The presence of microvascular invasion guides treatment strategy in recurrent HBV-related HCC.

OBJECTIVES: We used the status of microvascular invasion (MVI) at primary resection to help treatment selection for hepatitis B virus-positive (HBV+) recurrent hepatocellular carcinoma (rHCC) patients in Barcelona Clinic Liver Cancer (BCLC) stage B-C. METHODS: From 2009 to 2017, we enrolled 221 consecutive HBV+ rHCC patients at BCLC stage B-C who underwent re-resection (RR), radiofrequency ablation (RFA), or transarterial chemoembolization (TACE). Post recurrence survival (PRS) and overall survival (OS) were compared between RR/RFA and TACE according to MVI status. A one-to-one propensity score matching analysis was performed. RESULTS: For MVI(-) patients, the median PRS was 62.3 months for the RR/RFA group and 21.1 months for the TACE group (p = 0.039). The corresponding OS was 71.4 months and 26.6 months, respectively (p = 0.010). For MVI(+) patients, the median PRS in the RR/RFA group and TACE group was 14.7 months and 10.1 months (p = 0.115). The corresponding OS was 23.4 months and 16.4 months, respectively (p = 0.067). After matching, the dominance of RR/RFA over TACE remained in MVI(-) patients for both PRS (62.3 months vs 15.3 months, p = 0.019) and OS (98.1 months vs 33.4 months, p = 0.046). No significant difference was found in MVI(+) patients for either PRS (14.7 months vs 11.8 months, p = 0.593) or OS (23.4 months vs 28.1 months, p = 0.662). CONCLUSIONS: MVI status definitely helps select treatment options in HBV+ rHCC patients. For MVI(-) patients, RR/RFA provided better survival than TACE while for MVI(+) patients, TACE shared similar survival outcomes. KEY POINTS: • This study aimed at the determination of the optimal treatment options (ablation /resection vs TACE) in case of recurrent HBV-related HCC. • It showed that MVI status, established at primary resection of HCC, was a powerful marker for selecting the best treatment option in these patients. • In MVI(-) patients, RR/RFA achieved a better survival than TACE. In MVI(+) patients, TACE shared similar survival.

Selective targeting of lysyl oxidase-like 2 (LOXL2) suppresses hepatic fibrosis progression and accelerates its reversal.

BACKGROUND/AIMS: We studied the role of lysyl oxidase-like 2 (LOXL2) in collagen crosslinking and hepatic progenitor cell (HPC) differentiation, and the therapeutic efficacy of a LOXL2-blocking monoclonal antibody on liver fibrosis progression/reversal in mice. METHODS: Anti-LOXL2 antibody, control antilysyl oxidase antibody or placebo was administered during thioacetamide (TAA)-induced fibrosis progression or during recovery. Therapeutic efficacy in biliary fibrosis was tested in BALB/c.Mdr2-/- and 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-fed mice. Collagen crosslinking, fibrosis progression and reversal were assessed histologically and biochemically. HPC differentiation was studied in primary EpCAM(+) liver cells in vitro. RESULTS: LOXL2 was virtually absent from healthy but strongly induced in fibrotic liver, with predominant localisation within fibrotic septa. Delayed anti-LOXL2 treatment of active TAA fibrosis significantly reduced collagen crosslinking and histological signs of bridging fibrosis, with a 53% reduction in morphometric collagen deposition. In established TAA fibrosis, LOXL2 inhibition promoted fibrosis reversal, with enhanced splitting and thinning of fibrotic septa, and a 45% decrease in collagen area at 4 weeks of recovery. In the Mdr2-/- and DDC-induced models of biliary fibrosis, anti-LOXL2 antibody similarly achieved significant antifibrotic efficacy and suppressed the ductular reaction, while hepatocyte replication increased. Blocking LOXL2 had a profound direct effect on primary EpCAM(+) HPC behaviour in vitro, promoting their differentiation towards hepatocytes, while inhibiting ductal cell lineage commitment. CONCLUSIONS: LOXL2 mediates collagen crosslinking and fibrotic matrix stabilisation during liver fibrosis, and independently promotes fibrogenic HPC differentiation. By blocking these two convergent profibrotic pathways, therapeutic LOXL2 inhibition attenuates both parenchymal and biliary fibrosis and promotes fibrosis reversal.

Integrin αvß6 critically regulates hepatic progenitor cell function and promotes ductular reaction, fibrosis, and tumorigenesis.

