Recent advances in recurrent hepatocellular carcinoma therapy

Hepatocellular carcinoma(HCC)is the most prevalent form of primary liver cancer,accounting for 75%-85%of cases.Although treatments are given to cure early-stage HCC,up to 50%-70%of individuals may experience a relapse of the illness in the liver after 5 years.Research on the fundamental treatment modalities for recurrent HCC is moving significantly further.The precise selection of individuals for therapy strategies with established survival advantages is crucial to ensuring better outcomes.These strategies aim to minimize substantial morbidity,support good life quality,and enhance survival for patients with recurrent HCC.For individuals with recurring HCC after curative treatment,no approved therapeutic regimen is currently available.A recent study presented novel approaches,like immunotherapy and antiviral medication,to improve the prognosis of patients with recurring HCC with the apparent lack of data to guide the clinical treatment.The data supporting several neoadjuvant and adjuvant therapies for patients with recurring HCC are outlined in this review.We also discuss the potential for future clinical and translational investigations.

Immunotherapy for advanced or recurrent hepatocellular carcinoma

Hepatocellular carcinoma(HCC)is associated with high morbidity and mortality,and is prone to intra-and extrahepatic metastasis due to the anatomical and functional characteristics of the liver.Due to the complexity and high relapse rate associated with radical surgery or radiofrequency ablation,immune checkpoint inhibitors(ICIs)are increasingly being used to treat HCC.Several immunotherapeutic agents,along with their combinations,have been clinically approved to treat advanced or recurrent HCC.This review discusses the leading ICIs in practice and those currently undergoing randomized phase 1-3 trials as monotherapy or combination therapy.Furthermore,we summarize the rapidly developing alternative strategies such as chimeric antigen receptor-engineered T cell therapy and tumor vaccines.Combination therapy is a promising potential treatment option.These immunotherapies are also summarized in this review,which provides insights into the advantages,limitations,and novel angles for future research in establishing viable and alternative therapies against HCC.

Salvage locoregional therapies for recurrent hepatocellular carcinoma

Hepatocellular carcinoma(HCC)is the second most common cause of cancerrelated death worldwide.Despite the advent of screening efforts and algorithms to stratify patients into appropriate treatment strategies,recurrence rates remain high.In contrast to first-line treatment for HCC,which relies on several factors,including clinical staging,tumor burden,and liver function,there is no consensus or general treatment recommendations for recurrent HCC(R-HCC).Locoregional therapies include a spectrum of minimally invasive liver-directed treatments which can be used as either curative or neoadjuvant therapy for HCC.Herein,we provide a comprehensive review of recent evidence using salvage loco-regional therapies for R-HCC after failed curative-intent.

Transcriptome analysis creates a new era of precision medicine for managing recurrent hepatocellular carcinoma

The high incidence of hepatocellular carcinoma(HCC)recurrence negatively impacts outcomes of patients treated with curative intent despite advances in surgical techniques and other locoregional liver-targeting therapies.Over the past few decades,the emergence of transcriptome analysis tools,including real-time quantitative reverse transcription PCR,microarrays,and RNA sequencing,has not only largely contributed to our knowledge about the pathogenesis of recurrent HCC but also led to the development of outcome prediction models based on differentially expressed gene signatures.In recent years,the single-cell RNA sequencing technique has revolutionized our ability to study the complicated crosstalk between cancer cells and the immune environment,which may benefit further investigations on the role of different immune cells in HCC recurrence and the identification of potential therapeutic targets.In the present article,we summarized the major findings yielded with these transcriptome methods within the framework of a causal model consisting of three domains:primary cancer cells;carcinogenic stimuli;and tumor microenvironment.We provided a comprehensive review of the insights that transcriptome analyses have provided into diagnostics,surveillance,and treatment of HCC recurrence.

