Pancreatic Juice-Derived microRNA-4516 and microRNA-4674 as Novel Biomarkers for Pancreatic Ductal Adenocarcinoma.

Background and Aims: Precise diagnostic biomarkers are urgently required for pancreatic ductal adenocarcinoma (PDAC). Therefore, the aim of this study was to identify PDAC-specific exosomal microRNAs (Ex-miRs) from pancreatic juice (PJ) and evaluate their diagnostic potential. Methods: Exosomes in PJ and serum were extracted using ultracentrifugation and confirmed morphologically and biochemically. PDAC-specific Ex-miRs were identified using our original miR arrays, in which "Ex-miRs derived from the PJ of patients with chronic pancreatitis (CP)" were subtracted from Ex-miRs commonly expressed in both "human PDAC cell lines" and "the PJ of patients with PDAC." We verified the expression of these miRs using quantitative real-time reverse transcription polymerase chain reaction. Changes in serum Ex-miR levels were assessed in 2 patients with PDAC who underwent curative resection. In situ hybridization was performed to directly visualize PDAC-specific miR expression in cancer cells. Results: We identified novel Ex-miR-4516 and Ex-miR-4674 from the PJ of patients with PDAC, and they showed 80.0% and 81.8% sensitivity, 80.8% and 73.3% specificity, and 90.9% and 80.8% accuracy, respectively. The sensitivity, specificity, and accuracy of a triple assay of Ex-miR-4516/4674/PJ cytology increased to 93.3%, 81.8%, and 88.5%, respectively. In serum samples (n = 88), the sensitivity, specificity, and accuracy of Ex-miR-4516 were 97.5%, 34.3%, and 68%, respectively. Presurgical levels of serum-derived Ex-miR-4516 in 2 patients with relatively early disease stages declined after curative resection. In situ hybridization demonstrated that Ex-miR-4516 expression exclusively occurred in cancer cells. Conclusion: Liquid assays using the in situ-proven Ex-miR-4516 may have a high potential for detecting relatively early-stage PDAC and monitoring its clinical course.

Leucine drives LAT1-related SNAIL upregulation in glucose-starved pancreatic cancer cells.

Pancreatic cancer, a highly fibrotic and hypovascular tumor, is thought to have unique metabolic characteristics in surviving and proliferating in malnutritional microenvironments. In this study, we compared the differences in the ability of pancreatic cancer cells to adapt to glucose-free conditions with liver cancer cells, which are representative of hypervascular tumors. Three pancreatic cancer cells and two liver cancer cells were used to examine the transcriptional expression levels of molecules involved in intracellular amino acid uptake, epithelial-mesenchymal transition (EMT), and cancer stemness under glucose deprivation. The results showed that the proliferative activity of pancreatic cancer cells under glucose deprivation was significantly lower than that of liver cancer cells, but the expression levels of amino acid transporters were significantly higher. Among them, L-type amino acid transporter 1 (LAT1) upregulation was unique in concert with increased expression of the EMT regulator SNAIL and the cancer stemness marker doublecortin-like kinase 1. LAT1 knockdown canceled the upregulation of SNAIL in glucose-starved pancreatic cancer cells, suggesting a mechanistic link between the two molecules. When LAT1 was stimulated by its substrate leucine, the SNAIL expression was upregulated dose-dependently. Collectively, pancreatic cancer cells reprogrammed metabolism to adapt to energy crises involving leucine-induced SNAIL upregulation.

Dose-reduction of bevacizumab in atezolizumab plus bevacizumab therapy extends treatment duration with disease control in patients with hepatocellular carcinoma.

