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公務出國報告
（出國類別：進修）
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裝
「醫學影像無片化與院際整合」
進修報告
釘
線
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服務機關：台北市立聯合醫院仁愛院區
出 國 人 職
稱：主治醫師
姓
名：李兆祥
出國地區：美國波士頓市
出國期間：民國九十四年七月十一日至
民國九十五年六月三十日
報告日期：民國九十五年八月七日
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公務出國或赴大陸地區報告提要
類別：其他活動
出國或赴大陸地區報告名稱：「醫學影像無片化與院際整合」進修報告
含附件：是 V 否
出國計畫主辦機關：台北市立聯合醫院
聯絡人：黃詩芸
電話：25553000 轉 2659
出國人員姓名/服務機關/單位/職稱/電話
李兆祥/台北市立聯合醫院仁愛院區/放射線診斷科/主治醫師/
電話:(02)27093600 轉 5103
出國類別：V 其他□1 出 席 國 際 會 議 □2 表 演 □3 比 賽 □4 競 技 □5 洽 展 □6 海 外 檢 測
出國期間：民國九十四年七月十一日至 出國地區：美國波士頓市
民國九十五年六月三十日
報告日期：民國九十五年八月七日
內容摘要：
此次進修之主題為「醫學影像無片化與院際整合」
。職於民國九十四年七月抵達波士
頓麻州總醫院，一方面接觸了解其放射線部之 PACS 系統,一方面以 PACS 系統為基
礎，從事相關之臨床研究工作，包括射頻腫瘤滅除術之技術及觀念，以及奈米微粒
超順磁性氧化鐵對比劑在磁振造影之應用。檢討本院目前之情況,若能強化 PACS 系
統維護,擴充儲存影像之空間,將可加強本院 PACS 系統之便利性,減少醫師向系統維
護人員求助之需求,並降低故障之頻率,使醫療流程更為順暢,這些是我們應努力之
目標。醫學研究之進行,會因為完整的 PACS 系統,而變得方便,省去了過去調閱放射
科 X 光片之麻煩,也可以在 PACS 系統之工作站上,從事快速而正確的影像資料分析工
作。本報告亦附錄作者根據相關研究成果所撰寫之英文醫學期刊論文，提供給有興
趣之先進前賢作為參考。
關鍵詞：醫學影像無片化，影像擷取及傳輸系統(簡稱ＰＡＣＳ系統)，射頻腫瘤滅除術，奈
米微粒超順磁性氧化鐵對比劑(簡稱 USPIO)。
本文電子檔已上傳至出國報告資訊網（http://open.nat.gov.tw）
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本 文
目 次
第一章、目的 ………………………………………………………… 第 3 頁
第二章、過程 ………………………………………………………… 第 4 頁
第三章、心得 ………………………………………………………… 第 5 頁
第四章、建議 ………………………………………………………… 第 13 頁
第五章、英文版論文 ………………………………………………… 第 15 頁
第六章、參考資料 …………………………………………………… 第 43 頁
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【本文】
第一章、目的
此次進修之主題為「醫學影像無片化與院際整合」
，其主要目的有三:一為
觀摩美國知名醫學中心之醫學影像無片化之實施情況;二為學習射頻腫瘤滅除
術對癌症之治療;三為利用醫學影像無片化之便利性,從事相關之放射線醫學研
究。
本計劃（醫學影像無片化與院際整合乙案 ）原于民國九十一年提出，當時
背景為本院（台北市立聯合醫院成立前，原台北市立仁愛醫院）擬引進醫療影
像無片化，即為影像擷取及傳輸系統(picture archiving and communication
system, 以下簡稱ＰＡＣＳ系統），擬派員赴較早發展ＰＡＣＳ系統之美國著名
醫院觀摩學習。然而因為美國於九一一事件後,對於外國人赴美國停留之限制較
嚴,因此本計劃延後至民國九十四年才得以順利執行,此時台北市立聯合醫院之
PACS 系統已初步建構完成並應用於仁愛、忠孝、和平、 中興及陽明等院區。因
此,此次赴美國觀摩 PACS 系統之運作,可以觀察其應用於放射線科以及其他臨床
醫療科之效率、方便性、以及穩定度和系統維護。
同時,射頻腫瘤滅除術在美國已是相當成熟的腫瘤治療技術,仁愛院區在台
北市立聯合醫院之中是以癌症治療為醫療特色,所以赴美國學習射頻腫瘤滅除
術近年之新發展及觀念,期能更豐富本院區專業醫療團隊之癌症多元化治療策
略。
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除此之外,利用 PACS 系統之便利性,從事與放射線醫學相關之研究,包括
射頻腫瘤滅除術之治療效果研究,以及對於新型磁振造影對比劑之量化分析, 也
是此行重點之ㄧ。
第二章、過程
美國波士頓市之麻州總醫院(Massachusetts General Hospital, 簡稱 MGH)
是北美醫療品質名列前矛之醫院,其 PACS 系統建構亦有相當豐富之經驗。其放
射線部腹部影像科之科主任穆勒醫師(Peter R. Mueller, Dr. Mueller)於民國
九十三年五月間應邀來台演講,穆勒醫師為射頻腫瘤滅除術之專家,職於聆聽其
專題演講後向其請教相關問題,並提出前往美國麻州總醫院觀摩進修之請求,獲
得穆勒醫師慨然應允,並於職正式提出書面申請後,提供一個該院研究醫師
(research fellow)之機會。
職於民國九十四年七月抵達波士頓麻州總醫院後，一方面接觸了解其放射
線部之 PACS 系統,一方面向穆勒醫師及其團隊請教射頻腫瘤滅除術之技術及觀
念,並從事相關之臨床研究工作。除此之外,也向哈利辛哈尼醫師(Mukesh G.
