Faculty Profiles - HATTORI Norifumi

腹腔鏡下切除術を施行した食道重複嚢胞の一例

武田洋平, 清水大, 中西香企, 高見秀樹, 猪川祥邦, 服部憲史, 林真路, 神田光郎, 田中千恵, 中山吾郎, 藤原道隆, 小寺泰弘

日本臨床外科学会雑誌 Vol. 84 ( 7 ) page： 1129 - 1129 2023.7

胸骨後経路再建による食道亜全摘術後縫合不全と胸郭入口部気管食道間角度・胸骨椎骨間距離長の関連性の検討

呂成九, 神田光郎, 清水大, 田中千恵, 中西香企, 服部憲史, 林真路, 中山吾郎, 藤原道隆, 小寺泰弘

日本消化器外科学会総会 Vol. 78回 page： P206 - 2 2023.7

食道扁平上皮癌における術前凝固状態と術後再発の関連性

杉山史剛, 神田光郎, 清水大, 田中千恵, 中西香企, 服部憲史, 林真路, 中山吾郎, 藤原道隆, 小寺泰弘

日本消化器外科学会総会 Vol. 78回 page： P217 - 2 2023.7

Albumin-Globulin Ratio Indicates the Survival Outcome of Pancreatic Cancer Cases Who Underwent Preoperative Treatment and Curative Surgical Resection. International journal

Masamichi Hayashi, Daigo Kobayashi, Hideki Takami, Yoshikuni Inokawa, Nobutake Tanaka, Keisuke Kurimoto, Koki Nakanishi, Shinichi Umeda, Dai Shimizu, Norifumi Hattori, Mitsuro Kanda, Chie Tanaka, Goro Nakayama, Yasuhiro Kodera

Nutrition and cancer Vol. 75 ( 5 ) page： 1330 - 1339 2023.5

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

BACKGROUND: The pretreatment albumin-globulin ratio (AGR) is a frequently used inflammation-associated factor that has been reported to have associations with the survival outcomes of various malignancies. METHODS: We retrospectively analyzed 162 patients with pancreatic cancer who underwent preoperative treatment followed by curative surgery at Nagoya University Hospital between April 2010 and December 2020. Representative nutritional status indicators of neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), prognostic nutritional index (PNI), and albumin-globulin ratio (AGR) were calculated for each case. RESULTS: Among pretreatment blood examination parameters, only AGR (cutoff: 1.33) showed a significant difference in overall survival time (OS) and progression-free survival time (PFS) from the beginning of the preoperative treatment. Median PFS was 22.3 mo, in high AGR cases and 17.1 mo, in low AGR cases (P = 0.019). Median OS was 48.7 mo, in high AGR cases and 32.9 mo, in low AGR cases (P = 0.043). CONCLUSION: High pretreatment AGR may be a favorable prognostic factor for pancreatic cancer patients who received preoperative multimodal therapy followed by curative cancer resection. It may imply that nutritional status and inflammation control before the multimodal treatment affect the survival outcomes of pancreatic cancer cases and needs to be optimized.

DOI： 10.1080/01635581.2023.2191384

神経線維腫症I型に合併した巨大虫垂神経線維腫症の1例

野中有紀子, 上原圭, 小倉淳司, 村田悠記, 小林龍太朗, 伊神剛, 水野隆史, 山口淳平, 宮田一志, 尾上俊介, 梅田晋一, 服部憲史, 中山吾郎, 横山幸浩, 江畑智希

日本外科系連合学会誌 Vol. 48 ( 3 ) page： 436 - 436 2023.5

局所進行結腸癌に対する術前化学療法の臨床経験

田根雄一郎, 上原圭, 小倉淳司, 村田悠記, 小林龍太朗, 國料俊男, 伊神剛, 水野隆史, 山口淳平, 宮田一志, 尾上俊介, 砂川真輝, 渡辺伸元, 杉田静紀, 川勝章司, 中山吾郎, 服部憲史, 梅田晋一, 横山幸浩, 江畑智希

日本外科学会定期学術集会抄録集 Vol. 123回 page： DP - 7 2023.4

肛門管・直腸粘膜への進展を伴う肛門周囲Paget病に対する領域横断的手術治療戦略

深田浩志, 上原圭, 小倉淳司, 村田悠記, 小林龍太朗, 國料俊男, 伊神剛, 水野隆史, 山口淳平, 宮田一志, 尾上俊介, 砂川真輝, 渡辺伸元, 杉田静紀, 川勝章司, 中山吾郎, 服部憲史, 梅田晋一, 横山幸浩, 江畑智希

日本外科学会定期学術集会抄録集 Vol. 123回 page： DP - 4 2023.4

膵IPMN切除後予後に関連する因子および術後補助療法の影響に関する検討

猪川祥邦, 高見秀樹, 栗本景介, 田中伸孟, 林真路, 中西香企, 梅田晋一, 清水大, 服部憲史, 神田光郎, 田中千恵, 中山吾郎, 小寺泰弘

日本外科学会定期学術集会抄録集 Vol. 123回 page： DP - 5 2023.4

術前血清C reactive proteinとprognostic nutritional indexの組み合わせは大腸癌術後長期予後を予測する

梅田晋一, 中山吾郎, 服部憲史, 岸田貴喜, 小倉淳司, 村田悠紀, 中西香企, 清水大, 神田光郎, 田中千恵, 藤原道隆, 小寺泰弘

日本外科学会定期学術集会抄録集 Vol. 123回 page： SF - 8 2023.4

進行下部直腸癌に対する術前化学療法を基本とした治療戦略 Watch & Wait strategyを含めたresponse-guided strategyの導入経験

小倉淳司, 上原圭, 村田悠記, 小林龍太朗, 國料俊男, 伊神剛, 水野隆史, 山口淳平, 宮田一志, 尾上俊介, 砂川真輝, 渡辺伸元, 川勝章司, 杉田静紀, 梅田晋一, 服部憲史, 中山吾郎, 横山幸浩, 小寺泰弘, 江畑智希

日本外科学会定期学術集会抄録集 Vol. 123回 page： SF - 5 2023.4

局所再発直腸癌の最難関側方再発への手術戦略

上原圭, 小倉淳司, 村田悠記, 小林龍太郎, 神原祐一, 田根雄一郎, 杉田静紀, 川勝章司, 渡辺伸元, 砂川真輝, 尾上俊介, 宮田一志, 山口淳平, 水野隆史, 梅田晋一, 服部憲史, 中山吾郎, 伊神剛, 横山幸浩, 江畑智希

日本外科学会定期学術集会抄録集 Vol. 123回 page： SF - 2 2023.4

切除可能・切除可能境界型膵癌に対する腹腔洗浄細胞診の意義と治療戦略

田中伸孟, 高見秀樹, 栗本景介, 林真路, 中西香企, 梅田晋一, 清水大, 服部憲史, 神田光郎, 田中千恵, 中山吾郎, 小寺泰弘

日本外科学会定期学術集会抄録集 Vol. 123回 page： SF - 4 2023.4

右側結腸癌における病理学的転移陰性腫大間膜リンパ節の意義の検討

村田悠記, 小倉淳司, 上原圭, 小林龍太朗, 國料俊男, 伊神剛, 水野隆史, 山口淳平, 宮田一志, 尾上俊介, 砂川真輝, 渡辺伸元, 杉田静紀, 川勝章司, 中山吾郎, 服部憲史, 梅田晋一, 横山幸浩, 小寺泰弘, 江畑智希

日本外科学会定期学術集会抄録集 Vol. 123回 page： SF - 2[Y] 2023.4

薬物療法の新展開胃癌転移制御を目指した創薬研究の展開

神田光郎, 田中千恵, 清水大, 中西香企, 高見秀樹, 猪川祥邦, 服部憲史, 林真路, 中山吾郎, 藤原道隆, 小寺泰弘

日本胃癌学会総会記事 Vol. 95回 page： 164 - 164 2023.2

胃癌術後肺転移に対する手術の治療成績

野々垣彰, 中西香企, 田中千恵, 神田光郎, 清水大, 猪川祥邦, 服部憲史, 中山吾郎, 藤原道隆, 小寺泰弘

日本胃癌学会総会記事 Vol. 95回 page： 323 - 323 2023.2

内視鏡下胃切除の教育・トレーニング当院におけるロボット支援下胃切除術のトレーニング法

田中千恵, 中西香企, 清水大, 杉田静紀, 梅田晋一, 猪川祥邦, 高見秀樹, 服部憲史, 林真路, 神田光郎, 中山吾郎, 藤原道隆, 小寺泰弘

日本胃癌学会総会記事 Vol. 95回 page： 225 - 225 2023.2

下部進行直腸癌における術前化学療法後の側方リンパ節縮小の意義の検討

小倉淳司, 上原圭, 村田悠記, 神原祐一, 小池佳勇, 三品拓也, 小林龍太郎, 宮田一志, 水野隆史, 山口淳平, 國料俊男, 梅田晋一, 服部憲史, 中山吾郎, 横山幸浩, 小寺泰弘, 江畑智希

日本大腸肛門病学会雑誌 Vol. 76 ( 2 ) page： 184 - 184 2023.2

免疫チェックポイント阻害薬により病理学的完全奏功が得られたMSI-High大腸癌腹壁限局播種再発・小腸間膜リンパ節転移の1例

小林龍太朗, 上原圭, 小倉淳司, 村田悠記, 鳥居直矢, 深田浩志, 神原祐一, 梅田晋一, 服部憲史, 中山吾郎, 尾上俊介, 宮田一志, 山口淳平, 水野隆史, 伊神剛, 横山幸浩, 小寺泰弘, 江畑智希

日本大腸肛門病学会雑誌 Vol. 76 ( 2 ) page： 248 - 248 2023.2

骨盤外科手術に必要な外科解剖-拡大手術、他臓器合併切除を安全に行うために- 局所進行・再発直腸癌に対する腹腔鏡下骨盤内臓全摘術の安全な導入に向けた取り組み umbilical 1stアプローチの有用性

村田悠記, 上原圭, 小倉淳司, 小林龍太朗, 鳥居直矢, 深田浩志, 野中有紀子, 伊神剛, 水野隆史, 宮田一志, 尾上俊介, 中山吾郎, 服部憲史, 梅田晋一, 江畑智希

日本内視鏡外科学会雑誌 Vol. 27 ( 7 ) page： 908 - 908 2022.12

当院におけるロボット支援下胃切除術教育の工夫

田中千恵, 中西香企, 清水大, 梅田晋一, 猪川祥邦, 高見秀樹, 服部憲史, 林真路, 神田光郎, 中山吾郎, 小寺泰弘

日本内視鏡外科学会雑誌 Vol. 27 ( 7 ) page： 1649 - 1649 2022.12

当院におけるロボット支援下胃切除術教育の工夫

田中千恵, 中西香企, 清水大, 梅田晋一, 猪川祥邦, 高見秀樹, 服部憲史, 林真路, 神田光郎, 中山吾郎, 小寺泰弘

日本内視鏡外科学会雑誌 Vol. 27 ( 7 ) page： 1649 - 1649 2022.12

進行再発直腸癌に対する腹腔鏡拡大手術:手技の工夫と成績当科における局所再発直腸癌に対する腹腔鏡下拡大手術の治療成績

深田浩志, 上原圭, 小倉淳司, 村田悠記, 鳥居直矢, 小林龍太朗, 伊神剛, 水野隆史, 宮田一志, 尾上俊介, 砂川真輝, 杉田静紀, 服部憲史, 中山吾郎, 江畑智希

日本内視鏡外科学会雑誌 Vol. 27 ( 7 ) page： 933 - 933 2022.12

女性医師の活躍できる内視鏡外科手術と働き方改革の在り方とは? 腹腔鏡下手術における使用デバイスの操作性に関する検討

田中千恵, 中西香企, 清水大, 梅田晋一, 猪川祥邦, 田中伸孟, 高見秀樹, 服部憲史, 林真路, 神田光郎, 中山吾郎, 小寺泰弘

日本内視鏡外科学会雑誌 Vol. 27 ( 7 ) page： 415 - 415 2022.12

T4b大腸癌に対する腹腔鏡手術:手技の工夫と成績 cT4b大腸癌に対する腹腔鏡手術の適応と攻略法

上原圭, 小倉淳司, 村田悠記, 小林龍太郎, 神原祐一, 深田浩志, 野中有紀子, 伊神剛, 水野隆史, 宮田一志, 尾上俊介, 杉田静紀, 服部憲史, 中山吾郎, 江畑智希

日本内視鏡外科学会雑誌 Vol. 27 ( 7 ) page： 79 - 79 2022.12

イマチニブ投与後に経肛門アプローチを併用して前方臓器温存し得た直腸巨大GISTの1例

神原祐一, 上原圭, 小倉淳司, 村田悠記, 小林龍太朗, 伊神剛, 水野隆史, 宮田一志, 尾上俊介, 砂川真輝, 杉田静紀, 梅田晋一, 服部憲史, 中山吾郎, 江畑智希

日本内視鏡外科学会雑誌 Vol. 27 ( 7 ) page： 659 - 659 2022.12

困難症例に対する大腸癌手術:手技の工夫と成績他臓器浸潤結腸癌に対する腹腔鏡手術の実際と工夫

小倉淳司, 上原圭, 村田悠記, 鳥居直矢, 小林龍太朗, 深田浩志, 野中有紀子, 伊神剛, 水野隆史, 宮田一志, 尾上俊介, 中山吾郎, 服部憲史, 梅田晋一, 江畑智希

日本内視鏡外科学会雑誌 Vol. 27 ( 7 ) page： 1875 - 1875 2022.12

女性医師の活躍できる内視鏡外科手術と働き方改革の在り方とは? 腹腔鏡下手術における使用デバイスの操作性に関する検討

田中千恵, 中西香企, 清水大, 梅田晋一, 猪川祥邦, 田中伸孟, 高見秀樹, 服部憲史, 林真路, 神田光郎, 中山吾郎, 小寺泰弘

日本内視鏡外科学会雑誌 Vol. 27 ( 7 ) page： 415 - 415 2022.12

胃癌腹膜播種に対するPTEGの使用経験

杉山史剛, 中西香企, 田中千恵, 神田光郎, 清水大, 高見秀樹, 猪川祥邦, 服部憲史, 林真路, 中山吾郎, 藤原道隆, 小寺泰弘

日本消化器病学会東海支部例会プログラム抄録集 Vol. 137回 page： 73 - 73 2022.11

胃癌腹膜播種に対するPTEGの使用経験

杉山史剛, 中西香企, 田中千恵, 神田光郎, 清水大, 高見秀樹, 猪川祥邦, 服部憲史, 林真路, 中山吾郎, 藤原道隆, 小寺泰弘

日本消化器病学会東海支部例会プログラム抄録集 Vol. 137回 page： 73 - 73 2022.11

Downregulation of ROBO4 in Pancreatic Cancer Serves as a Biomarker of Poor Prognosis and Indicates Increased Cell Motility and Proliferation Through Activation of MMP-9. International journal

Masaya Yamanaka, Masamichi Hayashi, Fuminori Sonohara, Suguru Yamada, Haruyoshi Tanaka, Akihiro Sakai, Shinji Mii, Daigo Kobayashi, Keisuke Kurimoto, Nobutake Tanaka, Yoshikuni Inokawa, Hideki Takami, Norifumi Hattori, Mitsuro Kanda, Chie Tanaka, Goro Nakayama, Masahiko Koike, Yasuhiro Kodera

Annals of surgical oncology Vol. 29 ( 11 ) page： 7180 - 7189 2022.10

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

BACKGROUND: The axon guidance gene family, SLIT/ROBO pathway, controls neural network formation, which correlates with the development of several cancers. METHODS: We found through analysis of the public database that ROBO4, one of the axon guidance molecules among the SLIT/ROBO family, is significantly downregulated in primary pancreatic cancer tissues compared with adjacent normal tissues. We carried out transfection experiments using three pancreatic cancer cell lines (MiaPaCa-2, BxPC-3, and SW1990) and one pancreatic duct epithelial cell line (HPDE6c7). A total of 51 clinical samples were then examined by immunohistochemical staining to find an association between ROBO4 expression at the protein level, clinical characteristics, and surgical outcomes. RESULTS: ROBO4 overexpression suppressed the invasion and migration abilities in MiaPaCa-2 and BxPC-3, while ROBO4 siRNA transfection to SW1990 and HPDE6c7 enhanced those activities. PCR-based profiling detected MMP-9 as a candidate downstream target of ROBO4, which was validated by decreased MMP-9 activity after the ROBO4 overexpression assay. High ROBO4 expression clinical samples had significantly better overall survival rather than low ROBO4 cases (P = 0.048). CONCLUSION: These findings suggest that decreased ROBO4 expression activates malignant phenotypes in cancer cells and is correlated with poor survival outcomes in pancreatic cancer.

