2023/12/01 更新

写真a

シミズ ダイ
清水 大
SHIMIZU Dai
所属
医学部附属病院 消化器・腫瘍外科(消化管) 病院講師
大学院担当
大学院医学系研究科
職名
病院講師

学位 1

  1. 博士(医学) ( 2016年3月   名古屋大学 ) 

 

論文 96

  1. Subclonal accumulation of immune escape mechanisms in microsatellite instability-high colorectal cancers

    Kobayashi Yuta, Niida Atsushi, Nagayama Satoshi, Saeki Koichi, Haeno Hiroshi, Takahashi Kazuki K., Hayashi Shuto, Ozato Yuki, Saito Hideyuki, Hasegawa Takanori, Nakamura Hiromi, Tobo Taro, Kitagawa Akihiro, Sato Kuniaki, Shimizu Dai, Hirata Hidenari, Hisamatsu Yuichi, Toshima Takeo, Yonemura Yusuke, Masuda Takaaki, Mizuno Shinichi, Kawazu Masahito, Kohsaka Shinji, Ueno Toshihide, Mano Hiroyuki, Ishihara Soichiro, Uemura Mamoru, Mori Masaki, Doki Yuichiro, Eguchi Hidetoshi, Oshima Masanobu, Suzuki Yutaka, Shibata Tatsuhiro, Mimori Koshi

    BRITISH JOURNAL OF CANCER     2023年8月

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    記述言語:英語   出版者・発行元:British Journal of Cancer  

    Background: Intratumor heterogeneity (ITH) in microsatellite instability-high (MSI-H) colorectal cancer (CRC) has been poorly studied. We aimed to clarify how the ITH of MSI-H CRCs is generated in cancer evolution and how immune selective pressure affects ITH. Methods: We reanalyzed public whole-exome sequencing data on 246 MSI-H CRCs. In addition, we performed a multi-region analysis from 6 MSI-H CRCs. To verify the process of subclonal immune escape accumulation, a novel computational model of cancer evolution under immune pressure was developed. Results: Our analysis presented the enrichment of functional genomic alterations in antigen-presentation machinery (APM). Associative analysis of neoantigens indicated the generation of immune escape mechanisms via HLA alterations. Multiregion analysis revealed the clonal acquisition of driver mutations and subclonal accumulation of APM defects in MSI-H CRCs. Examination of variant allele frequencies demonstrated that subclonal mutations tend to be subjected to selective sweep. Computational simulations of tumour progression with the interaction of immune cells successfully verified the subclonal accumulation of immune escape mutations and suggested the efficacy of early initiation of an immune checkpoint inhibitor (ICI) -based treatment. Conclusions: Our results demonstrate the heterogeneous acquisition of immune escape mechanisms in MSI-H CRCs by Darwinian selection, providing novel insights into ICI-based treatment strategies.

    DOI: 10.1038/s41416-023-02395-8

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  2. The preoperative systemic immune-inflammation index is associated with an unfavorable prognosis for patients undergoing curative resection of esophageal squamous cell carcinoma after neoadjuvant therapy

    Obata Yuma, Kanda Mitsuro, Shimizu Dai, Takami Hideki, Inokawa Yoshikuni, Hattori Norifumi, Hayashi Masamichi, Tanaka Chie, Nakayama Goro, Kodera Yasuhiro

    SURGERY TODAY   53 巻 ( 8 ) 頁: 964 - 972   2023年8月

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    記述言語:英語   出版者・発行元:Surgery Today  

    Purposes: Systemic inflammation and immune status play a critical role in the development and progression of cancers. We evaluated the clinical significance of the preoperative systemic immune-inflammation index (SII) for predicting the long-term outcomes of patients who received neoadjuvant therapy for esophageal squamous cell carcinoma (ESCC). Methods: The subjects of this study were 277 patients who underwent curative resection of ESCC after neoadjuvant therapy. The SII was calculated as follows: SII = neutrophil × platelet/lymphocyte counts. Patients were stratified into high and low preoperative SII groups according to the cut-off value calculated by a receiver operating characteristic curve analysis. The Kaplan–Meier method and Cox proportional regression analysis were used to evaluate the correlation of SII to prognosis. Results: The optimal cutoff of the preoperative SII was set at 700. Patients were categorized into preoperative SII-low (n = 203) and SII-high (n = 74) groups. The preoperative SII was significantly associated with tumor size. The relapse-free survival of patients in the SII-high group was significantly shorter (P = 0.0087) and preoperative SII-high was identified as an independent prognostic factor (hazard ratio [HR] 1.55, 95% confidence interval [CI] 1.06–2.28, P = 0.0229). The prevalence of hematogenous recurrence was significantly higher in the SII-high group. When we stratified patients into three groups with an additional cutoff value of 1200, we observed an incremental decrease in relapse-free survival rates. Conclusions: High preoperative SII was associated with shorter relapse-free survival times for ESCC patients who underwent curative resection after neoadjuvant therapy.

    DOI: 10.1007/s00595-023-02658-0

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  3. A feasibility study of modified docetaxel, cisplatin, and capecitabine for advanced gastric cancer followed by gastrectomy

    Liang Yao, Maeda Osamu, Miyata Kazushi, Tanaka Chie, Kanda Mitsuro, Shimizu Dai, Fukaya Masahide, Koike Masahiko, Kodera Yasuhiro, Ando Yuichi

    ASIA-PACIFIC JOURNAL OF CLINICAL ONCOLOGY     2023年7月

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    記述言語:英語   出版者・発行元:Asia-Pacific Journal of Clinical Oncology  

    Aims: To explore the feasibility of modified docetaxel, cisplatin, and capecitabine (mDCX) chemotherapy with a lower dose of docetaxel than previously reported for stage III resectable gastric cancer patients with a high risk of recurrence or for stage IV gastric cancer patients aiming for conversion surgery. Methods: Patients with stage III resectable HER2-negative gastric cancer with large type 3 or type 4 tumors or extensive lymph node metastasis (bulky N or cN3) and those who had stage IV HER2-negative gastric cancer with distant metastasis were enrolled to receive 30 mg/m2 docetaxel and 60 mg/m2 cisplatin on day 1, followed by 2000 mg/m2 capecitabine per day for 2 weeks every 3 weeks. Results: Five patients with stage III gastric cancer with a high risk of recurrence received three courses of mDCX, and four patients with stage IV gastric cancer received three or four courses of mDCX. In terms of grade 3 or worse adverse events, leukopenia was observed in one (11%) patient, neutropenia in two (22%) patients, anemia in one (11%) patient, anorexia in two (22%) patients and nausea in two (22%) patients. All six patients with measurable lesions achieved a partial response. All nine patients underwent subsequent surgeries. The histological responses of the nine patients revealed grade 3 in one (11%) patient, grade 2 in five (56%) patients, and grade 1a in three (33%) patients. Three of the nine patients survived without recurrence, and two of them survived for more than four years. Conclusions: mDCX seems to be feasible and may be helpful as neoadjuvant chemotherapy for patients at high risk of recurrence or as chemotherapy for patients who are likely to undergo conversion surgery.

    DOI: 10.1111/ajco.13995

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  4. High Preoperative Serum D-dimer Predicts Unfavorable Survival Outcomes for Pancreatic Cancer Patients.

    Otsu T, Hayashi M, Takami H, Inokawa Y, Tanaka N, Kurimoto K, Nakanishi K, Umeda S, Shimizu D, Hattori N, Kanda M, Tanaka C, Nakayama G, Kodera Y

    Anticancer research   43 巻 ( 7 ) 頁: 3173 - 3181   2023年7月

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    記述言語:英語   出版者・発行元:Anticancer Research  

    Background/Aim: Pancreatic cancer cells release certain tissue factors into the bloodstream. It is well known that pancreatic cancer progresses with thrombus formation. Because we routinely measure serum D-dimer levels in preoperative patients as a screening marker of deep venous thrombosis, we examined its association with high serum D-dimer in our cohort of pancreatic cancer resected cases. Patients and Methods: We examined 315 patients with pancreatic ductal adenocarcinoma who underwent surgical resection in our department from January 2012 to July 2021. All cases were divided into high D-dimer cases (n=118) and low D-dimer cases (n=197) using the cut-off value of 1.0 μg/ml, an institutional upper limit. Clinicohistological characteristics and postoperative survival outcomes were evaluated. Results: Preoperative high D-dimer cases showed significantly worse progression-free survival (PFS) (p=0.021) and overall survival (OS) (p=0.027) than low D-dimer cases; median PFS was 13.9 months versus 21.4 months, and that of OS was 33.4 months versus 68.0 months. Clinicohistological characteristics of high D-dimer cases were age over 70 years (p<0.001), pathological portal vein invasion (p=0.003), and initially borderline resectable or unresectable cases (p=0.027). Multivariate analysis indicated that preoperative high D-dimer was a significant prognostic factor of PFS (hazard ratio=1.42, p=0.025) and OS (hazard ratio=1.51, p=0.036). Conclusion: Preoperative high serum D-dimer over 1.0 μg/ml was associated with pathological portal vein invasion and could be an unfavorable prognostic marker of PFS and OS after surgery, typically due to distant metastasis.

    DOI: 10.21873/anticanres.16491

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  5. High Preoperative Platelet to Lymphocyte Ratio is Associated with a Greater Risk of Postoperative Complications and Hematogenous Recurrences in Esophageal Squamous Cell Carcinoma Patients Receiving Neoadjuvant Treatment

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

    DIGESTIVE SURGERY   40 巻 ( 1-2 ) 頁: 48 - 57   2023年7月

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    記述言語:英語   出版者・発行元:Digestive Surgery  

    Introduction: Neoadjuvant treatment is currently the gold standard for advanced esophageal squamous cell carcinoma (ESCC). Several studies have examined the value of blood count-based indexes for predicting short- and long-term outcomes after esophagectomy for ESCC, but the relative predictive value of pretreatment, preoperative, and postoperative indexes has not yet been examined. Methods: This study included 320 patients with thoracic ESCC who underwent subtotal esophagectomy after neoadjuvant chemotherapy or chemoradiotherapy at our institution. A total of 19 candidate blood parameters were measured before neoadjuvant treatment as well as preoperatively and postoperatively. The ability of the parameters to predict postoperative complications, overall survival (OS), and relapse-free survival (RFS) was assessed using receiver operating characteristic (ROC) curve analysis and Cox regression analysis. Results: ROC curve analysis indicated that preoperative platelet to lymphocyte ratio (PLR) had the best predictive value with an optimal cutoff value of 166. Patients with high preoperative PLR (≥166) had significantly shorter OS and RFS and significantly higher incidences of hematogenous recurrence and postoperative pneumonia compared with patients with low preoperative PLR (<166). In multivariate analysis, high preoperative PLR and high preoperative serum carcinoembryonic antigen level were independent predictors of poor prognosis. Conclusion: Preoperative PLR is a good predictor of short- and long-term prognosis in patients with advanced ESCC who receive neoadjuvant treatment followed by radical resection.

    DOI: 10.1159/000530018

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  6. Convergent genomic diversity and novel BCAA metabolism in intrahepatic cholangiocarcinoma

    Kitagawa Akihiro, Osawa Tsuyoshi, Noda Miwa, Kobayashi Yuta, Aki Sho, Nakano Yusuke, Saito Tomoko, Shimizu Dai, Komatsu Hisateru, Sugaya Maki, Takahashi Junichi, Kosai Keisuke, Takao Seiichiro, Motomura Yushi, Sato Kuniaki, Hu Qingjiang, Fujii Atsushi, Wakiyama Hiroaki, Tobo Taro, Uchida Hiroki, Sugimachi Keishi, Shibata Kohei, Utsunomiya Tohru, Kobayashi Shogo, Ishii Hideshi, Hasegawa Takanori, Masuda Takaaki, Matsui Yusuke, Niida Atsushi, Soga Tomoyoshi, Suzuki Yutaka, Miyano Satoru, Aburatani Hiroyuki, Doki Yuichiro, Eguchi Hidetoshi, Mori Masaki, Nakayama Keiichi I., Shimamura Teppei, Shibata Tatsuhiro, Mimori Koshi

    BRITISH JOURNAL OF CANCER   128 巻 ( 12 ) 頁: 2206 - 2217   2023年6月

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    記述言語:英語   出版者・発行元:British Journal of Cancer  

    Background: Driver alterations may represent novel candidates for driver gene-guided therapy; however, intrahepatic cholangiocarcinoma (ICC) with multiple genomic aberrations makes them intractable. Therefore, the pathogenesis and metabolic changes of ICC need to be understood to develop new treatment strategies. We aimed to unravel the evolution of ICC and identify ICC-specific metabolic characteristics to investigate the metabolic pathway associated with ICC development using multiregional sampling to encompass the intra- and inter-tumoral heterogeneity. Methods: We performed the genomic, transcriptomic, proteomic and metabolomic analysis of 39–77 ICC tumour samples and eleven normal samples. Further, we analysed their cell proliferation and viability. Results: We demonstrated that intra-tumoral heterogeneity of ICCs with distinct driver genes per case exhibited neutral evolution, regardless of their tumour stage. Upregulation of BCAT1 and BCAT2 indicated the involvement of ‘Val Leu Ile degradation pathway’. ICCs exhibit the accumulation of ubiquitous metabolites, such as branched-chain amino acids including valine, leucine, and isoleucine, to negatively affect cancer prognosis. We revealed that this metabolic pathway was almost ubiquitously altered in all cases with genomic diversity and might play important roles in tumour progression and overall survival. Conclusions: We propose a novel ICC onco-metabolic pathway that could enable the development of new therapeutic interventions. [Figure not available: see fulltext.]

    DOI: 10.1038/s41416-023-02256-4

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

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

    NUTRITION AND CANCER-AN INTERNATIONAL JOURNAL   75 巻 ( 5 ) 頁: 1330 - 1339   2023年5月

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    記述言語:英語   出版者・発行元:Nutrition and Cancer  

    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

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  8. Feasibility assessment of global standard chemoradiotherapy followed by surgery in patients with esophageal cancer

    Liang Yao, Maeda Osamu, Miyata Kazushi, Kanda Mitsuro, Shimizu Dai, Sugita Shizuki, Okada Tohru, Ito Junji, Kawamura Mariko, Ishihara Shunichi, Nakatochi Masahiro, Ando Masahiko, Kodera Yasuhiro, Ando Yuichi

    MOLECULAR AND CLINICAL ONCOLOGY   18 巻 ( 4 ) 頁: 34   2023年4月

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    記述言語:英語   出版者・発行元:Molecular and Clinical Oncology  

    The present study aimed to assess the feasibility of global standard chemoradiotherapy (CRT) followed by surgery in patients with esophageal cancer. A prospective study was conducted at Nagoya University Hospital (Nagoya, Japan) to evaluate global standard CRT followed by surgery in patients with esophageal cancer. The CRT regimen consisted of 75 mg/m2 cisplatin on day 1 and 1,000 mg/m2 fluorouracil daily on days 1-4 given twice 4 weeks apart together with concurrent esophageal irradiation starting on day 1 (group A). For comparison, 17 patients with esophageal cancer who had received the same chemotherapy regimen but with lower drug doses were retrospectively reviewed: 70 mg/m2 cisplatin on day 1 and 700 mg/m2 fluorouracil daily on days 1-4 given twice 4 weeks apart together with concurrent esophageal irradiation starting on day 1 (group B). Grade 3 or worse adverse events were observed in 9 of the 12 patients (75%) in group A and in 5 of the 17 patients (29%) in group B. The patients in group A were more likely to experience grade 3 or worse neutropenia (50%) than those in group B (6%). No febrile neutropenia or treatment-related deaths occurred in either group. A total of 11 patients (92%) in group A and 16 patients (94%) in group B subsequently underwent an esophagectomy, and 9 (82%) and 14 (88%) of these patients, respectively, achieved microscopically margin-negative resection (R0 resection). In conclusion, global standard CRT was more likely to cause severe but manageable adverse events. There was no apparent difference in the R0 resection rate or postoperative complications between the two treatments. This clinical trial was registered at the Japan Registry of Clinical Trials (trial registration number: jRCT1041180004) on September 11, 2018.

