The utility of P-I-R classification in predicting the on-treatment histological and clinical outcomes of patients with hepatitis B and advanced liver fibrosis.

BACKGROUND AND AIMS: The predominantly progressive, indeterminate, and predominantly regressive (P-I-R) classification extends beyond staging and provides information on dynamic changes of liver fibrosis. However, the prognostic implication of P-I-R classification is not elucidated. Therefore, in the present research, we investigated the utility of P-I-R classification in predicting the on-treatment clinical outcomes. APPROACH AND RESULTS: In an extension study on a randomized controlled trial, we originally enrolled 1000 patients with chronic hepatitis B and biopsy-proven histological significant fibrosis, and treated them for more than 7 years with entecavir-based therapy. Among the 727 patients with a second biopsy at treatment week 72, we compared P-I-R classification and Ishak score changes in 646 patients with adequate liver sections for the histological evaluation. Progressive, indeterminate, and regressive cases were observed in 70%, 17%, and 13% of patients before treatments and 20%, 14%, and 64% after 72-week treatment, respectively, which could further differentiate the histological outcomes of patients with stable Ishak scores. The 7-year cumulative incidence of HCC was 1.5% for the regressive cases, 4.3% for the indeterminate cases, and 22.8% for the progressive cases ( p <0.001). After adjusting for age, treatment regimen, platelet counts, cirrhosis, Ishak fibrosis score changes, and Laennec staging, the posttreatment progressive had a HR of 17.77 (vs. posttreatment regressive; 95% CI: 5.55-56.88) for the incidence of liver-related events (decompensation, HCC, and death/liver transplantation). CONCLUSIONS: The P-I-R classification can be a meaningful complement to the Ishak fibrosis score not only in evaluating the histological changes but also in predicting the clinical outcomes.

aMAP Score and Its Combination With Liver Stiffness Measurement Accurately Assess Liver Fibrosis in Chronic Hepatitis B Patients.

BACKGROUND & AIMS: The changes in liver stiffness measurement (LSM) are unreliable to estimate regression of fibrosis during antiviral treatment for chronic hepatitis B (CHB) patients. The age-male-albumin-bilirubin-platelets score (aMAP), as an accurate hepatocellular carcinoma risk score, may reflect the liver fibrosis stage. Here, we aimed to evaluate the performance of aMAP for diagnosing liver fibrosis in CHB patients with or without treatment. METHODS: A total of 2053 patients from 2 real-world cohorts and 2 multicentric randomized controlled trials in China were enrolled, among which 2053 CHB patients were included in the cross-sectional analysis, and 889 CHB patients with paired liver biopsies before and after 72 or 104 weeks of treatment were included in the longitudinal analysis. RESULTS: In the cross-sectional analysis, the areas under the receiver operating characteristic curve of aMAP in diagnosing cirrhosis and advanced fibrosis were 0.788 and 0.757, which were comparable with or significantly higher than those of the fibrosis index based on 4 factors and the aspartate aminotransferase-platelet ratio. The stepwise approach using aMAP and LSM further improved performance in detecting cirrhosis and advanced fibrosis with the smallest uncertainty area (29.7% and 46.2%, respectively) and high accuracy (82.3% and 79.8%, respectively). In the longitudinal analysis, we established a novel model (aMAP-LSM model) by calculating aMAP and LSM results before and after treatment, which had satisfactory performance in diagnosing cirrhosis and advanced fibrosis after treatment (area under the receiver operating characteristic curve, 0.839 and 0.840, respectively), especially for those with a significant decrease in LSM after treatment (vs LSM alone, 0.828 vs 0.748; P < .001 [cirrhosis]; 0.825 vs 0.750; P < .001 [advanced fibrosis]). CONCLUSIONS: The aMAP score is a promising noninvasive tool for diagnosing fibrosis in CHB patients. The aMAP-LSM model could accurately estimate fibrosis stage for treated CHB patients.

Efficacy and safety of percutaneous cryoablation for elderly patients with small hepatocellular carcinoma: A prospective multicenter study.

