指南与共识
ENGLISH ABSTRACT
肝细胞癌免疫联合治疗多学科中国专家共识(2023版)
国际肝胆胰协会中国分会
中华医学会外科学分会肝脏外科学组
中国临床肿瘤学会(CSCO)肝癌专家委员会
作者及单位信息
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DOI: 10.3760/cma.j.cn115610-20230310-00103
Chinese multidisciplinary expert consensus on combined immunotherapy for hepatocellular carcinoma (2023 version)
The Chinese Chapter of the International Hepato-Pancreato-Biliary Association
Group of Liver Surgery, Surgical Society of Chinese Medical Association
Expert Committee on Liver Cancer, Chinese Society of Clinical Oncology
Chen Xiaoping
Xia Feng
Authors Info & Affiliations
The Chinese Chapter of the International Hepato-Pancreato-Biliary Association
Group of Liver Surgery, Surgical Society of Chinese Medical Association
Expert Committee on Liver Cancer, Chinese Society of Clinical Oncology
Chen Xiaoping
Department of Hepatobiliary Surgery, Tongji Hospital, Tongji Medical College of Huazhong University of Science & Technology, Wuhan 430030, China
Xia Feng
Department of Hepatobiliary Surgery, the First Affiliated Hospital of Army Medical University, Chongqing 400038, China
·
DOI: 10.3760/cma.j.cn115610-20230310-00103
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摘要

基于免疫节点抑制剂(ICIs)的肝细胞癌免疫联合治疗在临床研究和临床实践中已取得了显著的疗效,且已成为目前不可切除肝细胞癌治疗的最常用和最主要的疗法。为了更好地帮助临床医师合理、有效、安全地应用免疫联合治疗药物和方案,编委会组织了本领域的多学科专家团队共同进行研讨,采用“德尔菲(Delphi)”共识形成方法,在2021版基础上修订完成了《肝细胞癌免疫联合治疗多学科中国专家共识(2023版)》。该共识主要聚焦于ICIs联合疗法临床应用的原则和方法,结合最新的研究进展和专家经验,总结归纳出临床应用的推荐意见,旨在为肝癌治疗专业人员提供临床应用依据。

肝细胞癌;免疫治疗;联合治疗;免疫节点抑制剂;多学科诊疗;共识
ABSTRACT

Immune checkpoint inhibitors (ICIs)-based immunotherapy combined with other treatment for hepatocellular carcinoma (HCC) has achieved significant efficacy in clinical research and practice, and has become the most commonly used and mainstay therapy for the treatment of unresectable HCC. In order to help clinicians administrating immunotherapy drugs and regimens rationally, effectively and safely, the committee organized a multidisciplinary expert team to adopt the "Delphi" consensus formation method, and finally revised and completed the " Chinese Multidisciplinary Expert Consensus on Combined Immunotherapy for Hepatocellular Carcinoma ( 2023 Version)" on the basis of the 2021 version of consensus. This consensus mainly focuses on the principles and methods of clinical application of ICIs-based combination therapy, aiming to summarize the recommendations for clinical application based on the latest research and expert experience, and provide application guidance for clinicians.

Hepatocellular carcinoma;Immunotherapy;Combination therapy;Immune checkpoint inhibitors;Multi-disciplinary team;Consensus
Chen Xiaoping, Department of Hepatobiliary Surgery, Tongji Hospital, Tongji Medical College of Huazhong University of Science & Technology, Wuhan 430030, China, Email: mocdef.3ab61pxnehcpxnehc
Xia Feng, Department of Hepatobiliary Surgery, the First Affiliated Hospital of Army Medical University, Chongqing 400038, China, Email: mocdef.3ab61aixfknarf
引用本文

国际肝胆胰协会中国分会,中华医学会外科学分会肝脏外科学组,中国临床肿瘤学会(CSCO)肝癌专家委员会. 肝细胞癌免疫联合治疗多学科中国专家共识(2023版)[J]. 中华消化外科杂志,2023,22(03):293-315.

