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Hepatocellular carcinoma (HCC) is a common complication of cirrhosis. The incidence of HCC is rising and HCC-related mortality is rising in parallel such that there were more than 1,700 deaths in the UK in 2015. Since cirrhosis is a known risk factor for the development of HCC and early diagnosis is associated with improved outcomes, surveillance for the development of HCC using regular ultrasound scans is recommended by many expert bodies including the National Institute for Health and Care Excellence (NICE). This surveillance is not supported by high-quality evidence and there is an increasing appreciation of the associated harms. In this review the likely benefits of surveillance are discussed together with recommendations to increase the effectiveness of surveillance overall.

Alcohol-related liver disease (ARLD) and non-alcoholic fatty liver disease (NAFLD) are leading causes of chronic liver disease globally. Both ARLD and NAFLD are multifactorial and refer to a spectrum of disease severity, ranging from steatosis through steatohepatitis to fibrosis and cirrhosis. Both diseases exhibit substantial inter-patient variation in long-term outcomes and are best considered complex disease traits where genetic and environmental factors interact to mediate disease severity and progression. Here, we briefly review the current literature describing the best validated genetic modifiers that influence severity of these liver conditions, including variants of the genes PNPLA3, TM6SF2 and MBOAT7, which have also been implicated in lipid dysregulation.

Decompensated cirrhosis is a common reason for admission to the acute medical unit, and such patients typically have complex medical needs and are at high risk of in-hospital death. It is therefore vital that these patients receive appropriate investigations and management as early as possible in their patient journey. Typical presenting clinical features include jaundice, ascites, hepatic encephalopathy, hepato-renal syndrome or variceal haemorrhage. A careful history, examination and investigations can help identify the precipitating cause (infections, gastrointestinal bleeding, high alcohol intake / alcohol-related hepatitis or drug-induced liver injury), so appropriate treatment can be given. A ‘care bundle’ that has been endorsed by the British Society of Gastroenterology is available to help guide the management of patients with decompensated cirrhosis for the first 24 hours and ensure all aspects are addressed. Specific management of complications, such as infections, gastrointestinal bleeding, hepatic encephalopathy and hepatorenal syndrome, are discussed.

BackgroundBulevirtide (BLV) is a first-in-class entry inhibitor for chronic hepatitis D (CHD) which was conditionally approved in the EU. Results from the Week 48 primary endpoint analysis for MYR301, a phase 3 randomized study, showed monotherapy with BLV at 2 or 10 mg/d given subcutaneously was superior to no active anti-HDV treatment e. Here, we present findings from the predefined week 96 interim analysis of this ongoing study.Methods150 patients with CHD were randomized and stratified: Arm A: no active anti-HDV treatment for 48 weeks followed by BLV 10mg/d for 96 weeks (n=51), and Arms B or C: immediate treatment with BLV at 2 mg/d (n=49) or 10 mg/d (n=50), respectively, each for 144 weeks, with follow-up of 96 weeks after end of treatment. The combined response was defined as undetectable HDV RNA or decrease by ≥2 log10 IU/mL from baseline and ALT normalization; other endpoints included viral response, ALT normalization, log10 change in HDV RNA and change in liver stiffness by transient elastography.ResultsAt W24, 62% of participants were VR, of which 30 had ALT WNL, 22 were PR, of which 12 had ALT WNL, and 14 were NR, of which 2 had ALT WNL. (IDDF2024-ABS-0267 Table 1) Of the 36 NR or PR at W24 vs VR, mean baseline HDV RNA and median ALT at W96 were as follows: VR [5.1 log10 IU/mL, 77 U/mL], PR [4.9 log10 IU/mL, 120 U/mL], and NR [4.4 log10 IU/mL, 156 U/mL]. Of 22 PR participants at W24, 18 became VR by W96; 15 with ALT WNL) and 3 remained PR; 2 with ALT WNL.Abstract IDDF2024-ABS-0267 Table 1Shift Table for Non- and Partial Responders at Week 24 Through Week 48 and 96 BLV 2 mg Week 24 HDV RNA BLV 10 mg Week 24 HDV RNA BLV 2mg = 10 mg Week 24 HDV RNA NR PR VR NR PR VR NR PR VR n=10 n=12 n=25 n=4 n=10 n=33 n=14 n=22 n=58W48 HDV RNA Nonresponder8 (80)1 (8.3)0 (0)3 (75)0 (0)0 (0)11 (78.6)1 (4.6)0 (0) Partial Responder1 (10)0 (0)2 (8)0 (0)5 (50)1 (3)1 (7.1)5 (22.7)3 (5.2) Responder1 (10)11 (91.7)23 (92)1 (25)5 (50)32 (97)2 (14.3)16 (72.7)55 (94.8)W96 HDV RNA Nonresponder4 (40)1 (8.3)0 (0)1 (25)0 (0)0 (0)5 (35.7)1 (4.6)0 (0) Partial Responder3 (30)0 (0)2 (8)0 (0)3 (30)2 (6.1)3 (21.4)3 (13.6)4 (6.9) Responder3 (30)11 (91.7)23 (92)3 (75)7 (70)31 (93.9)6 (42.9)18 (81.8)54 (93.1)ConclusionsBLV continues to be safe and well tolerated as monotherapy for CHD through Week 96. Virological and biochemical responses increased with longer-term therapy.

