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志村 貴也シムラ タカヤ

所属部署医学研究科消化器・代謝内科学分野
職名講師
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Last Updated :2020/06/02

研究者基本情報

学位

  • 医学博士

所属学協会

  • 日本消化器癌発生学会:代議員
  • 日本癌治療学会
  • 日本癌学会
  • アメリカ臨床腫瘍学会(ASCO):Active Member
  • アメリカ癌学会(AACR):Active member
  • 日本消化管学会:認定医・専門医・代議員
  • 日本がん治療認定医機構:がん治療認定医
  • 日本臨床腫瘍学会:がん薬物療法専門医・指導医
  • 日本消化器内視鏡学会:専門医・指導医・学会評議員
  • 日本消化器病学会:専門医・指導医・学会評議員
  • 日本内科学会:認定医・専門医

研究活動情報

研究分野

  • ライフサイエンス, 腫瘍生物学
  • ライフサイエンス, 腫瘍診断、治療学
  • ライフサイエンス, 消化器内科学

研究キーワード

    バイオマーカー、尿、タンパク、マイクロRNA、エクソソーム、血管新生、微小環境、脂肪細胞、胃癌、大腸癌、食道癌、十二指腸腫瘍、内視鏡、閉塞性大腸癌

論文

  • Combination Therapy With Tofacitinib Plus Intensive Granulocyte and Monocyte Adsorptive Apheresis as Induction Therapy for Refractory Ulcerative Colitis., Satoshi Tanida, Keiji Ozeki, Tsutomu Mizoshita, Mika Kitagawa, Takanori Ozeki, Mamoru Tanaka, Hirotada Nishie, Takaya Shimura, Eiji Kubota, Hiromi Kataoka, Journal of clinical medicine research, 12, (1) 36 - 40,   2020年01月, 査読有り, Background: The use of monotherapy with intensive granulocyte and monocyte adsorptive apheresis (GMA) or a Janus kinase (JAK) inhibitor has been limited to patients with refractory ulcerative colitis (UC). The efficacy and safety of combination therapy with tofacitinib (TOF) plus intensive GMA (two sessions per week) for refractory UC have not been evaluated. Methods: This retrospective study evaluated the 10-week efficacy of combination therapy with TOF plus intensive GMA in patients with refractory UC. Results: Of seven patients who received a combination therapy with TOF plus intensive GMA, 71.4% achieved clinical remission at 10 weeks. The percentages of patients with mucosal healing and complete mucosal healing at 10 weeks were 100% and 42.9%, respectively. The mean full Mayo score and endoscopic subscore at baseline were 8.71 ± 0.80 and 2.4 ± 0.2, respectively, and the corresponding values at 10 weeks were 1.57 ± 0.48 and 0.6 ± 0.2 (P < 0.01), respectively. Adverse events of an orolabial herpes and temporary increase in creatinine phosphokinase (CK) and triglyceride were observed in three patients. Conclusions: Based on these outcomes, combination therapy with TOF plus intensive GMA was well tolerated and may be useful for induction of clinical remission in patients with refractory UC.
  • A novel urinary microRNA biomarker panel for detecting gastric cancer., Hiroyasu Iwasaki, Takaya Shimura, Tamaki Yamada, Yusuke Okuda, Makoto Natsume, Mika Kitagawa, Shin-Ichi Horike, Hiromi Kataoka, Journal of gastroenterology, 54, (12) 1061 - 1069,   2019年12月, 査読有り, BACKGROUND: Gastric cancer (GC) is one of the most common causes of cancer deaths worldwide; however, reliable and non-invasive screening methods for GC are not established. Therefore, we conducted this study to develop a biomarker for GC detection, consisting of urinary microRNAs (miRNAs). METHODS: We matched 306 participants by age and sex [153 pairs consisting of patients with GC and healthy controls (HCs)], then randomly divided them across three groups: (1) the discovery cohort (4 pairs); (2) the training cohort (95 pairs); and (3) the validation cohort (54 pairs). RESULTS: There were 22 urinary miRNAs with significantly aberrant expressions between the two groups in the discovery cohort. Upon multivariate analysis of the training cohort, urinary expression levels of miR-6807-5p and miR-6856-5p were significantly independent biomarkers for diagnosis of GC, in addition to Helicobacter pylori (H. pylori) status. A diagnostic panel that combined these 2 miRNAs and H. pylori status distinguished between HC and GC samples with an area under the curve (AUC) = 0.736. In the validation cohort, urinary miR-6807-5p and miR-6856-5p showed significantly higher expression levels in the GC group, and the combination biomarker panel of miR-6807-5p, miR-6856-5p, and H. pylori status also showed excellent performance (AUC = 0.885). In addition, this biomarker panel could distinguish between HC and stage I GC patients with an AUC = 0.748. Urinary expression levels of miR-6807-5p and miR-6856-5p significantly decreased to undetectable level after curative resection of GC. CONCLUSIONS: This novel biomarker panel enables early and non-invasive detection of GC.
  • A multicenter, single-blind randomized controlled trial of endoscopic clipping closure for preventing coagulation syndrome after colorectal endoscopic submucosal dissection., Satoshi Nomura, Takaya Shimura, Takahito Katano, Tomohiro Iwai, Yusuke Mizuno, Tomonori Yamada, Masahide Ebi, Yoshikazu Hirata, Hirotada Nishie, Takashi Mizushima, Yu Nojiri, Shozo Togawa, Shunsuke Shibata, Hiromi Kataoka, Gastrointestinal endoscopy,   2019年11月28日, 査読有り, BACKGROUND AND AIMS: Post endoscopic submucosal dissection coagulation syndrome (PECS) occasionally occurs after colorectal endoscopic submucosal dissection (ESD), presenting with localized abdominal pain and inflammation. We conducted a randomized controlled trial (RCT) to assess the usefulness of endoscopic clipping closure to prevent PECS and delayed perforation (DP). METHODS: This is a multicenter, single-blind RCT. Prospectively enrolled patients undergoing colorectal ESD were randomly allocated to endoscopic clipping closure and nonclosure after ESD, stratifying by institution and tumor size. All participants underwent a computed tomography scan after ESD. PECS was defined as visual analog scale (VAS) ≥30 mm, an increase in VAS ≥20 mm from baseline, body temperature ≥37.5°C or white blood cells ≥10,000/μL after colorectal ESD. DP was defined as PECS accompanied by extraluminal air. The preplanned sample size was 320 patients, and the primary endpoint was the rate of PECS/DP. RESULTS: At the planned interim analysis, this trial was terminated by recommendation of the independent data and safety monitoring committee because conditional power with superiority was lower than the preplanned futility limit. Finally, 155 patients were analyzed. The rate of PECS/DP was 16% (95% confidence interval [CI], 8%-23%) in the nonclosure group and 24% (95% CI, 14%-34%) in the closure group (P = .184). All cases of DP were within minor criteria, and all PECS/DP patients were managed conservatively without surgical treatment. Simple periluminal air without PECS was observed in 16% (95% CI, 8%-23%) in the nonclosure group and 10% (95% CI, 3%-17%) in the closure group. CONCLUSION: Endoscopic clipping closure could not reduce the high incidence of PECS/DP after colorectal ESD. (University Hospital Medical Network Clinical Trials Registry number: UMIN000027031.).
  • Current status of urinary diagnostic biomarkers for colorectal cancer., Hiroyasu Iwasaki, Takaya Shimura, Hiromi Kataoka, Clinica chimica acta; international journal of clinical chemistry, 498, 76 - 83,   2019年11月, 査読有り, Fecal occult blood test (FOBT) and flexible sigmoidoscopy are the currently using screening methods for colorectal cancer (CRC). However, these methods still have problems of high false positive rates in FOBT and increased invasiveness and cost associated with endoscopy. The development of non-invasive biomarkers is thus important for the diagnosis of CRC. Urine is one of the most commonly used samples for mass screening owing to its non-invasive and simple process of collection; however, the discovery of urinary diagnostic biomarkers for malignancies is still challenging and developing. Since urine contains abundant substances reflecting systemic body condition, urinary biomarker might contribute to detect CRC in a completely non-invasive manner. In this review, we describe the current utility of urinary diagnostic biomarkers for CRC.
  • Correction to: Pathological impact of transanal colorectal tube for obstructive colorectal cancer., Yusuke Okuda, Takaya Shimura, Hiroyuki Kato, Tomonori Yamada, Yoshikazu Hirata, Makoto Natsume, Hiroyasu Iwasaki, Ryuzo Yamaguchi, Eiji Sakamoto, Satoru Takahashi, Hiromi Kataoka, Surgical endoscopy,   2019年10月28日, 査読有り, In Methods of Abstract, the word "2015" should be changed to "2011".
  • Pathological impact of transanal colorectal tube for obstructive colorectal cancer., Yusuke Okuda, Takaya Shimura, Hiroyuki Kato, Tomonori Yamada, Yoshikazu Hirata, Makoto Natsume, Hiroyasu Iwasaki, Ryuzo Yamaguchi, Eiji Sakamoto, Satoru Takahashi, Hiromi Kataoka, Surgical endoscopy,   2019年10月17日, 査読有り, BACKGROUND: Colorectal cancer (CRC) with acute colorectal obstruction (ACO) is an emergency. Transanal colorectal tube (TCT) use can be a safe single-stage surgery with laparoscopy-assisted colectomy; it offers long-term outcomes equivalent to emergency surgery for stage-II/III CRC with ACO. Self-expanding metallic stent use, another alternative, may have detrimental pathological and molecular effects, whereas the pathological impact of TCT placement remains unclear. We hypothesized that TCT placement might exert little damage on primary tumor. Hence, the current study analyzed the pathological impact of TCT placement for CRC with ACO compared to emergency surgery. METHODS: Data from consecutive patients with stage-II/III distal CRC with ACO who underwent surgery between January 2007 and December 2015 were retrospectively reviewed at two Japanese affiliate hospitals. Inflammatory and malignant potential-related parameters were analyzed by a single blinded pathologist. We extracted mRNA from tumor tissues to analyze inflammatory cytokines. RESULTS: Sixty-eight patients with stage-II/III distal CRC with ACO were identified (surgery: 25 patients; TCT: 43 patients). Baseline characteristics were well balanced between the two groups. TCT showed a significantly lower frequency of abscess (surgery vs TCT, 36.0% vs 11.6%; P = 0.017) and a lower tendency of pathological perforation (surgery vs TCT, 20.0% vs 4.7%, respectively; P = 0.091), compared to the surgery group. There were no significant intergroup differences in oncological factors, including perineural invasion (surgery vs TCT, 52.0% vs 62.8%; P = 0.383), microlymphatic involvement (surgery vs TCT, 52.0% vs 58.1%; P = 0.623), and microvascular involvement (surgery vs TCT, 32.0% vs 25.6%; P = 0.570). No significant intergroup differences were found in interleukin (IL)-6, IL-8, or IL-1β gene expression levels (P = 0.580, 0.250, 0.941). CONCLUSIONS: TCT placement had no pathologically detrimental effects on the tumor or surrounding tissues and might be an attractive non-invasive strategy for cases of curative distal CRC with ACO.
  • Antitumor Effect of a Novel Photodynamic Therapy With Acetylated Glucose-conjugated Chlorin for Gastrointestinal Cancers., Hiroshi Ichikawa, Hirotada Nishie, Shigenobu Yano, Yuki Komai, Hiroaki Yamaguchi, Akihiro Nomoto, Taketo Suzuki, Mamoru Tanaka, Takaya Shimura, Tsutomu Mizoshita, Eiji Kubota, Satoshi Tanida, Hiromi Kataoka, Anticancer research, 39, (8) 4199 - 4206,   2019年08月, 査読有り, BACKGROUND/AIM: We previously synthesized a glucose-conjugated chlorin compound e6 (G-chlorin e6), and reported that it has very strong antitumor effects. The aim of the present study was to synthesize acetylated glucose-conjugated chlorin (AcN003HP) and evaluate its antitumor effect and excretion. MATERIALS AND METHODS: To evaluate the antitumor effect of AcN003HP, its IC50 was calculated as well as its accumulation in cancer cells was examined by flow cytometry. Confocal microscopy was used to observe the intracellular localization of AcN003HP. The excretion and antitumor effects of AcN003HP were also evaluated in vivo. RESULTS: AcN003HP showed stronger antitumor effects and accumulation into cancer cells compared to talaporfin sodium, a conventional photosensitizer. AcN003HP was localized in the endoplasmic reticulum. In a xenograft tumor mouse model, AcN003HP showed longer excretion time from the body than G-chlorin e6, and photodynamic therapy using AcN003HP showed very strong antitumor effects. CONCLUSION: The safety, improved controllability, and robust antitumor effects suggest AcN003HP as a good next-generation photosensitizer.
  • Placental growth factor is a predictive biomarker for ramucirumab treatment in advanced gastric cancer., Makoto Natsume, Takaya Shimura, Hiroyasu Iwasaki, Yusuke Okuda, Mika Kitagawa, Yasuyuki Okamoto, Kazuki Hayashi, Hiromi Kataoka, Cancer chemotherapy and pharmacology, 83, (6) 1037 - 1046,   2019年06月, 査読有り, PURPOSE: Ramucirumab (RAM) has been used as the second-line standard chemotherapy for advanced gastric cancer (AGC) either alone or combination with paclitaxel (PTX). However, no predictive biomarkers have been identified for RAM treatment in AGC. METHODS: We retrospectively identified 26 patients who received either RAM monotherapy or RAM + PTX therapy for AGC refractory to fluoropyrimidine and platinum agents from 2015 to 2018 at Nagoya City University Hospital. First, we extracted RNA using gastric cancer (GC) tissues from two responders and two non-responders, and then analyzed 24 VEGFR-related angiogenic genes. Subsequently, we examined the relationship between the expression of each angiogenic gene and RAM clinical activity in the entire cohort. Finally, we validated using in vitro angiogenesis assays using GC cells and microvascular endothelial cells. RESULTS: We identified five angiogenic genes with aberrant expression between RAM responders and non-responders and placental growth factor (PlGF) was the most significant gene among them. Overall survival (P = 0.046) and progression-free survival (P = 0.016) were significantly shorter in the PlGF-high group than in the PlGF-low group. Overall response rates were 50% in the PlGF-low group and 0% in the PlGF-high group. In GC cells co-cultured with endothelial cells, PlGF gene silencing from GC cells significantly reinforced the inhibitory effect of RAM in the in vitro angiogenesis assay (tube formation assay and endothelial migration) through the inactivation of ERK, in comparison to the control GC cells. CONCLUSIONS: PlGF gene expression in gastric cancer tissues could be a predictive indicator of AGC treatment by RAM.
  • Long-term Outcomes of One Stage Surgery Using Transanal Colorectal Tube for Acute Colorectal Obstruction of Stage II/III Distal Colon Cancer., Yusuke Okuda, Tomonori Yamada, Yoshikazu Hirata, Takaya Shimura, Ryuzo Yamaguchi, Eiji Sakamoto, Satoshi Sobue, Takahiro Nakazawa, Hiromi Kataoka, Takashi Joh, Cancer research and treatment : official journal of Korean Cancer Association, 51, (2) 474 - 482,   2019年04月, 査読有り, PURPOSE: Since oncological outcomes of transanal colorectal tube (TCT) placement, an endoscopic treatment for colorectal cancer (CRC) with acute colorectal obstruction (ACO), remain unknown, this study analyzed long-term outcomes of TCT placement for stage II/III CRC with ACO. Materials and Methods: Data were retrospectively reviewed from consecutive patients with distal stage II/III CRC who underwent surgery between January 2007 and December 2011 at two Japanese hospitals. One hospital conducted emergency surgery and the other performed TCT placement as the standard treatment for all CRCs with ACO. Propensity score (PS) matching was used to adjust baseline characteristics between two groups. RESULTS: Among 754 patients with distal stage II/III CRC, 680 did not have ACO (non-ACO group) and 74 had ACO (ACO group). The PS matching between both hospitals identified 234 pairs in the non-ACO group and 23 pairs in the ACO group. In the non-ACO group, the surgical quality was equivalent between the two institutions, with no significant differences in overall survival (OS) and disease-free survival (DFS). In the ACO group, the rate of primary resection/anastomosis was higher in the TCT group than in the surgery group (87.0% vs. 26.1%, p < 0.001). No significant differences were noted between the surgery and the TCT groups in OS (5-year OS, 61.9% vs. 51.5%; p=0.490) and DFS (5-year DFS, 45.9% vs. 38.3%; p=0.658). CONCLUSION: TCT placement can achieve similar long-term outcomes to emergency surgery, with a high rate of primary resection/anastomosis for distal stage II/III colon cancer with ACO.
  • aCGH Analysis of Predictive Biomarkers for Response to Bevacizumab plus Oxaliplatin- or Irinotecan-Based Chemotherapy in Patients with Metastatic Colorectal Cancer., Yoshihiko Fujita, Masataka Taguri, Kentaro Yamazaki, Junji Tsurutani, Kazuko Sakai, Takahiro Tsushima, Michitaka Nagase, Hiroshi Tamagawa, Shinya Ueda, Takao Tamura, Yasushi Tsuji, Kohei Murata, Koichi Taira, Tadamichi Denda, Toshikazu Moriwaki, Sadao Funai, Takako Eguchi Nakajima, Kei Muro, Akihito Tsuji, Motoki Yoshida, Koichi Suyama, Takuya Kurimoto, Naotoshi Sugimoto, Eishi Baba, Nobuhiko Seki, Mikio Sato, Takaya Shimura, Narikazu Boku, Ichinosuke Hyodo, Takeharu Yamanaka, Kazuto Nishio, The oncologist, 24, (3) 327 - 337,   2019年03月, 査読有り, BACKGROUND: The randomized phase III study (WJOG4407G) showed equivalent efficacy between FOLFOX and FOLFIRI in combination with bevacizumab as the first-line treatment for metastatic colorectal cancer (mCRC). We studied whole genome copy number profiles using array-based comparative genomic hybridization (aCGH) analysis of tumor tissue samples obtained in this study. The aim of this study was to identify gene copy number alterations that could aid in selecting either FOLFOX or FOLFIRI in combination with bevacizumab for patients with mCRC. MATERIALS AND METHODS: DNA was purified from 154 pretreatment formalin-fixed paraffin-embedded tissue samples (75 from the FOLFOX arm and 79 from the FOLFIRI arm) of 395 patients enrolled in the WJOG4407G trial and analyzed by aCGH. Genomic regions greater than 1.2-fold were regarded as copy number gain (CNG). RESULTS: Patient characteristics between the treatment arms were well balanced except for tumor laterality (left side; 64% in FOLFOX arm and 80% in FOLFIRI arm, p = .07). FOLFIRI showed a trend toward better response rate (RR), progression-free survival (PFS) and overall survival (OS) than FOLFOX in the patients with CNG of chromosome 8q24.1 (Fisher's exact test, p = .134 for RR; interaction test, p = .102 for PFS and p = .003 for OS) and 8q24.2 (Fisher's exact test, p = .179 for RR; interaction test, p = .144 for PFS and p = .002 for OS). CONCLUSION: Chromosome 8q24.1-q24.2 may contain genes that could potentially serve as predictive markers for selecting either FOLFOX or FOLFIRI in combination with bevacizumab for treatment of patients with mCRC. IMPLICATIONS FOR PRACTICE: Bevacizumab has been used as a standard first-line treatment for patients with metastatic colorectal cancer (mCRC) in combination with either oxaliplatin-based or irinotecan-based chemotherapy. Until now, there has been no predictive marker to choose between the two combination chemotherapies. This array-based comparative genomic hybridization analysis revealed that the difference in therapeutic effect between the two combination chemotherapies is prominent in patients with mCRC with gene copy number gain in chromosome 8p24.1-p24.2. Such patients showed more favorable response and survival when treated with irinotecan-based combination chemotherapy. Overlapping genes commonly found in this region may be predictive biomarkers of the efficacy of the combination chemotherapy with bevacizumab.
  • Urinary Cysteine-Rich Protein 61 and Trefoil Factor 3 as Diagnostic Biomarkers for Colorectal Cancer., Takaya Shimura, Hiroyasu Iwasaki, Mika Kitagawa, Masahide Ebi, Tamaki Yamada, Tomonori Yamada, Takahito Katano, Hirotada Nisie, Yasuyuki Okamoto, Keiji Ozeki, Tsutomu Mizoshita, Hiromi Kataoka, Translational oncology, 12, (3) 539 - 544,   2019年03月, 査読有り, Since a fecal occult blood test for colorectal cancer (CRC) does not offer sufficient diagnostic power for CRC, novel non-invasive biomarkers are hopeful for CRC screening. We conducted the current study to discover non-invasive urinary biomarkers for diagnosing CRC. Among urine samples from 258 patients (CRC, n = 148; healthy controls, n = 110), a cohort of 176 patients composed of 88 patients with GC and 88 healthy controls was selected after age- and sex-matching using propensity score. This cohort was then randomly divided into 2 groups: 53 pairs (106 patients) in the training cohort, and 35 pairs (70 patients) in the validation cohort. No significant differences were found for baseline characteristics between the CRC and healthy control groups in both training and validation cohorts. On multivariate analysis in the training cohort, urinary levels of cysteine-rich protein 61 (uCyr61) and trefoil factor 3 (uTFF3) were identified as independent significant diagnostic markers for CRC. Moreover, uCyr61 alone and the combination of uCyr61 and uTFF3 allowed significant differentiation between healthy controls and CRC groups in the training set (uCyr61: area under the curve (AUC) = 0.745 [95% CI, 0.653-0.838]; uCyr61 + uTFF3: AUC = 0.753 [95% CI, 0.659-0.847]). In the validation cohort, uCyr61 and uTFF3 were significantly higher in the CRC group than in the healthy control group, and they also allowed significant differentiation between healthy control and CRC groups (uCyr61: AUC = 0.696 [95% CI, 0.571-0.822]; uTFF3: AUC = 0.639 [95% CI, 0.508-0.770]; uCyr61 + uTFF3: AUC = 0.720 [95% CI, 0.599-0.841]), as in the training cohort. A panel combining uCyr61 and uTFF3 offers a promising non-invasive biomarker for diagnosing CRC.
