Immune checkpoint inhibitors (ICIs) have revolutionised the treatment landscape for advanced hepatocellular carcinoma (HCC). The combination of atezolizumab and bevacizumab has demonstrated efficacy, establishing a new standard of care for advanced HCC. Neoadjuvant studies have shown promising results with high response rates, increasing research into ICIs' role.
View Article and Find Full Text PDFHepatocytes are organized into distinct zonal subsets across the liver lobule, yet their contributions to liver homeostasis and regeneration remain controversial. Here, we developed multiple genetic lineage-tracing mouse models to systematically address this. We found that the liver lobule can be divided into two major zonal and molecular hepatocyte populations marked by Cyp2e1 or Gls2.
View Article and Find Full Text PDFBackground: Cholecystectomy (CCE) can affect the enterohepatic circulation of bile acids and result in gut microbiome changes. This systematic review aimed to clarify the effect of CCE on gut microbiome composition and its clinical impact.
Method: A systematic search was conducted in PubMed, Web of Science, and Scopus, combining keywords such as "cholecystectomy" or "post-cholecystectomy" with "gut microbiome," "stool microbiome," or "gut dysbiosis.
Background: Surgical resection is a curative therapy for early-stage hepatocellular carcinoma (HCC) patients meeting the Milan criteria as well as a widely used therapy in intermediate-stage HCC. However, intermediate-stage HCC encompasses a wide spectrum of disease and there is a lack of good predictive models for the long-term clinical outcome of HCC patients currently. Here, the authors adopt Mazzaferro's Metroticket 2.
View Article and Find Full Text PDFBackground: Hepatocellular carcinoma (HCC) is a deadly cancer with a high global mortality rate, and the downregulation of GATA binding protein 4 (GATA4) has been implicated in HCC progression. In this study, we investigated the role of GATA4 in shaping the immune landscape of HCC.
Methods: HCC tumor samples were classified into "low" or "normal/high" based on GATA4 RNA expression relative to adjacent non-tumor liver tissues.
Objective: Currently, little is known about the mechanism(s) regulating global and specific protein translation during metabolic dysfunction-associated steatohepatitis (MASH; previously known as non-alcoholic steatohepatitis, NASH).
Methods: Unbiased label-free quantitative proteome, puromycin-labelling and polysome profiling were used to understand protein translation activity in vitro and in vivo.
Results: We observed a global decrease in protein translation during lipotoxicity in human primary hepatocytes, mouse hepatic AML12 cells, and livers from a dietary mouse model of MASH.
Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related mortality worldwide. The emergence of combination therapy, atezolizumab (anti-PDL1, immune checkpoint inhibitor) and bevacizumab (anti-VEGF) has revolutionised the management of HCC. Despite this breakthrough, the best overall response rate with first-line systemic therapy is only about 30%, owing to intra-tumoural heterogeneity, complex tumour microenvironment and the lack of predictive biomarkers.
View Article and Find Full Text PDFThe coronavirus disease 2019 (COVID-19) pandemic drove many healthcare systems worldwide to postpone elective surgery to increase healthcare capacity, manpower, and reduce infection risk to staff. The aim of this study was to assess the impact of an elective surgery postponement policy in response to the COVID-19 pandemic on surgical volumes and patient outcomes for three emergency bellwether procedures. A retrospective cohort study of patients who underwent any of the three emergency procedures [Caesarean section (CS), emergency laparotomy (EL), and open fracture (OF) fixation] between 1 January 2018 and 31 December 2021 was conducted using clinical and surgical data from electronic medical records.
View Article and Find Full Text PDFBackground: No adjuvant treatment has been established for patients who remain at high risk for hepatocellular carcinoma recurrence after curative-intent resection or ablation. We aimed to assess the efficacy of adjuvant atezolizumab plus bevacizumab versus active surveillance in patients with high-risk hepatocellular carcinoma.
Methods: In the global, open-label, phase 3 IMbrave050 study, adult patients with high-risk surgically resected or ablated hepatocellular carcinoma were recruited from 134 hospitals and medical centres in 26 countries in four WHO regions (European region, region of the Americas, South-East Asia region, and Western Pacific region).
Introduction: Despite recent advances in immunotherapy for hepatocellular carcinoma (HCC), the overall modest response rate underscores the need for a better understanding of the tumor microenvironment (TME) of HCC. We have previously shown that CD38 is widely expressed on tumor-infiltrating leukocytes (TILs), predominantly on CD3 T cells and monocytes. However, its specific role in the HCC TME remains unclear.
