PDF(2335 KB)
基于全国多中心专病队列的中国胆囊癌病人预后因素探索与预后预测模型构建
孙旭恒, 王一钧, 郑志元, 冯佳毅, 李雪川, 任泰, 刘立果, 颜伟康, 央茂, 邹路, 陈涛, 陈炜, 耿亚军, 何敏, 李永盛, 王辉, 吴文广, 杨林华, 张军峰, 龚伟, 吴向嵩, 顾钧, 蔡鸿宇, 曹宏, 曹景玉, 陈晓亮, 戴朝六, 党学义, 段绍斌, 冯健, 顾剑峰, 韩玮, 姜小清, 李兵, 姚碧辉, 李其云, 李志臻, 刘昌军, 刘付宝, 刘建生, 刘军, 刘连新, 吕文才, 杞映华, 钱叶本, 邵成浩, 孙备, 王传磊, 王军华, 王雷, 徐红星, 武步强, 徐军明, 闫军, 杨佳华, 张斌, 张磊, 张启瑜, 张彤, 檀占海, 张学文, 郑进方, 朱春富, 朱海宏, 顾轩宇, 胡嘉铭, 李霖, 周政俊, 耿智敏, 李茂岚, 张薇, 刘颖斌
中国实用外科杂志 ›› 2026, Vol. 46 ›› Issue (3) : 343-360.
PDF(2335 KB)
PDF(2335 KB)
基于全国多中心专病队列的中国胆囊癌病人预后因素探索与预后预测模型构建
Exploration of prognostic factors and construction of a prognostic prediction model for Chinese patients with gallbladder cancer based on a national multicenter disease-specific cohort
目的 基于全国性专病队列数据挖掘中国胆囊癌（GBC）病人术后总生存期（OS）的预后因素，构建并验证中国GBC病人术后总体生存概率预测模型。 方法 基于中国胆囊癌研究小组（CRGGC）回顾性登记队列数据库，提取2010年1月至2017年12月间在全国50家医院接受手术治疗的5664例GBC病人的临床诊疗数据。以术后OS为主要结局指标，采用最小绝对收缩和选择算子（LASSO）回归模型筛选关键预后因素并构建预后预测模型，采用自助法（Bootstrap法）验证模型的区分能力及准确性。 结果 通过最小绝对收缩和LASSO回归方法筛选出与术后OS显著相关的因素。多因素回归分析显示，年龄>84岁、行非根治性手术、联合切除其他器官、术前血清癌胚抗原（CEA）及糖类抗原125（CA125）水平超出正常范围、术前行介入治疗、术后未接受内科辅助治疗、特定组织学类型（如神经内分泌癌、印戒细胞癌）、病理检查发现神经或肝脏侵犯以及较高的T、N、M分期等，均为影响预后的独立危险因素。据此建立预测中国GBC病人手术治疗后5年内生存概率的完整和精简列线图模型。完整模型纳入19个关键变量，精简模型纳入8个关键变量。内部验证结果显示，完整模型和精简模型的受试者工作特征（ROC）曲线下面积（AUC）分别为0.752（95%CI：0.697~0.803）和0.749（95%CI：0.694~0.802），一致性指数（C-index）分别为0.696（95%CI：0.695~0.696）和0.689（95%CI：0.689~0.690），提示模型预测效果与稳定性良好。 结论 基于全国多中心专病队列数据建立的中国GBC病人术后预后预测模型，分别纳入了较完整和最精简的关键预后因素组合。应用上述模型可以快捷、准确地评估接受手术治疗的GBC病人的预后情况，有助于临床医师精准识别高危人群，并为制定个体化综合治疗方案提供科学依据。
Objective To explore the prognostic factors for overall survival (OS) of Chinese patients with gallbladder cancer (GBC) after surgery based on a national disease-specific cohort data, and to construct and validate an OS probability prediction model for Chinese GBC patients. Methods Based on the retrospective registration cohort database of the Chinese Research Group of Gallbladder Cancer (CRGGC), clinical data of 5664 GBC patients who underwent surgical treatment at 50 hospitals nationwide between January 2010 and December 2017 were extracted. With postoperative OS as the primary outcome measure, the least absolute shrinkage and selection operator (LASSO) regression model was used to screen key prognostic factors and construct the prognostic prediction model. The discrimination ability and accuracy of the model were validated using the Bootstrap method. Results Factors significantly associated with postoperative OS were screened out through the LASSO regression method. Multivariate regression analysis showed that age > 84 years, non-radical surgery, combined resection of other organs, preoperative serum carcinoembryonic antigen (CEA) and cancer antigen 125 (CA125) levels exceeding the normal range, preoperative interventional therapy, no postoperative adjuvant medical therapy, specific histological types (such as neuroendocrine carcinoma, signet-ring cell carcinoma), neural or hepatic invasion found by pathological examination, and advanced T, N, M staging were all independent