UNLABELLED: Integrin αvß6 is rapidly up-regulated on cells of epithelial lineage during tissue injury, where one of its primary functions is activation of latent transforming growth factor beta 1 (TGFß1). In human liver cirrhosis, αvß6 is overexpressed by cells comprising the ductular reaction, and its inhibition suppresses experimental biliary fibrosis in rodents. Here, we show that αvß6 is expressed on the actively proliferating subset of hepatic progenitor cells and is required for their progenitor function in vivo and in vitro through integrin αvß6-dependent TGFß1 activation. Freshly isolated αvß6(+) liver cells demonstrate clonogenic potential and differentiate into cholangiocytes and functional hepatocytes in vitro, whereas colony formation by epithelial cell adhesion molecule-positive progenitor cells is blocked by αvß6-neutralizing antibody and in integrin beta 6-deficient cells. Inhibition of progenitors by anti-αvß6 antibody is recapitulated by TGFß1 neutralization and rescued by addition of bioactive TGFß1. Genetic disruption or selective targeting of αvß6 with 3G9 antibody potently inhibits progenitor cell responses in mouse models of chronic biliary injury and protects from liver fibrosis and tumorigenesis, two conditions clinically associated with exacerbated ductular reaction. CONCLUSION: These results suggest that αvß6 is a promising target for chronic fibrotic liver diseases and associated cancers.

Lysyl oxidase activity contributes to collagen stabilization during liver fibrosis progression and limits spontaneous fibrosis reversal in mice.

Collagen stabilization through irreversible cross-linking is thought to promote hepatic fibrosis progression and limit its reversibility. However, the mechanism of this process remains poorly defined. We studied the functional contribution of lysyl oxidase (LOX) to collagen stabilization and hepatic fibrosis progression/reversalin vivousing chronic administration of irreversible LOX inhibitor ß-aminopropionitrile (BAPN, or vehicle as control) in C57Bl/6J mice with carbon tetrachloride (CCl4)-induced fibrosis. Fibrotic matrix stability was directly assessed using a stepwise collagen extraction assay and fibrotic septae morphometry. Liver cells and fibrosis were studied by histologic, biochemical methods and quantitative real-time reverse-transcription PCR. During fibrosis progression, BAPN administration suppressed accumulation of cross-linked collagens, and fibrotic septae showed widening and collagen fibrils splitting, reminiscent of remodeling signs observed during fibrosis reversal. LOX inhibition attenuated hepatic stellate cell activation markers and promoted F4/80-positive scar-associated macrophage infiltration without an increase in liver injury. In reversal experiments, BAPN-treated fibrotic mice demonstrated accelerated fibrosis reversal after CCl4withdrawal. Our findings demonstrate for the first time that LOX contributes significantly to collagen stabilization in liver fibrosis, promotes fibrogenic activation of attenuated hepatic stellate cells, and limits fibrosis reversal. Our data support the concept of pharmacologic targeting of LOX pathway to inhibit liver fibrosis and promote its resolution.-Liu, S. B., Ikenaga, N., Peng, Z.-W., Sverdlov, D. Y., Greenstein, A., Smith, V., Schuppan, D., Popov, Y. Lysyl oxidase activity contributes to collagen stabilization during liver fibrosis progression and limits spontaneous fibrosis reversal in mice.

Prognostic nomogram for patients with unresectable hepatocellular carcinoma after transcatheter arterial chemoembolization.

BACKGROUND & AIMS: To establish an effective prognostic nomogram for patients with unresectable hepatocellular carcinoma (HCC) after transarterial chemoembolization (TACE). METHODS: The nomogram was constructed based on data obtained from a retrospective study on 2938 patients who received TACE as an initial therapy from 2000 to 2008. The predictive accuracy and discriminative ability of the nomogram were compared with seven current commonly used staging systems on HCC by using data obtained from a prospective study on a cohort of 647 patients treated from January 2011 to December 2011 at the same institution. Additional external validation was performed using a data set (n=221) from another institution. RESULTS: Portal vein invasion, tumor number, tumor capsule, alpha fetoprotein, aspartate aminotransferase, and indocyanine green retention at 15 min formed the basis of the nomogram. The concordance index (C-index) of the nomogram was 0.755, which was significantly better than the American Joint Committee on Cancer seventh edition (0.612), the Barcelona Clinic Liver Cancer system (0.692), the Okuda system (0.579), the Japan Integrated Staging system (0.637), Cancer of the Liver Italian Program system (0.683), the Chinese University Prognostic Index (0.637) and the Groupe d'Etude et de Traitement du Carcinome Hepatocellulaire (0.577) (p<0.001 for all). The calibration curve for predicting probability of survival showed a good agreement between the nomogram and actual observation. The findings were supported by the external validation cohort. The nomogram gave better discrimination than the seven staging systems. CONCLUSIONS: The proposed nomogram gave accurate prognostic prediction in patients with unresectable HCC after treatment with TACE.

