A randomised controlled trial of Standard Of Care versus RadioAblaTion in Early Stage HepatoCellular Carcinoma (SOCRATES HCC).

BACKGROUND: Therapeutic options for early-stage hepatocellular carcinoma (HCC) in individual patients can be limited by tumor and location, liver dysfunction and comorbidities. Many patients with early-stage HCC do not receive curative-intent therapies. Stereotactic ablative body radiotherapy (SABR) has emerged as an effective, non-invasive HCC treatment option, however, randomized evidence for SABR in the first line setting is lacking. METHODS: Trans-Tasman Radiation Oncology Group (TROG) 21.07 SOCRATES-HCC is a phase II, prospective, randomised trial comparing SABR to other current standard of care therapies for patients with a solitary HCC ≤ 8 cm, ineligible for surgical resection or transplantation. The study is divided into 2 cohorts. Cohort 1 will compromise 118 patients with tumors ≤ 3 cm eligible for thermal ablation randomly assigned (1:1 ratio) to thermal ablation or SABR. Cohort 2 will comprise 100 patients with tumors > 3 cm up to 8 cm in size, or tumors ≤ 3 cm ineligible for thermal ablation, randomly assigned (1:1 ratio) to SABR or best other standard of care therapy including transarterial therapies. The primary objective is to determine whether SABR results in superior freedom from local progression (FFLP) at 2 years compared to thermal ablation in cohort 1 and compared to best standard of care therapy in cohort 2. Secondary endpoints include progression free survival, overall survival, adverse events, patient reported outcomes and health economic analyses. DISCUSSION: The SOCRATES-HCC study will provide the first randomized, multicentre evaluation of the efficacy, safety and cost effectiveness of SABR versus other standard of care therapies in the first line treatment of unresectable, early-stage HCC. It is a broad, multicentre collaboration between hepatology, interventional radiology and radiation oncology groups around Australia, coordinated by TROG Cancer Research. TRIAL REGISTRATION: anzctr.org.au, ACTRN12621001444875, registered 21 October 2021.

Screening patients in general practice for advanced chronic liver disease using an innovative IT solution: The Liver Toolkit.

BACKGROUND: Identifying patients with undiagnosed advanced chronic liver disease (ACLD) is a public health challenge. Patients with advanced fibrosis or compensated cirrhosis have much better outcomes than those with decompensated disease and may be eligible for interventions to prevent disease progression. METHODS: A cloud-based software solution ("the Liver Toolkit") was developed to access primary care practice software to identify patients at risk of ACLD. Clinical history and laboratory results were extracted to calculate aspartate aminotransferase-to-platelet ratio index and fibrosis 4 scores. Patients identified were recalled for assessment, including Liver Stiffness Measurement (LSM) via transient elastography. Those with an existing diagnosis of cirrhosis were excluded. RESULTS: Existing laboratory results of more than 32,000 adults across nine general practices were assessed to identify 703 patients at increased risk of ACLD (2.2% of the cohort). One hundred seventy-nine patients (26%) were successfully recalled, and 23/179 (13%) were identified to have ACLD (LSM ≥10.0 kPa) (10% found at indeterminate risk [LSM 8.0-9.9 kPa] and 77% low risk of fibrosis [LSM <8.0 kPa]). In most cases, the diagnosis of liver disease was new, with the most common etiology being metabolic dysfunction-associated steatotic liver disease (n=20, 83%). Aspartate aminotransferase-to-platelet ratio index ≥1.0 and fibrosis 4 ≥3.25 had a positive predictive value for detecting ACLD of 19% and 24%, respectively. Patients who did not attend recall had markers of more severe disease with a higher median aspartate aminotransferase-to-platelet ratio index score (0.57 vs. 0.46, p=0.041). CONCLUSIONS: This novel information technology system successfully screened a large primary care cohort using existing laboratory results to identify patients at increased risk ACLD. More than 1 in 5 patients recalled were found to have liver disease requiring specialist follow-up.

Hepatitis C Virus Antiviral Drug Resistance and Salvage Therapy Outcomes Across Australia.