DOI:10.3760/cma.j.cn115610-20230310-00103

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原发性肝癌是我国常见的恶性肿瘤之一。国家癌症中心最新数据统计表明原发性肝癌的发病率位列我国常见恶性肿瘤的第四位、病死率的第二位 1。肝细胞癌(hepatocellular carcinoma,HCC)占原发性肝癌的75%~85%(本共识中的“肝癌”仅指HCC)。乙型肝炎病毒(hepatitis B virus,HBV)感染引起的肝硬化是我国肝癌最为重要的危险因素,但近年来非酒精性脂肪性肝病导致的肝癌呈逐渐上升趋势。目前,外科根治性治疗仍然是肝癌最有效的治疗手段,早期肝癌患者适合于手术切除、局部消融、肝移植等根治性治疗,中位生存期可超过5年。然而由于肝癌起病隐匿,导致我国肝癌患者初诊时70%以上已处于中晚期,失去了外科根治的机会。并且,肝癌术后复发率较高,5年内总复发率高达70%左右,复发后大多失去再次手术治疗机会。因此,目前系统抗肿瘤治疗,尤其是基于免疫节点抑制剂(immune checkpoint inhibitors,ICIs)的联合治疗,已成为不可切除肝癌最常用和最主要的治疗手段 2
2007年,索拉非尼成为肝癌首个获批的一线治疗靶向药物。自2018年后,更多靶向药物如仑伐替尼、阿帕替尼和多纳非尼等陆续上市。近年来,随着对肿瘤免疫学的深入探索,ICIs的临床应用开辟了肿瘤治疗新局面。以ICIs为基础的联合治疗模式在肝癌治疗中不断获得新的突破,进一步提升了肝癌患者的临床获益 3。ICIs包括程序性死亡[蛋白]-1(programmed death-1,PD-1)抗体、程序性死亡[蛋白]配体-1(PD-L1)抗体、细胞毒性T淋巴细胞相关抗原4(cytotoxic T lymphocyte-associated antigen-4,CTLA-4)抗体等。其中PD-1抗体包括纳武利尤单克隆抗体(简称单抗,Nivolumab)、帕博利珠单抗(Pembrolizumab)、信迪利单抗(Sintilimab)、卡瑞利珠单抗(Camrelizumab)、替雷利珠单抗(Tislelizu-mab)、特瑞普利单抗(Toripalimab)、派安普利单抗(Penpulimab)等;PD-L1抗体包括阿替利珠单抗(Atezolizumab)、度伐利尤单抗(Durvalumab)、恩沃利单抗(Envafolimab)等;CTLA-4抗体包括伊匹木单抗(Ipilimumab)和替西木单抗(Tremelimumab)。
《原发性肝癌诊疗指南(2022年版)》 2和2022版中国临床肿瘤学会(Chinese Society of Clinical Onco-logy,CSCO)《原发性肝癌诊疗指南》 4中均对肝癌免疫治疗进行了推荐。然而,因篇幅所限,论述相对简略,难以完全满足临床应用的需要。《肝细胞癌免疫联合治疗多学科中国专家共识(2023版)》(以下简称本共识)以ICIs为核心,聚焦于ICIs联合疗法的肝癌临床应用原则与方法,包括治疗方案选择、围手术期应用、转化治疗、适宜/禁用人群选择、疗效评估及不良反应管理等方面。在《基于免疫节点抑制剂的肝细胞癌免疫联合治疗多学科中国专家共识(2021版)》 5的基础上,结合最新研究进展和专家经验,总结归纳出翔实的临床应用细则,最终修订完成了本共识,旨在为ICIs在肝癌治疗中的全程管理提供参考。
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附录
附录1:HCC一线免疫联合治疗正在进行中的Ⅲ期临床研究
方案类别 注册号 一线方案 研究名称
免疫+靶向 NCT04523493 特瑞普利单抗(JS001)联合仑伐替尼 特瑞普利单抗联合仑伐替尼治疗晚期HCC的Ⅲ期临床研究
NCT04344158 AK105+安罗替尼 AK105联合安罗替尼与索拉非尼治疗晚期HCC的Ⅲ期临床研究
NCT04723004 特瑞普利单抗+贝伐珠单抗 评估特瑞普利单抗联合贝伐珠单抗与索拉非尼治疗HCC的疗效和安全性
NCT04465734 HLX10(PD-1)+HLX04(Beva) 评估HLX10(PD-1)+HLX04(贝伐珠单抗)与索拉非尼一线治疗晚期、转移性HCC的疗效和安全性
NCT04194775 CS1003+仑伐替尼 CS100联合仑伐替尼与安慰剂联合仑伐替尼作为一线治疗晚期HCC的有效性和安全性
NCT04777851 瑞戈非尼+纳武利尤单抗 瑞戈非尼联合纳武利尤单抗与TACE治疗中期HCC(超出“up-to-seven”标准)(RENOTACE)
免疫+免疫 NCT04039607 纳武利尤单抗+伊匹木单抗 评估纳武利尤单抗联合伊匹木单抗与索拉非尼或仑伐替尼一线治疗晚期HCC(CheckMate 9DW)
NCT04720716 IBI310+信迪利单抗 评估IBI310联合信迪利单抗与索拉非尼一线治疗晚期HCC的疗效和安全性

