今日の臨床サポート

胃粘膜下腫瘍

著者: 矢田智之 国立研究開発法人 国立国際医療研究センター国府台病院 消化器・肝臓内科

監修: 上村直実 国立国際医療研究センター 国府台病院

著者校正/監修レビュー済:2021/11/10
参考ガイドライン:
  1. 日本癌治療学会・日本胃癌学会・GIST研究会:GIST診療ガイドライン 第3版 (2014年4月改訂)
患者向け説明資料

概要・推奨   

  1. 胃粘膜下腫瘍にはGIST(消化管間質腫瘍)、平滑筋腫、平滑筋肉腫、神経鞘腫、神経線維腫などがあるが、malignant potentialを有するGISTをいかにほかの粘膜下腫瘍から鑑別するかが重要である。
  1. 切除可能GISTの治療では、外科的完全切除が強く推奨される(推奨度1)。
  1. 転移のみられないGISTの場合、腫瘍径と細胞増殖能などの指標を組み合わせて、リスク分類を行うことが推奨される(推奨度1)。
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧に
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧に
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要と
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となり
薬剤監修について:
オーダー内の薬剤用量は日本医科大学付属病院 薬剤部 部長 伊勢雄也 以下、林太祐、渡邉裕次、井ノ口岳洋、梅田将光による疑義照会のプロセスを実施、疑義照会の対象については著者の方による再確認を実施しております。
※薬剤中分類、用法、同効薬、診療報酬は、エルゼビアが独自に作成した薬剤情報であり、
著者により作成された情報ではありません。
尚、用法は添付文書より、同効薬は、薬剤師監修のもとで作成しております。
※薬剤情報の(適外/適内/⽤量内/⽤量外/㊜)等の表記は、エルゼビアジャパン編集部によって記載日時にレセプトチェックソフトなどで確認し作成しております。ただし、これらの記載は、実際の保険適用の査定において保険適用及び保険適用外と判断されることを保証するものではありません。また、検査薬、輸液、血液製剤、全身麻酔薬、抗癌剤等の薬剤は保険適用の記載の一部を割愛させていただいています。
(詳細はこちらを参照)
著者のCOI(Conflicts of Interest)開示:
矢田智之 : 未申告[2021年]
監修:上村直実 : 未申告[2021年]

改訂のポイント:
  1. 定期レビューを行った(変更なし)

病態・疫学・診察

疾患情報(疫学・病態)  
  1. 粘膜下腫瘍(submucosal tumor、SMT)は、「病変の主座が消化管粘膜下層以深に存在し、周辺粘膜と同様の粘膜で覆われ、半球状または球状に消化管内に突出した病変」の総称である。
 
胃粘膜下腫瘍の内視鏡像

胃体下部大彎に2cm大の粘膜下腫瘍を認める。

出典

img1:  著者提供
 
 
 
  1. 粘膜下腫瘍はあくまで形態的特徴からの臨床診断名であり、その構成組織は良性から悪性まで多岐にわたる。
  1. 上部消化管内視鏡検査において発見される胃粘膜下腫瘍の頻度は0.4%とされているが[1]、各々の疾患別の頻度に言及した報告はほとんどみられない。
  1. すべてのGIST(gastrointestinal stromal tumor)はmalignant potentialを有するとされており、診断のうえでは、いかにGISTをほかの粘膜下腫瘍から鑑別するかが重要となる[2][3]
  1. その他、悪性粘膜下腫瘍としてカルチノイド、悪性リンパ腫、転移性腫瘍などが挙げられるが、これらは生検で証明可能なことが多く、診断に難渋することは少ない。
  1. わが国で作成された「GIST診療ガイドライン 第3版 」(日本癌治療学会他、2014年)には、粘膜下腫瘍の診断と治療のアルゴリズムが記載されており、治療の絶対適応は、①2cm以上5cm以下の悪性所見のある腫瘍、②5cmを超える腫瘍、③有症状または生検でGISTが証明された場合――とされている。また、生検でGIST以外の腫瘍と診断されれば、それぞれの治療指針に準ずるとされている[4]
  1. 胃粘膜下腫瘍の治療方針:アルゴリズム
問診・診察のポイント  
  1. 通常は無症候性であり、検診の上部消化管造影検査や上部消化管内視鏡検査で指摘されることが多い。

これより先の閲覧には個人契約のトライアルまたはお申込みが必要です。

最新のエビデンスに基づいた二次文献データベース「今日の臨床サポート」。
常時アップデートされており、最新のエビデンスを各分野のエキスパートが豊富な図表や処方・検査例を交えて分かりやすく解説。日常臨床で遭遇するほぼ全ての症状・疾患から薬剤・検査情報まで瞬時に検索可能です。

まずは15日間無料トライアル
本サイトの知的財産権は全てエルゼビアまたはコンテンツのライセンサーに帰属します。私的利用及び別途規定されている場合を除き、本サイトの利用はいかなる許諾を与えるものでもありません。 本サイト、そのコンテンツ、製品およびサービスのご利用は、お客様ご自身の責任において行ってください。本サイトの利用に基づくいかなる損害についても、エルゼビアは一切の責任及び賠償義務を負いません。 また、本サイトの利用を以て、本サイト利用者は、本サイトの利用に基づき第三者に生じるいかなる損害についても、エルゼビアを免責することに合意したことになります。  本サイトを利用される医学・医療提供者は、独自の臨床的判断を行使するべきです。本サイト利用者の判断においてリスクを正当なものとして受け入れる用意がない限り、コンテンツにおいて提案されている検査または処置がなされるべきではありません。 医学の急速な進歩に鑑み、エルゼビアは、本サイト利用者が診断方法および投与量について、独自に検証を行うことを推奨いたします。

文献 

著者: J L Hedenbro, M Ekelund, P Wetterberg
雑誌名: Surg Endosc. 1991;5(1):20-3.
Abstract/Text The accurate diagnosis of submucosal gastric lesions is difficult. In an attempt to study this problem, the endoscopic records for 8 consecutive years (July 1976-June 1984) were scanned with the help of a computer-based registration of the endoscopic findings. The examinations were identified in which the endoscopic diagnosis indicated the presence of a submucosal tumor. Fifty-four such patients were found in 15,104 routine examinations, giving an incidence of 0.36%. Six patients were lost to follow-up, so the study is based on 48 patients. The most common reason these patients underwent endoscopy was abdominal pain. Five patient groups were identified: (a) nine patients were correctly diagnosed as having gastric wall neoplasia at the initial endoscopy + biopsy; (b) in an additional 13 patients, the suspected gastric wall neoplasia was verified by further nonoperative diagnostic procedures; (c) five patients were found to have benign non-neoplastic gastric disease; (d) five patients had extra-gastric disease that pressed against the gastric wall; (e) in 14 patients a further work-up indicated that the initial endoscopy was false-positive. These five groups were confirmed by additional diagnostic procedures (including laparotomy) and a follow-up time of more than 5 years or autopsy. Two patients refused further examinations and died shortly afterward. No autopsies were performed. Based on our data, it would seem that in the vast majority of patients the suspicion of a submucosal gastric lesion at endoscopy indicates the presence of a serious condition.