risk factors affecting the prognosis. Based on this, a complete and a streamlined nomogram model for predicting the 5-year survival probability of Chinese GBC patients after surgical treatment were established. The complete model incorporated 19 key variables, and the streamlined model incorporated 8 key variables. Internal validation results showed that the areas under the receiver operating characteristic (ROC) curves (AUC) of the complete and streamlined models were 0.752 (95%CI: 0.697-0.803) and 0.749 (95%CI: 0.694-0.802), respectively, and the concordance indices (C-index) were 0.696 (95%CI: 0.695-0.696) and 0.689 (95%CI: 0.689-0.690), respectively, indicating that the models have good prediction efficacy and stability. Conclusion Postoperative prognostic prediction models for Chinese GBC patients established based on national multicenter disease-specific cohort data have incorporated relatively complete and the most streamlined combinations of key prognostic factors, respectively. The application of these models can quickly and accurately evaluate the prognosis of GBC patients receiving surgical treatment, help clinicians accurately identify high-risk populations, and provide a scientific basis for formulating individualized comprehensive treatment plans.
胆囊癌 / 总体生存 / 预后因素 / 列线图 / 最小绝对收缩和选择算子 / 多中心队列 / 预测模型
gallbladder cancer / overall survival / prognostic factors / nomogram / least absolute shrinkage and selection operator / multicenter cohort / prediction model
| [1] |
中华医学会外科学分会胆道外科学组. 胆囊癌诊断和治疗指南(2019版)[J]. 中华外科杂志, 2020, 58(4):243-251.DOI:10.3760/cma.j.cn112139-20200106-00014.
|
| [2] |
中国临床肿瘤学会(CSCO)胆道系统肿瘤专家委员会. CSCO胆道系统肿瘤诊断治疗专家共识(2019年版)[J]. 临床肿瘤学杂志, 2019, 24(9):828-838.DOI:10.3969/j.issn.1009-0460.2019.09.014.
|
| [3] |
|
| [4] |
|
| [5] |
Union for International Cancer Control. TNM Classification of Malignant Tumours[M]. 8th ed. Oxford: Wiley-Blackwell, 2017.
|
| [6] |
American Joint Committee on Cancer. AJCC Cancer Staging Manual[M]. 8th ed. Chicago: Springer, 2017.
|
| [7] |
王泽宇, 黑振宇, 耿亚军, 等. 基于TNM分期的胆囊癌手术治疗[J]. 中国实用外科杂志, 2021, 41(2):236-238.DOI:10.19538/j.cjps.issn1005-2208.2021.02.25.
|
| [8] |
任泰, 李永盛, 耿亚军, 等. 中国2010—2017年胆囊癌治疗模式及预后分析[J]. 中华外科杂志, 2020, 58(9):697-706.DOI:10.3760/cma.j.cn112139-20200403-00279.
|
| [9] |
孙旭恒, 任泰, 耿亚军, 等. 中国胆囊癌外科治疗现状与病理学特征多中心回顾性研究(附4345例报告)[J]. 中国实用外科杂志, 2021, 41(1):99-106.DOI:10.19538/j.cjps.issn1005-2208.2021.01.18.
|
| [10] |
孙旭恒, 王一钧, 张薇, 等. 中国胆囊癌流行病学特征与诊治及预后分析(附6159例报告)[J]. 中华消化外科杂志, 2022, 21(1):114-128.DOI:10.3760/cma.j.cn115610-20220103-00004.
|
| [11] |
王一钧, 孙旭恒, 冯佳毅, 等. 2010—2017年中国胆囊癌诊治流程与预后分析(附7874例报告)[J]. 中国实用外科杂志, 2024, 44(9):1038-1054,1061.DOI:10.19538/j.cjps.issn1005-2208.2024.09.14.
|
| [12] |
Gallbladder cancer (GBC), the sixth most common gastrointestinal tract cancer, poses a significant disease burden in China. However, no national representative data are available on the clinical characteristics, treatment and prognosis of GBC in the Chinese population.
