Hepatocellular carcinoma recurrence after liver transplant:An Australian single-centre study

BACKGROUND Hepatocellular carcinoma(HCC)is a leading cause of cancer-related deaths worldwide.Liver transplantation(LT)offers the most effective treatment.HCC recurrence is the strongest risk factor that decreases post-LT survival in patients transplanted for HCC.The rate of HCC recurrence is generally reported as 8%-20%in the literature.Many predictors of HCC have already been researched,however,to our knowledge there are no published studies on this topic using Australian data.AIM To determine the rate and identify predictors of HCC recurrence in a contemporary Western Australian LT cohort.METHODS We performed a retrospective cohort study of all liver transplants in patients with HCC at Sir Charles Gairdner Hospital between 2006 and 2021.Data was collected from various health record databases and included recipient demographics,serum biochemistry,radiology,operation notes,explant histopathology and details of recurrence.Overall survival of HCC patients post-LT,stratified for recurrence,was calculated by Kaplan Meier analysis.Univariate and multivariate Cox regression was used to determine predictors of HCC recurrence post-LT.RESULTS Between 1/1/2006 and 12/31/2021,119 patients were transplanted with HCC.8.4%of subjects developed recurrent HCC after LT with median follow-up time of 5.4 years.The median time to recurrence was 2.9 years±0.75 years.When comparing baseline characteristics,a greater proportion of subjects with recurrence had common characteristics on explant histopathology,including>3 viable nodules(P=0.001),vascular invasion(P=0.003)and poorly differentiated HCC(P=0.03).Unadjusted survival curves showed lower 1-year,3-year,5-year and 10-year survival rates in subjects with HCC recurrence compared to those without HCC recurrence(90%vs 92%,70%vs 88%,42%vs 80%,14%vs 76%,respectively;log rank P<0.001).CONCLUSION HCC recurrence was low at 8.4%in this contemporary Australian cohort,however it significantly impacted post-LT survival.Further studies are required to confirm predictors of recurrence and improve recipient outcomes.

Assessing recent recurrence after hepatectomy for hepatitis Brelated hepatocellular carcinoma by a predictive model based on sarcopenia

BACKGROUND Sarcopenia may be associated with hepatocellular carcinoma(HCC)following hepatectomy.But traditional single clinical variables are still insufficient to predict recurrence.We still lack effective prediction models for recent recurrence(time to recurrence<2 years)after hepatectomy for HCC.AIM To establish an interventable prediction model to estimate recurrence-free survival(RFS)after hepatectomy for HCC based on sarcopenia.METHODS We retrospectively analyzed 283 hepatitis B-related HCC patients who underwent curative hepatectomy for the first time,and the skeletal muscle index at the third lumbar spine was measured by preoperative computed tomography.94 of these patients were enrolled for external validation.Cox multivariate analysis was per-formed to identify the risk factors of postoperative recurrence in training cohort.A nomogram model was developed to predict the RFS of HCC patients,and its predictive performance was validated.The predictive efficacy of this model was evaluated using the receiver operating characteristic curve.RESULTS Multivariate analysis showed that sarcopenia[Hazard ratio(HR)=1.767,95%CI:1.166-2.678,P<0.05],alpha-fetoprotein≥40 ng/mL(HR=1.984,95%CI:1.307-3.011,P<0.05),the maximum diameter of tumor>5 cm(HR=2.222,95%CI:1.285-3.842,P<0.05),and hepatitis B virus DNA level≥2000 IU/mL(HR=2.1,95%CI:1.407-3.135,P<0.05)were independent risk factors associated with postoperative recurrence of HCC.Based on the sarcopenia to assess the RFS model of hepatectomy with hepatitis B-related liver cancer disease(SAMD)was established combined with other the above risk factors.The area under the curve of the SAMD model was 0.782(95%CI:0.705-0.858)in the training cohort(sensitivity 81%,specificity 63%)and 0.773(95%CI:0.707-0.838)in the validation cohort.Besides,a SAMD score≥110 was better to distinguish the high-risk group of postoperative recurrence of HCC.CONCLUSION Sarcopenia is associated with recent recurrence after hepatectomy for hepatitis B-related HCC.A nutritional status-based prediction model is first established for postoperative recurrence of hepatitis B-related HCC,which is superior to other models and contributes to prognosis prediction.

