Model for End-Stage Liver Disease (MELD) incorporates serum creatinine (sCr), a poor measure of renal function in cirrhotic patients. Females have higher waitlist mortality, which is proposed to be due to lower muscle mass and consequent lower sCr values. This study evaluated the difference (ΔCr) between sCr and calculated creatinine (cCr) derived from measured glomerular filtration rate (mGFR) in cirrhosis. The effect of sex and muscle mass on ΔCr and MELD was studied for bias. One hundred thirty-nine cirrhotic patients assessed for liver transplantation (LT) from 2019 to 2024 were included. Forty-eight living kidney donors were the controls (n=48). The CKD-EPI equation was rearranged to determine cCr as a function of mGFR. MELD, MELD-Na, and MELD 3.0 scores were calculated using cCr and sCr; and the difference was ΔMELD, ΔMELD-Na, and ΔMELD 3.0. Skeletal muscle index (SMI, cm 2 /m 2 ) was calculated from CT images at the L3 level. Mean cCr was significantly higher than mean sCr ( p <0.001) in the study group but not the controls. In the study group, there was no difference in mean ΔCr between males (27.5±41.7 μmol/L) and females (33.9±53.1 μmol/L), p =0.45. SMI and bilirubin were independently associated with ΔCr after adjusting for sex, SMI, INR, albumin, and sodium ( p =0.01 and p =0.02, respectively). There was no difference between male and female values of ΔMELD ( p =0.76), ΔMELD-Na ( p =0.79), or ΔMELD 3.0 ( p =0.57). Low muscle mass was independently associated with ΔCr, ΔMELD, ΔMELD-Na, and ΔMELD 3.0 regardless of sex. There was also no difference in ΔCr, ΔMELD, ΔMELD-Na, and ΔMELD 3.0 between males and females in patients with measured GFR≤60 mL/min/1.73 m 2 . Serum creatinine and MELD scores are likely to be underestimated due to reduced muscle mass rather than female sex in cirrhotic patients on the LT waitlist.

INTRODUCTION:Portal vein tumour thrombus (PVTT) is a common complication of hepatocellular carcinoma (HCC) and has a poor prognosis. Selective internal radiation therapy (SIRT) with Yttrium-90 (Y90) microspheres is a minimally invasive treatment option that has shown promise in treating PVTT. Studies have suggested a survival advantage of SIRT in this population, but data in the Australasian population are lacking. The aim of this study was to evaluate the safety and efficacy of SIRT in a series of patients at an Australian hospital with advanced HCC and PVTT. METHOD:All patients underwent pre-treatment imaging with MRI or CT, and immediate post-treatment imaging with Y90 PET CT and MRIs at 3-, 6-, 9- and 12-months. The primary endpoints were time to progression (TTP) and overall survival (OS) post-SIRT. The secondary endpoint was safety. RESULTS:Of the 698 patients who underwent SIRT at our institution between 2007 and 2023, 64 patients had HCC and PVTT. 59/64 (92%) were male, with a median age of 61 years (range 37-86 years). The majority of patients had Child-Pugh a cirrhosis (87%), and the majority were ECOG 0 (91%). The majority had main PVTT at the time of SIRT. All patients underwent SIRT with Y90-coated resin microspheres (SIR-Spheres, Sirtex Medical, Australia). Personalised dosimetry planning was performed by the treating interventional radiologist. SIRT was well tolerated by most patients, with major complications reported in a minority of cases (19/64 patients had an episode of biochemical decompensation within 90 days following treatment). The median TTP was 4.8 months (range 1-48 months). The median OS was 11.5 months (range 1-80 months), with those with a favourable MAAPE score having a median OS of 21.2 months (12.6-29.7 months). CONCLUSIONS:Our cohort suggests that SIRT is a safe and effective treatment option for a difficult-to-treat patient population. Our data suggest a longer OS for those with preserved liver function, good functional status and low AFP levels at 21.2 months. Poor pre-treatment liver function and functional status are predictors of decompensation, and decompensation is a predictor of poor survival. These data provide an Australasian perspective and support the expanding role of SIRT in HCC treatment guidelines. Further prospective studies with larger sample sizes and longer follow-up are warranted to confirm these findings.

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.

Selective androgenic receptor modulators (SARMs) have not been approved by the U.S. Food and Drug Administration but they are heavily promoted as alternatives to androgenic anabolic steroids. We present two cases of liver injury associated with SARMs.

BACKGROUND:Clinical guidelines list active fungal infection and sepsis as contraindications to liver transplantation due to the risk of worsening infection with immunosuppression postoperatively. Mortality from systemic opportunistic infections in transplant recipients is high, approaching 100% for disseminated aspergillosis. However, the optimal duration of treatment required before transplant is unclear. Additionally, delaying surgery while the infection is treated risks death from hepatic decompensation and physical deconditioning, preventing progression to transplantation.CASE REPORT:Here, we present a patient who underwent successful repeat liver transplantation for recurrent autoimmune hepatitis and graft rejection while undergoing treatment for disseminated aspergillosis and nocardiosis. He had pulmonary, hepatic, and central nervous system involvement. He had received 2 months of antimicrobials but had ongoing radiologic evidence of infection when listed for retransplantation. He remains well and infection-free 1 year postoperatively.CONCLUSION:Few cases of successful liver transplantation in the setting of disseminated aspergillosis have been reported previously. To our knowledge, this is the first successful liver transplant in a patient with disseminated nocardial infection.