DOI： 10.1245/s10434-022-12039-5

高齢者に対する周術期感染症の予防策高齢者胃癌に対する術後感染性合併症発生の現状と対策肺炎を中心に

ASO Visual Abstract: Downregulation of ROBO4 in Pancreatic Cancer Serves as a Biomarker of Poor Prognosis and Indicates Increased Cell Motility and Proliferation Through Activation of MMP-9. International journal

Annals of surgical oncology Vol. 29 ( 11 ) page： 7192 - 7193 2022.10

田中千恵, 中西香企, 清水大, 猪川祥邦, 高見秀樹, 服部憲史, 神田光郎, 林真路, 中山吾郎, 藤原道隆, 小寺泰弘

日本外科感染症学会雑誌 Vol. 19 ( 1 ) page： 216 - 216 2022.10

術前治療後の食道癌患者における術前PLR値の術後合併症・予後予測因子としての意義

笹原正寛, 神田光郎, 清水大, 中西香企, 田中千恵, 猪川祥邦, 高見秀樹, 服部憲史, 林真路, 中山吾郎, 藤原道隆, 小寺泰弘

日本癌治療学会学術集会抄録集 Vol. 60回 page： P33 - 2 2022.10

術前治療後の食道癌患者における術前PLR値の術後合併症・予後予測因子としての意義

笹原正寛, 神田光郎, 清水大, 中西香企, 田中千恵, 猪川祥邦, 高見秀樹, 服部憲史, 林真路, 中山吾郎, 藤原道隆, 小寺泰弘

日本癌治療学会学術集会抄録集 Vol. 60回 page： P33 - 2 2022.10

高齢者に対する周術期感染症の予防策高齢者胃癌に対する術後感染性合併症発生の現状と対策肺炎を中心に

田中千恵, 中西香企, 清水大, 猪川祥邦, 高見秀樹, 服部憲史, 神田光郎, 林真路, 中山吾郎, 藤原道隆, 小寺泰弘

日本外科感染症学会雑誌 Vol. 19 ( 1 ) page： 216 - 216 2022.10

胃癌に対するナビゲーションサージェリーの工夫胃癌に対する低侵襲手術における術中マーキング法

田中千恵, 中西香企, 清水大, 猪川祥邦, 高見秀樹, 服部憲史, 神田光郎, 林真路, 中山吾郎, 藤原道隆, 小寺泰弘

日本臨床外科学会雑誌 Vol. 83 ( 増刊 ) page： S161 - S161 2022.10

Transcriptomic profiling on localized gastric cancer identified CPLX1 as a gene promoting malignant phenotype of gastric cancer and a predictor of recurrence after surgery and subsequent chemotherapy

Haruyoshi Tanaka, Mitsuro Kanda, Dai Shimizu, Chie Tanaka, Yoshikuni Inokawa, Norifumi Hattori, Masamichi Hayashi, Goro Nakayama, Yasuhiro Kodera

Journal of Gastroenterology Vol. 57 ( 9 ) page： 640 - 653 2022.9

直腸癌術後異時性肝・肺転移に対して化学療法開始後1年7ヵ月でconversion切除し得た1例

深田浩志, 上原圭, 小倉淳司, 村田悠記, 國料俊男, 伊神剛, 水野隆史, 山口淳平, 宮田一志, 尾上俊介, 砂川真輝, 渡辺伸元, 杉田静紀, 服部憲史, 中山吾郎, 横山幸浩, 小寺泰弘, 江畑智希

日本大腸肛門病学会雑誌 Vol. 75 ( 9 ) page： A221 - A221 2022.9

直腸癌術前集学的治療の成績:Watch & Waitを含めて局所進行直腸癌に対する術前化学療法を基本とした治療戦略Tripletレジメンの臨床経験とWatch and Wait strategyの安全な導入

小倉淳司, 上原圭, 村田悠記, 鳥居直矢, 小林龍太朗, 深田浩志, 國料俊男, 伊神剛, 水野隆史, 山口淳平, 宮田一志, 尾上俊介, 砂川真輝, 渡辺伸元, 杉田静紀, 服部憲史, 中山吾郎, 横山幸浩, 小寺泰弘, 江畑智希

日本大腸肛門病学会雑誌 Vol. 75 ( 9 ) page： A54 - A54 2022.9

Prognostic Value of a Modified Albumin-Bilirubin Score Designed for Patients with Esophageal Squamous Cell Carcinoma After Radical Resection. International journal

Takahiro Shinozuka, Mitsuro Kanda, Dai Shimizu, Chie Tanaka, Yoshikuni Inokawa, Norifumi Hattori, Masamichi Hayashi, Masahiko Koike, Yasuhiro Kodera

Annals of surgical oncology Vol. 29 ( 8 ) page： 4889 - 4896 2022.8

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

BACKGROUND: The albumin-bilirubin (ALBI) score was originally developed to assess the severity of liver dysfunction in patients with hepatocellular carcinoma and has subsequently been used as a prognostic marker for that disease. Here, we examined the value of the preoperative ALBI score as a prognostic marker for patients with esophageal squamous cell carcinoma (ESCC) after radical esophagectomy. METHODS: We retrospectively analyzed data from 449 patients who underwent curative resection for ESCC. The ALBI score was calculated as (log10 serum bilirubin [μmol/l] × 0.66) + (serum albumin [g/l] × - 0.0852). Receiver operating characteristic curve analysis was used to define a preoperative modified ALBI (mALBI) score for patient stratification. RESULTS: Of the 449 ESCC patients, 232 and 217 were assigned to mALBI Grade 1 or Grade 2 groups based on preoperative ALBI scores of ≤ - 3.33 or > - 3.33, respectively. Preoperative mALBI grade was significantly associated with age, excessive alcohol consumption, squamous cell carcinoma antigen level, and clinical disease stage. The mALBI Grade 2 group had significantly shorter disease-specific and recurrence-free survival than the mALBI Grade 1 group. Multivariate analysis demonstrated that mALBI Grade 2 was an independent prognostic factor for disease-specific survival (hazard ratio 1.86, 95% confidence interval 1.18-2.93, P = 0.0074). In most subgroup analyses, mALBI Grade 2 was associated with a greater risk of disease-specific death. CONCLUSIONS: mALBI grade serves as a simple and useful prognostic marker for disease-specific survival in patients with ESCC after radical esophagectomy.

DOI： 10.1245/s10434-022-11654-6

ASO Visual Abstract: Prognostic Value of a Modified Albumin-Bilirubin Grade Designed for Patients with Esophageal Squamous Cell Carcinoma after Radical Resection. International journal

Takahiro Shinozuka, Mitsuro Kanda, Dai Shimizu, Chie Tanaka, Yoshikuni Inokawa, Norifumi Hattori, Masamichi Hayashi, Masahiko Koike, Yasuhiro Kodera

Annals of surgical oncology Vol. 29 ( 8 ) page： 4899 - 4899 2022.8

胃癌術後早期ドレーンアミラーゼ値の有用性早期治療介入にむけて

中西香企, 神田光郎, 田中千恵, 清水大, 猪川祥邦, 服部憲史, 林真路, 中山吾郎, 藤原道隆, 小寺泰弘

日本消化器外科学会総会 Vol. 77回 page： O6 - 4 2022.7

Expression of cellular retinoic acid binding protein 1 predicts peritoneal recurrence of gastric cancer. International journal

Kazuki Sakata, Mitsuro Kanda, Dai Shimizu, Shunsuke Nakamura, Yoshikuni Inokawa, Norifumi Hattori, Masamichi Hayashi, Chie Tanaka, Goro Nakayama, Yasuhiro Kodera

International journal of oncology Vol. 60 ( 6 ) 2022.6

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

To improve the outcome of gastric cancer, novel markers that predict postoperative prognosis are required. For this purpose, the function of cellular retinoic acid binding protein 1 (CRABP1) in gastric cancer cells was investigated and it was determined whether it serves as a novel biomarker for gastric cancer. Reverse transcription‑quantitative (RT‑q)PCR and a PCR‑array method were used to determine whether the expression of CRABP1 mRNA in gastric cancer cell lines correlated with the expression of cancer‑related genes. The correlations of CRABP1 mRNA expression in tissues with clinicopathological factors of 230 patients who underwent radical gastrectomy were further evaluated. CRABP1 mRNA levels varied among gastric cancer cell lines and showed significant positive correlations with numerous epithelial‑mesenchymal transition factors. Additionally, CRABP1 knockdown significantly suppressed the proliferation, migration and invasion of gastric cancer cell lines. In a mouse xenograft model of peritoneal metastasis of gastric cancer, it was found that the total weight of disseminated nodules was lower in the group, in which CRABP1 mRNA levels were knocked down compared with those of the untransfected group. Disease‑free survival (DFS) was significantly shorter in patients with high expression of CRABP1, and multivariate analysis of DFS revealed that high expression of CRABP1 in the tumor area and lymph node metastasis served as an independent factor associated with poor prognosis. High expression of CRABP1 in cancer tissues was associated with a greater incidence of peritoneal recurrences after curative gastrectomy. These findings indicated that CRABP1 contributes to the malignant phenotype of gastric cancer cells and may serve as a biomarker for prognosing recurrence after curative resection, particularly peritoneal dissemination.

DOI： 10.3892/ijo.2022.5353

Lysosomal-associated membrane protein family member 5 promotes the metastatic potential of gastric cancer cells.

Shinichi Umeda, Mitsuro Kanda, Dai Shimizu, Shunsuke Nakamura, Koichi Sawaki, Yoshikuni Inokawa, Norifumi Hattori, Masamichi Hayashi, Chie Tanaka, Goro Nakayama, Yasuhiro Kodera

Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association Vol. 25 ( 3 ) page： 558 - 572 2022.5

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

BACKGROUND: Metastatic gastric cancer (GC) has a poor prognosis, and elucidating the molecular mechanisms involved in metastasis may lead to the development of novel therapeutic modalities. METHODS: Transcriptome analysis of surgically resected metastatic tissue from GC patients and noncancerous tissue was performed to identify novel metastasis-related genes. Analyses of in vitro cell function, apoptosis, the cell cycle and cancer stemness were performed using GC cell lines with a stable knockout of a candidate gene. In vivo percutaneous, peritoneal dissemination and liver metastasis xenograft models were also generated. PCR array and proteome analyses were performed. Expression of the candidate gene was analyzed in GC tissues from 300 patients. RESULTS: Lysosomal Associated Membrane Protein Family Member 5 (LAMP5) was upregulated in the metastatic tissues. LAMP5 knockout significantly suppressed proliferation, invasion, and migration of GC cells and increased apoptosis, cell cycle arrest and cancer stemness. LAMP5 knockout virtually suppressed tumor growth in in vivo percutaneous, peritoneal dissemination and liver metastasis models. EMT- and autophagy-related genes were associated with LAMP5. High LAMP5 mRNA levels were significantly associated with a worse prognosis. CONCLUSION: LAMP5 plays a vital role in metastasis formation and may be a promising novel target of drug development for metastatic GC in the future.

DOI： 10.1007/s10120-022-01284-y

がんトランスレーショナルリサーチ外科臨床検体を用いたトランスクリプトーム解析からの癌治療抗体医薬開発研究

神田光郎, 清水大, 中西香企, 田中千恵, 猪川祥邦, 高見秀樹, 服部憲史, 林真路, 中山吾郎, 藤原道隆, 小寺泰弘

日本外科系連合学会誌 Vol. 47 ( 3 ) page： 401 - 401 2022.5

腹腔鏡下直腸癌手術におけるエネルギーデバイスの選択腹腔鏡下直腸癌手術におけるエネルギーデバイスの選択電気メスを中心とした立場から

上原圭, 小倉淳司, 村田悠記, 小林龍太郎, 神原祐一, 深田浩志, 服部憲史, 中山吾郎, 伊神剛, 水野隆史, 山口淳平, 宮田一志, 尾上俊介, 渡辺伸元, 横山幸浩, 江畑智希

日本外科系連合学会誌 Vol. 47 ( 3 ) page： 413 - 413 2022.5

切除可能同時性肝転移症例の治療戦略肝実質温存術式の有用性

三品拓也, 水野隆史, 上原圭, 小倉淳司, 村田悠記, 小池佳勇, 神原祐一, 西村元伸, 小林龍太朗, 服部憲史, 中山吾郎, 國料俊男, 伊神剛, 山口淳平, 宮田一志, 尾上俊介, 砂川真輝, 渡辺伸元, 横山幸浩, 江畑智希

日本外科学会定期学術集会抄録集 Vol. 122回 page： SF - 7 2022.4

進行直腸癌に対する治療戦略【International】所進行直腸癌に対する術前化学療法におけるbevacizumabの意義の検討

小倉淳司, 上原圭, 村田悠記, 小池佳男, 三品拓也, 神原祐一, 西村元伸, 小林龍太郎, 服部憲史, 中山吾郎, 横山幸浩, 國料俊男, 伊神剛, 水野隆史, 山口淳平, 宮田一志, 尾上俊介, 砂川真輝, 渡辺伸元, 江畑智希

日本外科学会定期学術集会抄録集 Vol. 122回 page： PD - 1 2022.4

高齢者の上部消化管癌に対する治療方針高齢者機能評価から考える高齢者胃癌に対する治療法

田中千恵, 中西香企, 梅田晋一, 清水大, 猪川祥邦, 高見秀樹, 服部憲史, 神田光郎, 林真路, 中山吾郎, 藤原道隆, 小寺泰弘

日本外科学会定期学術集会抄録集 Vol. 122回 page： WS - 4 2022.4

骨盤内臓全摘術後の骨盤死腔炎のリスク因子から考える対策法

小林龍太朗, 上原圭, 小倉淳司, 村田悠記, 小池佳勇, 三品拓也, 神原祐一, 西村元伸, 服部憲史, 中山吾郎, 國料俊男, 伊神剛, 水野隆史, 山口淳平, 宮田一志, 尾上俊介, 砂川真輝, 渡邊伸元, 横山幸浩, 江畑智希

日本外科学会定期学術集会抄録集 Vol. 122回 page： DP - 4 2022.4

骨盤内臓全摘術後の骨盤死腔炎のリスク因子から考える対策法

日本外科学会定期学術集会抄録集 Vol. 122回 page： DP - 4 2022.4

進行直腸癌に対する治療戦略【International】所進行直腸癌に対する術前化学療法におけるbevacizumabの意義の検討

日本外科学会定期学術集会抄録集 Vol. 122回 page： PD - 1 2022.4

食道扁平上皮癌予後マーカーとしてのOPLAH発現

清水大, 神田光郎, 小池聖彦, 佐藤雄亮, 猪川祥邦, 高見秀樹, 服部憲史, 林真路, 田中千恵, 中山吾郎, 本山悟, 藤原道隆, 小寺泰弘

日本外科学会定期学術集会抄録集 Vol. 122回 page： DP - 5 2022.4

切除可能同時性肝転移症例の治療戦略肝実質温存術式の有用性

日本外科学会定期学術集会抄録集 Vol. 122回 page： SF - 7 2022.4

ウィズコロナ時代のオンライン補完型外科臨床実習

高見秀樹, 宮田一志, 渡辺伸元, 柴田雅央, 小倉淳司, 清水大, 服部憲史, 菊森豊根, 江畑智希, 小寺泰弘

日本外科学会定期学術集会抄録集 Vol. 122回 page： DP - 6 2022.4

Drain Amylase Concentrations at 3 h After Gastrectomy Enhance Early Prediction of Postoperative Peripancreatic Inflammatory Fluid Collection. International journal

Koki Nakanishi, Mitsuro Kanda, Chie Tanaka, Shigeomi Takeda, Katsuhito Tanaka, Dai Shimizu, Yoshikuni Inokawa, Norifumi Hattori, Masamichi Hayashi, Goro Nakayama, Michitaka Fujiwara, Yasuhiro Kodera

World journal of surgery Vol. 46 ( 3 ) page： 648 - 655 2022.3

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

BACKGROUND: Despite numerous studies of peripancreatic inflammatory fluid collection (PIFC) that report on the relevance of the drain amylase concentration (D-AMY), early prediction using this assay is problematic. This study aimed to investigate the clinical significance of measuring the D-AMY at 3 h after gastrectomy (POD0) for gastric cancer. METHODS: This retrospective analysis included consecutive patients who underwent gastrectomy combined with peripancreatic lymph node dissection. The predictive value of D-AMY on POD0 and postoperative day 1 (POD1) for clinically relevant PIFC was evaluated together or individually. RESULTS: Analyses were performed in 204 patients. Twenty (9.8%) patients experienced PIFC. D-AMY cutoffs of 721 IU/L on POD0 and 1695 IU/L on POD1 were determined using the receiver operating characteristic curve analysis for predicting PIFC. The D-AMY on POD0 had higher sensitivity (80%) but lower specificity (66.3%) for prediction of PIFC, compared with those of D-AMY on POD1 (65%, 89.1%, respectively). When combination marker analysis was performed, the highest risk group (D-AMY ≥ the cutoff values of POD0 and POD1) were associated with an elevated rate of occurrence (44%) and a high positive likelihood ratio (7.36) compared with those of the single cutoff group. The lowest risk group (D-AMY < the cutoff values on POD0 and POD1) was associated with a low rate of occurrence (2.5%) and low negative likelihood ratio (0.24) compared with those of the single cutoff group. CONCLUSIONS: Combined measurements of D-AMYs on POD0 and POD1 enhanced early prediction of PIFC after gastrectomy.

DOI： 10.1007/s00268-021-06401-z

The significance of the time to arterial perfusion in intraoperative ICG angiography during colorectal surgery. Reviewed International journal

Toshisada Aiba, Kay Uehara, Atsushi Ogura, Aya Tanaka, Yoshihiko Yonekawa, Norifumi Hattori, Goro Nakayama, Yasuhiro Kodera, Tomoki Ebata, Masato Nagino

Surgical endoscopy Vol. 35 ( 12 ) page： 7227 - 7235 2021.12

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

BACKGROUND: Intraoperative indocyanine green angiography (ICG-A) is a promising tool to confirm blood supply; however, the assessment is difficult without clear demarcation. In this study, the clinical impact of the time to arterial perfusion (TAP) on anastomotic leakage (AL) was evaluated, especially in patients without ICG demarcation. METHODS: The TAP was assessed using ICG-A during colorectal surgery in 110 patients. ICG demarcation required changing the transection line, and the TAP was measured at the new stump. The patients were divided into marginal flow (MF) and direct flow (DF) groups according to the arterial route. Delayed TAP was defined as the third quartile or slower TAP in each group. RESULTS: Sixty-six patients (60%) were classified into the MF group, including 64 patients who underwent rectal or sigmoid resection with high ligation of the inferior mesenteric artery. The cut-off value of the delayed TAP in the MF group was significantly slower than that in the DF group (30 and 22 s, respectively, p < 0.001). In the entire cohort, the transection line was changed in 2 patients, resulting in no AL. Nevertheless, AL still developed in 6 patients (5.4%), 5 of whom were in the MF group, and delayed TAP was found in 5 of 6 patients. Delayed TAP was significantly associated with AL in the MF group (p = 0.046). CONCLUSIONS: In patients without ICG demarcation, delayed TAP might be helpful for predicting the high-risk patients with AL in the MF group; however, performing diverting stoma or strictly careful observation might be a realistic reaction.

