Exploring the Evolving Landscape of Stereotactic Body Radiation Therapy in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) carries significant morbidity and mortality. Management of the HCC requires a multidisciplinary approach. Surgical resection and liver transplantation are the gold standard options for the appropriate settings. Stereotactic body radiation therapy (SBRT) has emerged as a promising treatment modality in managing HCC; its use is more studied and well-established in advanced HCC (aHCC). Current clinical guidelines universally endorse SBRT as a viable alternative to radiofrequency ablation (RFA), transarterial chemoembolisation (TACE), and transarterial radioembolisation (TARE), a recommendation substantiated by literature demonstrating comparable efficacy among these modalities. In early-stage HCC, SBRT primarily manages unresectable tumours unsuitable for ablative procedures such as microwave ablation and RFA. SBRT has been incorporated as a modality to downstage tumours or as a bridge to transplant. In the case of intermediate or advanced HCC, SBRT offers excellent results either as a single modality or adjunct to other locoregional modalities such as TACE/TARE. Recent data from late-stage HCC patients illustrate the effectiveness of SBRT in achieving local tumour control while minimising damage to surrounding healthy liver tissue. It has promising local control of approximately 80-90% in managing HCC. Additional prospective data comparing the efficacy of SBRT with the first-line recommended therapies such as RFA, TACE, and surgery are essential. The standard of care for patients with advanced/metastatic disease is systemic therapy (immunotherapy/tyrosine kinase inhibitors). SBRT, in combination with immune-checkpoint inhibitors, has an immune-modulatory effect that results in a synergistic effect. Recent findings indicate that the combination of immunotherapy and SBRT in HCC is well-tolerated and exhibits synergistic effects. Further exploration of diverse immunotherapy and radiotherapy strategies is essential to identify the appropriate time for combination treatments and to optimise dose and fraction regimens. Prospective, randomised studies are imperative to establish SBRT as the primary treatment for HCC.

Combination makes strength: a narrative review of transarterial radioembolization plus immune checkpoint inhibitors for hepatocellular carcinoma.

BACKGROUND AND OBJECTIVE: Immune checkpoint inhibitors (ICIs) and transarterial radioembolization (TARE) are now regarded as promising and versatile therapies for hepatocellular carcinoma (HCC). Combining TARE and ICIs may offer synergistic antineoplastic effects by integrating local and systemic tumor control. This review critically discusses recent preclinical evidence supporting the TARE-ICI combination strategy, completed and ongoing clinical trials, and the challenges in identifying optimal target populations and treatment protocols. METHODS: A comprehensive literature search was conducted in multiple electronic databases (PubMed, Scopus, and Web of Science) from January 1999 to January 2024. The first part of the search was directed at identifying concluded studies regarding the TARE-ICIs combination. The second part aimed at identifying ongoing clinical trials exploring the Clinicaltrials.gov database. KEY CONTENT AND FINDINGS: The combination of TARE and ICIs is a promising strategy, supported by preclinical evidence of immune activation post-TARE and potential synergies with ICIs. Early-phase clinical trials have reported encouraging efficacy. However, significant heterogeneity exists among these studies, particularly concerning target populations and treatment schedules. CONCLUSIONS: The current evidence on TARE-ICI is favorable and promising in improving outcomes of patients with HCC. Further conclusive and higher levels of evidence are pending.

The identification of potent dual-target monopolar spindle 1 (MPS1) and histone deacetylase 8 (HDAC8) inhibitors through pharmacophore modeling, molecular docking, molecular dynamics simulations, and biological evaluation.