Leveraging machine learning for early recurrence prediction in hepatocellular carcinoma:A step towards precision medicine

The high rate of early recurrence in hepatocellular carcinoma(HCC)post curative surgical intervention poses a substantial clinical hurdle,impacting patient outcomes and complicating postoperative management.The advent of machine learning provides a unique opportunity to harness vast datasets,identifying subtle patterns and factors that elude conventional prognostic methods.Machine learning models,equipped with the ability to analyse intricate relationships within datasets,have shown promise in predicting outcomes in various medical disciplines.In the context of HCC,the application of machine learning to predict early recurrence holds potential for personalized postoperative care strategies.This editorial comments on the study carried out exploring the merits and efficacy of random survival forests(RSF)in identifying significant risk factors for recurrence,stratifying patients at low and high risk of HCC recurrence and comparing this to traditional COX proportional hazard models(CPH).In doing so,the study demonstrated that the RSF models are superior to traditional CPH models in predicting recurrence of HCC and represent a giant leap towards precision medicine.

Computed tomography-based radiomics to predict early recurrence of hepatocellular carcinoma post-hepatectomy in patients background on cirrhosis

BACKGROUND The prognosis for hepatocellular carcinoma(HCC)in the presence of cirrhosis is unfavourable,primarily attributable to the high incidence of recurrence.AIM To develop a machine learning model for predicting early recurrence(ER)of posthepatectomy HCC in patients with cirrhosis and to stratify patients’overall survival(OS)based on the predicted risk of recurrence.METHODS In this retrospective study,214 HCC patients with cirrhosis who underwent curative hepatectomy were examined.Radiomics feature selection was conducted using the least absolute shrinkage and selection operator and recursive feature elimination methods.Clinical-radiologic features were selected through univariate and multivariate logistic regression analyses.Five machine learning methods were used for model comparison,aiming to identify the optimal model.The model’s performance was evaluated using the receiver operating characteristic curve[area under the curve(AUC)],calibration,and decision curve analysis.Additionally,the Kaplan-Meier(K-M)curve was used to evaluate the stratification effect of the model on patient OS.RESULTS Within this study,the most effective predictive performance for ER of post-hepatectomy HCC in the background of cirrhosis was demonstrated by a model that integrated radiomics features and clinical-radiologic features.In the training cohort,this model attained an AUC of 0.844,while in the validation cohort,it achieved a value of 0.790.The K-M curves illustrated that the combined model not only facilitated risk stratification but also exhibited significant discriminatory ability concerning patients’OS.CONCLUSION The combined model,integrating both radiomics and clinical-radiologic characteristics,exhibited excellent performance in HCC with cirrhosis.The K-M curves assessing OS revealed statistically significant differences.

From prediction to prevention:Machine learning revolutionizes hepatocellular carcinoma recurrence monitoring

In this editorial,we comment on the article by Zhang et al entitled Development of a machine learning-based model for predicting the risk of early postoperative recurrence of hepatocellular carcinoma.Hepatocellular carcinoma(HCC),which is characterized by high incidence and mortality rates,remains a major global health challenge primarily due to the critical issue of postoperative recurrence.Early recurrence,defined as recurrence that occurs within 2 years posttreatment,is linked to the hidden spread of the primary tumor and significantly impacts patient survival.Traditional predictive factors,including both patient-and treatment-related factors,have limited predictive ability with respect to HCC recurrence.The integration of machine learning algorithms is fueled by the exponential growth of computational power and has revolutionized HCC research.The study by Zhang et al demonstrated the use of a groundbreaking preoperative prediction model for early postoperative HCC recurrence.Challenges persist,including sample size constraints,issues with handling data,and the need for further validation and interpretability.This study emphasizes the need for collaborative efforts,multicenter studies and comparative analyses to validate and refine the model.Overcoming these challenges and exploring innovative approaches,such as multi-omics integration,will enhance personalized oncology care.This study marks a significant stride toward precise,efficient,and personalized oncology practices,thus offering hope for improved patient outcomes in the field of HCC treatment.

