Genetic/Epigenetic Alteration and Tumor Immune Microenvironment in Intrahepatic Cholangiocarcinoma: Transforming the Immune Microenvironment with Molecular-Targeted Agents.

Background: Intrahepatic cholangiocarcinoma (iCCA) is often diagnosed at an advanced stage, leading to limited treatment options and a poor prognosis. So far, standard systemic therapy for advanced iCCA has been a combination of gemcitabine and cisplatin. However, recent advancements in the understanding of the molecular characteristics of iCCA have opened new possibilities for molecular-targeted therapies and immunotherapy. Summary: Reportedly, 9-36% of iCCA cases have an inflamed tumor immune microenvironment (TME) based on the immune gene expression signature, which is characterized by the presence of immune cells involved in anti-tumor immune responses. The majority of iCCA cases have a non-inflamed TME with a lack of effector T cells, rendering immune checkpoint inhibitors (ICIs) ineffective in these cases. Interestingly, alterations in the fibroblast growth factor receptor (FGFR2) gene and IDH1/2 gene mutations are often observed in the non-inflamed TME in iCCA. Several mechanisms have been reported for the role of driver mutations on the establishment of TME unique for iCCA. For example, IDH1/2 mutations, which cause an increase in DNA methylation, are associated with the downregulation and hypermethylation of antigen processing and presentation machinery, which may contribute to the establishment of a non-inflamed TME. Therefore, inhibitors targeting IDH1/2 may restore the DNA methylation and expression status of molecules involved in antigen presentation, potentially improving the efficacy of ICIs. FGFR inhibitors may also have the potential to modulate immunosuppressive TME by inhibitingthe suppressor of cytokine signaling 1 and activating the interferon-γ signaling as a consequence of inhibition of the FGFR signal. From this perspective, understanding the molecular characteristics of iCCA, including the TME and driver mutations, is essential for the effective application of ICIs and molecular-targeted therapies. Key Messages: Combination approaches that target both the tumor and immune system hold promise for improving the outcomes of patients with iCCA. Further research and clinical trials are needed to validate these approaches and optimize the treatment strategies for iCCA.

Simultaneous and Sequential Use of Molecular Targeted Agents Plus Immune Checkpoint Inhibitors for Advanced Hepatocellular Carcinoma: A Real-World Practice in China.

Purpose: Molecular targeted agents (MTAs) plus immune checkpoint inhibitors (ICIs) treatment for advanced hepatocellular carcinoma (HCC) has shown an exciting prospect. This study aimed to report the efficacy of the Simultaneous and Sequential use of them in a real-world practice. Patients and Methods: From April 2019 to December 2020, patients with advanced HCC in three Chinese medical centers receiving MTAs and ICIs as their initial systemic therapy were enrolled. Participants were classified into the Simultaneous group (treated with them simultaneously) and the Sequential group (treated with MTAs initially and added ICIs after tumor progression). Toxicity, tumor response, survival outcomes and prognostic factors were investigated. Results: One hundred and ten consecutive patients participated in the study (64 in the Simultaneous group and 46 in the Sequential group). A total of 93 (84.5%) patients experienced treatment-related adverse events (AEs), of which 55 (85.9%) in the Simultaneous group and 38 (82.6%) in the Sequential group (P=0.19). Grade 3/4 AEs were observed in 9 (8.2%) patients. Patients in the Simultaneous group achieved a higher objective response rate than those in the Sequential group (25.0% vs 4.3%, p=0.04). The median overall survival (OS) of the entire cohort was 14.8 [95% confidence interval (CI): 4.6-25.5] months and the OS rates at 6 and 12 months were 80.6% and 60.9%, respectively. Patients in the Simultaneous group achieved better survival outcomes than those in the Sequential group, but without statistically significant differences. Child-Pugh 6 scores (HR: 2.97, 95% CI: 1.33-6.61, P=0.008), tumor number ≤3 (HR: 0.18, 95% CI: 0.04-0.78, P=0.022), extrahepatic metastasis (HR: 3.05, 95% CI: 1.35-6.87, P=0.007) were independent prognostic factors for survival. Conclusion: The combined treatment of MTAs and ICIs shows good tumor response and survival outcomes with acceptable toxicity for advanced HCC in the real-world practice, in particular when they are applied simultaneously.

Comparative efficacy and safety of molecular targeted agents combined with transarterial chemoembolization in the treatment of unresectable hepatocellular carcinoma: a network meta-analysis.