  • Colorectal obstruction is a potential prognostic factor for stage II colorectal cancer., Yusuke Okuda, Takaya Shimura, Tomonori Yamada, Yoshikazu Hirata, Ryuzo Yamaguchi, Eiji Sakamoto, Hiromi Kataoka, International journal of clinical oncology, 23, (6) 1101 - 1111,   2018年12月, 査読有り, BACKGROUND: Obstructive colorectal cancer (CRC) is an emergency situation with high morbidity and mortality, but long-term outcomes of stage II/III obstructive CRC remain unclear. The aim of this study was to evaluate prognostic factors, including colorectal obstruction. METHODS: Data were retrospectively reviewed from consecutive patients with stage II/III CRC who underwent curative surgery between January 2007 and December 2011 at two Japanese institutions. We analyzed overall survival (OS) and relapse-free survival (RFS), according to various prognostic factors including colorectal obstruction. RESULTS: In total, 979 patients with stage II/III CRC were identified for this study. Among these 979 patients, 94 patients showed colorectal obstruction (9.6%). In both stage II and stage III CRCs, colorectal obstruction showed significantly poorer OS and RFS compared to non-obstruction (5-year OS, obstruction vs. non-obstruction, stage II: 65.9 vs. 86.5%, P = 0.002; stage III: 55.9 vs. 73.6%, P = 0.007) (5-year RFS, obstruction vs. non-obstruction, stage II: 59.2 vs. 77.8%, P = 0.008; stage III 31.3 vs. 56.3%, P = 0.001). Multivariate analysis demonstrated colorectal obstruction as a significant independent and poor prognostic factor in terms of both OS (hazard ratio (HR) 2.469; 95% CI 1.339-4.545; P = 0.004) and RFS (HR 1.992; 95% CI 1.160-3.425; P = 0.012) for stage II CRC, as well as pT4 stage. On multivariate analysis for stage III CRC, colorectal obstruction was a significant predictor of poor RFS (HR 1.626; 95% CI 1.070-2.469; P = 0.023), but not poor OS. CONCLUSIONS: Colorectal obstruction is an independent poor prognostic factor for stage II CRC. Adjuvant chemotherapy might be feasible for stage II CRC with colorectal obstruction.
  • Endoscopic submucosal resection with an endoscopic variceal ligation device for the treatment of rectal neuroendocrine tumors., Masahide Ebi, Shoko Nakagawa, Yoshiharu Yamaguchi, Yasuhiro Tamura, Shinya Izawa, Yasutaka Hijikata, Takaya Shimura, Yasushi Funaki, Naotaka Ogasawara, Makoto Sasaki, Takashi Joh, Kunio Kasugai, International journal of colorectal disease, 33, (12) 1703 - 1708,   2018年12月, 査読有り, BACKGROUND: Endoscopic resection is recommended for rectal neuroendocrine tumors < 1 cm in diameter; the three techniques (mucosal resection, submucosal dissection, and mucosal resection with variceal ligation device) of endoscopic resection of neuroendocrine tumor were reported; however, the optimal endoscopic technique remains unclear. PURPOSE: We compared the efficacy and safety of three endoscopic rectal neuroendocrine tumor resection methods. METHODS: We retrospectively enrolled 52 patients with rectal neuroendocrine tumors treated by endoscopy at Aichi Medical University Hospital and Nagoya City University Hospital between May 2003 and June 2017. We compared clinical outcomes in three groups based on the endoscopic treatment method. RESULTS: Fifty-two patients underwent endoscopic rectal neuroendocrine tumor treatment (mucosal resection, 14; submucosal dissection, 19; mucosal resection with an endoscopic variceal ligation device, 19). In the endoscopic mucosal resection, submucosal dissection, and mucosal resection with variceal ligation device groups, R0 resection occurred in 50.0, 94.7, and 89.5%, respectively (mucosal resection vs. mucosal resection with variceal ligation device, p < 0.05; mucosal resection vs. submucosal dissection, p < 0.01), while the median procedure times were 6.5, 43, and 6.0 min, respectively (submucosal dissection vs. mucosal resection with variceal ligation device procedure times, p < 0.01; mucosal resection vs. submucosal resection procedure times, p < 0.01). Postoperative bleeding occurred after endoscopic mucosal resection (1/14) and endoscopic submucosal dissection (4/19), but not after endoscopic mucosal resection with a ligation device. CONCLUSION: Endoscopic mucosal resection with an endoscopic variceal ligation device was a safe, effective treatment for rectal neuroendocrine tumors.
  • Refractory gastric antral ulcers without Helicobacter pylori infection and non-steroidal anti-inflammatory drugs., Hirotada Nishie, Hiromi Kataoka, Hiroyuki Kato, Taketo Suzuki, Hiroshi Ichikawa, Yu Nojiri, Mika Kitagawa, Yusuke Inagaki, Hiroyasu Iwasaki, Mamoru Tanaka, Takahito Katano, Yasuyuki Okamoto, Keiji Ozeki, Tsutomu Mizoshita, Takaya Shimura, Eiji Kubota, Satoshi Tanida, Takashi Joh, Clinical journal of gastroenterology, 11, (3) 251 - 256,   2018年06月, 査読有り, Herein, we describe a rare case of refractory gastric antral ulcers. A woman in her 50 s was admitted to Nagoya City University Hospital with epigastric pain after being diagnosed with gastric antral submucosal tumor at another hospital. Findings from esophagogastroduodenoscopy and endoscopic ultrasound examination revealed that the lesion was a gastric ulcer. The patient had no Helicobacter pylori infection and no recent history of using non-steroidal anti-inflammatory drugs. On the basis of these findings, we diagnosed this as a case of refractory gastric antral ulcer (RGAU). RGAU is considered a new disease concept and detailed analyses are expected in the future.
  • Combination Therapy With Intensive Granulocyte and Monocyte Adsorptive Apheresis Plus Ustekinumab in Patients With Refractory Crohn's Disease., Satoshi Tanida, Tsutomu Mizoshita, Keiji Ozeki, Takahito Katano, Mamoru Tanaka, Hirotada Nishie, Takaya Shimura, Yasuyuki Okamoto, Eiji Kubota, Hiromi Kataoka, Takashi Joh, Therapeutic apheresis and dialysis : official peer-reviewed journal of the International Society for Apheresis, the Japanese Society for Apheresis, the Japanese Society for Dialysis Therapy, 22, (3) 295 - 300,   2018年06月, 査読有り, Ustekinumab is applied to induce clinical remission in patients with Crohn's disease. Granulocyte and monocyte absorptive apheresis depletes activated myeloid lineage leukocytes and has been applied for active Crohn's disease. This study retrospectively examined the efficacy and safety of combining intensive granulocyte and monocyte absorptive apheresis and ustekinumab for remission induction therapy in refractory Crohn's disease. Between June and September 2017, three consecutive cases (two females) with refractory Crohn's disease were treated with intensive granulocyte and monocyte absorptive apheresis plus ustekinumab. Crohn's disease activity index, and simple endoscopic score for Crohn's disease at baseline and 10 weeks were applied as treatment efficacy outcomes. In all three cases, at week 10, clinical remission was achieved, while simple endoscopic score for Crohn's disease reflected no improvement. Thus, combination therapy with intensive granulocyte and monocyte absorptive apheresis plus ustekinumab appeared to represent a safe and effective intervention for inducing clinical remission.
  • Excellent antitumor effects for gastrointestinal cancers using photodynamic therapy with a novel glucose conjugated chlorin e6., Hirotada Nishie, Hiromi Kataoka, Shigenobu Yano, Hiroaki Yamaguchi, Akihiro Nomoto, Mamoru Tanaka, Akihisa Kato, Takaya Shimura, Tsutomu Mizoshita, Eiji Kubota, Satoshi Tanida, Takashi Joh, Biochemical and biophysical research communications, 496, (4) 1204 - 1209,   2018年02月19日, 査読有り, BACKGROUND: Photodynamic therapy (PDT) exploits the reaction between photosensitizer and irradiated light to generate potentially therapeutic reactive oxygen species such as singlet oxygen in cancer cells. We have reported several sugar-conjugated chlorins that express stronger antitumor effects in PDT than talaporfin sodium (TS), a second-generation photosensitizer clinically used in Japan. In this study, we developed a novel glucose-conjugated chlorin e6 (G-chlorin e6) and evaluated its antitumor effects. METHODS: G-chlorin e6 was synthesized with a core photosensitizer chlorin e6 conjugated to glucose. We measured the half maximal inhibitory concentration (IC50) to compare the PDT effects of G-chlorin e6 and TS, and flow cytometry was performed to examine the accumulation of G-chlorin e6 in cancer cells. We also compared the accumulation of G-chlorin e6 between normal immortalized esophageal epithelial cells and esophageal cancer cells. Antitumor effects of G-chlorin e6 PDT were finally analyzed in allograft tumor mouse models. RESULTS: PDT in vitro using G-chlorin e6 elicited 9, 000-34,000 times stronger antitumor effects than TS, and there was 70-190 times more G-chlorin e6 accumulated than TS by flow cytometry. G-chlorin e6 accumulated more selectively in esophageal cancer cells than in esophageal immortalized epithelial cells, and in an allograft model, PDT with G-chlorin e6 showed very strong antitumor effects and a 40% complete response (CR) rate. CONCLUSIONS: G-chlorin e6 showed excellent tumor selectivity, and PDT using G-chlorin e6 revealed the strongest anti-tumor effects among all sugar-conjugated chlorins that we have studied. G-chlorin e6 is considered to be the best photosensitizer for next-generation PDT.
  • Expression and subcellular localization of AT motif binding factor 1 in colon tumours., Hiromi Kataoka, Yutaka Miura, Makoto Kawaguchi, Shugo Suzuki, Yasuyuki Okamoto, Keiji Ozeki, Takaya Shimura, Tsutomu Mizoshita, Eiji Kubota, Satoshi Tanida, Satoru Takahashi, Kiyofumi Asai, Takashi Joh, Molecular medicine reports, 16, (3) 3095 - 3102,   2017年09月, 査読有り, AT motif binding factor 1 (ATBF1) is a transcriptional regulator that functions as a tumour suppressor to negatively affect cancer cell growth. In the present study four specific polyclonal antibodies against ATBF1 were generated, and the expression and intracellular localization of ATBF1 in colonic mucosae, polyps, adenoma and adenocarcinoma tissue samples were investigated. The four polyclonal antibodies produced were as follows: MB34 and MB49, which recognize the N‑ and C‑terminal fragments of ATBF1, respectively; and D1‑120 and MB44, which recognize the middle fragments of ATBF1 that contain three nuclear localization signals (NLS). In total, 191 colon samples were examined by immunohistochemical analysis. In addition, colon cancer cells were transfected with four ATBF1 expression vectors, and the subcellular localization of each fragment was examined. Normal colon mucosal cells were not observed to express ATBF1. However, a small number of hyperplastic polyps, serrated adenomas and tubular adenomas expressed ATBF1. Colon cancer cells were observed to express D1‑120‑ and MB44‑reactive middle fragments of ATBF1 in their cell nuclei. However, the N‑ and C‑terminal fragments of ATBF1 did not translocate to the nucleus. Transfection of ATBF1 fragments revealed cleavage of the ATBF1 protein and nuclear translocation of the cleaved middle portion containing the NLS. A positive correlation between the cytoplasmic localization of the N‑ and C‑termini of ATBF1, nuclear localization of the middle portion of ATBF1 and malignant cancer cell invasion was observed. In conclusion, the results of the present study suggest that alterations in the expression and subcellular localization of ATBF1, as a result of post‑transcriptional modifications, are associated with malignant features of colon tumours.
  • Ectopic Gastric and Intestinal Phenotypes, Neuroendocrine Cell Differentiation, and SOX2 Expression Correlated With Early Tumor Progression in Colorectal Laterally Spreading Tumors., Takahito Katano, Tsutomu Mizoshita, Hironobu Tsukamoto, Hirotada Nishie, Yusuke Inagaki, Noriyuki Hayashi, Satoshi Nomura, Keiji Ozeki, Yasuyuki Okamoto, Takaya Shimura, Yoshinori Mori, Eiji Kubota, Satoshi Tanida, Hiromi Kataoka, Toshiya Kuno, Satoru Takahashi, Takashi Joh, Clinical colorectal cancer, 16, (2) 141 - 146,   2017年06月, 査読有り, INTRODUCTION: The significance of the ectopic gastric phenotype remains unclear in patients with colorectal laterally spreading tumors (LSTs). We investigated clinicopathologic differences among LST subtypes, aiming to identify factors indicative of malignant transformation and invasion that are linked to ectopic gastric phenotype and tumor progression. MATERIALS AND METHODS: We analyzed the morphologic characteristics of 105 colorectal LSTs resected by endoscopic submucosal dissection. LSTs were classified into 2 subtypes: granular (G-LST) and nongranular (NG-LST). Resected LSTs were analyzed histologically and were immunohistochemically stained for MUC5AC, MUC6, chromogranin A, CD10, and SOX2. RESULTS: The 105 LSTs included 60 G-LSTs and 45 NG-LSTs. By histology, G-LSTs comprised 5 adenomas with low-grade dysplasia (LAs), 45 adenomas with high-grade dysplasia (HAs), and 10 adenocarcinomas invading the submucosa (SMs). NG-LSTs comprised 8 LAs, 25 HAs, and 12 SMs. MUC5AC positivity was significantly higher in G-LSTs compared to NG-LSTs (P = .002), and MUC5AC positivity in HA lesions was significantly higher than in LA lesions (P = .01). MUC6 and SOX2 positivity in SM G-LSTs, and chromogranin A positivity in SM NG-LSTs were significantly higher than in HAs (P = .01, .01, and .03, respectively). CD10 positivity in SM NG-LSTs was significantly higher than in HAs and LAs (P = .02 and .01, respectively). CONCLUSION: Ectopic gastric and intestinal phenotypes, neuroendocrine cell differentiation, and SOX2 expression differ according to tumor grade in colorectal LSTs, and these markers are correlated with early tumor progression in each LST subtype.
  • Adalimumab therapy in a patient with Crohn's disease with a giant pelvic paraganglioma after chemotherapy., Tsutomu Mizoshita, Masashi Ando, Hiroyuki Sagawa, Yoshinori Mori, Takahito Katano, Keiji Ozeki, Satoshi Tanida, Yasuyuki Okamoto, Takaya Shimura, Eiji Kubota, Hiromi Kataoka, Takeshi Kamiya, Takashi Joh, Clinical journal of gastroenterology, 10, (3) 250 - 254,   2017年06月, 査読有り, A 23-year-old man was diagnosed with a giant pelvic paraganglioma in September 2013, and a 6-month chemotherapy course was performed. The chemotherapy resulted in stable disease of the tumor for about 1 year. However, in April 2015, the patient complained of fever and diarrhea of more than ten times a day. Endoscopy showed serpiginous (snake-like) ulcers in the cecum, ascending, descending, and sigmoid colons, with granulomas without caseation histologically. The patient was diagnosed with the active stage of Crohn's disease (CD) in June 2015. Oral mesalazine (3000 mg/day) and an elemental diet (900 kcal/day) led to temporary clinical remission. At the beginning of January in 2016, an abdominal abscess and fistula were detected by computed tomography, which needed surgical treatment. Adalimumab administration was started at the beginning of February, since active lesions were detected endoscopically. A second endoscopy showed improvement of the inflammatory lesions 3 months after induction therapy with adalimumab. Clinical remission has been maintained with adalimumab administration, with stable disease of the tumor and no adverse events. To the best of our knowledge, this is the first report of a patient with a paraganglioma who developed CD after chemotherapy. The patient was successfully treated with adalimumab after surgery for his CD.
  • Urinary kallikrein 10 predicts the incurability of gastric cancer., Takaya Shimura, Masahide Ebi, Tomonori Yamada, Tamaki Yamada, Takahito Katano, Yu Nojiri, Hiroyasu Iwasaki, Satoshi Nomura, Noriyuki Hayashi, Yoshinori Mori, Hiromi Kataoka, Marsha A Moses, Takashi Joh, Oncotarget, 8, (17) 29247 - 29257,   2017年04月25日, 査読有り, The current imaging modalities are not sufficient to identify inoperable tumor factors, including distant metastasis and local invasion. Hence, we conducted this study using urine samples to discover non-invasive biomarkers for the incurability of gastric cancer (GC). Urine samples from 111 GC patients were analyzed in this study. The GC cohort was categorized and analyzed according to disease stage and operability. In the discovery phase, protease protein array analysis identified 3 potential candidate proteins that were elevated in the urine of advanced GC patients compared to early GC patients. Among them, urinary kallikrein 10 (KLK10) was positively associated with tumor stage progression. Moreover, the urinary level of KLK10 (uKLK10) was significantly elevated in the urine of patients with inoperable GC compared to operable GC patients (median, 118 vs. 229; P=0.014). The combination of uKLK10, tumor location and tumor size distinguished operability of GC with an area under the curve of 0.859, 82.4% sensitivity and 86.2% specificity. Disease-free survival (DFS) was significantly shorter in GC patients with high uKLK10 compared to those with low uKLK10 (hazard ratio: 3.30 [95% confidence interval, 1.58-6.90] P<0.001). Immunohistochemical analyses also demonstrated a positive correlation between tumor stage and KLK10 expression in GC tissues (r=0.426, P<0.001). In addition, GC patients with high expression of pathological KLK10 (pKLK10) showed a significantly shorter DFS compared to those with low pKLK10 (hazard ratio: 3.79 [95% confidence interval, 1.27-11.24] P=0.010). uKLK10 is a promising non-invasive biomarker for the inoperability and incurability of GC.
  • Anticancer Effects of a New Aminosugar-conjugated Platinum Complex Agent Against Cisplatin-resistant Gastric Cancer., Noriyuki Hayashi, Hiromi Kataoka, Shigenobu Yano, Jun-Ichi Kikuchi, Mamoru Tanaka, Hirotada Nishie, Yuma Kinoshita, Miki Hatano, Akihiro Nomoto, Akiya Ogawa, Masahiro Inoue, Tsutomu Mizoshita, Takaya Shimura, Yoshinori Mori, Eiji Kubota, Satoshi Tanida, Takashi Joh, Anticancer research, 36, (11) 6005 - 6009,   2016年11月, 査読有り, BACKGROUND/AIM: Resistance against cisplatin is a problem for the success of gastric cancer chemotherapy. Herein, we evaluated the antitumor effect of a new aminosugar-conjugated, mono-functional platinum complex (Pt-Oqn), which forms a single covalent bond with DNA. MATERIALS AND METHODS: We compared the cytotoxicity of Pt-Oqn to that of cisplatin (CDDP), oxaliplatin (L-OHP) and carboplatin (CBDCA). We also compared Pt-Oqn and cisplatin for DNA double-strand breaks based on phosphorylated histone H2AX levels in cancer cells and antitumor effects in xenograft models. RESULTS: The resistance factor (RF) for Pt-Oqn was low among the four drugs, indicating the potential of Pt-Oqn for overcoming CDDP-induced resistance. In MKN45-R cells, γ-H2AX protein increased following treatment with Pt-Oqn, but not with cisplatin. Finally, Pt-Oqn, but not cisplatin, showed significant antitumor effects in MKN45-R xenografts. CONCLUSION: This new aminosugar-conjugated platinum complex is a promising candidate agent for overcoming the drug resistance of cisplatin-resistant stomach cancer.
  • Randomized phase III study of bevacizumab plus FOLFIRI and bevacizumab plus mFOLFOX6 as first-line treatment for patients with metastatic colorectal cancer (WJOG4407G)., K Yamazaki, M Nagase, H Tamagawa, S Ueda, T Tamura, K Murata, T Eguchi Nakajima, E Baba, M Tsuda, T Moriwaki, T Esaki, Y Tsuji, K Muro, K Taira, T Denda, S Funai, K Shinozaki, H Yamashita, N Sugimoto, T Okuno, T Nishina, M Umeki, T Kurimoto, T Takayama, A Tsuji, M Yoshida, A Hosokawa, Y Shibata, K Suyama, M Okabe, K Suzuki, N Seki, K Kawakami, M Sato, K Fujikawa, T Hirashima, T Shimura, K Taku, T Otsuji, F Tamura, E Shinozaki, K Nakashima, H Hara, T Tsushima, M Ando, S Morita, N Boku, I Hyodo, Annals of oncology : official journal of the European Society for Medical Oncology, 27, (8) 1539 - 46,   2016年08月, 査読有り, BACKGROUND: FOLFIRI and FOLFOX have shown equivalent efficacy for metastatic colorectal cancer (mCRC), but their comparative effectiveness is unknown when combined with bevacizumab. PATIENTS AND METHODS: WJOG4407G was a randomized, open-label, phase III trial conducted in Japan. Patients with previously untreated mCRC were randomized 1:1 to receive either FOLFIRI plus bevacizumab (FOLFIRI + Bev) or mFOLFOX6 plus bevacizumab (mFOLFOX6 + Bev), stratified by institution, adjuvant chemotherapy, and liver-limited disease. The primary end point was non-inferiority of FOLFIRI + Bev to mFOLFOX6 + Bev in progression-free survival (PFS), with an expected hazard ratio (HR) of 0.9 and non-inferiority margin of 1.25 (power 0.85, one-sided α-error 0.025). The secondary end points were response rate (RR), overall survival (OS), safety, and quality of life (QoL) during 18 months. This trial is registered to the University Hospital Medical Information Network, number UMIN000001396. RESULTS: Among 402 patients enrolled from September 2008 to January 2012, 395 patients were eligible for efficacy analysis. The median PFS for FOLFIRI + Bev (n = 197) and mFOLFOX6 + Bev (n = 198) were 12.1 and 10.7 months, respectively [HR, 0.905; 95% confidence interval (CI) 0.723-1.133; P = 0.003 for non-inferiority]. The median OS for FOLFIRI + Bev and mFOLFOX6 + Bev were 31.4 and 30.1 months, respectively (HR, 0.990; 95% CI 0.785-1.249). The best overall RRs were 64% for FOLFIRI + Bev and 62% for mFOLFOX6 + Bev. The common grade 3 or higher adverse events were leukopenia (11% in FOLFIRI + Bev/5% in mFOLFOX6 + Bev), neutropenia (46%/35%), diarrhea (9%/5%), febrile neutropenia (5%/2%), peripheral neuropathy (0%/22%), and venous thromboembolism (6%/2%). The QoL assessed by FACT-C (TOI-PFC) and FACT/GOG-Ntx was favorable for FOLFIRI + Bev during 18 months. CONCLUSION: FOLFIRI plus bevacizumab was non-inferior for PFS, compared with mFOLFOX6 plus bevacizumab, as the first-line systemic treatment for mCRC. CLINICAL TRIALS NUMBER: UMIN000001396.
