A recurrence of hepatocellular carcinoma (HCC) after living donor liver transplantation (LDLT) is one of the major concerns reflecting the higher mortality of HCC. This study aimed to explore the ...impact of circulating exosomes on HCC development and recurrence. One‐shot transfusion of hepatoma serum to naïve rats induced liver cancer development with gradual elevation of alpha‐fetoprotein (AFP), but exosome‐free hepatoma serum failed to induce AFP elevation. The microarray analysis revealed miR‐92b as one of the highly expressing microribonucleic acids in hepatoma serum exosomes. Overexpression of miR‐92b enhanced the migration ability of liver cancer cell lines with active release of exosomal miR‐92b. The hepatoma‐derived exosomal miR‐92b transferred to natural killer (NK) cells, resulting in the downregulation of CD69 and NK cell‐mediated cytotoxicity. Furthermore, higher expression of miR‐92b in serum exosomes was confirmed in HCC patients before LDLT, and its value at 1 month after LDLT was maintained at a higher level in the patients with posttransplant HCC recurrence. In summary, we demonstrated the impact of circulating exosomes on liver cancer development, partly through the suppression of CD69 on NK cells by hepatoma‐derived exosomal miR‐92b. The value of circulating exosomal miR‐92b may predict the risk of posttransplant HCC recurrence.
This study demonstrates the impact of circulating exosomes on liver cancer development in rats, explores functional roles of exosomal miR‐92b in the tumor microenvironment, and verifies its clinical value for early prediction of posttransplant hepatocellular carcinoma recurrence.
Summary
Background
Globally, chronic hepatitis B (CHB) is a major public health concern. Timely and effective management can prevent disease progression to cirrhosis and reduce the risk of ...hepatocellular carcinoma (HCC). Currently, there is no consensus on the clinical management of CHB in East Asia.
Aim
To establish an East Asia expert opinion on treatment initiation for CHB based on alanine aminotransferase (ALT) level, hepatitis B virus (HBV) deoxyribonucleic acid (DNA) level, cirrhosis and HCC risk scores.
Methods
A meeting was held online with a panel of 10 experts from East Asia to discuss ALT, HBV DNA, cirrhosis and HCC risk scores. Indications for CHB treatment in the latest international guidelines were reviewed. Consensus was summarised to provide recommendations on the initiation of treatment for CHB.
Results
Anti‐viral therapy is recommended for CHB patients with (a) HBV DNA ≥ 2000 IU/mL and ALT ≥ 1× upper limit of normal (ULN); (b) HBV DNA ≥ 2000 IU/mL, ALT < 1× ULN and ≥ F2 fibrosis and/or ≥ A2 necroinflammation occurs; (c) cirrhosis and detectable HBV DNA; or (d) HBV DNA ≥ 2000 IU/mL, ALT < 1× ULN and a family history of cirrhosis or HCC, extrahepatic manifestations or age > 40 years. Patients with cirrhosis and/or HCC should be treated regardless of ALT levels if HBV DNA level is detectable. Initiating anti‐viral therapy or close monitoring at 3‐month intervals is recommended for CHB patients with at least two HCC risk factors.
Conclusions
These expert recommendations will contribute to a new standard of daily clinical practice in East Asia.
Summary
Background
Entecavir (ETV) and tenofovir disoproxil fumarate (TDF) are first‐line long‐term monotherapy for treatment of chronic hepatitis B (CHB) infection. High virological relapse rates ...are found after cessation of either ETV or TDF in CHB patients.
Aim
To compare hepatitis B virus (HBV) relapse rates in CHB patients without cirrhosis who discontinued ETV or TDF.
Methods
A retrospective‐prospective study was conducted in 342 CHB patients (108 hepatitis B e antigen (HBeAg)‐positive and 234 HBeAg‐negative) who received ETV and 165 (46 HBeAg‐positive, 119 HBeAg‐negative) who received TDF were recruited. All patients had post‐treatment follow‐up for at least 6 months. All fulfilled the stopping criteria of the Asia‐Pacific Association for the Study of the Liver of 2012.
