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  • 1
    In: Hepatology Research, Wiley, Vol. 52, No. 9 ( 2022-09), p. 773-783
    Abstract: Atezolizumab plus bevacizumab (Atez/Bev) treatment is recommended for unresechepatocellular carcinoma (u‐HCC) patients classified as Child‐Pugh A (CP‐A). This study aimed to elucidate the prognosis of patients treated with Atez/Bev, especially CP‐A and ‐B cases. Materials/methods From September 2020 to March 2022, 457 u‐HCC patients treated with Atez/Bev were enrolled (median age 74 years, male:female = 368:89, CP‐A:CP‐B = 427:30, Child‐Pugh score [CPS] 5:6:7:8:9 = 271:156:21:8:1). Therapeutic response was evaluated using RECIST ver.1.1. Clinical features and prognosis were retrospectively evaluated. Results There were no significant differences between CP‐A and ‐B patients in regard to best response (CR:PR:SD:PD = 16:91:194:81 vs. 0:7:13:8, p  = 0.739; objective response rate/disease control rate = 28.0%/78.8% vs. 25.0%/71.4%). Analysis performed using inverse probability weighting adjustments of clinical factors other than those related to hepatic reserve function with a p value  〈  0.10 for comparisons between patients with CP‐A and ‐B showed that the progression‐free survival (PFS) rate for CP‐A cases was better (6‐/12‐/18‐month: 58.2%/36.1%/27.8% vs. 49.6%/8.7%/non‐estimable [NE], p   〈  0.001), as was overall survival (OS) rate (6‐/12‐/18‐month: 89.9%/71.7%/51.4% versus 63.6%/18.4%/NE; p   〈  0.001). Median PFS (mPFS) and median OS (mOS) for the CPS‐5 were 9.5 months/NE, and 5.1/14.0 months for the CPS‐6 (both p   〈  0.001). Furthermore, for modified albumin‐bilirubin grade (mALBI)‐1/2a/2b, mPFS was 9.4/8.5/5.3 months ( p   〈  0.001) and mOS was NE/17.8/13.4 months ( p   〈  0.001). Conclusion Better hepatic function, such as mALBI grade 1 or 2a are thought to indicate a better condition for obtaining sufficient prognosis with Atez/Bev treatment for u‐HCC patients, whereas for CP‐B patients, who mainly shown an mALBI grade of 2b or 3, Atez/Bev might have less therapeutic efficacy.
    Type of Medium: Online Resource
    ISSN: 1386-6346 , 1872-034X
    URL: Issue
    Language: English
    Publisher: Wiley
    Publication Date: 2022
    detail.hit.zdb_id: 2006439-1
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  • 2
    In: Oncology, S. Karger AG, Vol. 100, No. 12 ( 2022), p. 645-654
    Abstract: 〈 b 〉 〈 i 〉 Introduction: 〈 /i 〉 〈 /b 〉 Adverse events (AEs) of urinary protein from monoclonal antibodies against vascular endothelial growth factor are factors that often inhibit systemic therapy for unresectable hepatocellular carcinoma (uHCC). This study aimed to elucidate risk factors of urinary protein in the early period ( & #x3c;12 weeks) of atezolizumab plus bevacizumab treatment (Atez/Bev). 〈 b 〉 〈 i 〉 Methods: 〈 /i 〉 〈 /b 〉 From 2020 to June 2022, 193 uHCC patients treated with Atez/Bev at our affiliated hospitals were enrolled (median 73 years, 158 males, 183 Child-Pugh A, BCLC-0:A:B:C = 1:7:73:112). AEs related to urinary protein (≥G2) within 12 weeks were defined as significant, and related clinical features were analyzed retrospectively. 