Pre-operative enhanced magnetic resonance imaging combined with clinical features predict early recurrence of hepatocellular carcinoma after radical resection

BACKGROUND Indentifying predictive factors for postoperative recurrence of hepatocellular carcinoma(HCC)has great significance for patient prognosis.AIM To explore the value of gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid(Gd-EOB-DTPA)enhanced magnetic resonance imaging(MRI)combined with clinical features in predicting early recurrence of HCC after resection.METHODS A total of 161 patients with pathologically confirmed HCC were enrolled.The patients were divided into early recurrence and non-early recurrence group based on the follow-up results.The clinical,laboratory,pathological results and Gd-EOB-DTPA enhanced MRI imaging features were analyzed.RESULTS Of 161 patients,73 had early recurrence and 88 were had non-early recurrence.Univariate analysis showed that patient age,gender,serum alpha-fetoprotein level,the Barcelona Clinic Liver Cancer stage,China liver cancer(CNLC)stage,microvascular invasion(MVI),pathological satellite focus,tumor size,tumor number,tumor boundary,tumor capsule,intratumoral necrosis,portal vein tumor thrombus,large vessel invasion,nonperipheral washout,peritumoral enhancement,hepatobiliary phase(HBP)/tumor signal intensity(SI)/peritumoral SI,HBP peritumoral low signal and peritumoral delay enhancement were significantly associated with early recurrence of HCC after operation.Multivariate logistic regression analysis showed that patient age,MVI,CNLC stage,tumor boundary and large vessel invasion were independent predictive factors.External data validation indicated that the area under the curve of the combined predictors was 0.861,suggesting that multivariate logistic regression was a reasonable predictive model for early recurrence of HCC.CONCLUSION Gd-EOB-DTPA enhanced MRI combined with clinical features would help predicting the early recurrence of HCC after operation.

Challenges related to clinical decision-making in hepatocellular carcinoma recurrence post-liver transplantation: Is there a hope?

Hepatocellular carcinoma(HCC)is a common liver malignancy and represents a serious cause of cancer-related mortality and morbidity.One of the favourable curative surgical therapeutic options for HCC is liver transplantation(LT)in selected patients fulfilling the known standard Milan/University of California San Francisco criteria which have shown better outcomes and longer-term survival.Despite careful adherence to the strict HCC selection criteria for LT in different transplant centres,the recurrence rate still occurs which could negatively affect HCC patients’survival.Hence HCC recurrence post-LT could predict patients’survival and prognosis,depending on the exact timing of recurrence after LT(early or late),and whether intra/extrahepatic HCC recurrence.Several factors may aid in such a complication,particularly tumour-related criteria including larger sizes,higher grades or poor tumour differentiation,microvascular invasion,and elevated serum alpha-fetoprotein.Therefore,managing such cases is challenging,different therapeutic options have been proposed,including curative surgical and ablative treatments that have shown better outcomes,compared to the palliative locoregional and systemic therapies,which may be helpful in those with unresectable tumour burden.To handle all these issues in our review.

SIMAP500: A novel risk score to identify recipients at higher risk of hepatocellular carcinoma recurrence following liver transplantation

BACKGROUND Recurrence of hepatocellular carcinoma(HCC)following liver transplantation(LT)has a devastating influence on recipients’survival;however,the risk of recur-rence is not routinely stratified.Risk stratification is vital with a long LT waiting time,as that could influence the recurrence despite strict listing criteria.AIM This study aims to identify predictors of recurrence and develop a novel risk pre-diction score to forecast HCC recurrence following LT.METHODS A retrospective review of LT for HCC recipients at University Hospitals Bir-mingham between July 2011 and February 2020.Univariate and multivariate analyses were performed to identify recurrence predictors,based on which the novel SIMAP500(satellite nodules,increase in size,microvascular invasion,AFP>500,poor differentiation)risk score was proposed.RESULTS 234 LTs for HCC were performed with a median follow-up of 5.3 years.Recurrence developed in 25 patients(10.7%).On univariate analyses,RETREAT score>3,α-fetoprotein(AFP)at listing 100-500 and>500,bridging,increased tumour size between imaging at the listing time and explant histology,increase in the size of viable tumour between listing and explant,presence of satellite nodules,micro-and macrovascular invasion on explant and poor differentiation of tumours were significantly associated with recurrence,based on which,the SIMAP500 risk score is proposed.The SIMAP500 demonstrated an excellent predictive ability(c-index=0.803)and outper-formed the RETREAT score(c-index=0.73).SIMAP500 is indicative of the time to disease recurrence.CONCLUSION SIMAP500 risk score identifies the LT recipients at risk of HCC recurrence.Risk stratification allows patient-centric post-transplant surveillance programs.Further validation of the score is recommended.

