Late Recurrence Of Hepatocellular Carcinoma Research Articles

Prediction of late recurrence after curative-intent resection using MRI-measured spleen volume in patients with hepatocellular carcinoma and cirrhosis

BackgroundLate recurrence of hepatocellular carcinoma (HCC) after liver resection is regarded as a de novo tumor primarily related to the severity of underlying liver disease. We aimed to investigate risk factors, especially spleen volume, associated with late recurrence in patients with HCC and cirrhosis.MethodsWe retrospectively analyzed 301 patients with HCC and cirrhosis who received curative resection and preoperative MRI. Patients were followed for late recurrence for at least 2 years. Spleen volume was automatically measured on MRI with artificial intelligence techniques, and qualitative MRI imaging features reflecting tumor aggressiveness were evaluated. Uni- and multivariable Cox regression analyses were performed to identify independent predictors and a risk score was developed to predict late recurrence.ResultsEighty-four (27.9%) patients developed late recurrence during follow-up. Preoperative spleen volume was independently associated with late recurrence, and patients with a volume > 370 cm3 had significantly higher recurrence risk (hazard ratio 2.02, 95%CI 1.31–3.12, p = 0.002). Meanwhile, no qualitative imaging features were associated with late recurrence. A risk score was developed based on the APRI score, spleen volume, and tumor number, which had time-dependent area under the curve ranging from 0.700 to 0.751. The risk score at a cutoff of 0.42 allowed for the identification of two risk categories with distinct risk of late recurrence.ConclusionsPreoperative spleen volume on MRI was independently associated with late recurrence after curative-intent resection in patients with HCC and cirrhosis. A risk score was proposed for individualized risk prediction and tailoring of postoperative surveillance strategies.Critical relevance statementSpleen volume measured on MRI with the aid of AI techniques was independently predictive of late HCC recurrence after liver resection. A risk score based on spleen volume, APRI score, and tumor number was developed for accurate prediction of late recurrence.Key points• Preoperative spleen volume measured on MRI was independently associated with late recurrence after curative-intent resection in patients with HCC and cirrhosis.• Qualitative MRI features reflecting tumor aggressiveness were not associated with late recurrence.• A risk score based on spleen volume was developed for accurate prediction of late recurrence and risk stratification.Graphical

Smoking as a Risk Factor for Very Late Recurrence in Surgically Resected Early-Stage Primary Hepatocellular Carcinoma.

The risk of first recurrence of hepatocellular carcinoma (HCC) within years 5 to 10 after curative hepatectomy remains unknown. We aimed to assess the incidence and prognostic factors for very late recurrence among patients who achieved 5 years' recurrence-free survival (RFS) after primary resection. We retrospectively analyzed 337 patients with early-stage HCC underwent primary tumor resection and achieved more than 5 years' RFS. A total of 77 patients (22.8%) developed very late recurrence. The cumulative very late recurrence rate increased from 6.9% and 11.7% to 16.6% at 6, 7, and 8 years, respectively. Patients stopped smoking had a higher rate of very late RFS. The high rates of very late recurrence in HCC indicate that patients warrant continued surveillance, even after 5 recurrence-free years. Moreover, smoking is a risk factor for very late HCC recurrence, and quitting smoking may reduce the risk of very late recurrence.

Late hepatocellular carcinoma recurrence after living donor liver transplantation: unmet need

Late hepatocellular carcinoma recurrence after living donor liver transplantation: unmet need

Viral Status and Treatment Efficacy in Recurrent Hepatocellular Carcinoma After Primary Resection

BackgroundThe impact of viral background on long-term effectiveness of different treatment modalities for recurrent hepatocellular carcinoma (HCC) was not fully analyzed. MethodConsecutive 726 patients who developed intrahepatic recurrence after primary hepatectomy for HCC between 2008 and 2015 were retrospectively studied. Post-recurrence survival (PRS) and rerecurrence-free survival (R-RFS) and risk factors were analyzed. ResultsAfter a median follow-up period of 56 months, the 5-year PRS rates of the patients who underwent rehepatectomy, radiofrequency ablation (RFA), and transarterial chemoembolization (TACE) were 79.4%, 83.0%, and 54.6%, respectively. The treatment benefit for PRS was consistently observed in patients with hepatitis B virus (HBV) and non-B, non-C subgroups, but not hepatitis C virus (HCV). For patients with late recurrence of HCC, R-RFS was superior in HBV subgroup and HCV subgroup which received antiviral treatment (compared to naïve HCV subgroup). Survival difference triaged by viral status was lost in the counterpart with early recurrence. Overall, RFA improved PRS and R-RFS in patients receiving antiviral treatment. ConclusionTo achieve long-term survival after HCC recurrence, rehepatectomy and RFA were comparably effective, particularly among those with HBV. Antiviral treatment complemented survivals of patients with HCV after RFA, particularly in late first recurrence.

