Introduction: Atezolizumab plus bevacizumab treatment is highly effective in patients with unresectable hepatocellular carcinoma (HCC). However, progressive disease (PD) occurs in approximately 20% of HCC patients treated with atezolizumab plus bevacizumab, resulting in a poor prognosis. Thus, the prediction and early detection of HCC is crucial. Methods: Patients with unresectable HCC treated with atezolizumab plus bevacizumab and had baseline preserved serum (n = 68) were screened and classified according to their PD, 6 weeks after treatment initiation (early PD; n = 13). Of these, 4 patients each with and without early PD were selected for cytokine array and genetic analyses. The identified factors were validated in the validated cohort (n = 60) and evaluated in patients treated with lenvatinib. Results: No significant differences were observed in the genetic alterations in circulating tumor DNA. Cytokine array data revealed that baseline MIG (CXCL9), ENA-78, and RANTES differed substantially between patients with and without early PD. Subsequent analysis in the validation cohort revealed that baseline CXCL9 was significantly lower in patients with early PD than that in patients without early PD, and the best cut-off value of serum CXCL9 to predict early PD was 333 pg/mL (sensitivity: 0.600, specificity: 0.923, AUC = 0.75). In patients with lower serum CXCL9 (<333 pg/mL), 35.3% (12/34) experienced early PD with atezolizumab plus bevacizumab, while progression-free survival (PFS) was significantly shorter relative to that in patients without (median PFS, 126 days vs. 227 days; HR: 2.41, 95% CI: 1.22–4.80, p = 0.0084). While patients with objective response to lenvatinib had significantly lower CXCL9 levels compared with those of patients without. Conclusion: Baseline low serum CXCL9 (<333 pg/mL) levels may predict early PD in patients with unresectable HCC treated with atezolizumab plus bevacizumab.

Factors associated with liver stiffness (LS) are unknown and normal reference values for LS have not been established. Individuals at high risk for alcoholic (ALD) and non-alcoholic fatty (NAFLD) liver disease need to be non-invasively discriminated during routine health checks. Factors related to LS measured using a FibroScan and normal reference values for LS are presented in this report.

The IMbrave150 trial demonstrated the high efficacy and safety of atezolizumab and bevacizumab for unresectable hepatocellular carcinoma (HCC). In this multicenter study, the efficacy of this combination and its effect on liver functional reserve were evaluated in patients not meeting the eligibility criteria of IMbrave150. Of 115 patients with unresectable HCC treated with atezolizumab and bevacizumab between October 2020 and January 2022, 72 did not meet the eligibility criteria of IMbrave150, most frequently due to a history of systemic therapy (60/72), platelet counts < 75 × 10⁹/L (7/72), Child-Pugh B (9/72), and 2+ proteinuria (8/72). Atezolizumab and bevacizumab therapy was equally effective for patients who did or did not meet the eligibility criteria (PFS, 6.5 vs. 6.9 months, p = 0.765), consistent with subgroup analyses of histories of systemic therapy, platelet counts, Child-Pugh, and proteinuria. Baseline ALBI scores were worse in patients who did not meet the criteria than in those who did and significantly worsened after treatment initiation in patients not meeting the criteria (baseline vs. 12 weeks; 2.35 ± 0.43 vs. −2.18 ± 0.54; p = 0.007). Accordingly, atezolizumab plus bevacizumab was effective for patients not meeting the eligibility criteria of IMbrave150, although careful monitoring for changes in liver functional reserve is needed.

Fibroblast growth factor 21 (FGF21) is a crucial regulator of cell metabolism. Tumour-secreted FGF21 has shown immune-checkpoint factor functions, and high FGF21 levels are associated with a poor prognosis for patients. However, its prognostic value and impact on treatment response in patients with hepatocellular carcinoma (HCC) treated with immune-checkpoint inhibitors (ICIs) remain unclear. Thus, this study investigated the potential of high FGF21 levels as a prognostic marker and whether traditional ICI-based therapy can improve the prognosis of patients with high FGF21 levels. In this retrospective multicentre study, patients with unresectable HCC who received atezolizumab/bevacizumab in the NORTE study group (n = 117) were classified into high (≥915 pg/ml; n = 29) and non-high (n = 88) FGF21 groups. For validation, we investigated patients treated with atezolizumab/bevacizumab in an independent cohort (n = 285). Overall survival, progression-free survival, and treatment response were compared between patients with and without high baseline FGF21 levels. The median overall survival (p <0.001) and progression-free survival (p = 0.045) were significantly shorter in the high FGF21 group than in the non-high FGF21 group. Independent cohort analysis validated these results. In the overall cohort, the median progression-free survival (5.75 vs. 8.84 months; p = 0.027) and median overall survival (14.13 vs. 22.08 months; p <0.001) were significantly shorter in the high FGF21 group than in the non-high FGF21 group. The durable response (≥6 months) + complete response rate was significantly decreased in the high FGF21 group (p = 0.045). No patient with a high FGF21 level achieved a complete response, whereas this was achieved in 4.1% (13/319) of patients with non-high FGF21 levels. Multivariate Cox regression analysis identified high baseline serum FGF21 as an independent poor prognostic factor for overall survival (hazard ratio 2.20, p <0.001). Serum FGF21 may be a robust, non-invasive prognostic and treatment response marker for unresectable HCC treated with atezolizumab/bevacizumab. FGF21 has been reported to act as a secreted immune-checkpoint factor, and elevated levels of FGF21 are associated with a poor prognosis in patients with HCC. It is not fully understood whether ICIs can overcome the impact of high FGF21 levels on the shortened prognosis of patients with HCC. In this multicentre retrospective study, patients with HCC and high baseline levels of serum FGF21 who received atezolizumab/bevacizumab treatment exhibited a significantly shorter overall survival and shorter progression-free survival. These findings suggest serum FGF21 as a robust prognostic marker and an indicator of treatment response in unresectable HCC treated with ICI-based therapy. These findings could be crucial for the implementation of personalised treatment strategies for unresectable HCC. However, identifying optimal therapeutic options for patients with unresectable HCC and high serum FGF21 levels remains an urgent and critical clinical issue.

The liver-spleen contrast (LSC) using hepatobiliary-phase images could replace the receptor index (LHL15) in liver scintigraphy; however, few comparative studies exist. This study aimed to verify the convertibility from LSC into LHL15. In 136 patients, the LSC, not at 20 min, but at 60 min after injecting gadolinium-ethoxybenzyl-diethylenetriaminepentaacetic acid was compared with the LHL15, albumin–bilirubin (ALBI) score, and the related laboratory parameters. The LHL15 was also compared with their biochemical tests. The correlation coefficients of LSC with LHL15, ALBI score, total bilirubin, and albumin were 0.740, –0.624, –0.606, and 0.523 (P < 0.00001), respectively. The correlation coefficients of LHL15 with ALBI score, total bilirubin, and albumin were –0.647, –0.553, and 0.569 (P < 0.00001), respectively. The linear regression equation on the estimated LHL15 (eLHL15) from LSC was eLHL15 = 0.460 · LSC + 0.727 (P < 0.00001) and the coefficient of determination was 0.548. Regarding a contingency table using imaging-based clinical stage classification, the degree of agreement between eLHL15 and LHL15 was 65.4%, and Cramer's V was 0.568 (P < 0.00001). Therefore, although the LSC may be influenced by high total bilirubin, the eLHL15 can replace the LSC as an index to evaluate liver function.