Objective: At present, several molecular targeted agents(MTAs) combined with transarterial chemoembolization (TACE) have been employed to treat unresectable hepatocellular carcinoma (HCC). In this meta-analysis, we compared the efficacy and safety of different MTAs combined with TACE to enable effective decision-making for the clinical treatment of unresectable HCC. Methods: Pubmed, Web of Science, EMBASE, and Cochrane Library were retrieved to evaluate the efficacy and safety of different MTAs combined with TACE in cohort studies and randomized controlled trials. The hazard ratios and 95% confidence intervals (CIs) were calculated to investigate the impact of various therapies on overall survival (OS) and progression-free survival. However, the objective response rate (ORR), disease control rate (DCR), adverse events (AEs), and ≥grade-3 adverse events (≥G3-AEs) were calculated using odd ratios and 95% CIs. The node-splitting approach was used to test the heterogeneity. The funnel plot was utilized to analyze the publication bias. Additionally, according to the ranking plots, we ranked various treatments. Results: A total of 45 studies involving 10,774 patients with 8 treatment strategies were included in our network meta-analysis. Our network meta-analysis showed that apatinib+TACE provided the highest OS (62.2%), ORR (44.7%), and DCR (45.6%), while and lenvatinib+TACE offered the best PFS (78.9%). Besides, there was no statistically significant difference in AEs and ≥G3-AEs among treatment options. Conclusion: Apatinib+TACE demonstrated the best OS, ORR, and DCR with no additional AEs and ≥G3-AEs. Therefore, for the treatment scheme of MTAs combined with TACE, apatinib+TACE may be the best option for patients with unresectable HCC. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42023388609.

Clinical practice guidelines and real-life practice in hepatocellular carcinoma: A Japanese perspective.

Striking advances in systemic therapy for unresectable advanced hepatocellular carcinoma (HCC) have improved the average prognosis of patients with HCC. As a result, the guidelines for the treatment of HCC have changed significantly. However, various issues have emerged in clinical practice. First, there is no established biomarker that can predict response to systemic therapy. Second, there is no established treatment regimen after primary systemic therapy, including combined immunotherapy. Third, there is no established treatment regimen for intermediate-stage HCC. These points make the current guidelines ambiguous. In this review, we present the Japanese guidelines for the diagnosis and treatment of HCC based on the latest evidence; introduce various efforts mainly in Japanese real-life practice to update these guidelines; and present our perspectives on future guidelines.

Hepatic arterial infusion chemotherapy for advanced hepatocellular carcinoma in the era of chemo-diversity.

Recently, treatments for unresectable hepatocellular carcinoma (HCC) have undergone remarkable development. Various systemic chemotherapy drugs have been approved and are recommended by clinical guidelines worldwide. Although systemic treatments are effective and contribute to prolonged patient survival, their effects are unsatisfactory for some specific tumor conditions, such as macrovascular invasion. Hepatic arterial infusion chemotherapy (HAIC) is a traditional treatment for advanced HCC. As yet, there is no worldwide consensus recommending HAIC because no high-quality clinical trials have demonstrated its survival benefit. However, clinical evidence is gradually accumulating that shows its survival benefit, and it is recognized as an effective locoregional treatment for advanced HCC. Several HAIC regimens have been reported, including cisplatin monotherapy, cisplatin plus 5-fluorouracil (low-dose FP), lipiodol-suspended FP, and an oxaliplatin-based regimen. We have entered an era of chemo-diversity in the treatment of advanced HCC. This review aimed to clarify the relevance of HAIC in the era of chemo-diversity. We propose a multidisciplinary therapeutic strategy combining locoregional HAIC treatment with sequential drug therapy, with the aim of becoming cancer-free through conversion therapy.

Efficacy of rechallenge transcatheter arterial chemoembolization after lenvatinib treatment for advanced hepatocellular carcinoma.

