研究者業績

葛谷 貞二

クズヤ テイジ  (Teiji Kuzuya)

基本情報

所属
藤田医科大学 消化器内科学 教授
学位
博士(医学)(名古屋大学)

ORCID ID
 https://orcid.org/0000-0002-2229-990X
J-GLOBAL ID
201101073782477483
researchmap会員ID
6000030051

学歴

 2

主要な論文

 200
  • Teiji Kuzuya, Naoto Kawabe, Hisanori Muto, Yoshihiko Tachi, Takeshi Ukai, Yuryo Wada, Gakushi Komura, Takuji Nakano, Hiroyuki Tanaka, Kazunori Nakaoka, Eizaburo Ohno, Kohei Funasaka, Mitsuo Nagasaka, Ryoji Miyahara, Yoshiki Hirooka
    Current oncology (Toronto, Ont.) 31(10) 6218-6231 2024年10月16日  査読有り筆頭著者責任著者
    AIM: To investigate the characteristics and prognosis of patients with advanced hepatocellular carcinoma (HCC) treated with atezolizumab and bevacizumab (Atz/Bev) who achieved a complete response (CR) according to the modified Response Evaluation Criteria in Solid Tumors (mRECIST). METHODS: A total of 120 patients with Eastern Cooperative Oncology Group performance status (PS) 0 or 1 and Child-Pugh A at the start of Atz/Bev treatment were included. Barcelona Clinic Liver Cancer stage C was recorded in 59 patients. RESULTS: The CR rate with Atz/Bev alone was 15.0%. The median time to CR was 3.4 months, and the median duration of CR was 15.6 months. A significant factor associated with achieving CR with Atz/Bev alone was an AFP ratio of 0.34 or less at 3 weeks. Adding transarterial chemoembolization (TACE) in the six patients who achieved a partial response increased the overall CR rate to 20%. Among the 24 patients who achieved CR, the median progression-free survival was 19.3 months, the median overall survival was not reached, and 14 patients (58.3%) were able to discontinue Atz/Bev and achieve a drug-free status. Twelve of these patients developed progressive disease (PD), but eleven successfully received post-PD treatments and responded well. CONCLUSIONS: Achieving CR by mRECIST using Atz/Bev alone or with additional TACE can be expected to offer an extremely favorable prognosis.
  • Tadashi Fujii, Teiji Kuzuya, Nobuhiro Kondo, Kohei Funasaka, Eizaburo Ohno, Yoshiki Hirooka, Takumi Tochio
    Journal of medical microbiology 73(9) 2024年9月  査読有り
    Introduction. Hepatocellular carcinoma (HCC) is one of the deadliest cancers worldwide.Gap statement. Monitoring of HCC and predicting its immunotherapy responses are challenging.Aim. This study explored the potential of the gut microbiome for HCC monitoring and predicting HCC immunotherapy responses.Methods. DNA samples were collected from the faeces of 22 patients with HCC treated with atezolizumab/bevacizumab (Atz/Bev) and 85 healthy controls. The gut microbiome was analysed using 16S rRNA next-generation sequencing and quantitative PCR (qPCR).Results. The microbiomes of patients with HCC demonstrated significant enrichment of Lactobacillus, particularly Lactobacillus fermentum, and Streptococcus, notably Streptococcus anginosus. Comparative analysis between Atz/Bev responders (R) and non-responders (NR) revealed a higher abundance of Bacteroides stercoris in the NR group and Bacteroides coprocola in the R group. Using qPCR analysis, we observed elevated levels of S. anginosus and reduced levels of 5α-reductase genes, essential for the synthesis of isoallolithocholic acid, in HCC patients compared to controls. Additionally, the analysis confirmed a significantly lower abundance of B. stercoris in the Atz/Bev R group relative to the NR group.Conclusions. The gut microbiome analysis and specific gene quantification via qPCR could provide a rapid, less invasive, and cost-effective approach for assessing the increased risk of HCC, monitoring patient status, and predicting immunotherapy responses.
  • Teiji Kuzuya, Naoto Kawabe, Hisanori Muto, Yuryo Wada, Gakushi Komura, Takuji Nakano, Hiroyuki Tanaka, Kazunori Nakaoka, Eizaburo Ohno, Kohei Funasaka, Mitsuo Nagasaka, Ryoji Miyahara, Yoshiki Hirooka
    Current Oncology 31(8) 4225-4240 2024年7月26日  査読有り筆頭著者責任著者
    The relationship between antitumor response and tumor marker changes was evaluated in patients with advanced hepatocellular carcinoma treated with durvalumab plus tremelimumab (Dur/Tre). Forty patients were enrolled in this retrospective evaluation of treatment outcomes. According to the Response Evaluation Criteria for Solid Tumors version 1.1 at 8 weeks, the objective response (OR) rate was 25% and the disease control (DC) rate was 57.5%. The median alpha-fetoprotein (AFP) ratio at 4 weeks was 0.39 in patients who achieved OR at 8 weeks (8W-OR group), significantly lower than the 1.08 in the non-8W-OR group (p = 0.0068); however, it was 1.22 in patients who did not achieve DC at 8 weeks (non-8W-DC group), significantly higher than the 0.53 in the 8W-DC group (p = 0.0006). Similarly, the median des-γ-carboxy-prothrombin (DCP) ratio at 4 weeks was 0.15 in the 8W-OR group, significantly lower than the 1.46 in the non-8W-OR group (p < 0.0001); however, it was 1.23 in the non-8W-DC group, significantly higher than the 0.49 in the 8W-DC group (p = 0.0215). Early changes in tumor markers after Dur/Tre initiation were associated with antitumor response. In particular, changes in AFP and DCP at 4 weeks may offer useful biomarkers for early prediction of both response and progressive disease following Dur/Tre.
  • Hisanori Muto, Teiji Kuzuya, Naoto Kawabe, Eizaburo Ohno, Kohei Funasaka, Mitsuo Nagasaka, Yoshihito Nakagawa, Ryoji Miyahara, Tomoyuki Shibata, Senju Hashimoto, Yoshiaki Katano, Yoshiki Hirooka
    Anticancer research 43(10) 4673-4682 2023年10月  査読有り筆頭著者責任著者
    BACKGROUND/AIM: The combination of atezolizumab plus bevacizumab (Atz/Bev) has become widely used as a first-line therapy for advanced hepatocellular carcinoma (HCC). However, for post-Atz/Bev therapy, evidence on the outcomes of molecular targeted agents, such as lenvatinib, is limited. The present study aimed to assess the clinical effectiveness of lenvatinib on advanced HCC in patients who had previously undergone Atz/Bev treatment. PATIENTS AND METHODS: Twenty patients with HCC, who received lenvatinib after Atz/Bev treatment, were enrolled in the study. In particular, we examined the impact of adverse events (AEs), such as anorexia and general fatigue. During the treatment, lenvatinib dosages were adjusted or temporarily discontinued in response to AEs. Treatment outcomes were retrospectively evaluated. RESULTS: The objective response rate (ORR) and disease control rate (DCR) for lenvatinib treatment were 25.0% and 95.0%, respectively, according to the Response Evaluation Criteria in Solid Tumors. The median progression-free survival (PFS) was 6.0 months, and the median overall survival (OS) was 10.5 months. Eleven patients experienced anorexia or fatigue, leading to a reduction in the dose of lenvatinib but not to a significant difference in the time to drug discontinuation. Importantly, there were no significant differences between the 11 anorexia/fatigue-suffering patients and the nine other patients with regard to PFS and OS. CONCLUSION: Lenvatinib can be efficacious and safe for treating advanced HCC patients previously treated with Atz/Bev, and AEs such as anorexia and general fatigue can be effectively managed without losing lenvatinib's therapeutic benefits.
  • Teiji Kuzuya, Naoto Kawabe, Mizuki Ariga, Eizaburo Ohno, Kohei Funasaka, Mitsuo Nagasaka, Yoshihito Nakagawa, Ryoji Miyahara, Tomoyuki Shibata, Takeshi Takahara, Yutaro Kato, Yoshiki Hirooka
    Cancers 15(11) 2023年5月  査読有り筆頭著者責任著者
    (1) Background: This study aimed to investigate clinical outcomes for cabozantinib in clinical practice in patients with advanced hepatocellular carcinoma (HCC) previously treated with atezolizumab plus bevacizumab (Atz/Bev), with a focus on whether patients met criteria of Child-Pugh Class A and Eastern Cooperative Oncology Group performance status (ECOG-PS) score 0/1 at baseline. (2) Methods: Eleven patients (57.9%) met the criteria of both Child-Pugh class A and ECOG-PS score 0/1 (CP-A+PS-0/1 group) and eight patients (42.1%) did not (Non-CP-A+PS-0/1 group); efficacy and safety were retrospectively evaluated. (3) Results: Disease control rate was significantly higher in the CP-A+PS-0/1 group (81.1%) than in the non-CP-A+PS-0/1 group (12.5%). Median progression-free survival, overall survival and duration of cabozantinib treatment were significantly longer in the CP-A+PS-0/1 group (3.9 months, 13.4 months, and 8.3 months, respectively) than in the Non-CP-A+PS-0/1 group (1.2 months, 1.7 months, and 0.8 months, respectively). Median daily dose of cabozantinib was significantly higher in the CP-A+PS-0/1 group (22.9 mg/day) than in the non-CP-A+PS-0/1 group (16.9 mg/day). (4) Conclusions: Cabozantinib in patients previously treated with Atz/Bev has potential therapeutic efficacy and safety if patients have good liver function (Child-Pugh A) and are in good general condition (ECOG-PS 0/1).