Background: Overexpression of monopolar spindle 1 (MPS1) and histone deacetylase 8 (HDAC8) is associated with the proliferation of liver cancer cells, so simultaneous inhibition of both MPS1 and HDAC8 could offer a promising therapeutic approach for the treatment of liver cancer. Dual-targeted MPS1/HDAC8 inhibitors have not been reported. Methods: A combined approach of pharmacophore modeling and molecular docking was used to identify potent dual-target inhibitors of MPS1 and HDAC8. Enzyme inhibition assays were performed to evaluate the optimal compound with the strongest inhibitory activity against MPS1 and HDAC8. The selectivity of MPH-5 for MPS1 and HDAC8 was assessed on a panel of 68 kinases and other histone deacetylases. Subsequently, molecular dynamics (MD) simulation verified the binding stability of the optimal compound to MPS1 and HDAC8. Ultimately, in vitro cellular assays and in vivo antitumor assays evaluated the antitumor efficacy of the most promising compound for the treatment of hepatocellular carcinoma. Results: Six dual-target compounds (MPHs 1-6) of both MPS1 and HDAC8 were identified from the database using a combined virtual screening protocol. Notably, MPH-5 showed nanomolar inhibitory effect on both MPS1 (IC50 = 4.52 ± 0.21 nM) and HDAC8 (IC50 = 6.07 ± 0.37 nM). MD simulation indicated that MPH-5 stably binds to both MPS1 and HDAC8. Importantly, cellular assays revealed that MPH-5 exhibited significant antiproliferative activity against human liver cancer cells, especially HepG2 cells. Moreover, MPH-5 exhibited low toxicity and high efficacy against tumor cells, and it overcomes drug resistance to some extent. In addition, MPH-5 may exert its antitumor effects by downregulating MPS1-driven phosphorylation of histone H3 and upregulating HDAC8-mediated K62 acetylation of PKM2. Furthermore, MPH-5 showed potent inhibition of HepG2 xenograft tumor growth in mice with no apparent toxicity and presented favorable pharmacokinetics. Conclusion: The study suggests that MPH-5 is a potent, selective, high-efficacy, and low-toxicity antitumor candidate for the treatment of hepatocellular carcinoma.

Preoperative Serum Glycan Levels Reflect Progression of Patients With Hepatocellular Carcinoma.

BACKGROUND: Abnormal glycosylation is associated with tumors. The clinical value of serum glycans in assessing progression of hepatocellular carcinoma (HCC) patients remains a challenge. METHODS: A study dynamically comparing levels of fifteen lectin-specific glycans between preoperative and postoperative serum of 65 HCC patients was conducted via lectin biochip technology. Multivariable logistic regression analysis was used to address associations between serum glycan levels and clinicopathological characteristics. Kaplan-Meier analysis was used to evaluate the impacts of serum glycan levels on overall survival (OS) and progression-free survival (PFS) of the HCC patients. RESULTS: HCC patients presented significantly higher levels of the lectin-specific glycans in preoperative serum than disease-free individuals (p < 0.001 - p = 0.029), except ConA. The glycans in preoperative sera were significantly related to tumor size, pTNM, metastasis, BCLC stage, portal hypertension (PHT), and platelet count (PLT), respectively (p < 0.05). Multivariate logistic analyses indicated that tumor size and pTNM independently impact on glycan-specific lectins either LTL, UEA-I, VVL, NPL, WGA, PNA, MAL-I, SNA, or PHA-L (p = 0.003 - p = 0.044); BCLC stage and PLT were independent factors influencing the serum glycans recognizable DSA (p = 0.024) and SNA (p = 0.050), respectively. Surgical excision of tumor mass significantly reduced glycan levels in sera. Tumor differentiation, albumin, and ABO type significantly revealed independent influence on glycan-specific lectins, such as RCA-I (p = 0.024), VVL (p = 0.024), and Con A (p = 0.026) in the postoperative serum. HCC patients with high levels of VVL-binding glycans significantly benefited from a longer OS time (p = 0.016, HR: 0.460, 95% CI: 0.237-0.892) and a better PFS time (p = 0.004; HR: 0.435, 95% CI: 0.237-0.799), respectively. CONCLUSION: Serum glycans could reflect surgical outcomes in at-risk patients and become valuable biomarkers in evaluating the progression of HCC patients.

MicroRNA-450b-5p modulated RPLP0 promotes hepatocellular carcinoma progression via activating JAK/STAT3 pathway.