〈 b 〉 〈 i 〉 Results: 〈 /i 〉 〈 /b 〉 In analyses of risk factors of urinary protein-related AEs during the first 12 weeks after starting Atez/Bev using a logistic regression method, univariate analysis showed positive for hypertension (odds ratio [OR] 3.54, 95% CI: 1.28–9.80, 〈 i 〉 p 〈 /i 〉 = 0.015) and baseline urinary protein and urine creatinine ratio (UPC: ≥0.16) (OR: 2.52, 95% CI: 1.09–5.83, 〈 i 〉 p 〈 /i 〉 = 0.031) as pretreatment clinical factors, while elevation of urinary protein in the early period (baseline to 3 weeks) with delta UPC per 3 weeks (ΔUPC/3W) (≥0.23) (OR: 15.80, 95% CI: 6.15–40.50, 〈 i 〉 p 〈 /i 〉 & #x3c; 0.001) was a clinical factor after starting treatment. Multivariate analysis of only baseline clinical factors revealed positive for history of hypertension as the only predictive factor (OR: 3.20, 95% CI: 1.14–8.95, 〈 i 〉 p 〈 /i 〉 = 0.027), while only ΔUPC/3W (≥0.23) (OR: 14.40, 95% CI: 4.91–42.00, 〈 i 〉 p 〈 /i 〉 & #x3c; 0.001) were noted in multivariate analysis including ΔUPC/3W. Predictive factors for ΔUPC/3W (≥0.23) were hypertension (OR: 3.50, 95% CI: 1.23–99.90, 〈 i 〉 p 〈 /i 〉 = 0.019) and UPC (≥0.16) (OR: 6.12, 95% CI: 2.61–14.30, 〈 i 〉 p 〈 /i 〉 & #x3c; 0.001) in multiple analysis. 〈 b 〉 〈 i 〉 Discussion/Conclusion: 〈 /i 〉 〈 /b 〉 Urinary protein-related AEs are frequently observed during Atez/Bev treatment in uHCC patients with elevated ΔUPC/3W (≥0.23), and ΔUPC/3W (≥0.23) is often seen in patients with hypertension and/or UPC (≥0.16).
    Type of Medium: Online Resource
    ISSN: 0030-2414 , 1423-0232
    RVK:
    Language: English
    Publisher: S. Karger AG
    Publication Date: 2022
    detail.hit.zdb_id: 1483096-6
    detail.hit.zdb_id: 250101-6
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  • 3
    In: International Journal of Cancer, Wiley, Vol. 154, No. 6 ( 2024-03-15), p. 1043-1056
    Abstract: Atezolizumab plus bevacizumab (AB) and lenvatinib can be alternatively used as first‐line systemic treatment of unresectable hepatocellular carcinoma (HCC). However, no direct comparison of the two regimens has been performed in randomized clinical trials, making the identification of baseline differential predictors of response of major relevance to tailor the best therapeutic option to each patient. Baseline clinical and laboratory characteristics of real‐world AB‐treated HCC patients were analyzed in uni‐ and multivariate analyses to find potential prognostic factors of overall survival (OS). Significant variables were incorporated in a composite score (α‐FAtE) and it was tested for specificity and sensitivity in receiver operating characteristic (ROC) curve and in multivariate analysis for OS. The score was applied in uni‐ and multivariate analyses for OS of a comparable lenvatinib‐treated HCC population. Finally, comparison between treatments was performed in patients with low and high α‐FAtE scores and predictivity estimated by interaction analysis. Time‐to‐progression (TTP) was a secondary endpoint. OS of AB‐treated HCC patients was statistically longer in those with α‐fetoprotein 〈 400 ng/mL (HR 0.62, p = .0407), alkaline phosphatase (ALP) 〈 125 IU/L (HR 0.52, p = .0189) and eosinophil count ≥70/μL (HR 0.46, p = .0013). The α‐FAtE score was generated by the sum of single points attributed to each variable among the above reported. In ROC curve analysis, superior sensitivity and specificity were achieved by the score compared to individual variables (AUC 0.794, p 〈 .02). Patients with high score had longer OS (HR 0.44, p = .0009) and TTP (HR 0.34, p 〈 .0001) compared to low score if treated with AB, but not with lenvatinib. Overall, AB was superior to lenvatinib in high score patients (HR 0.55, p = .0043) and inferior in low score ones (HR 1.75, p = .0227). At interaction test, low α‐FAtE score resulted as negative predictive factor of response to AB ( p = .0004). In conclusion, α‐FAtE is a novel prognostic and predictive score of response to first‐line AB for HCC patients that, if validated in prospective studies, could drive therapeutic choice between lenvatinib and AB.
