γ-Glutamyltranspeptidase is a Prognostic Marker of Survival and Recurrence in Radiofrequency-Ablation Treatment of Hepatocellular Carcinoma

Purpose

Serum γ-glutamyltranspeptidase (GGT) level, which is often elevated in hepatocellular carcinoma (HCC), has now been found to be an oxidative stress marker which correlates with inflammation in the extracellular hepatic microenvironment. The aim of this study was to investigate the prognostic significance of GGT serum levels in patients undergoing radiofrequency ablation (RFA) therapy for the treatment of HCC.

Methods

This retrospective study included 254 patients with small liver cancer (tumor of ≤5 cm in diameter and nodule of ≤3 cm) who had been treated with RFA. Baseline serum GGT was examined before therapy, and overall survival (OS) and recurrence-free survival were evaluated by the Kaplan–Meier method. Univariate and multivariate analyses were used to analyze the significance of GGT and other serum markers as prognostic factors.

Results

After a median follow-up of 27 months, 51 patients had died and 123 had hepatic recurrence. After treatment with RFA, HCC patients with elevated GGT had a shorter OS versus those with normal GGT level (p = 0.001); they also had higher recurrence (p = 0.001). On multivariate analysis, albumin (p = 0.003), GGT (p = 0.035), and tumor size (p = 0.027) were independent risk factors for survival, and GGT (p = 0.010) and tumor size (p = 0.026) were significant risk factors for recurrence.

Conclusions

Serum GGT is a convenient prognostic biomarker related to OS and recurrence in HCC patients undergoing RFA treatment.     

Prediction of Recurrence after Curative Resection of Hepatocellular Carcinoma using Liver Stiffness Measurement (FibroScan?)

Background

The purpose of this study was to investigate whether preoperative liver stiffness measurement (LSM) can predict recurrence after curative resection of hepatocellular carcinoma (HCC). LSM using FibroScan^? can assess the severity of liver fibrosis, which is significantly associated with recurrence after curative resection of HCC.

Methods

Between February 2006 and March 2009, 133 patients who underwent preoperative LSM and curative resection for HCC were enrolled in this prospective study. LSM values were analyzed for association with recurrence, together with other clinical variables.

Results

The mean age of the patients (117 men and 16 women) was 57?years. During the follow-up period (median, 25.0 (range, 3.0?C54.6) months), HCC recurred in 62 (46.6?%) patients. In multivariate analysis, together with satellite nodule and Edmonson-Steiner grade III?CIV, LSM was selected as an independent predictor of recurrence (P?<?0.05; hazard ratio, 1.034; 95?% confidence interval, 1.007?C1.061). When the study population was stratified into two groups using the optimal cutoff value (13.4?kPa) that maximized the sum of sensitivity (64.7?%) and specificity (76.1?%) from time-dependent receiver operating characteristic curves (area under the receiver operating characteristic curve?=?0.676), patients with LSM values >13.4?kPa were at a significantly greater risk for recurrence with a hazard ratio of 1.925 (P?=?0.01; 95?% confidence interval, 1.17?C3.168) compared with those with LSM values ??13.4?kPa.

Conclusions

Our data suggest that LSM can be a useful predictor of recurrence after curative resection of HCC.     

ASO Author Reflections: Does Anatomic Resection Improve Prognosis for Hepatocellular Carcinoma? Assessment from Recurrence Treatment

Annals of Surgical Oncology -     

Antisense TGF-β2 Immunotherapy for Hepatocellular Carcinoma: Treatment in a Rat Tumor Model

Background: The overexpression of transforming growth factor-beta (TGF-) in hepatocellular carcinoma (HCC) appears to induce immunosuppression toward the tumor cells. Methods: A rat HCC cell line, Morris hepatoma rat cell line (MRH)-7777 (MRH), was transfected with antisense TGF-2 in pCEP-4 vector and used as immunotherapy against the development of wild-type tumors. An enzyme-linked immunosorbent assay (ELISA) confirmed that TGF-2 production was markedly lower for antisense modified cells as compared to wild-type tumor cells. Tumors were initiated by injecting MRH cells into the flanks of Buffalo rats. This was followed by biweekly vaccinations with irradiated MRH cells (unmodified, pCEP-4 alone, or antisense TGF-2 modified). Results: In the group that received irradiated MRH unmodified cells, 55% of rats died from tumor burden, and 36% developed tumor regression. In the group that received irradiated MRH cells modified with pCEP-4 vector alone, 50% died from tumors and 33% had spontaneous regression. In animals treated with pCEP-4/TGF- antisense modified cells, none developed tumors. Cell-mediated cytotoxicity assays demonstrated a twofold increase in lytic activity in the effector cells of the animals treated with antisense modified cells. Conclusions: These results demonstrate the successful treatment of HCC tumors in rats by a HCC vaccine genetically altered with antisense TGF-2. Decreased production of TGF- in HCC vaccine enhances immunogenicity against wild-type HCC tumor cells.Presented at the 53rd Annual Meeting of the Society of Surgical Oncology, New Orleans, Louisiana, March 16-19, 2000.     