Combining local regional therapy and systemic therapy:Expected changes in the treatment landscape of recurrent hepatocellular carcinoma

Improvements in early screening,new diagnostic techniques,and surgical treatment have led to continuous downward trends in hepatocellular carcinoma(HCC)morbidity and mortality rates.However,high recurrence and refractory cancer after hepatectomy remain important factors affecting the long-term prognosis of HCC.The clinical characteristics and prognosis of recurrent HCC are heterogeneous,and guidelines on treatment strategies for recurrent HCC are lacking.Therapies such as surgical resection,radiofrequency ablation,and transhepatic arterial chemoembolization are effective for tumors confined to the liver,and targeted therapy is a very important treatment for unresectable recurrent HCC with systemic metastasis.With the deepening of the understanding of the immune microenvironment of HCC,blocking immune checkpoints to enhance the antitumor immune response has become a new direction for the treatment of HCC.In addition,improvements in the tumor immune microenvironment caused by local treatment may provide an opportunity to improve the therapeutic effect of HCC treatment.Ongoing and future clinical trial data of combined therapy may develop the new treatment scheme for recurrent HCC.This paper reviews the pattern of recurrent HCC and the characteristics of the immune microenvironment,demonstrates the basis for combining local treatment and systemic treatment,and reports current evidence to better understand current progress and future approaches in the treatment of recurrent HCC.

A case of laparoscopic hepatectomy for recurrent hepatocellular carcinoma

Conventional hepatectomy is an effective way to treat hepatocellular carcinoma.However,it is invasive and stressful.The use of laparoscopy in hepatectomy,while technically demanding,reduces surgical invasiveness and stressfulness but still achieves complete resection with adequate margins.Compared with conventional hepatectomy,laparoscopic hepatectomy provides a better chance and situation for further surgery in the case of recurrence of hepatocellular carcinoma.Even aged patients can successfully endure repeated hepatectomy using laparoscopy,as shown in the present report.This report presents a case of repeated laparoscopic hepatectomy treating hepatocellular carcinoma and its recurrence in an aged patient having cirrhosis,a disease causing extra difficulty for performing laparoscopic hepatectomy.The report also describes techniques of the operation and displays characteristic results of laparoscopic hepatectomy such as smaller wounds,less blood loss,less pain,less scars and adhesion,shorter postoperative hospital stay,and faster recovery.

Clinical stages of recurrent hepatocellular carcinoma: A retrospective cohort study

BACKGROUND Hepatocellular carcinoma(HCC)is the second leading cause of cancer-related death worldwide,and has relatively high recurrence rates.Few studies have been published on the clinical stages of recurrent HCC.AIM To assess the applicability of the Barcelona Clinic Liver Cancer(BCLC)staging for recurrent HCC and the need to establish clinical stage criteria for recurrent HCC.METHODS The clinicopathological data of 81 patients with recurrent HCC who were admitted to the Hospital of Guangxi Zhuang Autonomous Region from January 2013 to December 2017 were collected.The patients were divided into three groups according to the BCLC staging system as follows:(1)Group A with BCLC stage A,51 patients;(2)Group B with BCLC stage B,14 patients;and(3)Group C with BCLC stage C,16 patients.The median time to tumor recurrence and the median overall survival were compared.RESULTS The median time to tumor recurrence in groups A,B,and C was 16±1.5 mo,10±2.8 mo,and 6±0.5 mo,respectively,with a statistically significant difference among them(χ^(2)=70.144,P<0.05);no statistically significant difference was noted between group A and group B(χ^(2)=2.659,P>0.05),although there were statistically significant differences between group A and group C and between group B and group C(χ^(2)=62.110,and 19.972,P<0.05).The median overall survival in groups A,B,and C were 42±5.1 mo,22±3.1 mo,and 13±1.8 mo,respectively,with a statistically significant difference among them(χ2=38.949,P<0.05);there were statistically significant differences between group A and group B,group A and group C,and group B and group C(χ2=9.577,37.172,and 7.183,respectively;P<0.05).CONCLUSION There are different prognoses in recurrent HCC patients according to the BCLC staging.Therefore,BCLC staging is applicable to recurrent HCC and it is essential to formulate clinical stage criteria for recurrent HCC.

