We examined the global incidence and mortality rates of liver cancer, and evaluated the association between incidence/mortality and socioeconomic development (Human Development Index HDI and Gross ...Domestic Product GDP) using linear regression analysis. The average annual percent change (AAPC) of the trends was evaluated from join-point regression analysis. The global incidence of liver cancer varied widely by nine-fold, and was negatively correlated with HDI (men: r = -0.232, p = 0.003; women: r = -0.369, p < 0.001) and GDP per capita (men: r = -0.164, p = 0.036; women: r = -0.212, p = 0.007). Its mortality showed a similarly negative correlation with both indices. The greatest incidence rise in men was observed in Poland (AAPC = 17.5, 95% C.I. = 5.6, 30.9) and Brazil (AAPC = 13.2, 95% C.I. = 5.9, 21.0), whereas Germany (AAPC = 6.6, 95% C.I = 2.0, 11.5) and Norway (AAPC = 6.5, 95% C.I. = 3.2, 10.0) had the greatest increase in women. The mortality rates paralleled the incidence rates in most countries. For mortality, Malta (AAPC = 11.5, 95% C.I. = 3.9, 19.8), Australia (AAPC = 6.8, 95% C.I. = 2.2, 11.5) and Norway (APCC = 5.6, 95% C.I. = 2.8, 8.5) reported the biggest increase among men; whilst Australia (AAPC = 13.4, 95% C.I. = 7.8, 19.4) and Singapore (AAPC = 7.7, 95% C.I. = 4.1, 11.5) showed the most prominent rise among women. These epidemiological data identified countries with potentially increasing trends of liver cancer for preventive actions.
Background
Approximately one-quarter of patients with Barcelona Clinic Liver Cancer (BCLC) stage 0/A hepatocellular carcinoma (HCC) suffer from tumor relapse within the first year after surgical ...resection. Little data is available for inflammatory indices, including neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and prognostic nutritional index (PNI), in predicting the clinical outcome of patients with very early/early stage HCC who underwent curative surgery.
Methods
A retrospective cohort study of 324 patients with BCLC stage 0/A primary HCC undergoing surgical resection was conducted to investigate the prognostic impacts of NLR, PLR, and PNI.
Results
The low-PNI group (<45) had an adverse overall survival (1-year survival rate of 92 vs. 97 %; 5-year survival rate of 57 vs. 82 %;
p
< 0.001) and disease-free survival (1-year survival rate of 69 vs. 85 %; 5-year survival rate of 39 vs. 63 %;
p
< 0.001). It was an independent predictor for disease-specific death, and early and late tumor relapses, with hazard ratios of 2.78 (
p
< 0.001), 1.82 (
p
= 0.011), and 2.55 (
p
= 0.013), respectively. Neither NLR nor PLR had any prognostic significance.
Conclusions
The PNI is a significant prognostic factor for OS and DFS of patients with very early/early stage HCC receiving curative surgery.
Significance We used massively parallel sequencing to study the size profiles of plasma DNA samples at single-base resolution and in a genome-wide manner. We used chromosome arm-level z -score ...analysis (CAZA) to identify tumor-derived plasma DNA for studying their specific size profiles. We showed that populations of aberrantly short and long DNA molecules existed in the plasma of patients with hepatocellular carcinoma. The short ones preferentially carried the tumor-associated copy number aberrations. We further showed that there were elevated amounts of mitochondrial DNA in the plasma of hepatocellular carcinoma patients. Such molecules were much shorter than the nuclear DNA in plasma. These findings have shed light on fundamental biological characteristics of plasma DNA and related diagnostic applications for cancer.
The analysis of tumor-derived circulating cell-free DNA opens up new possibilities for performing liquid biopsies for the assessment of solid tumors. Although its clinical potential has been increasingly recognized, many aspects of the biological characteristics of tumor-derived cell-free DNA remain unclear. With respect to the size profile of such plasma DNA molecules, a number of studies reported the finding of increased integrity of tumor-derived plasma DNA, whereas others found evidence to suggest that plasma DNA molecules released by tumors might be shorter. Here, we performed a detailed analysis of the size profiles of plasma DNA in 90 patients with hepatocellular carcinoma, 67 with chronic hepatitis B, 36 with hepatitis B-associated cirrhosis, and 32 healthy controls. We used massively parallel sequencing to achieve plasma DNA size measurement at single-base resolution and in a genome-wide manner. Tumor-derived plasma DNA molecules were further identified with the use of chromosome arm-level z -score analysis (CAZA), which facilitated the studying of their specific size profiles. We showed that populations of aberrantly short and long DNA molecules existed in the plasma of patients with hepatocellular carcinoma. The short ones preferentially carried the tumor-associated copy number aberrations. We further showed that there were elevated amounts of plasma mitochondrial DNA in the plasma of hepatocellular carcinoma patients. Such molecules were much shorter than the nuclear DNA in plasma. These results have improved our understanding of the size profile of tumor-derived circulating cell-free DNA and might further enhance our ability to use plasma DNA as a molecular diagnostic tool.