Background and Aim: We evaluated the efficacy of rechallenge transcatheter arterial chemoembolization (TACE) after lenvatinib (LEN) treatment in patients with previous TACE failure/refractoriness. Methods: We enrolled 63 consecutive patients with a history of TACE failure/refractoriness prior to LEN treatment as a first-line systemic therapy. We reviewed the clinical backgrounds and courses of the patients. Results: In total, 25 patients underwent rechallenge TACE after LEN due to LEN-refractoriness (17 cases) or intolerance (8 cases). A complete or partial response was obtained for 13 (65.0%) of the 20 patients whose therapeutic effects were determined. The survival rate of patients who underwent rechallenge TACE was significantly higher than that of patients who did not undergo rechallenge TACE (median survival time, not reached vs 403 days, P = 0.015). Rechallenge TACE significantly reduced the risk of death in univariate (hazard ratio [HR] 0.24, 95% confidence interval [CI] 0.08-0.69, P = 0.008) and multivariate analyses (HR 0.26, 95% CI 0.08-0.80, P = 0.019). If complete or partial response was obtained by rechallenge TACE, the median survival time of these patients was significantly longer than those of the progressive disease (PD) group (P = 0.05), and the median survival time of the PD group after rechallenge TACE was not different from that of the group who did not undergo rechallenge TACE (P = 0.36). We did not observe a decrease in the ALBI score after TACE. Conclusion: Rechallenge TACE after LEN is an effective treatment that may result in a favorable prognosis.

Identification of CT Values That Could Be Predictive of Necrosis (N-CTav) in Hepatocellular Carcinoma after Lenvatinib Treatment.

Purpose: To assess the utility of measurement of the computed tomography (CT) attenuation value (CTav) in predicting tumor necrosis in hepatocellular carcinoma (HCC) patients who achieve a complete response (CR), defined using modified Response Evaluation Criteria in Solid Tumors (mRECIST), after lenvatinib treatment. Method: We compared CTav in arterial phase CT images with postoperative histopathology in four patients who underwent HCC resection after lenvatinib treatment, to determine CTav thresholds indicative of histological necrosis (N-CTav). Next, we confirmed the accuracy of the determined N-CTav in 15 cases with histopathologically proven necrosis in surgical specimens. Furthermore, the percentage of the tumor with N-CTav, i.e., the N-CTav occupancy rate, assessed using Image J software in 30 tumors in 12 patients with CR out of 571 HCC patients treated with lenvatinib, and its correlation with local recurrence following CR were examined. Results: Receiver operating characteristic (ROC) curve analysis revealed an optimal cut-off value of CTav of 30.2 HU, with 90.0% specificity and 65.0% sensitivity in discriminating between pathologically identified necrosis and degeneration, with a CTav of less than 30.2 HU indicating necrosis after lenvatinib treatment (N30-CTav). Furthermore, the optimal cut-off value of 30.6% for the N30-CTav occupancy rate by ROC analysis was a significant indicator of local recurrence following CR with 76.9% specificity and sensitivity (area under the ROC curve; 0.939), with the CR group with high N30-CTav occupancy (≥30.6%) after lenvatinib treatment showing significantly lower local recurrence (8.3% at 1 year) compared with the low (<30.6%) N30-CTav group (p < 0.001, 61.5% at 1 year). Conclusion: The cut-off value of 30.2 HU for CTav (N30-CTav) might be appropriate for identifying post-lenvatinib necrosis in HCC, and an N30-CTav occupancy rate of >30.6% might be a predictor of maintenance of CR. Use of these indicators have the potential to impact systemic chemotherapy for HCC.

Rapidly Evolving Landscape and Future Horizons in Hepatocellular Carcinoma in the Era of Immuno-Oncology.

Hepatocellular carcinoma (HCC) is a serious global health problem as one of the leading causes of cancer-related death worldwide. Systemic therapy for advanced HCC has progressed with the development of molecular targeted agents, however survival benefits remain modest. More recently, immune checkpoint inhibitors (ICI) have emerged and exhibited promising therapeutic benefits in a subset of patients. Physiologically, the intrinsic microenvironment in the liver is immunosuppressive, which represents a major obstacle for effective immune therapies in primary and secondary liver malignancies. For this reason, combination therapies that can overcome immune inhibitory mechanisms and enhance the immune response are a rationale approach for drug development in HCC. A recent example is the combination of the anti-PD-L1 antibody (atezolizumab) and anti-VEGF-A antibody (bevacizumab), which has shown significant improvement in survival as compared to standard of care in the first-line treatment for HCC. Other immunotherapy approaches including cancer vaccines and adoptive cell therapy are also under investigation. This review summarizes the key trials leading to our current HCC treatment options and provides an overview of future immune-based strategies in development.

Intraoperative fluorescence molecular imaging accelerates the coming of precision surgery in China.