Hepatocellular carcinoma (HCC) is distinguished by its insidious onset, difficult treatment, and poor prognosis. Ribosomal Protein Lateral Stalk Subunit P0 (RPLP0) is implicated in numerous tumor progression processes. Nevertheless, the regulatory mechanism of RPLP0 in HCC progression remains unclear. Our study suggested that RPLP0 exhibits high expression levels in HCC and possesses promising diagnostic capabilities, as indicated by its area under the curve (AUC) of 0.908. Further analysis showed that RPLP0 was a significant independent prognostic factor, and elevated expression levels of RPLP0 were linked with poorer overall survival (OS) and progression-free interval (PFI) outcomes. Additionally, reducing RPLP0 levels led to a decrease in HCC cell proliferation, clonality, invasion, migration, and xenograft tumor growth, as well as an increase in apoptosis. Furthermore, our findings indicated that microRNA(miR)-450b-5p induced downregulation of RPLP0, leading to the suppression of the JAK/STAT3 pathway and consequently hindering the advancement of HCC. The study indicates that RPLP0 plays a role as a carcinogenic factor in HCC and carries important diagnostic and prognostic implications. Targeting the miR-450b-5p/RPLP0/JAK/STAT3 axis has potential clinical value in treating HCC.

ASH1L in Hepatoma Cells and Hepatic Stellate Cells Promotes Fibrosis-Associated Hepatocellular Carcinoma by Modulating Tumor-Associated Macrophages.

Hepatocellular carcinoma (HCC) often occurs in the context of fibrosis or cirrhosis. Methylation of histone is an important epigenetic mechanism, but it is unclear whether histone methyltransferases are potent targets for fibrosis-associated HCC therapy. ASH1L, an H3K4 methyltransferase, is found at higher levels in activated hepatic stellate cells (HSCs) and hepatoma cells. To determine the role of ASH1L in vivo, transgenic mice with conditional Ash1l depletion in the hepatocyte cell lineage (Ash1lflox/floxAlbcre) or HSCs (Ash1lflox/floxGFAPcreERT2) are generated, and these mice are challenged in a diethylnitrosamine (DEN)/carbon tetrachloride (CCl4)-induced model of liver fibrosis and HCC. Depleting Ash1l in both hepatocytes and HSCs mitigates hepatic fibrosis and HCC development. Multicolor flow cytometry, bulk, and single-cell transcriptomic sequencing reveal that ASH1L creates an immunosuppressive microenvironment. Mechanically, ASH1L-mediated H3K4me3 modification increases the expression of CCL2 and CSF1, which recruites and polarizes M2-like pro-tumorigenic macrophages. The M2-like macrophages further enhance tumor cell proliferation and suppress CD8+ T cell activation. AS-99, a small molecule inhibitor of ASH1L, demonstrates similar anti-fibrosis and tumor-suppressive effects. Of pathophysiological significance, the increased expression levels of mesenchymal ASH1L and M2 marker CD68 are associated with poor prognosis of HCC. The findings reveal ASH1L as a potential small-molecule therapeutic target against fibrosis-related HCC.

A case of immune checkpoint inhibitor-associated hemophagocytosis after initiation of atezolizumab plus bevacizumab therapy for advanced hepatocellular carcinoma.

A woman in the 70s with a decreased appetite and weight loss (4 kg) in the last 3 months was referred to our hospital. An enhanced CT scan of the abdomen showed a hepatocellular carcinoma (HCC) of 83 mm in diameter of the liver with metastasis to the para-aortic lymph nodes, the left adrenal gland, and the right lower lung lobe (cStage IVb). She was started on atezolizumab + bevacizumab (Atezo-Bev) therapy. A week after the treatment, she began to have a decreased appetite, fever in the 39 °C range, subcutaneous bleeding, and a slight headache when walking. So she was urgently admitted to our hospital. We diagnosed her as having a hemophagocytic syndrome and administered 1 g steroid pulse therapy for 3 days followed by 1 mg/kg of prednisone. Her condition began to improve. This is the first case report of a hemophagocytic syndrome in a patient with HCC treated with Atezo-Bev.

Epigenetic tuning of tumour-associated macrophages (TAMs): a potential approach in hepatocellular carcinoma (HCC) immunotherapy.