Extrahepatic platelet-derived growth factor-ß, delivered by platelets, promotes activation of hepatic stellate cells and biliary fibrosis in mice.

BACKGROUND & AIMS: Platelet-derived growth factor-ß (PDGFB) is a mitogen for hepatic stellate cells (HSCs). We studied the cellular sources of PDGFB and the effects of a high-affinity monoclonal antibody against PDGFB (MOR8457) in mouse models of biliary fibrosis. METHODS: Cellular sources of PDGFB were identified using quantitative reverse-transcription polymerase chain reaction, biochemical, and immunohistologic methods. Mice with advanced biliary fibrosis, MDR2(Abcb4)-null mice, and C57Bl/6 (control) mice were placed on 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-supplemented diets and were given weekly intraperitoneal injections of MOR8457. Platelets were depleted from MDR2-null mice by injection of an antibody against CD41, or inhibited with diets containing low-dose aspirin. Liver tissues were collected and analyzed by quantitative reverse-transcription PCR and histologic and biochemical analyses. RESULTS: Levels of PDGFB protein, but not messenger RNA, were increased in fibrotic livers of MDR2-null mice, compared with control mice. Platelet clusters were detected in the hepatic endothelium, in close proximity to HSCs, and were identified as a source of PDGFB protein in MDR2-null mice. Levels of the PDGFB were increased in serum samples from patients with early stages of liver fibrosis of various etiologies (F1-2, n = 16; P < .05), compared with nonfibrotic liver tissue (F0, n = 12). Depletion of platelets from MDR2-null mice normalized hepatic levels of PDGFB within 48 hours, reducing levels of a marker of HSC activation (α-smooth muscle actin) and expression of genes that promote fibrosis. Diets supplemented with low-dose aspirin reduced circulating serum and hepatic levels of PDGFB and significantly reduced progression of fibrosis in MDR2-null mice over 1 year. MOR8457 produced a dose-dependent decrease in liver fibrosis in MDR2-null mice, reducing collagen deposition by 45% and expression of fibrosis-associated genes by 50%, compared with mice given a control antibody. In vitro, platelets activated freshly isolated HSCs (induction of α-smooth muscle actin and fibrosis-associated genes) via a PDGFB-dependent mechanism. MOR8457 also reduced liver fibrosis in mice placed on DDC-supplemented diets. CONCLUSIONS: Platelets produce PDGFB to activate HSC and promote fibrosis in MDR2-null mice and mice on DDC-supplemented diets. Antiplatelet therapy or selective inhibition of PDGFB might reduce biliary fibrosis in patients with liver disease.

XPC gene polymorphisms contribute to bladder cancer susceptibility: a meta-analysis.

Numerous studies have investigated the association between three polymorphisms (Lys939Gln, Ala499Val and PAT-/+) of Xeroderma pigmentosum group C (XPC) gene and bladder cancer susceptibility; however, the findings are inconclusive. In order to acquire a more precise estimation of the relationship, we performed a meta-analysis based on 10 studies including 3,934 cases and 4,269 controls for Lys939Gln, five studies including 2,113 cases and 2,249 controls for Ala499Val, and seven studies including 2,834 cases and 3,048 controls for PAT-/+ polymorphism. We searched publications from EMBASE, MEDLINE, and Chinese Biomedical. We calculated pooled odds ratio (OR) and 95% confidence interval (CI) by using either fixed-effects or random-effects model according to the between-study heterogeneity. We found that all studied polymorphisms were individually associated with increased overall cancer risks, as shown by ORs (95% CIs) below: the Lys939Gln (Gln/Gln vs. Lys/Lys: OR = 1.39, 95% CI = 1.08-1.79; recessive model: OR = 1.42, 95% CI = 1.11-1.83; and allele comparing: OR = 1.12, 95% CI = 1.003-1.24), the Ala499Val (Val/Val vs. Ala/Ala: OR = 1.82, 95% CI = 1.19-2.79; recessive model: OR = 1.70, 95% CI = 1.18-2.46; and allele comparing: OR = 1.23, 95% CI = 1.01-1.50), and the PAT-/+ (+/+ vs. -/-: OR = 1.36, 95% CI = 1.03-1.79 and recessive model: OR = 1.34, 95% CI = 1.06-1.70). Furthermore, stratification analyses demonstrated an increased risk for Asian populations as to the Lys939Gln and PAT-/+ whereas for Caucasian populations as to the Ala499Val polymorphism in the homozygous and recessive models. Despite some limitations, this meta-analysis suggests that XPC polymorphisms are associated with bladder cancer risk, but this association warrants further validation in well-designed studies with large sample sizes.

