Liver cancer is the sixth most common cancer worldwide and 3rd most common cause of cancer-related death. Hepatocellular carcinoma (HCC) represents more than 90% of primary liver cancer and is a major public health problem. Due to the advanced stages of HCC at the time of diagnosis, utilizing the conventional treatment for solid tumors frequently ends with treatment failure, recurrence, or poor survival. HCC is highly refractory to chemotherapy and other systemic treatments, and locoregional therapies or selective internal radiation therapies are largely palliative. Considering how the pathogenesis of HCC often induces an immunosuppressed state which is further amplified by post-treatment recurrence and reactivation, immunostimulation provides a potential novel approach for the treatment of HCC. Immune response(s) of the body may be potentiated by immunomodulation of various effector cells such as B-cells, T-cells, Treg cells, natural killer cells, dendritic cells, cytotoxic T-lymphocytes, and other antigen-presenting cells; cellular components such as genes and microRNA; and molecules such as proteins, proteoglycans, surface receptors, chemokines, and cytokines. Targeting these effectors individually has helped in the development of newer therapeutic approaches; however, combinational therapies targeting multi-faceted biomarkers have yielded better results. Still, there is a need for further research to develop novel therapeutic strategies which may act as either complementary or an alternative treatment to the standard therapy protocols of HCC. This review focuses on potential cellular and molecular targets, as well as the role of virotherapy and combinational therapy in the treatment of HCC.

BackgroundHigh‐grade B‐cell lymphomas (HGBCL) with MYC and BCL2 or/and BCL6 rearrangements (R), so‐called double/triple‐hit lymphomas (DH/THL), are uncommon, clinically aggressive lymphomas that require a prompt diagnosis. We aim to identify flow cytometric immunophenotypic (IP) features of DH/THL that may aid in triaging these cases followed by a timely confirmatory cytogenetic study.MethodsWe compared the IP features of 43 cases of DH/THL to those of 55 cases of single‐hit lymphoma (SHL) and 59 cases of diffuse large B‐cell lymphoma (DLBCL) without MYC‐R (MYCneg DLBCL). We analyzed the expression patterns of CD10, CD19, CD20, CD38, and surface immunoglobulin light chain in lymphoma cells.ResultsBright CD38 expression (CD38bright) analyzed either qualitatively or semi‐quantitatively was more common in DH/THL (56%) than in MYCneg DLBCL (17%) but less common compared to SHL (82%), indicating that CD38bright can serve as a biomarker for DH/THL. Additionally, CD38bright may be a better indicator for predicting DH/THL‐BCL2 than DHL‐BCL6, and very bright CD38 expression was exclusive to MYC rearranged lymphomas. The expression patterns of other markers were similar among these lymphoma groups.ConclusionsCD38bright is a biomarker associated with DH/THL with a moderate sensitivity (~50%) and high specificity (~90%). While this marker cannot be used as a screening tool, awareness of this correlation may aid in expediting the diagnosis and prioritizing FISH testing in resource limited settings or situations when samples are limited. Future studies to combine immunohistochemical markers are needed to further enhance the predictive power of CD38bright in diagnosing DH/THL. © 2019 International Clinical Cytometry Society

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Objectives Diagnosis of high-grade B-cell lymphoma with MYC and BCL2 or BCL6 rearrangements (double-/triple-hit lymphoma [DTHL]) appears to mandate fluorescence in situ hybridization (FISH) testing for all large B-cell lymphoma (LBCL). Given the low incidence of DTHL, we aimed to identify flow cytometry (FC) and immunohistochemistry (IHC) features of DTHL that could be used to develop an optimal screening strategy. This combined FC-IHC approach has not yet been studied. Methods We compared features of 40 cases of DTHL and 39 cases of diffuse LBCL (DLBCL) without MYC rearrangement. Results Bright CD38 expression (CD38bright) by FC, high MYC expression (≥55%), and double-expressor phenotype by IHC were significantly associated with DTHL. The biomarker combining FC and IHC, CD38bright and/or MYC ≥55%, was superior to FC and IHC markers alone in predicting DTHL. Restricting FISH testing to approximately 25% of LBCL based on CD38brightand/or MYC ≥55% would detect approximately 95% of DTHL-BCL2 and approximately 75% of DHL-BCL6. Conclusions Our study demonstrated that the novel biomarker of CD38bright and/or MYC ≥55% is highly predictive of DTHL. Awareness of the advantages and limitations of this screening strategy would facilitate development of a rational diagnostic workflow to provide high-quality patient care.