BACKGROUND & AIMS: Management of elderly patients with hepatocellular carcinoma (HCC) has become a major concern. Some data suggest that cryoablation improves the outcomes of elderly patients with HCC, but its efficacy and safety remain unknown. This study aimed to evaluate and compare the efficacy and safety of percutaneous cryoablation with those of radiofrequency ablation (RFA) for elderly HCC patients. METHODS: In all, 223 patients with small HCC aged ≥70 years, treatment-naïve, without metastasis were enrolled and randomized into a cryoablation group (n = 112) or a RFA (n = 111) group from July 2015 to October 2018. The primary endpoint was local tumour progression (LTP) at 3 years after treatment. The secondary endpoints including overall survival (OS), tumour-free survival (TFS), LTP and safety were analysed for these two groups after both treatments. RESULTS: LTP rates at 1-, 3- and 5-year were 12%, 17% and 20% for cryoablation and 17%, 18% and 21% for RFA respectively (P = .735). For lesions >3 cm in diameter, LTP rates at 1- and 3-year were 13% and 22% in cryoablation group and 22% and 42% respectively, in the RFA group (P = .039). The 1-, 3- and 5-year OS rates were 90, 75% and 62% for cryoablation and 90%, 68% and 63% for RFA respectively (P = .331). The 1-, 3- and 5-year TFS rates were 59%, 32% and 25% in the cryoablation and 59%, 28% and 20% in the RFA respectively (P = .309). Major complications occurred in 6 patients (5%) following cryoablation and 6 patients (6%) following RFA (P = .886). CONCLUSION: Cryoablation and RFA had similar LTP in elderly patients with small HCC and this study failed to meet the primary endpoint, although for a relatively large early-stage HCC the LTP rate after cryoablation was significantly lower than that after RFA.

Influence of weight management on the prognosis of steatohepatitis in chronic hepatitis B patients during antiviral treatment.

BACKGROUND: Although concomitant nonalcoholic steatohepatitis (NASH) is common in chronic hepatitis B (CHB), the impact of viral factors on NASH and the outcome of CHB patients concomitant with NASH remain unclear. We aimed to investigate the outcomes of NASH in CHB patients receiving antiviral treatment. METHODS: In the post-hoc analysis of a multicenter trial, naïve CHB patients receiving 72-week entecavir treatment were enrolled. We evaluated the biochemical, viral and histopathological responses of these patients. The histopathological features of NASH were also evaluated, using paired liver biopsies at baseline and week 72. RESULTS: A total of 1000 CHB patients were finally enrolled for analysis, with 18.2% of whom fulfilling the criteria of NASH. A total of 727 patients completed entecavir antiviral treatment and received the second biopsy. Serum HBeAg loss, HBeAg seroconversion and HBV-DNA undetectable rates were similar between patients with or without NASH (P > 0.05). Among patients with NASH, the hepatic steatosis, ballooning, lobular inflammation scores and fibrosis stages all improved during follow-up (all P < 0.001), 46% (63/136) achieved NASH resolution. Patients with baseline body mass index (BMI) ≥ 23 kg/m2 (Asian criteria) [odds ratio (OR): 0.414; 95% confidence interval (95% CI): 0.190-0.899; P = 0.012] and weight gain (OR: 0.187; 95% CI: 0.050-0.693; P = 0.026) were less likely to have NASH resolution. Among patients without NASH at baseline, 22 (3.7%) developed NASH. Baseline BMI ≥ 23 kg/m2 (OR: 12.506; 95% CI: 2.813-55.606; P = 0.001) and weight gain (OR: 5.126; 95% CI: 1.674-15.694; P = 0.005) were predictors of incident NASH. CONCLUSIONS: Lower BMI and weight reduction but not virologic factors determine NASH resolution in CHB. The value of weight management in CHB patients during antiviral treatment deserves further evaluation.

Downregulated Expression of Tropomyosin 1 in Intrahepatic Cholangiocarcinoma: A Predictor of Recurrence and Prognosis.

