Artificial intelligence-enhanced Couinaud segmentation for precision liver cancer therapy

Immune checkpoints include stimulatory and inhibitory checkpoint molecules. In recent years, inhibitory checkpoints, including cytotoxic T lymphocyte–associated antigen 4 (CTLA-4), programmed cell death protein-1 (PD-1), and programmed cell death ligand 1 (PD-L1), have been identified to suppress anti-tumor immune responses in solid tumors. Novel drugs targeting immune checkpoints have succeeded in cancer treatment. Specific PD-1 blockades were approved for treatment of melanoma in 2014 and for treatment of non-small-cell lung cancer in 2015 in the United States, European Union, and Japan. Preclinical and clinical studies show immune checkpoint therapy provides survival benefit for greater numbers of patients with liver cancer, including hepatocellular carcinoma and cholangiocarcinoma, two main primary liver cancers. The combination of anti-PD-1/PD-L1 with anti-CTLA-4 antibodies is being evaluated in phase 1, 2 or 3 trials, and the results suggest that an anti-PD-1 antibody combined with locoregional therapy or other molecular targeted agents is an effective treatment strategy for HCC. In addition, studies on activating co-stimulatory receptors to enhance anti-tumor immune responses have increased our understanding regarding this immunotherapy in liver cancer. Epigenetic modulations of checkpoints for improving the tumor microenvironment also expand our knowledge of potential therapeutic targets in improving the tumor microenvironment and restoring immune recognition and immunogenicity. In this review, we summarize current knowledge and recent developments in immune checkpoint-based therapies for the treatment of hepatocellular carcinoma and cholangiocarcinoma and attempt to clarify the mechanisms underlying its effects.

The presence of tumor-associated macrophages (TAMs) characterized by an M2-like phenotype sustains a robust immunosuppressive tumor microenvironment (TME), promoting liver hepatocellular carcinoma (LIHC) progression. Here, we find that genetic deletion of cyclophilin J (CYPJ) in mice significantly accelerates the development of liver cancer. Analysis of immune cell infiltration reveals that high expression of CYPJ correlates with an increased proportion of M1-polarized, anti-tumor macrophages and CD8+ T cells in the TME. Mechanistically, we demonstrate that CYPJ interacts with AKT1 and inhibits the PI3K-AKT signaling pathway, which leads to polarization of TAMs toward the anti-tumor M1 phenotype, resulting in a tumor-suppressive effect. Collectively, our findings implicate CYPJ as a novel potential therapeutic target for macrophage-mediated therapy in liver cancer.

The phosphatidylinositol 3‐kinase/phosphatidylinositol 3,4,5‐trisphosphate 3‐phosphatase/protein kinase B/mammalian target of rapamycin (PI3K‐PTEN‐AKT‐mTOR) pathway is a central controller of cell growth and a key driver for human cancer. MAF1 is an mTOR downstream effector and transcriptional repressor of ribosomal and transfer RNA genes. MAF1 expression is markedly reduced in hepatocellular carcinomas, which is correlated with disease progression and poor prognosis. Consistently, MAF1 displays tumor‐suppressor activity toward in vitro and in vivo cancer models. Surprisingly, blocking the synthesis of ribosomal and transfer RNAs is insufficient to account for MAF1's tumor‐suppressor function. Instead, MAF1 down‐regulation paradoxically leads to activation of AKT‐mTOR signaling, which is mediated by decreased PTEN expression. MAF1 binds to the PTEN promoter, enhancing PTEN promoter acetylation and activity. Conclusion: In contrast to its canonical function as a transcriptional repressor, MAF1 can also act as a transcriptional activator for PTEN, which is important for MAF1's tumor‐suppressor function. These results have implications in disease staging, prognostic prediction, and AKT‐mTOR‐targeted therapy in liver cancer. (Hepatology 2016;63:1928‐1942)

