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试验及基础研究的最新进展。涵盖了胆囊癌机器人、腹腔镜、开放手术入路的网状meta分析， IHPBA-APHPBA的胆囊癌临床指南解读，3D打印构建模拟肿瘤微环境的三维多细胞模型，PTBP3介导IL-18外显子跳跃促进胆囊癌免疫逃逸，全外显子测序研究胆囊癌的基因图谱，德曲妥珠单抗（T-DXD）在BTC二线及以上治疗中的疗效和安全性,AI驱动的免疫表型分析预测BTC患者抗PD-1治疗的疗效。因此，我们特别鸣谢北京协和医院基本外科李秉璐教授，上海交通大学附属新华医院普外科吴向嵩教授、杨自逸医师，上海市胆道疾病研究重点实验室赵成博士、汤秋义博士、杨越硕士、董文君硕士做出的贡献！
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. 胆囊的机器人、腹腔镜和开腹手术：一项系统回顾和网络荟萃分析（IF：2.4）
Chee MYM, Wu AGR, Fong KY, Yew A, Koh YX, Goh BKP. Robotic, laparoscopic and open surgery for gallbladder cancer: a systematic review and network meta-analysis. Surg Endosc. 2024;38(9):4846-4857.
胆囊癌（GBC）是一种高度致命的恶性肿瘤，预后不良，5年生存率小于5%，中位生存期仅6个月。由于起病隐匿，许多患者是在体检时偶然被发现，就诊时往往已经是肿瘤进展期。对于尚无远处转移和广泛浸润的胆囊癌患者，手术切除是患者获益的唯一治疗方式，胆囊癌患者获得长期生存的唯一有效方法是早期发现并接受根治性切除。胆囊癌的外科治疗历经近百年的演变、发展，在手术安全性取得了长足的进步，但胆囊癌的手术治疗在几十年来仍然一直存在争议，包括不同分期的胆囊癌根治术中肝切除的范围、淋巴结清扫的范围，以及经腹腔镜手术和开放胆囊癌根治术的手术方式选择等等。
虽然腹腔镜肿瘤切除术在癌症治疗方面已经扩展得越来越广泛，包括胰腺癌、肝癌、肝门部胆管癌等手术操作非常复杂的肿瘤根治手术，已被证实具有与开放手术相当的术后恢复效果和预后生存结果。然而胆囊癌的腹腔镜下根治性手术一直是大家争论的焦点问题。本文是发表在Surgical Endoscopy(2024)文章，研究目的是评估腹腔镜和机器人手术在治疗胆囊癌方面的安全性和可行性，并与传统的开放手术比较。
这篇文章是一篇系统评价和网络荟萃分析，比较了胆囊癌治疗中机器人手术、腹腔镜手术和开放手术的安全性和可行性。通过PubMed/MEDLINE和EMBASE数据库检索文献，研究的主要结果是总生存率，次要结果包括术后并发症、严重并发症、胆漏发生率、住院时间、手术时间、R0切除率、局部复发率和淋巴结获取情况。一共有32篇文章符合检索条件，包括5883名接受治疗的胆囊癌患者。分析结果显示开放手术、腹腔镜和机器人手术在总生存率、R0切除率、淋巴结获取、肿瘤局部复发和术后并发症方面无显著差异。其中，与接受腹腔镜或机器人手术的患者相比，接受开放手术的患者住院时间更长，术中出血量更多。根据数据分析显示，未发现腹腔镜与机器人手术组在术后恢复效果和生存结果上有显著差异。因此文章结论提示，腹腔镜和机器人手术在治疗胆囊癌方面是安全有效的方法，与开放手术相比，术后恢复和生存结果相当。微创手术方法可能使住院时间更短，术中出血量和术后并发症更少。腹腔镜和机器人手术之间没有明显的优劣之分。文章的局限性在于没有针对不同分期的肿瘤进行深层次的分析和讨论，但总体来说，这篇文章提供了胆囊癌手术方法选择的临床指导，表明微创手术与传统开放手术相比，具有相似的治疗效果和可能更少的术后并发症。
2.IHPBA-APHPBA临床实践指南：针对胆囊癌的国际德尔菲共识建议（IF：2.7）
IHPBA-APHPBA International Study Group of Gallbladder Cancer, Palepu J, Endo I, et al. 'IHPBA-APHPBA clinical practice guidelines': international Delphi consensus recommendations for gallbladder cancer. HPB (Oxford). Published online July 25, 2024.