  • Naoki Dosoden, Teiji Kuzuya, Yumi Ito, Jo Nishino, Eizaburo Ohno, Naoto Kawabe, Senju Hashimoto, Yoshiki Hirooka, Hidekata Yasuoka
    Clinical journal of gastroenterology 16(4) 567-571 2023年4月18日  査読有り責任著者
    The combination therapy of atezolizumab, an anti-programmed cell death ligand-1 antibody, plus bevacizumab (Atz/Bev) is widely used to treat patients with advanced hepatocellular carcinoma (HCC). The development of polymyalgia rheumatica (PMR) during immune checkpoint inhibitor therapy for patients with HCC has not been reported to date. Two patients who developed PMR during Atz/Bev therapy for advanced HCC are reported. Both patients developed fever, bilateral symmetrical shoulder pain, morning stiffness, and an elevated C-reactive protein level. Their symptoms improved rapidly with prednisolone (PSL) 15-20 mg/d, and their C-reactive protein levels decreased. In PMR, long-term low-dose PSL should be administered. In the present patients who developed PMR as immune-related adverse events, starting with a small dose of PSL resulted in rapid improvement of symptoms.
  • Teiji Kuzuya, Naoto Kawabe, Senju Hashimoto, Kohei Funasaka, Mitsuo Nagasaka, Yoshihito Nakagawa, Ryoji Miyahara, Tomoyuki Shibata, Takeshi Takahara, Yutaro Kato, Atsushi Sugioka, Yoshiki Hirooka
    Anticancer research 42(4) 1905-1910 2022年4月  査読有り筆頭著者責任著者
    AIM: The present study evaluated the efficacy and safety of ramucirumab (RAM) in clinical practice as post-treatment, following atezolizumab plus bevacizumab (Atz/Bev) for advanced hepatocellular carcinoma (HCC) with alpha-fetoprotein (AFP) levels of ≥400 ng/ml. PATIENTS AND METHODS: Of the 77 patients treated with Atz/Bev at our institution, 13 patients for whom RAM was introduced as post-treatment following Atz/Bev were enrolled in this retrospective study. There were 9 patients (69.2%) with Child-Pugh A and 11 patients (84.6%) for whom RAM was initiated as 3rd- or later-line therapy. The median AFP level was 2259 ng/ml. RESULTS: The objective response rate by Response Evaluation Criteria in Solid Tumours at 6 weeks was 15.4%, and the disease control rate was 69.2%. The median time to progression was 3.0 months; AFP level decreased at 2 weeks in 11 patients (84.6%) and at 6 weeks in seven patients (53.8%). The most common adverse events (AEs) within 6 weeks were ascites, peripheral oedema, and proteinuria, while grade 3 AEs occurred in six patients (46.2%). Albumin-bilirubin scores at both 4 and 6 weeks were significantly worse than those at baseline. CONCLUSION: In HCC patients with AFP levels of ≥400 ng/mL, RAM after Atz/Bev is expected to be an effective treatment option. Careful attention should be paid to the development of AEs and deterioration of liver function, especially when RAM is used as 3rd- or later-line therapy. Additional studies are needed to confirm the efficacy and safety of RAM as 2nd-line treatment after Atz/Bev in Child-Pugh A patients.
  • Teiji Kuzuya, Naoto Kawabe, Senju Hashimoto, Ryoji Miyahara, Akira Sawaki, Takuji Nakano, Kazunori Nakaoka, Hiroyuki Tanaka, Yohei Miyachi, Arisa Mii, Sayaka Kamejima, Takeshi Takahara, Yutaro Kato, Atsushi Sugioka, Yoshiki Hirooka
    Oncology 100(1) 1-10 2021年11月3日  査読有り筆頭著者責任著者
    INTRODUCTION: The aim of this study was to investigate the early changes in alpha-fetoprotein (AFP) and des-γ-carboxy prothrombin (DCP) levels in patients with advanced hepatocellular carcinoma (HCC) treated with atezolizumab plus bevacizumab and to evaluate the relationship between changes in these tumor markers and treatment efficacy. METHODS: Of 58 consecutive patients who started atezolizumab plus bevacizumab at our institution, 50 patients with information on antitumor response obtained at 6 weeks after therapy were enrolled in this study and their treatment outcomes were retrospectively evaluated. RESULTS: According to the Response Evaluation Criteria in Solid Tumors at 6 weeks, the objective response (OR) rate was 22.0% and the disease control (DC) rate was 78.0%. In patients who achieved OR at 6 weeks, median AFP and DCP ratios at weeks 1, 2, 3, and 6 were significantly lower than those in patients who did not achieve OR. AFP ratios in patients who did not achieve DC at 6 weeks (Non-6W-DC group) were significantly higher than in those who achieved DC at week 6 (6W-DC group). Median overall survival in the Non-6W-DC group was significantly shorter than in the 6W-DC group (156 days vs. not reached, p = 0.0008). An AFP ratio of 1.4 or higher at 3 weeks had a specificity of 88.0% and a sensitivity of 88.9% for predicting Non-6W-DC. Median progression-free survival was significantly shorter in patients with an AFP ratio of 1.4 or higher at 3 weeks than in those with an AFP ratio of <1.4 (42 days vs. 210 days, p = 0.0003). CONCLUSION: Early changes in AFP might be useful for predicting the antitumor efficacy of atezolizumab plus bevacizumab in patients with advanced HCC. An AFP ratio of 1.4 or higher at 3 weeks might be an early predictor of refractoriness to atezolizumab plus bevacizumab therapy.
  • Hisanori Muto, Teiji Kuzuya, Takanori Ito, Yoji Ishizu, Takashi Honda, Tetsuya Ishikawa, Masatoshi Ishigami, Mitsuhiro Fujishiro
    Medicine 100(31) e26820 2021年8月6日  査読有り責任著者
    ABSTRACT: Real-world clinical cases of molecularly targeted agent (MTA) administration to patients with advanced hepatocellular carcinoma (HCC) with ≥50% liver occupation have been reported, but treatment outcomes have rarely been described. We have encountered several cases in which albumin-bilirubin (ALBI) scores deteriorated markedly and C-reactive protein (CRP) levels elevated in the early post-dose period. The present study therefore investigated early clinical changes in ALBI score and CRP levels after initiating MTA in advanced HCC patients with ≥50% liver occupation, focusing on antitumor response at 6 weeks.This retrospective study included 46 HCC patients with liver occupation ≥50% and 191 patients with <50%, Child-Pugh score ≤7, and Eastern Cooperative Oncology Group Performance Status scores of 0 or 1, who were treated with sorafenib or lenvatinib as first-line systemic therapy at our hospital between June 2011 and January 2020. We analyzed their medical records up to March 2020 and investigated the outcomes and changes in CRP and ALBI scores classified according to antitumor response at 6 weeks.Overall survival was significantly longer in patients with partial response (PR) + stable disease (SD) (13.7 months) than in patients with progressive disease (PD) (1.7 months, P < .001) in the ≥50% group. Patients with antitumor response of PR + SD at 6 weeks in the ≥50% group showed more marked deterioration of ALBI score at 2 weeks than those in the <50% group. These significant differences between groups had again disappeared at 4 and 6 weeks. Focusing on patients with PD at 6 weeks, ALBI score deteriorated over time in both groups. Regarding CRP, on 6-week PR + SD patients, a significant increase in CRP levels at 1 and 2 weeks was evident in the >50% group compared to the <50% group. These significant differences between groups had again disappeared at 4 and 6 weeks. In PD patients, no difference between groups in CRP elevation occurred at 1 and 2 weeks.In MTA treatment for patients with ≥50% liver occupation, to obtain an antitumor response of PR + SD, adequate management might be important considering transient deteriorated ALBI scores and elevated CRP levels.
