Publications by authors named "Norio Itokawa"

92 Publications

Efficacy and safety of oral semaglutide in patients with non-alcoholic fatty liver disease complicated by type 2 diabetes mellitus: A pilot study.

JGH Open 2022 Jul 16;6(7):503-511. Epub 2022 Jun 16.

Division of Gastroenterology and Hepatology Nippon Medical School Tokyo Japan.

Background And Aim: This study aimed to clarify the efficacy and safety of oral semaglutide treatment in patients with non-alcoholic fatty liver disease (NAFLD) complicated by type 2 diabetes mellitus (T2DM).

Methods: This was a single-arm, open-label pilot study. Sixteen patients with NAFLD who received oral semaglutide for T2DM were included in the analysis. Oral semaglutide was initiated at a dose of 3 mg once daily, and the dose was sequentially increased to 7 mg at 4 weeks and 14 mg at 8 weeks (maintenance dose) until the end of the 24-week trial.

Results: Body weight and levels of liver-related biochemistry, plasma glucose, and hemoglobin A1c decreased significantly from baseline to 12 weeks. These significant decreases were maintained until the end of the trial. Additionally, levels of the homeostasis model assessment-insulin resistance and triglyceride significantly decreased at 24 weeks. Controlled attenuation parameter (CAP) values significantly decreased from baseline to 24 weeks. Changes in body weight were correlated with those in levels of alanine aminotransferase ( = 0.52) and CAP ( = 0.72). As for liver fibrosis markers, significant decreases from baseline to 24 weeks in levels of the fibrosis-4 index, ferritin, and type IV collagen 7 s were found; however, the liver stiffness measurement did not significantly decrease. Most adverse events were grade 1-2 transient gastrointestinal disorders.

Conclusions: Oral semaglutide treatment in patients with NAFLD complicated by T2DM improved impaired liver function, hypertriglyceridemia, insulin resistance, and hepatic steatosis, as well as improving diabetic status and reducing body weight.
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http://dx.doi.org/10.1002/jgh3.12780DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9260206PMC
July 2022

Glasgow prognostic score predicts survival in patients with unresectable hepatocellular carcinoma treated with lenvatinib: a multicenter analysis.

Eur J Gastroenterol Hepatol 2022 Aug 29;34(8):857-864. Epub 2022 Jun 29.

Department of Gastroenterology, Saiseikai Niigata Hospital, Niigata.

Objective: The use of Glasgow prognostic score (GPS), calculated using the serum C-reactive protein and albumin levels, to predict the outcomes of patients with unresectable hepatocellular carcinoma (HCC) treated with lenvatinib was investigated in this study.

Methods: A total of 508 patients with Child-Pugh class A HCC treated with lenvatinib were included in this study.

Results: The median overall and progression-free survivals were 20.4 months [95% confidence interval (CI), 17.7-23.2 months] and 7.5 months (95% CI, 6.8-8.5 months), respectively. The median overall survivals of patients with a GPS of 0, 1, and 2 were 28.5, 16.0, and 9.1 months, respectively (P < 0.001). When adjusted for age, sex, performance status, etiology, α-fetoprotein, macroscopic vascular invasion, extrahepatic spread, history of sorafenib therapy, and GPS, a GPS of 1 [hazard ratio (HR), 1.664; 95% CI, 1.258-2.201; P < 0.001] and a GPS of 2 (HR, 2.664; 95% CI, 1.861-3.813; P < 0.001) were found to be independently associated with overall survival. The median progression-free survivals of patients with a GPS of 0, 1, and 2 were 8.8, 6.8, and 3.8 months, respectively (P < 0.001). When adjusted for the same factors of overall survival, a GPS of 2 (HR, 2.010; 95% CI, 1.452-2.784; P < 0.001) was found to be independently associated with progression-free survival. As the albumin-bilirubin with tumor node metastasis score increased, the proportion of patients with a GPS of 1 or 2 increased (P < 0.001).

Conclusions: GPS can be used to predict survival in patients with unresectable HCC who were treated with lenvatinib.
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http://dx.doi.org/10.1097/MEG.0000000000002398DOI Listing
August 2022

Prognostic impact of C-reactive protein and alpha-fetoprotein in immunotherapy score in hepatocellular carcinoma patients treated with atezolizumab plus bevacizumab: a multicenter retrospective study.

Hepatol Int 2022 Jun 24. Epub 2022 Jun 24.

Division of Gastroenterology and Hepatology, Department of Internal Medicine, Nippon Medical School, Tokyo, Japan.

Aim: This study aimed to investigate the utility of C-reactive protein (CRP) and alpha-fetoprotein (AFP) in immunotherapy (CRAFITY) score in hepatocellular carcinoma (HCC) patients receiving atezolizumab and bevacizumab (Atez/Bev).

Methods: This retrospective cohort study included a total of 297 patients receiving Atez/Bev from September 2020 to November 2021 at 21 different institutions and hospital groups in Japan. Patients with AFP ≥ 100 ng/mL and those with CRP ≥ 1 mg/dL were assigned a CRAFITY score of 1 point.

Results: The patients were assigned CRAFITY scores of 0 points (n = 147 [49.5%]), 1 point (n = 111 [37.4%]), and 2 points (n = 39 [13.1%]). AFP ≥ 100 ng/mL and CRP ≥ 1.0 mg/dL were significantly associated with progression-free survival (PFS) and overall survival (OS). The median PFS in the CRAFITY score 0, 1, and 2 groups was 11.8 months (95% confidence interval [CI] 6.4-not applicable [NA]), 6.5 months (95% CI 4.6-8.0), and 3.2 months (95% CI 1.9-5.0), respectively (p < 0.001). The median OS in patients with CRAFITY score 0, 1 and 2 was not reached, 14.3 months (95% CI 10.5-NA), and 11.6 months (95% CI 4.9-NA), respectively. The percentage of patients with grade ≥ 3 liver injury, any grade of decreased appetite, any grade of proteinuria, any grade of fever, and any grade of fatigue was lowest in patients with a CRAFITY score of 0, followed by patients with CRAFITY scores of 1 and 2.

Conclusions: The CRAFITY score is simple and could be useful for predicting therapeutic outcomes and treatment-related adverse events.
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http://dx.doi.org/10.1007/s12072-022-10358-zDOI Listing
June 2022

Does first-line treatment have prognostic impact for unresectable HCC?-Atezolizumab plus bevacizumab versus lenvatinib.

Cancer Med 2022 Jun 3. Epub 2022 Jun 3.

Department of Gastroenterology and Hepatology, Kagawa University, Kagawa, Japan.

Background/aim: 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.
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http://dx.doi.org/10.1002/cam4.4854DOI Listing
June 2022

Therapeutic efficacy of atezolizumab plus bevacizumab treatment for unresectable hepatocellular carcinoma in patients with Child-Pugh class A or B liver function in real-world clinical practice.

Hepatol Res 2022 May 28. Epub 2022 May 28.