Results
Patients who discontinued TDF had significantly higher rates and earlier times of virological and clinical relapse than those who discontinued ETV. This was also seen in propensity score (PS)‐matched HBeAg‐positive and HBeAg‐negative patients. Multivariate analysis showed that being in the TDF group was an independent factor for virological and clinical relapse in all patients and PS‐matched HBeAg‐positive and HBeAg‐negative patients. The rate of off‐therapy HBsAg loss was comparable between the ETV and TDF groups after 2‐3 years follow‐up. Clinical relapse tended to be more severe in the TDF group compared with the ETV group.
Conclusion
HBV relapse occurs sooner and is more severe after cessation of TDF than after cessation of ETV.
Recent progress in TGF-β inhibitors for cancer therapy Huang, Cheng-Yi; Chung, Chih-Ling; Hu, Tsung-Hui ...
Biomedicine & pharmacotherapy,
February 2021, 2021-Feb, 2021-02-00, 20210201, 2021-02-01, Volume:
134
Journal Article
Peer reviewed
Open access
Display omitted
•Summary of the basic studies, patents, and clinical trials inhibiting TGF-β signalling, a critical pathway in tumorigenesis and fibrosis.•Small molecular inhibitors and neutralizing ...antibodies against TGF-β signaling are potential strategies for cancer therapy.•Natural products and repurposed drugs should continue to be major resources for screening TGF-β inhibitors.•The future prospect of new sources and mechanisms of TGF-β inhibitors are discussed in this review.
Transforming growth factor-β (TGF-β) is a multifunctional cytokine that is involved in proliferation, metastasis, and many other important processes in malignancy. Inhibitors targeting TGF-β have been considered by pharmaceutical companies for cancer therapy, and some of them are in clinical trial now. Unfortunately, several of these programs have recently been relinquished, and most companies that remain in the contest are progressing slowly and cautiously. This review summarizes the TGF-β signal transduction pathway, its roles in oncogenesis and fibrotic diseases, and advancements in antibodies and small-molecule inhibitors of TGF-β.
Background and Aims
RO7062931 is an N‐acetylgalactosamine (GalNAc)‐conjugated single‐stranded locked nucleic acid oligonucleotide complementary to HBV RNA. GalNAc conjugation targets the liver ...through the asialoglycoprotein receptor (ASGPR). This two‐part phase 1 study evaluated the safety, pharmacokinetics, and pharmacodynamics of RO7062931 in healthy volunteers and patients with chronic hepatitis B (CHB) who were virologically suppressed.
Approach and Results
Part 1 was a single ascending dose study in healthy volunteers randomized to receive a single RO7062931 dose (0.1‐4.0 mg/kg), or placebo. Part 2 was a multiple ascending dose study in patients with CHB randomized to receive RO7062931 at 0.5, 1.5, or 3.0 mg/kg or placebo every month for a total of 2 doses (Part 2a) or RO7062931 at 3.0 mg/kg every 2 weeks, 3.0 mg/kg every week (QW), or 4.0 mg/kg QW or placebo for a total of 3‐5 doses (Part 2b). Sixty healthy volunteers and 59 patients received RO7062931 or placebo. The majority of adverse events (AEs) reported were mild in intensity. Common AEs included self‐limiting injection site reactions and influenza‐like illness. Supradose‐proportional increases in RO7062931 plasma exposure and urinary excretion occurred at doses ≥3.0 mg/kg. In patients with CHB, RO7062931 resulted in dose‐dependent and time‐dependent reduction in HBsAg versus placebo. The greatest HBsAg declines from baseline were achieved with the 3.0 mg/kg QW dose regimen (mean nadir ~0.5 log10 IU/mL) independent of HBeAg status.
Conclusions
RO7062931 is safe and well tolerated at doses up to 4.0 mg/kg QW. Supradose‐proportional exposure at doses of 3.0‐4.0 mg/kg was indicative of partial saturation of the ASGPR‐mediated liver uptake system. Dose‐dependent declines in HBsAg demonstrated target engagement with RO7062931.