  • Teiji Kuzuya, Naoto Kawabe, Senju Hashimoto, Ryoji Miyahara, Takuji Nakano, Kazunori Nakaoka, Hiroyuki Tanaka, Yohei Miyachi, Arisa Mii, Yoshinao TanahashiI, Yutaro Kato, Atsushi Sugioka, Yoshiki Hirooka
    CANCER DIAGNOSIS & PROGNOSIS 1(1) 19-22 2021年4月  査読有り筆頭著者責任著者
    Background/Aim: The aim of this study was to investigate the outcomes of atezolizumab plus bevacizumab in patients with advanced hepatocellular carcinoma (HCC), including those with disease refractory to lenvatinib, in clinical practice. Patients and Methods: Of 34 patients treated with atezolizumab plus bevacizumab, a total of 23, including 16 with lenvatinib failure, were enrolled in this retrospective study. The adverse events, changes in liver function and antitumor responses at 6 weeks after starting therapy were evaluated. Results: The incidence of grade 3 adverse events was low, at 13.0%. Albumin–bilirubin scores did not worsen at 3 and 6 weeks compared to baseline. The objective response rate and disease control rate at 6 weeks were 17.4% and 78.3% according to Response Evaluation Criteria in Solid Tumors (RECIST), and 30.4% and 78.3% according to modified RECIST, respectively. Conclusion: Our results suggest that atezolizumab plus bevacizumab might have potential therapeutic safety and efficacy in patients with advanced HCC, including those with disease refractory to lenvatinib. Further studies are needed to confirm the outcomes of atezolizumab plus bevacizumab after lenvatinib failure.
  • Hisanori Muto, Teiji Kuzuya, Takanori Ito, Yoji Ishizu, Takashi Honda, Tetsuya Ishikawa, Masatoshi Ishigami, Mitsuhiro Fujishiro
    Clinical journal of gastroenterology 13(3) 397-402 2020年6月  査読有り責任著者
    Few reports have described dose re-escalation after long-term low-dose sorafenib leading to good outcomes. Here, we report the case of an 80-year-old woman with advanced hepatocellular carcinoma who achieved complete response from sorafenib dose re-escalation after the failure of long-term low-dose sorafenib treatment combined with transcatheter arterial chemoembolization. Sorafenib therapy was initiated at 400 mg once daily due to old age and low platelet count. 5 months later, this dose was reduced to 200 mg once daily because of adverse events. Best radiological antitumor response by sorafenib treatment alone was judged as stable disease according to the modified Response Evaluation Criteria in Solid Tumors. 1 year later, she showed progressive disease owing to the progression of intrahepatic lesions. She received combination therapy with low-dose sorafenib (200 mg every other day) and transcatheter arterial chemoembolization, which proved relatively effective for three and a half years. Antitumor response by the fourth transcatheter arterial chemoembolization and subsequent low-dose sorafenib was clearly progressive disease. At that time, sorafenib-related adverse events were well-controlled. Sorafenib dose was re-escalated to 200 mg once daily. After this re-escalation, tumor markers declined rapidly, and adverse events remained tolerable. 4 months later, complete response was achieved.
  • Teiji Kuzuya, Masatoshi Ishigami, Takanori Ito, Yoji Ishizu, Takashi Honda, Tetsuya Ishikawa, Mitsuhiro Fujishiro
    Anticancer research 40(4) 2089-2093 2020年4月  査読有り筆頭著者責任著者
    BACKGROUND/AIM: The outcomes of ramucirumab after lenvatinib failure for hepatocellular carcinoma (HCC) patients with alpha fetoprotein (AFP) levels of ≥400 ng/ml are unknown. PATIENTS AND METHODS: Of 12 patients treated with ramucirumab after lenvatinib failure, 10 patients were enrolled in this retrospective study. RESULTS: The disease control rate of 80% at 6 weeks and the median time to progression of 3.1 months were the same by both the Response Evaluation Criteria in Solid Tumors (RECIST) and the modified RECIST. AFP reduction was seen in 5 patients at 2 weeks and in 3 patients at 6 weeks. The incidence of grade 3 adverse events was low at 10%. The albumin-bilirubin scores within 6 weeks did not worsen. CONCLUSION: Ramucirumab might have potential therapeutic efficacy and safety in advanced HCC patients after lenvatinib failure. Further studies are needed to confirm the outcomes of ramucirumab after lenvatinib failure.
  • Teiji Kuzuya, Masatoshi Ishigami, Takanori Ito, Yoji Ishizu, Takashi Honda, Tetsuya Ishikawa, Mitsuhiro Fujishiro
    Anticancer research 40(4) 2283-2290 2020年4月  査読有り筆頭著者責任著者
    BACKGROUND/AIM: We aimed to compare the outcomes between sorafenib and lenvatinib as first-line therapy for advanced hepatocellular carcinoma (HCC) with major portal vein tumor thrombosis (Vp3/4). PATIENTS AND METHODS: This retrospective study enrolled 41 HCC patients with Vp3/4 and Child-Pugh A. RESULTS: The outcomes in the lenvatinib group (n=13) were significantly better than those in the sorafenib group (n=28) [best objective response rate according to the modified Response Evaluation Criteria in Solid Tumors: 53.8% vs. 14.3%; p=0.0193, best disease control rate: 92.3% vs. 35.7%; p=0.0008, median overall survival (OS): not reached vs. 187 days; p=0.0040, respectively]. Lenvatinib treatment was the only significant predictor of better OS and time to tumor progression. No patient needed to discontinue lenvatinib treatment due to drug-related adverse events. CONCLUSION: Compared with sorafenib, lenvatinib treatment for advanced HCC with Vp3/4 may lead to more favorable outcomes.
  • Teiji Kuzuya, Masatoshi Ishigami, Takanori Ito, Yoji Ishizu, Takashi Honda, Tetsuya Ishikawa, Mitsuhiro Fujishiro
    Hepatology research : the official journal of the Japan Society of Hepatology 50(3) 374-381 2020年3月  査読有り筆頭著者
    AIM: We aimed to investigate the radiological antitumor response at 2 weeks after starting lenvatinib for patients with advanced hepatocellular carcinoma in real-world practice. METHODS: This retrospective study enrolled 40 patients who received lenvatinib. Radiological antitumor response was evaluated according to the modified Response Evaluation Criteria in Solid Tumors. RESULTS: The objective response rate at 2 weeks and best overall response on confirmation of complete response, partial response (PR), and stable disease required (confirmed response) were 57.5% and 32.5%, respectively. Based on confirmed response, the overall survival rate was significantly longer in patients with an objective response rate than in those with stable disease or progressive disease after 12 months (73.2% and 54.2%, P = 0.0358). All 13 patients with an objective response rate on confirmed response were evaluated as PR at 2 weeks. The alpha-fetoprotein ratio at 2 weeks was a significant factor associated with PR of response rate at 2 weeks. The median relative dose intensity from 2 to 6 weeks was significantly lower than that from 0 to 2 weeks (69.6% vs. 100%, P < 0.0001). Stratified by the antitumor response at 6 weeks considering the image evaluation at 2 weeks, the median relative dose intensity from 2 to 6 weeks was significantly lower in patients with progressive disease than in those with PR or stable disease (45.2% vs. 72.6%, P = 0.0482). CONCLUSIONS: The radiological antitumor response at 2 weeks was favorable. Information on a favorable visible therapeutic response very early after lenvatinib initiation can help patients maintain their motivation for treatment, and allow physicians to continue treatment effectively and safely.
  • Kenta Yamamoto, Teiji Kuzuya, Takashi Honda, Takanori Ito, Yoji Ishizu, Masanao Nakamura, Ryoji Miyahara, Hiroki Kawashima, Masatoshi Ishigami, Mitsuhiro Fujishiro
    Anticancer research 40(2) 665-676 2020年2月  査読有り
    BACKGROUND/AIM: Sorafenib results in several adverse events, the mechanism and predictors of which are unknown. Recently, it was reported that metabolism by microbiome changes the structure and effects of drugs. The blood levels of sorafenib may be affected by enterohepatic recycling of sorafenib due to microbial enzymes in the gut. We evaluated the relationship between adverse events caused by sorafenib treatment and microbiome in patients with advanced hepatocellular carcinoma. MATERIALS AND METHODS: Twenty-five patients were classified into two groups based on the presence of hand-foot syndrome (HFS) or diarrhea within 12 weeks post-sorafenib treatment. Before sorafenib treatment, the fecal samples were analyzed targeting the V3-V4 region of 16s ribosomal RNA. Microbiome and predicted functional gene were compared between two groups. RESULTS: The non-HFS group had a richer abundance of Veillonella, Bacillus, Enterobacter, Faecalibacterium, Lachnospira, Dialister, and Anaerostipes than the HFS group at genus level. Carotenoid biosynthesis and bacterial invasion of epithelial cells were enriched in the HFS group. The former three bacteria are classified as oral-origin bacteria, and the two predicted functions are associated with dysbiosis. The non-diarrhea group had a higher abundance of Butyricimonas and a lower abundance of Citrobacter, Peptostreptococcus, and Staphylococcaceae than the diarrhea group. Eight categories of predicted functional genes were detected with differences between the two groups. CONCLUSION: The non-HFS group had a higher relative abundance of oral-origin bacteria, which likely led to more robust dysbiosis in the gut. This dysbiosis may affect enterohepatic recycling. Additionally, the metabolism of these short-chain fatty acids in the gut may be different between the diarrhea and non-diarrhea groups.
