Faculty Profiles - TAKAKI Akinobu

Papers - TAKAKI Akinobu

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Diagnostic Utility of the PD-L1 Immunostaining in Biopsy Specimens of Patients with Biliary Tract Neoplasms. International journal

Kazuyuki Matsumoto, Toshiaki Ohara, Masayoshi Fujisawa, Akinobu Takaki, Masahiro Takahara, Hironari Kato, Ryuichi Yoshida, Yuzo Umeda, Takahito Yagi, Akihiro Matsukawa, Hiroyuki Okada

Journal of gastrointestinal surgery : official journal of the Society for Surgery of the Alimentary Tract 26 ( 6 ) 1213 - 1223 2022.2

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Anti-programmed death 1/programmed death ligand 1 (PD1/PD-L1) antibodies have been successfully used as treatment agents for several solid tumors; however, it is difficult to predict their effectiveness. We evaluated whether biopsy specimens could predict the positive status of PD-L1 in surgically resected tissue. METHODS: Among 91 patients who underwent tissue sampling with endoscopic or liver biopsy before surgery for biliary tract neoplasms in an academic center, 45 (49%) patients were selected for retrospective analysis because the quality and quantity of their biopsy specimens were adequate for histologic evaluation. We performed immunohistochemical staining to investigate the PD-L1 expression in both resected and biopsy specimens. The percentage of the positively stained cells was calculated for subsequent use in the correlation investigation. RESULTS: The biopsy methods were endoscopic retrograde cholangiopancreatography (ERCP) in 28 cases, percutaneous liver biopsy in 10 cases, and endoscopic ultrasound fine-needle aspiration in 7 cases. Among the 45 patients, when patients with > 10% positive tumor cells in surgically resected tissues were regarded as truly positive PD-L1, the positive and negative concordance rates between surgically resected tissues and biopsy samples were 56% (5/9) and 100% (36/36), respectively. With regard to the use of preoperative biopsy as a diagnostic tool, all (5/5) PD-L1-positive patients had a positive resected specimen. The accuracy of each biopsy method was as follows: ERCP, 89% (25/28); fine-needle aspiration, 86% (6/7); and liver biopsy, 100% (10/10). CONCLUSIONS: Biopsy samples could be a surrogate material for the assessment of the PD-L1 expression with substantial positive and high negative concordance rates.

DOI： 10.1007/s11605-021-05197-6

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FALDに挑む Fontan関連肝腫瘍肝細胞癌と良性肝結節

大西秀樹, 高木章乃夫, 岡田裕之

日本成人先天性心疾患学会雑誌 11 ( 1 ) 172 - 172 2022.1

Study Protocol for a Trial: A Single-Arm, Open-Labeled Study Evaluating Transcatheter Arterial Embolization Plus Everolimus Combination Therapy for Patients With Liver Metastasis of Gastroenteropancreatic Neuroendocrine Tumors. International journal

Yasuto Takeuchi, Hironari Kato, Shigeru Horiguchi, Atsushi Oyama, Takuya Adachi, Nozomu Wada, Hideki Onishi, Hidenori Shiraha, Akinobu Takaki

Clinical Medicine Insights. Oncology 16 11795549221127750 - 11795549221127750 2022

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: The number of patients with non-functional neuroendocrine tumors (NETs) has increased recently, and the rate of liver metastasis of NETs is about 20% in patients at the first diagnosis. Transcatheter arterial embolization (TAE) and everolimus are therapies with reported efficacy, but few reports have described their combined treatment. We therefore aim to evaluate the efficacy and safety of combination therapy with everolimus and TAE in patients with liver metastasis of gastroenteropancreatic neuroendocrine tumors (GEP-NETs) in a prospective study. METHODS: We design a single-arm, open-label, prospective study to evaluate the efficacy and safety of combination therapy with everolimus and TAE in patients with liver metastases of GEP-NETs. The study started in June 2021 at Okayama University Hospital and is expected to enroll 18 patients over a 2-year period. DISCUSSION: This study is a prospective study investigating a new treatment method for a rare disease called GEP-NETs. We may obtain useful information that contributes to the treatment guidelines in this study. However, NET is a rare disease, and although the number of cases is statistically established, it may not be possible to accurately assess causality.TRIAL REGISTRATION NUMBER: jRCT1061210015.

