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Background: Although the most common intracranial neoplasm in the adult population is metastatic tumors, brain metastasis from hepatocellular carcnoma (HCC) are very rare. The aim of this study is to analyze patients with advanced HCC, in order to determine the incidence of brain metastasis and evaluate the clinicopathologic properties. Methods: The records of HCC patients treated in our university between 2011 and 2019 were reviewed retrospectively. Patient characteristics, symptoms, laboratory data, treatment modalities, and survival after both the diagnosis of HCC and detection of brain metastasis were recorded. Results: Of the 119 hepatocellular carcinoma patients, 34 had metastasis, 8 of which were to the brain. The median time elapsed between the diagnosis of HCC and brain metastasis was 14.6 months and the median overall survival after the detection of brain metastasis was 1.6 months. In 34 patients with metastasis, median survival was 26.2 months for those without brain metastasis, whereas it was 15.8 months for those with brain metastasis (P = 0.460). The survival times after brain metastasis were 11.6 and 3.9 months for the two patients treated with regorafenib and sorafenib after the detection of brain metastasis, respectively. Conclusion: In this study, it was found that patients who were clinically eligible to receive tyrosine kinase inhibitors survived longer after the detection of brain metastasis. Our study shows that multidisciplinary evaluation of these patients is vital for treatment guidance, and survival outcomes can be improved with the advancements in surgical and radiotherapy techniques even in patients with poor prognosis. Keywords: Brain metastasis, hepatocellular carcinoma, survival, Author(s): Samed Rahatli (corresponding author) [1]; Arzu Oguz [1]; Zohrab Abduyev [1]; Ozden Altundag [1] Introduction Hepatocellular carcinoma (HCC) is a common malignancy worldwide, especially in Asia and South Africa. [...]

Metformin, a traditional first-line pharmacological treatment for type 2 diabetes, has recently been shown to have anti-cancer effects on hepatocellular carcinoma (HCC). However, the molecular mechanism underlying the anti-tumor activity of metformin remains unclear. The Sonic hedgehog (Shh) signaling pathway is closely associated with the initiation and progression of HCC. Therefore, the aim of the current study was to investigate the effects of metformin on the biological behavior of HCC and the underlying functional mechanism of metformin in the Shh pathway. HCC was induced in HepG2 cells using recombinant human Shh (rhShh). The effects of metformin on proliferation and metastasis were evaluated using in vitro proliferation, wound healing, and invasion assays. The mRNA and protein expression levels of proteins related to the Shh pathway were measured using western blotting, quantitative PCR, and immunofluorescence staining. Metformin inhibited rhShh-induced proliferation and metastasis. Furthermore, metformin decreased the mRNA and protein expression of Shh pathway components, including Shh, Ptch, Smo, and Gli-1. Silencing of AMPK in the presence of metformin revealed that metformin exerted its inhibitory effects via AMPK. Our findings demonstrate that metformin suppresses the migration and invasion of HepG2 cells via AMPK-mediated inhibition of the Shh pathway. Key words: liver cancer, Sonic hedgehog signaling pathway, metformin, AMPK, HepG2 cells. La metformine, un traitement pharmacologique conventionnel de premiere ligne pour le diabete de type 2, s'est recemment revelee exercer des effets anticancereux sur le carcinome hepatocellulaire (CHC). Cependant, le mecanisme moleculaire de la metformine quant a son activite antitumorale n'est pas encore completement elucide. La voie de signalisation Sonic Hedgehog (Shh) est etroitement associee a l'initiation et a la progression du CHC. Ainsi, l'objectif de la presente etude consistait a examiner les effets de la metformine sur le comportement biologique du CHC et le mecanisme fonctionnel sous-jacent de la metformine sur la voie Shh. Le CHC a ete induit dans les cellules HepG2 par la Shh humaine recombinante (rhShh). Les effets de la metformine sur la proliferation et la metastase ont ete evalues par des tests de proliferation, de cicatrisation et d'invasion in vitro. Les niveaux d'expression de l'ARNm et des proteines liees a la voie Shh ont ete mesures par transfert Western, PCR quantitative et coloration par immunofluorescence. La metformine inhibait la proliferation et la metastase induites par rhShh. En outre, la metformine diminuait l'expression de l'ARNm et des proteines des composants de la voie Shh, notamment Shh, Ptch, Smo et Gli-1. Le silencage de l'AMPK en presence de metformine a revele que la metformine pouvait exercer son effet inhibiteur par l'intermediaire de l'AMPK. Ces resultats demontrent que la metformine peut supprimer la migration et l'invasion des cellules HepG2 par une inhibition de la voie Shh mediee par l'AMPK. [Traduit par la Redaction] Mots-cles : cancer du foie, voie de signalisation Sonic Hedgehog, metformine, AMPK, cellules HepG2., Introduction In 2020, liver cancer was the sixth most commonly diagnosed cancer and the third leading cause of cancer-related deaths worldwide (Sung et al. 2021). The risk factors for liver [...]

Many patients with hepatocellular carcinoma (HCC) do not respond to the first-line immune checkpoint inhibitor treatment. Immunization with effective cancer vaccines is an attractive alternative approach to immunotherapy. However, its efficacy remains insufficiently evaluated in preclinical studies. Here, we investigated HCC-associated self/tumor antigen, [alpha]-fetoprotein-based (AFP-based) vaccine immunization for treating AFP (+) HCC mouse models. We found that AFP immunization effectively induced AFP-specific [CD8.sup.+] T cells in vivo. However, these [CD8.sup.+] T cells expressed exhaustion markers, including PD1, LAG3, and Tim3. Furthermore, the AFP vaccine effectively prevented c-MYC/Mcl1 HCC initiation when administered before tumor formation, while it was ineffective against full-blown c-MYC/Mcl1 tumors. Similarly, anti-PD1 and anti-PD-L1 monotherapy showed no efficacy in this murine HCC model. In striking contrast, AFP immunization combined with anti-PD-L1 treatment triggered significant inhibition of HCC progression in most liver tumor nodules, while in combination with anti-PD1, it induced slower tumor progression. Mechanistically, we demonstrated that HCC- intrinsic PD- L1 expression was the primary target of anti-PD-L1 in this combination therapy. Notably, the combination therapy had a similar therapeutic effect in the cMet/[beta]-catenin mouse HCC model. These findings suggest that combining the AFP vaccine and immune checkpoint inhibitors may be effective for AFP (+) HCC treatment., Introduction Hepatocellular carcinoma (HCC) accounts for most primary liver tumors and is one of the deadliest malignancies worldwide (1). Most HCCs are diagnosed in the advanced stage when limited therapeutic [...]