Division of Gastroenterology and Hepatology, Department of Internal Medicine, Nippon Medical School, Tokyo, Japan.

Background/aim: 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.
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http://dx.doi.org/10.1111/hepr.13797DOI Listing
May 2022

C-reactive protein to albumin ratio predicts survival in patients with unresectable hepatocellular carcinoma treated with lenvatinib.

Sci Rep 2022 05 19;12(1):8421. Epub 2022 May 19.

Department of Gastroenterology, Saiseikai Niigata Hospital, Niigata, Japan.

We investigated the impact of C-reactive protein to albumin ratio (CAR) on predicting outcomes in 522 patients with unresectable hepatocellular carcinoma (HCC) treated with lenvatinib. We determined the optimal CAR cutoff value with time-dependent receiver operating characteristic curve analysis. Additionally, we clarified the relationship between CAR and liver function or HCC progression. Median overall survival was 20.0 (95% confidence interval (CI), 17.2-22.6) months. The optimal CAR cutoff value was determined to be 0.108. Multivariate analysis showed that high CAR (≥ 0.108) (hazard ratio (HR), 1.915; 95% CI, 1.495-2.452), Eastern Cooperative Oncology Group performance status ≥ 1 (HR, 1.429), and α-fetoprotein ≥ 400 ng/mL (HR, 1.604) were independently associated with overall survival. Cumulative overall survival differed significantly between patients with low versus high CAR (p < 0.001). Median progression-free survival was 7.5 (95% CI, 6.7-8.1) months. Multivariate analysis showed that age, CAR ≥ 0.108 (HR, 1.644; 95% CI, 1.324-2.043), and non-hepatitis B, non-hepatitis C etiology (HR, 0.726) were independently associated with progression-free survival. Cumulative progression-free survival differed significantly between patients with low versus high CAR (p < 0.001). CAR values were significantly higher as Japan Integrated Staging score increased (p < 0.001). In conclusion, CAR can predict outcomes in patients with unresectable HCC treated with lenvatinib.
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http://dx.doi.org/10.1038/s41598-022-12058-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9120140PMC
May 2022

Shorter pruritus period and milder disease stage are associated with response to nalfurafine hydrochloride in patients with chronic liver disease.

Sci Rep 2022 05 4;12(1):7311. Epub 2022 May 4.

Division of Gastroenterology and Hepatology, Department of Internal Medicine, Nippon Medical School, 1-1-5, Sendagi, Bunkyo-ku, Tokyo, 113-8603, Japan.

Nalfurafine hydrochloride, a selective κ-opioid receptor agonist has been approved for pruritus in patients with chronic liver disease. However, not all patients respond to nalfurafine hydrochloride. The aim of this study was to clarify the efficacy of nalfurafine hydrochloride. The subjects were patients with chronic liver disease complicated by pruritus who were treated with nalfurafine hydrochloride between May, 2015, and May, 2021. The degree of pruritus was evaluated based on the Visual Analog Scale (VAS) score and the Kawashima's pruritus score. Nalfurafine hydrochloride 2.5 μg was orally administered once a day for 12 weeks. A decrease in the VAS score of ≥ 25 mm or the Kawashima's pruritus score of ≥ 1 scores was designated as relevant response. The former of ≥ 50 mm or the latter of ≥ 2 scores as remarkable response. The 326 patients who were evaluated the efficacy at 12 weeks. The median time suffering from pruritus to administration of nalfurafine hydrochloride was 4 months. The median VAS score improved from 70.0 mm before administration to 40.0 and 30.0 mm at 4 and 12 weeks of treatment, respectively. On multivariate analysis, shorter itching period and lower FIB-4 index value were extracted as the independent factors related to remarkable responder. On multivariate analysis, shorter itching period was extracted as the only independent factor related to relevant responder. In conclusion, this study suggested nalfurafine hydrochloride treatment markedly improves pruritus in patients with chronic liver disease. A short pruritus period and less-advanced fibrosis were associated with response to nalfurafine hydrochloride.
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http://dx.doi.org/10.1038/s41598-022-11431-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9068920PMC
May 2022

Safety and efficacy of atezolizumab plus bevacizumab in elderly patients with hepatocellular carcinoma: A multicenter analysis.

Cancer Med 2022 Apr 19. Epub 2022 Apr 19.

Division of Gastroenterology and Hepatology, Department of Internal Medicine, Nippon Medical School, Tokyo, Japan.

Aim: The safety and efficacy of atezolizumab plus bevacizumab (Atez/Bev) in elderly patients with unresectable hepatocellular carcinoma (HCC) have not been sufficiently investigated.

Methods: A total of 317 patients with HCC treated with Atez/Bev were studied. We compared the survival and frequency of adverse events in elderly versus non-elderly patients with HCC who were treated with Atez/Bev using an analysis of inverse probability weighting (IPW).

Results: Univariate analysis adjusted with IPW showed that being elderly is not associated with worse overall or progression-free survival (hazard ratio [HR], 1.239; 95% confidence interval [CI], 0.640-2.399; p = 0.526 and HR, 1.256; 95% CI, 0.871-1.811; p = 0.223, respectively). Regarding treatment-related adverse events, any grade of fatigue, proteinuria, decreased appetite, hypertension, and liver injury occurred in ≥10% of patients. There were no significant differences in treatment-related adverse events between the elderly and non-elderly groups. In a subgroup analysis of elderly patients aged 75-79, 80-84, or ≥ 85 years, there were no significant differences in cumulative overall or progression-free survival among these age groups (p = 0.960 and 0.566, respectively). In addition, there were no significant differences in treatment-related adverse events among these three age groups, except for proteinuria of any grade. In a subgroup analysis of patients treated with Atez/Bev as first-line systemic therapy, there were no significant differences in cumulative overall or progression-free survival between the elderly and non-elderly groups (p = 0.728 and 0.805, respectively).

Conclusions: Atez/Bev can be used efficaciously and safely in spite of age in patients with unresectable HCC.
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http://dx.doi.org/10.1002/cam4.4763DOI Listing
April 2022

Prophylactic clip closure for mucosal defects is associated with reduced adverse events after colorectal endoscopic submucosal dissection: a propensity-score matching analysis.

BMC Gastroenterol 2022 Mar 26;22(1):139. Epub 2022 Mar 26.

Department of Gastroenterology, Nippon Medical School, Graduate School of Medicine, 1-1-5, Sendagi, Bunkyo-ku, Tokyo, 113-8603, Japan.

Background: It is unclear whether prophylactic endoscopic closure after colorectal endoscopic submucosal dissection (ESD) reduces the risk of postoperative adverse events due to variability in lesion characteristics. Therefore, we conducted a retrospective study using propensity score matching to evaluate the efficacy of prophylactic clip closure in preventing postoperative adverse events after colorectal ESD.

Methods: This single-center retrospective cohort study included 219 colorectal neoplasms which were removed by ESD. The patients were allocated into the closure and non-closure groups, which were compared before and after propensity-score matching. Post-ESD adverse events including major and minor bleeding and delayed perforation were compared between the two groups.

