Background and Aims
Long‐term antiviral therapy can effectively suppress viral replication and improve clinical outcomes in patients with chronic hepatitis B (CHB), but it cannot eliminate risk of ...HCC. We investigated the association of metabolic risk factors with the risks of cancer and all‐cause mortality in patients with CHB.
Approach and Results
This nationwide population‐based study from the Korean National Health Insurance Service database consisted of adults with CHB who underwent health examinations from 2007 through 2012. We collected baseline data on metabolic risk factors, including obesity, high blood pressure, hypercholesterolemia, and diabetes. The risks of developing HCC, non‐HCC cancer, and overall death were analyzed according to the metabolic risk profile. The study population composed of 317,856 patients (median age, 46 years interquartile range, 37‐54 years; 219,418 men 69.0%) had 2,609,523.8 person‐years of follow‐up. A total of 18,850 HCCs, 22,164 non‐HCC cancers, and 15,768 deaths were observed during a median follow‐up period of 8.5 years. The metabolic risk factor burden was positively associated with the risks of HCC, non‐HCC cancer, and all‐cause mortality (all P < 0.0001 for trend). Patients with ≥3 metabolic risk factors, compared with those without metabolic risk factors, showed adjusted hazard ratios of 1.23 (95% CI, 1.16‐1.31) for HCC, 1.34 (95% CI, 1.27‐1.41) for non‐HCC cancer, and 1.31 (95% CI, 1.23‐1.39) for all‐cause mortality. Among patients receiving antiviral therapy for over 5 years, the risk‐increasing association of the sum of metabolic risk factors with the risks of HCC and overall death was consistent.
Conclusion
The metabolic risk factor burden was associated with increased risks of HCC, non‐HCC cancer, and all‐cause mortality in patients with CHB.
Background and Aims
Studies on differential effect of aspirin therapy on HCC risk across the spectrum of liver diseases are lacking. We investigated the association between aspirin use and risks of ...HCC, liver‐associated death, and major bleeding in chronic hepatitis B (CHB) patients with or without cirrhosis.
Approach and Results
We identified 329,635 eligible adults with CHB from 2007 through 2017, using the Korean National Health Insurance Service database, including patients who received aspirin for ≥90 consecutive days (n = 20,200) and patients who never received antiplatelet therapy (n = 309,435). Risks of HCC, liver‐associated mortality, and major bleeding were estimated in a propensity‐score–matched cohort (19,003 pairs), accounting for competing risks. With a median follow‐up of 6.7 years, 10‐year cumulative incidence of HCC was 9.5% in the aspirin‐treated group and 11.3% in the untreated group (adjusted subdistribution hazard ratio aSHR, 0.85; 95% CI, 0.78–0.92). However, among patients with cirrhosis (2479 pairs), an association of aspirin use with HCC risk was not evident (aSHR, 1.00; 95% CI, 0.85–1.18). Cirrhosis status had a significant effect on the association between aspirin use and HCC risk (pinteraction, n = 0.04). Aspirin use was also associated with lower liver‐associated mortality (aSHR, 0.80; 95% CI, 0.71–0.90). Moreover, aspirin use was not associated with major bleeding risk (aSHR, 1.09; 95% CI, 0.99–1.21).
Conclusions
Aspirin use was associated with reduced risks of HCC and liver‐associated mortality in adults with CHB. Cirrhosis status had a substantial effect on the association between aspirin use and HCC risk.
Background and Aims
ARC‐520, the first an RNA interference (RNAi) therapeutic, was designed to reduce all RNA transcripts derived from covalently closed circular DNA, leading to a reduction in viral ...antigens and hepatitis B virus (HBV) DNA.
Approach and Results
We aimed to evaluate the depth of hepatitis B surface antigen (HBsAg) decline in response to multiple doses of ARC‐520 compared to placebo (PBO) in two randomized, multicenter studies in nucleoside/nucleotide analogue reverse‐transcriptase inhibitor (NUC)–experienced patients with hepatitis B early antigen (HBeAg)–negative (E‐neg) or HBeAg‐positive (E‐pos) disease. A total of 58 E‐neg and 32 E‐pos patients were enrolled and received four monthly doses of PBO (n = 20 E‐neg, 11 E‐pos), 1 mg/kg ARC‐520 (n = 17 E‐neg, 10 E‐pos), or 2 mg/kg ARC‐520 (n = 21 E‐neg, 11 E‐pos) concomitantly with NUC. HBsAg change from baseline to 30 days after the last ARC‐520 dose were compared to PBO. Both E‐neg and E‐pos high‐dose groups significantly reduced HBsAg compared to PBO, with mean reductions of 0.38 and 0.54 log IU/mL, respectively. HBsAg reductions persisted for approximately 85 days and >85 days after the last dose in E‐neg and E‐pos patients, respectively. The low‐dose groups did not reach statistical significance in either study. E‐pos patients showed a dose‐dependent reduction in HBeAg from baseline. Mean maximum reduction was 0.23 and 0.69 log Paul Ehrlich IUs/mL in the low‐dose and high dose ARC‐520 groups respectively. ARC‐520 was well tolerated, with only two serious adverse events of pyrexia possibly related to study drug observed.