Background: Hepatitis C virus (HCV) infection can now be cured with well-tolerated direct-acting antiviral (DAA) therapy. However, a potential barrier to HCV elimination is the emergence of resistance-associated substitutions (RASs) that reduce the efficacy of antiviral drugs, but real-world studies assessing the clinical impact of RASs are limited. Here, an analysis of the impact of RASs on retreatment outcomes for different salvage regimens in patients nationally who failed first-line DAA therapy is reported. Methods: We collected data from 363 Australian patients who failed first-line DAA therapy, including: age, sex, fibrosis stage, HCV genotype, NS3/NS5A/NS5B RASs, details of failed first-line regimen, subsequent salvage regimens, and treatment outcome. Results: Of 240 patients who were initially retreated as per protocol, 210 (87.5%) achieved sustained virologic response (SVR) and 30 (12.5%) relapsed or did not respond. The SVR rate for salvage regimens that included sofosbuvir/velpatasvir/voxilaprevir was 94.3% (n = 140), sofosbuvir/velpatasvir 75.0% (n = 52), elbasvir/grazoprevir 81.6% (n = 38), and glecaprevir/pibrentasvir 84.6% (n = 13). NS5A RASs were present in 71.0% (n = 210) of patients who achieved SVR and in 66.7% (n = 30) of patients who subsequently relapsed. NS3 RASs were detected in 20 patients (20%) in the SVR group and 1 patient in the relapse group. NS5B RASs were observed in only 3 patients. Cirrhosis was a predictor of relapse after retreatment, as was previous treatment with sofosbuvir/velpatasvir. Conclusions: In our cohort, the SVR rate for sofosbuvir/velpatasvir/voxilaprevir was higher than with other salvage regimens. The presence of NS5A, NS5B, or NS3 RASs did not appear to negatively influence retreatment outcomes.

Broadening and strengthening the health providers caring for patients with chronic hepatitis C may improve continuity of care.

BACKGROUND: Direct-acting antiviral (DAA) therapies for hepatitis C virus infection (HCV) lead to excellent rates of sustained virological response (SVR). However, loss to follow-up (LTFU) for SVR testing remains a challenge. We examine factors associated with LTFU in a real-world setting. METHODS: Adults who received DAA therapy for HCV in one of 26 centers across Australia during 2016-2021 were followed up for 2 years. Data sources included the patient medical records and the national Pharmaceutical and Medicare Benefits Schemes. Linkage to Medicare provided utilization data of other health-care providers and re-treatment with DAAs. LTFU was defined as no clinic attendance for SVR testing by at least 52 weeks after DAA treatment commencement. Multivariable logistic regression assessed factors associated with LTFU. RESULTS: In 3619 patients included in the study (mean age 52.0 years; SD = 10.5), 33.6% had cirrhosis (69.4% Child-Pugh class B/C), and 19.3% had HCV treatment prior to the DAA era. Five hundred and fifteen patients (14.2%) were LTFU. HCV treatment initiation in 2017 or later (adj-OR = 2.82, 95% confidence interval [CI] 2.25-3.54), younger age (adj-OR = 2.63, 95% CI 1.80-3.84), Indigenous identification (adj-OR = 1.99, 95% CI 1.23-3.21), current injection drug use or opioid replacement therapy (adj-OR = 1.66, 95% CI 1.25-2.20), depression treatment (adj-OR = 1.49, 95% CI 1.17-1.90), and male gender (adj-OR = 1.31, 95% CI 1.04-1.66) were associated with LTFU. CONCLUSIONS: These findings stress the importance of strengthening the network of providers caring for patients with HCV. In particular, services targeting vulnerable groups of patients such as First Nations Peoples, youth health, and those with addiction and mental health disorders should be equipped to treat HCV.

Unveiling the complex relationship between gut microbiota and liver cancer: opportunities for novel therapeutic interventions.

Hepatocellular carcinoma (HCC) has been linked to the gut microbiota, with recent studies revealing the potential of gut-generated responses to influence several arms of the immune responses relevant to HCC formation. The pro- or anti-tumor effects of specific bacterial strains or gut microbiota-related metabolites, such as bile acids and short-chain fatty acids, have been highlighted in many human and animal studies. The critical role of the gut microbiota in HCC development has spurred interest in modulating the gut microbiota through dietary interventions, probiotics, and fecal microbiota transplantation as a potential strategy to improve liver cancer outcomes. Encouragingly, preclinical and clinical studies have demonstrated that modulation of the gut microbiota can ameliorate liver function, reduce inflammation, and inhibit liver tumor growth, underscoring the potential of this approach to improve HCC outcomes. As research continues to unravel the complex and dynamic mechanisms underlying the gut-liver axis, the development of safe and effective interventions to target this pathway for liver cancer prevention and treatment appears to be on the horizon, heralding a significant advance in our ongoing efforts to combat this devastating disease.