In this study we investigated the effects of curcumin, derived from plant Curcuma longa, on oxidative toxicity, and the possible molecular mechanism of antitumour of curcumin in liver cancer rats. Results showed that blood levels of Gamma-glutamyltransferase, aspartate aminotransferase, alanine aminotransferase, glutathione S-transferase, and liver level of MD were significantly decreased after curcumin feeding. Levels of the liver malondialdehyde MDA, nitric oxide and antioxidant enzymes were significantly increased. Moreover, RT-PCR and Western blot analysis results showed that curcumin treatment significantly decreased liver vascular endothelial growth factor (VEGF), CyclinD1 and CDK4 mRNA expression levels and CyclinD1 and CDK4 proteins levels in liver cancer rats. These findings were confirmed by histopathology. It is concluded that curcumin can protect the liver from the damage caused by N-nitrosodiethylamine. Moreover, curcumin has the potential to be used in a therapy for liver cancer. The present data provide evidence to support the presence of free radicals and VEGF, CyclinD1 and CDK4 mRNA in rat tumour cells. Studies are in progress in order to further characterize the role of VEGF, CyclinD1 and CDK4 mRNA in liver cancer cells and in hepatic therapeutics.

CD169-positive macrophages enhance abscopal effect of radiofrequency ablation therapy in liver cancer

To investigate the efficacy of individualized symptom management based on patients' self-reports during interventional therapy (IT) for liver cancer. Patients with liver cancer who recieved IT from April to August 2019 were assigned to either the intervention (n=70) or control group (n=70). The control group received routine nursing care and the intervention group received a nursing management program. The severity of specific symptoms, as measured by the Karnofsky Performance Scale (KPS), and satisfaction with nursing care, were analyzed. Compared to the control group, patients given individualized management experienced significantly less severe pain, nausea, anxiety, and fatigue (p < .05). The scores for KPS and satisfaction with care were both significantly improved in the intervention group than in the control group (p < .05). This high-quality nursing management program predicated on patients' self-reports is worthy of clinical application and popular adoption.

Liver cancer is a major contributor to cancer-related mortality. Selective internal radiation therapy (SIRT) for liver cancer has garnered increasing attention. This study aims to comprehensively describe the current status, hotspots and trends of SIRT. Publications from January 1, 1994, to May 31, 2024, were retrieved from the Web of Science Core Collection. CiteSpace, VOSviewer, the Bibliometrix package from R software, and an online analytical platform were used for knowledge mapping analysis and visualization. A total of 2046 publications were retrieved from the Web of Science Core Collection. The number of publications related to SIRT for liver cancer has been continuously increasing, particularly since 2005. The United States led in publications, and a strong collaboration network was observed among countries, particularly within Europe and America. The Northwestern University had the highest number of publications in the field of SIRT. Co-citation analysis identified "predictive dosimetry" and "atezolizumab" as current focal points within the field. High-frequency keywords include "transarterial radioembolization", "Y90 microspheres", "hepatocellular carcinoma", while recent citation bursts are predominantly centered on "lung shunt fraction," "tumor dose," "systemic therapy," "radiation segmentectomy," "Holmium-166," etc. CONCLUSION: As a local treatment, SIRT exhibits significant promise for its future role in the management of hepatic malignancies. Numerous studies on SIRT are actively in progress. Our study suggests that radiation segmentectomy may emerge as an important treatment in the future. Moreover, personalized dosimetry, the combination of SIRT with immunotherapy, and the development of novel radioactive agents are identified as pivotal areas for future research.

Because of its advantageous depth-dose relationship, proton radiotherapy is an emerging treatment modality for patients with liver cancer. Although the proton dose distribution conforms to the target, healthy tissues throughout the body receive low doses of stray radiation, particularly neutrons that originate in the treatment unit or in the patient. The aim of this study was to calculate the effective dose from stray radiation and estimate the corresponding risk of second cancer fatality for a patient receiving proton beam therapy for liver cancer. Effective dose from stray radiation was calculated using detailed Monte Carlo simulations of a double-scattering proton therapy treatment unit and a voxelized human phantom. The treatment plan and phantom were based on CT images of an actual adult patient diagnosed with primary hepatocellular carcinoma. For a prescribed dose of 60 Gy to the clinical target volume, the effective dose from stray radiation was 370 mSv; 61% of this dose was from neutrons originating outside of the patient while the remaining 39% was from neutrons originating within the patient. The excess lifetime risk of fatal second cancer corresponding to the total effective dose from stray radiation was 1.2%. The results of this study establish a baseline estimate of the stray radiation dose and corresponding risk for an adult patient undergoing proton radiotherapy for liver cancer and provide new evidence to corroborate the suitability of proton beam therapy for the treatment of liver tumors.

