胆囊癌文献月评（202404期）

健康健康 2024-05-31 08:41 上海

栏目寄语

胆囊癌是胆道系统最常见的恶性肿瘤，具有症状隐匿、发展迅速、早期转移、预后极差的特点，被称为新的“癌中之王”。我国是胆囊癌的高发地区之一，发病率和病死率近年来都呈持续缓慢上升趋势。胆囊慢性炎症、胆囊结石、胆囊息肉等都是胆囊癌的危险因素，但是胆囊癌目前仍缺乏特异性和敏感性都较好的早期诊断手段，临床发现的胆囊癌多为中晚期。尽管医学科技不断发展，根治性手术切除仍是当前唯一可能治愈胆囊癌的手段，行之有效的系统性治疗方法依然还在不断探索寻找中。因此，深入开展胆囊癌的临床和基础研究能够帮助我们更好地应对此类恶性肿瘤。

上海交通大学医学院附属新华医院普外科肝胆胰中心长期以来致力于胆道疾病诊治难点的攻关，形成了普外科、上海市胆道疾病研究重点实验室、上海市胆道疾病研究中心、Ⅰ期临床研究病房等多位一体的转化医学研究体系。尤其在胆囊癌的基础和临床研究方面的科研水平位于国内外领先水准，相关成果发表SCI论文50余篇，其中包括NatureGenetics、GUT、Hepatology等国际顶尖学术期刊，并获得了包括科技部新药创制项目、国家自然科学基金重点项目、上海市启明星、浦江人才、上海市优秀学科带头人、上海市卫健委新优靑等在内的多项科研及人才项目。

本期关于胆囊癌的研究主要聚焦于胆囊癌临床治疗及预后的最新进展。涵盖了运用CA199与总胆红素比值变化预测在胆囊癌术后患者的预后，孟德尔随机化在肠道菌群与胆道癌之间的潜在因果关系研究探索，辅助化疗对胆囊腺癌切除术后患者的生存获益研究以及白蛋白结合型紫杉醇联合信迪利单抗在晚期胆道肿瘤的疗效及生物标志物分析。因此，我们特别鸣谢上海交通大学附属新华医院普外科杨自逸医师，上海市胆道疾病研究重点实验室汤秋义博士、熊逸晨硕士、张宇硕士做出的贡献！

欢迎各位同道与我们积极交流探讨，共同推动胆囊癌研究和诊治的进步！

龚伟

1.基于糖类抗原199 与总胆红素（CA199/TB）比值变化预测胆囊癌根治性切除术后患者的长期预后：一项多中心回顾性队列研究（IF:15.3）

Li XL, Liu ZP, Su XX, et al. Long-term prognosis of patients with gallbladder carcinoma after curative-intent resection based on changes in the ratio of carbohydrate antigen 19-9 to total bilirubin (CA19-9/TB): a multicenter retrospective cohort study. Int J Surg. Published online April 17, 2024.

摘要：Background: The prognostic value of carbohydrate antigen 19-9 (CA19-9) is known to be affected by elevated bilirubin levels in patients with gallbladder carcinoma (GBC). The clinical significance of changes in the ratio of CA19-9 levels to total bilirubin (TB) levels in patients with GBC after curative-intent resection remains unknown. The aim of this study was to determine the prognostic value of changes in preoperative and postoperative CA19-9/TB ratio in these patients.

Methods: Prospectively colleced data on consecutive patients who underwent curative-intent resection for GBC between January 2015 and December 2020 stored in a multicenter database from 10 hospitals were analysed in this retrospective cohort study. Based on the adjusted CA19-9 defined as the ratio of CA19-9 to TB, and using 2×103 U/µmol as the upper normal value, patients were divided into a normal group (with normal preoperative and postoperative adjusted CA19-9), a normalization group (with abnormal preoperative but normal postoperative adjusted CA19-9), and a non-normalization group (with abnormal postoperative adjusted CA19-9). The primary outcomes were overall survival (OS) and recurrence-free survival (RFS). The log-rank test was used to compare OS and RFS among the groups. The Cox regression model was used to determine factors independently associated with OS and RFS.

