Bataille F, Rümmele P, Dietmaier W, Gaag D, Klebl F, Reichle A, Wild P, Hofstädter F, Hartmann A
Department of Pathology, University of Regensburg, 93042 Regensburg, Germany.
Mol Pathol. 2003 Oct;56(5):286-92. doi: 10.1136/mp.56.5.286.
To evaluate the usefulness of molecular markers in predicting histopathological and clinical response to preoperative high dose chemotherapy (HDCT) and survival of patients with advanced gastric cancer.
In a phase II trial, 25 patients with metastatic gastric cancer received preoperative tandem HDCT consisting of etoposide, cisplatin, and mitomycin, followed by autologous bone marrow transplantation to achieve surgical resectability. Samples before and after treatment, from normal and tumour tissue, were characterised histopathologically, and both p53 and BAX expression was analysed by immunohistochemistry. Pretreatment formalin fixed, paraffin wax embedded samples from normal and tumour tissue were microdissected, and the extracted DNA was preamplified using improved primer extension preamplification polymerase chain reaction. Detection of microsatellite instability (MSI) or loss of heterozygosity (LOH) was performed using markers for p53, BAX, BAT25, BAT26, D2S123, D17S250, and APC. Exons 5-9 of the p53 gene were sequenced directly on ABI 373.
Four parameters were significantly associated with response to chemotherapy and prolonged overall survival: positive p53 immunostaining, positive p53 mutation status before chemotherapy, strong histological regression induced by preoperative HDCT, and surgical treatment. Patients's sex or age, tumour location or stage, lymph node status, Lauren classification, MSI, or LOH did not influence duration of survival significantly in this high risk population.
Positive p53 immunostaining and p53 mutation status in pretreatment tumour biopsies might be useful molecular predictors of response and prognosis in patients with advanced gastric cancer treated by preoperative HDCT.
评估分子标志物在预测晚期胃癌患者术前大剂量化疗（HDCT）的组织病理学和临床反应以及生存情况方面的实用性。
在一项II期试验中，25例转移性胃癌患者接受了由依托泊苷、顺铂和丝裂霉素组成的术前串联HDCT，随后进行自体骨髓移植以实现手术可切除性。对治疗前后取自正常组织和肿瘤组织的样本进行组织病理学特征分析，并通过免疫组织化学分析p53和BAX的表达。对术前福尔马林固定、石蜡包埋的正常组织和肿瘤组织样本进行显微切割，提取的DNA使用改进的引物延伸预扩增聚合酶链反应进行预扩增。使用p53、BAX、BAT25、BAT26、D2S123、D17S250和APC的标志物检测微卫星不稳定性（MSI）或杂合性缺失（LOH）。p53基因的第5 - 9外显子在ABI 373上直接测序。
有四个参数与化疗反应及总体生存时间延长显著相关：p53免疫染色阳性、化疗前p53突变状态阳性、术前HDCT诱导的强烈组织学消退以及手术治疗。在这个高风险人群中，患者的性别或年龄、肿瘤位置或分期、淋巴结状态、劳伦分类、MSI或LOH对生存时间没有显著影响。
术前肿瘤活检中p53免疫染色阳性和p53突变状态可能是术前HDCT治疗的晚期胃癌患者反应和预后的有用分子预测指标。
