肝內(nèi)膽管癌的綜合治療

唐陳偉，童煥軍，湯朝暉

（上海交通大學(xué)醫(yī)學(xué)院附屬新華醫(yī)院  普通外科，上海 200092）

摘   要 肝內(nèi)膽管癌（ICC）具有惡性程度高，發(fā)現(xiàn)晚，容易發(fā)生淋巴結(jié)轉(zhuǎn)移、脈管侵潤及肝內(nèi)播散等特點，導(dǎo)致患者預(yù)后較差。根治性手術(shù)仍然是目前唯一可以使患者獲得長期生存的治療方式，但存在根治性切除率低、術(shù)后容易復(fù)發(fā)等諸多難題以及肝切除范圍和切緣寬度確定、淋巴結(jié)清掃與否等諸多爭議。輔助治療是綜合治療的重要組成部分，但放化療尚無規(guī)范、有效的方案，靶向治療與免疫治療正處于臨床探索階段。隨著分子生物學(xué)技術(shù)的進展，發(fā)現(xiàn)ICC在基因突變、信號傳導(dǎo)以及臨床病理特征上展現(xiàn)出高度的異質(zhì)性。筆者從ICC生物學(xué)特性及臨床特點的異質(zhì)性出發(fā)，結(jié)合ICC治療策略和新的綜合治療理念，為其個體化治療提供新的思路與研究方向。

關(guān)鍵詞 膽管腫瘤；膽管，肝內(nèi)；異質(zhì)性；腫瘤治療方案 

中圖分類號：R735.8

Multimodality treatment of intrahepatic cholangiocarcinoma

TANG Chenwei, TONG Huanjun, TANG Zhaohui

(Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai 200092, China)

Abstract   Intrahepatic cholangiocarcinoma (ICC) is characterized by highly malignant behavior, being difficult to make an early detection, and frequent lymph node metastasis, vascular invasion and intrahepatic dissemination, which lead to the poor prognosis of the patients. At present, radical operation is still the only therapy for providing a chance of long-term survival, but it faces many problems such as low radical-resection rate and high postoperative recurrence rate, as well as many controversies such as determinations for the scope of liver resection and the width of the surgical margin and whether the lymph node dissection should be done. Adjuvant therapy is a critical component of the multimodality treatment, but there are no standard directions and effective protocols for its chemoradiotherapy, and the targeted therapy and immunotherapy are at the stage of exploration. With the development of molecular biological techniques, high degree of heterogeneity has been found in ICC in terms of gene mutation, signal transduction and clinicopathologic features. Here, the authors from the heterogeneity of the biological characteristics and clinical features of ICC in combination with the treatment strategies and the new concept of integrated therapy for ICC, provide new insights and research directions for its individualized treatment.

Key words Bile Duct Neoplasms; Bile Ducts, Intrahepatic; Heterogeneity; Antineoplastic Protocols 

CLC number: R735.8

　　肝內(nèi)膽管癌（intrahepatic cholangiocarcinoma，ICC）是指位于肝內(nèi)二級及以上膽管上皮來源的惡性腫瘤^[1]，也稱肝內(nèi)膽管細胞癌（intrahepatic cholangiocellular carcinoma，ICC），是僅次于肝細胞肝癌（hepatocellular carcinoma，HCC）的肝臟惡性腫瘤。ICC發(fā)病率近20年來在世界范圍內(nèi)呈顯著上升趨勢^[2-3]。隨著外科技術(shù)的不斷改進，ICC根治性切除率得到提高，但其術(shù)后長期生存率并沒有得到明顯改善，在大多數(shù)研究中ICC術(shù)后5年生存率僅為25%~35%^[3-5]。外科手術(shù)作為ICC最有效的治療方式，目前尚存在包括肝切除范圍、切緣距離、淋巴結(jié)清掃等諸多重要環(huán)節(jié)的爭議，且輔助治療尚無明確規(guī)范的治療方案。極差的預(yù)后與治療爭議提示著外科醫(yī)生對ICC的理解存在盲區(qū)，也提示著治療理念與模式需要改進。研究^[6-7]發(fā)現(xiàn)，ICC在致病因素、地域分布、臨床表現(xiàn)、生物學(xué)特征、細胞起源以及分化等方面存在較大異質(zhì)性。新的理念提示，惡性腫瘤是一個全身性系統(tǒng)性疾病，需要全身治療而不是單純的局部切除，需要序貫治療而不是一個階段性的治療。本文從ICC生物學(xué)特性及臨床特點的異質(zhì)性出發(fā)，結(jié)合ICC治療爭議和新的綜合治療理念，為ICC的個體化綜合治療提供新的思路與研究方向。