Radiological Diagnosis of Chronic Liver Disease and Hepatocellular Carcinoma: A Review.

Medical image analysis plays a pivotal role in the evaluation of diseases, including screening, surveillance, diagnosis, and prognosis. Liver is one of the major organs responsible for key functions of metabolism, protein and hormone synthesis, detoxification, and waste excretion. Patients with advanced liver disease and Hepatocellular Carcinoma (HCC) are often asymptomatic in the early stages; however delays in diagnosis and treatment can lead to increased rates of decompensated liver diseases, late-stage HCC, morbidity and mortality. Ultrasound (US) is commonly used imaging modality for diagnosis of chronic liver diseases that includes fibrosis, cirrhosis and portal hypertension. In this paper, we first provide an overview of various diagnostic methods for stages of liver diseases and discuss the role of Computer-Aided Diagnosis (CAD) systems in diagnosing liver diseases. Second, we review the utility of machine learning and deep learning approaches as diagnostic tools. Finally, we present the limitations of existing studies and outline future directions to further improve diagnostic accuracy, as well as reduce cost and subjectivity, while also improving workflow for the clinicians.

Barriers to palliative care in hepatocellular carcinoma: A review of the literature.

Hepatocellular carcinoma (HCC) is a deadly and burdensome form of liver cancer with an increasing global prevalence. Its course is unpredictable as it frequently occurs in the context of underlying end-stage liver disease, and the associated symptoms and adverse effects of treatment cause severe suffering for patients. Palliative care (PC) is a medical specialty that addresses the physical, emotional, and spiritual needs of patients and their carers in the context of life-limiting illness. In other cancers, a growing body of evidence has demonstrated that the early introduction of PC at diagnosis improves patient and carer outcomes. Despite this, the integration of palliative care at the diagnosis of HCC remains suboptimal, as patients usually receive PC only at the very terminal phase of their disease, even when diagnosed early. Significant barriers to the uptake of palliative care in the treatment algorithm of hepatocellular carcinoma fall under four main themes: data limitations, disease, clinician, and patient factors. Barriers relating to data limitations mainly encapsulated the risk of bias inherent in published work in the field of PC. Clinician-reported barriers related to negative attitudes towards PC and a lack of time for PC discussions. Barriers related to the disease align with prognostic uncertainty due to the unpredictable course of HCC. Significantly, there exists a paucity of evidence exploring patient-perceived barriers to timely PC implementation in HCC. Given that patients are often the underrepresented stakeholder in the delivery of PC, future research should explore the patient perspective in adequately designed qualitative studies as the first step.

Liver Disease and Poor Adherence Limit Hepatitis C Cure: A Real-World Australian Treatment Cohort.

BACKGROUND AND AIMS: In 2016, direct-acting antiviral (DAA) treatment for hepatitis C (HCV) became available through Australia's universal health care system, with the aim of HCV elimination. We report real-world effectiveness of DAA HCV treatment in Australia from a clinically well-informed cohort, enriched for cirrhosis and prior HCV treatment. METHODS: 3413 patients were recruited from 26 hospital liver clinics across Australia from February 2016 to June 2020. Clinical history and sustained viral response (SVR) were obtained from medical records and data linkage to the Australian Pharmaceutical Benefits Scheme. Factors associated with SVR were assessed by multivariable logistic regression (MVR). RESULTS: At recruitment, 32.2% had cirrhosis (72.9% Child Pugh class B/C), and 19.9% were treatment experienced. Of the 2,939 with data, 93.3% confirmed SVR. 137 patients received second-line therapy. Patients with cirrhosis had lower SVR rate (88.4 vs. 95.8%; p < 0.001). On MVR, failure to achieve SVR was associated with Genotype 3 (adj-OR = 0.42, 95%CI 0.29-0.61), male gender (adj-OR = 0.49, 95%CI 0.31-0.77), fair/poor adherence (adj-OR = 0.52, 95%CI 0.28-0.94), cirrhosis (adj-OR = 0.57, 95%CI 0.36-0.88), FIB-4 > 3.25 (adj-OR = 0.52, 95%CI 0.33-0.83) and MELD score ≥ 20 (adj-OR = 0.25, 95%CI 0.08-0.80). Consistent results were seen in cirrhotic sub-analysis. CONCLUSIONS: Excellent SVR rates were achieved with DAAs in this real-world cohort of patients with chronic HCV infection. More advanced liver disease and clinician impression of poor adherence were associated with HCV treatment failure. Supports to improve liver fibrosis assessment skills for non-specialist DAA prescribers in the community and to optimize patient adherence are likely to enable more effective pursuit of HCV elimination in Australia.