    DOI: 10.3892/mco.2023.2630

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  9. Modified Albumin-Bilirubin Grade optimized for risk stratification of patients with stage II-III gastric cancer

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

    SURGERY TODAY     2023年3月

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    記述言語:英語   出版者・発行元:Surgery Today  

    Purpose: The albumin–bilirubin (ALBI) grade is calculated using albumin and bilirubin values. We determined the optimal cutoff value of the ALBI grade for predicting the postoperative prognosis of gastric cancer (GC). Methods: We retrospectively reviewed a multicenter database of 3571 patients who underwent gastrectomy for GC between January 2010 and December 2014. The modified ALBI (mALBI) grade was determined using cutoff values: grade 1 (mALBI ≤ − 2.70), 2 (mALBI − 2.70 to − 2.10), and 3 (mALBI > − 2.10). We used a validation cohort to evaluate reproducibility. Results: The entire cohort (n = 956) was randomly assigned to the learning or validation cohorts (n = 478 each). The former was categorized into the following groups by the preoperative mALBI grade: grade 1 (n = 235), grade 2 (n = 162), and grade 3 (n = 81). The disease-specific survival (DSS) rates of the learning and validation cohorts were significantly shortened in association with higher mALBI grade (learning, p = 0.0068; validation, p = 0.0100). A multivariate analysis revealed that mALBI grade 3 served as an independent prognostic factor for DSS. Furthermore, mALBI grade 2 or 3 was associated with a greater risk of disease-specific death in most subgroups. Conclusion: The mALBI grade accurately predicted the long-term postoperative prognosis of locally advanced GC.

    DOI: 10.1007/s00595-023-02669-x

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  10. Controlling Nutritional Status Score Serves as a Prognosticator in Esophageal Squamous Cell Carcinoma: Optimal Timing of Evaluation of Patients Undergoing Neoadjuvant Treatment

    Nonogaki Ikue, Kanda Mitsuro, Shimizu Dai, Inokawa Yoshikuni, Hattori Norifumi, Hayashi Masamichi, Tanaka Chie, Koike Masahiko, Nakayama Goro, Kodera Yasuhiro

    WORLD JOURNAL OF SURGERY   47 巻 ( 1 ) 頁: 217 - 226   2023年1月

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    記述言語:英語   出版者・発行元:World Journal of Surgery  

    Background: Usefulness of various nutritional indices for management of patients with esophageal squamous cell carcinoma (ESCC) has been reported. Although Controlling Nutritional Status (CONUT) score is among promising indices to predict outcome, the optimal timing for its measurement during the perioperative period remains unknown. Here the prognostic value of the CONUT score was assessed among patients with ESCC. Methods: We analyzed 464 patients who underwent subtotal esophagectomy of ESCC, of which 276 patients were treated with neoadjuvant treatment (NAT). The significance of the associations between candidate parameters including the CONUT score and postoperative prognosis were evaluated. Result: Among the 25 candidate predictors, the preoperative CONUT score had the highest correlation with overall survival (OS) after surgery. Patients were categorized as follows: normal, mild, and moderate or severe, on the basis of the preoperative CONUT score. OS was significantly shortened as the CONUT score worsened. Multivariable analysis revealed that the CONUT scores of the subgroups mild (Hazard ratio [HR] 1.69) and moderate or severe (HR 2.18) were independent predictors of poor prognosis for OS. Furthermore, in an analysis limited to patients who underwent NAT, OS was significantly shortened as the preoperative CONUT score worsened. On the contrary, there was no significant difference in RFS among patient groups stratified by the CONUT score determined before NAT. Conclusions: Our study indicates that the preoperative CONUT score serves as a prognosticator in resectable ESCC. The preoperative CONUT value was more useful than that before NAT in patients administered NAT.

    DOI: 10.1007/s00268-022-06773-w

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  11. Preoperative indocyanine green fluorescence injection to accurately determine a proximal margin during robotic distal gastrectomy

    Nakanishi Koki, Tanaka Chie, Kanda Mitsuro, Shimizu Dai, Furukawa Kazuhiro, Fujiwara Michitaka, Kawashima Hiroki, Kodera Yasuhiro

    ASIAN JOURNAL OF ENDOSCOPIC SURGERY   16 巻 ( 1 ) 頁: 152 - 156   2023年1月

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    記述言語:英語   出版者・発行元:Asian Journal of Endoscopic Surgery  

    Introduction: Adequate surgical margins following gastrectomy for gastric cancer are required. In addition, a method for accurately detecting tumor location without palpation is needed during robotic surgery. Although several methods have been reported, most of these either lack accuracy or require increased time and effort during intraoperative detection. Herein, we introduce a new method for detecting tumor location using preoperative indocyanine green (ICG) marking and the built-in ICG detection system of the da Vinci Xi Surgical System in robotic gastrectomy to determine appropriate surgical margins. Materials and Surgical Technique: We used this method to determine the resection line in six patients who underwent robotic distal gastrectomy for clinical T1 gastric cancer. One to three days before surgery, ICG was diluted to 1.0 mg/mL, and 0.1 mL of this diluted ICG solution was endoscopically injected at one site into the submucosal layer of the stomach, 1 cm proximal to the tumor edge. Gastrectomy was performed using the da Vinci Xi surgical platform, equipped with a near-infrared fluorescence imaging system (Firefly®). The diameter of the fluorescent signal during gastrectomy was estimated to be approximately 2 cm. The resection line was determined on the outer edge of the fluorescent signal, which ensured a tumor-free margin of ≥2 cm. Fluorescent signals were successfully observed in all cases. Moreover, the required 2-cm surgical margin was achieved in all cases. Discussion: We could successfully determine proximal margins using preoperative ICG injection marking during robotic distal gastrectomy for gastric cancer.

    DOI: 10.1111/ases.13121

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  12. OPLAH Protein Expression Stratifies the Prognosis of Patients With Squamous Cell Carcinoma of the Esophagus

    Shimizu Dai, Kanda Mitsuro, Kishida Takayoshi, Nakamura Shunsuke, Sasahara Masahiro, Ueda Sei, Sato Yusuke, Inokawa Yoshikuni, Hattori Norifumi, Hayashi Masamichi, Tanaka Chie, Motoyama Satoru, Kodera Yasuhiro

    CANCER GENOMICS & PROTEOMICS   20 巻 ( 4 ) 頁: 343 - 353   2023年

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    記述言語:英語   出版者・発行元:Cancer Genomics and Proteomics  

    Background/Aim: Squamous cell carcinoma is one of the major subtypes of esophageal carcinoma, and the 5-year overall survival rate of esophageal squamous cell carcinoma patients who underwent curative treatment remains below 40%. We aimed to detect and validate the prognosticators of esophageal squamous cell carcinoma in patients who underwent radical esophagectomy. Materials and Methods: Comprehensive analysis of transcriptome and clinical data from The Cancer Genome Atlas revealed OPLAH as one of the differentially expressed genes between esophageal squamous cell carcinoma tissues and normal esophageal mucosa. OPLAH expression changes were significantly associated with a patient prognosis. OPLAH protein levels were further evaluated by immunohistochemistry in esophageal squamous cell carcinoma tissues (n=177) as well as in serum samples (n=54) using ELISA. Results: OPLAH mRNA was significantly overexpressed in esophageal squamous cell carcinoma tissues compared to normal esophageal mucosa, and patients with high OPLAH mRNA expression have a significantly poorer prognosis, according to The Cancer Genome Atlas data. The high staining intensity of OPLAH protein in esophageal squamous cell carcinoma tissue clearly stratified patient prognosis. According to multivariable analysis, high OPLAH protein expression was an independent prognostic factor for survival after surgery. Pre-neoadjuvant chemotherapy serum OPLAH protein concentrations were significantly associated with clinical tumor depth and node positivity and, consequently, with advanced clinical stage. The serum OPLAH protein concentration was significantly decreased by neoadjuvant chemotherapy. Conclusion: OPLAH protein expression in cancerous tissue and serum may have clinical utility towards stratifying prognosis of patients with esophageal squamous cell carcinoma.

    DOI: 10.21873/cgp.20386

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  13. A Multicenter Randomized Phase II Trial Investigating the Effect of Polyglycolic Acid Sheet on the Prevention of Pancreatic Fistula After Gastrectomy with Prophylactic Lymph Node Dissection

    Shimizu Dai, Tanaka Chie, Kanda Mitsuro, Nakanishi Koki, Ito Seiji, Kuwatsuka Yachiyo, Ando Masahiko, Murotani Kenta, Fujiwara Michitaka, Kodera Yasuhiro

    CLINICAL AND EXPERIMENTAL GASTROENTEROLOGY   16 巻   頁: 169 - 172   2023年

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    記述言語:英語   出版者・発行元:Clinical and Experimental Gastroenterology  

    Pancreatic fistula after gastrectomy with lymph node dissection is associated with prolonged hospital stay and critical complications such as intra-abdominal bleeding and sepsis. Polyglycolic acid (PGA) sheets are absorbable suture reinforcement materials. A randomized Phase II trial has been planned to evaluate the effect of PGA sheets on preventing postoperative pancreatic fistula. A total of 320 patients will be recruited from thirteen institutions. Patients who are scheduled to undergo distal or total gastrectomy will be randomly allocated into the PGA group or control group, and the dissected area around the pancreas will be covered by the PGA sheet in the PGA group. The primary endpoint will be the maximum value of drain amylase concentration up to 5 days after surgery. The secondary endpoints will be as follows: transition of value of amylases of drain discharge, incidence of pancreatic fistula, incidence of intra-abdominal abscess, white blood cell count, value of C-reactive protein, incidence of postoperative complication, duration of antibiotic agents administration, duration of abdominal drainage, usage of octreotide, duration of hospital stay, incidence of bleeding in abdominal cavity, mortality, and incidence of reoperation.

    DOI: 10.2147/CEG.S421531

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  14. 特集 外科医が担う緩和治療 緩和治療における侵襲的処置 消化器癌緩和治療における腹腔鏡下人工肛門造設術

    梅田 晋一, 中山 吾郎, 服部 憲史, 岸田 貴喜, 真田 祥太郎, 岡野 佳奈, 飯塚 彬光, 吾妻 祐哉, 田中 健士郎, 呂 成九, 清水 大, 田中 千恵, 神田 光郎, 小寺 泰弘

    臨床外科   77 巻 ( 10 ) 頁: 1205 - 1210   2022年10月

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    出版者・発行元:株式会社医学書院  

    DOI: 10.11477/mf.1407213860

    CiNii Research

  15. Identification of the Minimum Combination of Serum microRNAs to Predict the Recurrence of Colorectal Cancer Cases.

    Yoshikawa Y, Fukunaga M, Takahashi J, Shimizu D, Masuda T, Mizushima T, Yamada K, Mori M, Eguchi H, Doki Y, Ochiya T, Mimori K

    Annals of surgical oncology     2022年9月

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    記述言語:英語  

    DOI: 10.1245/s10434-022-12355-w

    PubMed

  16. 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

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

    JOURNAL OF GASTROENTEROLOGY   57 巻 ( 9 ) 頁: 640 - 653   2022年9月

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    記述言語:日本語   出版者・発行元:Journal of Gastroenterology  

    Background: Localized gastric cancer (GC) becomes fatal once recurring. We still have room for improving their prognoses. Methods: Transcriptomic analysis was done on surgically resected specimens of 16 patients with UICC stage III GC who underwent curative gastrectomy and adjuvant oral fluoropyrimidine monotherapy. Four of them were free from disease for longer than 5 years, and the others experienced metachronous metastasis within 2 years after surgery. Quantitative RT-PCR determined mRNA expression levels of primary gastric cancer tissues, which were collected from 180 patients who underwent gastric resection for stage II–III GC without preoperative treatment between 2001 and 2014. We tested alteration of malignant phenotypes including drug resistance of GC cell lines by siRNA and shRNA-mediated knockdown and forced expression experiments. Results: CPLX1 was identified as a candidate biomarker for GC recurrence among 57,749 genes. Inhibiting and forced expression experiments indicated that CPLX1 promotes proliferation, motility, and invasiveness of GC cells, and decreases apoptosis and sensitivity to fluorouracil. Subcutaneous xenograft mouse models revealed that shRNA-mediated knockdown of CPLX1 also attenuated tumor growth of MKN1 cells in vivo. Overexpression of CPLX1 in gastric cancer tissue correlated with worse prognosis and was an independent risk factor for peritoneal recurrence in subgroups receiving adjuvant chemotherapy. Conclusions: CPLX1 may represent a biomarker for recurrence of gastric cancer and a target for therapy.

    DOI: 10.1007/s00535-022-01884-6

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

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

    ANNALS OF SURGICAL ONCOLOGY   29 巻 ( 8 ) 頁: 4889 - 4896   2022年8月

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    記述言語:日本語   出版者・発行元:Annals of Surgical Oncology  

    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.

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  18. Comparison Between FOLFIRINOX and nal-IRI/FL as Second-line Treatment After Gemcitabine Plus Nab-paclitaxel for Pancreatic Cancer br

    Otsu Tomohisa, Inokawa Yoshikuni, Takami Hideki, Hayashi Masamichi, Kurimoto Keisuke, Tanaka Nobutake, Tanaka Haruyoshi, Shimizu Dai, Hattori Norifumi, Kanda Mitsuro, Tanaka Chie, Nakayama Goro, Kodera Yasuhiro

    ANTICANCER RESEARCH   42 巻 ( 8 ) 頁: 3889 - 3894   2022年8月

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    記述言語:日本語   出版者・発行元:Anticancer Research  

    Background/Aim: The regimen of nanoliposomal irinotecan plus 5-fluorouracil and leucovorin (Nal-IRI/FL) was approved in Japan as second-line chemotherapy after gemcitabine-based treatment for pancreatic ductal adenocarcinoma (PDAC) in 2020. We examined the difference in outcome between patients treated with second-line folinic acid, fluorouracil, irinotecan hydrochloride and oxaliplatin (FOLFIRINOX) and those treated with nal-IRI/FL after first-line gemcitabine and nab-paclitaxel (GnP). Patients and Methods: The outcomes of 34 patients with PDAC who received second-line FOLFIRINOX (n=21) or nal-IRI/FL (n=13) after GnP at our Department from January 2016 to June 2021 were reviewed retrospectively. Results: Patient backgrounds did not differ between the groups. Dose reduction was more frequently required for treatment with FOLFIRINOX than with nal-IRI/FL (86% vs. 46%, p=0.022). Pegfilgrastim and aprepitant were used more frequently in the FOLFIRINOX group (both p<0.01). Progression-free survival (5.9 vs. 8.3 months) and overall survival (9.1 vs. 11.2 months) did not differ significantly between the groups. The frequency of grade 3 (Common Terminology Criteria for Adverse Events) or higher adverse events was similar between the groups. All-grade peripheral neuropathy was more common in the FOLFIRINOX group (100% vs. 77%, p=0.048). Conclusion: FOLFIRINOX and nal-IRI/FL as second-line therapy after GnP provided similar prognoses, although supportive treatment and dose reduction were more frequently required for FOLFIRINOX.

    DOI: 10.21873/anticanres.15882

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  19. E-PASS scoring system serves as a predictor of short- and long-term outcomes in gastric cancer surgery

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

    SURGERY TODAY   52 巻 ( 6 ) 頁: 914 - 922   2022年6月

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    記述言語:日本語   出版者・発行元:Surgery Today  

    Purposes: This study aimed to evaluate the estimation of the physiological ability and surgical stress (E-PASS) scoring system for predicting the short- and long-term outcomes in gastric cancer (GC) surgery. Methods: We analyzed a multi-institutional dataset to study patients who underwent gastrectomy with a curative intent between 2010 and 2014. This study evaluated the associations between the optimal E-PASS score cutoff value and the following outcomes: (1) the incidence of postoperative complications in stage I–III GC patients and (2) the prognosis in stage II–III GC patients. Results: A total of 2495 GC patients were included. A cutoff value of 0.419 was determined using the ROC curve analysis. Postoperative complications were observed more frequently in the E-PASS-high group than that in the E-PASS-low group (30% vs. 17%, p < 0.0001). Among pStage II–III GC patients (n = 1009), the overall survival time of the E-PASS-high group was significantly shorter than that of the E-PASS-low group (hazard ratio 2.08; 95% confidence interval 1.64–2.65; p < 0.0001). A forest plot revealed that E-PASS-high was associated with a greater prognostic factor for overall survival in most subgroups. Conclusions: The E-PASS scoring system may therefore be a useful predictor of the short- and long-term outcomes in patients with GC who have undergone radical gastrectomy.

