1138 POSTER Neutropenia as a Biomarker of Sunitinib Efficacy in Patients (Pts) With Gastrointestinal Stromal Tumour (GIST)
Frede DonskovMargaret von MehrenA. CamsSuzanne GeorgeR.G. CasaliS. LiJames D. PerkinsGeorge D. Demetri
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Objective To investigate the expression of bcl-2 in gastrointestinal stromal tumors (GIST). Methods The expression of bcl-2, CD 117 and CD 34 were detected in 51 cases of GIST with Envision immunohistochemical method. Results In 51 GIST, the positive rates of CD 117 and CD 34 were 100 % and 76. 5 % . The expression of bcl-2 were observed in 45 of 51 cases (88.2 % ), and the positive rates of the benign, borderline and the malignant GIST were 100%, 91. 7% and 82. 8% respectively. There was no significant difference in expression of bcl-2 between the benign GIST and malignant GIST. Conclusion Bcl-2 may serve as a supplemental marker of GIST for diagnosis, which may not be used as the index to distinguish the benign GIST from the malignant GIST.
Stromal tumor
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Gastrointestinal stromal tumor (GIST) is the most common soft tissue sarcoma of the gastrointestinal tract. With the development of diagnosis and treatment of GIST, the overall survival is significantly prolonged, and GIST may be classified as a "chronic disease". How to effectively manage the patients with whole-course information is an important problem faced by colleagues who are responsible for GIST patients. We believe that every GIST patient has a need for whole-course management, which is also an important factor related to efficacy. The concept of information-based management, the management system in line with the characteristics of GIST disease and full-time managers of GIST disease are the guarantees for the realization of whole-course management, and also the prerequisites for homogeneals diagnosis and treatment of GIST.胃肠间质瘤（GIST）是胃肠道最常见的间叶源性肿瘤。随着对GIST诊疗的进步，患者生存期显著延长，疾病进入"慢性病"范畴。因此，如何对患者进行有效的全程化信息化管理是每一位GIST同仁面临的重要问题。我们认为：每一位GIST患者都有进行全程化管理的需求，这也是保障患者疗效的重要因素；信息化管理的理念、符合GIST疾病特点的管理系统以及专职的GIST疾病管理员，是实现全程化管理的保障，也是实现GIST诊治同质化的必备条件。.
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The aim of the present study was to clarify the therapeutic range and adequate dose of sunitinib in Japanese renal cell carcinoma patients by means of a pharmacokinetic–pharmacodynamic analysis of sunitinib-induced thrombocytopenia. Six patients with renal cell carcinoma were enrolled in this study. After starting the sunitinib treatment, between three and seven blood samples were obtained from each patient just before the administration of sunitinib. Serum concentrations of sunitinib and its active metabolite N-desethyl-sunitinib were fit to the 1-compartment model with first-order absorption. Changes in platelet counts were fit to the pharmacokinetic–pharmacodynamic model, in which the proliferation of platelet progenitor cells was assumed to be linearly inhibited by sunitinib and its metabolite. All patients using 50 mg as an initial dose of sunitinib developed grade 2 or 3 thrombocytopenia. The pharmacokinetic–pharmacodynamic model created successfully described the time course of sunitinib-induced thrombocytopenia and could predict changes in platelet counts after alterations to the dosage of sunitinib administered. The simulation results indicated that the total trough level of sunitinib to avoid severe thrombocytopenia should be <100 ng/mL, and also that the initial daily dose of sunitinib could be reduced to 37.5 mg or 25 mg in most Japanese patients. In addition to the pharmacokinetic-guided dosage adjustment, the careful monitoring of platelet counts is required for the safe use of sunitinib.