Harisinghani, Dr. Harisinghani)請教新發展之奈米微粒超順磁性氧化鐵對比
劑(Ultrasmall superparamagnetic iron oxide,簡稱 USPIO)在磁振造影之應用,
此項研究工作需要測量許多在磁振造影影像上顯示之腫瘤之特徵, 而全部的研
究相關工作,都在便利而完整的 PACS 系統下,於其工作站上順利完成。完成這些
觀摩及研究之後，職於民國九十五年六月底返抵國門，重回工作崗位。
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第三章、心得
麻州總醫院位於人文薈萃,科學研究蓬勃發展的美國波士頓市,該院為「伙
伴」健康照護系統(Partners HealthCare System)之核心醫院之一(另一核心成
員為布莉根婦女醫院, Brigham and Woman’s Hospital)。置身其中觀摩學習,
可以感染到濃厚的學術研究氣息,以及對所有科學實事求是之態度。現在將職之
觀摩學習心得,分項敘述如下：
(一) 醫學影像無片化
雖然ＰＡＣＳ系統在台灣已有數年之使用經驗，但是其普及性、穩定性、
及週全性仍未如美國地區之健全。
麻州總醫院包括了三個院區:總院(main campus)、西院區(Mass General
West, Waltham)、及查爾斯鎮院區(Chelsea, Charles town)，目前放射線部(含
研究部門)共有十一部電腦斷層掃描儀、十部磁振造影掃描儀、以及其他一般 X
光攝影機及透視攝影儀，該院自 1996 年起使用艾格法(Agfa, Impax 3000)之
PACS 系統,將所有影像檢查之資料儲存於系統中。大約一年內之檢查儲存於快取
記憶體(cache)中,醫師可以從工作站中迅速瀏覽所需之檢查影像, 時間較久遠
之檢查,則儲存於系統檔案(Archive 或 Disc)中,選取欲查閱之檢查影像後,依照
檢查之時間久遠程度,需等待一分鐘至三十分鐘不等。這些步驟都於醫師選取患
者影像資料後自動完成,對放射線科及其他醫療科醫師相當便利。
在日常的醫療作業中,比較患者目前的狀況和過去的狀況之差異,對於放射
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科醫師做正確的診斷,或是醫療科醫師做正確的判斷,是很重要的一環。目前
本院之 PACS 系統於調閱患者先前檢查影像方面,仍需由醫師手動操作，使用上
略為不便,若能簡化程序,對於使用者而言將較為便利。
醫療影像系統的穩定性也是非常重要的一環，PACS 系統一旦不穩定，不但
放射科醫師無法及時發出報告，看診的臨床醫師也無法及時參考放射科醫師之
報告及瀏覽病患之影像。麻州總醫院的 PACS 系統非常穩定，職于進修的一年期
間，整個系統僅有兩次故障之記錄，導致無法調閱病患之影像及製發報告。相
較本院之系統，故障之頻率相對偏高，導致影響放射科醫師之工作效率,造成醫
療科醫師之診療流程不順暢,並影響患者就醫之權益。所以我們對於 PACS 系統
維護之要求,應再提高,以改善目前之情況。
在醫學影像無片化之臨床應用方面，近年來由於多層電腦斷層
(Multi-detector row computed tomography,簡稱 MDCT)之發展，而更顯得重要。
多層電腦斷層能夠於短時間內迅速掃描病患，得到高品質之醫學影像，進而正
確診斷疾病。然而多層電腦斷層掃描所得之影像相當多，因此有些多層電腦斷
層掃描影像檢查必須經過影像後處理，取得關鍵之醫學影像，傳輸至影像擷取
及傳輸系統之工作站上，以提供放射科醫師作診斷。
在一項針對因腎臟絞痛而至急診處就診之病患的研究裏，病患接受多層電
腦斷層掃描，不需靜脈注射含碘對比劑，在九成以上之病患皆能正確診斷腎結
石或輸尿管結石，特別是將多層電腦斷層掃描所得之原始影像資料，重組成矢
狀切面影像，再傳輸至影像擷取及傳輸系統之工作站上，提供放射科醫師作診
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斷。其優點為影像張數較少，判讀所需時間隨之較短，並且此矢狀切面影像
可以讓放射科醫師在較少之影像張數中，清楚看清泌尿系統之各器官，作出更
正確之診斷，的確是一項優異之診斷工具(附圖一)。
附圖一： 多層電腦斷層掃描之矢狀重組影像，箭號所示為一左
側輸尿管之結石。
本院計畫添購多層電腦斷層掃描儀，屆時亦可利用多層電腦斷層掃描與影
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像擷取及傳輸系統二者結合之方便性與準確性，達到嘉惠病患、造福市民之
目的。
(二) 射頻腫瘤滅除術
射頻腫瘤滅除術（Radiofrequency ablation，簡稱 RFA）為一種利用熱能
燒灼腫瘤組織，導致腫瘤壞死的一種治療方式，近十年間，在歐美國家已成為
手術之外的主要局部腫瘤治療方式之一。它的主要臨床用途在於肝臟及腎臟腫
瘤治療，近年來也逐漸應用於肺臟，骨骼及軟組織腫瘤之治療。麻州總醫院在
這些臨床應用方面，皆累積了相當經驗。本院於肝細胞癌患者之照顧，經過前
輩長久努力，亦累積了相當多的實力，可提供患者適當之醫療。本院內科于數
年前亦引進超音波導引之射頻腫瘤滅除術，用於肝細胞癌患者之治療。觀摩麻
州總醫院放射線部之臨床工作，可以發現一些新的技巧及觀念，可供本院醫療
團隊作為參考。
1. 水灌注剝離法(Hydrodissection technique)：
當腫瘤過度接近周圍器官,例如橫膈膜、結腸、或是腎臟等器官時,可以注射
百分之五 Dextrose Water (D5W)以隔開腫瘤及周圍器官,避免造成周圍器官
破壞之併發症。
2. 電 腦 斷 層 導 引 射 頻 腫 瘤 滅 除 術 (Computed tomography-guided
radiofrequency ablation,簡稱 CT-guided RFA)：
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有些腫瘤以電腦斷層做導引來做燒灼,會比超音波導引要準確且安全,但是
檢查期間佔用了一台電腦斷層掃描儀,若像本院一樣只有一部電腦斷層掃描
儀,這樣會影響到一般電腦斷層檢查的排程。
3. 穿 肺 途 徑 射 頻 滅 除 術 治 療 肝 腫 瘤 (RFA of hepatic tumor using
transpulmonary trajectory)：
對於肝臟頂部(hepatic dome)之腫瘤,若有需要,可以用電腦斷層作為導引,
將射頻探頭路徑穿過肺部實質。以此種以往認為危險性較高之方式來治療,
發生氣胸等併發症之機會並不高。
4. 間接途徑射頻滅除術治療肝腫瘤(RFA of hepatic tumor using indirect
trajectory of applicator)：
對於肝贓表淺部位之腫瘤,於進行射頻腫瘤滅除術時,不宜採用最近距離之直
接穿刺法(direct puncture),而應該採用穿過周圍正常肝臟組織之間接途徑
(附圖二)。研究顯示此種方式可以降低出血、腫瘤擴散等併發症(參考資料
一)。
附圖二甲： 磁振造影顯示一肝細胞癌
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附圖二乙： 以間接途徑射頻滅除術治
療肝腫瘤
5. 以射頻腫瘤滅除術治療肝細胞癌,作為等候肝臟移植手術期間之一種「橋樑」
：
肝細胞癌為國內男性最常見的惡性腫瘤之一，在本院主要之治療方式包括手
術切除、酒精注射療法、經動脈化學藥物栓塞、以及先前提到之超音波導引
之射頻腫瘤滅除術。這些治療方式，對於一些早期肝細胞癌之患者，大部分
可以達到暫時之治療效果，然而在長期的追蹤之後，我們可以發現許多患者
都會有腫瘤復發的情形。肝臟移植手術被認為是根治肝細胞癌的手術方式(參
考資料二)，然而器官捐贈來源不易,往往使得病人之病情變得嚴重,演變成不
符合可接受肝臟移植手術之條件,而被排除在可手術之病人名單之外。因此,
肝細胞癌病患在等候器官捐贈的期間,應該先接受其他之療法,以儘量殺死腫
瘤組織,避免腫瘤擴散。目前,射頻腫瘤滅除術被認為是一種很好的治療方式,
在西元 1998 年至西元 2006 年之間,麻州總醫院共有 27 位患者接受射頻腫瘤
滅除術治療肝細胞癌,平均等候 7.1 個月之後(範圍 1 至 29 個月)進行肝臟移
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植手術,手術後平均追蹤時間為 19 個月(範圍 1 至 76 個月),僅有一位病患
(佔所有病患之 3.7%)腫瘤復發,而統計之一年、二年、及三年之存活率分別
為 81.5%、74.2%、及 56.7%,此結果與直接進行肝臟移植手術之患者群無統計上
顯著之差異,但是肝臟移植手術之前接受射頻腫瘤滅除術治療之患者群,可以
容忍較長之等候器官捐贈之時間,且肝臟移植手術後之腫瘤復發率較低,職已
將此研究結果寫成論文,投稿至放射線醫學期刊,目前正接受編輯審閱之中
(請參閱本報告第五章英文版論文：論文一)。
這部份的研究,是以麻州總醫院之 PACS 系統儲存之影像為基礎,來分析研
究。因為其 PACS 系統使用方便,擷取影像快速,所以整個研究工作進行得非常順
利,讓職得以很快完成分析,以進行另外之研究計畫,增加觀摩學習之機會, 讓整
個進修計畫收穫更豐富。
(三) 奈米微粒超順磁性氧化鐵對比劑(Ultrasmall superparamagnetic iron
oxide,簡稱 USPIO)在磁振造影之應用
奈米微粒超順磁性氧化鐵對比劑(簡稱 USPIO)在過去數年間,經過一些動物
實驗以及人體試驗的研究,已經被證實為診斷淋巴結是否有癌症細胞侵犯的利
器(參考資料三)。麻州總醫院放射線部發現,在攝護腺癌患者的人體試驗中,奈
米微粒超順磁性氧化鐵對比劑(USPIO)也會造成攝護腺本身磁振訊號之變化。職
被 Dr. Harisinghani 指派分析此磁振訊號之變化與攝護腺癌之組織病理分級是
11
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否相關。
此項研究中,所有受檢之患者,接受磁振造影檢查,並接受奈米微粒超順磁
性氧化鐵對比劑注射,所得到之磁振造影影像,上傳至 PACS 系統,於是可以很方
便地在工作站上,測量分析攝護腺之磁振訊號。
研究結果發現,攝護腺癌患者於注射奈米微粒超順磁性氧化鐵對比劑二十
四小時後,攝護腺之磁振訊號呈現下降之情形(附圖三),而且此磁振訊號之下降,
與攝護腺癌之組織病理分級有關。職已將此研究結果寫成論文,投稿至放射線醫
學期刊,目前正接受編輯審閱之中(請參閱本報告第五章英文版論文：論文二)。
附圖三甲： 注射對比劑前之攝
護腺磁振造影影像
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附圖三乙： 注射奈米微粒超順
磁性氧化鐵對比劑二十四小時
後之磁振造影,攝護腺之磁振
訊號呈現下降之情形。
第四章、建議
綜合以上之敘述，職以為可以有以下數點之建議：
(一) 他山之石,可以攻錯。麻州總醫院建構影像擷取及傳輸系統(PACS 系統)已
有十年之經驗,而且該院為哈佛大學醫學院之主要教學醫院,擁有豐富之人才資
源,以及雄厚之經濟後盾,所使用之 PACS 系統,其功能性及系統維護之詳盡,不言
可喻；本院以有限之人力及財力,能建構目前擁有之系統,是相當用心且難得的。
檢討本院目前之情況,若能強化系統維護,擴充儲存影像之空間,將可加強
本院 PACS 系統之便利性,減少醫師向系統維護人員求助之需求,並降低故障之頻
率,使醫療流程更為順暢,這些是我們應努力之目標。這方面的改善需要人力、
時間、以及經費,希望在將來,我們可以有一個更完善且穩定的醫療影像系統。
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(二) 不論是放射科或是其他醫療科的醫師,其臨床醫學研究之進行,都必然會
因為有了完整的 PACS 系統,而變得更方便,省去了過去調閱放射科 X 光片之麻煩,
也可以在 PACS 系統之工作站上,從事快速而正確的影像資料分析工作。本院之
態度為鼓勵醫師從事研究發表,因此,在這一點上,更支持我們要有更完善、安
全、且穩定之 PACS 系統。本院目前之 PACS 系統,本來就是以兼顧臨床診療服務、
醫學教學、以及醫學研究之精神來建構,符合國際之潮流。希望在將來,能夠有
更多的經費和專家人力投入,讓我們可以有更理想的研究環境和工具,使本院出
現更多更好的原創性研究成果。
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第五章、英文版論文
停留麻州總醫院的一年期間，利用麻州總醫院建構之影像擷取及傳輸系統