DOI： 10.1177/11795549221127750

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A case of focal nodular hyperplasia with hepatic failure treated with liver transplantation.

Tetsuya Yasunaka, Yasuto Takeuchi, Akinobu Takaki, Fukuo Kondo, Tomoharu Yoshizumi, Kenichi Kohashi, Atsushi Oyama, Takuya Adachi, Nozomu Wada, Hideki Onishi, Hidenori Shiraha, Hiroyuki Okada

Clinical journal of gastroenterology 15 ( 1 ) 171 - 176 2021.11

Language：English Publishing type：Research paper (scientific journal)

Focal nodular hyperplasia (FNH) is a benign nodular lesion, but because of its feature of portal tract vessel abnormality, it may induce portal hypertension. A 27-year-old woman was admitted with a fever. A large nodule with satellite lesions was found in the liver and cotton wool-like feature of arteries were detected on angiography. Technetium galactosyl serum albumin scintigraphy and diagnostic laparoscopy showed that the tumor site was functional, while the surrounding area was a non-functional fibrotic area. A biopsy specimen indicated that the nodular lesion was an FNH-like lesion. She experienced several instances of variceal rupture and suffered liver failure, receiving liver transplantation. The excised liver showed a centrally scarred area in the nodule, indicating that the diagnosis was FNH. We herein report this case as a rare case of FNH that progressed to liver failure.

DOI： 10.1007/s12328-021-01529-w

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Circulating tumor DNA dynamics analysis in a xenograft mouse model with esophageal squamous cell carcinoma. International journal

Hiroyuki Terasawa, Hideaki Kinugasa, Kazuhiro Nouso, Shumpei Yamamoto, Mami Hirai, Takehiro Tanaka, Akinobu Takaki, Hiroyuki Okada

World journal of gastroenterology 27 ( 41 ) 7134 - 7143 2021.11

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: It remains unclear which factors, such as tumor volume and tumor invasion, influence circulating tumor DNA (ctDNA), and the origin of ctDNA in liquid biopsy is always problematic. To use liquid biopsies clinically, it will be very important to address these questions. AIM: To assess the origin of ctDNA, clarify the dynamics of ctDNA levels, assess ctDNA levels by using a xenograft mouse after treatment, and to determine whether tumor volume and invasion are related to ctDNA levels. METHODS: Tumor xenotransplants were established by inoculating BALB/c-nu/nu mice with the TE11 cell line. Groups of mice were injected with xenografts at two or four sites and sacrificed at the appropriate time point after xenotransplantation for ctDNA analysis. Analysis of ctDNA was performed by droplet digital PCR, using the human telomerase reverse transcriptase (hTERT) gene. RESULTS: Mice given two-site xenografts were sacrificed for ctDNA at week 4 and week 8. No hTERT was detected at week 4, but it was detected at week 8. However, in four-site xenograft mice, hTERT was detected both at week 4 and week 6. These experiments revealed that both tumor invasion and tumor volume were associated with the detection of ctDNA. In resection experiments, hTERT was detected at resection, but had decreased by 6 h, and was no longer detected 1 and 3 d after resection. CONCLUSION: We clarified the origin and dynamics of ctDNA, showing that tumor volume is an important factor. We also found that when the tumor was completely resected, ctDNA was absent after one or more days.

DOI： 10.3748/wjg.v27.i41.7134

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トルバプタンを導入した肝硬変患者における血管拡張抑制物質ADMA測定の意義