DOI： 10.1007/s00464-020-08185-0

肝門部胆管癌術後,三度の右側大腸癌を切除した一例

神原祐一, 上原圭, 小倉淳司, 村田悠記, 三品拓也, 鈴木優美, 國料俊男, 伊神剛, 水野隆史, 山口淳平, 宮田一志, 尾上俊介, 渡辺伸元, 佐藤雄介, 服部憲史, 中山吾郎, 相場利貞, 横山幸浩, 小寺泰弘, 江畑智希

日本消化器外科学会雑誌 Vol. 54 ( Suppl.2 ) page： 186 - 186 2021.11

腹腔鏡下仙骨合併腫瘍切除を施行した骨盤内巨大神経鞘腫の一例

西村元伸, 上原圭, 小倉淳司, 服部憲史, 中山吾郎, 國料俊男, 伊神剛, 水野隆史, 山口淳平, 宮田一志, 尾上俊介, 渡辺伸元, 横山幸浩, 小寺泰弘, 江畑智希

日本臨床外科学会雑誌 Vol. 82 ( 増刊 ) page： S932 - S932 2021.10

Blockade of CHRNB2 signaling with a therapeutic monoclonal antibody attenuates the aggressiveness of gastric cancer cells. Reviewed International journal

Mitsuro Kanda, Dai Shimizu, Shunsuke Nakamura, Koichi Sawaki, Shinichi Umeda, Takashi Miwa, Haruyoshi Tanaka, Yoshikuni Inokawa, Norifumi Hattori, Masamichi Hayashi, Chie Tanaka, Goro Nakayama, Yohei Iguchi, Masahisa Katsuno, Yasuhiro Kodera

Oncogene Vol. 40 ( 36 ) page： 5495 - 5504 2021.9

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

Here, we evaluated the therapeutic potential of antibodies (Abs) targeting cholinergic receptor nicotinic beta 2 subunit (CHRNB2) in gastric cancer. To investigate the effects of these Abs on malignant phenotypes in vitro and in mouse xenograft models, we generated gene knockouts through genome editing, performed RNA interference-mediated knockdown of gene expression, and ectopically expressed CHRNB2 in gastric cancer cells. The effects of anti-CHRNB2 Abs on the proliferation of cancer cells were evaluated both in vitro and in vivo. We determined the effects of Chrnb2 deficiency on mice and the clinical significance of CHRNB2 expression in gastric cancer clinical specimens. Knockdown of CHRNB2 attenuated gastric cancer cell proliferation, whereas forced overexpression of CHRNB2 increased cell proliferation. Knockout of CHRNB2 significantly influenced cell survival and functions associated with metastasis. The effects of polyclonal Abs targeting the C- and N-termini of CHRNB2 guided the development of anti-CHRNB2 monoclonal Abs that inhibited the growth of gastric cancer cells in vitro and in vivo. Pathway analysis revealed that CHRNB2 interfered with signaling through the PI3K-AKT and JAK-STAT pathways. Chrnb2-deficient mice exhibited normal reproduction, organ functions, and motor functions. CHRNB2 regulates multiple oncological phenotypes associated with metastasis, and blockade of CHRNB2 expression using specific Abs shows promise for controlling metastasis in gastric cancer.

DOI： 10.1038/s41388-021-01945-9

結腸癌腹膜播種に対する外科切除の意義

三品拓也, 上原圭, 小倉淳司, 村田悠記, 小池佳勇, 鈴木優美, 神原祐一, 西村元伸, 伊神剛, 水野隆史, 山口淳平, 宮田一志, 尾上俊介, 渡辺伸元, 佐藤雄介, 服部憲史, 中山吾郎, 横山幸浩, 小寺泰弘, 江畑智希

日本大腸肛門病学会雑誌 Vol. 74 ( 9 ) page： A209 - A209 2021.9

当科におけるBRAF V600E変異陽性大腸癌に対するBRAF阻害剤併用療法の使用経験

神野孝徳, 上原圭, 小倉淳司, 村田悠記, 三品拓也, 小池佳勇, 神原祐一, 鈴木優美, 西村元伸, 伊神剛, 水野隆史, 山口淳平, 宮田一志, 尾上俊介, 渡辺伸元, 服部憲史, 中山吾郎, 横山幸浩, 小寺泰弘, 江畑智希

日本大腸肛門病学会雑誌 Vol. 74 ( 9 ) page： A208 - A208 2021.9

当科における局所進行結腸癌に対する術前化学療法の臨床経験

小倉淳司, 上原圭, 小池佳勇, 村田悠記, 神野孝徳, 鈴木優美, 三品拓也, 神原祐一, 西村元伸, 伊神剛, 水野隆史, 山口淳平, 宮田一志, 尾上俊介, 渡辺伸元, 服部憲史, 中山吾郎, 横山幸浩, 小寺泰弘, 江畑智希

日本大腸肛門病学会雑誌 Vol. 74 ( 9 ) page： A200 - A200 2021.9

会陰部に広範に自壊した局所再発直腸粘液癌に対し、仙骨合併骨盤内臓全摘術+複数の筋皮弁再建を施行し、R0切除を達成し得た一例

神原祐一, 上原圭, 小倉淳司, 村田悠記, 三品拓也, 小池佳勇, 鈴木優美, 西村元伸, 伊神剛, 水野隆史, 山口淳平, 宮田一志, 尾上俊介, 渡辺伸元, 佐藤雄介, 服部憲史, 中山吾郎, 横山幸浩, 小寺泰弘, 江畑智希

日本大腸肛門病学会雑誌 Vol. 74 ( 9 ) page： A204 - A204 2021.9

A Possible Definition of Oligometastasis in Pancreatic Cancer and Associated Survival Outcomes. Reviewed International journal

Masaya Yamanaka, Masamichi Hayashi, Suguru Yamada, Fuminori Sonohara, Hideki Takami, Yoshikuni Inokawa, Dai Shimizu, Norifumi Hattori, Mitsuro Kanda, Chie Tanaka, Goro Nakayama, Masahiko Koike, Yasuhiro Kodera

Anticancer research Vol. 41 ( 8 ) page： 3933 - 3940 2021.8

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

BACKGROUND: Oligometastatic cancer (OM) is possibly associated with relatively better survival outcomes. We attempted to identify cases in line with this OM concept. PATIENTS AND METHODS: A total of 130 cases with unresectable metastatic pancreatic cancer underwent non-curative surgery from April 2001 to December 2019. Sites of metastasis, clinicopathological information, and surgical outcomes were collected to formulate a better definition of OM. RESULTS: OM criteria were defined as having metastasis to a single organ, few countable lesions and low serum cancer antigen 19-9 level. The median overall survival after non-curative surgery of OM cases was 13.0 months and was significantly better than that of non-OM cases (8.4 months, p=0.003). CONCLUSION: We propose single-organ metastasis of limited tumor volume (H1 or P1/2 by the Japanese Society of Cancer of the Colon and Rectum classification) and low serum cancer antigen 19-9 level (<2,000 U/ml) as new criteria for defining OM pancreatic cancer.

DOI： 10.21873/anticanres.15189

High Serum Uric Acid Levels Could Be a Risk Factor of Hepatocellular Carcinoma Recurrences. Reviewed International journal

Masamichi Hayashi, Suguru Yamada, Hiroshi Tanabe, Hideki Takami, Yoshikuni Inokawa, Fuminori Sonohara, Dai Shimizu, Norifumi Hattori, Mitsuro Kanda, Chie Tanaka, Goro Nakayama, Masahiko Koike, Michitaka Fujiwara, Yasuhiro Kodera

Nutrition and cancer Vol. 73 ( 6 ) page： 996 - 1003 2021.7

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

BACKGROUND: The Apolipoprotein-related MORtality RISk (AMORIS) study in Sweden revealed that serum uric acid (SUA) was significantly associated with hepatobiliary cancer occurrence. However, the association with postoperative hepatocellular carcinoma (HCC) recurrence has not been reported. METHODS: A total of 256 surgically resected HCC patients were included (from January 2003 to December 2017) in this study. Comparisons in terms of clinicopathologic factors and long-term outcomes were made between patients with high SUA (>6.1 mg/dl) at the time of hepatectomy and low SUA. Besides, SUA data at one postoperative year (1POY) of the same cohort were collected and analyzed in the same manner. RESULTS: About 88.8% of tumor relapse sites were the remnant liver. High SUA levels were associated with male and well-differentiated HCCs. Recurrence-free survival (RFS) of high SUA patients was significantly inferior to low SUA patients [median survival time (MST): 22.7 vs. 28.5 mo, P = 0.033], whereas no difference was observed in overall survival (MST: both not reached, P = 0.771). RFS of high SUA patients at 1POY also showed significantly poorer outcomes than low SUA patients (MST: 29.3 vs. 57.0 mo, P = 0.049). CONCLUSIONS: High SUA implies a significant risk factor of activating hepatocarcinogenesis. Keeping the SUA level low may be recommended after HCC resections.

DOI： 10.1080/01635581.2020.1779758

The carcinoembryonic antigen ratio is a potential predictor of survival in recurrent colorectal cancer. Reviewed

Yumi Suzuki, Atsushi Ogura, Kay Uehara, Toshisada Aiba, Noriaki Ohara, Yuki Murata, Takanori Jinno, Takuya Mishina, Yusuke Sato, Norifumi Hattori, Goro Nakayama, Yasuhiro Kodera, Tomoki Ebata

International journal of clinical oncology Vol. 26 ( 7 ) page： 1264 - 1271 2021.7

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

BACKGROUND: The carcinoembryonic antigen (CEA) "value" itself is often useless in patients with a normal CEA level at initial presentation and those with tumor-irrelevant elevated CEA. Although the unified marker using CEA has been desirable for recurrent tumor staging as well as for primary tumor staging, little is known concerning its relationship with the survival of patients with recurrent colorectal cancer in particular. METHODS: This retrospective historical study included patients who experienced disease relapse after curative surgery for stage I-III colorectal cancer between 2006 and 2018. A total of 129 patients with recurrent disease after curative surgery for colorectal cancer were included. We focused on the CEA "ratio" (CEA-R: the ratio of the CEA level at the time of recurrence to that measured 3 months before recurrence) and aimed to evaluate the correlation between CEA-R and survival in recurrent colorectal cancer. RESULTS: Patients with a high CEA-R (≥ 2) exhibited significantly worse 2 year survival than those with a low CEA-R (< 2) (88.1% vs. 44.9%, P < 0.001), irrespective of the CEA value before primary resection. Multivariate analyses demonstrated that the CEA-R (HR; 3.270, 95% CI 1.646-6.497, P = 0.001) was a significant prognostic factor. CONCLUSION: The CEA-R is a potential marker stratifying the survival of patients with disease relapse who exhibit aggressive biology at recurrent disease foci. As a novel marker, the CEA-R would serve as a clinical guide for tailoring treatment strategies at the time of disease relapse in patients with colorectal cancer.

DOI： 10.1007/s10147-021-01919-7

高齢者胃癌に対する治療の工夫高齢者胃癌手術症例に対する高齢者機能の転帰と工夫

田中千恵, 中西香企, 清水大, 服部憲史, 神田光郎, 中山吾郎, 小池聖彦, 小寺泰弘

日本消化器外科学会総会 Vol. 76回 page： WS10 - 9 2021.7

高齢者胃癌に対する治療の工夫高齢者胃癌手術症例に対する高齢者機能の転帰と工夫

田中千恵, 中西香企, 清水大, 服部憲史, 神田光郎, 中山吾郎, 小池聖彦, 小寺泰弘

日本消化器外科学会総会 Vol. 76回 page： WS10 - 9 2021.7

Indications for neoadjuvant treatment based on risk factors for poor prognosis before and after neoadjuvant chemotherapy alone in patients with locally advanced rectal cancer. Reviewed International journal

Atsushi Ogura, Kay Uehara, Toshisada Aiba, Masanori Sando, Aya Tanaka, Noriaki Ohara, Yuki Murata, Yusuke Sato, Norifumi Hattori, Goro Nakayama, Tomoki Ebata, Yasuhiro Kodera, Masato Nagino

European journal of surgical oncology : the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology Vol. 47 ( 5 ) page： 1005 - 1011 2021.5

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

INTRODUCTION: The oncological benefit of neoadjuvant chemotherapy (NAC) alone for locally advanced rectal cancer (LARC) remains controversial. The aim of this study was to clarify the clinical risk factors for poor prognosis before and after NAC for decision making regarding additional treatment in patients with LARC. MATERIALS AND METHODS: We examined a total of 96 patients with MRI-defined poor-risk locally advanced mid-low rectal cancer treated by NAC alone between 2006 and 2018. Survival outcomes and clinical risk factors for poor prognosis before and after NAC were analyzed. RESULTS: In the median follow-up duration after surgery of 60 months (3-120), the rates of 5-year overall survival (OS), relapse-free survival (RFS), and local recurrence (LR) were 83.6%, 78.4%, and 8.2%, respectively. In the multivariate analyses, patients with cT4 disease had a significantly higher risk of poor OS (HR; 6.10, 95% CI; 1.32-28.15, P = 0.021) than those with cT3 disease. After NAC, ycN+ was significantly associated with a higher risk of poor OS (HR; 5.92, 95% CI; 1.27-27.62, P = 0.024) and RFS (HR; 2.55, 95% CI; 1.01-6.48, P = 0.048) than ycN-. In addition, patients with CEA after NAC (post-CEA) ≥ 5 ng/ml had a significantly higher risk LR (HR; 5.63, 95% CI; 1.06-29.93, P = 0.043). CONCLUSION: NAC alone had an insufficient survival effect on patients with cT4 disease, ycN+, or an elevated post-CEA level. In contrast, NAC alone is a potential treatment for other patients with LARC.

DOI： 10.1016/j.ejso.2020.10.038

当院におけるアフリベルセプトの使用経験について

大原規彰, 上原圭介, 相場利貞, 小倉淳司, 山東雅紀, 田中綾, 村田悠記, 江畑智希, 横山幸浩, 伊神剛, 深谷昌秀, 水野隆史, 山口淳平, 中山吾郎, 服部憲史, 佐藤雄介, 小寺泰弘, 梛野正人

日本大腸肛門病学会雑誌 Vol. 74 ( 5 ) page： 342 - 342 2021.5

下部進行直腸癌に対する術前化学療法の効果と限界

小倉淳司, 上原圭介, 相場利貞, 山東雅紀, 田中綾, 大原規彰, 村田悠記, 江畑智希, 横山幸浩, 伊神剛, 深谷昌秀, 水野隆史, 山口淳平, 中山吾郎, 服部憲史, 佐藤雄介, 小寺泰弘, 梛野正人

日本大腸肛門病学会雑誌 Vol. 74 ( 5 ) page： 337 - 337 2021.5

Hepatic metastasis of gastric cancer is associated with enhanced expression of ethanolamine kinase 2 via the p53-Bcl-2 intrinsic apoptosis pathway. Reviewed International journal

Takashi Miwa, Mitsuro Kanda, Dai Shimizu, Shinichi Umeda, Koichi Sawaki, Haruyoshi Tanaka, Chie Tanaka, Norifumi Hattori, Masamichi Hayashi, Suguru Yamada, Goro Nakayama, Masahiko Koike, Yasuhiro Kodera

British journal of cancer Vol. 124 ( 8 ) page： 1449 - 1460 2021.4

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

BACKGROUND: Gastric cancer (GC) with hepatic metastasis has a poor prognosis. Understanding the molecular mechanisms involved in hepatic metastasis may contribute to the development of sensitive diagnostic biomarkers and novel therapeutic strategies. METHODS: We performed transcriptome analysis of surgically resected specimens from patients with advanced GC. One of the genes identified as specifically associated with hepatic metastasis was selected for detailed analysis. GC cell lines with knockout of the candidate gene were evaluated in vitro and in vivo. Expression of the candidate gene was analysed in GC tissues from 300 patients. RESULTS: Ethanolamine kinase 2 (ETNK2) was differentially upregulated in GC patients with hepatic metastasis. ETNK2 expression was elevated in GC cell lines derived from haematogenous metastases. ETNK2 knockout significantly suppressed proliferation, invasion, and migration; increased apoptosis; reduced Bcl-2 protein expression; and increased phosphorylated p53 expression. In mouse xenograft models, ETNK2 knockout virtually abolished hepatic metastasis. Stratification of GC patients based on ETNK2 mRNA level revealed significant associations between high ETNK2 tumour expression and both hepatic recurrence and worse prognosis. CONCLUSIONS: Upregulation of ETNK2 in GC enhances hepatic metastasis, possibly via dysregulation of p53-Bcl-2-associated apoptosis. ETNK2 expression may serve as a biomarker for predicting hepatic recurrence and a therapeutic target.