  • Taku Tanaka, Teiji Kuzuya, Masatoshi Ishigami, Takanori Ito, Yoji Ishizu, Takashi Honda, Tetsuya Ishikawa, Mitsuhiro Fujishiro
    Oncology 98(9) 621-629 2020年  査読有り責任著者
    INTRODUCTION: Because the frequency of bile duct invasion in hepatocellular carcinoma (HCC) patients is very rare, there is limited clinical evidence to demonstrate the outcomes of systemic therapy in HCC with bile duct invasion. OBJECTIVE: Our aim was to clarify the efficacy and safety of sorafenib treatment in patients with unresectable advanced HCC with bile duct invasion. METHODS: One hundred and seventy-five patients with advanced HCC were enrolled in this study. We retrospectively compared the outcomes of sorafenib between patients without bile duct invasion [B (-) group, n = 165] and those with bile duct invasion [B (+) group, n = 10]. RESULTS: There were no significant differences in the confirmed objective response rate (ORR) and the confirmed disease control (DC) rate between the B (-) and the B (+) groups (13.9 vs. 20.0%, p = 0.637 for ORR; 47.2 vs. 70.0%, p = 0.202 for DC rate, respectively). There were no significant differences in median overall survival (OS) and time to progression (TTP) between the B (-) group and the B (+) group (14.8 vs. 14.1 months, p = 0.780 for OS; 3.4 vs. 5.7 months, p = 0.277 for TTP, respectively). Post-treatment factors associated with good OS were changes in albumin-bilirubin score (0-6 weeks) of <0.25, and antitumor response at 6 weeks of DC. Though 5 of 10 patients (50%) in the B (+) group had bile duct complications, such as obstructive jaundice and biliary bleeding, these 5 patients were able to recover from biliary troubles by careful and vigorous management with biliary endoscopic intervention, and were able to continue sorafenib therapy safely. CONCLUSIONS: Our present results suggest that sorafenib might have potential therapeutic efficacy and safety in advanced HCC patients with bile duct invasion. In case of biliary tract troubles before and during sorafenib treatment, early biliary management may be important to continue sorafenib therapy safely. Further studies are needed to confirm the outcomes of sorafenib in advanced HCC patients with bile duct invasion.
  • Naoki Yoshioka, Teiji Kuzuya, Takanori Ito, Yoji Ishizu, Takashi Honda, Tetsuya Ishikawa, Masatoshi Ishigami, Mitsuhiro Fujishiro
    Internal medicine (Tokyo, Japan) 58(19) 2803-2808 2019年10月1日  査読有り責任著者
    Sorafenib and regorafenib are tyrosine kinase inhibitors that are used in the treatment of hepatocellular carcinoma and which have similar chemical structures and toxicity profiles. We herein report a case in which regorafenib treatment could be continued for 10 months and stable disease could be maintained for a long period despite the discontinuation of sorafenib due to grade 4 liver injury and grade 3 fever. The severe adverse events could be attributed to drug hypersensitivity, since a drug-induced lymphocyte stimulation test (DLST) indicated sensitivity to sorafenib. A DLST for regorafenib was negative. This is the first report showing that regorafenib could be safely administered after the discontinuation of sorafenib due to hypersensitivity.
  • Teiji Kuzuya, Masatoshi Ishigami, Takanori Ito, Yoji Ishizu, Takashi Honda, Tetsuya Ishikawa, Yoshiki Hirooka, Mitsuhiro Fujishiro
    Hepatology research : the official journal of the Japan Society of Hepatology 49(9) 1054-1065 2019年9月  査読有り筆頭著者責任著者
    AIM: This study aimed to investigate the clinical characteristics and outcomes of candidates for second-line therapy, including regorafenib and ramucirumab, for advanced hepatocellular carcinoma (HCC) after sorafenib treatment. METHODS: Of 122 patients, 103 were radiologically confirmed as progressive disease (PD) (sorafenib-refractory group), and 19 discontinued sorafenib therapy due to adverse events prior to radiologic PD (sorafenib-intolerant group). Patients in the sorafenib-refractory group were divided into two subgroups each, according to their eligibility for second-line treatment (second-line-in and -out group), regorafenib (RESORCE-in and -out group), or ramucirumab (REACH-2-in and -out group). RESULTS: Patients included in the non-candidate group were those with α-fetoprotein level <400 ng/mL (n = 51, 49.5%), daily sorafenib dose <400 mg (n = 44, 42.7%), Child-Pugh B or C (n = 40, 38.8%), and Eastern Cooperative Oncology Group performance status score ≥2 (n = 24, 23.3%). The percentages of candidates were 57.3% for second-line, 35.0% for regorafenib, and 23.3% for ramucirumab. The median post-progression survival (PPS) was significantly longer for the second-line-in and the RESORCE-in groups than in the non-candidate groups (12.6 and 11.0 months vs. 3.0 and 6.1 months, respectively). The PPS was not significantly different between the REACH-2-in and -out groups. A significant predictor of candidates for second-line treatment at sorafenib initiation was a Child-Pugh score of 5 (A5). CONCLUSIONS: Not all patients refractory to sorafenib were candidates for second-line therapy. A Child-Pugh score of A5 at sorafenib initiation was an important and favorable factor related to eligibility for second-line therapy and good outcomes.
  • Teiji Kuzuya, Masatoshi Ishigami, Yoji Ishizu, Takashi Honda, Kazuhiko Hayashi, Tetsuya Ishikawa, Yoshiki Hirooka, Hidemi Goto
    Hepatology research : the official journal of the Japan Society of Hepatology 49(3) 360-364 2019年3月  査読有り筆頭著者
    There have been reports that a vitamin K2 (VK2) analog is beneficial for the prevention of recurrence in hepatocellular carcinoma (HCC) patients after curative therapy. However, the VK2 analogs in current use do not appear to show dramatic antitumor effects when given alone. Here, we report the case of a 67-year-old male patient with sorafenib-failure advanced HCC who achieved complete response (CR) after VK2 analog monotherapy. At the time of sorafenib failure confirmation, the patient had multiple intrahepatic tumors, multiple lung metastases, and Vp3 portal vein tumor thrombosis. He had poor liver function (Child-Pugh score of 9, Child-Pugh class B) and poor performance status (Eastern Cooperative Oncology Group performance status 2). Both serum α-fetoprotein (AFP) and des-γ-carboxy prothrombin (DCP) levels were elevated (558 900 ng/mL and 917 300 mAU/mL, respectively). Treatment with VK2 analog was initiated at 45 mg/day. Five months later, both tumor markers had decreased to normal levels (AFP 8 ng/mL and DCP 10 mAU/mL). Contrast-enhanced computed tomography showed that all intrahepatic tumors had shrunk, there was no enhancement of tumor staining in the arterial phase, and all lung metastases and portal vein tumor thromboses had disappeared. We considered that CR was achieved according to the modified Response Evaluation Criteria in Solid Tumors. Eighteen months after the start of VK2 analog administration, the patient continues to receive treatment and has remained in CR without adverse events. Here, we report a rare case of sorafenib-failure advanced HCC in which sustained CR was achieved by VK2 analog monotherapy.
  • Teiji Kuzuya, Masatoshi Ishigami, Yoji Ishizu, Takashi Honda, Kazuhiko Hayashi, Tetsuya Ishikawa, Isao Nakano, Yoshiki Hirooka, Hidemi Goto
    Oncology 95(2) 91-99 2018年  査読有り筆頭著者
    OBJECTIVES: The aim of this study was to investigate the prognostic factors associated with postprogression survival (PPS) in advanced hepatocellular carcinoma (HCC) patients treated with sorafenib, who were not eligible for second-line treatment with regorafenib. METHODS: A total of 103 patients with radiological confirmation of progressive disease (PD) were enrolled. RESULTS: The median PPS (n = 67) was 6.1 months. Significant and independent prognostic factors at initial radiological PD associated with good PPS were an Eastern Cooperative Oncology Group Performance Status (ECOG-PS) score of 0, the absence of macrovascular invasion (MVI), and time to progression (TTP) ≥4 months. Upon scoring these three variables as good PPS factors, the median PPS in the good PPS score of 3 or 2 group (n = 38) was significantly longer than that in the good PPS score of 1 or 0 group (n = 29) (16.6 vs. 2.9 months; p < 0.0001, respectively). CONCLUSIONS: An ECOG-PS score of 0, the absence of MVI, and TTP ≥4 months at first radiological confirmation of PD may be useful for predicting good PPS in patients with advanced HCC who do not meet the eligibility criteria for the RESORCE trial.