Pharmacodynamics
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목적: Sunitinib 치료 후 발생하는 갑상선기능저하증은 흔한 부작용이다. 발병 기전으로 sunitinib에 의한 파괴성 갑상선염, 갑상선으로의 요오드 운반 억제, 갑상선호르몬 합성과정의 억제 등이 제시되었다. 이는 요오드 섭취 정도에 따라서도 sunitinib에 의한 갑상선기능이상의 발생률이나 임상적 특성이 다를 수 있음을 시사한다. 이에 본 연구에서는 요오드 풍부 지역의 하나인 한국인에서 sunitinib 투여로 인한 갑상선기능저하증의 발생률 및 특성에 대해 조사해 보고자 하였다. 방법: 2005년 11월부터 2007년 7월까지 서울대학교병원에서 sunitinib을 투약했던 환자 중 sunitinib 치료 기간 혹은 후에 갑상선호르몬을 측정한 환자 25명을 대상으로 하였다. 13명은 sunitinib 투여 기간 혹은 후에 갑상선기능저하증을 의심할 수 있는 임상상을 보여 갑상선호르몬을 측정하였고, 12명은 임상상에 관계없이 추적관찰 위해 sunitinib 치료 기간 동안 갑상선호르몬을 측정하였다. 결과: 갑상선기능저하증을 의심할 수 있는 임상상을 보여 갑상선호르몬을 측정한 13명에서는 모두 갑상선기능저하증 소견을 보였으며(현성 9명, 무증상 4명), 임상상에 관계없이 sunitinib 투여 기간 중 갑상선호르몬을 측정한 12명에서는 6명이 갑상선기능저하증 소견을 보였고(현성 2명, 무증상 4명), 2명이 갑상선중독증 소견을 보였다. 19명의 갑상선기능저하증 환자들을 현성과 무증상 갑상선기능저하증으로 나누어 비교해 본 결과 갑상선자극호르몬 상승이 발견된 시기가 현성 갑상선기능저하증 환자들에서 유의하게 늦게 나타났고(44.5 대. 14.8주, p<0.05), sunitinib 누적 투여량은 유의하게 높게 나타났다(8050±3211 대. 3718±1961 mg, p<0.05). 19명의 환자에서 갑상선자극호르몬 수치와 갑상선자극호르몬 상승시까지의 sunitinib 투여 기간 및 투여 누적량 사이에는 상관성이 있는 것으로 나타났다. 결론: Sunitinib 투여 후 갑상선기능저하증의 발생률은 50% 이상일 것으로 예상되었으며, 다른 지역에서 시행된 연구와 비교해 볼 때 요오드 섭취 정도가 sunitinib에 의한 갑상선기능저하증 발병에 영향을 준다고 말하기는 어려운 결과를 보였다. 갑상선 기능저하증 정도는 sunitinib 투여기간 및 용량에 비례하였다. 향후 전향적 연구를 통해 정확한 발생률 및 요오드 섭취에 의한 영향을 평가해 보는 것이 필요하겠다.
Sunitinib malate
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【背景と目的】 原発GISTに対する治療の第一選択は外科切除であるが, 再発症例に対する積極的治療がGISTの治療成績向上に繋がる. 2008年にGIST診療ガイドラインが示されてから, 再発症例に対する治療の原則はイマチニブの投与である. 教室の再発GIST症例を臨床病理学的に検討し治療法について検討した. 【結 果】 男性3例女性4例の7例で, 平均年齢は61.9歳であった. 原発は胃 : 1例, 十二指腸 : 1例, 小腸 : 4例, 直腸 : 1例であった. リスク分類では中間 : 2例, 中間~高 : 2例, 高 : 3例で, 初再発は全例肝転移を伴い, 再発までの期間は14-77ヶ月であった. 再発巣切除は3例で, イマチニブ投与は4例であった. 7例中5例が再再発または耐性になった. イマチニブを投与した4例中3例は耐性になり, 1例はスニチニブに変更し2例は局所耐性部を切除しイマチニブを継続した. 7例中2例死亡したが5例は長期生存中である. 【結 語】 GIST再発ではイマチニブ投与が第一選択であるが, 耐性になった場合, 全身性の場合はスニチニブ投与, 局所性では切除後イマチニブを継続投与するのがよい.