本指南是国际肝胆胰协会和亚太肝胆胰协会的60多位国际专家形成的关于胆囊癌临床工作指南。指南通过Delphi共识形成方法，围绕胆囊癌流行病学、高危因素、病理学检查、外科手术及可切除性等方面提出了相应指导意见。比较已有的其他共识指南，该指南关注胆囊癌的外科治疗相关争议所在，这可能与本次参与专家75%为外科医生有关。
该指南的主要亮点包括了几个方面：1.强调胆囊切除标本均需由外科医生剖开检查是否存在粘膜面的新生物，同时也强调胆囊切除标本应常规行病理检查，避免可切除性胆囊癌的漏诊。这个情况在国内医生而言，简直难以置信，竟然有国家因为医疗成本问题而对胆囊切除标本不常规进行病理诊断。2.本指南对胆囊癌区域淋巴结清扫范围达成了共识，虽然如AJCC等指南对胆囊癌区域淋巴结有所说明，但不同国家的或地区指南共识关于胆囊癌淋巴结清扫范围的推荐仍存在差异或解释不清等现象，本次指南提出对于T1b以上的胆囊癌应该清扫包括第8、12、13a组等区域淋巴结，也是第一次在全球范围就这一问题达成共识。3.本次指南也对胆囊癌可切除性评估形成了一定共识，提出了边界可切除和局部进展期不可切除胆囊癌的概念，其中关于淋巴结、血管和胆管侵犯相关内容，与我们新华团队提出的关于边界可切除和局部进展期胆囊癌的诊断标准和理念[1,2]不谋而合，认为对于转移淋巴结侵犯血管的情况，应该更加谨慎对待。这也是第一次国际指南共识提出较为具体的胆囊癌可切除性评估标准。
当然，该指南也指出，胆囊癌治疗过程中的部分争议仍难以达成共识，具体包括：1.T3期胆囊癌的肝切除范围存在争议，专家在胆囊床肝楔形切除肝IVb/V段切除之间难以达成共识；2.意外胆囊癌再次手术的具体时间也同样无法达成共识；3.第16b1组淋巴结是否需要术中常规活检，本指南也未达成共识，有意思的是，指南中指出不是所有医院都常规配备术中冰冻病理的设备是该意见未达成共识的一个原因，由此可见经济发展确实是影响胆囊癌诊疗规范开展的一大限制性因素，而对于具备术中冰冻病理条件的单位，笔者认为第16b1组淋巴结的常规病理活检对于指导患者手术方案和治疗计划意义重大，应常规开展。
总体而言，本次指南对于手术相关议题做了着重的说明，是近年来相关指南共识中对胆囊癌手术规范着墨最多的一次，从侧面反映了胆囊癌手术规范化推广任重而道远。因此本指南对于规范胆囊癌手术治疗有不错的指导作用，值得深入解读。但是，读者对于部分推荐内容也应结合地区以及医疗机构实际情况进行批判性解读。
参考文献：[1]龚伟，吴向嵩，杨自逸.胆囊癌转化治疗模式探索与思考[J]. 中国实用外科杂志，2022，42（2）：163-166.
[2]Yang Z，Wu Z，Xiong Y，et al.Successful conversion surgery for locally advanced gallbladder cancer after gemcitabine and nab-paclitaxel chemotherapy[J].Front Oncol，2022，12：977963.
3. 模拟肿瘤微环境和瘤内异质性的多细胞3D打印人源胆囊癌模型（IF：8.2）
Jin Y, Zhang J, Xing J, et al. Multicellular 3D bioprinted human gallbladder carcinoma forin vitromimicry of tumor microenvironment and intratumoral heterogeneity. Biofabrication. 2024;16(4):10.1088/1758-5090/ad6d8c. Published 2024 Aug 22.