BACKGROUND The downregulation of tropomyosin 1 (TPM1) has been observed in various tumors, but few studies have focused on the clinical significance of TPM1 in intrahepatic cholangiocarcinoma (ICC). In the present study, we investigated the prognostic significance of TPM1 in ICC. MATERIAL AND METHODS A total of 124 patients with ICC were enrolled in this study. Quantitative real-time polymerase chain reaction (qRT-RCR) was performed to examine the mRNA levels of TPM1 in ICC tissue samples and adjacent noncancerous tissue specimens, while the protein level of TPM1 in tissue specimens were investigated using immunohistochemistry assay. The correlation of TPM1 with clinicopathological features of ICC was analyzed by chi-square test. Survival analysis was performed with Kaplan-Meier method. The Cox proportional hazards model was used to evaluate the prognostic value of TPM1 in patients with ICC. RESULTS TPM1 expression was significantly downregulated in ICC tissues at mRNA and protein levels (P<0.001 for both). Downregulated TPM1 mRNA was negatively associated with tumor size (P=0.001) and TNM stage (P=0.007). Moreover, survival analysis demonstrated that patients with low TPM1 expression had a shorter overall survival (OS) (P<0.001) and recurrence-free survival (RFS) (P<0.001) than those with high TPM1 expression. Additionally, multivariate analysis showed that TPM1 could be a potential biomarker for predicting the recurrence (HR=4.632, 95% CI: 3.832-10.368, P<0.001) and survival outcome (HR=5.320, 95% CI: 2.627-11.776, P<0.001) of ICC. CONCLUSIONS TPM1 may serve as a useful biomarker for predicting tumor recurrence and prognosis in patients with ICC.

Early activated hepatic stellate cell-derived paracrine molecules modulate acute liver injury and regeneration.

The effects of paracrine action from early activated hepatic stellate cells (HSCs) on resident liver epithelium cells are not clear. Here, we investigated whether a systemic infusion of early activated HSC-derived paracrine factors (HSC-CM) would evoke an enhanced liver protective response in acetaminophen (APAP)-induced acute liver injury (ALI) in mice and explored the possible underlying mechanisms. The survival rate, liver injury, and liver regeneration were analyzed in mice with or without HSC-CM treatment in vivo. A systemic infusion of HSC-CM provided a significant survival benefit in APAP-induced ALI. HSC-CM therapy resulted in a reduction of hepatocellular death and increased numbers of both proliferating hepatocytes and adult hepatic progenitor cells (AHPCs) with up-regulation of liver regeneration relevant genes. The HSC-CM treatment reduced leukocyte infiltration and down-regulated systemic inflammation with decreases in IFN-γ, IL-1ra, IL-1ß, TNF-α, and increases in IL-10. The direct anti-death and pro-regeneration effects of HSC-CM on AHPCs were demonstrated using in vitro assays. Treatment with HSC-CM promoted AHPCs proliferation and resulted in increased pAkt expression in vitro, and this effect was abolished by the PI3K/Akt inhibitor LY294002. These data provide evidence that early activated HSC-CM therapy offered trophic support to the acutely injured liver by inhibiting liver cell death and stimulating regeneration, potentially creating a new method for the treatment of ALI.

MiR-223 modulates hepatocellular carcinoma cell proliferation through promoting apoptosis via the Rab1-mediated mTOR activation.

Hepatocellular carcinoma (HCC) is a common digestive malignancy. MiR-223, a well-identified miRNA, exhibits diverse properties in different cancers. In this study, we demonstrated that miR-223 could suppress cell growth and promote apoptosis in HepG2 and Bel-7402 HCC cell lines. We screened and identified a novel miR-223 target, Ras-related protein Rab-1(Rab1). Upregulation of miR-223 would specifically and markedly down-regulate Rab1 expression. In addition, miR-223-overexpressing subclones showed significant cell growth inhibition by increasing cell apoptosis in HepG2 and Bel-7402 cells. To identify the mechanisms, we firstly investigated the mTOR pathway and found that pmTOR, p70S6K and Bcl-2 were dramatically down-regulated after miR-223 transfection, while no changes in the level of Bax was visualized. Furthermore, our data showed that the anti-tumor effects arising from miR-223 transfection in HCC cells may be due to the deactivation of mTOR pathway caused by the suppression of Rab1 expression when miR-223 is overexpressed. In summary, our results indicate that miR-223 functions as a tumor suppressor and plays a critical role in inhibiting the tumorigenesis and promoting the apoptosis of HCC through the mTOR signaling pathway in vitro. By targeting Rab1, miR-223 efficiently mediates the mTOR pathway. Given these, miR-223 may be a potential therapeutic target for treating HCC.

Alternative splicing of the cell fate determinant Numb in hepatocellular carcinoma.

