中国实用外科杂志

中国实用外科杂志 ›› 2025, Vol. 45 ›› Issue (08): 931-937.DOI: 10.19538/j.cjps.issn1005-2208.2025.08.15

• 论著 • 上一篇    下一篇

肝内胆管细胞癌类器官对吉西他滨联合顺铂化疗方案疗效预测价值研究

董志涛1a，朱妍静2，钱尤雯1b，段克才1a，郭俊武1a，戴炳华1a，隋承军1a，耿    利1a，杨甲梅1a   

  1. 1上海东方肝胆外科医院  a.特需诊疗科  b.病理科，上海 200438；2复旦大学附属中山医院肿瘤内科，上海 200032
  • 出版日期:2025-08-01 发布日期:2025-09-02

  • Online:2025-08-01 Published:2025-09-02

摘要： 目的    建立肝内胆管细胞癌（ICC）病人来源的肿瘤类器官，通过体外模拟ICC的生物学行为，探讨肿瘤类器官作为临床前模型预测晚期ICC病人应用吉西他滨联合顺铂（GC）化疗方案的疗效。方法    前瞻性收集2023年1月至2024年3月于上海东方肝胆外科医院就诊的晚期ICC病人的肿瘤组织，分离并培养ICC类器官，并对其组织形态学和免疫组化特征同病人肿瘤组织进行对比评估。使用GC方案化疗药物处理ICC类器官，采用不同药物浓度方案检测类器官组织对化疗的敏感性，比较类器官药敏试验结果不同病人的实际临床疗效。结果    52例病人中，成功建立25例（48.1%）ICC类器官。构建成功组病人穿刺样本>2条、起始活细胞数≥1×105个、运送时间<60 min比例显著高于构建失败组，差异有统计学意义（P<0.05）。类器官组织形态学和免疫组化特征在连续传代后与原始肿瘤组织仍保持基本一致。类器官药敏检测结果显示，16例类器官药敏结果为敏感，9例为耐药，并据此分组，两组病人一般资料比较差异均无统计学意义（P>0.05）。治疗后，敏感组病人肿瘤最大径小于耐药组，差异有统计学意义［（3.40±0.62）cm vs. （6.95±0.57）cm，χ²=5.672，P<0.001］。类器官敏感组病人临床部分缓解例数（8例 vs. 1例，P=0.027）和客观缓解率均高于类器官耐药组（50% vs. 11%，P=0.027），差异有统计学意义。两组病人临床治疗反应差异有统计学意义（P<0.001）。ICC类器官对GC化疗方案的敏感性预测病人临床疗效的准确率为88.0%（22/25），敏感度为87.5%，特异度为88.9%。所有病人中位随访时间16（8～24）个月，类器官敏感组病人中位总生存期（OS）和无进展生存期均显著高于耐药组［OS：13.0（95% CI 10.2-15.8）个月 vs. 9.0（95% CI 6.7-11.2）个月，P=0.029；PFS：9.3（95% CI 7.1-11.4）个月 vs. 4.9（95% CI 3.5-6.2）个月，P=0.007］，差异有统计学意义。结论    ICC类器官作为临床前模型在预测GC方案疗效方面有一定的参考意义和临床应用价值。

关键词: 肝内胆管细胞癌, 晚期肝癌, 化疗, 类器官

Abstract: To establish patient-derived tumor organoids from intrahepatic cholangiocarcinoma (ICC), simulate the biological behavior of ICC in vitro, and evaluate the value of organoids as a preclinical model for guiding gemcitabine plus cisplatin (GC) chemotherapy in patients with advanced ICC. Methods  Tumor tissues of patients with advanced ICC who were treated at Shanghai Eastern Hepatobiliary Surgery Hospital from January 2023 to March 2024, were prospectively collected, and ICC organoids were isolated and cultured. The morphological and immunohistochemical characteristics of the organoids were compared and evaluated with the tumor tissues of the patients. The ICC organoids were treated with chemotherapy drugs of the GC regimen, and the sensitivity of the organoid tissues to chemotherapy was detected using different drug concentration regimens. Compare the actual clinical therapeutic effects of different patients based on the results of organoid drug sensitivity tests. Results    Among the 52 patients, 25 cases (48.1%) successfully established ICC organoids. The proportion of patients in the successful group who had ≥2 biopsy samples, a starting number of living cells ≥1×105, and a transportation time of ＜60 min was significantly higher than that in the failed group, and the difference was statistically significant (P<0.05). The morphological and immunohistochemical characteristics of the organoid tissues remained basically consistent after continuous passages compared to the original tumor tissues. The drug sensitivity test results of the organoids showed that 16 cases were sensitive, and 9 cases were resistant. Based on this classification, there were no statistically significant differences in the clinical data between the two groups (P>0.05). After treatment, the maximum diameter of the tumors in the sensitive group was smaller than that in the resistant group, and the difference was statistically significant ［(3.40±0.62) cm vs. (6.95±0.57) cm, χ²=5.672, P<0.001］. The number of patients with partial clinical remission in the organoid sensitive group (8 cases vs. 1 case, P=0.027) and the objective response rate were higher than those in the organoid resistant group (50% vs. 11%, P=0.027), and the differences were statistically significant. There was a statistically significant difference in the clinical treatment responses between the two groups of patients (P<0.001). The accuracy rate of predicting the clinical efficacy of patients by the sensitivity of ICC organ to the GC chemotherapy regimen was 88.0% (22/25), with a sensitivity of 87.5% and a specificity of 88.9%. The median follow-up time for all patients was 16 (8-24) months. The median overall survival (OS) and progression-free survival (PFS) of the organoid sensitive group were significantly higher than those of the resistant group ［OS: 13.0 (95%CI 10.2-15.8) months vs. 9.0 (95%CI 6.7-11.2) months, P=0.029; PFS: 9.3 (95%CI 7.1-11.4) months vs. 4.9 (95%CI 3.5-6.2) months, P=0.007］, and the differences were statistically significant. Conclusion    Patient-derived ICC organoids reliably predict GC chemotherapy efficacy and may serve as a clinically relevant preclinical platform for personalized treatment decision-making in advanced ICC.

Key words: intrahepatic cholangiocarcinoma, advanced liver cancer, chemotherapy, organoids