Successful hepatic resection for recurrent hepatocellular carcinoma after lenvatinib treatment:A case report

BACKGROUND Lenvatinib has been shown to be noninferior to sorafenib regarding prognosis and recurrence rate in patients with unresectable hepatocellular carcinoma(HCC)who have not received prior systemic chemotherapy.In patients treated with lenvatinib,40%of cases achieved sufficient tumor reduction to make potential surgery possible.However,the outcomes of such surgery are unknown.We report a successful case of hepatic resection for recurrent HCC after lenvatinib treatment.CASE SUMMARY A 69-year-old man underwent right anterior sectionectomy for HCC in segment 8 of the liver.Ten months later,he was found to have an intrahepatic HCC recurrence that grew rapidly to 10 cm in diameter with sternal bone metastases.After confirming partial response to lenvatinib administration for 2 mo,a second hepatectomy was performed.Pathological examination showed that 80%of the tumor was necrotic.The patient did not develop any adverse effects under lenvatinib treatment.He was discharged at 25 d after surgery.Radiation therapy for bone metastases continued to be given under lenvatinib,and the patient has remained alive for 1 year after the second hepatectomy.CONCLUSION The prognosis of patients with recurrent HCC may be improved by liver resection combined with prior lenvatinib therapy.

Effectiveness and safety of irreversible electroporation for recurrent hepatocellular carcinoma ineligible for thermal ablation after surgery

Objectives:To preliminarily evaluate the clinical effectiveness and safety of computed tomography(CT)imageguided irreversible electroporation(IRE)for the treatment of recurrent hepatocellular carcinoma(HCC)after surgical resection.Methods:From January 2016 to February 2018,18 patients diagnosed with recurrent HCC after surgical resection received IRE under CT image guidance for 22 tumors.Patients were enrolled for IRE when ineligible for thermal ablation due to tumor location.Clinical records and imaging data were reviewed to assess complete ablation rate,local tumor progression free rate(LTPFR),local tumor progression free survival(LTPFS)and complications after a median follow-up time of 14 months.Results:Successful complete ablations were achieved in 20/22(90.1%)tumors.Mean LTPFS was 10.5?9.4 months.Overall 3-,6-and 12-months LTPFR in 22 tumors following IRE were 68.2%(95%confidence interval[CI]:45%–83%),59.1%(95%CI:33%–76%)and 36.4%(95%CI:17%–56%),respectively.Complications included pneumothorax(2/18,11.1%),localized pain(3/18,16.7%),bile duct dilation(1/18,5.6%)and transient hypertension(1/18,5.6%).No major complications or treatment-related deaths were observed.The alphafetoprotein levels of two patients decreased to the normal range at 3 and 4 months,respectively.Conclusions:This study showed that percutaneous CT image-guided IRE can serve as a safe and effective treatment for recurrent HCC not suitable for thermal ablation.

Anti-programmed cell death ligand 1-based immunotherapy in recurrent hepatocellular carcinoma with inferior vena cava tumor thrombus and metastasis:Three case reports

BACKGROUND Recurrent hepatocellular carcinoma(HCC)with inferior vena cava tumor thrombus is a great challenge for oncologists and has a poor prognosis.To date,the safety and efficacy of programmed cell death ligand 1(PD-L1)inhibitors are still unknown.CASE SUMMARY A 59-year-old male was identified as having a tumor thrombus in the inferior vena cava 3 years after surgery.The patient underwent a second surgery and adjuvant chemotherapy.However,the level of alpha-fetoprotein was elevated after 2 mo,and lung metastases and mediastinal lymph node metastases were identified.The expression of PD-L1 in HCC and inferior vena cava tumor thrombus tissues was analyzed by immunohistochemistry.Then,the patient received atezolizumab immunotherapy.The level of alpha-fetoprotein dropped to normal,the mediastinal lymph node metastases decreased in size and the lung metastases disappeared after 3 mo of immunotherapy.The patient had no signs of recurrence at 21 mo of follow-up.A 60-year-old male underwent left hepatic tumor resection,inferior vena cava incision and thrombus removal,followed by regular chemotherapy.The patient developed lung and splenic metastases after surgery.Pembrolizumab was used for six courses,and the splenic metastasis shrank,after which splenectomy was performed.The patient continued to receive pembrolizumab for thirteen courses,and the lung metastases showed no progression.A 34-year-old male was diagnosed with liver cancer with inferior vena cava tumor thrombus.The patient underwent right hepatectomy and received tislelizumab for three courses.He is still receiving immunotherapy and in good condition.CONCLUSION Anti-PD-L1 therapy in HCC patients with inferior vena cava tumor thrombus and metastasis is associated with relatively good patient outcomes.