免疫+(靶向/

免疫)+局部

NCT03605706 SHR-1210+FOLFOX4 评估SHR-1210联合FOLFOX4 与安慰剂治疗既往未接受系统治疗的晚期HCC
NCT04268888 纳武利尤单抗+TACE/TAE 纳武利尤单抗联合TACE/TAE治疗中期HCC
NCT05198609

卡瑞利珠单抗、阿帕替尼+HAIC+

贝伐珠单抗

卡瑞利珠单抗、阿帕替尼联合 HAIC与卡瑞利珠单抗、阿帕替尼治疗门静脉侵犯HCC
NCT03778957 TACE+度伐利尤单抗+贝伐珠单抗 TACE联合度伐利尤单抗或度伐利尤单抗和贝伐珠单抗治疗局部HCC(EMERALD-1)
NCT05301842

度伐利尤单抗+曲美木单抗+/-仑伐

替尼+TACE

HCC评估度伐利尤单抗联合曲美木单抗+/-仑伐替尼+TACE 治疗局部HCC(EMERALD-3)
NCT04246177 仑伐替尼+帕博利珠单抗+TACE 评估仑伐替尼+帕博利珠单抗+TACE治疗无法根治性/非转移HCC的疗效和安全性(MK-7902-012/E7080-G000-318/LEAP-012)
展开表格
方案类别

研究组患者数

(例)

用法用量
免疫+靶向 519 特瑞普利单抗:240 mg,静脉注射,每3周1次;仑伐替尼:12 mg(体质量≥60 kg)或8 mg(体质量<60 kg),口服,1次/d
648 AK105:200 mg,静脉注射,每3周1次;安罗替尼:10 mg/kg,口服,1次/d,21 d为1个周期(第15~21天不用药)
280 特瑞普利单抗:240 mg,静脉注射,每3周1次;贝伐珠单抗:15 mg/kg,静脉注射,每3周1次
477 -
525 CS1003:静脉注射,每3周1次;仑伐替尼:口服,1次/d
496 瑞戈非尼:90 mg,口服,28 d为1个周期,第1~21天,每天服药;纳武利尤单抗:480 mg,静脉注射,每4周1次
免疫+免疫 728 4剂次纳武利尤单抗1 mg/kg联合伊匹木单抗3 mg/kg,每3周1次,随后纳武利尤单抗240 mg,每2周1次
490 IBI310:静脉注射,每6周1次;信迪利单抗:静脉注射,每3周1次
免疫+(靶向/免疫)+局部 396 SHR-1210:3 mg/kg,静脉注射,每2周1次;FOLFOX4:每2周1次
522 -
214 卡瑞利珠单抗:200 mg,静脉注射,每2周1次;阿帕替尼:250 mg,口服,1次/d
724 -
525 -
950 帕博利珠单抗:400 mg,静脉注射,每6周1次;仑伐替尼,12 mg(体质量≥60 kg)或8 mg(体质量<60 kg),口服,1次/d
展开表格
附录2:HCC 一线免疫联合治疗Ⅰ期/Ⅱ期研究/小样本临床研究的疗效对比
方案类别 研究类型 一线方案 研究名称 临床分期 用法用量
免疫+靶向 Ⅱ期