Summary
Background
Non‐alcoholic fatty liver disease (NAFLD) and non‐alcoholic steatohepatitis (NASH) account for an increasing proportion of liver disease in the Asia‐Pacific region. Many areas in ...the region are experiencing epidemics of metabolic syndrome among rapidly ageing populations.
Aims
To estimate using modelling the growth in NAFLD populations, including cases with significant fibrosis that are most likely to experience advanced liver disease and related mortality.
Methods
A disease progression model was used to summarise and project fibrosis progression among the NAFLD populations of Hong Kong, Singapore, South Korea and Taiwan. For each area, changes in the adult prevalence of obesity was used to extrapolate long‐term trends in NAFLD incidence.
Results
In the areas studied, prevalent NAFLD cases were projected to increase 6%‐20% during 2019‐2030, while prevalent NASH cases increase 20%‐35%. Incident cases of hepatocellular carcinoma are projected to increase by 65%‐85%, while incident decompensated cirrhosis cases increase 65%‐100% by 2030. Likewise, NAFLD‐related mortality is projected to increase between 65% and 100% from 2019 to 2030. NAFLD disease burden is expected to increase alongside rising trends in metabolic syndrome and obesity among populations in the region. This leads to more cases of advanced liver disease and associated mortality.
Conclusions
Preventing the growth of diabetic and obese populations will be a key factor in reducing ongoing increases in NAFLD‐related disease burden in the Asia‐Pacific region.
Summary Background Present guidelines are conflicting for patients at high risk of both cardiovascular and gastrointestinal events who continue to require non-steroidal anti-inflammatory drugs ...(NSAIDs). We hypothesised that a cyclooxygenase-2-selective NSAID plus proton-pump inhibitor is superior to a non-selective NSAID plus proton-pump inhibitor for prevention of recurrent ulcer bleeding in concomitant users of aspirin with previous ulcer bleeding. Methods For this industry-independent, double-blind, double-dummy, randomised trial done in one academic hospital in Hong Kong, we screened patients with arthritis and cardiothrombotic diseases who were presenting with upper gastrointestinal bleeding, were on NSAIDs, and require concomitant aspirin. After ulcer healing, an independent staff member randomly assigned (1:1) patients who were negative for Helicobacter pylori with a computer-generated list of random numbers to receive oral administrations of either celecoxib 100 mg twice per day plus esomeprazole 20 mg once per day or naproxen 500 mg twice per day plus esomeprazole 20 mg once per day for 18 months. All patients resumed aspirin 80 mg once per day. Both patients and investigators were masked to their treatments. The primary endpoint was recurrent upper gastrointestinal bleeding within 18 months. The primary endpoint and secondary safety endpoints were analysed in the modified intention-to-treat population. This study was registered with ClinicalTrials.gov , number NCT00153660. Findings Between May 24, 2005, and Nov 28, 2012, we enrolled 514 patients, assigning 257 patients to each study group, all of whom were included in the intention-to-treat population. Recurrent upper gastrointestinal bleeding occurred in 14 patients in the celecoxib group (nine gastric ulcers and five duodenal ulcers) and 31 patients in the naproxen group (25 gastric ulcers, three duodenal ulcers, one gastric ulcer and duodenal ulcer, and two bleeding erosions). The cumulative incidence of recurrent bleeding in 18 months was 5·6% (95% CI 3·3–9·2) in the celecoxib group and 12·3% (8·8–17·1) in the naproxen group (p=0·008; crude hazard ratio 0·44, 95% CI 0·23–0·82; p=0·010). Excluding patients who reached study endpoints, 21 (8%) patients in the celecoxib group and 17 (7%) patients in the naproxen group had adverse events leading to discontinuation of treatment. No treatment-related deaths occurred during the study. Interpretation In patients at high risk of both cardiovascular and gastrointestinal events who require concomitant aspirin and NSAID, celecoxib plus proton-pump inhibitor is the preferred treatment to reduce the risk of recurrent upper gastrointestinal bleeding. Naproxen should be avoided despite its perceived cardiovascular safety. Funding The Research Grant Council of Hong Kong.