PURPOSE: China has the largest cancer population globally. Surgery is the main choice for most solid cancer patients. Intraoperative fluorescence molecular imaging (FMI) has shown its great potential in assisting surgeons in achieving precise resection. We summarized the typical applications of intraoperative FMI and several new trends to promote the development of precision surgery. METHODS: The academic database and NIH clinical trial platform were systematically evaluated. We focused on the clinical application of intraoperative FMI in China. Special emphasis was placed on a series of typical studies with new technologies or high-level evidence. The emerging strategy of combining FMI with other modalities was also discussed. RESULTS: The clinical applications of clinically approved indocyanine green (ICG), methylene blue (MB), or fluorescein are on the rise in different surgical departments. Intraoperative FMI has achieved precise lesion detection, sentinel lymph node mapping, and lymphangiography for many cancers. Nerve imaging is also exploring to reduce iatrogenic injuries. Through different administration routes, these fluorescent imaging agents provided encouraging results in surgical navigation. Meanwhile, designing new cancer-specific fluorescent tracers is expected to be a promising trend to further improve the surgical outcome. CONCLUSIONS: Intraoperative FMI is in a rapid development in China. In-depth understanding of cancer-related molecular mechanisms is necessary to achieve precision surgery. Molecular-targeted fluorescent agents and multi-modal imaging techniques might play crucial roles in the era of precision surgery.

An Unfolded Protein Response-Related mRNA Signature Predicting the Survival and Therapeutic Effect of Hepatocellular Carcinoma.

BACKGROUND: Tumorigenesis, metastasis, and treatment response of hepatocellular carcinoma (HCC) are regulated by unfolded protein responses (UPR) signaling pathways, including IRE1a, PERK, and ATF6, but little is known about UPR related genes with HCC prognosis and therapeutic indicators. OBJECTIVE: We aimed to identify a UPR related prognostic signature (UPRRPS) for HCC and explore the potential effect of the current signature on the existing molecular targeted agents and immune checkpoint inhibitors (ICIs). METHODS: We used The Cancer Genome Atlas (TCGA) database to screen candidate UPR genes (UPRGs), which are expressed differentially between hepatocellular carcinoma and normal liver tissue and associated with prognosis. A gene risk score for overall survival prediction was established using the least absolute shrinkage and selection operator (LASSO) regression analysis, which was validated using data from the International Cancer Genome Consortium (ICGC) database and evaluated by the C-index. Then immune and molecular characteristics stratified by the current UPRRPS were analyzed, and the corresponding drug sensitivity was conducted. RESULTS: Initially, 42 UPRGs from the TCGA database were screened as differentially expressed genes, which were also associated with HCC prognosis. Using the LASSO regression analysis, nine UPRGs (EXTL3, PPP2R5B, ZBTB17, EIF2S2, EIF2S3, HDGF, SRPRB, EXTL2, and TPP1) were used to develop a UPRRPS to predict the OS of HCC patients in the TCGA set with the Cindex of 0.763. The current UPRRPS was also well-validated in the ICGC set with the C-index of 0.700. Multivariate Cox regression analyses also confirmed that the risk score was an independent risk factor for HCC in both the TCGA and ICGC sets (both P<0.05). Functional analyses showed that low-risk score was associated with increased natural killer cells, T helpers, tumor immune dysfunction and exclusion score, microsatellite instability expression, and more benefit from ICIs; the high-risk score was associated with increased active dendritic cells, Tregs, T-cell exclusion score, and less benefit from ICIs. Gene set enrichment analyses showed that the signaling pathways of VEGF, MAPK, and mTOR were enriched in high UPRRPS, and the drug sensitivities of the corresponding inhibitors were all significantly higher in the high UPRRPS subgroup (all P<0.001). CONCLUSION: With the current findings, UPRRPS was a promising biomarker for predicting the prognosis of HCC patients. UPRRPS might also be taken as a potential indicator to guide the management of immune checkpoint inhibitors and molecular targeted agents.

miR-140-3p enhances the sensitivity of LUAD cells to antitumor agents by targeting the ADAM10/Notch pathway.