1　手術(shù)治療

1.1  肝切除術(shù)  

　　根治性切除是目前得到廣泛認可的ICC首選治療方式，包括腫瘤的完全切除，切緣陰性，同時能保留足夠肝組織（剩余至少兩個連續(xù)肝段，且具有充分血流灌注，靜脈回流和膽汁引流）。術(shù)前需要準確評估其手術(shù)切除的安全性和有效性，在盡量達到R₀切除的前提下，同時考慮殘余肝臟能否有效代償?shù)陌踩詥栴}。美國肝膽胰協(xié)會2015版ICC診治專家共識將遠處轉(zhuǎn)移、超出區(qū)域淋巴結(jié)轉(zhuǎn)移如腹主動脈旁淋巴結(jié)轉(zhuǎn)移、雙側(cè)肝內(nèi)多發(fā)病灶或多中心病灶視為手術(shù)禁忌證^[8]。肝切除的范圍與手術(shù)切緣尚無統(tǒng)一意見。具體切除范圍根據(jù)病灶位置、大小和器官侵犯情況而定。術(shù)中為了獲得根治性切除，可能傾向于切除更多的肝臟。但Zhang等^[9]研究指出，大范圍肝切除對術(shù)后整體生存率并無獲益，卻會增加圍手術(shù)期并發(fā)癥的發(fā)生。該研究進一步指出，切緣寬度，而不是切除范圍，影響長期生存結(jié)果，如果能實現(xiàn)切緣寬度≥5 mm，應(yīng)提倡保留肝實質(zhì)的根治性切除。也有研究^[10]指出，切緣>10 mm可延長患者術(shù)后生存期，手術(shù)切緣寬度越小其復(fù)發(fā)的風(fēng)險越高。目前已普遍認識到R₀切除對ICC根治的重要性，

R₀切除通常定義為完整切除大體可見腫瘤及切緣陰性，但各中心報道的R₀切除率差異較大，可能的原因包括腫瘤分期、手術(shù)方式和手術(shù)水平，而R₀本身定義也尚為完全統(tǒng)一^[11-12]。中國抗癌協(xié)會ICC診治指南提出，R₀切除腫瘤距切緣至少5~10 mm^[13]。綜上，ICC肝切除術(shù)在肝切除范圍、切緣寬度以及R₀準確定義上均尚未完全統(tǒng)一，立足具體病例，根據(jù)ICC不同臨床病理類型選擇合適的切除范圍成為外科醫(yī)生首要考慮。