INTRODUCTION: Atezolizumab (ATZ) and bevacizumab (BEV) combination therapy is widely used in patients with unresectable hepatocellular carcinoma (HCC). However, combination therapy is typically interrupted or discontinued owing to BEV-related adverse events. In this study, we examined the effects of BEV dose-reduction on the treatment of unresectable HCC using propensity score matching (PSM). METHOD: Overall, 119 patients with HCC who were treated with ATZ + BEV between November 2020 and October 2022 were enrolled retrospectively at our institute. The therapeutic effects and safety of BEV dose-reduction and non-dose reduction after PSM were compared. Decision-tree analysis was used to investigate treatment duration in the patients. RESULTS: Significant differences were not observed between the two groups after PSM. The objective response rate (ORR) and disease control rate (DCR) assessed by modified RECIST did not differ significantly between the two groups (BEV non-dose-reduction/dose-reduction: ORR; 46/34%, DCR; 80/91%). Progression-free survival (PFS) and overall survival (OS) also did not differ significantly between the two groups (BEV non-dose-reduction /dose-reduction: PFS; 5.6/8.6 months, OS; 18.6/15.5 months). The median duration of treatment in the BEV dose-reduction group was significantly longer than that in the non-dose-reduction group (BEV non-dose-reduction /dose-reduction: 4.8/9.1 months, P = 0.038). Decision-tree analysis revealed that dose-reduction of BEV was the first distinguishae factor for the extension of treatment duration with ATZ + BEV. CONCLUSION: BEV dose-reduction can be effectively used in maintaining the treatment duration of ATZ + BEV while maintaining therapeutic effects and safety in real-world clinical practice.

Impact of Bevacizumab Being Skipped due to Adverse Events of Special Interest for Bevacizumab in Patients with Unresectable Hepatocellular Carcinoma Treated with Atezolizumab plus Bevacizumab: An Exploratory Analysis of the Phase III IMbrave150 Study.

Introduction: The phase III IMbrave150 study established atezolizumab + bevacizumab as the global standard of care in patients with unresectable hepatocellular carcinoma (HCC). This exploratory analysis examined the impact of bevacizumab interruption due to bevacizumab adverse events of special interest (AESIs). Methods: Patients in IMbrave150 who were randomized to atezolizumab + bevacizumab and received treatment for ≥6 months (to reduce immortal time bias) were included in group A-1 if bevacizumab had ever been skipped due to bevacizumab AESIs or to group A-2 otherwise. Efficacy analyses included overall survival (OS) and progression-free survival (PFS) by whether bevacizumab was skipped (group A-1 vs. A-2). PFS was evaluated per independent review facility (IRF)-assessed Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1 and HCC-modified RECIST (IRF-HCC mRECIST). Safety was also evaluated. Results: Of the 210 patients who received ≥6 months of atezolizumab + bevacizumab, 69 were assigned to group A-1 and 141 to A-2. At data cutoff (August 20, 2020), hazard ratio (HR) for OS was 1.04 (95% CI: 0.64, 1.69) for group A-1 versus A-2. HR for PFS was 1.07 (95% CI: 0.74, 1.55) per IRF-assessed RECIST 1.1 and 1.10 (95% CI: 0.76, 1.59; 15.5 vs. 9.7 months) per IRF-HCC mRECIST for group A-1 versus A-2. Safety profiles for atezolizumab and bevacizumab were largely similar between groups. More group A-1 patients had grade 3/4 adverse events. A separate analysis investigating the impact of immortal time bias in patients who received ≥3 months of atezolizumab + bevacizumab supported the appropriateness of the ≥6-month landmark analysis. Discussion/Conclusion: Efficacy was similar between patients who skipped bevacizumab due to bevacizumab AESIs and those who did not. Although this comparison was nonrandomized and exploratory, results suggest that skipping bevacizumab due to bevacizumab AESIs did not considerably impact the efficacy and safety of atezolizumab + bevacizumab.

Hepatic arterial infusion of autologous CD34+ cells for hepatitis C virus-related decompensated cirrhosis: A multicenter, open-label, exploratory randomized controlled trial.