Monitoring quality of care in hepatocellular carcinoma: A modified Delphi consensus.

Although there are several established international guidelines on the management of hepatocellular carcinoma (HCC), there is limited information detailing specific indicators of good quality care. The aim of this study was to develop a core set of quality indicators (QIs) to underpin the management of HCC. We undertook a modified, two-round, Delphi consensus study comprising a working group and experts involved in the management of HCC as well as consumer representatives. QIs were derived from an extensive review of the literature. The role of the participants was to identify the most important and measurable QIs for inclusion in an HCC clinical quality registry. From an initial 94 QIs, 40 were proposed to the participants. Of these, 23 QIs ultimately met the inclusion criteria and were included in the final set. This included (a) nine related to the initial diagnosis and staging, including timing to diagnosis, required baseline clinical and laboratory assessments, prior surveillance for HCC, diagnostic imaging and pathology, tumor staging, and multidisciplinary care; (b) thirteen related to treatment and management, including role of antiviral therapy, timing to treatment, localized ablation and locoregional therapy, surgery, transplantation, systemic therapy, method of response assessment, and supportive care; and (c) one outcome assessment related to surgical mortality. Conclusion: We identified a core set of nationally agreed measurable QIs for the diagnosis, staging, and management of HCC. The adherence to these best practice QIs may lead to system-level improvement in quality of care and, ultimately, improvement in patient outcomes, including survival.

Selective internal radiation therapy for hepatocellular carcinoma: A 15-year multicenter Australian cohort study.

BACKGROUND AND AIM: The exact place for selective internal radiation therapy (SIRT) in the therapeutic algorithm for hepatocellular carcinoma (HCC) is debated. There are limited data on its indications, efficacy, and safety in Australia. METHODS: We performed a multicenter retrospective cohort study of patients undergoing SIRT for HCC in all Sydney hospitals between 2005 and 2019. The primary outcome was overall survival. Secondary outcomes were progression-free survival and adverse events. RESULTS: During the study period, 156 patients underwent SIRT across 10 institutions (mean age 67 years, 81% male). SIRT use progressively increased from 2005 (n = 2), peaking in 2017 (n = 42) before declining (2019: n = 21). Barcelona Clinic Liver Cancer stages at treatment were A (13%), B (33%), C (52%), and D (2%). Forty-four (28%) patients had tumor thrombus. After a median follow-up of 13.9 months, there were 117 deaths. Median overall survival was 15 months (95% confidence interval 11-19). Independent predictors of mortality on multivariable analysis were extent of liver involvement, Barcelona Clinic Liver Cancer stage, baseline ascites, alpha fetoprotein, and model for end-stage liver disease score. Median progression-free survival was 6.0 months (95% confidence interval 5.1-6.9 months). Following SIRT, 11% of patients were downstaged to curative therapy. SIRT-related complications occurred in 17%: radioembolization-induced liver disease (11%), pneumonitis (3%), gastrointestinal ulceration, and cholecystitis (1% each). Baseline ascites predicted for radioembolization-induced liver disease. CONCLUSION: We present the largest Australian SIRT cohort for HCC. We have identified several factors associated with a poor outcome following SIRT. Patients with early-stage disease had the best survival with some being downstaged to curative therapy.

Hepatitis C treatment outcomes for Australian First Nations Peoples: equivalent SVR rate but higher rates of loss to follow-up.