    Type of Medium: Online Resource
    ISSN: 0020-7136 , 1097-0215
    URL: Issue
    RVK:
    Language: English
    Publisher: Wiley
    Publication Date: 2024
    detail.hit.zdb_id: 218257-9
    detail.hit.zdb_id: 1474822-8
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  • 4
    In: Mediators of Inflammation, Hindawi Limited, Vol. 2015 ( 2015), p. 1-9
    Abstract: The liver biopsy remains a valuable tool in the diagnosis of drug-induced liver injury (DILI). The Digestive Disease Week Japan 2004 (DDW-J) scale proposed as an objective tool for the diagnosis of DILI has been widely used in Japan. So far, the histological features have not been compared with DDW-J scale in detail. Herein, we examined the correlation between liver biopsy findings and clinical features, particularly DDW-J scales. A total of 80 patients with liver injuries of unknown cause were enrolled. Based on the histological findings, these cases were categorized into 3 groups: A (DILI was strongly suspected), B (DILI was suspected), and C (DILI should be considered in the differential diagnosis). Histological groups and DDW-J scale were moderately correlated ( κ = 0.60 ). The mean total DDW-J scale scores were as follows: 4.89 for A, 3.26 for B, and 0.75 for C ( p 〈 0.05 ). While hepatocellular type was coincided in a majority of cases by histological and DDW-J scale evaluation, cholestatic type was not well coincided. In conclusion, biopsy findings and DDW-J scale were well correlated, and the hepatocellular type of liver injuries was well coincided by both evaluations, though there were several discrepant cases, particularly in cholestatic type.
    Type of Medium: Online Resource
    ISSN: 0962-9351 , 1466-1861
    Language: English
    Publisher: Hindawi Limited
    Publication Date: 2015
    detail.hit.zdb_id: 2008065-7
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  • 5
    In: Hepatology Research, Wiley, Vol. 52, No. 3 ( 2022-03), p. 308-316
    Abstract: Although systemic therapy is recommended for patients with multiple intermediate stage unresectable hepatocellular carcinoma (u‐HCC) classified as beyond the up‐to‐7 criteria (UT‐7 out/multiple) as a transcatheter arterial chemoembolization (TACE) unsuitable condition, few reports have examined the therapeutic efficacy of atezolizumab plus bevacizumab combination therapy (Atez/Bev) in such cases. This study aimed to elucidate the therapeutic response of Atez/Bev in u‐HCC patients classified as UT‐7 out/multiple. Material/Methods From September 2020 to September 2021, 95 u‐HCC Japanese patients classified as UT‐7 out/multiple/Child‐Pugh A were enrolled from 21 institutions (median age 76 years, males 73, Child‐Pugh 5:6 = 68:27, TNM stage II:III = 17:78). Therapeutic response was retrospectively evaluated using Response Evaluation Criteria in Solid Tumors (RECIST), ver. 1.1 and modified RECIST (mRECIST). Results Atez/Bev was given as first‐line treatment to 52 (54.7%). Objective response rate (ORR)/disease control rate (DCR) at six weeks of RECIST and mRECIST were 17.7%/84.7% and 42.5%/86.2%, respectively. Median PFS was 8.0 months (median observation period: 6.0 months). Child‐Pugh A/modified Albumin‐bilirubin grade (mALBI) 1 and 2a at baseline, 3, 6, and 9 weeks, were 100%/69.4%, 89.8%/57.3%, 94.8%/65.3%, and 91.4%/60.0%, respectively. Among adverse events (any‐grade, 〉 10%) during the present observation period, general fatigue was most frequent (23.2%), followed by urine protein (21.1%), appetite loss (20.0%), and hypertension (13.7%). Conclusion Atez/Bev treatment showed favorable therapeutic response with less influence on hepatic function, suggesting it as a useful therapeutic option for patients with such condition.