Is Timing of Death from Tumor Recurrence Predictable after Curative Resection for Gastric Cancer?

It is still difficult to predict whether cancer in patients who undergo curative gastrectomy for gastric cancer will recur and when they will die of recurrence. This study clarified predictive factors related to timing of death from tumor recurrence. A multivariate analysis was used to assess the dependence of death on postoperative tumor recurrence and were the dependence of the timing of death on tumor recurrence. Patients were divided into two groups according to the timing of death: those who died of tumor recurrence less than 2 years after surgery and those who died more than 2 years after surgery. Depth of cancer invasion, regional lymph node metastasis, and tumor size were independently correlated with tumor recurrence after curative gastrectomy. Onlv the depth of cancer invasion independently correlated with the timing of death due to tumor recurrence. It might be possible to predict the timing of death from tumor recurrence by the depth of cancer invasion into the gastric wall.     

Overexpression of miR-21 Is Associated With Recurrence in Patients With Hepatitis B Virus–Mediated Hepatocellular Carcinoma Undergoing Liver Transplantation

Liver transplantation (LT) is the best treatment option for hepatitis B virus (HBV)–mediated hepatocellular carcinoma (HCC). Nevertheless, recurrence is the most important issue after LT. The aims of the present study were to evaluate the relation of dysregulated expression of microRNAs (miRNAs) in recurrence formation in HBV-mediated HCC cases. A total of 42 HBV-mediated HCC patients were evaluated in this study.Among 21 miRNAs, the expression level of miR-106a and miR-21 were higher and miR-143 and miR145 were lower in patients with HCC compared with noncancerous liver tissues (P = .0388, P = .0214, P = .0321, and P = .002, respectively). Compared with nonrecurrent patients, the expression level of miR-21 was 3.54-fold higher and miR-145 was 2.42-fold lower in patients with recurrence during the 5-year follow-up (P = .004 and P = .032; respectively). In addition, according to multivariate Cox regression analysis, the overexpression of miR-21 was found to be a prognostic indicator in HBV-mediated HCC patients (P = .002).In conclusion, we show a significant association between high expression of miR-21 and recurrence in HBV-mediated HCC. Therefore, up-regulation of miR-21 could serve as a promising prognostic marker for HCC.     

Comparing Hepatic Resection and Transarterial Chemoembolization for Barcelona Clinic Liver Cancer (BCLC) Stage B Hepatocellular Carcinoma: Change for Treatment of Choice?

Background

Compared to transarterial chemoembolization (TACE) for patients with hepatocellular carcinoma (HCC), stage B in the Barcelona Clinic Liver Cancer (BCLC) classification, the role of hepatic resection remains unclear. The present study compared the long-term outcome of hepatic resection with TACE in the treatment of BCLC stage B HCC.

Methods

A total of 171 patients with BCLC stage B, Child’s classification A (Child A), HCC were included in this retrospective study. Of these, 93 patients underwent hepatic resection (group I) and 73 patients received TACE (group II). We evaluated the long-term outcome and therapy-related mortality in both groups. The risk factors of mortality were assessed. The survival curve was analyzed by the Kaplan–Meier method.

Results

The 1-, 2-, and 3-year overall survival rates for the two groups after hepatic resection and TACE were 83%, 62%, 49% and 39%, 5%, 2%, respectively (P < 0.0001). We did not observe significant differences in the therapy-related mortality between the two groups (P = 0.78). Treatment modality and serum albumin level were independent risk factors for survival by Cox regression analysis.

Conclusions

Our study demonstrated that hepatic resection for BCLC stage B, Child A HCC patients had better survival rates than TACE group. Thus, hepatic resection is indicated in selected patients with BCLC stage B.     

Combination of Morphologic Criteria and α-Fetoprotein in Selection of Patients With Hepatocellular Carcinoma for Liver Transplantation Minimizes the Problem of Posttransplant Tumor Recurrence

Background

Serum α-fetoprotein concentration (AFP) might be a useful addition to morphologic criteria for selecting patients with hepatocellular carcinoma (HCC) for liver transplantation (LT). The aim of this study was to evaluate the role of AFP in selecting HCC patients at minimal risk of posttransplant tumor recurrence in the setting of existing criteria.