  • Teiji Kuzuya, Masatoshi Ishigami, Yoji Ishizu, Takashi Honda, Kazuhiko Hayashi, Tetsuya Ishikawa, Isao Nakano, Hidemi Goto, Yoshiki Hirooka
    Oncology 91(5) 261-266 2016年  査読有り筆頭著者
    OBJECTIVES: The aim of this study was to investigate the relationship between fever within 2 weeks after the start of sorafenib therapy and treatment efficacy in patients with advanced hepatocellular carcinoma (HCC). METHODS: One hundred and two patients with advanced HCC were enrolled in this study. We retrospectively compared patients with fever (more than 38°C) within 2 weeks after the start of sorafenib therapy (fever group, n = 34) and patients without fever (non-fever group, n = 68) in terms of survival, best antitumor response, and change in intratumor blood on contrast-enhanced computed tomography (CE-CT) after 2 weeks of sorafenib therapy. RESULTS: Fever was the only significant and independent predictor of better outcomes (hazard ratio, 0.517; 95% confidence interval, 0.319-0.838; p = 0.0071). In the fever group, the partial response rate, the disease control rate, and the rate of disappearance of arterial tumor enhancement on CE-CT after 2 weeks of sorafenib therapy were significantly higher than those in the non-fever group (38.2 vs. 5.9%, respectively, p = 0.0001; 85.3 vs. 60.3%, respectively, p = 0.0103; 76.5 vs. 35.3%, respectively, p < 0.0001). CONCLUSIONS: Fever within 2 weeks after the start of sorafenib therapy may be a useful predictor of a favorable treatment response in patients with advanced HCC.
  • Teiji Kuzuya, Masatoshi Ishigami, Yoji Ishizu, Takashi Honda, Kazuhiko Hayashi, Yoshiaki Katano, Yoshiki Hirooka, Tetsuya Ishikawa, Isao Nakano, Hidemi Goto
    PloS one 10(9) e0138776 2015年  査読有り筆頭著者
    BACKGROUND & AIMS: We evaluated the relationship between the early clinical response after 2 weeks of sorafenib therapy and the outcomes and anti-tumor response in patients with advanced hepatocellular carcinoma. METHODS: Fifty-seven patients who had intrahepatic hypervascular hepatocellular carcinoma and Child-Pugh (CP) class A disease at baseline were enrolled in this prospective, multicenter, observational, non-interventional study. As an early clinical response after 2 weeks of sorafenib therapy, changes in intra-tumor blood flow on contrast-enhanced computed tomography (CE-CT), alpha-fetoprotein (AFP) levels, and remnant liver function were investigated. RESULTS: After 2 weeks of sorafenib therapy, there were 26 patients (45.6%) without disappearance of arterial tumor enhancement on CE-CT, 15 patients (26.3%) with an AFP ratio of >1.2, and seven patients (12.3%) with two or more increments in the CP score. Multivariate analysis showed that the absence of disappearance of arterial tumor enhancement on CE-CT, AFP ratio of >1.2, and two or more increments in the CP score after 2 weeks of sorafenib therapy were significant and independent predictors of worse survival. Upon scoring these three variables as "poor prognostic factors", patients with poor prognostic score 4, 3 or 2 (n = 17) had significantly worse outcomes and a significantly higher progressive disease (PD) rate based on modified Response Evaluation Criteria in Solid Tumors at 6 weeks after sorafenib therapy than those with poor prognostic score 1 or 0 (n = 40) (median overall survival: 194 days vs. 378 days; p = 0.0010, PD rate: 70.6% vs. 20.0%; p = 0.0003, respectively). CONCLUSIONS: Changes in intra-tumor blood flow on CE-CT, AFP levels, and remnant liver function after 2 weeks of sorafenib therapy may be useful for predicting the outcomes and anti-tumor response to sorafenib in patients with advanced hepatocellular carcinoma.
  • Teiji Kuzuya, Yasuhiro Asahina, Kaoru Tsuchiya, Keisuke Tanaka, Yuichiro Suzuki, Takahide Hoshioka, Shinji Tamaki, Tomoji Kato, Yutaka Yasui, Takahiro Hosokawa, Ken Ueda, Hiroyuki Nakanishi, Jun Itakura, Yuka Takahashi, Masayuki Kurosaki, Namiki Izumi
    Oncology 81(3-4) 251-8 2011年  査読有り筆頭著者
    OBJECTIVES: The aim of this study was to investigate the relationships between early changes in the tumor markers α-fetoprotein (AFP) and des-γ-carboxy prothrombin (DCP), and antitumor response in the early period following administration of sorafenib in patients with advanced hepatocellular carcinoma (HCC). METHODS: Forty-eight advanced HCC patients were evaluated. AFP and DCP were measured at baseline, and after 2 and 4 weeks, and the antitumor responses were evaluated according to the RECIST criteria 4 weeks after starting sorafenib therapy. The ratios of each tumor marker were compared by stratifying the patients into the partial response (PR) + stable disease (SD) group or the progressive disease (PD) group. RESULTS: Both 2 and 4 weeks after starting sorafenib therapy, the AFP ratio in the PR + SD group (n = 32) was significantly lower than in the PD group (n = 16; p = 0.002, p = 0.002). DCP was elevated in both the PR + SD group and the PD group 2 weeks and 4 weeks after starting sorafenib therapy. CONCLUSIONS: Evaluation of AFP ratios 2 and 4 weeks after starting sorafenib therapy may be useful for predicting antitumor response. On the other hand, early elevation of DCP does not necessarily suggest treatment failure by sorafenib, as DCP elevation can occur despite therapeutic efficacy.
  • Teiji Kuzuya, Yoshiaki Katano, Isao Nakano, Yoshiki Hirooka, Akihiro Itoh, Masatoshi Ishigami, Kazuhiko Hayashi, Takashi Honda, Hidemi Goto, Yuko Fujita, Rie Shikano, Yuji Muramatsu, Gustavo Bajotto, Tomohiro Tamura, Noriko Tamura, Yoshiharu Shimomura
    Biochemical and biophysical research communications 373(1) 94-8 2008年8月15日  査読有り筆頭著者
    The branched-chain alpha-keto acid dehydrogenase (BCKDH) complex is the most important regulatory enzyme in branched-chain amino acid (BCAA) catabolism. We examined the regulation of hepatic BCKDH complex activity in spontaneous type 2 diabetes Otsuka Long-Evans Tokushima Fatty (OLETF) rats and Zucker diabetic fatty rats. Hepatic BCKDH complex activity in these rats was significantly lower than in corresponding control rats. The amount of BCKDH complex in OLETF rats corresponded to the total activity of the complex. Activity and abundance of the bound form of BCKDH kinase, which is responsible for inactivation of the complex, showed an inverse correlation to BCKDH complex activity in OLETF rats. Dietary supplementation of 5% BCAAs for 10 weeks markedly increased BCKDH complex activity, and decreased the activity and bound form of BCKDH kinase in the rats. These results suggest that BCAA catabolism in type 2 diabetes is downregulated and enhanced by BCAA supplementation.
  • Teiji Kuzuya, Yoshiaki Katano, Takashi Kumada, Hidenori Toyoda, Isao Nakano, Yoshiki Hirooka, Akihiro Itoh, Masatoshi Ishigami, Kazuhiko Hayashi, Takashi Honda, Hidemi Goto
    Journal of gastroenterology and hepatology 22(11) 1929-35 2007年11月  査読有り筆頭著者
    AIM: The aim of this study was to determine whether antiviral therapy with lamivudine is beneficial in patients after initial treatment for hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). METHODS: Forty-nine consecutive patients with HBV-related HCC completely treated by hepatic resection or radiofrequency ablation were retrospectively enrolled in this study. Comparison was made between 16 patients who received lamivudine therapy at a dose of 100 mg/day after treatment for HCC (lamivudine group) and 33 patients who did not (control group) in terms of changes in remnant liver function, HCC recurrence and survival. RESULTS: Cumulative recurrence rates of HCC did not significantly differ between the two groups (P = 0.622). However, median Child-Pugh score at the time of HCC recurrence was significantly different; 5 (range 5-6) in the lamivudine group versus 7 (range 5-12) in the control group (P = 0.005). All patients in the lamivudine group were able to receive curative treatment for recurrent HCC. In contrast, 10 of 15 patients in the control group were unable to receive curative optimal therapy for recurrent HCC due to deterioration of remnant liver function. The cumulative survival rates of patients in the lamivudine group tended to be higher than those of patients in the control group (P = 0.063). CONCLUSION: It is suggested that lamivudine therapy is beneficial for patients after initial treatment for HBV-related HCC because it contributes to improving remnant liver function, thus decreasing the risk of liver failure and increasing the chances of receiving available treatment modalities for recurrent HCC.