Summary
Background/Aims
To compare the rates of hepatitis B surface antigen (HBsAg) loss after discontinuation of entecavir versus tenofovir disoproxil fumarate (TDF) in patients with chronic ...hepatitis B (CHB) without cirrhosis.
Methods
A total of 891 patients who received entecavir (n = 556) or TDF (n = 335) followed up post‐treatment for at least 12 months were retrospectively assessed. A total of 677 patients who had continued entecavir or TDF therapy for at least 4 years were enrolled as the continued group.
Results
Patients who discontinued TDF had higher rates of virological and clinical relapse and retreatment than patients who discontinued entecavir in both the HBeAg‐positive and HBeAg‐negative subgroups. In the entire discontinued cohort, the cumulative rates of HBsAg loss at 7 years were 22.6% and 35.4% in the entecavir and TDF groups respectively. Patients who discontinued TDF had significantly higher rates of HBsAg loss than patients who discontinued entecavir therapy in all (p = 0.019) and propensity score‐matched (p = 0.015) patients, especially among the subgroups who achieved a sustained response (p < 0.001). Cox regression analysis revealed that TDF, longer treatment duration and lower HBsAg levels at end of treatment were independently associated with HBsAg loss in the entire discontinued group. The incidence of HBsAg loss was significantly higher in the discontinued group than in the continued group after propensity score matching (p < 0.001), including HBeAg‐positive and HBeAg‐negative patients.
Conclusions
Patients who discontinued TDF had significantly higher rates of HBsAg loss than patients who discontinued entecavir, especially among the subgroups without HBV relapse after cessation of therapy.
Comparision of HBsAg loss rates between patients who discontined entecavir and TDF therapy after PSM.
Summary
Background
Comparative long‐term efficacy of entecavir (ETV) and tenofovir disoproxil fumarate (TDF) for prevention of disease progression to hepatocellular carcinoma (HCC) among high‐risk ...patients with chronic hepatitis B (CHB)‐related compensated cirrhosis is controversial.
Aims
To compare the long‐term efficacy of ETV and TDF in HCC prevention in patients with CHB‐related cirrhosis, and to evaluate predictive risk factors for HCC development.
Methods
From January 2008 to March 2018, 894 treatment‐naïve patients with CHB‐related compensated cirrhosis on ETV or TDF were enrolled based on the longitudinal cohort study. Data were originally collected for 7.3 years of follow‐up or after the launch of TDF in 2011. Only the 5‐year cumulative incidence and risk factors of HCC were assessed.
Result
Total 678 and 216 patients received ETV and TDF, respectively. The cumulative risk of HCC at 1, 3 and 5 years of follow‐up was 1.6%, 11.3% and 18.7%, respectively, in the ETV group; and 0.9%, 6.7% and 10.7%, respectively, in the TDF group (P = 0.0305). Univariate and adjusted‐multivariable models revealed that platelet count, alpha‐fetoprotein (AFP) levels and upper gastrointestinal (UGI) varices were independent risk factors for HCC development. TDF resulted in risk of HCC development compared to ETV with adjusted hazard ratios (aHRs) of 0.66 (95% confidence interval CI:0.40, 1.08; P = 0.0971), 0.69 (95% CI: 0.42, 1.14; P = 0.1488) and 0.66 (95% CI: 0.38, 1.14; P = 0.1407) under stepwise selection, propensity score adjustment, and propensity score matching multivariable models, respectively.
Conclusions
For treatment‐naïve patients with CHB‐related compensated cirrhosis with 5‐year follow‐up, after variable adjustments, propensity score approaches and subgroup analyses, TDF showed a lower rate of HCC development that did not reach statistical significance, compared to the ETV.
Brivanib is a dual inhibitor of vascular-endothelial growth factor and fibroblast growth factor receptors that are implicated in the pathogenesis of hepatocellular carcinoma (HCC). Our multinational, ...randomized, double-blind, phase III trial compared brivanib with sorafenib as first-line treatment for HCC.
Advanced HCC patients who had no prior systemic therapy were randomly assigned (ratio, 1:1) to receive sorafenib 400 mg twice daily orally (n = 578) or brivanib 800 mg once daily orally (n = 577). Primary end point was overall survival (OS). Secondary end points included time to progression (TTP), objective response rate (ORR), disease control rate (DCR) based on modified Response Evaluation Criteria in Solid Tumors (mRECIST), and safety.
