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.

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.

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.

Deterioration of liver function and aging disturb sequential systemic therapy for unresectable hepatocellular carcinoma.

This study aimed to investigate the clinical characteristics of patients with unresectable hepatocellular carcinoma (HCC), who were eligible for sequential systemic therapy. We evaluated 365 patients with HCC who underwent systemic therapy after 2017. The overall survival (OS) was 13.7 months, 19.2 months, and 35.6 months in the first-line, second-line, and third-line or later therapy groups, respectively. Multivariate analysis revealed that the modified-albumin-bilirubin (m-ALBI) grade, macrovascular invasion, extrahepatic spread, discontinuation due to adverse events (AEs), and sequential therapy were independent factors for OS. At the end of each therapy, the ALBI score was significantly worse among patients with discontinuation due to AEs than among those without. The conversion rate to second-line and third-line therapy among patients with discontinuation due to AEs was significantly lower than that among patients without (30.4% vs. 69.2%, p < 0.001; 6.7% vs. 58.3%; p < 0.001, respectively). In the decision tree analysis, m-ALBI grade 1 or 2a and non-advanced age were selected splitting variables, respectively, for sequential systemic therapy. In conclusion, sequential therapy prolonged the OS of unresectable HCC. Additionally, good hepatic function and non-advanced age were clinically eligible characteristics for sequential systemic therapy.

Association between Adverse Events and Prognosis in Patients with Hepatocellular Carcinoma Treated with Atezolizumab Plus Bevacizumab: A Multicenter Retrospective Study.

This study aimed to evaluate the correlation between adverse events (AEs) and overall survival (OS) in patients with unresectable hepatocellular carcinoma treated with atezolizumab plus bevacizumab (atezo/beva). This was a multicenter study in which 130 patients were enrolled. Hypertension and skin disorders had a significant correlation with longer survival (median survival time (MST): not reached vs. 14.3 months and not reached vs. 14.8 months, p = 0.001 and p = 0.047, respectively). In contrast, liver injuries were significantly correlated with shorter survival (MST: 14.7 months vs. not reached, p = 0.036), and the median development time was 21 days. In a logistic regression analysis, fatigue ≥ grade 2, liver injury ≥ grade 3, and modified albumin-bilirubin grade 2b were identified as independent factors for discontinuation due to AEs. The OS in the no discontinuation due to AE group was significantly longer than that in the discontinuation due to AEs group (MST not reached vs. 11.2 months, p = 0.001). We concluded that the development of liver injury was a negative factor for OS and that we should be vigilant in monitoring AE during atezo/beva treatments.

Case Report: Exacerbation of varices following atezolizumab plus bevacizumab treatment of hepatocellular carcinoma: A case series and literature review.

Recently, a combined regimen of atezolizumab and bevacizumab (AB) treatment has been approved as a first-line treatment in patients with advanced hepatocellular carcinoma (HCC), contributing to prolonged survival. However, we often encounter cases where treatment must be discontinued due to the occurrence of adverse events. One of these events, which is often fatal, is gastrointestinal bleeding. To clarify the clinical effects of gastrointestinal bleeding after AB treatment, we evaluated patients with HCC who were treated with AB at our institution. Of the 105 patients, five treated with AB developed gastrointestinal bleeding, necessitating treatment discontinuation. Additionally, we encountered two cases where exacerbation of varicose veins was observed, and AB therapy could be continued by preventive treatment of varices. In conclusion, an appropriate follow-up is required during treatment with AB to prevent possible exacerbation of varicose veins.

Durable complete response is achieved by balloon-occluded transcatheter arterial chemoembolization for hepatocellular carcinoma.

