World Journal of - Microsoft · 2017-05-14 · World Journal of W J R Radiology The World Journal of Radiology Editorial Board consists of 365 members, representing a team of worldwide

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World Journal of RadiologyWorld J Radiol 2017 March 28; 9(3): 91-147

ISSN 1949-8470 (online)

EDITORS-IN-CHIEFKai U Juergens, BremenEdwin JR van Beek, EdinburghThomas J Vogl, Frankfurt

GUEST EDITORIAL BOARD MEMBERSWing P Chan, TaipeiChung-Huei Hsu, Taipei Chin-Chang Huang, TaipeiTsong-Long Hwang, TaoyuanJung-Lung Hsu, TaipeiChia-Hung Kao, TaichungYu-Ting Kuo, Tainan Hon-Man Liu, Taipei Hui-Lung Liang, KaohsiungChun Chung Lui, KaohsiungSen-Wen Teng, Taipei Yung-Liang (William) Wan, Taoyuan

MEMBERS OF THE EDITORIAL BOARD

Afghanistan

Takao Hiraki, Okayama

Argentina

Patricia Carrascosa, Vicente LopezMaria C Ziadi, Rosario

Australia

Lourens Bester, SydneyGemma A Figtree, Sydney

Stuart M Grieve, SydneyWai-Kit Lee, FitzroyPrabhakar Ramachandran, Melbourne

Austria

Herwig R Cerwenka, GrazGudrun M Feuchtner, InnsbruckBenjamin Henninger, InnsbruckRupert Lanzenberger, ViennaShu-Ren Li, ViennaVeronika Schopf, ViennaTobias De Zordo, Innsbruck

Belgium

Steve Majerus, LiegeKathelijne Peremans, Merelbeke

Brazil

Clerio F Azevedo, Rio de JaneiroPatrícia P Alfredo, São PauloEduardo FC Fleury, São PauloEdward Araujo Júnior, São PauloWellington P Martins, Ribeirao PretoRicardo A Mesquita, Belo HorizonteVera MC Salemi, São PauloClaudia Szobot, Porto AlegreLilian YI Yamaga, São Paulo

Canada

Marie Arsalidou, TorontoOtman A Basir, Waterloo

Tarik Zine Belhocine, TorontoJames Chow, TorontoTae K Kim, TorontoAnastasia Oikonomou, Toronto

China

Hong-Wei Chen, WuxiFeng Chen, HangzhouJian-Ping Chu, GuangzhouGuo-Guang Fan, ShenyangBu-Lang Gao, ShijiazhuangQi-Yong Gong, ChengduYing Han, BeijingXian-Li Lv, BeijingYi-Zhuo Li, GuangzhouXiang-Xi Meng, HarbinYun Peng, BeijingJun Shen, GuangzhouZe-Zhou Song, HangzhouWai Kwong Tang, Hong KongGang-Hua Tang, GuangzhouJie Tian, BeijingLu-Hua Wang, BeijingXiao-bing Wang, Xi'anYi-Gen Wu, NanjingKai Wu, GuangzhouHui-Xiong Xu, ShanghaiZuo-Zhang Yang, KunmingXiao-Dan Ye, ShanghaiDavid T Yew, Hong KongTing-He Yu, ChongqingZheng Yuan, ShanghaiMin-Ming Zhang, HangzhouYudong Zhang, NanjingDong Zhang, ChongQingWen-Bin Zeng, Changsha

Editorial Board2014-2017

World Journal of RadiologyW J R

The World Journal of Radiology Editorial Board consists of 365 members, representing a team of worldwide experts in radiology. They are from 36 countries, including Afghanistan (1), Argentina (2), Australia (5), Austria (7), Belgium (2), Brazil (8), Canada (6), Chile (1), China (43), Croatia (1), Denmark (4), Egypt (6), France (5), Germany (22), Greece (10), India (12), Iran (6), Ireland (2), Israel (3), Italy (47), Japan (13), Netherlands (1), New Zealand (1), Pakistan (1), Poland (2), Portugal (1), Serbia (1), Singapore (3), Slovakia (1), South Korea (18), Spain (4), Sweden (2), Switzerland (4), Thailand (1), Turkey (26), United Kingdom (11), and United States (82).

I January 28, 2014WJR|www.wjgnet.com

Yue-Qi Zhu, Shanghai

Croatia

Goran Kusec, Osijek

Denmark

Poul E Andersen, OdenseLars J Petersen, AalborgThomas Z Ramsoy, FrederiksbergMorten Ziebell, Copenhagen

Egypt

Mohamed F Bazeed, MansouraMohamed Abou El-Ghar, MansouraReem HA Mohamed, CairoMohamed R Nouh, AlexandriaAhmed AKA Razek, MansouraAshraf A Zytoon, Shebin El-Koom

France

Sabine F Bensamoun, CompiègneRomaric Loffroy, DijonStephanie Nougaret, MontpellierHassane Oudadesse, RennesVincent Vinh-Hung, Fort-de-France