(PACS 系統)，職進行了一些相關之醫學研究，並將研究成果撰寫成兩篇醫學論
文，投稿至放射線醫學期刊，目前正接受期刊編輯審閱之中。
此二篇醫學論文之結論，於本報告第三章心得部份已做了簡單之敘述，為
了更完整呈現研究之成果，現在將論文之原文(以英文撰寫)附錄於此，以供參
考。
論文一、以射頻腫瘤滅除術治療肝細胞癌,作為等候肝臟移植手術期間之一種
「橋樑」：
英文標題：Thermal ablation of hepatocellular carcinoma before liver transplantation: patient
outcome and tumor necrosis in explanted livers
作者：Chao-Shiang Li M.D.1,5,6(李兆祥醫師), Ronald S. Arellano M.D.1, Debra A. Gervais
M.D.1, Elkan F. Halpern PhD2, Raul N. Uppot M.D.1, John Y. Kim M.D.1, Gregory Y. Lauwers
M.D.3, Martin Hertl M.D.4, Peter R. Mueller M.D.1
作者服務機構：Departments of Radiology1, Institute for Technology Assessment 2, Pathology3
and Transplant Surgery4, Massachusetts General Hospital, Harvard Medical School, Boston,
Massachusetts; 5Department of Radiology, Renai Branch, Taipei City Hospital, Taipei, Taiwan(台
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北市立聯合醫院仁愛院區); 6School of Medicine, National Yang-Ming University, Taipei,
Taiwan
論文摘要：
Purpose: To assess efficacy and outcome of thermal ablation for hepatocellular carcinoma (HCC)
prior to liver transplantation.
Materials and Methods: Twenty-seven patients with 32 HCC underwent 42 thermal ablations
before liver transplantation were retrospectively reviewed. Pre-transplant CT or MR and
histopathologic examination of the explanted livers evaluated effectiveness of ablation. Histology
served as reference standard. A second group of 25 patients with HCC underwent liver
transplantation without prior thermal ablation was compared with the ablation group with respect to
waiting time, recurrent HCC and survival.
Results: In the thermal ablation group, the mean waiting time for liver transplantation was
7.1±6.8-months. Imaging showed 87.5% (25 of 28 HCC) complete necrosis. Three patients with 4
tumors underwent transplantation within one month of ablation and therefore had no post-ablation
imaging prior to transplantation.
Histology showed 77.4% (24 of 31) tumors had complete or
greater than 75% necrosis. Imaging accuracy was 92.6%, sensitivity 60% and specificity 100% in
detecting suboptimal necrosis. One (3.7%) ablation patient developed diffuse metastases to the
adrenal gland and bone 19 months after transplantation. Twenty-one (77.8%) patients were alive
without recurrence after follow-up of 19.0±17.1 months. The 25 patients without pre-transplant
treatment had similar survival rate (p=0.6085) but shorter waiting time of 4.2±4.2 months (p=0.03).
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Three non-ablation patients (12%) developed recurrent disease after transplant.
Conclusion: Thermal ablation of HCC may serve as an effective treatment option for patients
awaiting liver transplantation.
Keywords: Cancer; Hepatocellular carcinoma (HCC); Liver transplantation; Radiofrequency
ablation (RFA).
論文本文部份：
Introduction
Hepatocellular carcinoma (HCC) is one of the most common malignancies in the world, and the
incidence is increasing in both eastern and western countries (1, 2). Liver transplantation is
considered the only definitive treatment for HCC (3, 4). Highly selected patients with unresectable
HCC may undergo liver transplantation with 1- and 3-year patient and graft survival rates of 90%
and 70%, respectively (3, 5, 6). In 1996, Mazzaferro et al. evaluated the outcome of patients with
HCC who underwent liver transplantation and recommended liver transplantation in patients with
HCC who had up to 3 tumors all less than 3 cm in diameter or a single lesion up to 5 cm.
This is
commonly referred to as the Milan criteria, which are the most widely accepted criteria to select
and maintain patients with HCC on the liver transplant waiting lists (3). However, limited supply of
donor organs prolongs the waiting time for transplantation and causes high dropout rates from
tumor progression (7, 8). As a result, safe and effective means of treating and delaying the
progression of HCC in liver transplant candidates are urgently needed.
Recently radiofrequency ablation (RFA) has emerged as a safe and effective treatment for small,
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unresectable cases of HCC (9-12). Therefore, the potential beneficial role of RFA for the patients
of HCC while awaiting liver transplantation has emerged in recent years (13-20). These studies
have reported varying results regarding treatment response of RFA, rate of patient dropout from
waiting lists for liver transplantation, and patient outcome following liver transplantation. The aims
of current study are to evaluate the outcome of patients who underwent thermal ablation therapy as
a bridge to liver transplantation for HCC; secondarily, to evaluate the treatment efficacy of
pre-transplant thermal ablation therapy in livers, which provides an opportunity to
histopathologically determine the extent of necrosis of tumor in a more rigorous and accurate
manner.
Materials and methods
The institutional review board approved the study design and review of patient records and
images. All patients provided written informed consents for the thermal ablation therapy procedures
and liver transplantation.
Patients
From April 1998 to January 2006, there were 82 patients who underwent percutaneous
radiofrequency or microwave ablation for treatment of HCC at our institution. Twenty-seven of the
82 patients (21 men and 6 women, mean age: 56.9±1.4 years, age range: 42 – 71 years) ultimately
underwent liver transplantation for potentially curative treatment, and were included in this study.