BackgroundTransjugular intrahepatic portosystemic shunt (TIPS) is a minimally invasive therapeutic option to treat complications of portal hypertension. TIPS can provide long-term symptom control and prolong transplant-free survival. Recently, novel endovascular techniques, improved TIPS stent technology, and extended indications have emerged, prompting updates to international guidelines. It is unclear whether these updates are reflected in current clinical practice across TIPS centres in Australia. Moreover, there is a paucity of real-life data regarding TIPS indications, patient selection, and outcomes. Here, we investigated existing practices and benchmarked the current landscape of TIPS provision in Australia against international guidelines to assess the need for a national clinical practice guideline.MethodsWe designed a 42-item questionnaire to investigate the current landscape of TIPS services across four key domains: patient selection, best procedure practice, post-operative management, and service development.Results23 (68%) TIPS centres completed the questionnaire. This nationwide study demonstrated that the TIPS procedure is not commonly performed. Between 2017 and 2019, there were only 456 elective TIPS insertions. Units offering TIPS had a low annual caseload with 7 TIPS implantations per year. Remarkably, more than half of TIPS centres (56%) lacked institutional clinical practice guidance or any standard of care protocols, for many aspects of the TIPS procedure. More than one-third of TIPS centres are not providing pre-emptive ‘early’ TIPS for qualifying patients. There was marked variation in routine clinical practice across institutions for TIPS indications and patient selection. Despite this variation, success rates of elective procedures were high (92%), while the success rate of rescue TIPS was 87%. There was significant variation in post-TIPS follow-up care.ConclusionsThis survey represents a baseline snapshot of TIPS in ‘real life’ in Australia. The current practices differ drastically across institutions. Significant discrepancies between international guidelines for TIPS and current Australian practice exist, underscoring the need for a national consensus and registry to reduce clinical variation, improve TIPS uptake, and monitor the quality of care and outcomes.

BackgroundMacrophages are crucial in managing microbial infections. In the liver, monocyte-derived macrophages (MDMs) constitute the predominant group, representing more than half of all myeloid cells, as revealed by single-cell RNA sequencing (scRNA-seq). Despite their significance, there is still a lack of comprehensive understanding of MDMs biology during CHB.MethodsscRNA-seq data of liver samples from 23 individuals, including 6 immune tolerant (IT), 5 CHB/immune active (IA), 3 acute resolved (AR), 3 chronic resolved (CR), and 6 HBV-free healthy controls (HC) were downloaded from GSE140228. Gene expression and clinical information of liver biopsy samples from 124 CHB were downloaded from GSE84044. scRNA-seq data processing, cell pseudotime trajectory analysis and cell-cell interaction analysis were performed.ResultsHepatic MDMs could be classified into CD14_high MDMs, CD14+MDMs and CD16+MDMs based on the expression of CD14 and CD16 (IDDF2024-ABS-0359 Figure 1 (A,B)). Higher frequency of CD14_high MDMs and decreased frequency of CD14+MDMs were found in CHB (IDDF2024-ABS-035 Figure 1 (C)). In CHB, CD16+MDMs mainly diverged towards CD14_high MDMs; while in AR, CR, and HC, CD16+MDMs mainly diverged towards CD14+MDMs (IDDF2024-ABS-0359 Figure 1 (D,E)). A signature score of CD14_high MDMs was significantly associated with ALT, AST, HBV-DNA, Scheuer grade, and Scheuer stage as the higher signature score of CD14_high MDMs, the higher levels of ALT, AST, HBV-DNA, Scheuer grade, and Scheuer stage (IDDF2024-ABS-0359 Figure 2). CD14_high MDMs exhibited anti-inflammatory phenotype and MDSC-like phenotype, with decreased production of IL-1β and TNF-α and with increased expression of TGF-β1 LILRB3, VSIR, and LGALS9 (IDDF2024-ABS-0359 Figure 3). Cell-cell interaction analysis showed that CD14_high MDMs could interact with other immune cells through TGF-β-( TGF-βR1+ TGF-βR2) signaling pathway and LGALS9-CD45 signaling pathway (IDDF2024-ABS-0359 Figure 4). Pseudotime trajectory analysis showed that CD16+MDMs differentiated into CD14_high MDMs, and transcription factors of EGR1 regulated the differentiation (IDDF2024-ABS-0359 Figure 5).Abstract IDDF2024-ABS-0359 Figure 1Abstract IDDF2024-ABS-0359 Figure 2Abstract IDDF2024-ABS-0359 Figure 3Abstract IDDF2024-ABS-0359 Figure 4Abstract IDDF2024-ABS-0359 Figure 5Abstract IDDF2024-ABS-0359 Figure 6ConclusionsEGR1 drives the transition of hepatic MDMs from a pro-inflammatory phenotype to an anti-inflammatory phenotype to promote the chronic infection of HBV (IDDF2024-ABS-0359 Figure 6).

