Clinical Significance of Spleen–Remnant Liver Volume Ratio in Hepatocellular Carcinoma Surgery

The objective of this study was to explore the value of spleen–remnant liver volume ratio for hepatocellular carcinoma surgery and liver reserve assessment. Spleen–remnant liver volume ratio postoperation was measured with imageological methods and water displacement, and the liver function postoperation and hospital stay of patients with different spleen–remnant liver volume ratios were compared. Spleen–remnant liver volume ratio was closely related to liver function assessment postoperation. The higher the ratio, the higher the assessment score of liver function postoperation would be. When spleen–remnant liver volume ratio was ≤0.9, the patients had a fast recovery and short hospital stay. Spleen–remnant liver volume ratio can effectively predict the recovery and liver reserve of patients with hepatocellular carcinoma postoperation. When postoperative spleen–remnant liver volume ratio is predicted to be ≤0.9, the operation can be performed; and when the ratio is predicted to be ≥1.2, the operation is not suggested.     

CpG Island Methylator Phenotype Associated with Tumor Recurrence in Tumor–Node–Metastasis Stage I Hepatocellular Carcinoma

Background  

CpG island methylator phenotype (CIMP), characterized by simultaneous methylation of multiple tumor suppressor genes (TSGs), has been reported to be associated with biological malignancy in many cancers. Whether CIMP is potentially predictive of clinical outcome in hepatocellular carcinoma (HCC) remains unknown.     

Alkaline Phosphatase: Does it have a Role in Predicting Hepatocellular Carcinoma Recurrence?

Backgrounds  

Surgical resection remains the first line of treatment for earlier stages of hepatocellular carcinoma (HCC), and it offers the best prognosis for long-term survival. Nevertheless, the recurrence rates after resection are still high in reports. Therefore, it is still essential to explore any potential prognostic factors to attain relatively longer-term survival of HCC patients.     

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.     

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.     

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.     

Targeting MEK is Effective Chemoprevention of Hepatocellular Carcinoma in TGF-α-Transgenic Mice

Hepatocellular carcinoma (HCC) causes 600,000 mortalities per year worldwide. Previous studies from our lab provide evidence for altered mitogen-activated protein kinase and extracellular signal-regulated kinase kinase (MEK) signaling in HCC pathogenesis. We hypothesized that pharmacologic targeting of MEK may prevent HCC. Transforming growth factor-alpha-transgenic mice (CD1-MT42) exposed to diethylnitrosamine were randomized to 20 (trial I) or 35 (trial II) weeks of MEK inhibitor PD0325901 (1, 10 mg/kg) or control via orogastric gavage. Ten HCC (44%) formed in trial I controls versus 0 in treatment arms (p < 0.05). Fourteen HCC (50%) formed in trial II controls versus 1 (9%) in treatment arms (p < 0.05). Mean HCC volume was 578 mm³ in control versus 46 mm³ in the single tumor formed in trial II. In trial I, foci of altered hepatocytes (FAH) formed in 78% of control versus 40% and 0% (1 and 10 mg/kg PD0325901) in treatment arms (p < 0.05). In trial II, incidence of FAH was 80% in control versus 20% and 50% (1 and 10 mg/kg PD0325901) in treatment arms (p < 0.05). Hepatocyte expression of phosphorylated extracellular signal-regulated kinase dose-dependently decreased in trial I but remained the same in trial II. Control and treated HCC demonstrated similar proliferation rates, but apoptosis appeared increased with treatment. MEK targeting is effective HCC chemoprevention, perhaps by lowering the apoptotic threshold. The data herein were presented at the Society for Surgery of the Alimentary Tract/Digestive Disease Week, May 19–24, 2007, Washington, DC. Supported by a grant from the NIH (P50 AA07611-16-20).     

Factors Related to Hepatocellular Carcinoma Recurrence After Liver Transplantation—A Brazilian Multicenter Study

Background

Liver transplantation (LT) is a curative treatment option for hepatocellular carcinoma (HCC); recurrent HCC after liver transplantation (HCC-R) is diagnosed in 9%–16%. The objective of this study was to evaluate which factors are associated with R-HCC after liver transplantation.