Recent development in immunotherapy for cancer treatment has substantiated to be more effective than most of the other treatments. Immunity is the first line of defence of the body; nevertheless, cancerous cells can manipulate immunity compartments to play several roles in tumour progression. Tumour-associated macrophages (TAMs), one of the most dominant components in the tumour microenvironment, are recognized as anti-tumour suppressors. Unfortunately, the complete behaviour of TAMs is still unclear and understudied. TAM density is directly correlated with the progression and poor prognosis of hepatocellular carcinoma (HCC), therefore studying TAMs from different points of view passing by all the factors that may affect its existence, polarization, functions and repolarization are of great importance. Different epigenetic regulations were reported to have a direct relation with both HCC and TAMs. Here, this review discusses different epigenetic regulations that can affect TAMs in HCC whether positively or negatively.

OncomiR-181a promotes carcinogenesis by repressing the extracellular matrix proteoglycan decorin in hepatocellular carcinoma.

BACKGROUND: Proteoglycans are important tumor microenvironment extracellular matrix components. The regulation of key proteoglycans, such as decorin (DCN), by miRNAs has drawn attention since they have surfaced as novel therapeutic targets in cancer. Accordingly, this study aimed at identifying the impact of miR-181a in liver cancer and its regulatory role on the extracellular matrix proteoglycan, DCN, and hence on downstream oncogenes and tumor suppressor genes. RESULTS: DCN was under-expressed in 22 cirrhotic and HCC liver tissues compared to that in 11 healthy tissues of liver transplantation donors. Conversely, miR-181a was over-expressed in HCC liver tissues compared to that in healthy liver tissues. In silico analysis predicted that DCN 3'UTR harbors two high-score oncomiR-181a binding regions. This was validated by pmiRGLO luciferase reporter assay. Ectopic miR-181a expression into HuH-7 cells repressed the transcript and protein levels of DCN as assessed fluorometrically and by western blotting. DCN siRNAs showed similar results to miR-181a, where they both enhanced the cellular viability, proliferation, and clonogenicity. They also increased Myc and E2F and decreased p53 and Rb signaling as assessed using reporter vectors harboring p53, Rb, Myc, and E2F response elements. Our findings demonstrated that miR-181a directly downregulated the expression of its direct downstream target DCN, which in turn affected downstream targets related to cellular proliferation and apoptosis. CONCLUSION: To our knowledge, this is the first study to unveil the direct targeting of DCN by oncomiR-181a. We also highlighted that miR-181a affects targets related to cellular proliferation in HCC which may be partly mediated through inhibition of DCN transcription. Thus, miR-181a could be a promising biomarker for the early detection and monitoring of liver cancer progression. This would pave the way for the future targeting of the oncomiR-181a as a therapeutic approach in liver cancer, where miR-181a-based therapy approach could be potentially combined with chemotherapy and immunotherapy for the management of liver cancer.

Prognostic nomogram of overall survival for radiation therapy in hepatocellular carcinoma: a population study based on the SEER database and an external cohort.