BackgroundImmune checkpoint blockade (ICB) therapies by antibodies have revolutionized the treatment paradigm for a variety of cancers. Although subsets of people exhibit durable responses, resistance and relapse are common in hepatocellular carcinoma (HCC). We, therefore, aim to delineate the mechanism underlying the failure of ICB therapy in HCC, and more importantly, to identify ICB-sensitizing therapeutic approaches.MethodsICB-resistant orthotopic-grafted murine models were established via a serial selection of HCC cells in ICB-treated mice. A genetically engineered mouse model was established via hydrodynamic tail-vein delivery of oncogenes. Integrated multi-omics analysis (single-cell RNA-seq, single-cell ATAC-seq and ChIP-seq) was applied to decode the mechanisms underlying the ICB resistance.ResultsWe successfully established the ICB-resistant murine models of HCC, in which tumor intrinsic interferon-gamma (IFNγ) response was most significantly suppressed and characterized by a ‘cold’ tumor microenvironment with decreased lymphocyte activation and intratumoral infiltration. Notably, we found that a novel specific class I histone deacetylase (HDAC) inhibitor CXD101 synergised with PD-(L)1 antibody to eradicate the tumor and prolong survival in our ICB-resistant mouse models, which was accompanied by enhanced intratumoral infiltration, activation and anti-tumor memory formation of cytotoxic lymphocytes. Mechanistically, CXD101 combined with PD-(L)1 inhibition synergistically recovered the silenced tumor IFNγ pathway via enhancing Stat1 enhancer activation and chromatin accessibility, thereby triggering the expression of antigen presentation and lymphocyte recruitment-associated genes. Moreover, the activated immune system induced tumor cell pyroptosis via GSDME, which was epigenetically upregulated by CXD101 treatment, further igniting antitumor immunity and ICB response.ConclusionsOur findings suggest that corruption of tumor intrinsic IFNγ signaling may confer ICB resistance upon ICB therapy, which can be rectified by class I HDAC inhibitor mediated IFNγ response and tumor cell pyroptosis. Based on these findings, industrial support for the Phase II clinical study of CXD101 plus anti-PD-1 has been secured to provide new epigenetic immunotherapy for ICB-resistant patients.This project is supported by the CRF (C4045-18W), GRF (14115820), TRS (T11-706/18-N), Li Ka Shing Foundation, CUHK Strategic Seed Funding for Collaborative Research Scheme.

BackgroundApproximately 700 dialysis patients are seen at our hospital. Among them are patients with HCC that develop viral hepatitis. Advances in ultrasound systems have improved the accuracy of HCC treatment and diagnosis. This time, we had the opportunity to use microwaves for dialysis patients using Smart Fusion and needle navigation installed in APLIOi800 so that we will report it.MethodsTen dialysis patients were treated from January 2018 to February 2023. An Emprint (Covidien, USA) antenna was used for treatment. Canon APLIOi800(Canon, Tochigi, Japan) was used. The built-in function is Smart Fusion. This method can display ultrasound imaging and volume data from other modalities, such as CT and MRI, in association with positional information using a magnetic sensor. Needle navigation has a function that can confirm the position of the needle. It is possible to treat even when the tumor is overprinted and the visualization is poor due to bubbles. Informed consent was obtained from all patients and the treatment was performed.ResultsIt was possible to visualize all tumors. In this study, CT images were used in 0 cases, and MRI was used in 1 Case. No serious side effects occurred after treatment.ConclusionsUsing this method, it was thought that dialysis patients could be safely and accurately treated.