In 2013 and 2014, the development of microcatheters with balloons for the 4-Fr system and new embolization materials provided various options for transarterial chemoembolization (TACE), expanding the range of treatment strategies. At our hospital, balloon-occluded TACE (B-TACE), conventional TACE (C-TACE), and drug-eluting bead TACE (DEB-TACE) have been actively performed for hepatocellular carcinoma (HCC). This study compared the local recurrence-free (LRF) periods of nodules with complete necrosis (TE4) obtained using each treatment method by extracting the nodules evaluated as complete response by the modified Response Evaluation Criteria in Solid Tumors. We performed 580 TACE procedures between June 2013 and April 2019. Among them, 58 HCC nodules in 43 patients, 33 nodules in 30 patients, and 45 nodules in 25 patients were evaluated as having complete necrosis after C-TACE, DEB-TACE, and B-TACE, respectively. The time to local recurrence for each nodule was defined as the LRF period, and the quality of TE4 for each TACE was examined. Factors related to overall survival and the LRF period were determined by univariate and multivariate analyses, and overall survival and the LRF period were analyzed using the Kaplan-Meier method. Multivariate analysis of the LRF period showed that B-TACE was an independent factor. The median LRF periods were 39.3, 13, and 9.1 months for B-TACE, C-TACE, and DEB-TACE, respectively. Moreover, B-TACE had a significantly longer LRF period than C-TACE and DEB-TACE. Conclusion: There was no significant difference between C-TACE and DEB-TACE. The LRF period of nodules with TE4 was the longest with B-TACE, suggesting that B-TACE should be used to achieve a radical cure in patients with HCC.

Hepatitis C Virus Elimination Using Direct Acting Antivirals after the Radical Cure of Hepatocellular Carcinoma Suppresses the Recurrence of the Cancer.

It remains unclear whether hepatocellular carcinoma (HCC) recurrence in hepatitis C virus (HCV)-infected patients can be suppressed by the elimination of the virus using direct-acting antivirals (DAAs) after radical HCC treatment. We evaluated the sustained inhibitory effect of DAAs on HCC recurrence after curative treatment. This multicenter retrospective study included 190 HCV-positive patients after radical treatment for early-stage HCC. Patients were classified into the DAA treatment group (n = 70) and the non-DAA treatment group (n = 120) after HCC treatment. After propensity score matching (PSM), 112 patients were assessed for first and second recurrences using the Kaplan-Meier method and analyzed using a log-rank test. The first recurrence rates at 1 and 3 years were 3.6% and 42.1% in the DAA treatment group and 21.7% and 61.9% in the non-DAA treatment group, respectively (p = 0.0026). Among 85 patients who received radical treatment, the second recurrence rate at 3 years was 2.2% in the DAA treatment group and 33.9% in the non-DAA treatment group (p = 0.0128). In HCV-positive patients with early-stage HCC, the first and second recurrences were suppressed by DAA therapy after radical treatment, suggesting that the inhibitory effect of DAA therapy on HCC recurrence was sustained.

Evaluating the therapeutic effect of lenvatinib against advanced hepatocellular carcinoma by measuring blood flow changes using contrast-enhanced ultrasound.

BACKGROUND: The antitumor effect of a drug is considered to be associated with a decrease in tumor blood flow. AIMS: We investigated whether the efficacy of lenvatinib (LEN) could be accurately assessed by measuring blood flow in hepatocellular carcinoma (HCC) during early treatment stages. METHODS AND RESULTS: Blood flow changes and treatment results of 19 patients who underwent contrast-enhanced ultrasound (CEUS), before and after LEN administration, in Kurume University Hospital from July 2018 to June 2020 were examined. Blood flow was evaluated after the intravenous administration of perflubutane (0.015 ml/kg). The vascular phase was photographed and used as RAW data, and time-intensity curve analysis was used to obtain the region of interest (ROI) on the entire tumor nodule and quantify tumor blood flow. The evaluation was performed before and 1 and 4 weeks after LEN administration. Mean ± standard deviation (SD) values of the brightness of blood flow in the background liver before and 1 and 4 weeks after LEN administration were 2.84 × 10-4 ± 2.94 × 10-4 , 3.07 × 10-4 ± 3.79 × 10-4 , and 10.0 × 10-4 ± 20.8 × 10-4 dB, respectively. Blood flow in the background liver did not significantly decrease at 1 and 4 weeks compared with that before treatment. Mean ± SD values of the brightness of blood flow in HCC before and 1 and 4 weeks after administration were 3.49 × 10-3 ± 4.58 × 10-3 , 1.16 × 10-3 ± 1.57 × 10-3 , and 6.39 × 10-3 ± 22.8 × 10-3 dB, respectively. Blood flow in HCC after 1 week was significantly lower than that before administration (p = .0192). The therapeutic effects were significantly higher in the group with ≥50% blood flow reduction in HCC at 1 week after administration (p = .0038) and the group with reduced blood flow in HCC at 4 weeks after administration (p = .0051) than those before administration. CONCLUSION: Early blood flow evaluation by CEUS may be useful in predicting the therapeutic effect of LEN for unresectable advanced HCC.

