The Ying and the Yang

Summary Background Data:Although extensively studied in animal models, ischemic preconditioning has not yet been studied in clinical transplantation. Objective:To compare the results of cadaveric liver transplantation with and without ischemic liver preconditioning in the donor. Patients and Methods:Alternate patients were transplanted with liver grafts that had (n = 46, GroupPrecond) or had not (n = 45, GroupControl) been subjected to ischemic preconditioning. Liver ischemia-reperfusion injury, liver and kidney function, morbidity, and in-hospital mortality rates were compared in the 2 groups. Initial poor function was defined as a minimal prothrombin time within 10 days of transplantation <30% of normal and/or bilirubin >200 &mgr;mol/L. Results:The postoperative peaks of ASAT (IU/L) and ALAT (IU/L) were significantly lower in GroupPrecond (556 ± 968 and 461±495, respectively) than in the GroupControl (1073 ± 1112 and 997±1071, respectively). The rate of technical morbidity and the incidence of acute rejection were similar in both groups. Initial poor function was significantly more frequent in the GroupPrecond (10 of 46 cases) than in the GroupControl (3 of 45 cases). Hospital mortality rates were similar in the 2 groups. In multivariate analysis, body mass index of the donor, graft steatosis, and ischemic preconditioning were significantly predictive of the posttransplant peak of ASAT. In univariate analysis, only preconditioning was significantly associated with initial poor function. Conclusions:Compared with standard orthotopic liver transplant, ischemic preconditioning of the liver graft in the donor is associated with better tolerance to ischemia. However, this is at the price of decreased early function. Until further studies are available, the clinical value of preconditioning liver grafts remains uncertain.

Liver transplantation for Wilson's disease: The burden of neurological and psychiatric disorders

A retrospective data analysis on liver transplantation for Wilsons disease (WD) was performed among Italian Liver Transplant Centers. Thirty‐seven cases were identified. The main indication for liver transplantation was chronic advanced liver disease in 78% of patients. Mixed hepatic and neuropsychiatric symptoms were recorded in 32.3%. Eight patients presented with fulminant liver failure; 44.8% were on medical treatment. Patient and graft survival at 3 months, 12 months, 3 years, 5 years, and 10 years after transplantation were, respectively, 91.8%, 89.1%, 82.9%, 75.6%, and 58.8%, and 85.3%, 83.0%, 77.1%, 70.3%, and 47.2%. Neurological symptoms significantly improved after orthotopic liver transplantation (OLT), but the survival of patients with mixed hepatic and neuropsychiatric involvement was significantly lower than in patients with liver disease alone (P = 0.04). WD characterized by hepatic involvement alone is a rare but good indication for liver transplantation when specific medical therapy fails. Patients with neuropsychiatric signs have a significantly shorter survival even though liver transplantation has a positive impact on neurological symptoms. In conclusion, a combination of hepatic and neuropsychiatric conditions deserves careful neurological evaluation, which should contraindicate OLT in case of severe neurological impairment. (Liver Transpl 2005;11:1056–1063.)

The Role of Lymphadenectomy for Liver Tumors: Further Considerations on the Appropriateness of Treatment Strategy

Objective:To evaluate the role of regional lymphadenectomy in patients with liver tumors. Background:Lymph node status is 1 of the most important prognostic factors in oncologic surgery; however, the role of lymph node dissection remains unclear for hepatic tumors. Methods:A total of 120 consecutive patients undergoing liver resections for primary and secondary hepatic tumors were prospectively enrolled in the study. “Regional” lymphadenectomy was carried out routinely after specimen removal. Incidence, site, and influence on survival of node metastases were analyzed. Results:Only 1 postoperative complication (intra-abdominal bleeding) was related to lymph node excision. Median number of dissected nodes was 6.8 ± 3.6. Periportal, pericholedochal, and common hepatic artery stations were always removed. Lymph node metastases were found in 17 (16.5%) patients. The percentage rises to 20.3% when considering only noncirrhotic patients. The incidence of lymph node metastases was 7.5% for hepatocellular carcinoma, 14% for colorectal metastases, 40% for noncolorectal metastases, and 40% for intrahepatic cholangiocarcinoma (P < 0.002). Median survival time was 486 ± 93.2 days among all patients with node metastases and 725 ± 29.7 among patients without node metastases. The 2-year survival was 37.1% and 86.7%, in the 2 groups (P < 0.05). The 2-year recurrence rate was 77.6% and 45.3%, respectively (P < 0.05). Conclusions:Regional lymphadenectomy is a safe procedure after liver resection, and it should be routinely applied in patients with primary and secondary hepatic tumors, particularly in those without chronic disease. A careful evaluation of node status is nevertheless advisable also in patients with hepatocellular carcinoma on cirrhosis.

Effect of different immunosuppressive schedules on recurrence-free survival after liver transplantation for hepatocellular carcinoma

Background. Tumor recurrence represents the main limitation of liver transplantation in patients with hepatocellular carcinoma (HCC) and can be favored by exposure to calcineurin inhibitors. Methods. We investigated the effect of an immunosuppressant schedule that minimizes the exposure to calcineurin inhibitors on patients transplanted for HCC to ascertain whether this can reduce the tumor recurrence rate. For this purpose, we conducted a matched-cohort study: 31 patients with HCC transplanted between 2004 and 2007 who received sirolimus as part of their immunosuppression (group A) were compared with a control group of 31 patients (group B) transplanted in the same period who had the same prognostic factors but were given standard immunosuppression based on tacrolimus. Results. Three-year recurrence-free survival was 86% in group A and 56% in group B (P=0.04). Although the prevalence of microvascular invasion G3-G4 grading and alpha-fetoprotein more than 200 ng/mL was identical in the two groups, exposure to tacrolimus was significantly higher in patients of group B (median, 8.54; range, 5.5–13.5) in comparison with those of group A (median, 4.6; range, 1.8–9.1) (P=0.0001). Conclusions. By using sirolimus, exposure to calcineurin inhibitors can be minimized, reducing the risk of HCC recurrence.

Analysis of factors affecting recurrence of hepatocellular carcinoma after liver transplantation with a special focus on inflammation markers.

Background. Systemic inflammation markers, such as neutrophil-to-lymphocyte ratio (NLR), have recently emerged as the prognostic factors for recurrence of liver tumors. Methods. We assessed the ability of NLR and of other variables to predict the outcomes of orthotopic liver transplantation (OLT) for hepatocellular carcinoma (HCC). A retrospective analysis was performed in 219 patients with HCC who underwent OLT between 1997 and 2009, with a median follow-up of 40 months. Results. Overall 3- and 5-year patient survival rates were 76.6% and 70.7%, respectively. Overall 3- and 5-year recurrence-free survival (RFS) rates were 83.8% and 82.1%, respectively. On univariate analysis, the factors affecting overall survival were &agr;-fetoprotein more than 30 ng/mL (P=0.006), NLR more than or equal to 5 (P<0.0001), hepatitis C infection (P=0.043), and presence of microvascular invasion (MVI; P=0.006). Preoperative treatments (P=0.006), &agr;-fetoprotein more than 30 ng/mL (P=0.003), NLR more than or equal to 5 (P<0.0001), exceeding Milan criteria at final histology (P=0.001), poor tumor differentiation (P=0.02), and presence of MVI (P<0.0001) predicted a lower RFS. Coxs proportional hazard model showed that only increased NLR and presence of MVI independently predicted overall survival and RFS. Conclusions. NLR is an important predictor of outcome after OLT for HCC and should be used to identify OLT candidates at high risk of recurrence.