Stromal tumor
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Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor in the gastrointestinal tract. The successful application of molecular targeted agents has promoted the clinical diagnosis and treatment of GIST into the era of precision medicine. There are some pitfalls in the diagnosis (including preoperative diagnosis and pathological diagnosis), surgical treatment (including surgical procedure, minimally invasive surgery, and surgery for recurrent/metastatic GIST) and drug treatment (including duration of adjuvant therapy for very high risk GIST and timing of intervention during preoperative treatment) of GIST. In addition to difficulties of doctors, these pitfalls can also lead to waste of medical resources, and even endanger the health and life of patients. Each doctor engaged in the diagnosis and treatment of GIST needs to fully understand the biological characteristics and disease development pattern of GIST, and accurately recognize every possible trap in the clinical management. This paper analyzes the pitfalls and misunderstandings in various aspects of GIST diagnosis and treatment in order to provide clues for promoting more reasonable clinical decision-making.胃肠间质瘤（GIST）是胃肠道最常见的间叶源性肿瘤，分子靶向药物的成功应用推动了GIST的临床诊疗进入了精准医学时代。GIST的诊断（包括术前诊断和病理诊断）、外科治疗（包括外科手术、微创治疗、复发转移性GIST的外科手术）和药物治疗（包括极高危GIST辅助治疗时限、术前治疗的干预时机）环环相扣，各个环节都存在一定的陷阱和误区，一旦误入，除了给医者带来困境，更可致医疗资源浪费，甚至危及患者的健康乃至生命。每位从事GIST诊疗的医师需要充分认识GIST的生物学特性和疾病发展规律，在诊疗工作中准确识别每一个可能的陷阱。本文从GIST诊疗的各个环节浅析可能存在的陷阱和误区，以期为推进更合理的临床决策提供参考。.
Stromal tumor
Adjuvant Therapy
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Abstract Background: Resistance to sunitinib, a broad spectrum tyrosine kinase inhibitor considered as first-line therapy for advanced clear cell renal carcinoma (ccRCC), is almost inevitable in patients. However, understanding the mechanisms underlying resistance to sunitinib remains incomplete. In order to decipher underlying drug-induced resistance mechanisms and identify potential targets to overcome sunitinib resistance in ccRCC, we developed a unique ccRCC xenograft model that mimicked clinical resistance to sunitinib. Methods: Untreated and sunitinib-treated Balb/C mice xenografted with RENCA cells were monitored for tumor growth. Sunitinib (40 mg/kg/day) administered 5 days/7 initially inhibited growth of xenografts, but tumors escaped after 6 weeks of continuous therapy. These sunitinib-induced resistant tumors were then removed and re-implanted to naïve Balb/C mice where re-implanted tumors exhibited immediately an aggressive phenotype. Re-implanted sunitinib-resistant tumors remained refractory to further treatment with sunitinib but responded to treatment with sorafenib and rapamycine, mimicking a strategy and tumor response that is often observed in the clinical setting. Transcriptomic and proteomic analyses of untreated, sunitinib-responsive and sunitinib-resistant tumors were performed, as well as evaluations of microvessel densities and host circulating angiogenic cells. Results: The aggressive phenotype of re-implanted sunitinib-resistant tumors suggested that the drug-induced acquired resistance was of intrinsic nature. However, transcriptomic analyses showed no differences in gene expression levels between untreated, sunitinib-responsive and sunitinib-resistant tumors. Proteomic analyses of tumors and serum samples are ongoing, as well as thorough analyses of the different angiogenic cellular compartments underlying host microenvironment responses. Conclusion: We have established a unique xenograft ccRCC model that mimicks clinical resistance to sunitinib. Our results show that while sunitinib-induced resistance is apparently intrinsic, tumor and host microenvironment are most likely critical mediators of resistance. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1377. doi:1538-7445.AM2012-1377
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Stromal tumor
Targeted Therapy
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Renal cell carcinoma (RCC) is a treatment resistant cancer. The identification of the link between the von Hippel Lindau (VHL) gene and the vascular endothelial growth factor (VEGF) pathway has led to development of the multi-tyrosine kinase inhibitor sunitinib. The introduction of sunitinib in clinical practice for the treatment of metastatic RCC has significantly increased the overall survival of patients. However resistance to sunitinib is emerging as a challenge. About 30% of patients are intrinsically resistant to sunitinib and almost all patients who show initial response to sunitinib develop extrinsic (acquired) resistance after a median of 6-15 months. While the molecular mechanisms of sunitinib resistance are multifactorial, the emerging consensus is that, sustained VEGF/VEGF receptor (VEGFR) inhibition by sunitinib 'resets' the tumor microenvironment leading to the development of VEGF/VEGFRindependent alternate angiogenic pathways. This chapter summarises the advances in understanding of the molecular mechanisms of sunitinib resistance in RCC.
Kidney cancer
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