Treatment Strategy for Post-Hepatectomy Recurrent Hepatocellular Carcinoma: A Single Center Experience with 556 Consecutive Cases in China

Background: Treatment strategy for recurrent hepatocellular carcinoma (HCC) remains scantily defined. This study was aimed to establish a treatment strategy to manage post-hepatectomy recurrent HCC and report the clinical outcomes. Methods: From January 2006 to December 2016, 556 consecutive patients who developed post-hepatectomy HCC recurrence were enrolled in the study. The patients were clinically stratified and treated according to a strategy established by a multi-disciplinary team. Clinical data and survival times were collected prospectively and analyzed retrospectively. Results: According to the strategy, there were 298 (53.6%), 214 (38.5%), 32 (5.7%) and 12 (2.2%) patients stratified into Early, Intermediate, Advanced and Terminal stages, respectively. In Early stage patients, 164 (55.0%) received curative treatment in the form of repeat resection or local ablation, 134 (45.0%) received transarterial chemoembolization (TACE), and the 1-, 3-, and 5-year overall survival (OS) rates were 82.0%, 46.8% and 37.3%, respectively. In Intermediate stage patients, 207 (96.7%) received TACE, 7 (3.3%) radiotherapy, and the 1-, 3-, and 5-year OS rates were 73.2%, 31.8% and 15.9%, respectively. In Advanced stage patients, 22 patients received sorafenib, 10 radiotherapy, and the mean survival time (MST) was 25.1 ± 3.1 months. All the 12 patients in Terminal stage received the best supportive treatment, and the MST was 6.5 ± 3.4 months. Clinical stages and duration of disease-free interval were independent factors relating to overall survival. Conclusions: A treatment strategy derived from the Barcelona Clinic Liver Cancer staging system, with some modifications, has been successfully established to manage post-hepatectomy recurrent HCC, and the clinical outcomes were commendable.

Predictive value of tumor markers in patients with recurrent hepatocellular carcinoma in different vascular invasion pattern

BACKGROUND： Four tumor markers for hepatocellular carcinoma（HCC）, alpha-fetoprotein（AFP）, glypican-3（GPC3）, vascular endothelial growth factor（VEGF） and des-gammacarboxy prothrombin（DCP）, are closely associated with tumor invasion and patient＇s survival. This study estimated the predictability of preoperative tumor marker levels along with pathological parameters on HCC recurrence after hepatectomy.METHODS： A total of 140 patients with HCC who underwent hepatectomy between January 2012 and August 2012 were enrolled. The demographics, clinical and follow-up data were collected and analyzed. The patients were divided into two groups： patients with macroscopic vascular invasion（Ma VI ＋） and those without Ma VI（Ma VI-）. The predictive value of tumor markers and clinical parameters were evaluated by univariate and multivariate analysis.RESULTS： In all patients, tumor size（〉8 cm） and Ma VI were closely related to HCC recurrence after hepatectomy. For Ma VI＋ patients, VEGF（〉900 pg/m L） was a significant predictor for recurrence（RR=2.421; 95% CI： 1.272-4.606; P=0.007）. The 1- and 2-year tumor-free survival rates for Ma VI＋ patients with VEGF ≤900 pg/m L versus for those with VEGF 〉900 pg/m L were 51.5% and 17.6% versus 19.0% and 4.8%（P〈0.001）. For Ma VI- patients, DCP 〉445 m Au/m L and tumor size 〉8 cm were two independent risk factors for tumor recurrence（RR=2.307, 95% CI： 1.132-4.703, P=0.021; RR=3.150, 95% CI： 1.392-7.127, P=0.006; respectively）. The 1- and 2-year tumor-free survival rates for the patients with DCP ≤445 m Au/m L and those with DCP 〉445 m Au/m L were 90.4% and 70.7% versus 73.2% and 50.5% respectively（P=0.048）. The 1-and 2-year tumor-free survival rates for the patients with tumor size ≤8 cm and 〉8 cm were 83.2% and 62.1% versus 50.0% and 30.0%, respectively（P=0.003）.CONCLUSIONS： The Ma VI＋ patients with VEGF ≤900 pg/m L had a relatively high tumor-free survival than those with VEGF 〉900 pg/m L. In the Ma VI- patients, DCP 〉445 m Au/m L and tumor size 〉8 cm were predictive factors for postoperative recurrence.