Introduction: In this multicenter clinical study, we aimed to investigate the efficacy and safety of the transhepatic arterial administration of granulocyte-colony stimulating factor (G-CSF)-mobilized autologous peripheral blood (PB)-CD34+ cells compared with standard therapy in patients with decompensated cirrhosis type C. Methods: Patients were randomly assigned (2:1) to the CD34+ cell transplant (CD34+ cell) or standard-of-care (SOC) group and followed up for 52 weeks. The primary endpoints were the non-progression rate of Child-Pugh (CP) scores at 24 weeks post-enrollment and the safety of the protocol treatment. Results: Fourteen patients (CD34+ cell group: 10; SOC group: 4) were enrolled. CP scores at 24 weeks had a non-progression rate of 90% in the CD34+ cell group and 100% in the SOC group, with no significant difference between groups. Importantly, 4 out of 10 patients in the CD34+ cell group exhibited an improvement from decompensated to compensated cirrhosis, whereas all patients in the SOC group remained in decompensated cirrhosis. With regard to secondary endpoints, a trend toward increased serum albumin levels in the CD34+ cell group was noted. Serious adverse events (SAEs) occurred in three patients in the CD34+ cell group and in one patient in the SOC group. No causal relationship was observed between all SAEs and G-CSF, leukapheresis, or cell transplantation in the CD34+ cell group. No patients died and no hepatocellular carcinoma occurred within the study period. Conclusions: PB-CD34+ cell infusion therapy may have the potential to circumvent the decompensated stage of cirrhosis, thus avoiding the need for liver transplantation.

Ex-vivo expanded CD34+ cell transplantation alleviates fibrotic liver injury via innate immune modulation in metabolic dysfunction-associated steatohepatitis mice.

BACKGROUND: In drug-induced liver injury, vascular endothelial progenitor cells, specifically the CD34+ cell fractions, have been found to decrease liver fibrosis and promote regeneration. However, it is unclear whether CD34+ cell transplantation has anti-fibrogenic effects on MASH, which has previously been treated effectively with anti-angiogenic therapy. We investigated the efficacy of ex vivo-expanded CD34+ cells in treating MASH livers. MATERIALS AND METHODS: Diet-induced MASH mice were fed a choline-deficient, L-amino acid-defined, high-fat diet for 12 or 20 weeks, and were designated as a mild and a severe fibrosis model, respectively. Mouse bone marrow CD34+ cells were expanded for 7 days, transplanted into each mouse once or twice 2 weeks later, and sacrificed at 4 weeks after the first transplantation. RESULTS: Expanded CD34+ cell transplantation ameliorated liver fibrosis, regardless of fibrosis degree, as indicated by the decrease in α-smooth muscle actin-positive cells, hydroxyproline concentration, and fibrogenic gene expression of Col1a1 and Timp1. Furthermore, engrafted CD34+ cells reduced alanine transaminase levels, the number of TUNEL+ hepatocytes, and 8-OHdG concentration. RNA-sequencing data showed that "defense response to virus" was the most down-regulated category in the Gene Ontology analysis and subsequent analysis revealed the suppression of RIG-I-like receptors/Irf7/Stat1/Cxcl10 axis in expanded CD34+ cell-transplanted livers. Finally, the downregulation of CXCL10 expression inhibits the mobilization of inflammatory immune cells, macrophages, T cells, and natural killer cells to the MASH liver. CONCLUSIONS: These findings suggest that transplanted expanded CD34+ cells alleviate fibrotic liver injury in MASH mouse models through possible modulation of the innate immune response, which is abnormally activated by hepatocyte lipotoxicity.

A tumor endothelial cell-specific microRNA replacement therapy for hepatocellular carcinoma.

Current approved anti-angiogenic drugs (AAD) for hepatocellular carcinoma (HCC) inhibit tumor angiogenesis, but affect the hepatic vasculature resulting in adverse effects. Tumor endothelial cells (TECs) differ from normal endothelial cells. In this study, we aimed to detect TEC-specific miRNAs and develop an anti-angiogenic treatment specific for TECs. We established HCC orthotopic mouse models. TEC-specific miRNAs were detected using a microRNA array. Finally, we evaluated the therapeutic effects of the TEC-specific miRNA agonist cocktail. In total, 260 TEC-specific genes were detected. Among the top ten downregulated TEC-specific miRNAs, miR-139-3p and 214-3p were important for the TEC phenotype. The TEC-specific microRNA agonist cocktail showed significant anti-tumor effects by inhibiting tumor angiogenesis without affecting hepatic vasculatures in HCC orthotopic mouse models. Moreover, it significantly downregulated tip-cell sprouting-related genes. We identified two downregulated TEC-specific miRNAs; microRNA replacement therapy, which targets the downregulated TEC-specific miRNAs, is an effective and promising treatment for HCC.