PMID 1871670  Surg Endosc. 1991;5(1):20-3.
著者: George D Demetri, Robert Benjamin, Charles D Blanke, Haesun Choi, Chris Corless, Ronald P DeMatteo, Burton L Eisenberg, Christopher D M Fletcher, Robert G Maki, Brian P Rubin, Annick D Van den Abbeele, Margaret von Mehren, NCCN GIST Task Force
雑誌名: J Natl Compr Canc Netw. 2004 May;2 Suppl 1:S-1-26; quiz 27-30.
Abstract/Text NCCN's Sarcoma Clinical Practice Guidelines in Oncology include a subsection regarding treatment recommendations on gastrointestinal stromal tumors (GISTs). GIST is one area of medicine where the standard of practice has been affected rapidly and dramatically by the introduction of effective molecularly targeted therapy for this disease. There are few examples in modern medicine in which the implementation of new technologies into practice has so radically and rapidly affected clinical diagnostic strategies and treatments with significant implications for the care of patients. Because of these recent changes, NCCN organized a broad multidisciplinary panel composed of experts in the fields of diagnostic radiology, pathology, molecular diagnostics, surgery, medical oncology, and radiation oncology to discuss the optimal approach for the care of patients with GIST at all stages of the disease. The GIST task force is composed of NCCN faculty and other key experts from North America, comprising the United States and Canada. The purpose of this meeting was to expand on the existing NCCN clinical practice guidelines for gastrointestinal sarcomas and to identify areas of future research to optimize our understanding and treatment of this disease.

PMID 23573667  J Natl Compr Canc Netw. 2004 May;2 Suppl 1:S-1-26; quiz・・・
著者: J-Y Blay, S Bonvalot, P Casali, H Choi, M Debiec-Richter, A P Dei Tos, J-F Emile, A Gronchi, P C W Hogendoorn, H Joensuu, A Le Cesne, J McClure, J Mac Clure, J Maurel, N Nupponen, I Ray-Coquard, P Reichardt, R Sciot, S Stroobants, M van Glabbeke, A van Oosterom, G D Demetri, GIST consensus meeting panelists
雑誌名: Ann Oncol. 2005 Apr;16(4):566-78. doi: 10.1093/annonc/mdi127.
Abstract/Text BACKGROUND: The management of gastrointestinal stromal tumors (GIST) has evolved very rapidly in the last 4 years. The objectives of this international consensus meeting were to describe the optimal management procedures for patients with GIST in localized and advanced stages, as well as research issues for the future.
MATERIALS AND METHODS: A panel of experts from six specialties, including pathology, molecular biology, imaging, surgery, medical oncology and methodologists for clinical practice guidelines from different European and extra European sarcoma societies were invited to a 2-day workshop. Several questions were selected by the organizing committee prior to the conference. Selected panelists reviewed the current levels of evidence for each point, and presented their conclusions during the meeting. These proposals were discussed, and consensus points were identified and categorized according to the Standard Options Recommandations (SOR) of the French Federation of Cancer Centers and National Comprehensive Cancer Network (NCCN).
RESULTS: Thirty-two consensus points were identified, most from categories 2A of the NCCN and B2 of the SOR. Among these, the standard histological examination with immunohistochemical analysis using CD117, CD34, PS100, desmin and smooth muscle actin is considered standard. Molecular biology for the identification of KIT and PDGFRA mutation is an optional diagnostic procedure for GIST with negative CD117 staining, and otherwise is considered a research procedure. Complete tumor resection with negative tumor margins is the standard surgical treatment. Adjuvant imatinib after optimal tumor resection as well as neo-adjuvant imatinib remain experimental approaches to be performed within prospective clinical studies. Imatinib should be started at the date of diagnosis of metastatic relapse and given until development of intolerance or progressive disease. The optimal criteria for tumor response to imatinib remain to be delineated, and should include not only tumor size reduction or disease stabilization, but also reduction of tumor density (Hounsfield Units) on computed tomography and metabolic activity (i.e. reduction of FDG uptake on positron emission tomography). In a substantial proportion of patients, stable disease and even increase in tumor size may be associated with pathologic response to imatinib therapy, and available survival data indicate that the survival of these patients is similar to that of patients with conventional tumor response. Metastasis resection is an experimental procedure.
CONCLUSIONS: Consensus points in clinical management of GIST as well as questions for future clinical trials were identified during this consensus conference on GIST management.

PMID 15781488  Ann Oncol. 2005 Apr;16(4):566-78. doi: 10.1093/annonc/m・・・
著者: Bruno Landi, Laurent Palazzo
雑誌名: Best Pract Res Clin Gastroenterol. 2009;23(5):679-701. doi: 10.1016/j.bpg.2009.05.009.
Abstract/Text Submucosal tumours (SMTs) are relatively common findings in patients undergoing endoscopy, especially in upper gastrointestinal (GI) tract. This term includes various non-neoplastic and neoplastic conditions. Endoscopic ultrasonography (EUS) is the best imaging procedure to characterise SMT and to determine the need for further explorations. In this review, the following issues will be addressed: the endosonographic features of SMT; the diagnostic accuracy of EUS; the ability of EUS to distinguish benign and malignant SMTs; the value of EUS-guided fine-needle aspiration (FNA); and the influence of EUS on clinical management.

PMID 19744633  Best Pract Res Clin Gastroenterol. 2009;23(5):679-701. ・・・
著者: Ukihide Tateishi, Tadashi Hasegawa, Mitsuo Satake, Noriyuki Moriyama
雑誌名: J Comput Assist Tomogr. 2003 Sep-Oct;27(5):792-8.
Abstract/Text OBJECTIVES: To assess computed tomography (CT) findings to assist in the distinction of low- and high-grade gastrointestinal stromal tumors (GISTs) and to estimate their relative risk (RR) for mortality.
METHODS: Sixty-nine patients with clinicopathologically and immunohistochemically proven GISTs, including 44 patients with low-grade tumors and 25 with high-grade tumors, who underwent dual-phase CT for initial examination were included. Images were assessed retrospectively for tumor size, location, epicenter, types of surface, boundary, presence of invasion, enhancement pattern, hepatic metastasis, and peritoneal dissemination. Their RR for mortality was estimated by using a multiple logistic regression model.
RESULTS: Statistically significant CT findings favoring a diagnosis of high-grade GIST and affecting the 5-year survival rate included a lesion larger than 11.1 cm (median + 1 SD), irregular surface, unclear boundary, presence of invasion, heterogeneous enhancement, hepatic metastasis, and peritoneal dissemination. Multivariate analysis showed RRs for mortality in lesions larger than 11.1 cm (RR=3.9), with the presence of wall invasion (RR=5.1), and with hepatic metastasis (RR=11.3), respectively.
CONCLUSIONS: The CT features that suggest a high-grade GIST and predict poor outcome include hepatic metastasis, presence of wall invasion, and lesions larger than 11.1 cm.

