Perihilar cholangiocarcinoma (pCCA) accounts for approximately 50% of all cholangiocarcinomas and carries a dismal prognosis owing to late diagnosis and high post-resection recurrence rates. Over the past two decades, liver transplantation (LT) following neoadjuvant therapy according to the Mayo Criteria has yielded acceptable long-term survival in highly selected patients with unresectable pCCA, establishing LT as an established treatment option. Nevertheless, substantial challenges remain, including tumor progression on the waiting list, intolerance to neoadjuvant therapy, and postoperative complications from prior chemoradiation. Moreover, pCCA recurrence is closely linked to post-transplant immunosuppressive management, and minimizing long-term immunosuppression may be critical. This review analytically examines the current role of LT for pCCA, emphasizing patient selection, standardized neoadjuvant regimens, immunological considerations, and favorable prognostic factors. The emerging potential and risks of incorporating immune checkpoint inhibitors in the pre-transplant setting are also explored. By synthesizing available evidence, we aim to define the clinical contexts in which LT may confer durable benefit and to highlight the key obstacles limiting its broader application.

Plasmid dosages used for HCC murine models

Intraoperative intraperitoneal lavage with lobaplatin is widely used in the treatment of colorectal and gastric cancers. This study aimed to explore the efficacy of lobaplatin lavage in patients with ruptured hepatocellular carcinoma (HCC) administered radical hepatectomy. Ruptured HCC patients who underwent hepatectomy between September 2007 and March 2022 were divided into the distilled water lavage and lobaplatin lavage groups. Survival curves for RFS and OS were generated by the Kaplan-Meier method and compared by the log-rank test using Propensity Score Matching (PSM). Cox regression analysis was conducted to identify independent prognostic factors of RFS and OS. This study included 201 patients, with 114 cases (89.1

Histology analysis of liver tissues from Akt/NRas and sgGSK3α/β/NRas mice

Introduction:Adoptive cell therapy derived from autologous tumor-infiltrating lymphocytes (TILs) has demonstrated promising therapeutic efficacy in several cancers. However, its possible synergistic effects with anti-PD-1 therapy in advanced hepatocellular carcinoma (aHCC) remain unexplored. This study aimed to investigate the efficacy of TIL infusion combined with anti-PD-1 therapy for aHCC. Case Presentation:Referring to the current protocol of our clinical trial (NCT03658785), 2 patients with HCC at BCLC stage C were enrolled to receive autologous TIL infusion combined with anti-PD-1 therapy. They underwent unplanned palliative tumor resection to alleviate pain caused by tumor rupture prior to receiving TIL infusion plus anti-PD-1 therapy. Long-term outcomes and treatment-related adverse events were evaluated. Throughout the entire treatment process, both patients experienced only mild symptoms. Notably, both patients achieved complete responses to the treatment and have remained tumor-free for 2 and 4 years, respectively. Conclusion:Autologous TIL infusion combined with anti-PD-1 therapy is a safe and feasible strategy for patients with aHCC. Palliative hepatectomy with maximal tumor burden reduction may significantly improve its efficacy and even results in cure for aHCC patients.

Gene expression pattern in Akt/NRas and Akt/NRas/pT3-FoxoAAA liver tumors

Pathways commonly upregulated and co-downregulated in Akt/NRas, Tsc2-/-/NRas, and sgGSK3α/β/NRas liver tumors

Gene expression pattern in Akt/NRas and Tsc2-/-/NRas/sgGSK3α/β liver tumors

List of up-regulated genes in Akt/NRas and Tsc2-/-/NRas, but not in sgGSK3α/β/NRas liver tumors

Main characteristics of the plasmids used in the experiments

List of gene expression patterns correlated with Foxm1 expression in human HCC samples

Basic information of HCC murine models

Gene list up- and down-regulated by Foxo1 in Akt/NRas/Foxo1AAA liver tumors

Pathways involved in Akt/NRas liver tumors, but not engaged in Tsc2-/-/NRas/sgGSK3α/β liver tumors

Unique pathways downregulated in Tsc2-/-/NRas and sgGSK3α/β/NRas liver tumors

Correlation analysis between p-AKTSer473 and FOXM1 in human HCC samples from TCPA database

Designing the CRISPR guide RNA against mouse GSK3α and GSK3β gene

Effect of CRISPR KO Foxm1 gene on the liver cancer cell growth

Deletion of either GSK3α or GSK3β in combination with activated NRas slowly induces HCC development

Aberrant activation of AKT is a key oncogenic driver in hepatocellular carcinoma (HCC). As AKT activates multiple downstream signaling pathways, the key mechanisms mediating AKT-driven tumorigenesis must be elucidated to develop optimal treatment strategies. Using an Akt/NRas-induced HCC mouse model, we found that AKT promotes tumorigenesis by targeting tuberous sclerosis complex 2 (TSC2) and glycogen synthase kinase 3 α/β (GSK3α/β) rather than forkhead box O protein family members. Loss of either TSC2, leading to mTORC1 activation, or both GSK3 isoforms cooperated with activated NRAS to promote HCC formation in vivo, albeit with different latencies. Simultaneous TSC2 and GSK3α/β deletion cooperated with NRAS to rapidly induce HCC formation, mirroring observations from the Akt/NRas HCC model. RNA sequencing studies indicated distinct pathways regulated by TSC2/mTORC1 and GSK3α/β during hepatocarcinogenesis, with FOXM1 functioning as a major effector of GSK3. In summary, these findings uncover AKT’s role in suppressing the TSC complex and GSK3 to drive HCC, offering mechanistic insights into oncogenic signaling and potential therapeutic targets. Significance: GSK3α/β and TSC2/mTORC1 are key downstream effectors of AKT in liver tumorigenesis that can potentially be targeted to benefit patients with hepatocellular carcinoma harboring aberrantly activated AKT.