DOI： 10.1038/s41416-021-01271-7

GAD1の食道扁平上皮癌根治的切除後予後予測バイオマーカーとしての意義

岸田貴喜, 神田光郎, 清水大, 田中千恵, 園原史訓, 猪川祥邦, 高見秀樹, 服部憲史, 林真路, 山田豪, 中山吾郎, 小池聖彦, 藤原道隆, 小寺泰弘

日本外科学会定期学術集会抄録集 Vol. 121回 page： PS - 4 2021.4

転移性肝腫瘍に対する至適治療戦略術前化学療法の可否につき考える

林真路, 山田豪, 高見秀樹, 猪川祥邦, 園原史訓, 田中伸孟, 栗本景介, 砂川祐輝, 加藤吉康, 中川暢彦, 鈴木雄之典, 山中雅也, 清水大, 服部憲史, 神田光郎, 田中千恵, 中山吾郎, 小池聖彦, 小寺泰弘

日本外科学会定期学術集会抄録集 Vol. 121回 page： SF - 5 2021.4

膵癌における術前治療中の腫瘍マーカーの比較・検討

砂川祐輝, 山田豪, 田中伸孟, 園原史訓, 猪川祥邦, 高見秀樹, 林真路, 服部憲史, 神田光郎, 田中千恵, 中山吾郎, 小池聖彦, 小寺泰弘

日本外科学会定期学術集会抄録集 Vol. 121回 page： PS - 4 2021.4

膵癌におけるオリゴメタスタシスの臨床的意義

山中雅也, 山田豪, 林真路, 園原史訓, 猪川祥邦, 高見秀樹, 服部憲史, 神田光郎, 田中千恵, 中山吾郎, 小池聖彦, 藤原道隆, 小寺泰弘

日本外科学会定期学術集会抄録集 Vol. 121回 page： SF - 5 2021.4

胃癌切除後予後と原発巣組織中CRABP1発現の相関性の検討

坂田和規, 神田光郎, 清水大, 園原史訓, 高見秀樹, 猪川祥邦, 服部憲史, 林真路, 田中千恵, 山田豪, 中山吾郎, 小池聖彦, 藤原道隆, 小寺泰弘

日本外科学会定期学術集会抄録集 Vol. 121回 page： PS - 5 2021.4

胃癌に対する腹腔鏡下手術でのIndocyanine Green蛍光法を用いたマーキング法の成績

佐藤敏, 田中千恵, 園原史訓, 清水大, 高見秀樹, 猪川祥邦, 服部憲史, 林真路, 神田光郎, 山田豪, 中山吾郎, 小池聖彦, 藤原道隆, 小寺泰弘

日本外科学会定期学術集会抄録集 Vol. 121回 page： PS - 6 2021.4

胃癌における組織中RNFT2遺伝子発現と予後の関連性の検討

笹原正寛, 神田光郎, 清水大, 田中千恵, 園原史訓, 高見秀樹, 猪川祥邦, 服部憲史, 林真路, 山田豪, 中山吾郎, 小池聖彦, 藤原道隆, 小寺泰弘

日本外科学会定期学術集会抄録集 Vol. 121回 page： PS - 4 2021.4

肝胆膵領域癌におけるサルコペニアの臨床的意義と当教室の周術期対策

猪川祥邦, 山田豪, 横山幸浩, 薮崎紀充, 二宮豪, 田中伸孟, 園原史訓, 高見秀樹, 服部憲史, 林真路, 神田光郎, 田中千恵, 中山吾郎, 小池聖彦, 小寺泰弘

日本外科学会定期学術集会抄録集 Vol. 121回 page： SF - 3 2021.4

片側肝動脈合併切除を伴う膵頭十二指腸切除後の肝動脈血流の評価と早期合併症に関する検討

鈴木雄之典, 山田豪, 猪川祥邦, 田中伸孟, 園原史訓, 高見秀樹, 服部憲史, 林真路, 神田光郎, 田中千恵, 中山吾郎, 小池聖彦, 小寺泰弘

日本外科学会定期学術集会抄録集 Vol. 121回 page： PS - 1 2021.4

当教室における膵頭十二指腸切除術後出血に対する対策と治療効果の検討

田中伸孟, 山田豪, 園原史訓, 猪川祥邦, 高見秀樹, 服部憲史, 林真路, 神田光郎, 田中千恵, 中山吾郎, 小池聖彦, 小寺泰弘

日本外科学会定期学術集会抄録集 Vol. 121回 page： SF - 4 2021.4

パンデミック下における外科卒前教育の工夫

高見秀樹, 小池聖彦, 鈴木雄之典, 栗本景介, 田中伸孟, 柴田雅央, 園原史訓, 武内大, 猪川祥邦, 服部憲史, 林真路, 神田光郎, 田中知恵, 山田豪, 中山吾郎, 菊森豊根, 藤原道隆, 小寺泰弘

日本外科学会定期学術集会抄録集 Vol. 121回 page： SP - 7 2021.4

ゲノム編集技術を用いたLAMP5遺伝子の胃癌転移巣形成における役割の検討

梅田晋一, 神田光郎, 清水大, 田中千恵, 園原史訓, 高見秀樹, 猪川祥邦, 服部憲史, 林真路, 山田豪, 中山吾郎, 小池聖彦, Fujiwara Michitaka, 小寺泰弘

日本外科学会定期学術集会抄録集 Vol. 121回 page： SF - 5 2021.4

UR-M膵癌に対するconversion surgeryの課題

加藤吉康, 山田豪, 田中伸孟, 園原史訓, 高見秀樹, 猪川祥邦, 林真路, 服部憲史, 清水大, 神田光郎, 田中千恵, 中山吾郎, 小池聖彦, 小寺泰弘

日本外科学会定期学術集会抄録集 Vol. 121回 page： SF - 6 2021.4

食道扁平上皮癌術後長期生存例における多重癌発生状況

清水大, 小池聖彦, 神田光郎, 園原史訓, 高見秀樹, 猪川祥邦, 服部憲史, 林真路, 田中千恵, 山田豪, 中山吾郎, 藤原道隆, 小寺泰弘

日本外科学会定期学術集会抄録集 Vol. 121回 page： SF - 1 2021.4

クローン病再手術症例に対する腹腔鏡手術の検討

服部憲史, 中山吾郎, 上原圭, 相場利貞, 佐藤雄介, 小倉淳司, 神田光郎, 田中千恵, 山田豪, 小池聖彦, 藤原道隆, 江畑智希, 小寺泰弘

日本外科学会定期学術集会抄録集 Vol. 121回 page： PS - 2 2021.4

当科における痔瘻癌の治療経験

稲垣公太, 中山吾郎, 服部憲史, 上原圭, 相場利貞, 佐藤雄介, 小倉淳司, 山田豪, 小池聖彦, 藤原道隆, 江畑智希, 小寺泰弘

日本外科学会定期学術集会抄録集 Vol. 121回 page： PS - 4 2021.4

局所進行直腸癌における術前化学療法後の病理学的リンパ節転移奏功度の意義

相場利貞, 上原圭, 小倉淳司, 大原規彰, 神野孝徳, 鈴木優美, 三品拓也, 村田悠記, 渡辺伸元, 尾上俊介, 宮田一志, 山口淳平, 水野隆史, 深谷昌秀, 伊神剛, 服部憲史, 中山吾郎, 横山幸浩, 小寺泰弘, 江畑智希

日本外科学会定期学術集会抄録集 Vol. 121回 page： SF - 5 2021.4

大腸癌術後ストマ造設症例における腹壁瘢痕および傍ストマヘルニアの因果関係

大原規彰, 上原圭, 相場利貞, 小倉淳司, 村田悠記, 神野孝徳, 三品拓也, 佐藤雄介, 服部憲史, 中山吾郎, 横山幸浩, 伊神剛, 深谷昌秀, 水野隆史, 山口淳平, 宮田一志, 尾上俊介, 渡辺伸元, 小寺泰弘, 江畑智希

日本外科学会定期学術集会抄録集 Vol. 121回 page： SF - 8 2021.4

再発大腸癌における予後予測マーカーとしてのCEA比の有用性

鈴木優美, 小倉淳司, 上原圭, 相場利貞, 大原規彰, 村田悠記, 神野孝徳, 三品拓也, 服部憲史, 中山吾郎, 横山幸浩, 伊神剛, 深谷昌秀, 水野隆史, 山口淳平, 宮田一志, 尾上俊介, 渡辺伸元, 小寺泰弘, 江畑智希

日本外科学会定期学術集会抄録集 Vol. 121回 page： PS - 1 2021.4

下部直腸癌術後患者の長期腎機能へ影響を与える因子の検討

山東雅紀, 上原圭, 相場利貞, 小倉淳司, 大原規彰, 村田悠記, 三品拓也, 服部憲史, 中山吾郎, 横山幸浩, 伊神剛, 深谷昌秀, 水野隆, 山口淳平, 宮田一志, 尾上俊介, 渡辺伸元, 川井覚, 小寺泰弘, 江畑智希

日本外科学会定期学術集会抄録集 Vol. 121回 page： SF - 5 2021.4

直腸癌同時性肝転移に対する手術治療戦略

米川佳彦, 上原圭, 相場利貞, 小倉淳司, 大原規彰, 村田悠記, 神野孝徳, 鈴木優美, 三品拓也, 服部憲史, 中山吾郎, 横山幸浩, 伊神剛, 深谷昌秀, 水野隆史, 山口淳平, 宮田一志, 尾上俊介, 小寺泰弘, 江畑智希

日本外科学会定期学術集会抄録集 Vol. 121回 page： PS - 8 2021.4

骨盤内臓全摘術後のサルコペニア内腸骨動脈血管処理に着目して

村田悠記, 上原圭, 相場利貞, 小倉淳司, 大原規彰, 神野孝徳, 三品拓也, 鈴木優美, 服部憲史, 中山吾郎, 横山幸浩, 伊神剛, 深谷昌秀, 水野隆史, 山口淳平, 宮田一志, 尾上俊介, 渡辺伸元, 小寺泰弘, 江畑智希

日本外科学会定期学術集会抄録集 Vol. 121回 page： SF - 4 2021.4

進行再発大腸癌に対する集学的アプローチの最先端結腸癌非肝肺転移に対する外科切除の意義

三品拓也, 上原圭, 相場利貞, 小倉淳司, 大原規彰, 村田悠記, 神野孝徳, 鈴木優美, 服部憲史, 中山吾郎, 横山幸浩, 伊神剛, 深谷昌秀, 水野隆史, 山口淳平, 宮田一志, 尾上俊介, 渡辺伸元, 小寺泰弘, 江畑智希

日本外科学会定期学術集会抄録集 Vol. 121回 page： WS - 2 2021.4

進行再発大腸癌における3次治療以降の予後予測因子の検討

神野孝徳, 上原圭, 相場利貞, 小倉淳司, 大原規彰, 村田悠記, 鈴木優美, 三品拓也, 服部憲史, 中山吾郎, 横山幸浩, 伊神剛, 深谷昌秀, 水野隆史, 山口淳平, 宮田一志, 尾上俊介, 渡辺伸元, 小寺泰弘, 江畑智希

日本外科学会定期学術集会抄録集 Vol. 121回 page： SF - 7 2021.4

骨盤内臓全摘術後のサルコペニア内腸骨動脈血管処理に着目して

日本外科学会定期学術集会抄録集 Vol. 121回 page： SF - 4 2021.4

直腸癌同時性肝転移に対する手術治療戦略

日本外科学会定期学術集会抄録集 Vol. 121回 page： PS - 8 2021.4

進行再発大腸癌における3次治療以降の予後予測因子の検討

日本外科学会定期学術集会抄録集 Vol. 121回 page： SF - 7 2021.4

進行再発大腸癌に対する集学的アプローチの最先端結腸癌非肝肺転移に対する外科切除の意義

日本外科学会定期学術集会抄録集 Vol. 121回 page： WS - 2 2021.4

局所進行直腸癌における術前化学療法後の病理学的リンパ節転移奏功度の意義

日本外科学会定期学術集会抄録集 Vol. 121回 page： SF - 5 2021.4

下部直腸癌術後患者の長期腎機能へ影響を与える因子の検討

日本外科学会定期学術集会抄録集 Vol. 121回 page： SF - 5 2021.4

再発大腸癌における予後予測マーカーとしてのCEA比の有用性

日本外科学会定期学術集会抄録集 Vol. 121回 page： PS - 1 2021.4

大腸癌術後ストマ造設症例における腹壁瘢痕および傍ストマヘルニアの因果関係

日本外科学会定期学術集会抄録集 Vol. 121回 page： SF - 8 2021.4

ETNK2のアポトーシス調整を介した胃癌肝転移形成との関連性(ETNK2 promotes hepatic metastasis of gastric cancer via the p53-Bcl-2 related apoptosis)

三輪高嗣, 神田光郎, 田中千恵, 清水大, 園原史訓, 高見秀樹, 猪川祥邦, 服部憲史, 林真路, 山田豪, 中山吾郎, 小池聖彦, 藤原道隆, 小寺泰弘

日本胃癌学会総会記事 Vol. 93回 page： 244 - 244 2021.3

直腸がんの治療戦略-内視鏡外科をどう活かすか? 骨盤拡大手術における内視鏡外科手術での後腹膜アプローチ

上原圭, 相場利貞, 小倉淳司, 村田悠記, 松村卓樹, 三品拓也, 大原規彰, 鈴木優美, 伊神剛, 水野隆史, 宮田一志, 服部憲史, 中山吾郎, 小寺泰弘, 江畑智希

日本内視鏡外科学会雑誌 Vol. 25 ( 7 ) page： SSY5 - 3 2021.3

直腸がんの治療戦略-内視鏡外科をどう活かすか? 骨盤拡大手術における内視鏡外科手術での後腹膜アプローチ

日本内視鏡外科学会雑誌 Vol. 25 ( 7 ) page： SSY5 - 3 2021.3

Randomised phase II trial of capecitabine plus oxaliplatin with continuous versus intermittent use of oxaliplatin as adjuvant chemotherapy for stage II/III colon cancer (CCOG-1302 study). Reviewed International journal

Goro Nakayama, Nao Takano, Hiroya Taniguchi, Kiyoshi Ishigure, Hiroyuki Yokoyama, Hitoshi Teramoto, Ryoji Hashimoto, Mitsuru Sakai, Akiharu Ishiyama, Takashi Kinoshita, Naomi Hayashi, Masanori Nakamura, Norifumi Hattori, Yusuke Sato, Shinichi Umeda, Kei Uehara, Toshisada Aiba, Fuminori Sonohara, Masamichi Hayashi, Mitsuro Kanda, Daisuke Kobayashi, Chie Tanaka, Suguru Yamada, Masahiko Koike, Michitaka Fujiwara, Kenta Murotani, Masahiko Ando, Yuichi Ando, Kei Muro, Yasuhiro Kodera

European journal of cancer (Oxford, England : 1990) Vol. 144 page： 61 - 71 2021.2

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

BACKGROUND: Peripheral sensory neuropathy (PSN) caused by oxaliplatin-based adjuvant chemotherapy adversely affects patients' quality of life. This study evaluated the efficacy and safety of capecitabine plus oxaliplatin (CAPOX) with intermittent oxaliplatin use compared with the standard CAPOX in adjuvant therapy for colon cancer. PATIENTS AND METHODS: Patients with curative resection for stage II/III colon cancer were randomly assigned to receive either CAPOX with continuous oxaliplatin (eight cycles of CAPOX) or CAPOX with intermittent oxaliplatin (two cycles of CAPOX, four cycles of capecitabine and two cycles of CAPOX). The primary end-point was the 1-year PSN rate, and the key secondary end-point was disease-free survival (DFS). RESULTS: Two hundred patients were enrolled in the intent-to-treat population. After 4 patients withdrew, 196 patients were included in the safety analysis. The overall treatment completion rate was 65% for continuous vs. 89% for intermittent treatment (p < 0.001). The 1-year PSN rate was 60% (95% confidence interval [CI], 50%-70%) for continuous and 16% (95% CI, 10%-25%) for intermittent treatment (p < 0.001). After a median follow-up of 52 months, 40 events (20%) were observed. The 3-year DFS was 81% (95% CI, 71%-87%) for continuous and 84% (95% CI, 75%-90%) for intermittent treatment (hazard ratio [HR], 0.87; 95% CI, 0.47-1.63). Among patients with high-risk disease (T4 or N2-3), the 3-year DFS was 57% for continuous vs. 74% for intermittent treatment (HR, 0.66). CONCLUSION: CAPOX with planned intermittent oxaliplatin may be feasible as an adjuvant therapy for colon cancer and substantially reduce the duration of long-lasting PSN. TRIAL IDENTIFIER: UMIN000012535.

DOI： 10.1016/j.ejca.2020.11.007

Tissue RNFT2 Expression Levels Are Associated With Peritoneal Recurrence and Poor Prognosis in Gastric Cancer. Reviewed International journal

Masahiro Sasahara, Mitsuro Kanda, Dai Shimizu, Chie Tanaka, Yoshikuni Inokawa, Norifumi Hattori, Masamichi Hayashi, Goro Nakayama, Yasuhiro Kodera

Anticancer research Vol. 41 ( 2 ) page： 609 - 617 2021.2

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

BACKGROUND/AIM: Disease recurrence is frequently observed after curative resection of advanced gastric cancer resulting in a poor prognosis. In the present study, we identified a candidate biomarker to predict recurrence and prognosis after curative resection of gastric cancer. MATERIALS AND METHODS: A transcriptome analysis was conducted using surgically resected cancerous tissue from patients with metastatic gastric cancer to identify genes that are upregulated in primary and metastatic tissues. RESULTS: Ring finger protein, transmembrane 2 (RNFT2) mRNA expression was upregulated in primary gastric cancer tissues and metastases compared with non-cancerous tissues. RNFT2 expression in gastric cancer cell lines was positively correlated with the EMT-related molecules GSC, MMP9, and RAC1. The RNFT2 high expression group exhibited a significantly shorter postoperative overall survival. Peritoneal recurrence was significantly higher in the RNFT2 high expression group. CONCLUSION: RNFT2 mRNA expression predicts peritoneal recurrence and is a potential prognostic biomarker for gastric cancer following curative gastrectomy.

DOI： 10.21873/anticanres.14812

Fuminori Sonohara, Suguru Yamada, Keisuke Kurimoto, Yoshikuni Inokawa, Hideki Takami, Masamichi Hayashi, Dai Shimizu, Norifumi Hattori, Mitsuro Kanda, Chie Tanaka, Goro Nakayama, Masahiko Koike, Tsutomu Fujii, Yasuhiro Kodera

Pancreas Vol. 50 ( 1 ) page： 37 - 46 2021.1

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

OBJECTIVES: In this study, we retrospectively assessed the feasibility and prognostic efficacy of perioperative chemo(radio)therapy for pancreatic cancer (PC) patients according to age. METHODS: A total of 556 consecutive patients who underwent curative-intent pancreatectomy for PC between 2000 and 2018 were enrolled. RESULTS: Of the 556 patients who underwent resection, 95 (17%) were elderly (age, ≥75 years). Postoperative complications did not significantly differ between the 2 age groups, and postoperative prognoses were also similar (recurrence-free survival [RFS], P = 0.68; overall survival [OS], P = 0.28). In this cohort, 103 patients (19%) underwent preoperative chemo(radio)therapy, and 417 (77%) underwent postoperative chemotherapy. Perioperative therapy was found to be significantly beneficial for younger patients (preoperative therapy: RFS, P = 0.006; OS, P < 0.001; postoperative therapy: RFS, P < 0.001; OS, P < 0.001). Conversely, no significant survival benefit of perioperative therapy was found for the elderly (preoperative therapy: RFS, P = 0.28; OS, P = 0.44; postoperative therapy: RFS, P = 0.77; OS, P = 0.08). CONCLUSIONS: This study demonstrated that, although perioperative therapy is feasible for selected elderly patients with PC, this approach might not be as beneficial as it is for younger PC patients.

DOI： 10.1097/MPA.0000000000001712

Newly developed primary malignancies in long-term survivors who underwent curative esophagectomy for squamous cell carcinoma of the esophagus. Reviewed

Dai Shimizu, Masahiko Koike, Mitsuro Kanda, Fuminori Sonohara, Norifumi Hattori, Masamichi Hayashi, Chie Tanaka, Suguru Yamada, Yasuhiro Kodera

Surgery today Vol. 51 ( 1 ) page： 153 - 158 2021.1

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

PURPOSE: We evaluated the efficacy of the long-term follow-up of patients who underwent radical esophagectomy for esophageal squamous cell carcinoma (ESCC) to screen for recurrence and new primary malignancies. METHODS: We retrospectively collected 448 ESCC patients who underwent radical esophagectomy. Esophagogastroduodenoscopy, computed tomography, a stool test and the assessment of the serum concentration of squamous cell carcinoma antigen and carcinoembryonic antigen were performed annually, even over 5 years after esophagectomy. The incidence of ESCC recurrence and new primary malignancies was investigated. RESULTS: We enrolled 222 patients who survived at least 5 years after esophagectomy. A total of 104 new primary malignancies occurred in 82 patients (36.9%) after esophagectomy. Twenty-one malignancies were in the head and neck region, 14 in the residual esophagus, 13 in the prostate and 11 in the gastric tube and lung. Patients who developed new primary malignancies after esophagectomy had a significantly higher Brinkman index than those without new malignancies. An endoscopic approach successfully treated 92.9% of carcinomas in the residual esophagus, 90.9% of cancers in the gastric tube and 42.9% of carcinomas in the head and neck region. CONCLUSION: The incidence of new primary malignancies was higher than the age-standardized incidence. Long-term follow-up and systemic screening may increase the probability of an early diagnosis and subsequent low-invasive treatment.