Methods

This retrospective cohort study was based on 121 HCC patients after LT performed at a single institution. AFP was evaluated as a predictor of posttransplant tumor recurrence with respect to fulfillment of the Milan, University of California, San Francisco (UCSF), and Up-to-7 criteria.

Results

There was a nearly linear association between AFP and the risk of HCC recurrence (p < 0.001 for linear effect; p = 0.434 for nonlinear effect). AFP predicted HCC recurrence in patients (1) beyond the Milan criteria (p < 0.001; optimal cutoff 200 ng/ml); (2) within the UCSF criteria (p = 0.001; optimal cutoff 100 ng/ml) and beyond them (p = 0.015; optimal cutoff 200 ng/ml); and (3) within the Up-to-7 criteria (p = 0.001; optimal cutoff 100 ng/ml) and beyond them (p = 0.023; optimal cutoff 100 ng/ml) but not in patients within the Milan criteria (p = 0.834). Patients within either UCSF and Up-to-7 criteria with AFP level <100 ng/ml exhibited superior (100 %) 5-year recurrence-free survival—significantly higher than those within UCSF (p = 0.005) or Up-to-7 (p = 0.001) criteria with AFP levels higher than the estimated cutoffs or beyond with AFP levels less than the estimated cutoffs.

Conclusions

Combining the UCSF and Up-to-7 criteria with an AFP level <100 ng/ml is associated with minimal risk of tumor recurrence. Hence, this combination might be useful for selecting HCC patients for LT.     

Impact of Preoperative Hepatitis B Virus Levels on Prognosis After Primary and Repeat Hepatectomies for Hepatocellular Carcinoma Patients—a Retrospective Study

Background

Chronic HBV plays an important role in hepatocellular carcinoma pathogenesis. Previously, most studies have been focusing on HBV DNA levels before the primary curative hepatectomy. However, the association of virus level before repeat hepatectomy with the degrees of inflammation and fibrosis on histopathology and prognosis has not been surveyed.

Methods

From January 2002 to December 2009, all patients who were seropositive for hepatitis B surface antigen (HBsAg) were enrolled and assigned into four groups based on their HBV DNA levels before the primary and repeat hepatectomies. The cancer prognoses of these four groups of patients after the first and second operations were assessed and compared. The disease-free survival and overall survival were estimated by the Kaplan-Meier method. Univariate and multivariate analyses were performed to identify risk factors for the primary and repeat hepatectomies.

Results

For the 385 patients in this study, a low level of serum HBV DNA before repeat hepatectomy, but not primary hepatectomy, was significantly associated with improvement in prognosis, in terms of tumor recurrence, liver fibrosis, and liver-related mortality.

Conclusion

The levels of HBV DNA before hepatectomies were crucial prognostic risk factors of HBV-related hepatocellular carcinoma patients. Surveillance of serum HBV DNA levels at multiple time points, rather than at a single time point, and antiviral therapy to suppress the virus to a low level had beneficial effects for these patients.

     

Volume–Outcome Associations after Major Hepatectomy for Hepatocellular Carcinoma: a Nationwide Taiwan Study

Objective

The objective of this study was to explore volume–outcome associations after major hepatectomy for hepatocellular carcinoma (HCC).

Methods

This population-based cohort study retrospectively analyzed 23,107 major hepatectomies for HCC patients from 1998 to 2009. Relationships between hospital/surgeon volume and patient outcome were analyzed by propensity score matching (PSM). Five-year overall survival (OS) was estimated by Kaplan–Meier method, and differences were compared by log-rank test.

Results

The mean length of stay (LOS) after major hepatectomy was 18.1 days, and the mean hospital cost was US$5,088.2. After PSM, the mean OS in high- and low-volume hospitals was 71.1 months (standard deviation (SD) 0.7 months) and 68.6 months (SD 0.6 months), respectively; the mean OS in high- and low-volume surgeons was 78.5 months (SD 0.7 months) and 66.9 months (SD 0.7 months), respectively. The PSM analysis showed that treatment by high-volume hospitals and treatment by high-volume surgeons were both associated with significantly shorter LOS, lower hospital cost, and longer survival compared to their low-volume counterparts (P?<?0.001).