Background: The Notch pathway, which is related to the drug-resistance of lung adenocarcinoma (LUAD) type of non-small cell lung cancer (NSCLC) cells, is activated by cleavage of Notch proteins mediated by ADAMs, ADAM10 or ADAM17. Methods: In the present study, our results demonstrated that of these two ADAMs, the expression of ADAM10 in clinical samples of the LUAD type of NSCLC was much higher than that of ADAM17, while miR-140-3p - an miRNA that could target ADAM10 - was identified by an online tool: miRDB (miRNA database). The detail function and mechanism of miR-140-3p in regulating the sensitivity of NSCLC cells to antitumor drugs was systematically explored in vitro and in vivo. Results: In A549, a typical NSCLC LUAD cell line, miR-140-3p decreased ADAM10 expression and repressed activation of the Notch pathway by repressing cleavage of Notch proteins. The expression of miR-140-3p was negatively related to ADAM10 in clinical specimens. Nucleocytoplasmic separation/subfraction assays showed that miR-140-3p was able to inhibit the cleavage of Notch protein, and led to the accumulation of Notch intracellular domains (NICD) in the nucleus. Overexpression of miR-140-3p enhanced the sensitivity of A549 cells to antitumor agents by targeting the 3'UTR region of ADAM10 mRNA in both cultured cells and in vivo models. Conclusion: ADAM10 plays a major role in LUAD, and miR-140-3p acts on ADAM10 and inhibits its expression and the cleavage of Notch protein, leading to the inhibition the activity of the Notch pathway, and ultimately upregulating LUAD cell sensitivity to anti- tumor drugs.

Precision medicine for patients with gastro-oesophageal cancer: A subset analysis of the ProfiLER program.

BACKGROUND: Chemotherapy, anti-HER2 and PD-1 antibodies are standard treatments but only a minority of patients derive long-term benefit from these agents. METHODS: In this report we describe the mutational landscape and outcome of patients with gastroesophageal cancers enroled in the ProfiLER program. RESULTS: Adenocarcinoma (n = 86, 59%), signet-cell (n = 37, 25%) and squamous-cell (n = 21, 14%) were the dominant histology amongst 147 patients. Genomic analyses could be performed for 114 (78%) patients. The most common genomic alterations involved ERBB2 (15%), KRAS (12%), CCND1 (7%), FGFR1-3 (8%), EGFR (5%) and MET (3%), TP53 (51%) and CDKN2A/B (10%). ERBB2, MET and FGFR alterations were found exclusively in the adenocarcinoma and signet-cell subtypes, while CCND1 amplification, TP53 mutations and CDKN2A/B loss were found in both adenocarcinoma and squamous-cell subtypes. Nine patients (8%) received therapy matched to their genomic alteration, with 5 of them achieving disease control. In an exploratory analysis, patients with stage IV disease at diagnosis who had an actionable alteration had longer overall survival compared to those without. CONCLUSION: Genomic profiling for patients with advanced gastroesophageal cancers allows the identification of actionable alterations in large proportion of patients. Increased accessibility to molecularly matched therapy may improve survival in this disease.

Safety and efficacy of atezolizumab plus bevacizumab in patients with unresectable hepatocellular carcinoma in early clinical practice: A multicenter analysis.

PURPOSE: To assess the impact of clinical factors on the safety and efficacy of atezolizumab plus bevacizumab (ATZ + BV) treatment in patients with unresectable hepatocellular carcinoma (u-HCC). METHOD: Ninety-four u-HCC patients who were treated with ATZ + BV at multiple centers were enrolled. We defined Child-Pugh (CP)-A patients who received ATZ + BV treatment as a first line therapy as the 'meets the broad sense of the IMbrave150 criteria' group (B-IMbrave150-in, n = 46), and patients who received ATZ + BV treatment as a later line therapy or CP-B patients (regardless of whether ATZ + BV was a first line or later line therapy) as the B-IMbrave150-out group (n = 48). Patients were retrospectively analyzed for adverse events (AEs) and treatment outcomes according to their clinical characteristics, including neutrophil lymphocyte ratio (NLR) at baseline. RESULTS: The overall incidence of AEs was 87.2% (82/94 patients). The frequency of interruption of ATZ + BV treatment due to fatigue was higher in CP-B than CP-A patients (p = 0.030). Objective response (OR) rates of the B-IMbrave150-in group (28.3%, 39.1%) were significantly higher than those of the B-IMbrave150-out group (8.3%, 18.8%; p = 0.0157, 0.0401) using Response Evaluation Criteria in Solid Tumors (RECIST) and modified RECIST, respectively. In multivariate analysis, NLR (hazard ratio (HR), 4.591; p = 0.0160) and B-IMbrave150 criteria (HR, 4.108; p = 0.0261) were independent factors associated with the OR of ATZ + BV treatment using RECIST. CONCLUSION: In real-world practice, ATZ + BV treatment might offer significant benefits in patients who meet B-IMbrave150 criteria or have low NLR.