Results: The normal group (n=179 patients) and the normalization group (n=73 patients) had better OS and RFS than the non-normalization group (n=65 patients) (the 3-year OS rates 72.0%, 58.4% and 24.2%, respectively; the RFS rates 54.5%, 25.5% and 11.8%, respectively; both P<0.001). There were no significant differences between the normal and the normalization groups in OS and RFS (OS, P=0.255; RFS, P=0.130). Cox regression analysis confirmed that the non-normalization group was independently associated with worse OS and RFS. Subgroup analysis revealed that the non-normalization group of patients who received adjuvant therapy had significantly improved OS and RFS as compared to those who did not receive adjuvant therapy (OS, P=0.025; RFS, P=0.003).、Conclusions: Patients with GBC who underwent curative-intent surgical resection with postoperative abnormal levels of adjusted CA19-9 (the CA19-9/TB ratio) were associated with poorer long-term survival outcomes. Adjuvant therapy after surgery improved the long-term outcomes of these patients.

杨自逸医师（上海交通大学附属新华医院普外科）：

这是一项由陈志宇教授、刘允怡院士、戴海粟教授等牵头组织的全国多中心回顾性研究，分析鉴定出了胆囊癌根治切除术后的新型预后预测标志物——CA199/总胆红素（TB）比值。众所周知，CA199是胆囊癌最常用的肿瘤标志物之一，广泛用于胆囊癌治疗疗效的监测，但单独使用CA199来判读胆囊癌预后的准确性并不令人满意。这项研究创新性地提出可以使用CA199/TB比值来进行预测，依据CA199正常值37U/ml及TB正常值17umol/L作为参考，判定CA199/TB比值＞2000U/L为异常。研究按照STROCSS标准进行分析，总计纳入317例患者，共分为三组：正常组（术前术后CA199/TB比值均正常），下降组（术前CA199/TB比值异常，术后降为正常），异常组（术前CA199/TB比值异常，术后未降至正常）。OS及RFS生存分析结果显示正常组＞下降组＞异常组，提示CA199/TB比值可作为一种可靠的预后预测标志物。进一步分析表明，对于术后CA199/TB比值仍然异常的患者，化疗等辅助治疗可以帮助改善预后。总体而言，CA199/TB比值是一种新颖且便捷的标志物，未来可以继续开展前瞻性队列研究进行验证。

2.肠道菌群与胆道癌的因果关系：综合双向孟德尔随机化分析（IF:5.7）

Wang K, Wang S, Qin X, et al. The causal relationship between gut microbiota and biliary tract cancer: comprehensive bidirectional Mendelian randomization analysis. Front Cell Infect Microbiol. 2024;14:1308742.

摘要：Background: Growing evidence has shown that gut microbiome composition is associated with Biliary tract cancer (BTC), but the causality remains unknown. This study aimed to explore the causal relationship between gut microbiota and BTC, conduct an appraisal of the gut microbiome's utility in facilitating the early diagnosis of BTC.

Methods: We acquired the summary data for Genome-wide Association Studies (GWAS) pertaining to BTC (418 cases and 159,201 controls) from the Biobank Japan (BBJ) database. Additionally, the GWAS summary data relevant to gut microbiota (N = 18,340) were sourced from the MiBioGen consortium. The primary methodology employed for the analysis consisted of Inverse Variance Weighting (IVW). Evaluations for sensitivity were carried out through the utilization of multiple statistical techniques, encompassing Cochrane's Q test, the MR-Egger intercept evaluation, the global test of MR-PRESSO, and a leave-one-out methodological analysis. Ultimately, a reverse Mendelian Randomization analysis was conducted to assess the potential for reciprocal causality.

Results: The outcomes derived from IVW substantiated that the presence of Family Streptococcaceae (OR = 0.44, P = 0.034), Family Veillonellaceae (OR = 0.46, P = 0.018), and Genus Dorea (OR = 0.29, P = 0.041) exerted a protective influence against BTC. Conversely, Class Lentisphaeria (OR = 2.21, P = 0.017), Genus Lachnospiraceae FCS020 Group (OR = 2.30, P = 0.013), and Order Victivallales (OR = 2.21, P = 0.017) were associated with an adverse impact. To assess any reverse causal effect, we used BTC as the exposure and the gut microbiota as the outcome, and this analysis revealed associations between BTC and five different types of gut microbiota. The sensitivity analysis disclosed an absence of empirical indicators for either heterogeneity or pleiotropy.