BACKGROUND:Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths worldwide. Liver transplantation (LT) offers the most effective treatment. HCC recurrence is the strongest risk factor that decreases post-LT survival in patients transplanted for HCC. The rate of HCC recurrence is generally reported as 8%-20% in the literature. Many predictors of HCC have already been researched, however, to our knowledge there are no published studies on this topic using Australian data. AIM:To determine the rate and identify predictors of HCC recurrence in a contemporary Western Australian LT cohort. METHODS:We performed a retrospective cohort study of all liver transplants in patients with HCC at Sir Charles Gairdner Hospital between 2006 and 2021. Data was collected from various health record databases and included recipient demographics, serum biochemistry, radiology, operation notes, explant histopathology and details of recurrence. Overall survival of HCC patients post-LT, stratified for recurrence, was calculated by Kaplan Meier analysis. Univariate and multivariate Cox regression was used to determine predictors of HCC recurrence post-LT. RESULTS:Between 1/1/2006 and 12/31/2021, 119 patients were transplanted with HCC. 8.4% of subjects developed recurrent HCC after LT with median follow-up time of 5.4 years. The median time to recurrence was 2.9 years ± 0.75 years. When comparing baseline characteristics, a greater proportion of subjects with recurrence had common characteristics on explant histopathology, including > 3 viable nodules (P = 0.001), vascular invasion (P = 0.003) and poorly differentiated HCC (P = 0.03). Unadjusted survival curves showed lower 1-year, 3-year, 5-year and 10-year survival rates in subjects with HCC recurrence compared to those without HCC recurrence (90% vs 92%, 70% vs 88%, 42% vs 80%, 14% vs 76%, respectively; log rank P < 0.001). CONCLUSION:HCC recurrence was low at 8.4% in this contemporary Australian cohort, however it significantly impacted post-LT survival. Further studies are required to confirm predictors of recurrence and improve recipient outcomes.

Onco-fetal reprogramming of the tumor ecosystem induces fetal developmental signatures in the tumor microenvironment, leading to immunosuppressive features. Here, we employed single-cell RNA sequencing, spatial transcriptomics and bulk RNA sequencing to delineate specific cell subsets involved in hepatocellular carcinoma (HCC) relapse and response to immunotherapy. We identified POSTN + extracellular matrix cancer-associated fibroblasts (EM CAFs) as a prominent onco-fetal interacting hub, promoting tumor progression. Cell–cell communication and spatial transcriptomics analysis revealed crosstalk and co-localization of onco-fetal cells, including POSTN + CAFs, FOLR2 + macrophages and PLVAP + endothelial cells. Further analyses suggest an association between onco-fetal reprogramming and epithelial–mesenchymal transition (EMT), tumor cell proliferation and recruitment of T reg cells, ultimately influencing early relapse and response to immunotherapy. In summary, our study identifies POSTN + CAFs as part of the HCC onco-fetal niche and highlights its potential influence in EMT, relapse and immunotherapy response, paving the way for the use of onco-fetal signatures for therapeutic stratification.

AbstractAn 81 year old male with Child‐Pugh A cirrhosis and metastatic hepatocellular carcinoma (HCC) treated with 3‐weekly atezolizumab and bevacizumab developed a pulmonary sarcoid‐like reaction (SLR) after 5 months. Atezolizumab, an immune checkpoint inhibitor, was identified as the likely culprit. He was treated with prednisolone, resulting in improvement, and was successfully rechallenged with both atezolizumab and bevacizumab.

Both fetal and tumor tissue microenvironments display immunosuppressive features characterized by the presence of specific immunomodulatory stromal and immune cell populations. Recently, we discovered shared microenvironments between hepatocellular carcinoma (HCC) and fetal tissues and described this phenomenon as an oncofetal ecosystem. This ecosystem includes fetal-like immune (macrophage) and stromal (endothelial) cells within the tumor microenvironment (TME). This discovery highlights reciprocal interactions between fetal-like macrophages and T cells which result in the orchestration of an immunosuppressive TME. Importantly, VEGF-A protein expression by tumor cells and fetal-like macrophages plays an important role in oncofetal reprogramming of the TME in HCCs. Interestingly, recent clinical data indicate that blocking VEGF-A or CTLA4 alongside PD-L1 is effective in treating advanced HCC. Consequently, some immunotherapies may target and rely on oncofetal cells for clinical responsiveness. This understanding provides exciting opportunities to utilize oncofetal niche characteristics as biomarkers of immunotherapy response in HCC and might also have validity for predicting responses to immunotherapy in other cancers. In this review, we explore the immunosuppressive mechanisms and interactions of oncofetal cells in the TME of HCC and their potential implications for immunotherapy response.