Radiofrequency ablation versus open hepatic resection for elderly patients (> 65 years) with very early or early hepatocellular carcinoma.

BACKGROUND: This study retrospectively compared the safety and efficacy of percutaneous radiofrequency ablation (RFA) with open hepatic resection (HR) in elderly patients (age > 65 years) with very early or early hepatocellular carcinoma (HCC). METHODS: Elderly patients (n = 180) with very early or early HCC were studied. This study was approved by the Ethics Committee of the Cancer Center of Sun Yat-Sen University, Guangzhou, China. Written informed consent was obtained from each patient before treatment. As an initial treatment, 89 patients were treated by RFA and 91 patients by HR. The survival curves were constructed by the Kaplan-Meier method and compared by log-rank test. RESULTS: The 1-, 3-, and 5-year overall survivals were 93.2%, 71.1%, and 55.2% for the RFA group and 88.8%, 62.8%, and 51.9% for the HR group, respectively (P = .305). The corresponding recurrence-free survivals for these 2 groups were 84.1%, 62.7%, and 35.5% and 76.7%, 39.3%, and 33.1%, respectively (P = .035). On subgroup analysis for tumor ≤ 3 cm, the 1-, 3-, and 5-year overall survivals were 94.2%, 82.6%, and 67.5% for the RFA group and 90.1%, 65.0%, and 55.1% for the HR group, respectively (P = .038). The corresponding recurrence-free survivals for the 2 groups were 85.5%, 69.1%, and 40.7%, and 82.2%, 40.1%, and 31.8%, respectively (P = .049). For tumor > 3 cm, there was no significant difference between these 2 groups for overall survivals and recurrence-free survivals (P = .543, P = .356, respectively). A multivariate regression analysis showed that treatment type was the only significant prognostic factor for recurrence-free survival (P = .039). CONCLUSIONS: There was no difference between the HR and RFA groups for overall survival, but RFA had better efficacy than HR for elderly patients with HCC ≤ 3 cm.

Transcatheter arterial chemoembolization combined with radiofrequency ablation for the treatment of hepatocellular carcinoma.

Radiofrequency ablation (RFA) has become an important treatment for hepatocellular carcinoma (HCC). Nowadays, RFA is generally recognized as an alternative treatment to partial hepatectomy for early HCC, especially for patients with impaired liver function and when liver transplantation is not indicated, although some authors consider that RFA can be used as a first-line treatment for early HCC. Transcatheter arterial chemoembolization (TACE) is most commonly classified as palliative rather than potentially curative; there is evidence that TACE prolongs survival in patients with well-compensated liver disease and intermediate-stage HCC. Alone, TACE and RFA have their limitations; in particular, neither can result in adequate control of medium or large HCC. Sequential application of TACE and RFA is, therefore, increasingly being used in the treatment of HCC in patients with well-compensated liver disease. In this study, we will introduce our experience of TACE combined with RFA in the treatment of HCC in a cancer center in China.

Can Epstein-Barr virus-deoxyribonucleic acid load after induction chemotherapy combined with American Joint Committee on Cancer stage determine the chemotherapy intensity of locally advanced nasopharyngeal carcinoma?

BACKGROUND: Induction chemotherapy (IC) comprising docetaxel, cisplatin, and fluorouracil (TPF), combined with concurrent chemoradiotherapy (CCRT) effectively improves the survival rate of locally advanced nasopharyngeal carcinoma (LA-NPC). Selecting patients whose risk of tumor recurrence and metastasis is high and the appropriate chemotherapy intensity is a concern. We combined tumor-node-metastasis staging with the load of Epstein-Barr virus (EBV) after IC to select the individualized chemotherapy strength. METHODS: The clinical data and prognostic factors of patients with stage III-IV LA-NPC treated with TPF IC combined with CCRT were analyzed retrospectively. The conventional treatment group received the standard three cycles TPF IC combined with CCRT. For the new treatment group, the cycles of IC were determined according to whether the EBV-DNA disappeared completely after a certain course of IC, if so, subsequent IC was stopped and the chemoradiotherapy stage was entered. Propensity score matching (PSM) was performed at a ratio of 1:1 to balance baseline characteristics. Survival outcomes and adverse events between the conventional treatment group and the new method treatment group were compared. RESULTS: The study included 256 patients, among whom 192 were matched successfully into 96 pairs. The patients were followed up for a median of 51 months. The proportions of patients receiving three, two, and one cycle of IC after PSM in the routine and new treatment cohorts were 93.8%, 3.1%, 3.1% versus 21.9%, 49.0%, 24.0%, respectively. However, their 3-year distant metastasis-free survival, local recurrence-free survival, progression-free survival, and overall survival did not differ significantly. The incidence of grade 3-4 neutropenia toxicity in CCRT decreased significantly in patients receiving the new treatment method compared with that in the conventional treatment group (p = 0.026). CONCLUSION: Combining TNM stage and EBV-DNA load after IC to determine the courses of IC in patients with LA-NPC did not alter the curative effect but decreased toxicity.