Surgical Treatment of Recurrent Hepatocellular Carcinoma (A report of 112 cases)

Objective The aim of this study was to evaluate the long term results of treatment and prognositic factors in patients with recurrent hepatocellular carcinoma after curative resection of hepatocellular carcinoma. Methods 112 patients of recurrent hepatocellular carcinoma who underwent surgical treatment were studied. Survival results after recurrence and from first hepatectomy were analyzed, and prognostic factors were determined by analyzing the clinicopathological variables.Results The mean survival of 112 patients was 26 months (4 to 76 months). 30 patients with tumor free state were still living. 1 year, 3 year and 5 year survival rates were 81.0%, 43.3% and 32 0%, respectively, and the 58 patients with hepatic resection were 87%, 59% and 38%, respectively. Among the 9 patients with secondary re resection, 6 had lived for over 3 years, and two for over 5 years. There were no operative death in this series, and few complications were found.Conclusion Early detection of recurrence depends on AFP measurements and ultrasonography follow up monitoring after resection. Re resection for recurrent hepatocellular carcinoma has been proved to be the most effective treatment modality. Aggressive treatment with a multimodality strategy is an option to improve long term survival in some patients with unresectable recurrent hepatocellular carcinoma.\;

Preoperative serum liver enzyme markers for predicting early recurrence after curative resection of hepatocellular carcinoma

BACKGROUND：Early recurrence of hepatocellular carcinoma（HCC）is associated with worse prognosis after liver resection This study aimed to investigate the prognostic value of com mon liver enzyme markers in HCC early recurrence after cu rative hepatectomy and to establish a simple predictive model for HCC early recurrence.METHODS： A total of 200 patients who had undergone curative resection for HCC were retrospectively analyzed. The patients were divided into early recurrence （within 2 years） and non-early recurrence groups. Demographical characteristics, preopera- tive liver function parameters, surgical factors and tumor related factors of the patients were assessed by univariate analysis to identify potential significant predictors for early recurrence after resection of HCC. Parameters with statisti- cal significance were entered into a Cox proportional hazard model to find independent risk factors. Receiver operating characteristic analysis was done to determine optimal cut-off values and the number of combined factors in multi-factor predictive model. RESULTS： Of 13 potential risk factors for early recurrence identified by univariate analysis, high lactate dehydrogenase （LDH〉206 U/L, HR=1.711, P=0.006）, high aspartate aminotransferase （AST）/alanine aminotransferase （ALT） ratio （AST/ ALT〉0.96, HR=1.769, P=0.006）, elevated alpha-fetoprotein （AFP〉8.6 ng/mL, HR=2.079, P=0.007）, small resection margin （〈1 cm, HR=2.354, P〈0.001） and advanced TNM stage （TNM III-IV, HR=2.164, P〈0.001） were independent risk factors for early recurrence of HCC shown by multivariate analysis. Patients with three or more concurrent independent risk factors had significantly higher risk for early recurrence than those with low risk factors. The sensitivity and specificity of this predictive model are 53.6% and 80.7%, respectively （area under curve=0.741, 95% CI 0.674-0.800, P〈0.0001）. CONCLUSIONS： Preoperative common fiver enzyme markers, LDH and AST/ALT ratio, were independently associated with early recurrence of HCC. The combination of serum liver enzyme markers with AFP, resection margin and TNM stage bet- ter predicted early recurrence of HCC after curative resection in a simple multi-factor model.