Of these patients, Child-Turcotte-Pugh class was A in 15 patients, B in 9, and C in 3. Diagnosis of
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HCC was confirmed on biopsy in 17 (63.0%) of 27 patients. In the remaining 10 patients, the
diagnosis of HCC was based on hypervascular tumors present on computed tomography (CT) or
magnetic resonance(MR) imaging as well as growth of tumors over time. In all but 3 patients, the
pre-ablation alpha-fetoprotein (α-FP) serum levels were determined. A total of 32 tumors were
treated with thermal ablation therapy prior to liver transplantation.
During the same period, a total of 25 patients with HCC who underwent liver transplantation
without pre-operative treatment were included in this study for comparison. This group was
composed of 24 men and one woman, with mean age of 54.5±7.1 years (range: 38 – 69 years). Of
these patients, Child-Turcotte-Pugh class was A in 2 patients, B in 10, and C in 13. The diagnosis of
HCC was established prior to liver transplantation in 23 out of 25 patients (92%).
Radiofrequency ablation
Thermal ablation of HCC was performed with a manufacturers recommend protocol using the
Cool-Tip radiofrequency system (Radionics Inc., Burlington, MA), Starburst RITA system (RITA
Medical, Mountain View, CA), or VivaWave microwave ablation system (Vivant Medical, Inc.,
Mountain View, CA). Seven ablations were performed using general anesthesia. The remainders
were performed with the use of intravenous procedural sedation and local anesthesia.
Imaging follow-up
Contrast-enhanced dynamic CT or gadolinium-enhanced MR imaging was obtained at 1 month, 3,
6, 9 and 12 months intervals after thermal ablation. Subsequent imaging follow-up depended on the
clinical condition of the patient and co-morbid conditions, but was generally at 6- to 12-month
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intervals.
Post-ablation images were analyzed and compared with pre-ablation images. A thin rim of
contrast enhancement at the periphery of the coagulation zone identified during the
arterial-dominant phase of CT or MR imaging was considered inflammatory reaction to the thermal
damage (21). Nodular enhancement within or along the margin of the coagulation zone was
considered a residual tumor (22). Any pre-existing tumor region not encompassed by the new
coagulation zone was considered incomplete treatment. In cases of uncertainty, additional
follow-up scans were obtained to determine stability, with interval growth of the area considered to
represent a residual tumor. Residual tumors were re-treated with radiofrequency ablations if
clinically feasible. Final imaging determination of completeness of tumor coagulation was made
using the last available follow-up imaging study before liver transplantation. Incomplete necrosis of
target tumor was defined as presence of residual tumor or incomplete treatment.
Pre-ablation, post-ablation and post-transplant images were retrospectively reviewed by two
board-certified abdominal radiologists (C.S.L. and R.S.A.). Disagreements were resolved by
consensus.
Evaluation of explanted liver
The explanted livers were evaluated by a pathologist with special interest and training in hepatic
diseases using standard procedures at our institution. The explanted livers were fixed in 10%
formalin and then cut into slides of 1 cm or less. All treated tumors, together with all
macroscopically visible untreated neoplastic nodules, were evaluated by conventional optical
microscopy after hematoxylin-eosin (H&E) staining. Considering the treated tumors, necrosis of
tumor was defined as the absence of neoplastic cells along with the presence of amorphous material,
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while the diagnosis of viable tumor was based on the demonstration of neoplastic hepatocytes at
the ablated site.
Comparison between pre-transplant images and histopathologic findings
The interpretations of pre-transplant CT or MR images were compared with histopathologic
findings of the explanted liver. Three patients with 4 tumors underwent liver transplantation within
1 month of the last ablation and therefore had no post-ablation imaging prior to transplantation. In
one patient, liver transplantation was performed at an outside hospital, and the histopathologic
diagnosis of explanted liver was not available. Therefore, a total of 23 patients with 27 tumors were
included in the imaging-pathology comparison portion of this study. In this imaging-pathology
comparison analysis, ablated tumors with complete or partial necrosis greater than 75% as
determined by histopathologic analysis were considered as one group of significant necrosis, and
those with partial necrosis less than 75% including less than 25% were considered another group of
suboptimal necrosis (Table 1).
Statistical analysis
Continuous variables were expressed as mean  standard deviation (SD), and t test was used for
comparison. Selected variables associated with patients, tumors and thermal ablation procedures
were evaluated for possible influence on efficacy of thermal ablation therapy, based on evaluation
of explanted liver. Fisher exact test was used for analysis of these nominal variables. A threshold P
value of 0.05 was chosen for statistical significance.
Results
The size of the 32 HCC ranged from 1.2-cm to 4.4-cm (mean: 2.5±0.8-cm). On initial staging, 24
out of 27 patients (88.9%) fit the Milan criteria for liver transplantation. There were 3 patients who
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did not fit the Milan criteria. One patient had 5 tumors less than 3-cm and the largest tumor was
treated by 1 session of RFA. One patient had 4 tumors less than 3-cm, and 2 of the 4 tumors were
treated by 1 session of RFA. Another patient had 2 tumors, and 1 session of RFA was performed on
1 tumor, which was greater than 3-cm in diameter.
Thermal ablation treatment and outcome
A total of 39 radiofrequency ablations and 3 microwave ablations were performed for 32 HCC.
Among these treatment sessions, a total of 10 repeat radiofrequency ablation sessions were
performed for 6 patients with residual tumors, and two successive transcatheter arterial
chemoembolizations (TACE) were performed for one patient with residual tumor. Twenty-three
(85.2%) of the 27 patients were treated exclusively with radiofrequency ablation.
Based on pre-transplant CT or MR imaging, complete necrosis was achieved in 25 (89.3%) out of
the 28 HCC before liver transplantation. Pre-transplant imaging studies were not available for 4
tumors because the patients underwent liver transplantation within one month of their last thermal
ablation. All of the 27 patients ultimately underwent liver transplantation. The mean waiting time
between the first RFA and liver transplantation was 7.16.8-months (range: 1 – 29 months), while
the mean time between last loco-regional treatment and liver transplantation was 5.5±5.9 months
(range: 0 - 29 months). Histopathologic evaluation of explanted livers showed complete necrosis in
11 out of the 31 HCC (35.5%), partial necrosis higher than 75% in 13 tumors (41.9%), partial
necrosis between 75% and 25% in 5 tumors (16.1%), and partial necrosis less than 25% in 2 tumors
(6.5%). One patient underwent liver transplantation at an outside institution, and preventing
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histopathologic analysis of the explanted liver.
Comparison of pre-transplant images and histopathologic findings
The mean interval between pre-transplant imaging procedure and transplantation was 41.4±34.3
days (range: 1-150 days). Pre-transplant images were 92.6% accurate in facilitating the diagnosis of
histopathologically evident significant (higher than 75%) necrosis of HCC at the ablated site (Table
1) (Fig 1). The use of contrast material-enhanced CT or MR imaging after thermal ablation therapy
showed a specificity of 100%, positive predictive value of 100%, sensitivity of 60.0% and negative
predictive value of 91.7% to detect suboptimal ablation of HCC using necrosis of 75% tumor
burden as cutoff value.
Factors affecting complete or partial necrosis of tumor after ablation
The mean diameter of completely necrotic tumors was 2.1±0.7-cm, and for those with partial
necrosis was 2.6±0.7-cm. The mean size of partially necrotic tumors was larger than that of
completely necrotic tumors (P= 0.03, t test).
Nine (43%) out of 21 non-perivascular tumors showed complete necrosis, however, only 2 (20%)
out of 10 perivascular tumors in our study showed complete necrosis. Nevertheless, the difference
could not draw statistical significance (p = 0.20, Fisher exact test) (Table 2).
Complications and post-transplant follow-up
Percutaneous thermal ablation therapy was associated with a low rate of peri-procedural
complications. Major complication was recorded in one patient (3.7%) who developed a
pneumothorax necessitating chest tube insertion. Minor complications including small right pleural
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effusion (n=1), asymptomatic peri-hepatic hematoma (n=1), and persistent nausea requiring
overnight observation (n=1) were recorded in 3 patients. No mortality or exclusion from the
waiting list of liver transplantation resulted from these complications. No patient developed tumor
implantation along the needle track of thermal ablation therapy.
