Faculty Profiles - KANDA Mitsuro

Papers - KANDA Mitsuro

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Pattern-specific Transcriptomics Identifies ASGR2 as a Predictor of Hematogenous Recurrence of Gastric Cancer Reviewed

Tanaka Haruyoshi, Kanda Mitsuro, Suenaga Masaya, Hayashi Masamichi, Tanaka Chie, Yamada Suguru, Nakayama Goro, Koike Masahiko, Fujiwara Michitaka, Kodera Yasuhiro

CANCER SCIENCE Vol. 109 page： 1128 - 1128 2018.12

Troponin I2 as a specific biomarker for prediction of peritoneal metastasis in gastric cancer Reviewed

Sawaki Koichi, Kanda Mitsuro, Suenaga Masaya, Hayashi Masamichi, Tanaka Chie, Yamada Suguru, Nakayama Goro, Koike Masahiko, Fujiwara Michitaka, Kodera Yasuhiro

CANCER SCIENCE Vol. 109 page： 765 - 765 2018.12

A New Biomarker for Peritoneal Lavage Using Digital PCR in Patients with Pancreatic Ductal Adenocarcinoma

Suenaga Masaya, Yamada Suguru, Hayashi Masamichi, Kanda Mitsuro, Tanaka Chie, Nakayama Goro, Koike Masahiko, Fujiwara Michitaka, Kodera Yasuhiro

CANCER SCIENCE Vol. 109 page： 650-650 2018.12

FRAS1 expression reflects the malignancy potential of gastric cancer

Umeda Shinichi, Kanda Mitsuro, Tanaka Chie, Yamada Suguru, Nakayama Goro, Koike Masahiko, Fujiwara Michitaka, Kodera Yasuhiro

CANCER SCIENCE Vol. 109 page： 1128-1128 2018.12

Pattern-specific Transcriptomics Identifies ASGR2 as a Predictor of Hematogenous Recurrence of Gastric Cancer Reviewed

Tanaka Haruyoshi, Kanda Mitsuro, Suenaga Masaya, Hayashi Masamichi, Tanaka Chie, Yamada Suguru, Nakayama Goro, Koike Masahiko, Fujiwara Michitaka, Kodera Yasuhiro

CANCER SCIENCE Vol. 109 page： 1128-1128 2018.12

Homeobox C10 correlates with the malignant phenotype of gastric cancer and its recurrence and poor survival

Miwa Takashi, Kanda Mitsuro, Tanaka Chie, Yamada Suguru, Koike Masahiko, Fujiwara Michitaka, Kodera Yasuhiro

CANCER SCIENCE Vol. 109 page： 1127-1127 2018.12

Cutting-edge evidence of adjuvant treatments for gastric cancer

Shimizu Dai, Kanda Mitsuro, Kodera Yasuhiro, Sakamoto Junichi

EXPERT REVIEW OF GASTROENTEROLOGY & HEPATOLOGY Vol. 12 ( 11 ) page： 1109 - 1122 2018.11

A randomized phase II multicenter trial to explore efficacy of weekly intraperitoneal in comparison with intravenous paclitaxel administered immediately after gastrectomy to the patients with high risk of peritoneal recurrence: final results of the INPACT trial Reviewed

Naoto Takahashi, Mitsuro Kanda, Takaki Yoshikawa, Nobuhiro Takiguchi, Kazumasa Fujitani, Katsufumi Miyamoto, Yuichi Ito, Osamu Takayama, Motohiro Imano, Norio Mitsumori, Junichi Sakamoto, Satoshi Morita, Yasuhiro Kodera

Gastric Cancer Vol. 21 ( 6 ) page： 1014 - 1023 2018.11

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

Background: Intraperitoneal administration of paclitaxel had been considered a promising option to treat peritoneal metastasis, the most frequent pattern of recurrence in gastric cancer after D2 gastrectomy, but its safety and efficacy after gastrectomy had not been fully explored. Methods: A phase II randomized comparison of postoperative intraperitoneal (IP) vs. intravenous (IV) paclitaxel was conducted. Patients with resectable gastric linitis plastica, cancer with minimal amount of peritoneal deposits (P1), or cancer positive for the peritoneal washing cytology (CY1) were eligible. After intraoperative confirmation of the above disease status and of resectability, patients were randomized to be treated either by the IP therapy (paclitaxel 60 mg/m2 delivered intraperitoneally on days 0, 14, 21, 28, 42, 49, and 56) or the IV therapy (80 mg/m2 administered intravenously using the identical schedule) before receiving further treatments with evidence-based systemic chemotherapy. The primary endpoint was 2-year survival rate. Results: Of the 86 patients who were randomized intraoperatively, 83 who actually started the protocol treatment were eligible for analysis (n = 39, IP group
n = 44, IV group). The 2-year survival rate of the IP and IV groups was 64.1% (95% CI 47.9–76.9) and 72.3% (95% CI 56.3–83.2%), respectively (p = 0.5731). The IP treatment did not confer significant overall or progression-free survival benefits, and was associated with particularly poor performance in patients with residual disease, including the CY1 P0 population. Conclusions: We were unable to prove superiority of the IP paclitaxel over IV paclitaxel delivered after surgery to control advanced gastric cancer with high risk of peritoneal recurrence.