Results: In this present study, 97 and 122 lesions were allocated to the closure and non-closure groups, respectively, and propensity score matching created 61 matched pairs. The rate of adverse events was significantly lower in the closure group than in the non-closure group (8% vs. 28%, P = 0.008). Delayed perforation occurred in two patients in the non-closure group, whereas no patient in the closure group developed delayed perforation. In contrast, there were no significant differences in other postoperative events including the rate of abdominal pain; fever, white blood cell count, and C-reactive protein; and appetite loss between the two groups.

Conclusions: Propensity score matching analysis demonstrated that prophylactic closure was associated with a significantly reduced rate of adverse events after colorectal ESD. When technically feasible, mucosal defect closure after colorectal ESD may result in a favorable postoperative course.
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http://dx.doi.org/10.1186/s12876-022-02202-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8962491PMC
March 2022

Type III procollagen peptide level can indicate liver dysfunction associated with volume overload in acute heart failure.

ESC Heart Fail 2022 06 14;9(3):1832-1843. Epub 2022 Mar 14.

Division of Intensive Care Unit, Nippon Medical School Chiba Hokusoh Hospital, 1715 Kamagari, Inzai, Chiba, 270-1694, Japan.

Aim: The role of serum type III procollagen peptide (P3P) level in the acute phase of acute heart failure (AHF) requires clarification. We hypothesized that serum P3P level is temporarily higher during the acute phase, reflecting liver dysfunction due to congestion.

Methods And Results: A total of 800 AHF patients were screened, and data from 643 patients were analysed. Heart failure was diagnosed by the treating physician according to the European Society of Cardiology (ESC) guidelines, and included patients being treated with high-concentration oxygen inhalation (including mechanical support) for orthopnea, inotrope administration, or mechanical support for low blood pressure, and various types of diuretics for peripheral or pulmonary oedema. In all cases, diuretics or vasodilators were administered to treat AHF. The patients were divided into three groups according to their quartile (Q) serum P3P level: low-P3P (Q1, P3P ≤ 0.6 U/mL), mid-P3P (Q2/Q3, 0.6 < P3P <1.2 U/mL), and high-P3P (Q4, P3P ≥ 1.2 U/mL). The plasma volume status (PVS) was calculated using the following formula: ([actual PV - ideal PV]/ideal PV) × 100 (%). The primary endpoint was 365 day mortality. A Kaplan-Meier curve analysis showed that prognoses, including all-cause mortality and heart failure events within 365 days, were significantly (P < 0.001) worse in the high-P3P group when compared with the mid-P3P and low-P3P groups. A multivariate logistic regression analysis showed that high PVS (Q4, odds ratio [OR]: 4.702, 95% CI: 2.012-20.989, P < 0.001), high fibrosis-4 index (Q4, OR: 2.627, 95% CI: 1.311-5.261, P = 0.006), and low estimated glomerular filtration rate per 10 mL/min/1.73 m decrease (OR: 1.996, 95% CI: 1.718-2.326, P < 0.001) were associated with high P3P values. The Kaplan-Meier curve analysis demonstrated a significantly lower survival rate, as well as a higher rate of heart failure events, in the high-P3P and high-PVS groups when compared with the other groups. A multivariate Cox regression model identified high P3P level and high PVS as an independent predictor of 365 day all-cause mortality (hazard ratio [HR]: 2.249; 95% CI: 1.081-3.356; P = 0.026) and heart failure events (HR: 1.586, 95% CI: 1.005-2.503, P = 0.048).

Conclusion: A high P3P level during the acute phase of AHF served as a comprehensive biomarker of liver dysfunction with volume overload (i.e. liver congestion) and renal dysfunction. A high P3P level at admission may be able to predict adverse outcomes in AHF patients.
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http://dx.doi.org/10.1002/ehf2.13878DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9065836PMC
June 2022

Neutrophil-lymphocyte ratio predicts early outcomes in patients with unresectable hepatocellular carcinoma treated with atezolizumab plus bevacizumab: a multicenter analysis.

Eur J Gastroenterol Hepatol 2022 06 14;34(6):698-706. Epub 2022 Feb 14.

Division of Gastroenterology and Hepatology, Department of Internal Medicine, Nippon Medical School, Tokyo.

Objective: To investigate whether neutrophil-to-lymphocyte ratio (NLR) can predict outcomes in patients with unresectable hepatocellular carcinoma (HCC) treated with atezolizumab plus bevacizumab (Atez/Bev).

Methods: A total of 249 patients with unresectable HCC treated with Atez/Bev were included. We analyzed survival and discontinuation of this therapy in this cohort.

Results: Cumulative overall survival at 2, 4, 6, and 8 months was 97.6%, 94.9%, 88.9%, and 82.8%, respectively. Cumulative overall survival differed significantly between patients with low (<3.0) versus high (≥3.0) NLR (P = 0.001). Conversely, cumulative progression-free survival did not differ between patients with low versus high NLR. The distribution of response was 1.5% for complete response, 17.1% for partial response, 60.5% for stable disease, and 21.0% for progressive disease. Responses were not different between patients with low and high NLR. Regarding adverse events, immune-related liver injury of any grade and grade of at least 3, decreased appetite of any grade, grade of at least 3 proteinuria, and other adverse events of any grade differed significantly between patients with low and high NLR. There were 56, 18, and 2 patients who discontinued Atez/Bev therapy due to progression of disease, adverse event, and other reasons, respectively. The cumulative discontinuation rate for Atez/Bev therapy due to adverse events differed significantly between patients with low versus high NLR (P = 0.022). Cox proportional hazards modeling analysis with inverse probability weighting showed that NLR of at least 3.0 was significantly associated with overall survival (hazard ratio, 3.369; 95% confidence interval, 1.024-11.080).

Conclusions: NLR can predict outcomes in patients with unresectable HCC treated with Atez/Bev.
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http://dx.doi.org/10.1097/MEG.0000000000002356DOI Listing
June 2022

Association of early bevacizumab interruption with efficacy of atezolizumab plus bevacizumab for advanced hepatocellular carcinoma: A landmark analysis.

Hepatol Res 2022 May 9;52(5):462-470. Epub 2022 Feb 9.

Division of Gastroenterology and Hepatology, Department of Internal Medicine, Nippon Medical School, Tokyo, Japan.

Aim: The present study focused on the association of early bevacizumab (Bev) interruption with the clinical outcome of atezolizumab plus bevacizumab.

Methods: This retrospective study included 239 patients with advanced hepatocellular carcinoma receiving atezolizumab/Bev from September 2020 to June 2021 at 16 different institutions in Japan. We conducted a 9-week landmark analysis to investigate the association of Bev interruption due to adverse events with the therapeutic efficacy.

