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| 1.
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Fujimura, Takashi ; Ohta, Tetsuo ; Oyama, Katsunobu ; Miyashita, Tomoharu ; Miwa, Koichi ; 藤村, 隆 ; 太田, 哲生 ; 尾山, 勝信 ; 宮下, 知治 ; 三輪, 晃一
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金沢大学医薬保健研究域医学系<br />Selective cyclooxygenase (COX)-2 inhibitors (coxibs) were developed as one of the anti-inflammatory
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drugs to avoid the various side effects of non-steroidal anti-inflammatory drugs (NSAIDs). However, coxibs also have an ability to inhibit tumor development of various kinds the same way that NSAIDs do. Many experimental studies using cell lines and animal models demonstrated an ability to prevent tumor proliferation of COX-2 inhibitors. After performing a randomized study for polyp chemoprevention study in patients with familial adenomatous polyposis (FAP), which showed that the treatment with celecoxib, one of the coxibs, significantly reduced the number of colorectal polyps in 2000, the U.S. Food and Drug Administration (FDA) immediately approved the clinical use of celecoxib for FAP patients. However, some coxibs were recently reported to increase the risk of serious cardiovascular events including heart attack and stroke. In this article we review a role of COX-2 in carcinogenesis of gastrointestinal tract, such as the esophagus, stomach and colorectum, and also analyze the prospect of coxibs for chemoprevention of gastrointestinal tract tumors. © 2006 The WJG Press. All rights reserved.
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| 2.
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Mitsui, Fumihiko ; Dobashi, Yoh ; Imoto, Issei ; Inazawa, Johji ; Kono, Koji ; Fujii, Hideki ; Ooi, Akishi
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金沢大学大学院医学系研究科がん細胞学<br />This study was conducted to assess the frequencies of protein overexpression and gene amplificat
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ion of Myc and to identify the mechanisms of Myc gene amplification, especially with regards to its possible coamplification with ERBB2 or EGFR in gastric adenocarcinomas. By immunohistochemical analysis of a total of 300 formalin-fixed and paraffin-embedded gastric adenocarcinomas, the nuclear overexpression of MYC was found in 47 tumors (16%). A fluorescence in situ hybridization (FISH) analysis revealed that nine (19%) of the 47 tumors with protein overexpression had cancer cells with high levels of Myc amplification, whereas only seven (6%) of the 122 tumors without protein overexpression showed high-level Myc gene amplification. Such Myc amplification was significantly correlated with positive nuclear protein overexpression. The coamplification of ERBB2 or EGFR with Myc that was found in six and four cases, respectively, is believed to be non-incidental because those frequencies were significantly higher than the individual frequencies observed for the total examined cases (ERBB2: 7%; EGFR: 4%). The high levels of gene amplification of these three genes, as visualized by FISH, could be broadly classified into two typical types, namely, 'multiple scattered signals' and 'large clustered signals'. Using two-color FISH, the coexistence of coamplified Myc and ERBB2, or Myc and EGFR, within single nuclei in various combinations of amplification types and copy numbers, could be ascertained in all nine cases, including one in which the synchronous 'multiple scattered type' coamplification of Myc and ERBB2 was observed. In three tumors, coamplification of ERBB2 and EGFR was found; however, ERBB2- and EGFR-amplified cell populations were separate and mutually exclusive. We propose that the non-incidental coamplification of Myc and either ERBB2 or EGFR occurred through translocation and subsequent rearrangement. © 2007 USCAP, Inc All rights reserved.
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| 3.