DOI： 10.1007/s10120-018-0817-y

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

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

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

結腸癌における腫瘍局在の臨床病理学的意義の検討 3つの第三相試験の統合解析結果 Reviewed

青山徹, 大庭幸治, 本多通孝, 貞廣荘太郎, 眞柳修平, 神田光郎, 前田広道, 柏原康佑, 坂本純一, 前原喜彦, 吉川貴己

日本消化器外科学会雑誌 Vol. 51 ( Suppl.2 ) page： 294 - 294 2018.11

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

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

Cancer medicine Vol. 7 ( 10 ) page： 5194 - 5204 2018.10

Language：Japanese 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

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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：Japanese 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

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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：Japanese 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

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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

Synaptotagmin XIII expression and peritoneal metastasis in gastric cancer Reviewed

Kanda M, Shimizu D, Tanaka H, Tanaka C, Kobayashi D, Hayashi M, Takami H, Niwa Y, Yamada S, Fujii T, Sugimoto H, Kodera Y

BRITISH JOURNAL OF SURGERY Vol. 105 ( 10 ) page： 1349 - 1358 2018.9

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

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

MOLECULAR CANCER RESEARCH Vol. 16 ( 9 ) page： 1420 - 1429 2018.9

Language：Japanese 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

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大腸癌におけるAGAP3の分子生物学的意義の検討(Biological significance of ArfGAP with GTPase domain, ankyrin repeat and PH domain 3(AGAP3) in colorectal cancer(CRC)) Reviewed

清水大, 佐藤晋彰, 増田隆明, 大津甫, 黒田陽介, 江口英利, 神田光郎, 小寺泰弘, 三森功士

日本癌学会総会記事 Vol. 77回 page： 2066 - 2066 2018.9

＜Editors' Choice＞ Efficacy of enteral nutrients containing β-hydroxy-β-methylbutyrate, glutamine, and arginine for the patients with anastomotic leakage after gastrectomy: study protocol of a multicenter phase II clinical trial. Reviewed

Mitsuro Kanda, Chie Tanaka, Kenta Murotani, Daisuke Kobayashi, Seiji Ito, Yoshinari Mochizuki, Kiyoshi Ishigure, Akiharu Ishiyama, Hitoshi Teramoto, Toshifumi Murai, Takahiro Asada, Hidenobu Matsushita, Michitaka Fujiwara, Yasuhiro Kodera

Nagoya journal of medical science Vol. 80 ( 3 ) page： 351 - 355 2018.8

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

Anastomotic leakage is a major cause of prolonged hospitalization after gastrectomy and sometimes leads to fatal complications, such as abdominal abscess and sepsis. Arginine, glutamine, and β-hydroxy-β-methylbutyrate (HMB) are indispensable for biosynthesis of collagen, which plays an important role in the process of wound healing. However, treatment effects of amino acid supplements containing HMB on the healing process of anastomotic leakage after gastrectomy remain unclear. We designed an open-label, multicenter, phase II clinical trial to evaluate the therapeutic efficacy of an enteral amino acid supplement consisting of arginine, glutamine, and HMB (Abound, Abbott Japan Co., Ltd., Tokyo, Japan) in patients with anastomotic leakage after gastrectomy. Patients who are diagnosed with anastomotic leakage within 14 days after gastrectomy are eligible for this trial and the target sample size is 20. A pack of Abound is administered twice a day for 2 weeks. The primary objective of this clinical trial is to determine the length of time between diagnosis and cure of anastomotic leakage. The secondary endpoints include the safety of Abound, duration of drainage placement and fasting, postoperative hospital stay, surgical procedure, and blood test data. Variables are compared between enrolled patients and a historical control consisting of 20 patients who underwent gastrectomy between 2004 and 2016 at Nagoya University Hospital. We herein describe the study design and the concept in this protocol paper.

DOI： 10.18999/nagjms.80.3.351

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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：Japanese 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

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Papers - KANDA Mitsuro