    DOI: 10.1007/s00595-021-02394-3

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

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

    INTERNATIONAL JOURNAL OF ONCOLOGY   60 巻 ( 6 )   2022年6月

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    記述言語:日本語   出版者・発行元:International Journal of Oncology  

    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

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  21. Pan-cancer methylome analysis for cancer diagnosis and classification of cancer cell of origin

    Shimizu Dai, Taniue Kenzui, Matsui Yusuke, Haeno Hiroshi, Araki Hiromitsu, Miura Fumihito, Fukunaga Mitsuko, Shiraishi Kenji, Miyamoto Yuji, Tsukamoto Seiichi, Komine Aya, Kobayashi Yuta, Kitagawa Akihiro, Yoshikawa Yukihiro, Sato Kuniaki, Saito Tomoko, Ito Shuhei, Masuda Takaaki, Niida Atsushi, Suzuki Makoto, Baba Hideo, Ito Takashi, Akimitsu Nobuyoshi, Kodera Yasuhiro, Mimori Koshi

    CANCER GENE THERAPY   29 巻 ( 5 ) 頁: 428 - 436   2022年5月

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    記述言語:日本語   出版者・発行元:Cancer Gene Therapy  

    The accurate and early diagnosis and classification of cancer origin from either tissue or liquid biopsy is crucial for selecting the appropriate treatment and reducing cancer-related mortality. Here, we established the CAncer Cell-of-Origin (CACO) methylation panel using the methylation data of the 28 types of cancer in The Cancer Genome Atlas (7950 patients and 707 normal controls) as well as healthy whole blood samples (95 subjects). We showed that the CACO methylation panel had high diagnostic potential with high sensitivity and specificity in the discovery (maximum AUC = 0.998) and validation (maximum AUC = 1.000) cohorts. Moreover, we confirmed that the CACO methylation panel could identify the cancer cell type of origin using the methylation profile from liquid as well as tissue biopsy, including primary, metastatic, and multiregional cancer samples and cancer of unknown primary, independent of the methylation analysis platform and specimen preparation method. Together, the CACO methylation panel can be a powerful tool for the classification and diagnosis of cancer.

    DOI: 10.1038/s41417-021-00401-w

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

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

    GASTRIC CANCER   25 巻 ( 3 ) 頁: 558 - 572   2022年5月

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    記述言語:日本語   出版者・発行元:Gastric Cancer  

    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

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

    Shinozuka T, Kanda M, Shimizu D, Tanaka C, Inokawa Y, Hattori N, Hayashi M, Koike M, Kodera Y

    Annals of surgical oncology     2022年4月

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    記述言語:英語  

    DOI: 10.1245/s10434-022-11784-x

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  24. SLC7A9 as a Potential Biomarker for Lymph Node Metastasis of Esophageal Squamous Cell Carcinoma

    Baba Hayato, Kanda Mitsuro, Sawaki Koichi, Nakamura Shunsuke, Ueda Sei, Shimizu Dai, Koike Masahiko, Kodera Yasuhiro, Fujii Tsutomu

    ANNALS OF SURGICAL ONCOLOGY   29 巻 ( 4 ) 頁: 2699 - 2709   2022年4月

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    記述言語:日本語   出版者・発行元:Annals of Surgical Oncology  

    Background: The expression of solute carrier (SLC) 7 family genes is reportedly associated with several malignancies. Here, we focused on SLC7A9 and investigated its expression, function, and clinical significance in esophageal squamous cell carcinoma (ESCC). Methods: SLC7A9 transcription levels were evaluated in 13 ESCC cell lines, and polymerase chain reaction (PCR) array analysis was conducted to detect coordinately expressed genes with SLC7A9. SLC7A9 contributions to proliferation, invasion, and migration were evaluated in ESCC cells subjected to siRNA-mediated gene knockdown and pCMV6-entry plasmid-mediated overexpression. SLC7A9 expression was detected in 189 ESCC tissues by quantitative reverse-transcription (qRT)-PCR and correlated with clinicopathological parameters. Results: The expression levels of SLC7A9 varied widely in ESCC cell lines and correlated with FGFBP1 expression. Knockdown of SLC7A9 significantly suppressed the proliferation, invasion, and migration of the ESCC cell lines. Moreover, overexpression of SLC7A9 enhanced cell proliferation and migration. In analyses of clinical specimens, SLC7A9 mRNA was overexpressed in the ESCC tissues compared with the adjacent normal esophageal tissues. High mRNA expression was significantly associated with high levels of squamous cell carcinoma-related antigen and carcinoembryonic antigen, advanced disease stage, and lymph node metastasis. High SLC7A9 expression was also significantly associated with poor disease-specific and disease-free survival, and lymph node recurrence after radical surgery, but not with the other recurrence patterns. On multivariate analysis, high SLC7A9 expression was an independent predictor of lymph node recurrence. Conclusions: SLC7A9 influences the malignant behavior of ESCC cells. Tumor SLC7A9 expression may serve as a novel biomarker for predicting lymph node metastasis and recurrence in ESCC patients.

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  25. Prognostic impact of a microscopic positive margin in patients undergoing gastrectomy for gastric cancer: a propensity score-matched analysis of a multi-institutional dataset

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

    SURGERY TODAY   52 巻 ( 4 ) 頁: 559 - 566   2022年4月

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    記述言語:日本語   出版者・発行元:Surgery Today  

    Purpose: We analyzed the effect of a microscopic positive margin on survival outcomes after gastrectomy for gastric cancer Methods: We analyzed a multi-institutional dataset to study patients who underwent gastrectomy with curative intent between 2010 and 2014. We used propensity score matching to strictly balance the patients’ oncological features, backgrounds, and postoperative treatment to compare the survival outcomes of those with microscopic positive margins and those with negative margins. Results: Among 3029 patients, 32 (1.1%) had positive margins. After matching, we enrolled 128 patients in this retrospective analysis: 32 with a positive margin and 96 with a negative margin. The recurrence-free survival of the positive-margin group was significantly shorter than that of the negative-margin group (hazard ratio [HR], 1.62, 95% confidence interval, 1.00–2.63, p = 0.0485). Consistent results were observed for patients with pStages I–III disease (HR, 1.65, p = 0.0835), whereas the survival curves overlapped in those with pStage IV disease (HR, 1.29, p = 0.5934). The prevalence of overall recurrence in the positive-margin group was higher than that in the negative-margin group (75% vs 58%, p = 0.0917). This trend was consistent with locoregional recurrence (9% vs 3%) and distant recurrence (69% vs 55%). Conclusions: The survival of patients after curative gastrectomy for gastric cancer was worse in those with microscopic positive margins than in those with negative margins.

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  26. ASO Visual Abstract: SLC7A9 as a Potential Biomarker for Lymph Node Metastasis of Esophageal Squamous Cell Carcinoma

    Baba Hayato, Kanda Mitsuro, Sawaki Koichi, Nakamura Shunsuke, Ueda Sei, Shimizu Dai, Koike Masahiko, Kodera Yasuhiro, Fujii Tsutomu

    ANNALS OF SURGICAL ONCOLOGY   29 巻 ( 4 ) 頁: 2710 - 2710   2022年4月

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    記述言語:日本語   出版者・発行元:Annals of surgical oncology  

    DOI: 10.1245/s10434-021-11065-z

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

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

    WORLD JOURNAL OF SURGERY   46 巻 ( 3 ) 頁: 648 - 655   2022年3月

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    記述言語:日本語   出版者・発行元:World Journal of Surgery  

    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.

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  28. 食道扁平上皮癌における OPLAH タンパク発現意義

    清水 大, 神田 光郎, 佐藤 雄亮, 本山 悟, 小寺 泰弘

    日本分子腫瘍マーカー研究会誌   38 巻 ( 0 ) 頁: 49 - 50   2022年

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    記述言語:日本語   出版者・発行元:日本分子腫瘍マーカー研究会  

    DOI: 10.11241/jsmtmr.38.49

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  29. Feasibility of oral microbiome profiles associated with oral squamous cell carcinoma

    Hashimoto K., Shimizu D., Ueda S., Miyabe S., Oh-Iwa I., Nagao T., Shimozato K., Nomoto S.

    Journal of Oral Microbiology   14 巻 ( 1 ) 頁: 2105574   2022年

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    記述言語:英語   出版者・発行元:Journal of Oral Microbiology  

    Objective: Recently, the possibility that oral microbiomes is associated with oral squamous cell carcinoma (OSCC) initiation and progression has attracted attention; however, this association is still unclear. Here, we comprehensively analyze the microbiome profiles of saliva samples using next-generation sequencing followed by determining the association between oral microbiome profiles and OSCC. Materials and Methods: Microbiome profiles in saliva samples from patients with OSCC, oral leukoplakia (OLK), and postoperative OSCC (Post) were analyzed. Candidate OSCC-associated bacteria were identified by comparing the bacterial diversity and relative abundance of each group based on these microbiome profiles, and their applicability as OSCC detection tools were evaluated. Results: There were significant differences in genus abundances (Streptococcus, Aggregatibacter, and Alloprevotella) among the groups from saliva samples. In the OSCC group, compared with the OLK and Post groups, abundances of the genus Fusobacterium, phylum Fusobacteria and phylum Bacteroidetes were markedly increased and that of the genus Streptococcus and phylum Firmicutes were decreased. Conclusion: The results suggested a strong association of these bacteria with OSCC. Especially, phylum Fusobacterium was significantly associated with early recurrence of OSCC. Thus, oral microbiome analysis may have a potential of novel OSCC detection and prognostic tool.

    DOI: 10.1080/20002297.2022.2105574

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  30. Neoadjuvant docetaxel, oxaliplatin plus S-1 for treating clinical stage III squamous cell carcinoma of the esophagus: Study protocol of an open-label phase II trial

    Kanda Mitsuro, Shimizu Dai, Miyata Kazushi, Maeda Osamu, Tanaka Chie, Inokawa Yoshikuni, Hattori Norofumi, Hayashi Masamichi, Ando Masahiko, Kuwatsuka Yachiyo, Murotani Kenta, Nakayama Goro, Koike Masahiko, Ando Yuichi, Ebata Tomoki, Kodera Yasuhiro

    CONTEMPORARY CLINICAL TRIALS COMMUNICATIONS   24 巻   頁: 100853   2021年12月

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    記述言語:日本語   出版者・発行元:Contemporary Clinical Trials Communications  

    In Japan, esophagectomy after two courses of 5-fluorouracil plus cisplatin is regarded a standard strategy for treating resectable 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 requirement for a more effective regimen. We are conducting a single-arm phase II study to assess the safety and efficacy of neoadjuvant docetaxel, oxaliplatin plus S-1 (DOS) for treating patients with clinical stage III ESCC. The primary endpoint is the pathological response rate, and the target number is 45 patients. Safety, response rate, R0 resection rate, and survival are secondary endpoints. This trial is registered in the Japan Registry of Clinical Trials as jRCTs041210023. We are conducting a prospective phase II trial to evaluate the safety and efficacy of three courses of neoadjuvant DOS treatment followed by radical esophagectomy for clinical stage III ESCC.

    DOI: 10.1016/j.conctc.2021.100853

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  31. Identifying the tumor-progressive gene expression profile in high-risk papillary thyroid cancer

    Shibata Masahiro, Inaishi Takahiro, Ichikawa Takahiro, Shimizu Dai, Soeda Ikumi, Takano Yuko, Takeuchi Dai, Tsunoda Nobuyuki, Kikumori Toyone

    SURGERY TODAY   51 巻 ( 10 ) 頁: 1703 - 1712   2021年10月

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    記述言語:日本語   出版者・発行元:Surgery Today  

    Purpose: Papillary thyroid cancer (PTC) is generally associated with a favorable prognosis. However, some patients have fatal disease, with locally infiltrating tumors or progressive distant metastases; yet few studies have investigated the characteristics of the tumor-progressive gene expression profile in advanced PTC. We conducted this study to clarify the gene expression status in advanced PTC and identify candidate molecules for prognostic biomarkers. Methods: We analyzed 740 tumor-progressive gene expression levels from formalin-fixed paraffin-embedded blocks of samples from six patients with low-risk PTC and six patients with high-risk PTC, using the nCounter PanCancer Progression panel. Then, we investigated the association between the expression levels of focused genes and pathological factors in PTC patients in The Cancer Genome Atlas (TCGA) database. Results: The expression levels of 14 genes in the high-risk PTC specimens were more than two-fold those in the low-risk PTC specimens. In the TCGA database, expression levels of four genes (CCL11, COL6A3, INHBA, and SRPX2) were significantly higher in patients with advanced PTC. Among the patients with advanced PTC, those with high SRPX2 expression levels had poor disease-free survival. Univariate and multivariate analyses revealed that high SRPX2 expression was an independent prognostic factor. Conclusion: Based on the findings of this study, CCL11, COL6A3, INHBA, and SRPX2 are potential biomarkers that indicate advanced PTC. SRPX2, in particular, is considered a prognostic biomarker.

    DOI: 10.1007/s00595-021-02262-0

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

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

    ONCOGENE   40 巻 ( 36 ) 頁: 5495 - 5504   2021年9月

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    記述言語:日本語   出版者・発行元:Oncogene  

    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

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  33. Mitotic checkpoint regulator RAE1 promotes tumor growth in colorectal cancer.

    Kobayashi Y, Masuda T, Fujii A, Shimizu D, Sato K, Kitagawa A, Tobo T, Ozato Y, Saito H, Kuramitsu S, Noda M, Otsu H, Mizushima T, Doki Y, Eguchi H, Mori M, Mimori K

    Cancer science   112 巻 ( 8 ) 頁: 3173 - 3189   2021年8月

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    記述言語:英語  

    DOI: 10.1111/cas.14969

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  34. A Possible Definition of Oligometastasis in Pancreatic Cancer and Associated Survival Outcomes

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

    ANTICANCER RESEARCH   41 巻 ( 8 ) 頁: 3933 - 3940   2021年8月

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    記述言語:日本語   出版者・発行元:Anticancer Research  

    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

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  35. High Serum Uric Acid Levels Could Be a Risk Factor of Hepatocellular Carcinoma Recurrences

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

    NUTRITION AND CANCER-AN INTERNATIONAL JOURNAL   73 巻 ( 6 ) 頁: 996 - 1003   2021年7月

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    記述言語:日本語   出版者・発行元:Nutrition and Cancer  

    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

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  36. Short-term outcomes of gastrectomy after neoadjuvant chemotherapy for clinical stage III gastric cancer: propensity score-matched analysis of a multi-institutional database

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

    SURGERY TODAY   51 巻 ( 5 ) 頁: 821 - 828   2021年5月

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    記述言語:日本語   出版者・発行元:Surgery Today  

    Purpose: Preoperative chemotherapy for gastric cancer may be effective from the standpoint of compliance, although there is insufficient evidence of its efficacy. We analyzed a multicenter database to clarify whether preoperative chemotherapy influenced the short-term outcomes of gastrectomy. Methods: We analyzed, retrospectively, 3571 patients who underwent gastrectomy between January, 2010 and December, 2014. Patients with clinical stage-III gastric adenocarcinoma were divided into a neoadjuvant chemotherapy (NAC) group and a non-NAC group. We performed propensity-matched comparative analysis to stratify the groups according to age, sex, tumor region, tumor type, preoperative stage, procedure, lymph node dissection, and tumor differentiation. Preoperative blood data, surgical findings, and postoperative complications were analyzed. Results: Analysis of the matched NAC (n = 64) and non-NAC (n = 128) groups revealed that the preoperative values of neutrophils, platelets, and Hb were significantly lower in the NAC group. Blood loss during surgery was significantly higher, surgical times were longer, and the rate of repeat surgery was significantly lower in the NAC group; however, the rates of rehospitalization did not differ between the groups and mortality was 0% in both groups. Postoperative complications were not significantly different between the groups. Conclusions: NAC did not increase the complication rate of gastrectomy for gastric cancer.