A Phase 2, Prospective, Multicenter, Single-Arm Trial of Transarterial Chemoembolization Therapy in Combination Strategy with Lenvatinib in Patients with Unresectable Intermediate-Stage Hepatocellular Carcinoma: TACTICS-L Trial.

Introduction: Transarterial chemoembolization (TACE) is the standard treatment for unresectable intermediate-stage hepatocellular carcinoma (HCC), but recurrence after TACE is common. The present phase 2, prospective, multicenter, single-arm trial, the TACTICS-L trial, investigated the efficacy and safety of TACE plus lenvatinib (LEN), a drug that more strongly promotes vascular normalization and has a better objective response rate (ORR) than sorafenib (jRCTs031180074). Methods: Participants were patients with HCC who had not previously received systemic therapy, hepatic arterial infusion chemotherapy, or immunotherapy and who were ineligible for resection or percutaneous ablation therapy. LEN was to be administered 14-21 days before the first TACE, stopped 2 days before TACE, and resumed 3 days after TACE. Key inclusion criteria were unresectable HCC, Child-Pugh A liver function, 0-2 prior TACE sessions, tumor size ≤10 cm, number of tumors ≤10, and ECOG performance status 0-1. Key exclusion criteria were vascular invasion and extrahepatic spread. The primary endpoint was progression-free survival (PFS) by RECICL, and secondary endpoints were time to untreatable progression, ORR, overall survival (OS), and safety. Results: A total of 62 HCC patients were enrolled in this trial. The median age was 72 years, 77.4% of patients were men, and 95.2% had PS 0. The primary endpoint of median PFS was 28.0 months (90% confidence interval [CI] 25.1-31.0) after a minimum 24 months of follow-up. The secondary endpoint of median OS was not reached (90% CI 35.5 months-NR). LEN-TACE achieved a high response rate and high complete response (CR) rate (4 weeks after the first TACE: ORR 79.0%, CR rate 53.2%; best response: ORR 88.7%, CR rate 67.7%) by RECICL. Exploratory subgroup analyses showed that the characteristics of responders/nonresponders (ORR and CR rate) were similar and that LEN-TACE would be effective in all subgroups, including the population in whom TACE alone would be less likely to be curative (e.g., patients with the non-simple nodular type or a high tumor burden). The relative dose intensity of LEN before the first TACE was important for achieving higher CR rate/ORR by LEN-TACE. No new safety concerns were observed. Conclusion: The results of this trial provide encouraging evidence, supporting the efficacy and favorable safety profile of LEN-TACE in patients who are ineligible for locoregional therapy.

Fibroblast growth factor inhibition by molecular-targeted agents mitigates immunosuppressive tissue microenvironment in hepatocellular carcinoma.

BACKGROUND & AIMS: Combination immunotherapy refers to the use of immune checkpoint inhibitors (ICI) and molecular-targeted agents (MTA), which have recently been approved for the treatment of advanced hepatocellular carcinoma (HCC). Owing to its relatively low antitumor effect (up to 30%), sequential therapy following ICIs treatment is required in patients with HCC. This study aimed to determine the impact of MTAs on the tumor immune microenvironment (TIME). METHODS: We established immune syngeneic orthotopic HCC mouse models using Hep-55.1C and Hep-53.4, and treated them with MTAs (lenvatinib, sorafenib, regorafenib, cabozantinib, and DC101 as anti-vascular endothelial growth factor receptor-2 antibodies, and AZD4547 as a fibroblast growth factor receptor (FGFR)-1/2/3/4 inhibitor) for 2 weeks. Subsequently, alterations in the TIME caused by MTAs were evaluated using immunohistochemistry (antibodies for CD3, CD8, Foxp3, Granzyme B, Arginase-1, NK1.1, F4/80, CD11c, PD-1, and PD-L1). We conducted RNA-seq analysis using lenvatinib- and AZD4547-treated tumors. To confirm the clinical relevance of these findings, we analyzed the transcriptome data of human HCC cells (MHCC-97H) treated with various concentrations of lenvatinib for 24 h using RNA-seq data from the Gene Expression Omnibus database. RESULTS: The number of Foxp3- and F4/80-positive cells in the TIME was decreased in many MTAs. Cabozantinib increased the numbers in NK1.1-, Granzyme B, and CD11c-positive cells. Lenvatinib and AZD4547 increased the number of CD8, Granzyme B, and PD-L1-positive cells. Gene ontology enrichment analysis revealed that lipid metabolism-related genes were downregulated by lenvatinib and AZD4547. In total, 161 genes downregulated by FGFR inhibition in rodent models overlapped with those downregulated by lenvatinib in human HCC cells. CONCLUSIONS: In this study, we showed that cabozantinib activated the innate immune system, and lenvatinib and AZD4547, which commonly inhibit FGFR signaling, altered TIME to a hot immune state by downregulating lipid metabolism-related genes. These findings support the therapeutic use of combination immunotherapies.

