High Expression of Ribonucleotide Reductase Subunit M2 Correlates with Poor Prognosis of Hepatocellular Carcinoma

Background/Aims

Ribonucleotide reductase subunit M2 (RRM2) catalyzes the production of deoxynucleotide triphosphates, which are necessary for DNA synthesis. RRM2 has been reported to play an active role in tumor progression, and elevated RRM2 levels have been correlated with poor prognosis for colorectal cancer patients. This study aimed to elucidate the prognostic significance of RRM2 protein expression in hepatocellular carcinoma after surgery.

Methods

RRM2 protein expression was evaluated using immunohistochemistry in tumor tissues from 259 hepatocellular carcinoma patients who underwent curative hepatectomy.

Results

High RRM2 expression was observed in 210 of 259 patients (81.1%) with hepatocellular carcinomas. High RRM2 expression was significantly associated with viral etiology (p=0.035) and liver cirrhosis (p=0.036). High RRM2 expression was correlated with early recurrence (p=0.004) but not with late recurrence (p=0.144). Logistic regression analysis revealed that high RRM2 expression (p=0.040) and intrahepatic metastasis (p<0.001) were independent predictors of early recurrence. High RRM2 expression unfavorably influenced both shorter recurrence-free survival (p=0.011) and shorter disease-specific survival (p=0.002) and was an independent predictor of shorter disease-specific survival (p=0.008).

Conclusions

High RRM2 protein expression might be a useful marker for predicting early recurrence and may be a marker for poor prognosis of hepatocellular carcinoma after curative hepatectomy.     

Causes of Death in Patients with Unresectable Hepatocellular Carcinoma

Most patients with hepatocellular carcinoma (HCC) also have cirrhosis, an independent cause of death. We considered an alternative definition of tumor-related death in patients with HCC and attempted to validate our definition. Two hundred thirty-seven HCC patients were diagnosed, followed, and died over a 12-year period and were evaluated every 2 months, including their last 6 months of life. We defined death by cancer if there was, in the last 6 months of life, a CT scan increase of >25% in the sum of tumor index lesions’ cross-sectional areas or new onset of, or increase in, either vascular invasion or metastatic disease (Group 1). Patients with stable cancer were considered to have died from any other cause (Group 2). We found that 135 (57%) patients died from cancer progression (Group 1), whereas 102 (43%) patients did not (Group 2). There was a statistically significant difference between Group 1 and Group 2 patients in percentage with bilobar disease (P = 0.03), more than one tumor (P = 0.01), an increase in AFP (P = 0.04), vascular invasion (P = 0.001), and the presence of metastases (P = 0.01). We conclude that 57% of patients with unresectable HCC died as a direct result of cancer progression, but 43% did not. The latter died from complications of their cirrhosis, including sepsis, GI bleeds, and renal failure.     

Hepatocellular Carcinoma with Portal Vein Tumor Thrombosis: Clinical Characteristics, Prognosis, and Patient Survival Analysis

Hepatocellular carcinoma (HCC) with portal vein tumor thrombosis (PVTT) is associated with a poor prognosis. New therapeutic modalities, such as continuous hepatic arterial infusion chemotherapy (CHAIC), have recently been reported to be promising strategies. The aim of this study was to evaluate the clinical characteristics, prognosis, and survival of patients with PVTT according to treatment regimen. One hundred ninety-three patients with HCC complicated with PVTT at the time of diagnosis were included in this study. All patients were newly diagnosed to have HCC and were observed from January 1992 to December 2003. CHAIC was performed using an implanted drug delivery system with low-dose cisplatin and 5-fluorouracil. Clinical characteristics, prognosis, and patient survival were analyzed by the Kaplan-Meier method and Cox's proportional hazards model. The mean age of the patients complicated with PVTT was 64.3+/-10.3 years (range, 20-88 years). The survival of the 193 patients with PVTT was 37.5%, 24.0%, 18.9%, and 8.3% at 1, 2, 3, and 5 years, respectively. According to treatment, the survival of patients who underwent surgical treatment was the best, followed by CHAIC, transcatheter arterial infusion/embolization, and supportive care. The 3-year survivals for each treatment regimen were 53.0%, 19.3%, 15.0%, and 4.0%, respectively. Although the survival of patients who received surgical treatment was best, such patients were restricted. There was no difference in survival between treated and untreated patients demonstrating Child-Pugh grade C. In Child B patients, treatment for HCC significantly increased survival (P<0.01). Cox's proportional hazards model revealed the Child-Pugh classification to be an independent prognostic factor for patients with HCC and PVTT (P<0.01). We conclude that the prognosis of HCC with PVTT was quite poor. The treatment did not improve the survival of Child C patients. As a result, the prevention, early diagnosis, and development of new treatment strategies are required.     