  • Immunogenic cell death due to a new photodynamic therapy (PDT) with glycoconjugated chlorin (G-chlorin)., Mamoru Tanaka, Hiromi Kataoka, Shigenobu Yano, Takuya Sawada, Haruo Akashi, Masahiro Inoue, Shugo Suzuki, Yusuke Inagaki, Noriyuki Hayashi, Hirotada Nishie, Takaya Shimura, Tsutomu Mizoshita, Yoshinori Mori, Eiji Kubota, Satoshi Tanida, Satoru Takahashi, Takashi Joh, Oncotarget, 7, (30) 47242 - 47251,   2016年07月26日, 査読有り, Both the pre-apoptotic exposure to calreticulin (CRT) and the post-apoptotic release of high-mobility group box 1 protein (HMGB1) are required for immunogenic cell death. Photodynamic therapy (PDT) uses non-toxic photosensitizers and visible light at a specific wavelength in combination with oxygen to produce cytotoxic reactive oxygen species that kill malignant cells by apoptosis and/or necrosis, shut down the tumor microvasculature, and stimulate the host immune system. We have previously shown that glycoconjugated chlorin (G-chlorin) has superior cancer cell selectivity and effectively suppresses the growth of xenograft tumors. In the present study, we evaluated the immunogenicity of PDT with G-chlorin treatment in colon cancer cells. PDT with G-chlorin suppressed CT26 (mouse colon cancer cells) tumor growth considerably more efficiently in immunocompetent mice (wild-type mice, allograft model) than in immune-deficient mice (nude mice, xenograft model), although control treatments were not different between the two. This treatment also induced CRT translocation and HMGB1 release in cells, as shown by western blot and immunofluorescence staining. To evaluate the use of PDT-treated cells as a tumor vaccine, we employed a syngeneic mouse tumor model (allograft model). Mice inoculated with PDT-treated CT26 cells were significantly protected against a subsequent challenge with live CT26 cells, and this protection was inhibited by siRNA for CRT or HMGB1. In conclusion, PDT with G-chlorin treatment induced immunogenic cell death in a mouse model, where the immunogenicity of this treatment was directed by CRT expression and HMGB1 release.
  • Long-Term Clinical Remission in Biologically Naïve Crohn's Disease Patients with Adalimumab Therapy, Including Analyses of Switch from Adalimumab to Infliximab., Mizoshita T, Tanida S, Ozeki K, Katano T, Shimura T, Mori Y, Kubota E, Kataoka H, Kamiya T, Joh T, Case Rep Gastroenterol., 10, (2) 283 - 91,   2016年06月14日, 査読有り, There is little evidence regarding the maintenance of long-term clinical remission by adalimumab (ADA) therapy in Crohn's disease (CD) patients naïve to anti-tumor necrosis factor treatment (naïve CD patients), since most CD patients are treated with ADA after infliximab (IFX) therapy. The long-term clinical response to ADA was retrospectively analyzed in 17 naïve CD patients for at least 24 months, and the serum trough IFX levels were evaluated in patients switching from ADA to IFX. Of the 17 naïve CD patients, 14 (82.4%) maintained long-term clinical remission with ADA therapy for at least 24 months, without serious adverse events. The clinical condition of 7 patients was observed for more than 36 months, and 3, 1, 1, and 2 cases maintained remission at months 42, 48, 54, and 60 after ADA therapy, respectively. Three patients (17.6%) switched from ADA to IFX less than 24 months after the start of ADA therapy, and they had remission, retaining trough levels of IFX higher than 1 μg/ml, occasionally by dose escalation. In conclusion, maintenance ADA therapy achieves long-term clinical remission in naïve CD patients. Switching from ADA to IFX is an important therapeutic option in CD patients showing loss of response to ADA, occasionally with dose escalation, based on the analysis of serum IFX trough levels.
  • A phase II prospective study of the trastuzumab combined with 5-weekly S-1 and CDDP therapy for HER2-positive advanced gastric cancer., Hiromi Kataoka, Yoshinori Mori, Takaya Shimura, Hirotada Nishie, Makoto Natsume, Hisato Mochizuki, Yoshikazu Hirata, Satoshi Sobue, Takashi Mizushima, Hitoshi Sano, Yusuke Mizuno, Makoto Nakamura, Atsuyuki Hirano, Kenji Tsuchida, Kazunori Adachi, Kyoji Seno, Mika Kitagawa, Takashi Kawai, Takashi Joh, Cancer chemotherapy and pharmacology, 77, (5) 957 - 62,   2016年05月, 査読有り, BACKGROUND: We evaluated the efficacy and safety of 5-weekly S-1 and cisplatin combined with trastuzumab, a monoclonal antibody against human epidermal growth factor receptor type 2 (HER2) for HER2-positive advanced gastric cancer (AGC). METHODS: This phase II study treatment consisted of S-1 (80-120 mg per day) orally on day 1-21, cisplatin (60 mg/m(2)) intravenously on day 8, and trastuzumab (8 mg/kg on day 1 of the first cycle, followed by 6 mg/kg every 3 weeks) intravenously. The primary end point was 1-year survival rate. The secondary end points included overall survival, progression-free survival (PFS), response rate (RR), and safety. RESULTS: A total 22 patients from seven centers were enrolled. In the 20 patients evaluable for analysis, the 1-year survival rate was 70 % (95 % confidence interval (CI) 49.9-90.1 %), and median survival time, PFS, and RR were 15.3, 7.5 months and 41.2 %, respectively. Major grade 3/4 adverse events were neutropenia (30 %), anorexia (30 %), leukopenia (25 %), fatigue (20 %), and anemia (15 %). CONCLUSIONS: Five-weekly S-1 and cisplatin combined with trastuzumab showed effective with favorable safety profile in patients with HER2-positive AGC.
  • Evidence-based Clinical Management of Acute Malignant Colorectal Obstruction., Takaya Shimura, Takashi Joh, Journal of clinical gastroenterology, 50, (4) 273 - 85,   2016年04月, 査読有り, Acute malignant colorectal obstruction (AMCO) is an emergency associated with colorectal cancer (CRC). Emergency surgery is standard therapy for AMCO, and 1-stage surgery without colostomy is preferable, but it is occasionally difficult in the emergency setting. A self-expandable metallic stent (SEMS) enables noninvasive colonic decompression and subsequent 1-stage surgery, which has been widely applied for CRC with AMCO. However, recent accumulation of high-quality evidence has highlighted some problems and the limited efficacy of SEMS for AMCO. In palliative settings, SEMS placement reduces hospital stay and short-term complication rates, whereas it increases the frequency of long-term complications, such as delayed perforation. SEMS placement does not seem compatible with recent standard chemotherapy including bevacizumab. As a bridge to surgery, while SEMS placement provides a lower clinical success rate than emergency surgery, it can facilitate primary anastomosis without stoma. However, evidence regarding long-term survival outcomes with SEMS in both palliative and bridge to surgery settings is lacking. The efficacy of transanal colorectal tube placement, another endoscopic treatment, has been reported, but its clinical evidence level is low due to the limited number of studies. This review article comprehensively summarizes the current knowledge about surgical and endoscopic management of CRC with AMCO.
  • Long-Term Efficacy of Adalimumab in Patients With Intestinal Behcet's Disease: Eight Consecutive Cases., Satoshi Tanida, Tsutomu Mizoshita, Hirotada Nishie, Keiji Ozeki, Takahito Katano, Takaya Shimura, Eiji Kubota, Hiromi Kataoka, Takeshi Kamiya, Takashi Joh, Journal of clinical medicine research, 8, (4) 334 - 7,   2016年04月, 査読有り, The long-term efficacy and safety of adalimumab (ADA) for the treatment of intestinal Behcet's disease (BD) in the clinical setting have not been evaluated previously. This retrospective study evaluated the 52-week efficacy of ADA in BD patients. A total of eight patients who were refractory to conventional therapy were given ADA (160/80/40 mg every other week). Marked improvement (MI) was achieved by 10 weeks in five patients (62.5%), and by 52 weeks in six patients (75%). In addition, complete remission was obtained in two patients (25%) at both 10 and 52 weeks. Improvement of global gastrointestinal (GI) symptoms to score 0 was observed in three patients (37.5%) at 10 weeks and four patients (50%) at 52 weeks. Moreover, improvement of endoscopic assessment to score 0 was also seen in four patients (50%) at both 10 and 52 weeks. No adverse events were observed in any patients during the 52 weeks. In conclusion, ADA offers an effective, well-tolerated treatment for intestinal BD in patients who are refractory to conventional therapy.
  • Autonomic nervous responses in colorectal polypectomy: Randomized controlled trial comparing air and carbon dioxide insufflation., Kenji Murakami, Hiromi Kataoka, Junichiro Hayano, Hidekatsu Fukuta, Yoshinori Mori, Hirotaka Nishiwaki, Tsutomu Mizoshita, Mamoru Tanaka, Yasuyuki Okamoto, Takaya Shimura, Yoshikazu Hirata, Takashi Mizushima, Masahide Ebi, Takashi Joh, Digestive endoscopy : official journal of the Japan Gastroenterological Endoscopy Society, 28, (2) 203 - 9,   2016年03月, 査読有り, BACKGROUND AND AIM: Carbon dioxide (CO2) insufflation devices are commonly used for endoscopic examination and treatment. In this prospective randomized controlled trial (RCT), we compared patient acceptance, cardiovascular tolerance,and autonomic nervous responses between patients receiving air insufflation and CO2 insufflation. METHODS: We initially enrolled 170 patients and, of these, 158 patients in total were analyzed (air group, 83; CO2 group, 75). Autonomic nervous responses were evaluated by analysis of heart rate variability (HRV). Primary end point was superiority in the effects of CO2 insufflation on the autonomic nervous system by HRV analysis. RESULTS: Visual analog scale disclosed significantly less abdominal pain and abdominal fullness with CO2. Percentage heart rate change rate at 1 h and 4 h after the procedure was also significantly lower in the CO2 group than in the air group (1 h after: P < 0.01, 4 h after: P < 0.05). Comparison based on age showed that % heart rate change was significantly lower in the younger CO2 patients (just after colonoscopy and 1 h after: P < 0.01, 4 h after: P < 0.05), but this difference was not apparent in an older group of patients. CONCLUSIONS: This is the first RCT showing that colorectal polypectomy using CO2 insufflation significantly decreases abdominal pain and abdominal fullness common in such patients with lowered stress to the autonomous nervous system. The effects using CO2 insufflation on the sympathetic nervous system also seemed to be more prominent among younger patients.
  • Organizing Pneumonia in a Patient with Quiescent Crohn's Disease., Satoshi Tanida, Masaya Takemura, Tsutomu Mizoshita, Keiji Ozeki, Takahito Katano, Takaya Shimura, Yoshinori Mori, Eiji Kubota, Hiromi Kataoka, Takeshi Kamiya, Takashi Joh, Case reports in gastrointestinal medicine, 2016, 8129864 - 8129864,   2016年, 査読有り, A 64-year-old man with Crohn's disease (CD) was admitted to our hospital due to moderate risk of pneumonia while receiving scheduled adalimumab maintenance therapy. Symptoms remained virtually unchanged following administration of antibiotics. A final diagnosis of organizing pneumonia (OP) was made based on findings of intra-alveolar buds of granulation tissue and fibrous thickening of the alveolar walls on pathological examination and patchy consolidations and ground glass opacities on computed tomography. Immediate administration of prednisolone provided rapid, sustained improvement. Although a rare complication, OP is a pulmonary manifestation that requires attention in CD patients.
  • Urinary ADAM12 and MMP-9/NGAL complex detect the presence of gastric cancer., Takaya Shimura, Adelle Dagher, Monisha Sachdev, Masahide Ebi, Tamaki Yamada, Tomonori Yamada, Takashi Joh, Marsha A Moses, Cancer prevention research (Philadelphia, Pa.), 8, (3) 240 - 8,   2015年03月, 査読有り, Although the early diagnosis of gastric cancer provides the opportunity for curative endoscopic resection, comprehensive screening endoscopy would be invasive and expensive. To date, there is a complete absence of clinically useful gastric cancer biomarkers. With the goal of discovering noninvasive biomarkers for the early diagnosis of gastric cancer, we have conducted a case-control study using urine samples from individuals with gastric cancer versus healthy control samples. Of the enrolled 106 patients from September, 2012 to April, 2013, a cohort of 70 patients composed of 35 patients with gastric cancer and 35 age- and sex-matched healthy controls was analyzed. The gastric cancer group was composed of stage IA of 62.9% (22/35). The urinary levels of MMP-9/NGAL complex (uMMP-9/NGAL) and ADAM12 (uADAM12) were significantly higher in the gastric cancer group compared with the healthy control group as determined by monospecific ELISAs (uMMP-9/NGAL: median, 85 pg/mL vs. 0 pg/mL; P = 0.020; uADAM12: median, 3.35 ng/mL vs. 1.44 ng/mL; P < 0.001). Multivariate analysis demonstrated that both uMMP-9/NGAL and uADAM12 were significant, independent diagnostic biomarkers for gastric cancer. Moreover, MMP-9/NGAL activity was significantly elevated as determined by gelatin zymography. The combination of uMMP-9/NGAL with uADAM12 distinguished between control samples and gastric cancer samples with an AUC of 0.825 (P < 0.001) in an ROC analysis. Significantly, immunohistochemical analyses demonstrated a high coexpression of MMP-9 and NGAL (P < 0.001) and high expression of ADAM12 (P < 0.001) in gastric cancer tissues compared with adjacent normal tissues (N = 35). In summary, uMMP-9/NGAL and uADAM12 are potential noninvasive biomarkers for gastric cancer, including early-stage disease.
  • Preventive effect of rebamipide on N-methyl-N'-nitro-N-nitrosoguanidine-induced gastric carcinogenesis in rats., Hironobu Tsukamoto, Tsutomu Mizoshita, Takahito Katano, Noriyuki Hayashi, Keiji Ozeki, Masahide Ebi, Takaya Shimura, Yoshinori Mori, Satoshi Tanida, Hiromi Kataoka, Tetsuya Tsukamoto, Masae Tatematsu, Takashi Joh, Experimental and toxicologic pathology : official journal of the Gesellschaft fur Toxikologische Pathologie, 67, (3) 271 - 7,   2015年03月, 査読有り, Chemoprevention strategies against gastric cancer (GC) need to be explored in light of the fact that stomach cancer still occurs in the absence of Helicobacter pylori (HP) infection and following HP eradication. We evaluated the effect of rebamipide on N-methyl-N'-nitro-N-nitrosoguanidine (MNNG)-induced carcinogenesis in SD rats. Thirty-nine male rats were divided into four groups based on whether or not they were treated with rebamipide and/or MNNG: Control, Rebamipide, Control-M, and Rebamipide-M groups. From 8 weeks of age, rats in the Control-M and Rebamipide-M groups received MNNG in drinking water for 30 weeks. The Rebamipide and Rebamipide-M groups were administered 5mg/kg/day of rebamipide. At 50 weeks, cancerous lesions were not observed in either the Control or Rebamipide groups. Nine rats in the Control-M group had developed GC, while four rats in the Rebamipide-M group had developed GC. The incidence of cancer in the Rebamipide-M group was significantly less than in the Control-M group (p<0.05), with a trend toward a lower incidence of invasive carcinoma in the Rebamipide-M group. Carcinomatous invasion into the muscularis propria was not observed in the Rebamipide-M group. In conclusion, the present study demonstrates that rebamipide suppresses. MNNG-induced carcinogenesis and may also inhibit progression of cancer in rats.
  • Multicenter, prospective trial of white-light imaging alone versus white-light imaging followed by magnifying endoscopy with narrow-band imaging for the real-time imaging and diagnosis of invasion depth in superficial esophageal squamous cell carcinoma., Masahide Ebi, Takaya Shimura, Tomonori Yamada, Takashi Mizushima, Keisuke Itoh, Hironobu Tsukamoto, Kenji Tsuchida, Yoshikazu Hirata, Kenji Murakami, Hiroshi Kanie, Satoshi Nomura, Hiroyasu Iwasaki, Mika Kitagawa, Satoru Takahashi, Takashi Joh, Gastrointestinal endoscopy, 81, (6) 1355 - 1361,   2015年, 査読有り, BACKGROUND: Magnifying endoscopy with narrow-band imaging (ME-NBI) has been used to estimate the invasion depth of superficial esophageal squamous cell carcinoma (SESCC), but the real diagnostic power of ME-NBI remains unclear because of few prospective studies. OBJECTIVES: To evaluate whether ME-NBI adds additional information to white-light imaging (WLI) for the diagnosis of invasion depth of SESCC. DESIGN: Multicenter, prospective trial using real-time imaging and diagnosis. SETTING: Seven Japanese institutions. PATIENTS: Fifty-five patients with SESCC were enrolled from June 2011 to October 2013, and the results for 49 lesions were analyzed. INTERVENTIONS: Patients underwent primary WLI followed by ME-NBI, and reports of primary WLI (WLI alone) were completed before secondary ME-NBI (WLI followed by ME-NBI). To standardize diagnosis among examiners, this trial was started after achievement of a mean κ value≥.6 among 11 participating endoscopists. MAIN OUTCOME MEASUREMENTS: Diagnosis of invasion depth by each tool was divided into cancer limited to the epithelium and the lamina propria mucosa and cancer invading beyond the muscularis mucosae (≥T1a-MM) and then collated with the final pathologic diagnosis by an independent pathologist blinded to the clinical data. RESULTS: The accuracy of invasion depth in WLI alone and WLI followed by ME-NBI was 71.4% and 65.3% (P=.375), respectively. Sensitivity for ≥T1a-MM was 61.1% for both groups (P=1.000), and specificity for ≥T1a-MM was 77.4% for WLI alone and 67.7% for WLI followed by ME-NBI (P=.375). LIMITATION: Open-label trial. CONCLUSIONS: ME-NBI showed no additional benefit to WLI for diagnosis of invasion depth of SESCC. (University Hospital Network Clinical Trials Registry number: UMIN000005632.).
  • Subset Analysis of a Multicenter, Randomized Controlled Trial to Compare Magnifying Chromoendoscopy with Endoscopic Ultrasonography for Stage Diagnosis of Early Stage Colorectal Cancer., Tomonori Yamada, Takaya Shimura, Masahide Ebi, Yoshikazu Hirata, Hirotaka Nishiwaki, Takashi Mizushima, Koki Asukai, Shozo Togawa, Satoru Takahashi, Takashi Joh, PloS one, 10, (8) ,   2015年, 査読有り, BACKGROUND: Our recent prospective study found equivalent accuracy of magnifying chromoendoscopy (MC) and endoscopic ultrasonography (EUS) for diagnosing the invasion depth of colorectal cancer (CRC); however, whether these tools show diagnostic differences in categories such as tumor size and morphology remains unclear. Hence, we conducted detailed subset analysis of the prospective data. METHODS: In this multicenter, prospective, comparative trial, a total of 70 patients with early, flat CRC were enrolled from February 2011 to December 2012, and the results of 66 lesions were finally analyzed. Patients were randomly allocated to primary MC followed by EUS or to primary EUS followed by MC. Diagnoses of invasion depth by each tool were divided into intramucosal to slight submucosal invasion (invasion depth <1000 μm) and deep submucosal invasion (invasion depth ≥1000 μm), and then compared with the final pathological diagnosis by an independent pathologist blinded to clinical data. To standardize diagnoses among examiners, this trial was started after achievement of a mean κ value of ≥0.6 which was calculated from the average of κ values between each pair of participating endoscopists. RESULTS: Both MC and EUS showed similar diagnostic outcomes, with no significant differences in prediction of invasion depth in subset analyses according to tumor size, location, and morphology. Lesions that were consistently diagnosed as Tis/T1-SMS or ≥T1-SMD with both tools revealed accuracy of 76-78%. Accuracy was low in borderline lesions with irregular pit pattern in MC and distorted findings of the third layer in EUS (MC, 58.5%; EUS, 50.0%). CONCLUSIONS: MC and EUS showed the same limited accuracy for predicting invasion depth in all categories of early CRC. Since the irregular pit pattern in MC, distorted findings to the third layer in EUS and inconsistent diagnosis between both tools were associated with low accuracy, further refinements or even novel methods are still needed for such lesions. TRIAL REGISTRATION: University hospital Medical Information Network Clinical Trials Registry UMIN 000005085.
  • Management of systolic blood pressure after endoscopic submucosal dissection is crucial for prevention of post-ESD gastric bleeding., Masahide Ebi, Takaya Shimura, Hirotaka Nishiwaki, Mamoru Tanaka, Hironobu Tsukamoto, Keiji Ozeki, Takeshi Sawada, Tsutomu Mizoshita, Yoshinori Mori, Eiji Kubota, Satoshi Tanida, Hiromi Kataoka, Takashi Joh, European journal of gastroenterology & hepatology, 26, (5) 504 - 9,   2014年05月, 査読有り, OBJECTIVE: Endoscopic submucosal dissection (ESD) is a useful technique for early gastric neoplasms without lymph node metastasis. However, a critical complication is unpredictable post-ESD bleeding. Some risk factors for post-ESD bleeding have been reported previously, although those risk factors have not directly contributed toward prevention of post-ESD bleeding. MATERIALS AND METHODS: We retrospectively identified 186 gastric neoplasms in 183 consecutive patients treated with ESD from 2005 to 2012 at Nagoya City University Hospital, and divided them into two groups on the basis of the presence or absence of post-ESD bleeding. RESULTS: Of the 186 lesions, eight lesions (4.2%) developed post-ESD bleeding. Univariate analysis identified hypertension (38.8% in nonbleeding vs. 87.5% in bleeding; P=0.009) and depressed-type tumors (26.4% in nonbleeding vs. 62.5% in bleeding; P=0.040) as significantly related to the incidence of post-ESD bleeding. On multivariate analysis, hypertension (odds ratio, 11.55; 95% confidence interval, 1.20-111.66; P=0.034) and depressed-type tumors (odds ratio, 5.36; 95% confidence interval, 1.12-25.73; P=0.036) were independent risk factors for post-ESD bleeding. Systolic blood pressure (SBP) after ESD was significantly higher in the post-ESD bleeding group than in the post-ESD non-bleeding group (P=0.021), with the comorbidity of hypertension significantly correlating with SBP after ESD (ρ=0.332, P<0.001). CONCLUSION: Control of SBP after ESD is important for the prevention of post-ESD bleeding because hypertension as a comorbidity, which is associated positively with SBP after ESD, is a significant risk factor for post-ESD bleeding.