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Mitsui, Fumihiko ; Dobashi, Yoh ; Imoto, Issei ; Inazawa, Johji ; Kono, Koji ; Fujii, Hideki ; Ooi, Akishi
概要:
金沢大学医薬保健研究域医学系<br />医薬保健研究域・薬学系<br />This study was conducted to assess the frequencies of protein overexpression and ge
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ne amplification of Myc and to identify the mechanisms of Myc gene amplification, especially with regards to its possible coamplification with ERBB2 or EGFR in gastric adenocarcinomas. By immunohistochemical analysis of a total of 300 formalin-fixed and paraffin-embedded gastric adenocarcinomas, the nuclear overexpression of MYC was found in 47 tumors (16%). A fluorescence in situ hybridization (FISH) analysis revealed that nine (19%) of the 47 tumors with protein overexpression had cancer cells with high levels of Myc amplification, whereas only seven (6%) of the 122 tumors without protein overexpression showed high-level Myc gene amplification. Such Myc amplification was significantly correlated with positive nuclear protein overexpression. The coamplification of ERBB2 or EGFR with Myc that was found in six and four cases, respectively, is believed to be non-incidental because those frequencies were significantly higher than the individual frequencies observed for the total examined cases (ERBB2: 7%; EGFR: 4%). The high levels of gene amplification of these three genes, as visualized by FISH, could be broadly classified into two typical types, namely, 'multiple scattered signals' and 'large clustered signals'. Using two-color FISH, the coexistence of coamplified Myc and ERBB2, or Myc and EGFR, within single nuclei in various combinations of amplification types and copy numbers, could be ascertained in all nine cases, including one in which the synchronous 'multiple scattered type' coamplification of Myc and ERBB2 was observed. In three tumors, coamplification of ERBB2 and EGFR was found; however, ERBB2- and EGFR-amplified cell populations were separate and mutually exclusive. We propose that the non-incidental coamplification of Myc and either ERBB2 or EGFR occurred through translocation and subsequent rearrangement. © 2007 USCAP, Inc All rights reserved.
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Oyama, Katsunobu ; Fushida, Sachio ; Kaji, Masahide ; Takeda, Toshiya ; Kinami, Shinichi ; Hirono, Yasuo ; Yoshimoto, Katsuhiro ; Yabushita, Kazuhisa ; Hirosawa, Hisashi ; Takai, Yuki ; Nakano, Tatsuo ; Kimura, Hironobu ; Yasui, Toshiaki ; Tsuneda, Atsushi ; Tsukada, Tomoya ; Kinoshita, Jun ; Fujimura, Takashi ; Ohta, Tetsuo
概要:
Background: We aimed to evaluate the efficacy of a new combination antiemetic therapy comprising aprepitant, granisetron
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, and dexamethasone in gastric cancer patients undergoing chemotherapy with cisplatin and S-1. Methods: Gastric cancer patients scheduled to receive their first course of chemotherapy with cisplatin (60 mg/m2) and S-1 (80 mg/m2) were treated with a new combination antiemetic therapy aprepitant, granisetron, and dexamethasone on day 1; aprepitant and dexamethasone on days 2 and 3; and dexamethasone on day 4. The patients reported vomiting, nausea, use of rescue therapy, and change in the amount of diet intake, and completed the Functional Living Index-Emesis (FLIE) questionnaire. The primary endpoint was complete response (CR; no emesis and use of no rescue antiemetics) during the overall study phase (0-120 h after cisplatin administration). The secondary endpoints included complete protection (CP; CR plus no significant nausea); change in the amount of diet intake; and the impact of chemotherapy-induced nausea and vomiting (CINV) on daily life during the overall, acute (0-24 h), and delayed (24-120 h) phases. Results: Fifty-three patients were included. CR was achieved in 88.7, 98.1, and 88.7 % of patients in the overall, acute, and delayed phases, respectively. The corresponding rates of CP were 67.9, 96.2, and 67.9 %. Approximately half of the patients had some degree of anorexia. FLIE results indicated that 79.5 % of patients reported "minimal or no impact of CINV on daily life". Conclusions: Addition of aprepitant to standard antiemetic therapy was effective in gastric cancer patients undergoing treatment with cisplatin and S-1. © 2013 Springer Japan.
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| 5.