竹内康人, 大山淳史, 足立卓哉, 和田望, 大西秀樹, 白羽英則, 高木章乃夫, 岡田裕之

肝臓 62 ( Suppl.3 ) A740 - A740 2021.11

Fontan関連肝疾患を背景に肝細胞腺腫を発症した一例

國富恵実, 大西秀樹, 大山淳史, 足立卓哉, 和田望, 竹内康人, 白羽英則, 高木章乃夫, 岡田裕之

日本消化器病学会中国支部例会・日本消化器内視鏡学会中国支部例会プログラム・抄録集 116回・127回 85 - 85 2021.11

アテゾリズマブ・ベバシズマブ併用療法の実臨床での治療効果

足立卓哉, 能祖一裕, 大山淳史, 和田望, 竹内康人, 大西秀樹, 白羽英則, 高木章乃夫, 守屋昭男, 小橋春彦, 岩堂昭太, 岡田裕之

肝臓 62 ( Suppl.3 ) A759 - A759 2021.11

Transformation to diffuse large B-cell lymphoma with germinal center B-cell like subtype and discordant light chain expression in a patient with Waldenström macroglobulinemia/lymphoplasmacytic lymphoma.

Hiroki Kobayashi, Noboru Asada, Yuria Egusa, Tomoka Ikeda, Misa Sakamoto, Masaya Abe, Daisuke Ennishi, Masahiro Sakata, Akinobu Takaki, Soichiro Kawahara, Yusuke Meguri, Hisakazu Nishimori, Nobuharu Fujii, Ken-Ichi Matsuoka, Yasuharu Sato, Tadashi Yoshino, Yoshinobu Maeda

International journal of hematology 114 ( 3 ) 401 - 407 2021.9

Language：English Publishing type：Research paper (scientific journal)

Waldenström macroglobulinemia (WM)/lymphoplasmacytic lymphoma (LPL) is a rare indolent B-cell neoplasm, and a gain-of-function mutation in the myeloid differentiation primary response 88 (MYD88), L265P, is a commonly recurring mutation in patients with WM/LPL. Histological transformation of WM/LPL to an aggressive lymphoma such as diffuse large B-cell lymphoma (DLBCL) is rare, and transformed DLBCL has a worse prognosis than de novo DLBCL, partly because transformed DLBCL is mostly classified as non-germinal center B-cell-like (non-GCB) subtype. We herein describe a 75-year-old man with DLBCL with a history of WM/LPL. DLBCL in this patient showed the GCB subtype, and the light chain restriction of DLBCL was different from that of the antecedent WM/LPL, indicating that the two types of lymphoma cells had distinctive origins. However, DLBCL in this patient harbored the MYD88 L265P mutation, and polymerase chain reaction and Sanger sequencing of the DLBCL and WM/LPL for immunoglobulin heavy chain gene rearrangement suggested a clonal relationship between the two lymphomas. Since the outcome of transformed DLBCL is worse than for de novo DLBCL, it is important to evaluate the clonal relationship between primary WM/LPL and the corresponding transformed DLBCL, even if the DLBCL expresses a GCB subtype or discordant light chain restriction.