卡瑞利珠单抗+

阿帕替尼

RESCUE

NCT03463876 33

卡瑞利珠单抗:200 mg(体质量≥50 kg)或 3 mg/kg(体质量<50 kg),静脉注射,每2周1次;阿帕替尼:250 mg,口服,1次/d
AK104(PD-1/CTLA- 4)+仑伐替尼

NCT04444167 69

AK104:6 mg/kg,静脉注射,每2周1次或15 mg/kg,静脉注射,每3周1次;仑伐替尼:12 mg(体质量≥60 kg)或8 mg(体质量<60 kg),口服,1次/d
KN046(PD-L1/CTLA- 4)+仑伐替尼 NCT04542837 70 KN046:5 mg/kg,每3周1次;仑伐替尼:12 mg(体质量≥60 kg)或8 mg(体质量<60 kg),口服,1次/d

特瑞普利单抗+

贝伐珠单抗

NCT04605796 71 特瑞普利单抗:240 mg,静脉注射,每3周1次;贝伐珠单抗:15 mg/kg,静脉注射,每3周1次

替雷利珠单抗+

仑伐替尼

NCT04401800 72 替雷利珠单抗:200 mg,静脉注射,每3周1次;仑伐替尼:12 mg(体质量≥60 kg)或8 mg(体质量<60 kg),口服,1次/d
安罗替尼+派安普利单抗 NCT04344158 73 Ⅰb/Ⅱ 派安普利单抗:200 mg,静脉注射,每3周1次;安罗替尼:8 mg,口服,2周服用/1周停药
瑞戈非尼+纳武利尤单抗

RENOBATE

NCT04310709 74

瑞戈非尼:80 mg,1次/d,3周服用/1周停药,4周为1个周期;纳武利尤单抗:480 mg,静脉注射,每4周1次
Ociperlimab(OCI)+替雷利珠单抗+ BAT1706

AdvanTIG-206

NCT04948697 75

OCI:900 mg,静脉注射,每3周1次;替雷利珠单抗:200 mg,静脉注射,每3周1次;BAT1706:15 mg/kg,静脉注射,每3周1次
Ⅰ期/Ⅰb期 仑伐替尼+纳武利尤单抗 Study 117 13 Ⅰb 仑伐替尼:12 mg(体质量≥60 kg)或 8 mg(体质量<60 kg),口服,1次/d;纳武利尤单抗:240 mg,静脉注射,每2周1次
仑伐替尼+帕博利珠单抗 Keynote 524 15 Ⅰb 仑伐替尼:12 mg(体质量≥60 kg)或 8 mg(体质量<60 kg),口服,1次/d;帕博利珠单抗:200 mg,静脉注射,每3周1次
瑞戈非尼+帕博利珠单抗

NCT03347292 76

Ⅰb

瑞戈非尼:120 mg(可降低至80 mg,或增加至160 mg),3周服用/1周停药,4周为1个周期;帕博利珠单抗:200 mg,静脉注射,每3周1次
Avelumab+Axitinib

VEGF Liver 100

NCT03289533 77

Ⅰb Avelumab:10 mg/kg,静脉注射,每2周1次;Axitinib:5 mg,口服,2次/d
免疫+免疫 Ⅰ期/Ⅰb期 HBM4003+特瑞普利单抗 NCT05149027 -
免疫+化疗 Ⅱ期 卡瑞利珠单抗+ FOLFOX4 NCT03092895 78 卡瑞利珠单抗:3 mg/kg,静脉注射,每2周1次
展开表格
方案类别 联合组患者数(例) 中位总生存期(月) 中位无进展生存期(月) 应答率(RECIST 1.1,%) 应答率(mRECIST,%)
免疫+靶向 70(1L)

NR

(12个月OS率74.7%)

5.7

34.3(IRC)

34.3(研究者评估)

45.7(IRC)
30 NR NR 44.4 -
30 - - 57.1 76.2
54 NR 9.9 32.7 46.2
64 NR 9.6 38.7 46.8
31 - 7.6 31.0 -
42 NR 5.5 31.0 35.7
60 - - - -
30 - 7.39 54.2 66.7
100 22.0 8.6 36.0 46.0
29 - - 30.0 -
22 14.1

5.5(RECIST 1.1),

3.8(mRECIST)