The cumulative one-, two-, and three-year post-transplant survival rates were 81.5%, 74.2%, and
56.7%, respectively (Fig 3). For analysis of influence of complete or partial necrosis on patient
survival, the subjects in our study group were divided into two sub-groups. The first sub-group was
composed of 8 patients with 9 tumors, which showed complete necrosis on explanted livers. The
second sub-group was composed of 18 patients in whom one partially necrotic tumor (n=14), two
partially necrotic tumors (n=2), or one partially necrotic tumor together with one completely
necrotic tumor (n=2) were noted. Comparison of the survival rates between the two sub-groups
showed no statistically significant difference (P=0.3992, Log-Rank test).
Patients group with no thermal ablation prior to liver transplantation
A total of 40 HCC were detected by imaging prior to liver transplantation in this group of 25
patients (mean: 1.6±0.2, range: 0 – 5). A small HCC less than 1.0-cm in one patient and a 12.5-cm
diffuse HCC in the other patient were found in the explanted livers, whose pre-operative imaging
could not identify the presence of tumor.
On initial staging, 22 out of 25 patients (88%) fit the Milan criteria for liver transplantation.
There were 3 patients who did not meet the Milan criteria. One patient had 5 tumors with the
largest one of 1.6-cm. One patient had 4 tumors with the largest one of 3.5-cm. Another patient had
3 tumors with the largest one of 3.2-cm.
The basic characteristics of these 25 patients were compared to those of 27 patients in thermal
ablation group (Table 3). The severity of liver cirrhosis was significantly higher in the group of no
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thermal ablation (P=0.0002). The percentage of patients underwent liver biopsies for diagnosis
of HCC was significantly lower in the group of no thermal ablation (P=0.005) (Table 3).
The cumulative one-, two-, and three-year post-transplant survival rates in this group were 63.3%,
62.3%, and 57.5%, respectively (Fig. 3). The survival rate showed no statistically significant
difference with that of 27 patients in the thermal ablation group (P=0.6085) (Fig 3).
Discussion
Liver transplantation is universally regarded as the main curative therapeutic option for selected
patients with HCC (3). However, donor organs are limited while demand for organs remains high.
Therefore, time on the transplant waiting list is up to 6 or 12 months in Europe and the United
States with up to 30-40% dropouts per year (23, 24) due to progression of disease while awaiting
transplantation. The Milan criteria provide patient selection guidelines based on tumor size and
nodule number for liver transplant candidates (25, 26). Adjuvant treatments were given in many
centers to HCC patients on waiting lists in order to destroy as much neoplasm as possible, reducing
tumor progression and the risk of dropout due to progression of disease based on the exceeding the
Milan criteria (19). Recent studies have suggested that pre-transplant loco-regional therapy
conferred a survival benefit and was cost effective (23, 27).
The general goal of RF ablation is complete thermal coagulation of the tumor. Most clinical
studies on the performance of RF ablation have relied on imaging characteristics to assess treatment
response (28, 29). Using established imaging criteria (21, 22), 25 (89.3%) out of the 28 HCC
showed complete local response in our study. This result is similar to that of a recent study by Lu et
al, in which 43 (91%) of 47 HCC showed complete radiological response (30).
Histopathologic examination of explanted livers can offer a definitive diagnosis of complete
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necrosis or residual viable tumor within ablated sites (31). Our study showed that complete
necrosis was achieved in 11 (35.5%) out of the 31 HCC based on histopathologic findings. However,
a total of 24 (77.4%) out of the 31 HCC showed significant necrosis in our study using higher than
75% necrosis as the criterion. Few previous studies which evaluated explanted livers to determine
the success rate of radiofrequency ablation showed rates of complete necrosis between 21% and
75% (13, 14, 20, 30). The wide variability of complete necrosis rate may result from various
intervals between pre-transplant imaging and liver transplantation, different histopathologic criteria
to define complete necrosis, and different treatment strategy of thermal ablation for HCC patients.
Lu et al reported 74% (35 of 47) radiofrequency ablated HCC showed complete necrosis based on
histopathologic findings (30). Recently, Brillet et al reported a 75% (12 of 16 radiofrequency
ablated HCC) complete necrosis rate based on a smaller number of cases underwent liver
transplantation (20). In our study, the discrepancy of complete necrosis rates between radiologic
(89.3%) and histopathologic (35.5%) criteria may be attributed mostly to insensitivity of CT and
MR imaging in demonstrating small remnants of residual carcinoma. Alternatively, the time interval
between the last imaging study and post-transplant histopathologic analysis may have been
sufficient for the development of new disease along the treatment margin.
Our study showed a low sensitivity of CT or MR imaging to depict suboptimal necrosis, i.e. less
than 75% necrosis, of thermal ablated HCC. Only 3 of 5 (60%) ablated HCC with less than 75%
necrosis were detected on pre-transplant images. Lu et al also reported a low sensitivity of 36% in
their study, in which only 4 out of 11 tumors with positive histopathologic findings were detected
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by images (30). Previously Dromain et al reported a CT sensitivity of 44% for depicting residual
tumor at 2 months after ablation (22). However, their study was not based on findings at explanted
liver but relied on tumor growth detected by follow-up images. In a preliminary study (33),
Fluorodeoxyglucose positive emission tomography (FDG-PET) was considered superior to CT or
MR imaging in the surveillance of patients treated with RFA for malignant hepatic tumors.
However, the use of this technique in the follow-up of HCC after thermal ablation therapy remains
under investigation.
However, our study showed an excellent specificity of 100% for CT or MR imaging to detect
suboptimal necrosis of HCC after thermal ablation. Lu et al also reported 100% specificity of
post-ablation imaging to detect histopathologically evident residual or viable HCC (30). Given the
low sensitivity of cross-sectional imaging for early detection of small remnants of viable HCC, we
recommended post-ablation imaging follow-up at short intervals to identify residual tumor
amenable to repeated ablation. At our institution, contrast-enhanced dynamic CT or
gadolinium-enhanced MR imaging was obtained at 1 month, 3, 6, 9 and 12 months after
radiofrequency ablation, as well as subsequent imaging follow-up at 6- to 12-month intervals.
We acknowledge that this is a retrospective study in which there may be selection bias with
respect to patient referral to thermal ablation therapy. As a result, the advanced stage of liver
cirrhosis may contribute to the shorter waiting time in those patients without pre-transplant thermal
ablation. We lack information to obtain the percentage of patients who underwent percutaneous
thermal ablation for HCC and were ultimately excluded dropout from the transplant waiting list due
to progression of HCC, due to the retrospective study design.
In conclusion, percutaneous thermal ablation therapy for HCC is a safe pre-transplant treatment
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modality, and can achieve satisfactory coagulative necrosis of HCC. Thermal ablation therapy
may keep patients as suitable candidates while awaiting a new liver and as such may serve as an
effective bridge to liver transplantation.
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8:1165-1174.
15. Mazzaferro V, Battiston C, Perrone S, et al. Radiofrequency ablation of small hepatocellular
carcinoma in cirrhotic patients awaiting liver transplantation: a prospective study. Ann Surg 2004;
240:900-909.
16. Fisher RA, Maluf D, Cotterell AH, et al. Non-resective ablation therapy for hepatocellular
carcinoma: effectiveness measured by intention-to-treat and dropout from liver transplant waiting
list. Clin Transplant 2004; 18:502-512.
17. Moreno Planas JM, Lopez Monclus J, Gomez Cruz A, et al. Efficacy of hepatocellular
carcinoma locoregional therapies on patients waiting for liver transplantation. Transplant Proc 2005;
37:1484-1485.
18. Lu DS, Yu NC, Raman SS, et al. Percutaneous radiofrequency ablation of hepatocellular
carcinoma as a bridge to liver transplantation. Hepatology 2005; 41:1130-1137.
19. Pompili M, Mirante VG, Rondinara G, et al. Percutaneous ablation procedures in cirrhotic
patients with hepatocellular carcinoma submitted to liver transplantation: Assessment of efficacy at
explant analysis and of safety for tumor recurrence. Liver Transpl 2005; 11:1117-1126. (The
references list has been truncated due to limited pages.)