Purpose: Radiotherapy (RT) plays an important role in the treatment of hepatocellular carcinoma (HCC). To screen patients who benefit most from RT, a nomogram for survival prediction of RT based on a large sample of patients with HCC was created and validated. Methods: A total of 2,252 cases collected from the Surveillance, Epidemiology, and End Results (SEER) database were separated into a training or an internal validation cohort in a 7:3 ratio (n = 1,565:650). An external validation cohort of cases from our institute was obtained (n = 403). LASSO regression and Cox analyses were adopted to develop a nomogram for survival prediction. The decision curve analysis (DCA), calibration curve, and time-dependent receiver operating characteristic curves (TROCs) demonstrated the reliability of the predictive model. Results: For patients with HCC who received RT, the analyses revealed that the independent survival prediction factors were T stage {T2 vs. T1, hazard ratio (HR) =1.452 [95% CI, 1.195-1.765], p < 0.001; T3 vs. T1, HR = 1.469 [95% CI, 1.168-1.846], p < 0.001; T4 vs. T1, HR = 1.291 [95% CI, 0.951-1.754], p = 0.101}, N stage (HR = 1.555 [95% CI, 1.338-1.805], p < 0.001), M stage (HR = 3.007 [95% CI, 2.645-3.418], p < 0.001), max tumor size (>2 and ≤5 vs. ≤2 cm, HR = 1.273 [95% CI, 0.992-1.633], p = 0.057; >5 and ≤10 vs. ≤2 cm, HR = 1.625 [95% CI, 1.246-2.118], p < 0.001; >10 vs. ≤2 cm, HR = 1.784 [95% CI, 1.335-2.385], p < 0.001), major vascular invasion (MVI) (HR = 1.454 [95% CI, 1.028-2.057], p = 0.034), alpha fetoprotein (AFP) (HR = 1.573 [95% CI, 1.315-1.882], p < 0.001), and chemotherapy (HR = 0.511 [95% CI, 0.454-0.576], p < 0.001). A nomogram constructed with these prognostic factors demonstrated outstanding predictive accuracy. The area under the curve (AUC) in the training cohort for predicting overall survival (OS) at 6, 12, 18, and 24 months was 0.824 (95% CI, 0.803-0.846), 0.824 (95% CI, 0.802-0.845), 0.816 (95% CI, 0.792-0.840), and 0.820 (95% CI, 0.794-0.846), respectively. The AUCs were similar in the other two cohorts. The DCA and calibration curve demonstrated the reliability of the predictive model. Conclusion: For patients who have been treated with RT, a nomogram constructed with T stage, N stage, M stage, tumor size, MVI, AFP, and chemotherapy has good survival prediction ability.

Low CD8+ Density Variation and R1 Surgical Margin as Independent Predictors of Early Post-Resection Recurrence in HCC Patients Meeting Milan Criteria.

Our study included 41 patients fulfilling the Milan criteria preoperatively and aimed to identify individuals at high risk of post-resection HCC relapse, which occurred in 18 out of 41 patients (43.9%), retrospectively. We analyzed whole slide images of CD8 immunohistochemistry with automated segmentation of tissue classes and detection of CD8+ lymphocytes. The image analysis outputs were subsampled using a hexagonal grid-based method to assess spatial distribution of CD8+ lymphocytes with regards to the epithelial edges. The CD8+ lymphocyte density indicators, along with clinical, radiological, post-surgical and pathological variables, were tested to predict HCC relapse. Low standard deviation of CD8+ density along the tumor edge and R1 resection emerged as independent predictors of shorter recurrence-free survival (RFS). In particular, patients presenting with both adverse predictors exhibited 100% risk of relapse within 200 days. Our results highlight the potential utility of integrating CD8+ density variability and surgical margin to identify a high relapse-risk group among Milan criteria-fulfilling HCC patients. Validation in cohorts with core biopsy could provide CD8+ distribution data preoperatively and guide preoperative decisions, potentially prioritizing liver transplantation for patients at risk of incomplete resection (R1) and thereby improving overall treatment outcomes significantly.

Comparison between Trans-Arterial Chemoembolization Followed by Stereotactic Body Radiation Rherapy and Trans-Arterial Chemoembolization Alone in BCLC Stage B Hepatocellular Carcinoma: A Pilot Study.

OBJECTIVE: Both Stereotactic Body Radiation Therapy (SBRT) and Trans-arterial Chemoembolization (TACE) are now being widely used to treat advanced hepatocellular carcinoma (HCC) and can improve tumor local control rates. We aimed at evaluating the efficacy and toxicity of combining SBRT and TACE in comparison to TACE alone in unresectable HCC. METHODS: 42 unresectable Barcelona Clinic Liver Cancer (BCLC) stage B HCC Child Pugh (CP) A patients were randomized to receive either: TACE alone (Arm A) or TACE followed by SBRT (Arm B). Dose prescribed was 40Gy in 5consecutive daily fractions over 1 week . We compared the local control (LC), Progression free survival (PFS), overall survival (OS) and toxicity between the two arms. RESULTS: 22 patients were in arm A versus 20 patients in arm B with median follow up 20 months starting recruitment from April 2021 till January 2023. Both LC, PFS were significantly better in Arm B. Complete remission (CR) rate was 54.5% and 75% in Arm A and B, respectively. Median PFS was 16 months in Arm B compared to 11 months in Arm A (p =0.003). Median OS was not reached in both arms. Both arms had comparable toxicities. CONCLUSION: Adding SBRT to TACE in advanced HCC, is safe and feasible with better efficacy in terms of LC and PFS with comparable side effects, in comparison to TACE alone.