Imaging-based prediction of hepatocellular carcinoma recurrence after microwave ablation as bridge therapy: A glimpse into the future

Liver transplantation(LT)remains the treatment of choice for early-stage hepato-cellular carcinoma(HCC)and offers the best long-term oncological outcomes.However,the increasing waiting list for LT has led to a significant dropout rate as patients experience tumor progression beyond the Milan criteria.Currently,locoregional therapies,such as microwave ablation(MWA),have emerged as promising bridge treatments for patients awaiting LT.These therapies have shown promising results in preventing tumor progression,thus reducing the dropout rate of LT candidates.Despite the efficacy of MWA in treating HCC,tumoral recurrence after ablation remains a major challenge and significantly impacts the prognosis of HCC patients.Therefore,accurately diagnosing tumoral recurrence post-ablation is crucial.Recent studies have developed novel imaging features based on magnetic resonance imaging of HCC,which could provide essential information for predicting early tumoral recurrence after MWA.These advancements could address this unresolved challenge,improving the clinical outcomes of patients on the LT waiting list.This article explored the current landscape of MWA as a bridge therapy for HCC within the Milan criteria,high-lighting the emerging role of novel imaging-based features aimed at improving the prediction of tumor recurrence after MWA.

Predictors of early and late hepatocellular carcinoma recurrence

Hepatocellular carcinoma(HCC)is the most frequent liver neoplasm,and its incidence rates are constantly increasing.Despite the availability of potentially curative treatments(liver transplantation,surgical resection,thermal ablation),long-term outcomes are affected by a high recurrence rate(up to 70%of cases 5 years after treatment).HCC recurrence within 2 years of treatment is defined as“early”and is generally caused by the occult intrahepatic spread of the primary neoplasm and related to the tumor burden.A recurrence that occurs after 2 years of treatment is defined as“late”and is related to de novo HCC,independent of the primary neoplasm.Early HCC recurrence has a significantly poorer prognosis and outcome than late recurrence.Different pathogenesis corresponds to different predictors of the risk of early or late recurrence.An adequate knowledge of predictive factors and recurrence risk stratification guides the therapeutic strategy and post-treatment surveillance.Patients at high risk of HCC recurrence should be referred to treatments with the lowest recurrence rate and when standardized to combined or adjuvant therapy regimens.This review aimed to expose the recurrence predictors and examine the differences between predictors of early and late recurrence.

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.

Traditional herbal medicine in preventing recurrence after resection of small hepatocellular carcinoma: a multicenter randomized controlled trial

BACKGROUND： Disease recurrence is a main challenge in treatment of hepatocellular carcinoma （HCC）. There is no generally accepted method for preventing recurrence of HCC after resection. OBJECTIVE： To compare the efficacy of a traditional herbal medicine （THM） regimen and transarterial chemoembolization （TACE） in preventing recurrence in post-resection patients with small HCC. DESIGN, SETTING, PARTICIPANTS AND INTERVENTIONS： This is a multicenter, open- label, randomized, controlled study, which was undertaken in five centers of China. A total of 379 patients who met the eligibility criteria and underwent randomization were enrolled in this trial. One hundred and eighty-eight patients were assigned to the THM group and received Cinobufacini injection and Jiedu Granule, and the other 191 patients were assigned to the TACE group and received one single course of TACE. MAIN OUTCOME MEASURES： Primary outcome measures were the annual recurrence rate and the time to recurrence. Incidence of adverse events was regarded as the secondary outcome measure. RESULTS： Among the 364 patients who were included in the intention-to-treat analysis, 67 patients of the THM group and 87 of the TACE group had recurrence, with a hazard ratio of 0.695 （P = 0.048）. Median recurrence-free survival of the patients in the THM and TACE groups was 46.89 and 34.49 months, respectively. Recurrence rates at 1, 2 and 3 years were 17.7%, 33.0% and 43.5% for the THM group, and 28.8%, 42.5% and 54.0% for the TACE group, respectively （P = 0.026）. Multivariate analysis indicated that the THM regimen had a big advantage for prolonging the recurrence-free survival. Adverse events were mild and abnormality of laboratory indices of the two groups were similar. CONCLUSION： In comparison with TACE therapy, the THM regimen was associated with diminished risk of recurrence of small-sized HCC after resection, with comparable adverse events. TRIAL REGISTRTION IDENTIFIER： This trial was registered in the Chinese Clinical Trial Registry with the identifier ChiCTR-TRC-07000033.