Table 1. Post-thermal ablation necrosis of 27 hepatocellular carcinomas: correlation between
imaging assessment and examination of explanted livers
Imaging findings
Histopathologic findings
Partial necrosis
Complete or partial
<75%
necrosis >75%
Incomplete necrosis
3
0
Complete necrosis
2
22
Total
5
22
Note. —Data were the number of lesions.
29
Total
3
24
27
30
Table 2. Efficacy of thermal ablation therapy in 26 patients with 31 hepatocellular carcinomas
Prognostic factors
Post-ablation response
Complete
Partial
P value
Child-Pugh classification
A
7 (39%)
11 (61%)
1.0000
B
3 (30%)
7 (70%)
C
1 (33%)
2 (67%)
Pre-ablation α-FP serum level
< 100 ng/mL
8 (35%)
15 (65%)
0.47
> 100 ng/mL
1 (20%)
4 (80%)
Prior liver biopsy
No
4 (31%)
9 (69%)
0.72
Yes
7 (39%)
11 (61%)
Tumor size
2.1±0.7-cm
2.6±0.7-cm
0.03*
Tumor location
Non-perivascular
9 (43%)
12 (57%)
0.20
Perivascular
2 (20%)
8 (80%)
Number of thermal ablation sessions
1
9 (35%)
17 (65%)
1.0000
2 or more
2 (40%)
3 (60%)
Note. — Unless otherwise indicated, data were the number of lesions. Numbers in parentheses
were percentages. Complete or partial necrosis was determined by evaluation of explanted liver.
The superscript * indicated statistical significance.
論文二、奈米微粒超順磁性氧化鐵對比劑(USPIO)之攝護腺磁振訊號變化與攝護
腺癌組織病理分級相關性之研究：
英文標題：Analysis of ultrasmall superparamagnetic iron oxide uptake in the prostate gland of
patients with primary prostate cancer: Preliminary results
作者：Chao-Shiang Li1,2,3(李兆祥醫師), MD; Mukesh G. Harisinghani1, MD; Wen-Chiung
Lin1,4, MD; Martha Braschi1, MD; Peter F. Hahn1, MD, PhD; Peter R. Mueller1, MD
作者服務機構：1Department of Radiology, Massachusetts General Hospital, Harvard Medical
School, Boston, Massachusetts; 2Department of Radiology, Renai Branch, Taipei City Hospital,
Taipei, Taiwan(台北市立聯合醫院仁愛院區); 3School of Medicine, National Yang-Ming
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University, Taipei, Taiwan; 4Department of Radiology, Tri-service General Hospital and National
Defense Medical Center, Taipei, Taiwan
論文摘要：
Purpose: To analyze the MR signals change of prostate gland after ultrasmall superparamagnetic
iron oxide (USPIO) enhancement in primary prostate cancer.
Materials and Methods: Sixty patients with prostate cancer who underwent USPIO-enhanced MR
imaging for staging of nodal metastasis were enrolled. The central zones (CZ) and peripheral zones
(PZ) of prostate gland were evaluated on T2-weighted imaging (T2WI) and T2*-weighted MR
imaging (T2*WI) before and 24 hours after USPIO enhancement. The signal-to-noise ratio (SNR)
of each anatomic zone was evaluated using region of interest measurements. The change of SNR
after USPIO enhancement was analyzed and correlated with serum level of prostate-specific
antigen (PSA) and histopathologic findings of surgically removed prostate gland.
Results: Significant decrease of SNR was noted in each anatomic zone of prostate gland after
USPIO enhancement (P<0.001). The mean percentage of SNR decrease in CZ was significantly
higher than that in PZ (P<0.05). High-grade prostate cancer was associated with significantly
higher decrease of SNR than that of intermediate grade (P<0.05). The change of SNR using T2*WI
was significantly correlated with serum PSA level (correlation coefficient=-0.568, P<0.05).
Conclusion: The preliminary results show characteristic SNR decrease within the prostate gland
with primary prostate cancer after USPIO enhancement.
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Key words: magnetic resonance imaging (MRI); prostate cancer; ultrasmall superparamagnetic
iron oxide (USPIO)
論文本文部份：
Introduction:
Prostate cancer is the most common malignancy and the third leading cause of cancer death in
the United States (1). The development of increasingly sensitive early detection strategies for
clinically localized prostate cancer, including serum prostate specific antigen (PSA) and transrectal
ultrasonography, has led to an increased number of patients who undergo radical prostatectomy for
potential cure (2). Recently magnetic resonance (MR) imaging including magnetic resonance
spectroscopy (MRS) has shown promise in detecting primary prostate cancer with reported
sensitivity of 71-97% and specificity of 88-90% (3, 4). However, there are a few important
limitations regarding MRS evaluation of prostate cancer. First, it is difficult to create a standardized,
vendor independent protocol to evaluate prostate cancer because the application is variable across
different imaging platforms. Second, patient accessibility to MRS is a problem because it is still an
expensive medical tool (5).
In recent years, ultrasmall superparamagnetic iron oxide (USPIO)-enhanced MR imaging
showed improved accuracy to differentiate benign from malignant lymph nodes in patients with
prostate cancer and various other primary tumors (6-11). Accumulation of USPIO nanoparticles in
tumors with subsequent change of MR signals has been investigated in a few experimental and
clinical studies (12-17). The purposes of our study are primarily to analyze the MR signals change
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of prostate gland using USPIO contrast agent, and secondarily to evaluate the correlation
between the MR signals change and the histopathologic findings of prostate cancer.
Materials and Methods:
The institutional review board approved the study design and review of patient records and
images. All patients provided written informed consents for the examinations that were performed
and for receipt of the contrast material, which is not approved for clinical use.
Patients
From October 2000 to November 2004, ninety-eight patients with recently diagnosed or
recurrent prostate cancer were scheduled for MR imaging with USPIO contrast agent for evaluation
of lymph node metastasis at our hospital.
Transrectal ultrasound (TRUS)-guided biopsy of prostate prior to MR imaging was performed
in 48 (80%) of 60 patients. For these patients, the mean interval between biopsy and MR imaging
was 54.0±30.0 days (range: 17-135 days). In 4 patients, the prostate biopsy was performed after
MR imaging study. There was no history of recent prostate biopsy for the remaining 8 patients.
T1-weighted MR imaging was carefully reviewed to exclude the possibility of hemorrhage in the
prostate due to prior biopsy. Recent (less than 2 months) serum levels of prostate-specific antigen
(PSA) were obtained in 51 patients (85%), in whom the mean level of total PSA was 18.8±30.5
ng/mL (range: 1.4-178.8 ng/mL; normal range: 0-4.0 ng/mL).
MR imaging
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MR imaging was performed on a 1.5 T scanner (System 9X, GE Healthcare) with
region-specific phased-array coils. Identical sequences were obtained before and 24 hours after the
administration of ferumoxtran-10 (Combidex, Advanced Magnetics; or Sinerem, Guerbet). The
pulse sequences performed included T2-weighted fast spin-echo (TR/TE, 4,500/80 ms; flip angle,
90°; field of view, 24-28 cm; slice thickness, 3 mm; matrix, 256 x 256; number of excitations, 3;
average acquisition time, 4.2 minutes), T2*-weighted gradient-echo (TR/TE, 2,100/12; flip angle,
70°; field of view, 26-28 cm; slice thickness, 3 mm; matrix, 160 x 256; number of excitations, 2;
average acquisition time, 6.4 minutes), and T1-weighted gradient-refocused echo (GRE) (TR/TE,
175/1.8; flip angle, 80°; field of view, 22-30 cm; slice thickness, 4 mm; matrix, 128 x 256; number
of excitations, 1; average acquisition time, 22 seconds) sequences obtained in different anatomic
planes.