Advances in Immune Checkpoint Therapy in Hepatocellular Carcinoma.

The incidence and lethality of hepatocellular carcinoma (HCC) are increasing annually, and traditional treatments have been proven to be ineffective for patients with advanced stages of the disease. In recent years, immune checkpoint therapy has rapidly evolved, demonstrating promising results across a wide range of cancers and offering new hope for cancer treatment. However, the efficacy of immune checkpoint therapy in HCC varies greatly among individuals, with only a small proportion of HCC patients responding positively. A major cause of immune resistance and poor efficacy in HCC patients is immune evasion, which is often due to insufficient infiltration of immune cells. Understanding the mechanisms underlying immune evasion is crucial for enhancing the efficacy of immune therapies. In this review, we aim to summarize the mechanisms of immune evasion observed during immune checkpoint therapy and discuss future directions for this therapeutic approach. Our goal is to provide insights that could help overcome immune evasion, thereby improving the efficacy of immune therapies and extending patient survival time.

Efficacy of associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) in hepatocellular carcinoma with macrovascular invasion: a single-center retrospective analysis.

Objective The influence of macrovascular invasion on the therapeutic efficacy of Associating Liver Partition and Portal Vein Ligation for Staged Hepatectomy (ALPPS) in hepatocellular carcinoma (HCC) patients has not been previously reported. This study primarily examines the therapeutic effect of ALPPS in treating HCC with macrovascular invasion. Methods 89 patients who underwent ALPPS at the First Affiliated Hospital of Guangxi Medical University from December 2016 to December 2021 were included. Patients were categorized into three groups based on macrovascular invasion status: pure HCC, HCC with portal vein tumor thrombus (PVTT), and HCC with hepatic vein tumor thrombus (HVTT). Outcome measures such as postoperative complications, liver hyperplasia rates, and survival times were compared across the groups. Results The study comprised 44 patients without macrovascular invasion and 45 cases with it, including 37 PVTT and 8 HVTT cases. Patients with PVTT or HVTT had a higher rate of complications and liver failure after the first ALPPS stage compared to those without macrovascular invasion (P = 0.018, P = 0.036). This trend was also observed in the stratified analysis of severe complications. However, no significant differences were found in these outcomes after the second ALPPS stage among the groups. The volume and rate of future liver remnant proliferation between the two stages of ALPPS were not statistically different among the groups, with median overall survival times of 42, 39, and 33 months, and progression-free survival times of 30, 24, and 14 months, respectively (P = 0.412 and P = 0.281). Conclusion ALPPS for HCC with macrovascular invasion was considered safe, feasible, and effective, as it achieved therapeutic effects comparable to those in cases without macrovascular invasion.

AFP-DIAM Score to Predict Survival in Patients with Hepatocellular Carcinoma Before TACE: A French Multicenter Study.

BACKGROUND: Transarterial chemoembolization (TACE) is recommended as a palliative treatment for patients of the B stage of the Barcelona Clinic Liver Cancer (BCLC) classification. AIMS: To identify clinical, biological, and radiological predictors of survival in patients undergoing TACE and develop a pre-therapeutic prognostic score. METHODS: 191 adult cirrhotic patients treated for HCC with TACE at the University Hospital (UH) of Clermont-Ferrand (France) from 2007-2017 were retrospectively included. We investigated the impact of baseline liver function, patient characteristics, and tumor burden on overall survival and developed a prognostic score. RESULTS: Patients had a median age of 66 years and 126 patients were Child A. The AFP-DIAM score distinguishes two groups with a significant difference in survival time (median OS 28.3 months in patients with a score = 0 versus 17.7 months in patients with a score > 0). AFP-DIAM was validated on an external cohort, is well calibrated, and has the best discrimination capacity (C-index) as compared to NIACE, HAP, STATE, and SIX TO TWELVE. AFP-DIAM and SIX TO TWELVE are the more easy-to-use scores. When AFP-DIAM and the SIX TO TWELVE scores were tested in the same statistical model, results confirmed a better AFP-DIAM performance. CONCLUSIONS: The AFP-DIAM is an easy-to-use score which allows to distinguish two groups with different prognosis before the first TACE session. Its use could provide further support to BCLC system to guide the therapeutic strategy of patients with HCC.