Recurrence and metastasis of hepatocellular carcinoma: progress and prospects

Background: Recurrence after resection of hepatocellu-lar carcinoma(HCC) is a major obstacle to improveprognosis. Therefore, further improvement of long-term survival may depend on prevention and treat-ment of the recurrent tumor.Objective: To evaluate the progress of surgery forHCC, the risk factors for recurrence, and clinical andbasic studies on the prevention and management of re-currence and metastasis after resection of HCC.Data sources: A review of currently available data inthe mentioned areas.Data synthesis: Encouraging changes in the prognosticpattern were observed when the primary liver cancer(PLC) data of 1958-1967 (n=118), 1968-1977 (n=356), 1978-1987(n=715) and 1988-1997 (n=2038)were compared. The 5-year survival was 2.8%, 7.3%,27.1% and 52.5%, respectively, and the 10-yearsurvival 2.8%, 4.3%, 19.8% and 39.9%, respective-ly. Risk factors for recurrence included symptomaticpatient, high γ-glutamyl-peptidase (γ-PGT), largetumor size, portal vein embolus, advanced tumorstage, etc. Active hepatitis activity in the nontumorousliver and perioperative transfusion enhanced the re-currence. Molecular research into the invasiveness ofHCC identified some factors positively related to inva-siveness: p16 and p53 mutation, H-ras, c-cerbB2,mdm2, transforming growth factor (TGF), epidermalgrowth factor receptor (EGF-R), matrix metallopro-teinase-2 (MMP-2), urokinasetype plasminogen acti-vator (uPA), its receptor (uPA-R) and inhibitor(PAI-1), intercellular adhesion molecule-1 (ICAM-1), vascular endothelial growth factor (VEGF),platelet-derived endothelial cell growth factor (PD-ECGF), and basic fibroblast growth factor (bFGF).In contrast, some factors were negatively related toHCC invasiveness: nm23-H1, Kai-1, tissue inhibitor ofmetalloproteinase-2 (TIMP-2), integrin 5, and E-cadherin. Re-resection of subclinical recurrence yield-ed a 5-year survival of 56.0% calculated from the firstresection (n=202) .Postoperative transarterialchemoembolization (TACE, n=103), hepatic arterycannulation during operation (n=105), postoperativebiotherapy (n=49), and cryohepatectomy (cryosurgeryfollowed by immediate resection of the frozen tumor,n=84) might decrease the recurrence rate, and the3-year recurrence rate was 7.6%, 18.0%, 11.1%, and30.1%, respectively. Minimal intraoperative blood lossand transfusion could reduce postoperative recurrence,although the exact mechanism remains to be elucidat-ed.Conlusions: HCC invasiveness is the major topic to bestudied, particularly in the molecular level. Anti-an-giogenesis, biotherapy, novel approach based on molec-ular findings, and multidisciplinary interventions mightalso be important for HCC.

Risk factors associated with early and late recurrence after curative resection of hepatocellular carcinoma: a single institution's experience with 398 consecutive patients

BACKGROUND: Surgical resection is an important curative treatment for hepatocellular carcinoma (HCC); however, some patients experience an unexpected recurrence even after hepatectomy. The present study aimed to investigate risk factors and predictive criteria for early and late recurrence of HCC after resection.METHODS: A retrospective analysis of 398 Chinese patients who received curative resection for HCC was conducted. Patients were divided into three groups: without recurrence, early recurrence and late recurrence. Prognostic factors and predictive criteria for early and late recurrence were statistically analyzed. RESULTS: The cumulative recurrence-free survival rates at1, 2, 3, 4, and 5 years were 75.5%, 58.2%, 54.1%, 40.5%, and28.7%, respectively. The distribution of the time to recurrence suggested that recurrence could be divided into early phase(before 2 years; n=164) and late phase (after 2 years; n=83)Cox’s multivariate proportional hazard model analysis revealed that multiplicity of tumors (P=0.004) and venous infiltration(P=0.002) were independent risk factors associated with early recurrence. In contrast, indocyanine green retention rate at 15minutes (P=0.007), serum albumin level (P=0.045), and HBeAg status ( =0.028) proved to be significant independent adverse prognostic factors for late recurrence. Patients with at least 1of the 2 early recurrence risk factors (multiplicity of tumors ≥2and venous infiltration) or with 2 or more late recurrence risk factors are often susceptible to recurrence (P=1.36e-4 and 1.0e-6respectively).CONCLUSIONS: Early and late recurrences correlate with different risk factors and predictive criteria. Early recurrence primarily results from intrahepatic metastases, while late recurrence may be multicentric in origin.