A reasonable identification of the early recurrence time based on microvascular invasion for hepatocellular carcinoma after R0 resection: A multicenter retrospective study.

Early and late recurrence of hepatocellular carcinoma (HCC) have different clinical outcomes, especially for those accompanied by microvascular invasion (MVI), but the definition of early recurrence remains controversial. Therefore, a reasonable identification of the early recurrence time for HCC is urgently needed. Resected recurrence patients were enrolled and divided into two cohorts, one for identification of the early recurrence time and another for verification of the accuracy of the point. Univariable and multivariable Cox regression analyses were adopted to identify the prognostic factors of recurrence HCC (rHCC) and Kaplan-Meier method was applied to analyze the overall survival (OS). The appropriate cutoff value was determined by the exhaustive method using different recurrence intervals from 1 to 24 months in turn. In total, 292 resected rHCC patients were analyzed to calculate the early recurrence interval, and another 421 resected rHCC patients with MVI were enrolled to verify the efficacy of adjuvant transarterial chemoembolization (TACE) in this recurrence interval. MVI was identified as an independent risk factor by multivariable analysis. The OS of rHCC patients without MVI is better than that of patients with MVI when the recurrence time was within 13 months, while not beyond 13 months. The verification cohort demonstrated that adjuvant TACE provided longer survival for rHCC with MVI when the recurrence time was within 13 months, while not beyond 13 months. For HCC patients with MVI who underwent R0 resection, 13 months may be a reasonable early recurrence time point, and within this interval, postoperative adjuvant TACE may result in longer survival compared with surgery alone.

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.

Impact of HBsAg seroclearance on late recurrence of hepatitis B virus-related hepatocellular carcinoma after surgical resection.

It is unknown whether HBsAg seroclearance affects the risk of hepatocellular carcinoma (HCC) recurrence after liver resection. We aimed to investigate the impact of HBsAg seroclearance on the recurrence of HCC after curative liver resection, with a focus on late recurrence. This study comprised 2,520 consecutive patients who received curative liver resection for HBV-related HCC of Barcelona Clinic Liver Cancer stage 0 or A in Korea between 2000 and 2017. To focus on late recurrence, patients with recurrence or a follow-up duration less than 2 years were excluded. The impact of HBsAg seroclearance on HCC recurrence was assessed by landmark analysis (2-, 5-and 8-year after liver resection), time-dependent Cox and multistate modeling. The mean patient age was 54.4 years and 75.7% were men. A total of 891 (35.4%) patients developed HCC recurrence at rates of 11.2%, 25.5%, and 46.8% at 3, 5, and 10 years after resection. HBsAg seroclearance was achieved in 172 (6.8%) patients during a median follow-up duration of 6.9 years after resection. HBsAg seroclearance, compared with persistent HBsAg positivity, was associated with a lower risk of late HCC recurrence in the 2-, 5-, and 8-year landmark analysis (p= 0.04, p= 0.02 and p= 0.03, respectively) and on time-dependent multivariable Cox modeling (adjusted hazard ratio 0.62; p= 0.005). Based on a 3-state unidirectional illness-death model, patients without HBsAg seroclearance transitioned to HCC recurrence more rapidly than patients who experienced HBsAg seroclearance. HBsAg seroclearance is associated with a lower risk of late recurrence of HBV-related HCC among Korean patients who undergo curative liver resection. Hepatitis B virus (HBV) infection is a leading cause of chronic liver disease and hepatocellular carcinoma (HCC). Suppression of HBV replication is known to lower the risk of HCC recurrence after liver resection (a procedure used to treat and in some cases cure HCC). However, whether the loss of a specific HBV protein (hepatitis B surface antigen or HBsAg) has an impact on recurrence after liver resection remains unknown. Herein, we show that loss of HBsAg is associated with a reduce risk of late recurrence of HCC after liver resection in patients with HBV-related HCC.