Conclusion: This investigation represents the inaugural identification of indicative data supporting either beneficial or detrimental causal relationships between gut microbiota and the risk of BTC, as determined through the utilization of MR methodologies. These outcomes could hold significance for the formulation of individualized therapeutic strategies aimed at BTC prevention and survival enhancement.

汤秋义博士（上海市胆道疾病研究重点实验室）：

这是一项探索肠道菌群与胆道癌之间因果关系的研究。该研究采用了孟德尔随机化分析方法，通过遗传变异数据评估了菌群对胆道癌的影响，并采用反向孟德尔随机化分析评估了潜在的反向因果关系。

该研究使用了来自Biobank Japan的418例胆道癌患者和159,201例对照组的全基因组关联研究（GWAS）总结数据，以及来自MiBioGen联盟的18,340个与菌群相关的GWAS总结数据。研究主要采用逆方差加权法进行孟德尔随机化分析，并使用多种统计方法进行敏感性评估。研究结果表明特定的菌群与胆道癌之间存在潜在的因果关系。具体来说，Streptococcaceae科、Veillonellaceae科和Dorea属菌群与胆道癌的易感性呈负相关，具有保护作用，而Lentisphaeria纲、Victivallales目和Lachnospiraceae FCS020 Group属与胆道癌的风险呈正相关。这些结果提示不同成分的肠道菌群可能对胆道癌的发生和发展起重要影响。

这项研究的结果具有一定的临床意义。首先，结果为进一步理解胆道癌的发病机制提供了新的视角，增加了对该疾病的认识。其次，该研究结果提示通过调节和改善肠道菌群的平衡，可能有助于预防胆道癌的发生和发展。然而，该研究仍存在一些不足之处和局限性。首先，胆道癌包括肝内胆管癌、肝外胆管癌和胆囊癌等不同类型，在遗传特征、发生发展机制和临床预后等方面存在显著异质性。因此，如果能在细分的胆道癌类型中探索肠道菌群的作用，可能更有助于理解菌群对胆道癌发生的因果作用。其次，该研究使用了跨族裔的遗传变异数据，这可能会降低结论的证据等级。第三，作者将P < 1 × 10⁻⁵ 作为选择工具变量的阈值，而大型队列的GWAS研究通常采用1 × 10⁻⁸ 作为P的筛选阈值，以确保SNP和暴露之间的强关联。该研究中的菌群GWAS总结数据包括了18,340名受试者，作者未能清楚解释工具变量筛选参数的确定，这也降低了结论的可靠性。第四，作为研究结局的GWAS样本量相对较小，特别是在应用GWAS数据进行反向孟德尔随机化分析时，需要谨慎对待结果。最后，与孟德尔随机化研究常见的问题一样，缺乏其他证据对结论进行佐证。理想情况下，孟德尔随机化研究应该在严格符合前提假设的基础上提供不亚于RCT研究的证据等级结论。然而，在实际情况下，由于数据质量不理想、样本量不足、环境和人为因素对暴露/结局的影响过大，孟德尔随机化研究的结论往往需要其他方面的证据支持，以确保其真实可靠。

总的来说，通过孟德尔随机化方法，该研究验证了肠道菌群与胆道癌之间的潜在因果关系。这一发现有助于更深入地理解胆道癌的发病机制，并为预防和治疗胆道癌提供了新思路。然而，仍需要进一步的研究来验证和延伸这些结果，并探究肠道菌群如何影响胆道癌的发生和发展。

3.辅助化疗对胆囊腺癌切除术后患者的生存获益的回顾性队列分析（IF:3.8）

Wang Y, Kong Y, Yang Q, Zhong C, Zhou D, Wang W. Survival benefit of adjuvant chemotherapy in patients with resected gallbladder adenocarcinoma: An updated retrospective cohort analysis. Eur J Surg Oncol. 2024;50(4):108047.