Imaging analysis
Within the prostate, the signal intensities (SI) in four areas (central zone and peripheral zone in
each side of prostate gland) were evaluated by quantitative measurements before and after USPIO
enhanced on both T2-weighted imaging (T2WI) and T2*-weighted imaging (T2*WI). The
measurement of background noise was also performed in which the ROI was placed in the
phase-encoding direction outside the anterior abdominal wall. The size of ROI in prostate gland
varied 0.1-0.15 cm2 according to the size of gland. The size of ROI for the measurement of
background noise was limited to 0.25 cm2. The signal-to-noise ratio (SNR) in each area of prostate
gland was calculated by dividing the measured mean SI by the standard deviation (SD) of the
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background noise to normalize the SI.
To verify the MR signals change of prostate gland after enhanced with USPIO, the mean values
of SNR of all patients in each area before and after USPIO administration were compared on T2WI
and T2*WI.
Furthermore, the SNR changes of CZ and PZ of prostate gland were evaluated. Within each
area of prostate gland, the SNR change after USPIO enhancement was calculated as
SNR change= (SNRpost - SNRpre)/SNRpre 100%
Where SNRpre and SNRpost denote the signal-to-noise ratios before and after the administration of
USPIO. The mean SNR change in central zone versus that in peripheral zone, in each side of
prostate, was compared.
MR imaging and tumor characteristics
In 20 of these 60 (33%) patients (mean age: 59.1±5.8 years; range: 46-67 years), retrospective
pathologic correlation was possible between the radical prostatectomy (RP) specimen and the
USPIO-enhanced MR imaging. Using histopathologic findings of surgical specimens in these
patients, the Gleason score for prostate cancer and presence of extra-prostatic extension were
recorded. In this preliminary study, the prostate cancer was grouped based on Gleason score into
low histologic grade (Gleason score 2-5), intermediate grade (Gleason score 6-7) and high grade
(Gleason score 8-10) (21).
Statistical analysis
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36
The mean value of SNR and percentage of SNR change in each area or zone of prostate
gland on T2WI and T2*WI were presented as mean ± SD. The comparison of SNR in each area of
prostate gland before and after USPIO administration was performed using the paired Student’s
t-test. Comparison of the SNR change between central zone and peripheral zone of prostate gland
was performed using Student’s t-test also.
Results:
MR signals of prostate gland
By quantitative measurements using ROI cursors, decreased signal intensities of prostate gland
after USPIO administration were noted on both T2WI and T2*WI. Specifically, the signal-to-noise
ratios in all four areas were significantly lower on USPIO-enhanced than those on unenhanced
images (P<0.001) (Table 1).
In the 20 patients with histopathology correlation between RP specimens and USPIO enhanced
MR images, the mean interval between MR imaging and surgery was 36.9±25.6 days (range: 2-83
days). Recent serum levels of total PSA were obtained in all 20 patients, with a mean value of
9.2±8.1 ng/mL (range: 2.7-34 ng/mL). The histopathologic examination proved the diagnosis of
prostate adenocarcinoma with Gleason score of 6 (n=9), 7 (n=7), 8 (n=2), or 9 (n=2). For the
purpose of our study, there were 16 patients of intermediate-grade (Gleason score 6 and 7) and 4
patients of high-grade (Gleason score 8 and 9) prostate cancer. In 13 patients, the histopathologic
examination showed that the tumors were confined within the prostate gland. There was
extra-prostatic extension of prostate cancer in the remaining 7 patients.
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37
For patients with high-grade prostate cancer, there were significantly higher percentages of
SNR decrease in peripheral zone (P=0.001) and whole prostate gland (P=0.02) than those with
intermediate-grade prostate cancer using T2*WI (Table 3). There was no significant difference of
SNR change within the prostate gland between high-grade and intermediate-grade prostate cancer
using T2WI (P>0.05, t-test).
Using the Spearman rank correlation test, the percentage of SNR change in each zone of
prostate gland was not significantly correlated with serum level of total PSA. Using T2WI, the
Spearman correlation coefficient (rs) was –0.282 for CZ, -0.323 for PZ and –0.261 for whole
prostate gland (P>0.05). Using T2*WI, the rs was –0.426 for CZ, -0.426 for PZ and –0.412 for
whole prostate gland (P>0.05). However, observation of patients with normal (0-4ng/mL), mild
(4-10ng/mL) and moderate (10-20ng/mL) elevation of total PSA (22) revealed significant
correlation with SNR change using T2*WI. The rs was –0.586 for CZ, -0.611 for PZ and –0.568 for
whole prostate gland (P<0.05) (Fig. 2).
Discussion:
The results of our study summarize empiric observations of signal intensities change of prostate
gland on USPIO-enhanced MR imaging in patients with prostate cancer. In our study, the visual
observation was confirmed by quantitative analysis that demonstrated statistically significant lower
signal-to-noise ratios of prostate gland on USPIO-enhanced T2WI and T2*WI. Our study also
showed the decrease of SNR in CZ was higher than that in PZ of prostate gland, which indicated
that the uptake of USPIO in the CZ is greater than that of PZ. To our knowledge, there is no
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previous literature describing these findings on MR imaging after USPIO administration.
Superparamagnetic iron oxide (SPIO) particles have been used for years as negative MR
imaging contrast agents. They have marked T2 relaxivity due to their high magnetic moment, which
generates microscopic field inhomogeneities. Consequently, they produce a strong decrease in
signal intensity of the organs in which they accumulate (19, 23). USPIO nanoparticles constitute a
distinct class in this family of products. Ferumoxtran-10 is an USPIO contrast agent under clinical
development for the differentiation of metastatic or non-metastatic lymph nodes (6-11) as well as
other applications such as visualization of atherosclerotic plaque (24), imaging infection or
inflammation (25), vascular imaging (26), and demonstration and characterization of various
primary tumors (12-17).
The mechanism for the distribution of USPIO nanoparticles in tumor was considered depending
on vascular permeability and interstitial trafficking in the tumor (12, 17, 27). In Moore’s study (17)
using a gliosarcoma rodent model, the nanoparticles were identified in several cell populations,
including endothelial cells, tumor-associated macrophages, and tumor cells. In Neuwelt’s small
clinical study (28) of 7 patients with primary or metastatic brain tumors, stainable ferumoxtran-10
iron appeared in reactive cells, i.e. astrocytes and macrophages, rather than tumor cells themselves.
Neoplasm typically was infiltrated by macrophages derived from monocytes recruited from the
circulation, and these cells represented a target population that avidly internalizes USPIO
nanoparticles (17, 29).
Using T2*-weighted imaging, our study demonstrated the relationships between higher SNR
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change within prostate gland and high-grade prostate cancer, and higher PSA level in the range
of less than 20ng/mL. The relationship was not demonstrated using T2-weighted imaging, which
may be partly attributed to relative insensitivity of T2-weighted MR sequence to magnetic
susceptibility effect (35). Previous studies (36, 37) have reported that the degree of intra-tumoral
infiltration of macrophages was associated with stage of tumor development and angiogenesis. We
hypothesized that prostate cancer of high histologic grade may recruit more macrophages, and as a
result, there was more uptake of USPIO and consequently more SNR decrease of prostate gland.
Our results raise the potential to use USPIO-enhanced MR imaging in the detection and
characterization of primary prostate cancer. At present, the conventional MR imaging assessment of
prostate cancer was focused on the peripheral zone, with central zone cancer remained a
challenging issue (38).
There were limitations recognized in our study. As this was a retrospective analysis of a study,
primarily performed for lymph node imaging, we lacked a detailed and robust anatomic correlation
between MR imaging and the surgical specimen of the removed prostate gland, which precluded us
from drawing stronger conclusions with respect to distribution of USPIO uptake and the differential
uptake of tumors with various histopathologic grade.
In conclusion, in patients with prostate cancer, the use of USPIO-enhanced MR imaging may
demonstrate decrease of signal-to-noise ratio of prostate gland. The decrease of SNR may be due to
uptake of USPIO by tumor-associated macrophages. The current study raises the potential to apply
USPIO-enhanced MR imaging to the detection and characterization of primary prostate cancer.
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References:
1.
Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2006. CA Cancer J Clin 2006:56:106-130.
2. Cheng L, Jones TD, Lin H, et al. Lymphovascular invasion is an independent prognostic factor
in prostatic adenocarcinoma. J Urol 2005:174:2181-2185.
