Irene Oi-Lin Ng

MicroRNA Expression, Survival, and Response to Interferon in Liver Cancer

BACKGROUND Hepatocellular carcinoma is a common and aggressive cancer that occurs mainly in men. We examined microRNA expression patterns, survival, and response to interferon alfa in both men and women with the disease. METHODS We analyzed three independent cohorts that included a total of 455 patients with hepatocellular carcinoma who had undergone radical tumor resection between 1999 and 2003. MicroRNA-expression profiling was performed in a cohort of 241 patients with hepatocellular carcinoma to identify tumor-related microRNAs and determine their association with survival in men and women. In addition, to validate our findings, we used quantitative reverse-transcriptase-polymerase-chain-reaction assays to measure microRNAs and assess their association with survival and response to therapy with interferon alfa in 214 patients from two independent, prospective, randomized, controlled trials of adjuvant interferon therapy. RESULTS In patients with hepatocellular carcinoma, the expression of miR-26a and miR-26b in nontumor liver tissue was higher in women than in men. Tumors had reduced levels of miR-26 expression, as compared with paired noncancerous tissues, which indicated that the level of miR-26 expression was also associated with hepatocellular carcinoma. Moreover, tumors with reduced miR-26 expression had a distinct transcriptomic pattern, and analyses of gene networks revealed that activation of signaling pathways between nuclear factor kappaB and interleukin-6 might play a role in tumor development. Patients whose tumors had low miR-26 expression had shorter overall survival but a better response to interferon therapy than did patients whose tumors had high expression of the microRNA. CONCLUSIONS The expression patterns of microRNAs in liver tissue differ between men and women with hepatocellular carcinoma. The miR-26 expression status of such patients is associated with survival and response to adjuvant therapy with interferon alfa.

Adult-to-adult Living Donor Liver Transplantation Using Extended Right Lobe Grafts

OBJECTIVE The authors report their experience with living donor liver transplantation (LDLT) using extended right lobe grafts for adult patients under high-urgency situations. SUMMARY BACKGROUND DATA The efficacy of LDLT in the treatment of children has been established. The major limitation of adult-to-adult LDLT is the adequacy of the graft size. A left lobe graft from a relatively small volunteer donor will not meet the metabolic demand of a larger recipient. METHODS From May 1996 to November 1996, seven LDLTs, using extended right lobe grafts, were performed under high-urgency situations. All recipients were in intensive care units before transplantation with five having acute renal failure, three on mechanical ventilation, and all with hepatic encephalopathy. The median body weight for the donors and recipients was 58 kg (range, 41-84 kg) and 65 kg (range, 53-90 kg), respectively. The body weights of four donors were less than those of the corresponding recipients, and the lowest donor-to-recipient body weight ratio was 0.62:1. The extended right lobe graft was chosen because the left lobe volume was <40% of the ideal liver mass of the recipient. RESULTS Median blood loss for the donors was 900 mL (range, 700-1600 mL) and hospital stay was 19 days (range, 8-22 days). Homologous blood transfusion was not required. Two donors had complications (one incisional hernia and one bile duct stricture) requiring reoperation after discharge. All were well with normal liver function 5 to 10 months after surgery. The graft weight ranged from 490 g to 1140 g. All grafts showed immediate function with normalization of prothrombin time and recovery of conscious state of the recipients. There was no vascular complication, but six recipients required reoperation. One recipient died of systemic candidiasis 16 days after transplantation and 6 (86%) were alive with the original graft at a median follow-up of 6.5 months (range, 5-10 months). CONCLUSIONS When performed by a team with experience in hepatectomy and transplantation, LDLT, using an extended right lobe graft, can achieve superior results. The technique extends the success of LDLT from pediatric recipients to adult recipients and opens a new donor pool for adults to receive a timely graft of adequate function.

Improving Survival Results After Resection of Hepatocellular Carcinoma: A Prospective Study of 377 Patients Over 10 Years

ObjectiveTo investigate whether the survival results after resection of hepatocellular carcinoma (HCC) have improved within the past decade by an analysis of a prospective cohort of patients over a 10-year period. Summary Background DataThe surgical death rate after resection of HCC has greatly improved in recent years, but the long-term prognosis remains unsatisfactory. It remains unknown whether the survival results after resection of HCC have improved within the past decade. MethodsThe clinicopathologic and follow-up data of 377 patients who underwent curative resection of HCC between January 1989 and January 1999 were prospectively collected. These patients were categorized according to two time periods: before 1994 (group 1, n = 136) and after 1994 (group 2, n = 241). The two groups were compared for clinicopathologic data and survival results. The prognostic factors for disease-free survival were further analyzed to identify the factors that might have led to improved survival outcomes. ResultsThe overall and disease-free survival results were significantly better in group 2 compared with group 1. Patients in group 2 had significantly higher proportions of subclinical presentation, small tumors, and tumors of early pTNM stage. There were also significantly lower frequencies of histologic margin involvement, less intraoperative blood loss, and a lower transfusion rate in group 2. By multivariate analysis, early pTNM stage, subclinical HCC, and no perioperative transfusion were independent favorable prognostic factors for disease-free survival. ConclusionsSignificant improvement of overall and disease-free survival results after resection of HCC has been achieved within the past decade as a result of advances in the diagnosis and surgical management of HCC. Earlier diagnosis of HCC by better imaging modalities, increased detection of subclinical HCC by screening of high-risk patients, and a reduced perioperative transfusion rate were identified as the major contributory factors for the improved outcomes.