摘要：Gallbladder carcinoma (GBC) is a malignant hepatobiliary cancer characterized by an intricate tumor microenvironments (TME) and heterogeneity. The traditional GBC 2D culture models cannot faithfully recapitulate the characteristics of the TME. Three-dimensional (3D) bioprinting enables the establishment of high-throughput and high-fidelity multicellular GBC models. In this study, we designed a concentric cylindrical tetra-culture model to reconstitute the spatial distribution of cells in tumor tissue, with the inner portion containing GBC cells, and the outer ring containing a mixture of endothelial cells, fibroblasts, and macrophages. We confirmed the survival, proliferation, biomarker expression and gene expression profiles of GBC 3D tetra-culture models. Hematoxylin-eosin (HE) and immunofluorescence staining verified the morphology and robust expression of GBC/endothelial/fibroblast/macrophage biomarkers in GBC 3D tetra-culture models. Single-cell RNA sequencing revealed two distinct subtypes of GBC cells within the model, glandular epithelial and squamous epithelial cells, suggesting the mimicry of intratumoral heterogeneity. Comparative transcriptome profile analysis among variousin vitromodels revealed that cellular interactions and the TME in 3D tetra-culture models reshaped the biological processes of tumor cells to a more aggressive phenotype. GBC 3D tetra-culture models restored the characteristics of the TME as well as intratumoral heterogeneity. Therefore, this model is expected to have future applications in tumor biology research and antitumor drug development.
不过，相比于肿瘤类器官技术已经走向产业化、市场化，肿瘤三维生物打印仍然停留在实验室探索阶段，其临床应用前景仍需进一步探索。未来，利用患者来源的肿瘤细胞开展前瞻性研究；或者结合动物模型进行体内验证，将有助于深化对肿瘤生物学的理解并推动个体化治疗策略制定。此外，如何优化三维打印模型的结构以更好地模拟真实肿瘤环境，也将是未来研究的重要方向。
4. PTBP3 介导 IL-18 外显子跳跃促进胆囊癌免疫逃逸（IF：14.3）
Zhao C, Zhao JW, Zhang YH, et al. PTBP3 Mediates IL-18 Exon Skipping to Promote Immune Escape in Gallbladder Cancer. Adv Sci (Weinh). Published online August 8, 2024.
摘要：Gallbladder cancer (GBC) is the most common malignant tumor of the biliary system, with poor response to current treatments. Abnormal alternative splicing has been associated with the development of a variety of tumors. Combining the GEO database and GBC mRNA-seq analysis, it is found high expression of the splicing factor polypyrimidine region- binding protein 3 (PTBP3) in GBC. Multi-omics analysis revealed that PTBP3 promoted exon skipping of interleukin-18 (IL-18), resulting in the expression of ΔIL-18, an isoform specifically expressed in tumors. That ΔIL-18 promotes GBC immune escape by down-regulating FBXO38 transcription levels in CD8+T cells to reduce PD-1 ubiquitin-mediated degradation is revealed. Using a HuPBMC mouse model, the role of PTBP3 and ΔIL-18 in promoting GBC growth is confirmed, and showed that an antisense oligonucleotide that blocked ΔIL-18 production displayed anti-tumor activity. Furthermore, that the H3K36me3 promotes exon skipping of IL-18 by recruiting PTBP3 via MRG15 is demonstrated, thereby coupling the processes of IL-18 transcription and alternative splicing. Interestingly, it is also found that the H3K36 methyltransferase SETD2 binds to hnRNPL, thereby interfering with PTBP3 binding to IL-18 pre-mRNA. Overall, this study provides new insights into how aberrant alternative splicing mechanisms affect immune escape, and provides potential new perspectives for improving GBC immunotherapy.