Conclusions

The results of this nationwide study support the regionalization of HCC treatment by hospital volume and by surgeon volume. High surgeon volume revealed both short- and long-term benefits. The applicability of PSM in volume–outcome analysis may also be confirmed.     

Laparoscopic vs. Open Liver Resection for Hepatocellular Carcinoma of Cirrhotic Liver: A Case–Control Study

Background

Laparoscopic liver resection is considered a safe and feasible alternative to open surgery for malignant liver lesions. However, laparoscopic surgery in cirrhotic patients remains challenging. The aim of this retrospective case–control study was to compare morbidity, mortality, and long-term patient survival between laparoscopic liver resections (LLR) and open liver resections (OLR) for hepatocellular carcinoma (HCC) in patients with histologically proven cirrhosis.

Methods

A total of 45 patients treated with LLR were matched by cause of cirrhosis, Child-Pugh score, type of surgical resection (subsegmentectomy, segmentectomy, and bisegmentectomy), tumor number, tumor size, and alpha-fetoprotein value with 45 patients treated with OLR. Pre-, intra-, and post-operative variables were compared between groups.

Results

Compared with OLR, the LLR group displayed a significantly shorter operative time (140 vs. 180 min; p = 0.02), shorter hospital stay (7 vs. 12 days; p < 0.0001), and lower morbidity rate (20 vs. 45 % of patients; p = 0.01). A higher rate of R0 resection was observed in the LLR group than in the OLR group (95 vs. 85 %; p = 0.03). Postoperative ascites was more frequently observed in the OLR group (18 vs. 2 %; p = 0.01). Mortality, patient, and disease-free survival rates were similar between groups. The 1-, 5-, and 10-year survival rates were 88, 59, and 12 %, respectively, in the LLR group and 63, 44, and 22 % in the OLR group (p = 0.27).

Conclusions

Significantly shorter operative times, better resection margins, lower postoperative complications, and shorter hospital stay were observed in the LLR group compared with the OLR group. LLR and OLR have similar overall and disease-free survival rates in cirrhotic HCC patients.     

Radiofrequency Ablation Versus Surgical Resection for Hepatocellular Carcinoma in Childs A Cirrhotics—a Retrospective Study of 1,061 Cases

Introduction  

The long-term outcomes of radiofrequency ablation (RFA) vs. surgical resection in cirrhotic patients with hepatocellular carcinoma (HCC) remain controversial. One thousand sixty-one cirrhotic HCC patients were included into a retrospective study. Four hundred thirteen received RFA and 648 received surgical resection.     

Improvement of Long-Term Outcomes in Hepatitis C Virus Antibody–Positive Patients with Hepatocellular Carcinoma after Hepatectomy in the Modern Era

Background  

The present study was conducted to clarify the causes of recent improvement of outcomes after hepatectomy in patients with hepatitis C (HC)–related hepatocellular carcinoma (HCC).     

Recurrence of Hepatitis D Virus in Liver Transplant Recipients With Hepatitis B and D Virus–Related Chronic Liver Disease

PurposeData on recurrence of hepatitis D virus (HDV) and its long-term impact on liver transplant (LT) are limited. In this study, we investigated the incidence of hepatitis B virus (HBV) and the long-term effect of postoperative HDV recurrence HDV coinfection in our liver transplant patients.Patients and MethodsBetween 2004 and 2018, all patients with LT because of HBV (n = 361; 37.3%) were reviewed, and those with HBV and HDV coinfection (n = 104; 30% of all HBV patients) were enrolled in our study. All patients received post-transplant combination therapy with nucleos(t)ide analogue and antihepatitis B immunoglobulins. Breakthrough infection was defined as reemergence of HBV DNA or hepatitis B surface antigen during postoperative treatment. In case of recurrence, another oral nucleos(t)ide analogue was added and antihepatitis B immunoglobulins were stopped.ResultsDuring the study period, the frequency of HDV (+) was decreased (41% to 14%). Median follow-up time was 82 months (range, 1-274 months). Post LT survival and HBV recurrence were 97% (n = 15) and 13.4%, respectively. Only 15 patients (14%) developed breakthrough infection. There was no predictive factor for recurrent HDV infection, including demographics data and concomitant hepatocellular carcinoma (P = .73). Mortality was similar between patients with and without recurrence (2.2% vs 7.1%, P = .35)ConclusionsPatients who received transplants for hepatitis B and D virus cirrhosis had favorable prognosis and good long-term results despite recurrent infection. Close follow-up of patients and effective postoperative viral suppression with appropriate medications seems to be favorable for both prevention and management of recurrence and provides comparable outcome with patients without recurrence.