Hepatic resection versus transcatheter arterial chemoembolization for the treatment of hepatocellular carcinoma with portal vein tumor thrombus.

BACKGROUND: The long-term survival outcomes of hepatic resection (HR) compared with transcatheter arterial chemoembolization (TACE) for resectable hepatocellular carcinoma (HCC) with portal vein tumor thrombus (PVTT) are unclear. MATERIALS AND METHODS: Between December 2002 and December 2007, 201 consecutive patients diagnosed with resectable HCC with PVTT received HR as an initial treatment in our center. These patients were compared with 402 case-matched controls selected from a pool of 1798 patients (with a 1:2 ratio) who received TACE as an initial treatment during the study period. PVTT was classified to 4 types: PVTT involving the segmental branches of the portal vein or above (type I), PVTT extending to involve the right/left portal vein (type II), the main portal vein (type III), or the superior mesenteric vein (type IV). RESULTS: The 1-, 3-, and 5-year overall survivals for the HR and TACE groups were 42.0%, 14.1%, and 11.1% and 37.8%, 7.3%, and 0.5%, respectively (P < .001). On subgroup analyses, the overall survivals for the HR group were better than the TACE group for type I PVTT, type II PVTT, single tumor, and tumor size >5 cm (P < .001, P = .002, P < .001, P < .001, respectively), but not for type III PVTT, type IV PVTT, multiple tumors, and tumor size <5 cm (P = .541, P = .371, P = .264, P = .338, P = .125, respectively). Multivariate analysis showed the type of PVTT and initial treatment allocation were significant prognostic factors for overall survival. CONCLUSIONS: Compared with TACE, HR provided survival benefits for patients with resectable HCC with PVTT, especially for those with a type I PVTT or a type II PVTT.

Recurrent hepatocellular carcinoma treated with sequential transcatheter arterial chemoembolization and RF ablation versus RF ablation alone: a prospective randomized trial.

PURPOSE: To compare prospectively the effects of radiofrequency (RF) ablation after transcatheter arterial chemoembolization (TACE) with those of RF ablation alone in the treatment of recurrent hepatocellular carcinoma (HCC). MATERIALS AND METHODS: This study was approved by the institutional ethics committee, and all patients gave written informed consent. From January 2002 to December 2006, 139 patients with recurrent HCC measuring 5 cm in diameter or smaller were randomized to receive either sequential TACE and RF ablation (sequential treatment group, n=69) or RF ablation alone (RF ablation group, n=70). The survival curves were constructed with the Kaplan-Meier method and compared by using the log-rank test. Bonferroni correction was applied when multiple comparisons were performed. P<.0083 (.05÷6) was considered indicative of a statistically significant difference. RESULTS: The 1-, 3-, and 5-year overall survival rates were 94%, 69%, and 46%, respectively, for the sequential treatment group and 82%, 47%, and 36% for the RF ablation group (P=.037). The corresponding recurrence-free survival rates were 80%, 45%, and 40% for the sequential treatment group and 64%, 18%, and 18% for the ablation group (P=.005). At subgroup analyses, the overall survival for the sequential treatment group was better than that for the RF ablation group for patients with tumor recurrence 1 year or less after initial treatment (P=.004) and those with tumors measuring 3.1-5.0 cm (P=.002) but not for those with tumor recurrence more than 1 year after initial treatment (P=.421) and those with tumors 3.0 cm or smaller (P=.478). The recurrence-free survival in the sequential treatment group was better than that in the RF ablation group for patients with tumors measuring 3.1-5.0 cm (P<.001) but not for those with tumors 3.0 cm or smaller (P=.204). For recurrence-free survival, there was no significant difference between the two groups for patients with tumor recurrence 1 year or less or more than 1 year after initial treatment (P=.020 and P=.111, respectively). Logistic regression analysis showed that treatment allocation and the interval between initial treatment and tumor recurrence were significant prognostic factors for overall survival, whereas the interval between initial treatment and tumor recurrence, treatment allocation, and tumor size were significant prognostic factors for recurrence-free survival. CONCLUSION: The efficacy of sequential TACE-RF ablation is better than that of RF ablation alone for recurrent HCC.