Results: The median age was 73.0 (68.0-80.0) years old, with 195 (81.6%) men. The objective response rate was significantly higher in patients without Bev interruption than in those with it (34.5% vs. 17.3%, p = 0.038). The median progression-free survival (PFS) was 6.5 months (95% confidence interval [CI] 4.5-9.7) and 9.0 months (95% CI 7.1-not applicable) in patients with and without Bev interruption, respectively, with statistical significance (p = 0.021). The 12-month overall survival (OS) rates in patients with and without Bev interruption were 49.4% (CI 27.7%-67.9%) and 82.2% (95% CI 70.3%-89.6%), respectively, showing a significant difference (p = 0.004). The presence of Bev interruption was a significant factor associated with the PFS (p = 0.021) and OS (p = 0.008). A multivariate analysis showed that modified albumin-bilirubin 2b (p < 0.001) and later-line treatment (p = 0.018) were unfavorable factors associated with Bev interruption. Liver injury, appetite loss, protein urea, and ascites or hepatic edema were more frequently found in patients with Bev interruption than in those without it.

Conclusions: Early Bev interruption was an unfavorable factor associated with the PFS and OS. Good liver function and treatment settings may be associated with maintaining Bev treatment.
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http://dx.doi.org/10.1111/hepr.13748DOI Listing
May 2022

Early experience of atezolizumab plus bevacizumab treatment for unresectable hepatocellular carcinoma BCLC-B stage patients classified as beyond up to seven criteria - Multicenter analysis.

Hepatol Res 2022 Mar 2;52(3):308-316. Epub 2021 Dec 2.

Division of Gastroenterology and Hepatology, Department of Internal Medicine, Nippon Medical School, Tokyo, Japan.

Background/aim: 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.
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http://dx.doi.org/10.1111/hepr.13734DOI Listing
March 2022

Posttreatment after Lenvatinib in Patients with Advanced Hepatocellular Carcinoma.

Liver Cancer 2021 Sep 20;10(5):473-484. Epub 2021 Apr 20.

Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan.

Background: There is no standard posttreatment for patients with advanced hepatocellular carcinoma (HCC) in whom lenvatinib therapy has failed. This study aimed to investigate rates of migration to posttreatment after lenvatinib and to explore candidates for second-line agents in the patients with failed lenvatinib therapy.

Methods: We retrospectively collected data on patients with advanced HCC who received lenvatinib as the first-line agent in 7 institutions.

Results: Overall survival and progression-free survival (PFS) of 178 patients who received lenvatinib as the first-line agent were 13.3 months (95% confidence interval [CI], 11.5-15.2) and 6.7 months (95% CI, 5.6-7.8), respectively. Sixty-nine of 151 patients (45.7%) who discontinued lenvatinib moved on to posttreatment. The migration rates from lenvatinib to the second-line agent and from the second-line agent to the third-line agent were 41.7 and 44.4%, respectively. Based on multivariate analysis, response to lenvatinib (complete or partial response according to modified RECIST) and discontinuation of lenvatinib due to radiological progression, as well as male were associated with a significantly higher probability of migration to posttreatment after lenvatinib. On the other hand, alpha-fetoprotein levels of 400 ng/mL or higher was correlated with a significantly lower probability of migration to posttreatment after lenvatinib. Of 63 patients who received second-line systemic therapy, 53 (84.2%) were administered sorafenib. PFS, objective response rate (ORR), and disease control rate (DCR) for sorafenib treatment were 1.8 months (95% CI, 0.6-3.0), 1.8%, and 20.8%, respectively. According to the Cox regression hazard model, Child-Pugh class B significantly contributed to shorter PFS. PFS, ORR, and DCR of 22 patients who received regorafenib after lenvatinib in any lines were 3.2 months (range, 1.5-4.9 months), 13.6%, and 36.3%, respectively. Similarly, PFS, ORR, and DCR of 17 patients who received regorafenib after lenvatinib in the third-line (after sorafenib) were 3.8 months (range, 1.1-6.5 months), 17.6%, and 41.2%, respectively.

Conclusion: Sorafenib may not be a candidate for use as a posttreatment agent after lenvatinib, according to the results of the present study. Regorafenib has the potential to become an appropriate posttreatment agent after lenvatinib.
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http://dx.doi.org/10.1159/000515552DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8527907PMC
September 2021

A novel noninvasive formula for predicting cirrhosis in patients with chronic hepatitis C.

PLoS One 2021 10;16(9):e0257166. Epub 2021 Sep 10.

Division of Gastroenterology and Hepatology, Nippon Medical School, Tokyo, Japan.

Evaluating liver fibrosis is crucial for disease severity assessment, treatment decisions, and hepatocarcinogenic risk prediction among patients with chronic hepatitis C. In this retrospective multicenter study, we aimed to construct a novel model formula to predict cirrhosis. A total of 749 patients were randomly allocated to training and validation sets at a ratio of 2:1. Liver stiffness measurement (LSM) was made via transient elastography using FibroScan. Patients with LSM ≥12.5 kPa were regarded as having cirrhosis. The best model formula for predicting cirrhosis was constructed based on factors significantly and independently associated with LSM (≥12.5 kPa) using multivariate regression analysis. Among the 749 patients, 198 (26.4%) had LSM ≥12.5 kPa. In the training set, multivariate analysis identified logarithm natural (ln) type IV collagen 7S, ln hyaluronic acid, and ln Wisteria floribunda agglutinin positive Mac-2-binding protein (WFA+-Mac-2 BP) as the factors that were significantly and independently associated with LSM ≥12.5 kPa. Thus, the formula was constructed as follows: score = -6.154 + 1.166 × ln type IV collagen 7S + 0.526 × ln hyaluronic acid + 1.069 × WFA+-Mac-2 BP. The novel formula yielded the highest area under the curve (0.882; optimal cutoff, -0.381), specificity (81.5%), positive predictive values (62.6%), and predictive accuracy (81.6%) for predicting LSM ≥12.5 kPa among fibrosis markers and indices. These results were almost similar to those in the validated set, indicating the reproducibility and validity of the novel formula. The novel formula scores were significantly, strongly, and positively correlated with LSM values in both the training and validation data sets (correlation coefficient, 0.721 and 0.762; p = 2.67 × 10-81 and 1.88 × 10-48, respectively). In conclusion, the novel formula was highly capable of diagnosing cirrhosis in patients with chronic hepatitis C and exhibited better diagnostic performance compared to conventional fibrosis markers and indices.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0257166PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8432856PMC
November 2021

Efficacy of lenvatinib for unresectable hepatocellular carcinoma based on background liver disease etiology: multi-center retrospective study.

Sci Rep 2021 08 17;11(1):16663. Epub 2021 Aug 17.

Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Ehime, Japan.