DOI： 10.1007/s00595-020-02072-w

消化管腫瘍の新展開進行消化管癌における集学的治療の実際と課題局所進行直腸癌に対する術前化学療法の効果と限界

上原圭, 相場利貞, 小倉淳司, 大原規彰, 神野孝徳, 村田悠記, 三品拓也, 鈴木優美, 佐藤雄介, 服部憲史, 中山吾郎, 横山幸浩, 國料俊男, 伊神剛, 深谷昌秀, 水野隆史, 山口淳平, 宮田一志, 小寺泰弘, 江畑智希

日本消化管学会雑誌 Vol. 5 ( Suppl. ) page： 142 - 142 2021.1

AMIGO2 Expression as a Potential Prognostic Biomarker for Gastric Cancer. International journal

Shunsuke Nakamura, Mitsuro Kanda, Dai Shimizu, Chie Tanaka, Yoshikuni Inokawa, Norifumi Hattori, Masamichi Hayashi, Suguru Yamada, Goro Nakayama, Kenji Omae, Masahiko Koike, Yasuhiro Kodera

Anticancer research Vol. 40 ( 12 ) page： 6713 - 6721 2020.12

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

BACKGROUND/AIM: Although our understanding of the molecular mechanisms of gastric cancer (GC) development and progression is steadily deepening, the clinical outcome of GC patients remains inadequate. The identification of molecules associated with GC will help improve prognosis. We aimed to identify the molecules involved in GC progression and metastasis. MATERIALS AND METHODS: Transcriptome analysis was performed on surgically resected gastric tissue from patients with hepatic metastasis. Fourteen cell lines and 230 pairs of primary GC tissues and their corresponding normal adjacent tissues were included in the mRNA expression analysis. RESULTS: Adhesion molecule with Ig like domain 2 (AMIGO2) was identified as a gene of interest. The levels of AMIGO2 mRNA positively correlated with those encoding FOXC2, NODAL, GEMIN2 and negatively correlated with TFPI2. Patients with high AMIGO2 expression experienced significantly shorter disease-free survival and overall survival. High levels of AMIGO2 were associated with poor prognosis. CONCLUSION: Patients with GC with high AMIGO2 mRNA levels experienced significantly shorter survival, suggesting that AMIGO2 may serve as a prognostic biomarker for GC.

DOI： 10.21873/anticanres.14694

局所再発直腸癌および肝転移切除後の長期生存例に発症した下行結腸ストマ部癌の一例

下部進行直腸癌における側方リンパ節に対する術前化学療法の治療効果と限界

小倉淳司, 上原圭介, 相場利貞, 佐藤雄介, 服部憲史, 中山吾郎, 江畑智希, 小寺泰弘, 梛野正人

日本消化器外科学会総会 Vol. 75回 page： O6 - 4 2020.12

当院における進行再発大腸癌に対するFOLFIRI+Ramucirumab投与症例の検討

村田悠記, 上原圭介, 相場利貞, 小倉淳司, 佐藤雄介, 中山吾郎, 服部憲史, 江畑智希, 小寺泰弘, 梛野正人

日本消化器外科学会総会 Vol. 75回 page： P127 - 5 2020.12

当院における進行再発大腸癌に対するAflibercept治療成績の検討

大原規彰, 上原圭介, 相場利貞, 小倉淳司, 佐藤雄介, 中山吾郎, 服部憲史, 江畑智希, 小寺泰弘, 梛野正人

日本消化器外科学会総会 Vol. 75回 page： P128 - 3 2020.12

局所再発直腸癌に対する骨盤内臓全摘術後の治療成績

山東雅紀, 上原圭介, 相場利貞, 小倉淳司, 佐藤雄介, 中山吾郎, 服部憲史, 江畑智希, 小寺泰弘, 梛野正人

日本消化器外科学会総会 Vol. 75回 page： P181 - 7 2020.12

村田悠記, 上原圭介, 相場利貞, 小倉淳司, 山東雅紀, 田中綾, 大原規彰, 神野孝徳, 佐藤雄三, 服部憲史, 中山吾郎, 江畑智希, 小寺泰弘, 梛野正人

日本ストーマ・排泄リハビリテーション学会誌 Vol. 36 ( 3 ) page： 128 - 128 2020.12

大腸切除術中のICG angiographyによる腸管血流描出時間の検討

田中綾, 上原圭介, 相場利貞, 小倉淳司, 佐藤雄介, 服部憲史, 中山吾郎, 江畑智希, 小寺泰弘, 梛野正人

日本消化器外科学会総会 Vol. 75回 page： O18 - 4 2020.12

結腸切除術における下剤+経口抗菌薬による腸管前処置法の治療成績

相場利貞, 上原圭介, 小倉淳司, 佐藤雄介, 服部憲史, 中山吾郎, 江畑智希, 小寺泰弘, 梛野正人

日本消化器外科学会総会 Vol. 75回 page： P134 - 2 2020.12

What is the impact of systemic chemotherapy for lateral lymph nodes in patients with locally advanced low rectal cancer? International journal

Atsushi Ogura, Kay Uehara, Toshisada Aiba, Norifumi Hattori, Goro Nakayama, Osamu Maeda, Yuichi Ando, Yasuhiro Kodera, Tomoki Ebata, Masato Nagino

International journal of colorectal disease Vol. 35 ( 11 ) page： 2073 - 2080 2020.11

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

PURPOSE: Systemic chemotherapy (SC) before surgery is a potential treatment to improve survival in patients with advanced rectal cancer. However, the impact of SC on lateral lymph nodes (LLNs) remains unclear. METHODS: A total of 78 patients with stage II/III low rectal cancer, who received 3-month oxaliplatin-based SC followed by LLN dissection (LLND) in principle, were analysed retrospectively. "Total lateral lymph node metastases (tLLNMs)" was defined as having either pathological LLNMs (pLLNMs) or lateral local recurrences (LLRs). Patients with the maximum short-axis size of LLNs ≥ 7 mm were classified into the swollen group (n = 21). RESULTS: In the total cohort, tLLNMs included 6 pLLNMs (7.7%) and 2 LLRs (2.6%). In the non-swollen group, no patients had pLLNMs, but one had LLR (1.8%). In the swollen group, pLLNMs and LLRs were detected in 6 (28.6%) and 1 (4.8%), respectively. The swollen group was an independent risk factor for tLLNMs (P < 0.001), leading to the significantly worse 5-year relapse-free survival (RFS) of 52.4% than the others. CONCLUSION: For patients without swollen LLNs, SC could allow for omission both of lateral irradiation and LLND. For patients with swollen LLNs, the lateral local control was favourable after SC and LLND without chemoradiotherapy (CRT); however, oxaliplatin-based SC might be insufficient to improve survival, requiring more intensive chemotherapy. CRT should be indicated according to the other risk factors of central local recurrence, although the swollen LLNs should be removed.

DOI： 10.1007/s00384-020-03690-z

An Open-Label Single-Arm Phase II Study of Treatment with Neoadjuvant S-1 Plus Cisplatin for Clinical Stage III Squamous Cell Carcinoma of the Esophagus. Reviewed International journal

Mitsuro Kanda, Masahiko Koike, Naoki Iwata, Dai Shimizu, Chie Tanaka, Norifumi Hattori, Masamichi Hayashi, Suguru Yamada, Kenji Omae, Goro Nakayama, Yasuhiro Kodera

The oncologist Vol. 25 ( 11 ) page： E1650 - E1654 2020.11

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

LESSONS LEARNED: Two courses of neoadjuvant therapy using S-1 plus cisplatin for clinical stage III esophageal squamous cell carcinoma did not achieve expected response rate according to endoscopic evaluation of primary tumors. Subsequent esophagectomy was safely performed. BACKGROUND: In Japan, esophagectomy after two courses of 5-fluorouracil plus cisplatin is regarded a standard strategy for treating stage II or III esophageal squamous cell carcinoma (ESCC). However, 5-fluorouracil plus cisplatin does not benefit cohorts with clinical stage III ESCC, suggesting the need for a more effective regimen. METHODS: A single-arm, open-label phase II trial was conducted to evaluate the safety and efficacy of two courses of neoadjuvant chemotherapy using S-1 plus cisplatin (NAC-SP) for clinical stage III ESCC. The primary endpoint was overall response rate as defined by endoscopic evaluation of primary tumors. RESULTS: We enrolled 26 patients. The completion rate for the two courses of NAC-SP was 61.5%. Grade 3 or higher adverse events were experienced by 38.4% of patients. The treatment response rate according to endoscopic findings, acquired before the second course, was 34.6% and below the expected level (55.0%). The morbidity rate of patients who underwent radical subtotal esophagectomy (96.2%) was 32.0%. Repeat surgery was unnecessary, and surgery-associated deaths did not occur. The 5-year progression-free survival (PFS) and overall survival (OS) rates were 84.6% and 92.2%, respectively. CONCLUSION: We demonstrate safety of NAC-SP, but not its efficacy, for patients with clinical stage III ESCC. Subsequent esophagectomy was safely performed.

DOI： 10.1634/theoncologist.2020-0546

【大腸癌術前治療up-to-date】大腸癌術前化学療法のup-to-date

胃診断

中村俊介, 神田光郎, 清水大, 澤木康一, 田中千恵, 服部憲史, 園原史訓, 高見秀樹, 猪川祥邦, 林真路, 山田豪, 小池聖彦, 小寺泰弘

日本消化器外科学会雑誌 Vol. 53 ( Suppl.2 ) page： 296 - 296 2020.11

膵臓悪性

山田豪, 高見秀樹, 園原史訓, 猪川祥邦, 林真路, 服部憲史, 神田光郎, 田中千恵, 中山吾郎, 小池聖彦, 藤井努, 小寺泰弘

日本消化器外科学会雑誌 Vol. 53 ( Suppl.2 ) page： 316 - 316 2020.11

大腸症例(悪性)

村田悠記, 上原圭, 相場利貞, 小倉淳司, 山東雅紀, 田中綾, 大原規彰, 神野孝徳, 佐藤雄介, 服部憲史, 中山吾郎, 横山幸浩, 國料俊男, 伊神剛, 深谷昌秀, 水野隆史, 山口淳平, 江畑智希, 小寺泰弘, 梛野正人

日本消化器外科学会雑誌 Vol. 53 ( Suppl.2 ) page： 210 - 210 2020.11

肝臓集学的治療

米川佳彦, 上原圭, 相場利貞, 小倉淳司, 山東雅紀, 田中綾, 大原規彰, 村田悠記, 神野孝徳, 佐藤雄介, 服部憲史, 中山吾郎, 横山幸浩, 國料俊男, 伊神剛, 深谷昌秀, 水野隆史, 江畑智希, 小寺泰弘, 梛野正人

日本消化器外科学会雑誌 Vol. 53 ( Suppl.2 ) page： 254 - 254 2020.11

予定残肝ICG消失率(ICG-Krem)の術後肝不全発症予測因子としての有用性

砂川祐輝, 山田豪, 園原史訓, 猪川祥邦, 高見秀樹, 林真路, 服部憲史, 神田光郎, 田中千恵, 中山吾郎, 小池聖彦, 小寺泰弘

日本癌治療学会学術集会抄録集 Vol. 58回 page： O60 - 4 2020.10

上原圭, 相場利貞, 小倉淳司, 村田悠記, 佐藤雄介, 服部憲史, 中山吾郎, 小寺泰弘, 江畑智希

日本大腸肛門病学会雑誌 Vol. 73 ( 10 ) page： 417 - 423 2020.10

Language：Japanese Publisher：(一社)日本大腸肛門病学会

本邦での遠隔転移を伴わない局所進行大腸癌の標準治療は手術+術後補助化学療法であるものの,その治療成績が満足できるものとはいい難い.一方,近年の著しい薬物療法の進歩を背景に,術前化学療法(NAC)は日常臨床の中で徐々に普及しているが,その長期成績は明らかでない.直腸癌に対する術前化学療法(NAC)は欧米では放射線化学療法(CRT)を省略することになり,高リスク症例では受け入れられ難い.しかし,術前治療を一般的に行って来なかった本邦では,NACは単に術後補助化学療法の前倒しであり,可能な施設に限りがあるCRTと比較して,多くの施設で受け入れられやすい.NACはCRTと比較して局所効果はやや劣るものの,生存率は遜色ない.今後は,リスク分類により個別化治療を提供していく必要がある.(著者抄録)

Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2020&ichushi_jid=J01146&link_issn=&doc_id=20201202370004&doc_link_id=10.3862%2Fjcoloproctology.73.417&url=https%3A%2F%2Fdoi.org%2F10.3862%2Fjcoloproctology.73.417&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

高齢大腸癌患者に対する外科治療の成績

相場利貞, 上原圭, 小倉淳司, 山東雅紀, 田中綾, 大原規彰, 神野孝徳, 村田悠記, 佐藤雄介, 服部憲史, 中山吾郎, 横山幸浩, 國料俊男, 伊神剛, 深谷昌秀, 水野隆史, 山口淳平, 江畑智希, 小寺泰弘, 梛野正人

日本消化器病学会雑誌 Vol. 117 ( 臨増大会 ) page： A717 - A717 2020.10

Characteristics Associated with Nodal and Distant Recurrence After Radical Esophagectomy for Squamous Cell Carcinoma of the Thoracic Esophagus. Reviewed International journal

Mitsuro Kanda, Masahiko Koike, Dai Shimizu, Chie Tanaka, Norifumi Hattori, Masamichi Hayashi, Suguru Yamada, Kenji Omae, Yasuhiro Kodera

Annals of surgical oncology Vol. 27 ( 9 ) page： 3195 - 3205 2020.9

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

BACKGROUND: Recurrence after radical resection of esophageal squamous cell carcinoma (ESCC) is common. Limited evidence is available about the differences in clinical characteristics, risk factors, and prognostic significance between nodal and distant recurrence of thoracic ESCC. PATIENTS AND METHODS: We retrospectively analyzed 341 patients who underwent radical resection of thoracic ESCC and experienced (1) initial recurrence only in lymph nodes (n = 39), (2) recurrence only at distant organs (n = 57), or (3) no recurrences (n = 245) after follow-up ≥ 24 months. Clinicopathological characteristics, survival times, and risk factors were compared between the nodal and distant recurrence groups. RESULTS: The median follow-up time was 57.8 months. Metastasectomy as initial treatment for the recurrence was performed for six (15.4%) patients in the nodal recurrence group and one patient in the distant recurrence group. Compared with the nodal recurrence group, patients with distant recurrence had significantly shorter disease-free survival [hazard ratio (HR) 1.68, 95% confidence interval (CI) 1.10-2.57, P = 0.0169], postrecurrence survival (HR 1.77, 95% CI 1.01-3.10, P = 0.0476), and overall survival (HR 1.98, 95% CI 1.12-3.51, P = 0.0193). The distant recurrence group had significantly larger macroscopic tumor size and more advanced pathological T stage than the nodal recurrence group, whereas preoperative treatment, tumor location, number of fields dissected, tumor differentiation, lymphatic involvement, and vessel invasion were not significantly different between the two groups. CONCLUSIONS: Survival times and recurrence risk factors differed between patients with nodal and distant recurrence after radical resection of thoracic ESCC.

DOI： 10.1245/s10434-020-08433-6

Importance of the neoadjuvant rectal (NAR) score to the outcome of neoadjuvant chemotherapy alone for locally advanced rectal cancer.

Chemotherapy-free intervalを得るため積極的に手術適応としたBRAF V600E変異型盲腸癌腹膜播種再発の1例

神野孝徳, 上原圭, 相場利貞, 小倉淳司, 田中綾, 大原規彰, 村田悠記, 鈴木優美, 三品拓也, 佐藤雄介, 服部憲史, 中山吾郎, 小寺泰弘, 江畑智希

日本大腸肛門病学会雑誌 Vol. 73 ( 9 ) page： A185 - A185 2020.9

有茎腹直筋皮弁による会陰部再建を伴う腹会陰式直腸切断術後の局所再発痔瘻癌の1例筋皮弁および血管茎を完全温存した骨盤内臓全摘術

村田悠記, 上原圭, 相場利貞, 小倉淳司, 田中綾, 大原規彰, 神野孝徳, 鈴木優美, 三品拓也, 佐藤雄介, 服部憲史, 中山吾郎, 小寺泰弘, 江畑智希

日本大腸肛門病学会雑誌 Vol. 73 ( 9 ) page： A143 - A143 2020.9

大腸癌手術の精度とCMEとTMEの意義直腸癌他臓器合併切除標本の環状切開処理によるCRMの意義

相場利貞, 上原圭, 小倉淳司, 田中綾, 大原規彰, 村田悠記, 鈴木優美, 三品拓也, 佐藤雄介, 服部憲史, 中山吾郎, 小寺泰弘, 江畑智希

日本大腸肛門病学会雑誌 Vol. 73 ( 9 ) page： A41 - A41 2020.9

傍仙骨会陰アプローチにて切除しえた坐骨直腸窩平滑筋肉腫の1例

服部憲史, 中山吾郎, 上原圭, 相場利貞, 佐藤雄介, 小倉淳司, 田中千恵, 小寺泰弘

日本大腸肛門病学会雑誌 Vol. 73 ( 9 ) page： A112 - A112 2020.9

直腸癌に対する術前治療の現状と展望下部進行直腸癌に対するpatient-adopted strategyを目指した当科の術前治療と成績

小倉淳司, 上原圭, 相場利貞, 田中綾, 大原規彰, 村田悠記, 神野孝徳, 鈴木優美, 三品拓也, 佐藤雄介, 服部憲史, 中山吾郎, 小寺泰弘, 江畑智希

日本大腸肛門病学会雑誌 Vol. 73 ( 9 ) page： A52 - A52 2020.9

骨盤内臓全摘術の手術手技と成績骨盤内臓全摘術の基本と応用

上原圭, 相場利貞, 小倉淳司, 田中綾, 大原規彰, 村田悠記, 鈴木優美, 三品拓也, 佐藤雄介, 服部憲史, 中山吾郎, 小寺泰弘, 江畑智希

日本大腸肛門病学会雑誌 Vol. 73 ( 9 ) page： A68 - A68 2020.9

Toshiki Mukai, Keisuke Uehara, Toshisada Aiba, Atsushi Ogura, Toyonori Tsuzuki, Aya Tanaka, Masanori Sando, Noriyuki Ohara, Yusuke Sato, Norifumi Hattori, Goro Nakayama, Yasuhiro Kodera, Masato Nagino

Surgery today Vol. 50 ( 8 ) page： 912 - 919 2020.8

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

PURPOSE: The neoadjuvant rectal (NAR) score is a promising indicator of survival after preoperative chemoradiotherapy for rectal cancer. However, its effectiveness after neoadjuvant chemotherapy (NAC) alone has not been fully investigated. METHODS: We analyzed data retrospectively on 61 patients with rectal cancer, who received NAC followed by surgical resection between 2010 and 2015, and evaluated the impact of the NAR score on survival. RESULTS: The median NAR score was 14.9. Of the 61 patients, 13, 35, and 13 were classified as having NAR-low (< 8), NAR-intermediate (8-16), and NAR-high (> 16) scores, respectively. The median observation period was 49.0 months. According to the NAR score, the 3-year DFS in the NAR-low group was 100%, which was significantly better than that in the NAR-intermediate (64.8%, p = 0.041), and NAR-high (61.5%, p = 0.018) groups. When the NAR-intermediate and NAR-high groups were investigated as a single high-risk group, the 3-year DFS of the patients who received adjuvant chemotherapy was 88.7%, which was significantly better than that of the patients who did not receive adjuvant chemotherapy (53.3%, p = 0.042). CONCLUSIONS: The NAR score may predict the DFS and could serve as a favorable indicator of adjuvant chemotherapy after NAC alone.