Efficacy of Lenvatinib Combined with Transcatheter Intra-Arterial Therapies for Patients with Advanced-Stage of Hepatocellular Carcinoma: A Propensity Score Matching.

This study aimed to evaluate the effect of lenvatinib (LEN) combined with transcatheter intra-arterial therapy (TIT) for advanced-stage hepatocellular carcinoma (HCC) after propensity score matching (PSM). This retrospective study enrolled 115 patients with advanced-stage HCC who received LEN treatment. The patients were categorized into the LEN combined with TIT group (n = 30) or the LEN monotherapy group (n = 85). After PSM, 38 patients (LEN + TIT group, n = 19; LEN monotherapy group, n = 19) were analyzed. The median overall survival (OS) in the LEN + TIT group was significantly higher than that in the LEN monotherapy group (median survival time (MST): 28.1 months vs. 11.6 months, p = 0.014). The OS in the LEN combined with transcatheter arterial chemoembolization and LEN combined with hepatic arterial infusion chemotherapy groups was significantly higher than that in the LEN monotherapy group (MST 20.0 vs. 11.6 months, 30.2 vs. 11.6 months, p = 0.048, and p = 0.029, respectively). Independent factors associated with OS were alpha-fetoprotein and LEN combined with TIT. The indications for LEN combined with TIT were age <75 years and modified albumin bilirubin (m-ALBI) grade 1. We concluded that LEN combined with TIT may improve prognosis compared with LEN monotherapy in patients with advanced-stage HCC.

Anti-PD-L1 antibodies promote cellular proliferation by activating the PD-L1-AXL signal relay in liver cancer cells.

BACKGROUND: Immune checkpoint inhibitors (ICIs) are emerging treatments for advanced hepatocellular carcinoma (HCC); however, evidence has shown they may induce hyperprogressive disease via unexplained mechanisms. METHODS: In this study, we investigated the possible stimulative effect of ICIs on programmed cell death-ligand 1 (PD-L1)-harboring liver cancer cells under immunocompetent cell-free conditions. RESULTS: The sarcomatous HAK-5 cell line displayed the highest expression of PD-L1 among 11 human liver cancer cell lines used in this study. HLF showed moderate expression, while HepG2, Hep3B, and HuH-7 did not show any. Moreover, sarcomatous HCC tissues expressed high levels of PD-L1. We observed approximately 20% increase in cell proliferation in HAK-5 cells treated with anti-PD-L1 antibodies, such as durvalumab and atezolizumab, for 48 h compared with that of those treated with the control IgG and the anti-PD-1 antibody pembrolizumab. No response to durvalumab or atezolizumab was shown in PD-L1-nonexpressing cells. Loss-of-function and gain-of-function experiments for PD-L1 in HAK-5 and HepG2 cells resulted in a significant decrease and increase in cell proliferation, respectively. Phosphorylated receptor tyrosine kinase array and immunoprecipitation revealed direct interactions between PD-L1 and AXL in tumor cells. This was stabilized by extrinsic anti-PD-L1 antibodies in a glycosylated PD-L1-dependent manner. Activation of AXL, triggering signal relay to the Akt and Erk pathways, boosted tumor cell proliferation both in vitro and in xenografted tumors in NOD/SCID mice. CONCLUSION: Collectively, this suggests that anti-PD-L1 antibodies stimulate cell proliferation via stabilization of the PD-L1-AXL complex in specific types of liver cancer, including in HCC with mesenchymal components. SIGNIFICANCE: Therapeutic anti-PD-L1 antibodies promote cell proliferation by stabilizing the PD-L1-AXL complex in PD-L1-abundant neoplasms, including in HCC with mesenchymal components. Such a mechanism may contribute to the development of hyperprogressive disease.