Usefulness of a novel transarterial chemoinfusion plus external-beam radiation therapy for advanced hepatocellular carcinoma with tumor thrombi in the inferior vena cava and right atrium: Case study.

BACKGROUND: Invasion beyond inferior vena cava (IVC) to right atrium (RA) is a rare complication in patients with advanced hepatocellular carcinoma (HCC), and results in fatal oncologic emergencies, including pulmonary embolism and right heart failure. AIM: As there is no gold standard treatment for unresectable HCC with tumor thrombi involving IVC and RA, we considered it valuable to assess safety and efficacy of a combination of hepatic arterial infusion chemoembolization (HAIC) therapy and external-beam radiation therapy (EBRT). METHODS AND RESULTS: The "New FP" was chosen as the HAIC therapy, in which the enhanced permeation and retention effect was achieved using a cisplatin-Lipiodol suspension combined with continuous infusion of 5-fluorouracil (5-FU). Sixteen patients with HCC with tumor thrombi in IVC, RA, and pulmonary arteries were enrolled. modified response evaluation criteria in solid tumors-based evaluation of response to the combination treatment was as follows: complete response, 6.2% (1 patient); partial response, 81.3% (13 patients); stable disease, 12.5% (2 patients); progressive disease, 0%. The median overall survival time (MST) was 19.0 months. Notably, MST of patients receiving sequential sorafenib monotherapy (39.0 months) was significantly longer than that of the rest (15.3 months). CONCLUSION: The combination of New FP and EBRT is an efficacious treatment option for unresectable HCC involving IVC and RA, complicated with pulmonary embolism. Sequential administration of molecular-targeted drugs may prolong survival in such patients.

Association between contrast enhancement on contrast-enhanced CT and lenvatinib effectiveness in hepatocellular carcinoma.

The aim of the present study was to investigate whether the degree of contrast enhancement on contrast-enhanced (CE)-CT can predict the prognosis of patients with hepatocellular carcinoma (HCC) treated with lenvatinib (LEN). A total of 67 consecutive patients with LEN-treated HCC were retrospectively analysed. In the pretreatment CE-CT, the CT values were measured using a region of interest within the main nodule and the liver parenchyma in the arterial phase, and the macroscopic degree of contrast enhancement of the tumour area was quantified by calculating the enhancement ratio (ER) of the liver parenchyma. The associations of pretreatment ER with progression-free survival (PFS) and overall survival (OS) were then investigated. There were 20, 27 and 20 patients in the ER ≥1.5, 1.0≤ ER <1.5 and ER <1.0 groups, respectively. There was no significant difference in the PFS and OS among the three ER groups (PFS, P=0.63; OS, P=0.455). The ER <1.0 group had significantly more patients with larger tumour diameters, Barcelona Clinic Liver Cancer (BCLC) stage C with extrahepatic metastases, and higher des-γ-carboxy prothrombin values compared with the ER ≥1.0 group, suggesting that ER <1.0 reflected more aggressive types of HCC. The multivariate analysis revealed tumour size and α-fetoprotein as independent predictors of shorter PFS. Albumin-bilirubin grade 2 and BCLC stage C were significant predictors of poor OS, whereas the ER was confirmed as a non-significant predictor of both PFS and OS. Only non-alternating LEN and transarterial therapy (AT) were identified as independent predictors of unfavourable OS in patients with BCLC stage B HCC. Therefore, LEN has a strong therapeutic effect on HCC, regardless of the degree of contrast enhancement. Furthermore, AT may prolong the OS of LEN-treated patients with BCLC stage B HCC, regardless of tumour vascularity.

Robust Effect of Hepatic Arterial Infusion Chemotherapy and Radiation Therapy on Hepatocellular Carcinoma Arising from Fontan-associated Liver Disease.

Fontan-associated liver disease (FALD) caused by long-term systemic venous congestion following the Fontan procedure may eventually lead to hepatocellular carcinoma (HCC). Treatment strategies for HCC due to FALD (FALD-HCC) remain unclear. We herein report a 35-year-old man with FALD-HCC that was well controlled by 3 cycles of continuous infusion of 5-fluorouracil and low-dose cisplatin (low-dose FP therapy) combined with 60 Gy of radiation therapy. However, the patient ultimately died of extrahepatic metastases. A pathological autopsy revealed more than 90% necrosis in the primary HCC lesion. This case suggests that low-dose FP therapy might be effective in FALD-HCC.