The growing epidemic of obesity, which causes nonalcoholic fatty liver disease (NAFLD) and the more severe phenotype nonalcoholic steatohepatitis (NASH), has paralleled the increasing incidence of ...hepatocellular carcinoma (HCC). Accumulating evidence demonstrates that overnutrition and metabolic pathways can trigger modifications of DNA and histones via deregulation of chromatin modifiers, resulting in aberrant transcriptional activity. However, the epigenetic regulation of HCC development in NAFLD remains obscure. Here, we uncover key epigenetic regulators using both dietary and genetic obesity-promoted HCC models through quantitative expression profiling and characterize the oncogenic activities of histone deacetylase HDAC8 in NAFLD-associated hepatocarcinogenesis. HDAC8 is directly upregulated by the lipogenic transcription factor SREBP-1 where they are coexpressed in dietary obesity models of NASH and HCC. Lentiviral-mediated HDAC8 attenuation in vivo reversed insulin resistance and reduced NAFLD-associated tumorigenicity. HDAC8 modulation by genetic and pharmacologic approaches inhibited p53/p21-mediated apoptosis and G2-M phase cell-cycle arrest and stimulated β-catenin-dependent cell proliferation. Mechanistically, HDAC8 physically interacted with the chromatin modifier EZH2 to concordantly repress Wnt antagonists via histone H4 deacetylation and H3 lysine 27 trimethylation. In human NAFLD-associated HCC, levels of SREBP-1, HDAC8, EZH2, H4 deacetylation, H3K27me3, and active β-catenin were all correlated positively in tumors compared with nontumor tissues. Overall, our findings show how HDAC8 drives NAFLD-associated hepatocarcinogenesis, offering a novel epigenetic target to prevent or treat HCC in obese patients.
Background & Aims Liver biopsy is the gold standard for diagnosing non-alcoholic fatty liver disease (NAFLD) but with practical constraints. Phosphorus magnetic resonance spectroscopy (31 P-MRS) ...allows in vivo assessment of hepatocellular metabolism and has shown potential for biochemical differentiation in diffuse liver disease. Our aims were to describe spectroscopic signatures in biopsy-proven NAFLD and to determine diagnostic performance of31 P-MRS for non-alcoholic steatohepatitis (NASH). Methods31 P-MRS was performed in 151 subjects, comprised of healthy controls (n = 19) and NAFLD patients with non-NASH (n = 37) and NASH (n = 95). Signal intensity ratios for phosphomonoesters (PME) including phosphoethanolamine (PE), phosphodiesters (PDE) including glycerophosphocholine (GPC), total nucleotide triphosphate (NTP) including α-NTP, and inorganic phosphate (Pi), expressed relative to total phosphate (TP) or PME+PDE and converted to percentage, were obtained. Results Compared to controls, both NAFLD groups had increased PDE/TP ( p <0.001) and decreased Pi/TP ( p = 0.011). Non-NASH patients showed decreased PE/PME+PDE ( p = 0.048), increased GPC/PME+PDE ( p <0.001), and normal NTP/TP and α-NTP/TP. Whereas, NASH patients had normal PE/PME+PDE and GPC/PME+PDE, but decreased NTP/TP ( p = 0.004) and α-NTP/TP ( p <0.001). The latter was significantly different between non-NASH and NASH ( p = 0.047) and selected as discriminating parameter, with area under the receiver-operating characteristics curve of 0.71 (95% confidence interval, 0.62–0.79). An α-NTP/TP cutoff of 16.36% gave 91% sensitivity and cutoff of 10.57% gave 91% specificity for NASH. Conclusions31 P-MRS shows distinct biochemical changes in different NAFLD states, and has fair diagnostic accuracy for NASH.
Background & Aims
How adiposity influences the effect of genetic variants on non‐alcoholic fatty liver disease (NAFLD) in the Asian population remains unclear. We aimed to study the association ...between genetic risk variants and susceptibility/severity of NAFLD in the lean, overweight and obese individuals.