Preoperative Chemotherapy Followed by Hepatectomy for Potentially Resectable UICC7 Stage IIIA, IIIB Hepatocellular Carcinoma; A Phase II Clinical Trial.

BACKGROUND: The Japanese guideline for therapeutic strategy in HCC does not recognize any benefit of preoperative chemotherapy for potentially resectable hepatocellular carcinoma (HCC), and only upfront resec tion is recommended even for an advanced HCC. Data on preoperative chemotherapy for advanced HCC is still limited. Poor prognostic factors of HCC after resection are tumor more than 5 cm in diameter, multiple lesions, and gross tumor thrombosis, which constitute UICC7 Stage IIIA and IIIB HCC. There are no prospective studies about preoperative chemotherapy in these patients. AIM: To evaluate the benefit of preoperative chemotherapy for UICC7 Stage IIIA and IIIB potentially resectable HCC. DISCUSSION: Our recent study demonstrated that the 5-year overall survival rate (OS) of patients diagnosed as UICC7 Stage IIIA and IIIB who had received upfront resection was only 16.5%. In contrast, the 5-year OS of UICC7 Stage IIIA and IIIB initially unresectable patients who had achieved conversion from unresectable to resect able status under successful hepatic infusion chemotherapy prior to resection was as high as 61.3%. Additionally, recent studies reported transarterial chemoembolization achieved outcomes comparable with those of resection. Therefore, we believe that patients with UICC7 Stage IIIA and IIIB should be considered borderline resectable. To evaluate this hypothesis we registered the present phase II clinical trial to assess the benefit of preoperative chemo therapy followed by hepatectomy in potentially resectable UICC7 Stage IIIA and IIIB HCC patients.

The impact of curative conversion therapy aimed at a cancer-free state in patients with hepatocellular carcinoma treated with atezolizumab plus bevacizumab.

BACKGROUND AND AIMS: We aimed to validate the predictive factors for tumor response and the prognostic impact of conversion therapy aimed at cancer- and drug-free states in patients with unresectable hepatocellular carcinoma (u-HCC) undergoing atezolizumab plus bevacizumab (Atez/Bev) therapy. METHODS: This retrospective study enrolled 156 patients who were Child-Pugh class A with u-HCC treated using Atez/Beva. The profile of objective response was investigated using decision-tree analysis. Progression-free, recurrence-free, and overall survival were assessed. RESULTS: The progression-free and overall survival were 6.1 and 18.0 months, respectively. Objective response and disease control rates were 32.0% and 84.0%, respectively. Decision-tree analysis revealed that neutrophil-to-lymphocyte ratio (NLR) <3, modified albumin-bilirubin grade (m-ALBI) 1 or 2a, and age < 75 were sequential splitting variables for the objective response, respectively. In the multivariate analysis, NLR <3 and m-ALBI grade 1 or 2a were identified as predictive factors for objective response. We successfully achieved eligibility for conversion therapy in 17 patients after Atez/Bev therapy significant response. Following conversion therapy, the curative therapy group, including surgical resection or radiofrequency ablation (RFA), had significantly higher recurrence-free survival than did the transcatheter arterial chemoembolization (TACE) and Atez/Bev discontinuation (surgical resection or RFA; not reached vs. TACE; 5.3 months, p = 0.008, Atez/Bev discontinuation; 3.9 months, p = 0.048, respectively) groups. CONCLUSIONS: NLR <3 and m-ALBI grade 1 or 2a were predictive factors for conversion therapy, leading to cancer- and drug-free states in patients with u-HCC undergoing Atez/Bev therapy. Moreover, surgery or RFA may be suitable for conversion therapy for cancer-free status.

Telephone follow-up contributes to improving adherence and treatment duration in patients with hepatocellular carcinoma treated with lenvatinib.