13.6 31.8
免疫+免疫 67 - - - -
免疫+化疗 34 7.4 11.7 26.5 -
展开表格
附录3:HCC免疫/免疫联合治疗在转化治疗中的研究进展
方案类别 研究类型 治疗方式 研究来源
免疫+靶向 前瞻性研究 TKI(仑伐替尼)+PD-1(帕博利珠单抗/信迪利单抗/特瑞普利单抗) Zhang等(2020) 38
回顾性研究

TKI(仑伐替尼/阿帕替尼)+PD-1(帕博利珠单抗/信迪利单抗/卡瑞

利珠单抗/纳武利尤单抗)

Zhu等(2021) 79
真实世界研究

TKI(仑伐替尼)+PD-1(帕博利珠单抗/信迪利单抗/卡瑞利珠单抗/

纳武利尤单抗/特瑞普利单抗)

Sun等(2020) 80
Ⅱ期研究 仑伐替尼+信迪利单抗 Wang等(2022) 39
Ⅰb期研究 卡博替尼+纳武利尤单抗 Ho等(2021) 40
免疫+靶向+局部 前瞻性研究 TACE+仑伐替尼+PD-1 Zhang等(2022) 43
回顾性研究 HAIC+TKI+PD-1 Zhang等(ASCO 2021) 81
回顾性研究 仑伐替尼+特瑞普利单抗+HAIC He等(2021) 42
展开表格
方案类别 用法用量 联合组病例数(例) 应答率(%)

转化切除率

(%)

免疫+靶向 TKI:仑伐替尼12 mg(体质量≥60 kg)或8 mg/d(体质量<60 kg),口服,1次/d;PD-1:静脉注射,每3周1次(帕博利珠单抗/信迪利单抗/特瑞普利单抗)

33

45.5

30.3

TKI:仑伐替尼12 mg(体质量≥60 kg)或8 mg(体质量<60 kg),口服,1次/d;阿帕替尼:250 mg,口服,1次/d;PD-1:静脉注射,每2周1次(卡瑞利珠单抗/纳武利尤单抗)或每3周1次(帕博利珠单抗/信迪利单抗)

63

-

15.9

仑伐替尼:12 mg(体质量≥60 kg)或8 mg(体质量<60 kg),口服,1次/d;

PD-1:静脉注射(帕博利珠单抗/信迪利单抗/卡瑞利珠单抗/纳武利尤单抗/特瑞普利单抗)

59

37.3(RECIST 1.1)

55.9(mRECIST)

10.2

TKI:仑伐替尼12 mg(体质量≥60 kg)或8 mg(体质量<60 kg),口服,1次/d;信迪利单抗:200 mg,静脉注射,每3周1次 29 38.0(RECIST 1.1) 34.0
卡博替尼:40 mg,口服,1次/d,用药8周;纳武利尤单抗:240 mg,静脉注射,每2周1次,用药8周 15 - 80.0
免疫+靶向+局部 TKI:仑伐替尼12 mg(体质量≥60 kg)或8 mg(体质量<60 kg),口服,1次/d;PD-1:卡瑞利珠单抗/信迪利单抗,200 mg,静脉注射,每3周1次 38 84.2(mRECIST) 50.0

TKI:口服,阿帕替尼250 mg/d,仑伐替尼8 mg/d或索拉非尼400 mg 2次/d;

PD-1:卡瑞利珠单抗/信迪利单抗,200 mg,静脉注射,每3周1次

34

84.0(RECIST 1.1)

96.0(mRECIST)

56.0
仑伐替尼:12 mg(体质量≥60 kg)或8 mg(体质量<60 kg),口服,1次/d;特瑞普利单抗:240 mg,静脉注射,每3周1次 71

59.2(RECIST 1.1)

67.6(mRECIST)