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Oyama, Katsunobu ; Fushida, Sachio ; Kinoshita, Jun ; Makino, Isamu ; Nakamura, Keishi ; Hayashi, Hironori ; Nakagawara, Hisatoshi ; Tajima, Hidehiro ; Fujita, Hideto ; Takamura, Hiroyuki ; Ninomiya, Itasu ; Kitagawa, Hirohisa ; Tani, Takashi ; Fujimura, Takashi ; Ohta, Tetsuo
概要:
Background: The prognosis of gastric cancer with para-aortic lymph node (PAN) metastasis is poor. We applied triple comb
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ination chemotherapy with docetaxel, cisplatin, and S-1 (DCS therapy) as pre-operative chemotherapy and investigated the outcome of the combination of this therapy and gastrectomy with para-aortic lymph node dissection (PAND). Methods: We retrospectively identified 44 patients with pathologically positive PAN who underwent curative surgery at Kanazawa University Hospital between 1990 and 2008. Among the 44 patients, 16 received pre-operative DCS therapy and subsequent surgical resection after two courses of the therapy. Results: Pre-operative DCS therapy showed high clinical response ratio (68.8%) and disease control ratio (100%). The pathological response ratio of resected specimen was 87.5%. At 2 years after surgery, the overall survival ratio was 93.8% and relapse-free survival was 75.0%. Pre-operative DCS therapy was only independent prognostic factor in multivariate analysis. Grade 3/4 toxicity was observed only in 25.0% of patients who underwent DCS therapy. Surgical complication was observed in 31.3% of patients, and this ratio was equal to that of patients who did not receive DCS therapy. Conclusion: Multimodal therapy comprising combined pre-operative DCS therapy and gastrectomy with PAND was extremely effective and feasible for advanced gastric cancer with PAN metastasis. J. Surg. Oncol © 2011 Wiley Periodicals, Inc.
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| 6.
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Oyama, Katsunobu ; Fushida, Sachio ; Kinoshita, Jun ; Okamoto, Koichi ; Makino, Isamu ; Nakamura, Keishi ; Hayashi, Hironori ; Inokuchi, Masafumi ; Nakagawara, Hisatoshi ; Tajima, Hidehiro ; Fujita, Hideto ; Takamura, Hiroyuki ; Ninomiya, Itasu ; Kitagawa, Hirohisa ; Fujimura, Takashi ; Ohta, Tetsuo
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Cytokeratin 18 (CK18) fragments are released into circulation during epithelial cell death. M30 (reflects caspase-cleave
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d CK18 fragment) and M65 (reflects total CK18 fragment) enzyme-linked immunosorbent assay (ELISA) detect circulating CK18 fragments released during caspase-dependent or total cell death, respectively; thus, CK18 has the potential of being a biomarker for epithelial cancers. In the present study, we investigated the serum levels of M30 and M65 in patients with gastric cancer, determined correlation of these levels with clinical features, and evaluated the usefulness of these enzymes as diagnostic and prognostic markers. We enrolled 54 gastric cancer patients and 12 healthy volunteers in this study. We measured the serum levels of M30 and M65 by quantitative ELISA. The levels of M30 and M65 in gastric cancer patients were significantly higher than those in healthy volunteers (P = 0.001, P < 0.001). The enzyme levels were elevated with the progress of gastric cancer. The sensitivity and specificity of M30 as a diagnostic marker were 67.5 and 90.9 %, respectively, and those of M65 were 70.1 and 90.9 %, respectively. The serum levels of M30 and M65 in patient with early gastric cancer were elevated in 38.1 and 66.7 %, respectively. Further, increased serum level of M65 is an independent indicator of poor prognosis (P = 0.036). The serum levels of M30 and M65 may be useful biomarkers for gastric cancer as diagnostic markers that can reflect the extent of cancer. Moreover, M65 levels can be used as a prognostic indicator. © 2012 Springer-Verlag.
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| 7.