    Type of Medium: Online Resource
    ISSN: 1386-6346 , 1872-034X
    URL: Issue
    Language: English
    Publisher: Wiley
    Publication Date: 2022
    detail.hit.zdb_id: 2006439-1
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  • 6
    In: Cancer Medicine, Wiley, Vol. 12, No. 6 ( 2023-03), p. 6980-6993
    Abstract: Recently, the neo‐Glasgow prognostic score (GPS), a composite biomarker determined by the C‐reactive protein level and albumin–bilirubin grade, was developed to predict outcomes in hepatocellular carcinoma (HCC) patients who undergo hepatic resection. The present research investigated whether the neo‐GPS could predict prognosis in HCC patients treated with atezolizumab plus bevacizumab (Atez/Bev). Methods A total of 421 patients with HCC who were treated with Atez/Bev were investigated. Results Multivariate Cox hazards analysis showed that a GPS of 1 (hazard ratio (HR), 1.711; 95% confidence interval (CI), 1.106–2.646) and a GPS of 2 (HR, 4.643; 95% CI, 2.778–7.762) were independently associated with overall survival. Conversely, multivariate Cox hazards analysis showed that a neo‐GPS of 1 (HR, 3.038; 95% CI, 1.715–5.383) and a neo‐GPS of 2 (HR, 5.312; 95% CI, 2.853–9.890) were also independently associated with overall survival in this cohort. Additionally, cumulative overall survival rates differed significantly by GPS and neo‐GPS ( p   〈  0.001). The neo‐GPS, compared with the GPS, had a lower Akaike information criterion (1207 vs. 1,211, respectively) and a higher c‐index (0.677 vs. 0.652, respectively) regarding to overall survival. In a subgroup analysis of patients considered to have a good prognosis as confirmed using a Child–Pugh score of 5 ( p  = 0.001), a neutrophil‐to‐lymphocyte ratio  〈 3 ( p  = 0.001), or an α‐fetoprotein level  〈  100 ng/mL ( p   〈  0.001), those with a high neo‐GPS (≥1) had a statistically poorer overall survival than those with a low neo‐GPS. Conclusions The neo‐GPS can predict prognosis in advanced unresectable HCC patients treated with Atez/Bev.
    Type of Medium: Online Resource
    ISSN: 2045-7634 , 2045-7634
    URL: Issue
    Language: English
    Publisher: Wiley
    Publication Date: 2023
    detail.hit.zdb_id: 2659751-2
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  • 7
    In: Cancer Medicine, Wiley, Vol. 12, No. 4 ( 2023-02), p. 4259-4269
    Abstract: This study investigated whether or not the hepatocellular carcinoma modified Gustave Roussy Immune Score (HCC‐GRIm‐Score) serves as a prognostic indicator for HCC patients treated with atezolizumab and bevacizumab (Atez/Bev). Methods A total of 405 HCC patients who received Atez/Bev from September 2020 to January 2022 at 22 different institutions were included in this retrospective study. The HCC‐GRIm score was based on the combination of the albumin level ( 〈 3.5 g/L = 1 point), lactate dehydrogenase (≥245 U/L = 1 point), neutrophil‐to‐lymphocyte ratio (≥4.8 = 1 point), aspartate aminotransferase‐to‐alanine aminotransferase ratio (≥1.44 = 1 point), and total bilirubin level (≥1.3 mg/dl = 1 point). Patients were divided into the low‐score group (0, 1, or 2 points) and the high‐score group (3, 4, or 5 points). Results There were 89 (22.0%), 141 (34.8%), 106 (26.2%), 49 (12.1%), 16 (4.0%), and 4 (1.0%) patients with scores of 0, 1, 2, 3, 4, 5, respectively. The progression‐free survival (PFS) in the low‐score group was significantly longer than that in the high‐score group (median 7.8 vs. 3.5 months, p   〈  0.001). The median overall survival (OS) of the low‐score group was not reached at the time cutoff, with a 1‐year survival rate of 75.5%, whereas the median OS of the high‐score group was 8.5 months, showing a significant difference ( p   〈  0.001). A high HCC‐GRIm score was a significant unfavorable factor associated with the PFS and OS in multivariate analyses ( p  = 0.002 and p   〈  0.001, respectively). Conclusions The HCC‐GRIm score serves as a novel prognostic score for HCC patients treated with Atez/Bev.