BACKGROUND AND AIM: This study aimed to investigate whether telephone follow-up by clinical pharmacists for unresectable hepatocellular carcinoma (HCC) patients treated with lenvatinib (LEN) contributes to improved adherence and treatment duration for LEN. METHODS: This retrospective study enrolled 132 patients with HCC who were treated with LEN. The patients were classified into non-telephone follow-up (n = 32) or telephone follow-up groups (n = 100) [the latter group was further classified into family-pharmacist (FP) telephone follow-up (n = 18), or hospital family-pharmacist (HFP) telephone follow-up (n = 82) groups]. RESULTS: The progression-free survival (PFS) in the telephone follow-up group was significantly higher than that in the non-telephone follow-up group (PFS 6.1 months vs 3.7 months, P = 0.001, respectively). Although treatment duration was significantly longer in the telephone follow-up group than in the non-telephone follow-up group [median treatment duration: 10.4 months vs 4.1 months, P = 0.001, respectively.], no significant differences were noted between the HFP telephone follow-up group and FP telephone follow-up groups (10.3 months vs 13.3 months, P = 0.543). Self-interruption and adverse-event discontinuation in the HFP-telephone follow-up group were significantly lower than those in the FP-telephone and non-telephone groups (0% vs 11.1% vs 18.8%; P < 0.001, 25.6% vs 33.3% vs 53.1%; P = 0.022, respectively). CONCLUSIONS: Telephone follow-up contributes to prolonged treatment duration for LEN in patients with HCC treated. Moreover, telephone follow-up with an HFP may further improve treatment adherence.

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.

Tumor-derived insulin-like growth factor-binding protein-1 contributes to resistance of hepatocellular carcinoma to tyrosine kinase inhibitors.

BACKGROUND: Antiangiogenic tyrosine kinase inhibitors (TKIs) provide one of the few therapeutic options for effective treatment of hepatocellular carcinoma (HCC). However, patients with HCC often develop resistance toward antiangiogenic TKIs, and the underlying mechanisms are not understood. The aim of this study was to determine the mechanisms underlying antiangiogenic TKI resistance in HCC. METHODS: We used an unbiased proteomic approach to define proteins that were responsible for the resistance to antiangiogenic TKIs in HCC patients. We evaluated the prognosis, therapeutic response, and serum insulin-like growth factor-binding protein-1 (IGFBP-1) levels of 31 lenvatinib-treated HCC patients. Based on the array of results, a retrospective clinical study and preclinical experiments using mouse and human hepatoma cells were conducted. Additionally, in vivo genetic and pharmacological gain- and loss-of-function experiments were performed. RESULTS: In the patient cohort, IGFBP-1 was identified as the signaling molecule with the highest expression that was inversely associated with overall survival. Mechanistically, antiangiogenic TKI treatment markedly elevated tumor IGFBP-1 levels via the hypoxia-hypoxia inducible factor signaling. IGFBP-1 stimulated angiogenesis through activation of the integrin α5ß1-focal adhesion kinase pathway. Consequently, loss of IGFBP-1 and integrin α5ß1 by genetic and pharmacological approaches re-sensitized HCC to lenvatinib treatment. CONCLUSIONS: Together, our data shed light on mechanisms underlying acquired resistance of HCC to antiangiogenic TKIs. Antiangiogenic TKIs induced an increase of tumor IGFBP-1, which promoted angiogenesis through activating the IGFBP-1-integrin α5ß1 pathway. These data bolster the application of a new therapeutic concept by combining antiangiogenic TKIs with IGFBP-1 inhibitors.

Significance of ramucirumab following atezolizumab plus bevacizumab therapy for hepatocellular carcinoma using real-world data.