Tumor and peritumor radiomics analysis based on contrast-enhanced CT for predicting early and late recurrence of hepatocellular carcinoma after liver resection

BackgroundIn China, liver resection has been proven to be one of the most important strategies for hepatocellular carcinoma patients, but the recurrence rate is high. This study sought to investigate the prognostic value of pretreatment tumor and peritumor contrast-enhanced CT radiomics features for early and late recurrence of BCLC stage 0-B hepatocellular carcinoma after liver resection.MethodsThis study involved 329 hepatocellular carcinoma patients after liver resection. A radiomics model was built by using Lasso-Cox regression model. Association between radiomics model and recurrence-free survival was explored by using Harrell’s concordance index (C-Index) and receiver operating characteristic (ROC) curves. Then, we combined the radiomics model and clinical factors to establish a nomogram whose calibration and discriminatory ability were revealed.ResultsTen significant tumor and peritumor features were screened to build the radiomics model whose C-indices were 0.743 [95% CI, 0.707 to 0.778] and 0.69 [95% CI, 0.629 to 0.751] in the training and validation cohorts. Moreover, the discriminative accuracy of the radiomics model improved with peritumor features entry. The C-indices of the combined model were 0.773 [95% CI, 0.739 to 0.806] and 0.727 [95% CI, 0.667 to 0.787] in the training and validation cohorts, outperforming the radiomics model.ConclusionsThe tumor and peritumor contrast-enhanced CT radiomic signature is a quantitative imaging biomarker that could improve the prediction of early and late recurrence after liver resection for hepatocellular carcinoma patients when used in addition to clinical predictors.

Aspartate aminotransferase-to-platelet ratio index for predicting late recurrence of hepatocellular carcinoma after radiofrequency ablation

Background Our study aimed to explore the prognostic value of the aspartate aminotransferase–platelet ratio index (APRI) and to develop a new nomogram for patients with hepatocellular carcinoma (HCC) who experience late recurrence after radiofrequency ablation (RFA). To date, no study has explored the value of APRI for assessing the late recurrence of HCC after RFA. Materials and Methods The prognostic value of APRI was evaluated and validated in our multicenter retrospective analysis. A total of 466 HCC patients undergoing RFA were reviewed as a training cohort, and 234 HCC patients were included in the external validation cohort. The nomogram was built based on significant prognostic factors in a multivariate analysis and validated in the external validation cohort. Results The cutoff APRI score was 0.78, and it appropriately discriminated between low- and high-risk groups for late recurrence in HCC patients. The cumulative recurrence-free survival rates of the low-risk group were significantly higher than those of the high-risk group (p < 0.001), according to the Kaplan–Meier curves. Late recurrence in HCC patients after RFA was associated with APRI, sex and multiple tumors. The nomogram based on potential risk factors (APRI score, sex and multiple tumors) as indicated by multivariate Cox regression analysis showed good discrimination and calibration in the training and external verification groups. Conclusions The APRI score is a feasible independent prognostic factor for the late recurrence of HCC after RFA. The proposed nomogram could aid clinicians in following disease progression and providing tailored therapy for patients.

Comprehensive Molecular Analyses of a Six-Gene Signature for Predicting Late Recurrence of Hepatocellular Carcinoma.