Hepatic Arterial Infusion Chemotherapy with Cisplatin versus Sorafenib for Intrahepatic Advanced Hepatocellular Carcinoma: A Propensity Score-Matched Analysis.

Given that the outcome of hepatic arterial infusion chemotherapy (HAIC) with cisplatin for intrahepatic advanced hepatocellular carcinoma (HCC) is unclear, we aimed to compare prognostic factors for overall survival (OS) following HAIC with cisplatin versus sorafenib for intrahepatic advanced HCC using propensity score-matched analysis. We enrolled 331 patients with intrahepatic advanced HCC who received HAIC with cisplatin (n = 88) or sorafenib (n = 243) between June 2006 and March 2020. No significant difference was observed in OS between HAIC with cisplatin and sorafenib cohorts (median survival time [MST]: 14.0 vs. 12.3 months; p = 0.0721). To reduce confounding effects, 166 patients were selected using propensity score-matched analysis (n = 83 for each treatment). HAIC with cisplatin significantly prolonged OS compared with sorafenib (MST: 15.6 vs. 11.0 months; p = 0.0157). Following stratification according to the Child-Pugh classification, for patients with class A (MST: 24.0 vs. 15.0 months; p = 0.0145), HAIC with cisplatin rather than sorafenib significantly prolonged OS. Our findings suggest that HAIC with cisplatin demonstrates longer prognostic effects than sorafenib in intrahepatic advanced HCC.

First-line sorafenib sequential therapy and liver disease etiology for unresectable hepatocellular carcinoma using inverse probability weighting: A multicenter retrospective study.

BACKGROUND AND AIMS: Sequential therapy with molecular-targeted agents (MTAs) is considered effective for unresectable hepatocellular carcinoma (HCC) patients. This study purposed to evaluate the efficacy of sequential therapy with sorafenib (SORA) as a first-line therapy and to investigate the therapeutic impact of SORA in nonalcoholic fatty liver disease (NAFLD) or nonalcoholic steato hepatitis (NASH)-related HCC. METHODS: We evaluated 504 HCC patients treated with SORA (Study-1). The times of administration for sorafenib from 2009 to 2015, 2016 to 2017, and 2018 and later were defined as the early-, mid-, and late-term periods, respectively. Among them, 180 HCC patients treated with SORA in addition to MTAs in the mid- and late-term periods were divided into groups based on disease etiology (NAFLD or NASH [n = 37] and viral or alcohol [n = 143]), and outcomes were compared after inverse probability weighting (IPW) (Study-2). RESULTS: Overall survival (OS) of HCC patients who received sequential MTA therapy after first-line SORA was significantly longer. The median survival times (MST) were 12.6 versus 17.6 versus 17.4 months in the early-term group, mid-term group, and the later-time group (early vs. mid, p = 0.014, early vs. later. p = 0.045), respectively. (Study-1). In Study-2, there was no significant differences in OS between the Virus/alcohol group and the NAFLD/NASH group in patients who received sequential therapy (MST was 23.4 and 27.0 months p = 0.173, respectively). The NAFLD or NASH, female sex, albumin-bilirubin (ALBI) grade 2b, and major Vp (Vp3/Vp4) were significant factors for OS treated with SORA. CONCLUSIONS: Sequential therapy with SORA as the first-line treatment improved the prognosis of unresectable HCC patients and was effective regardless of HCC etiology.

Clinical Importance of Regimens in Hepatic Arterial Infusion Chemotherapy for Advanced Hepatocellular Carcinoma with Macrovascular Invasion.

