Prasun K. Jalal

The microbiome is pivotal in maintaining health and influencing disease by modulating essential inflammatory and immune responses. Hepatocellular carcinoma (HCC), ranking as the third most common cause of cancer-related fatalities globally, is influenced by the gut microbiome through bidirectional interactions between the gut and liver, as evidenced in both mouse models and human studies. Consequently, biomarkers based on gut microbiota represent promising non-invasive tools for the early detection of HCC. There is a growing body of evidence suggesting that the composition of the gut microbiota may play a role in the efficacy of immunotherapy in different types of cancer; thus, it could be used as a predictive biomarker. In this review, we will dissect the gut microbiome’s role as a potential predictive and diagnostic marker in HCC and evaluate the latest progress in leveraging the gut microbiome as a novel therapeutic avenue for HCC patients, with a special emphasis on immunotherapy.

Background and Aims Contrast‐enhanced cross‐sectional imaging is the cornerstone in the diagnosis, staging, and management of HCC, including eligibility for liver transplantation (LT). Radiological‐histopathological discordance may lead to improper staging and may impact patient outcomes. We aimed to assess the radiological‐histopathological discordance at the time of LT in HCC patients and its impact on the post‐LT outcomes. Methods We analyzed further the effect of 6‐month waiting policy on the discordance. Using United Network for Organ Sharing—Organ Procurement and Transplantation Network (UNOS‐OPTN) database, we examined the discordance between pre‐LT imaging and explant histopathology for all adult HCC patients who received liver transplants from deceased donors between April 2012 and December 2017. Kaplan–Meier methods and Cox regression analyses were used to evaluate the impact of discordance on 3‐year HCC recurrence and mortality. Results Of 6842 patients included in the study, 66.7% were within Milan criteria on both imaging and explant histopathology, and 33.3% were within the Milan based on imaging but extended beyond Milan on explant histopathology. Male gender, increasing numbers of tumors, bilobar distribution, larger tumor size, and increasing AFP are associated with increased discordance. Post‐LT HCC recurrence and death were significantly higher in patients who were discordant, with histopathology beyond Milan (adj HR 1.86, 95% CI 1.32–2.63 for mortality and 1.32, 95% CI 1.03–1.70 for recurrence). Graft allocation policy with 6‐month waiting time led to increased discordance (OR 1.19, CI 1.01–1.41), although it did not impact post‐LT outcome. Conclusion Current practice for staging of HCC based on radiological imaging features alone results in underestimation of HCC burden in one out of three patients with HCC. This discordance is associated with a higher risk of post‐LT HCC recurrence and mortality. These patients will need enhanced surveillance to optimize patient selection and aggressive LRT to reduce post‐LT recurrence and increase survival.