  • Magnifying chromoendoscopy and endoscopic ultrasonography measure invasion depth of early stage colorectal cancer with equal accuracy on the basis of a prospective trial., Takaya Shimura, Masahide Ebi, Tomonori Yamada, Yoshikazu Hirata, Hirotaka Nishiwaki, Takashi Mizushima, Koki Asukai, Shozo Togawa, Satoru Takahashi, Takashi Joh, Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association, 12, (4) 662 - 8,   2014年04月, 査読有り, BACKGROUND & AIMS: Magnifying chromoendoscopy (MC) and endoscopic ultrasonography (EUS) are used to estimate the depth of colorectal cancer (CRC) invasion, but it is not clear which procedure is more accurate. We performed a prospective study to compare MC and EUS. METHODS: A total of 70 patients with an early stage flat CRC lesion were enrolled at 6 institutions in Japan and randomly assigned to groups assessed by MC followed by EUS or EUS followed by MC. Results from MC and EUS measurements of 66 lesions were included in the final analysis. The invasion depth of each lesion was measured by each procedure and categorized as mucosal to slight submucosal (depth <1000 μm) or deep submucosal (depth ≥ 1000 μm); measurements were compared with the final diagnosis on the basis of the pathology analysis. All participating examiners achieved a mean κ value ≥ 0.6 for both MC and EUS before this trial. RESULTS: MC and EUS each measured the depth of lesion invasion with 71.2% accuracy (correctly for 47 of 66 lesions). MC identified lesions with deep submucosal invasion with 74.2% sensitivity and 68.6% specificity, whereas EUS identified them with 67.7% sensitivity and 74.3% specificity. The differences between MC and EUS measurements did not differ significantly. However, MC required significantly shorter observation time than EUS (361.7 ± 164.5 seconds vs 451.2 ± 209.4 seconds, P = .002). CONCLUSIONS: MC and EUS are equally accurate in estimating the invasion depth of early stage CRC lesions. However, neither procedure has sufficient diagnostic accuracy to be used as the standard. University Hospital Medical Network Clinical Trials Registry, Number: UMIN 000005085.
  • Novel nasogastric tube-related criteria for urgent endoscopy in nonvariceal upper gastrointestinal bleeding., Hiroyasu Iwasaki, Takaya Shimura, Tomonori Yamada, Miho Aoki, Satoshi Nomura, Atsunori Kusakabe, Hiroshi Kanie, Tesshin Ban, Katsumi Hayashi, Takashi Joh, Etsuro Orito, Digestive diseases and sciences, 58, (9) 2564 - 71,   2013年09月, 査読有り, BACKGROUND: Patients with active upper gastrointestinal bleeding (UGIB) require urgent endoscopy, but appropriate criteria for urgent endoscopy in these patients have not yet been established. AIMS: The goal of this study is to establish a simple system for the selection of UGIB patients who may benefit from urgent endoscopy. METHODS: Of the 335 patients who required emergency hospitalization for UGIB from May 2010 to March 2012 at Nagoya Daini Red Cross Hospital, 166 patients who underwent placement of a nasogastric tube (NGT) were retrospectively identified. Active bleeding on the endoscopic image was used as an endpoint that reflected the need for urgent endoscopy. RESULTS: The ratio of the heart rate to the systolic blood pressure (HR/SBP ratio) and aspiration of fresh or dark red fluid from the NGT [NGT(+)] were significant predictors of active bleeding in the univariate analysis [HR/SBP ratio, P=0.016; NGT(+), P<0.001]. The HR/SBP ratio [odds ratio (OR) 8.118; 95% confidence intervals (CI) 1.696-38.850; P=0.009] and NGT(+) (OR 4.630; 95% CI 2.092-10.204; P<0.001) were also significantly associated with active bleeding in the multivariate analysis. Moreover, receiver operating characteristic analysis revealed a setting with HR/SBP ratio>1.4 or NGT(+) to be optimal criteria to predict active bleeding. These criteria were associated with a sensitivity of 64.9% (24/37) and a specificity of 76.7% (99/129) for the prediction of active bleeding; consequently, they are superior to the sensitivity and specificity of previously proposed criteria. CONCLUSIONS: A novel and simple criteria system using NGT(+) and HR/SBP is a good predictor of the need for urgent endoscopy in patients with nonvariceal UGIB.
  • Infliximab salvage therapy for patients with ulcerative colitis who failed to respond to tacrolimus., Hironobu Tsukamoto, Satoshi Tanida, Tsutomu Mizoshita, Keiji Ozeki, Masahide Ebi, Takaya Shimura, Yoshinori Mori, Hiromi Kataoka, Takeshi Kamiya, Takashi Joh, European journal of gastroenterology & hepatology, 25, (6) 714 - 8,   2013年06月, 査読有り, OBJECTIVE: Infliximab and tacrolimus are effective for the treatment of patients with moderate or severe corticosteroid-dependent/refractory ulcerative colitis. However, regarding treatment for these patients, whether tacrolimus therapy should precede infliximab as a second-line therapy remains controversial. To address this issue, we retrospectively investigated the efficacy of infliximab salvage therapy for patients with severe or moderate ulcerative colitis who failed to respond to tacrolimus. METHODS: We assessed clinical backgrounds and therapeutic outcomes at baseline, 8, and 30 weeks for 13 patients receiving infliximab for severe or moderate ulcerative colitis who showed refractoriness or loss of response to tacrolimus, or no tolerance. RESULTS: Mean partial Mayo score was significantly decreased (P<0.05) to 5.69, 3.07, and 2.77 at baseline, 8, and 30 weeks, respectively. Six of 13 patients (46.2%) showed clinical remission at 8 weeks and four (30.8%) showed clinical remission at 30 weeks. Two patients who did not respond to infliximab finally underwent colectomy. Rates of clinical remission at 8 and 30 weeks were 60.0 and 40.0% in tacrolimus responders, and good remission rates of 37.5 and 25.0%, respectively, were also obtained in tacrolimus nonresponders. No serious adverse events were encountered. CONCLUSION: Infliximab salvage therapy following tacrolimus tended to appear more efficacious in tacrolimus responders (loss of response or no tolerance) than in nonresponders (refractoriness), although nonresponders also achieved satisfactory results. Sequential therapy may thus prove useful and well tolerated. In addition, we should avoid missing the proper timing of colectomy, and care is warranted regarding adverse events.
  • Annexin A2 regulates a disintegrin and metalloproteinase 17-mediated ectodomain shedding of pro-tumor necrosis factor-α in monocytes and colon epithelial cells., Hironobu Tsukamoto, Satoshi Tanida, Keiji Ozeki, Masahide Ebi, Tsutomu Mizoshita, Takaya Shimura, Yoshinori Mori, Hiromi Kataoka, Takeshi Kamiya, Shinji Fukuda, Shigeki Higashiyama, Takashi Joh, Inflammatory bowel diseases, 19, (7) 1365 - 73,   2013年06月, 査読有り, BACKGROUND: Understanding the mechanism of tumor necrosis factor (TNF)-α shedding is important because TNF-α triggers inflammatory bowel disease development. A disintegrin and metalloproteinase (ADAM) 17 is a key enzyme for the shedding of not only the type 1 membrane-anchored protein, amphiregulin, but also the type 2 protein, TNF-α. However, the detailed mechanism by which ADAM17 cleaves type 1 and 2 membrane-anchored proteins is unclear. Annexin (ANX) A2 is involved in ADAM17-mediated amphiregulin shedding. In this study, we examined whether ANX A2 is involved in TNF-α shedding. METHODS: We prepared U937, HT29, and HCT116 cells overexpressing alkaline phosphatase (AP)-tagged proTNF-α and depleted ADAM17 and ANX A2. We assessed TNF-α release and shedding by measuring the TNF-α release concentration and AP activities in conditioned media after interleukin-1β or 12-O-tetradecanoylphorbol-13-acetate (TPA) stimulation by enzyme-linked immunosorbent assay and AP assay, respectively. A direct association of ANX A2 with ADAM17 was examined with immunoprecipitation and Western blotting. RESULTS: Enzyme-linked immunosorbent assay and AP assay showed interleukin-1β-induced TNF-α shedding in HCT116 and HT29 cells and TPA-induced TNF-α release in U937 cells. KB-R7785 and ADAM17 depletion significantly blocked TNF-α shedding by TPA. ANX A2 depletion significantly inhibited TNF-α shedding by interleukin-1β and TPA. In contrast, ANX A2 depletion did not abrogate ADAM17-mediated amphiregulin and heparin-binding epidermal growth factor-like growth factor shedding. ANX A2 was directly associated with ADAM17. CONCLUSIONS: ANX A2 was closely associated with ADAM17 and played an important role in TNF-α shedding by TPA. Inhibition of ANX A2 might be a new therapeutic strategy for prevention of TNF-α shedding during inflammatory bowel disease inflammation.
  • A novel predictive strategy by immunohistochemical analysis of four EGFR ligands in metastatic colorectal cancer treated with anti-EGFR antibodies., Michihiro Yoshida, Takaya Shimura, Mikinori Sato, Masahide Ebi, Takahiro Nakazawa, Hiromitsu Takeyama, Takashi Joh, Journal of cancer research and clinical oncology, 139, (3) 367 - 78,   2013年03月, 査読有り, PURPOSE: Although KRAS mutation has been identified as a negative predictive biomarker of anti-EGFR antibodies in metastatic colorectal cancer (mCRC), the efficacy in mCRC patients with KRAS wild-type status remains limited. Anti-EGFR antibodies work by blocking ligand binding, but the significance of EGFR ligands in mCRC has not been completely described. This study was conducted to identify the correlation between all seven EGFR ligands and clinical outcomes in mCRC treated with anti-EGFR antibodies. Furthermore, we determined an appropriate predictive strategy for anti-EGFR antibodies using these EGFR ligands. METHODS: Among 36 mCRC patients who had been treated with cetuximab or panitumumab, we identified 26 mCRC patients with wild-type KRAS status treated properly as the second and further lines and analyzed the relationship between immunoreactivity to seven EGFR ligands and clinical outcomes. RESULTS: Good clinical outcomes were associated with immunoreactivity against amphiregulin (AR), heparin-binding epidermal growth factor (HB-EGF), transforming growth factor-α (TGF-α), and epiregulin (EREG). Further, patients with immunoreactivity to greater than two of these four ligands (AR, HB-EGF, TGF-α, and EREG) had significantly higher response rate (53.3 vs. 0.0 %, p = 0.004) and disease control rate (93.3 vs. 9.0 %, p = 0.00002) and longer progression-free survival (median PFS: 231 vs. 79 days, p = 0.000008), when compared with patients with immunoreactivity against zero or one ligand. CONCLUSIONS: Immunohistochemical analysis of four EGFR ligands (AR, HB-EGF, TGF-α, and EREG) might be a novel predictive biomarker and may help optimize patient selection for cetuximab and panitumumab therapy in patients with mCRC.
  • Preoperative drainage using a transanal tube enables elective laparoscopic colectomy for obstructive distal colorectal cancer., T Yamada, T Shimura, E Sakamoto, Y Kurumiya, S Komatsu, H Iwasaki, S Nomura, H Kanie, H Hasegawa, E Orito, T Joh, Endoscopy, 45, (4) 265 - 71,   2013年, 査読有り, BACKGROUND AND STUDY AIMS: Acute colorectal obstruction (ACO) often accompanies colorectal cancer (CRC) and requires urgent treatment, but achieving elective laparoscopy-assisted colectomy (LAC) is difficult in this setting. The aim of the current study was to assess the clinical outcomes of a transanal tube (Dennis colorectal tube [DCT]) for CRC with ACO, focusing in particular on the impact of the DCT on subsequent elective LAC. PATIENTS AND METHODS: Among 1142 patients who underwent surgery for CRC between January 2007 and December 2011, 92 patients with ACO were identified retrospectively. Of these 92 patients, the DCT procedure was performed in 66 patients who fulfilled the indications for DCT, and these patients were included in the study. RESULTS: All 66 patients presented with complete obstruction. Technical and clinical success rates for DCT were 93.9 % and 86.4 %, respectively. Perforation after DCT occurred in 4.5 % and the mortality rate was 1.5 %. The rate of LAC was 48.5 %, and the rate of primary stoma was 13.6 %. For curative stage II/III CRC with ACO, DCT resulted in a primary stoma rate of 13.6 %, a one-stage surgery rate of 90.9 %, a LAC rate of 50.0 %, and a 3-year survival rate of 73.1 %. For stage II/III CRC cases with clinical success by DCT, the one-stage surgery rate was 97.4 % and the LAC rate was 56.4 %. CONCLUSIONS: DCT achieved a high rate of clinical success and enabled safe one-stage surgery and LAC for CRC with ACO. DCT followed by LAC is proposed as a promising non-invasive strategy for CRC with ACO.
  • Telmisartan inhibits cell proliferation by blocking nuclear translocation of ProHB-EGF C-terminal fragment in colon cancer cells., Keiji Ozeki, Satoshi Tanida, Chie Morimoto, Yoshimasa Inoue, Tsutomu Mizoshita, Hironobu Tsukamoto, Takaya Shimura, Hiromi Kataoka, Takeshi Kamiya, Eiji Nishiwaki, Hiroshi Ishiguro, Shigeki Higashiyama, Takashi Joh, PloS one, 8, (2) ,   2013年, 査読有り, BACKGROUND AIMS: Current treatment target toward advanced colorectal cancers is mainly focused on the epidermal growth factor receptor (EGFR) signaling, but its additive effects with chemotherapy are still limited. A disintegrin and metalloproteinase (ADAM) cleaves the proheparin-binding epidermal growth factor like growth factor (proHB-EGF). And soluble HB-EGF activates EGFR. In parallel, the carboxy-terminal fragment of proHB-EGF (HB-EGF-CTF) translocates into the inner nuclear membrane, and subsequently exerts on the regulation of cell proliferation by binding nuclear promyelocytic leukemia zinc finger (PLZF) protein, a transcriptional repressor, thereby causing its nuclear export. We hypothesized that the inhibition of HB-EGF-CTF nuclear translocation may be a new strategy in preventing cell proliferation. METHODS: 12-O-tetradecanoylphorbor-13-acetate (TPA) was treated to activate ADAM. Nine-thousand chemical compounds were screened for their efficacies in blocking the binding of HB-EGF-CTF to promyelocytic leukemia zinc finger (PLZF) with Alphascreen system. The obtained candidates were then used to block the binding of HB-EGF-CTF to PLZF in colon cancer cells, HT29 and HCT116. Cell proliferation was investigated with a growth curve assay. The intracellular localization, and association between HB-EGF-CTF and PLZF, was assessed with immunofluorescent staining, and immunoprecipitation and Western blotting, respectively. The effects of obtained candidates on EGFR phosphorylation and on nuclear translocation of HB-EGF-CTF and export of PLZF during the angiotensin II type1 receptor (AT1R) knockdown were also investigated. RESULTS: Telmisartan and candesartan were found to be potential candidates. Telmisartan inhibited TPA-induced cell proliferation stronger than candesartan. Telmisartan, but not candesartan blocked the nuclear translocation of HB-EGF-CTF, and binding of HB-EGF-CTF to PLZF, during TPA stimulation. Both telmisartan and candesartan did not inhibit TPA-induced EGFR phosphorylation, and telmisartan, but not candesartan, inhibited TPA-induced nuclear translocation of HB-EGF-CTF after knockdown of AT1R. CONCLUSIONS: The inhibition of HB-EGF-CTF nuclear translocation with telmisartan may be a novel strategy in preventing cell proliferation.
  • Comparison of staging diagnosis by two magnifying endoscopy classification for superficial oesophageal cancer., Masahide Ebi, Takaya Shimura, Kenji Murakami, Tomonori Yamada, Yoshikazu Hirata, Hironobu Tsukamoto, Tsutomu Mizoshita, Satoshi Tanida, Hiromi Kataoka, Takeshi Kamiya, Takashi Joh, Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver, 44, (11) 940 - 4,   2012年11月, 査読有り, BACKGROUND: Due to the possibility of lymph node metastasis, surgical resection is indicated for superficial oesophageal cancer with invasion to a depth greater than the muscularis mucosa. Although two magnifying endoscopy classifications are currently used to diagnose the depth of invasion, which classification is more suitable remains controversial. AIMS: To compare and evaluate the clinical outcomes of two classifications for superficial oesophageal squamous cell carcinoma. METHODS: This cross-sectional study consists of 44 superficial oesophageal squamous cell carcinoma lesions with magnification image-enhanced endoscopy images. Only magnifying endoscopic images were displayed to two experienced endoscopists who independently diagnosed the depth of invasion according to both classifications. RESULTS: The sensitivity of invasion greater than the muscularis mucosa tended to be higher in Inoue's classification than Arima's classification (78.3±6.2% vs. 50.0±3.0%; P=0.144), whereas the specificity was significantly lower in Inoue's classification than in Arima's classification (61.9±0.0% vs. 97.6±3.4%; P=0.043). For both classifications, rates of concordance were 90.9% and 84.4%, and κ statistics were 0.81 and 0.66, respectively. CONCLUSIONS: Our results suggest that Arima's classification is suitable for general screening before treatment to avoid unnecessary surgery. Inoue's classification is appropriate for assessing wide lesion.
  • Nuclear translocation of the cytoplasmic domain of HB-EGF induces gastric cancer invasion., Takaya Shimura, Michihiro Yoshida, Shinji Fukuda, Masahide Ebi, Yoshikazu Hirata, Tsutomu Mizoshita, Satoshi Tanida, Hiromi Kataoka, Takeshi Kamiya, Shigeki Higashiyama, Takashi Joh, BMC cancer, 12, 205 - 205,   2012年05月30日, 査読有り, BACKGROUND: Membrane-anchored heparin-binding epidermal growth factor-like growth factor (proHB-EGF) yields soluble HB-EGF, which is an epidermal growth factor receptor (EGFR) ligand, and a carboxy-terminal fragment of HB-EGF (HB-EGF-CTF) after ectodomain shedding. We previously reported that HB-EGF-CTF and unshed proHB-EGF which has the cytoplasmic domain of proHB-EGF (HB-EGF-C), translocate from the plasma membrane to the nucleus and regulate cell cycle after shedding stimuli. However, the significance of nuclear exported HB-EGF-C in human gastric cancer is unclear. METHODS: We investigated the relationship between intracellular localization of HB-EGF-C and clinical outcome in 96 gastric cancer patients treated with gastrectomy. Moreover, we established stable gastric cancer cell lines overexpressing wild-type HB-EGF (wt-HB-EGF) and mutated HB-EGF (HB-EGF-mC), which prevented HB-EGF-C nuclear translocation after shedding. Cell motility between these 2 gastric cancer cell lines was investigated using a transwell invasion assay and a wound healing assay. RESULTS: Of the 96 gastric cancer cases, HB-EGF-C immunoreactivity was detected in both the nucleus and cytoplasm in 19 cases (19.8 %) and in the cytoplasm only in 25 cases (26.0 %). The nuclear immunoreactivity of HB-EGF-C was significantly increased in stage pT3/4 tumors compared with pT1/2 tumors (T1/2 vs. T3/4: 11.1 % vs. 36.4 %, P < 0.01). The growth of wt-HB-EGF- and HB-EGF-mC-expressing cells significantly increased compared with control cells, but the growth of HB-EGF-mC-expressing cells was significantly decreased compared with wt-HB-EGF-expressing cells. Gastric cancer cell invasion obviously increased in wt-HB-EGF-expressing cells, but invasion in HB-EGF-mC-expressing cells showed a slight increase compared with control cells. Moreover, wt-HB-EGF overexpression increased the effectiveness of wound healing, but had no significant effect in HB-EGF-mC-expressing cells. CONCLUSIONS: Both the function of HB-EGF as an EGFR ligand and a novel signal for HB-EGF-C nuclear translocation induce gastric cancer growth, whereas HB-EGF-C nuclear translocation independently plays a critical role in gastric cancer invasion. The present study demonstrated that HB-EGF-C nuclear translocation might be crucial in gastric cancer invasion. HB-EGF-C nuclear translocation may offer a prognostic marker and a new molecular target for gastric cancer therapy.
  • The relationship between antitumor effects and relative dose intensity of S-1 plus cisplatin treatment for metastatic gastric cancer., Mika Kitagawa, Takaya Shimura, Tomonori Yamada, Masahide Ebi, Yoshikazu Hirata, Tsutomu Mizoshita, Satoshi Tanida, Hiromi Kataoka, Takeshi Kamiya, Takashi Joh, Anticancer research, 32, (5) 1763 - 8,   2012年05月, 査読有り, BACKGROUND/AIM: S-1 plus cisplatin is the standard first-line chemotherapy for metastatic gastric cancer (MGC) in Japan, but the relationship between dose intensity and antitumor effects remains unclear. PATIENTS AND METHODS: We retrospectively studied 64 patients who received S-1 plus cisplatin for MGC from January 2006 to December 2010 in two Japanese hospitals. RESULTS: The median relative dose intensity (RDI) of S-1 plus cisplatin was 87% (range, 59.5%-100%). The cut-off value of RDI of S-1 plus cisplatin was identified to be 80% by a receiver operating characteristic analysis of the tumor response. In the RDI<80% (n=19) and the RDI≥80% (n=45) groups, the response rates were 20.0% and 37.5% (p=0.182), the median survival times were 394 and 376 days (p=0.915), and the median progression-free survival (PFS) was 188 and 170 days (p=0.851), respectively. CONCLUSION: An appropriate RDI reduction may be permitted for patients with MGC in palliative settings.
  • Nuclear translocation of pro-amphiregulin induces chemoresistance in gastric cancer., Michihiro Yoshida, Takaya Shimura, Shinji Fukuda, Tsutomu Mizoshita, Satoshi Tanida, Hiromi Kataoka, Takeshi Kamiya, Takahiro Nakazawa, Shigeki Higashiyama, Takashi Joh, Cancer science, 103, (4) 708 - 15,   2012年04月, 査読有り, Amphiregulin (AR) is derived from a membrane-anchored form (proAR) by ectodomain shedding, and is a ligand that activates epidermal growth factor receptor (EGFR). We have recently shown that proAR translocates from the plasma membrane to the nucleus after truncation of 11 amino acids at the C-terminus, which is independent of the conventional EGFR signaling pathway. Although proAR immunoreactivity has reportedly been detected in the nucleus of cancer cells, its biological meaning has never been investigated. This study was performed to investigate the roles of proAR nuclear translocation in human gastric cancer. We constructed proAR truncated 11 amino acids at the C-terminus (proARΔC11) that spontaneously translocates to the nucleus, and established proARΔC11-expression regulatable gastric cancer cells (MKN45, MKN28) using the tet-off system. Using these cells, we found that proAR nuclear translocation significantly induced chemoresistance in vitro and in vivo. Analyzing the relationship between immunoreactive localization of proAR and the clinical outcome for 46 advanced gastric cancer cases treated with chemotherapy, median survival time was 311 days in 16 patients with AR-positive staining in the nucleus and 387 days in 30 patients with AR-negative staining (P < 0.05). The present study demonstrates that proAR nuclear translocation increases resistance to anti-cancer drugs, which might be associated with poor prognosis in human gastric cancer.
