Background: Hepatocellular carcinoma (HCC) poses a significant public health challenge in Australia, with poorer survival observed in non-metropolitan populations. This study investigated whether survival disparities persist between non-metropolitan and metropolitan patients if only those with early-stage HCC treated at metropolitan tertiary referral centres are considered. Methods: We performed a retrospective cohort study across ten Australian tertiary centres involving patients with a new diagnosis of Barcelona Clinic Liver Cancer (BCLC) stage 0 or A, recorded from 1 January 2016 to 31 December 2020. Residential postcodes were entered using the Modified Monash (MM) model to define metropolitan versus non-metropolitan residence. The primary endpoint was adjusted for all-cause mortality. Results: Our study included 854 patients (metropolitan n = 612, and non-metropolitan n = 242) with a median follow-up of 42.6 months. We found no significant survival or mortality differences between the two groups with the unadjusted Kaplan–Meier survival analysis (log-rank test p = 0.612) and with the Cox proportional hazards regression analysis (adjusted HR 0.93, 95% CI 0.64–1.34, p = 0.690). As expected, tumour burden, Child–Pugh Score, and Charlson Comorbidity Index (CCI) were significant predictors of mortality. Conclusions: Our findings suggest that previously observed survival disparities may stem from delayed diagnosis and reduced access to tertiary care in non-metropolitan regions and highlight the need for improved HCC surveillance and referral pathways, particularly for rural and Indigenous communities, to mitigate geographic inequities.

Introduction Chronic liver disease (CLD) is a known risk factor for osteoporosis and minimal trauma fracture through multiple mechanisms including cholestasis, alcohol, malnutrition, sarcopenia and hypogonadism. The evidence for bisphosphonates is mostly seen in primary biliary cholangitis and liver transplantation. Methods This is a retrospective observational study of adult CLD patients, examining changes in bone mineral density (BMD) and bone turnover markers in the 12 months following zoledronic acid (ZA) compared to an age- and sex-matched population of CLD patients. Results 20 adults with CLD who received ZA were matched to 20 adults who had not received bone-specific treatment. Mean age of all participants was 59.7 ± 1.5 years and 55% were female. Baseline mean T-scores at the lumbar spine (LS) was -1.8 ± 1.3, left femoral neck (LFN) was -2.0 ± 0.9 and the left total hip (LTH) was -1.7 ± 1.0. There was a 3.61% difference in change in BMD per year at the LS (p=0.001) and 1.73% difference at the LTH between those who received ZA and those who did not (p=0.037). There was no difference at the LFN. In those who received ZA, mean change in procollagen type 1 N-propeptide was 3.0% p=0.051 and mean change in C-telopeptide was -10.4%, p= 0.032. Conclusion Zoledronic acid increases bone mineral density in a chronic liver disease population with reduction in bone resorption markers. This requires confirmation in a randomised setting.

PurposeBiannual ultrasound-based hepatocellular carcinoma (HCC) surveillance is standard practice for individuals with cirrhosis and subgroups with non-cirrhotic hepatitis B. While this practice improves cancer-related survival, the detection of false-positive results can lead to additional testing which poses both physical and psychosocial risks. Our study explored the psychosocial consequences of false-positive ultrasound results in participants undergoing HCC surveillance.MethodsWe performed a qualitative study with semi-structured interviews to understand the psychosocial impact of participants who received a false-positive ultrasound result during HCC surveillance until no new themes emerged. Key themes were analysed using the Framework Approach.ResultsTen participants with cirrhosis or non-cirrhotic hepatitis B were recruited. Most had a poor understanding of the role of ultrasound in HCC surveillance. Some participants experienced significant anxiety with existential concerns impacting family and work life. Others remained uninformed about the risk for HCC and did not experience significant psychosocial impacts. The lack of understanding about the role of surveillance and the potential for false positives contributed to unpredictable psychosocial consequences. Despite experiencing surveillance-related harm, all participants wished to continue regular surveillance.ConclusionOur findings highlight a need for improved health literacy about the purpose and potential harms of HCC surveillance. Optimising surveillance protocols to minimise false-positive findings may also further alleviate physical and psychosocial harm.