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山崎, 祐樹 ; 伏田, 幸夫 ; 尾山, 勝信 ; 木下, 淳 ; 牧野, 勇 ; 中村, 慶史 ; 藤田, 秀人 ; 二宮, 致 ; 藤村, 隆 ; 太田, 哲生
概要:
We report a case of advanced gastric cancer with para-aortic lymph node metastasis that underwent radical gastrectomy af
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ter neoadjuvant chemotherapy, and in this case, thoracoscopy was useful in excluding mediastinal lymph node metastasis. The patient was a 70-year-old man in whom a large type 2 advanced gastric cancer accompanied with para-aortic and mediastinal lymph node metastasis was diagnosed. We attempted combination therapy of Docetaxel, CDDP and TS-1. After 2 courses of treatment, the primary lesion and regional and para-aortic lymph nodes were significantly reduced in size, suggesting that this therapy had induced a partial response (PR). However, the size of mediastinal lymph node did not change. FDG-PET showed accumulation of FDG located in the mediastinal lymph node, in which metastasis was suspected. To judge the possibility of radical excision, we performed tho-racoscopic biopsy of the mediastinal lymph node. No metastasis was shown in the mediastinal lymph node biopsy, so we performed curative total gastrectomy with D3 lymph node dissection and cholecys-tectomy with curative intent. The pathological findings showed that there were very few cancer cells either in the primary lesion and only one lymph node (No.3). There has been no recurrence for two years after the operation. © 2012 The Japanese Society of Gastroenterological Surgery. 術前DCS（docetaxel，cisplatin，TS-1併用）療法が著効した大動脈周囲リンパ節転移を伴う進行胃癌を経験した．また，胸腔鏡下生検が縦隔リンパ節転移の除外診断に有用であったので報告する．症例は70歳の男性で，噴門直下から角上部に及ぶ大型の2型腫瘍を認めた．大動脈周囲・縦隔を含め多数のリンパ節腫大を認めた．DCS療法を2コース行い，原発巣・リンパ節転移巣ともに著明に縮小した．しかし，縦隔リンパ節に変化はなくPET-CTでも淡い集積を認め転移も否定できないため，胸腔鏡下に縦隔リンパ節生検を行ったところ，転移を認めなかった．根治切除可能と判断し大動脈周囲リンパ節郭清を伴う胃全摘術を行った．組織学的に腫瘍の大部分は壊死に陥り，原発巣の一部と壁在リンパ節1個にごく僅かに腫瘍細胞が残存していた．現在，術後2年が経過しているが，無再発生存中である．
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| 8.
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Tajiri, Ryosuke ; Ooi, Akishi ; Fujimura, Takashi ; Dobashi, Yoh ; Oyama, Takeru ; Nakamura, Ritsuko ; Ikeda, Hiroko
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A humanized monoclonal antibody against ERBB2 is used in neoadjuvant therapy for patients with gastric cancer. A critica
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l factor in determining patient eligibility and predicting outcomes of this therapy is the intratumoral heterogeneity of ERBB2 amplification in gastric adenocarcinomas. The aims of this study are to assess the underlying mechanisms of intratumoral heterogeneity of ERBB2 amplification; to characterize the diversity of coamplified oncogenes such as EGFR, FGFR2, MET, MYC, CCND1, and MDM2; and to examine the usefulness of multiple ligation-dependent probe amplification (MLPA) in the semicomprehensive detection of these gene amplifications. A combined analysis of immunohistochemistry and fluorescence in situ hybridization revealed ERBB2-amplified cancer cells in 51 of 475 formalin-fixed, paraffin-embedded gastric adenocarcinomas. The fraction of amplification-positive cells in each tumor ranged from less than 10% to almost 100%. Intratumoral heterogeneity of ERBB2 amplification, defined as less than 50% of cancer cells positive for ERBB2 amplification, was found in 41% (21/51) of ERBB2-amplified tumors. The combined analysis of MLPA and fluorescence in situ hybridization revealed that ERBB2 was coamplified with EGFR in 7 tumors, FGFR2 in 1 tumor, and FGFR2 and MET in 1 tumor; however, the respective genes were amplified in mutually exclusive cells. Coamplified ERBB2 and MYC coexisted within single nuclei in 4 tumors, and one of these cases had suspected coamplification in the same amplicon of ERBB2 with MYC. In conclusion, the amplification status of ERBB2 and other genes can be obtained semicomprehensively by MLPA and could be useful to plan individualized molecularly targeted therapy against gastric cancers. © 2014 Elsevier Inc.
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| 9.