  • C-reactive protein is a potential prognostic factor for metastatic gastric cancer., Takaya Shimura, Mika Kitagawa, Tomonori Yamada, Masahide Ebi, Tsutomu Mizoshita, Satoshi Tanida, Hiromi Kataoka, Takeshi Kamiya, Takashi Joh, Anticancer research, 32, (2) 491 - 6,   2012年02月, 査読有り, BACKGROUND/AIM: C-reactive protein (CRP) has been associated with the development of many carcinomas, but the significance of CRP remains unclear for metastatic gastric cancer (MGC). PATIENTS AND METHODS: Sixty one patients who received S-1 plus cisplatin for MGC were retrospectively identified and categorized into two groups depending on the serum CRP level before chemotherapy. RESULTS: Overall survival was significantly shorter in the CRP≥1.0 group than in the CRP<1.0 group (median, 292 days versus 451 days; p=0.0004). Moreover, progression-free survival was significantly shorter in the CRP≥1.0 group than in the CRP<1.0 group (median, 115 days versus 188 days; p=0.0010). In a multivariate analysis, serum CRP level before chemotherapy was an independent prognostic factor for MGC (hazard ratio 4.20 [95% CI, 1.66 to 10.64] p=0.002). CONCLUSION: Serum CRP level before chemotherapy might be a potential prognostic factor for MGC.
  • Combination therapy with adalimumab plus intensive granulocyte and monocyte adsorptive apheresis induced clinical remission in a Crohn's disease patient with the loss of response to scheduled adalimumab maintenance therapy: a case report., Keiji Ozeki, Satoshi Tanida, Takashi Mizushima, Tsutomu Mizoshita, Hironobu Tsukamoto, Yoshikazu Hirata, Kenji Murakami, Takaya Shimura, Hiromi Kataoka, Takeshi Kamiya, Takashi Joh, Internal medicine (Tokyo, Japan), 51, (6) 595 - 9,   2012年, 査読有り, A 21-year-old Caucasian man with a diagnosis of Crohn's disease (CD) at the age of 14 was admitted to our hospital due to CD flare-up while under scheduled adalimumab (ADA) maintenance therapy. His symptoms remained virtually unchanged following high dose corticosteroid therapy. Seven days later, combination therapy with ADA plus intensive granulocyte/monocyte adsorptive apheresis (GMA) was initiated, which induced clinical remission. Therefore, combination therapy with ADA plus intensive GMA appears to be an effective therapeutic option for patients with severe CD while under scheduled ADA maintenance therapy.
  • The impact of cross-resistance between paclitaxel and docetaxel for metastatic gastric cancer., Takaya Shimura, Mika Kitagawa, Tomonori Yamada, Michihiro Yoshida, Masahide Ebi, Yoshikazu Hirata, Takashi Mizushima, Tsutomu Mizoshita, Satoshi Tanida, Hiromi Kataoka, Takeshi Kamiya, Takashi Joh, Onkologie, 35, (4) 176 - 83,   2012年, 査読有り, BACKGROUND: Paclitaxel and docetaxel show similar anticancer mechanisms, but cross-resistance for gastric cancer chemotherapy remains unclear. PATIENTS AND METHODS: Among 484 patients with metastatic gastric cancer, who had received chemotherapy in 4 Japanese hospitals, we identified 28 patients who had received either paclitaxel- or docetaxel-containing chemotherapy and who were refractory to the other taxane. RESULTS: The median age was 65 years, and target lesions were present in 20 patients and absent in 8. The first taxane was administered to 16 patients as first-line chemotherapy and to 12 patients as second-line chemotherapy, while the second taxane was administered to 5 patients as second-line, 13 as third-line, and 10 as fourth-line or beyond. The median survival time was 456 days (95% confidence interval (CI) 145-767 days), and the median survival time and median progression-free survival after the second taxane were 119 days (95% CI 85-153 days) and 50 days (95% CI 42-58 days), respectively. The second taxane chemotherapy achieved a response rate of 5% (1/20 patients) and an overall disease control rate of 17.9% (5/28 patients). CONCLUSIONS: Paclitaxel and docetaxel might show a large degree of cross-resistance for gastric cancer. Paclitaxel and docetaxel should not be routinely administered for metastatic gastric cancer after failure of the other taxane.
  • A patient with gastric adenosquamous carcinoma with intraperitoneal free cancer cells who remained recurrence-free with postoperative S-1 chemotherapy., Masahide Ebi, Takaya Shimura, Seiji Yamada, Yoshikazu Hirata, Hironobu Tsukamoto, Yasuyuki Okamoto, Tsutomu Mizoshita, Satoshi Tanida, Hiromi Kataoka, Takeshi Kamiya, Hiroshi Inagaki, Takashi Joh, Internal medicine (Tokyo, Japan), 51, (22) 3125 - 9,   2012年, 査読有り, The case of a patient with gastric adenosquamous carcinoma with positive cancer cells on intraperitoneal washing cytology (CY1) who achieved a long recurrence-free survival is herein reported. A 74-year-old man was found to have adenosquamous carcinoma of the stomach. Partial gastrectomy was performed, and a pathological examination confirmed a diagnosis of adenosquamous carcinoma with invasion into the serosa and lymph node metastasis. S-1 monotherapy was administered because a cytologic examination revealed that the patient's peritoneal washings were positive for cancer cells. The patient remains alive with no recurrence two years and 10 months after undergoing surgery. Postoperative chemotherapy with S-1 monotherapy is effective for treating adenosquamous carcinoma of the stomach with CY1 and might contribute to long-term survival.
  • The role of neuregulin4 and HER4 in gastrointestinal malignant lymphoma, Masahide Ebi, Hiromi Kataoka, Takaya Shimura, Yoshikazu Hirata, Takashi Mizushima, Tsutomu Mizoshita, Mamoru Tanaka, Hironobu Tsukamoto, Keiji Ozeki, Satoshi Tanida, Takeshi Kamiya, Hiroshi Inagaki, Takashi Joh, MOLECULAR MEDICINE REPORTS, 4, (6) 1151 - 1155,   2011年11月, 査読有り, The human epidermal growth factor (EGF) receptor (HER) family consists of four receptors that bind to ligands sharing an EGF-like motif. The HER family of receptor tyrosine kinases and their ligands (EGF family) are known to play a significant role in gastrointestinal cancer. In particular, the EGF receptor, HER1, is one of the main candidates for the molecular-targeted therapy of colon cancer, and HER2 is a candidate for the treatment of gastric cancer which overexpresses HER2. In contrast, the role of the HER and EGF families in malignant lymphoma has not been fully elucidated. In this study, we investigated the expression and function of the HER and EGF families in lymphoma cell lines and tumor samples. Reverse transcription polymerase chain reaction revealed that the ligands for HER1 were mainly expressed in gastric cancer and colon cancer cell lines, but not in lymphoma cell lines. On the other hand, the EGF family member, neuregulin (NRG)4, was highly expressed in lymphoma cell lines. Immunohistochemical analyses of malignant lymphoma clinical samples revealed that NRG4 and HER4 were mainly expressed in mucosa-associated lymphoid tissue (MALT) and follicular lymphoma. Immunoprecipitation of Raji and Daudi cell lines revealed that recombinant NRG4 induced the tyrosine phosphorylation of HER4. Additionally, recombinant NRG4 activated the proliferation of lymphoma cell lines. These findings suggest that the NRG4-HER4 axis plays a major role in the proliferation of malignant lymphoma cells in the gastrointestinal tract.
  • Acid inhibits TRPV4-mediated Ca²⁺ influx in mouse esophageal epithelial cells., M Shikano, T Ueda, T Kamiya, Y Ishida, T Yamada, T Mizushima, T Shimura, T Mizoshita, S Tanida, H Kataoka, S Shimada, S Ugawa, T Joh, Neurogastroenterology and motility : the official journal of the European Gastrointestinal Motility Society, 23, (11) 1020 - 8,   2011年11月, 査読有り, BACKGROUND: The transient receptor potential vanilloid 4 (TRPV4), a thermo-sensitive stretch-activated cation channel, is expressed in the skin stratified squamous epithelium, contributing to the acquisition of barrier function. Similarly, functional TRPV4 may be located in the stratified squamous epithelial lining of the esophagus, being involved in the pathogenesis of gastroesophageal reflux disease (GERD). Here we investigated the expression of TRPV4 in the mouse esophageal epithelium. METHODS: TRPV4 expression at the mRNA and protein levels was examined by reverse transcription-polymerase chain reaction (RT-PCR), in situ hybridization, and immunohistochemistry. A calcium imaging technique and ATP assay were used to evaluate the functionality of TRPV4 in freshly isolated esophageal epithelial cells. KEY RESULTS: Transcripts and proteins encoding TRPV4 were colocalized in the basal and intermediate layers of the esophageal epithelium. Both 4α-phorbol 12,13- didecanoate (4α-PDD), a selective agonist for TRPV4, and hypo-osmolar solution (160 mOsm) elevated the intracellular calcium concentration ([Ca(2+) ](i) ) in a subset of the isolated cells (70%). These [Ca(2+) ](i) increases were potently inhibited by ruthenium red (RuR), a TRPV4 channel antagonist, and were suppressed by extracellular protons (pH 5.0). Finally, application of 4α-PDD evoked ATP release in primary esophageal epithelial cells. CONCLUSIONS & INFERENCES: Acid-sensitive TRPV4 channels were mainly expressed in the esophageal epithelial cells of the basal and intermediate layers. Direct exposure of TRPV4-expressing cells to gastric acid, as would occur in cases of GERD, could influence their cellular functions, possibly aggravating the disease state.
  • ERas enhances resistance to CPT-11 in gastric cancer., Eiji Kubota, Hiromi Kataoka, Mamoru Tanaka, Yasuyuki Okamoto, Masahide Ebi, Yoshikazu Hirata, Kenji Murakami, Tsutomu Mizoshita, Takaya Shimura, Yoshinori Mori, Satoshi Tanida, Takeshi Kamiya, Mineyoshi Aoyama, Kiyofumi Asai, Takashi Joh, Anticancer research, 31, (10) 3353 - 60,   2011年10月, 査読有り, BACKGROUND/AIM: We have reported that embryonic stem cell-expressed Ras (ERas) is expressed in human gastric cancer and is associated with its tumorigenicity. Here, we asked whether ERas plays a role in resistance to chemotherapy in gastric cancer. MATERIALS AND METHODS: To assess the cytotoxicity of chemotherapeutic agents, ERas-overexpressing human gastric cancer GCIY cells were exposed to anticancer agents, including CPT-11 and inhibitor of mammalian target of rapamycin (mTOR). We also investigated the mechanisms by which ERas induces chemoresistance. RESULTS: ERas-overexpressing clones were significantly more resistant to CPT-11 than were the control (p<0.001). Administration of rapamycin was significantly cytotoxic to the ERas-overexpressing clones compared with the control (p<0.01). Electrophoresis mobility shift assay revealed that ERas enhanced nuclear factor (NF)-κB activity. PCR array demonstrated that ERas up-regulated several multidrug efflux transporter genes, including ABCG2. CONCLUSION: ERas induces chemoresistance to CPT-11 via activation of phosphatidylinositol-3 kinase-protein kinase β mTOR pathway and NF-κB, and consequently results in up-regulation of ABCG2.
  • Incidence of gastrointestinal bleeding in patients with cardiovascular disease: buffered aspirin versus enteric-coated aspirin., Yoshikazu Hirata, Hiromi Kataoka, Takaya Shimura, Takashi Mizushima, Tsutomu Mizoshita, Satoshi Tanida, Takeshi Kamiya, Takashi Joh, Scandinavian journal of gastroenterology, 46, (7-8) 803 - 9,   2011年07月, 査読有り, OBJECTIVE: Aspirin-induced enteropathy is increasing, but whether the type of aspirin affects the gastrointestinal (GI) bleeding, especially small intestine, is unclear. The incidence of GI bleeding for buffered aspirin and enteric-coated aspirin was evaluated in patients receiving long-term low-dose aspirin (LDA) for cardiovascular (CV) diseases. METHODS: This retrospective cohort study assessed overt GI bleeding, decreased hemoglobin levels suspecting small bowel blood loss, and CV death in patients taking LDA for more than 1 year (LDA group) and in patients not taking LDA (control group). The LDA group was divided into two subgroups, patients taking either buffered aspirin (buffered subgroup) or enteric-coated aspirin (enteric subgroup), and their outcomes were compared. RESULTS: A total of 1402 patients (LDA group 701, control group 701; median follow-up duration 1778 ± 747 days) were assessed. The incidences of overt GI bleeding and decreased hemoglobin were 3.9% and 1.4% in LDA group, respectively, significantly higher than the control group (p < 0.01; p < 0.01). In the LDA group, 3% died during the follow-up period. Ten (3.7%) in the buffered subgroup (n = 267) and 17 (3.9%) in the enteric subgroup (n = 434) developed GI bleeding (p = 0.92). One (0.3%) in the buffered subgroup and nine (2%) in the enteric subgroup developed decreased hemoglobin (p = 0.06, log-rank test). CONCLUSIONS: The type of aspirin does not affect the incidence of overt GI bleeding and decreased hemoglobin, but enteric-coated aspirin may be associated with an increased incidence of decreased hemoglobin.
  • A complicated case of tacrolimus-induced rapid remission after cesarean section in the early third trimester for refractory severe ulcerative colitis flaring in the initial period of gestation., Takashi Mizushima, Satoshi Tanida, Tsutomu Mizoshita, Yoshikazu Hirata, Kenji Murakami, Takaya Shimura, Hiromi Kataoka, Takeshi Kamiya, Takashi Joh, Case reports in gastroenterology, 5, (1) 144 - 51,   2011年04月12日, 査読有り, A 36-year-old woman who had been diagnosed with ulcerative colitis at the age of 17 years was referred to our hospital because of severe abdominal pain and repeated bloody diarrhea that persisted during pregnancy despite combination therapy with high-dose corticosteroids and weekly granulocyte and monocyte adsorptive apheresis (GMA). She underwent combination therapy consisting of high-dose corticosteroids, intensive GMA (two sessions per week) and vancomycin, which was used to eradicate Clostridium difficile, under total parenteral nutrition control until the estimated weight of her fetus reached 1,000 g. This combination therapy was partially successful, resulting in almost complete disappearance of abdominal pain and a marked decrease in stool frequency. However bloody diarrhea persisted and the patient developed anemia and hypoalbuminemia and was unable to prolong her gestation time. Cesarean section was conducted at 28 weeks of gestation without any congenital abnormalities or neurological defects. Oral administration of tacrolimus was begun 7 days after cesarean section, which was followed by rapid induction of remission. Corticosteroids were then gradually tapered off. Tacrolimus is one therapeutic option after cesarean section in pregnant patients who do not respond well to GMA and high-dose corticosteroids for persistent active ulcerative colitis.
  • Metastatic colorectal cancer with severe liver dysfunction successfully treated using FOLFOX therapy., Takaya Shimura, Hiromi Kataoka, Yoshikazu Hirata, Takashi Mizushima, Kenji Murakami, Motoshi Mabuchi, Tsutomu Mizoshita, Eiji Kubota, Satoshi Tanida, Takeshi Kamiya, Takashi Joh, Journal of gastrointestinal cancer, 42, (1) 68 - 72,   2011年03月, 査読有り, INTRODUCTION: The liver is the most frequent site of metastases from colorectal cancer (CRC), and extensive liver metastases often cause severe secondary liver dysfunction. However, whether chemotherapy for metastatic CRC with severe liver dysfunction offers any clinical benefit is unclear since patients in this setting are typically excluded from clinical trials. DISCUSSION: We report herein a case of metastatic sigmoid colon cancer with severe liver dysfunction that was successfully treated using infusional 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX). FOLFOX was effective and well tolerated in the present case, and subsequent addition of bevacizumab to FOLFOX after disease progression was similarly feasible.
  • Involvement of oxidative stress and mucosal addressin cell adhesion molecule-1 (MAdCAM-1) in inflammatory bowel disease., Satoshi Tanida, Tsutomu Mizoshita, Takashi Mizushima, Makoto Sasaki, Takaya Shimura, Takeshi Kamiya, Hiromi Kataoka, Takashi Joh, Journal of clinical biochemistry and nutrition, 48, (2) 112 - 6,   2011年03月, 査読有り, The pathophysiology of inflammatory bowel disease involves excessive immune effects of inflammatory cells against gut microbes. In genetically predisposed individuals, these effects are considered to contribute to the initiation and perpetuation of mucosal injury. Oxidative stress is a fundamental tissue-destructive mechanisms that can occur due to the reactive oxygen species and reactive nitrogen metabolites which are released in abundance from numerous inflammatory cells that have extravasated from lymphatics and blood vessels to the lamina propria. This extravasation is mediated by interactions between adhesion molecules including mucosal addressin cell adhesion molecule-1 and vascular cell adhesion molecule-1 on the surface of lymphocytes or neutrophils and their ligands on endothelial cells. Thus, reactive oxygen species and adhesion molecules play an important role in the development of inflammatory bowel disease. The present review focuses on the involvement of oxidative stress and adhesion molecules, in particular mucosal addressin cell adhesion molecule-1, in inflammatory bowel disease.
  • Cardiovascular tolerance and autonomic nervous responses in unsedated upper gastrointestinal small-caliber endoscopy: a comparison between transnasal and peroral procedures with newly developed mouthpiece., Hiromi Kataoka, Junichiro Hayano, Takashi Mizushima, Mamoru Tanaka, Eiji Kubota, Takaya Shimura, Tsutomu Mizoshita, Satoshi Tanida, Takeshi Kamiya, Shunsuke Nojiri, Seiji Mukai, Kiyoshi Mizuno, Takashi Joh, Digestive endoscopy : official journal of the Japan Gastroenterological Endoscopy Society, 23, (1) 78 - 85,   2011年01月, 査読有り, BACKGROUND: Transnasal esophagogastroduodenoscopy (EGD) with small-caliber endoscopy appears to be less stressful to the cardiovascular system and has good patient tolerance. ENDO LEADER, a newly developed mouthpiece for peroral EGD with small-caliber endoscopy, is expected to reduce patient stress. We compared the patient acceptance, cardiovascular tolerance and autonomic nervous responses between transnasal EGD and peroral EGD with ENDO LEADER. PATIENTS AND METHODS: A total of 130 patients (transnasal group, 77; peroral group, 53) were enrolled. Pulse rate (P), blood pressure (BP), and peripheral blood oxygen saturation (SpO(2) ) were monitored. Acceptance of EGD was also assessed. Autonomic nervous responses were evaluated through analysis of heart rate variability using amplitude of the high-frequency component (HF) and low-frequency-to-high-frequency power ratio (LF/HF) as indices of cardiac vagal activity and sympathetic activity, respectively. RESULTS: Analysis of patient acceptance showed no differences between the two groups, except with regard to nasal pain. Increases in BP and P between before and during EGD examination were significantly higher in the peroral group. Although throat pain and overall tolerance scores were significantly correlated with ΔBP and ΔP, no correlations with nasal pain score were noted. Heart rate variability analysis revealed that heart rate increased significantly in the peroral group, but there were no differences in ΔHF or ΔLF/HF between the two groups. CONCLUSIONS: Patient acceptance was not significantly different between the transnasal and peroral with ENDO LEADER groups; however, transnasal EGD appears to be less stressful to the sympathetic nervous system, leading to smaller elevations in BP, P and heart rate.
  • Long-term high-dose proton pump inhibitor administration to Helicobacter pylori-infected Mongolian gerbils enhances neuroendocrine tumor development in the glandular stomach., Hironobu Tsukamoto, Tsutomu Mizoshita, Makoto Sasaki, Takashi Mizushima, Satoshi Tanida, Keiji Ozeki, Yoshikazu Hirata, Takaya Shimura, Hiromi Kataoka, Takeshi Kamiya, Shunsuke Nojiri, Tetsuya Tsukamoto, Masae Tatematsu, Takashi Joh, Asian Pacific journal of cancer prevention : APJCP, 12, (4) 1049 - 54,   2011年, 査読有り, Proton pump inhibitors (PPIs) are routinely used for control of upper gastrointestinal disorders, often with long-term application. However, there has been some concern about the long-term safety and the possibility of cancer induction and development of neuroendocrine tumors (NET) in the stomach. We therefore analyzed the influence of PPI use on tumor development histologically, immunohistochemically, and serologically in the glandular stomachs of Helicobacter pylori (Hp)-infected and uninfected Mongolian gerbils (MGs). 53 MGs were divided into 6 groups: Hp+25PPI, Hp+5PPI, Hp, 25PPI, 5PPI, and controls. The high-dose Hp+25PPI and 25PPI groups received the PPI (lansoprazole) at 25mg/kg/day, and the low-dose Hp+5PPI and 5PPI groups were given 5mg/kg/day. After 50 or 100 weeks, animals were sacrificed humanely, and the glandular stomach samples were evaluated histologically and phenotypically, using antibodies against chromogranin A (CgA), gastrin and gastric inhibitory polypeptide (GIP). Serum gastrin levels were also examined. NETs occurred in the Hp+25PPI, Hp+5PPI, Hp, and 25PPI groups, but there was no synergistic effect between Hp-infection and high-dose PPI administration. Serum gastrin was increased statistically by Hp infection and high-dose PPI administration, but not influenced by the low-dose. The NETs featured expression of CgA, but not gastrin or GIP. In conclusions, PPI at low dose had no influence on development of carcinomas and NETs in the Hp-infected and uninfected glandular MG stomach, suggesting clinical safety. However, PPI at high dose increased NET development and serum gastrin in the MG model.