Hepatocellular carcinoma (HCC) is a rapidly increasing healthcare burden in Australia. We aimed to evaluate the contemporary epidemiology, clinical characteristics, and real-world patterns of care for HCC in Australia using a prospective multicentre clinical quality registry. This interim analysis utilised data from the Upper Gastrointestinal Cancer Registry (UGICR) HCC module, a multicentre clinical quality registry involving 17 major centres across all mainland Australian states. Patients with a new diagnosis of HCC from 1 January 2021 were included. Clinical characteristics and initial treatment modalities were compared between liver transplant centres (LTCs) and non-transplant centres (NTCs). A total of 489 patients were analysed (333 LTC, 156 NTC). The cohort was predominantly male (76.7

Background: Transjugular intrahepatic portosystemic shunt (TIPS) is one of the preferred interventional radiology techniques for reducing clinically significant portal pressures in patients with cirrhosis and complications from portal hypertension when pharmacological therapy or endoscopic interventions have failed or been insufficient. Recent advances in TIPS procedural techniques and stent technology, along with emerging indications for TIPS, warrant a review of current practices and establishment of consensus recommendations in Australia, where TIPS remains underused. This TIPS consensus statement is the first such guideline in Australia. It outlines 69 evidence-based practice recommendations and the evidence underlying them. The recommendations are intended for use by health care professionals in Australia who manage adult patients with portal hypertensive complications of liver disease, where such patients are being considered for TIPS implantation, including pre-, peri- and post-procedural aspects of care. Methods and results: This consensus statement has been developed by specialists in hepatology and interventional radiology, with input from specialists in cardiology, hematology and primary care, including medical practitioners, nurses and clinical researchers. The statement deals with four domains related to TIPS: preparation for TIPS, patient selection and pre-TIPS workup; best procedural practice; postoperative care and follow-up; and indications for TIPS. Two rounds of a modified Delphi process were used to reach consensus on the recommendations. Conclusions: Adoption of and adherence to the evidence-based recommendations in this consensus statement should reduce clinical variation. Ultimately, this should lead to system-level improvements in quality of care and outcomes for patients undergoing TIPS implantation. These recommendations summarize the complete document, available at https://www.gesa.org.au/resources/ .

Aim: Novel biomarker panels may have comparable performance to ultrasound with alpha-fetoprotein (US-AFP) in the surveillance of hepatocellular carcinoma (HCC) among individuals with cirrhosis. We performed an economic modeling study to estimate the threshold price at which biomarker-based surveillance would be cost-effective in the Australian healthcare setting. Methods: We constructed a Markov model to evaluate three strategies: no surveillance, US-AFP surveillance, and biomarker surveillance based on the recently reported GAAD algorithm (gender, age, AFP and des-γ-carboxy prothrombin). The threshold price of biomarker surveillance was estimated relative to US-AFP, using a willingness-to-pay threshold of A$50,000 per quality-adjusted life year (QALY). The base-case analysis assumed an annual HCC incidence of 2% and 70% adherence to surveillance. Sensitivity analyses were performed to evaluate uncertainty in biomarker performance, HCC incidence, and surveillance adherence. Results: In the base-case scenario, biomarker surveillance yielded a 0.02 QALY gain compared with US-AFP surveillance and a 0.07 QALY gain compared with no surveillance. Relative to US-AFP, biomarker surveillance was cost-effective if priced at ≤ A$454 and dominant if priced at ≤ A$310. Sensitivity analyses showed that the biomarker threshold price ranged from A$165 (with 50% adherence) to A$838 (with an annual HCC incidence of 5%). Discussion: Biomarker surveillance is a promising intervention for HCC surveillance in people with cirrhosis. Our results suggest that, in the Australian context, it is likely to be cost-effective - and potentially cost-saving - when compared with the existing standard of US-AFP surveillance.