Prospective evaluation of Pringle maneuver in hepatectomy for liver tumors by a randomized study.

OBJECTIVE To evaluate whether vascular inflow occlusion by the Pringle maneuver during hepatectomy can be safe and effective in reducing blood loss. SUMMARY BACKGROUND DATA Hepatectomy can be performed with a low mortality rate, but massive hemorrhage during surgery remains a potentially lethal problem. The Pringle maneuver is traditionally used during hepatectomy to reduce blood loss, but there is a potential harmful effect on the metabolic function of hepatocytes. There has been no prospective randomized study to determine whether the Pringle maneuver can decrease blood loss during hepatectomy, improve outcome, or affect the metabolism of hepatocytes. METHODS From July 1995 to February 1997, we studied 100 consecutive patients who underwent hepatectomy for liver tumors. The patients were randomly assigned to liver transection under intermittent Pringle maneuver of 20 minutes and a 5-minute clamp-free interval (n = 50), or liver transection without the Pringle maneuver (n = 50). The surface area of liver transection was measured and blood loss during transection per square centimeter of transection area was calculated. Routine liver biochemistry, arterial ketone body ratio (AKBR), and the indocyanine green (ICG) clearance test were done. RESULTS The two groups were comparable in terms of preoperative liver function and in the proportion of patients having major hepatectomy. The Pringle maneuver resulted in less blood loss per square centimeter of transection area (12 mL/cm2 vs. 22 mL/cm2, p = 0.0001), a shorter transection time per square centimeter of transection area (2 min/cm2 vs. 2.8 min/cm2, p = 0.016), a significantly higher AKBR in the first 2 hours after hepatectomy, lower serum bilirubin levels in the early postoperative period, and, in cirrhotic patients, higher serum transferrin levels on postoperative days 1 and 8. The complication rate, the hospital mortality rate, and the ICG retention at 15 minutes on postoperative day 8 were equal for the two groups. CONCLUSION Performing the Pringle maneuver during liver transection resulted in less blood loss and better preservation of liver function in the early postoperative period. This is probably because there was less hemodynamic disturbance induced by the bleeding.

Tumor size predicts vascular invasion and histologic grade : Implications for selection of surgical treatment for hepatocellular carcinoma

Vascular invasion and high histologic grade predict poor outcome after surgical resection or liver transplantation for hepatocellular carcinoma (HCC). Despite the known association between tumor size and vascular invasion, a proportion of patients with large tumors can be treated surgically with excellent outcomes. Clarification of the association between tumor size, histologic grade, and vascular invasion has implications for patient selection for resection and transplantation. The objective of this study was to examine the relationship between HCC tumor size and microscopic (occult) vascular invasion and histologic grade in a multicenter international database of 1,073 patients who underwent resection of HCC. The incidence of microscopic vascular invasion increased with tumor size (≤3 cm, 25%; 3.1‐5 cm, 40%; 5.1‐6.5 cm, 55%; >6.5 cm, 63%) (P < 0.005). Both size and number of tumors were important factors predicting vascular invasion. Among all patients with tumors 5.1 to 6.5 cm, microscopic vascular invasion was present in 55% compared with 31% for all patients with tumors 5 cm or smaller (P < 0.001). Among patients with solitary tumors only, microscopic vascular invasion was significantly more common in tumors measuring 5.1 to 6.5 cm (41%) compared with 27% of tumors 5 cm or smaller (P < 0.003). Tumor size also predicted histologic grade: 36% of tumors 5 cm or smaller were high grade, compared with 54% of lesions 5.1 to 6.5 cm (P = 0.01). High histologic grade, an alpha‐fetoprotein level of at least 1000 ng/mL, and multiple tumor nodules each predicted occult vascular invasion in tumors larger than 5 cm. The high incidence of occult vascular invasion and advanced histologic grade in HCC tumors larger than 5 cm, as well as biologic predictors of poor prognosis, should be considered before criteria for transplantation are expanded to include these patients. (Liver Transpl 2005;11:1086–1092.)

Yes-Associated Protein Is an Independent Prognostic Marker in Hepatocellular Carcinoma

Yes‐associated protein (YAP), a downstream target of the Hippo signaling pathway, was recently linked to hepatocarcinogenesis in a mouse hepatocellular carcinoma (HCC) model. The objective of the current study was to investigate the clinical significance of YAP in HCC and its prognostic values in predicting survival and tumor recurrence.