DOI： 10.1007/s12185-021-03157-z

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トルバプタンによる腹水治療に伴う肝移植時状態の変化

和田望, 高木章乃夫, 大山淳史, 足立卓哉, 竹内康人, 大西秀樹, 白羽英則, 岡田裕之

肝臓 62 ( Suppl.2 ) A537 - A537 2021.9

アテゾリズマブとベバシズマブの併用療法おける1stライン使用と2ndライン以降の使用の違いについて

足立卓哉, 能祖一裕, 大山淳史, 和田望, 竹内康人, 大西秀樹, 白羽英則, 高木章乃夫, 狩山和也, 岩堂昭太, 守屋昭男, 岡田裕之

肝臓 62 ( Suppl.2 ) A551 - A551 2021.9

急性肝不全に陥ることなく致死的経過を辿った急性E型肝炎の1例

山内菜緒, 安中哲也, 高木章乃夫, 日並義統, 木野村賢, 河原明奈, 足立卓哉, 大山淳史, 和田望, 竹内康人, 大西秀樹, 白羽英則, 岡田裕之

肝臓 62 ( 8 ) 463 - 470 2021.8

急性肝不全に陥ることなく致死的経過を辿った急性E型肝炎の1例

山内菜緒, 安中哲也, 高木章乃夫, 日並義統, 木野村賢, 河原明奈, 足立卓哉, 大山淳史, 和田望, 竹内康人, 大西秀樹, 白羽英則, 岡田裕之

肝臓 62 ( 8 ) 463 - 470 2021.8

Language：Japanese Publisher：(一社)日本肝臓学会

症例は64歳,男性.過去の健診でビリルビン高値の指摘あり.家人に黄疸を指摘され,前医を受診,AST 1526U/l,ALT 2058U/lと肝障害を認め入院,ビリルビン上昇も伴っていたが,PT正常で急性肝不全には陥っていなかった.HEV RNA陽性が判明,肝生検で急性肝炎像を呈しており,急性E型肝炎として保存的加療となった.Transaminseは低下,PTも正常範囲を維持,HEV RNA陰性化したが高ビリルビン血症悪化,第75病日に転院.急性腎不全を合併,消化管出血,更に細菌性・真菌性敗血症を合併し,第169病日に死亡した.病理解剖にて,肝臓は萎縮もなく,肝細胞壊死や肝線維化は軽度で強い胆汁栓を認める所見であった.肝合成能は維持されるも胆汁うっ滞が遷延し,全身合併症により死亡したと考えられ,移植適応をどう考えていくかを含めて示唆に富む症例であり,報告する.(著者抄録)

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Other Link： https://search-tp.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2021&ichushi_jid=J00263&link_issn=&doc_id=20210811100004&doc_link_id=10.2957%2Fkanzo.62.463&url=https%3A%2F%2Fdoi.org%2F10.2957%2Fkanzo.62.463&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

Randomized controlled study to examine the efficacy of hepatic arterial infusion chemotherapy with cisplatin before radiofrequency ablation for hepatocellular carcinoma. International journal

Atsushi Oyama, Kazuhiro Nouso, Kenichi Yoshimura, Yuki Morimoto, Shinichiro Nakamura, Hideki Onishi, Akinobu Takaki, Shouta Iwadou, Kazuya Kariyama, Kenji Kuwaki, Kazuhisa Yabushita, Kosaku Sakaguchi, Jyunichi Toshimori, Haruhiko Kobashi, Akio Moriya, Masaharu Ando, Hiroyuki Okada

Hepatology research : the official journal of the Japan Society of Hepatology 51 ( 6 ) 694 - 701 2021.6

Language：English Publishing type：Research paper (scientific journal)

AIM: Hepatic arterial infusion chemotherapy (HAIC) with cisplatin is beneficial to patients with advanced hepatocellular carcinoma (HCC) treated with sorafenib. This study aimed to examine the effect of HAIC with cisplatin before radiofrequency ablation (RFA) in patients with HCC. METHODS: This was a multicenter, single-blinded, randomized controlled study (UMIN000007267). Early-stage HCC patients were randomly assigned (1:1) to receive HAIC with cisplatin before RFA therapy (HAIC group) or RFA monotherapy (non-HAIC group). The primary end-point was recurrence-free survival. Efficacy analysis and safety analysis followed the intention-to-treat principle. RESULTS: Between August 2012 and July 2016, 74 patients were recruited. A total of 70 eligible patients were randomly assigned to the HAIC group (n = 35) and non-HAIC group (n = 35). Recurrence-free survival rates at 1 (3) year in the HAIC group and non-HAIC group were 82.9% (54.3%) and 74.3% (34.3%), respectively (hazard ratio [HR], 0.597; 95% confidence interval [CI], 0.320-1.091; p = 0.094]. Subgroup analysis showed that the beneficial effect of HAIC was observed in patients with a single nodule and Child-Pugh score 5. Intrahepatic distant recurrence-free survival rate in the HAIC group was significantly better than that in the non-HAIC group (HR, 0.468; 95% CI, 0.235-0.896; p = 0.022). Adverse events were observed in just two patients in the HAIC group (6%) - grade 2 cholecystitis and grade 2 hyperkalemia. CONCLUSIONS: HAIC with cisplatin before RFA did not significantly decrease recurrence in patients with early-stage HCC. However, it might be effective in preventing intrahepatic distant recurrence.