|
| [13] |
World Health Organization. International Statistical Classification of Diseases and Related Health Problems 10th Revision[M]. 5th ed. Geneva: World Health Organization, 2019.
|
| [14] |
中华人民共和国民政部. 2023年中华人民共和国县以上行政区划代码[EB/OL].(2024-01-20)[2026-01-18].https://www.mca.gov.cn/mzsj/xzqh/2023/202301xzqh.html.
|
| [15] |
|
| [16] |
万学红, 卢雪峰. 诊断学[M]. 9版. 北京: 人民卫生出版社, 2018.
|
| [17] |
刘立果, 张一鉴, 王许安, 等. 免疫治疗在胆道恶性肿瘤中的应用进展[J]. 中华外科杂志, 2021, 59(2):156-160.DOI:10.3760/cma.j.cn112139-20200515-00382.
|
| [18] |
| [19] |
| [20] |
中华医学会外科学分会胆道外科学组, 中国医师协会外科医师分会胆道外科专家工作组.胆道恶性肿瘤全程规范化管理中国专家共识(2023)[J]. 中华外科杂志, 2024, 62(6):504-513.DOI:10.3760/cma.j.cn112139-20240203-00062.
|
| [21] |
International Agency for Research on Cancer. International classification of diseases for oncology(ICD-O)[M]. 3rd ed. Geneva: World Health Organization, 2000.
|
| [22] |
Gallbladder cancer (GBC) is the most common cancer of the biliary tract, characterized by a very poor prognosis when diagnosed at advanced stages owing to its aggressive behaviour and limited therapeutic options. Early detection at a curable stage remains challenging because patients rarely exhibit symptoms; indeed, most GBCs are discovered incidentally following cholecystectomy for symptomatic gallbladder stones. Long-standing chronic inflammation is an important driver of GBC, regardless of the lithiasic or non-lithiasic origin. Advances in omics technologies have provided a deeper understanding of GBC pathogenesis, uncovering mechanisms associated with inflammation-driven tumour initiation and progression. Surgical resection is the only treatment with curative intent for GBC but very few cases are suitable for resection and most adjuvant therapy has a very low response rate. Several unmet clinical needs require to be addressed to improve GBC management, including discovery and validation of reliable biomarkers for screening, therapy selection and prognosis. Standardization of preneoplastic and neoplastic lesion nomenclature, as well as surgical specimen processing and sampling, now provides reproducible and comparable research data that provide a basis for identifying and implementing early detection strategies and improving drug discovery. Advances in the understanding of next-generation sequencing, multidisciplinary care for GBC, neoadjuvant and adjuvant strategies, and novel systemic therapies including chemotherapy and immunotherapies are gradually changing the treatment paradigm and prognosis of this recalcitrant cancer.© 2022. Springer Nature Limited.
|
| [23] |
Gallbladder cancer, though generally considered rare, is the most common malignancy of the biliary tract, accounting for 80%-95% of biliary tract cancers. An early diagnosis is essential as this malignancy progresses silently with a late diagnosis, often proving fatal. Its carcinogenesis follows a progression through a metaplasia-dysplasia-carcinoma sequence. This comprehensive review focuses on and explores the risks, management, and outcomes for primary gallbladder carcinoma. Epidemiological studies have identified striking geographic and ethnic disparities - inordinately high occurrence in American Indians, elevated in Southeast Asia, yet quite low elsewhere in the Americas and the world. Age, female sex, congenital biliary tract anomalies, and a genetic predisposition represent important risk factors that are immutable. Environmental triggers play a critical role in eliciting cancer developing in the gallbladder, best exemplified by cholelithiasis and chronic inflammation from biliary tract and parasitic infections. Mortality rates closely follow incidence; those countries with the highest prevalence of gallstones experience the greatest mortality from gallbladder cancer. Vague symptoms often delay the diagnosis of gallbladder cancer, contributing to its overall progression and poor outcome. Surgery represents the only potential for cure. Some individuals are fortunate to be incidentally found to have gallbladder cancer at the time of cholecystectomy being performed for cholelithiasis. Such an early diagnosis is imperative as a late presentation connotes advanced staging, nodal involvement, and possible recurrence following attempted resection. Overall mean survival is a mere 6 months, while 5-year survival rate is only 5%. The dismal prognosis, in part, relates to the gallbladder lacking a serosal layer adjacent to the liver, enabling hepatic invasion and metastatic progression. Improved imaging modalities are helping to diagnose patients at an earlier stage. The last decade has witnessed improved outcomes as aggressive surgical management and preoperative adjuvant therapy has helped prolong survival in patients with gallbladder cancer. In the future, the development of potential diagnostic markers for disease will yield screening opportunities for those at risk either with ethnic susceptibility or known anatomic anomalies of the biliary tract. Meanwhile, clarification of the value of prophylactic cholecystectomy should provide an opportunity for secondary prevention. Primary prevention will arrive once the predictive biomarkers and environmental risk factors are more clearly identified.
