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Despite the latest advances in hepatocellular carcinoma (HCC) screening and treatment modalities, HCC is still representing a global burden. Most HCC patients present at later stages to an extent that conventional curative options are ineffective. Hence, systemic therapy represented by the tyrosine kinase inhibitor, sorafenib, in the first-line setting is the main treatment modality for advanced-stage HCC. However, in the two groundbreaking phase III clinical trials, the SHARP and Asia-Pacific trials, sorafenib has demonstrated a modest prolongation of overall survival in almost 30% of HCC patients. As HCC develops in an immune-rich milieu, particular attention has been placed on immune checkpoint inhibitors (ICIs) as a novel therapeutic modality for HCC. Yet, HCC therapy is hampered by the resistance to chemotherapeutic drugs and the subsequent tumor recurrence. HCC is characterized by substantial genomic heterogeneity that has an impact on cellular response to the applied therapy. And hence, this review aims at giving an insight into the therapeutic impact and the different mechanisms of resistance to sorafenib and ICIs as well as, discussing the genomic heterogeneity associated with such mechanisms.

Background. Deregulation of the Wnt signaling pathway had a role in haematological malignancies. Previous studies reported that lymphoid enhancer factor 1 (LEF1) expression and serum Galectin-3 level could affect clinical parameters and outcome in acute myeloid leukemia patients, but as far as we know, no study has addressed their combined effect on AML patients. Aim. We studied the expression of LEF1 by real-time qPCR and measured serum level of Gal.3 by ELISA technique in peripheral blood of 69 AML patients and correlated it with different clinicopathological criteria of patients, response, PFS and OS. Results. We found high expression (LEF1high) was associated with better OS (p=0.02) and EFS (p=0.019) compared to LEF1low, low serum Gal.3 level had better OS (p=0.014) and EFS (p=0.02) compared to high serum Gal.3 level. LEF1high less likely to carry a FLT3-ITD (p=0.047) compared to LEF1low patient, also LEF1high characterized by favorable risk (p=0.02) than LEF1low patients. While patients with higher Gal-3 levels characterized by poor risk (p=0.02) than lower Gal.3 lels, also more likely to carry a FLT3-ITD with borderline significance (p=0.054). Combined LEF1high/Gal.3 low patients had lower baseline blast percentages (p=0.02), favorable risk (p=0.01), less likely to carry FLT3-ITD (p=0.02), higher CR rate (p=0.055), shorter time to CR (0.001) than other groups. Among high Gal.3 level group, LEF1high expression improved OS and EFS (20 and 15 months respectively) vs LEF1low expression (13 and 8 months respectively). Conclusion. We conclude that high LEF1 expression was a favorable prognostic marker which can define AML patient risk and outcome independent from assessing the serum galectin.3 level.

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