    Type of Medium: Online Resource
    ISSN: 2045-7634 , 2045-7634
    URL: Issue
    Language: English
    Publisher: Wiley
    Publication Date: 2023
    detail.hit.zdb_id: 2659751-2
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  • 8
    In: Cancer Medicine, Wiley, Vol. 12, No. 7 ( 2023-04), p. 7772-7783
    Abstract: To investigate the possible correlation between the development of adverse events (AEs) and prognosis in patients with unresectable hepatocellular carcinoma (HCC) treated with atezolizumab plus bevacizumab (Atez/Bev). Methods A total of 286 patients with unresectable HCC treated with Atez/Bev as first‐line systematic therapy were included. Results Regarding treatment‐related AEs, decreased appetite of any grade, proteinuria of any grade, and fatigue of any grade were found with a frequency of ≥20%. Multivariate analysis adjusted for immune‐related liver injury, immune‐related endocrine dysfunction, proteinuria, fatigue, decreased appetite, hypertension, sex, age, Eastern Cooperative Oncology Group performance status, HCC etiology, HCC stage, Child–Pugh score, and α‐fetoprotein showed that hypertension of any grade (hazard ratio [HR], 0.527; 95% confidence interval [CI] , 0.326–0.854; p  = 0.009) and α‐fetoprotein ≥100 ng/ml (HR, 1.642; 95% CI, 1.111–2.427; p  = 0.013) were independently associated with progression‐free survival. Multivariate analysis adjusted for the same AEs showed that fatigue (HR, 2.354; 95% CI, 1.299–4.510; p  = 0.010) was independently associated with overall survival. Median progression‐free survival was 6.5 months (95% CI, 5.2–8.1) in patients without hypertension of any grade and 12.6 months (95% CI, 6.7–not available) in patients with hypertension of any grade ( p  = 0.035). The overall survival was significantly shorter in patients in whom treatment‐related fatigue of any grade was observed ( p   〈  0.001). Regarding response rates, the disease control rate of patients who developed treatment‐related hypertension (94.2%) was significantly higher than those who did not (79.1%) ( p  = 0.009). Conclusions Treatment‐related hypertension is associated with good outcomes in patients with HCC treated with Atez/Bev.
    Type of Medium: Online Resource
    ISSN: 2045-7634 , 2045-7634
    URL: Issue
    Language: English
    Publisher: Wiley
    Publication Date: 2023
    detail.hit.zdb_id: 2659751-2
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  • 9
    In: Cancer Medicine, Wiley, Vol. 12, No. 1 ( 2023-01), p. 325-334
    Abstract: A comparison of therapeutic efficacy between atezolizumab plus bevacizumab (Atez/Bev) and lenvatinib treatment given as first‐line therapy for unresectable hepatocellular carcinoma (u‐HCC) in regard to progression‐free survival (PFS) overall survival (OS) has not been reported. We aimed to elucidate which of those given as initial treatment for u‐HCC has greater prognostic impact on PFS and OS of affected patients, retrospectively. Materials/Methods From 2020 to January 2022, 251 u‐HCC (Child–Pugh A, ECOG PS 0/1, BCLC‐B/C) treated were enrolled (Atez/Bev‐group, n  = 194; lenvatinib‐group, n  = 57). PFS and OS were analyzed following adjustment based on inverse probability weighting (IPW). Results There was a greater number of patients with macro‐vascular invasion in Atez/Bev‐group (22.7% vs. 8.8%, p  = 0.022). In lenvatinib‐group, the frequencies of