  • Teiji Kuzuya, Takashi Kumada, Seiki Kiriyama, Yasuhiro Sone, Makoto Tanikawa, Yasuhiro Hisanaga, Hidenori Toyoda, Kazuhiko Hayashi, Koji Nonogaki, Junichi Shimizu, Naoto Kawase, Takahiro Yamauchi, Toshiaki Kawachi, Hideo Ichikawa
    Journal of ultrasound in medicine : official journal of the American Institute of Ultrasound in Medicine 25(8) 1099-103 2006年8月  査読有り筆頭著者

主要なMISC

 709
  • 中本 安成, 山下 竜也, 葛谷 貞二, 平岡 淳, 小笠原 定久
    肝臓 64(5) 217-234 2023年5月  
  • 葛谷貞二, 廣岡芳樹
    Medical Practice 40(9) 1405-1407 2023年  筆頭著者
  • 葛谷 貞二, 川部 直人, 廣岡 芳樹
    肝胆膵 85(3) 383-391 2022年9月  筆頭著者
  • 葛谷 貞二, 川部 直人, 廣岡 芳樹
    臨床消化器内科 37(8) 940-946 2022年7月  筆頭著者
    <文献概要>2021年,「NASH関連肝細胞癌(HCC)に対する免疫チェックポイント阻害薬(ICI)の効果は限定的である」といった衝撃的な趣旨の英語論文がNatureに発表された.実臨床で使用可能なアテゾリズマブ+ベバシズマブは,ICIと抗VEGF阻害薬との併用療法である.ICIに抗VEGF阻害薬を加えることで,NASH-HCC患者に対しても,抗腫瘍効果が高められる可能性がある.現時点では,組織学的に診断されたNASHにはICIが効きにくい可能性があることを念頭においたうえで,アテゾリズマブ+ベバシズマブを第一選択として投与し,効果が悪ければ次治療へ変更するといった治療方針が適切と考えられる.
  • 葛谷 貞二, 川部 直人, 廣岡 芳樹
    肝胆膵 84(5) 700-701 2022年5月  筆頭著者
  • 葛谷 貞二, 川部 直人, 廣岡 芳樹
    肝臓クリニカルアップデート 7(1) 13-18 2021年10月  筆頭著者
    進行肝細胞癌に対するアテゾリズマブとベバシズマブの実臨床下での初期治療成績に関する報告例についてまとめた。IMbrave150試験と比して、高齢、NBNC、2ndライン以降の症例が多かった。6週後の抗腫瘍効果はRECISTで奏効率が10.6~25.4%、病態制御率が78.3~86.3%であった。臨床的な肝予備能悪化はみられなかった。アテゾリズマブ+ベバシズマブの登場により進行HCCのさらなる予後延長が期待される。(著者抄録)
  • 宮地 洋平, 葛谷 貞二, 廣岡 芳樹
    臨床消化器内科 36(12) 1586-1591 2021年10月  責任著者
    症例は80歳代男性。肝障害、食思不振、下痢、体重減少を主訴に、精査加療目的で入院となった。腹部超音波検査にて、グリソン鞘の肥厚、胆嚢の軽度虚脱と壁肥厚を認め、1ヵ月間で体重が10kg減少したことや、著明なるいそうを認めたことから、飢餓に関連する肝障害が考えられた。絶食、カロリー制限および1,000ml/dayの維持液にて治療を開始したところ、第4病日には下痢が治まり、電解質異常も認められず、800kcal/dayの食事を開始した。経口摂取では十分なカロリーが摂取できず、肝障害の改善はみられなかった。第7病日から持続点滴にて560kcal/dayのカロリーを投与したところ、肝障害は改善傾向となったが、リンとマグネシウムの低下を認め、リフィーディング症候群が生じた。その後、肺炎を発症し、肝生検を施行できず肺炎治療として抗菌薬投与を開始した。第11病日には、肝障害はさらに改善を認めたが、肺炎が経時的に悪化し、第15病日に死亡した。
  • 三井 有紗, 葛谷 貞二, 廣岡 芳樹
    臨床消化器内科 36(6) 686-691 2021年5月  責任著者
    症例は50歳代男性で、アルコール性肝硬変にて通院中で、今回、腹部緊満感、腹痛、下腿浮腫、発熱を主訴に来院した。アルコール性肝硬変に起因した特発性細菌性腹膜炎と診断したが、腹水検査では腹水中の好中球数が細菌性腹膜炎の診断基準を満たさなかった。入院後に撮像した胸腹部造影CT検査では肝硬変と多量腹水を認めた。また膵尾部には膵石を認め、同部に隣接して被包化された液貯留(仮性膵嚢胞)を認めた。被包化液貯留は、膵尾部以外に胃噴門右側、胃体部背側、右腎内側にもみられた。多量腹水の原因は、細菌性腹膜炎ではなく、膵石による膵管閉塞によって膵液瘻をきたしたことによる膵性腹水と診断し、絶食、点滴、抗菌薬にて加療を開始した。第5病日、症状改善がみられなかったため、膵液ドレナージ目的で内視鏡的逆行性膵管造影を施行した。第8病日、腹水による腹部膨満感が改善しなかったため、経皮的に腹水ドレナージチューブを留置した。以後、2000ml/dayの腹水ドレナージを連日行った。第14病日、胃噴門および膵尾側に隣接した被包化液貯留(仮性膵嚢胞)に対して超音波内視鏡下穿刺ドレナージを経胃的に施行した。ドレナージ後は食事摂取量も増え、第19病日に撮影したCTでは、ドレナージを施行した被包化液貯留はいずれも縮小し、内腔の虚脱が確認された。第30病日、経過良好にて退院となった。
  • 葛谷 貞二, 川部 直人, 廣岡 芳樹
    医学と薬学 78(4) 371-376 2021年3月  筆頭著者
  • 葛谷 貞二, 川部 直人, 廣岡 芳樹
    医学と薬学 78(4) 371-376 2021年3月  筆頭著者
  • 葛谷 貞二, 石上 雅敏, 杉山 由晃, 吉岡 直輝, 水野 和幸, 武藤 久哲, 横山 晋也, 田中 卓, 山本 健太, 伊藤 隆徳, 石津 洋二, 本多 隆, 石川 哲也, 藤城 光弘
    Pharma Medica 39(2) 72-73 2021年2月  筆頭著者
  • 宮地 洋平, 葛谷 貞二, 廣岡 芳樹
    臨床消化器内科 36(2) 223-228 2021年1月  責任著者
    70歳代女性。Stanford A型の大動脈解離に対し人工血管置換術を施行した。術後感染予防のため、セファゾリンナトリウムを投与した。投与終了後、ランソプラゾール、大建中湯、L-カルボシステイン、ビソプロロールフマル酸塩の内服を開始した。開始後、軽度の肺炎が認められ、スルバクタムナトリウム・アンピシリンナトリウム配合を投与した。その後、皮疹を発症したため、薬疹と判断し、ランソプラゾール、大建中湯、L-カルボシステイン、ビソプロロールフマル酸塩の内服を中止し、カルベジロールのみの内服に変更した。さらに、オロパタジン塩酸塩の内服とベタメタゾンジプロピオン酸エステル軟膏での治療を開始した。しかし、皮疹の改善が認められなかったため、プレドニゾロンを追加し、皮疹は軽快した。その後、創部感染を認め、バンコマイシン塩酸塩を投与した。投与後、ALP、γ-GTP、AST、ALT、T-bilの上昇を認め、胆管炎が疑われ、ERCPを施行した。施行後、T-bilのみ持続的な上昇を認め、ウルソデオキシコール酸(UDCA)を開始し、カルベジロール内服を中止したが、T-bilの上昇は継続した。肝生検にて胆管消失症候群と診断され、UDCA内服とステロイド投与が行われたが、改善は認めず肝不全のため死亡した。
  • 葛谷 貞二, 川部 直人, 廣岡 芳樹
    消化器・肝臓内科 8(5) 494-501 2020年11月  筆頭著者
  • 葛谷 貞二, 石上 雅敏, 藤城 光弘
    肝臓クリニカルアップデート 6(1) 63-69 2020年5月  筆頭著者
    進行HCCに対するラムシルマブの有効性および安全性がREACH-2試験にて確認され、2019年6月より日常臨床で使用可能となった。当院におけるレンバチニブPD後のラムシルマブの治療成績(n=10)は、病態制御率(6週後)が80%、無増悪期間が3.1ヵ月であった。AFP低下は2週で5例、6週で3例にみられた。G3以上の有害事象の発生頻度は10%と低く、忍容性は高かった。新規分子標的治療薬ラムシルマブの登場によりHCC患者のさらなる予後延長が期待される。(著者抄録)
  • 葛谷 貞二, 石上 雅敏
    Medicina 56(1) 144-147 2019年1月  筆頭著者
    <文献概要>Point ◎肝細胞がん(HCC)に対する分子標的治療薬としては,ソラフェニブ,レゴラフェニブ,レンバチニブの3種類が実臨床で投与可能である.◎進行がんであっても肝予備能や全身状態が良好であれば分子標的治療薬の投与対象となる.◎HCCに対する薬物療法の進歩は目覚ましく,さらに良好な抗腫瘍効果が期待されている.