From cardio-oncology to cardio-onco-pharmacology: Towards a multidisciplinary approach in the understanding and management of cardiotoxicity.

Cardio-oncology is an emerging field that transformed the medical management of patients with cancer. It encompasses the prevention and treatment of cardiovascular toxicities related to cancer treatments, aiming to reduce cardiac adverse events among cancer survivors. Cardiovascular toxicities related to cancer treatments are described through data collected during phase I to phase III therapeutic trials, and post-marketing surveillance (phase IV). Pharmacovigilance analyses, based on datamining from these extensive databases, allowed to understanding and identifying new adverse drug reactions, some recently made available, such as immunotherapy or inhibitor of Bruton tyrosine kinase (IBTK).

Knockdown of FBI-1 Inhibits the Warburg Effect and Enhances the Sensitivity of Hepatocellular Carcinoma Cells to Molecular Targeted Agents via miR-3692/HIF-1α.

The transcription suppressor factor FBI-1 (the factor that binds to inducer of short transcripts-1) is an important regulator of hepatocellular carcinoma (HCC). In this work, the results showed that FBI-1 promoted the Warburg effect and enhances the resistance of hepatocellular carcinoma cells to molecular targeted agents. Knockdown of FBI-1 via its small-interfering RNA (siRNA) inhibited the ATP level, lactate productions, glucose uptake or lactate dehydrogenase (LDH) activation of HCC cells. Transfection of siFBI-1 also decreased the expression of the Warburg-effect-related factors: hypoxia-inducible factor-1 alpha (HIF-1α), lactate dehydrogenase A (LDHA), or GLUT1, and the epithelial-mesenchymal transition-related factors, Vimentin or N-cadherin. The positive correlation between the expression of FBI-1 with HIF-1α, LDHA, or GLUT1 was confirmed in HCC tissues. Mechanistically, the miR-30c repressed the expression of HIF-1α by binding to the 3'-untranslated region (3'-UTR) of HIF-1α in a sequence-specific manner, and FBI-1 enhanced the expression of HIF-1α and HIF-1α pathway's activation by repressing the expression of miR. By modulating the miR-30c/HIF-1α, FBI-1 promoted the Warburg effect or the epithelial-mesenchymal transition of HCC cells and promoted the resistance of HCC cells to molecular targeted agents.

Novel Microcrystal Formulations of Sorafenib Facilitate a Long-Acting Antitumor Effect and Relieve Treatment Side Effects as Observed With Fundus Microcirculation Imaging.

The tyrosine kinase inhibitors (TKIs), including sorafenib, remain one first-line antitumor treatment strategy for advanced hepatocellular carcinoma (HCC). However, many problems exist with the current orally administered TKIs, creating a heavy medical burden and causing severe side effects. In this work, we prepared a novel microcrystalline formulation of sorafenib that not only achieved sustainable release and long action in HCC tumors but also relieved side effects, as demonstrated by fundus microcirculation imaging. The larger the size of the microcrystalline formulation of sorafenib particle, the slower the release rates of sorafenib from the tumor tissues. The microcrystalline formulation of sorafenib with the largest particle size was named as Sor-MS. One intratumor injection (once administration) of Sor-MS, but not Sor-Sol (the solution formulation of sorafenib as a control), could slow the release of sorafenib in HCC tumor tissues and in turn inhibited the in vivo proliferation of HCC or the expression of EMT/pro-survival-related factors in a long-acting manner. Moreover, compared with oral administration, one intratumor injection of Sor-MS not only facilitated a long-acting antitumor effect but also relieved side effects of sorafenib, avoiding damage to the capillary network of the eye fundus, as evidenced by fundus microcirculation imaging. Therefore, preparing sorafenib as a novel microcrystal formulation could facilitate a long-acting antitumor effect and relieve drug-related side effects.

Increased Liquefactive Necrosis Formation After Transarterial Chemoembolization Combined with Molecular Targeted Agents Plus Immune Checkpoint Inhibitors for Hepatocellular Carcinoma.