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齋藤, 裕人 ; 尾山, 勝信 ; 伏田, 幸夫 ; 柄田, 智也 ; 岡本, 浩一 ; 中沼, 伸一 ; 木下, 淳 ; 牧野, 勇 ; 中村, 慶史 ; 林, 泰寛 ; 井口, 雅史 ; 中川原, 寿俊 ; 宮下, 知治 ; 藤田, 秀人 ; 田島, 秀浩 ; 高村, 博之 ; 二宮, 致 ; 北川, 裕久 ; 藤村, 隆 ; 太田, 哲生
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We report a case of gastric adenosquamous carcinoma producing granulocyte-colony stimulating factor (G-CSF). A 60-year-o
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ld man was admitted to our hospital complaining of upper abdominal pain. Endoscopic examination revealed a large type 5 advanced gastric cancer with bleeding from the low body of stomach to the antrum, accompanied with para-aortic and mesenteric lymph node metastasis. He had marked leukocytosis, and serum levels of G-CSF were elevated. Histological diag-nosis of the biopsy specimen was adenosquamous carcinoma producing G-CSF. We attempted combination chemotherapy with docetaxel, cisplatin and S-1 (DCS). After 1 course of treatment, the primary lesion was reduced in size. However, the size of the metastatic lymph node was larger. Chemotherapy was not effective enough, and the patient died 3 months after ending chemotherapy. 症例は60歳、男性。上腹部痛を主訴に受診。上部消化管内視鏡で胃体下部から前庭部の小弯後壁に易出血性の5型胃癌を認め、画像所見で傍大動脈・腸間膜リンパ節転移を認めた。生検にて腺癌成分と扁平上皮癌成分の混在を認めた。来院時より白血球数が著明に増多し、血清G-CSF高値、生検組織の免疫組織染色で腫瘍組織のG-CSF発現を認めた。以上よりG-CSF産生胃腺扁平上皮癌と診断し、化学療法（DCS (docetaxel/ cisplatin/ S-1併用)療法）を1コース行ったところ原発巣の縮小を認めたが、転移リンパ節の増大を認めた。急激な病状悪化により3ヶ月の経過で死亡した。
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| 10.
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寺川, 裕史 ; 尾山, 勝信 ; 渡邉, 利史 ; 柄田, 智也 ; 岡本, 浩一 ; 木下, 淳 ; 古河, 浩之 ; 牧野, 勇 ; 中村, 慶史 ; 林, 泰寛 ; 井口, 雅史 ; 中川原, 寿俊 ; 宮下, 知治 ; 田島, 秀浩 ; 高村, 博之 ; 二宮, 致 ; 北川, 裕久 ; 伏田, 幸夫 ; 藤村, 隆 ; 太田, 哲生
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An 83-year-old woman was diagnosed as having advanced gastric cancer with multiple lymph node and hepatic metastases. Hi
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stopathological examination revealed that the tissue was human epidermal growth factor receptor 2 (HER2) positive. The patient underwent gastrojejunostomy to improve stomach obstruction. Thereafter, S-1 and trastuzumab combination chemotherapy was administered as first-line treatment; irinotecan (CPT-11), cisplatin, and trastuzumab combination chemotherapy, as second-line treatment; and docetaxel plus trastuzumab combination chemotherapy, as third-line treatment. Although both primary and metastatic lesions decreased in size temporarily, their size increased again, and the patient died 1 year and 7 months later. The level of serum HER2-extracellular domain (ECD) was a valuable indicator of response to chemotherapy. Thus, serum HER2-ECD could be a useful biomarker for HER2-positive gastric cancer.症例は83歳, 女性. 多発リンパ節転移, 多発肝転移を伴う進行胃癌を指摘された. 生検検体のHER2判定は陽性であった. 通過障害改善目的の胃空腸バイパス術後に化学療法を開始した. first-lineにS-1+trastuzumab, second-lineとしてirinotecan(CPT-11)+cisplatin+trastuzumab, third-lineとしてdocetaxel+trastuzumabを行った. いずれも一時的には治療効果が得られたが不応となり, 1年7か月後に永眠された. 経過中, 血清HER2-ECD値の増減と治療効果に相関を認めた. 血清HER2-ECD値はHER2陽性胃癌の治療効果を反映するバイオマーカーとなる可能性が示唆された.
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