Crohn's Disease, Hemochromatosis, Hepatocellular Carcinoma, and Liver Cirrhosis: A Case Study.

Hemochromatosis, an inherited disorder characterized by excessive iron absorption and accumulation, can lead to organ damage and is a known contributor to liver cirrhosis. This case report discusses a 57-year-old man with a history of Crohn's disease, whose general practitioner identified elevated ferritin levels, cirrhotic liver features, and abnormal liver function tests. Further investigation revealed non-hereditary hemochromatosis, hepatic cirrhosis, and hepatocellular carcinoma (HCC). This case highlights the rare coexistence of hemochromatosis and Crohn's disease, underscoring the diagnostic and therapeutic challenges of managing these concurrent conditions. It also emphasizes the importance of prompt and effective treatment to prevent severe complications.

Identification of two heterogeneous subtypes of hepatocellular carcinoma with distinct pathway activities and clinical outcomes based on gene set variation analysis.

Background: High heterogeneity is an essential feature of malignant tumors. This study aims to reveal the drivers of hepatocellular carcinoma heterogeneity for prognostic stratification and to guide individualized treatment. Methods: Omics data and clinical data for two HCC cohorts were derived from the Cancer Genome Atlas (TCGA) and the International Cancer Genome Atlas (ICGC), respectively. CNV data and methylation data were downloaded from the GSCA database. GSVA was used to estimate the transcriptional activity of KEGG pathways, and consensus clustering was used to categorize the HCC samples. The pRRophetic package was used to predict the sensitivity of samples to anticancer drugs. TIMER, MCPcounter, quanTIseq, and TIDE algorithms were used to assess the components of TME. LASSO and COX analyses were used to establish a prognostic gene signature. The biological role played by genes in HCC cells was confirmed by in vitro experiments. Results: We classified HCC tissues into two categories based on the activity of prognostic pathways. Among them, the transcriptional profile of cluster A HCC is similar to that of normal tissue, dominated by cancer-suppressive metabolic pathways, and has a better prognosis. In contrast, cluster B HCC is dominated by high proliferative activity and has significant genetic heterogeneity. Meanwhile, cluster B HCC is often poorly differentiated, has a high rate of serum AFP positivity, is prone to microvascular invasion, and has shorter overall survival. In addition, we found that mutations, copy number variations, and aberrant methylation were also crucial drivers of the differences in heterogeneity between the two HCC subtypes. Meanwhile, the TME of the two HCC subtypes is also significantly different, which offers the possibility of precision immunotherapy for HCC patients. Finally, based on the prognostic value of molecular subtypes, we developed a gene signature that could accurately predict patients' OS. The riskscore quantified by the signature could evaluate the heterogeneity of HCC and guide clinical treatment. Finally, we confirmed through in vitro experiments that RFPL4B could promote the progression of Huh7 cells. Conclusion: The molecular subtypes we identified effectively exposed the heterogeneity of HCC, which is important for discovering new effective therapeutic targets.