Genome-Wide Association Study in Asian Populations Identifies Variants in ETS1 and WDFY4 Associated with Systemic Lupus Erythematosus

Systemic lupus erythematosus is a complex and potentially fatal autoimmune disease, characterized by autoantibody production and multi-organ damage. By a genome-wide association study (320 patients and 1,500 controls) and subsequent replication altogether involving a total of 3,300 Asian SLE patients from Hong Kong, Mainland China, and Thailand, as well as 4,200 ethnically and geographically matched controls, genetic variants in ETS1 and WDFY4 were found to be associated with SLE (ETS1: rs1128334, P = 2.33×10−11, OR = 1.29; WDFY4: rs7097397, P = 8.15×10−12, OR = 1.30). ETS1 encodes for a transcription factor known to be involved in a wide range of immune functions, including Th17 cell development and terminal differentiation of B lymphocytes. SNP rs1128334 is located in the 3′-UTR of ETS1, and allelic expression analysis from peripheral blood mononuclear cells showed significantly lower expression level from the risk allele. WDFY4 is a conserved protein with unknown function, but is predominantly expressed in primary and secondary immune tissues, and rs7097397 in WDFY4 changes an arginine residue to glutamine (R1816Q) in this protein. Our study also confirmed association of the HLA locus, STAT4, TNFSF4, BLK, BANK1, IRF5, and TNFAIP3 with SLE in Asians. These new genetic findings may help us to gain a better understanding of the disease and the functions of the genes involved.

β-catenin mutation and overexpression in hepatocellular carcinoma: Clinicopathologic and prognostic significance

β‐Catenin has been recognized as a critical member of the Wnt signaling pathway, and inappropriate activation of this pathway has been implicated in carcinogenesis.

Significance of resection margin in hepatectomy for hepatocellular carcinoma: A critical reappraisal.

OBJECTIVE To evaluate the influence of the width and histologic involvement of the resection margin on postoperative recurrence after resection of hepatocellular carcinoma (HCC). SUMMARY BACKGROUND DATA The significance of the resection margin in hepatectomy for HCC remains controversial. A precise evaluation of the effects of the width and histologic involvement of the resection margin on postoperative recurrence is required to clarify the issue. METHODS Two hundred eighty-eight patients with macroscopically complete resection of HCC were divided into groups with narrow (<1 cm) or wide (>/=1 cm) resection margins. The two groups were compared for postoperative recurrence rate and pattern of recurrence. A further analysis was performed to investigate the effects of histologic involvement of the resection margin on postoperative recurrence. RESULTS Recurrence rates were similar between 150 patients with a narrow margin and 138 patients with a wide margin; the groups were comparable in other clinicopathologic variables. Most recurrent tumors occurred in the liver remnant at a segment distant from the resection margin or at multiple segments. Thirty-four patients had margin involved histologically by microscopic invasion from the main tumor (n = 13), venous tumor thrombi (n = 13), or microsatellites separate from the main tumor (n = 8). These patients had significantly higher recurrence rates than those with a histologically clear margin. However, a positive histologic margin was not a significant risk factor for recurrence by multivariate analysis. Tumor stage and perioperative transfusion were the only independent risk factors. CONCLUSIONS The width of the resection margin did not influence the postoperative recurrence rates after hepatectomy for HCC. A positive histologic margin was associated with a higher incidence of postoperative recurrence, but in most patients this was related to the underlying venous invasion or microsatellites. Most intrahepatic recurrences were considered to arise from intrahepatic metastasis by means of venous dissemination, which a wide resection margin could not prevent.

Tumor Microvessel Density as a Predictor of Recurrence After Resection of Hepatocellular Carcinoma: A Prospective Study

PURPOSE This study prospectively evaluated the correlation of tumor microvessel density (MVD) with clinicopathologic features and postoperative recurrence in patients undergoing resection of hepatocellular carcinoma (HCC). PATIENTS AND METHODS Tumor MVD was assessed in 100 patients with resection of HCC using a computer image analyzer after immunostaining for CD34 (MVD-CD34) and von Willebrand factor (MVD-vWF), respectively. Patients were prospectively followed for recurrence. RESULTS Mean tumor MVD-CD34 (236/0.74 mm(2)) was higher than mean tumor MVD-vWF (87/0.74 mm(2)) (P <.001). By multiple regression analysis, tumor size was the only pathologic feature significantly related to tumor MVD-CD34. The median MVD-CD34 was 316/0.74 mm(2) in HCCs < or = 5 cm (n = 46) and 146/0.74 mm(2) in HCCs more than 5 cm (n = 54) (P <.001). Among patients with HCCs < or = 5 cm, those with higher than median MVD-CD34 had worse disease-free survival (at 3 years, 13%) than those with a lower MVD-CD34 (at 3 year, 74%) (P =.002). Multivariate analysis showed that tumor MVD-CD34 was the only significant factor predictive of disease-free survival in patients with HCC < or = 5 cm. For HCCs more than 5 cm, MVD-CD34 did not have a significant prognostic influence. MVD-vWF did not have a significant prognostic influence on disease-free survival in either HCCs < or = 5 cm or more than 5 cm. CONCLUSION This study shows that a high MVD-CD34 was predictive of early postresection recurrence in patients with HCCs < or = 5 cm and, therefore, may be a novel prognostic marker in this subset of patients.