Macroscopic vascular invasion (MVI) is a poor prognostic factor in hepatocellular carcinoma (HCC). Hepatic arterial infusion chemotherapy (HAIC) is a promising treatment in MVI-HCC. However, it is not clear which regimens are suitable for HAIC. In this study, we aimed to compare the therapeutic effects between New FP (a fine-powder cisplatin suspended with lipiodol plus 5-fluorouracil) and low dose FP (LFP/cisplatin plus 5-fluorouracil) in the treatment of MVI-HCC patients with Child-Pugh class A. New FP is a regimen that consists of a fine-powder cisplatin suspended with lipiodol and 5-fluorouracil. Fifty-one patients were treated with LFP, and 99 patients were New FP. We compared the therapeutic effects of LFP and New FP and assessed factors that associated with the therapeutic effects. The median survival and progression-free survival times of LFP and New FP were 16.1/24.7 and 5.4/8.8 months, respectively (p < 0.05, p < 0.05). The complete response (29%) and objective response rate (76%) of New FP were significantly higher than those of LFP (p < 0.001, p < 0.01). Factors associated with better therapeutic response were better ALBI-grade and New FP treatment choice. New FP is a more powerful regimen than LFP in HAIC for MVI-HCC. New FP represents a recommended HAIC regimen for the treatment of patients with MVI-HCC.

Multimolecular-Targeted Agents for Intermediate-Stage Hepatocellular Carcinoma Influence Time to Stage Progression and Overall Survival.

Background & Aims: Intermediate hepatocellular carcinoma (HCC) treatment has become complicated due to the development of various molecular-targeted agents (MTAs). We aimed to determine whether the administration of MTAs in patients with intermediate-stage HCC contributed to the prevention of progression to an advanced stage. METHODS: We enrolled and retrospectively examined 289 patients with Child-Pugh class A who had been diagnosed with intermediate-stage HCC and underwent initial trans-arterial chemoembolization (TACE). Patients were classified into 2 groups: a group in which MTAs were administered to patients whose condition was refractory to TACE (n = 65) and a group in which MTAs were not administered (n = 65) at intermediate-stage HCC after propensity score matching (PSM). Time to stage progression (TTSP) and overall survival (OS) were calculated using the Kaplan-Meier method and analyzed using a log-rank test after PSM. RESULTS: TTSP and OS of the group with MTA administration were significantly longer than those of the group without MTA administration (TTSP: 36.4 vs. 17.9 months, p < 0.001; median survival time [MST]: 44.6 vs. 26.6 months, p = 0.001). Within the up-to-seven criteria and administration of MTAs at the intermediate-stage HCC were identified as independent factors for TTSP and OS in the multivariate analysis. TTSP and OS in the era of the multi-MTA group were significantly longer than those in the era of the mono-MTA group (TTSP: 44.8 vs. 27.4 months, p = 0.01; MST: 53.4 vs. 33.3 months, p = 0.01). CONCLUSION: The administration of MTAs in patients with intermediate-stage HCC contributes to the prevention of stage progression and prolongs OS.

Efficacy and tolerability of Sorafenib plus metronomic chemotherapy S-1 for advanced hepatocellular carcinoma in preclinical and clinical assessments.

OBJECTIVE: Although sorafenib, a molecular targeted agent, has survival benefits for advanced hepatocellular carcinoma (HCC) patients, its disease control rate remains limited. To explore the potential for augmenting its antitumor effect, we assessed the preclinical and clinical efficacy and tolerability of S-1 metronomic chemotherapy (MC) plus sorafenib. METHODS: Antitumor effects and toxicity of this combination were tested with HAK-1B xenograft and spontaneous HCC mouse models, and a prospective pilot study was performed to compare therapeutic effects and safety between sorafenib plus MC S-1 for 12 advanced HCC cases and the historical control of 363 sorafenib-treated advanced HCC patients at our hospital from July 2011 to June 2015. RESULTS: In mice, the combination chemotherapy enhanced anti-angiogenic effects, resulting in a stronger tumor hypoxic environment and increased tumor cell apoptosis. Clinically, the objective response rate of the combination chemotherapy was higher than that of sorafenib mono therapy (16.7%; 2/12 vs 5.2%; 19/363, p < 0.05); however, there were no significant differences in overall survival and time to progression. Adverse events including alopecia, thrombocytopenia, and pancreatic enzymes elevation in the combination chemotherapy were higher than those of sorafenib. No patient treated with the combination chemotherapy discontinued treatment due to severe adverse events. CONCLUSIONS: Sorafenib plus MC S-1 seems to be effective and tolerable for patients with advanced HCC and could be considered a treatment option for these patients.

Initial Experience of Atezolizumab Plus Bevacizumab for Unresectable Hepatocellular Carcinoma in Real-World Clinical Practice.