AIM: Few studies have reported the efficacy and safety of ramucirumab (RAM) after atezolizumab plus bevacizumab (Atezo/Beva) treatment and the overall associated outcomes. Thus, we aimed to evaluate the therapeutic effects and safety of RAM post-treatment with Atezo/Beva. METHODS: This retrospective study enrolled 46 patients with unresectable hepatocellular carcinoma who were treated with RAM. The patients were classified into the RAM administered following Atezo/Beva failure (n = 12) or RAM administered following other drug failure (n = 34) groups. Progression-free survival (PFS), overall survival (OS), and adverse event (AE) rates were assessed. RESULTS: There were significant differences in the objective response rates and disease control rates between the RAM administered following Atezo/Beva and RAM administered following others groups (objective response rate 33.3%. vs. 0.0%, p = 0.001; disease control rate 83.3% vs. 32.3, p = 0.001). Although there was no significant difference in the OS rates, the median PFS rates in the RAM administered following Atezo/Beva group was significantly higher than in the RAM administered following others group (PFS 3.9 months. vs. 1.9 months, p = 0.047). The AE rates were comparable between the two groups; ascites was the most common AE (45.6%). Using decision tree analysis, the presence of splenomegaly and body mass index (BMI) < 19.8 were the first and second splitting variables for RAM-related ascites, respectively. CONCLUSIONS: The therapeutic effect of RAM increased in patients with Atezo/Beva failure. Patients with splenomegaly and low BMI should be monitored for ascites during RAM treatment.

The beneficial impact of metabolic dysfunction-associated fatty liver disease on lenvatinib treatment in patients with non-viral hepatocellular carcinoma.

AIM: Lenvatinib is used to treat advanced hepatocellular carcinoma (HCC). Metabolic dysfunction-associated fatty liver disease (MAFLD) is becoming a major etiology of HCC. We aimed to evaluate the impact of MAFLD on the efficacy of lenvatinib. METHODS: We enrolled 320 patients with HCC who were treated with lenvatinib. All patients were classified into the MAFLD (n = 155) and non-MAFLD (n = 165) groups. Independent factors for overall survival (OS) were analyzed. In the stratification analysis, HCC was categorized as non-viral (n = 115) or viral HCC (n = 205). RESULTS: The OS rate was significantly higher in the MAFLD group than in the non-MAFLD group (median 21.1 vs. 15.1 months, p = 0.002). Multivariate analysis demonstrated that, in addition to albumin-bilirubin grade and Barcelona Clinic Liver Cancer stage, MAFLD was identified as an independent factor for OS (HR 0.722, 95% CI 0.539-0.966, p = 0.028). In the stratification analysis, the OS rate was significantly higher in the MAFLD group than in the non-MAFLD group among patients with non-viral HCC (median 21.1 vs. 15.1 months, p = 0.002), but not in patients with viral HCC. Furthermore, MAFLD was an independent negative risk factor for OS in patients with non-viral HCC (HR 0.506, 95% CI 0.297-0.864, P < 0.01). However, MAFLD was not an independent factor for OS in patients with viral HCC. CONCLUSIONS: MAFLD was a beneficial factor for survival in patients with HCC treated with lenvatinib. Moreover, the better OS of the MAFLD group was more pronounced in patients with non-viral HCC. Lenvatinib may be a suitable agent for patients with non-viral HCC and MAFLD.

The Clinical Impact of Hepatic Arterial Infusion Chemotherapy New-FP for Hepatocellular Carcinoma with Preserved Liver Function.

Background: Systemic treatments are recommended for advanced hepatocellular carcinoma (HCC) in preserved liver function. However, their effects are unsatisfactory in some tumor conditions, particularly macrovascular invasion (MVI) including major portal vein tumor thrombus (PVTT). We compared the efficacy of hepatic arterial infusion chemotherapy (HAIC) regimens New-FP and sorafenib for various tumor conditions in preserved liver function. Methods: We retrospectively collected the data of 1709 patients with HCC who were treated with New-FP or sorafenib. Survival was assessed after propensity score matching. Subgroup analyses were conducted: cohort 1 (no MVI or extrahepatic spread (EHS)), cohort 2 (MVI only), cohort 3 (EHS only), cohort 4 (MVI and EHS), and cohort 5 (major PVTT). Results: The New-FP group had a longer median survival time (MST) than the sorafenib in the whole analysis (18 vs. 9 months; p < 0.0001). New-FP demonstrated a longer MST compared with sorafenib in cohort 2 and cohort 4. In cohort 5, the MST of the New-FP group was 16 months, while that of sorafenib was 6 months (p < 0.0001). For major PVTT-HCC, the response rate of New-FP was 73.0%. The MST of patients who achieved complete response with New-FP was 59 months. Conclusions: HAIC using New-FP is promising for patients with MVI- and major PVTT-HCC in preserved liver function.