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

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

    BRITISH JOURNAL OF CANCER   124 巻 ( 8 ) 頁: 1449 - 1460   2021年4月

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    記述言語:日本語   出版者・発行元:British Journal of Cancer  

    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

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  38. Peritoneal Lavage Tumor DNA as a Novel Biomarker for Predicting Peritoneal Recurrence in Pancreatic Ductal Adenocarcinoma

    Suenaga Masaya, Fujii Tsutomu, Yamada Suguru, Hayashi Masamichi, Shinjo Keiko, Takami Hideki, Niwa Yukiko, Sonohara Fuminori, Shimizu Dai, Kanda Mitsuro, Kobayashi Daisuke, Tanaka Chie, Nakayama Goro, Koike Masahiko, Fujiwara Michitaka, Kondo Yutaka, Kodera Yasuhiro

    ANNALS OF SURGICAL ONCOLOGY   28 巻 ( 4 ) 頁: 2277 - 2286   2021年4月

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    記述言語:日本語   出版者・発行元:Annals of Surgical Oncology  

    Background: The clinical role of peritoneal lavage cytology (CY) in pancreatic ductal adenocarcinoma (PDAC) remains controversial, partly due to its low sensitivity. This study aimed to develop a new biomarker, defined as peritoneal lavage tumor DNA (ptDNA), using DNAs extracted from peritoneal lavage samples from patients with PDAC. Methods: Samples were collected intraoperatively from 89 PDAC patients who underwent pancreatectomy between 2012 and 2017. Droplet digital polymerase chain reaction (PCR) was used to measure ptDNA for detection of KRAS mutations. The ptDNA status and clinical characteristics were retrospectively evaluated. Results: Positive ptDNA was found in 41 patients, including all 9 patients positive for CY (CY+) and 32 patients negative for CY (CY−). The mutant allele frequency was significantly higher in the CY+ patients than in the CY− patients. The disease-free survival (DFS) and overall survival (OS) were significantly poorer in the high-ptDNA group than in the low-ptDNA group (median DFS, 11.0 vs. 18.8 months; p = 0.007; median OS, 28.7 vs not reached; p = 0.001). The survival curves of DFS and OS in the CY+ group were almost equal to those in the CY− and high-ptDNA group. In a multivariable analysis, ptDNA was an independent predictive factor for DFS (p = 0.025) and OS (p = 0.047). The estimated cumulative incidence of peritoneal recurrence was 45.5% in the high-ptDNA group. The ptDNA biomarker had a much higher sensitivity for peritoneal recurrence than CY, whereas CY had higher specificity. Conclusions: As a promising biomarker, ptDNA may predict poor prognosis and peritoneal recurrence in PDAC, resolving the controversy surrounding CY.

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  39. The novel driver gene ASAP2 is a potential druggable target in pancreatic cancer.

    Fujii A, Masuda T, Iwata M, Tobo T, Wakiyama H, Koike K, Kosai K, Nakano T, Kuramitsu S, Kitagawa A, Sato K, Kouyama Y, Shimizu D, Matsumoto Y, Utsunomiya T, Ohtsuka T, Yamanishi Y, Nakamura M, Mimori K

    Cancer science   112 巻 ( 4 ) 頁: 1655 - 1668   2021年4月

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  40. Function and prognostic value of melanoma-associated antigen-D4 protein in esophageal squamous cell carcinoma

    Sawaki Koichi, Kanda Mitsuro, Sato Yusuke, Shimizu Dai, Uno Yasuo, Umeda Shinichi, Hattori Norifumi, Hayashi Masamichi, Tanaka Chie, Yamada Suguru, Nakayama Goro, Motoyama Satoru, Koike Masahiko, Fujiwara Michitaka, Kodera Yasuhiro

    CANCER SCIENCE   112 巻   頁: 531 - 531   2021年2月

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  41. STRA6 expression serves as a prognostic biomarker of gastric cancer

    Nakamura Shunsuke, Kanda Mitsuro, Shimizu Dai, Sawaki Koichi, Tanaka Chie, Hattori Norifumi, Hayashi Masamichi, Yamada Suguru, Koike Masahiko, Kodera Yasuhiro

    CANCER SCIENCE   112 巻   頁: 780 - 780   2021年2月

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

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

    ANTICANCER RESEARCH   41 巻 ( 2 ) 頁: 609 - 617   2021年2月

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

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

    ANTICANCER RESEARCH   41 巻 ( 2 ) 頁: 609 - 617   2021年2月

  44. Tissue RNFT2 expression levels are associated with peritoneal recurrence and poor prognosis in gastric cancer

    Sasahara M.

    Anticancer Research   41 巻 ( 2 ) 頁: 609 - 617   2021年2月

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    出版者・発行元:Anticancer Research  

    DOI: 10.21873/ANTICANRES.14812

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  45. Tissue <i>RNFT2</i> Expression Levels Are Associated With Peritoneal Recurrence and Poor Prognosis in Gastric Cancer.

    Sasahara M, Kanda M, Shimizu D, Tanaka C, Inokawa Y, Hattori N, Hayashi M, Nakayama G, Kodera Y

    Anticancer research   41 巻 ( 2 ) 頁: 609 - 617   2021年2月

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  46. Impaired tumor immune response in metastatic tumors is a selective pressure for neutral evolution in CRC cases.

    Sakimura S, Nagayama S, Fukunaga M, Hu Q, Kitagawa A, Kobayashi Y, Hasegawa T, Noda M, Kouyama Y, Shimizu D, Saito T, Niida A, Tsuruda Y, Otsu H, Matsumoto Y, Uchida H, Masuda T, Sugimachi K, Sasaki S, Yamada K, Takahashi K, Innan H, Suzuki Y, Nakamura H, Totoki Y, Mizuno S, Ohshima M, Shibata T, Mimori K

    PLoS genetics   17 巻 ( 1 ) 頁: e1009113   2021年1月

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

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

    SURGERY TODAY   51 巻 ( 1 ) 頁: 153 - 158   2021年1月

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    記述言語:日本語   出版者・発行元:Surgery Today  

    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.

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  48. Age-Related Differences in the Prognosis of Pancreatic Cancer According to Perioperative Systemic Therapy

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

    PANCREAS   50 巻 ( 1 ) 頁: 37 - 46   2021年1月

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    記述言語:日本語   出版者・発行元:Pancreas  

    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.

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  49. Different Characteristics of Serum Alfa Fetoprotein and Serum Des-gamma-carboxy Prothrombin in Resected Hepatocellular Carcinoma

    Hayashi Masamichi, Yamada Suguru, Takano Nao, Okamura Yukiyasu, Takami Hideki, Inokawa Yoshikuni, Sonohara Fuminori, Tanaka Nobutake, Shimizu Dai, Hattori Norifumi, Kanda Mitsuro, Tanaka Chie, Nakayama Goro, Koike Masahiko, Kodera Yasuhiro

    IN VIVO   35 巻 ( 3 ) 頁: 1749 - 1760   2021年

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    記述言語:日本語   出版者・発行元:In Vivo  

    Background/Aim: Hepatocellular carcinoma (HCC) mainly develops in the damaged liver from hepatitis C virus (HCV) or hepatitis B virus (HBV) infection in Japan. On the other hand, the occurrence of HCCs derived from the liver without viral infection has recently been increasing. Our aim was to identify characteristics specific to HCCs with virus-infected liver (HCC-BC) or those with non-B- and non-C-infected liver (HCC-NBNC), Patients and Methods: We collected preoperative serum α-fetoprotein (AFP) and Des-Gamma-Carboxy Prothrombin (DCP), also known as PIVKA-II values from surgically resected HCC cases during 1994-2017 in our department. Results: Preoperative serum AFP values of HCC-BC cases (n=284) were higher compared to HCC-NBNC cases (n=88) (p=0.016), whereas serum DCP values of HCC-NBNC cases were higher compared to HCC-BC cases (p<0.001). Multivariable analyses indicated that abnormal serum AFP [hazard ratio (HR)=1.46, 95% conficdence interval (CI)=1.03-2.07, p=0.035) was one of the significant recurrence-free survival predictors of HCC-BC cases, while abnormal serum DCP (HR=4.99, 95%CI=1.91-13.01, p=0.001) was one of the significant recurrence-free survival predictors of HCC-NBNC cases. Conclusion: HCC-NBNC cases have a different tumor marker profile from HCC-BC cases. Elevated DCP could be both a diagnostic and prognostic marker of HCC-NBNC patients.

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  50. Amido-Bridged Nucleic Acid-Modified Antisense Oligonucleotides Targeting SYT13 to Treat Peritoneal Metastasis of Gastric Cancer

    Kanda Mitsuro, Kasahara Yuuya, Shimizu Dai, Miwa Takashi, Umeda Shinichi, Sawaki Koichi, Nakamura Shunsuke, Kodera Yasuhiro, Obika Satoshi

    MOLECULAR THERAPY-NUCLEIC ACIDS   22 巻   頁: 791 - 802   2020年12月

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    記述言語:日本語   出版者・発行元:Molecular Therapy - Nucleic Acids  

    Patients with peritoneal metastasis of gastric cancer have dismal prognosis, mainly because of inefficient systemic delivery of drugs to peritoneal tumors. We aimed to develop an intraperitoneal treatment strategy using amido-bridged nucleic acid (AmNA)-modified antisense oligonucleotides (ASOs) targeting synaptotagmin XIII (SYT13) and to identify the function of SYT13 in gastric cancer cells. We screened 71 candidate oligonucleotide sequences according to SYT13-knockdown efficacy, in vitro activity, and off-target effects. We evaluated the effects of SYT13 knockdown on cellular functions and signaling pathways, as well as the effects of intraperitoneal administration to mice of AmNA-modified anti-SYT13 ASOs. We selected the ASOs (designated hSYT13-4378 and hSYT13-4733) with the highest knockdown efficiencies and lowest off-target effects and determined their abilities to inhibit cellular functions associated with the metastatic potential of gastric cancer cells. We found that SYT13 interfered with focal adhesion kinase (FAK)-mediated intracellular signals. Intraperitoneal administration of hSYT13-4378 and hSYT13-4733 in a mouse xenograft model of metastasis inhibited the formation of peritoneal nodules and significantly increased survival. Reversible, dose- and sequence-dependent liver damage was induced by ASO treatment without causing abnormal morphological and histological changes in the brain. Intra-abdominal administration of AmNA-modified anti-SYT13 ASOs represents a promising strategy for treating peritoneal metastasis of gastric cancer.

    DOI: 10.1016/j.omtn.2020.10.001

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  51. AMIGO2 Expression as a Potential Prognostic Biomarker for Gastric Cancer

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

    ANTICANCER RESEARCH   40 巻 ( 12 ) 頁: 6713 - 6721   2020年12月

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    記述言語:日本語   出版者・発行元:Anticancer Research  

    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.

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  52. AnOpen-Label Single-ArmPhaseIIStudy of Treatment with Neoadjuvant S-1 Plus Cisplatin for Clinical StageIIISquamous Cell Carcinoma of the Esophagus

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

    ONCOLOGIST   25 巻 ( 11 ) 頁: E1650 - E1654   2020年11月

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    記述言語:日本語   出版者・発行元:Oncologist  

    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.

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  53. Characteristics Associated with Nodal and Distant Recurrence after Curative Resection of Squamous Cell Carcinoma of the Thoracic Esophagus

    Kanda Mitsuro, Koike Masahiko, Shimizu Dai, Tanaka Chie, Hayashi Masamichi, Hattori Norifumi, Yamada Suguru, Nakayama Goro, Fujiwara Michitaka, Kodera Yasuhiro

    JOURNAL OF THE AMERICAN COLLEGE OF SURGEONS   231 巻 ( 4 ) 頁: E121 - E121   2020年10月

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  54. Circulating PD-1 mRNA in Peripheral Blood is a Potential Biomarker for Predicting Survival of Breast Cancer Patients.

    Noda M, Masuda T, Ito S, Tobo T, Kitagawa A, Hu Q, Shimizu D, Eguchi H, Etoh T, Ohno S, Inomata M, Mimori K

    Annals of surgical oncology   27 巻 ( 10 ) 頁: 4035 - 4043   2020年10月

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

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

    ANNALS OF SURGICAL ONCOLOGY   27 巻 ( 9 ) 頁: 3195 - 3205   2020年9月

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    記述言語:日本語   出版者・発行元:Annals of Surgical Oncology  

    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.

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  56. Expression and Malignant Potential of B4GALNT4 in Esophageal Squamous Cell Carcinoma

    Baba Hayato, Kanda Mitsuro, Sato Yusuke, Sawaki Koichi, Shimizu Dai, Koike Masahiko, Motoyama Satoru, Kodera Yasuhiro, Fujii Tsutomu

    ANNALS OF SURGICAL ONCOLOGY   27 巻 ( 9 ) 頁: 3247 - 3256   2020年9月

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    記述言語:日本語   出版者・発行元:Annals of Surgical Oncology  

    Background: β-1,4-N-Acetyl-galactosaminyltransferase 4 (B4GALNT4), an enzyme involved in ganglioside synthesis, is upregulated in many cancers. We examine B4GALNT4 expression and its relationship to prognosis in esophageal squamous cell carcinoma (ESCC). Patients and Methods: Expression of B4GALNT4 mRNA and B4GALNT4 protein was analyzed by quantitative reverse-transcription polymerase chain reaction (qRT-PCR) and immunohistochemistry, respectively, in 17 human ESCC cell lines and/or clinical specimens from two independent cohorts of 147 and 159 ESCC patients. The contributions of B4GALNT4 to proliferation, invasion, migration, and adhesion was evaluated in ESCC cells subjected to siRNA-mediated gene knockdown. Correlations between clinicopathological parameters and B4GALNT4 expression in clinical specimens were analyzed in both patient cohorts. Results: B4GALNT4 mRNA expression levels varied widely in ESCC cell lines, regardless of differentiation status or the originating tissue. Knockdown of B4GALNT4 significantly suppressed the proliferation, invasion, migration, and adhesion of ESCC cell lines compared with control cells. B4GALNT4 mRNA was overexpressed in ESCC tissues compared with adjacent normal esophageal tissues. High mRNA expression was significantly associated with poor disease-free survival and hematogenous recurrence, and high B4GALNT4 protein expression was also significantly related to poor disease-specific survival. On multivariable analysis, high B4GALNT4 expression was an independent predictor of poor prognosis. In both patient cohorts, high B4GALNT4 expression did not correlate with known prognostic factors, such as disease stage, lymphovascular invasion, or squamous cell-carcinoma-related antigen level. Conclusions: B4GALNT4 influences the malignant behavior of ESCC cells. B4GALNT4 expression may serve as a novel prognostic marker, independent of established risk factors, for ESCC patients.

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  57. Therapeutic monoclonal antibody targeting of neuronal pentraxin receptor to control metastasis in gastric cancer

    Kanda Mitsuro, Shimizu Dai, Sawaki Koichi, Nakamura Shunsuke, Umeda Shinichi, Miwa Takashi, Tanaka Haruyoshi, Tanaka Chie, Hayashi Masamichi, Iguchi Yohei, Yamada Suguru, Katsuno Masahisa, Kodera Yasuhiro

    MOLECULAR CANCER   19 巻 ( 1 ) 頁: 131   2020年8月

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    記述言語:日本語   出版者・発行元:Molecular Cancer  

    Background: Controlling metastasis is essential for improving the prognosis of patients with gastric cancer (GC). Here, we aimed to identify a molecule required for GC metastasis and to investigate its potential utility as a target for the development of therapeutic antibodies (Abs). Methods: Transcriptome and bioinformatics analyses of human GC cell lines identified the neuronal pentraxin receptor (NPTXR) as a candidate molecule. NPTXR function was probed by modulating its expression in GC cells and assessing the effects on intracellular signaling and malignant behaviors in vitro and in mouse xenograft models. We also generated anti-NPTXR Abs and Nptxr -/- mice, and assessed the clinical significance of NPTXR expression in GC specimens. Results: NPTXR mRNA expression in clinical specimens was associated with disease progression and was significantly higher in tissues from GC patients with distant metastasis compared with those without. NPTXR regulated expression of genes involved in metastatic behaviors as well as activation of the PI3K-AKT-mTOR, FAK-JNK, and YAP signaling pathways. NPTXR silencing promoted caspase-mediated apoptosis and attenuated GC cell proliferation, cell cycle progression, migration, invasion, adhesion, stem cell-like properties, and resistance to 5-fluorouracil in vitro, and also inhibited the tumorigenicity of GC cells in vivo. Anti-NPTXR Abs inhibited GC peritoneal metastasis in mice. Nptxr -/- mice showed no abnormalities in reproduction, development, metabolism, or motor function. Conclusions: NPTXR plays an essential role in controlling the malignant behavior of GC cells in vitro and in vivo. NPTXR-targeting Abs may thus have utility as novel diagnostic tools and/or treatment modalities for GC.

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  58. 特集 解剖学的変異を考慮した上部消化管手術 局所微細解剖からみた幽門下リンパ節郭清のコツ─腹腔鏡手術を中心に

    田中 千恵, 佐藤 敏, 神田 光郎, 清水 大, 小寺 泰弘

    手術   74 巻 ( 9 ) 頁: 1339 - 1346   2020年8月

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    出版者・発行元:金原出版  

    DOI: 10.18888/op.0000001828

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  59. Diagnostic and therapeutic role of endoscopic retrograde pancreatography and stent placement for grade IV blunt pancreatic trauma: A case report.

    Shimizu D, Yamano T, Kudo Y, Kuroda M, Takagi S, Ikeda E, Kenmotsu M, Tsuji H

    Trauma case reports   28 巻   頁: 100319   2020年8月

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  60. KCNJ15 Expression and Malignant Behavior of Esophageal Squamous Cell Carcinoma

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

    ANNALS OF SURGICAL ONCOLOGY   27 巻 ( 7 ) 頁: 2559 - 2568   2020年7月

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    記述言語:日本語   出版者・発行元:Annals of Surgical Oncology  

    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.