Background and Aims: Management of NAFLD involves noninvasive prediction of fibrosis, which is a surrogate for patient outcomes. We aimed to develop and validate a model predictive of liver-related events (LREs) of decompensation and/or HCC and compare its accuracy with fibrosis models. Approach and Results: Patients with NAFLD from Australia and Spain who were followed for up to 28 years formed derivation (n = 584) and validation (n = 477) cohorts. Competing risk regression and information criteria were used for model development. Accuracy was compared with fibrosis models using time-dependent AUC analysis. During follow-up, LREs occurred in 52 (9%) and 11 (2.3%) patients in derivation and validation cohorts, respectively. Age, type 2 diabetes, albumin, bilirubin, platelet count, and international normalized ratio were independent predictors of LRE and were combined into a model [NAFLD outcomes score (NOS)]. The NOS model calibrated well [calibration slope, 0.99 (derivation), 0.98 (validation)] with excellent overall performance [integrated Brier score, 0.07 (derivation) and 0.01 (validation)]. A cutoff ≥1.3 identified subjects at a higher risk of LRE, (sub-HR 24.6, p < 0.001, 5-year cumulative incidence 38% vs 1.0%, respectively). The predictive accuracy at 5 and 10 years was excellent in both derivation (time-dependent AUC,0.92 and 0.90, respectively) and validation cohorts (time-dependent AUC,0.80 and 0.82, respectively). The NOS was more accurate than the fibrosis-4 or NAFLD fibrosis score for predicting LREs at 5 and 10 years ( p < 0.001). Conclusions: The NOS model consists of readily available measures and has greater accuracy in predicting outcomes in patients with NAFLD than existing fibrosis models.

Liver fibrosis predicts adverse clinical outcomes, such as liver-related death (LRD) and hepatocellular carcinoma (HCC) in patients with non-alcoholic fatty liver disease (NAFLD). We aimed to investigate the accuracy of semi-automated quantification of collagen proportionate area (CPA) as an objective new method for predicting clinical outcomes. Liver biopsies from patients with NAFLD underwent computerized image morphometry of Sirius Red staining with CPA quantification performed by ImageScope. Clinical outcomes, including total mortality, LRD, and combined liver outcomes (liver decompensation, HCC, or LRD), were determined by medical records and population-based data-linkage. The accuracy of CPA for predicting outcomes was compared with non-invasive fibrosis tests (Hepascore, FIB-4, APRI). A total of 295 patients (mean age 50 years) were followed for a median (range) of 9 (0.2–25) years totalling 3253 person-years. Patients with CPA ≥ 10

Non-invasive tests are widely used to diagnose fibrosis in patients with non-alcoholic fatty liver disease (NAFLD), however, the optimal method remains unclear. We compared the accuracy of simple serum models, a serum model incorporating direct measures of fibrogenesis (Hepascore), and Fibroscan®, for detecting fibrosis in NAFLD. NAFLD patients undergoing liver biopsy were evaluated with Hepascore, NAFLD Fibrosis Score (NFS), FIB-4 and AST-platelet ratio index (APRI), with a subset (n = 131) undergoing Fibroscan®. Fibrosis on liver biopsy was categorized as advanced (F3–4) or cirrhosis (F4). Accuracy was determined by area under receiving operating characteristic curves (AUC). Indeterminate ranges were calculated using published cut-offs. In 271 NAFLD patients, 83 (31

BACKGROUND & AIMS: Metabolic dysfunction-associated fatty liver disease (MAFLD) is managed predominately in primary care, however, there is uncertainty regarding how to best identify patients for specialist referral. We examined the accuracy of noninvasive tests as screening tools for the prediction of outcomes in MAFLD patients referred from primary care. METHODS: Patients with MAFLD referred by primary care for specialist review to Sir Charles Gairdner Hospital (cohort 1, n = 626) or tertiary centers within Western Australia (cohort 2, n = 246) were examined. Hepascore, aspartate aminotransferase to platelet ratio, Fibrosis-4 (FIB-4), and nonalcoholic fatty liver disease fibrosis score performed at baseline were examined for their accuracy in predicting liver-related death (LRD), decompensation, and hepatocellular carcinoma. Outcomes were collected from hospital records and data linkage. RESULTS: The median follow-up period was 5.0 years (range, 0.1-13.0 y) and 3.8 years (range, 0.1-10.0 y) in cohorts 1 and 2, respectively. In both cohorts, Hepascore and FIB-4 had the highest area under the curve for the prediction of LRD (0.90-0.95 and 0.83-0.94, respectively), decompensation (0.86-0.91 and 0.86-0.87, respectively), and hepatocellular carcinoma (0.750.90 and 0.67-0.85, respectively). The sensitivity and negative predictive values were high (>90%) for Hepascore (cut-off value, 0.60), FIB-4 (cut-off value, 1.30), and nonalcoholic fatty liver disease fibrosis score (cut-off value, -1.455) for all outcomes in cohort 1, and for predicting LRD in cohort 2. Hepascore had the highest specificity, classified the greatest proportion of patients as low risk, and was favored by decision curve analysis as providing the greatest net benefit. CONCLUSIONS: Serum noninvasive tests accurately stratify risk of liver-related outcomes in MAFLD patients and can be used as a screening tool for patients referred for specialist review by primary care.