BACKGROUND: First Nations Peoples of Australia are disproportionally affected by hepatitis C (HCV) infection. Through a prospective study we evaluated the outcome of direct-acting antiviral (DAA) therapy among First Nations Peoples with HCV infection. METHODS: Adults who initiated DAA therapy at one of 26 hospitals across Australia, 2016-2019 were included in the study. Clinical data were obtained from medical records and the Pharmaceutical and Medicare Benefits Schemes. Outcomes included sustained virologic response (SVR) and loss to follow-up (LTFU). A multivariable analysis assessed factors associated with LTFU. RESULTS: Compared to non-Indigenous Australians (n = 3206), First Nations Peoples (n = 89) were younger (p < 0.001), morel likely to reside in most disadvantaged (p = 0.002) and in regional/remote areas (p < 0.001), and had similar liver disease severity. Medicines for mental health conditions were most commonly dispensed among First Nations Peoples (55.2% vs. 42.8%; p = 0.022). Of 2910 patients with follow-up data, both groups had high SVR rates (95.3% of First Nations Peoples vs. 93.2% of non-Indigenous patients; p = 0.51) and 'good' adherence (90.0% vs. 86.9%, respectively; p = 0.43). However, 28.1% of First Nations Peoples were LTFU vs. 11.2% of non-Indigenous patients (p < 0.001). Among First Nations Peoples, younger age (adj-OR = 0.93, 95% CI 0.87-0.99) and treatment initiation in 2018-2019 vs. 2016 (adj-OR = 5.14, 95% CI 1.23-21.36) predicted LTFU, while higher fibrosis score was associated with better engagement in HCV care (adj-OR = 0.71, 95% CI 0.50-0.99). CONCLUSIONS: Our data showed that First Nations Peoples have an equivalent HCV cure rate, but higher rates of LTFU. Better strategies to increase engagement of First Nations Peoples with HCV care are needed.

Modulation of the Gut Microbiome to Improve Clinical Outcomes in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related mortality worldwide. Recently, the gut microbiota has been shown to be closely linked to modulation of the immune and inflammatory responses, hence its potential as a therapeutic target. Although still under intense investigation, there exists a 'gut-liver axis' that links changes in the gut to the liver. In this regard, composition of gut microbiota and related metabolites, such as bile acids and short-chain fatty acids, have been shown to orchestrate key immune-metabolic events in liver disease and liver cancer. As hepatic immune cells are important determinants of antitumor responses, it is now increasingly recognized that the gut-liver axis plays a key role in influencing the intrahepatic immune response in HCC to favor a pro- or antitumor immune milieu. Hence, modulation of gut microbiota is potentially an attractive option to reinvigorate the antitumor responses. In this regard, promising evidence from melanoma preclinical and clinical studies has demonstrated the efficacy of gut-based intervention in reinvigorating the antitumor responses and improving responses to immunotherapy. However, the role of gut-based interventions as a therapeutic option in HCC remains to be elucidated. This review details how the gut microbiota and bacterial metabolites affect gut barrier function and ultimately immune response in HCC and raises the question of the potential of gut-based interventions as an adjunct therapy for patients with HCC receiving immunotherapy.

Refining a Protocol for Faecal Microbiota Engraftment in Animal Models After Successful Antibiotic-Induced Gut Decontamination.

BACKGROUND: There is mounting evidence for the therapeutic use of faecal microbiota transplant (FMT) in numerous chronic inflammatory diseases. Germ free mice are not always accessible for FMT research and hence alternative approaches using antibiotic depletion prior to FMT in animal studies are often used. Hence, there is a need for standardising gut microbiota depletion and FMT methodologies in animal studies. The aim of this study was to refine gut decontamination protocols prior to FMT engraftment and determine efficiency and stability of FMT engraftment over time. METHODS: Male C57BL/6J mice received an antibiotic cocktail consisting of ampicillin, vancomycin, neomycin, and metronidazole in drinking water for 21 days ad libitum. After antibiotic treatment, animals received either FMT or saline by weekly oral gavage for 3 weeks (FMT group or Sham group, respectively), and followed up for a further 5 weeks. At multiple timepoints throughout the model, stool samples were collected and subjected to bacterial culture, qPCR of bacterial DNA, and fluorescent in-situ hybridisation (FISH) to determine bacterial presence and load. Additionally, 16S rRNA sequencing of stool was used to confirm gut decontamination and subsequent FMT engraftment. RESULTS: Antibiotic treatment for 7 days was most effective in gut decontamination, as evidenced by absence of bacteria observed in culture, and reduced bacterial concentration, as determined by FISH as well as qPCR. Continued antibiotic administration had no further efficacy on gut decontamination from days 7 to 21. Following gut decontamination, 3 weekly doses of FMT was sufficient for the successful engraftment of donor microbiota in animals. The recolonised animal gut microbiota was similar in composition to the donor sample, and significantly different from the Sham controls as assessed by 16S rRNA sequencing. Importantly, this similarity in composition to the donor sample persisted for 5 weeks following the final FMT dose. CONCLUSIONS: Our results showed that 7 days of broad-spectrum antibiotics in drinking water followed by 3 weekly doses of FMT provides a simple, reliable, and cost-effective methodology for FMT in animal research.