Current strategies for preventing the recurrence of hepatocellular carcinoma after liver transplantation

BACKGROUND：Liver transplantation is the optimal treatment for a selected group of patients with moderate to severe cirrhosis and hepatocellular carcinoma（HCC）.Despite the strict selection of candidates,post-transplant recurrence often occurs and markedly reduces the long-term survival of patients with HCC.The present review focuses on the current strategies on preventing the recurrence of HCC after liver transplantation.DATA SOURCES： Relevant articles were identified by exten- sive searching of PubMed using the keywords ＂hepatocellular carcinoma＂, ＂recurrence＂ and ＂liver transplantation＂ between January 1996 and January 2014. Additional papers were searched manually from the references in key articles. RESULTS： The current theories of HCC recurrence after liver transplantation are： （i） the growth of pre-transplant occult metastases; （ii） the engraftment of circulating tumor cells released at the time of transplantation. Pre-transplant treatment aims to control local tumor by radiofrequency ablation, transarterial embolization and transarterial chemoembolization. The main objective during the operation is to prevent tumor cell dissemination. Post-transplant treatment includes systemic anticancer therapy, antiviral therapy, and most recently, immunotherapy. These strategies concentrate on the control of the tumor when the patients are waiting for transplant, to reduce the release of HCC cells during surgical procedures and to dear the occult HCC cells after transplantation.CONCLUSIONS： Much can be done to prevent HCC recurrence after liver transplantation. In future, effort is likely to be di- rected towards combining multidisciplinary approaches and various treatment modalities.

Finding the seed of recurrence:Hepatocellular carcinoma circulating tumor cells and their potential to drive the surgical treatment

The treatment for hepatocellular carcinoma(HCC)relies on liver resection,which is,however,burdened by a high rate of recurrence after surgery,up to 60%at 5 years.No pre-operative tools are currently available to assess the recurrence risk tailored to every single patient.Recently liquid biopsy has shown interesting results in diagnosis,prognosis and treatment allocation strategies in other types of cancers,since its ability to identify circulating tumor cells(CTCs)derived from the primary tumor.Those cells were advocated to be responsible for the majority of cases of recurrence and cancer-related deaths for HCC.In fact,after being modified by the epithelial-mesenchymal transition,CTCs circulate as“seeds”in peripheral blood,then reach the target organ as dormant cells which could be subsequently“awakened”and activated,and then initiate metastasis.Their presence may justify the disagreement registered in terms of efficacy of anatomic vs non-anatomic resections,particularly in the case of microvascular invasion,which has been recently pointed as a histological sign of the spread of those cells.Thus,their presence,also in the early stages,may justify the recurrence event also in the contest of liver transplant.Understanding the mechanism behind the tumor progression may allow improving the treatment selection according to the biological patient-based characteristics.Moreover,it may drive the development of novel biological tailored tests which could address a specific patient to neoadjuvant or adjuvant strategies,and in perspective,it could also become a new method to allocate organs for transplantation,according to the risk of relapse after liver transplant.The present paper will describe the most recent evidence on the role of CTCs in determining the relapse of HCC,highlighting their potential clinical implication as novel tumor behavior biomarkers able to influence the surgical choice.

Liver transplantation for hepatocellular carcinoma： is zero recurrence theoretically possible？

BACKGROUND： Hepatocellular carcinoma（HCC） recurrence remains a key issue after liver transplantation. This study aimed to determine a subgroup of HCC patients within the Milan criteria who could achieve a theoretical goal of zero recurrence rates after liver transplantation.METHODS： Between 1999 and 2009, 179 patients who received liver transplantation for HCC within the Milan criteria were retrospectively included. Analysis of the factors associated with HCC recurrence was performed to determine the subgroup of patients at the lowest risk of recurrence.RESULTS： Seventy-two percent of the patients received a bridging therapy, including 54 liver resections. Eleven（6.1%） patients recurred within a delay of 19±22 months and ultimately died. Factors associated with recurrence were serum alpha-fetoprotein level 〉400 ng/m L, satellite nodules, poor differentiation, microvascular invasion and cholangiocarcinoma component. Recurrence rates decreased from 6.1% to 3.1% in patients without any of these factors.CONCLUSIONS： Among HCC patients within the Milan criteria, selecting patients with factors based on histology would allow tending towards zero recurrence, and prior histological assessment by liver biopsy or resection may be essential to rule out poorly differentiated tumors, microvascular invasion,and cholangiocarcinoma component.