  • The effect of omeprazole on gastric myoelectrical activity and emptying., Takeshi Kamiya, Michiko Shikano, Mamoru Tanaka, Hironobu Tsukamoto, Masahide Ebi, Yoshikazu Hirata, Takashi Mizushima, Kenji Murakami, Takaya Shimura, Tsutomu Mizoshita, Yoshinori Mori, Satoshi Tanida, Takashi Kato, Kenro Imaeda, Hiromi Kataoka, Takashi Joh, Journal of smooth muscle research = Nihon Heikatsukin Gakkai kikanshi, 47, (3-4) 79 - 87,   2011年, 査読有り, Omeprazole, a proton pump inhibitor, is widely used for the treatment of patients with peptic ulcer, gastroesophageal reflux disease and functional dyspepsia (FD), although some studies have demonstrated that omeprazole delays gastric emptying. The purpose of this study was to investigate the efficacy of omeprazole on gastric motility including gastric myoelectrical activity and gastric emptying. This study was performed on 12 healthy volunteers. Gastric motility was evaluated with cutaneously recorded electrogastrography (EGG) and gastric emptying of semi-solid meals using the (13)C-acetic acid breath test. EGG and gastric emptying were measured before and after treatment with 20 mg omeprazole orally for 7 days. In the fasting state, the percentage of EGG normogastria increased significantly compared to the baseline. No significant changes were observed in other EGG parameters including the percentage of tachygastria and bradygastria in both fasting and postprandial states, and the power ratios between both before and after ingestion of omeprazole. In addition, administrated omeprazole did not show any significant differences in the gastric emptying parameters such as the half emptying time. We conclude that administration of omeprazole did not affect gastric motility but improved gastric myoelectrical activity. These effects of omeprazole may be one of the mechanisms involved in its efficacy in relieving dyspeptic symptoms in FD patients.
  • A rare case of infectious colitis with ulcers in the cecum caused by Mycobacterium gordonae., Tsutomu Mizoshita, Satoshi Tanida, Takashi Mizushima, Yoshikazu Hirata, Kenji Murakami, Takaya Shimura, Yoshinori Mori, Hiromi Kataoka, Takeshi Kamiya, Takashi Joh, Internal medicine (Tokyo, Japan), 50, (21) 2583 - 6,   2011年, 査読有り, A 69-year-old female complained of persistent abdominal pain, and annular ulcers and ulcer scars were detected endoscopically in the cecum. Pathological findings included caseous granulomas with some Langhans giant cells, and Ziehl-Neelsen staining was negative. Mycobacterium gordonae (M. gordonae) was identified by the DNA-DNA hybridization method and culture (Ogawa medium) of biopsy samples from ulcerous cecal lesions. After 6 months of antibiotic therapy, ulcerous cecal lesions were healed, and no acid-fast bacteria were detected by culture of biopsy samples from scar tissue. We believe this is the first report of M. gordonae infection in the alimentary tract.
  • Lansoprazole induces collagenous colitis in the colon of Mongolian gerbils., Takashi Mizushima, Tsutomu Mizoshita, Makoto Sasaki, Satoshi Tanida, Hironobu Tsukamoto, Takaya Shimura, Takayoshi Kanematsu, Hiromi Kataoka, Takeshi Kamiya, Tetsuya Tsukamoto, Masae Tatematsu, Takashi Joh, Asian Pacific journal of cancer prevention : APJCP, 12, (10) 2759 - 62,   2011年, 査読有り, Collagenous colitis (CC) is an illness characterized by chronic diarrhea with possible effects on neoplastic development, but there have been no reports in animals. We therefore tried to establish CC development in a Mongolian gerbil (MG) model by long-term continuous lansoprazole (LPZ) administration and aimed to clarify the relationship between LPZ administration and CC occurrence. We divided 69 gerbils into 6 groups: Helicobacter pylori (Hp)-infected+high-dose LPZ, Hp-infected+low-dose-LPZ, Hp-infected, high-dose-LPZ, low- dose-LPZ, and control. The gerbils were sacrificed and entire colons were excised at experimental weeks 27, 54, and 108. We examined colonic lesions by staining of Swiss-roll intestines pathologically. A total of 3 gerbils had CC-like lesions in the proximal colon. All MGs with CC-like lesions were from LPZ treated groups (3 of 35; 8.6%). The thickened subepithelial collagen band detected in these lesions strongly resembled that of human CC lesions. Immunohistochemical analysis indicated a tendency for more chromogranin A-positive cells in the upper layer of colonic crypt following continuous LPZ administration. In conclusion, we successfully established development of CC-like lesions in an MG model by continuous LPZ administration and determined that the ectopic endocrine cells that were induced by LPZ administration may influence the occurrence of these lesions in the colon.
  • TGFβ induces proHB-EGF shedding and EGFR transactivation through ADAM activation in gastric cancer cells., Masahide Ebi, Hiromi Kataoka, Takaya Shimura, Eiji Kubota, Yoshikazu Hirata, Takashi Mizushima, Tsutomu Mizoshita, Mamoru Tanaka, Motoshi Mabuchi, Hironobu Tsukamoto, Satoshi Tanida, Takeshi Kamiya, Shigeki Higashiyama, Takashi Joh, Biochemical and biophysical research communications, 402, (3) 449 - 54,   2010年11月19日, 査読有り, BACKGROUND AND AIMS: Transforming growth factor-beta (TGFβ) is known to potently inhibit cell growth. Loss of responsiveness to TGFβ inhibition on cell growth is a hallmark of many types of cancer, yet its mechanism is not fully understood. Membrane-anchored heparin-binding EGF-like growth factor (proHB-EGF) ectodomain is cleaved by a disintegrin and metalloproteinase (ADAM) members and is implicated in epidermal growth factor receptor (EGFR) transactivation. Recently, nuclear translocation of the C-terminal fragment (CTF) of pro-HB-EGF was found to induce cell growth. We investigated the association between TGFβ and HB-EGF signal transduction via ADAM activation. MATERIALS AND METHODS: The CCK-8 assay in two gastric cancer cell lines was used to determine the effect for cell growth by TGFβ. The effect of two ADAM inhibitors was also evaluated. Induction of EGFR phosphorylation by TGFβ was analyzed and the effect of the ADAM inhibitors was also examined. Nuclear translocation of HB-EGF-CTF by shedding through ADAM activated by TGFβ was also analyzed. EGFR transactivation, HB-EGF-CTF nuclear translocation, and cell growth were examined under the condition of ADAM17 knockdown. RESULT: TGFβ-induced EGFR phosphorylation of which ADAM inhibitors were able to inhibit. TGFβ induced shedding of proHB-EGF allowing HB-EGF-CTF to translocate to the nucleus. ADAM inhibitors blocked this nuclear translocation. TGFβ enhanced gastric cancer cell growth and ADAM inhibitors suppressed this effect. EGFR phosphorylation, HB-EGF-CTF nuclear translocation, and cell growth were suppressed in ADAM17 knockdown cells. CONCLUSION: HB-EGF-CTF nuclear translocation and EGFR transactivation from proHB-EGF shedding mediated by ADAM17 activated by TGFβ might be an important pathway of gastric cancer cell proliferation by TGFβ.
  • Clinical features of interstitial lung disease induced by standard chemotherapy (FOLFOX or FOLFIRI) for colorectal cancer., T Shimura, N Fuse, T Yoshino, K Minashi, M Tahara, T Doi, T Joh, A Ohtsu, Annals of oncology : official journal of the European Society for Medical Oncology, 21, (10) 2005 - 10,   2010年10月, 査読有り, BACKGROUND: Chemotherapy-induced interstitial lung disease (ILD) in colorectal cancer (CRC) patients is rarely reported, but its clinical features remain to be clarified. PATIENTS AND METHODS: Using a computerized database, we retrospectively identified patients who developed ILD from 734 patients with CRC treated with infusional 5-fluorouracil, leucovorin and oxaliplatin (FOLFOX) or infusional 5-fluorouracil, leucovorin and irinotecan (FOLFIRI) from April 2005 to December 2008 at the National Cancer Center Hospital East. RESULTS: Of 734 patients, 11 patients developed ILD (1.5%) and 4 of those patients died (0.54%). Of the 11 patients, 10 showed pulmonary shadows other than lung metastases before chemotherapy. ILD developed during FOLFOX in six patients, at 137 days after completion of FOLFOX in one patient, during oxaliplatin interruption of FOLFOX in one patient and during FOLFIRI in the remaining three patients. FOLFOX had been administered at some point for all ILD patients, with a median of 10 cycles (range 2-17 cycles) and a median dose of administered oxaliplatin of 850 mg/m(2) (range 170-1445 mg/m(2)). CONCLUSIONS: ILD following FOLFOX or FOLFIRI is an uncommon but life-threatening complication. Care must be taken regarding the onset of ILD, not only during but also after chemotherapy for CRC.
  • Role of ES cell-expressed Ras (ERas) in tumorigenicity of gastric cancer., Eiji Kubota, Hiromi Kataoka, Mineyoshi Aoyama, Tsutomu Mizoshita, Yoshinori Mori, Takaya Shimura, Mamoru Tanaka, Makoto Sasaki, Satoru Takahashi, Kiyofumi Asai, Takashi Joh, The American journal of pathology, 177, (2) 955 - 63,   2010年08月, 査読有り, ERas, a unique member of the Ras family, was initially found only in embryonic stem (ES) cells, where it plays a crucial role in the transformation of transplanted ES cells to teratomas. ERas is involved in ES cell survival, and unlike other Ras family members, is constitutively active without any mutations. The aim of this study was to investigate the expression and role of ERas in human gastric cancer. To test whether ERas played a significant role in human cancer cells, we examined its expression and function in gastric cancer. ERas was expressed in gastric cancer cell lines at different levels. Induction of ERas expression activated the phosphatidylinositol 3 kinase (PI3K)/Akt axis and then enhanced anchorage-independent growth and ERas knockdown by siRNA suppressed cell invasion. Immunohistochemical analyses revealed that ERas was expressed in 38.7% (55/142) of human gastric carcinoma tissues, and its expression was significantly associated with metastasis to the liver (P < 0.0001) and lymph nodes (P < 0.05). ERas up-regulated transcription regulatory factors including ZFHX1A, ZFHX1B, and TCF3, which repress E-cadherin. These data suggest that ERas is activated in a significant population of gastric cancer, where it may play a crucial role in gastric cancer cell survival and metastases to liver via down-regulation of E-cadherin.
  • Tumor suppressor, AT motif binding factor 1 (ATBF1), translocates to the nucleus with runt domain transcription factor 3 (RUNX3) in response to TGF-beta signal transduction., Motoshi Mabuchi, Hiromi Kataoka, Yutaka Miura, Tae-Sun Kim, Makoto Kawaguchi, Masahide Ebi, Mamoru Tanaka, Yoshinori Mori, Eiji Kubota, Takashi Mizushima, Takaya Shimura, Tsutomu Mizoshita, Satoshi Tanida, Takeshi Kamiya, Kiyofumi Asai, Takashi Joh, Biochemical and biophysical research communications, 398, (2) 321 - 5,   2010年07月23日, 査読有り, BACKGROUND AND AIMS: AT motif binding factor 1 (ATBF1), a homeotic transcription factor, was identified as a tumor suppressor, and loss of heterozygosity at ATBF1 locus occurs frequently in gastric cancers. We previously showed that ATBF1 expression inversely correlated with the malignant character of gastric cancer and that ATBF1 enhanced the promoter activity of p21Waf1/Cip1. We also found that ATBF1 moves between cytoplasm and nucleus, but the precise mechanism of translocation is unknown. In this study, we investigated the mechanism of ATBF1 translocation to the nucleus with the runt domain transcription factor 3 (RUNX3) in cooperation with TGF-beta signal transduction. MATERIALS AND METHODS: To analyze the expression of ATBF1 and RUNX3 in gastric cancer cells, we performed immunohistochemistry on 98 resected gastric cancer tissue samples and scored the nuclear staining intensity as grade 0 to grade 5. Co-immunoprecipitation (co-IP) of ATBF1 and RUNX3 was performed. Dual luciferase assays were performed by transfecting ATBF1 and RUNX3 with a p21Waf1/Cip1 reporter vector. To investigate the nuclear translocation of endogenous ATBF1 and RUNX3 in response to TGF-beta signal, we examined the subcellular localization of ATBF1 and RUNX3 in gastric cancer cells treated with recombinant TGF-beta1 using confocal laser scanning microscopy. RESULTS: Strong immunohistochemical nuclear staining of ATBF1 was observed in 37 (37.8%) of the gastric cancer tissue samples, and RUNX3 nuclear staining was observed in 15 (15.3%). There was a statistically significant correlation between ATBF1 and RUNX3 nuclear localization (rs=0.433, p<0.001). Co-IP revealed a physical association between ATBF1 and RUNX3. ATBF1 and RUNX3 up-regulated p21Waf1/Cip1 promoter activity synergistically. In SNU16 gastric cancer cells, ATBF1 and RUNX3 were cytoplasmic before TGF-beta1 stimulation, but after 24h of TGF-beta1 stimulation, endogenous ATBF1 and RUNX3 translocated to the nucleus. CONCLUSION: ATBF1 associates with RUNX3 and translocates to the nucleus in response to TGF-beta signal transduction and might function in the nucleus as tumor suppressor and transcriptional regulator.
  • The effectiveness of packed therapy with three drugs in Helicobacter pylori eradication in Japan., M Sasaki, N Ogasawara, K Utsumi, T Kamiya, H Kataoka, S Tanida, T Mizoshita, T Shimura, Y Hirata, K Kasugai, T Joh, Methods and findings in experimental and clinical pharmacology, 32, (4) 243 - 6,   2010年05月, 査読有り, Primary Helicobacter pylori eradication rate using triple therapy (a proton pump inhibitor [PPI] + amoxicillin [AMPC] + clarithromycin [CAM], over 7 days) is showing a declining trend. In this study we report recent eradication rates and have evaluated the usefulness of a pack preparation of three drugs. H. pylori eradication rate was 85.1% (57/67) in 2004 but then fell to 75.2% (79/105) in 2005, 70.1% (68/97) in 2006 and 69.9% (58/83) in 2007. With the introduction of packs (lansoprazole [LPZ] 60 mg, AMPC 1500 mg, CAM 400 mg) the eradication rate recovered to 78.0% (110/141) in 2008. A comparative study in 2008 delineated that the eradication rate in the pack group (88.4%, 38/43) was significantly higher than that of the conventional group (73.5%, 72/98). These results suggest that packs of eradication medicine are useful in increasing eradication success.
  • Blockage of angiotensin II type 1 receptor regulates TNF-alpha-induced MAdCAM-1 expression via inhibition of NF-kappaB translocation to the nucleus and ameliorates colitis., Takashi Mizushima, Makoto Sasaki, Tomoaki Ando, Tsuneya Wada, Mamoru Tanaka, Yasuyuki Okamoto, Masahide Ebi, Yosikazu Hirata, Kenji Murakami, Tsutomu Mizoshita, Takaya Shimura, Eiji Kubota, Naotaka Ogasawara, Satoshi Tanida, Hiromi Kataoka, Takeshi Kamiya, J S Alexander, Takashi Joh, American journal of physiology. Gastrointestinal and liver physiology, 298, (2) ,   2010年02月, 査読有り, Mucosal vascular addressin cell adhesion molecule 1 (MAdCAM-1) is an important target in the treatment of inflammatory bowel disease (IBD). Recently, treatment of IBD with an antibody to alpha4beta7-integrin, a ligand for MAdCAM-1, has been an intense focus of research. Our aim was to clarify the mechanism by which MAdCAM-1 is regulated via angiotensin II type 1 receptor (AT1R), and to verify if AT1R might be a novel target for IBD treatment. The role of AT1R in the expression of MAdCAM-1 in SVEC (a murine high endothelial venule cell) and MJC-1 (a mouse colonic endothelial cell) was examined following cytokine stimulation. We further evaluated the effect of AT1R on the pathogenesis of immune-mediated colitis using AT1R-deficient (AT1R-/-) mice and a selective AT1R blocker. AT1R blocker significantly suppressed MAdCAM-1 expression induced by TNF-alpha, but did not inhibit phosphorylation of p38 MAPK or of IkappaB that modulate MAdCAM-1 expression. However, NF-kappaB translocation into the nucleus was inhibited by these treatments. In a murine colitis model induced by dextran sulfate sodium, the degree of colitis, judged by body weight loss, histological damage, and the disease activity index, was much milder in AT1R-/- than in wild-type mice. The expression of MAdCAM-1 was also significantly lower in AT1R-/- than in wild-type mice. These results suggest that AT1R regulates the expression of MAdCAM-1 under colonic inflammatory conditions through regulation of the translocation of NF-kappaB into the nucleus. Furthermore, inhibition of AT1R ameliorates colitis in a mouse colitis model. Therefore, AT1R might be one of new therapeutic target of IBD via regulation of MAdCAM-1.
  • Intranuclear translocation signaling of HB-EGF carboxy-terminal fragment and mucosal defense through cell proliferation and migration in digestive tracts., Satoshi Tanida, Hiromi Kataoka, Tsutomu Mizoshita, Takaya Shimura, Takeshi Kamiya, Takashi Joh, Digestion, 82, (3) 145 - 9,   2010年, 査読有り, Mucosal integrity in the digestive tracts is maintained by defense mechanisms which comprise mucin production, microcirculatory blood flow, intercellular junctions, cell growth and mucosal repair. These physiological features are known to be regulated by prostaglandins, nitric oxides, growth factors, and cytokines. Mucosal injury and inflammation occur when cytotoxic attacks overwhelm cellular capacity for defense or repair. Interleukin-8 (IL-8) promotes tumor cell proliferation in colon cancer cells after binding to its receptors, which are members of the G-protein-coupled receptor (GPCR) family. Stimulation of GPCR can induce shedding of epidermal growth factor (EGF) ligands via activation of A disintegrin and metalloprotease (ADAM), with subsequent transactivation of the EGF receptor (EGFR). In parallel with EGF signaling through EGFR activation, heparin-binding (HB)-EGF carboxy-terminal fragment (CTF) signaling is also involved in cell proliferation through nuclear export of promyelocytic leukemia zinc finger. IL-8 induces cell proliferation and migration by an ADAM-dependent intranuclear translocation pathway of HB-EGF-CTF. Here, we focus on the mechanisms of IL-8-induced HB-EGF-CTF signaling, which is involved in cytoprotection and cellular repair.
  • An endocrine cell carcinoma with gastric-and-intestinal mixed phenotype adenocarcinoma component in the stomach., Tsutomu Mizoshita, Hiromi Kataoka, Eiji Kubota, Takaya Shimura, Yoshinori Mori, Tsuneya Wada, Naotaka Ogasawara, Makoto Sasaki, Takeshi Kamiya, Masaki Sakamoto, Yoshimi Akamo, Takashi Joh, Digestive endoscopy : official journal of the Japan Gastroenterological Endoscopy Society, 21, (4) 258 - 61,   2009年10月, 査読有り, A 77-year-old man complained of bodyweight loss, and a Borrmann 3 type lesion was observed endoscopically in the anterior wall of angular region of the stomach. The endocrine cell carcinoma (ECC) having the cytoplasmic staining of chromogranin A (CgA) was detected pathologically in the biopsy samples. The patient underwent distal gastrectomy plus systemic lymph node (LN) dissection (D2 LN dissection), and pathological examination revealed ECC invading the subserosa, and no LN metastasis (pT2N0M0). None of the gastric and intestinal endocrine cell marker expression was apparent in the ECC cells. The lesion also contained a moderately differentiated type tubular adenocarcinoma component, which was judged to be gastric-and-intestinal mixed (GI type) phenotype, using gastric and intestinal exocrine cell markers. After the surgery, he left the hospital and started oral doxifluridine (600 mg/day). The patient now (March 2008, about 19 months since the surgery) continues this chemotherapy with no recurrence. In conclusion, we experienced ECC with a GI type adenocarcinoma component. The ECC cases with the GI type adenocarcinoma component may have a relatively good prognosis, being similar to the results of advanced gastric cancers from the viewpoint of gastric and intestinal phenotypic expression.
  • Feasibility of self-expandable metallic stent plus chemotherapy for metastatic gastric cancer with pyloric stenosis., Takaya Shimura, Hiromi Kataoka, Makoto Sasaki, Tomonori Yamada, Kazuki Hayashi, Shozo Togawa, Fumihiro Okumura, Eiji Kubota, Hirotaka Ohara, Takashi Joh, Journal of gastroenterology and hepatology, 24, (8) 1358 - 64,   2009年08月, 査読有り, BACKGROUND AND AIM: Self-expandable metallic stent placement is accepted as palliative therapy for advanced gastric cancer with gastric outlet obstruction, but data are lacking for chemotherapy after self-expandable metallic stent insertion. This study retrospectively compared results between surgery plus chemotherapy and stenting plus chemotherapy for metastatic gastric cancer with pyloric stenosis. METHODS: Subjects comprised 26 patients who received chemotherapy after surgery or endoscopic stenting for metastatic gastric cancer with pyloric stenosis between April 2000 and December 2007 in four Japanese hospitals. Patients were categorized into two groups: 15 patients who received chemotherapy after surgery for pyloric stenosis (Surgery group); and 11 patients who received chemotherapy after self-expandable metallic stent placement for pyloric stenosis (Stent group). RESULTS: Median survival time and median time to treatment failure were 284 days and 226 days in the Surgery group and 337 days and 247 days in the Stent group, respectively. No significant differences were noted between survival and time to treatment failure. No significant differences were found in median oral intake rate (Surgery, 93.1%; Stent, 93.2%) or median hospital stay rate (Surgery, 24.6%; Stent, 23.7%) during survival. Response rate was 45.5% in the Surgery group and 50% in the Stent group, with no significant difference. Likewise, no significant differences were noted between groups for frequencies of toxicity or complications. CONCLUSIONS: The present results suggest that chemotherapy after stenting is as effective and safe as chemotherapy after surgery. Stents may replace surgery in combination therapy with chemotherapy for metastatic gastric cancer with gastric outlet obstruction.