Gastroenterology hospital outpatients report high rates of satisfaction with a Telehealth model of care.

AIMS: This study aimed to capture patient satisfaction with a Telehealth model of care in a tertiary hospital gastroenterology outpatient setting. An in-depth patient questionnaire addressed patients' experience with telephone based consultations, as well as capturing demographic data to predict patients who may benefit from a Telehealth model of care. METHODS: Patients aged ≥ 18 years who had a telephone appointment from 1st March 2020 to 1st September 2020 at the St George Hospital and Sutherland Hospital Gastroenterology Clinics in Sydney, Australia, were invited to complete an anonymous online survey detailing their experience. Clinics included general gastroenterology, inflammatory bowel disease, hepatology and swallow disorders. Chi squared analysis was used to investigate if demographic data (age, gender, educational status, English-spoken at home, and presence of IBD or cirrhosis) impacted on a patients rating of care they received. RESULTS: 1894 patients were invited to complete with survey, with 302 responses. 294 respondents (88.4%) rated the care they received as "very good" or "good". 254 (84.1%) stated the main reason for attending the clinic was dealt with to their satisfaction. There was no statistical relationship between age, gender, educational status and the rating of care received. 49.7% preferred their telephone appointment, and 63.6% would like the option of a telephone appointment in the future. CONCLUSION: Gastroenterology outpatients reported a very high satisfaction with Telehealth, demonstrating a potential for Telehealth to be incorporated into usual care.

Virtual clinic for positive faecal occult blood tests enhances early access to bowel cancer screening and is well received by patients.

BACKGROUND: Colorectal cancer is the second most common cause of cancer-related mortality in Australia. As such, timely access to colonoscopy following a positive faecal occult blood test (FOBT) is an important aspect of the National Bowel Cancer Screening Program to reduce morbidity and mortality related to this condition. To reduce waiting times, a Sydney-based referral centre introduced a nurse-led virtual clinic (VC) in order to facilitate direct access colonoscopy for patients referred with a positive FOBT. AIMS: To evaluate the efficacy of a nurse-led VC model to reduce waiting time to colonoscopy and to determine the patient experience of the model. METHODS: The VC model, piloted for a 14-month period, was compared with the standard outpatient clinic (SOC) model over the 14-month period preceding the VC. Primary outcomes included time to colonoscopy and secondary outcomes included adverse events, bowel preparation and cancellation rates. Patient experience was evaluated through an emailed survey. RESULTS: Compared to the SOC model, the VC model reduced waiting time to colonoscopy from date of positive FOBT by 71 days (P = 0.0006) and from date of referral by 66 days (P < 0.0001). There was no significant difference in secondary outcomes. All respondents to the survey (n = 30) reported a positive experience. CONCLUSIONS: Nursing-led VC, with direct access colonoscopy for patients at increased risk of colorectal cancer, reduce waiting times to colonoscopy without an increase in adverse events and is well received by patients.

Critical Assessment of Whole Genome and Viral Enrichment Shotgun Metagenome on the Characterization of Stool Total Virome in Hepatocellular Carcinoma Patients.