1.2  淋巴結(jié)清掃 

　　ICC具有高度惡性的生物學(xué)行為，淋巴轉(zhuǎn)移發(fā)生早。據(jù)報道，ICC淋巴轉(zhuǎn)移率可達30%~65%^[14-17]。肝內(nèi)膽管癌的淋巴播散主要沿如下3條途徑^[13]：⑴ 通過肝十二指腸韌帶；⑵ 通過賁門旁、胃小彎及胃左動脈；⑶ 通過隔下動脈或直接從右肝到主動脈旁的外側(cè)組。ICC是否常規(guī)行淋巴結(jié)清掃以及清掃范圍均存在較大爭議。較大宗病例研究^[17-18]指出，肝門部淋巴結(jié)清掃對ICC患者并無明顯生存獲益，但其有助于獲得準確的腫瘤分期，可為手術(shù)后或無法根治性切除的患者行輔助治療提供分期依據(jù)，建議常規(guī)行肝門淋巴結(jié)清掃術(shù)。而Miyata等^[19]發(fā)現(xiàn)，無論肝門部淋巴結(jié)有無轉(zhuǎn)移，清掃組和未清掃組在術(shù)后生存期和無復(fù)發(fā)生存期上差異無統(tǒng)計學(xué)意義，并建議臨床實踐中嚴格把控肝門部淋巴結(jié)清掃的指征，不建議常規(guī)執(zhí)行清掃。類似報道^[20]指出在沒有區(qū)域淋巴結(jié)轉(zhuǎn)移的情況下，ICC患者不會受益于淋巴結(jié)清掃術(shù)。然而，如已明確淋巴轉(zhuǎn)移的位置，系統(tǒng)性淋巴結(jié)切除術(shù)可以改善ICC預(yù)后，建議嚴格選擇病例行淋巴結(jié)清掃。尚有報道^[21]指出，以性別、年齡或腫瘤大小區(qū)分的特定亞組可從淋巴結(jié)清掃中獲益，如60歲以下的腫塊型ICC可從淋巴結(jié)清掃中獲益。國內(nèi)學(xué)者^[22]回顧性研究分析190例ICC患者臨床病理資料，對比評估CT、MRI、PET-CT在ICC臨床分期中的價值，結(jié)果發(fā)現(xiàn)PET-CT在檢測區(qū)域淋巴結(jié)轉(zhuǎn)移的準確率和靈敏度分別為86.7%和80.0%，檢測遠處轉(zhuǎn)移的準確率為98.42%，與CT、MRI相比差異均有統(tǒng)計學(xué)意義。PET-CT檢查彌補了CT和MRI檢查診斷ICC分期中區(qū)域淋巴結(jié)轉(zhuǎn)移和遠處轉(zhuǎn)移的不足，有助于術(shù)前明確淋巴結(jié)轉(zhuǎn)移情況，決定術(shù)中是否行淋巴結(jié)清掃術(shù)。綜上，ICC患者能否從淋巴結(jié)清掃中獲益涉及淋巴結(jié)具體轉(zhuǎn)移部位、腫瘤類型、患者一般情況等因素，是否行淋巴結(jié)清掃需結(jié)合患者具體情況決定。

1.3  ICC異質(zhì)性與肝切除、淋巴結(jié)清掃

　　ICC在致病因素、地域分布、臨床表現(xiàn)、生物學(xué)特征等方面存在較大異質(zhì)性。近年來的研究^[23]發(fā)現(xiàn)，ICC的細胞起源呈多元化，包括肝細胞、膽管上皮細胞、管周腺體細胞和肝干細胞等，同時其發(fā)生、發(fā)展及轉(zhuǎn)移等與糖代謝、脂代謝等多種代謝密切相關(guān)^[24]，提示ICC的生物學(xué)特征、臨床表現(xiàn)的異質(zhì)性可能與其多元化細胞起源、多種代謝機制及途徑密切相關(guān)^[7]。筆者團隊^[25]曾研究報道的國內(nèi)首個ICC臨床異質(zhì)性及淋巴結(jié)轉(zhuǎn)移多中心大樣本（1 321例）臨床研究，就ICC發(fā)病因素與腫瘤原發(fā)位置、淋巴結(jié)轉(zhuǎn)移高危因素等得出重要結(jié)論。同時就ICC細胞起源總結(jié)了最新的實驗證據(jù)和相關(guān)文獻，以提供ICC細胞起源的最新觀點，幫助建立ICC發(fā)生的分層模型，改進ICC基于解剖學(xué)的分類標準^[6]。

　　日本肝癌研究協(xié)會（LCSGJ）^[26]將ICC分為3種大體類型：腫塊型（mass-forming type，MF）、管周浸潤型（periductal infiltrating type，PI）和管內(nèi)生長型（intraductal growth type，IG）。Shimada等^[27]指出，MF+PI型ICC與黃疸、膽管侵犯、門靜脈侵犯、淋巴結(jié)侵犯及腫瘤切緣陽性密切相關(guān)，其復(fù)發(fā)率高于其他類型的ICC，預(yù)后更差。ICC的大體分型與淋巴結(jié)轉(zhuǎn)移發(fā)生率相關(guān)（IG︰MF︰MF+PI︰PI=0︰16%︰50%︰66%）^[28]。Suzuki等^[29]研究發(fā)現(xiàn)，MF型和MF+PI型ICC的5年生存率分別為47%和0。 