Introduction: Turmeric is a common spice used in traditional Chinese and Ayurvedic medicine for a variety of purported health benefits. Recent concerns have arisen regarding turmeric-induced liver injury linked to formulations with enhanced bioavailability, often including piperine found in black pepper. Case Presentation: We explore a case of a 40-year-old female with increasing fatigue, pruritus, and dark urine following consumption of turmeric and black pepper "wellness shots" leading to a significant drug-induced liver injury. Conclusion: This case underscores the critical need to recognise herbal remedies, such as turmeric, as potential sources of hepatotoxicity. Despite a reputation of safety, limited regulation and testing of turmeric may mean potential adverse effects are under-recognised. Understanding the mechanisms behind turmeric and black pepper's hepatotoxicity, including the role of potential genetic predispositions, requires further investigation for its safe use.Introduction: Turmeric is a common spice used in traditional Chinese and Ayurvedic medicine for a variety of purported health benefits. Recent concerns have arisen regarding turmeric-induced liver injury linked to formulations with enhanced bioavailability, often including piperine found in black pepper. Case Presentation: We explore a case of a 40-year-old female with increasing fatigue, pruritus, and dark urine following consumption of turmeric and black pepper "wellness shots" leading to a significant drug-induced liver injury. Conclusion: This case underscores the critical need to recognise herbal remedies, such as turmeric, as potential sources of hepatotoxicity. Despite a reputation of safety, limited regulation and testing of turmeric may mean potential adverse effects are under-recognised. Understanding the mechanisms behind turmeric and black pepper's hepatotoxicity, including the role of potential genetic predispositions, requires further investigation for its safe use.

Abstract 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.

BACKGROUND:Ultrasound surveillance for hepatocellular carcinoma (HCC) may improve early tumour detection but may additionally result in surveillance-related harm through increased evaluation of non-HCC lesions. The incidence of these outcomes has not been reported outside North America. AIMS:We aimed to report the outcomes of HCC surveillance with respect to both surveillance-related benefits and harms. METHODS:We reviewed all HCC surveillance ultrasounds at a large Victorian tertiary hospital network in 2017 and followed their outcomes until 2021. Surveillance-related benefits were defined as early-stage HCC detection. Surveillance-related harm was defined as contrast imaging, biopsies or surgery performed to evaluate non-HCC liver lesions or false-positive alpha-fetoprotein levels. RESULTS:Five hundred and fifty-three patients were included (mean age 54.5 ± 12.3 years, males 67.5%, cirrhosis 50.3%). The most common liver disease aetiology was hepatitis B (53.9%). Over a median of 4.7 years follow-up, early-stage HCC was detected in 3.3% (5.4% in cirrhotic vs 1.1% in non-cirrhotic patients, P < 0.01). 75% of all HCCs were early-stage. Surveillance-related harm occurred in 12.5% (15.5% in cirrhotic vs 9.5% in non-cirrhotic patients, P < 0.04), although most harm was mild (12.1%). In subgroup analysis, the detection of early-stage HCC ranged between 0% (screened outside of guideline criteria and alcoholic cirrhotic patients) and 7.2% (hepatitis C cirrhosis). Harm occurred between 9% (non-cirrhotic hepatitis B) and 20.8% (thrombocytopenia). CONCLUSION:In our study, HCC surveillance was associated with early tumour detection, although many patients experienced mild surveillance-related harm. Novel surveillance strategies and pathways are required to improve detection in high-risk patients and minimise harm in low-risk patients.

The optimal treatment approach in very-early and early-stage hepatocellular carcinoma (HCC) is not precisely defined, and there is ambiguity in the literature around the comparative efficacy of surgical resection versus ablation as curative therapies for limited disease. We performed this real-world propensity-matched, multi-centre cohort study to assess for differences in survival outcomes between those undergoing resection and those receiving ablation. Patients with Barcelona Clinic Liver Cancer (BCLC) 0/A HCC first diagnosed between 1 January 2016 and 31 December 2020 who received ablation or resection as initial treatment were included in the study. A total of 450 patients were included in the study from 10 major liver centres including two transplant centres. Following propensity score matching using key covariates, 156 patients were available for analysis with 78 in each group. Patients who underwent resection had significantly improved overall survival (log-rank test p = 0.023) and local recurrence-free survival (log rank test p = 0.027) compared to those who received ablation. Based on real-world data, our study supports the use of surgical resection in preference to ablation as first-line curative therapy in appropriately selected BCLC 0/A HCC patients.