  • 伊藤 隆徳, 葛谷 貞二, 石上 雅敏, 廣岡 芳樹
    消化器・肝臓内科 4(1) 86-92 2018年7月  責任著者
  • 武藤 久哲, 葛谷 貞二, 横山 晋也, 田中 卓, 山本 健太, 安藤 祐資, 伊藤 隆徳, 安田 諭, 石津 洋二, 本多 隆, 林 和彦, 石上 雅敏, 石川 哲也, 廣岡 芳樹, 後藤 秀実
    The Liver Cancer Journal (Suppl.1) 52-53 2018年6月  
  • 葛谷 貞二, 石上 雅敏, 後藤 秀実
    消化器・肝臓内科 2(1) 76-82 2017年7月  筆頭著者
  • 安田 諭, 葛谷 貞二, 田中 卓, 山本 健太, 安藤 祐資, 伊藤 隆徳, 野村 彩, 加藤 幸一郎, 石津 洋二, 本多 隆, 林 和彦, 石上 雅敏, 後藤 秀実
    The Liver Cancer Journal 9(1) 80-81 2017年6月  責任著者
  • 葛谷 貞二, 石津 洋二, 新家 卓郎, 今井 則博, 阿知波 宏一, 荒川 恭宏, 山田 恵一, 中野 聡, 本多 隆, 林 和彦, 石上 雅敏, 石川 哲也, 中野 功, 片野 義明, 伊藤 彰浩, 廣岡 芳樹, 泉 並木, 後藤 秀実
    肝臓 54(12) 850-853 2013年12月  筆頭著者
    穿刺治療支援アプリケーションVirtuTRAXを用いた2ステップ法によるラジオ波焼灼術の手技を紹介し、同手術施行の肝細胞癌患者16例23結節における実際の針先端と仮想の針先端との位置ずれについて報告した。横方向の位置ずれに関しては、外筒針が肝表面を貫く際に仮想穿刺ライナーが一時的にずれるケースがあり、肝表面がたわんだ3例、肝自体が押され変位した2例、人工腹水を用いた2例で1cm以上のずれを認めたが、外筒針が肝表面を貫いた後は認めなかった。その後の治療過程では、呼吸性変動や針先端の位置調整時において1〜5mm程度ずれるケースがみられたが、いずれもほぼ平行なずれであった。一方縦方向の位置ずれに関しては、外筒針と肝表面とのたわみがとれた後はそれぞれの穿刺ライン上での体表からの距離が一致し、問題となるケースはなかった。
  • 葛谷 貞二, 石上 雅敏, 新家 卓郎, 今井 則博, 阿知波 宏一, 荒川 恭宏, 山田 恵一, 中野 聡, 石津 洋二, 本多 隆, 林 和彦, 片野 義明, 石川 哲也, 後藤 秀実
    Liver Cancer 19 71-75 2013年11月  筆頭著者
    症例は80歳男性。主訴は右下肢痛および歩行困難。既往歴はC型慢性肝炎。近医で施行したCT検査にて右骨盤部に長径140mm大の骨破壊を伴う腫瘍を認めた。同病変の腫瘍生検では低分化肝細胞癌の所見であり、精査加療目的で当院に紹介となった。原発と考えられた肝内病変は骨盤転移巣に比して小さく長径10mm大の乏血性病変1ヶ所であった。腫瘍マーカーはAFP 311,200ng/mL、PIVKA II 11,221mAU/mLといずれも高値であった。まず骨盤転移巣に対し放射線治療を施行(45Gy/15Fr)し、その後引き続いてソラフェニブを400mg/日で開始した。ソラフェニブ投与6週間後のmRECIST基準による抗腫瘍効果判定はPRで、腫瘍マーカーもAFP 8490、PIVKA II 855mAU/mLと低下した。腫瘍生検に免疫染色を追加したところCK19(Cytokeratin 19)陽性であった。(著者抄録)
  • 葛谷 貞二, 石上 雅敏, 新家 卓郎, 今井 則博, 阿知波 宏一, 荒川 恭宏, 山田 恵一, 中野 聡, 石津 洋二, 本多 隆, 林 和彦, 石川 哲也, 中野 功, 片野 義明, 伊藤 彰浩, 廣岡 芳樹, 後藤 秀実
    肝臓 54(7) 505-506 2013年7月  筆頭著者
    進行肝細胞癌に対するソラフェニブ投与後2週間以内にみられる発熱と造影CT上の阻血性変化との関係について検討した。対象は64例(平均66.9歳)でStage IIIが27例、Stage IVAが21例、Stage IVBが16例であった。その結果、38度以上の発熱が認められたのは23例で、阻血性変化が認められた46例は発熱が認められた症例において有意に多く認め、更に30%以上の阻血性変化が認められた症例の割合も発熱が認められた症例において有意に高かった。
  • 葛谷 貞二, 片野 義明, 今井 則博, 阿知波 宏一, 荒川 恭宏, 山田 恵一, 中野 聡, 増田 寛子, 石津 洋二, 本多 隆, 林 和彦, 石上 雅敏, 石川 哲也, 後藤 秀実
    The Liver Cancer Journal 4(2) 140-141 2012年6月  筆頭著者
  • 葛谷 貞二, 竹田 欽一, 宇都宮 節夫, 多賀 雅浩, 川田 登, 池田 誉, 今井 則博, 水谷 佳貴, 広瀬 健, 石川 哲也
    癌と化学療法 38(6) 995-1001 2011年6月  筆頭著者
    症例は80歳、男性。C型肝硬変、肝細胞癌で通院していた。2007年秋ごろから肝性脳症を繰り返すようになり、頻回の外来通院と入院加療を必要とした。肝予備能の低下により、肝細胞癌に対する治療は不可能となった。肝性脳症に対して緩下剤、ラクツロース、カナマイシン内服などの投与を行ったが、脳症のコントロールは困難であった。血中アンモニア値は130μg/dL前後で、時に200μg/dL以上となった。12月よりバンコマイシン内服(0.5g/回、3日に1回投与)を追加したところ、アンモニア値は速やかに50μg/dL低下となり、意識レベルの正常化、ADL、QOLの改善など著明な効果が得られた。バンコマイシン内服開始3ヵ月後には、Child C(10点)からChild B(7点)と肝予備能も改善、肝細胞癌に対し肝動脈化学塞栓療法が可能となった。(著者抄録)
  • 葛谷 貞二, 土谷 薫, 田中 佳祐, 鈴木 雄一朗, 星岡 賢英, 玉城 信治, 加藤 知爾, 安井 豊, 細川 貴範, 上田 研, 中西 裕之, 板倉 潤, 高橋 有香, 黒崎 雅之, 朝比奈 靖浩, 泉 並木
    肝臓 52(5) 325-326 2011年5月  筆頭著者
    進行肝細胞癌に対しソラフェニブを導入し、1ヵ月後にmRECIST基準で抗腫瘍効果が判定可能であった41例を対象とし、高度門脈腫瘍栓(Vp3/4)を伴う11例とVp0/2の30例に分け治療成績を比較した。抗腫瘍効果(PR/SD/PD)はVp0/2群8/14/8例、Vp3/4群5/2/4例で、奏功率、Disease control rate、累積無増悪率に有意差は認めず、累積生存率はVp3/4群で有意に低く、また1ヵ月後のChild-PughスコアもVp3/4群で有意に悪化していた。Vp3/4と1ヵ月後のChild-Pughスコアは、独立した予後不良因子であった。以上、ソラフェニブはVp3/4症例に対し効果のある治療法であると考えられた。
  • 葛谷 貞二, 泉 並木
    臨床透析 27(4) 405-411 2011年4月  筆頭著者
    透析患者はC型やB型肝炎ウイルスの合併頻度が高く,透析患者に対するウイルス性肝炎や肝細胞癌のスクリーニングは重要である.HCV抗体やHBs抗原が陽性であった場合,HCV RNAあるいはHBV DNAを測定し感染の有無を確認する.透析患者のALT値は一般的に低値であるが,ウイルス性肝炎を合併した患者ではALT値の上昇が軽度であっても肝臓の炎症や線維化を伴っていることがある.肝細胞癌の腫瘍マーカーにはAFP,AFP-L3,PIVKA-IIの3種があるが,透析患者においても異常値の判定は健常人と同じでよいとされる.これらを定期的に測定することは,肝細胞癌の早期発見,早期治療のために重要である.(著者抄録)
  • 黒崎 雅之, 葛谷 貞二, 泉 並木
    消化器内科 52(1) 99-102 2011年1月  