Methods
Nine hundred and four community subjects underwent proton‐magnetic resonance spectroscopy and transient elastography examination. Lean (<23 kg/m2), overweight (23‐24.9 kg/m2) and obesity (≥25 kg/m2) were defined according to the body mass index cut‐offs for Asians. NAFLD was defined as intrahepatic triglycerides ≥5%. PNPLA3, TM6SF2, MBOAT7 and 9 other gene polymorphisms were analysed by rhAMPTM SNP assays.
Results
Five hundred and twenty‐nine (58.5%), 162 (17.9%) and 213 (23.6%) subjects were lean, overweight and obese, respectively. The prevalence of NAFLD was 12.4%, 41.4% and 59.1% in the three groups (P < .001). Amongst those with NAFLD, lean subjects (30.3%) were more likely to carry the PNPLA3 rs738409 GG genotype than overweight (17.9%) and obese subjects (17.4%) (P = .003). Compared with the CC genotype, the GG genotype was associated with the greatest increase in the risk of NAFLD in lean subjects (odds ratio OR 6.04), compared with overweight (OR 3.43, 95% CI 1.06, 11.14) and obese subjects (OR 2.51, 95% CI 0.93, 6.78). Additionally, the TM6SF2 rs58542926 TT genotype was associated with reduced serum triglycerides only in lean subjects. A gene‐BMI effect was not observed for the other gene polymorphisms.
Conclusions
The PNPLA3 rs738409 gene polymorphism has a greater effect on liver fat in Asian lean individuals than in overweight or obese ones.
Obesity increases the risk of hepatocellular carcinoma (HCC) especially in men, but the molecular mechanism remains obscure. Here, we show that an androgen receptor (AR)-driven oncogene, cell ...cycle-related kinase (CCRK), collaborates with obesity-induced pro-inflammatory signaling to promote non-alcoholic steatohepatitis (NASH)-related hepatocarcinogenesis. Lentivirus-mediated Ccrk ablation in liver of male mice fed with high-fat high-carbohydrate diet abrogates not only obesity-associated lipid accumulation, glucose intolerance and insulin resistance, but also HCC development. Mechanistically, CCRK fuels a feedforward loop by inducing STAT3-AR promoter co-occupancy and transcriptional up-regulation, which in turn activates mTORC1/4E-BP1/S6K/SREBP1 cascades via GSK3β phosphorylation. Moreover, hepatic CCRK induction in transgenic mice stimulates mTORC1-dependent G
csf expression to enhance polymorphonuclear myeloid-derived suppressor cell recruitment and tumorigenicity. Finally, the STAT3-AR-CCRK-mTORC1 pathway components are concordantly over-expressed in human NASH-associated HCCs. These findings unveil the dual roles of an inflammatory-CCRK circuitry in driving metabolic and immunosuppressive reprogramming through mTORC1 activation, thereby establishing a pro-tumorigenic microenvironment for HCC development.
Background and Aim
Serum albumin and bilirubin are the most significant independent prognostic factors to predict hepatic events in patients with primary biliary cirrhosis (PBC). We aimed to ...investigate the prognostic significance of a new prognostic score, the albumin‐bilirubin (ALBI) score, among PBC patients.
Methods
In a retrospective longitudinal cohort of 61 Chinese PBC patients with follow‐up period up to 18.3 years, the prognostic performance of the ALBI in prediction of hepatic events was compared with other well‐established prognostic scores: Child–Pugh score, model of end‐stage liver disease, Mayo risk score, Yale, European, and Newcastle models.
Results
Fifteen patients (24.6%) developed hepatic events during follow‐up. The c‐index (0.894) and χ2 by likelihood ratio test (36.34) of the ALBI score were highest in comparison to other models. The ALBI score was the only independent prognostic factor by multivariate analysis and its adjusted hazard ratio of developing hepatic event was 27.8 (P < 0.001). There were three prognostically different groups stratified by the ALBI score: ALBI grade 1 (≤ −2.60), grade 2 (> −2.60 to −1.39), and grade 3 (> −1.39) groups. The 2‐, 5‐, and 10‐year event‐free survivals for grade 1, grade 2, and grade 3 groups were 100.0% versus 100.0% versus 57.1%, 100.0% versus 88.5% versus 14.3%, and 100.0% versus 81.7% versus 0.0%, respectively (P < 0.001).
Conclusion
The ALBI score is readily derived from a blood test without using those factors evaluated subjectively or obtained by invasive procedures. It is an independent prognostic factor for PBC patients and provides better/similar prognostic performance compared with other prognostic scores.
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