肝门部胆管癌内镜下支架引流的研究进展.pdf

赵义军）（本文编辑Journal,Jun.2023肝胆外科杂志2 0 2 3年6 月第31卷第3期23649 Lorenzo-Zuniga V,Bartoli R,Planas R,et al.Oral bile acids reducebacterial overgrowth,bacterial translocation,and endotoxemia in cir-rhotic rats.Hepatology,2003,37(3):551-7.50 Fouts D E,Torralba M,Nelson K E,et al.Bacterial translocationand changes in the intestinal microbiome in mouse models of liver dis-ease.J Hepatol,2012,56(6):1283-92.51 Ganapathy V,Thangaraju M,Prasad P D,et al.Transporters and re-ceptors for short-chain fatty acids as the molecular link between colon-ic bacteria and the host.Curr Opin Pharmacol,2013,13(6):869-74.52 Blaak E E,Canfora E E,Theis S,et al.Short chain fatty acids inhuman gut and metabolic health.Benef Microbes,2020,11(5):411-55.53 Mirzaei R,Afaghi A,Babakhani S,et al.Role of microbiota-derivedshort-chain fatty acids in cancer development and prevention.BiomedPharmacother,2021,139:111619.54 Yang Q,Ouyang J,Sun F,et al.Short-Chain Fatty Acids:A SoldierFighting Against Inflammation and Protecting From 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hepatocellular carcinoma growth in mice.Proc Natl AcadSci U S A,2016,113(9):E1306-15.61 Gopalakrishnan V,Spencer C N,Nezi L,et al.Gut microbiomemodulates response to anti-PD-1 immunotherapy in melanoma pa-tients.Science,2018,359(6371):97-103.62 Matson V,Fessler J,Bao R,et al.The commensal microbiome is as-sociated with anti-PD-1 efficacy in metastatic melanoma patients.Sci-ence,2018,359(6371):104-8.肝门部胆管癌内镜下支架引流的研究进展方东，石振旺【关键词】肝门部胆管癌；内镜逆行性胰胆管造影；支架引流；研究进展【中图分类号】R 735.8【文献标识码】C【文章编号】1006-4761(2023)03-0236-05肝门部胆管癌（Hilar Cholangiocarcinoma,HCCA）是指位于肝总管、左右肝管的胆管腺上皮来源肿瘤，约占肝外胆管癌的2/3,是发病率仅次于原发性肝癌之后的第二大肝脏恶性肿瘤性疾病 。与远端胆管癌不同的是,HCCA起病隐匿、多极化侵犯，出现黄疽首发症状的患者中淋巴转移和神经侵犯率高达36.3%和7 3.9%，因此HCCA手术RO切除率相对较低,5年生存率低于30%，总体预后差 2 。胆汁引流【基金项目】合肥市卫健委2 0 19年应用研究重点项目，（h w k 2 0 19ZD 0 0 8）；蚌埠医学院2 0 2 0 年自然科学类重点项目，（2 0 2 0 BYZD298）【作者单位】合肥市第二人民医院（安徽医科大学附属合肥医院），合肥2 30 0 11是HCCA的主要治疗手段之一,对于可手术切除的 HCCA，术前胆红素 10 mg/L时应尽早建立通畅胆汁引流，可以降低术后死亡风险，对残留肝脏体积 3月的HCCA患者中优先选择SEMS16。