It was recently reported that hepatocellular carcinoma (HCC) patients with non-alcoholic steatohepatitis (NASH) are not responsive to immune-checkpoint inhibitor (ICI) treatment. The present study aimed to evaluate the therapeutic efficacy of lenvatinib in patients with non-alcoholic fatty liver disease (NAFLD)/NASH-related unresectable-HCC (u-HCC). Five hundred thirty u-HCC patients with Child-Pugh A were enrolled, and divided into the NAFLD/NASH (n = 103) and Viral/Alcohol (n = 427) groups. Clinical features were compared in a retrospective manner. Progression-free survival (PFS) was better in the NAFLD/NASH than the Viral/Alcohol group (median 9.3 vs. 7.5 months, P = 0.012), while there was no significant difference in overall survival (OS) (20.5 vs. 16.9 months, P = 0.057). In Cox-hazard analysis of prognostic factors for PFS, elevated ALT (≥ 30 U/L) (HR 1.247, P = 0.029), modified ALBI grade 2b (HR 1.236, P = 0.047), elevated AFP (≥ 400 ng/mL) (HR 1.294, P = 0.014), and NAFLD/NASH etiology (HR 0.763, P = 0.036) were significant prognostic factors. NAFLD/NASH etiology was not a significant prognostic factor in Cox-hazard analysis for OS (HR0.758, P = 0.092), whereas AFP (≥ 400 ng/mL) (HR 1.402, P = 0.009), BCLC C stage (HR 1.297, P = 0.035), later line use (HR 0.737, P = 0.014), and modified ALBI grade 2b (HR 1.875, P < 0.001) were significant. Lenvatinib can improve the prognosis of patients affected by u-HCC irrespective of HCC etiology or its line of treatment.
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http://dx.doi.org/10.1038/s41598-021-96089-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8370989PMC
August 2021

Liver fibrosis is associated with carotid atherosclerosis in patients with liver biopsy-proven nonalcoholic fatty liver disease.

Sci Rep 2021 08 5;11(1):15938. Epub 2021 Aug 5.

Division of Gastroenterology and Hepatology, Nippon Medical School, 1-1-5, Sendagi, Bunkyo-ku, Tokyo, 113-8603, Japan.

Nonalcoholic fatty liver disease (NAFLD) is related to subclinical atherosclerosis. However, whether the severity of the disease (or which histopathological component) is associated with subclinical atherosclerosis remains controversial. This study aimed to investigate the association between the histopathological severity of NAFLD and carotid intima-media thickness (CIMT) in Japanese patients with liver biopsy-proven NAFLD. Maximum-CIMT (max-CIMT) was measured as an index of carotid atherosclerosis in 195 biopsy-proven NAFLD patients. A significant association was observed between the severity of fibrosis (but not steatosis, inflammation, and ballooning) and max-CIMT. Older age, male gender, hypertension, and advanced fibrosis were independently linked to max-CIMT ≥ 1.2 mm. The prevalence of max-CIMT ≥ 1.2 mm was significantly higher in the advanced fibrosis group than in the non-advanced fibrosis group (75.4% versus 44.0%; p < 0.01). Non-invasive liver fibrosis markers and scoring systems, including fibrosis-4 index, NAFLD fibrosis score, hyaluronic acid, and Wisteria floribunda agglutinin positive Mac-2-binding protein, demonstrated that the diagnostic performance for max-CIMT ≥ 1.2 mm was similar to that of biopsy-based fibrosis staging. In conclusion, advanced fibrosis is significantly and independently associated with high-risk CIMT. Non-invasive fibrosis markers and scoring systems could help estimate the risk of atherosclerosis progression in patients with NAFLD.
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http://dx.doi.org/10.1038/s41598-021-95581-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8342487PMC
August 2021

Clinical Significance of the Fibrosis-4 Index in Patients with Acute Heart Failure Requiring Intensive Care.

Int Heart J 2021 Jul 17;62(4):858-865. Epub 2021 Jul 17.

Department of Cardiovascular Medicine, Nippon Medical School.

The Fibrosis-4 (FIB4) index could indicate the liver fibrosis in patients with chronic hepatic diseases. It was calculated using the following formula: (age × aspartate aminotransferase [U/L]) / (platelet count [10/μL] × √alanine aminotransferase [U/L]). However, the clinical impact of the FIB4 index in the acute phase of acute heart failure (AHF) has not been sufficiently investigated.A total 1,468 AHF patients were analyzed. The median FIB4 index was 2.71 [1.85-4.22]. The patients were divided into three groups according to the quartiles of their FIB4 index (low-FIB4 [Q1, ≤ 1.847], middle-FIB4 [Q2/Q3, 1.848-4.216], and high-FIB4 [Q4, ≥ 4.216] groups). A Kaplan-Meier curve analysis showed that the prognosis, such as all-cause mortality and HF events within 365 days, was significantly poorer in the high-FIB4 group than in the middle-FIB4 and low-FIB4 groups. A multivariate Cox regression model identified high FIB4 index as an independent predictor of 365-day all-cause death (hazard ratio (HR): 1.660, 95% CI: 1.136-2.427) and HF events (HR: 1.505, 95% CI: 1.145-1.978). The multivariate logistic regression analysis showed that the high plasma volume status (PVS) (Q4, odds ratio [OR]: 2.099, 95% CI: 1.429-3.082), low systolic blood pressure (SBP) (< 100 mmHg, OR: 3.825, 95% CI: 2.504-5.840), and low left ventricular ejection fraction (< 40%, OR: 1.321, 95% CI: 1.002-1.741) were associated with a high FIB4 index.A high FIB4 index can predict adverse outcomes in AHF patients, which indicate that congestive liver and liver hypoperfusion occur due to low cardiac output in the acute phase of AHF.
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http://dx.doi.org/10.1536/ihj.20-793DOI Listing
July 2021

Impact of modified albumin-bilirubin grade on survival in patients with HCC who received lenvatinib.

Sci Rep 2021 07 14;11(1):14474. Epub 2021 Jul 14.

Hepato-Biliary Center, Matsuyama Red Cross Hospital, Matsuyama, Japan.

We investigated the impact on survival of modified albumin-bilirubin (mALBI) grade versus Child-Pugh classification in patients with hepatocellular carcinoma (HCC) who received lenvatinib. A total of 524 patients with HCC who received lenvatinib were included. Univariate analysis showed that mALBI grade 2b/3 and Child-Pugh class B/C were significantly associated with survival [hazard ratio (HR), 2.471; 95% confidence interval (CI), 1.944-3.141 and HR, 2.178; 95%CI, 1.591-2.982]. In patients with a Child-Pugh score of 5, multivariate analysis showed that mALBI grade 2b/3 was independently associated with survival (HR, 1.814; 95%CI, 1.083-3.037). Conversely, among patients with mALBI grade 1/2a, there was no difference in survival between those with a Child-Pugh class of 5 or 6 (p = 0.735). Time-dependent receiver operating characteristic analysis showed that the ALBI score predicted survival better than the Child-Pugh score. The optimal cut-off value of the ALBI score for predicting survival was nearly the same as the value separating mALBI grades 2a and 2b. In conclusion, the mALBI grade was a better predictor of survival than the Child-Pugh classification in patients with unresectable HCC who received lenvatinib therapy.
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http://dx.doi.org/10.1038/s41598-021-93794-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8280227PMC
July 2021

Adverse events as potential predictive factors of activity in patients with advanced hepatocellular carcinoma treated with lenvatinib.