BACKGROUND:The benefits of regular surveillance imaging for cholangiocarcinoma in patients with primary sclerosing cholangitis (PSC) are unclear. Hence, we aimed to evaluate the impact of regular magnetic resonance cholangiopancreatography (MRCP) on outcomes of patients with PSC in Australia, where the practice of MRCP surveillance is variable. METHODS:The relationship between MRCP surveillance and survival outcomes was assessed in a multicenter, retrospective cohort of patients with PSC from 9 tertiary liver centers in Australia. An inverse probability of treatment weighting approach was used to balance groups across potentially confounding covariates. RESULTS:A total of 298 patients with PSC with 2117 person-years of follow-up were included. Two hundred and twenty patients (73.8%) had undergone MRCP surveillance. Regular surveillance was associated with a 71% reduced risk of death on multivariate weighted Cox analysis (HR: 0.29, 95% CI: 0.14-0.59, p < 0.001) and increased likelihood of having earlier endoscopic retrograde cholangiopancreatography from the date of PSC diagnosis in patients with a dominant stricture (p < 0.001). However, survival posthepatobiliary cancer diagnosis was not significantly different between both groups (p = 0.74). Patients who had surveillance of less than 1 scan a year (n = 41) had comparable survival (HR: 0.46, 95% CI 0.16-1.35, p = 0.16) compared to patients who had surveillance at least yearly (n = 172). CONCLUSIONS:In this multicenter cohort study that employed inverse probability of treatment weighting to minimize selection bias, regular MRCP was associated with improved overall survival in patients with PSC; however, there was no difference in survival after hepatobiliary cancer diagnosis. Further prospective studies are needed to confirm the benefits of regular MRCP and optimal imaging interval in patients with PSC.

The management of early-stage hepatocellular carcinoma (HCC) is complex, with multiple treatment strategies available. There is a paucity of literature regarding variations in the patterns of care and outcomes between transplant and non-transplant centres. We conducted this real-world multi-centre cohort study in two liver cancer referral centres with an integrated liver transplant program and an additional eight non-transplant HCC referral centres across Australia to identify variation in patterns of care and key survival outcomes. Patients with stage Barcelona Clinic Liver Cancer (BCLC) 0/A HCC, first diagnosed between 1 January 2016 and 31 December 2020, who were managed at a participating site, were included in the study. Patients were excluded if they had a history of prior HCC or if they received upfront liver transplantation. A total of 887 patients were included in the study, with 433 patients managed at a liver cancer centre with a transplant program (LTC) and 454 patients managed at a non-transplant centre (NTC). Management at an LTC did not significantly predict allocation to resection (adjusted OR 0.75, 95% CI 0.50 to 1.11, p = 0.148). However, in those not receiving resection, LTC and NTC patients were systematically managed differently, with LTC patients five times less likely to receive upfront ablation than NTC patients (adjusted OR 0.19, 95% CI 0.13 to 0.28, p < 0.001), even after adjusting for tumour burden, as well as for age, gender, liver disease aetiology, liver disease severity, and medical comorbidities. LTCs exhibited significantly higher proportions of patients undergoing TACE for every tumour burden category, including those with a single tumour measuring 2 cm or less (p < 0.001). Using multivariable Cox proportional hazards analysis, management at a transplant centre was associated with reduced all-cause mortality (adjusted HR 0.71, 95% CI 0.51 to 0.98, p = 0.036), and competing-risk regression analysis, considering liver transplant as a competing event, demonstrated a similar reduction in risk (adjusted HR 0.70, 95% CI 0.50 to 0.99, p = 0.041), suggesting that the reduced risk of death is not fully explained by higher rates of transplantation. Our study highlights systematic differences in HCC care between large volume liver transplant centres and other sites, which has not previously been well-described. Further work is needed to better define the reasons for differences in treatment allocation and to aim to minimise unwarranted treatment variation to maximise patient outcomes across Australia.