Preoperative inflammation-based markers predict early and late recurrence of hepatocellular carcinoma after curative hepatectomy

BACKGROUND： Recurrence of hepatocellular carcinoma （HCC） after curative resection remains a major cause of treatment failure and tumor-related death. Patterns of HCC recur- rence can be categorized into early recurrence and late recurrence which have different underlying mechanisms. In this study, we investigated if simple inflammation-based clinical markers can distinguish patterns of recurrence after curative resection of HCC.

Risk factors for fatal recurrence of hepatocellular carcinoma and their role in selecting candidates for liver transplantation

BACKGROUND: With the maturation and popularization of skills in liver transplantation (LT), patients with hepatocellular carcinoma (HCC) have an alternative choice. LT as a curative treatment for HCC provides good liver function and systemic condition to recipients. Preoperative tumor characteristics are critical in selecting optimal candidates for LT to optimize the use of donor livers and to achieve a long-term survival. The present study aimed to elucidate the risk factors of HCC involved in fatal recurrence in the first year after LT and to investigate their utility in selecting suitable candidates for LT. METHODS: From April 2002 to October 2005, 303 patients who had received orthotopic LT for HCC were reviewed. Of these patients, those with diffuse intrahepatic or multiple systemic recurrent lesions who died within I year after surgery were investigated as fatal recurrence group (48 patients) and the remaining patients including those who were disease-free without recurrence, those who were alive with recurrence in the first year, or those who died in the first year of other causes, served as control group (255). The two groups were compared by demographics, tumor, and histopathological characteristics for their prognostic significance by logistic regression analysis. RESULTS: Multivariate analysis between the fatal recurrence group and the control group showed that the presence of vascular invasion, a tumor size greater than 6.5 cm, and a preoperative serum alpha-fetoprotein (AFP) level greater than 1000 mu g/L were risk factors for fatal recurrence. Increased risk factors reduced the suitability of candidates for LT and diminished survival in the first year. 85.71% of the patients with all three risk factors, 37.84% of those with two factors, 13.64% of those with one factor, and 6.71% of those without risk factors died from tumor recurrence within I year after transplantation. CONCLUSIONS: Vascular invasion, tumor size >= 16.5 cm, and preoperative serum AFP level >= 1000 mu g/L, were significant predictors of fatal recurrence after LT for HCC. Patients with two or more risk factors should not be candidates for LT.

Patients with early recurrence of hepatocellular carcinoma have poor prognosis

BACKGROUND： Early recurrence （ER） after hepatic resection （HR） is a poor prognostic factor for patients with hepatocellular carcinoma （HCC）. This study aimed to identify the clinico- pathological features, outcomes, and risk factors for ER after HR for small HCC in order to clarify the reasons why ER is a worse recurrence pattern. METHODS： We retrospectively examined 130 patients who underwent HR for small HCC （___30 mm）. Recurrence was clas- sifted into ER （〈2 years） and late recurrence （LR） （_〉2 years）. The clinicopathological features, outcomes, and risk factors for ER were analyzed by multivariate analysis. RESULTS： ER was observed in 39 patients （30.0%）. The sur- vival rate of the ER group was significantly lower than that of the LR group （P〈0.005）, and ER was an independent prognos- tic factor for poor survival （P=0.0001）. The ER group had a significantly higher frequency （P=0.0039） and shorter interval （P=0.027） of development to carcinoma beyond the Milan criteria （DBMC） compared with the LR group, and ER was an independent risk factor for DBMC （P〈0.0001）. Multi-nodularity, non-simple nodular type, and microvascular invasion were independent predictors for ER （P=0.012, 0.010, and 0.019, respectively）.CONCLUSIONS： ER was a highly malignant recurrence pattern associated with DBMC and subsequent poor survival after HR for small HCC. Multi-nodularity, non-simple nodular type, and microvascular invasion predict ER, and taking these factors into consideration may be useful for the decision of the treatment strategy for small HCC after HR.

Is inconsistency of α-fetoprotein level a good prognosticator for hepatocellular carcinoma recurrence?