PMID 14501372  J Comput Assist Tomogr. 2003 Sep-Oct;27(5):792-8.
著者: Hyo-Cheol Kim, Jeong Min Lee, Kyoung Won Kim, Seong Ho Park, Se Hyung Kim, Jae Young Lee, Joon Koo Han, Byung Ihn Choi
雑誌名: AJR Am J Roentgenol. 2004 Oct;183(4):893-8. doi: 10.2214/ajr.183.4.1830893.
Abstract/Text OBJECTIVE: The purpose of this study was to identify predictors of malignancy on CT for the evaluation of gastrointestinal stromal tumors of the stomach.
MATERIALS AND METHODS: The medical records at our institution of 81 patients with a histologic diagnosis of gastrointestinal stromal tumor of the stomach were reviewed. Two radiologists retrospectively reviewed the CT findings by consensus with respect to lesion size, contour, tumor growth pattern, enhancing pattern, degree of enhancement, mesenteric fat infiltration, ulceration, calcification, lymphadenopathy, direct invasion to adjacent organ, and distant metastasis. Categoric variables were compared using the chi-square or Fisher's exact test. Multiple stepwise logistic regression analysis by means of forward selection was performed to determine significant predictors of high mitotic rate. Univariate analysis and multivariate analysis were also performed in a subgroup of 36 tumors with maximal diameter of 5 cm or smaller.
RESULTS: Size, presence of an ulcer, mesenteric fat infiltration, direct organ invasion, and metastasis were more frequently observed during univariate analysis in tumors with a high mitotic rate (p < 0.05). With stepwise logistic regression analysis, the size (odds ratio, 2.57; 95% CI; 1.42-4.67) was the only significant predictor of a high mitotic rate. In a subgroup of 36 tumors 5 cm or smaller, differentiation of benign from malignant tumors was not possible using CT.
CONCLUSION: Although presence of an ulcer, mesenteric fat infiltration, direct organ invasion, and metastasis were more frequently observed in tumors with a high mitotic rate, no CT feature, other than size, was found to have predictive value with respect to malignant gastrointestinal stromal tumors of the stomach.

PMID 15385278  AJR Am J Roentgenol. 2004 Oct;183(4):893-8. doi: 10.221・・・
著者: Mohamed A Mekky, Kenji Yamao, Akira Sawaki, Nobumasa Mizuno, Kazuo Hara, Mohamed A Nafeh, Ashraf M Osman, Takashi Koshikawa, Yasushi Yatabe, Vikram Bhatia
雑誌名: Gastrointest Endosc. 2010 May;71(6):913-9. doi: 10.1016/j.gie.2009.11.044. Epub 2010 Mar 11.
Abstract/Text BACKGROUND: Submucosal tumors (SMTs) comprise both benign and malignant lesions, and most of the gastric lesions tend to be malignant. The addition of EUS-guided FNA (EUS-FNA) has the potential to improve this distinction, but published series are limited.
OBJECTIVE: To evaluate the yield of EUS-FNA in gastric SMTs with referral to a criterion standard final diagnosis.
DESIGN: Retrospective study.
SETTING: Tertiary-care referral center.
PATIENTS: This study involved 141 consecutive patients with gastric SMTs, who underwent EUS-FNA from January 2000 to December 2008. Immunohistochemical staining with c-kit, CD34, actin, and S-100 antibodies was done if a spindle cell tumor was found. Based on FNA sample adequacy, and whether a specific diagnosis could be established, EUS-FNA results were categorized as diagnostic, suggestive, or nondiagnostic. The criterion standards for final diagnosis were the surgical histopathological results or the follow-up course for malignant, inoperable cases.
INTERVENTION: EUS-FNA.
MAIN OUTCOME MEASUREMENTS: Diagnostic yield of EUS-FNA and factors related to sampling adequacy for cytological and immunohistochemical evaluation.
RESULTS: A total of 141 patients (52% female, mean age 56.7 years) underwent EUS-FNA (range 1-5 passes). The overall results of EUS-FNA were diagnostic, suggestive, and nondiagnostic in 43.3%, 39%, and 17.7% of cases, respectively. Adequate specimens were obtained in 83% of cases, and 69 cases (48.9%) had a definitive final diagnosis. The most common gastric SMT was GI stromal tumor (59.5%). EUS-FNA results were 95.6% accurate (95% confidence interval [CI], 87.5%-99%) for the final diagnosis and 94.2% (95% CI, 85.6%-98.1%) accurate for differentiating potentially malignant lesions. A heterogeneous echo pattern was the only independent predictor for sampling adequacy (adjusted odds ratio 6.15; P = .002). There were no procedure-related complications.
LIMITATIONS: Possibility of selection bias.
CONCLUSION: EUS-FNA is an accurate method for diagnosis of gastric SMTs and for differentiating malignant lesions.

2010 American Society for Gastrointestinal Endoscopy. Published by Mosby, Inc. All rights reserved.
PMID 20226456  Gastrointest Endosc. 2010 May;71(6):913-9. doi: 10.1016・・・
著者: Kenji Okubo, Kenji Yamao, Tsuneya Nakamura, Masahiro Tajika, Akira Sawaki, Kazuo Hara, Hiroki Kawai, Yoshitaka Yamamura, Yoshinari Mochizuki, Takashi Koshikawa, Ken-Ichi Inada
雑誌名: J Gastroenterol. 2004 Aug;39(8):747-53. doi: 10.1007/s00535-004-1383-0.
Abstract/Text BACKGROUND: For the diagnosis of gastric submucosal tumors (SMTs), endoscopic ultrasound (EUS) alone does not reveal the complete pathology, such as the degree of malignancy, and EUS-guided fine-needle aspiration biopsy (EUS-FNAB) has been reported to be more useful. Recently, most cases initially diagnosed as leiomyosarcomas have received further study with immunohistochemical staining and have been given the new diagnosis of gastrointestinal stromal tumors (GISTs). The degree of malignancy of GISTs differs widely in clinical aspects. In this study, we examined whether EUS-FNAB was useful in diagnosing GISTs and differentiating their degrees of malignancy.
METHODS: From January 1997 to March 2002, 21 cases of gastric GISTs were diagnosed from the immunohistochemical staining of specimens resected at Aichi Cancer Center Hospital. Of these 21 patients, 14 (5 with high-grade malignancy and 9 with low-grade malignancy) underwent EUS-FNAB preoperatively, and were examined further: their EUS-FNAB specimens were submitted for additional immunohistochemical testing.
RESULTS: The EUS-FNAB specimens from all patients were positive for c-kit and CD34 immunohistochemical testing, coinciding with the staining results of the resected specimens. The MIB-1 labeling indices in specimens of high-grade malignancy were significantly higher than those of low-grade malignancy. If we assumed that a tumor with an MIB-1 labeling index of more than 5% was a high-grade malignancy, the diagnostic accuracy was 85.7%.
CONCLUSIONS: The EUS-FNAB procedure is a useful tool for diagnosing GISTs of the stomach with immunohistochemical staining. When used with MIB-1 staining, the procedure may indicate GIST prognosis and influence decisions regarding therapeutic strategies.

PMID 15338368  J Gastroenterol. 2004 Aug;39(8):747-53. doi: 10.1007/s0・・・
著者: Christopher D M Fletcher, Jules J Berman, Christopher Corless, Fred Gorstein, Jerzy Lasota, B Jack Longley, Markku Miettinen, Timothy J O'Leary, Helen Remotti, Brian P Rubin, Barry Shmookler, Leslie H Sobin, Sharon W Weiss
雑誌名: Hum Pathol. 2002 May;33(5):459-65.
Abstract/Text As a result of major recent advances in understanding the biology of gastrointestinal stromal tumors (GISTs), specifically recognition of the central role of activating KIT mutations and associated KIT protein expression in these lesions, and the development of novel and effective therapy for GISTs using the receptor tyrosine kinase inhibitor STI-571, these tumors have become the focus of considerable attention by pathologists, clinicians, and patients. Stromal/mesenchymal tumors of the gastrointestinal tract have long been a source of confusion and controversy with regard to classification, line(s) of differentiation, and prognostication. Characterization of the KIT pathway and its phenotypic implications has helped to resolve some but not all of these issues. Given the now critical role of accurate and reproducible pathologic diagnosis in ensuring appropriate treatment for patients with GIST, the National Institutes of Health convened a GIST workshop in April 2001 with the goal of developing a consensus approach to diagnosis and morphologic prognostication. Key elements of the consensus, as described herein, are the defining role of KIT immunopositivity in diagnosis and a proposed scheme for estimating metastatic risk in these lesions, based on tumor size and mitotic count, recognizing that it is probably unwise to use the definitive term "benign" for any GIST, at least at the present time.

