胆囊癌文献月评(202310期)

健康   健康   2023-11-30 11:00   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。


本月胆囊癌的研究依然聚焦于综合治疗新进展,一些II期临床研究顺利开展,为胆囊癌治疗临床决策提供更多选择。预后评估也是目前临床研究的热点,不少学者积极寻找胆囊癌新型预后预测指标,如基因组学、循环生物学标志物等,以便后续的危险分层、指导治疗及随访。因此,我们特别鸣谢华西医院普外科李富宇教授,以及上海市胆道疾病研究重点实验室熊逸晨硕士、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.肝外胆管切除术治疗T2胆囊癌的临床意义(IF:3.0)

Kato H, Horiguchi A, Ishihara S, Nakamura M, Endo I. Clinical significance of extrahepatic bile duct resection for T2 gallbladder cancer using data from the Japanese Biliary Tract Cancer Registry between 2014 and 2018. J Hepatobiliary Pancreat Sci. 2023 Oct 4.

摘要:Purpose: The present study aimed to determine whether concomitant extrahepatic bile duct resection (EHBDR) improves the prognosis of patients with T2 gallbladder cancer (GBC).

Methods: Between 2014 and 2018, 4947 patients with GBC were registered in the National Biliary Tract Cancer Registry in Japan. This included 3804 patients (76.9%) who underwent curative-intent surgical resection; 1609 of these patients had pT2 GBC with no distant metastasis. Of the 1609 patients with GBC, 520 underwent EHBDR and 1089 did not. We compared the patients' backgrounds and disease-specific survival rates between the groups.

Results: The frequency of lymph node metastasis was significantly higher in the EHBDR group than in the non-EHBDR group (38.2% vs. 20.7%, p<.001). In the entire cohort, however, there was no significant difference in disease-specific survival between the two groups (76% vs. 79%, p=.410). The EHBDR group had a significantly higher incidence of postoperative complications (Clavien-Dindo classification grade=3) (32.4% vs. 11.7%, p<.001). When we focused on the survival of only T2N1 patients who underwent gallbladder bed resection, the prognosis was significantly improved for the EHBDR group (5-year survival rate: 64% vs. 54%, p=.017). The non-EHBDR group was subcategorized into two groups: D2 dissection and D1 dissection or sampling, and survival curves were compared between these subgroups. Although the EHBDR group tended to have a favorable prognosis compared to the D2 group, this difference was not significant (p=.167). However, the EHBDR group had a significantly greater prognosis than the D1 dissection or sampling group (5 year-survival rate: 64 vs. 49%, p=.027).

Conclusions:The EHBDR may improve the prognosis of patients with T2 gallbladder cancer with lymph node metastases; however, its indication should be carefully determined because of the increased risk of postoperative complications.



李富宇教授(四川大学华西医院普外科


目前,对于T2期胆囊癌患者的手术治疗是否需要常规联合肝外胆管切除还尚不清楚。一些研究表明常规进行肝外胆管切除对肝十二指肠韧带淋巴结和隐匿肿瘤细胞的完全清扫具有潜在的优势;然而,也有研究者提到常规进行肝外胆管切除对患者的生存没有益处,并增加了术后并发症,如胆漏。该文章回顾性分析了2014年至2018年日本胆道肿瘤登记处登记的1609例T2期胆囊癌患者的临床病理学资料和预后。患者5年总体生存率和疾病特异性生存率分别为71% 和80%。在1609例胆囊癌患者中,520名接受了联合肝外胆管切除,1089名没有联合肝外胆管切除。研究发现在淋巴结转移率上,联合肝外胆管切除组明显高于非联合肝外胆管切除组(38.2% vs 20.7%, p<0.001);同时,联合肝外胆管切除组术后并发症(Clavien-Dindo分类等级=3)发生率明显增高(32.4% vs 11.7%,p< 0.001);此外,两组的疾病特异性存活率没有显著差异(76% vs 79%, p=0.410)。针对进行胆囊合并肝脏胆囊床切除的T2N1期患者,联合肝外胆管切除可以显著提升患者的预后(5年生存率: 64% vs 54%, p=0.017)。进一步将非联合肝外胆管切除组患者根据淋巴结清扫范围(D2淋巴结清扫定义为肝-十二指肠韧带淋巴结清扫、肝总动脉周围淋巴结清扫、胰十二指肠后淋巴结清扫;D1淋巴结清扫定义为胆囊管和胆总管周围淋巴结清扫)进行亚组分析,发现与D2组相比,联合肝外胆管切除组预后较好,但差异无统计学意义(5年生存率: 64% vs 58%,p= 0.167);然而,联合肝外胆管切除组的预后明显优于D1组(5年生存率: 64% vs 49%,p= 0.027)。综上,本研究发现联合肝外胆管切除可改善T2期伴淋巴结转移胆囊癌患者的预后;然而,联合肝外胆管切除有增加术后并发症的风险,其适应症应仔细确定。
         
 

2.基于SEER数据库研究胆囊癌骨转移的预后和治疗结局(IF:5.2)

Gera K, Kahramangil D, Fenton GA, et al. Prognosis and Treatment Outcomes of Bone Metastasis in Gallbladder Adenocarcinoma: A SEER-Based Study. Cancers (Basel). 2023;15(20):5055. Published 2023 Oct 19.