12.7
展开表格
附录4:HCC免疫/免疫联合治疗在新辅助及辅助治疗中的研究进展
方案类别 分期 注册号 研究代号 方案
新辅助 免疫+靶向 NCT04615143 RHCC2020 替雷利珠单抗±仑伐替尼
NCT04297202 2019-SR-332 SHR-1210+阿帕替尼
免疫+免疫 I NCT04658147 J20121 纳武利尤单抗±Relatlimab
免疫+靶向+局部 NCT05250843 - TACE/HAIC+仑伐替尼+信迪利单抗
新辅助/辅助 免疫单药 NCT03630640 NIVOLEP 纳武利尤单抗
免疫+免疫 NCT03222076 - 纳武利尤单抗±伊匹木单抗
辅助 免疫单药 NCT03383458 CheckMate 9DX 纳武利尤单抗
NCT03867084 Keynote 937 帕博利珠单抗
Ⅱ/Ⅲ NCT03859128 JUPITER 04 特瑞普利单抗
免疫+靶向 NCT04682210 DaDaLi 信迪利单抗+贝伐珠单抗
NCT04102098 IMbrave050 阿替利珠单抗+贝伐珠单抗
NCT03722875 - SHR-1210+阿帕替尼
NCT03847428 EMERALD-2 度伐利尤单抗±贝伐珠单抗
NCT04639180 SHR-1210-Ⅲ-325 卡瑞利珠单抗+阿帕替尼
免疫+局部 NCT04663035 B2020-195-01 消融+替雷利珠单抗
展开表格
方案类别 研究名称 患者数(例)
新辅助 替雷利珠单抗或替雷利珠单抗联合仑伐替尼作为新辅助治疗复发可切的HCC 80
SHR-1210联合阿帕替尼在HCC围手术期治疗HCC(HCC-009) 20
纳武利尤单抗联合或不联合Relatlimab治疗潜在可切HCC的可行性和疗效 20
TACE/HAIC+仑伐替尼+信迪利单抗作为新辅助治疗中期HCC 90
新辅助/辅助 电消融HCC患者接受纳武利尤单抗作为新辅助和辅助治疗(NIVOLEP) 43
纳武利尤单抗联合或不联合伊匹木单抗治疗可切除肝癌患者 30
辅助 纳武利尤单抗辅助治疗根治性肝切除术或消融术后复发风险高的HCC 545

帕博利珠单抗与安慰剂作为辅助治疗术后或消融完全缓解HCC的疗效和安全性(MK-3475-937/

Keynote 937)

950
特瑞普利单抗或安慰剂作为术后根治HCC辅助治疗 402
信迪利单抗联合贝伐珠单抗作为根治性术后高复发风险HCC的辅助治疗 246
阿替利珠单抗联合贝伐珠单抗与主动监测作为根治性术后或消融的高复发风险HCC的辅助治疗 668
SHR-1210 联合阿帕替尼作为HCC患者辅助治疗 45
度伐利尤单抗单独或联合贝伐珠单抗作为根治性治疗后高复发风险HCC的辅助治疗(EMERALD-2) 877
卡瑞利珠单抗联合阿帕替尼作为根治性术后或消融的高复发风险HCC的辅助治疗 674
消融联合替雷利珠单抗与消融治疗早期HCC肝内复发 120
展开表格
附录5:针对肝炎病毒感染相关肝癌的临床研究
注册号 研究设计 研究类型 样本量(例)
NCT04294498 度伐利尤单抗治疗活动性慢性HBV感染晚期HCC 43
NCT04044651 仑伐替尼+纳武利尤单抗与仑伐替尼治疗晚期HBV感染HCC Ⅱ/Ⅲ -
NCT04180072 阿替利珠单抗联合贝伐珠单抗治疗晚期HBV感染相关HCC - 48
NCT03419481 帕博利珠单抗在HBV相关HCC患者中的研究 30
NCT04680598

高HBV DNA和低HBV DNA载量患者接受ICI和同时抗病毒预防HBV再活化的比较:

一项前瞻性观察研究

观察性研究 800
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备注信息
A
陈孝平,华中科技大学同济医学院附属同济医院肝脏外科中心,武汉 430030,Email: mocdef.3ab61pxnehcpxnehc
B
夏锋,陆军军医大学第一附属医院肝胆外科,重庆 400038,Email: mocdef.3ab61aixfknarf
C
国际肝胆胰协会中国分会, 中华医学会外科学分会肝脏外科学组, 中国临床肿瘤学会(CSCO)肝癌专家委员会. 肝细胞癌免疫联合治疗多学科中国专家共识2023版)[J]. 中华消化外科杂志, 2023, 22(3: 293-315. DOI: 10.3760/cma.j.cn115610-20230310-00103.
D
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