Copyright 2002, Elsevier Science (USA). All rights reserved.
PMID 12094370  Hum Pathol. 2002 May;33(5):459-65.
著者: N A C S Wong, R Young, R D G Malcomson, A G Nayar, L A Jamieson, V E Save, F A Carey, D H Brewster, C Han, A Al-Nafussi
雑誌名: Histopathology. 2003 Aug;43(2):118-26.
Abstract/Text AIMS: Whether immunohistochemical markers increase accuracy in predicting prognosis for gastrointestinal stromal tumours (GISTs) remains uncertain. However, past studies have used only small, heterogeneous patient groups. Our aim was to test previously studied and more novel morphological features as well as four immunohistochemical markers as prognostic indicators amongst a large cohort of surgically resected, gastric GISTs.
METHODS AND RESULTS: Tissues from 127 gastric mesenchymal tumours were collected retrospectively and subjected to repeat histological assessment and immunophenotyping. Further immunohistochemistry was performed for Ki67, p53, Bcl-2 and cyclin D1. Complete follow-up data were collected for 108 patients with immunophenotyped diagnoses of GIST (i.e. c-kit+ tumours). At the census point, 52 patients were alive, 24 had died from their GISTs and the remainder of other causes. Univariate analysis showed the following predicted for shorter disease-specific survival: size > or =50 mm; necrosis, no intratumoral lymphocytes; mitotic count > or =5/50 high power fields; Ki67 labelling index > or =5%; p53 immunopositivity. Of these variables, multivariate analyses showed only mitotic count and, to a lesser extent, Ki67 labelling to be independent prognostic indicators.
CONCLUSIONS: Mitotic count remains the best predictor of outcome following surgical resection of gastric GISTs. Ki67 immunohistochemistry does not provide better prognostication and p53, Bcl-2 and cyclin D1 immunohistochemistry provide no additional prognostication.

PMID 12877726  Histopathology. 2003 Aug;43(2):118-26.
著者: Samuel Singer, Brian P Rubin, Marcia L Lux, Chang-Jie Chen, George D Demetri, Christopher D M Fletcher, Jonathan A Fletcher
雑誌名: J Clin Oncol. 2002 Sep 15;20(18):3898-905.
Abstract/Text PURPOSE: Previous studies have reported clinical correlates for KIT mutations in GISTs, but in most of those studies the KIT mutations were found in less than 50% of the GISTs. The aim of this study was to evaluate the prognostic relevance for KIT mutations in a series of GISTs in which the mutations were evaluated intensively by genomic and cDNA sequencing.
PATIENTS AND METHODS: A comprehensive clinical and pathologic analysis of 48 patients with GISTs who had snap-frozen tissue was performed. The median tumor size was 10 cm (range, 2 to 30 cm). Median follow-up for disease-free patients was 48 months. KIT genomic and cDNA was sequenced by using nucleic acid templates isolated from frozen tumors.
RESULTS: The overall 5-year recurrence-free survival was 41% +/- 6%. Five-year recurrence-free survival for patients with tumors that had mitotic counts of three mitoses or fewer per 30 high-power fields (HPF), more than three to CONCLUSION: In this series of KIT-expressing GISTs, tumor mitotic activity and histologic subtype were the most important prognostic features. The majority of GISTs contain KIT-activating mutations with the type/location of mutation serving as an independent predictor for disease-free survival. These results suggest that KIT mutation and activation are important in GIST pathogenesis and also may provide important prognostic information.

PMID 12228211  J Clin Oncol. 2002 Sep 15;20(18):3898-905.
著者: Markku Miettinen, Jerzy Lasota
雑誌名: Semin Diagn Pathol. 2006 May;23(2):70-83.
Abstract/Text Gastrointestinal (GI) stromal tumors (GISTs) are the most common mesenchymal tumors specific to the GI tract, generally defined as KIT (CD117)-positive tumors with a characteristic set of histologic features. These tumors, derived from Cajal cells or their precursors, most commonly occur at the age >50 years in the stomach (60%), jejunum and ileum (30%), duodenum (4-5%), rectum (4%), colon and appendix (1-2%), and esophagus (<1%), and rarely as apparent primary extragastrointestinal tumors in the vicinity of stomach or intestines. Their overall incidence has been estimated as 10 to 20 per million, including incidental minimal tumors. GISTs are rare in children (<1%) and almost exclusively occur in stomach. They are common in patients with neurofibromatosis 1, who have a predisposition to (multiple) small intestinal GISTs. GISTs contain a spectrum from minute indolent tumors to sarcomas at all sites of occurrence. Their gross patterns are diverse, including nodular, cystic, and diverticular tumors. External involvement of pancreas and liver can simulate primary tumor in these organs. In general, gastric tumors have a more favorable prognosis than the intestinal ones with similar parameters. Gastric GISTs < or =10 cm and < or =5 mitoses per 50 HPFs have a low risk for metastasis, whereas those with >5 per 50 HPFs and >5 cm in diameter have a high risk for metastasis. In contrast, all intestinal GISTs >5 cm independent of mitotic rate have at least moderate risk for metastases, and all >5 mitoses per 50 HPFs have a high risk for metastases. Intestinal GISTs < or =5 cm with < or =5 mitoses per 50 HPFs have a low risk for metastases. Gastric GISTs can be divided into histologic subgroups including 4 spindle cell and 4 epithelioid variants. Intestinal GISTs are a histologically more homogeneous group and often contain distinctive extracellular collagen globules, skeinoid fibers. Immunohistochemical demonstration of KIT, CD34, or protein kinase theta positivity helps to properly identify these tumors.

PMID 17193820  Semin Diagn Pathol. 2006 May;23(2):70-83.
著者: R P DeMatteo, J J Lewis, D Leung, S S Mudan, J M Woodruff, M F Brennan
雑誌名: Ann Surg. 2000 Jan;231(1):51-8.
Abstract/Text OBJECTIVE: To analyze the outcome of 200 patients with gastrointestinal stromal tumor (GIST) who were treated at a single institution and followed up prospectively.
SUMMARY BACKGROUND DATA: A GIST is a visceral sarcoma that arises from the gastrointestinal tract. Surgical resection is the mainstay of treatment because adjuvant therapy is unproven.
METHODS: Two hundred patients with malignant GIST were admitted and treated at Memorial Hospital during the past 16 years. Patient, tumor, and treatment variables were analyzed to identify patterns of tumor recurrence and factors that predict survival.
RESULTS: Of the 200 patients, 46% had primary disease without metastasis, 47% had metastasis, and 7% had isolated local recurrence. In patients with primary disease who underwent complete resection of gross disease (n = 80), the 5-year actuarial survival rate was 54%, and survival was predicted by tumor size but not microscopic margins of resection. Recurrence of disease after resection was predominantly intraabdominal and involved the original tumor site, peritoneum, and liver.
CONCLUSIONS: GISTs are uncommon sarcomas. Tumor size predicts disease-specific survival in patients with primary disease who undergo complete gross resection. Tumor recurrence tends to be intraabdominal. Investigational protocols are indicated to reduce the rate of recurrence after resection and to improve the outcome for patients with GIST.