Postoperative Serum Osteopontin Level is a Novel Monitor for Treatment Response and Tumor Recurrence after Resection of Hepatitis B–related Hepatocellular Carcinoma

Background

Presurgery serum osteopontin (OPN) level has been demonstrated to correlate to tumor recurrence and survival of hepatocellular carcinoma (HCC) patients. This study investigated the postoperative dynamic changes of serum OPN level and its clinical significance in HCC patients.

Methods

Presurgery serum OPN levels were measured by enzyme-linked immunosorbent assay in cohort A of 179 HCC patients and were compared with the multiple controls including different kinds of liver diseases and healthy individuals. In cohort B of 110 patients with resectable HCCs, besides preoperative assays, serum OPN was monitored at 1 week, 1, and ≥2 months after operation.

Results

The baseline presurgery serum OPN of HCC patients was significantly higher than that of the patients with the other kinds of liver diseases (p < 0.0001). The prognostic values of presurgery serum OPN level in HCC patients were further confirmed. The postsurgery OPN levels were significantly elevated within 1 week after HCC resection, then decreased at 1 month and reached the nadir later than 2 months after operations. It increased again at the time of tumor recurrence, then declined after the second removal of recurrent HCCs. Moreover, postoperative OPN in α-fetoprotein-negative and -positive HCC patients had the same changing pattern; it only correlated to liver function and C-reactive protein level.

Conclusions

After a transient fluctuation, serum OPN levels significantly decrease after curative resection of HCCs. Postoperative serum OPN could serve as a surrogate serologic biomarker for monitoring treatment response and tumor recurrence after HCC resection, including α-fetoprotein-negative ones.     

Does Preoperative Neutrophil Lymphocyte Ratio Predict Risk of Recurrence and Occult Central Nodal Metastasis in Papillary Thyroid Carcinoma?

Background

Preoperative neutrophil to lymphocyte ratio (NLR) might be prognostic in papillary thyroid carcinoma (PTC). Given the controversy of prophylactic central neck dissection (pCND) in clinically nodal-negative (cN0) PTC, our study evaluated whether preoperative NLR predicted disease-free survival (DFS) and occult central nodal metastasis (CNM) in cN0 PTC.

Methods

A total of 191 patients who underwent pCND were analyzed. Complete blood counts with differential counts were taken before operation. NLR was calculated by dividing preoperative neutrophil count with lymphocyte count. Patients were categorized into NLR tertiles: first (NLR < 1.93; n = 63), second (NLR = 1.93–2.79; n = 64), and third tertile (NLR > 2.79; n = 64). Four other patient types, namely, benign nodular goiter, clinically nodal-positive (cN1) PTC, poorly differentiated thyroid carcinoma, and anaplastic thyroid carcinoma (ATC), were used as references.

Results

Age at operation (p < 0.001) and tumor size (p = 0.037) significantly increased with higher NLR. First tertile had significantly more TNM stage I tumors (p = 0.01) and lowest MACIS score (p = 0.002). Tumor size [hazard ratio (HR) 1.422, 95% confidence interval (CI) 1.119–1.809, p = 0.004] and multicentricity (HR = 2.545, 95% CI 1.073–6.024, p = 0.034) independently predicted DFS, whereas old age [odds ratio (OR) 1.026, 95% CI 1.006–1.046, p = 0.009), male (OR 2.882, 95% CI 1.348–6.172, p = 0.006), and large tumor (OR 1.567, 95% CI 1.209–2.032, p = 0.001) independently predicted occult CNM. NLR was not significantly associated with DFS or occult CNM. ATC had significantly higher NLR than cN1 PTC (7.28 vs. 2.74, p < 0.001).

Conclusions

Although a higher NLR may imply a poorer tumor profile, it was not significantly associated with a worse DFS or higher risk of occult CNM in cN0 PTC. Perhaps, future research should focus on the prognostic value in other thyroid cancer types with a poorer prognosis.     

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.     

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.     

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

Annals of Surgical Oncology -     

ASO Author Reflections: Impact of Bile Duct Tumor Thrombus in Hepatocellular Carcinoma—Does it Influence Staging Systems?

Annals of Surgical Oncology -     

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.