DOI： 10.1007/s00595-020-01964-1

KCNJ15 Expression and Malignant Behavior of Esophageal Squamous Cell Carcinoma. Reviewed International journal

Shunsuke Nakamura, Mitsuro Kanda, Masahiko Koike, Dai Shimizu, Shinichi Umeda, Norifumi Hattori, Masamichi Hayashi, Chie Tanaka, Daisuke Kobayashi, Suguru Yamada, Kenji Omae, Yasuhiro Kodera

Annals of surgical oncology Vol. 27 ( 7 ) page： 2559 - 2568 2020.7

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

BACKGROUND: We aimed to clarify the role of potassium voltage-gated channel subfamily J member 15 (KCNJ15) in esophageal squamous cell carcinoma (ESCC) cells and its potential as a prognosticator in ESCC patients. METHODS: KCNJ15 transcription levels were evaluated in 13 ESCC cell lines and polymerase chain reaction (PCR) array analysis was conducted to detect coordinately expressed genes with KCNJ15. The biological functions of KCNJ15 in cell invasion, proliferation, migration, and adhesion were validated through small interfering RNA-mediated knockdown experiments. Cell proliferation was further evaluated through the forced expression experiment. KCNJ15 expression was detected in 200 ESCC tissues by quantitative real-time reverse transcription PCR (qRT-PCR) and analyzed in 64 representative tissues by immunohistochemistry. Correlations between KCNJ15 expression levels and clinicopathological features were also analyzed. RESULTS: The KCNJ15 expression levels varied widely in ESCC cell lines and correlated with COL3A1, JAG1, and F11R. Knockdown of KCNJ15 expression significantly repressed cell invasion, proliferation, and migration of ESCC cells in vitro. Furthermore, overexpression of KCNJ15 resulted in increased cell proliferation. Patients were stratified using the cut-off value of KCNJ15 messenger RNA (mRNA) levels in 200 ESCC tissues using receiver operating characteristic curve analysis; the high KCNJ15 expression group had significantly shorter overall and disease-free survival times. In multivariable analysis, high expression of KCNJ15 was identified as an independent poor prognostic factor. Staining intensity of in situ KCNJ15 protein expression tended to be associated with KCNJ15 mRNA expression levels. CONCLUSIONS: KCNJ15 is involved in aggressive tumor phenotypes of ESCC cells and its tissue expression levels may be useful as a prognosticator of patients with ESCC.

DOI： 10.1245/s10434-019-08189-8

Tumor Location Is Associated With the Prevalence of Braf And Pik3ca Mutations in Patients with Wild-Type Ras Colorectal Cancer: A Prospective Multi-Center Cohort Study in Japan. International journal

Hiroya Taniguchi, Keisuke Uehara, Goro Nakayama, Hiroshi Nakayama, Toshisada Aiba, Norifumi Hattori, Masato Kataoka, Yasuyuki Nakano, Yoshihisa Kawase, Osamu Okochi, Hiroshi Matsuoka, Setsuo Utsunomiya, Eiji Sakamoto, Yoshinori Mori, Shinichi Umeda, Toshio Shikano, Koji Komori, Masahiro Tajika, Shigenori Kadowaki, Kei Muro, Yasushi Yatabe

Translational oncology Vol. 13 ( 7 ) page： 100786 - 100786 2020.7

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

BACKGROUND: Primary tumor location is a critical prognostic factor that also impacts the efficacy of anti-epidermal growth factor receptor (EGFR) therapy in wild-type RAS (KRAS/NRAS) metastatic colorectal cancer (CRC). However, the association between the incidence of BRAF and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) mutations and primary tumor location remains unclear. METHODS: We prospectively collected tumor samples and clinical data of patients from 15 hospitals between August 2014 and April 2016 to investigate RAS, BRAF, and PIK3CA mutations using a polymerase chain reaction-based assay. According to the primary tumor location, patients were classified to right-sided (from cecum to splenic flexure) and left-sided (from descending colon to rectum) tumor groups. RESULTS: In total, 577 patients with CRC were investigated, 331 patients (57%) had CRC with wild-type RAS; of these 331 patients, 10.5%, 4.8%, and 5.9% patients harbored BRAFV600E, BRAFnon-V600E, and PIK3CA mutations, respectively. BRAF/PIK3CA mutations were more frequent in females, patients with right-sided tumors, and patients with peritoneal metastasis cases and less frequent in patients with liver metastases. The prevalence rates of BRAFV600E and PIK3CA mutations were higher in patients with right-sided tumors than in those with left-sided tumors (32.3% vs. 4.8% and 17.2% vs. 3.6%, respectively). CONCLUSIONS: More than half of the patients with right-sided CRC and wild-type RAS harbored BRAF/PIK3CA mutations, including BRAFnon-V600E, which may contribute to the difference in the anti-EGFR efficacy between the right- and left-sided CRC.

DOI： 10.1016/j.tranon.2020.100786

Optimized Cutoff Value of Serum Squamous Cell Carcinoma Antigen Concentration Accurately Predicts Recurrence After Curative Resection of Squamous Cell Carcinoma of the Esophagus. Reviewed International journal

Kanda M, Koike M, Shimizu D, Tanaka C, Kobayashi D, Hattori N, Hayashi M, Omae K, Yamada S, Nakayama G, Kodera Y

Annals of surgical oncology Vol. 27 ( 4 ) page： 1233 - 1240 2020.4

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

BACKGROUND: Squamous cell carcinoma antigen (SCC-Ag) and carcinoembryonic antigen (CEA) are widely used in clinical practice to predict the prognosis of patients with esophageal squamous cell carcinoma (ESCC). However, their predictive values for prognosis are controversial. This study determined optimal cutoff values of serum SCC-Ag and CEA concentrations for predicting postoperative recurrence of ESCC, which enabled selection of high-risk patients. METHODS: The study retrospectively analyzed 427 patients who underwent curative resection for ESCC. The optimal cutoff values of preoperative SCC-Ag and CEA concentrations for predicting postoperative recurrence were determined using combined analysis of hazard ratios and sensitivities for recurrence. Using the optimal cutoff value, the study evaluated survival, recurrence patterns, and temporal changes in marker concentrations. RESULTS: The preoperative SCC-Ag concentration of 1.1 ng/ml was the optimal cutoff value for predicting postoperative recurrence, whereas precise cutoff values could not be determined for preoperative CEA concentrations. High preoperative SCC-Ag concentrations (> 1.1 ng/ml), which were significantly associated with more aggressive tumor phenotypes and shorter disease-free survival, were identified as an independent prognostic factor in the multivariable analysis. High preoperative SCC-Ag concentrations were significantly associated with greater prevalence of lung/pleura and local recurrences. Normalization of serum SCC-Ag concentrations after neoadjuvant treatment or esophagectomy was not associated with a decreased risk of postoperative recurrence. CONCLUSIONS: The optimal cutoff value of preoperative SCC-Ag concentrations that predicted recurrence of ESCC was 1.1 ng/ml, illuminating the utility of serum SCC-Ag concentrations as an easily measurable tool for selecting a perioperative management strategy.

DOI： 10.1245/s10434-019-07977-6

Phase II study of capecitabine plus oxaliplatin (CapOX) as adjuvant chemotherapy for locally advanced rectal cancer (CORONA II).

FGFR1は胃癌細胞のEMTを促進し腹膜播種形成に関連する

清水大, 園原史訓, 高見秀樹, 猪川祥邦, 服部憲史, 林真路, 神田光郎, 田中千恵, 小林大介, 山田豪, 中山吾郎, 小池聖彦, 藤原道隆, 三森功士, 小寺泰弘

日本胃癌学会総会記事 Vol. 92回 page： 393 - 393 2020.3

今後の胃癌バイオマーカー胃癌腹膜播種再発を予測する腹膜洗浄液中の分子バイオマーカー(Upcoming biomarkers for gastric cancer Molecular biomarkers in peritoneal lavages to predict the peritoneal recurrences of gastric cancer)

Kanda Mitsuro, Nakanishi Koki, Tanaka Chie, Kobayashi Daisuke, Shimizu Dai, Sonohara Fuminori, Takami Hideki, Inokawa Yoshikuni, Hattori Norifumi, Hayashi Masamichi, Yamada Suguru, Nakayama Goro, Koike Masahiko, Fujiwara Michitaka, Kodera Yasuhiro

日本胃癌学会総会記事 Vol. 92回 page： 233 - 233 2020.3

高齢者胃切除手術症例における自立度の転帰

田中千恵, 神田光郎, 猪川祥邦, 清水大, 園原史訓, 小林大介, 高見秀樹, 服部憲史, 林真路, 山田豪, 中山吾郎, 小池聖彦, 藤原道隆, 小寺泰弘

日本胃癌学会総会記事 Vol. 92回 page： 251 - 251 2020.3

Norifumi Hattori, Goro Nakayama, Keisuke Uehara, Toshisada Aiba, Kiyoshi Ishigure, Eiji Sakamoto, Yuichiro Tojima, Mitsuro Kanda, Daisuke Kobayashi, Chie Tanaka, Suguru Yamada, Masahiko Koike, Michitaka Fujiwara, Masato Nagino, Yasuhiro Kodera

International journal of clinical oncology Vol. 25 ( 1 ) page： 118 - 125 2020.1

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

OBJECTIVE: This multicenter, single-arm phase II study (UMIN000008429) aimed to evaluate the efficacy and safety of capecitabine plus oxaliplatin (CapOX) as postoperative adjuvant chemotherapy for patients with locally advanced rectal cancer. METHODS: Patients with resectable clinical Stage II or III rectal cancer were enrolled to receive eight cycles of CapOX therapy (130 mg/m2 oxaliplatin on day 1 and 2000 mg/m2 oral capecitabine on days 1-14, every 3 weeks) after curative surgical resection. The primary endpoint was 3-year relapse-free survival (RFS) rate, and secondary endpoints were 3-year overall survival (OS) rate, treatment compliance, and safety. RESULTS: A total of 40 patients (Stage II, 21; Stage III, 19) were enrolled between September 2012 and November 2015 from seven institutions. Thirty-nine patients (97%) received R0 resection, and 32 patients (84%) received postoperative CapOX therapy. The completion rate of all eight cycles of CapOX therapy was 66%. Relative dose intensities were 87% for oxaliplatin and 84% for capecitabine. At a median follow-up period of 46 months, disease recurrence was observed in nine patients, including three with local recurrence. Three-year RFS and OS rates were 75% (95% CI 57-86%) and 96% (95% CI 80-99%), respectively. Frequencies of Grade ≥ 3 hematological and non-hematologic adverse events were 19% and 38%, respectively. CONCLUSION: CapOX therapy is feasible as adjuvant chemotherapy for locally advanced rectal cancer.

DOI： 10.1007/s10147-019-01546-3

The Significance of Molecular Biomarkers on Clinical Survival Outcome Differs Depending on Colon Cancer Sidedness. International journal

Sho Hirabayashi, Masamichi Hayashi, Goro Nakayama, Shinji Mii, Norifumi Hattori, Hiroshi Tanabe, Mitsuro Kanda, Chie Tanaka, Daisuke Kobayashi, Suguru Yamada, Masahiko Koike, Michitaka Fujiwara, Masahide Takahashi, Yasuhiro Kodera

Anticancer research Vol. 40 ( 1 ) page： 201 - 211 2020.1

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

BACKGROUND/AIM: This retrospective study focused on the correlation between molecular markers and prognostic outcomes of colon cancer patients depending on sidedness. MATERIALS AND METHODS: A total of 117 stage I-III colon cancer patients who underwent colectomy were enrolled. Novel methylation markers (KIF1A, PAX5 and VGF) were selected for epigenetic evaluation and p53 and ERCC1 protein expression was examined for the investigation of genetic alterations. RESULTS: High frequency of methylation was observed in 68.2% of right-sided and 39.7% of left-sided colon cancer cases (p=0.004). Abnormal p53 was identified in 52.3% of right-sided and 75.3% of left-sided cases (p=0.015). In right-sided cases, highly methylated genes demonstrated significantly favorable disease-free survival (p=0.049). Regarding left-sided cases, advanced T stage (p=0.028) and abnormal p53 (p=0.028) were revealed to be significant predictive factors of the disease-free survival outcome. CONCLUSION: Molecular alterations, as significant prognostic factors, might differ depending on the sidedness of colon cancers.

DOI： 10.21873/anticanres.13941

Modified Systemic Inflammation Score is Useful for Risk Stratification After Radical Resection of Squamous Cell Carcinoma of the Esophagus. Reviewed International journal

Kanda M, Koike M, Tanaka C, Kobayashi D, Hattori N, Hayashi M, Yamada S, Omae K, Fujiwara M, Kodera Y

Annals of surgical oncology Vol. 26 ( 13 ) page： 4773 - 4781 2019.12

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

BACKGROUND: Inflammation plays a critical role in the development and progression of cancers. We evaluated the clinical significance of the preoperative modified systemic inflammation score (mSIS) to predict long-term outcomes of patients with esophageal squamous cell carcinoma (ESCC). METHODS: We included 443 patients who underwent curative resection of ESCC. The mSIS was formulated according to the serum albumin level (ALB) and lymphocyte-to-monocyte ratio (LMR) as follows: mSIS 0 (ALB ≥ 4.0 g/dL and LMR ≥ 3.4), mSIS 1 (ALB < 4.0 g/dL or LMR < 3.4), and mSIS 2 (ALB < 4.0 g/dL and LMR < 3.4). RESULTS: Patients were categorized into preoperative mSIS 0 (n = 165), mSIS 1 (n = 183), and mSIS 2 (n = 95) groups. Preoperative mSIS was significantly associated with age, preoperative body mass index, and pathological disease stage. The disease-specific survival times of patients in preoperative mSIS 0, 1, and 2 sequentially shortened (P = 0.009), and mSIS 2 was identified as an independent prognostic factor (hazard ratio 2.63, 95% confidence interval 1.33-5.27, P = 0.0053). In most patient subgroups, the mSIS was associated with greater risk of disease-specific death. A stepwise increase in the prevalence of hematogenous recurrences was directly proportion to the mSIS. When patients were subdivided by mSIS before neoadjuvant treatment, there were no significant differences in disease-specific survival. CONCLUSIONS: Our findings demonstrate that the preoperative mSIS may serve as a powerful prognosticator of ESCC that definitively stratifies clinical outcomes as well as a tool for selecting treatment strategies.

DOI： 10.1245/s10434-019-07914-7

Expression, Function, and Prognostic Value of MAGE-D4 Protein in Esophageal Squamous Cell Carcinoma. Reviewed International journal

Uno Y, Kanda M, Sato Y, Shimizu D, Umeda S, Hattori N, Hayashi M, Tanaka C, Kobayashi D, Yamada S, Nakayama G, Motoyama S, Koike M, Kodera Y

Anticancer research Vol. 39 ( 11 ) page： 6015 - 6023 2019.11

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

BACKGROUND/AIM: We previously reported that expression of melanoma-associated antigen (MAGE)-D4 mRNA was a prognostic factor for esophageal squamous cell carcinoma (ESCC). The aim of this study was to validate the expression of MAGE-D4 in two additional patient cohorts, and to investigate its biological functions. MATERIALS AND METHODS: The role of MAGE-D4 in cell proliferation, adhesion, and migration was determined by gene knockdown experiments in the KYSE590 cell line. MAGE-D4 protein expression was analyzed in ESCC tissues by immunohistochemistry. A second validation cohort consisted of an ESCC mRNA dataset from The Cancer Genome Atlas. RESULTS: Knockdown of MAGE-D4 significantly decreased cell proliferation and migration. Expression of MAGE-D4 protein was significantly associated with disease-free survival. In the second validation cohort, high MAGE-D4 mRNA expression was associated with significantly shorter overall survival and disease-free survival. CONCLUSION: MAGE-D4 plays an important role in the malignant behavior of ESCC. MAGE-D4 was validated as a prognostic indicator in two independent ESCC patient cohorts.