A larger number of patients with stages I–III hepatocellular carcinoma (HCC) experience late recurrence (LR) after surgery. We sought to develop a novel tool to stratify patients with different LR risk for tailoring decision-making for postoperative recurrence surveillance and therapy modalities. We retrospectively enrolled two independent public cohorts and 103 HCC tissues. Using LASSO logical analysis, a six-gene model was developed in the The Cancer Genome Atlas liver hepatocellular carcinoma (TCGA-LIHC) and independently validated in GSE76427. Further experimental validation using qRT-PCR assays was performed to ensure the robustness and clinical feasible of this signature. We developed a novel LR-related signature consisting of six genes. This signature was validated to be significantly associated with dismal recurrence-free survival in three cohorts TCGA-LIHC, GSE76427, and qPCR assays [HR: 2.007 (1.200–3.357), p = 0.008; HR: 2.171 (1.068, 4.412), p-value = 0.032; HR: 3.383 (2.100, 5.450), p-value <0.001]. More importantly, this signature displayed robust discrimination in predicting the LR risk, with AUCs being 0.73 (TCGA-LIHC), 0.93 (GSE76427), and 0.85 (in-house cohort). Furthermore, we deciphered the specific landscape of molecular alterations among patients in nonrecurrence (NR) and LR group to analyze the mechanism contributing to LR. For high-risk group, we also identified several potential drugs with specific sensitivity to high- and low-risk groups, which is vital to improve prognosis of LR-HCC after surgery. We discovered and experimentally validated a novel gene signature with powerful performance for identifying patients at high LR risk in stages I–III HCC.

Long-term assessment of recurrence of hepatocellular carcinoma in patients with chronic hepatitis C after viral cure by direct-acting antivirals.

Background and AimEarly hepatocellular carcinoma (HCC) recurrence is common, even after achieving hepatitis C virus (HCV) cure. This study was carried out to assess the long‐term trends and predictors of recurrence after HCV cure by direct‐acting antivirals (DAAs).MethodsThis retrospective, multicenter cohort study enrolled 365 consecutive patients with chronic hepatitis C who required HCC treatment following sustained viral response (SVR) by DAA administration. Patients with HCC recurrence before SVR were excluded. Late HCC recurrence and its predictors beyond the post‐treatment early phase (24 weeks after SVR) were evaluated.ResultsThe data of 326 patients were available for the final analysis. The median follow‐up duration from SVR determination was 2.7 years. Median age was 74, and 220 (67.5%) were 70 or over. The corresponding 5‐year cumulative HCC recurrence rates of previous curative and palliative treatment groups were 45.4% and 65.7%, respectively (log‐rank test: P < 0.001). Cox regression multivariable analysis revealed that cirrhosis (hazard ratio [HR] 1.85, P = 0.021), the number of HCC nodules (≥ 2) (HR 1.52, P = 0.031), and previous palliative HCC treatment (HR 1.71, P = 0.012) were independent predictors of late recurrence, in addition to the predictors of early recurrence; AFP > 7 ng/mL at 12 weeks after DAA administration, time from HCC complete response (CR) to DAA initiation (< 1 year), and the number of HCC treatments necessary to achieve CR (≥ 2).ConclusionsThe evaluation of fibrosis and characteristics of the previous HCC would allow for better HCC recurrence stratification, which would be helpful for developing long‐term surveillance strategies.

Using the aMAP Risk Score to Predict Late Recurrence Following Radiofrequency Ablation for Hepatocellular Carcinoma in Chinese Population: A Multicenter Study.

ObjectiveThis study was conducted to explore the application of age-male-ALBI-platelets (aMAP) score for predicting late recurrence of hepatocellular carcinoma (HCC) following radiofrequency ablation (RFA) and develop an aMAP score based-nomogram to predict prognosis in Chinese population.Materials and MethodsHCC patients who developed late recurrence following RFA at National Cancer Center (NCC) of China, First Hospital of Shanxi Medical University and Beijing Hospital of Traditional Chinese Medicine from January 2011 to December 2016 were included as a training cohort, and patients who were treated at Affiliated Cancer Hospital of Zhengzhou University between January 2012 and December 2016 were included as an external validation cohort. The optimal cut-off value for aMAP score was determined using X-tile software to discriminate the performance of recurrence-free survival (RFS).ResultsA total of 339 eligible patients were included in this study. Patients were grouped into low-risk (aMAP score ≤64.2), medium-risk (64.3 ≤aMAP score ≤68.6) and high-risk (aMAP score ≥68.7) groups by X-tile plots. The prognostic factors that affected RFS were the number of lesions and aMAP score. A nomogram was constructed to predict the RFS with a C-index of 0.793 (95% CI: 0.744–0.842). The time-dependent receiver operating characteristic curves (t-AUCs) of the nomogram to predict 3, 4 and 5-year RFS were 0.808, 0.820 and 0.764, respectively. The model was then tested with data from an external validation cohort. The calibration curve confirmed the optimal agreement between the predicted and observed values.ConclusionThe aMAP score provided a well-discriminated risk stratification and is an independent prognostic factor for the late recurrence of HCC following RFA. The aMAP score-based nomogram could help to strengthen prognosis-based decision making and formulate adjuvant therapeutic and preventive strategies.