Metadherin Is a Prognostic Predictor of Hepatocellular Carcinoma after Curative Hepatectomy

Background/AimsThe prognosis after surgical resection of hepatocellular carcinoma (HCC) remains poor because of a high rate of recurrence. Thus, it is crucial to identify patients with a high risk of recurrence after curative hepatectomy and to develop more effective and targeted treatment strategies to improve disease outcomes. In this study, we investigated the roles of metadherin (MTDH) in the prognosis of HCC.MethodsWe investigated MTDH expression using immunohistochemistry in tumor tissue microarrays of 288 primary HCC patients who underwent curative surgical resection.ResultsHigh MTDH expression was observed in 138 of the 288 HCC cases (47.9%). High MTDH expression was associated with a younger age (p<0.001), higher Edmondson grade (p<0.001), microvascular invasion (p<0.001), higher American Joint Committee on Cancer T stage (p=0.001), and higher α-fetoprotein level (p=0.003). Multivariate analyses revealed that high MTDH expression (p=0.014), higher Barcelona-Clinic Liver Cancer (BCLC) stage (p<0.001), and Edmondson grade III (p=0.042) were independent predictors of shorter disease-free survival (DFS). Higher BCLC stage (p<0.001) and Edmondson grade III (p=0.047) were also independent predictors of shorter disease-specific survival.ConclusionsHigh MTDH expression may be a prognostic predictor of shorter DFS in HCC patients after curative hepatectomy.     

Hepatocellular Carcinoma in Young Adults: The Clinical Characteristics, Prognosis, and Findings of a Patient Survival Analysis

Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. However, HCC is rare in young Japanese patients and the clinical features of young patients with HCC have not yet been fully studied. This study was designed to determine the clinical characteristics and prognosis of patients with HCC who are younger than aged 40 years. A retrospective analysis was performed for patients newly diagnosed with HCC and observed from January 1990 to December 2003 at our hospitals. Patients younger than aged 40 years at the diagnosis of HCC were defined as the young group and were reviewed. There were 20 patients (16 males) with HCC who were younger than aged 40 years. The mean age at diagnosis was 33.6 (range, 20–39) years. Fifteen of 20 patients were positive for hepatitis B surface antigen (HBsAg) and 2 patients were positive for hepatitis C virus antibody. According to the Child-Pugh grading, the liver function was relatively good in all patients. Because most of the patients did not receive periodic follow-up, this disease often was discovered at an advanced stage, usually after the appearance of some symptoms. Although intensive treatment was performed for such young patients, the survival was nevertheless poor. Most patients died from this cancer within 1 year. However, one patient who received periodic follow-up and also was in relatively good physical condition had a better prognosis, and he survived for 88 months. Young patients with HCC tended to have a poor prognosis because of advanced stage of HCC, despite a well-preserved liver function and aggressive treatment. Screening for HCC and an early diagnosis is needed for such patients to demonstrate an improved prognosis, especially for HBsAg-positive patients.     