Conclusions
ARC‐520 was active in both E‐neg and E‐pos, NUC‐experienced HBV patients; but absolute HBsAg reductions were moderate, possibly due to expression of HBsAg from integrated HBV DNA, indicating the need for RNAi therapeutics that can target viral transcripts regardless of origin.
Bone marrow‐derived mesenchymal stem cell (BM‐MSC) transplantation has been suggested as an effective therapy for liver cirrhosis. The efficacy and safety of autologous BM‐MSC transplantation in the ...treatment of alcoholic cirrhosis were investigated. Seventy‐two patients with baseline biopsy‐proven alcoholic cirrhosis who had been alcohol‐abstinent for more than 6 months underwent a multicenter, randomized, open‐label, phase 2 trial. Patients were randomly assigned to three groups: one control group and two autologous BM‐MSC groups that underwent either one‐time or two‐time hepatic arterial injections of 5 × 107 BM‐MSCs 30 days after BM aspiration. A follow‐up biopsy was performed 6 months after enrollment, and adverse events were monitored for 12 months. The primary endpoint was improvement in fibrosis quantification based on picrosirius red staining. The secondary endpoints included liver function tests, Child‐Pugh score, and Model for End‐stage Liver Disease score. Outcomes were analyzed by per‐protocol analysis. In terms of fibrosis quantification (before versus after), the one‐time and two‐time BM‐MSC groups were associated with 25% (19.5 ± 9.5% versus 14.5 ± 7.1%) and 37% (21.1 ± 8.9% versus 13.2 ± 6.7%) reductions in the proportion of collagen, respectively (P < 0.001). In the intergroup comparison, two‐time BM‐MSC transplantation in comparison with one‐time BM‐MSC transplantation was not associated with improved results in fibrosis quantification (P > 0.05). The Child‐Pugh scores of both BM‐MSC groups (one‐time 7.6 ± 1.0 versus 6.3 ± 1.3 and two‐time 7.8 ± 1.2 versus 6.8 ± 1.6) were also significantly improved following BM‐MSC transplantation (P < 0.05). The proportion of patients with adverse events did not differ among the three groups. Conclusion: Autologous BM‐MSC transplantation safely improved histologic fibrosis and liver function in patients with alcoholic cirrhosis. (Hepatology 2016;64:2185‐2197)
Hepatocellular carcinoma harbors numerous genomic and epigenomic aberrations of DNA copy numbers and DNA methylation. Transcriptomic deregulation by these aberrations plays key driver roles in ...heterogeneous progression of cancers. Here, we profile DNA copy numbers, DNA methylation, and messenger RNA expression levels from 64 cases of hepatocellular carcinoma specimens. We find that the frequencies of the aberrancies of the DNA copy-number-correlated (CNVcor) expression genes and the methylation-correlated expression (METcor) genes are co-regulated significantly. Multi-omics integration of the CNVcor and METcor genes reveal three prognostic subtypes of hepatocellular carcinoma, which can be validated by an independent data. The most aggressive subtype expressing stemness genes has frequent BAP1 mutations, implying its pivotal role in the aggressive tumor progression. In conclusion, our integrative analysis of genomic and epigenomic regulation provides new insights on the multi-layered pathobiology of hepatocellular carcinoma, which might be helpful in developing precision management for hepatocellular carcinoma patients.Hepatocellular carcinoma is known to harbour numerous genomic and epigenomic aberrations, driving transcriptomic deregulation. Here, the authors integrate genomic, epigenomic, and expression data to reveal three prognostic subtypes, providing insight to the pathobiology of hepatocellular carcinoma.