UNLABELLED: The cell fate determinant Numb is aberrantly expressed in cancer. Numb is alternatively spliced, with one isoform containing a long proline-rich region (PRR(L) ) compared to the other with a short PRR (PRR(S) ). Recently, PRR(L) was reported to enhance proliferation of breast and lung cancer cells. However, the importance of Numb alternative splicing in hepatocellular carcinoma (HCC) remains unexplored. We report here that Numb PRR(L) expression is increased in HCC and associated with early recurrence and reduced overall survival after surgery. In a panel of HCC cell lines, PRR(L) generally promotes and PRR(S) suppresses proliferation, migration, invasion, and colony formation. Knockdown of PRR(S) leads to increased Akt phosphorylation and c-Myc expression, and Akt inhibition or c-Myc silencing dampens the proliferative impact of Numb PRR(S) knockdown. In the cell models explored in this study, alternative splicing of Numb PRR isoforms is coordinately regulated by the splicing factor RNA-binding Fox domain containing 2 (RbFox2) and the kinase serine/arginine protein-specific kinase 2 (SRPK2). Knockdown of the former causes accumulation of PRR(L) , while SRPK2 knockdown causes accumulation of PRR(S) . The subcellular location of SRPK2 is regulated by the molecular chaperone heat shock protein 90, and heat shock protein 90 inhibition or knockdown phenocopies SRPK2 knockdown in promoting accumulation of Numb PRR(S) . Finally, HCC cell lines that predominantly express PRR(L) are differentially sensitive to heat shock protein 90 inhibition. CONCLUSION: Alternative splicing of Numb may provide a useful prognostic biomarker in HCC and is pharmacologically tractable.

Multicenter randomized controlled trial of percutaneous cryoablation versus radiofrequency ablation in hepatocellular carcinoma.

UNLABELLED: Radiofrequency ablation (RFA) is considered a curative treatment option for hepatocellular carcinoma (HCC). Growing data have demonstrated that cryoablation represents a safe and effective alternative therapy for HCC, but no randomized controlled trial (RCT) has been reported to compare cryoablation with RFA in HCC treatment. The present study was a multicenter RCT aimed to compare the outcomes of percutaneous cryoablation with RFA for the treatment of HCC. In all, 360 patients with Child-Pugh class A or B cirrhosis and one or two HCC lesions ≤ 4 cm, treatment-naïve, without metastasis were randomly assigned to cryoablation (n = 180) or RFA (n = 180). The primary endpoints were local tumor progression at 3 years after treatment and safety. Local tumor progression rates at 1, 2, and 3 years were 3%, 7%, and 7% for cryoablation and 9%, 11%, and 11% for RFA, respectively (P = 0.043). For lesions >3 cm in diameter, the local tumor progression rate was significantly lower in the cryoablation group versus the RFA group (7.7% versus 18.2%, P = 0.041). The 1-, 3-, and 5-year overall survival rates were 97%, 67%, and 40% for cryoablation and 97%, 66%, and 38% for RFA, respectively (P = 0.747). The 1-, 3-, and 5-year tumor-free survival rates were 89%, 54%, and 35% in the cryoablation group and 84%, 50%, and 34% in the RFA group, respectively (P = 0.628). Multivariate analyses demonstrated that Child-Pugh class B and distant intrahepatic recurrence were significant negative predictors for overall survival. Major complications occurred in seven patients (3.9%) following cryoablation and in six patients (3.3%) following RFA (P = 0.776). CONCLUSION: Cryoablation resulted in a significantly lower local tumor progression than RFA, although both cryoablation and RFA were equally safe and effective, with similar 5-year survival rates.

Design, synthesis, and biological evaluation of anti-EV71 agents.

Enterovirus 71 (EV71) is a major causative agent of hand, foot and mouth disease (HFMD), which can spread its infections to the central nervous and other systems with severe consequences. In this article, design, chemical synthesis, and biological evaluation of various anti-EV71 agents which incorporate Michael acceptors are described. Further SAR study demonstrated that lactone type of Michael acceptor provided a new lead of anti-EV71 drug candidates with high anti-EV71 activity in cell-based assay and enhanced mouse plasma stability. One of the most potent compounds (2K, cell-based anti-EV71 EC50=0.028µM), showed acceptable stability profile towards mouse plasma, which resulted into promising pharmacokinetics in mouse via IP administration.

Self-expandable metallic stent as a bridge to elective surgery versus emergency surgery for acute malignant colorectal obstruction.