Immunohistochemical Expression of Components of the Akt-mTORC1 Pathway is Associated with Hepatocellular Carcinoma in Patients with Chronic Liver Disease

Activation of the Akt-mTORC1 signaling pathway was evaluated in premalignant and hepatocellular carcinoma (HCC) lesions by assessing the expression of pS6, an Akt effector, and PTEN, an Akt suppressor. Methods: Immunohistochemical staining for pS6 and PTEN was performed on liver tissue from 52 patients with cirrhosis, with and without HCC. Two pathologists independently evaluated pS6 staining on a semiquantitative scale and categorized PTEN staining as present or absent. Results: In the HCC group, pS6 staining was greatest in HCC, followed by dysplasia, and benign cirrhotic tissue (P < 0.001). pS6 staining was greater in cirrhotic tissue from patients with HCC compared to cirrhosis in patients without HCC (P = 0.03). PTEN staining in tumor was absent in 8/33 (24%) cases. Loss of PTEN expression was more common in patients with higher tumor stage, compared to those with stage 1 tumors (P = 0.04). Conclusion: Immunohistochemical evidence of activation of the Akt-mTORC1 pathway is associated with HCC.     

Elevated Expression of Autocrine Motility Factor Receptor Correlates with Overexpression of RhoC and Indicates Poor Prognosis in Hepatocellular Carcinoma

Our previous study identified RhoC as an invasion and metastasis marker in hepatocellular carcinoma patients. Recent document suggested RhoGTPase is required for autocrine motility factor signaling. In this study, we questioned whether there is a correlation between expression of autocrine motility factor receptor and RhoC. Furthermore, we questioned whether elevated expression of autocrine motility factor correlates with metastasis and poor prognosis of HCC. The mRNA expression level of AMFR and RhoC were examined by RT-PCR in 25 cases of HCC and pericarcinomatous liver tissues (PCLT). In addition, the correlation between the expression level of AMFR and clinical pathologic parameters was analyzed. Furthermore, follow-up information was collected to evaluate the prognostic value of AMFR for HCC patients. Our results showed that the expression of AMFR and RhoC significantly increased in HCC compared with PCLT; extrahepatic metastatic lesions expressed significantly higher levels of AMFR and RhoC than corresponding intrahepatic HCC tissues. There is a highly significant correlation of AMFR expression levels with tumor vein invasion, number of tumor nodes, and tumor stage. Anticipatively, positive correlation was observed between mRNA expression of AMFR and RhoC gene. Furthermore, the HCC patients with high-expression of AMFR had significant high recurrence/metastasis and shorter survival than those with low-expression of AMFR. Together, our findings suggested a strong correlation between the expression of AMFR and RhoC and also a correlation between overexpression of them and invasion and metastasis of HCC. Furthermore, our data indicated AMFR as a potential prognosis for HCC.     

Clinicopathological and Prognostic Significance of Klotho and Estrogen Receptors Expression in Human Hepatocellular Carcinoma

Background: Hepatocellular carcinoma (HCC) is male-predominant cancer, but the underlying mechanism remains unclear. This study aimed to investigate the expression of the age-suppressing gene klotho and estrogen receptors (ERs) in HCC patients and analyze their association with clinicopathological variables and their effects on prognosis.Methods: The expression patterns of klotho, ERα, and ERβ were determined by tissue microarray and immunohistochemical technique, and their correlations with clinicopathological characteristics were investigated using univariate and multivariate analysis. Results: Klotho expression was significantly lower in HCC than in the adjacent noncancerous tissues (52.7% (49/93) vs. 90.8% (79/87), P = .000), and its protein level in HCC tissue was negatively correlated with clinical staging, histological grade, and stage of the primary tumor (T) (P < .05). Whereas the expression of nuclear ERα and ERβ was higher in HCC than their corresponding non-neoplastic tissues (55.9% (52/93) vs. 35.6% (31/87), P = .006; 59.1% (55/93) vs. 43.7% (38/87), P = .038), and the level of nuclear ERα and ERβ in HCC tissue was inversely correlated with T stage, tumor size, and clinical staging (P < .05). Correlation analysis showed the expression level of klotho, which is positively correlated with that of nuclear ERα (r = 0.243, P = .019). Patients with klotho-positive tumors had longer survival than those with klotho-negative tumors (P = .002). Cox proportional hazards model analysis demonstrated that positive expression of klotho was an important factor indicating good prognosis (P = .003).Conclusion: Klotho, partially regulated by ERα-mediated estrogen pathway, acts as a tumor suppressor and might be a novel biomarker candidate for predicting progression and prognosis in HCC patients.     