BACKGROUND: Atezolizumab plus bevacizumab was approved for patients with hepatocellular carcinoma (HCC). Although clinical trials have revealed its efficacy, the outcomes in the real-world clinical practice are unclear. We retrospectively evaluated the efficacy and safety of atezolizumab plus bevacizumab for HCC. MATERIALS AND METHODS: This is a multicenter study conducted between November 2020 and March 2021. Among the 61 patients, 51 were assessed for progression-free survival (PFS), therapeutic response, and adverse events (AEs). RESULTS: The median PFS was 5.4 months. The objective response rate (ORR) was 35.3%. The disease control rate (DCR) was 86.3%. The incidence rates of AEs at any grade and grade >3 were 98.0% and 29.4%, respectively. The most frequent AE at any grade and grade >3 was hepatic disorder. In patients with a previous history of molecular targeted agent (MTA) or the degree of albumin-bilirubin (ALBI) grade, there were no significant differences in the PFS, ORR, DCR, and incidence rates of AEs. CONCLUSION: The study demonstrated that atezolizumab plus bevacizumab was effective and safe for patients with HCC even in the real-world setting including patients with a previous MTA history or other than ALBI grade 1.

Therapeutic Outcomes and Prognostic Factors of Unresectable Intrahepatic Cholangiocarcinoma: A Data Mining Analysis.

Prognosis of patients with intrahepatic cholangiocarcinoma (ICC) is unsatisfactory. Tumor, host, and treatment factors including hepatic arterial infusion chemotherapy (HAIC) are intricately involved in the progression of ICC. We aimed to identify profiles associated with disease control rate (DCR) and the prognosis of patients with unresectable ICC by decision tree analysis. We analyzed 31 consecutive patients with unresectable ICC (median age, 71 years; the male ratio was 58.1%). Stage IVB occupied 51.6% of patients, and 38.7% and 58.1% of patients were treated with gemcitabine plus cisplatin combination therapy and HAIC, respectively. Profiles associated with prognosis as well as DCR were investigated by decision tree analysis. The median survival time (MST) of the patients was 11.6 months, and the DCR was 70.9%. Multivariate correlation analysis showed that albumin levels and WBC levels were significantly correlated with survival time (albumin, ρ = 0.3572, p = 0.0485; WBC, ρ = -0.4008, p = 0.0280). In decision tree analysis, WBC level was selected as the initial split variable, and subjects with WBC levels of 6800/µL or less (45.1%) showed a long survival time (MST 476 days). We also demonstrated that the profile associated with the highest DCR was "less than 4.46 mg/dL of CRP levels and treatment with HAIC". We demonstrated a new prognostic profile for ICC patients, which consisted of WBC and CRP levels. Moreover, we demonstrated that HAIC was associated with better disease control in ICC patients with low CPR levels. Thus, these new profiles may be useful for the management of ICC patients.

Prevalence and profiles of ramucirumab-associated severe ascites in patients with hepatocellular carcinoma.

Severe ascites is an adverse event of ramucirumab (RAM), a second-line treatment for hepatocellular carcinoma (HCC). Ascites can be associated with various factors, including nutritional status and muscle quality. The aim of the present study was to investigate the prevalence and profiles of RAM-associated severe ascites in patients with HCC. This retrospective study enrolled 14 consecutive patients with HCC treated with RAM (median age, 72 years; Barcelona Clinic Liver Cancer stage B/C, 6/8). Nutritional status and muscle quality were evaluated using the controlling nutritional status (CONUT) score and intramuscular adipose tissue (IMAT) content, respectively. Factors associated with severe ascites were evaluated using decision-tree analysis. The median progression-free survival (PFS) time was 2.1 months, and the overall objective response and disease control rates were 14 and 50%, respectively. Severe ascites developed in 57.1% of the patients, and the median onset was 37.5 days (range, 14-61 days) after initiation of RAM treatment. In the decision-tree analysis, the CONUT score and IMAT content were the first and second splitting variables for the development of severe ascites. In patients with a CONUT score ≥5 and IMAT <-0.54, the prevalence of severe ascites was 80 and 100%, respectively. A high incidence of severe ascites was observed in patients treated with RAM. A CONUT score ≥5 and an IMAT <-0.54 were associated with severe ascites. Thus, caution must be taken for severe ascites in patients with HCC treated with RAM, in particular patients with malnutrition and fat infiltration in muscle.