DOI： 10.21873/anticanres.13807

Tissue Expression of Melanoma-associated Antigen A6 and Clinical Characteristics of Gastric Cancer. Reviewed International journal

Endo M, Kanda M, Sawaki K, Shimizu D, Tanaka C, Kobayashi D, Hattori N, Hayashi M, Yamada S, Koike M, Omae K, Kodera Y

Anticancer research Vol. 39 ( 11 ) page： 5903 - 5910 2019.11

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

BACKGROUND: Gastric cancer (GC) exhibits heterogeneous clinical and molecular features, requiring the development of new biomarkers to further understand this disease. Our transcriptomic analysis detected overexpression of melanoma-associated antigen A6 (MAGEA6) in metastatic GC, leading us to determine the clinical significance of MAGEA6 in GC. MATERIALS AND METHODS: Fourteen GC cell lines and 230 pairs of surgically resected gastric tissues were subjected to mRNA expression analysis. Polymerase chain reaction array analysis was performed to identify coordinately expressed cancer-related genes, and immunohistochemistry (IHC) was used to detected MAGEA6 expression in situ. RESULTS: MAGEA6 mRNA levels were positively correlated with the expression of matrix metallopeptidase 9 mRNA. MAGEA6 mRNA levels were higher in GC tissues compared with those in normal adjacent tissues. Patients with high MAGEA6 expression had significantly worse prognosis. MAGEA6 protein levels in primary lesions predicted the likelihood of recurrence. CONCLUSION: Overexpression of MAGEA6 in GC tissues represents a promising biomarker for assessing the malignant phenotype of GC.

DOI： 10.21873/anticanres.13794

分子生物学的手法を応用した微小腹腔内遊離胃癌細胞検出法

中西香企, 神田光郎, 梅田晋一, 田中千恵, 小林大介, 林真路, 服部憲史, 高見秀樹, 園原史訓, 山田豪, 中山吾郎, 小池聖彦, 藤原道隆, 小寺泰弘

日本消化器外科学会雑誌 Vol. 52 ( Suppl.2 ) page： 102 - 102 2019.11

直腸癌局所再発に対する治療戦略局所再発直腸癌に対する手術治療

相場利貞, 上原圭介, 中山吾郎, 服部憲史, 冨田明宏, 小池佳勇, 山東雅紀, 田中綾, 江畑智希, 横山幸浩, 國料俊男, 角田伸行, 伊神剛, 深谷昌秀, 水野隆史, 山口淳平, 宮田一志, 尾上俊介, 渡辺伸元, 小寺泰弘, 梛野正人

日本外科学会定期学術集会抄録集 Vol. 119回 page： PD - 2 2019.4

局所進行直腸癌に対する術前化学療法の現状と展望

田中征洋, 上原圭介, 相場利貞, 中山吾郎, 服部憲史, 冨田明宏, 田中綾, 江畑智希, 横山幸浩, 國料俊男, 角田伸行, 伊神剛, 深谷昌秀, 水野隆史, 山口淳平, 宮田一志, 尾上俊介, 渡辺伸元, 小寺泰弘, 梛野正人

日本外科学会定期学術集会抄録集 Vol. 119回 page： PS - 1 2019.4

下部直腸癌に対する新しい手技の工夫下部進行直腸癌に対する経肛門的な側方LNへのアプローチ

田中綾, 上原圭介, 相場利貞, 中山吾郎, 服部憲史, 冨田明宏, 山東雅紀, 小池佳勇, 江畑智希, 横山幸浩, 國料俊男, 角田伸行, 伊神剛, 深谷昌秀, 水野隆史, 山口淳平, 宮田一志, 尾上俊介, 渡辺伸元, 小寺泰弘, 梛野正人

日本外科学会定期学術集会抄録集 Vol. 119回 page： WS - 4 2019.4

Increased Expression of DNAJC12 is Associated with Aggressive Phenotype of Gastric Cancer. International journal

Uno Y, Kanda M, Miwa T, Umeda S, Tanaka H, Tanaka C, Kobayashi D, Suenaga M, Hattori N, Hayashi M, Yamada S, Nakayama G, Fujiwara M, Kodera Y

Annals of surgical oncology Vol. 26 ( 3 ) page： 836 - 844 2019.3

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

BACKGROUND: Identification of gastric cancer-related molecules is necessary to elucidate the pathological mechanisms of this heterogeneous disease. The purpose of this study was to identify novel genes associated with aggressive phenotypes of gastric cancer. METHODS: Global expression profiling was conducted using tissues from four patients with metastatic gastric cancer to identify genes overexpressed in gastric cancer. Fifteen gastric cell lines and 262 pairs of surgically resected gastric tissues were subjected to mRNA expression analysis. The contribution of the candidate gene on gastric cancer cell proliferation, invasion, adhesion, and migration were evaluated using small interfering RNA. RESULTS: DnaJ heat shock protein family (Hsp40) member C12 (DNAJC12) was identified as a candidate gene by transcriptome analysis. In clinical samples, DNAJC12 mRNA levels were higher in gastric cancer tissues compared with normal adjacent tissues. Patients with high DNAJC12 expression showed significantly shorter overall survival in our cohort and in the extra-validation cohort analyzed by a published microarray dataset. High DNAJC12 expression in gastric cancer tissues was significantly associated with lymphatic involvement, infiltrative growth type, lymph node metastasis, and advanced stage and was identified as an independent prognostic factor for overall survival in multivariable analysis. Increased expression of DNAJC12 was found in 12 of 14 examined gastric cancer cell lines. Knockdown of DNAJC12 expression significantly decreased the proliferation and invasion abilities of gastric cancer cells. CONCLUSIONS: Our findings support DNAJC12 as a candidate gene associated with aggressive phenotypes of gastric cancer.

DOI： 10.1245/s10434-018-07149-y

Perioperative and prognostic implication of albumin-bilirubin-TNM score in Child-Pugh class A hepatocellular carcinoma.

Sonohara F, Yamada S, Tanaka N, Suenaga M, Takami H, Hayashi M, Niwa Y, Sugimoto H, Hattori N, Kanda M, Tanaka C, Kobayashi D, Nakayama G, Koike M, Fujiwara M, Kodera Y

Annals of gastroenterological surgery Vol. 3 ( 1 ) page： 65 - 74 2019.1

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

BACKGROUND AND AIM: A reliable classification for predicting postoperative prognosis and perioperative risk of hepatocellular carcinoma (HCC) patients is required to make a precise decision for HCC treatment. In the present study, we assessed the perioperative and prognostic importance of indocyanine green (ICG) testing, tumor-node-metastasis (TNM) stage, albumin-bilirubin (ALBI) grade, and ALBI-TNM (ALBI-T) score using consecutive resected HCC cases. METHODS: Between 1998 and 2011, 273 consecutive patients who underwent primary and curative hepatectomy for HCC were identified. Among these 273 cases, 235 Child-Pugh class A patients were enrolled in the present study. RESULTS: Correlation analysis showed that the value of linear predictor for ALBI grade was significantly correlated with ICG 15-minute retention rates (r = 0.51, P < 0.0001). Survival analysis for both recurrence-free survival (RFS) and overall survival (OS) showed there were significant differences between the two groups stratified by stage or ALBI-T score (stage, RFS: P = 0.01, OS: P = 0.003; ALBI-T, RFS: P < 0.0001, OS: P < 0.0001). In addition, Cox proportional hazard model identified ALBI-T score was a significant predictor for both RFS and OS (RFS, P = 0.001; OS, P = 0.004). Furthermore, ALBI-T score could predict perioperative risk in hepatectomy such as longer operation time and excessive intraoperative blood loss. CONCLUSIONS: This study showed a robust association of ALBI-T score with postoperative HCC patient survival and perioperative risk in hepatectomy. ALBI-T score can be used as a simple and powerful tool for assessing HCC patients with further study.

DOI： 10.1002/ags3.12212

Prognostic Impact of Portal System Invasion in Pancreatic Cancer Based on Image Classification

Morimoto Daishi, Yamada Suguru, Murotani Kenta, Sonohara Fuminori, Takami Hideki, Suenaga Masaya, Hayashi Masamichi, Niwa Yukiko, Tashiro Mitsuru, Hattori Norifumi, Iwata Naoki, Kanda Mitsuro, Tanaka Chie, Kobayashi Daisuke, Nakayama Goro, Koike Masahiko, Fujiwara Michitaka, Fujii Tsutomu, Kodera Yasuhiro

PANCREAS Vol. 47 ( 10 ) page： 1350 - 1356 2018.11

Treatment strategy of intraperitoneal and systemic chemotherapy combined with gastrectomy for gastric cancer with peritoneal metastasis

JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY Vol. 33 page： 98-98 2018.11

Significance of Preoperative Systemic Inflammation Score in Short-Term and Long-Term Outcomes of Patients with Pathological T2-4 Gastric Cancer After Radical Gastrectomy. Reviewed International journal

Bin Sato, Mitsuro Kanda, Chie Tanaka, Daisuke Kobayashi, Naoki Iwata, Norifumi Hattori, Masaya Suenaga, Masamichi Hayashi, Suguru Yamada, Kenta Murotani, Michitaka Fujiwara, Yasuhiro Kodera

World journal of surgery Vol. 42 ( 10 ) page： 3277 - 3285 2018.10

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

BACKGROUND: Surgical resection is the mainstay of treatment for patients with gastric cancer (GC). Development of a simple, high-performance, integrated scoring system is needed to provide appropriate management. This study aimed to evaluate predictive values of the systemic inflammation score (SIS) for short- and long-term outcomes of patients who underwent surgery for GC. METHODS: A total of 187 patients who underwent gastrectomy for pT2-4 GC without preoperative treatment were analyzed. SIS was formulated based on serum albumin level and lymphocyte-monocyte ratio, and graded into SIS 0, 1, and 2. RESULTS: Preoperative SIS was significantly associated with incidence of postoperative complications, showing a stepwise increased incidence in proportion to SIS in the entire cohort and all subgroups according to operative procedure and disease stage. Overall and disease-free survival times of patients in SIS 0, 1, and 2 shortened in a stepwise fashion. SIS was linked to prevalence of hematogenous metastasis as initial recurrence site. Survival differences between patients with SIS 2 and the others were particularly large in patients who underwent adjuvant chemotherapy. The continuation rate of adjuvant S-1 was lower in the SIS 2 group. CONCLUSION: SIS represents a simple predictor for incidence of postoperative complications and survival in patients with pT2-4 GC.

DOI： 10.1007/s00268-018-4597-7

Expression of sushi domain containing two reflects the malignant potential of gastric cancer International journal

Umeda Shinichi, Kanda Mitsuro, Miwa Takashi, Tanaka Haruyoshi, Tanaka Chie, Kobayashi Daisuke, Suenaga Masaya, Hattori Norifumi, Hayashi Masamichi, Yamada Suguru, Nakayama Goro, Fujiwara Michitaka, Kodera Yasuhiro

CANCER MEDICINE Vol. 7 ( 10 ) page： 5194 - 5204 2018.10

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

Hepatic recurrence of gastric cancer (GC) is uncontrollable. Discovery of causative oncogenes and the development of sensitive biomarkers to predict hepatic recurrence are required to improve patients' outcomes. In this study, recurrence pattern-specific transcriptome analysis of 57 749 genes was conducted to identify mRNAs specifically associated with hepatic metastasis of patients with stage III GC who underwent curative resection. GC cell lines were subjected to mRNA expression analysis, PCR array analysis, and siRNA-mediated knockdown. The expression levels of primary cancer tissues from 154 patients with resectable GC were determined and correlated with clinicopathological variables. Among 21 genes significantly overexpressed specifically in patients with hepatic recurrence, Sushi domain containing 2 (SUSD2) was selected as a promising target. PCR array analysis revealed that SUSD2 mRNA levels positively correlated with those of FZD7, CDH2, TGFB1, SPARC, ITGA5, and ZEB1. Functional analysis revealed that knockdown of SUSD2 significantly reduced the proliferation, migration, and invasiveness GC cell lines. Patients with high SUSD2 expression were more likely to experience shorter disease-free and overall survival. Analysis of the relation between disease recurrence pattern and SUSD2 levels revealed that significantly more patients with hepatic metastases expressed higher levels of SUSD2 mRNA. The cumulative incidence of hepatic recurrence was greater in patients with high SUSD2 expression. In conclusion, SUSD2 likely contributes to the malignant potential of GC and may serve as a novel biomarker that predicts hepatic recurrence after curative resection.

DOI： 10.1002/cam4.1793

SYT7 acts as a driver of hepatic metastasis formation of gastric cancer cells Reviewed

Mitsuro Kanda, Haruyoshi Tanaka, Dai Shimizu, Takashi Miwa, Shinichi Umeda, Chie Tanaka, Daisuke Kobayashi, Norifumi Hattori, Masaya Suenaga, Masamichi Hayashi, Naoki Iwata, Suguru Yamada, Michitaka Fujiwara, Yasuhiro Kodera

Oncogene Vol. 37 ( 39 ) page： 5355 - 5366 2018.9

Language：English Publishing type：Research paper (scientific journal) Publisher：Nature Publishing Group

Liver metastasis remains a serious problem in the management of gastric cancer (GC). Our aims were to identify through transcriptome analysis a molecule that mediates hepatic metastasis in GC, and to evaluate its potential as a diagnostic marker and a therapeutic target. The effects of knocking out a relevant molecule using genome editing were evaluated in vitro experiments and in mouse xenograft models. Expression levels of candidate molecule in 300 pairs of gastric tissues were determined to assess whether differentially expressed genes predicted hepatic recurrence, metastasis, or both. Transcriptome data identified the overexpression of synaptotagmin VII (SYT7) in GC tissues with hepatic metastasis. Its expression in the GC cell lines was high, particularly in those that exhibited a differentiated phenotype, and positively correlated with the expression of SNAI1 and TGFB3, and inversely with RGS2. SYT7 knockout inhibited the proliferation of GC cells, indicated by increased apoptosis with activated caspase and loss of mitochondria membrane potential, G2/M cell-cycle arrest and attenuated cell migration, invasion, and adhesion. The tumorigenicity of SYT7-knockout cells was moderately reduced in a mouse model of subcutaneous metastasis in which the levels of BCL2 and HIF1A were decreased and was more strikingly attenuated in a model of hepatic metastasis. The SYT7 levels in the primary GC tissues were significantly associated with hepatic recurrence, metastasis, and adverse prognosis. SYT7 represents a tool for prediction and monitoring of hepatic metastasis from GC as well as being a promising therapeutic target.

DOI： 10.1038/s41388-018-0335-8

Comparison of the Survival Outcomes of Pancreatic Cancer and Intraductal Papillary Mucinous Neoplasms. Reviewed

Yamada S, Fujii T, Hirakawa A, Takami H, Suenaga M, Hayashi M, Niwa Y, Hattori N, Iwata N, Kanda M, Tanaka C, Kobayashi D, Nakayama G, Koike M, Fujiwara M, Kodera Y

Pancreas Vol. 47 ( 8 ) page： 974 - 979 2018.9

Pattern-Specific Transcriptomics Identifies ASGR2 as a Predictor of Hematogenous Recurrence of Gastric Cancer. Reviewed International journal

Tanaka H, Kanda M, Miwa T, Tanaka C, Kobayashi D, Umeda S, Shibata M, Suenaga M, Hattori N, Hayashi M, Iwata N, Yamada S, Nakayama G, Fujiwara M, Kodera Y

Molecular cancer research : MCR Vol. 16 ( 9 ) page： 1420 - 1429 2018.9

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

Hematogenous recurrence is a challenging clinical finding that often leads to fatalities of patients with gastric cancer. Therefore, the identification of specific biomarkers and potential therapeutic target molecules for hematogenous recurrence is required to improve the outcomes of these patients. Here, transcriptome and bioinformatics analyses were conducted to uncover candidate molecules differentially expressed in patients with hematogenous recurrence of gastric cancer. One potential candidate identified was asialoglycoprotein receptor 2 (ASGR2), and siRNA experiments were conducted to determine the effect of manipulating ASGR2 expression has on cell phenotypes. ASGR2 mRNA expression analysis using quantitative real-time reverse-transcription PCR was conducted with stage II/III gastric cancer clinical specimens (n = 95). Transcript levels were increased in gastric cancer cells as compared with a control nontumorigenic epithelial cell line. Knockdown of ASGR2 decreased the adhesion and migration potential. Thus, although gastric cancer cell-invasive activity was significantly decreased by knockdown, forced expression of ASGR2 promoted invasive activity. Using a mouse hepatic metastasis model, knockdown of ASGR2 resulted in the absence of hepatic metastasis formation. High ASGR2 expression in primary gastric cancer tissues was an independent predictor of shorter disease-free and overall survival. Finally, patients with high ASGR2 expression were more likely to have a high cumulative rate of hematogenous recurrence but not peritoneal or nodal recurrence.Implications:ASGR2 expression is associated with the malignant phenotypes in gastric cancer and represents a specific biomarker of hematogenous recurrences after curative resection for gastric cancer. Mol Cancer Res; 16(9); 1420-9. ©2018 AACR.

DOI： 10.1158/1541-7786.MCR-17-0467

Randomized Phase II Trial of CapOX plus Bevacizumab and CapIRI plus Bevacizumab as First-Line Treatment for Japanese Patients with Metastatic Colorectal Cancer (CCOG-1201 Study). Reviewed International journal

Goro Nakayama, Ayako Mitsuma, Yuki Sunagawa, Kiyoshi Ishigure, Hiroyuki Yokoyama, Takanori Matsui, Hiroshi Nakayama, Kazuhiko Nakata, Akiharu Ishiyama, Takahiro Asada, Shinichi Umeda, Kazuhiro Ezaka, Norifumi Hattori, Hideki Takami, Daisuke Kobayashi, Chie Tanaka, Mitsuro Kanda, Suguru Yamada, Masahiko Koike, Michitaka Fujiwara, Tsutomu Fujii, Kenta Murotani, Yuichi Ando, Yasuhiro Kodera

The oncologist Vol. 23 ( 8 ) page： 919 - 927 2018.8

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

PURPOSE: The aim of this randomized, multicenter, noncomparative, phase II trial was to investigate the efficacy and safety of two potential first-line treatments, capecitabine and oxaliplatin (CapOX) plus bevacizumab (BEV) and capecitabine and irinotecan (CapIRI) plus bevacizumab, in Japanese patients with metastatic colorectal cancer (mCRC). PATIENTS AND METHODS: Patients with untreated mCRC were randomly assigned to receive either CapOX plus bevacizumab (CapOX/BEV arm: bevacizumab 7.5 mg/kg and oxaliplatin 130 mg/m2 on day 1 and oral capecitabine 2,000 mg/m2 on days 1-14, every 3 weeks) or CapIRI plus bevacizumab (CapIRI/BEV arm: bevacizumab 7.5 mg/kg and irinotecan 200 mg/m2 on day 1 and capecitabine 1,600 mg/m2 on days 1-14, every 3 weeks). The primary endpoint was overall response rate (ORR), and the secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety. RESULTS: A total of 107 patients were enrolled. The intent-to-treat population comprised 54 patients in the CapOX/BEV arm and 53 patients in the CapIRI/BEV arm. The median follow-up period was 35.5 months. ORR was 56% in the CapOX/BEV arm and 55% in the CapIRI/BEV arm. Median PFS and OS were 12.4 and 26.7 months in the CapOX/BEV arm and 11.5 and 28.7 months in the CapIRI/BEV arm, respectively. The frequencies of hematological and nonhematological adverse events above grade 3 were 13% and 30% in the CapOX/BEV arm and 25% and 23% in the CapIRI/BEV arm, respectively. CONCLUSION: CapOX plus bevacizumab and CapIRI plus bevacizumab are equally effective and feasible as the first-line treatments in Japanese patients with mCRC. IMPLICATIONS FOR PRACTICE: The CCOG-1201 study was designed to evaluate the efficacy and safety of capecitabine and oxaliplatin plus bevacizumab and capecitabine and irinotecan plus bevacizumab as a first-line treatment in Japanese patients with metastatic colorectal cancer. This article reports on the trial and efforts to define the role of these regimens, including the effect of KRAS status and UGT1A1 polymorphisms in metastatic colorectal cancer.