PMID 10636102  Ann Surg. 2000 Jan;231(1):51-8.
著者: Y Fong, D G Coit, J M Woodruff, M F Brennan
雑誌名: Ann Surg. 1993 Jan;217(1):72-7.
Abstract/Text To examine the natural history of lymph node metastasis from sarcomas and the utility of therapeutic lymphadenectomy, clinical histories of all adult patients identified by a prospective sarcoma database for the 10-year period July 1982 to July 1991 were examined. Of the 1772 sarcoma patients, 46 (2.6%) were identified with lymph node metastasis. Median follow-up of all patients from diagnosis of lymph node metastasis was 12.9 months (range, 0 to 100 months). Median survival for nonsurvivors was 12.7 months (range, 0 to 40.7). The tumor types with the highest incidence of lymph node metastasis are angiosarcoma (5/37 total cases; 13.5%), embryonal rhabdomyosarcoma (ERMS) (12/88 total cases; 13.6%), and epithelioid sarcoma (2/12 total cases; 16.7%). Lymph node metastasis from visceral primary (p = 0.004) and malignant fibrous histiocytomas (p = 0.006) were associated with particularly poor prognosis. Thirty-one patients underwent radical, therapeutic lymphadenectomy with curative intent, whereas 15 patients had less than curative procedures, in most cases biopsy only. Patients not treated with radical lymphadenectomy had a median survival of 4.3 months (range, 1 to 32) whereas radical lymphadenectomy was associated with a 16.3 month median survival and the only long-term survivors (46% 5-year survival by Kaplan-Meier). The authors conclude that lymph node metastases from sarcoma are rare in adults, but vigilance is warranted, especially in angiosarcoma, ERMS, and epithelioid subtypes. Radical lymphadenectomy is appropriate treatment for isolated metastasis to regional lymph nodes and may provide long-term survival.

PMID 8424704  Ann Surg. 1993 Jan;217(1):72-7.
著者: Junichi Nishimura, Kiyokazu Nakajima, Takeshi Omori, Tsuyoshi Takahashi, Akiko Nishitani, Toshinori Ito, Toshirou Nishida
雑誌名: Surg Endosc. 2007 Jun;21(6):875-8. doi: 10.1007/s00464-006-9065-z. Epub 2006 Dec 16.
Abstract/Text BACKGROUND: Because wide resections and extensive lymphadenectomies are usually not required, the laparoscopic approach has been considered reasonable for gastrointestinal stromal tumors (GISTs) of gastric origin and has been reported with increased frequency. However, its long-term oncologic outcome has not been fully assessed.
METHODS: We reviewed 67 consecutive patients who underwent laparoscopic (LAP) or traditional open (OPEN) resection of gastric GISTs from January 1993 to May 2004.
RESULTS: There were 39 LAP and 28 OPEN cases. One LAP case was converted to open (2.6%). Patients in both groups had comparable backgrounds. Tumor location, size, and risk classification were similar. There was no difference in operating time and blood loss. Five patients (one in LAP and four in OPEN) showed recurrence and/or metastases after a median followup period of 26 months. Tumor enucleation resulted in a higher recurrence rate in both groups: one after three enucleations in LAP and two after six in OPEN. In cases with tumors that were larger than 5 cm, laparoscopic manipulation became technically challenging, although no recurrence was noted in this subgroup. Overall recurrence rate was comparable in the two groups.
CONCLUSION: Laparoscopic surgery is oncologically justified for gastric GISTs, while its indication should be carefully discussed for cases with bulky and high-risk tumors. Tumor enucleations should be avoided whichever approach (open/laparoscopic) is selected.

PMID 17180273  Surg Endosc. 2007 Jun;21(6):875-8. doi: 10.1007/s00464-・・・
著者: George D Demetri, Margaret von Mehren, Charles D Blanke, Annick D Van den Abbeele, Burton Eisenberg, Peter J Roberts, Michael C Heinrich, David A Tuveson, Samuel Singer, Milos Janicek, Jonathan A Fletcher, Stuart G Silverman, Sandra L Silberman, Renaud Capdeville, Beate Kiese, Bin Peng, Sasa Dimitrijevic, Brian J Druker, Christopher Corless, Christopher D M Fletcher, Heikki Joensuu
雑誌名: N Engl J Med. 2002 Aug 15;347(7):472-80. doi: 10.1056/NEJMoa020461.
Abstract/Text BACKGROUND: Constitutive activation of KIT receptor tyrosine kinase is critical in the pathogenesis of gastrointestinal stromal tumors. Imatinib mesylate, a selective tyrosine kinase inhibitor, has been shown in preclinical models and preliminary clinical studies to have activity against such tumors.
METHODS: We conducted an open-label, randomized, multicenter trial to evaluate the activity of imatinib in patients with advanced gastrointestinal stromal tumor. We assessed antitumor response and the safety and tolerability of the drug. Pharmacokinetics were assessed in a subgroup of patients.
RESULTS: A total of 147 patients were randomly assigned to receive 400 mg or 600 mg of imatinib daily. Overall, 79 patients (53.7 percent) had a partial response, 41 patients (27.9 percent) had stable disease, and for technical reasons, response could not be evaluated in 7 patients (4.8 percent). No patient had a complete response to the treatment. The median duration of response had not been reached after a median follow-up of 24 weeks after the onset of response. Early resistance to imatinib was noted in 20 patients (13.6 percent). Therapy was well tolerated, although mild-to-moderate edema, diarrhea, and fatigue were common. Gastrointestinal or intraabdominal hemorrhage occurred in approximately 5 percent of patients. There were no significant differences in toxic effects or response between the two doses. Imatinib was well absorbed, with pharmacokinetics similar to those reported in patients with chronic myeloid leukemia.
CONCLUSIONS: Imatinib induced a sustained objective response in more than half of patients with an advanced unresectable or metastatic gastrointestinal stromal tumor. Inhibition of the KIT signal-transduction pathway is a promising treatment for advanced gastrointestinal stromal tumors, which resist conventional chemotherapy.

Copyright 2002 Massachusetts Medical Society
PMID 12181401  N Engl J Med. 2002 Aug 15;347(7):472-80. doi: 10.1056/N・・・
著者: Jaap Verweij, Paolo G Casali, John Zalcberg, Axel LeCesne, Peter Reichardt, Jean-Yves Blay, Rolf Issels, Allan van Oosterom, Pancras C W Hogendoorn, Martine Van Glabbeke, Rossella Bertulli, Ian Judson
雑誌名: Lancet. 2004 Sep 25-Oct 1;364(9440):1127-34. doi: 10.1016/S0140-6736(04)17098-0.
Abstract/Text BACKGROUND: Imatinib is approved worldwide for use in gastrointestinal stromal tumours (GIST). We aimed to assess dose dependency of response and progression-free survival with imatinib for metastatic GIST.
METHODS: 946 patients were randomly allocated imatinib 400 mg either once or twice a day. Those assigned the once a day regimen who had progression were offered the option of crossover. The primary endpoint was progression-free survival. Analysis was by intention to treat.
FINDINGS: At median follow-up of 760 days (IQR 644-859), 263 (56%) of 473 patients allocated imatinib once a day had progressed compared with 235 (50%) of 473 who were assigned treatment twice a day (estimated hazard ratio 0.82 [95% CI 0.69-0.98]; p=0.026). Side-effects arose in 465/470 (99%) patients allocated the once daily regimen compared with 468/472 (99%) assigned treatment twice a day. By comparison with the group treated once a day, more dose reductions (77 [16%] vs 282 [60%]) and treatment interruptions (189 [40%] vs 302 [64%]) were recorded in patients allocated the twice daily regimen, but treatment in both arms was fairly well tolerated. 52 (5%) patients achieved a complete response, 442 (47%) a partial response, and 300 (32%) stable disease, with no difference between groups. Median time to best response was 107 days (IQR 58-172).
INTERPRETATION: If response induction is the only aim of treatment, a daily dose of 400 mg of imatinib is sufficient; however, a dose of 400 mg twice a day achieves significantly longer progression-free survival.