Aptamers are small synthetic oligonucleotides that bind to target proteins with high specificity and affinity. AS1411 is an aptamer that binds to nucleolin, which is overexpressed in the cytoplasm ...and occurs on the surface of cancer cells. We investigated the therapeutic potential of aptamers in hepatocellular carcinoma (HCC) by evaluating anti-tumor effects and confirming the affinity and specificity of AS1411- and modified AS1411-aptamers in HCC cells. Cell growth was assessed using the MTS assay, and cell death signaling was explored by immunoblot analysis. Fluorescence-activated cell sorting was performed to evaluate the affinity and specificity of AS1411-aptamers in SNU-761 HCC cells. We investigated the in vivo effects of the AS1411-aptamer using BALB/c nude mice in a subcutaneous xenograft model with SNU-761 cells. Treatment with a modified AS1411-aptamer significantly decreased in vitro (under normoxic P = 0.035 and hypoxic P = 0.018 conditions) and in vivo (under normoxic conditions, P = 0.041) HCC cell proliferation compared to control aptamers. AS1411- and control aptamers failed to control HCC cell proliferation. However, AS1411- and the modified AS1411-aptamer did not induce caspase activation. Decrease in cell growth by AS1411 or modified AS1411 was not prevented by caspase or necrosis inhibitors. In a microarray, AS1411 significantly enhanced galectin-14 expression. Suppression of HCC cell proliferation by the modified AS1411-aptamer was attenuated by galectin-14 siRNA transfection. Modified AS1411-aptamer suppressed HCC cell growth in vitro and in vivo by up-regulating galectin-14 expressions. Modified AS1411-aptamers may have therapeutic potential as a novel targeted therapy for HCC.
Antiplatelet therapy has shown protective effects against hepatocellular carcinoma (HCC) in preclinical studies. However, it is unclear whether antiplatelet therapy lowers the risk of HCC in patients ...with chronic hepatitis B. A retrospective analysis was conducted of data from 1,674 chronic hepatitis B patients, enrolled between January 2002 and May 2015, whose serum hepatitis B virus DNA levels were suppressed by antivirals to <2,000 IU/mL. The primary and secondary outcomes were development of HCC and bleeding events, respectively. Risk was compared between patients with antiplatelet treatment (aspirin, clopidogrel, or both; antiplatelet group) and patients who were not treated (non‐antiplatelet group) using a time‐varying Cox proportional hazards model for total population and propensity score–matching analysis. The antiplatelet group included 558 patients, and the non‐antiplatelet group had 1,116 patients. During the study period, 63 patients (3.8%) developed HCC. In time‐varying Cox proportional analyses, the antiplatelet group showed a significantly lower risk of HCC (hazard ratio HR, 0.44; 95% confidence interval CI, 0.23–0.85; P = 0.01), regardless of antiplatelet agent. In propensity score–matched pairs, antiplatelet therapy significantly reduced the risk of HCC (HR, 0.34; 95% CI, 0.15‐0.77; P = 0.01). However, the overall risk of bleeding was higher in the antiplatelet group (HR, 3.28; 95% CI, 1.98‐5.42; P < 0.001), particularly for clopidogrel with or without aspirin. Treatment with aspirin alone was not associated with a higher bleeding risk (HR, 1.11; 95% CI, 0.48‐2.54; P = 0.81). Conclusion: Antiplatelet therapy reduces the risk of HCC in chronic hepatitis B patients whose hepatitis B virus is effectively suppressed. However, antiplatelet therapy containing clopidogrel may increase the risk of bleeding. (Hepatology 2017;66:1556–1569)
Background and Aim
This study aimed to investigate the clinical benefits of locoregional radiation therapy (RT) before, after, and concurrent with sorafenib therapy for Barcelona Clinic Liver Cancer ...(BCLC) stage C hepatocellular carcinoma (HCC) patients.
Methods
Patients treated with sorafenib for BCLC stage C HCC between January 2015 and December 2017 were retrospectively reviewed. In this study, only RT to locoregional sites, including the primary HCC, tumor thrombosis, or lymph node metastasis, was analyzed. Propensity score matching was used to adjust important baseline characteristics between groups.
Results
Among 398 patients treated with sorafenib, 68 (17.1%) patients were treated with locoregional RT. Median progression‐free survival and overall survival (OS) were 2.2 and 9.5 months, respectively. In the multivariate analysis, locoregional RT (P < 0.001) was associated with a favorable OS. After 1:1 propensity score matching, patients who did not receive locoregional RT showed a worse OS than those who received RT (median 9.6 vs 15.7 months, P = 0.017). Whereas locoregional RT before/concurrent with sorafenib did not result in prolonged OS, locoregional RT after sorafenib showed significantly prolonged OS compared with sorafenib without locoregional RT (P = 0.003). Moreover, patients treated with ≥ 12 weeks of sorafenib significantly benefited from locoregional RT (15.3 vs 23.6 months, P = 0.046).