肝癌组织中ICAM-1的表达和意义

目的研究细胞间黏附分子-1(1CAM-1)在原发性肝癌中的临床意义.方法以免疫组化方法结合全自动图像分析观察40例肝细胞癌组织及其癌旁组织和28例肝硬化组织中ICAM-1的表达.结果40例肝细胞癌组织ICAM-1表达阳性率为80.0%(32/40)、癌旁组织为57.5%(23/40)、肝硬化为53.6%(15/28),阳性率与组织学分类相关.肝癌组织中ICAM-1含量明显高于癌旁及肝硬化组织(P＜0.05),转移组肝癌中ICAM-1的含量明显高于非转移组(P＜0.05),而癌旁及肝硬化组织中表达差异无显著性(P＞0.05).结论肝癌组织中高度表达ICAM-1,ICAM-1有可能作为判断肝硬化及肝癌发展程度及预后的指标之一.     

nm23基因在食管癌及贲门癌中的表达

采用ＬＳＡＢ免疫组化法,对４６例食管癌及３１例贲门癌患者的癌组织进行了ｎｍ２３基因（下简称ｎｍ２３）染色检测,结果显示,食管癌组织染色阳性率明显低于癌旁组织,分化较好的癌组织染色阳性率明显高于分化差的癌组织,原发灶染色阳性率明显高于转移灶,有淋巴结转移的食管癌组织染色阳性率明显低于无转移者,贲门癌中,除有淋巴结转移的贲门癌组织与无淋巴结转移的贲门癌组织染色阳性率差异不显著小,其他相关性同食管癌,两     

Prognostic Index for Survival in Patients After Treatment for Primary Hepatocellular Carcinoma

We retrospectively evaluated clinical factors affecting long-term survival after treatment for hepatocellular carcinoma (HCC) to predict the reliability of the prognosis of patients with HCC. We analyzed 157 patients who received treatment for HCC. The prognostic index (PI) was evaluated using the Cox regression model. The overall cumulative survival rates were 79.7% at 1 year, 51.1% at 3 years, and 24.9% at 5 years. The PI was calculated by the following formula, consisting of five factors: PI=0.637×number of tumor lesions+0.103×tumor diameter+1.003×ascites+0.915×portal vein tumor thrombosis – 0.006×cholinesterase+2.0. It was found that liver function and progression of the tumor are the most important factors for prognosis after treatment for HCC. The PI, based on five factors, will in future be an appropriate index to predict the prognosis of patients with HCC.     

量子点免疫荧光组化技术检测肝细胞癌中窖蛋白1的表达

目的 研究窖蛋白1在人肝细胞癌组织芯片中的表达,并探讨其在肝细胞癌发生过程中的可能作用。方法采用量子点免疫荧光组织化学技术检测60例肝细胞癌及其对应的癌旁组织芯片中窖蛋白1的表达,并就其表达与临床病理学特征之间的关系进行分析。结果窖蛋白1表达水平在肝细胞癌与癌旁组织芯片中分别为364．75±114．67、281．14±57．08,两者相比差异有统计学意义（P〈0．05）。但窖蛋白1表达水平在患者的年龄、性别、肿瘤大小、组织学分级、TNM分期中差异无统计学意义（P〉0．05）。结论人肝细胞癌组织中存在着窖蛋白1的表达,可能参与了肝细胞癌发生的早期过程。     

Treatment Outcomes of Helical Intensity-Modulated Radiotherapy for Unresectable Hepatocellular Carcinoma

Background/Aims

This study reports treatment outcomes after helical intensity-modulated radiotherapy (IMRT) in unresectable hepatocellular carcinoma (HCC) patients for whom transarterial chemoembolization (TACE) was considered ineffective or unsuitable.

Methods

From January 2008 to December 2011, 22 unresectable HCC patients received helical IMRT. A daily dose of 1.8 to 4 Gy was delivered at five fractions per week to deliver a total dose of 30 to 60 Gy. The most-prescribed dose fractionation was a total dose of 50 to 57.5 Gy, with a daily dose of 2.3 to 2.5 Gy.