Percutaneous ablation is recommended in Barcelona Clinic Liver Cancer (BCLC) stage 0/A patients with HCC ≤3 cm as a curative treatment modality alongside surgical resection and liver transplantation. However, trans-arterial chemo-embolisation (TACE) is commonly used in the real-world as an initial treatment in patients with single small HCC in contrast to widely accepted clinical practice guidelines which typically describe TACE as a treatment for intermediate-stage HCC. We performed this real-world propensity-matched multi-centre cohort study in patients with single HCC ≤ 3 cm to assess for differences in survival outcomes between those undergoing initial TACE and those receiving upfront ablation. Patients with a new diagnosis of BCLC 0/A HCC with a single tumour ≤3 cm first diagnosed between 1 January 2016 and 31 December 2020 who received initial TACE or ablation were included in the study. A total of 348 patients were included in the study, with 147 patients receiving initial TACE and 201 patients undergoing upfront ablation. After propensity score matching using key covariates, 230 patients were available for analysis with 115 in each group. There were no significant differences in overall survival (log-rank test p = 0.652) or liver-related survival (log-rank test p = 0.495) over a median follow-up of 43 months. While rates of CR were superior after ablation compared to TACE as a first treatment (74% vs. 56%, p < 0.004), there was no significant difference in CR rates when allowing for further subsequent treatments (86% vs. 80% p = 0.219). In those who achieved CR, recurrence-free survival and local recurrence-free survival were similar (log rank test p = 0.355 and p = 0.390, respectively). Our study provides valuable real-world evidence that TACE when offered with appropriate follow-up treatment is a reasonable initial management strategy in very early/early-stage HCC, with similar survival outcomes as compared to those managed with upfront ablation. Further work is needed to better define the role for TACE in BCLC 0/A HCC.

BACKGROUND Highly effective and well-tolerated direct-acting antiviral (DAA) therapies have revolutionised the management of hepatitis C virus (HCV); however, niche populations face treatment barriers. DAAs co-prescribed with several first-generation anti-epileptic drugs (AEDs) are contraindicated due to drug-drug interactions. A common example is carbamazepine whereby steady-state carbamazepine reduces the maximum concentration and area under the curve of velpatasvir, glecaprevir and pibrentasvir due to potent cytochrome P450 (CYP) 3A4 induction. Carbamazepine also induces P-glycoprotein which reduces glecaprevir and pibrentasvir’s area under curve to infinite time. Sofosbuvir-velpatasvir and glecaprevir-pibrentasvir are contraindicated in patients who are co-prescribed carbamazepine due to the risk of reduced DAA therapeutic effect and consequently, virological treatment failure. This presents a challenge for patients in whom carbamazepine substitution is medically unfeasible, impractical or unacceptable. However, the properties of current generation DAA therapies, including high-potency non-structural protein 5A inhibitory effect, may be sufficient to overcome reduced bioavailability arising from carbamazepine related CYP 3A4 and P-glycoprotein induction. CASE SUMMARY We present a case series of three patients with non-cirrhotic, treatment-naïve, genotype 1a, 1b, and 3a HCV who were treated with a 12 wk course of glecaprevir-pibrentasvir, while co-prescribed carbamazepine for seizure disorders. Glecaprevir-pibrentasvir combination therapy was chosen due to its potent in vitro activity and low barrier to pan-genotypic resistance associated variants. DAA therapy was dose-separated from carbamazepine to maximise time to peak concentration, and taken with meals to improve absorption. Sustained virological response at 12 wk was achieved in each patient with no adverse outcomes. CONCLUSION DAA therapies, including glecaprevir-pibrentasvir, warrant consideration as a therapeutic agent in people with HCV who are co-prescribed carbamazepine, particularly if AED substitution is not feasible.