BACKGROUD: The efficacy and safety of self-expandable metallic stents (SEMSs) as a bridge for patients with acute malignant colorectal obstructions (AMCOs) are still controversial. We conducted this study to evaluate the outcomes of patients with AMCOs treated by different strategies. METHODS: From January 2010 to March 2014, a total of 171 patients with AMCOs from Zhongshan Hospital were retrospectively enrolled in this study. One hundred twenty patients successfully received stent placement followed by one-stage laparoscopic or open resection in the stent group, and 51 patients received emergency operations in the emergency group. RESULTS: The operation duration and postoperative hospital stay were significantly shorter in the stent group (114.51 ± 28.65 vs. 160.39 ± 58.94 min, P < 0.001; 8.00 ± 3.97 vs. 12.59 ± 9.07 days, P = 0.001). The stent group also had significantly reduced intraoperative blood loss and the incidence of postoperative complications compared with the emergency group (61.00 ± 43.70 vs. 121.18 ± 85.90 ml, P < 0.001; 16.7 vs. 37.3%, P = 0.003). Kaplan-Meier survival curves showed that the median survival time in the stent group was significantly longer than that in the emergency group (53 vs. 41 months, P = 0.034). In subgroup analysis of stent group, the stent laparoscopy group had significantly decreased postoperative complications (P = 0.025), and similar long-term survival (P = 0.81). CONCLUSIONS: Stent placement as a bridge to surgery is a safe and feasible procedure and provides significant advantages in terms of short-term outcomes and favorable prognoses for patients with AMCOs. Laparoscopic surgery could be considered as an optimal treatment after stent placement.

[Optimization of alcohol precipitation technology of Biqiu granules based on index components and pharmacodynamics].

To evaluate the rationality of alcohol precipitation technology of Biqiu granule by investigating its effect on serum histamine, IgE, IL-4, IFN and TNF-α. The contents of cafferic acid and rosmarinic acid were used as the evaluation indexes, and some factors affecting index were firstly evaluated by Plackett-Burman design; then alcohol precipitation technology was further optimized by Box-Behnken design to determine the optimal alcohol precipitation conditions. The best alcohol precipitation conditions were as follows: the relative density of herb liquor was 1.15 (65 ℃); the concentration of alcohol was 70%, and standing time was 12 hours. Optimal alcohol precipitation technology of Biqiu granules determined by pharmacodynamic screening, Plackett-Burman and Box-Behnken design tests, was stable and feasible with good predictability, providing reliable basis for the industrialization production of Biqiu granules.

Hypomethylation of long interspersed nuclear element-1 promoter is associated with poor outcomes for curative resected hepatocellular carcinoma.

BACKGROUND: Epigenetic alterations are well documented in hepatocarcinogenesis. However, hypomethylation of long interspersed nuclear element 1(LINE-1) promoter and its relationship with clinicopathological features in hepatocellular carcinoma(HCC) remain unknown. METHODS: The bisulfite-specific PCR and DNA sequencing analysis was performed to assess the methylation status of LINE-1 promoter in a pilot cohort of 71 patients with HCC. Additionally,methylation levels of two hot CpG sites of LINE-1 promoter, site 7 and 18 were measured by real-time PCR and compared with clinicopathological parameters in a cohort of 172 HCC. All the patients included were in BCLC stage A or B. RESULTS: Most patients with HCC (87.3%) showed hypomethylation of LINE-1 promoter compared with HBV-related cirrhosis and normal controls (P < 0.001). The HCC patients with LINE-1 promoter hypomethylation had a median tumour-free survival (TFS) and overall survival (OS)post-resection of 22.0 (95% CI: 13.3­30.7) months and 35.0 (95% CI: 24.0­46.1) months, respectively, compared with 40 months and ~60 months for those with LINE-1 promoter hypermethylation (P < 0.05). Multivariate analyses showed that the hypomethylation level at CpG site 7 and 18 of LINE-1 promoter, along with tumour size and tumour differentiation, was independently associated with both TFS and OS for patients with HCC after resection. CONCLUSION: Promoter hypomethylation of LINE-1, especially at the CpG site 7 and 18, was associated with a poor prognosis in HCC.

[Effects of guizhi fuling capsule on sex hormone levels and breast issue morphology of mammary gland hyperplasia model rats].