可变剪切是重要的转录后调节机制，其异常与多种人类肿瘤的发生发展密切相关。我们团队在胆囊癌可变剪切领域做了深入而长足的研究：今年两月份发表于cancer letters的研究，首次报道了胆囊癌中异常的可变剪切促进胆囊癌细胞增殖的机制；而今年八月份发表于Advanced science的这项研究，则创新性揭示了异常的可变剪切在适应性免疫反应层面促进胆囊癌免疫逃逸的机制。我们结合GEO数据库和胆囊癌标本的mRNA-seq分析后发现可变剪切因子PTBP3在胆囊癌中高表达，进一步联合多组学分析表明，高表达的PTBP3促进了胆囊癌细胞IL-18发生外显子6跳跃，产生了肿瘤所特异表达的ΔIL-18。体内外的功能实验显示ΔIL-18能通过下调CD8+T细胞中的FBXO38转录水平以减少PD-1泛素化降解，从而促进胆囊癌的免疫逃逸。我们也开发了一系列针对IL-18外显子跳跃的寡核苷酸药物ASOs，以此阻断肿瘤细胞中ΔIL-18的产生；发现其中ASO4能够加强抗PD-1药物的疗效，且小鼠体内实验表明其具有良好的生物安全性。pre-mRNA 发生的可变剪切过程经常与基因转录过程同时进行，而可变剪切位点的选择受到RNA聚合酶II延长率、染色质重塑剂和组蛋白去乙酰化酶抑制剂的影响。我们发现在剪切过程中，组蛋白修饰H3K36me3通过MRG15招募PTBP3，耦合IL-18的剪切和转录过程，从而促进IL-18的外显子6跳跃。在此过程中，H3K36甲基转移酶SETD2通过SHI结构域与hnRNPL结合，从而干扰了PTBP3与IL-18 pre-mRNA的结合。这项研究的完成有助于阐明胆囊癌发生过程中可变剪切异常导致免疫逃逸的机制，并有助于通过阻断可变剪切产生的ΔIL-18对PD-1的异常，为临床工作提高胆囊癌免疫治疗的疗效提供了新的视角和作用靶点。我们团队长期继续耕耘于此领域，以期多层次、多角度、系统性地阐明胆囊癌可变剪切异常与肿瘤微环境的调控关系。
5.胆囊癌的基因组图谱：全外显子测序的启示（IF：12.5）
Awasthi S, Kumar R, Pradhan D, et al. Genomic landscape of gallbladder cancer: insights from whole exome sequencing. Int J Surg. Published online August 14, 2024.
摘要：Background: Gallbladder carcinoma (GBC) is a common gastrointestinal malignancy noted for its aggressive characteristics and poor prognosis, which is mostly caused by delayed detection. However, the scarcity of information regarding somatic mutations in Indian patients with GBC has hampered the development of efficient therapeutic options. In the present study, we attempted to bridge this gap by revealing the mutational profile of GBC.
Materials and methods: To evaluate the somatic mutation profile, whole exome sequencing (WES) was performed on 66 matched tumor and blood samples from individuals with GBC. Somatic variant calling was performed using GATK pipeline. Variants were annotated at pathogenic and oncogenic levels, using ANNOVAR, VEP tools and the OncoKB database. Mutational signature analysis, oncogenic pathway analysis and cancer driver genes identification were performed at the functional level by using the maftools package.
Results: Our findings focused on the eight most altered genes with pathogenic and oncogenic mutations: TP53, SMAD4, ERBB3, KRAS, ARID1A, PIK3CA, RB1, and AXIN1. Genes with pathogenic single nucleotide variations (SNVs) were enriched in oncogenic signaling pathways, particularly RTK-RAS, WNT, and TP53 pathways. Furthermore, our research related certain mutational signatures, such as cosmic 1, cosmic 6, and cosmic 18, 29, to known characteristics including patient age and tobacco smoking, providing important insights into disease etiology.
Conclusions: Given the scarcity of exome-based sequencing studies focusing on the Indian population, this study represents a significant step forward in providing a framework for additional in-depth mutational analysis. Genes with substantial oncogenic and pathogenic mutations are promising candidates for developing targeted mutation panels, particularly for GBC detection.