3. Squillaci E, Manenti G, Mancino S, et al. MR spectroscopy of prostate cancer. Initial clinical
experience. J Exp Clin Cancer Res 2005:24:523-530.
4. Swindle P, McCredie S, Russell P, et al. Pathologic characterization of human prostate tissue
with proton MR spectroscopy. Radiology 2003:228:144-151.
5. Shah N, Sattar A, Benanti M, Hollander S, Cheuck L. Magnetic resonance spectroscopy as an
imaging tool for cancer: a review of the literature. J Am Osteopath Assoc 2006:106:23-27.
6. Harisinghani MG, Barentsz J, Hahn PF, et al. Noninvasive detection of clinically occult
lymph-node metastases in prostate cancer. N Engl J Med 2003:348:2491-2499.
7. Harisinghani MG, Saksena MA, Hahn PF, et al. Ferumoxtran-10-enhanced MR
lymphangiography: does contrast-enhanced imaging alone suffice for accurate lymph node
characterization? AJR Am J Roentgenol 2006:186:144-148.
8. Heesakkers RA, Futterer JJ, Hovels AM, et al. Prostate cancer evaluated with
ferumoxtran-10-enhanced T2*-weighted MR Imaging at 1.5 and 3.0 T: early experience. Radiology
2006:239:481-487.
9. Nishimura H, Tanigawa N, Hiramatsu M, Tatsumi Y, Matsuki M, Narabayashi I. Preoperative
esophageal cancer staging: magnetic resonance imaging of lymph node with ferumoxtran-10, an
ultrasmall superparamagnetic iron oxide. J Am Coll Surg 2006:202:604-611.
10. Will O, Purkayastha S, Chan C, et al. Diagnostic precision of nanoparticle-enhanced MRI for
lymph-node metastases: a meta-analysis. Lancet Oncol 2006:7:52-60.
11. Curvo-Semedo L, Diniz M, Migueis J, et al. USPIO-enhanced magnetic resonance imaging for
nodal staging in patients with head and neck cancer. J Magn Reson Imaging 2006:24:123-131.
12. Brillet PY, Gazeau F, Luciani A, et al. Evaluation of tumoral enhancement by
superparamagnetic iron oxide particles: comparative studies with ferumoxtran and anionic iron
oxide nanoparticles. Eur Radiol 2005:15:1369-1377.
13. Taschner CA, Wetzel SG, Tolnay M, Froehlich J, Merlo A, Radue EW. Characteristics of
ultrasmall superparamagnetic iron oxides in patients with brain tumors. AJR Am J Roentgenol
2005:185:1477-1486.
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14. Muldoon LL, Sandor M, Pinkston KE, Neuwelt EA. Imaging, distribution, and toxicity of
superparamagnetic iron oxide magnetic resonance nanoparticles in the rat brain and intracerebral
tumor. Neurosurgery 2005:57:785-96; discussion 785-96.
15. Turetschek K, Huber S, Floyd E, et al. MR imaging characterization of microvessels in
experimental breast tumors by using a particulate contrast agent with histopathologic correlation.
Radiology 2001:218:562-569.
16. Fleige G, Nolte C, Synowitz M, Seeberger F, Kettenmann H, Zimmer C. Magnetic labeling of
activated microglia in experimental gliomas. Neoplasia 2001:3:489-499.
17. Moore A, Marecos E, Bogdanov A,Jr, Weissleder R. Tumoral distribution of long-circulating
dextran-coated iron oxide nanoparticles in a rodent model. Radiology 2000:214:568-574.
18. McLachlan SJ, Morris MR, Lucas MA, et al. Phase I clinical evaluation of a new iron oxide
MR contrast agent. J Magn Reson Imaging 1994:4:301-307.
19. Bourrinet P, Bengele HH, Bonnemain B, et al. Preclinical safety and pharmacokinetic profile
of ferumoxtran-10, an ultrasmall superparamagnetic iron oxide magnetic resonance contrast agent.
Invest Radiol 2006:41:313-324.
20. Akin O, Sala E, Moskowitz CS, et al. Transition Zone Prostate Cancers: Features, Detection,
Localization, and Staging at Endorectal MR Imaging. Radiology 2006:239:784-792.
21. Bostwick DG, Grignon DJ, Hammond ME, et al. Prognostic factors in prostate cancer. College
of American Pathologists Consensus Statement 1999. Arch Pathol Lab Med 2000:124:995-1000.
(The references list has been truncated due to limited pages.)
Table 1. Ultrasmall superparamagnetic iron oxide (USPIO)-enhanced MR imaging of prostate:
mean signal-to-noise ratio (SNR) before and after enhanced in 60 patients
T2WI
P value
T2*WI
P value
Right CZ SNRpre
99.0±9.7
99.5±17.4
<0.001
<0.001
SNRpost
194.3±7.0
95.9±11.9
Right PZ SNRpre
93.1±10.3
99.4±17.3
<0.001
<0.001
SNRpost
998.6±7.7
90.2±13.4
Left CZ SNRpre
99.9±9.3
99.3±17.4
<0.001
<0.001
SNRpost
94.9±6.5
99.9±12.6
Left PZ SNRpre
93.6±10.3
99.3±17.4
<0.001
<0.001
SNRpost
98.6±8.0
99.1±13.9
Note: 1. Data are mean SNR in each area. 2. A threshold P value of less than 0.05 indicates
statistical significance. 3. CZ and PZ indicate central and peripheral zones, respectively; SNRpre
and SNRpost denote the SNR before and after enhanced with USPIO.
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42
Table 2. Comparison of MR signal-to-noise ratio (SNR) change after administration of ultrasmall
superparamagnetic iron oxide (USPIO) in 60 patients: central zone versus peripheral zone of
prostate gland
T2WI
P value
T2*WI
P value
Right CZ (%)
-29.4±20.3
-90.1±29.2
0.003
0.011
Right PZ (%)
-19.2±24.8
-29.6±21.9
Left CZ (%)
-29.3±22.7
-99.8±92.1
0.047
0.018
Left PZ (%)
-94.8±32.5
-29.8±99.9
Note: 1. Data are percentages of SNR change. 2. A threshold P value of less than 0.05 indicates
statistical significance. 3. CZ and PZ indicate central and peripheral zones, respectively.
Table 3. Change of signal-to-noise ratio (SNR) on T2*-weighted MR imaging after ultrasmall
superparamagnetic iron oxide enhancement in 16 patients followed by radical prostatectomy:
comparison between intermediate (Gleason score 6 and 7) and high (Gleason score 8 and 9) grades
of prostate cancer
Histologic grade of prostate
Central zone Peripheral zone Whole prostate gland
cancer
Intermediate (n=12)
-39.3±4.6
-19.8±19.0*
-99.9±19.1
*
High (n=4)
-39.9±12.9
-39.7±19.0
-39.7±19.9
Note: 1. Data are percentage of SNR change. 2. The symbols * (P=0.001) and  (P=0.02) indicate
statistically significant difference. 3. CZ and PZ indicate central and peripheral zones of prostate
gland.
(註：此論文尚未正式發表，故表一至表三中之資料已略作修改，有興趣了解之
先進前賢，煩請逕向作者詢問，作者感謝大家之指教！)
在美國進修的一年期間，暫時擺脫繁重的臨床工作以及教學工作，加上麻
州總醫院便利及功能良好之醫學影像擷取及傳輸系統(PACS 系統)，得以專心從
事觀摩學習以及研究工作，確實是一次難得且收獲豐富的行程。
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第六章、參考資料：
一、 醫學期刊 Poon RT, Ng KK, Lam CM, Ai V, Yuen J, Fan ST. Radiofrequency ablation for
subcapsular hepatocellular carcinoma. Ann Surg Oncol 2004; 11:281-289.
二、 醫學期刊 Mazzaferro V, Regalia E, Doci R, et al. Liver transplantation for the treatment
of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med 1996; 334:693-699.
三、 醫學期刊 Harisinghani MG, Barentsz J, Hahn PF, et al. Noninvasive detection of clinically
occult lymph-node metastases in prostate cancer. N Engl J Med 2003:348:2491-2499.
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