而对于生存期难以超出3个月、总体预后极差的IV型HCCA患者也可将双侧塑料支架作为首选 17 。除此之外，近年来报道了一些新型材料支架，例如含有放射性12 51粒子的支架（半衰期约6 0 天）、药物（紫杉醇）洗脱支架等 18 。目前对新型支架的研究仍处于起步阶段，部分报道指出药物洗脱支架在抑制肿瘤向腔内生长、延长支架通畅时间方面具有一定优势，但也学者认为药物洗脱支架的引流效率和总体生存时间与普通支架无明显差异 19,2 0 ,因此仍需要进一步大样本高质量对照研究评估应用效果。2.2覆膜程度SEMS根据覆膜程度分为裸支架（uncoverdself-expand-able metal stent,UCSEMS）、半覆膜（partail-coverd self-expand-ablemetalstent，PCSEM S）和全覆膜金属支架（fully-coverdself-expandable metal stent,FCSEMS）。少数研究报道 FC-SEMS的中位引流通畅时间短于UCSEMS21，但主流观点认为，UCSEMS和FCSEMS在生存获益、通畅期限以及不良事件发生率等方面并无显著差异 2 。两种支架引流失败的原因各不相同，FCSEMS表面覆膜可以阻止肿瘤通过网眼向腔内浸润，但也容易刺激肿瘤和结缔组织增生堵塞支架开口以及引起支架移位，SeoDW23等报道显示6.8%的FCSEMS发生支架移位，而且覆膜影响胆囊管和胰管开口排泄增加梗阻性胆囊炎（9.3%）和胰腺炎机率，这在未行EST和胆囊在位的患者中风险相对更高。除此之外，一项荟萃分析指出，FCSEMS早期（13月内）可出现胆泥沉积、长期（3月以上）可诱导肿瘤水平方向过度增殖，与UCSEMS相比未能显示出足够优势 2 4。因此,FCSEMS主要应用于胆管术后、慢性胰腺炎等胆道良性狭窄,而UCSEMS在恶性胆道梗阻中的应用相对广泛。UCSEMS一经释放则难以取出,在置人支架前建议经ERCP活检或EUS-FNA等检查明确病灶良恶性质，并充分预估患者生存期限。除此之外，目前也有不同种类的半覆膜（PCSEMS）支架应用报道，包括近端裸露、远端覆膜的PCSEMS，带有多个侧JournalJun.2023肝胆外科杂志2 0 2 3年6 月第31卷第3期238孔的PCSEMS等，这些支架的设计初衷在整合UCSEMS和FCSEMS的优势以及规避两者的弊端，但是其临床应用效果充满争议。理论上而言，PCSEMS近端裸露部分不影响胆囊排泄，与管壁剪切力增加可以避免支架脱落移位，而远端覆膜可以阻止肿瘤网眼浸润、预防胆道出血，但是最新研究显示，无论8 mm和10 mm直径的SEMS，PCSEM S和UCSEMS两者的引流成功率无差异,PCSEMS早期并发症（胆囊炎、胆管炎、胰腺炎、出血、穿孔)和远期并发症（支架堵塞、移位)也未发现显著下降 2 5。因此,PCSEMS对HCCA的引流效果和预后影响仍有待进一步研究验证。2.3支架数量美国消化内镜协会（ASGE）最新推出的指南建议，无法切除的HCCA姑息性胆汁引流首选双侧金属支架引流，与单侧引流方法相比，在左、右两侧2 级胆管同时置入SEMS更容易达到50%肝脏引流容积的目标 2 6 。双侧支架置人是引流通畅的保护性因素，双侧引流在延长胆汁通畅时间和总体生存期方面更具有优势 2 7 。7。一项迄今为止纳人最大HCCA样本（30 0 例）的研究，采用倾向性评分匹配法比较双侧和单侧SEMS的临床疗效,前者的总干预次数、通畅期和临床成功率均优于单根支架，并指出在技术条件允许下对BismuthIIIV型患者优先选择双支架置人 2 8 。与此同时，一项以死亡为终点的HCCA病例随访研究显示,双侧和单侧支架的手术相关并发症、不良事件以及导管功能异常发生率均无显著差异,双侧SEMS置人不会增加并发症发生风险 2 9。由此可见，双侧支架在提高引流效率、改善总体预后方面均优于单根支架，尤其在高位梗阻的患者中应尽可能同时置入两根支架。临床操作时导丝超选目标胆管并置入2 根金属支架仍具有一定挑战性，属于ERCP操作难度分级中的第三级，尤其是第一根支架置人完成后，放置第二根支架时可能引起首个支架移位、继发胆管损伤，如果第二根支架置入失败，则可能由造影剂残留诱发胆管炎、败血症。虽然Ashat M30等荟萃分析指出双侧和单侧引流的操作技术成功率无明显差异，但是这些研究往往是由一些具有丰富ERCP经验的内镜医师或者高级医学中心完成。