　　通過前期關(guān)于ICC細胞起源的基礎(chǔ)研究與ICC臨床特點與淋巴結(jié)轉(zhuǎn)移的臨床研究，結(jié)合日本LCSGJ的大體病理分類（腫塊型、管周浸潤型、肝內(nèi)生長型），筆者認為起源于肝細胞的ICC大體表現(xiàn)為MF型，其生物學(xué)特性與HCC類似；管周腺體細胞來源的ICC則表現(xiàn)為PI型，可沿門靜脈系統(tǒng)周圍的淋巴、神經(jīng)轉(zhuǎn)移，侵襲性較強，易造成早期淋巴結(jié)轉(zhuǎn)移及神經(jīng)侵犯，預(yù)后較差；起源于膽管上皮細胞的ICC表現(xiàn)為IG型，惡性程度低，沿管壁環(huán)形生長，惡性程度相對最低，預(yù)后較好；而MF+PI型ICC可能與肝前體細胞、肝干細胞起源有關(guān)，惡性轉(zhuǎn)化能力強，惡性程度最高。術(shù)前通過影像學(xué)檢查大多能夠明確ICC分型，而相應(yīng)的外科治療方式是否可根據(jù)分型進行相應(yīng)調(diào)整，如：MF型ICC治療策略參照原發(fā)性肝細胞癌，淋巴結(jié)不做常規(guī)清掃，如術(shù)前術(shù)中懷疑，則行淋巴結(jié)清掃；PI型和MF+PI型ICC的治療應(yīng)盡量在解剖性肝切除的基礎(chǔ)上，擴大肝切除范圍，保證切緣陰性，同時行常規(guī)淋巴結(jié)清掃，術(shù)后輔助放化療改善預(yù)后；IG型ICC可行解剖性肝切除，需注意膽管切緣陰性和有無膽管癌栓。根據(jù)術(shù)前影像學(xué)檢查及術(shù)中探查情況確定是否行淋巴結(jié)清掃以及什么部位的淋巴結(jié)清掃。對于近肝門部ICC考慮開展胃小彎淋巴結(jié)清掃，對于左肝外周型ICC選擇性地開展胃底周圍淋巴結(jié)清掃，但對于術(shù)前影像學(xué)檢查提示有淋巴結(jié)轉(zhuǎn)移但無特殊部位或遠處轉(zhuǎn)移的ICC，不建議擴大清掃范圍^[30]。基于ICC細胞起源及大體分型異質(zhì)性而提出的不同手術(shù)方法，符合疾病個體化治療的理念，結(jié)合癌癥綜合治療思想，是實現(xiàn)ICC個體化、規(guī)范化治療、改善ICC患者預(yù)后的一個可能的方向。

1.4  聯(lián)合肝外膽管和血管切除 

　　對術(shù)中病理證實膽管切緣陽性的較晚期患者, 需在肝切除基礎(chǔ)上聯(lián)合肝外膽管切除。如左右肝管匯合部膽管侵犯范圍較局限, 可行受侵膽管匯合部切除，證實保留肝內(nèi)膽管切緣及肝外膽管切緣陰性后，行膽管兩切緣對端吻合^[13]。既往通常將肝臟惡性腫瘤合并門靜脈、下腔靜脈等主要血管侵犯視為手術(shù)治療的禁忌證，隨著外科技術(shù)的發(fā)展，越來越多的學(xué)者認為合并肝靜脈、門靜脈、下腔靜脈侵犯的肝臟惡性腫瘤可行手術(shù)切除、人造血管重建^[31]。Miyata等^[32]研究報道，合并肝中靜脈切除與否的兩組ICC根治患者，術(shù)后五年總體生存率和陰性切緣率之間差異無統(tǒng)計學(xué)意義。一項多中心大宗病例（1 087例）研究^[33]報道指出，ICC根治術(shù)時聯(lián)合主要血管切除，并不會增加患者術(shù)后并發(fā)癥發(fā)生率，其術(shù)后整體生存率和無復(fù)發(fā)生存率與單純解剖性肝切除組相比差異無統(tǒng)計學(xué)意義，認為在ICC手術(shù)治療中實施下腔靜脈切除、門靜脈切除或兩者聯(lián)合切除是安全可行的。