AFP and eGFR are related to early and late recurrence of HCC following antiviral therapy

BackgroundAn unexpected recurrence of hepatocellular carcinoma (HCC) sometimes occurs in patients with hepatitis C virus (HCV) after treatment with direct-acting antivirals (DAAs). However, the characteristics of patients with HCC recurrence may differ depending on time after DAA treatment. We aimed to identify risk factors related to HCC recurrence according to time after DAA treatment.MethodsOf 1663 patients with HCV treated with a DAA, 199 patients had a previous history of HCC. We defined HCC recurrence within 1 year after DAA treatment as ‘early recurrence’, and recurrence more than 1 year after as ‘late recurrence’. The different risk factors between the early and late phases of HCC recurrence after the end of DAA therapy were investigated.ResultsNinety-seven patients experienced HCC recurrence during the study period. Incidences of recurrence were 29.8, 41.0, and 53.4% at 1, 2, and 3 years, respectively, after the end of DAA therapy. Multivariate analysis identified post-treatment α-fetoprotein (AFP) as an independent factor contributing to HCC recurrence in the early phase (hazard ratio, 1.056; 95% confidence interval, 1.026–1.087, p < 0.001) and post-treatment estimated glomerular filtration rate (eGFR) (hazard ratio, 0.98; 95% confidence interval, 0.96–0.99, p = 0.032) as a predictor of HCC recurrence in the late phase.ConclusionPatients with higher post-treatment AFP in the early phase and those with lower post-treatment eGFR in the late phase had a high risk of HCC recurrence. The risk factors associated with HCC recurrence after DAA treatment were different between the early and late phases.

Pathological predictive factors for late recurrence of hepatocellular carcinoma in chronic liver disease.

Late recurrence of hepatocellular carcinoma (HCC) is regarded as de novo HCC from chronic hepatitis. This study investigated clinicopathological and molecular factors to develop a nomogram for predicting late HCC recurrence (>2years after curative resection). The training and validation cohorts included HCC patients with a major aetiology of hepatitis B who underwent curative resection. Clinicopathological features including lobular and porto-periportal inflammatory activity, fibrosis and liver cell change were evaluated. Proteins encoded by genes related to late recurrence were identified using a reverse phase protein array of 95 non-tumourous liver tissues. Immunoexpression of phosphorylated signal transducer and activator of transcription 3 (pSTAT3), plasminogen activator inhibitor-1, phosphorylated extracellular signal-regulated kinase 1/2 (pERK1/2) and spleen tyrosine kinase (SYK) was measured. Late recurrence occurred in 74/402 (18%) and 47/243 (19%) in the training and validation cohorts respectively. Cirrhosis, moderate/severe lobular inflammatory activity, and expression of pSTAT3, pERK1/2, and SYK proteins correlated to the gene signature of hepatocyte injury and regeneration were independently associated with late recurrence, with odds ratios (95% confidence intervals) of 2.0 (1.2-3.3), 21.1 (4.3-102.7) and 6.0 (2.1-17.7) respectively (P<.05 for all). A nomogram based on these variables (histological parameters and immunohistochemical marker combinations) showed high reliability in both the training and validation cohorts (Harrell's C index: 0.701 and 0.716; 95% confidence intervals: 0.64-0.76 and 0.64-0.79 respectively). The combination of pSTAT3, pERK1/2 and SYK immunoexpression with high lobular inflammatory activity and cirrhosis (fibrosis) predicts late HCC recurrence.