摘要:Background: Gallbladder carcinoma (GBC) is a rare, aggressive malignancy comprising 0.5% of gastrointestinal cancers. It has poor survival outcomes due to its insidious onset, lack of standardized screening, and limitedtherapies. Advanced-stage diagnosis with liver, lymph node, and peritoneal metastasis is common, while bone metastasis is rare. The knowledge on bone metastasis in GBC is limited to case reports and small series, and its clinical significance is largely unexplored.

Methods: The study extracted the demographic and clinical variables of patients with metastatic (M1) gallbladder adenocarcinoma from the Surveillance, Epidemiology, and End Results (SEER) database between 2011 and 2020. Descriptive statistics were used to analyze the demographic characteristics. The multivariate Cox regression analysis was used to calculate the hazard ratio. The overall survival (OS) was assessed using the Kaplan-Meier method, and the log-rank test was utilized to compare the survival between the groups. 

Results: A total of 2724 patients were included in the study. A total of 69% of the patients were female, and the median age was 68 (range 24–90+). A total of 7.4% of the patients had bone metastasis on diagnosis. The multivariate Cox analysis identified bone metastasis as an independent mortality risk factor in metastatic GBC (HR 1.50, p < 0.001). The patients were divided into two age groups: a younger age group (18–74 years) and an older age group (75+ years). In the younger group, the median OS with and without bone metastasis was 3 and 5 months, respectively (p < 0.0001). In the older age group, there was no significant difference in the OS between the patients with and without bone metastasis (p = 0.35). In the younger group who were treated with chemotherapy, the patients with bone metastasis had a significantly worse OS (median OS 5 months vs. 8 months, p < 0.0001). In the untreated group, the patients with bone metastasis in the younger age group had a significantly worse OS (median OS 1 month vs. 2 months, p = 0.014). In the patients with bone metastasis, those who did not receive chemotherapy had a significantly worse OS than those who were treated with chemotherapy in both age groups (younger age group: median OS 1 month vs. 5 months, p < 0.0001 and older age group: median OS 1 month vs. 5 months, p = 0.041).

Conclusions:Our findings suggest that the presence of bone metastasis in gallbladder adenocarcinoma is an independent prognostic factor associated with unfavorable survival outcomes in the younger age group (18–74 years). However, in the older age group (75+ years), the presence of bone metastasis did not impact the survival. Treatment with chemotherapy was associated with extended survival in all patients. Thus, early detection and aggressive management of bone metastasis, including the consideration of chemotherapy, may be crucial in improving the OS and quality of life for individuals with gallbladder adenocarcinoma.


熊逸晨硕士(上海市胆道疾病研究重点实验室

胆囊癌恶性程度高,极具侵袭性、隐匿性,大多数患者在诊断时已经表现为转移性疾病。胆囊癌最常见的转移部位是肝脏、局部淋巴结和腹膜,只有20%的病例以非腹部转移为特征,主要转移到肺和脑。胆囊癌骨转移发病率可达10%,与孤立的肺和远处淋巴结转移相比,胆囊癌骨转移的预后更差。大部分关于胆囊癌骨转移的研究数据来自于小型单中心临床研究和零星的病例报告,数据十分有限,针对这一空白,这篇文章基于SEER数据库(美国一个大型的癌症登记处数据库)对胆囊癌骨转移患者进行生存分析,并评估化疗对这类患者的潜在临床益处。

这项研究表明,在所有M1的胆囊癌患者中,骨转移患者的生存时间明显减少,无骨转移患者中位OS为6个月,而有骨转移的患者中位OS仅为3个月。但在老年人群中,骨转移与否并不影响转移性胆囊癌患者的预后(中位OS均为3个月),这可能与老年年龄组自身预测生存期低相关。此外,该研究显示,化疗能为胆囊癌骨转移患者带来生存获益(中位OS为5个月vs 8个月)。但值得注意的是,SEER数据缺乏化疗相关不良反应和患者既往病史,化疗组患者比未接受化疗组患者平均年轻7岁,这种年龄差异可能导致治疗组患者与非治疗组患者在合并症、存活率等方面的偏倚,这与化疗的实施需要较高的总体基线健康状况相关。