Liver Int 2021 12 22;41(12):2997-3008. Epub 2021 Jul 22.

Department of Gastroenterology, Tokushima Prefectural Central Hospital, Tokushima, Japan.

Background And Aim: Lenvatinib is a standard of care option in first-line therapy of advanced hepatocellular carcinoma (HCC). In the present study, we aim to identify, in patients with HCC treated with lenvatinib, a possible association between occurrence and grading of adverse events (AEs) and outcome.

Methods: We performed a retrospective analysis of 606 Japanese and Italian patients treated with lenvatinib in first-line setting and investigated the possible correlation between the onset of AEs, toxicity grade (G) and outcome measures such as overall survival (OS) and progression-free survival (PFS).

Results: The appearance of arterial hypertension G ≥ 2 independently predicted prolonged OS [hazard ratio (HR) 0.66, 95% confidence interval (CI) 0.46-0.93, P = .0188], whereas decreased appetite G ≥ 2 independently predicted decreased OS (HR 1.70, 95% CI 1.25-2.32, P = .0007) by multivariate analysis. Appearance of hand-foot skin reaction independently predicted prolonged PFS (HR 0.72, 95% CI 0.56-0.93, P = .0149), whereas decreased appetite G ≥ 2 predicted decreased PFS (HR 1.36, 95% CI 1.04-1.77, P = .0277).

Conclusions: Our main findings are that the occurrence of arterial hypertension G ≥ 2 is a predictor of longer survival, whereas decreased appetite G ≥ 2 predicts for a poor prognosis. A careful management of AEs under lenvatinib treatment for HCC is required, to improve patients' quality of life, minimize the need for treatment discontinuation and achieve optimal outcome.
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http://dx.doi.org/10.1111/liv.15014DOI Listing
December 2021

Atezolizumab plus bevacizumab treatment for unresectable hepatocellular carcinoma: Early clinical experience.

Cancer Rep (Hoboken) 2022 02 11;5(2):e1464. Epub 2021 Jun 11.

Department of Internal Medicine, Himeji Red Cross Hospital, Hyogo, Japan.

Background: Although atezolizumab plus bevacizumab (Atez/bev) treatment has been developed for unresectable hepatocellular carcinoma (u-HCC), changes in hepatic function during therapy have yet to be reported.

Aim: This retrospective clinical study aimed to elucidate early responses to Atez/Bev.

Methods: From September 2020 to April 2021, 171 u-HCC patients undergoing Atez/Bev treatment were enrolled (BCLC stage A:B:C:D = 5:68:96:2). Of those, 75 had no prior history of systemic treatment. Relative changes in hepatic function and therapeutic response were assessed using albumin-bilirubin (ALBI) score and Response Evaluation Criteria in Solid Tumors (RECIST), ver. 1.1, respectively.

Results: In initial imaging examination findings, objective response rates for early tumor shrinkage and disease control after 6 weeks (ORR-6W/DCR-6W) were 10.6%/79.6%. Similar response results were observed in patients with and without a past history of systemic treatment (ORR-6W/DCR-6W = 9.7%/77.8% and 12.2%/82.9%), as well as patients in whom Atez/Bev was used as post-progression treatment following lenvatinib (ORR-6W/DCR-6W = 7.7%/79.5%), for which no known effective post-progression treatment has been established. In 111 patients who underwent a 6-week observation period, ALBI score was significantly worsened at 3 weeks after introducing Atez/Bev (-2.525 ± 0.419 vs -2.323 ± 0.445, p < .001), but then recovered at 6-weeks (-2.403 ± 0.452) as compared to 3-weeks (p = .001). During the observation period, the most common adverse events were appetite loss (all grades) (12.3%), general fatigue/hypertension (all grades) (11.1%, respectively), and urine protein (all grades) (10.5%).

Conclusion: Atez/Bev might have therapeutic potential not only as first but also later-line treatment of existing molecular target agents. In addition, this drug combination may have less influence on hepatic function during the early period, as the present patients showed a good initial therapeutic response.
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http://dx.doi.org/10.1002/cnr2.1464DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8842687PMC
February 2022

Effect of Vitamin D Supplementation on Skeletal Muscle Volume and Strength in Patients with Decompensated Liver Cirrhosis Undergoing Branched Chain Amino Acids Supplementation: A Prospective, Randomized, Controlled Pilot Trial.

Nutrients 2021 May 30;13(6). Epub 2021 May 30.

Department of Internal Medicine, Division of Gastroenterology and Hepatology, Nippon Medical School, Tokyo 113-8603, Japan.

Background: Sarcopenia worsens patient prognoses in chronic liver disease. This study aimed to elucidate the effects of vitamin D supplementation on skeletal muscle volume and strength in patients with decompensated cirrhosis.

Methods: Thirty-three patients were entered into the study based on the criteria and then randomly assigned to two groups: Group A ( = 17), the control group, and Group B ( = 16), those who received oral native vitamin D3 at a dose of 2000 IU once a day for 12 months.

Results: SMI values in Group B were significantly increased at 12 months (7.64 × 10). The extent of changes in the SMI and grip strength in Group B were significantly greater than that in Group A at 12 months ( = 2.57 × 10 and 9.07 × 10). The median change rates in the SMI were +5.8% and the prevalence of sarcopenia was significantly decreased from 80.0% (12/15) to 33.3% (5/15; = 2.53 × 10) in Group B.

Conclusions: Vitamin D supplementation might be an effective and safe treatment option for patients with decompensated cirrhosis to increase or restore the skeletal muscle volume and strength or prevent the muscle volume and strength losses.
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http://dx.doi.org/10.3390/nu13061874DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8228227PMC
May 2021

Therapeutic efficacy of ramucirumab after lenvatinib for post-progression treatment of unresectable hepatocellular carcinoma.

Gastroenterol Rep (Oxf) 2021 Apr 10;9(2):133-138. Epub 2020 Oct 10.

Gastroenterology Center, Ehime Prefectural Central Hospital, Ehime, Japan.

Background: Lenvatinib is used for unresectable hepatocellular carcinoma (u-HCC) as first-line, as well as second- and third-line therapy in Japan. We evaluated the therapeutic efficacy of newly developed ramucirumab when given after lenvatinib for post-progression treatment.

Methods: Of 385 patients with u-HCC and treated with lenvatinib at 16 different institutions in Japan between May 2018 and January 2020, 28 who received ramucirumab as the next treatment were enrolled and therapeutic responses were evaluated in a retrospective manner.