Liver stiffness measurement predicts short-term and long-term outcomes in patients with hepatocellular carcinoma after curative liver resection

Background and aimHepatocellular carcinoma is one of the commonest cancer in the world. Despite curative resection, recurrence remains the largest challenge. Many risk factors were identified for predicting recurrence, including liver fibrosis and cirrhosis. Transient elastography (Fibroscan) is an accurate tool in measuring liver fibrosis. This study aimed to evaluate the use of preoperative liver stiffness measurement (LSM), with Fibroscan in predicting long-term recurrence of hepatocellular carcinoma (HCC) after curative resection. MethodA prospective cohort study was conducted from February 2010 – June 2017 in Prince of Wales hospital. All consecutive patients with HCC undergone hepatectomy were included. Demographic factors, preoperative LSM, tumor characteristics and operative details were assessed. Primary outcome and secondary outcome were overall survival and disease free survival at 1 year, 3 year and 5 year respectively. ResultsA total of 401 cases were included. Patients with LSM ≥12kPa had significantly lower 5-year overall survival rate (75.1% vs 57.3%, p < 0.001) and disease free survival rate (45.8% vs. 26.7%, p < 0.001). On multivariate analysis, pre-operative creatinine and vascular invasion of tumor were significant factors in predicting early recurrence (p = 0.012 and p = 0.004). LSM ≥12kPa were the only significant factor in predicting late recurrence (p = 0.048). ConclusionPre-operative liver stiffness measurement could predict the late recurrence of hepatocellular carcinoma after curative resection.

Repeat Hepatectomy for Early and Late Recurrence of Hepatocellular Carcinoma: A Multicenter Study with Propensity Score Matching Analysis

Repeat Hepatectomy for Early and Late Recurrence of Hepatocellular Carcinoma: A Multicenter Study with Propensity Score Matching Analysis

Nomograms based on clinicopathological factors and inflammatory indicators for prediction of early and late recurrence of hepatocellular carcinoma after surgical resection for patients with chronic hepatitis B.

BackgroundFew studies have focused on the prognostic values of inflammation-related factors for different phases of recurrence in hepatocellular carcinoma (HCC). We aimed to identify the different risk factors for overall, early, and late recurrence, and to establish nomograms based on inflammation-related parameters for predicting the risks of recurrence in a group of HCC patients undergoing hepatectomy.MethodsWe retrospectively enrolled 383 HCC patients with chronic hepatitis B (CHB) who underwent hepatectomy. Univariate and multivariate Cox analyses were conducted to identify independent risk factors for recurrence. Nomograms for overall, early, and late recurrence-free survival (RFS) were established. The discrimination and calibration abilities of the nomograms were evaluated by concordance indexes (C-index), calibration plots, and Kaplan-Meier curves. Finally, receiver operating characteristic (ROC) curves were used to compare the derived nomograms with other existing models.ResultsFibrinogen, lymphocyte-to-monocyte ratio, and S-index inflammation-related factors were independently related to overall and early RFS, but only the S-index correlated with late recurrence. Nomograms with tumor number, diameter, and pathological differentiation for overall and early RFS were established, while nomogram for late recurrence was constructed with tumor number and Child-Pugh grade. The C-indexes for overall, early, and late RFS were 0.679, 0.677, and 0.728, respectively. The calibration plots fit well. The nomograms showed superior discrimination capacities and better performance prediction with larger areas under the curve for recurrence.ConclusionsThe developed nomograms that integrated inflammation-related factors showed high predictive accuracy for overall, early, and late recurrence in HCC patients with CHB after hepatectomy.

Early versus Late Recurrence of Hepatocellular Carcinoma after Surgical Resection Based on Post-recurrence Survival: An International Multi-institutional Analysis

Introduction: To define early versus late recurrence based on post-recurrence survival (PRS) among patients undergoing curative resection for hepatocellular carcinoma (HCC). Method: Patients who underwent curative-intent resection for HCC between 2000 and 2017 were identified from an international multi-institutional database. The optimal cut-off time point to discriminate early versus late recurrence was determined relative to PRS. Results: Among 1,004 patients, 443 (44.1%) patients experienced recurrence with a median recurrence-free survival time of 12 months. A cut-off time point of 8 months was defined as the optimal threshold based on sensitivity analyses relative to PRS for early (n=165, 37.2%) versus late relapse (n=278, 62.8%)(p=0.008). Early recurrence was associated with worse PRS (median PRS, 27.0 vs. 43.0 months, p=0.019), as well as Overall survival (OS) (median OS, 32.0 versus 74.0 months, p< 0.001) versus late recurrence. In addition, patients who recurred early were more likely to recur at extra- ± intrahepatic (35.5% vs. 19.8%, p=0.003) sites. Patients undergoing curative re-treatment of late recurrence had a comparable OS with patients who had no recurrence (median OS, 139.0 vs. 140.0 months); patients with early recurrence had inferior OS after curative re-treatment versus patients with no recurrence (median OS, 69.0 vs. 140.0 months, p=0.036), yet still better than patients who received palliative treatment for early recurrence (median OS, 69.0 vs. 21.0 months, p< 0.001). Conclusions: Eight months was identified as the cut-off value to differentiate early versus late recurrence. Curative-intent treatment for recurrent intrahepatic tumors was associated with reasonable long-term outcomes.