尽管这是一项回顾性研究,不可避免地存在选择偏倚和一些混杂因素干扰,但总的来说,这篇文章是迄今为止最大的多中心回顾性研究,探讨了胆囊癌骨转移的临床影响,以及化疗在转移性胆囊癌中的应用。骨转移与较低的总生存率有关,虽然化疗能延长生存时间,但其总体预后仍然严峻。根治性手术是目前胆囊癌的主要治愈性措施,但对于M1的胆囊癌患者而言,包括化疗、靶免治疗等在内的综合治疗能够为他们带来希望的曙光。现有研究发现,在一半的胆囊癌患者中存在至少一种潜在的可操作的分子靶点,未来的研究可以探索如何应用分子检测结合后续的靶向治疗来提高这些个体的生存率,但需要前瞻性研究来证实胆囊癌骨转移的独特特征及其治疗靶点,为临床实践提供有价值的治疗策略。

           
 

3.胆囊癌全球流行病学趋势(GLOBOCAN 2020 数据库)(IF: 2.5)

Vuthaluru S, Sharma P, Chowdhury S, Are C. Global epidemiological trends and variations in the burden of gallbladder cancer. J Surg Oncol. 2023;128(6):980-988.

摘要:Background: Gallbladder cancer (GBC) is a rare but lethal malignancy with a dismal prognosis. The aim of this study is to analyze the burdens and trends of GBC across the world based on geography, socioeconomic development (based on human development index [HDI]), and gender.

Methods: GLOBOCAN 2020 database was used to extract data (2020−2040) relating to the incidence and mortality of GBC across the world.

Results: Asia had the highest burden of GBC with India and China contributing to majority of the absolute burden. The burden of GBC by age standardized rate was highest in Latin America (Bolivia and Chile) and Southeast Asia (Bangladesh and Nepal). Medium HDI countries had a higher mortality rate compared to very high HDI countries. Females had a higher predilection for GBC across different regions and socioeconomic groups. GBC burden is expected to significantly increase across the world by 2040 with variable trends across different regions, age groups, and genders.

Conclusion: The global burden of GBC will significantly increase over the next two decades with marked regional and demographic variations. The results of this study will empower national and global health leaders to develop policies to address the increasing burden of this lethal malignancy.


张宇硕士(上海市胆道疾病研究重点实验室

本篇文章的研究背景是关于胆囊癌(GBC)的全球流行病学趋势和负担变化。GBC是一种罕见但具有高度致死性的恶性肿瘤,其发病率和死亡率在全球范围内存在差异。文章指出,亚洲地区(尤其是中国和印度)是GBC的高发地区,而拉丁美洲和一些低收入国家也存在较高的GBC负担。文章作者通过分析全球GBC的负担和趋势,根据地理、社会经济发展(基于人类发展指数[HDI])和性别等因素,来了解GBC的全球流行病学趋势和变异情况。研究使用了GLOBOCAN 2020数据库获取了与世界区域范围内的GBC发病率和死亡率相关的数据。通过对各地区的数据进行分析,研究发现亚洲是GBC的主要负担地区,其中印度和中国占据了了大部分的绝对负担。此外,拉丁美洲(玻利维亚和智利)和东南亚(孟加拉国和尼泊尔)的GBC负担也较高。研究还发现,中等HDI国家的GBC死亡率较高,而非常高HDI国家的死亡率较低。此外,女性在不同地区和社会经济群体中患GBC的倾向较高。通过对全球GBC负担的分析,研究揭示了未来20年GBC负担将显著增加,并且在不同地区、年龄组和性别之间存在着不同的趋势和变化。这些研究结果将有助于国家和全球卫生领导者制定政策,以应对胆囊癌的不断增加的负担。

文章创新性主要体现在以下几个方面:

1.全球范围内的GBC负担分析:该研究通过对全球范围内的GBC发病率和死亡率进行分析,揭示了不同地理区域和社会经济发展水平下的GBC负担差异。这为制定全球范围内的GBC防控策略提供了重要的参考依据。

2.GBC与人类发展指数的关联:研究发现,GBC的发病率和死亡率与国家的人类发展指数密切相关。高人类发展指数国家的GBC负担更高,而低人类发展指数国家的GBC负担较低。这一发现提示了社会经济发展水平对GBC的影响,为改善低人类发展指数国家的GBC防治水平提供了指导。

3.年龄标准化率的应用:研究中使用了年龄标准化率(ASR)来比较不同国家之间的GBC负担。ASR可以消除不同国家人口年龄结构的影响,使得比较更加准确和可靠。总之,这项研究通过全球范围内的数据分析,揭示了GBC的全球负担情况,并探讨了GBC与社会经济发展的关系,为GBC的防控提供了新的视角和策略。

可能的不足之处包括:

1.数据来源限制:研究使用了GLOBOCAN 2020数据库的数据,但全球范围内的数据质量存在相当大的差异,且没有标准化的全球数据收集方法。这可能导致数据的准确性和完整性受到限制。

2.忽略其他潜在因素:研究主要关注GBC的地理和社会经济发展的影响,但可能忽略了其他潜在的影响因素,如遗传因素、环境因素和生活方式等。这些因素可能对GBC的发病率和死亡率产生重要影响。

综上,本研究的结果将有助于各国的学者进一步了解GBC的流行病学特征、风险因素和治疗策略,并为预防和管理GBC的提供科学依据。

              

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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。
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