摘要：Background: The rarity yet high malignancy of gallbladder adenocarcinoma (GBA) endows it with a distinctive nature. Radical resection remains the foremost therapeutic approach for GBA, while the impact of early recurrence and metastasis on patient prognosis necessitates the utilization of adjuvant chemotherapy (AC). Despite numerous previous studies on this topic, a consensus regarding the authentic efficacy of AC has yet to be reached.

Methods: We conducted an updated retrospective cohort analysis utilizing data from the Surveillance, Epidemiology, and End Results (SEER) database spanning from 2010 to 2020 to explore the association between AC and survival outcomes in patients with resected GBA.

Results: Our study included 2782 patients from the SEER database, with further evaluation of 843 patients in each cohort following meticulous execution of a 1:1 propensity score matching. Remarkably, the AC cohort exhibited a significant survival advantage when juxtaposed against the non-AC cohort. Multivariable Cox regression analysis identified age at diagnosis, year at diagnosis, grade, AJCC T stage, AJCC N stage as well as AC as independent prognostic factors. Furthermore, our findings unveiled that poor/undifferentiated tumor histology, pathological T2 or higher category and pathological N1 category were significantly associated with improved survival when treated with AC while simultaneously observing improved survival across all age categories.

Conclusion: These results provide additional evidence supporting the survival benefits of AC and offer guidance for personalized therapy in patients with resected GBA.

熊逸晨硕士（上海市胆道疾病研究重点实验室）：

GBC极具侵袭性，易侵犯邻近器官、淋巴或远处转移，在选择对患者进行手术治疗前，必须充分考虑 GBC 潜在复发风险。尽管手术切除为 GBC 患者提供了治愈的可能性，术后高复发风险和高死亡率是目前 GBC 外科治疗面临的挑战。鉴于此，术后辅助治疗治疗策略对GBC 患者至关重要。

这篇文章基于SEER数据库为GBC的辅助化疗策略提供了最新的依据。研究纳入2010年至2020年的GBC患者数据进行了一项多中心的回顾性分析，在进行1:1倾向平分匹配后，辅助化疗队列和非辅助化疗队列各有843名GBC患者。结果表明，辅助化疗作为GBC患者的独立预后因素，显著延长了患者的总生存期和癌症特异性生存期。亚组分析显示，低分化/未分化肿瘤、肿瘤分期T2以上和N1分期的GBC患者在进行术后辅助化疗后生存时间显著改善。

然而，这篇文章存在一定局限性。首先，SEER数据库患者来源主要是欧美人群，而非亚洲人群，尽管在影响因素分析中，种族并不是影响预后的独立因素，但未来的研究还应该建立在全球多中心数据库的基础上进行进一步探讨。其次，SEER数据库中缺乏一些与预后相关的关键变量，如切缘状态、CA19-9水平、辅助化疗具体方案和具体手术方式等。未来也应开展更多的高质量前瞻性临床研究，解决以上不足之处，为更多的 GBC 患者带来生存优势。

4.白蛋白结合型紫杉醇联合信迪利单抗二线治疗晚期胆道癌患者的疗效及生物标志物分析（IF: 5.7）

Li X, Zhou N, Yang Y, Lu Z, Gou H. Efficacy and biomarker analysis of second-line nab-paclitaxel plus sintilimab in patients with advanced biliary tract cancer. Cancer Sci. Published online April 18, 2024.

摘要：Biliary tract cancer (BTC) is a highly aggressive malignancy with limited second-line therapy. We conducted this phase 2 trial to evaluate the efficacy and safety of second-line nab-paclitaxel plus sintilimab in advanced BTC. Histologically confirmed advanced BTC patients with documented disease progression after first-line chemotherapy were enrolled. Subjects received nab-paclitaxel 125 mg/m2 on days 1 and 8 plus sintilimab 200 mg on day 1, administered every 3 weeks. The primary end point was the objective response rate (ORR). The secondary end points were progression-free survival (PFS), overall survival (OS), and adverse reactions. Simultaneously, next-generation sequencing, programmed cell death ligand 1 immunohistochemistry and multiplex immunofluorescence of tumor-infiltrating lymphocytes were applied to explore potential biomarkers. Twenty-six subjects were consecutively enrolled. The ORR was 26.9% (7/26), including two complete responses and five partial responses, which met the primary end point. The disease control rate was 61.5% (16/26). The median PFS was 169 days (about 5.6 months, 95% confidence interval [CI] 60-278 days). The median OS was 442 days (about 14.7 months, 95% CI 298-586 days). Grade 3 treatment-related adverse events (TRAEs) were mainly anemia (27%), leukopenia (23%), neutropenia (19%), and peripheral sensory neuropathy (8%). No grade 4 or 5 TRAEs occurred. Biomarker analysis suggested that positive PD-L1 and high proportions of CD8+ T-cell infiltration were correlated with improved clinical outcome. Nab-paclitaxel plus sintilimab is a potentially effective and tolerable second-line regimen for advanced BTC that deserves to be studied in large-scale trials. PD-L1 status and CD8+ T cell infiltration might be promising biomarkers for efficacy prediction.

