Diagnosis and Treatment for Hepatocellular Tumors (Volume II)

Dear Colleagues,

This Special Issue is the Second Edition of a previous Special Issue, “Diagnosis and Treatment for Hepatocellular Tumors” (https://www.mdpi.com/journal/cancers/special_issues/Diagnosis_Treatment_Hepatocellular).

Hepatocellular carcinoma (HCC) is the most prevalent primary liver cancer, accounting for >80% of primary liver cancers worldwide, with geographical variations among its prevalence. It is the leading cause of death in patients with cirrhosis, with an annual HCC incidence of 1–6%. The diagnosis of HCC, relying solely on noninvasive criteria, is currently under debate due to the need for molecular information that necessitates tissue biopsies, while therapy is provided in accordance with tumor stages and the anticipated advantages of major interventions, following the Barcelona Clinic Liver Cancer (BCLC) staging system. Principally, resection, transplantation and local ablation are most commonly performed in patients with early-stage HCC tumors, while TACE and systemic therapy are respectively the preferred treatment options for intermediate- and advanced-stage tumors. However, the HCC tumor immune microenvironment (TME) affects response to current anti-PD-1/PD-L1 immunotherapies. Therefore, an enhanced understanding of the immunobiology of TME is essential for the development of predictive biomarkers of patient stratification and strategies of drug combinations to improve therapeutic efficacy, especially for patients with tumors unresponsive to anti-PD-1/PD-L1 therapy. Taking into account the health burden of HCC worldwide, with this Special Issue we aim to enhance our knowledge of innovative diagnostic and prognostic methods, and to discuss experimentation with different novel treatment modalities, believed to be of utmost priority to progress in our seemingly never-ending fight against hepatocellular cancer.

To date, there are no definite biomarkers in HCC that can accurately predict response or resistance to ICIs, while as the HCC treatment regimens have shifted towards immunotherapy, the identification of potent predictive and prognostic biomarkers has attracted attention. Although HCC formation has been attributed to certain viral or non-viral causes, nonalcoholic steatohepatitis (NASH), is a major driver of HCC as well . Recent data suggest that NASH-related HCC might have decreased sensitivity to immunotherapy, due to the presence of CD8+ T cells and, especially, of the hepatic steatosis-induced CXCR6+ subset that was correlated with hepatocyte injury and potentiated the pathogenesis of NASH-related HCC via the secretion of pro-inflammatory cytokines and direct hepatocyte killing, mediated by the tumor necrosis factor (TNF) . Moreover, local and systemic inflammation are considered hallmarks of cancer, and they have a pivotal role in HCC pathogenesis and progression . An increased peripheral blood absolute neutrophil count and an elevated neutrophil to lymphocyte ratio (NLR ≥ 5) are considered markers of advanced disease, poor prognosis, and poor response to treatment with hepatic resection, transplantation, locoregional therapy, and tyrosine kinase inhibitors in patients with HCC. Indeed, systemic inflammation measured by NLR is independently a negative prognostic factor for patients with HCC under ICI therapy [6]. The measurement of the NLR across various time points could provide insight into how different values of this inflammatory marker could accurately predict patient response to systemic therapy, patient outcomes, or the development of adverse events (AEs).

In the clinical setting of early-stage, operable HCC, the optimal liver function reserve, good performance status, greater potential to tolerate immune-related toxicities, and increased chances of cure in this patient population provide support for the neoadjuvant use of immunotherapy. For patients with inoperable disease at diagnosis, immunotherapy may provide a downstaging strategy capable of converting a patient into a resection candidate. Similarly, neoadjuvant immunotherapy administered to patients awaiting LT may achieve downstaging of patients within the MC or provide prognostic information useful when deciding transplant eligibility, although safety data regarding the risk of immunotherapy-induced rejection represent a significant knowledge gap, given the long half-lives of commonly used agents. Neoadjuvant immunotherapy in HCC may improve surgical outcomes, treat micrometastatic disease early in the disease trajectory , but objectives for future studies will include understanding the characteristics and prognostic importance of response to neoadjuvant therapy, devising the optimal combinations of agents and duration of therapy in the neoadjuvant setting, and determining whether subsequent adjuvant therapy after definitive surgical treatment will be required in all patients.

Prof. Dr. Georgios Germanidis
Prof. Dr. Dimitris C. Zacharoulis
Guest Editors

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