Results: The median age of the 28 patients given ramucirumab was 70 years and the median albumin-bilirubin score was -2.19. Of the 28 patients, 23 were male, 21 were classified as Child-Pugh A and 7 as Child-Pugh B, and 25 were Barcelona Clinic Liver Cancer Stage C. Ramucirumab was given as second-line therapy in 14, third-line in 9, and fourth-line in 5. Therapeutic response was obtained in only 26 patients; the objective response rate was 3.8% (1/26) and the disease-control rate was 42.3% (11/26), with a median period to progression of 2.0 months. The reasons for discontinuation of ramucirumab were progression of disease in 16 and Grade 3 adverse events (gastrointestinal bleeding, ascites) in 2.

Conclusions: The anticipated therapeutic efficacy of ramucirumab for post-progression treatment following lenvatinib was not seen in our early experience.
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http://dx.doi.org/10.1093/gastro/goaa042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8128005PMC
April 2021

What Can Be Done to Solve the Unmet Clinical Need of Hepatocellular Carcinoma Patients following Lenvatinib Failure?

Liver Cancer 2021 Apr 25;10(2):115-125. Epub 2021 Feb 25.

Hepato-biliary Center, Matsuyama Red Cross Hospital, Matsuyama, Japan.

Background/aim: An effective postprogression treatment of lenvatinib (LEN) against unresectable hepatocellular carcinoma (u-HCC) has not been established. We aimed to elucidate the clinical role of continuing LEN beyond progression of disease (PD).

Methods: From March 2018 to October 2020, 99 u-HCC patients, in whom PD was confirmed (male:female = 78:21, median age 72 years, Child-Pugh A = 99, Barcelona Clinic Liver Cancer stage A:B:C = 2:43:54, LEN as first-line = 55), were enrolled (stopped LEN at PD [A group], = 26; continued LEN beyond PD [B group], = 73). Radiological response was evaluated with RECIST 1.1. Clinical features and prognostic factors for overall survival (OS) were retrospectively investigated using inverse probability weighting (IPW) calculated by propensity score.

Results: Median time to progression, best response, and modified albumin-bilirubin grade (mALBI) at both baseline and PD did not show significant difference between the groups. Postprogression treatment in the A group was best supportive care in 17, sorafenib in 4, regorafenib in 3, ramucirumab in 1, and hepatic arterial infusion chemotherapy in 1. After adjusting with IPW, the B group showed better prognosis in regard to OS after PD and OS after introducing LEN than the A group (10.8/19.6 vs. 5.8/11.2 months, < 0.001, respectively). In IPW-adjusted Cox hazard multivariate analysis, significant prognostic factors for OS after PD were mALBI 2b/3 at PD (HR 1.983, = 0.021), decline of Eastern Cooperative Oncology Group performance status (ECOG PS) from baseline at PD (HR 3.180, < 0.001), elevated alpha-fetoprotein (≥100 ng/mL) at introducing LEN (HR 2.511, = 0.004), appearance of new extrahepatic metastasis (HR 2.396, = 0.006), positive for hand-foot skin reaction (HFSR) before PD (any grade) (HR 0.292, < 0.001), and continuing LEN beyond PD (HR 0.297, < 0.001).

Conclusion: When ECOG PS and hepatic reserve function permit, continuing LEN treatment beyond PD, especially in u-HCC patients showed HFSR during LEN treatment, might be a good therapeutic option, at least until a more effective drug as a postprogression treatment after LEN failure is developed.
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http://dx.doi.org/10.1159/000513355DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8077500PMC
April 2021

Impact of Early Lenvatinib Administration on Survival in Patients with Intermediate-Stage Hepatocellular Carcinoma: A Multicenter, Inverse Probability Weighting Analysis.

Oncology 2021 27;99(8):518-527. Epub 2021 Apr 27.

Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Matsuyama, Japan.

Aim/background: Transarterial chemoembolization (TACE) is recommended for patients with intermediate-stage hepatocellular carcinoma (HCC). In this study, we investigated the impact of early lenvatinib administration in patients with intermediate-stage HCC, especially those with tumors beyond the up-to-7 criteria.

Materials/methods: A total of 208 patients with intermediate-stage HCC whose initial treatment was early lenvatinib administration or TACE were enrolled. Multivariate overall survival analysis was performed in this cohort. In addition, the impact of early lenvatinib administration on survival in patients with HCC beyond the up-to-7 criteria was clarified using inverse probability weighting (IPW) analysis.

Results: The overall cumulative survival rates at 6, 12, 18, and 24 months were 94.4, 79.9, 65.8, and 50.1%, respectively. Multivariate analysis with Cox proportional hazards modeling showed that HCC treatment with lenvatinib (hazard ratio [HR], 0.199; 95% confidence interval [CI], 0.077-0.517; p < 0.001), α-fetoprotein ≥100 ng/mL (HR, 1.687), Child-Pugh class B disease (HR, 1.825), and beyond the up-to-7 criteria (HR, 2.016) were independently associated with overall survival. The 6-, 12-, 18-, and 24-month cumulative survival rates were 96.0, 90.4, 65.7, and 65.7%, respectively, in patients treated with lenvatinib, and 94.1, 78.5, 65.3, and 48.4%, respectively, in patients who received TACE (p < 0.001). In addition, univariate analysis with Cox proportional hazards modeling adjusted by IPW showed that lenvatinib therapy was significantly associated with overall survival in patients with HCC beyond the up-to-7 criteria (HR, 0.230; 95% CI, 0.059-0.904; p = 0.035).

Conclusions: Lenvatinib may be a suitable first-line treatment for patients with intermediate-stage HCC beyond the up-to-7 criteria.
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http://dx.doi.org/10.1159/000515896DOI Listing
August 2021

Therapeutic efficacy of lenvatinib as third-line treatment after regorafenib for unresectable hepatocellular carcinoma progression.

Hepatol Res 2021 Aug 5;51(8):880-889. Epub 2021 May 5.

Department of Gastroenterology, Okayama City Hospital, Okayama, Japan.

Aim: Multiple molecular agents have been developed for treating unresectable hepatocellular carcinoma. This study aimed to elucidate the clinical efficacy of sequential treatment with lenvatinib after regorafenib failure.

Methods: From June 2017 to October 2020, 63 patients with Child-Pugh A and treated with regorafenib followed by sorafenib were enrolled (median age 71 years, 52 men, Barcelona Clinic Liver Cancer B:C = 23:40). They were divided into two groups, those treated with lenvatinib after regorafenib treatment (R-L group, n = 47) and those who did not receive lenvatinib after regorafenib (non-R-L group, n = 16). Prognostic factors were retrospectively analyzed after adjustment with inverse probability weighting.

Results: Serum albumin level at the start of regorafenib and reasons for discontinuation of regorafenib were significantly different between the R-L and non-R-L groups, whereas the albumin-bilirubin score, Child-Pugh class, and tumor burden were not. Progression-free survival was also not significantly different (median 4.1 vs. 3.8 months, p = 0.586). As for overall survival, the R-L group showed better prognosis after introducing regorafenib and after introducing sorafenib, following inverse probability weighting adjustment (MST 19.7 vs. 10.3 months, 33.8 vs. 15.3 months, p < 0.001 and p = 0.022, respectively). Modified albumin-bilirubin grade 2b (score >-2.27) at the start of regorafenib (HR 2.074, p = 0.041) and the presence of lenvatinib treatment after regorafenib failure (HR 0.355, p = 0.004) were found to be significant prognostic factors in Cox proportional hazards multivariate analysis, after inverse probability weighting adjustment.