双侧支架的技术成功率受肿瘤部位影响较大，因此，有研究认为在对比单侧和双侧支架技术成功率时应根据Bismuth分型情况进行分层研究，进一步指出对于BismuthI型HCCA患者可以单根SEMS置人后密切随访,BismuthIIIV型需要综合堵塞部位、耐受程度、后续治疗以及短期预后等因素个体化选择支架数量 31。现有资料显示，在国内双侧SEMS置人的报道相对少见，多数中心在双侧引流时选择两根塑料支架或一侧SEMS搭配另一侧塑料支架的方法。2.4排列方式双侧SEMS置人的排列方式分为并排式和套人式两种，并排式两根支架平行排列、互不交叉，近端分别位于左侧和右侧肝内胆管，远端对齐露出十二指肠乳头；套人式第二根支架穿过第一根支架呈“Y”型分布，远端呈同心圆状排列隐藏于胆总管壁内段。两种排列方式各具有优缺点，并排式操作相对简单，支架堵塞后仅需更换目标支架而不影响对侧支架使用，但是并列分布会显著增加胆总管壁张力，诱发门静脉栓子以及刺激肿瘤浸润生长。套人式支架更符合生理性胆管走行，远端双层套人模式不影响管壁压力，且支架头端未漏出乳头可避免肠液反流继发胆管炎并发症，但临床操作时将第二根导丝穿过首根支架的网眼后超选对侧胆管的难度颇大，且一旦堵塞难以开展再介人治疗。现有资料表明，并排式和套人式两种方法的技术成功率、临床成功率、并发症发生率以及对总体预后的影响方面可能无明显差异，两者并非优势竞争、优先选择的关系 32 。两种排列方式的通畅时间是近期的热门话题,Zhouwz33等报道并排式支架中位通畅时间为149天，长于套人组的7 9天;Ishigaki K34等发现,并排组支架置人术后再次发生胆道梗阻的时间为2 0 5天，也明显长于套人组。但是，也有研究认为套入式支架通畅期限优于并排式，并指出这可能与研究中使用的具有更大网眼的SEMS有关 35。并排式支架堵塞部位往往位于远端，而套人式更多发生在支架“Y”两侧头端汇合的部位。当支架发生堵塞需要内镜再介人，可以在SEMS内再次置入单根或多根塑料支架，此时并排式的置人成功率（10 0%）则明显高于套人式（6 3.4%）【3。因此，当前国内研究普遍采用并排法SEMS进行HCCA胆汁引流，套人法的报道相对少见。2.5支架堵塞的再处置金属支架堵塞的原因包括肿瘤过度增殖、肿瘤腔内浸润、胆泥沉积、胆管炎症以及食物残渣返流等。研究显示，杂质沉积所致堵塞占比6 5.9%，可以通过内镜下疏通处理恢复通畅，另外34.1%的堵塞与肿瘤生长有关，需要再次置人支架 37 。SEMS堵塞后再介人的方法首选仍为ERBD,再次ERBD的成功率高于PTBD后补救ERBD手术，可以延迟通畅时间达数月，其后约半数患者在生存期内再次出现支架堵塞 38 ,对总体预后的改善效果可能有限,这与HCCA的高度恶性潜能密切相关。再干预时优先选择何种材料的支架尚未定论，首次采用两根SEMS并排式放置，堵塞后再次置人塑料支架可以达到部分引流效果，但是通畅时间短于SEMS再置人 39。对于肿瘤生长引起的顽固性堵塞，在置入塑料支架之前，可以在原先SEMS内使用扩张工具，如球囊、Soehendra支架扩张器等,对提高引流效率有积极效果 40 。首次为套人式SEMS的再干预难度增加,Lee TH41等人再次采用套人式方法在目标肝内胆管内置人第三根SEMS,技术成功率和临床有效率分别为8 8.9%和8 7.5%，可视为潜在的处置策略之一，也Journalof,Jun.2023肝胆外科杂志2 0 2 3年6 月第31卷第3期239对操作经验和技术支持提出更高的要求。3小结胆汁引流是HCCA治疗中的重要环节,BismuthI型患者首选ERBD,而对于IIIV型患者除了传统PTBD以外，随着技术应用的进步，ERBD也凸显出良好优势。金属支架具有更强的引流效率和通畅时间，双侧置人能提高肝脏引流体积，目前已逐步得到广泛认可。但是，对于姑息性塑料支架置人的效果，SEMS的排列方式以及再干预策略等多个方面仍存在争议。除此之外，如何对目前的支架进行改良，包括新型材料选择、半覆膜设计、特殊形态和功能的规划等方面仍具有较大的进步空间，这也是未来可能研究的热点方向。参考文献1 Liu ZP,Chen WY,Zhang YQ,et al.Postoperative morbidity ad-versely impacts oncological prognosis after curative resection for 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