Radiofrequency ablation versus hepatic resection for the treatment of hepatocellular carcinomas 2 cm or smaller: a retrospective comparative study.

PURPOSE: To compare retrospectively the effects of percutaneous radiofrequency (RF) ablation with those of hepatic resection in the treatment of hepatocellular carcinoma (HCC) measuring 2 cm or smaller. MATERIALS AND METHODS: This study was approved by the institutional ethics committee, and all patients provided written informed consent before treatment. From December 2003 to December 2008, 145 patients with a resectable HCC measuring 2 cm or smaller were studied. Sixty-six patients had a central HCC (located at least 3 cm from the liver capsule). As an initial treatment, 71 patients were treated with percutaneous RF ablation and 74 with surgical resection. Of the patients with central HCC, 37 underwent percutaneous RF ablation and 29 underwent surgical resection. Survival curves were constructed with the Kaplan-Meier method and compared by using the log-rank test. The relative prognostic significance of the variables for predicting overall survival rates was assessed with multivariate Cox proportional hazards regression analysis. Complications were observed clinically when patients were admitted and assessed by telephone interview after patients were discharged. RESULTS: One death was considered to be related to treatment after surgical resection. Major complications occurred significantly more often in the surgical resection group (38 of 74 patients) than in the RF ablation group (14 of 71 patients) (P = .009). The 1-, 3-, and 5-year overall survival rates were 98.5%, 87.7%, and 71.9%, respectively, with RF ablation and 90.5%, 70.9%, and 62.1% with surgical resection (P = .048). The corresponding recurrence-free survival rates were 76.4%, 65.2%, and 59.8% with RF ablation and 75.6%, 56.1%, and 51.3% with surgical resection (P = .548). At subgroup analysis of patients with central HCC, 1-, 3-, and 5-year overall survival rates were 96.6%, 93.0%, and 79.9% with RF ablation and 92.0%, 71.6%, and 61.5% with surgical resection (P = .020). The corresponding recurrence-free survival rates were 86.5%, 74.0%, and 67.0% with RF ablation and 68.0%, 40.0%, and 40.0% with surgical resection (P = .033). For patients with peripheral HCC, 1-, 3-, and 5-year overall survival rates were 97.3%, 83.3%, and 65.1% with RF ablation and 87.8%, 68.4%, and 62.9% with surgical resection (P = .464). The corresponding recurrence-free survival rates were 68.7%, 59.2%, and 54.9% with RF ablation and 82.9%, 66.6%, and 52.9% with surgical resection (P = .351). CONCLUSION: The efficacy and safety of percutaneous RF ablation were better than those of surgical resection in patients with HCC measuring 2 cm or smaller, especially those with central HCC.

Adjuvant Sorafenib Following Radiofrequency Ablation for Early-Stage Recurrent Hepatocellular Carcinoma With Microvascular Invasion at the Initial Hepatectomy.

Background: The efficacy of radiofrequency ablation (RFA) for patients with early-stage recurrent hepatocellular carcinoma (HCC) with microvascular invasion (MVI) at the initial hepatectomy is limited. Our study aimed to explore whether adjuvant sorafenib following RFA could improve the situation. Methods: We retrospectively included 211 patients with early-stage (tumor number of ≤3 and tumor size of 2-5 cm) recurrent HCC with MVI at the initial hepatectomy who underwent adjuvant sorafenib following RFA or RFA alone in 13 centers from June 2013 to June 2020. In the combination group, sorafenib of 400 mg twice daily was administered within 7 days after RFA. Overall survival (OS) and recurrence-free survival (RFS) were compared. Subgroup analysis based on MVI grade was performed. MVI grade was based on the practice guidelines for the pathological diagnosis of HCC and included M1 (≤5 MVI sites, all located within adjacent peritumoral liver tissues 0-1 cm away from the tumor margin) and M2 (>5 MVI sites, or any MVI site located within adjacent peritumoral liver tissues > 1 cm away from the tumor margin). Results: A total of 103 patients received the combination therapy and 108 patients received RFA alone. The combination therapy provided better survival than RFA alone (median RFS: 17.7 vs. 13.1 months, P < 0.001; median OS: 32.0 vs. 25.0 months, P = 0.002). Multivariable analysis revealed that treatment allocation was an independent prognostic factor. On subgroup analysis, the combination therapy provided better survival than RFA alone in patients with M1 along with either a tumor size of 3-5 cm, tumor number of two to three, or alpha-fetoprotein (AFP) > 400 µg/L, and in those with M2 along with either a tumor size of 2-3 cm, one recurrent tumor, or AFP ≤ 400 µg/L. Conclusions: Adjuvant sorafenib following RFA was associated with better survival than RFA alone in patients with early-stage recurrent HCC with MVI at the initial hepatectomy. Moreover, MVI grade could guide the application of adjuvant sorafenib.