Viruses are the most abundant form of life on earth and play important roles in a broad range of ecosystems. Currently, two methods, whole genome shotgun metagenome (WGSM) and viral-like particle enriched metagenome (VLPM) sequencing, are widely applied to compare viruses in various environments. However, there is no critical assessment of their performance in recovering viruses and biological interpretation in comparative viral metagenomic studies. To fill this gap, we applied the two methods to investigate the stool virome in hepatocellular carcinoma (HCC) patients and healthy controls. Both WGSM and VLPM methods can capture the major diversity patterns of alpha and beta diversities and identify the altered viral profiles in the HCC stool samples compared with healthy controls. Viral signatures identified by both methods showed reductions of Faecalibacterium virus Taranis in HCC patients' stool. Ultra-deep sequencing recovered more viruses in both methods, however, generally, 3 or 5 Gb were sufficient to capture the non-fragmented long viral contigs. More lytic viruses were detected than lysogenetic viruses in both methods, and the VLPM can detect the RNA viruses. Using both methods would identify shared and specific viral signatures and would capture different parts of the total virome.

Community screening identifies undiagnosed chronic liver disease in high-risk populations.

BACKGROUND AND AIM: Liver cirrhosis is the primary risk factor for the development of hepatocellular carcinoma. Most conditions that lead to cirrhosis are treatable, or modifiable. Therefore, a community-based screening program targeting high-risk groups was designed for early diagnosis and intervention of liver disease, to offset the rising burden of hepatocellular carcinoma in Australia. METHODS: Two nurse consultants from a tertiary liver center performed community screening of pre-identified cohorts at risk of viral hepatitis and chronic liver disease, with transient elastography and/or serology testing for chronic hepatitis B virus (HBV) and hepatitis C virus (HCV), in addition to standard blood tests. A positive screening result was defined as any of the following: liver stiffness measurement (LSM) ≥ 9.5 kPa, positive HCV RNA, or positive HBV surface antigen. Individuals who screened positive were linked to the liver center for management. RESULTS: Nine hundred and twenty-six subjects were screened over a 6-year period, of which 122/926 (13.2%) had evidence of chronic liver disease. Chronic viral hepatitis was diagnosed in 91 participants (HBV = 23, HCV = 67, and co-infection = 1), while non-alcoholic fatty liver disease was diagnosed in 14 participants. Advanced fibrosis (LSM ≥ 9.5 kPa) was detected in 42/866 (4.9%) subjects with available LSM. Loss to follow-up occurred in 36/91 (39.6%) participants with chronic viral hepatitis. CONCLUSIONS: Targeting high-risk populations for community screening and intervention increases early identification of chronic liver disease. This may reduce the incidence of liver cirrhosis and hepatocellular carcinoma. Loss to follow-up remains an ongoing challenge, requiring better strategies.

Gut microbiota impact on the peripheral immune response in non-alcoholic fatty liver disease related hepatocellular carcinoma.

The gut microbiota is reported to modulate the immune response in hepatocellular carcinoma (HCC). Here, we employ metagenomic and metabolomic studies to characterise gut microbiota in patients with non-alcoholic fatty liver disease (NAFLD) related cirrhosis, with or without HCC, and evaluate its effect on the peripheral immune response in an ex vivo model. We find that dysbiosis characterises the microbiota of patients with NAFLD-cirrhosis, with compositional and functional shifts occurring with HCC development. Gene function of the microbiota in NAFLD-HCC supports short chain fatty acid production, and this is confirmed by metabolomic studies. Ex vivo studies show that bacterial extracts from the NAFLD-HCC microbiota, but not from the control groups, elicit a T cell immunosuppressive phenotype, characterised by expansion of regulatory T cells and attenuation of CD8 + T cells. Our study suggest that the gut microbiota in NAFLD-HCC is characterised by a distinctive microbiome/metabolomic profile, and can modulate the peripheral immune response.

Non-alcoholic fatty liver disease: a review of epidemiology, risk factors, diagnosis and management.

Due to the rising prevalence of obesity and type II diabetes mellitus, non-alcoholic fatty liver disease is becoming the leading cause of chronic liver disease in the Western world. In some patients, simple steatosis can result in non-alcoholic steatohepatitis which over time can lead to liver cirrhosis and its associated sequelae, including hepatocellular carcinoma. Early identification and management of patients at risk with intensive dietary and lifestyle modification are essential to prevent the development of advanced liver disease and its complications. In this review, we will discuss the epidemiology of non-alcoholic fatty liver disease, pathogenesis, diagnosis, management and surveillance strategies to offset the morbidity and mortality of this disease, as well as liver and non-liver-related complications.