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  61. Propensity-score-matched analysis of a multi-institutional dataset to compare postoperative complications between Billroth I and Roux-en-Y reconstructions after distal gastrectomy

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

    GASTRIC CANCER   23 巻 ( 4 ) 頁: 734 - 745   2020年7月

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    記述言語:日本語   出版者・発行元:Gastric Cancer  

    Background: Few well-controlled studies have compared postoperative complications between Billroth I (B-I) and Roux-en-Y (R-Y). The aim of the present study was to compare the incidence of overall and severe postoperative complications by reconstruction method after distal gastrectomy. Methods: We performed a multi-institutional dataset study of patients who underwent distal gastrectomy with B-I or R-Y reconstruction from 2010 to 2014. Using propensity scores to strictly balance the significant variables, we compared postoperative complications between the techniques. Results: After matching, we enrolled 1014 patients (n = 507 in each group). The incidence of postoperative complications in the R-Y group was significantly higher vs the B-I group (29% vs 17%, P < 0.0001). The incidence of intra-abdominal abscess (4.3% vs 1.8%, P = 0.0177), bowel obstruction (2.6% vs 0.6%, P = 0.0203), and delayed gastric emptying (5.3% vs 1.0%, P < 0.0001) in the R-Y group was significantly higher vs the B-I group, respectively; we saw no significant difference in leakage (3.4% vs 4.1%, P = 0.5084). The incidence of grade ≥ III severe postoperative complications in the R-Y group was significantly higher vs the B-I group (13% vs 7.1%, P = 0.0013). Multivariable analysis showed that R-Y reconstruction was a strong independent risk factor for overall postoperative complications (odds ratio 1.58, P = 0.0044) and grade ≥ III severe postoperative complications (odds ratio 1.75, P = 0.0127). A forest plot revealed that R-Y reconstruction was associated with a greater risk of both overall and grade ≥ III severe postoperative complications in any subgroups. Conclusions: R-Y reconstruction was associated with increasing overall postoperative complications, as well as severe postoperative complications.

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  62. PRAME as a Potential Biomarker for Liver Metastasis of Gastric Cancer

    Baba Hayato, Kanda Mitsuro, Sawaki Koichi, Umeda Shinichi, Miwa Takashi, Shimizu Dai, Tanaka Chie, Kobayashi Daisuke, Fujiwara Michitaka, Kodera Yasuhiro, Fujii Tsutomu

    ANNALS OF SURGICAL ONCOLOGY   27 巻 ( 6 ) 頁: 2071 - 2080   2020年6月

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    記述言語:日本語   出版者・発行元:Annals of Surgical Oncology  

    Background: Liver metastasis of gastric cancer (GC) is highly associated with poor prognosis. The development of sensitive biomarkers for detecting and predicting liver metastasis is required for better clinical outcome. Objective: In this study, we aimed to identify novel genes associated with liver metastasis of GC. Methods: Global expression profiling of 57,749 genes was performed using surgically resected gastric tissues from four patients with liver metastasis to identify candidate genes. The mRNA expression levels of the selected candidate gene were analyzed in the resected gastric tissues of 300 GC patients and correlated with clinicopathological parameters. Fourteen GC cell lines were subjected to mRNA expression and polymerase chain reaction (PCR) array analysis. Results: Among 25 candidate genes identified by transcriptome analysis, preferentially expressed antigen of melanoma (PRAME) was selected for subsequent analyses. mRNA expression analysis of clinical samples revealed the aberrant expression of PRAME in GC tissues, and its high expression was significantly related to differentiated phenotype and vessel invasion, as well as liver metastasis. High PRAME expression was significantly associated with hepatic recurrence after curative surgery, and cumulative incidences of hepatic recurrence were significantly greater in patients with high PRAME expression compared with patients with low PRAME expression. In an in vitro analysis, overexpression was observed in all GC cell lines compared with a normal epithelial cell line. PCR array analysis revealed the coordinate expression of MMP9, OCLN, IL1RN, and MST1R. Conclusions: PRAME is related to the malignant potential of GC and could serve as a novel biomarker for the detection and prediction of liver metastasis.

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

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

    ANNALS OF SURGICAL ONCOLOGY   27 巻 ( 4 ) 頁: 1233 - 1240   2020年4月

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    記述言語:日本語   出版者・発行元:Annals of Surgical Oncology  

    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.

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  64. KIF15 Expression in Tumor-associated Monocytes Is a Prognostic Biomarker in Hepatocellular Carcinoma.

    Kitagawa A, Masuda T, Takahashi J, Tobo T, Noda M, Kuroda Y, Hu Q, Kouyama Y, Kobayashi Y, Kuramitsu S, Sato K, Fujii A, Yoshikawa Y, Wakiyama H, Shimizu D, Tsuruda Y, Eguchi H, Doki Y, Mori M, Mimori K

    Cancer genomics & proteomics   17 巻 ( 2 ) 頁: 141 - 149   2020年3月

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  65. Predictive value of the modified systemic inflammation score in patients undergoing curative resection of squamous cell carcinoma of the esophagus

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

    JOURNAL OF CLINICAL ONCOLOGY   38 巻 ( 4 )   2020年2月

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  66. Propensity-score-matched analysis of a multi-institutional dataset to compare the postoperative complications after distal gastrectomy between Billroth I and Roux-en-Y

    Nakanishi Koki, Kanda Mitsuro, Ito Seiji, Mochizuki Yoshinari, Teramoto Hitoshi, Ishigure Kiyoshi, Mmurai Toshifumi, Asada Takahiro, Ishiyama Akiharu, Matsushita Hidenobu, Shimizu Dai, Tanaka Chie, Kobayashi Daisuke, Fujiwara Michitaka, Kodera Yasuhiro

    JOURNAL OF CLINICAL ONCOLOGY   38 巻 ( 4 )   2020年2月

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  67. Chromobox 2 Expression Predicts Prognosis After Curative Resection of Oesophageal Squamous Cell Carcinoma

    Ueda Sei, Kanda Mitsuro, Sato Yusuke, Baba Hayato, Nakamura Shunsuke, Sawaki Koichi, Shimizu Dai, Motoyama Satoru, Fujii Tsutomu, Kodera Yasuhiro, Nomoto Shuji

    CANCER GENOMICS & PROTEOMICS   17 巻 ( 4 ) 頁: 391 - 400   2020年

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    記述言語:日本語   出版者・発行元:Cancer Genomics and Proteomics  

    Background/Aim: To investigate the function of chromobox 2 (CBX2) in oesophageal squamous cell carcinoma (OSCC). Materials and Methods: We used real-time quantitative reverse transcription PCR (qRT-PCR) and immunohisto-chemistry to determine CBX2 expression levels in 13 human OSCC cell lines and clinical specimens of two independent cohorts of patients with OSCC. Results: PCR array analysis revealed that CBX2 was co-ordinately expressed with WNT5B in OSCC cell lines. RT-qPCR analysis of clinical samples revealed a high tumour-specific CBX2 expression compared with normal oesophageal tissues. High CBX2 expression was significantly associated with shorter disease-specific survival, hematogenous recurrence, and overall recurrence. Analysis of tissue microarrays of one cohort revealed that patients with higher CBX2 levels tended to have a shorter disease-specific survival. Conclusion: CBX2 overexpression in OSCC tissues may serve as a novel biomarker for predicting survival and hematogenous recurrence.

    DOI: 10.21873/cgp.20198

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  68. Prognostic Significance of PD-1, PD-L1 and CD8 Gene Expression Levels in Gastric Cancer.

    Ito S, Masuda T, Noda M, Hu Q, Shimizu D, Kuroda Y, Eguchi H, Tobo T, Utsunomiya T, Mimori K

    Oncology   98 巻 ( 7 ) 頁: 501 - 511   2020年

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  69. 食道癌術後の心房細動発症が術後経過、身体機能に及ぼす影響

    白井 祐也, 水野 陽太, 清水 大, 井上 貴行, 岡田 貴士, 西田 佳弘, 小池 聖彦, 永谷 元基

    理学療法学Supplement   47S1 巻 ( 0 ) 頁: C-17_2 - C-17_2   2020年

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    記述言語:日本語   出版者・発行元:公益社団法人 日本理学療法士協会  

    DOI: 10.14900/cjpt.47s1.c-17_2

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  70. STRA6 Expression Serves as a Prognostic Biomarker of Gastric Cancer

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

    CANCER GENOMICS & PROTEOMICS   17 巻 ( 5 ) 頁: 509 - 516   2020年

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    記述言語:日本語   出版者・発行元:Cancer Genomics and Proteomics  

    Background: Despite advances in our understanding on the pathogenesis of gastric cancer (GC), patients face a poor prognosis. To improve clinical outcomes, effective approaches to diagnosis and treatment employing new diagnostic biomarkers are required to achieve early detection and predict recurrence and prognosis. Materials and Methods: Transcriptome analysis was conducted using surgically resected gastric tissues from four patients with metastatic GC. A total of 228 pairs of primary GC tissues and corresponding normal adjacent tissues were subjected to mRNA expression analysis. To validate our findings, we accessed an integrated microarray dataset and RNA sequencing data of GC cell lines. Results: We identified stimulated by retinoic acid 6 (STRA6) as a differentially overexpressed gene, which encodes a transmembrane protein that mediates the cellular uptake of retinol. To investigate how STRA6 contributes to the malignant phenotype of GC cells, we mined public datasets and found the mRNA encoding retinol binding protein 1 (RBP1), which is associated with retinoid metabolism, was co-expressed with STRA6. Furthermore, STRA6 mRNA levels were significantly higher in GC tissues compared to the corresponding noncancerous adjacent tissues of 228 surgically resected gastric tissue samples. Moreover, patients with high levels of STRA6 mRNA experienced significantly shorter disease-free survival and overall survival. Multivariate analysis revealed that high levels of STRA6 served as a significant risk factor. Conclusion: Patients with high levels of STRA6 mRNA experienced significantly worse clinical outcomes, indicating that STRA6 may serve as a diagnostic and prognostic biomarker of GC.

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  71. Salivary NUS1 and RCN1 Levels as Biomarkers for Oral Squamous Cell Carcinoma Diagnosis

    Ueda Sei, Hashimoto Kengo, Miyabe Satoru, Hasegawa Shogo, Goto Mitsuo, Shimizu Dai, Oh-Iwa Ichiro, Shimozato Kazuo, Nagao Toru, Nomoto Shuji

    IN VIVO   34 巻 ( 5 ) 頁: 2353 - 2361   2020年

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    記述言語:日本語   出版者・発行元:In Vivo  

    Background/Aim: Oral cancer may become advanced because of delay in diagnosis. In order to promote oral cancer screening, simple and highly reliable screening methods that can be implemented at general dental clinics are required. Herein we investigated differential salivary gene expression between oral squamous cell carcinoma (OSCC) patients and healthy volunteers (HV) to identify new biomarkers for OSCC detection. Materials and Methods: Candidate genes were selected by microarrays, nuclear undecaprenyl pyrophosphate synthase 1 (NUS1) and reticulocalbin 1 (RCN1) were selected for further investigation. We used real-time quantitative reverse transcription PCR (qRT-PCR) to determine NUS1 and RCN1 expression levels in saliva and tissues. Results: QRTPCR analysis of clinical samples revealed that OSCC patients had significantly higher expression of salivary NUS1 and RCN1 than HV. Conclusion: A combination of NUS1 and RCN1 accurately distinguished patients from controls, and this combination can be implemented as a screening test for OSCC.

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  72. Changes in oral microbial profiles associated with oral squamous cell carcinoma vs leukoplakia

    Hashimoto K., Shimizu D., Hirabayashi S., Ueda S., Miyabe S., Oh-iwa I., Nagao T., Shimozato K., Nomoto S.

    Journal of Investigative and Clinical Dentistry   10 巻 ( 4 ) 頁: e12445   2019年11月

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    記述言語:英語   出版者・発行元:Journal of Investigative and Clinical Dentistry  

    Aim: Oral squamous cell carcinoma (OSCC) is the most frequently occurring cancer among head and neck SCC worldwide. The identification of novel effective biomarkers for early detection may greatly improve the survival rate and prognosis of patients with OSCC. This study aimed to identify specific oral microbial profiles associated with OSCC. Methods: Saliva samples were collected from oral leukoplakia (OLK) and OSCC patients (N = 6 each) and healthy controls (HC; N = 4). Total bacterial genomic DNA was isolated and 16S rRNA gene survey was performed by next-generation sequencing of the V4 region. The relative distribution of abundance for phylogenetic groups was compared among the OSCC and OLK groups. Results: The 448 operational taxonomic units detected from the libraries were classified into 133 genera, 69 families, 41 orders, 26 classes and 12 phyla. The abundance of phyla Bacteroidetes and genus Solobacterium was notably higher in the OSCC group when compared with the OLK group, whereas those of genus Streptococcus was significantly lower in the OSCC group when compared with the OLK. Conclusion: These changes in the salivary microbiome may have potential applications as a novel diagnostic tool for the early detection of OSCC.

    DOI: 10.1111/jicd.12445

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

    Uno Yasuo, Kanda Mitsuro, Sato Yusuke, Shimizu Dai, Umeda Shinichi, Hattori Norifumi, Hayashi Masamichi, Tanaka Chie, Kobayashi Daisuke, Yamada Suguru, Nakayama Goro, Motoyama Satoru, Koike Masahiko, Kodera Yasuhiro

    ANTICANCER RESEARCH   39 巻 ( 11 ) 頁: 6015 - 6023   2019年11月

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    記述言語:日本語   出版者・発行元:Anticancer Research  

    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.

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  74. PRAME Expression as a Potential Biomarker for Hematogenous Recurrence of Esophageal Squamous Cell Carcinoma

    Baba Hayato, Kanda Mitsuro, Sawaki Koichi, Shimizu Dai, Umeda Shinichi, Koike Masahiko, Kodera Yasuhiro, Fujii Tsutomu

    ANTICANCER RESEARCH   39 巻 ( 11 ) 頁: 5943 - 5951   2019年11月

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    記述言語:日本語   出版者・発行元:Anticancer Research  

    Background/Aim: To investigate the function of preferentially expressed antigen of melanoma (PRAME) in esophageal squamous cell carcinoma (ESCC). Materials and Methods: mRNA expression levels of PRAME were analyzed in resected esophageal tissues of 150 ESCC patients and correlated with clinicopathological parameters. We also investigated the potential function of PRAME by analyzing coordinately expressed genes in 13 ESCC cell lines. Results: RT-qPCR analysis of clinical samples revealed aberrantly high PRAME expression in tumors compared with normal esophageal tissues. High PRAME expression was significantly associated with shorter disease-specific survival and hematogenous recurrence, but not with overall recurrence. The cumulative incidence of hematogenous recurrence was significantly greater for patients with high compared to those with low PRAME expression. In vitro, PCR array analysis revealed that PRAME was coordinately expressed with EGFR, ITGB, and TCF3. Conclusion: PRAME is overexpressed in ESCC tissues and may serve as a novel biomarker for predicting hematogenous recurrence.

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  75. Tissue Expression of Melanoma-associated Antigen A6 and Clinical Characteristics of Gastric Cancer

    Endo Miyo, Kanda Mitsuro, Sawaki Koichi, Shimizu Dai, Tanaka Chie, Kobayashi Daisuke, Hattori Norifumi, Hayashi Masamichi, Yamada Suguru, Koike Masahiko, Omae Kenji, Kodera Yasuhiro

    ANTICANCER RESEARCH   39 巻 ( 11 ) 頁: 5903 - 5910   2019年11月

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    記述言語:日本語   出版者・発行元:Anticancer Research  

    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.

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  76. CRMP5-associated GTPase (CRAG) Is a Candidate Driver Gene for Colorectal Cancer Carcinogenesis

    Shimizu Dai, Masuda Takaaki, Sato Kuniaki, Tsuruda Yusuke, Otsu Hajime, Kuroda Yosuke, Eguchi Hidetoshi, Kodera Yasuhiro, Mimori Koshi

    ANTICANCER RESEARCH   39 巻 ( 1 ) 頁: 99 - 106   2019年1月

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    記述言語:日本語   出版者・発行元:Anticancer Research  

    Background/Aim: Certain chromosomal arms are clonally amplified in colorectal cancer (CRC) and may contain novel driver genes. The aim of this study was to identify a novel driver gene for colorectal cancer carcinogenesis on long arm of chromosome 7 and the clarify its biological function. Materials and Methods: We identified ArfGAP with GTPase domain, ankyrin repeat and PH domain 3 (AGAP3) as a putative driver gene using the CRC dataset in The Cancer Genome Atlas (TCGA). Biological functions of AGAP3 and CRMP5-associated GTPase (CRAG), a splicing variant of AGAP3, were explored by overexpression. AGAP3/CRAG expression in our cohort was examined by quantitative reverse transcription polymerase chain reaction. Clinical significance of AGAP3/CRAG expression in TCGA dataset, Gene Expression Omnibus datasets and our clinical cohort was evaluated. Results: AGAP3 expression was significantly increased in CRC and colorectal adenoma compared to normal tissue. CRAG overexpression up-regulated c-Jun expression, and significantly increased cell proliferation and colony formation capability. AGAP3 expression did not have a concordant association with patient prognosis among datasets. Conclusion: CRAG may contribute to development of CRC via activator protein 1 activation.