OBJECTIVE: To research the effects of Guizhi Fuling capsule on sex hormones levels in blood serum and breast issue morphology of hyperplasia of mammary glands model rats. METHOD: The unpregnancy SD rat models of hyperplasia of mammary glands were established by injecting 0.5 mg x kg(-1) benzoate estradiol. After five weeks doses,the effects of Guizhi Fuling capsule 2.0, 1.0, 0.5 g x kg(-1) and Rupixiao tablet 0.5 g x kg(-1) on the changes of papilla diameter, height and breast issue morphology of the naimal models were explored, and sex hormones levels in blood serum were measured. RESULT: Guizhi Fuling capsule can inhibitnipple swell, improve breast tissue morphology pathological profiles of the animal models, and decrease oestradiol (E2) level and increase progesterone (P) level in blood serum. CONCLUSION: These results suggested that Guizhi Fuling capsule could, improve mammary gland pathological profiles. Regulating sex hormone levels may be its important mechanism for treatment of hyperplasia of mammary glands.

Serum high-density lipoprotein cholesterol levels predict early recurrence and prognosis of intrahepatic cholangiocarcinoma after surgical resection.

Introduction: Dysregulation in lipid metabolism contributes to the occurrence and development of various cancers. The connection between changes in lipid metabolism and the development of intrahepatic cholangiocarcinoma remains uncertain. Our objective was to investigate the significance of blood lipid levels in patients with intrahepatic cholangiocarcinoma who have undergone surgery. Methods: Ninety-seven ICC patients who underwent surgery were retrospectively enrolled. After 92.2 months of follow-up, the Kaplan-Meier analysis and Cox proportional hazard model were used to calculate overall survival and recurrence-free survival. Results: The median age of this cohort was 56 years, and 79 (81.4 %) of them were male. Eighty-eight (90.7 %) patients presented with tumor recurrence and 73 (75.3 %) died. In multivariate analyses, high-density lipoprotein cholesterol level (<0.91 vs. ≥ 0.91 mmol/L, hazard ratio [HR] = 2.55; 95 % CI: 1.38-4.71), lymph node metastasis (Yes vs. No, HR = 2.58; 95 % CI: 1.28-5.19), etiology factor (chronic HBV infection vs. others, HR = 0.5; 95 % CI: 0.28-0.88) and multiple tumor lesions (Yes vs. No, HR = 1.85; 95 % CI: 1.01-3.39) were independent predictors of overall survival. However, only high-density lipoprotein cholesterol level (HR = 1.86; 95 % CI: 1.19-2.92) emerged as the independent factor for recurrence-free survival. High-density lipoprotein cholesterol level (HR = 2.07; 95 % CI: 1.26-3.41), etiology factor (HR = 0.49; 95 % CI: 0.29-0.84), and multiple tumor lesions (HR = 2.00; 95 % CI: 1.14-3.51) were independent predictors of early recurrence. For patients who did not experience the spread of cancer to the lymph nodes, there was a significant correlation between the level of high-density lipoprotein cholesterol and their overall survival, recurrence-free survival, and early recurrence. For patients with low pre-operation high-density lipoprotein cholesterol levels, high post-operation high-density lipoprotein cholesterol levels were associated with better prognosis. Conclusions: Low serum high-density lipoprotein cholesterol level might serve as a sign of poor clinical outcomes (overall survival and recurrence-free survival) and early recurrence among intrahepatic cholangiocarcinoma patients. Strengthening the monitoring and intervention of intrahepatic cholangiocarcinoma patients with poor prognosis might be critical for improving the prognosis.

HAND2-AS1 Promotes Ferroptosis to Reverse Lenvatinib Resistance in Hepatocellular Carcinoma by TLR4/NOX2/DUOX2 Axis.