Conclusion
Locoregional RT was associated with significantly longer survival in BCLC stage C HCC patients who were treated with sorafenib. Therefore, incorporating locoregional RT could improve the dismal prognosis for these patients.
Purpose
Microplastics have been widely reported to contaminate aquatic environments, particularly impacting marine organisms, but little is known of microplastic contamination of the soil ...environment. This study compared the distribution of microplastics in forest, urban, and agricultural soils, investigating the reasons for differences in abundance associated with land use.
Materials and methods
We analyzed distribution and abundance of microplastics in 100 soils, representing different land use types that include forest, urban (traffic and residence), and agriculture the environs of Yeoju City. Sampling plots were located on a systematic grid with 2.5 km × 2.5km spacing. Topsoil (0–5 cm) was collected with a hand auger and samples were pretreated by drying, density separation using ZnCl
2
solution, organic matter digestion, and decompression filtration. Abundance of microplastics was measured by counting using a digital stereo microscope; microplastics were grouped by shapes (fragment, film, fiber, and sphere) and color (black, red, green, blue, yellow, white, and transparent). Fourier-transform infrared spectroscopy (FT-IR) analysis was used to identify polymer type of the microplastics.
Results and discussion
Soils of Yeoju contained an average 700 pieces·kg
−1
of microplastics, but this greatly varied with land use types. Roadside soils had more microplastics (1108 pieces kg
−1
), mostly black styrene-butadiene rubber (SBR) fragments associated with tire dust. Unexpectedly, the largest amount of microplastics was detected not from urban soils but from an upland soil (3440 pieces kg
−1
). The mean abundance of microplastics in agricultural soil was 664 pieces kg
−1
, varying with farming types; the highest abundance was at orchard sites, followed by upland, greenhouse, and then paddy field sites. Polyethylene (PE) and polypropylene (PP) were identified from microplastics sampled at upland, greenhouse, and orchard sites, while SBR-derived microplastics were found more widely in all farmland soils, implicating that mulching film usage and farm machinery.
Conclusions
Soil microplastic contamination is significant and widespread in urban and agricultural soils of Yeoju, but differs in form and distribution, according to the locality of traffic and farming. Atmospheric fallout to forest soils is quantified and found to be significantly impacted by microplastics. The use of mulching film as a source of PE and PP presents particular concern in terms of the effects of microplastic contamination on soil quality, health, and functionality in agroecosystems.
Background & Aims The aim of this study was to characterize the relationship between the broad spectrum of hypothyroidism and NAFLD. Methods A cross-sectional study with 4648 health check-up subjects ...(2324 cases with hypothyroidism vs. age- and sex-matched controls) was conducted. The subjects were categorized as having either subclinical thyroid-stimulating hormone (TSH) ⩾4.1 mIU/L and normal free thyroixine (T4 ) level (0.7–1.8 ng/dl) or overt hypothyroidism free T4 <0.7 ng/dl. NAFLD was diagnosed on the basis of typical ultrasonographic findings, and alcohol consumption of less than 20 g/day in the absence of other causes of liver disease. Results The mean age of the subjects was 48.6 ± 11.8 years and 62.4% were female. NAFLD was significantly associated with hypothyroidism (30.2% patients vs. 19.5% control, p <0.001). The prevalence of NAFLD and abnormal liver enzyme levels (ALT >33/25 IU/L) increased steadily with increasing grades of hypothyroidism (for NAFLD, subclinical: 29.9% and overt: 36.3%; for abnormal ALT, 20.1% and 25.9%, p <0.001, respectively). Multivariate regression analysis showed that NAFLD was statistically significantly associated with hypothyroidism (odds ratio (OR) 1.38, 95% confidence interval (CI), 1.17–1.62) and the grade of hypothyroidism in a dose-dependent manner (OR 1.36, 95% CI, 1.16–1.61 in subclinical hypothyroidism and OR 1.71, 95% CI, 1.10–2.66 in overt hypothyroidism). Conclusions Subclinical hypothyroidism, even in the range of upper normal TSH levels, was found to be related to NAFLD in a dose-dependent manner. Hypothyroidism is closely associated with NAFLD independently of known metabolic risk factors, confirming a relevant clinical relationship between these two diseases.
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