  • Combination chemotherapy with cisplatin and gemcitabine in malignant peritoneal mesothelioma., Satoshi Tanida, Hiromi Kataoka, Eiji Kubota, Yoshinori Mori, Makoto Sasaki, Naotaka Ogasawara, Tsuneya Wada, Tsutomu Mizoshita, Takaya Shimura, Kenji Murakami, Takashi Mizushima, Yoshikazu Hirata, Yasuyuki Okamoto, Motoshi Mabuchi, Masahide Ebi, Mamoru Tanaka, Takeshi Kamiya, Satoru Takahashi, Takashi Joh, International journal of clinical oncology, 14, (3) 266 - 9,   2009年06月, 査読有り, Malignant peritoneal mesothelioma is a rare neoplasm with a rapidly fatal course. The response of this disease to treatment is poor because it tends to be advanced at diagnosis and tends to have inherent resistance to chemotherapeutic treatment. We describe three patients with malignant peritoneal mesothelioma who received combination chemotherapy with cisplatin and gemcitabine. After a histopathological diagnosis of epithelial-type malignant peritoneal mesothelioma, all patients underwent systemic chemotherapy because of the advanced disease stage. Moreover, one patient would have been at high risk of cardiac events, because of congenital heart malformation if complete surgical resection had been performed. This chemotherapy achieved a partial response in two patients, but had no effect in one. Combination chemotherapy with cisplatin and gemcitabine may prove to be one of the recommended treatments for patients with malignant peritoneal mesothelioma in the near future.
  • BCL6 degradation caused by the interaction with the C-terminus of pro-HB-EGF induces cyclin D2 expression in gastric cancers., Y Hirata, N Ogasawara, M Sasaki, T Mizushima, T Shimura, T Mizoshita, Y Mori, E Kubota, T Wada, S Tanida, H Kataoka, T Kamiya, S Higashiyama, T Joh, British journal of cancer, 100, (8) 1320 - 9,   2009年04月21日, 査読有り, BCL6 is a transcriptional repressor that has important functions in lymphocyte differentiation and lymphomagenesis, but there have been no reports of BCL6 expression in gastric cancers. In the present study, we investigated the BCL6 function in gastric cancers. Treatment with TPA resulted in BCL6 degradation and cyclin D2 upregulation. This phenomenon was inhibited by the suppression of the nuclear translocation of HB-EGF-CTF (C-terminal fragment of pro-HB-EGF). The HB-EGF-CTF nuclear translocation leads to the interaction of BCL6 with HB-EGF-CTF and the nuclear export of BCL6, and after that BCL6 degradation was mediated by ubiquitin/proteasome pathway. Real-time RT-PCR and siRNA targeting BCL6 revealed that BCL6 suppresses cyclin D2 expression. Our data indicate that BCL6 interacts with nuclear-translocated HB-EGF-CTF and that the nuclear export and degradation of BCL6 induces cyclin D2 upregulation. We performed immunohistochemical analyses of BCL6, HB-EGF and cyclin D2 in human gastric cancers. The inverse correlation between BCL6 and cyclin D2 was also found in HB-EGF-positive human gastric cancers. BCL6 degradation caused by the HB-EGF-CTF also might induce cyclin D2 expression in human gastric cancers. Inhibition of HB-EGF-CTF nuclear translocation and maintenance of BCL6 function are important for the regulation of gastric cancer progression.
  • Lentinan with S-1 and paclitaxel for gastric cancer chemotherapy improve patient quality of life., Kataoka H, Shimura T, Mizoshita T, Kubota E, Mori Y, Mizushima T, Wada T, Ogasawara N, Tanida S, Sasaki M, Togawa S, Sano H, Hirata Y, Ikai M, Mochizuki H, Seno K, Itoh S, Kawai T, Joh T, Hepatogastroenterology., 56, (90) 547 - 50,   2009年03月, 査読有り, BACKGROUND/AIMS: Lentinan (LNT), a purified beta-glucan, is a biological and immunological modifier and has been used as an anticancer drug in combination with 5-fluorouracil for gastric cancer in Japan. In this prospective randomized study, we evaluated the effects of LNT combination with regard to quality of life (QOL) and LNT binding ratio in monocytes. METHODOLOGY: Twenty patients were evaluated for 12 weeks. One cycle was 3 weeks and S-1 (day1-14) and Paclitaxel (days1 and 8) were administered. LNT was used once a week (days 1, 8 and 15) and it was used for all 12 weeks in the LNT 12-wk group and only for the last 6 weeks in the LNT 6-wk group. QOL was evaluated weekly by QOL-ACD, and binding of LNT to monocytes was measured by flow cytometry. RESULTS: There were individual variations in the binding ratio of LNT to monocytes from 0.16% to 11.95%. Toxicity with chemotherapy was not improved in the LNT 12-wk group, however, the total QOL score was significantly elevated in the LNT 12-wk group (p = 0.018) but not in the LNT 6-wk group. CONCLUSION: LNT combination from the beginning of the chemotherapy may be an important factor for the improvement of patient QOL.
  • Gastric phenotypic expression and histogenesis of metachronous gastric cancers endoscopically resected., Mizoshita T, Kataoka H, Tanida S, Sasaki M, Ogasawara N, Kubota E, Wada T, Yamada T, Mori Y, Shimura T, Tsukamoto T, Tatematsu M, Joh T, Hepatogastroenterology., 56, (90) 542 - 6,   2009年03月, 査読有り, BACKGROUND/AIMS: Endoscopic Resection (ER) has been performed for early gastric cancers, and metachronous gastric cancers (MGCs) were occasionally observed. Most MGCs were classified histologically as the differentiated type. However, there have been no data on the gastric and intestinal phenotypic classification of MGCs. In our previous study, Hp-infection in MG may trigger intestinalization of gastric cancers. We therefore speculate the phenotype shift in MGC lesions under Hp-chronic-infection. METHODOLOGY: We examined the 17 MGC lesions phenotypically and histologically by using several gastric and intestinal epithelial cell markers, MUC5AC, MUC6, MUC2 and villin. RESULTS: Most lesions (16/17) exhibited the differentiated type. In 8 first cancers, the lesions were divided phenotypically into 2 G, 4 GI, 1 I, and 1 N types. In 9 second/third cancers, the lesions were divided phenotypically into 3 G, 1 GI, 4 I, and 1 N types. The first lesions (6/8) had more gastric phenotypic expression compared with the second/third ones (4/9) in the MGCs, although there was no significant difference between two groups (P = 0.28). CONCLUSION: Our present data suggest the possibility that the cancer retaining G type is detected endoscopically earlier than that obtaining the intestinal phenotypic expression by the phenotypic shift, which may partially explain the MGC occurrence.
  • Advanced stomach and pancreas cancer successfully treated with combination chemotherapy with S-1/paclitaxel/lentinan., Kubota E, Kataoka H, Hayashi K, Kamiya T, Sasaki M, Ogasawara N, Yamada T, Wada T, Mori Y, Mizoshita T, Shimura T, Mizushima T, Okamoto Y, Ohara H, Joh T, Hepatogastroenterology., 56, (89) 106 - 10,   2009年01月, 査読有り, We report a case of stomach and pancreas cancers that showed marked responses to combination chemotherapy consisting of S-1, paclitaxel (PTX), and lentinan (LNT). A 67-year-old Japanese man was referred to our hospital in July 2005, diagnosed with advanced gastric cancer. Subsequent examination revealed the existence of cancers in the stomach and pancreas, with lymph nodes and peritoneal metastasis and ascites. The patient received combined chemotherapy (one course comprised 3 weeks) with S-1 (100 mg/body, day 1-14 followed by withdrawal for 1 week), PTX (50 mg/m2, day 1 and day 8), and LNT (2 mg/m2, day 1, day 8 and day 15). After completion of 4 courses, the patient achieved partial response (PR), with complete disappearance of the primary gastric tumor and ascites. He maintained in PR for 17 months. We analyzed Th1/ Th2 ratio and LNT binding rate to monocytes by flow cytometry. Combination chemotherapy with S-1/PTX/LNT can be an effective treatment for unresectable advanced gastric carcinoma.
  • Gastric-and-intestinal mixed endocrine cell phenotypic expression of carcinoid tumors in the rectum., Yoshikazu Hirata, Tsutomu Mizoshita, Takashi Mizushima, Takaya Shimura, Yoshinori Mori, Eiji Kubota, Tsuneya Wada, Naotaka Ogasawara, Satoshi Tanida, Hiromi Kataoka, Makoto Sasaki, Takeshi Kamiya, Tetsuya Tsukamoto, Masae Tatematsu, Takashi Joh, Oncology reports, 21, (1) 107 - 12,   2009年01月, 査読有り, We have previously demonstrated that gastric and intestinal endocrine cell (End-cell) marker expression is important for assessment of the histogenesis of endocrine cell tumors. However, the End-cell phenotypes of carcinoid tumors in the rectum remain largely unclear. We therefore examined marker expression of rectal carcinoid tumors. We evaluated 20 rectal carcinoid tumors (as well as 8 from the stomach for comparison) phenotypically, using gastrin, gastric inhibitory polypeptide (GIP) and glucagons-like peptide-1 (GLP-1) as End-cell markers. Rectal carcinoid tumors were divided into 3 endocrine-gastric (e-G), 16 endocrine-gastric-and-intestinal mixed (e-GI), 1 endocrine-intestinal (e-I), and 0 endocrine-null (e-N) types, thus 19 (e-G+ e-GI types, 95%) had gastric phenotypic expression, while 17 (e-GI+ e-I types, 85%) harbored intestinal elements. Stomach carcinoid tumors were classified as 6 e-G and 2 e-N types, respectively. In conclusion, most rectal carcinoid tumors exhibited the e-GI type, suggesting the importance of gastric End-cell marker expression for histogenesis of the rectal carcinoid tumors. Further studies of pathological and biological analyses are needed to clarify the histogenesis of the carcinoid tumors.
  • Gastric phenotype signet-ring cell carcinoma of the stomach with multiple bone metastases effectively treated with sequential methotrexate and 5-fluorouracil., Tsutomu Mizoshita, Hiromi Kataoka, Eiji Kubota, Yasuyuki Okamoto, Takaya Shimura, Yoshinori Mori, Tsuneya Wada, Naotaka Ogasawara, Makoto Sasaki, Takeshi Kamiya, Takashi Joh, International journal of clinical oncology, 13, (4) 373 - 6,   2008年08月, 査読有り, A 63-year-old woman presented with an abnormal serum alkaline phosphatase (ALP) level. Computed tomography (CT) scan of the abdomen and pelvis and radioisotope (RI) examination led to a strong suspicion of systemic bone metastatic tumors, although the origin was not known. Biopsies from bone metastatic lesions in the left ilium were performed under CT scan, and signet-ring cell carcinoma cells were detected pathologically. Also, a 0-IIc-like lesion was observed endoscopically in the stomach, and signet-ring cell carcinoma cells were also detected histologically. The patient's platelet (Plt) levels were reduced and slight bleeding from the gingiva was detected when she brushed her teeth. Both the stomach and the bone metastatic lesions exhibited a gastric phenotype (G type) phenotypically. From these findings, we diagnosed the patient as having advanced (inoperable) stomach cancer with multiple bone metastases; she also exhibited disseminated intravascular coagulation (DIC). We treated her with sequential methotrexate and 5-fluorouracil (sequential MTX/5-FU) therapy after obtaining her informed consent. After six cycles of the chemotherapy, the abnormal ALP and Plt levels were alleviated. At present, she is receiving weekly sequential MTX/5-FU therapy at the outpatient oncology unit; she has been receiving the therapy for about 7 months since the detection of the bone metastases and has had a total of 17 cycles. In conclusion, sequential MTX/5-FU therapy was effective for a patient with G-type signet-ring cell carcinoma of the stomach with bone metastases, suggesting that the phenotypic classification may be one of the useful markers for prediction of the effectiveness of chemotherapy in patients with inoperable advanced stomach cancer.
  • Suppression of proHB-EGF carboxy-terminal fragment nuclear translocation: a new molecular target therapy for gastric cancer., Takaya Shimura, Hiromi Kataoka, Naotaka Ogasawara, Eiji Kubota, Makoto Sasaki, Satoshi Tanida, Takashi Joh, Clinical cancer research : an official journal of the American Association for Cancer Research, 14, (12) 3956 - 65,   2008年06月15日, 査読有り, PURPOSE: Inactivation of epidermal growth factor (EGF) receptor (EGFR) represents a promising strategy for the development of selective therapies against epithelial cancers and has been extensively studied as a molecular target for cancer therapy. However, little attention has been paid to remnant cell-associated domains created by cleavage of EGFR ligands. The present study focused on recent findings that cleavage of membrane-anchored heparin-binding EGF-like growth factor (proHB-EGF), an EGFR ligand, induces translocation of the carboxyl-terminal fragment (CTF) of HB-EGF from the plasma membrane to the nucleus and regulates cell cycle. EXPERIMENTAL DESIGN: Two gastric cancer cell lines, MKN28 and NUGC4, were used. KB-R7785, an inhibitor of proHB-EGF shedding, was used to suppress HB-EGF-CTF nuclear translocation with cetuximab, which inhibits EGFR phosphorylation. Cell growth was analyzed using 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt assay, apoptosis was evaluated by assay of caspase-3 and caspase-7, and cell cycle was investigated by flow cytometry. RESULTS: Immunofluorescence study confirmed that KB-R7785 inhibited HB-EGF-CTF nuclear translocation under conditions of proHB-EGF shedding induction by 12-O-tetradecanoylphorbol-13-acetate in gastric cancer cells. KB-R7785 inhibited cell growth in a dose-dependent manner and high-dose KB-R7785 induced apoptosis. Moreover, KB-R7785 induced cell cycle arrest and increased sub-G1 DNA content. KB-R7785 suppressed cyclin A and c-Myc expression. All effects of KB-R7785 were reinforced by combination with cetuximab. CONCLUSIONS: These results suggest that both inhibition of EGFR phosphorylation and inhibition of HB-EGF-CTF nuclear translocation play crucial roles in inhibitory regulation of cancer cell growth. Suppression of HB-EGF-CTF nuclear translocation might offer a new strategy for treating gastric cancer.
  • Rectal inflammatory fibroid polyp resected with endoscopic submucosal dissection., Takaya Shimura, Hiromi Kataoka, Makoto Sasaki, Eiji Kubota, Shigehiro Shiraki, Kei Matsusako, Yoshihide Nakayama, Tsutomu Mizoshita, Takashi Mizushima, Takashi Joh, Internal medicine (Tokyo, Japan), 47, (23) 2029 - 31,   2008年, 査読有り, Inflammatory fibroid polyp (IFP) is a rare benign tumor originating from the submucosa of the gastrointestinal tract. Most are found in the stomach, with only one previous case reported in the rectum. IFPs are typically larger than 1 cm in diameter and present symptoms. Colonoscopic examination of an asymptomatic 66-year-old man revealed a small submucosal tumor, 3 mm in diameter, in the rectum. The lesion was completely resected by endoscopic submucosal dissection (ESD) and was histopathologically diagnosed as IFP. We report herein a very rare rectal IFP that could be treated and diagnosed with ESD.
  • Effect of plaunotol in combination with clarithromycin against clarithromycin-resistant Helicobacter pylori in vitro and in vivo., Makoto Sasaki, Tsutomu Mizoshita, Takashi Mizushima, Harumi Inoue, Takeshi Kamiya, Hiromi Kataoka, Naotaka Ogaswara, Tsuneya Wada, Eiji Kubota, Yoshinori Mori, Takaya Shimura, Hirokazu Hirata, Kenji Ando, Yasuyuki Okamoto, Hirotaka Ohara, Haruhisa Nakao, Takashi Joh, The Journal of antimicrobial chemotherapy, 60, (5) 1060 - 3,   2007年11月, 査読有り, OBJECTIVES: Recently, there has been a decrease in the eradication rate of Helicobacter pylori due to the increase in antibiotic resistance of this bacterium. Plaunotol, a cytoprotective anti-ulcer agent, exhibits antibacterial activity against H. pylori. The purpose of the present study was to investigate the effect of plaunotol in combination with clarithromycin against clarithromycin-resistant H. pylori clinical isolates. METHODS AND RESULTS: In the chequerboard titration method, the combination of plaunotol and clarithromycin showed a synergistic effect against 67% (10/15) clarithromycin-resistant strains and an additive effect against the other strains. No indifferent and antagonistic effects were observed against any of the strains tested. In a gastritis model of Mongolian gerbils infected with clarithromycin-resistant H. pylori, the plaunotol (40 mg/kg) and clarithromycin (66.6 mg/kg) combination exhibited synergistic effects; however, neither plaunotol nor clarithromycin alone showed bactericidal effects. CONCLUSIONS: These results suggest that plaunotol may play a useful role in combination with anti-H. pylori drugs in the treatment of diseases associated with clarithromycin-resistant H. pylori.
  • Endoscopic submucosal dissection is useful and safe for intramucosal gastric neoplasms in the elderly., Shimura T, Joh T, Sasaki M, Kataoka H, Tanida S, Ogasawara N, Yamada T, Kubota E, Wada T, Inukai M, Yoshioka N, Saida Y, Acta Gastroenterol Belg., 70, (4) 323 - 30,   2007年10月
  • Advantages of endoscopic submucosal dissection over conventional endoscopic mucosal resection., Takaya Shimura, Makoto Sasaki, Hiromi Kataoka, Satoshi Tanida, Tadayuki Oshima, Naotaka Ogasawara, Tsuneya Wada, Eiji Kubota, Tomonori Yamada, Yoshinori Mori, Fumitaka Fujita, Haruhisa Nakao, Hirotaka Ohara, Masami Inukai, Kunio Kasugai, Takashi Joh, Journal of gastroenterology and hepatology, 22, (6) 821 - 6,   2007年06月, 査読有り, BACKGROUND: Endoscopic mucosal resection is an established method for treating intramucosal gastric neoplasms. Conventional endoscopic mucosal resection has predominantly been performed using strip biopsy, but local recurrence sometimes occurs due to such piecemeal resection. Endoscopic submucosal dissection has recently been performed in Japan using new devices such as an insulation-tip diathermic knife. The efficacy and problems associated with endoscopic submucosal dissection were evaluated by comparison with conventional endoscopic mucosal resection. METHODS: Treatment consisted of conventional endoscopic mucosal resection for 48 lesions from January 1999 to October 2002, and endoscopic submucosal dissection for 59 lesions from November 2002 to June 2005. Endoscopic submucosal dissection was performed using an insulation-tip diathermic knife and flex and hook knives, as appropriate. RESULTS: For lesions >or=11 mm in size, en bloc resection rates were significantly higher with endoscopic submucosal dissection than with conventional endoscopic mucosal resection, but treatment time was significantly longer. En bloc resection rates were higher with endoscopic submucosal dissection than with conventional endoscopic mucosal resection in all areas. Treatment of lesions in the upper one-third of the stomach took a long time using endoscopic submucosal dissection, and intraoperative bleeding was frequent. However, en bloc resection rates and intraoperative bleeding with endoscopic submucosal dissection were improved using various knives. CONCLUSIONS: Endoscopic submucosal dissection can take a long time, but is superior to conventional endoscopic mucosal resection for treating intramucosal gastric neoplasms.
  • Contribution of Helicobacter pylori infection and obesity on heartburn in a Japanese population, Eiji Kubota, Satoshi Tanida, Makoto Sasaki, Hiromi Kataoka, Tadayuki Oshima, Naotaka Ogasawara, Tsuneya Wada, Tomonori Yamada, Yoshinori Mori, Fumitaka Fujita, Takaya Shimura, Hirotaka Ohara, Tamaki Yamada, Takashi Joh, Journal of Clinical Biochemistry and Nutrition, 39, 168 - 173,   2006年12月, 査読有り
  • Oral vaccination against Helicobacter pylori with recombinant cholera toxin B-subunit., Eiji Kubota, Takashi Joh, Satoshi Tanida, Makoto Sasaki, Hiromi Kataoka, Katsushi Watanabe, Keisuke Itoh, Tadayuki Oshima, Naotaka Ogasawara, Shouzo Togawa, Tsuneya Wada, Tomonori Yamada, Yoshinori Mori, Fumitaka Fujita, Takaya Shimura, Hirotaka Ohara, Masanori Isaka, Yoko Yasuda, Makoto Itoh, Helicobacter, 10, (4) 345 - 52,   2005年08月, 査読有り, BACKGROUND: The innocuous pure recombinant cholera toxin B-subunit (rCTB) is very attractive as a strong adjuvant for host immunization, but little is known about rCTB's gastric mucosal immunoadjuvanticity against Helicobacter pylori. The immunoadjuvanticity of rCTB against H. pylori was tested. MATERIAL AND METHODS: Mice were immunized with sonicated H. pylori and rCTB orally or intranasally and sacrificed on day 42 after immunization. Passive cutaneous anaphylaxis (PCA) test was performed to evaluate IgE-mediated anaphylaxis with serum from mice to which H. pylori-antigen with rCTB had been administered. Immunoglobulin titer specific to H. pylori in serum, lavation of the gastrointestinal tracts and feces were examined. Gastritis in vaccinated mice after a challenge was assessed with the scoring defined from grading of gastric inflammation. H. pylori proliferation after immunization was investigated by counting colony forming units (CFU) per gram of stomach tissue. RESULTS: PCA test exhibited no reactions against the serum from mice immunized with H. pylori-antigen with rCTB administered orally and intranasally. Oral and nasal coadministrations of rCTB significantly raised systemic and mucosal immunities against H. pylori and suppressed proliferation of H. pylori in gastric mucosa. The score of gastritis in mice immunized orally was significantly higher than that of mice immunized nasally due to postimmunization gastritis. Only oral administration of rCTB suppressed H. pylori proliferation as compared with intranasal administration and without rCTB. CONCLUSIONS: The present study indicated that rCTB has systemic and mucosal immunoadjuvanticities against H. pylori and that oral vaccination with rCTB might additively support antibiotic eradication.