Hepatic resection versus transarterial lipiodol chemoembolization as the initial treatment for large, multiple, and resectable hepatocellular carcinomas: a prospective nonrandomized analysis.

PURPOSE: To compare the survival outcomes between hepatic resection and transarterial lipiodol chemoembolization (TACE) used as the initial treatment in patients with large (≥5 cm), multiple, and resectable hepatocellular carcinomas. MATERIALS AND METHODS: This study had local ethical committee approval; all patients gave written informed consent. Between January 2004 and December 2006, 168 consecutive patients were prospectively studied. As an initial treatment, 85 patients underwent hepatic resection and 83 underwent TACE. Of the 29 of 83 patients in whom there was a good response to TACE, 13 underwent subsequent hepatic resection. The remaining 16 patients, who refused hepatic resection, underwent TACE and local ablation. Repeated TACE was performed in patients with stable disease or progressive disease after initial TACE. The differences in survival between groups and subgroups were calculated with the Kaplan-Meier method. Univariate and multivariate analyses were performed to clarify the prognostic factors for survival. RESULTS: The 1-, 3-, and 5-year overall survival rates for the initial hepatic resection group and the initial TACE group were 70.6%, 35.3%, 23.9% and 67.2%, 26.0%, 18.9%, respectively (P = .26). Complication rates were significantly higher in the initial hepatic resection group than in the initial TACE group (P < .01). The 1-, 3-, and 5-year overall survival rates in patients who underwent initial TACE and subsequent hepatic resection were 92.3%, 67.3%, and 50.5%, respectively, which were significantly higher than rates in patients treated with initial hepatic resection (P = .04) but were not significantly higher than in patients who responded well to TACE but refused hepatic resection (P = .07). Tumor size was the independent risk factor for survival. CONCLUSION: TACE might be a better initial treatment in patients with large, multiple, and resectable hepatocellular carcinomas; hepatic resection should be recommended to patients who respond well to TACE.

Role of radiofrequency ablation in the treatment of hepatocellular carcinoma: experience of a cancer center in China.

Radiofrequency ablation (RFA) has become an important treatment for hepatocellular carcinoma (HCC). The good candidates for RFA are patients with HCC at an early stage (solitary tumor ≤ 5 cm in diameter or ≤ 3 nodules ≤ 3 cm in diameter). Several clinical trials have shown that RFA is effective in resection for the treatment of small HCC. Until now, RFA has been widely used as a radical treatment for small HCC. RFA also plays an important role in the multidisciplinary treatment of HCC and is usually combined with other therapies such as resection, vascular intervention, intratumor ethanol injection, radiotherapy, chemotherapy, targeted drug therapy, and biological immune therapy. In this study, we will introduce our experience of RFA in the treatment of HCC in a cancer center in China.

Conformal radiofrequency ablation of hepatocellular carcinoma with a multi-pin bipolar system.

BACKGROUND: To retrospectively evaluate the effectiveness and safety of radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC) with a multi-pin bipolar system. METHODS: Between August 2005 and December 2006, 18 patients with 30 HCCs (3.40 ± 1.24 cm, range 1.30-6.0 cm; median number of treated lesions is two per patient, range, 1-3) underwent percutaneous RFA with a multi-pin bipolar system under ultrasound guidance. The primary end-point were treatment efficacy, major and minor complications, and the secondary end-point were overall survival and tumor-free survival. RESULTS: Complete ablation with conformed shape to the index tumor was achieved in 16 of 18 patients, and 28 of the 30 tumors were completely ablated. On follow-up, local and distant intrahepatic tumor progression rates were 12.5% (2 of 16 patients) and 62.5% (10 of 16 patients). There was no patient who developed extrahepatic metastasis. There were no major complications. The 1-, 2-year overall survival rates for all patients were 83.3%, 55.6%, respectively, and the corresponding tumor-free survivals were 50.0%, 22.2%, respectively. CONCLUSION: RFA with a multi-pin bipolar system was effective and safe for HCC. A large ablation volume could be achieved which conformed to the shape of the index tumor.

A Pre-Operative Prognostic Score for Patients With Advanced Hepatocellular Carcinoma Who Underwent Resection.