View Article and Find Full Text PDFSpalt-like transcription factor 4 (SALL4) is an oncofetal protein that has been identified to drive cancer progression in hepatocellular carcinoma (HCC) and hematological malignancies. Furthermore, a high SALL4 expression level is correlated to poor prognosis in these cancers. However, SALL4 lacks well-structured small-molecule binding pockets, making it difficult to design targeted inhibitors.
View Article and Find Full Text PDFBackground: Liver transplantation remains the optimal treatment for multifocal hepatocellular carcinoma (HCC). However, due to resource constrains, other therapeutic modalities such as liver resection (LR), are frequently utilized. LR, however, has to be balanced against potential morbidity and mortality along with the risks of early recurrence leading to futile surgery.
View Article and Find Full Text PDFBackground: Conventional differential expression (DE) testing compares the grouped mean value of tumour samples to the grouped mean value of the normal samples, and may miss out dysregulated genes in small subgroup of patients. This is especially so for highly heterogeneous cancer like Hepatocellular Carcinoma (HCC).
Methods: Using multi-region sampled RNA-seq data of 90 patients, we performed patient-specific differential expression testing, together with the patients' matched adjacent normal samples.
Introduction: Our primary objective was to determine if receiving intraoperative blood transfusion was a significant prognostic factor for overall and recurrence-free survival after curative resection of hepatic cellular carcinoma (HCC).
Methodology: Between 2001 and 2018, 1092 patients with histologically proven primary HCC who underwent curative liver resection were retrospectively reviewed. Primary study endpoints were recurrence-free survival (RFS) and overall survival (OS).
IL-17-producing CD8 (Tc17) T cells have been shown to play an important role in infection and chronic inflammation, however their implications in hepatocellular carcinoma (HCC) remain elusive. In this study, we performed cytometry by time-of-flight (CyTOF) and revealed the distinctive immunological phenotypes of two IFNγ and IFNγ Tc17 subsets that were preferentially enriched in human HCC. Single-cell RNA-sequencing analysis further revealed regulatory circuits governing the different phenotypes of these Tc17 subsets.
View Article and Find Full Text PDFBackground: The Memorial Sloan Kettering Cancer Center nomogram, the predictive scoring system of Yamamoto et al, and the 3-point transfusion risk score of Lemke et al are models used to determine the probability of receiving intraoperative blood transfusion in patients undergoing liver resection. However, the external validity of these models remains unknown. The objective of this study was to evaluate their predictive performance in an external cohort of patients with hepatocellular carcinoma.
View Article and Find Full Text PDFObjective: We aimed to prognosticate survival after surgical resection of HCC stratified by stage with amalgamation of the modified Barcelona Clinic Liver Cancer (BCLC) staging system and location of tumour.
Methods: This single-institutional retrospective cohort study included patients with HCC who underwent surgical resection between 1st January 2000 to 30th June 2016. Participants were divided into 6 different subgroups: A-u) Within MC with Unilobar lesions; A-b) Within MC + Bilobar lesions; B1-u) Out of MC + within Up-To-7 + Unilobar lesions; B1-b) Out of MC + within Up-to-7 + Bilobar lesions; B2-u) Out of MC + Out of Up-To-7 + Unilobar lesions; B2-b) Out of MC + Out of Up-To-7 + Bilobar lesions.
Background: Hepatocellular carcinoma (HCC) remains difficult to treat due to limited effective treatment options. While the proteasome inhibitor bortezomib has shown promising preclinical activity in HCC, clinical trials of bortezomib showed no advantage over the standard-of-care treatment sorafenib, highlighting the need for more clinically relevant therapeutic strategies. Here, we propose that rational drug combination design and validation in patient-derived HCC avatar models such as patient-derived xenografts (PDXs) and organoids can improve proteasome inhibitor-based therapeutic efficacy and clinical potential.
View Article and Find Full Text PDFHepatocellular carcinoma (HCC) is one of the deadliest cancer types with diverse etiological factors across the world. Although large scale genomic studies have been conducted in different countries, integrative analysis of HCC genomes and ethnic comparison across cohorts are lacking. We first integrated genomes of 1,349 HCC patients from five large cohorts across the world and applied multiple statistical methods in identifying driver genes.
View Article and Find Full Text PDFBackground & Aims: Several recent clinical studies have shown that serum homocysteine (Hcy) levels are positively correlated, while vitamin B (B) and folate levels are negative correlated, with non-alcoholic steatohepatitis (NASH) severity. However, it is not known whether hyperhomocysteinemia (HHcy) plays a pathogenic role in NASH.
Methods: We examined the effects of HHcy on NASH progression, metabolism, and autophagy in dietary and genetic mouse models, patients, and primates.