|
| [24] |
|
| [25] |
Gallbladder cancer (GBC) frequently mimics gallbladder benign lesions (GBBLs) in radiological images, leading to preoperative misdiagnoses. To address this challenge, we initiated a prospective, multicenter clinical trial (ChicCTR2100049249) and proposed a multimodal, non-invasive diagnostic model to distinguish GBC from GBBLs. A total of 301 patients diagnosed with gallbladder-occupying lesions (GBOLs) from 11 medical centers across 7 provinces in China were enrolled and divided into a discovery cohort and an independent external validation cohort. An artificial intelligence (AI)-based integrated model, GBCseeker, is created using cell-free DNA (cfDNA) genetic signatures, radiomic features, and clinical information. It achieves high accuracy in distinguishing GBC from GBBL patients (93.33% in the discovery cohort and 87.76% in the external validation cohort), reduces surgeons' diagnostic errors by 56.24%, and reclassifies GBOL patients into three categories to guide surgical options. Overall, our study establishes a tool for the preoperative diagnosis of GBC, facilitating surgical decision-making.Copyright © 2025 Elsevier Inc. All rights reserved.
|
| [26] |
央茂, 李永盛, 吴文广, 等. 液态活检技术在胆道肿瘤诊治中的应用进展[J]. 中华肝胆外科杂志, 2021, 27(6):472-476.DOI:10.3760/cma.j.cn113884-20200902-00469.
|
| [27] |
董家鸿, 项灿宏, 白志清. 精准外科理念在胆囊癌治疗中的应用[J]. 中国实用外科杂志, 2023, 43(11):1201-1207.DOI:10.19538/j.cjps.issn1005-2208.2023.11.01.
|
| [28] |
| [29] |
刘颖斌, 王许安. 胆道恶性肿瘤外科治疗的问题和对策[J]. 中华消化外科杂志, 2019, 18(2):117-122.DOI:10.3760/cma.j.issn.1673-9752.2019.02.003.
|
| [30] |
李茂岚, 朱逸荻, 吴向嵩, 等. 精准胆道外科技术与传统手术治疗胆囊癌临床疗效对比研究[J]. 中国实用外科杂志, 2018, 38(9):1039-1044.DOI:10.19538/j.cjps.issn1005-2208.2018.09.19.
|
| [31] |
|
| [32] |
步宏, 李一雷. 病理学[M]. 9版. 北京: 人民卫生出版社, 2018.
|
| [33] |
Patients with gallbladder carcinoma (GBC) lack effective treatment methods largely due to the inadequacy of both molecular characterisation and potential therapeutic targets. We previously uncovered a spectrum of genomic alterations and identified recurrent mutations in the ErbB pathway in GBC. Here, we aimed to study recurrent mutations of genes and pathways in a larger cohort of patients with GBC and investigate the potential mechanisms and clinical significance of these mutations.
|
| [34] |
欧美同学会医师协会肝胆分会, 中国研究型医院学会分子诊断专委会, 中国临床肿瘤学会肝癌专委会, 等. 肝胆肿瘤分子诊断临床应用专家共识[J]. 中华肝胆外科杂志, 2020, 26(2):81-89.DOI:10.3760/cma.j.issn.1007-8118.2020.02.001.
|
| [35] |
邱世梅, 刘法涛, 吴文广, 等. 胆道恶性肿瘤的基因组突变谱研究进展[J]. 中华外科杂志, 2023, 61(12):1124-1129.DOI:10.3760/cma.j.cn112139-20230518-00208.
|
| [36] |
|
| [37] |
Nomograms are widely used for cancer prognosis, primarily because of their ability to reduce statistical predictive models into a single numerical estimate of the probability of an event, such as death or recurrence, that is tailored to the profile of an individual patient. User-friendly graphical interfaces for generating these estimates facilitate the use of nomograms during clinical encounters to inform clinical decision making. However, the statistical underpinnings of these models require careful scrutiny, and the degree of uncertainty surrounding the point estimates requires attention. This guide provides a nonstatistical audience with a methodological approach for building, interpreting, and using nomograms to estimate cancer prognosis or other health outcomes.