研究团队收集了66对胆囊癌肿瘤样本及其配对的血液样本，进行全外显子测序。利用一系列生物信息学工具和算法对测序数据进行处理和分析。主要分析方法有：肿瘤突变负荷分析，并将胆囊癌样本与其他33种TCGA癌症类型进行比较；癌基因信号通路评估，基于之前的TCGA研究，评估10个常见的信号通路，从而全面了解胆囊癌的突变特征。
通过测序分析，研究团队发现了22,285个变异，其中16,834个体细胞非同义突变。胆囊癌的整体突变负荷较低，为1.6 muts/Mb，类似于肝细胞癌，但高于胆管癌，表明胆囊癌的基因突变频率相对较低。在与单核苷酸变异相关的10个重要癌基因信号通路中，RTK-RAS通路在78.78%的样本中出现突变，主要突变基因包括TP53、SMAD4、ERBB3、KRAS、ARID1A、PIK3CA、RB1和AXIN1。研究发现，54%的胆囊癌样本显示出与年龄相关的COSMIC_6和COSMIC_1特征，28.8%的样本表现出COSMIC_29、COSMIC_24和COSMIC_4特征，与吸烟相关的特征存在于15%的患者中。
这些结果具有一定的临床意义：1. 针对KRAS、PIK3CA、ERBB3等基因或相应信号通路开发靶向药物，有望提高胆囊癌患者的治疗效果，特别是对携带特定突变的患者。2. 基因TP53、ARID1A和SMAD4等可作为胆囊癌的潜在诊断标志物，帮助早期筛查和诊断，提高患者生存率。3. 特定基因突变与胆囊癌预后相关的信息，为临床医生提供更准确的预后评估工具，有助于制定个性化治疗方案，提高治疗的有效性。
这项研究为深入理解胆囊癌的分子机制提供了新的视角，揭示了多种潜在治疗靶点和诊断标志物，推动了个性化医学在胆囊癌领域的应用。
6.德曲妥珠单抗（T-DXd）治疗HER-2阳性的胆道恶性肿瘤 （HERB;NCCH1805）：一项多中心、单臂、II 期试验（IF：42.1）
Ohba A, Morizane C, Kawamoto Y, et al. Trastuzumab Deruxtecan in Human Epidermal Growth Factor Receptor 2-Expressing Biliary Tract Cancer (HERB; NCCH1805): A Multicenter, Single-Arm, Phase II Trial. J Clin Oncol. 2024;42(27):3207-3217.
摘要：Purpose: Treatment options for patients with unresectable or recurrent biliary tract cancer (BTC) who progress on a gemcitabine-containing regimen are limited. In addition, the significance of anti-human epidermal growth factor receptor 2 (HER2) therapy in HER2-expressing BTC has not been sufficiently investigated.
Methods: In this phase II trial, participants from five institutions in Japan were enrolled. Eligible patients had pathologically confirmed unresectable or recurrent BTC with centrally confirmed HER2-positive (immunohistochemistry [IHC]3+ or IHC2+ and in situ hybridization [ISH]+) or HER2-low (IHC2+ and ISH-, IHC1+, and IHC0 and ISH+) and were refractory or intolerant to a gemcitabine-containing regimen. The patients received 5.4 mg/kg trastuzumab deruxtecan (T-DXd) once every 3 weeks until disease progression or unacceptable toxicity. The primary end point was the confirmed objective response rate (ORR) in HER2-positive BTC by an independent central review (threshold ORR, 15%; expected ORR, 40%).
Results: A total of 32 patients were enrolled and treated. Among these patients, 22 with HER2-positive disease comprised the primary efficacy population and had a confirmed ORR of 36.4% (90% CI, 19.6 to 56.1; P = .01), meeting the primary end point. Eight with HER2-low disease comprised the exploratory population and had a confirmed ORR of 12.5%. The most common ≥grade 3 treatment-related adverse events were anemia (53.1%) and neutropenia (31.3%). Eight patients (25.0%) had interstitial lung disease (ILD), including two grade 5 events.
Conclusion: T-DXd showed promising activity in patients with HER2-positive BTC and a signal of efficacy in patients with HER2-low BTC. Although the safety profile was generally manageable, ILD requires careful monitoring and early intervention.
在安全性评估方面，≥3级的不良事件发生率为81.3%，导致治疗中断的不良事件发生率为37.5%，与治疗相关的不良事件相关死亡发生率为6.3%。8名患者（25.0%）发生了间质性肺病（ILD），其中包括2例5级事件（治疗相关死亡）。
这项研究提供了T-DXd在HER2高表达BTC患者后线治疗的初步证据，这为后续T-DXd在晚期BTC进一步的探索和使用奠定了基础。但其不良事件发生率尤其是ILD发生率较高，应用时应予以关注。HER2作为BTC的重要靶点之一，既往研究证实其表达与患者治疗效果和预后关系密切，针对性的药物不断涌现和更新，相关临床试验结果也展示了其临床应用潜力；期待更大样本量和多中心的大型研究的开展能进一步完善BTC的靶向治疗策略。
7.AI驱动的肿瘤浸润淋巴细胞空间分析作为胆道恶性肿瘤免疫检查点抑制剂的预测生物标志物（IF：10.0）
Bang YH, Lee CK, Bang K, et al. Artificial intelligence-powered spatial analysis of tumor-infiltrating lymphocytes as a predictive biomarker for immune checkpoint inhibitors in biliary tract cancer. Clin Cancer Res. Published online August 16, 2024.