PMID 15451219  Lancet. 2004 Sep 25-Oct 1;364(9440):1127-34. doi: 10.10・・・
著者: John R Zalcberg, Jaap Verweij, Paolo G Casali, Axel Le Cesne, Peter Reichardt, Jean-Yves Blay, Marcus Schlemmer, Martine Van Glabbeke, Michelle Brown, Ian R Judson, EORTC Soft Tissue and Bone Sarcoma Group, the Italian Sarcoma Group, Australasian Gastrointestinal Trials Group
雑誌名: Eur J Cancer. 2005 Aug;41(12):1751-7. doi: 10.1016/j.ejca.2005.04.034.
Abstract/Text In the EORTC-ISG-AGITG trial 946 patients with advanced gastro-intestinal stromal tumours (GIST) were randomised to receive 400 or 800 mg of imatinib daily. An increase in progression free survival (PFS) was demonstrated for patients randomised to the high-dose arm. Patients randomised to low-dose could cross-over to high-dose upon progression. We evaluated the feasibility, safety and efficacy of this policy. Of the 241 patients available for follow-up, 133 patients (55%) crossed over to high-dose imatinib according to the protocol. Of these patients, 92% had not had a prior dose reduction. The cumulative incidence of subsequent dose reductions after cross-over was 17% after six months with 51% discontinuing therapy without requiring a dose reduction. The extent of anaemia and fatigue increased significantly after cross-over, whilst neutropenia was less severe than during low-dose treatment. Objective responses after cross-over included three patients (2%) with a partial response and 36 (27%) with stable disease. The median PFS after cross-over was 81 days, although 18.1% of patients were still alive and progression free one year after cross-over. We conclude that a cross-over to high-dose imatinib is feasible and safe in GIST patients who progress on low-dose therapy.

PMID 16098458  Eur J Cancer. 2005 Aug;41(12):1751-7. doi: 10.1016/j.ej・・・
著者: Charles D Blanke, Cathryn Rankin, George D Demetri, Christopher W Ryan, Margaret von Mehren, Robert S Benjamin, A Kevin Raymond, Vivien H C Bramwell, Laurence H Baker, Robert G Maki, Michael Tanaka, J Randolph Hecht, Michael C Heinrich, Christopher D M Fletcher, John J Crowley, Ernest C Borden
雑誌名: J Clin Oncol. 2008 Feb 1;26(4):626-32. doi: 10.1200/JCO.2007.13.4452.
Abstract/Text PURPOSE: To assess potential differences in progression-free or overall survival when imatinib mesylate is administered to patients with incurable gastrointestinal stromal tumors (GIST) at a standard dose (400 mg daily) versus a high dose (400 mg twice daily).
PATIENTS AND METHODS: Patients with metastatic or surgically unresectable GIST were eligible for this phase III open-label clinical trial. At registration, patients were randomly assigned to either standard or high-dose imatinib, with close interval follow-up. If objective progression occurred by Response Evaluation Criteria in Solid Tumors, patients on the standard-dose arm could reregister to the trial and receive the high-dose imatinib regimen.
RESULTS: Seven hundred forty-six patients with advanced GIST from 148 centers across the United States and Canada were enrolled onto this trial in 9 months. With a median follow-up of 4.5 years, median progression-free survival was 18 months for patients on the standard-dose arm, and 20 months for those receiving high-dose imatinib. Median overall survival was 55 and 51 months, respectively. There were no statistically significant differences in objective response rates, progression-free survival, or overall survival. After progression on standard-dose imatinib, 33% of patients who crossed over to the high-dose imatinib regimen achieved either an objective response or stable disease. There were more grade 3, 4, and 5 toxicities noted on the high-dose imatinib arm.
CONCLUSION: This trial confirms the effectiveness of imatinib as primary systemic therapy for patients with incurable GIST but did not show any advantage to higher dose treatment. It appears reasonable to initiate therapy with 400 mg daily and to consider dose escalation on progression of disease.

PMID 18235122  J Clin Oncol. 2008 Feb 1;26(4):626-32. doi: 10.1200/JCO・・・
著者: Markku Miettinen, Leslie H Sobin, Jerzy Lasota
雑誌名: Am J Surg Pathol. 2005 Jan;29(1):52-68.
Abstract/Text Gastrointestinal (GI) stromal tumors (GISTs), the specific KIT- or PDFGRA-signaling driven mesenchymal tumors, are the most common mesenchymal tumors of the GI tract. In this study, we analyzed 1869 cases originally classified as smooth muscle tumors of the stomach and found that 1765 (94%) of these were GISTs. The GISTs had a slight male predominance (55%) with a median age of 63 years. Only 2.7% of tumors occurred before the age of 21 years and 9.1% before the age of 40 years. The tumors varied from 0.5 to 44 cm (median, 6.0 cm) and most commonly presented with GI bleeding; 12% were incidentally detected. Several histologic variants were recognized among the spindle cell tumors (sclerosing, palisaded-vacuolated, hypercellular, and sarcomatous) and of epithelioid tumors (sclerosing, dyscohesive, hypercellular, and sarcomatous). Outcome was strongly dependent on tumor size and mitotic activity. Only 2% to 3% of tumors <10 cm and <5 mitoses/50 HPFs metastasized, whereas 86% of tumors >10 cm and >5 mitoses/50 HPFs metastasized. However, tumors >10 cm with mitotic activity <5/50 HPFs and those <5 cm with mitoses >5/50 HPFs had a relatively low metastatic rate (11% and 15%). A small number of patients survived intra-abdominal metastasis up to over 20 years. Tumor location in fundus or gastroesophageal junction, coagulative necrosis, ulceration, and mucosal invasion were unfavorable factors (P <0.001), whereas tumor location in antrum was favorable (P <0.001). KIT expression was detected in 91% of the cases, CD34 in 82%, smooth muscle actin in 18%, and desmin in 5%; the latter two were favorable (P <0.001). KIT exon 11 mutations were detected in 119 cases; patients with point mutations fared better than those with deletions (P <0.01). PDGFRA exon 18 mutations (total 86 cases) were common in epithelioid GISTs and most commonly represented a D842V point mutation; none of these was prognostically significant. The above results may be helpful for setting the criteria for adjuvant treatment such as Gleevec.