RISK FACTORS FOR RECURRENCE IN PATIENTS WITH HEPATOCELLULAR CARCINOMA AFTER RADICAL RESECTION

Three hundred and eight patients with hepatocellular carcinoma underwent radical resection during 1975- 1991.The 1-,2-, 3-,4-,5-,and 10-year recurrent rates were 12.7%,28.7%,41.2%, 47.5%,54.1% and 64.4% respectively.By the end of March 1992,recurrence had occurred in 134 patients.Risk factors for recurrence were analyzed.Cox univariate analysts identified the following five factors to be correlated with increasing risk: high γ-GT,discovery by clinical,macronodular cirrhosis,minor resection and portal vein embolus.However,only high γ-GT,macronodular cirrhosis,and minor resection have been proved significant risk factors for recurrence in Cox multivariate analysis.Larger hepatic resection might reduce recurrence,intra-andlor post-operation comprehensive treatments are adevocated.

Expression of prothymosin α predicts early recurrence and poor prognosis of hepatocellular carcinoma

BACKGROUND：Prothymosinα（PTMA）is a nuclear oncoprotein-transcription factor essential for cell cycle progression and proliferation.PTMA was overexpressed in several human malignancies including hepatocellular carcinoma（HCC）.However,the prognostic significance of PTMA protein expression in HCC remains unclear.In the present study,we evaluated PTMA protein expression by immunohistochemistry in order to elucidate the prognostic roles of PTMA in HCC patients.METHODS： By immunohistochemistry, we investigated the expression of PTMA protein in tumor tissue from 226 HCC patients who underwent curative hepatectomy. Univariate and multivariate analyses were performed to evaluate its predic- tive value for tumor recurrence and survival of patients. The median follow-up period was 120 months. RESULTS： PTMA expression was observed in 162 （71.7%） of the 226 HCC patients and was significantly associated with higher Edmondson grade, microvascular invasion, intrahe- patic metastasis, higher American Joint Committee on Cancer （AJCC） T-stage, and lower albumin level. PTMA expression was an independent predictor of early recurrence （P=0.001）. PTMA expression showed an unfavorable influence on recurrence- free survival （RFS） （P〈0.001）. Subgroup analysis showed that among patients with tumor size _〈5.0 cm （140 patients）, patients at AJCC T-stage I （95 patients） and patients with a-fetoprotein ≤20 ng/mL （83 patients）, the differences in RFS between PTMA- positive and PTMA-negative groups were also statistically sig- nificant （P=0.017, P=0.002 and P=0.002, respectively）. In addi- tion, PTMA expression was an independent predictor of shorter RFS （P=0.011）. PTMA expression showed an unfavorable influ- ence on overall survival （P=0.014）, but was not an independent predictor of shorter overall survival （P=0.161）. CONCLUSIONS： PTMA protein expression might be a novel predictor of early recurrence and RFS in HCC patients, even those at early stage or with a-fetoprotein-negative after curative hepatectomy. PTMA could be used as an immunohistochemical biomarker to detect patients with a high risk of recurrence.

Loss of membranous carcinoembryonic antigen-related cell adhesion molecule 1 expression is related to decreased relapse-free survival of hepatocellular carcinoma following liver transplantation

Background Loss of carcinoembryonic antigen-related cell adhesion molecule 1 （CEACAM1） expression is an adverse prognostic factor in hepatocellular carcinoma （HCC）. The purpose of this study was to investigate the expression of CEACAM1 and its effect on relapse-free survival （RFS） following liver transplantation （LT） for HCC. Methods Expression of CEACAM1 was immunohistochemically detected in HCC specimens from 48 patients. The relationship between CEACAM1 expression and clinicopathologic variables, as well as tumor recurrence, was further analyzed. Results Of the 48 HCC specimens, membranous CEACAM1 expression was detected in 25 specimens and cytoplasmic CEACAM1 expression was detected in 19 specimens. Four specimens had loss of CEACAM1 expression. Loss of membranous CEACAM1 expression was significantly associated with tumor size, tumor number, and serum （z-fetoprotein levels （all P 〈0.05）. Patients with loss of membranous CEACAM1 had significantly poorer RFS than patients with membranous expression, determined via Kaplan-Meier analysis （P=0.027）. Multivariate analysis revealed that loss of membranous CEACAM1 expression might be an independent prognostic factor of RFS for HCC patients after liver transplantation （P=0.037）. Conclusion Loss of membranous CEACAM1 expression in HCC was closely associated with aggressive tumor biology and might be a relapsing biomarker of HCC treated with LT.