摘要：Purpose: Anti-PD-1/L1 has been demonstrated for its efficacy when combined with cytotoxic chemotherapy in randomized phase 3 trials for advanced biliary tract cancer (BTC). However, no biomarker predictive of benefit has been established for anti-PD-1/L1 in BTC. Here, we evaluated tumor-infiltrating lymphocytes (TILs) using artificial intelligence-powered immune phenotype (AI-IP) analysis in advanced BTC treated with anti-PD-1.
Patients and methods: Pre-treatment H&E-stained whole-slide images from 339 advanced BTC patients who received anti-PD-1 as second-line treatment or beyond, were utilized for AI-IP analysis and correlative analysis between AI-IP and efficacy outcomes with anti-PD-1. Next, data and images of BTC cohort from The Cancer Genome Atlas (TCGA) were additionally analyzed to evaluate the transcriptomic and mutational characteristics of various AI-IPs in BTC.
Results: Overall, AI-IPs were classified as inflamed (high intratumoral TIL [iTIL]) in 40 patients (11.8%), immune-excluded (low iTIL and high stromal TIL) in 167 (49.3%), and immune-deserted (low TIL overall) in 132 (38.9%). The inflamed IP group showed a significantly higher overall response rate compared to the non-inflamed IP groups (27.5% vs. 7.7%, P<0.001). Median overall survival and progression-free survival were significantly longer in the inflamed IP group than in the non-inflamed IP group (OS: 12.6 vs. 5.1 months, P=0.002; PFS: 4.5 vs. 1.9 months, P<0.001). In the analysis using TCGA cohort, the inflamed IP showed increased cytolytic activity scores and an interferon-gamma signature compared to the non-inflamed IP.
Conclusions: AI-powered IP based on spatial TIL analysis was effective in predicting the efficacy outcomes in patients with BTC treated with anti-PD-1.
本研究收集了339例接受抗PD-1二线及以上治疗的晚期BTC患者，采用预处理苏木精和伊红(HE)染色整片图像进行AI-IP分析，将40名患者（11.8％）分类为免疫炎症型，167名患者（49.3％）为免疫排除型，132名患者（38.9％）为免疫沙漠型。并分析AI-IP与抗PD-1疗效结局的相关性，发现炎症IP组的总缓解率显著高于非炎症IP组（27.5％vs 7.7％）；炎症IP组的中位总生存期和无进展生存期显著长于非炎症IP组（OS：12.6个月 vs 5.1个月；PFS：4.5 个月 vs 1.9 个月）；炎症IP与更好的OS和PFS显著相关，而PD-L1CPS与OS和PFS均无关。
对入选前瞻性队列研究的29名患者亚组进行了多色流式细胞术，发现在炎症IP 组中，CD69 + CD8 + T细胞和CD8 +效应记忆T细胞的比例高于非炎症 IP组。提示炎症IP组对抗PD-1治疗有更好的反应，
在癌症基因组图谱TCGA BTC队列的36例HE染的WSI，使用TME亚型进一步分类，可观察到大多数炎症IP是免疫富集亚型(80.0%)。炎症IP组表现出更高的IFN信号、细胞溶解评分和免疫排斥恒定评分，表明其免疫微环境更活跃。炎症IP组中BRCA2 突变的比例显著高于非炎症IP 组（50.0％ vs 4.2％）。
然而，本研究也存在一些局限性，其中最突出的是其回顾性设计。还包括未评估MSI - H/dMMR与AI-IP的关系、样本量小、未涵盖当前标准治疗人群、缺乏独立的验证队列。这些局限性需要在未来的研究中加以解决，以进一步验证和完善研究结果。
综上所述，该研究首次成功地通过AI-IP分析对BTC患者进行分层，以预测抗PD-1治疗的疗效。为BTC的治疗提供了潜在的生物标志物。同时利用TCGA数据探究了不同IP组的转录组学和突变特征，从多个维度揭示了免疫表型的生物学背景，为BTC的免疫治疗提供新视角。
