Table_1_Early Initiation of Temozolomide Therapy May Improve Response in Aggressive Pituitary Adenomas.docx

IntroductionAggressive pituitary adenomas (APAs) are, by definition, resistant to optimal multimodality therapy. The challenge lies in their early recognition and timely management. Temozolomide is increasingly being used in patients with APAs, but evidence supporting a favorable response with early initiation is lacking.
MethodsThis was a single-center study of all patients with APAs who received at least 3 cycles of temozolomide (150–200 mg/m2). Their baseline clinico-biochemical and radiological profiles were recorded. Immunohistochemical evaluation for cell-cycle markers O6-methylguanine-DNA methyltransferase (MGMT), MutS homolog 2 (MSH2), MutS homolog 6 (MSH6), MutL homolog 1 (MLH1), and postmeiotic segregation increased 2 (PMS2) was performed, and h-scores (product of the number of positive cells and staining intensity) were calculated. Response was assessed in terms of radiological response using the RECIST criteria. Patients with controlled disease (≥30% reduction in tumor volume) were classified as responders.
ResultsThe study comprised 35 patients (48.6% acromegaly, 37.1% prolactinomas, and 14.3% non-functioning pituitary adenomas). The median number of temozolomide (TMZ) cycles was 9 (IQR 6–14). Responders constituted 68.6% of the cohort and were more likely to have functional tumors, a lower percentage of MGMT-positive staining cells, and lower MGMT h-scores. There was a significantly longer lag period in the initiation of TMZ therapy in non-responders as compared with responders (median 36 vs. 15 months, p = 0.01). ROC-derived cutoffs of 31 months for the duration between diagnosis and TMZ initiation, low-to-intermediate MGMT positivity (40% tumor cells), and MGMT h-score of 80 all had a sensitivity exceeding 80% and a specificity exceeding 70% to predict response.
ConclusionEarly initiation of TMZ therapy, functional tumors, and low MGMT h-score predict a favorable response to TMZ in APAs.

引言：侵袭性垂体腺瘤（Aggressive pituitary adenomas, APAs）按定义对最优多模式治疗耐药，其诊疗难点在于早期识别与及时干预。替莫唑胺（Temozolomide）在APAs患者中的应用日益广泛，但支持早期启动治疗可获得良好应答的证据仍较为匮乏。
方法：本研究为单中心研究，纳入所有接受至少3个周期替莫唑胺（150~200 mg/m²）治疗的APAs患者。收集患者的基线临床生化与影像学资料。对细胞周期标志物O6-甲基鸟嘌呤-DNA甲基转移酶（O6-methylguanine-DNA methyltransferase, MGMT）、MutS同源蛋白2（MutS homolog 2, MSH2）、MutS同源蛋白6（MutS homolog 6, MSH6）、MutL同源蛋白1（MutL homolog 1, MLH1）及减数分裂后分离增加蛋白2（postmeiotic segregation increased 2, PMS2）进行免疫组化检测，并计算h评分（阳性细胞数与染色强度的乘积）。采用实体瘤疗效评价标准（Response Evaluation Criteria in Solid Tumors, RECIST）评估影像学应答。将疾病得到控制（肿瘤体积缩小≥30%）的患者归类为应答者。
结果：本研究共纳入35例患者，其中肢端肥大症占48.6%、催乳素瘤占37.1%、无功能垂体腺瘤占14.3%。替莫唑胺（TMZ）治疗周期的中位数为9（四分位距6~14）。应答者占研究队列的68.6%，这类患者更常为功能性腺瘤、MGMT阳性细胞占比更低且MGMT h评分更低。与应答者相比，无应答者启动TMZ治疗的间隔时间显著更长（中位数分别为36个月与15个月，p=0.01）。受试者工作特征曲线（Receiver Operating Characteristic, ROC）推导得到的预测阈值为：确诊至TMZ启动间隔时长31个月、MGMT阳性比例为低至中等水平（肿瘤细胞占比40%）、MGMT h评分为80，上述指标预测治疗应答的灵敏度均超过80%，特异度均超过70%。
结论：早期启动TMZ治疗、功能性腺瘤及低MGMT h评分可预测APAs患者对TMZ治疗的良好应答。