1.5  復(fù)發(fā)ICC外科治療 

　　文獻^[34-35]報道ICC術(shù)后復(fù)發(fā)率可高達55%~70%，肝臟是最常見的復(fù)發(fā)部位。Ohira等^[34]發(fā)現(xiàn)再次行手術(shù)治療的復(fù)發(fā)ICC患者中位生存期（36.7個月）顯著高于未再行手術(shù)治療者（13.1個月），并指出再次手術(shù)、腫塊型腫瘤、無膽管侵犯是復(fù)發(fā)型ICC患者的有利預(yù)后因素，建議對局部復(fù)發(fā)的ICC患者行手術(shù)治療。Si等^[36]回顧性分析了72例ICC復(fù)發(fā)并再次獲得R₀切除的患者資料，發(fā)現(xiàn)復(fù)發(fā)的ICC患者經(jīng)再次手術(shù)后的1、2、3年術(shù)后生存率分別為82.9%、53.0%、35.3%，認為再次肝切除術(shù)對于部分復(fù)發(fā)ICC可獲得較好的生存預(yù)后，而多復(fù)發(fā)灶、1年內(nèi)復(fù)發(fā)、復(fù)發(fā)病灶直徑>3 cm和肝硬化是影響再次手術(shù)預(yù)后的獨立危險因素。Bartsch等^[37]亦指出，與接受化療、經(jīng)動脈化療栓塞、選擇性內(nèi)部放療、射頻消融或支持治療的復(fù)發(fā)ICC患者相比，接受再次手術(shù)的患者有更長的總體生存時間（P<0.001）。

1.6  其他外科治療

　　目前多認為ICC患者肝移植效果治療效果差，有限的資料表明，移植術(shù)后腫瘤復(fù)發(fā)時間短、生存率低，甚至將ICC作為肝移植的禁忌證^[38]。但Fu等^[39]研究了11例ICC患者行肝移植術(shù)的術(shù)后生存資料，發(fā)現(xiàn)患者術(shù)后4年無復(fù)發(fā)生存率可達51.9%，整體生存率為50.5%，認為對于部分不可切除的ICC患者可經(jīng)肝移植獲得較好的預(yù)后。ICC局部治療方法包括經(jīng)動脈化療栓塞術(shù)（TACE）、射頻消融（RAF）、放射性釔栓塞等。Boehm等^[40]通過Meta分析發(fā)現(xiàn)，在無法手術(shù)切除的ICC患者中，行肝動脈灌注（hepatic arterial infusion，HAI）、放射性釔栓塞、TACE和藥物洗脫珠TACE的患者中位生存時間分別為22.8、13.9、12.4個月和12.3個月。

2　輔助治療 

2.1  輔助放化療 

　　ICC輔助性化療的主要適應(yīng)證為術(shù)后存在殘余腫瘤或淋巴結(jié)轉(zhuǎn)移患者^[41]，可使用的化療藥物包括吉西他濱、鉑類、卡培他濱或氟尿嘧啶類等抗腫瘤藥。ICC的全身化療一般參考晚期胰腺癌的方案，包括吉西他濱單藥，吉西他濱與卡培他濱聯(lián)合應(yīng)用，以及吉西他濱與鉑類似物(順鉑、奧沙利鉑和卡鉑)聯(lián)合應(yīng)用等。Valle等 ^[42]針對晚期膽道腫瘤的臨床研究結(jié)果表明：吉西他濱和順鉑聯(lián)合應(yīng)用后的患者生存率優(yōu)于吉西他濱單藥。但ICC整體化療效果欠佳，獲益患者比例并不高，這與ICC高度異質(zhì)性不無關(guān)系，而關(guān)于不同類型的ICC化療反應(yīng)性的研究也相對較少。研究^[43]研究報道，以吉西他濱為基礎(chǔ)的化療可以提高管周浸潤型、腫塊型+管周浸潤型患者（8% vs. 37%，P<0.001）和有淋巴結(jié)轉(zhuǎn)移ICC患者的5年生存率。針對ICC術(shù)后輔助性放療的研究同樣較少。Jiang等^[44]納入了90例行手術(shù)治療的ICC，放療組（24例）的中位生存時間是19.1個月，無放療組（66例）的中位生存時間是9.5個月，兩者之間存在統(tǒng)計學(xué)差異（P=0.011）。Shroff等^[45]進行的一項II期臨床試驗表明，與吉西他濱/順鉑治療進展期膽管癌的歷史對照相比，吉西他濱/順鉑聯(lián)合白蛋白結(jié)合性紫杉醇（albumin-bound paclitaxel）治療延長了患者總體生存時間和無病生存時間。