Introduction Conventional drug delivery for cancer therapy often suffer from poor targeting efficiency, limited bioavailability, and severe off-target toxicity. Nanoparticle-based approaches have emerged as transformative alternatives, particularly when integrated with microfluidic technologies. In the context of liver cancer, microfluidic-assisted polymeric nanocarriers provide a highly controllable and reproducible route for improving drug delivery outcomes. Areas covered We cover recent developments in polymeric nanoparticle systems; their integration with microfluidic fabrication platforms for liver cancer therapy; the ability to encapsulate therapeutic agents, achieve controlled release, and facilitate passive and active tumor targeting through physicochemical modulation and ligand functionalization; microfluidic-assisted synthesis, which enables fine-tuned control over particle size, surface chemistry, and payload distribution with minimal batch-to-batch variation; PEGylated PLGA, cyclodextrin-based, and stimuli-responsive polymeric nanocarriers, highlighting their potential in overcoming biological barriers and enhancing therapeutic index. Expert opinion Microfluidic-assisted nanoparticle fabrication represents a paradigm shift in the design and clinical translation of targeted therapies for liver cancer. By allowing real-time control over nanoparticle synthesis and enabling combination delivery strategies, this approach holds great promise for personalized and precision oncology. Continued integration of microfluidic engineering with biomaterial science and clinical insights is expected to accelerate the realization of safe, reproducible, and patient-tailored nanotherapeutics for hepatocellular carcinoma.

Clinical Outcome of Hypofractionated Radiation Therapy for Lung, Liver, and Pancreatic Cancer

Correction: Preclinical advance in nanoliposomemediated photothermal therapy in liver cancer

Niche-Specific Reprogramming of Macrophages Reveals Myeloid Cell-Centric Targets During Pro-Senescence Therapy in Liver Cancer

Liver cancer is a significant cause of cancer-related death worldwide. We previously showed that the imipridone class of small molecule therapeutics is active against hepatocellular malignancies. ONC201, the first imipridone to reach clinical trials, antagonizes the G protein-coupled receptor DRD2 and is an agonist of mitochondrial caseinolytic protease ClpP. ONC206 also antagonizes DRD2 and is a ClpP agonist. ONC212 is an agonist of both the orphan G protein-coupled receptor GPR132 and ClpP. We investigated the efficacy of ONC201, ONC206, and ONC212 in combination with histone deacetylase inhibition (HDACi), poly ADP ribose polymerase inhibition (PARPi), proteasome inhibition, and current standard of care multi-kinase inhibitor sorafenib. Liver cancer cell lines Hep3B and HepG2 were treated with ONC201, ONC206, and ONC212 to determine dose-response effect. Both cell lines were also treated with each imipridone in combination with sorafenib. Combination treatment effect was also tested between ONC201 and the HDACi vorinostat, PARPi nariparib, and the proteasome inhibitor marizomib. Cell viability was measured with CellTiter-Glo. Synergy was quantified using the combination index (CI). Protein expression was assessed using Western blot. As has been previously reported, both HepG2 and Hep3B cell lines were sensitive to ONC201 (Hep3B IC50 = 2.29μM; HepG2 IC50 = 2.69μM), ONC206 (Hep3B IC50 = 0.11μM; HepG2 IC50 = 0.15μM), and ONC212 (Hep3B IC50 = 0.07μM; HepG2 IC50 = 0.05μM) administered as single-agent therapy with ONC212 demonstrating the greatest potency. In combination with sorafenib, all three imipridones demonstrated synergy in both cell lines. ONC201 and ONC206 exhibited stronger synergy with CI &amp;lt; 0.3 at multiple dose combinations. ONC201 was also found to exert a synergistic reduction in cell viability when Hep3B and HepG2 cells were treated with vorinostat, nariparib, and marizomib. These results suggest that the imipridone family of small molecules is a novel therapy for liver cancer with efficacy as a single agent and in combination with existing targeted agents. Future studies will clarify the mechanisms of synergy and expand the findings into small animal models. Citation Format: Joshua N. Honeyman, Wen-I Chang, Varun V. Prabhu, Joshua E. Allen, Lanlan Zhou, Wafik S. El-Deiry. Imipridones exhibit synergy with sorafenib, HDAC inhibition, PARP inhibition, and proteasome inhibition in liver cancer cell lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1040.

Antiviral Therapy in Liver Cancer

Imaging and Image-Guided Radiation Therapy in Liver Cancer