appetite loss (38.6% vs. 19.6%, p  = 0.002), hypothyroidism (21.1% vs. 6.7%, p  = 0.004), hand foot skin reaction (19.3% vs. 1.0%, p   〈  0.001), and diarrhea (10.5% vs. 4.6%, p  = 0.012) were greater, while that of general fatigue was lower (22.8% vs. 26.3%, p  = 0.008). Comparisons of therapeutic best response using modified response evaluation criteria in solid tumors (mRECIST) did not show significant differences between the present groups (Atez/Bev vs. lenvatinib: CR/PR/SD/PD = 6.1%/39.1%/39.1%/15.6% vs. 0%/48.0%/38.0%/14.0%, p  = 0.285). In patients of discontinuation of treatments, 48.2% switched to lenvatinib, 10.6% continued beyond PD, 8.2% received another systemic treatment, 5.9% underwent transcatheter arterial chemoembolization (TACE), 3.5% received hepatic arterial infusion chemotherapy (HAIC), and 1.2% underwent surgical resection in Atez/Bev‐group, while 42.2% switched to Atez/Bev, 4.4% continued beyond PD, 4.4% received another systemic treatment, 2.2% nivolumab, 6.7% received TACE, and 2.2% received HAIC in lenvatinib‐group. Following adjustment with inverse probability weighting (IPW), Atez/Bev‐group showed better PFS (0.5−/1−/1.5‐years: 56.6%/31.6%/non‐estimable vs. 48.6%/20.4%/11.2%, p   〈  0.0001) and OS rates (0.5−/1−/1.5‐years: 89.6%/67.2%/58.1% vs. 77.8%/66.2%/52.7%, p  = 0.002). Conclusion The present study showed that u‐HCC patients who received Atez/Bev as a first‐line treatment may have a better prognosis than those who received lenvatinib.
    Type of Medium: Online Resource
    ISSN: 2045-7634 , 2045-7634
    URL: Issue
    Language: English
    Publisher: Wiley
    Publication Date: 2023
    detail.hit.zdb_id: 2659751-2
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  • 10
    In: Liver International, Wiley
    Abstract: The study goal was to compare the outcomes of patients with intermediate‐stage (Barcelona Clinic Liver Cancer [BCLC]‐B) hepatocellular carcinoma (HCC) who received atezolizumab plus bevacizumab (Atezo/Bev) or lenvatinib (LEN) as first‐line systemic therapy. Methods A total of 358 patients with BCLC‐B HCC treated with Atezo/Bev ( n  = 177) or LEN ( n  = 181) as first‐line systemic therapy were included. Results The median progression‐free survival (PFS) times in the Atezo/Bev and LEN groups were 10.8 months (95% confidence interval [CI], 7.8–12.6) and 7.3 months (95% CI, 6.3–8.5), respectively ( p  = .019). In the propensity score‐matched cohort, the median PFS times in the Atezo/Bev ( n  = 151) and LEN ( n  = 151) groups were 10.2 months (95% CI, 7.0–12.3) and 6.9 months (95% CI, 5.9–8.1), respectively ( p  = .020). Restricted mean survival times of PFS were significantly higher in the Atezo/Bev group than in the LEN group at landmarks of 12 and 18 months ( p  = .031 and .012, respectively). In a subgroup analysis of patients with HCC beyond the up‐to‐seven criteria, the median PFS times in the Atezo/Bev ( n  = 134) and LEN ( n  = 117) groups were 10.5 months (95% CI, 7.0–11.8) and 6.3 months (95% CI, 5.5–7.3), respectively ( p  = .044). Conclusions The use of Atezo/Bev as first‐line systemic therapy in patients with BCLC‐B HCC is expected to result in good PFS.
    Type of Medium: Online Resource
    ISSN: 1478-3223 , 1478-3231
    Language: English
    Publisher: Wiley
    Publication Date: 2023
    detail.hit.zdb_id: 2124684-1
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