DOI： 10.1634/theoncologist.2017-0640

Troponin I2 as a Specific Biomarker for Prediction of Peritoneal Metastasis in Gastric Cancer Reviewed

Koichi Sawaki, Mitsuro Kanda, Takashi Miwa, Shinichi Umeda, Haruyoshi Tanaka, Chie Tanaka, Daisuke Kobayashi, Masaya Suenaga, Norifumi Hattori, Masamichi Hayashi, Suguru Yamada, Goro Nakayama, Michitaka Fujiwara, Yasuhiro Kodera

Annals of Surgical Oncology Vol. 25 ( 7 ) page： 2083 - 2090 2018.7

Language：English Publishing type：Research paper (scientific journal) Publisher：Springer New York LLC

Background: Although peritoneal metastasis is a serious concern in patients with gastric cancer, no acceptable and specific biomarker is available. We aimed to identify a candidate biomarker to predict peritoneal metastasis of gastric cancer. Methods: Metastatic pathway-specific transcriptome analysis was conducted by comparison of patient groups with no recurrence and with peritoneal, hepatic, and nodal recurrence. Fifteen cell lines and 262 pairs of surgically resected gastric tissues were subjected to messenger RNA (mRNA) expression analysis. Polymerase chain reaction array analysis was performed to explore coordinately expressed cancer-related genes. To evaluate the in situ protein localization and expression patterns, immunohistochemical staining was performed. Results: From transcriptome data, troponin I2 (TNNI2) was identified as a candidate molecule specifically overexpressed in gastric cancer prone to peritoneal metastasis. TNNI2 mRNA was expressed at differential levels, independent of differentiated phenotype of cell lines. Epithelial to mesenchymal transition-related genes, tumor inhibitor of metalloproteinase 1 (TIMP1), and vacuolar protein sorting 13 homolog A (VPS13A) were expressed with TNNI2 at correlation coefficient &gt
0.7. The optimal cutoff of TNNI2 expression was determined as 0.00017. High TNNI2 expression was significantly and specifically associated with peritoneal metastasis and served as an independent risk marker for peritoneal recurrence after curative gastrectomy. Prevalence of peritoneal recurrence increased in parallel with staining intensity of TNNI2. Conclusions: TNNI2 expression in gastric tissues may serve as a specific biomarker for prediction of peritoneal metastasis of gastric cancer and contribute to improvement of patient management.

DOI： 10.1245/s10434-018-6480-z

Clinical Implications of Lysyl Oxidase-Like Protein 2 Expression in Pancreatic Cancer. Reviewed

Tanaka N, Yamada S, Sonohara F, Suenaga M, Hayashi M, Takami H, Niwa Y, Hattori N, Iwata N, Kanda M, Tanaka C, Kobayashi D, Nakayama G, Koike M, Fujiwara M, Fujii T, Kodera Y

Scientific reports Vol. 8 ( 1 ) page： 9846 2018.6

Postoperative adalimumab maintenance therapy for Japanese patients with Crohn’s disease: a single-center, single-arm phase II trial (CCOG-1107 study) Reviewed

Takahiro Asada, Goro Nakayama, Chie Tanaka, Daisuke Kobayashi, Kazuhiro Ezaka, Norifumi Hattori, Mitsuro Kanda, Suguru Yamada, Masahiko Koike, Yasuhiro Kodera

Surgery Today Vol. 48 ( 6 ) page： 609 - 617 2018.6

Language：English Publishing type：Research paper (scientific journal) Publisher：Springer Tokyo

Purpose: To investigate the efficacy and safety of planned postoperative adalimumab (ADA) therapy for Japanese patients with Crohn’s disease (CD). Methods: The subjects of this study were 26 patients who underwent bowel resection for CD. All patients received subcutaneous injections of ADA 160/80 mg at the time of surgery and 2 weeks later, followed by 40 mg every 2 weeks thereafter. The primary endpoint of this study was the incidence of endoscopic recurrence, defined by Rutgeerts endoscopic recurrence scale ≥ i2, 1 year after surgery. Results: After the median follow-up period of 41.3 months, the median number of treatments with ADA was 56 and the median time-to-treatment failure was 25.6 months. Endoscopic recurrence was observed in 34.6% of the patients 1 year after surgery. Univariate analyses showed that preoperative ADA therapy was significantly associated with endoscopic recurrence. Clinical recurrence developed in 16.7% of the patients within 1 year after surgery. Secondary surgery for recurrence was not required. Although adverse events (≥ grade 3) were experienced by 15.4% of patients, none was withdrawn from this study. Conclusion: Planned postoperative ADA therapy reduced the incidence of endoscopic and clinical recurrence after bowel resection in Japanese patients with CD. Trial registration: This trial is registered with the University Hospital Medical Information Network (UMIN000007514).

DOI： 10.1007/s00595-018-1634-y

IDENTIFICATION OF MOLECULES DRIVING HEPATIC METASTASIS FORMATION OF GASTRIC CANCER CELLS

Kanda Mitsuro, Tanaka Chie, Kobayashi Daisuke, Suenaga Masaya, Takami Hideki, Hattori Norifumi, Niwa Yukiko, Hayashi Masamichi, Yamada Suguru, Nakayama Goro, Koike Masahiko, Fujiwara Michitaka, Kodera Yasuhiro

GUT Vol. 67 page： A5 - A5 2018.6

A novel dual-marker expression panel for easy and accurate risk stratification of patients with gastric cancer. Reviewed International journal

Mitsuro Kanda, Kenta Murotani, Haruyoshi Tanaka, Takashi Miwa, Shinichi Umeda, Chie Tanaka, Daisuke Kobayashi, Masamichi Hayashi, Norifumi Hattori, Masaya Suenaga, Suguru Yamada, Goro Nakayama, Michitaka Fujiwara, Yasuhiro Kodera

Cancer medicine Vol. 7 ( 6 ) page： 2463 - 2471 2018.6

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

Development of specific biomarkers is necessary for individualized management of patients with gastric cancer. The aim of this study was to design a simple expression panel comprising novel molecular markers for precise risk stratification. Patients (n = 200) who underwent gastrectomy for gastric cancer were randomly assigned into learning and validation sets. Tissue mRNA expression levels of 15 candidate molecular markers were determined using quantitative PCR analysis. A dual-marker expression panel was created according to concordance index (C-index) values of overall survival for all 105 combinations of two markers in the learning set. The reproducibility and clinical significance of the dual-marker expression panel were evaluated in the validation set. The patient characteristics of the learning and validation sets were well balanced. The C-index values of combinations were significantly higher compared with those of single markers. The panel with the highest C-index (0.718) of the learning set comprised SYT8 and MAGED2, which clearly stratified patients into low-, intermediate-, and high-risk groups. The reproducibility of the panel was demonstrated in the validation set. High expression scores were significantly associated with larger tumor size, vascular invasion, lymph node metastasis, peritoneal metastasis, and advanced disease. The dual-marker expression panel provides a simple tool that clearly stratifies patients with gastric cancer into low-, intermediate-, and high risk after gastrectomy.

DOI： 10.1002/cam4.1522

Integrated multigene expression panel to prognosticate patients with gastric cancer. Reviewed International journal

Oncotarget Vol. 9 ( 27 ) page： 18775 - 18785 2018.4

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

Most of the proposed individual markers had limited clinical utility due to the inherent biological and genetic heterogeneity of gastric cancer. We aimed to build a new molecular-based model to predict prognosis in patients with gastric cancer. A total of 200 patients who underwent gastric resection for gastric cancer were divided into learning and validation cohorts using a table of random numbers in a 1:1 ratio. In the learning cohort, mRNA expression levels of 15 molecular markers in gastric tissues were analyzed and concordance index (C-index) values of all single and combinations of the 15 candidate markers for overall survival were calculated. The multigene expression panel was designed according to C-index values and the subpopulation index. Expression scores were determined with weighting according to the coefficient of each constituent. The reproducibility of the panel was evaluated in the validation cohort. C-index values of the 15 single candidate markers ranged from 0.506-0.653. Among 32,767 combinations, the optimal and balanced expression panel comprised four constituents (MAGED2, SYT8, BTG1, and FAM46) and the C-index value was 0.793. Using this panel, patients were provisionally categorized with scores of 1-3, and clearly stratified into favorable, intermediate, and poor overall survival groups. In the validation cohort, both overall and disease-free survival rates decreased incrementally with increasing expression scores. Multivariate analysis revealed that the expression score was an independent prognostic factor for overall survival after curative gastrectomy. We developed an integrated multigene expression panel that simply and accurately stratified risk of patients with gastric cancer.

DOI： 10.18632/oncotarget.24661

Effect of Plasma-Activated Lactated Ringer’s Solution on Pancreatic Cancer Cells In Vitro and In Vivo Reviewed

Clinical implication of nutrition for neoadjuvant therapy and impact of nutritional support in pancreatic cancer.

JOURNAL OF CLINICAL ONCOLOGY Vol. 36 ( 4 ) page： . 2018.2

Yusuke Sato, Suguru Yamada, Shigeomi Takeda, Norifumi Hattori, Kae Nakamura, Hiromasa Tanaka, Masaaki Mizuno, Masaru Hori, Yasuhiro Kodera

Annals of Surgical Oncology Vol. 25 ( 1 ) page： 299 - 307 2018.1

Language：English Publishing type：Research paper (scientific journal) Publisher：Springer New York LLC

Background: The medical applications of nonequilibrium atmospheric pressure plasma in cancer therapy have attracted attention. We previously reported on the antitumor effect of plasma-activated medium. However, this approach requires plasma-activated liquids that are administrable to the human body. In this study, we produced plasma-activated lactated Ringer’s solution (PAL) and evaluated its antitumor effect and mechanism. Furthermore, we evaluated the effect of the intraperitoneal administration of PAL using a peritoneal dissemination mouse tumor model. Methods: The antitumor effect of PAL on pancreatic cancer cell lines was evaluated using proliferation and apoptosis assays. In addition, cellular reactive oxygen species (ROS) generation was examined. The role of ROS was assessed using a proliferation assay with N-acetyl cysteine (NAC). An adhesion assay was performed to evaluate the effect of PAL on cell adhesion. Finally, pancreatic cancer cells stably expressing luciferase (AsPC-1/CMV-Luc) were injected intraperitoneally into mice, followed by intraperitoneal injection of PAL. Peritoneal dissemination was monitored using in vivo bioluminescent imaging. Results: The antitumor effect of PAL was shown in all cell lines in vitro. The TUNEL assay showed that PAL induced apoptosis. ROS uptake was observed in PAL-treated cells, and the antitumor effect was inhibited by NAC. Cell adhesion also was suppressed by PAL. The intraperitoneal administration of PAL suppressed the formation of peritoneal nodules in vivo. Conclusions: Our study demonstrated the antitumor effects of PAL in vitro and in vivo. Intraperitoneal administration of PAL may be a novel therapeutic option for peritoneal metastases.

DOI： 10.1245/s10434-017-6239-y

An integrated multigene expression panel to predict long-term survival after curative hepatectomy in patients with hepatocellular carcinoma Reviewed

Mitsuro Kanda, Kenta Murotani, Hiroyuki Sugimoto, Takashi Miwa, Shinichi Umeda, Masaya Suenaga, Masamichi Hayashi, Norifumi Hattori, Chie Tanaka, Daisuke Kobayashi, Suguru Yamada, Michitaka Fujiwara, Yasuhiro Kodera

ONCOTARGET Vol. 8 ( 41 ) page： 71070 - 71079 2017.9

Language：English Publishing type：Research paper (scientific journal) Publisher：IMPACT JOURNALS LLC

Hepatocellular carcinoma (HCC) frequently recurs even after curative hepatectomy. To develop an integrated multigene expression panel, 144 patients were randomly assigned to either discovery or validation set in a 1: 2 ratio. Using surgically resected HCC specimens, expression levels of 12 candidate molecular markers were determined using quantitative reverse-transcriptase PCR. In the discovery set, an expression panel was developed according to the concordance index (C-index) values for overall survival from all 4095 combinations of the 12 candidate molecular markers. Expression scores was determined with weighting according to the coefficient in a Cox regression, and patients were classified into grade 1, 2 and 3. Reproducibility was then tested in the validation set. A panel consisting of four markers, PRMT5, MAGED4, DPYSL3 and AJAP1 was selected as the optimal and most well-balanced set with a C-index value of 0.707. Patient prognosis was clearly stratified by the expression grade using this panel. In the validation set, both overall and disease-free survival rates decreased incrementally with as the grade increased. Higher grades were significantly associated with tumor multiplicity and vessel invasion. The prevalence of extrahepatic recurrences was increased in grade 3 patients. The integrated multigene expression panel clearly stratified HCC patients into low, intermediate and high risk.

DOI： 10.18632/oncotarget.20369

Intraperitoneal Administration of Plasma-Activated Medium: Proposal of a Novel Treatment Option for Peritoneal Metastasis From Gastric Cancer Reviewed

Shigeomi Takeda, Suguru Yamada, Norifumi Hattori, Kae Nakamura, Hiromasa Tanaka, Hiroaki Kajiyama, Mitsuro Kanda, Daisuke Kobayashi, Chie Tanaka, Tsutomu Fujii, Michitaka Fujiwara, Masaaki Mizuno, Masaru Hori, Yasuhiro Kodera

ANNALS OF SURGICAL ONCOLOGY Vol. 24 ( 5 ) page： 1188 - 1194 2017.5

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

The administration of fluid irradiated with non-equilibrium atmospheric pressure plasma (NEAPP) has attracted much interest as a novel therapeutic method for cancer. The authors previously reported on the efficacy of plasma-activated medium (PAM) for treating cancer cell lines through the induction of apoptosis. In this study, the therapeutic effect of PAM was evaluated in vivo using a peritoneal metastasis mouse model.
Two gastric cancer cell lines were used in proliferation assays performed to optimize the production of PAM by changing the distance between the plasma source and the medium surface and by altering the volume of irradiated medium. Wound-healing and adhesion assays were conducted to determine the effect of PAM therapy on cell migration and adhesion capacity in vitro. Finally, a mouse model established by the intraperitoneal injection of enhanced green fluorescent protein-tagged gastric cancer cells was used to explore the efficacy of PAM administered intraperitoneally in inhibiting peritoneal metastasis formation.
Shorter distances between the plasma source and the medium surface and smaller volumes of treated medium increased the anti-tumor effect of PAM. The PAM treatment attenuated gastric cancer cell migration and adhesion in vitro. The intraperitoneal administration of PAM decreased the formation of peritoneal metastatic nodules by 60% in the mouse model, and no adverse events were observed.
Plasma-activated liquids may represent a novel therapeutic method for the treatment of peritoneal metastases in gastric cancer.

DOI： 10.1245/s10434-016-5759-1

The efficacy and safety of CapeOX plus bevacizumab therapy followed by capecitabine plus bevacizumab maintenance therapy in patients with metastatic colorectal cancer: a multi-center, single-arm, phase II study (CCOG-0902) Reviewed

Goro Nakayama, Kiyoshi Ishigure, Hiroyuki Yokoyama, Keisuke Uehara, Hiroshi Kojima, Akiharu Ishiyama, Naomi Hayashi, Nao Takano, Norifumi Hattori, Daisuke Kobayashi, Chie Tanaka, Masamichi Hayashi, Mitsuro Kanda, Suguru Yamada, Hiroyuki Sugimoto, Masahiko Koike, Michitaka Fujiwara, Tsutomu Fujii, Kenta Murotani, Yuichi Ando, Yasuhiro Kodera

BMC CANCER Vol. 17 ( 1 ) page： 243 2017.4

Language：English Publishing type：Research paper (scientific journal) Publisher：BIOMED CENTRAL LTD

Background: The aim of this study was to evaluate the efficacy and safety of CapeOX plus bevacizumab with a planned oxaliplatin stop-and-go strategy in Japanese patients with metastatic colorectal cancer (mCRC).
Methods: Patients with untreated mCRC were treated with 4 cycles of CapeOX plus bevacizumab therapy, followed by capecitabine plus bevacizumab maintenance therapy. Reintroduction of oxaliplatin was scheduled after 8 cycles of maintenance therapy or upon tumor progression. The primary endpoint was progression-free survival (PFS), and secondary end points included overall survival (OS), objective response rate to each treatment, reintroduction rate of oxaliplatin, frequency of peripheral sensory neuropathy (PSN), and safety.
Results: The 52 patients who received the protocol treatment were included in the evaluation of efficacy and safety. Median PFS and OS were 12.4 months (95% confidence interval [CI], 10.0-14.8) and 30.6 months (95% CI, 27. 6-33.5), respectively. The objective response rates were 55.8% for the initial CapeOX plus bevacizumab therapy, 17. 8% for capecitabine plus bevacizumab maintenance therapy, and 31.0% for reintroduced CapeOX plus bevacizumab therapy. The frequency of PSN was 63.5%, including 3.8% of patients with grade 3 PSN. No patients required treatment discontinuation because of PSN during the induction or maintenance therapy.
Conclusions: CapeOX plus bevacizumab therapy with a planned oxaliplatin stop-and-go strategy is a feasible first-line treatment for Japanese patients with mCRC.

DOI： 10.1186/s12885-017-3245-1