DOI： 10.1111/hepr.13633

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Management of Cirrhotic Ascites under the Add-on Administration of Tolvaptan. International journal

Takuya Adachi, Yasuto Takeuchi, Akinobu Takaki, Atsushi Oyama, Nozomu Wada, Hideki Onishi, Hidenori Shiraha, Hiroyuki Okada

International journal of molecular sciences 22 ( 11 ) 2021.5

Language：English Publishing type：Research paper (scientific journal)

Tolvaptan is a recently available diuretic that blocks arginine vasopressin receptor 2 in the renal collecting duct. Its diuretic mechanism involves selective water reabsorption by affecting the water reabsorption receptor aquaporin 2. Given that liver cirrhosis patients exhibit hyponatremia due to their pseudo-aldosteronism and usage of natriuretic agents, a sodium maintaining agent, such as tolvaptan, is physiologically preferable. However, large scale studies indicating the patients for whom this would be effective and describing management under its use have been insufficient. The appropriate management of cirrhosis patients treated with tolvaptan should be investigated. In the present review, we collected articles investigating the effectiveness of tolvaptan and factors associated with survival and summarized their management reports. Earlier administration of tolvaptan before increasing the doses of natriuretic agents is recommended because this may preserve effective arterial blood volume.

DOI： 10.3390/ijms22115582

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Abnormal fucosylation of alpha-fetoprotein in patients with nonalcoholic steatohepatitis. International journal

Kazuhiro Nouso, Yoshie Furubayashi, Kazuya Kariyama, Akiko Wakuta, Nozomi Miyake, Kanae Inoue, Yuta Nagai, Shiho Murakami, Takuya Adachi, Atsushi Oyama, Nozomu Wada, Yasuto Takeuchi, Masahiro Sakata, Tetsuya Yasunaka, Hideki Onishi, Hidenori Shiraha, Akinobu Takaki, Shohei Shiota, Satoshi Yasuda, Hidenori Toyoda, Miwa Kawanaka, Takashi Kumada, Hiroyuki Okada

Hepatology research : the official journal of the Japan Society of Hepatology 51 ( 5 ) 548 - 553 2021.5

Language：English Publishing type：Research paper (scientific journal)

AIM: Nonalcoholic steatohepatitis (NASH) is a risk factor for nonvirus-related hepatocellular carcinoma, which is increasing in prevalence. The aim of this study was to clarify the clinical application of fucosylated alpha-fetoprotein (AFP-L3) in the process of nonalcoholic fatty liver (NAFL) disease development. METHODS: Serum samples from 115 diabetes mellitus (DM), 36 NAFL, and 119 NASH patients were analyzed for AFP-L3 expression using raw data of a micro total analysis system. These data were then compared with the clinical characteristics of the patients. A validation study was also undertaken with 55 samples (17 NAFL and 38 NASH). RESULTS: Trace amounts of AFP-L3 were detected in 3.5%, 16.7%, and 58.0% of patients with DM, NAFL, and NASH, respectively. The odds ratio of AFP-L3 positivity for the diagnosis of NASH in multivariate analysis was 9.81 (95% confidence interval, 3.77-25.5). The rates in patients without fibrosis or with stage 1, stage 2, stage 3, and stage 4 fibrosis were 14.7%, 31.3%, 63.0%, 86.2%, and 100%, respectively. The rates were significantly increased according to the advancement of liver fibrosis (p < 0.001); however, no difference in the positive rate of AFP-L3 was observed between patients with and without fatty livers and between patients with normal and abnormal transaminase. The same relationship was also observed in the validation cohort. CONCLUSION: Abnormal fucosylation of AFP occurred in patients with NASH, so it could be useful for the screening of NASH in patients with DM, as well as for the differential diagnosis of NASH and the evaluation of fibrosis.

DOI： 10.1111/hepr.13626

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好中球性白血病との鑑別が問題となったアルコール性肝炎増悪による急性肝不全症例

稲生祥子, 安中哲也, 高木章乃夫, 大山敦史, 足立卓哉, 和田望, 竹内康人, 大西秀樹, 白羽英則, 岡田裕之

日本消化器病学会中国支部例会プログラム・抄録集 115回 88 - 88 2021.5

Prediction of the prognosis of advanced hepatocellular carcinoma by TERT promoter mutations in circulating tumor DNA. International journal