    著者らはB型慢性肝炎の核酸アナログ治療に対するウイルス学的治療反応性、耐性リスクおよびコア関連抗原陰性化の関連性を検討した。その結果、1)LAM治療歴のある症例に対してETVを投与した際には、治療反応性不良(P-VR、NR)が耐性出現と関連するため、耐性変異を念頭に置いた慎重な経過観察と耐性変異の検索が必要であると考えられた。2)12週以内のHBV DNA陰性化(VR-12W)により、ETVでは40%、ADVでは33%にコア関連抗原の陰性化が得られ、このような治療反応性良好な症例では薬剤中止を検討するための必要条件に該当した。
  • 葛谷 貞二, 土谷 薫, 田中 佳祐, 鈴木 雄一朗, 星岡 賢英, 玉城 信治, 加藤 知爾, 安井 豊, 田中 智大, 細川 貴範, 上田 研, 中西 裕之, 板倉 潤, 黒崎 雅之, 朝比奈 靖浩, 泉 並木
    肝臓 51(7) 403-404 2010年7月  筆頭著者
    ソラフェニブ投与前後の腫瘍マーカーの推移を検討した。ソラフェニブを開始した進行肝細胞癌31例のうち、画像による治療効果判定が可能であった28例を対象とした。AFPおよびAFP-L3は治療前後で有意差を認めなかった。PIVKA-IIは治療前に比して、治療1ヵ月後は有意に上昇した。RECIST基準による治療成績別の検討でも同様で、PRまたはSD群においても有意に上昇していた。PIVKA-II上昇率の比較では、PRまたはSD群2.6、PD群4.5であり、両群間に有意差はなかった。AST、ALT、LDH、PTの治療前後(治療前、治療1ヵ月後)の推移は、それぞれAST 76IU/l、93.5IU/l、ALT 46.5IU/l、69.5IU/l、LDH 240.5IU/l、338.5IU/l、PT 109%、110%であった。
  • 葛谷 貞二, 竹田 欽一, 宇都宮 節夫, 多賀 雅浩, 川田 登, 池田 誉, 今井 則博, 水谷 佳貴, 広瀬 健, 石川 哲也, 片野 義明, 後藤 秀実
    癌と化学療法 36(12) 2377-2379 2009年11月  査読有り筆頭著者
    GDAコイル法による肝動脈リザーバーカテーテル留置後、カテーテル留置自体によって腫瘍の大部分が壊死したと考えられた多発肝細胞癌の1例を経験したので報告する。症例は59歳、男性。近医にてB型慢性肝炎で通院中、多発肝細胞癌と診断され、当院紹介となった。肝S4の80mm大の腫瘍をはじめ、多血性の肝細胞癌が両葉に多発していた。肝動注リザーバー化学療法を行うため、5Fr留置カテーテルをGDAコイル法で留置した。留置後から、腹痛を伴わない熱発および著明なALT上昇を認めた。肝予備能も徐々に低下し動注化学療法は施行できなかった。留置3週間後の造影CTでは、動脈相で大部分の腫瘍が早期濃染を認めない腫瘍壊死の所見であった。カテーテル留置により肝への血流低下を来し、腫瘍壊死に至ったものと考えられた。(著者抄録)
  • 葛谷 貞二, 竹田 欽一, 宇都宮 節夫, 川田 登, 池田 誉, 今井 則博, 水谷 佳貴, 広瀬 健, 石川 哲也, 伊藤 将倫, 今泉 延, 小栗 健二
    肝胆膵治療研究会誌 7(1) 112-112 2009年8月  筆頭著者
  • 藤田 裕子, 葛谷 貞二, 村松 雄治, Bajotto Gustavo, 下村 吉治
    アミノ酸研究 1(1) 71-72 2008年3月  
  • 葛谷 貞二, 片野 義明, 熊田 卓, 豊田 秀徳, 土居崎 正雄, 岩田 浩史, 後藤 新太郎, 舘 佳彦, 竹田 泰史, 西野 正路, 森井 正哉, 本多 隆, 林 和彦, 石上 雅敏, 中野 功, 後藤 秀実
    消化器科 44(5) 500-505 2007年5月  筆頭著者
    初発B型肝細胞癌の治療(肝切除またはRFA)後にラミブジン投与を行った16例(lam群)を対象に、その治療成績を非投与のコントロール群33例(con群)と比較検討した。その結果、1)累積再発率は両群間で有意差を認めず、ラミブジンによる再発予防効果は示されなかった。2)lam群のALT値およびHBV-DNA量の推移は、再発の有無にかかわらず、治療前に比して有意に低下し、HCC治療後のALT値やHBV-DNA量の低下による再発への影響はみられなかった。3)HCCが再発した22例(lam群7例、con群15例)において初回治療時と再発治療時の肝予備能や治療法を比較したところ、lam群では再発治療時の肝予備能が良好に保たれており、再発時の治療法として肝切除あるいはRFAを全例に選択できた。一方、con群では再発治療時に初回治療時よりも肝予備能が悪化した症例を10例認め、それら症例ではTAEや無治療といった選択肢を取らざるを得なかった。4)累積生存率はlam群がcon群に比して予後良好な傾向を示した。以上より、初発B型HCC治療後のラミブジン投与は、背景の肝予備能を良好に維持または改善させ、またそれにより仮にHCCが再発したとしても治療選択の幅が広がるため有用であると考えられた。
  • 葛谷 貞二, 熊田 卓, 豊田 秀徳, 桐山 勢生, 曽根 康博, 谷川 誠, 久永 康宏, 野々垣 浩二, 清水 潤一, 山内 貴裕, 川瀬 直登, 市川 秀男, 川地 俊明, 日比 敏男, 小川 定信
    消化器画像 6(4) 490-497 2004年7月  筆頭著者
    ラジオ波焼灼療法(RFA)の治療効果判定における造影超音波検査(CEUS)の有用性について,ダイナミックMRIと比較した.対象は,RFA前後にCEUSとダイナミックMRIを行った肝細胞癌124例141結節とした.両者の効果判定の一致率は高く,141例中130例(92.2%)であった.両方法で効果十分と判定した群の再発率は8.9%(8/122),MRIのみで効果十分と判定した群は40%(4/10)と,後者が有意に高率であった.しかし,CEUSではsafety marginの評価が困難な症例や,治療による変化を癌の遺残とover diagnosisしてしまった症例もみられた.次世代の超音波造影剤が使用可能となればリアルタイムに長時間の造影が可能で,治療への応用も容易となり,CEUSの有用性は更に高まると思われた
  • 葛谷 貞二, 熊田 卓, 豊田 秀徳, 桐山 勢生, 曽根 康博, 谷川 誠, 久永 康宏, 野々垣 浩二, 清水 潤一, 川瀬 直登, 山内 貴裕, 何森 晶
    消化器科 38(5) 504-512 2004年5月  筆頭著者
    1993〜2002年に治療を行った初発肝細胞癌811例(肝切除179例,局所療法232例,塞栓術213例,リザーバー動注化学療法40例など)を対象に治療法別・JIS score別・CLIP score別の生存率を検討した.治療法別の生存率は肝切除群が最も高く,以下,局所療法,塞栓術,リザーバー療法の順であった.JIS scoreとCLIP scoreではいずれもスコアが大きくなるにつれて生存率が有意に低下した.肝切除群と局所療法群の生存率をJIS score別・CLIP score別およびAFP-L3分画別に比較検討したところ,JIS scoreとCLIP scoreではいずれのスコアにおいても有意差は認められなかった.AFP-L3分画陰性例の比較においても有意差は認められなかったが,AFP-L3分画陽性例においては肝切除群の生存率が有意に高かった
  • 葛谷 貞二, 林 繁和, 小池 光正
    日本大腸検査学会雑誌 18(1) 124-127 2001年9月  筆頭著者
    病原性大腸菌腸炎10例の大腸内視鏡所見について検討した.10例中8例に全周性,縦走性の粘膜の発赤,糜爛,潰瘍,浮腫を認め,虚血性大腸炎の所見と類似していた.腸管病原性大腸菌腸炎6例中4例は,S状結腸,下行結腸に限局して病変を認め,腸管出血性大腸菌腸炎3例はS状結腸より連続して病変が見られ,深部大腸ほど病変が高度であった.血便を伴う腸炎患者の大腸内視鏡所見で,粘膜の虚血性変化が見られた場合,病原性大腸菌腸炎も鑑別の1つとして考えることが重要であり,病変の主座が,深部大腸である場合,腸管出血性大腸菌腸炎を疑う必要がある

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