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  77. Multiregion Genomic Analysis of Serially Transplanted Patient-derived Xenograft Tumors.

    Sato K, Niida A, Masuda T, Shimizu D, Tobo T, Kuroda Y, Eguchi H, Nakagawa T, Suzuki Y, Mimori K

    Cancer genomics & proteomics   16 巻 ( 1 ) 頁: 21 - 27   2019年1月

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  78. Establishment of Peritoneal and Hepatic Metastasis Mouse Xenograft Models Using Gastric Cancer Cell Lines

    Miwa Takashi, Kanda Mitsuro, Umeda Shinichi, Tanaka Haruyoshi, Shimizu Dai, Tanaka Chie, Kobayashi Daisuke, Hayashi Masamichi, Yamada Suguru, Nakayama Goro, Koike Masahiko, Kodera Yasuhiro

    IN VIVO   33 巻 ( 6 ) 頁: 1785 - 1792   2019年

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    記述言語:日本語   出版者・発行元:In Vivo  

    Background/Aim: Establishment of mouse xenograft models is necessary for oncological research and depends on the characteristics of the cell lines and the immune system of the host. In this study, we describe the development of mouse xenograft models using human gastric cancer (GC) cell lines. Materials and Methods: MKN1 stably-expressing luciferase (MKN1-Luc), N87, KATO III, MKN45 stably-expressing luciferase (MKN45-Luc), NUGC4, and OCUM-1 human GC cell lines were injected intraperitoneally into mice to establish peritoneal metastasis models. MKN45-Luc were injected into subcutaneously implanted spleen, and MKN1-Luc and MKN45-Luc were injected directly into the portal veins of mice for the establishment of hepatic metastasis models. Results: Peritoneal metastasis was formed after implantation of MKN1-Luc, N87, KATO III, MKN45-Luc, and NUGC4 in nude mice, but not formed in OCUM-1 even in NOD/SCID mice. After intrasplenic injection of MKN45-Luc, we found no hepatic metastasis formation. We identified hepatic metastasis formation after direct injection of MKN45-Luc and MKN1-Luc into the portal veins of NOD/SCID mice. Conclusion: Peritoneal and hepatic metastasis mouse xenograft models were successfully established using several human GC cell lines.

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  79. A case of renal salt-wasting syndrome induced by cisplatin and 5-FU during treatment of esophageal squamous cell carcinoma

    Shimizu D., Kanda M., Koike M., Umeda S., Sonohara F., Takami H., Inokawa Y., Hattori N., Hayashi M., Tanaka C., Kobayashi D., Yamada S., Nakayama G., Fujiwara M., Kodera Y.

    Annals of Cancer Research and Therapy   27 巻 ( 2 ) 頁: 64 - 66   2019年

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    記述言語:日本語   出版者・発行元:Annals of Cancer Research and Therapy  

    The combination regimen of cisplatin (CDDP) and fluorouracil (5-FU) (FP) is a standard regimen for definitive chemora-diotherapy, neoadjuvant chemotherapy, and for treatment of unresectable or recurrent esophageal squamous cell carcinoma (ESCC). Here, we report a patient with FP-induced renal salt-wasting syndrome (RSWS) who presented with severe hyponatremia with disturbance of consciousness and was admitted to the intensive care unit (ICU). A 66-year-old man with recurrent ESCC was admitted and started on chemotherapy with FP. From day 3 of the first course of FP, he presented with anorexia and vomiting (grade 3). At day 6, he experienced disturbance of consciousness and blood test showed severe hyponatremia (sodium (Na): 119 mmol/L) accompanied with excessive urinary excretion of Na (181 mmol/L). He was diagnosed with RSWS because of CDDP and was transferred to the ICU. Through intensive monitoring and 3% NaCl infusion, serum Na level and symptoms recovered with no sequelae and he was discharged from the ICU after a 4-day stay. RSWS is sometimes difficult to diagnose because of its low recognition and is misdiagnosed as the syndrome of inappropriate secretion of antidiuretic hormone. During chemotherapy with platinum-based agents, RSWS should be kept in mind as a disorder that causes hyponatremia.

    DOI: 10.4993/acrt.27.64

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  80. Peritoneal Lavage Tumor DNA as a Novel Biomarker for Predicting Peritoneal Recurrence in Pancreatic Ductal Adenocarcinoma

    Suenaga M., Fujii T., Yamada S., Hayashi M., Shinjo K., Takami H., Niwa Y., Sonohara F., Shimizu D., Kanda M., Kobayashi D., Tanaka C., Nakayama G., Koike M., Fujiwara M., Kondo Y., Kodera Y.

    PANCREAS   48 巻 ( 10 ) 頁: 1528 - 1528   2019年

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  81. Biological significance of ArfGAP with GTPase domain, ankyrin repeat and PH domain 3 (AGAP3) in colorectal cancer (CRC)

    Shimizu Dai, Sato Kuniaki, Masuda Takaaki, Otsu Hajime, Kuroda Yousuke, Eguchi Hidetoshi, Kanda Mitsuro, Kodera Yasuhiro, Mimori Koshi

    CANCER SCIENCE   109 巻   頁: 1235 - 1235   2018年12月

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  82. RASEF expression correlates with hormone receptor status in breast cancer

    Shibata Masahiro, Kanda Mitsuro, Shimizu Dai, Tanaka Haruyoshi, Umeda Shinichi, Miwa Takashi, Hayashi Masamichi, Inaishi Takahiro, Miyajima Noriyuki, Adachi Yayoi, Takano Yuko, Nakanishi Kenichi, Takeuchi Dai, Noda Sumiyo, Kodera Yasuhiro, Kikumori Toyone

    ONCOLOGY LETTERS   16 巻 ( 6 ) 頁: 7223 - 7230   2018年12月

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    記述言語:日本語   出版者・発行元:Oncology Letters  

    Breast cancer (BC) is the most frequently diagnosed malignant tumor in women worldwide, and the development of new molecules associated with BC is essential for the management of this disease. RAS and EF-hand domain-containing (RASEF) encodes the GTPase enzyme that belongs to the Rab family. Although the effects of this gene have been reported in several malignant tumor types, the role of RASEF in BC has not been completely elucidated. The aim of the present study was to investigate the importance of RASEF expression in BC. RASEF mRNA expression levels were evaluated in BC and non-cancerous mammary cell lines. The association between RASEF mRNA expression levels and clinicopathological factors in 167 patients with BC were then determined. Among the 13 examined BC cell lines, ER-negative/HER2-negative cell lines expressed lower RASEF mRNA levels, when compared with the other examined cell lines (P=0.014). Of the 167 patients examined, patients with negative hormone receptor status exhibited significantly lower RASEF mRNA expression levels (P<0.001). In addition low RASEF expression in BC tissues was associated with negative estrogen receptor status (P<0.001), negative progesterone receptor status (P<0.001), and triple-negative status (P<0.001). Additionally, although the differences were not statistically significant, patients with low RASEF expression levels exhibited poorer disease-free survival (P=0.123) and overall survival (P=0.086) than other patients. The results of the present study indicate that RASEF mRNA expression levels are associated with hormone receptor status in BC.

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  83. Cutting-edge evidence of adjuvant treatments for gastric cancer

    Shimizu Dai, Kanda Mitsuro, Kodera Yasuhiro, Sakamoto Junichi

    EXPERT REVIEW OF GASTROENTEROLOGY & HEPATOLOGY   12 巻 ( 11 ) 頁: 1109 - 1122   2018年11月

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    記述言語:日本語   出版者・発行元:Expert Review of Gastroenterology and Hepatology  

    Introduction: In recent decades, adjuvant therapy has secured a firm position in the treatment of gastric cancer by improving patient prognosis. Currently, standard therapy varies between East Asia, Europe and North America due to heterogeneities of the tumor, race, medical environment and/or surgical procedure. Although adjuvant strategies, proved effective in each region and implemented to clinical practice, certain patient populations with advanced gastric cancer show recurrence and a fatal prognosis. The development of a universal adjuvant therapy with a high efficacy and acceptable adverse events or with less toxicity and non-inferiority seems to have become urgent and imperative. Areas covered: In this review, we aimed to summarize the current knowledge regarding adjuvant therapies for gastric cancer, including chemotherapy, chemoradiotherapy and molecular targeted therapy, based on clinical trials and to introduce the pivotal ongoing phase III trials. Expert commentary: The efficacy of adjuvant therapy to prevent recurrence remains insufficient although several trials have shown a significant benefit in patients with localized advanced gastric cancer. The development of more effective and universal multimodal adjuvant therapy is required.

    DOI: 10.1080/17474124.2018.1530985

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  84. Prognostic Impact of Immune-Related Gene Expression in Preoperative Peripheral Blood from Gastric Cancer Patients.

    Ito S, Fukagawa T, Noda M, Hu Q, Nambara S, Shimizu D, Kuroda Y, Eguchi H, Masuda T, Sato T, Katai H, Sasako M, Mimori K

    Annals of surgical oncology   25 巻 ( 12 ) 頁: 3755 - 3763   2018年11月

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

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

    ONCOGENE   37 巻 ( 39 ) 頁: 5355 - 5366   2018年9月

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    記述言語:日本語   出版者・発行元:Oncogene  

    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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  86. Synaptotagmin XIII expression and peritoneal metastasis in gastric cancer

    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   105 巻 ( 10 ) 頁: 1349 - 1358   2018年9月

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    記述言語:英語   出版者・発行元:British Journal of Surgery  

    Background: Peritoneal metastasis is a frequent cause of death in patients with gastric cancer. The aim of this study was to identify molecules responsible for mediating peritoneal metastasis of gastric cancer. Methods: Transcriptome and bioinformatics analyses were conducted to identify molecules associated with peritoneal metastasis. The therapeutic effects of intraperitoneally administered small interfering (si) RNA were evaluated using mouse xenograft models. Expression of mRNA and protein was determined in gastric tissues from patients with gastric cancer. Results: Synaptotagmin XIII (SYT13) was expressed at significantly higher levels in patients with peritoneal recurrence, but not in those with hepatic or distant lymph node recurrence. Inhibition of SYT13 expression in a gastric cancer cell line transfected with SYT13-specific siRNA (siSYT13) was associated with decreased invasion and migration ability of the cells, but not with proliferation and apoptosis. Intraperitoneal administration of siSYT13 significantly inhibited the growth of peritoneal nodules and prolonged survival in mice. In an analysis of 200 patients with gastric cancer, SYT13 expression in primary gastric cancer tissues was significantly greater in patients with peritoneal recurrence or metastasis. A high level of SYT13 expression in primary gastric cancer tissues was an independent risk factor for peritoneal recurrence. Conclusion: SYT13 expression in gastric cancer is associated with perioneal metatases and is a potential target for treatment.

    DOI: 10.1002/bjs.10876

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  87. Emerging evidence of the molecular landscape specific for hematogenous metastasis from gastric cancer

    Shimizu Dai, Kanda Mitsuro, Kodera Yasuhiro

    WORLD JOURNAL OF GASTROINTESTINAL ONCOLOGY   10 巻 ( 6 ) 頁: 124 - 136   2018年6月

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    記述言語:日本語   出版者・発行元:World Journal of Gastrointestinal Oncology  

    Gastric cancer (GC) is one of the most frequently diagnosed cancers in the world. Most GC patients are diagnosed when the cancer is in an advanced stage, and consequently, some develop metastatic lesions that generally cause cancer-related death. Metastasis establishment is affected by various conditions, such as tumor location, hemodynamics and organotropism. While digestive cancers may share a primary site, certain cases develop hematogenous metastasis with the absence of peritoneal metastasis, and vice versa. Numerous studies have revealed the clinicopathological risk factors for hematogenous metastasis from GC, such as vascular invasion, advanced age, differentiation, Borrmann type 1 or 2 and expansive growth. Recently, molecular mechanisms that contribute to metastatic site determination have been elucidated by advanced molecular biological techniques. Investigating the molecules that specifically participate in metastasis establishment in distinct secondary organs will lead to the development of novel biomarkers for patient stratification according to their metastatic risk and strategies for preventing and treating distinct metastases. We reviewed articles related to the molecular landscape of hematogenous metastasis from GC.

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  88. Significance of SYT8 For the Detection, Prediction, and Treatment of Peritoneal Metastasis From Gastric Cancer

    Kanda Mitsuro, Shimizu Dai, Tanaka Haruyoshi, Tanaka Chie, Kobayashi Daisuke, Hayashi Masamichi, Iwata Naoki, Niwa Yukiko, Yamada Suguru, Fujii Tsutomu, Sugimoto Hiroyuki, Murotani Kenta, Fujiwara Michitaka, Kodera Yasuhiro

    ANNALS OF SURGERY   267 巻 ( 3 ) 頁: 495 - 503   2018年3月

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    記述言語:日本語   出版者・発行元:Annals of Surgery  

    Objective: To develop novel diagnostic and therapeutic targets specific for peritoneal metastasis of gastric cancer (GC). Background: Advanced GC frequently recurs because of undetected micrometastases even after curative resection. Peritoneal metastasis has been the most frequent recurrent pattern after gastrectomy and is incurable. Methods: We conducted a recurrence pattern-specific transcriptome analysis in an independent cohort of 16 patients with stage III GC who underwent curative gastrectomy and adjuvant S-1 for screening candidate molecules specific for peritoneal metastasis of GC. Next, another 340 patients were allocated to discovery and validation sets (1:2) to evaluate the diagnostic and predictive value of the candidate molecule. The results of quantitative reverse-transcription PCR and immunohistochemical analysis were correlated with clinical characteristics and survival. The effects of siRNA-mediated knockdown on phenotype and fluorouracil sensitivity of GC cells were evaluated in vitro, and the therapeutic effects of siRNAs were evaluated using a mouse xenograft model. Results: Synaptotagmin VIII (SYT8) was identified as a candidate biomarker specific to peritoneal metastasis. In the discovery set, the optimal cut-off of SYT8 expression was established as 0.005. Expression levels of SYT8 mRNA in GC tissues were elevated in the validation set comprising patients with peritoneal recurrence or metastasis. SYT8 levels above the cut-off value were significantly and specifically associated with peritoneal metastasis, and served as an independent prognostic marker for peritoneal recurrence-free survival of patients with stage II/III GC. The survival difference between patients with SYT8 levels above and below the cut-off was associated with patients who received adjuvant chemotherapy. Inhibition of SYT8 expression by GC cells correlated with decreased invasion, migration, and fluorouracil resistance. Intraperitoneal administration of SYT8-siRNA inhibited the growth of peritoneal nodules and prolonged survival of mice engrafted with GC cells. Conclusions: SYT8 represents a promising target for the detection, prediction, and treatment of peritoneal metastasis of GC.

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  89. Review of recent molecular landscape knowledge of gastric cancer

    Shimizu Dai, Kanda Mitsuro, Kodera Yasuhiro

    HISTOLOGY AND HISTOPATHOLOGY   33 巻 ( 1 ) 頁: 11 - 26   2018年1月

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    記述言語:日本語   出版者・発行元:Histology and Histopathology  

    Gastric cancer (GC) is one of the most frequently diagnosed cancers worldwide and its prognosis remains dismal. One reason for poor outcomes of GC patients is that most are diagnosed when the cancer has already advanced. Novel biomarkers with high sensitivity and specificity are needed to diagnose GC in the early stage. In addition, to improve the outcome of patients with GC, patient stratification according to prognostic factors and sensitivity to chemo(radio)therapy are necessary. Appropriate followup criteria and individualized treatment will contribute to improvement in prognosis. Over the past decades, development of microarray and sequencing technology have coalesced to increase reports regarding epigenetic alterations that affect the character of malignancies including GC. These advances help our understanding of gastric carcinogenesis and have the possibility of improving the prognosis of GC by contributing to the optimization of therapeutic strategies. Further development of biomarkers for diagnosis and prognosis are desperately needed. Here, we enumerate and describe some GC-related molecules reported over the past few years that may be useful biomarkers.

