Inflamed and non-inflamed classes of HCC: a revised immunogenomic classification.

OBJECTIVE: We previously reported a characterisation of the hepatocellular carcinoma (HCC) immune contexture and described an immune-specific class. We now aim to further delineate the immunogenomic classification of HCC to incorporate features that explain responses/resistance to immunotherapy. DESIGN: We performed RNA and whole-exome sequencing, T-cell receptor (TCR)-sequencing, multiplex immunofluorescence and immunohistochemistry in a novel cohort of 240 HCC patients and validated our results in other cohorts comprising 660 patients. RESULTS: Our integrative analysis led to define: (1) the inflamed class of HCC (37%), which includes the previously reported immune subclass (22%) and a new immune-like subclass (15%) with high interferon signalling, cytolytic activity, expression of immune-effector cytokines and a more diverse T-cell repertoire. A 20-gene signature was able to capture ~90% of these tumours and is associated with response to immunotherapy. Proteins identified in liquid biopsies recapitulated the inflamed class with an area under the ROC curve (AUC) of 0.91; (2) The intermediate class, enriched in TP53 mutations (49% vs 29%, p=0.035), and chromosomal losses involving immune-related genes and; (3) the excluded class, enriched in CTNNB1 mutations (93% vs 27%, p<0.001) and PTK2 overexpression due to gene amplification and promoter hypomethylation. CTNNB1 mutations outside the excluded class led to weak activation of the Wnt-ßcatenin pathway or occurred in HCCs dominated by high interferon signalling and type I antigen presenting genes. CONCLUSION: We have characterised the immunogenomic contexture of HCC and defined inflamed and non-inflamed tumours. Two distinct CTNNB1 patterns associated with a differential role in immune evasion are described. These features may help predict immune response in HCC.

Using a breathing simulator to improve simulation-based education for noninvasive ventilation.

Simulation-based medical education is recognised as a highly effective training tool. Novel technologies such as breathing simulators have the potential to revolutionise how we train healthcare professionals to manage patients requiring NIV. https://bit.ly/3f4Hnt1.

Surveillance for hepatocellular carcinoma in a mixed-aetiology UK cohort with cirrhosis: does α-fetoprotein still have a role?

Mortality from hepatocellular carcinoma (HCC) in people with cirrhosis is increasing whereas mortality from other causes is declining. Surveillance appears to reduce mortality but the optimal strategy is uncertain. Current guidelines differ by recommending ultrasonography alone or with α-fetoprotein (αFP). Records in three UK hospitals were analysed from 2006 to 2011. Of 111 HCC cases identified, 24 (47.1%) of those eligible were under surveillance: 21 (87.5%) were under combined ultrasonography-αFP, 2 (8.3%) ultrasonography-only and 1 (4.2%) αFP-only surveillance. αFP was elevated in 19 (86.4%), and αFP alone triggered a confirmatory study in 11 (9.9%) overall and 7 (29.1%) under surveillance. Surveillance, but not αFP, correlated with smaller tumours. Survival did not differ significantly between groups. Given that αFP use is associated with identifying smaller HCCs and that several diagnoses would have been delayed without αFP in this real-life cohort, these data support ongoing αFP use. However, further work is necessary with regard to whether αFP translates into improved clinical outcome and overall cost effects. In our area, stopping αFP use would also represent a significant change in practice.