PMID 15613856  Am J Surg Pathol. 2005 Jan;29(1):52-68.
著者: Jean-Yves Blay, Axel Le Cesne, Isabelle Ray-Coquard, Binh Bui, Florence Duffaud, Catherine Delbaldo, Antoine Adenis, Patrice Viens, Maria Rios, Emmanuelle Bompas, Didier Cupissol, Cecile Guillemet, Pierre Kerbrat, Jérome Fayette, Sylvie Chabaud, Patrice Berthaud, David Perol
雑誌名: J Clin Oncol. 2007 Mar 20;25(9):1107-13. doi: 10.1200/JCO.2006.09.0183.
Abstract/Text PURPOSE: Imatinib is the standard treatment of advanced GI stromal tumors (GISTs). It is not known whether imatinib may be stopped in patients in whom disease is controlled.
METHODS: This prospective, randomized, multicentric phase III study was designed to compare continuous (CONT) compared with interrupted (INT) imatinib beyond 1 year of treatment in patients with advanced GIST. The primary end point was progression-free survival. Secondary end points included overall survival, response rate after reinitiation of imatinib, and quality of life. Early stopping rules in cases of rapid progression of disease were defined, with preplanned interim analyses.
RESULTS: Between May 2002 and April 2004, 182 patients with advanced GIST were enrolled. Between May 2003 and April 2004, 98 patients in response or stable disease under imatinib reached more than 1 year of follow-up. Forty were not eligible for randomization, and 58 patients were randomly assigned, 32 and 26 patients in the INT and CONT arms, respectively. As of October 15, 2005, eight of 26 patients in the CONT group and 26 of 32 patients in the INT group had documented disease progression (P < .0001). Twenty-four of 26 patients with documented progression in the INT arm responded to imatinib reintroduction. No differences in overall survival or imatinib resistance were observed between the two arms. Quality of life evaluated 6 months after random assignment using the 30-item Quality of Life Questionnaire was not significantly different between the two groups of randomly assigned patients.
CONCLUSION: Imatinib interruption results in rapid progression in most patients with advanced GIST, and cannot be recommended in routine practice unless patient experience significant toxicity

PMID 17369574  J Clin Oncol. 2007 Mar 20;25(9):1107-13. doi: 10.1200/J・・・
著者: George D Demetri, Allan T van Oosterom, Christopher R Garrett, Martin E Blackstein, Manisha H Shah, Jaap Verweij, Grant McArthur, Ian R Judson, Michael C Heinrich, Jeffrey A Morgan, Jayesh Desai, Christopher D Fletcher, Suzanne George, Carlo L Bello, Xin Huang, Charles M Baum, Paolo G Casali
雑誌名: Lancet. 2006 Oct 14;368(9544):1329-38. doi: 10.1016/S0140-6736(06)69446-4.
Abstract/Text BACKGROUND: No effective therapeutic options for patients with unresectable imatinib-resistant gastrointestinal stromal tumour are available. We did a randomised, double-blind, placebo-controlled, multicentre, international trial to assess tolerability and anticancer efficacy of sunitinib, a multitargeted tyrosine kinase inhibitor, in patients with advanced gastrointestinal stromal tumour who were resistant to or intolerant of previous treatment with imatinib.
METHODS: Blinded sunitinib or placebo was given orally once daily at a 50-mg starting dose in 6-week cycles with 4 weeks on and 2 weeks off treatment. The primary endpoint was time to tumour progression. Intention-to-treat, modified intention-to-treat, and per-protocol analyses were done. This study is registered at ClinicalTrials.gov, number NCT00075218.
FINDINGS: 312 patients were randomised in a 2:1 ratio to receive sunitinib (n=207) or placebo (n=105); the trial was unblinded early when a planned interim analysis showed significantly longer time to tumour progression with sunitinib. Median time to tumour progression was 27.3 weeks (95% CI 16.0-32.1) in patients receiving sunitinib and 6.4 weeks (4.4-10.0) in those on placebo (hazard ratio 0.33; p<0.0001). Therapy was reasonably well tolerated; the most common treatment-related adverse events were fatigue, diarrhoea, skin discolouration, and nausea.
INTERPRETATION: We noted significant clinical benefit, including disease control and superior survival, with sunitinib compared with placebo in patients with advanced gastrointestinal stromal tumour after failure and discontinuation of imatinab. Tolerability was acceptable.

PMID 17046465  Lancet. 2006 Oct 14;368(9544):1329-38. doi: 10.1016/S01・・・
著者: George D Demetri, Peter Reichardt, Yoon-Koo Kang, Jean-Yves Blay, Piotr Rutkowski, Hans Gelderblom, Peter Hohenberger, Michael Leahy, Margaret von Mehren, Heikki Joensuu, Giuseppe Badalamenti, Martin Blackstein, Axel Le Cesne, Patrick Schöffski, Robert G Maki, Sebastian Bauer, Binh Bui Nguyen, Jianming Xu, Toshirou Nishida, John Chung, Christian Kappeler, Iris Kuss, Dirk Laurent, Paolo G Casali, GRID study investigators
雑誌名: Lancet. 2013 Jan 26;381(9863):295-302. doi: 10.1016/S0140-6736(12)61857-1. Epub 2012 Nov 22.
Abstract/Text BACKGROUND: Until now, only imatinib and sunitinib have proven clinical benefit in patients with gastrointestinal stromal tumours (GIST), but almost all metastatic GIST eventually develop resistance to these agents, resulting in fatal disease progression. We aimed to assess efficacy and safety of regorafenib in patients with metastatic or unresectable GIST progressing after failure of at least imatinib and sunitinib.
METHODS: We did this phase 3 trial at 57 hospitals in 17 countries. Patients with histologically confirmed, metastatic or unresectable GIST, with failure of at least previous imatinib and sunitinib were randomised in a 2:1 ratio (by computer-generated randomisation list and interactive voice response system; preallocated block design (block size 12); stratified by treatment line and geographical region) to receive either oral regorafenib 160 mg daily or placebo, plus best supportive care in both groups, for the first 3 weeks of each 4 week cycle. The study sponsor, participants, and investigators were masked to treatment assignment. The primary endpoint was progression-free survival (PFS). At disease progression, patients assigned placebo could crossover to open-label regorafenib. Analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01271712.
RESULTS: From Jan 4, to Aug 18, 2011, 240 patients were screened and 199 were randomised to receive regorafenib (n=133) or matching placebo (n=66). Data cutoff was Jan 26, 2012. Median PFS per independent blinded central review was 4·8 months (IQR 1·4-9·2) for regorafenib and 0·9 months (0·9-1·8) for placebo (hazard ratio [HR] 0·27, 95% CI 0·19-0·39; p<0·0001). After progression, 56 patients (85%) assigned placebo crossed over to regorafenib. Drug-related adverse events were reported in 130 (98%) patients assigned regorafenib and 45 (68%) patients assigned placebo. The most common regorafenib-related adverse events of grade 3 or higher were hypertension (31 of 132, 23%), hand-foot skin reaction (26 of 132, 20%), and diarrhoea (seven of 132, 5%).
INTERPRETATION: The results of this study show that oral regorafenib can provide a significant improvement in progression-free survival compared with placebo in patients with metastatic GIST after progression on standard treatments. As far as we are aware, this is the first clinical trial to show benefit from a kinase inhibitor in this highly refractory population of patients.
FUNDING: Bayer HealthCare Pharmaceuticals.