    DOI: 10.14670/HH-11-898

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  90. Overexpression of FGFR1 Promotes Peritoneal Dissemination Via Epithelial-to-Mesenchymal Transition in Gastric Cancer

    Shimizu Dai, Saito Tomoko, Ito Shuhei, Masuda Takaaki, Kurashige Junji, Kuroda Yosuke, Eguchi Hidetoshi, Kodera Yasuhiro, Mimori Koshi

    CANCER GENOMICS & PROTEOMICS   15 巻 ( 4 ) 頁: 313 - 320   2018年

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    記述言語:日本語   出版者・発行元:Cancer Genomics and Proteomics  

    Background: Peritoneal dissemination (PD) is one of the most common causes of cancer-related mortality in gastric cancer (GC). We aimed to identify PD-associated genes and investigate their role in GC. Materials and Methods: We identified FGFR1 as a putative PD-associated gene using a bioinformatics approach. The biological significance of FGFR1 in epithelial-to-mesenchymal transition (EMT) was evaluated according to the correlation with genes that participated in EMT and FGFR1 knockdown experiments. The associations between FGFR1 expression and the clinicopathological features were examined. Results: FGFR1 expression positively correlated with SNAI1, VIM and ZEB1 expression, and negatively correlated with CDH1 expression. Knockdown of FGFR1 suppressed the malignant phenotype of GC cells. High FGFR1 expression significantly correlated with the peritoneal lavage cytology and synchronous PD positivity as well as poor prognosis. Conclusion: High FGFR1 expression was associated with PD via promotion of EMT and led to a poor prognosis of GC patients.

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  91. FAM46C Serves as a Predictor of Hepatic Recurrence in Patients with Resectable Gastric Cancer

    Tanaka Haruyoshi, Kanda Mitsuro, Shimizu Dai, Tanaka Chie, Kobayashi Daisuke, Hayashi Masamichi, Iwata Naoki, Yamada Suguru, Fujii Tsutomu, Nakayama Goro, Sugimoto Hiroyuki, Fujiwara Michitaka, Niwa Yukiko, Kodera Yasuhiro

    ANNALS OF SURGICAL ONCOLOGY   24 巻 ( 11 ) 頁: 3438 - 3445   2017年10月

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    記述言語:日本語   出版者・発行元:Annals of Surgical Oncology  

    Background: Gastric cancer (GC) relapse can occur even if curative resection is achieved. Biomarkers predicting recurrence are needed to provide appropriate postoperative surveillance and perioperative therapeutic strategy. Methods: A global expression profiling was performed using tissues from GC patients with synchronous liver-confined metastasis. Family with sequence similarity 46, member C (FAM46C), was identified as a candidate biomarker. mRNA expression analysis, direct nucleotide sequencing, bisulfite sequencing and copy number assays for FAM46C were performed with eleven GC cell lines. Expression levels of FAM46C in primary GC tissues from 129 patients who underwent curative GC resection were determined and correlated with clinicopathological factors, including postoperative outcome. Results: Levels of FAM46C mRNA differed among GC cell lines. Point mutations in FAM46C were detected in five GC cell lines accompanied with reduced FAM46C transcription. No hypermethylation was found in the promoter region of FAM46C. Copy number alterations were found in six GC cell lines with differing FAM46C transcription levels. Reduced FAM46C mRNA expression levels were detected in 117 (91 %) GC specimens compared with adjacent noncancerous tissues. Low FAM46C expression levels were significantly associated with larger macroscopic GC tumor sizes. The low FAM46C expression group was likely to have shorter disease-free survival than the high group and low FAM46C level was identified as an independent risk factor for recurrence after curative resection. FAM46C expression levels were low in all cases that were later found to have hepatic recurrence. Conclusions: Reduced GC expression of FAM46C is a potential biomarker to predict hepatic recurrence after curative gastrectomy.

    DOI: 10.1245/s10434-016-5636-y

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  92. Overexpression of Derlin 3 is associated with malignant phenotype of breast cancer cells

    Shibata Masahiro, Kanda Mitsuro, Tanaka Haruyoshi, Umeda Shinichi, Miwa Takashi, Shimizu Dai, Hayashi Masamichi, Inaishi Takahiro, Miyajima Noriyuki, Adachi Yayoi, Takano Yuko, Nakanishi Kenichi, Takeuchi Dai, Noda Sumiyo, Kodera Yasuhiro, Kikumori Toyone

    ONCOLOGY REPORTS   38 巻 ( 3 ) 頁: 1760 - 1766   2017年9月

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    記述言語:日本語   出版者・発行元:Oncology Reports  

    Breast cancer (BC) is the most common malignant tumor among women worldwide. Development of novel molecular targets is important to improve prognosis of BC patients. Derlin 3 (DERL3) gene is a member of derlin family, and its coding protein is critical to the endoplasmic reticulumassociated degradation mechanism. However, its oncological role in breast cancer remains unclear. This study evaluated DERL3 expression and function in BC. We analyzed DERL3 mRNA in 13 BC and two non-cancerous cell lines, and explored effects of DERL3 knockdown on BC proliferation, invasion and migration. We also evaluated correlation of DERL3 mRNA expression levels with clinicopathological factors and prognosis in 167 BC patients. DERL3 mRNA expression was detected in five (38%) BC cell lines. Inhibiting DERL3 expression significantly decreased proliferation and invasion in BC cells. Specimens from patients with lymph node metastasis had higher DERL3 mRNA expression than those without (P=0.030). Patients in the highest quartile for DERL3 mRNA expression (n=42) were more likely to experience shorter overall survival than other patients (P=0.032). These findings indicate that DERL3 promotes malignant phenotype in BC cells. DERL3 may serve as a potential prognostic marker and therapeutic target for BC.

    DOI: 10.3892/or.2017.5800

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  93. Expression of regulatory factor X1 can predict the prognosis of breast cancer

    Shibata Masahiro, Kanda Mitsuro, Shimizu Dai, Tanaka Haruyoshi, Umeda Shinichi, Hayashi Masamichi, Inaishi Takahiro, Miyajima Noriyuki, Adachi Yayoi, Takano Yuko, Nakanishi Kenichi, Takeuchi Dai, Noda Sumiyo, Kodera Yasuhiro, Kikumori Toyone

    ONCOLOGY LETTERS   13 巻 ( 6 ) 頁: 4334 - 4340   2017年6月

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    記述言語:日本語   出版者・発行元:Oncology Letters  

    Breast cancer (BC) is the most common malignancy among women. Identifying novel biomarkers to predict prognosis accurately is important in managing this disease. The regulatory factor X1 (RFX1) gene is a member of the regulatory factor X gene family. Its protein reportedly downregulates the proto-oncogene c-myc, but its role in BC has been unclear. In this study, expression and methylation status of RFX1 were determined in BC cell lines. We then evaluated RFX1 mRNA expression levels with regard to clinicopathological factors including postoperative prognosis in 167 patients with BC. Expression of RFX1 was heterogeneous among cell lines, and we found no DNA methylation at the RFX1 promoter region. Patients were categorized into groups with high or low RFX1 expression, based on ratio of RFX1 mRNA expression in BC and adjacent non-cancerous tissues. The high RFX1 group was significantly associated with low T factor (P=0.028), earlier disease stage (P=0.015), positive expression of estrogen receptor (P=0.005) and progesterone receptor (P=0.011), negative expression of human epidermal growth factor receptor 2 (P=0.001). The high RFX1 group experienced more favorable disease-free survival (P=0.007) and overall survival (P=0.013). In multivariate analysis, RFX1 expression was an independent prognostic factor for disease-free survival. Our findings indicate that RFX1 may serve as a prognostic marker for BC.

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  94. Search for useful biomarkers in hepatocellular carcinoma, tumor factors and background liver factors (Review).

    Shimizu D, Inokawa Y, Sonohara F, Inaoka K, Nomoto S

    Oncology reports   37 巻 ( 5 ) 頁: 2527 - 2542   2017年5月

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  95. GPR155 Serves as a Predictive Biomarker for Hematogenous Metastasis in Patients with Gastric Cancer

    Shimizu Dai, Kanda Mitsuro, Tanaka Haruyoshi, Kobayashi Daisuke, Tanaka Chie, Hayashi Masamichi, Iwata Naoki, Niwa Yukiko, Takami Hideki, Yamada Suguru, Fujii Tsutomu, Nakayama Goro, Fujiwara Michitaka, Kodera Yasuhiro

    SCIENTIFIC REPORTS   7 巻   頁: 42089   2017年2月

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    記述言語:日本語   出版者・発行元:Scientific Reports  

    The prognosis of patients with gastric cancer (GC) with hematogenous metastasis is dismal. Identification of biomarkers specific for hematogenous metastasis is required to develop personalized treatments that improve patients' outcomes. Global expression profiling of GC tissues with synchronous hepatic metastasis without metastasis to the peritoneal cavity or distant lymph nodes was conducted using next-generation sequencing and identified the G protein-coupled receptor 155 (GPR155) as a candidate biomarker. GPR155 transcription was suppressed in GC cell lines compared with a nontumorigenic cell line. DNA methylation of the GPR155 promoter region was not detected, albeit 20% of GC cell lines harbored copy number loss at GPR155 locus. The expression levels of GPR155 mRNA correlated inversely with those of TWIST1 and WNT5B. Inhibition of GPR155 expression increased the levels of p-ERK1/2 and p-STAT1, significantly increased cell proliferation, and increased the invasiveness of a GC cell lines. GPR155 mRNA levels in GC clinical samples correlated with hematogenous metastasis and recurrence. Multivariate analysis revealed that reduced expression of GPR155 mRNA was an independent predictive marker of hematogenous metastasis. GPR155 may represent a biomarker for diagnosing and predicting hematogenous metastasis of GC.

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  96. The protein arginine methyltransferase 5 promotes malignant phenotype of hepatocellular carcinoma cells and is associated with adverse patient outcomes after curative hepatectomy

    Shimizu Dai, Kanda Mitsuro, Sugimoto Hiroyuki, Shibata Masahiro, Tanaka Haruyoshi, Takami Hideki, Iwata Naoki, Hayashi Masamichi, Tanaka Chie, Kobayashi Daisuke, Yamada Suguru, Nakayama Goro, Koike Masahiko, Fujiwara Michitaka, Fujii Tsutomu, Kodera Yasuhiro

    INTERNATIONAL JOURNAL OF ONCOLOGY   50 巻 ( 2 ) 頁: 381 - 386   2017年2月

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    記述言語:日本語   出版者・発行元:International Journal of Oncology  

    The prognosis of advanced hepatocellular carcinoma (HCC) is dismal. Novel molecular targets for diagnosis and therapy is urgently required. This study evaluated expression and functions of the protein arginine methyltransferase 5 (PRMT5) in HCC. Using HCC cell lines, the expression levels of PRMT5 mRNA were determined using the quantitative real-time reverse-transcription polymerase chain reaction, and the effect of a small interfering PRMT5-siRNA on cell phenotype was evaluated. Further, PRMT5 expression was determined in 144 pairs of resected liver tissues to evaluate its clinical significance. Regardless of their differentiated phenotypes, nine HCC cell lines expressed different levels of PRMT5 mRNA. Inhibition of PRMT5 expression significantly decreased the proliferation, invasion, and migration of HCC cell lines. Although the level of PRMT5 mRNA was not influenced by patient's background liver status, it was significantly higher in HCC tissues than in the corresponding noncancerous tissues. High levels of PRMT5 mRNA in HCC tissues were significantly associated with advanced disease stage and adverse prognosis. In conclusion, our results indicate that PRMT5 may act as a putative oncogene in HCC and that the levels of PRMT5 mRNA represent a promising prognostic marker and a potential target of molecular therapy for HCC.

    DOI: 10.3892/ijo.2017.3833

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▼全件表示

科研費 7

  1. 臓器嗜好性に焦点をあてた食道癌転移の分子機序解明からの創薬研究

    研究課題/研究課題番号:21K19525  2021年7月 - 2024年3月

    科学研究費助成事業  挑戦的研究(萌芽)

    小寺 泰弘, 神田 光郎, 田中 千恵, 清水 大

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    担当区分:研究分担者 

    食道癌転移経路特異的Transcriptome解析により、申請者らの仮説に一致して血行性転移群とリンパ行性転移で発現パターンが明瞭に異なるクラスターがあることが示され、血行性転移関連5分子(VWA5B2、CFAP47、NECAB2、SYCE3、RPL3L)、リンパ行性転移関連3分子(C1QL4、CCDC87、CAMK2N2)を厳選している。
    これらの食道癌転移形式別関連分子の機能解析・発現解析を行うことで、食道癌転移の分子生物学的機序の解明を通じ、食道癌予後を劇的に改善しうる分子標的治療薬と、その奏効度を事前に予測しうるコンパニオン診断法開発の基盤となるデータを得ることを目的とする。
    食道癌は多様な進展経路を持つ予後不良な疾患であり、転移を制御できない限り治療成績の大幅な改善を得ることは不可能である。食道癌の予後を左右する主な転移再発形式として血行性転移とリンパ節転移が存在するが、この2つの転移の経路やメカニズムは全く性質が異なるものであり、転移経路ごとに特異的な分子が存在という仮説を立てた。本研究は、各転移形式に特有の責任分子を同定し、その食道癌転移における役割を解明することを目的として遂行している。食道癌転移経路特異的Transcriptome解析により、血行性転移群とリンパ行性転移で発現パターンが明瞭に異なるクラスターがあることが示され、血行性転移関連分子とリンパ行性転移関連分子から候補分子を厳選した。まず、より予後が不良な血行性転移群から、NECAB2を抽出し実験系を確立する意味でもこれについて詳細な解析を進めている。令和3年度は、NECAB2の発現解析と、人為的発現調節による食道癌細胞株の悪性形質がどのように変化するかについて実験を行った。siRNAを用いたノックダウンにより、癌転移に重要な細胞機能である浸潤能、遊走能、接着能が抑制された。shRNAによる安定的ノックダウン株を樹立し、同様に細胞機能を調査したところ、再現性のある結果が得られた。発現ベクターによりNECAB2を強制発現すると、食道癌細胞株の増殖能が増強した。多施設共同研究体制による独立した2つの食道扁平上皮癌コホートにおいてNECAB2のmRNAおよびタンパク発現レベルを調査したところ、いずれにおいてもNECAB2高発現症例群で有意に予後不良であり血行性再発頻度も高かった。NECAB2を追って、血行性転移関連分子2分子、リンパ行性転移関連分子2分子について同様の実験系を進めており、令和5年度までの解析対象を厳選していく。
    令和3年度は計画した実験系を確立すること、仮説の実現性を得ることに重きを置き、重要度の高い血行性転移に関連の高いNECAB2について集中的に解析を進めた。発現調節の条件設定が順調に完了したことで、機能解析データの構築が順調に進んだ。発現解析データについても、入口の網羅的遺伝子発現データの結果と一致しており、本コンセプトの再現性を示すことができた。令和4年度は先行している分子についてin vivoデータを取得するとともに、リンパ行性転移関連分子に解析対象を拡大していく。
    令和4年度は、データ構築の先行している食道癌血行性転移関連分子NECAB2については、以下の実験を行う。
    1) 発現調節による癌細胞機能の評価:人工的発現抑制により、アポトーシス、細胞周期、スフェロイド形成能、食道癌のKey drugである5-FUおよびCDDP感受性、マウス皮下腫瘍モデルでの造腫瘍能がどのように変化するかについて解析する。
    2) シグナル解析:癌関連主要細胞内シグナル伝達経路の発現、リン酸化がNECAB2発現とどのような関連性をもつかについて調査する。
    3) in vivo転移形成能の比較:マウス全身転移モデルにおける転移形成能についてモニタリングする。マウスモデルはすでに確立している。
    NECAB2以外の候補分子についても、in vitro機能解析、発現解析を進めていく。

  2. 細胞接着因子を標的とするデュアル修飾型アンチセンス核酸を用いた革新的癌治療薬創出

    研究課題/研究課題番号:21H02984  2021年4月 - 2025年3月

    科学研究費助成事業  基盤研究(B)