Results

In the entire group, the objective response rate of the primary tumor was 72.7%. In the eight patients with portal vein thrombosis (PVT), the objective response rate of PVT was 50.0%. Median disease progression-free survival was 11.8 months, and the 1-year disease progression-free survival rate was 40.2%. The median overall survival was 14.4 months, and the 1- and 2-year overall survival rates were 86.4% and 69.1%, respectively. PVT and Child-Pugh classifications were significant prognostic factors for overall survival in multivariate analyses.

Conclusions

Helical IMRT in patients with unresectable HCC resulted in high treatment response and survival rates. This study suggests helical IMRT is a practical treatment option for HCC patients in whom TACE is unsuitable or ineffective.     

Sorafenib in the Treatment of Advanced Hepatocellular Carcinoma

Management of advanced hepatocellular carcinoma (HCC) is still a challenge to physicians since these patients are not candidates for surgical or ablative therapy. The disease carries a very poor prognosis with an expected survival of 4–6 months. No chemotherapeutic agent has been proven to improve the clinical outcome in such patients. A multikinase inhibitor, sorafenib, previously tested and found effective in other solid tumors recently found to significantly improve survival in patients with advanced HCC. Sorafenib exerts its action through inhibition of several kinases involved in both tumour cell proliferation and angiogenesis. It was well tolerated at a dose of 400 mg twice daily and permanent discontinuation of the drug was rarely required.     

肝硬化 肝癌患者血清循环免疫复合物的研究

采用一种简单、敏感的放射免疫法测定了101例肝病患者(25例肝癌,17例肝硬化,26例慢迁肝,33例乙肝病毒携带着)的血清循环免疫复合物,并观察了各组肝功能的变化以及HBV标志.结果表明:肝癌组的IgG-CIC含量及γ-GT含量明显高于其它各组.IgG-CIC 5.21(PHC),3.43(LC),2.41(CPH)及1.92(ASC),P<0.01.γ-GT 262(PHC).63.1(LC),44.7(CPH)以及18.7(ASC),P<0.01.伴有HBV感染的肝癌组中有80%可检出IgG-CIC,而CPH及ASC组中仅有50%可检出IgG-CIC.研究结果还表明:肝癌组中,IgG-CIC含量随着AFP含量的升高而上升.但在AFP过度升高时,IgG-GIC反而降低.这可能提示:随着肿瘤的生长,IgG-CIC升高,AFP值随肿瘤恶化逐渐上升,致使IgG-CIC从结合补体转变成非结合补体,导致IgG-CIC的下降.根据结果提示:HBV感染与肝癌发生有着密切关系.     

A Novel mRNA Signature Related to Immunity to Predict Survival and Immunotherapy Response in Hepatocellular Carcinoma

Background and AimsHepatocellular carcinoma (HCC) is the most common primary liver cancer and the incidence and mortality rates are increasing. Given the limited treatments of HCC and promising application of immunotherapy for cancer, we aimed to identify an immune-related prognostic signature that can predict overall survival (OS) rates and immunotherapy response in HCC.MethodsThe initial signature development was conducted using a training dataset from the Cancer Genome Atlas followed by independent internal and external validations from that resource and the Gene Expression Omnibus. A signature based nomogram was generated using multivariate Cox regression analysis. The associations of signature score with tumor immune phenotype and response to immunotherapy were analyzed using single-sample gene set enrichment analysis and tumor immune dysfunction and exclusion algorithm. A cohort from Zhongshan Hospital was employed to verify the predictive robustness of the signature regarding prognostic risk and immunotherapy response.ResultsThe prognostic signature, IGS_HCC, consisting of 22 immune-related genes, had independent prognostic ability, with training and validation cohorts. Also, IGS_HCC stratified HCC patients with different outcomes in subgroups. The prognostic accuracy of IGS_HCC was better than three reported prognostic signatures. The IGS_HCC-based nomogram had high accuracy and significant clinical benefits in predicting 3- and 5-year OS. IGS_HCC reflected distinct immunosuppressive phenotypes in low- and high-score groups. Patients with low IGS_HCC scores were more likely than those with high scores to benefit from immunotherapy.ConclusionsIGS_HCC predicted HCC prognosis and response to immunotherapy, and contributed to individualized clinical management.