PURPOSE: In clinical practice, we found some of the patients who received transarterial chemoembolization (TACE) with molecular targeted agents (MTGs) plus immune checkpoint inhibitors (ICIs) for hepatocellular carcinoma (HCC) had obvious liquefactive necrosis formation within the tumor and some even progressed to a liver abscess, which seems more frequent than patients who received other treatments. Thus, we aim to identify this condition and analyze the potential risk factors. PATIENTS AND METHODS: Medical records of 72 consecutive patients with intermediate (BCLC B) and advanced (BCLC C) HCC who received TACE plus MTGs combined with (n=30) or without (n=42) ICIs were reviewed. Liquefactive necrosis formation was defined as the presence of obvious liquefactive necrosis within the tumor that required intervention. RESULTS: The liquefactive necrosis rate was higher in the TACE+MTGs+ICIs group than in the TACE+MTGs group (30% vs 4.8%, P=0.006). Moreover, 18.2% (2/11) of the patients with liquefactive necrosis within the tumor had a bacterial infection. We then take the binary logistic regression analysis model to identify the predictors of liquefactive necrosis formation, and which showed the tumor size (P=0.006, OR=1.355, 95% CI: 1.090-1.684), alpha-fetoprotein level (P=0.036, OR=6.745, 95% CI: 1.130-40.262) and treatment modality (P=0.015, OR=11.717, 95% CI: 1.617-84.887) were the independent risk factor for liquefactive necrosis formation within the tumor. CONCLUSION: Patients with HCC who received TACE combined with MTGs plus ICIs have increased liquefactive necrosis formation, and the larger tumor size and higher alpha-fetoprotein level were associated with more liquefactive necrosis formation within the tumor.

Role of Oncogenic Pathways on the Cancer Immunosuppressive Microenvironment and Its Clinical Implications in Hepatocellular Carcinoma.

The tumor immune microenvironment, including hepatocellular carcinoma (HCC), is complex, consisting of crosstalk among tumor components such as the cancer cells, stromal cells and immune cells. It is conceivable that phenotypic changes in cancer cells by genetic and epigenetic alterations affect the cancer-stroma interaction and anti-cancer immunity through the expression of immune checkpoint molecules, growth factors, cytokines, chemokines and metabolites that may act on the immune system in tumors. Therefore, predicting the outcome of ICI therapy requires a thorough understanding of the oncogenic signaling pathways in cancer and how they affect tumor immune evasion. In this review, we have detailed how oncogenic signaling pathways can play a role in altering the condition of the cellular components of the tumor immune microenvironment such as tumor-associated macrophages, regulatory T cells and myeloid-derived suppressor cells. The RAS/MAPK, PI3K/Akt, Wnt/ß-catenin and JAK/STAT pathways have all been implicated in anti-tumor immunity. We also found that factors that reflect the immune microenvironment of the tumor, including the status of oncogenic pathways such as the volume of tumor-infiltrating T cells, expression of the immune checkpoint protein PD-1 and its ligand PD-L1, and activation of the Wnt/ß-catenin signaling pathway, predict a response to ICI therapy in HCC cases.

Early Tumor Response and Safety of Atezolizumab Plus Bevacizumab for Patients with Unresectable Hepatocellular Carcinoma in Real-World Practice.

The aim of this study was to investigate the early tumor response and safety of atezolizumab plus bevacizumab for patients with unresectable hepatocellular carcinoma in real-world practice. Forty patients with Child-Pugh class A liver function and eastern cooperative oncology group performance status 0 or 1 were enrolled. The objective response rate (ORR) at six weeks after the start of treatment, changes in α-fetoprotein (AFP) and des-γ-carboxyprothrombin, incidence of adverse events (AEs), and changes in albumin-bilirubin (ALBI) score and serum ammonia level, were evaluated. Among 40 patients, 24 had histories of prior molecular targeted agents (MTAs). The ORR was 22.5% based on mRECIST. Multivariate analysis showed that an AFP ratio <1.0 at three weeks (odds ratio 39.2, 95% confidence interval CI 2.37-649.0, p = 0.0103) was the only significant factor for predicting early response. There was no significant difference in the frequency of AEs between patients receiving first-line treatments and others. Fatigue, proteinuria, and ascites were more frequent in patients who experienced prior treatment. No decrease in ALBI score or increase in serum ammonia level was observed. Our study demonstrated that AFP may be useful in assessing early response and that this treatment is safe, including in patients with prior MTA treatments.