MISC

  • 消化器癌に対する尿中診断バイオマーカーの現況と将来展望, 志村貴也, 奥田悠介, 岩崎弘靖, 片岡洋望, 消化器・肝臓内科, 7, (2) 128 - 135,   2020年02月, 招待有り
  • 十二指腸腫瘍に対する内視鏡治療 ー表在性非乳頭部十二指腸上皮性腫瘍を中心にー, 志村貴也, 第30回日本消化器内視鏡学会東海セミナー,   2020年01月, 招待有り
  • 東海地区におけるH.Pylori感染症の現状をみる-名古屋市立大学病院におけるH.Pylori感染症診療の現状-, 溝下 勤, 佐々木誠人, 谷田諭史, 水島隆史, 志村貴也, 片岡洋望, 神谷 武, 城 卓志, 14, (5) 381 - 384,   2010年10月, 招待有り
  • 糖鎖連結クロリンによる消化管癌に対する新規光線力学的治療法の開発 活性酸素の産生とアポトーシス誘導の検討, 田中 守, 片岡 洋望, 志村 貴也, 溝下 勤, 谷田 諭史, 神谷 武, 森田 明理, 矢野 重信, 城 卓志, G.I.Research, 18, (4) 374 - 375,   2010年08月
  • 消化性潰瘍の症状,QOLと診断, 谷田諭史, 神谷 武, 溝下 勤, 志村貴也, 片岡洋望, 城 卓志, 治療, 92, (3) 424 - 427,   2010年03月, 招待有り
  • 胃癌の胃型腸型粘液形質制御における転写因子型癌抑制因子ATBF1の役割 -核・細胞質移行の意義-, 片岡洋望, 三浦 裕, 馬渕元志, 森 義徳, 志村貴也, 溝下 勤, 谷田諭史, 神谷 武, 川口 誠, 城 卓志, Progress in Medicine., 30, (3) 787 - 790,   2010年, 招待有り
  • 消化管がん分子標的治療薬最新のエビデンス 5)mTOR阻害剤,c-Met阻害剤, 志村貴也, 布施望, 大津敦, 腫瘍内科, 3, (2) 200 - 207,   2009年02月, 招待有り
  • オリゴ糖生成酵素による国民健康維持の試み(解説), 佐々木誠人, 神谷吉宣, 岡山直司, 神谷 武, 片岡洋望, 今枝憲郎, 小笠原尚高, 久保田英嗣, 和田恒哉, 志村貴也, 溝下 勤, 村上賢治, 水島隆史, 平田慶和, 水野達夫, 海老正秀, 岡本泰幸, 田中 守, 城 卓志, 消化と吸収, 31, (1) 48 - 51,   2009年, 招待有り
  • HB-EGF-CTFを標的とした新規胃癌分子標的治療の可能性, 志村貴也, Nagoya Med J., 50,   2009年, 招待有り
  • レニン・アンギオテンシン系(RAS)と炎症性腸疾患, 佐々木誠人, 和田恒哉, 水島隆史, 小笠原尚高, 久保田英嗣, 森 義徳, 志村貴也, 溝下 勤, 平田慶和, 岡本泰幸, 片岡洋望, 神谷 武, 城 卓志, 潰瘍 Ulcer Research, 35, (1) 71 - 74,   2008年, 招待有り
  • 新消化管の分子生物学 消化管のEGFRリガンド群の放出にはたらく分子機構, 谷田諭史, 片岡洋望, 志村貴也, 佐々木誠人, 小笠原尚高, 神谷 武, 城 卓志, G.I. Research, 16, (6) 540 - 545,   2008年, 招待有り
  • 炎症性サイトカインによるEGF受容体リガンドC末端を介した細胞増殖機序, 谷田諭史, 佐々木誠人, 片岡洋望, 小笠原尚高, 久保田英嗣, 和田恒哉, 志村貴也, 溝下 勤, 村上賢治, 平田慶和, 水島隆史, 馬渕元志, 海老正秀, 岡本泰幸, 田中 守, 神谷 武, 城 卓志, 消化器と免疫, 45,   2008年, 招待有り
  • 非びらん性胃食道逆流症に対するクエン酸モサプリドの効果, 神谷 武, 安達 啓, 鹿野美千子, 松久映理子, 岡本泰幸, 水島隆史, 志村貴也, 溝下 勤, 森 義徳, 和田恒哉, 久保田英嗣, 小笠原尚高, 片岡洋望, 佐々木誠人, 城 卓志, 新薬と臨床, 56, (11) 1809 - 1812,   2007年, 招待有り
  • オリゴ糖生成酵素による腸管内環境改善を介した炎症性腸疾患予防への試み, 佐々木誠人, 神谷 武, 片岡洋望, 小笠原尚高, 久保田英嗣, 和田恒哉, 志村貴也, 溝下 勤, 水島隆史, 平田慶和, 岡本泰幸, 城 卓志, The Japanesse Society of Digestion and Absorption, 31, (1) 20 - 22,   2007年, 招待有り
  • びまん性胃・十二指腸炎を合併した潰瘍性大腸炎の一例, 志村貴也, 犬飼政美, 吉岡宣夫, 齋田康彦, 村上賢治, 小林邦生, 谷岡書彦, 日本消化器病学会雑誌, 103, (1) 30 - 36,   2006年, 査読有り
  • 胃食道逆流症(GERD)の長期予後, 和田恒哉, 佐々木誠人, 志村貴也, 藤田史岳, 森 義徳, 久保田英嗣, 山田智則, 小笠原尚高, 大島忠之, 谷田諭史, 片岡洋望, 城 卓志, Therapeutic Research, 27, (4) 683 - 685,   2006年, 招待有り
  • 上部消化器癌の内視鏡治療の概要 上部消化器癌の内視鏡治療と偶発症, 山田智則, 志村貴也, 城 卓志, Mebio, 23, (10) 33 - 37,   2006年, 招待有り
  • 転移巣に横紋筋成分の出現を認めた食道の「いわゆる癌肉腫」の一例, 志村貴也, 犬飼政美, 吉岡宣夫, 齋田康彦, 山田智則, 今井堅吾, 鈴木大輔, 谷岡書彦, Gastroenterological Endoscopy, 46,   2004年, 査読有り
  • 繰り返す腸炎症状で発症した特発性門脈血栓症の1例, 今井堅吾, 犬飼政美, 吉岡宣夫, 齋田康彦, 鈴木大介, 山田智則, 志村貴也, 日本内科学会雑誌, 92, (8) 1524 - 1527,   2003年, 査読有り

特許

  • 大腸癌診断用マーカー、大腸癌の診断を補助する方法、大腸癌の診断のためにデータを収集する方法、大腸癌の診断用キット, 特願2019-149338
  • 食道癌バイオマーカー及びその用途, 特願2019-139247
  • 胃癌バイオマーカー及びその用途, 特願2018-118340

受賞

  •   2014年03月, The Surgical Research Council’s, 10th Annual Symposium in Cellular, Molecular, and Clinical Research in Surgery., The Winner, Potential of urinary MMP-9/NGAL complex as a novel non-invasive biomarker for the early detection of gastric cancer
  •   2009年02月, 日本消化管学会, 日本消化管学会学会賞最優秀賞(基礎部門), Suppression of proHB-EGF Carboxy-terminal Fragment Nuclear Translocation: A New Molecular Target Therapy for Gastric Cancer
  •   2008年12月, 名古屋市立大学医学会, 名古屋市立大学医学会賞, HB-EGF-CTFを標的とした新規胃癌分子標的治療の可能性

競争的資金

  • 腫瘍特異的siRNAデリバリーによるKRAS変異型大腸癌に対する新規治療法開発, 日本学術振興会, 科学研究費助成事業 基盤研究(C),   2018年04月 - 2021年03月, KRAS変異型大腸癌に有意に高発現する膜結合性タンパクに対する抗体:抗MBP-X抗体をリポソーム表面に結合させたリポソームを担体としKRAS siRNAを内包したPEG化リポソームを作成することに成功した。表面に抗MBP-X抗体を結合させ内部にsiKRASを内包した新規リポソームである①siKRAS-MBP-X-LPの他、コントロールとして表面にIgGを結合した②siKRAS-IgG-LP、非特異的siRNAのコントロール(siNT)を内包した③siNT-MBP-X-LP、④siNT-IgG-LPを作成し、各リポソームのキャラクタリゼーションを完了した。 蛍光免疫染色やフローサイトメトリーを使用してsiKRAS-MBP-X-LPがKRAS変異型大腸癌細胞表面へ集積・結合することを確認するとともにKRASタンパクの発現抑制効率を検討・確認した。現在、KRAS変異型大腸癌細胞株に対する細胞増殖抑制効果を検討中である。
  • 体内循環miRNAによる食道癌内視鏡治療適応診断バイオマーカーの開発, 公益財団法人 内視鏡医学研究振興財団, 2019年度研究助成,   2020年02月 - 2020年12月
  • 尿中タンパクバイオマーカーによる大腸がん早期診断法の開発, 日本医療研究開発機構(AMED), 橋渡し研究戦略的推進プログラム,   2019年04月 - 2020年03月, 課題番号:A98
  • 膵癌における新規分子標的療法の解明;オートタキシンは治療ターゲットになるか?, 日本学術振興会, 科学研究費助成事業 基盤研究(C),   2017年04月 - 2020年03月, A. オートタキシン阻害剤による膵癌細胞増殖抑制効果 ①膵癌増殖抑制効果の検証 (in vitro研究):膵癌細胞株を培養ディッシュにまき、PF-8380 投与・非投与環境下での増殖能について比較したところ、両群に有意な差は認めなかった。②膵癌細胞増殖抑制効果の検証 (in vivo研究):PF-8380を腹腔内に投与し、腫瘍の増大について経時変化を追ったところ、3週間の経時観察により、治療群で腫瘍増大抑制効果がみられた。B. オートタキシン阻害剤による膵癌細胞浸潤・転移抑制効果 ① 膵癌細胞浸潤抑制効果の検証:上記と同様にLPCから産生するLPA量が培地内では十分量ではないためか、in vitroでは有意な差が得られなかった。 ② 膵癌細胞転移抑制効果の検証:ルシフェラーゼ発現膵癌細胞株をマウスに移植。PF-8380投与 ・非投与群の2群に分け、イメージシステムを用いて追跡観察を行ったところ、3週間の経時観察の後、治療群では転移・播種巣の抑制が確認された。 C.オートタキシンの膵癌抗癌剤耐性獲得に関わる評価:In vitro実験ではPF-8380の効果が十分でないことが疑われたため、LPA存在・非存在下でのIC50の変化をまず確認した。すると、LPA存在下の方が抗癌剤感受性が低下していることがわかり、やはりLPAをターゲットとする意義が明らかとなった。本実験は現プロトコールではin vitroではなくin vivoの方が評価しやすいと判断された。 興味深いことに、マウスへの腫瘍移植モデルを用いてGEM投与によるオートタキシンの発現の変化が確認でき、腫瘍の増大および抗癌剤投与治療によりオートタキシン活性が変化していることが確認できた。
  • 血清エクソソームによる消化器癌診断バイオマーカーの開発, 公益財団法人 鈴木謙三記念医科学応用研究財団, 平成30年度調査研究助成金,   2019年01月 - 2019年12月
  • 腫瘍特異的ドラッグデリバリーシステムを用いたKRAS変異型大腸癌に対しする新規治療法の開発, 喜谷記念トラスト, がん治療プロジェクト事業計画,   2018年04月 - 2019年03月
  • 癒着性小腸イレウスに対するロングチューブ vs. 経鼻胃管ガストログラフィン造影のランダム化比較試験, 一般社団法人 日本消化管学会, 2017年度多施設研究助成,   2017年04月 - 2019年03月
  • 胃がん早期診断のための尿中バイオマーカーの開発, 日本医療研究開発機構(AMED), 橋渡し研究戦略的推進プログラム,   2017年04月 - 2019年03月, 課題番号:A66
  • 胃癌・大網相互コミュニケーションからみた胃癌腹膜播種メカニズムの解明, 日本学術振興会, 科学研究費助成事業 挑戦的萌芽研究,   2015年04月 - 2019年03月, 大網脂肪細胞の培養液の刺激により、有意な胃癌細胞の細胞増殖・運動能が増強した。また、大網脂肪細胞により刺激をうけた胃癌細胞と血管内皮細胞の共培養により、血管新生能が亢進することが明らかとなった。網羅的解析により、大網脂肪細胞培養液にはprotein-Xが高発現していることがわかり、protein-X familyのなかでも「Y」が有意に高発現していることが明らかになった。大網脂肪細胞から「Y」をsiRNAによりノックダウンすると、大網脂肪細胞刺激による胃癌細胞の増殖能や運動能・血管新生能は有意に低下した。また、胃癌細胞が大網脂肪細胞からの刺激をうけると、胃癌細胞中の複数の血管新生因子の発現が亢進し、AKTのリン酸化を誘導し、その結果胃癌細胞の悪性化の増殖能や浸潤能をもたらし、結果腹膜への癌浸潤を誘導することが示唆された。 以上の現象は、腫瘍移植動物実験においても確認され、腹膜転移をともなった胃癌患者の尿中では「Y」の濃度が有意に高値を示した。
  • 無侵襲尿中マイクロRNAによる大腸癌の早期診断法の開発, 公益財団法人 日東学術振興財団, 第34回(平成29年度)研究助成金,   2018年01月 - 2018年12月
  • グローバルポピュレーションを用いた胃癌診断尿中バイオマーカーの開発, 公益財団法人 武田科学振興財団, 2016年度「医学系研究奨励(がん領域・臨床)」,   2016年 - 2018年12月
  • 胃癌・大腸癌早期診断のためのグローバル尿中バイオマーカーの開発, 公立法人名古屋市立大学, 特別研究奨励費,   2016年 - 2017年12月
  • グローバル検体を用いた胃癌診断尿中バイオマーカーの開発, 公益財団法人 愛知県がん研究振興会, 第41回(平成28年度)がんその他の悪性新生物研究助成金,   2016年 - 2017年12月
  • 大腸がん早期診断のための無侵襲尿中バイオマーカーの開発, 公益財団法人 小林がん学術振興会, 第1回研究助成金,   2016年05月 - 2017年03月
  • 消化器癌に対するHB-EGF-CTFを標的とした新規治療法とバイオマーカーの開発, 日本学術振興会, 科学研究費助成事業 基盤研究(C),   2012年04月 - 2016年03月, KRAS野生型の切除不能進行再発大腸癌に対する抗EGFR抗体療法において、大腸癌組織内のHB-EGF-CTFの局在と抗腫瘍効果との関連はみとめなかったが、HB-EGFの発現が治療効果予測に有用であることを示した (Yoshida M, Shimura T, et al. J Cancer Res Clin Oncol.2013: 367-78)。 HB-EGF-CTFの核移行を制御する機能をもつADAM12の尿中濃度と胃癌組織発現が、胃癌の早期診断に有用であることを示した (Shimura T, et al. Cancer Prev Res. 2015:240-248)。
  • 消化器癌に対するトランスレーショナルリサーチ, 上原記念生命科学財団, 平成23年度海外留学助成リサーチフェローシップ,   2011年04月 - 2011年12月
  • EGFRリガンドCTFの核内移行シグナルを標的とした新規胃癌分子標的治療の研究, 日本学術振興会, 科学研究費助成事業 若手研究(B),   2010年 - 2011年, HB-EGF-CTFの核移行により胃癌細胞の遊走能・浸潤能の増加をみとめ、ヒト胃癌においても進行胃癌においてHB-EGF-CTFの核内発現の有意な増加をみとめた。これらのことからHB-EGF-CTFの核移行は胃癌浸潤を誘導すると考えられた。 胃癌細胞および腫瘍移植動物モデルにおいてARの核移行により抗がん剤感受性の低下をみとめた。さらに抗がん剤施行したstage4進行胃癌においてARの核発現は有意な予後不良因子であった。これらのことからARの核移行は胃癌の抗がん剤感受性を低下させ予後不良因子であると考えられた。
  • Chemotherapy after stenting is feasible for metastatic gastric cancer with pyloric stenosis., 名古屋市立大学医師会, 第15回名古屋市立大学医師会海外研修助成,   2009年05月 - 2009年05月
  • Advantages of endoscopic submucosal dissection over conventional endoscopic mucosal resection for neoplasms. Poster presentation, 公益財団法人 豊秋奨学会, 海外研究渡航助成,   2007年05月 - 2007年05月
  • ADAM familyおよびHB-EGF-CTF核内移行を標的とした新規消化器癌分子標的治療法の探索, 文部科学省, 教育研究高度化のための支援体制整備事業

その他

  • 論文査読委員(Ad hoc), American Journal of Gastroenterology, Cancer, International Journal of Cancer, British Journal of Cancer, Journal of Gastroenterology, Cancer Science, Scientific Reports, Journal of Gastroenterology and Hepatology, Digestive Endoscopy, Digestive Diseases and Sciences, Plos One, Oncotarget, Cancer Medicine, World Journal of Gastroenterology, Medical Oncology, BMC Gastroenterology, Diseases of Esophagus, Translational Cancer Research, World Journal of Surgical Oncology, The Journal of Physiological Sciences, Scandinavian Journal of Gastroenterology, BioMed Research International, Internal Medicine


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