|
| [38] |
|
| [39] |
|
| [40] |
: According to the stage of tumor, it's hard suitable to predict the prognosis for gallbladder cancer, especially for node-negative gallbladder cancer. Therefore, we aimed to create a nomogram based on demographic and clinicopathologic characteristics to estimate individualized potential impacts on postoperative overall survival. : 789 patients with node-negative gallbladder cancer were selected from the Surveillance, Epidemiology, and End Results and randomly divided into training and internal validation group. Univariate and multivariate survival analysis were used to identify prognostic factors. The nomogram was constructed using Cox proportional hazards models. We evaluated the performance of the nomogram with Harrell's concordance index and calibration curve. The nomogram was externally validated in 115 patients with node-negative gallbladder cancer from the Sir Run Run Shaw hospital. : The nomogram for overall survival was built on the basis of five independent factors, such as age, sex, histology, T-stage, and number of examined lymph nodes. The C-index of nomogram for overall survival in the internal and external validation group was up to 0.724 and 0.716, respectively. Both of those calibration curves showed good agreement between predicted and observed outcomes in the 1-, 3-, 5-year overall survival. Compared to the 7th edition AJCC stage, the nomogram had a better difference in predicting overall survival, even could further classify patients into four risk subgroups in each stage. : This nomogram can be used as a decision model to predict the outcomes of postoperative overall survival for node-negative gallbladder cancer, and may give useful guidance to clinicians for next treatment.
|
| [41] |
National Cancer Institute. Surveillance, Epidemiology, and End Results(SEER)Program[EB/OL].(2021-04-15)[2026-02-28].https://seer.cancer.gov/.
|
| [42] |
|
| [43] |
刘颖斌, 孙旭恒, 王一钧, 等. 以胆道肿瘤为例浅谈基于外科中心的非高发肿瘤专病队列建设[J]. 中华外科杂志, 2025, 63(4):276-283.DOI:10.3760/cma.j.cn112139-20241225-00588.
|
| [44] |
郭孙伟, 张照寰, 许世瑾, 等. Cox回归模型及其在医学中的应用[J]. 复旦学报(医学版), 1985, 12(4):289-295.DOI:10.16527/j.cnki.1672-8610.1985.04.015.
|
| [45] |
|
| [46] |
|
| [47] |
闫丽娜, 覃婷, 王彤. LASSO方法在Cox回归模型中的应用[J]. 中国卫生统计, 2012, 29(1):58-60,64.DOI:10.3969/j.issn.1002-3674.2012.01.017.
|
| [48] |
| [49] |
中国胆囊癌研究小组. 中国胆囊癌研究小组胆囊癌专病队列数据平台[EB/OL].(2025-01-10)[2026-02-28].https://crggc.sjtu.edu.cn/multicenter/index.html.
|
利益冲突 所有作者声明不存在利益冲突
中国胆囊癌研究小组（CRGGC）相关研究工作的顺利推进，离不开全国各分中心工作人员的专业支持与辛勤付出。值此本文付梓之际，笔者谨向除本文署名作者外，其他为CRGGC研究作出贡献的专家和同仁致以诚挚的敬意与衷心的感谢。现按单位拼音首字母排序列示如下：四川省阿坝藏族羌族自治州人民医院喻定刚，包头市中心医院李明章，云南省保山市第二人民医院李国松，云南省楚雄彝族自治州人民医院赵辉，云南省大姚县人民医院白俊超，福建省肿瘤医院刘景丰，广西医科大学第一附属医院何松青，贵州医科大学附属医院左石，哈尔滨医科大学附属第二医院崔云甫，空军军医大学西京医院王琳，江南大学附属中心医院金慧涵，天津市肿瘤医院郝继辉，云南省弥勒第一医院聂高华，宁夏医科大学总医院王琦，日喀则市人民医院巴桑，上海交通大学医学院附属同仁医院王志强，汕头大学医学院第一附属医院杨填，温州医科大学附属第五医院徐民，中国人民解放军总医院张煊，中国医科大学附属第一医院李桂臣，中山大学孙逸仙纪念医院刘超，以及上海交通大学医学院附属仁济医院胆胰外科贾子衡、刘兆南、陶雯琦等参与并协助CRGGC研究的同仁。
/
| 〈 |
|
〉 |