2.2  靶向治療

　　隨著二代測序等分子檢測技術(shù)的完善，ICC突變基因和信號通路異質(zhì)性得以逐漸揭示^{[1, 46]}。隨著精準醫(yī)療計劃的提出和癌癥基因組學(xué)的研究進展，靶向治療有望實現(xiàn)真正意義上的根據(jù)ICC基因異質(zhì)性進行的治療。目前已有靶向IDH基因、FGFR通路EGFR受體、RAS/RAF/MEK/MAPK通路等大量的分子靶向治療的臨床試驗。Saha等^[47]通過對17種膽管癌在內(nèi)的一大組癌細胞系的高通量藥物篩選的研究發(fā)現(xiàn)，達沙替尼對于IDH突變的ICC效果顯著，達沙替尼處理后的IDH突變異體種植瘤表現(xiàn)出明顯的細胞凋亡和腫瘤消退。Loaiza-Bonilla等^[48]報道了1例放化療低反應(yīng)性伴全身多發(fā)轉(zhuǎn)移的IV期ICC患者，基于其BRAF V600E突變陽性的特點，將其作為dual-BRAF和MEK抑制劑治療的候選者使用達帕菲尼聯(lián)合曲美替尼治療，結(jié)果展現(xiàn)出了良好的耐受性和反應(yīng)性，達到了持續(xù)的癥狀和影像學(xué)改善，成為首個依據(jù)個體化基因組信息成功治療ICC的案例。

2.3  免疫治療 

　　尋找ICC突變基因中的免疫原性表位是檢查點抑制劑發(fā)揮作用的關(guān)鍵。Schumacher等^[49]研究表明，20%的ICC存在IDH1（R132H）基因突變，含有適用于突變特異性疫苗接種的免疫原性表位，該突變區(qū)域的肽誘導(dǎo)CD4+免疫應(yīng)答反應(yīng)具有用于制備特異性IDH1（RI32H）基因疫苗的潛力。FDA于2017年批準PD-1抑制劑Pembrolizumab（Keytruda）用于治療攜帶一種特定基因特征（高度微衛(wèi)星不穩(wěn)定性，MSI-H或錯配修復(fù)缺陷，dMMR）的任何實體瘤，包括膽道惡性腫瘤。成功治療案例已見報道，Sui等^[50]報道了2例IIIb期ICC（基因特點：dMMR陽性，MSS，腫瘤負荷為2.95~7.09個/Mb）患者，在化療結(jié)合PD-1阻斷后達到完全緩解。

2.4  新輔助治療

　　ICC新輔助治療臨床應(yīng)用較少，NCCN指南亦未無ICC患者術(shù)前行新輔助治療療相關(guān)問題的解釋。Le Roy等^[51]研究發(fā)現(xiàn)，39例進展期ICC在接受中位時間為6個周期的術(shù)前化療后行手術(shù)治療，其術(shù)后復(fù)發(fā)率、病死率和中位生存時間與112例單純早期手術(shù)者相比差異無統(tǒng)計學(xué)意義（24.1個月vs. 25.7個月），認為新輔助化療序貫手術(shù)治療的局部晚期ICC患者的短期和長期預(yù)后與單純早期手術(shù)切除的ICC患者相似，對局部進展期ICC具有降期作用，可增加手術(shù)機會。Kato等^[52]報道1例局部進展期的ICC患者行新輔助放化療，使用吉西他濱聯(lián)合順鉑化療、聯(lián)合放療后，成功進行左肝聯(lián)合尾狀葉切除。

2.5  結(jié)語

　　從ICC生物學(xué)異質(zhì)性出發(fā)，結(jié)合個體化基因特點和大體分型，采取相應(yīng)的手術(shù)方式和輔助治療方案是改善ICC患者預(yù)后的新思路，尤其是在二代測序等生物技術(shù)飛速發(fā)展的今天，與患者分子生物病理學(xué)、基因表達特征相匹配的個體化診斷和綜合治療將成為可能，但仍需要更多的基礎(chǔ)與臨床研究對ICC患者進行分層或分子分型，區(qū)分化療獲益、靶向治療獲益或者免疫治療獲益的人群。

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（本文編輯　宋濤）

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