Copyright © 2013 Elsevier Ltd. All rights reserved.
PMID 23177515  Lancet. 2013 Jan 26;381(9863):295-302. doi: 10.1016/S01・・・
著者: Michael C Heinrich, Christopher L Corless, Anette Duensing, Laura McGreevey, Chang-Jie Chen, Nora Joseph, Samuel Singer, Diana J Griffith, Andrea Haley, Ajia Town, George D Demetri, Christopher D M Fletcher, Jonathan A Fletcher
雑誌名: Science. 2003 Jan 31;299(5607):708-10. doi: 10.1126/science.1079666. Epub 2003 Jan 9.
Abstract/Text Most gastrointestinal stromal tumors (GISTs) have activating mutations in the KIT receptor tyrosine kinase, and most patients with GISTs respond well to Gleevec, which inhibits KIT kinase activity. Here we show that approximately 35% (14 of 40) of GISTs lacking KIT mutations have intragenic activation mutations in the related receptor tyrosine kinase, platelet-derived growth factor receptor alpha (PDGFRA). Tumors expressing KIT or PDGFRA oncoproteins were indistinguishable with respect to activation of downstream signaling intermediates and cytogenetic changes associated with tumor progression. Thus, KIT and PDGFRA mutations appear to be alternative and mutually exclusive oncogenic mechanisms in GISTs.

PMID 12522257  Science. 2003 Jan 31;299(5607):708-10. doi: 10.1126/sci・・・
著者: Seiichi Hirota, Akiko Ohashi, Toshirou Nishida, Koji Isozaki, Kazuo Kinoshita, Yasuhisa Shinomura, Yukihiko Kitamura
雑誌名: Gastroenterology. 2003 Sep;125(3):660-7.
Abstract/Text BACKGROUND & AIMS: Most gastrointestinal stromal tumors (GISTs) have gain-of-function mutations of c-kit receptor tyrosine kinase (KIT) gene, but some GISTs do not. We investigated the cause of GISTs without KIT mutations. Because GISTs apparently expressed platelet-derived growth factor receptor (PDGFR) alpha, we examined whether GISTs without KIT mutations had a mutation of PDGFR alpha.
METHODS: Whole coding region of PDGFR alpha complementary DNA (cDNA) was sequenced in GISTs with or without KIT mutations. Mutant PDGFR alpha cDNA was transfected into 293T human embryonic kidney cells, and autophosphorylation of PDGFR alpha was examined. Proliferation of Ba/F3 murine lymphoid cells stably transfected with mutant PDGFR alpha cDNA was estimated by tritium thymidine incorporation. Wild-type KIT cDNA was cotransfected with mutant PDGFR alpha cDNA, and immunoprecipitation by anti-KIT antibody was performed. Inhibitory effect of Imatinib mesylate on activated PDGFR alpha was examined.
RESULTS: We found 2 types of constitutively activated mutations of PDGFR alpha, Val-561 to Asp or Asp-842 to Val, in 5 of 8 GISTs without KIT mutations but not in 10 GISTs with KIT mutations. Stable transfection of each mutation induced autonomous proliferation of Ba/F3 cells. Constitutively activated mutant PDGFR alpha bound and activated the cotransfected wild-type KIT. The constitutive activation of PDGFR alpha with Val-561 to Asp was inhibited effectively by Imatinib mesylate but that of PDGFR alpha with Asp-842 to Val was inhibited only weakly, even at the concentration of 10 micromol/L.
CONCLUSIONS: The gain-of-function mutations of PDGFR alpha appear to play an important role in development of GISTs without KIT mutations.

PMID 12949711  Gastroenterology. 2003 Sep;125(3):660-7.
著者: S Hirota, K Isozaki, Y Moriyama, K Hashimoto, T Nishida, S Ishiguro, K Kawano, M Hanada, A Kurata, M Takeda, G Muhammad Tunio, Y Matsuzawa, Y Kanakura, Y Shinomura, Y Kitamura
雑誌名: Science. 1998 Jan 23;279(5350):577-80.
Abstract/Text Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors in the human digestive tract, but their molecular etiology and cellular origin are unknown. Sequencing of c-kit complementary DNA, which encodes a proto-oncogenic receptor tyrosine kinase (KIT), from five GISTs revealed mutations in the region between the transmembrane and tyrosine kinase domains. All of the corresponding mutant KIT proteins were constitutively activated without the KIT ligand, stem cell factor (SCF). Stable transfection of the mutant c-kit complementary DNAs induced malignant transformation of Ba/F3 murine lymphoid cells, suggesting that the mutations contribute to tumor development. GISTs may originate from the interstitial cells of Cajal (ICCs) because the development of ICCs is dependent on the SCF-KIT interaction and because, like GISTs, these cells express both KIT and CD34.

PMID 9438854  Science. 1998 Jan 23;279(5350):577-80.
著者: M Miettinen, L H Sobin, M Sarlomo-Rikala
雑誌名: Mod Pathol. 2000 Oct;13(10):1134-42. doi: 10.1038/modpathol.3880210.
Abstract/Text Gastrointestinal (GI) stromal tumor (GIST) is the designation for the major subset of GI mesenchymal tumors and encompasses most tumors previously classified as GI smooth muscle tumors. Although GISTs typically express CD117 (KIT), often express CD34, and sometimes express alpha-smooth muscle actin (SMA), the relative frequency of these markers has not been characterized in large series of GISTs of different sites, and the CD117 expression has not been fully characterized in intra-abdominal tumors. In this study, we immunohistochemically analyzed 292 GISTs throughout the GI tract, including omentum and mesentery, and compared the immunoreactivities with 211 other tumors that may enter in the differential diagnosis. GISTs were defined in this study as CD117-positive primary spindied or epithelioid mesenchymal tumors of the GI tract, omentum, or mesentery. The CD34 positivity of GISTs varied from 47% in small bowel to 96 to 100% in rectum and esophagus, whereas SMA expression showed the opposite patterns and was most frequent in the GISTs of small bowel (47%) and rarest in the GISTs of rectum and esophagus (10-13%). Desmin was seen only occasionally. S100 positivity was rare but was seen most frequently in small intestinal GISTs (15%). True leiomyomas from esophagus, muscularis mucosae of colorectum, and pericolic leiomyomas similar to uterine leiomyomas were negative for CD117 and CD34 and positive for SMA and desmin (46 of 46). Inflammatory fibroid polyps of stomach and small intestine were negative for CD117 but were often positive for CD34 (6 of 8) and variable for SMA (3 of 8). Inflammatory myofibroblastic tumors involving gastric or colonic wall were negative for CD117 but some showed CD117-positive endothelia. GI schwannomas were all negative for CD117 and positive for S100 protein (11 of 11). Extremely focal CD117 positivity was seen in the neoplastic cells of some retroperitoneal leiomyosarcomas and liposarcomas. Among other CD117-positive tumors were intestinal metastatic melanomas (8 of 11) and extraskeletal Ewing's sarcomas (5 of 11), two of which were abdominal. In conclusion, strong CD117 expression defines most primary GI mesenchymal tumors as GISTs, which show different patterns for CD34 and SMA in various parts of the GI tract. Some unrelated CD117-positive tumors (melanomas, Ewing's sarcomas) should not be confused with GISTs.

PMID 11048809  Mod Pathol. 2000 Oct;13(10):1134-42. doi: 10.1038/modpa・・・

ページ上部に戻る

戻る

さらなるご利用にはご登録が必要です。

こちらよりご契約または優待日間無料トライアルお申込みをお願いします。

(※トライアルご登録は1名様につき、一度となります)


ご契約の場合はご招待された方だけのご優待特典があります。

以下の優待コードを入力いただくと、

契約期間が通常12ヵ月のところ、14ヵ月ご利用いただけます。

優待コード: (利用期限:まで)

ご契約はこちらから