The primary end point of OS noninferiority for brivanib versus sorafenib in the per-protocol population (n = 1,150) was not met (hazard ratio HR, 1.06; 95.8% CI, 0.93 to 1.22), based on the prespecified margin (upper CI limit for HR ≤ 1.08). Median OS was 9.9 months for sorafenib and 9.5 months for brivanib. TTP, ORR, and DCR were similar between the study arms. Most frequent grade 3/4 adverse events for sorafenib and brivanib were hyponatremia (9% and 23%, respectively), AST elevation (17% and 14%), fatigue (7% and 15%), hand-foot-skin reaction (15% and 2%), and hypertension (5% and 13%). Discontinuation as a result of adverse events was 33% for sorafenib and 43% for brivanib; rates for dose reduction were 50% and 49%, respectively.
Our study did not meet its primary end point of OS noninferiority for brivanib versus sorafenib. However, both agents had similar antitumor activity, based on secondary efficacy end points. Brivanib had an acceptable safety profile, but was less well-tolerated than sorafenib.
Changes in TCA cycle enzymes or respiratory activity are possible mechanisms of aerobic glycolysis that contributes to tumor progression. To clarify whether the decrease of succinate dehydrogenase B ...(SDHB) alters energy metabolism, induces the Warburg effect and results in tumor malignancy, SDHB expression was examined and modulated in hepatocellular carcinoma (HCC) tissues and cells, respectively. SDHB level was often decreased in malignant HCC cells and tissues. Furthermore, the reduced SDHB expression was associated with advanced tumor stage and poor survival rate. Moreover, silencing of SDHB altered energy metabolism switched from aerobic respiration to glycolysis, resulted in the Warburg effect, and enhanced cell proliferation and motility. In contrast, the SDHB overexpression deregulated bioenergetic metabolism and decreased cell growth and migration. In mouse xenograft models, subcutaneous implantation and tail vein injection with SDHB knockdown cells resulted in a larger tumor volume and accelerated cancer metastasis, respectively. A mutation or decrease in SDHB induced the switch from aerobic respiration to glycolysis. This metabolic alteration was associated with tumor cell dedifferentiation, proliferation, motility and overall patient survival in HCC.
This study investigated the ability of hepatitis B core‐related antigen (HBcrAg) to predict hepatitis B virus (HBV) relapse in HBeAg‐negative patients after cessation of entecavir therapy. A total of ...301 HBeAg‐negative patients without cirrhosis who had stopped entecavir therapy for at least 12 months were recruited. All patients fulfilled the stopping criteria proposed by the APASL 2012 guidelines. The five‐year cumulative rates of virological relapse, clinical relapse and HBsAg loss were 71.6%, 57.3% and 18.7%, respectively. Serum HBsAg at end of treatment (EOT) was an independent predictor of virological relapse, clinical relapse and HBsAg loss; an EOT HBsAg of 150 IU/ml was the optimal cut‐off value. The 5‐year virological relapse rates for patients with <150 and ≥150 IU/ml HBsAg at EOT were 43.3% and 82.2% (p < 0.001), clinical relapse rates were 32.3% and 66.3% (p < 0.001), and HBsAg loss rates were 46.1% and 5.2% (p < 0.001), respectively. A baseline HBcrAg of 4 IU/ml was the optimal cut‐off value for predicting HBV relapse. Among patients with an EOT HBsAg <150 IU/ml, the five‐year virological relapse rates for patients with baseline HBcrAg levels ≤4 and >4 log U/ml were 27.9% and 59.1% (p = 0.006) and the clinical relapse rates were 18% and 48.1% (p = 0.014), respectively. EOT HBcrAg was not a significant predictor of virological or clinical relapse after cessation of entecavir. In conclusion, the combination of an EOT HBsAg of 150 IU/ml and baseline HBcrAg of 4 log U/ml can effectively predict the risk of HBV relapse after stopping entecavir therapy.
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