Mami Hirai, Hideaki Kinugasa, Kazuhiro Nouso, Shumpei Yamamoto, Hiroyuki Terasawa, Yuma Onishi, Atsushi Oyama, Takuya Adachi, Nozomu Wada, Masahiro Sakata, Tetsuya Yasunaka, Hideki Onishi, Hidenori Shiraha, Akinobu Takaki, Hiroyuki Okada

Journal of gastroenterology and hepatology 36 ( 4 ) 1118 - 1125 2021.4

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND ANDAIM: Human telomerase reverse transcriptase (TERT) promoter mutations were the most prevalent mutations in patients with hepatocellular carcinoma (HCC). We tried to detect the mutations with plasma circulating tumor DNA (ctDNA) in patients with advanced HCC and elucidated their clinical utility. METHODS: Circulating tumor DNA in plasma was extracted from 130 patients with advanced HCC who were treated with systemic chemotherapy (n = 86) or transcatheter arterial chemoembolization (n = 44), and TERT promoter mutations were examined with digital droplet polymerase chain reaction. The correlations between these mutations and the clinical outcome of patients were analyzed. RESULTS: Of the 130 patients examined, 71 patients (54.6%) were positive for TERT promoter mutations in ctDNA, of which 64 patients were -124bp G > A and 10 were -146bp G > A. The presence of TERT promoter mutations was correlated with large intrahepatic tumor size (P = 0.05) and high des-gamma carboxyprothrombin (P = 0.005). Overall survival of the patients with the mutations was significantly shorter than those without them (P < 0.001), and the patients with high (≥ 1%) fractional abundance of the mutant alleles showed shorter survival than those with low (< 1%) fractional abundance. Multivariate analysis revealed that TERT promoter mutation (hazard ratio [HR]: 1.94; 95% confidence interval [CI], 1.18-3.24; P < 0.01), systemic chemotherapy (HR: 2.38; 95% CI, 1.29-4.57; P < 0.01), and vascular invasion (HR: 2.16; 95% CI, 1.22-3.76; P < 0.01) were significant factors for poor overall survival. CONCLUSIONS: TERT promoter mutations in ctDNA were associated with short survival and could be a valuable biomarker for predicting the prognosis of patients with advanced HCC.

DOI： 10.1111/jgh.15227

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肝疾患移行期医療の現状と問題点移行期医療におけるFontan関連肝疾患(FALD)診療の現状と問題

大西秀樹, 高木章乃夫, 岡田裕之

肝臓 62 ( Suppl.1 ) A166 - A166 2021.4

Differences in autoimmune hepatitis based on inflammation localization

Atsushi Takahashi, Hiromasa Ohira, Kazumichi Abe, Mikio Zeniya, Masanori Abe, Teruko Arinaga-Hino, Takuji Torimura, Kaname Yoshizawa, Akinobu Takaki, Jong-Hon Kang, Yoshiyuki Suzuki, Nobuhiro Nakamoto, Ayano Inui, Atsushi Tanaka, Hajime Takikawa

Medical Molecular Morphology 54 ( 1 ) 8 - 13 2021.3

Language：English Publishing type：Research paper (scientific journal) Publisher：Springer Science and Business Media LLC

Histopathology is essential for the diagnosis and evaluation of disease activity of autoimmune hepatitis (AIH). We aimed to elucidate the characteristics of AIH from the localization of inflammation. We re-evaluated a nationwide survey that was performed in Japan in 2018 of AIH patients diagnosed between 2014 and 2017. A total of 303 patients were enrolled, and the clinical and treatment characteristics were compared between the patients with predominantly portal inflammation (230 patients) or lobular inflammation (73 patients). AIH patients with lobular inflammation had a higher probability of being diagnosed with acute hepatitis than those with portal inflammation. Liver enzyme levels were higher in patients with lobular inflammation, whereas immunoglobulin G levels were higher in patients with portal inflammation. The prevalence of an alanine aminotransferase level < 30 U/L after 6 months of treatment was significantly higher in patients with lobular inflammation than in those with portal inflammation (81.7% vs. 67.3%, P = 0.046). The localization of inflammation may be useful for evaluating the onset of AIH.

DOI： 10.1007/s00795-020-00255-5

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Other Link： https://link.springer.com/article/10.1007/s00795-020-00255-5/fulltext.html

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