Conclusion: These results show that lenvatinib is a good sequential treatment option after progression under regorafenib therapy in unresectable hepatocellular carcinoma patients with better hepatic reserve function.
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http://dx.doi.org/10.1111/hepr.13644DOI Listing
August 2021

Effect of sodium-glucose cotransporter 2 inhibitor in patients with non-alcoholic fatty liver disease and type 2 diabetes mellitus: a propensity score-matched analysis of real-world data.

Ther Adv Endocrinol Metab 2021 21;12:20420188211000243. Epub 2021 Mar 21.

Division of Gastroenterology and Hepatology, Nippon Medical School, Bunkyo-ku, Tokyo, Japan.

Background: Although sodium-glucose cotransporter 2 inhibitors (SGLT2-Is) improve not only glycemic control but also liver inflammation and fatty changes in patients with non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM), its sustainability and effect on liver fibrosis have remained unclear. The current study aimed to clarify the effects of 48-week SGLT2-I therapy on liver inflammation, fatty changes, and fibrosis in NAFLD patients with T2DM.

Methods: This study evaluated the effects of SGLT2-I on NAFLD, including liver fibrosis assessed transient elastography, in 56 patients with NAFLD who received SGLT2-I for 48 weeks. Moreover, changes in each clinical parameter between patients receiving SGLT2-I (the SGLT2-I group) and those receiving other oral hypoglycemic agents (OHAs) (the non-SGLT2-I group) were compared, using 1:1 propensity score matching to adjust for baseline factors.

Results: The SGLT2-I group exhibited a significant decrease in controlled attenuation parameter (312 dB/m at baseline to 280 dB/m at week 48) and liver stiffness measurement (9.1-6.7 kPa) ( < 0.001 for both). After propensity score matching (44 patients each in the SGLT2-I and non-SGLT2-I groups), no significant difference in HbA1c decrease was observed between the two groups. However, compared with the non-SGLT2-I group, the SGLT2-I group showed a significant decrease in body weight ( < 0.001), alanine aminotransferase ( = 0.02), uric acid ( < 0.001), and Fibrosis-4 (FIB-4) index ( = 0.01) at week 48. The improvement in FIB-4 index, defined as a ⩾10% decline from baseline at week 48, was 56.8% (25/44) in the SGLT2-I group and 20.5% (9/44) in the non-SGLT2-I group ( < 0.001).

Conclusion: SGLT2-Is improved not only glycemic control but also liver fatty infiltration and fibrosis in patients with NAFLD and T2DM, suggesting their possible superiority to other OHAs concerning these effects.
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http://dx.doi.org/10.1177/20420188211000243DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7989116PMC
March 2021

Increased Frequency of Dysfunctional Siglec-7CD57PD-1 Natural Killer Cells in Patients With Non-alcoholic Fatty Liver Disease.

Front Immunol 2021 22;12:603133. Epub 2021 Feb 22.

Department of Liver Diseases, The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Tokyo, Japan.

Non-alcoholic fatty liver disease (NAFLD) is a progressive disorder that can develop into liver fibrosis and hepatocellular carcinoma. Natural killer (NK) cells have been shown to protect against liver fibrosis and tumorigenesis, suggesting that they may also play a role in the pathogenesis of NAFLD. Sialic acid-binding immunoglobulin-like lectins (Siglecs) are a family of inhibitory and activating receptors expressed by many cell types, including NK cells. Here, we investigated the phenotypic profiles of peripheral blood and intrahepatic NK cells, including expression of Siglecs and immune checkpoint molecules, and their association with NK cell function in patients with NAFLD. Immune cells in the peripheral blood of 42 patients with biopsy-proven NAFLD and 13 healthy volunteers (HVs) were identified by mass cytometry. The function of various NK cell subpopulations was assessed by flow cytometric detection of intracellular IFN-γ and CD107a/LAMP-1, a degranulation marker, after stimulation. We found that peripheral blood from NAFLD patients, regardless of fibrosis stage, contained significantly fewer total CD56 NK cell and CD56 NK cell populations compared with HVs, and the CD56 cells from NAFLD patients were functionally impaired. Among the Siglecs examined, NK cells predominantly expressed Siglec-7 and Siglec-9, and both the expression levels of Siglec-7 and Siglec-9 on NK cells and the frequencies of Siglec-7CD56 NK cells were reduced in NAFLD patients. Notably, Siglec-7 levels on CD56 NK cells were inversely correlated with PD-1, CD57, and ILT2 levels and positively correlated with NKp30 and NKp46 levels. Further subtyping of NK cells identified a highly dysfunctional Siglec-7CD57PD-1CD56 NK cell subset that was increased in patients with NAFLD, even those with mild liver fibrosis. Intrahepatic NK cells from NAFLD patients expressed elevated levels of NKG2D and CD69, suggesting a more activated phenotype than normal liver NK cells. These data identify a close association between NK cell function and expression of Siglec-7, CD57, and PD-1 that could potentially be therapeutically targeted in NAFLD.
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http://dx.doi.org/10.3389/fimmu.2021.603133DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7938755PMC
June 2021

Development of Interferon-Free, Direct-Acting Antivirals Treatment for Japanese Patients with Chronic Hepatitis C Infection and Chronic Kidney Disease.

J Nippon Med Sch 2021 Jun 9;88(3):163-170. Epub 2021 Mar 9.

Division of Gastroenterology and Hepatology, Nippon Medical School.

Chronic hepatitis C virus (HCV) infection can progress to liver cirrhosis and hepatocellular carcinoma. Interferon-based treatment was previously the only antiviral therapy for chronic hepatitis C infection; however, development of interferon-free, direct-acting antivirals, in 2014, markedly improved treatment efficacy and safety. Treatment indications were expanded to include elderly adults, patients with advanced liver fibrosis, and patients with chronic hepatitis C infection complicated by chronic kidney disease, for whom antiviral therapy had been difficult or contraindicated. The median age of patients with chronic HCV infection in Japan is 70 years, older than in other countries. Because diminished renal function is common in elderly adults, a safe and effective treatment for chronic hepatitis C complicated by chronic kidney disease has been expected in Japan. In addition, the HCV antibody-positive rate is higher in hemodialysis patients than in non-hemodialysis patients in Japan. Numerous studies have reported that direct-acting antivirals are safe and effective for hepatitis C patients on hemodialysis. This review summarizes treatments available in Japanese clinical practice for patients with chronic HCV infection complicated by chronic kidney disease, including hemodialysis patients.
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http://dx.doi.org/10.1272/jnms.JNMS.2021_88-316DOI Listing
June 2021
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