The optimal timing and management of hepatitis B and C in patients with hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the fourth most common cause of cancer related mortality worldwide, with the most common underlying etiologies being chronic hepatitis B and hepatitis C infections. Treatment of these viral hepatidities in the setting of HCC has been debated, and there is increasing study addressing this topic. Patients with advanced HCC of either etiology are unlikely to benefit from antiviral treatments, and futility should be considered prior to starting antiviral therapy. Hepatitis B treatment has demonstrated improved survival, decreased risk of hepatitis B reactivation, and decreased risk of late HCC recurrence. The mainstay treatment of chronic hepatitis B has been nucleos(t)ide analogues (NAs), and in the setting of HCC, entecavir and tenofovir are preferred given their higher potency and barriers to resistance. Those who were already on a NAs at the time of HCC diagnosis should be continued on them regardless of the HCC management planned. Patients who are suitable candidates to start NAs should start them at the time of HCC diagnosis. Direct-acting antivirals (DAAs) are the first line therapies for hepatitis C. Unlike with hepatitis B, those with HCV-associated HCC are recommended to start treatment 3-6 months after complete treatment of their HCC, given lower rates of sustained virologic response (SVR) with active HCC. There are also controversial concerns about DAAs contributing to a more aggressive HCC phenotype, but data are limited by retrospective studies, and more recent retrospective studies are more reassuring. In transplant candidates, starting DAAs may be deferred until after transplant depending on median regional wait times, availability of HCV positive organs, and the degree of the patient's liver dysfunction. Overall, in patients with HCC from hepatitis B or C, treatment of the underlying viral hepatitis should be considered unless advanced stage limits benefits and results in futility.

Late recurrence of hepatocellular carcinoma after radiofrequency ablation: a multicenter study of risk factors, patterns, and survival.

This study aims to determine the risk factors, patterns, and long-term survival outcomes of late recurrence after radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC) within the Milan criteria and develop a nomogram to predict the recurrence-free survival (RFS). This retrospective study included patients with HCC within the Milan criteria, who received RFA at three hospitals in China from January 2011 to December 2016. The clinical variables were assessed by univariate and multivariate Cox regression analyses. A total of 398 patients were included. The median follow-up was 58.7months (range: 24.1-96.0). Ninety-eight patients had late recurrence. Furthermore, 14 patients (14.29%) had local tumor progression (LTP) alone, 43 patients (43.88%) had intrahepatic distant recurrence (IDR) alone, 15 patients (15.31%) had extrahepatic recurrence (ER) alone, three patients (3.06%) had both LTP and IDR, six patients (6.12%) had both LTP and ER, and 17 patients (17.35%) had both IDR and ER. Patients without late recurrence had better long-term overall survival (OS) compared to those with late recurrence (p < 0.001). Male gender, multiple tumors, and cirrhosis were the independent risk factors of late recurrence. A well-discriminated and calibrated nomogram was constructed to predict the probability of RFS. Male gender, multiple tumors, and cirrhosis are the independent risk factors of late recurrence after RFA for HCC within the Milan criteria. Late recurrence might mainly occur from de novo HCC under the background of cirrhosis. An individualized surveillance and prevention strategy for HCC patients after RFA should be developed. • In the present retrospective study of 398 patients, male gender, multiple tumors, and cirrhosis were the independent risk factors of late recurrence (> 2years) of HCC after RFA. • The most common pattern of late recurrence was intrahepatic distant recurrence alone (n = 43, 43.88%). Late recurrence might mainly occur from de novo HCC under the background of cirrhosis. • A prognostic nomogram was built to predict the individualized recurrence-free survival after RFA, which achieved good calibration and discriminatory ability with a concordance index of 0.763.