BACKGROUND: Previous studies demonstrated a promising prognosis in advanced hepatocellular carcinoma (HCC) patients who underwent surgery, yet a consensus of which population would benefit most from surgery is still unreached. METHOD: A total of 496 advanced HCC patients who initially underwent liver resection were consecutively collected. Least absolute shrinkage and selection operator (LASSO) regression was performed to select significant pre-operative factors for recurrence-free survival (RFS). A prognostic score constructed from these factors was used to divide patients into different risk groups. Survivals were compared between groups with log-rank test. The area under curves (AUC) of the time-dependent receiver operating characteristics was used to evaluate the predictive accuracy of prognostic score. RESULT: For the entire cohort, the median overall survival (OS) was 23.0 months and the median RFS was 12.1 months. Patients were divided into two risk groups according to the prognostic score constructed with ALBI score, tumor size, tumor-invaded liver segments, gamma-glutamyl transpeptidase, alpha fetoprotein, and portal vein tumor thrombus stage. The median RFS of the low-risk group was significantly longer than that of the high-risk group in both the training (10.1 vs 2.9 months, P<0.001) and the validation groups (13.7 vs 4.6 months, P=0.002). The AUCs of the prognostic score in predicting survival were 0.70 to 0.71 in the training group and 0.71 to 0.72 in the validation group. CONCLUSION: Surgery could provide promising survival for HCC patients at an advanced stage. Our developed pre-operative prognostic score is effective in identifying advanced-stage HCC patients with better survival benefit for surgery.

Efficacy of combining temperature- and power-controlled radiofrequency ablation for malignant liver tumors.

BACKGROUND AND OBJECTIVE: Single mode of radiofrequency ablation (RFA) often leads to limited ablation in the zone of necrosis. This study clarifies the efficacy of combining temperature- and power-controlled RFA for malignant liver tumors. METHODS: Between April 2008 and August 2008, 58 patients with malignant liver tumors received RFA at Sun Yat-sen University Cancer Center. The patients were divided into 2 groups using a random number table: one group received combined temperature- and power-controlled RFA (the combination group), and the other group received power-controlled RFA alone (the control group). RESULTS: Three patients were lost to follow-up and 55 patients were included for evaluation. Twenty-five patients with 29 tumors were treated by the combination RFA, and 27 tumors (93.1%) achieved either complete response (CR) or partial response (PR). One patient had a seriously decreased heart rate. In the control group, 30 patients with 32 tumors received power-controlled RFA, and 29 tumors (90.6%) achieved CR or PR. There were no serious complications. There was no difference between the combination and control groups in treatment time ((13.3 +/- 1.3) min vs. (10.2 +/- 2.3) min, P = 0.459). The number of sessions of RFA for the combination group was less than that of control group (1.3 sessions vs. 2.4 sessions), but the difference was not significant (P = 0.579). CONCLUSION: RFA controlling both temperature and power is effective and safe for patients with malignant liver tumors, and the number of sessions of RFA for the combination group was less than that of the control group.

Anti-PD-1 Immunotherapy and Radiotherapy for Stage IV Intrahepatic Cholangiocarcinoma: A Case Report.

Due to the unsatisfactory robustness of current predictive biomarkers in many cases, application of immunotherapy in advanced cancers with limited treatment options, such as stage IV intrahepatic cholangiocarcinoma (ICC), was quite common. Hence, strategies to enhance the therapeutic effect of immunotherapy or to extend the scope of potential beneficial patients were urgently needed. Combination of radiotherapy and anti-programmed death receptor-1 (PD-1) immunotherapy was a promising one, since they were found to have a synergistic anti-tumor effect in animal models and a couple of patients. We here present a 68-years-old male with chemotherapy-intolerable stage IV ICC, whose primary tumor had low PD-L1 expression level, scarce CD8+ cells in tumor microenvironment, high microsatellite instability (MSI), and high tumor mutation burden (TMB). These biomarkers showed a conflicting prediction of the treatment response and clinical benefit of anti-PD-1 immunotherapy. Combination therapy of anti-PD-1 immunotherapy and radiotherapy was adopted as first-line treatment for the patient. After six cycles of immunotherapy, shrinkage of the primary liver tumor and metastatic lymph nodes happened, alongside with new lung metastasis, which indicated a mixed response. Radiotherapy was then administered to both the liver and lung lesions, accompanied with continued immunotherapy. The combined therapy eventually led to a complete response for both the primary tumor and all metastases without treatment-related adverse effects. The patient has survived for 26 months after the combined therapy and remains tumor-free currently. This case demonstrates the high inconsistency between immunotherapy response biomarkers and the synergetic anti-tumor effect of immunotherapy and radiotherapy in ICC.