INTRODUCTION: Lenvatinib resistance causes less than 40% of the objective response rate. Therefore, it is urgent to explore new therapeutic targets to reverse the lenvatinib resistance for HCC. HAND2-AS1 is a critical tumor suppressor gene in various cancers. METHODS: Here, we investigated the role of HAND2-AS1 in the molecular mechanism of lenvatinib resistance in HCC. It was found that HAND2-AS1 was lowly expressed in the HepG2 lenvatinib resistance (HepG2-LR) cells and HCC tissues and associated with progression-free intervals via TCGA. Overexpression of HAND2-AS1 (OE-HAND2-AS1) decreased the IC50 of lenvatinib in HepG2-LR cells to reverse lenvatinib resistance. Moreover, OE-HAND2-AS1 induced intracellular concentrations of malondialdehyde (MDA) and lipid ROS and decreased the ratio of glutathione to glutathione disulfide (GSH/GSSG) to promote ferroptosis. RESULTS: A xenograft model in which nude mice were injected with OE-HAND2-AS1 HepG2-LR cells confirmed that OE-HAND2-AS1 could reverse lenvatinib resistance and decrease tumor formation in vivo. HAND2-AS1 promoted the expression of ferroptosis-related genes (TLR4, NOX2, and DUOX2) and promoted ferroptosis to reverse lenvatinib resistance by increasing TLR4/ NOX2/DUOX2 via competing endogenous miR-219a-1-3p in HCC cells. Besides, patients with a low HAND2-AS1 level had early recurrence after resection. CONCLUSION: These findings suggested that HAND2-AS1 may be a potential therapeutic target and an indicator of early recurrence for HCC.

High intratumoral metastasis-associated in colon cancer-1 expression predicts poor outcomes of cryoablation therapy for advanced hepatocellular carcinoma.

BACKGROUND: Cryoablation is one of the local therapies for hepatocellular carcinoma (HCC), but its safety and effect has not been studied in patients with Child class A or B and Barcelona Clinic Liver Cancer (BCLC) stage C HCC. Metastasis-associated in colon cancer-1 (MACC1) overexpression has been associated with poor prognosis of HCC, but its predictive value to post-cryoablation outcomes remains unknown in patients with BCLC stage C HCC. METHODS: This study assessed the safety and outcomes of cryoablation measured by time to progression (TTP) and overall survival (OS), and predictive value of MACC1 mRNA and protein overexpression in tumorous tissue to post-cryoablation outcomes in 120 advanced HCC patients with child-pugh class A or B by quantitative polymerase chain reaction and immunohistochemical staining. The potenial correlation of MACC1 and c-Met expression to tumor cell proliferation and apoptosis was also analyzed. RESULTS: The cryoablation in patients with advanced unresectable HCC resulted in a median TTP and OS of 5.5 (4.2- 6.7) months and 10.5 (9.0-12.0) months, respectively and no significant complications, comparable to the historical report for RFA therapy. The MACC1 mRNA and nuclear protein expression was significantly increased in tumorous tissues in these patients than that in normal liver tissue controls. Higher expression of MACC1 mRNA and nuclear protein in tumorous tissues in these patients was associated with shorter post cryoablation median TTP and OS than that with lower MACC1 expression. CONCLUSIONS: Cryoablation is a safe and effective therapeutic option for patients with advanced HCC and Child-pugh class A or B cirrhosis; and a higher intratumoral expression of MACC1 or nuclear translocation predicts poor outcomes of cryotherapy in these patients.

Age independent survival benefit for patients with small hepatocellular carcinoma undergoing percutaneous cryoablation: A propensity scores matching study.

Background: Hepatocellular carcinoma (HCC) is the major cause of malignancy-related deaths worldwide, and its incidence is likely to increase in the future as life expectancy increases. Therefore, the management of elderly patients with HCC has become a global issue. Aim of this study was to assess whether elderly patients with small HCC could obtain survival benefit from cryoablation (CRYO) in a real-world. Materials and methods: From July 2007 to June 2013, 185 patients with small HCC who underwent curative-intent percutaneous CRYO. All patients were divided into three groups according to age distribution. Overall survival (OS) and tumor-free survival (TFS) were compared between among of groups before and after the 1:1 propensity score matching, respectively. Univariate and multivariate Cox analyses were performed to determine the potential relationships between variables and prognostic outcomes. Results: One hundred and eighty-five patients (144 men, 41 women) received CRYO for small HCC, including 59 patients with age <50 years, 105 patients with age between 50 and 65 years, and 21 patients with age >65 years. The three age groups showed significant differences in the terms of underlying chronic liver disease and the number of patients with minor postoperative complications. After propensity score matching, the younger and elderly groups showed significant differences in mean OS (P=0.008) and tumor progression (P=0.050). However, no significant differences were shown in mean progression-free survival (PFS) (P=0.303). The Cox multivariate analysis showed that the Child-Pugh grade (HR=3.1, P<0.001), albumin (HR=0.85, P=0.004) and total of bilirubin (HR=1, P=0.024) were the independent prognostic factor for mean OS. Conclusion: Our propensity-score-matched study suggested that elderly patients with small HCC can achieve acceptable prognostic outcomes with PFS similar to those of younger patients with small HCC after treatment with CRYO, while Child-Pugh grade, bilirubin and serum albumin levels were associated with the prognosis of small HCCs.