Evaluation of different scoring systems for repeating Transarterial Chemoembolization in Egyptian patients with Hepatocellular Carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) patients undergoing transarterial chemoembolization (TACE) have a diverse range of outcomes due to their high degree of heterogeneity. Therefore, different predictive scoring systems have been created to assist in decision-making regarding retreatment with TACE. We compared the predictive capabilities of different scoring systems, such as ART, ABCR, and SNACOR, for prediction of the outcome of subsequent TACE in HCC patients. METHOD: In this retrospective study, the three scoring systems were compared for their capability of predicting the outcome of repeating TACE in 149 HCC patients treated at the National Liver Institute, Egypt, between January 2017 and December 2019. We used the likelihood ratio to select the model with the highest predictive capability for overall survival (OS). RESULTS: According to our data, the amount of tumor, the change in Barcelona Clinic Liver Cancer (BCLC) stage following TACE, and the SNACOR score (with a 95% confidence range for HR 1.0305-1.256 and p-value = 0.0106) were the most predictive variables. It was also shown that the ABCR score was a good predictor of survival (90 patients had an ABCR score ≤ 0 with a P- value <0.0001, 56 patients had 0 < ABCR < 4 with a P-value <0.0001, and the ART score was not useful in predicting OS (P-value = 0.18). CONCLUSION: The SNACOR score is the most predictive score for OS and would be the most helpful scoring system in decision-making regarding retreatment with TACE.

Sex-specific effects of PNPLA3 I148M.

Metabolic dysfunction-associated steatotic liver disease (MASLD, previously termed NAFLD, nonalcoholic fatty liver disease) is a complex multifactorial disease showing generally higher prevalence and severity in men than in women. With respect to women, men are also more prone to develop metabolic dysfunction-associated steatohepatitis, fibrosis and liver-related complications. Several genetic, hormonal, environmental and lifestyle factors may contribute to sex differences in MASLD development, progression and outcomes. However, after menopause, the sex-specific prevalence of MASLD shows an opposite trend between men and women, pointing to the relevance of oestrogen signalling in the sexual dimorphism of MASLD. The patatin-like phospholipase domain-containing protein 3 (PNPLA3) gene, that encodes a triacylglycerol lipase that plays a crucial role in lipid metabolism, has emerged as a key player in the pathogenesis of MASLD, with the I148M variant being strongly associated with increased liver fat content and disease severity. Recent advances indicate that carrying the PNPLA3 I148M variant can be a risk factor for MASLD especially for women. To elucidate the molecular mechanisms underlying the sex-specific role of PNPLA3 I148M in the development of MASLD, several in vitro, ex vivo and in vivo models have been developed.

Impact of Microparticle Transarterial Chemoembolization (mTACE) on myeloid-derived suppressor cell subtypes in hepatocellular carcinoma: Clinical correlations and therapeutic implications.

BACKGROUND: Myeloid-derived suppressor cells (MDSCs) play a pivotal role in immunosuppression and tumor progression in hepatocellular carcinoma (HCC). While various treatments like surgical resection, ablation, and radiotherapy have been studied for their effects on circulating MDSC frequencies in HCC patients, the findings remain inconclusive. Transarterial Chemoembolization (TACE) stands as the standard care for unresectable HCC, with Microparticle TACE (mTACE) gaining prominence for its capacity to induce significant tumor necrosis. However, the immunological ramifications of such pathological outcomes are scarcely reported. METHODS AND RESULTS: This study aims to elucidate the alterations in MDSC subtypes, specifically monocytic MDSCs (mMDSCs) and early-stage MDSCs (eMDSCs), post-mTACE and to investigate their clinical correlations in HCC patients. A cohort comprising 75 HCC patients, 16 liver cirrhosis patients, and 20 healthy controls (HC) was studied. Peripheral blood samples were collected and analyzed for MDSC subtypes. The study also explored the associations between MDSC frequencies and various clinical parameters in HCC patients. The frequency of mMDSCs was significantly elevated in the HCC group compared to liver cirrhosis and HC. Importantly, mMDSC levels were strongly correlated with aggressive clinical features of HCC, including tumor size, vascular invasion, and distant metastasis. Post-mTACE, a marked reduction in mMDSC frequencies was observed, while eMDSC levels remained stable. CONCLUSIONS: Our findings underscore the critical role of mMDSCs in HCC pathogenesis and their potential as a therapeutic target. The study also highlights the efficacy of mTACE in modulating the immunosuppressive tumor microenvironment, thereby opening new avenues for combinatorial immunotherapeutic strategies in HCC management.