    小寺 泰弘, 神田 光郎, 笠原 勇矢, 田中 千恵, 清水 大, 小比賀 聡

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    担当区分:研究分担者 

    本研究では、細胞接着因子を標的としたアンチセンス核酸医薬による新たな胃癌分子標的治療薬およびコンパニオン診断技術開発を目指して、以下を実施する。
    1) アンチセンス核酸スクリーニング、2) メカニズム解明(機能解析、シグナル解析、KOマウス解析、正常組織中発現解析)、3) in vitro活性評価(濃度依存性の活性、癌種横断的活性評価)、4) in vivo活性評価(皮下腫瘍モデル、同所移植モデルでの薬効評価)、5) 毒性評価とオフターゲット探索、6) コンパニオン診断(治療前生検、手術検体での免疫染色法による発現解析)
    本研究では、細胞接着因子を標的としたアンチセンス核酸医薬による新たな胃癌分子標的治療薬およびコンパニオン診断技術開発を目指して実験を進めている。令和3年度は、以下の進捗を得ている。
    1) アンチセンス核酸スクリーニング:アクセス効率を最大化するmRNAの二次構造予測システムを用いて候補配列をデザインし、29配列の中からノックダウン効率とin vitroでの胃癌細胞機能阻害効果から2つの有望配列を取得した。これら配列については、標的分子の発現レベルが低い癌細胞では抑制活性を示さず、オンターゲット活性であることも確認できている。
    2) メカニズム解明:同分子阻害の作用機序を調査している。2つの有望アンチセンス核酸配列を用いた標的細胞接着因子ノックダウンにより、胃癌細胞接着能および浸潤能が低下することを明らかにした。標的細胞接着因子無発現癌細胞株であるKATOIIIに対して標的分子の強制発現を行うと、胃癌細胞の増殖能が増強した。細胞内シグナル伝達系のリン酸化状態を網羅的に調査可能なPTM Scanを用いてアンチセンス核酸による標的細胞接着因子ノックダウン前後の細胞内シグナルの変化についてデータを得た。
    3) in vitro活性評価:選抜した有望アンチセンス核酸配列の濃度依存性なin vitro細胞増殖能阻害活性について、0.25nMから800nMの濃度域で検証した。このデータをもとに、翌年度以降のin vivo解析の投与量を設定していく。
    令和3年度は、序盤での有望配列スクリーニングが速やかに完了し、取得した2配列を用いた基礎データの構築が順調に進んだ。in vivo毒性テストの結果をみるまでは最終配列決定には至らないが、これら2配列を主軸に研究計画を進めていく。また、シグナル解析の第一歩としての網羅的リン酸化解析のデータを取得できたため、翌年度以降に再現性確認を含めて詳細に検討していく。標的細胞接着因子の阻害が生体に致命的な影響を与えないかを調べるためのノックアウトマウスの合成にも着手した。
    研究計画は順調に推移しており、当初の計画に沿って令和4年度も研究を進めていく。メカニズム解明(担当:研究代表者 小寺、研究分担者 神田、清水)として、癌細胞の転移能や薬剤抵抗性に重要である癌幹細胞性について調査する。アンチセンス核酸による標的分子ノックダウン前後でのスフェロイド形成能について調べる。また、胃癌を含むさまざまな固形癌におけるkey drugである5-FUおよびシスプラチン感受性への影響についても解析する。令和3年度にPTM Scanで抽出された候補シグナル系に着目してwestern blotting法で詳細に検討する。ゲノム編集技術を用いたノックアウトマウスを樹立する。
    ついで、in vitro活性評価(担当:研究分担者 神田)も拡大する。選抜配列を用いて、癌種横断的(食道癌、膵癌、大腸癌、肝癌、乳癌)に細胞株に対する細胞増殖阻害能をin vitroで調べる。in vivo活性評価(担当:研究代表者 小寺、研究分担者 清水)として、有望2配列のマウス皮下腫瘍モデルに対するアンチセンス核酸腹腔内投与での造腫瘍能抑制効果を評価する。

  3. DNAメチル化パネルによる多癌種鑑別診断技術の確立

    研究課題/研究課題番号:21K07240  2021年4月 - 2024年3月

    科学研究費助成事業  基盤研究(C)

    清水 大

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    担当区分:研究代表者 

    配分額:4030000円 ( 直接経費:3100000円 、 間接経費:930000円 )

    低侵襲な癌診断手法として血液や尿を対象としたliquid biopsyが注目されており、その多くは癌特異的な体細胞変異を対象としている。しかし、単一の癌種の中で特定の体細胞変異が画一的に共有されることはなく、さらには発癌に関与する体細胞変異のほとんどが癌種特異的ではなく複数の癌種にまたがって観察されるため、体細胞変異のみを対象とした癌診断は癌種特異性が低い。本研究では組織・腫瘍特異性が高いDNAメチル化解析を広く臨床検体に応用し、多癌種での組織およびliquid biopsyでの診断能の検証を行うことで、単回の検査で多癌種の診断を可能とする診断技術の開発を目指す。
    研究代表者は、2019年度若手研究での「cfDNAを用いた大腸癌特異的メチル化マーカーによる大腸癌存在診断法の開発」を発展させ、27癌種にのぼる多癌種を鑑別診断し得るメチル化パネルの構築に成功している。作成したメチル化パネルの診断能は、自施設で入手した大腸癌・胃癌・乳癌の組織検体や、別の公共データベースから得られた腫瘍組織のメチル化データを用いることで検証し、その結果、人種・組織検体の保存法(凍結もしくはパラフィン包埋)・DNAメチル化の検出手法(アレイもしくはシーケンス)によらず、さらに腫瘍内不均一性の影響を受けずに、高い精度で27種の悪性腫瘍の診断に用いることができることを示した。また、血液中のcirculating tumor DNA(ctDNA)のメチル化状態からも、どの臓器由来の悪性腫瘍が存在するかを診断できる可能性が示された。さらには、原発不明癌症例の血液検体からも原発臓器を同定できる可能性が示された。上記結果は国際科学誌「Cancer Gene Therapy」に2021年11月8日付で掲載された。
    本研究では、その先行研究で得られた知見を発展させるため、多癌種でのctDNA解析を計画実行中である。現在は、検体収集中の段階であり、新たな結果は得られていないが、研究は着実に進行している。診療各科に協力を要請し、血液検体の収集を進めている。また、ctDNAのメチル化解析技術は未だに開発段階であり、世界的にも確立されたものはないのが現状である。当初の研究計画に記載したGenomedia社での開発に限らず、有用なものを選択して用いる方針である。
    現在、ゲノム解析研究として試料収集中であるが、十分量が収集できておらず、解析に至っておらず、想定した予定より遅れている。
    当初の研究計画に従い、まずは粛々と試料を収集する。各診療科の協力を得ながら可及的速やかに試料を収集し、ctDNAメチル化解析を行っていく。

  4. 高機能性人工核酸を用いたアンチセンス核酸医薬による革新的消化器系癌創薬研究

    研究課題/研究課題番号:20K21629  2020年7月 - 2022年3月

    科学研究費助成事業  挑戦的研究(萌芽)

    神田 光郎, 小比賀 聡, 笠原 勇矢, 清水 大, 田中 千恵, 小寺 泰弘

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    担当区分:研究分担者 

    早期根治切除例の予後は期待できるものの、転移・再発性となるときわめて予後不良であることは、全ての消化器癌における共通かつ重大な問題点である。全身化学療法は分子標的治療薬を中心に徐々にラインナップを増やしているが、不応・耐性が治療成績の限界を産んでおり、全く別の作用機序を有するアプローチの開発が必要である。本研究では、新規標的分子に対する優れた阻害効果を有するアンチセンス核酸を創製し、革新的な効果を発揮する癌治療核酸医薬を開発していく。
    予後不良な転移・再発性消化器癌に対するアンチセンス核酸医薬を用いた新規治療薬開発を目的とした。Transcriptome解析を経て癌転移を司る候補分子としてCSRNP3、CPLX1、RNFT2を厳選し、これらに重点を置いてデータ構築した。mRNA二次構造予測システムを用いてデザインしたアンチセンス核酸は、癌種横断的な癌細胞増殖能抑制効果を示した。CSRNP3に対するアンチセンス核酸は、マウス腹膜播種モデルで腫瘍進展を抑制した。CSRNP3ノックダウンによりシスプラチンの抗腫瘍効果が増強した。これら分子の組織中発現度は、胃癌症例の生存期間や転移再発率に相関していた。
    本研究で解析した標的分子群は、試験管内の細胞株でなく治療抵抗性を示した癌の臨床検体から見出したシーズである。既存の治療法では制御できなかった状況を克服するための鍵となり得る分子であると考えている。また、悪性腫瘍と標的分子群を関連づける報告はこれまでに皆無であり、新規性が高く、既存の治療薬の標的と異なるため、新しい作用機序を有する治療薬となることが期待される。さらに、アンチセンス核酸医薬開発という明確な創薬コンセプトをもってデータ構築している。個別化治療において重要な、対象選別のためのコンパニオン診断技術の基盤となる発現データも取得した。

  5. CHRNB2を標的とした革新的がん抗体医薬とコンパニオン診断技術の創出研究

    研究課題/研究課題番号:20H03750  2020年4月 - 2024年3月

    科学研究費助成事業  基盤研究(B)

    神田 光郎, 小寺 泰弘, 横島 聡, 田中 千恵, 清水 大, 山口 繭美

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    担当区分:研究分担者 

    CHRNB2を標的とした抗体医薬創薬ならびに治療奏効度を予測するコンパニオン診断技術の開発を目的として、以下の実験を行う。
    Ⅰ. メカニズム解明:KOマウス解析、機能解析、シグナル解析、正常組織中発現解析
    Ⅱ. ヒト化抗CHRNB2抗体:抗体合成、薬効評価
    Ⅲ. 抗体のprofiling:アフィニティ測定、エピトープマッピング
    Ⅳ. 抗体-化合物複合体:化合物スクリーニング、複合体合成、薬効評価
    Ⅴ. コンパニオン診断:臨床検体でのCHRNB2発現解析、臨床病理学的因子との相関解析
    切除不能・再発胃癌は依然として予後不良であり、治療成績改善のためには「転移」を制御しうる、新しい作用機序の薬剤開発が求められている。本研究では、実際に転移をきたした症例から得た組織検体を用いた網羅的発現解析を切り口に同定した標的分子cholinergic receptor nicotinic beta 2 subunit (CHRNB2)を狙い撃つ分子標的治療薬開発を目指している。ゲノム編集技術を応用したCHRNB2安定的ノックアウトによりアポトーシス誘導を介した胃癌細胞増殖能低下を起こすことが明らかになった。一方、低発現胃癌細胞株にウイルスベクターによってCHRNB2を強制発現させることにより細胞増殖能は亢進した。ゲノム編集により作成したChrnb2欠損マウスでは、生殖・発生・臓器機能・認知行動機能に異常を認めなかった。ハイブリドーマを樹立して取得したマウスCHRNB2モノクローナル抗体は、単独で中等度の細胞増殖抑制能を示した。蛍光細胞染色を行うと、このモノクローナル抗体はがん細胞の膜上に発現するCHRNB2タンパクおよび、293細胞に強制発現させたCHRNB2タンパクに特異的結合していることが示された。細胞内signalの発現およびリン酸化を調査すると、上皮間葉移行を通じて癌細胞の転移に関与するZEB2およびJAK-STATシグナルのSTAT3、PI3K-Aktの発現もしくはリン酸化にCHRNB2が干渉することが示唆された。蛍光細胞染色結果からCHRNB2は抗体付加後の内在化が示されており、抗体-薬物複合体合成を進めている。試作品としてモノクローナル抗体と天然化合物lomaiviticin類の抗体・化合物複合体を合成した。マウスモノクローナル抗体のアフィニティ解析と、ヒト化抗CHRNB2抗体合成に着手している。
    lomaiviticin類と抗CHRNB2モノクローナル抗体を用いた抗体・化合物複合体を合成したが、安定的にin vitro活性を示す複合体を取得するのに難渋しており、若干の計画遅延をきたしている。各種条件設定を試しており、この点が解決すれば研究期間内に計画を完遂できると考えている。
    CHRNB2モノクローナル抗体単体のin vivoにおける癌細胞転移抑制効果を評価するため、マウス腹膜播種モデルに対する腹腔内投与の効果を調べる。モノクローナル抗体のヒト化を進めるとともに、アフィニティ測定とエピトープマッピングを実施する。モノクローナル抗体とlomaiviticin、リンカー (SMCC) を用いて複合体を合成し、安定的な合成確認を経て、in vitroついでin vivoでの活性を評価する。特に、モノクローナル抗体単体からの上乗せ効果に着目する。
    CHRN family遺伝子の発現とCHRNB2発現がどの程度、交互作用を有しているかを調べるため、胃がん細胞株およびヒト胃組織検体におけるCHRNA2-6、CHRNB6発現を評価して相関解析を行う。また、これらに対するCHRNB2の後天的発現阻害による変化についても調べる。
    胃組織検体を対象として、CHRNB2のmRNAおよびタンパク発現を調べ、特に再発転移発生との関連性を調査する。特に、汎用性の高い免疫組織化学染色法はコンパニオン診断法確立に重要と考えている。

  6. cfDNAを用いた大腸癌特異的メチル化マーカーによる大腸癌存在診断法の開発

    研究課題/研究課題番号:19K16868  2019年4月 - 2022年3月

    科学研究費助成事業  若手研究

    清水 大

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    担当区分:研究代表者 

    配分額:4290000円 ( 直接経費:3300000円 、 間接経費:990000円 )

    体細胞変異に比べて一般に症例間や腫瘍内での不均一性が少ないDNAメチル化異常を標的として癌の存在診断を行う。Public databaseを用い、32種類という多癌腫間での比較から大腸癌特異的なメチル化異常部位を抽出し、ctDNA解析に応用する。すなわち、採血のみで他癌腫を鑑別し、大腸癌原発巣および転移巣の早期発見を可能とする技術開発を目指す。また、本アプローチは他癌腫にも応用可能であることから、各癌腫特異的なメチル化異常部位を標的として、採血のみで癌腫診断を可能にする検診技術の確立への発展性を有する研究である。
    大規模公共データを用いて27種類の臓器由来悪性腫瘍に特徴的なDNAメチル化部位を抽出し、DNAメチル化診断パネルを作成した。パネルの診断能は、自施設の大腸癌・胃癌・乳癌の組織検体や、別の公共データベースから得られた腫瘍組織のデータを用いて検証した。結果、人種・検体保存法・DNAメチル化の検出手法によらず、さらに腫瘍内不均一性の影響を受けずに、27種の悪性腫瘍の診断に用いることができることが示された。また、ctDNAのメチル化状態からも、どの臓器由来の悪性腫瘍が存在するかを診断できる可能性が示された。さらには、原発不明癌症例の血液検体からも原発臓器を同定できる可能性が示された。
    本研究の結果を発展させることにより、1回の採血や尿検査などのリキッドバイオプシー検査を用いることで、最大27種類の悪性腫瘍の存在を的確に識別可能な検診技術への発展が期待される。単回検査で多癌種の診断が可能となれば、受診負担軽減から検診受診率が向上し、健康予後の改善が期待できる。また、原発不明癌の正確な原発巣診断に活用できる可能性があり、原発不明癌に対してより客観的な原発巣診断ツールとして用いることができ、より適した治療を提供できる可能性が示唆された。

  7. FRAS1 を標的とした胃癌肝転移特異的な治療・診断法の開発

    研究課題/研究課題番号:17K16521  2017年4月 - 2019年3月

    清水 大

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    担当区分:研究代表者 

    配分額:4030000円 ( 直接経費:3100000円 、 間接経費:930000円 )

    我々は、肝転移を有する胃癌患者の原発巣で有意に発現が上昇している遺伝子群をRNA sequencingの結果から抽出し、その遺伝子群からFRAS1を胃癌肝転移関連分子として着目した。CRISPR-Cas9システムを用いてFRAS1のノックアウト株を作成し、FRAS1ノックアウトに伴い増殖能・接着能・遊走能・浸潤能が有意に低下することを示した。また、FRAS1高発現症例は有意に累積肝転移発生率が高かった。マウス肝転移モデルをを用いて、FRAS1が転移巣形成においてより肝転移巣形成に重要な役割を果たしている事を示した。
    胃癌肝転移は有効な根治治療が確立されておらず致死的な病態である。胃癌が肝転移をきたすメカニズムや、肝転移を誘導する分子の解明は、胃癌の肝転移予測ならびに治療法の開発に不可欠である。今回我々はFRAS1を胃癌肝転移関連分子として同定し、その遺伝子発現が胃癌細胞の悪性度に関与することを明らかにした。また、胃癌患者コホートにおいてFRAS1発現は独立した肝転移予測因子であった。さらに動物実験では、FRAS1発現が肝転移に特徴的に関与する可能性を示した。今後、FRAS1が胃癌肝転移の予測マーカーならびに治療標的となる事が期待される。

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