Population Sensitive to Lenvatinib Plus Anti-PD-1 for Unresectable Hepatocellular Carcinoma Infected with Hepatitis B Virus.

Background: We explore the dose-efficacy relationship of lenvatinib plus anti-PD-1 in patients with unresectable hepatocellular carcinoma (u-HCC) infected with hepatitis B virus (HBV) in real-world practice. Furthermore, we identify the population sensitive to lenvatinib plus anti-PD-1 treatments. Methods: This retrospective study included 70 patients treated with lenvatinib plus at least 3 cycles of anti-PD-1 and 140 with lenvatinib alone. Stabilized inverse probability of treatment weighting (SIPTW) was used to balance clinical features between the two groups. The overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and adverse events (AEs) were analyzed. Subpopulation treatment effect pattern plot (STEPP) estimated treatment-effect differences between the two groups. Results: The median age was 54 years, and 189 (90%) cases were male. A total of 180 (85%) patients were infected with HBV. A slowly increasing 12-month survival rate was with the cycles of anti-PD-1, and 5 cycles and more of anti-PD-1 appeared the most beneficial and stable survival rate. The lenvatinib plus at least 3 cycles anti-PD-1 group had better OS (21.4 vs 14 months, p = 0.041), PFS (8.0 vs 6.3 months, p = 0.015) than the lenvatinib alone group in unadjusted cohorts, and the SIPTW adjusted cohorts had confirmed it. For patients with portal vein trunk invasion (PVTI) or extrahepatic spread (EHS) combined with Child-Pugh class B (CPB), lenvatinib plus anti-PD-1 made the 12-month survival rate increase by 38%, while, in the other population, it did only 18%. The two groups had similar AEs (p ≥ 0.05). Conclusion: The lenvatinib combined with at least 3 cycles of anti-PD-1 was efficacy and safe for u-HCC patients infected with HBV. Especially, patients with PVTI or EHS combined with CPB may benefit most from the combination therapy.

High-risk population of progressive hepatic fibrosis in chronic hepatitis B patients on antiviral therapy.

BACKGROUND: Progressive hepatic fibrosis leads to hepatocellular carcinoma (HCC) and decompensated cirrhosis. The aim of this study was to identify the high-risk population for progressive hepatic fibrosis and the incidence of HCC and decompensated cirrhosis in chronic hepatitis B (CHB) patients with antiviral therapy. METHODS: The data came from a multicenter, center-randomized, double-blind clinical trial that analyzed only patients in the ETV-treated arm. There was 156 hepatitis B e antigen (HBeAg)-positive and 135 HBeAg-negative patients in 14 institutions. The primary endpoint was fibrosis reversal on 72-week Entecavir (ETV) treatment. The 7-year cumulative incidence of HCC and decompensated cirrhosis were analyzed. Multivariate logistic and LASSO regression analyses were used to screen variables associated with fibrosis reversal. RESULTS: 86/156 (55%) HBeAg-positive and 58/135 (43%) HBeAg-negative patients achieved fibrosis reversal on 72-week ETV treatment. Average age was 43 years, 203 (69.8%) was male, and 144 (49.5%) patients had cirrhosis. Age ≥ 40 years (OR: 0.46, 95% CI 0.23-0.93) and HBcrAg ≥ 8.23 log U/ml (OR: 2.72, 95% CI 1.33-5.54) in HBeAg-positive patients and HBV genotype C (OR: 0.44, 95% CI 0.21-0.97) in HBeAg-negative patients were independent factors of fibrosis reversal. It was confirmed in patients with cirrhosis. After 7-year ETV treatment, seven (4.5%) HBeAg-positive patients occurred HCC or decompensated cirrhosis, including four patients with age ≥ 40 years and six with HBcrAg 8.23log U/ml, while twelve (8.9%) HBeAg-negative patients occurred, including eleven with HBV genotype C. CONCLUSIONS: HBeAg-positive patients with a low HBcrAg level or old age, and HBeAg-negative patients with HBV genotype C tended to develop progressive hepatic fibrosis and had a high incidence of HCC and decompensated cirrhosis, even on ETV treatment.