张宇硕士（上海市胆道疾病研究重点实验室）：

华西医院勾红峰教授、李晓芬教授团队的开展的这项前瞻性、单臂、II期研究，旨在探索白蛋白结合型紫杉醇联合信迪利单抗用于晚期BTC患者二线治疗的疗效和安全性。研究共招募了26名晚期胆道癌患者（7名胆囊癌患者），入组患者为经病理学检查确诊的局部晚期不可切除或转移性胆管/胆囊腺癌或胆管细胞癌患者、年龄18-75岁、具有良好的体能状态和足够的器官功能、既往吉西他滨或含氟尿嘧啶全身化疗后疾病进展、既往未接受过紫杉醇类药物或免疫检查点抑制剂治疗。患者在第1、8天接受白蛋白结合紫杉醇（125mg/㎡），第1天使用信迪利单抗（200mg），每三周静脉注射一次。研究的主要终点是ORR。次要终点包括PFS、OS和不良事件。研究结果显示：截至数据截止(2023年2月2日)，19例(73.1%)患者确诊疾病进展，14例(53.8%)患者死亡。ORR为26.9%(7/26)，包括2例完全缓解和5例部分缓解；其中GBC患者的ORR相对较高，为42.9%，ECC患者的ORR为33.3%，ICC患者的ORR为15.4%，但由于样本量小，不同肿瘤类型的ORR无统计学差异。疾病控制率为61.5%(16/26)。中位PFS为169天(约5.6个月)。中位OS为442天(约14.7个月)。此外，GBC患者的中位PFS为314天，ECC患者的中位PFS为48天，ICC患者的中位PFS为77天。GBC患者的中位OS为378天， ECC患者的中位OS为142天，ICC患者的中位OS为442天。三种肿瘤类型的PFS和OS均无显著差异，这可能是由于样本量小所致。在安全性方面，3级治疗相关不良事件(TRAEs)主要是贫血(27%)、白细胞减少(23%)、中性粒细胞减少(19%)和周围感觉神经病变(8%)，未发生4级或5级治疗相关不良事件。此外，研究还分析了肿瘤浸润淋巴细胞（TILs）的密度与治疗效果和生存期的关系。研究结果表明，CD8+T细胞和CD8+ PD-1-T细胞的高密度与良好的临床预后相关，而肿瘤区CD8+ PD-1+T细胞的高密度与较差的总生存期相关。

与已发表的文献相比，这是第一个研究白蛋白结合型紫杉醇联合信迪利单抗为晚期BTC患者二线治疗的有效性和安全性的研究。研究结果显示的良好的抗肿瘤活性和可控的耐受性提示白蛋白结合型紫杉醇联合信迪利单抗是一种有前景的晚期胆道癌患者的二线治疗选择，并且PD-L1阳性和CD8+T细胞浸润可能是潜在的疗效预测生物标志物。由于本研究的样本量较小且仅包括中国患者，导致亚组分析中可能存在偏倚和不准确性。因此，未来需要进一步进行大规模、随机、前瞻性的临床试验和全基因组测序来验证这些结果。

-END-

上海交通大学附属新华医院普外科

上海交通大学医学院附属新华医院普外科创建于1958年，学科医、教、研水平居国内领先，以消化道肿瘤、器官移植、甲乳外科、微创外科为特色。普外科是卫生部国家临床重点专科，是卫生部首批批准的肝移植定点医院。2016年成立上海市胆道疾病研究中心。