AIM: To identify the clinical outcomes of hepato-cellular carcinoma (HCC) patients with inconsistent α-fetoprotein (AFP) levels which were initially high and then low at recurrence.METHODS: We retrospectively included 178 patients who underwent liver resection with high preoperative AFP levels (≥ 200 ng/dL). Sixty-nine HCC patients had recurrence during follow-up and were grouped by their AFP levels at recurrence: group Ⅰ, AFP ≤ 20 ng/dL (n = 16); group Ⅱ, AFP 20-200 ng/dL (n = 24); and group Ⅲ, AFP ≥ 200 ng/dL (n = 29). Their preoperative clinical characteristics, accumulated recurrence rate, and recurrence-to-death survival rate were compared. Three patients, one in each group, underwentliver resection twice for primary and recurrent HCC. AFP immunohistochemistry of primary and recurrent HCC specimens were examined.RESULTS: In this study, 23% of patients demon-strated normal AFP levels at HCC recurrence. The AFP levels in these patients were initially high. There were no significant differences in clinical characteristics between the three groups except for the mean recur-rence interval (21.8 ± 14.6, 12.3 ± 7.7, 8.3 ± 6.6 mo, respectively, P < 0.001) and survival time (40.2 ± 19.9, 36.1 ± 22.4, 21.9 ± 22.0 mo, respectively, P = 0.013). Tumor size > 5 cm, total bilirubin > 1.2 mg/dL, vessel invasion, Child classification B, group Ⅲ, and recurrence interval < 12 mo, were risk factors for survival rate. Cox regression analysis was performed and vessel invasion, group Ⅲ, and recurrence interval were independent risk factors. The recurrence inter-val was significant longer in group Ⅰ (P < 0.001). The recurrence-to-death survival rate was significantly bet-ter in group Ⅱ (P = 0.016). AFP staining was strong in the primary HCC specimens and was reduced at recur-rence in group Ⅰ specimens.CONCLUSION: Patients in group Ⅰ with inconsistent AFP levels had a longer recurrence interval and worse recurrence-to-death survival rate than those in group Ⅱ. This clinical presentation may be caused by a delay in the detection of HCC recurrence.

Tumor vaccine against recurrence of hepatocellular carcinoma

AIM: To investigate the effects of autologous tumor vaccine on recurrence of hepatocellular carcinoma (HCC). METHODS: Sixty patients with HCC who had undergone curative resection, were randomly divided into HCC vaccine group and control group. Three vaccinations at 2-wk intervals were performed after curative hepatic resection. Delayed-type- hypersensitivity (DTH) test was performed before and after vaccination. Primary endpoints were the time of recurrence. RESULTS: Four patients in control group and 6 patients in HCC vaccine group were withdrawn from the study. The vaccine containing human autologous HCC fragments showed no essential adverse effect in a phase II clinical trial and 17 of 24 patients developed a DTH response against the fragments. Three of 17 DTH-positive response patients and 5 of 7 DTH- negative response patients had recurrences after curative resection. After the operation, 1-, 2- and 3-year recurrence rates of HCC vaccine group were 16.7%, 29.2% and 33.3%, respectively. But, 1-, 2- and 3-year recurrence rates of the control group were 30.8%, 53.8% and 61.5%, respectively. The time before the first recurrence in the vaccinated patients was significantly longer than that in the control patients (P<0.05). CONCLUSION: Autologous tumor vaccine is of promise in decreasing recurrence of human HCC.

Targeting of circulating hepatocellular carcinoma cells to prevent postoperative recurrence and metastasis

Currently,the main treatment for hepatocellular carcinoma(HCC)involves the surgical removal of tumors or liver transplantation.However,these treatments are often not completely curative,as they are associated with a risk for postoperative recurrence and metastasis.Circulating tumor cells(CTCs)are increasingly recognized as the main source for recurrence and metastasis after radical hepatectomies are performed.Many studies have demonstrated the association between the presence of either pre-or postoperative CTCs and an increased risk for HCC recurrence.To improve the therapeutic outcome of HCC,a personalized,comprehensive and multidisciplinary approach should be considered,involving the application of appropriate diagnostic and therapeutic measures targeting HCC CTCs in different stages throughout the course of treatment.This article proposes some HCC CTC-based strategies for the treatment of HCC,including the monitoring of HCC CTCs before,during and after radical hepatectomy,therapeutic targeting of HCC CTCs,prevention of the generation and colonization of CTCs,as well as the use of CTC indexes for the selection of indications,prediction of prognoses,and planning of individualized therapeutic regimens.Innovation and technological development of therapies targeting CTCs,as well as their translation into clinical practice,will help to effectively reduce postoperative recurrence and metastasis,and significantly prolong the survival of HCC patients.