Germany

Henryk Barthel, LeipzigPeter Bannas, HamburgMartin Beeres, FrankfurtIlja F Ciernik, DessauA Dimitrakopoulou-Strauss, HeidelbergPeter A Fasching, ErlanegnAndreas G Schreyer, RegensburgPhilipp Heusch, DuesseldorfSonja M Kirchhoff, MunichSebastian Ley, MunichAdel Maataoui, Frankfurt am MainStephan M Meckel, FreiburgHans W Muller, DuesseldorfKay Raum, BerlinDirk Rades, LuebeckMarc-Ulrich Regier, HamburgAlexey Surov, HalleMartin Walter, MagdeburgAxel Wetter, EssenChristoph Zilkens, Düsseldorf

Greece

Panagiotis Antoniou, ThessalonikiNikos Efthimiou, AthensDimitris Karnabatidis, PatrasGeorge Latsios, AthensStylianos Megremis, Iraklion

Alexander D Rapidis, AthensKiki Theodorou, LarissaIoannis A Tsalafoutas, AthensEvanthia E Tripoliti, IoanninaAthina C Tsili, Ioannina

India

Ritesh Agarwal, ChandigarhChandan J Das, New DelhiPrathamesh V Joshi, MumbaiNaveen Kalra, ChandigarhChandrasekharan Kesavadas, TrivandrumJyoti Kumar, New DelhiAtin Kumar, New DelhiKaushala P Mishra, AllahabadDaya N Sharma, New DelhiBinit Sureka, New DelhiSanjay Sharma, New DelhiRaja R Yadav, Allahabad

Iran

Majid Assadi, BushehrSeyedReza Najafizadeh, TehranMohammad Ali Oghabian, TehranAmir Reza Radmard, TehranRamin Sadeghi, MashhadHadi Rokni Yazdi, Tehran

Ireland

Tadhg Gleeson, WexfordFrederik JAI Vernimmen, Cork

Israel

Dafna Ben Bashat, Tel AvivAmit Gefen, Tel AvivTamar Sella, Jerusalem

ItalyAdriano Alippi, RomeDante Amelio, TrentoMichele Anzidei, Rome Filippo F Angileri, MessinasStefano Arcangeli, RomeRoberto Azzoni, San Donato milaneseTommaso V Bartolotta, PalermoTommaso Bartalena, ImolaLivia Bernardin, San BonifacioFederico Boschi, VeronaSergio Casciaro, LecceEmanuele Casciani, RomeMusa M Can, NapoliAlberto Cuocolo, NapoliMichele Ferrara, Coppito Mauro Feola, FossanoGiampiero Francica, Castel VolturnoLuigi De Gennaro, RomeGiulio Giovannetti, Pisa

Francesca Iacobellis, NapoliFormato Invernizzi, Monza BrianzaFrancesco Lassandro, NaplesLorenzo Livi, FlorencePier P Mainenti, NapoliLaura Marzetti, ChietiGiuseppe Malinverni, CrescentinoEnrica Milanesi, TurinGiovanni Morana, TrevisoLorenzo Monti, MilanSilvia D Morbelli, GenoaBarbara Palumbo, PerugiaCecilia Parazzini, MilanStefano Pergolizzi, MessinaAntonio Pinto, NaplesCamillo Porcaro, RomeCarlo C Quattrocchi, RomeAlberto Rebonato, PerugiaGiuseppe Rizzo, RomeRoberto De Rosa, NaplesDomenico Rubello, RovigoAndrea Salvati, BariSergio Sartori, FerraraLuca M Sconfienza, MilanoGiovanni Storto, RioneroNicola Sverzellati, ParmaAlberto S Tagliafico, GenovaNicola Troisi, Florence

JapanYasuhiko Hori, ChibaHidetoshi Ikeda, KoriyamaMasahito Kawabori, SapporoTamotsu Kamishima, SapporoHiro Kiyosue, YufuYasunori Minami, Osaka-sayamaYasuhiro Morimoto, KitakyushuSatoru Murata, TokyoShigeki Nagamachi, MiyazakiHiroshi Onishi, YamanashiMorio Sato, Wakayama ShiYoshito Tsushima, MaebashiMasahiro Yanagawa, Suita

Netherlands

Willem Jan van Rooij, Tilburg

New Zealand

W Howell Round, Hamilton

Pakistan

Wazir Muhammad, Abbottabad

Poland

Maciej S Baglaj, Wroclaw

II January 28, 2014WJR|www.wjgnet.com

Piotr Czauderna, Gdansk

Portugal

Joao Manuel RS Tavares, Porto

Serbia

Olivera Ciraj-Bjelac, Belgrade

Singapore

Gopinathan Anil, SingaporeTerence KB Teo, SingaporeCher Heng Tan, Singapore

Slovakia

Stefan Sivak, Martin

South Korea

Ki Seok Choo, BusanSeung Hong Choi, SeoulDae-Seob Choi, Jinju Hong-Seok Jang, SeoulYong Jeong, DaejeonChan Kyo Kim, SeoulSe Hyung Kim, SeoulJoong-Seok Kim, SeoulSang Eun Kim, SeongnamSung Joon Kwon, SeoulJeong Min Lee, SeoulIn Sook Lee, BusanNoh Park, GoyangChang Min Park, SeoulSung Bin Park, SeoulDeuk Jae Sung, SeoulChoongsoo Shin, SeoulKwon-Ha Yoon, Iksan

Spain

Miguel A De Gregorio, ZaragozaAntonio Luna, JaénEnrique Marco de Lucas, SantanderFernando Ruiz Santiago, Granada

Sweden

Dmitry Grishenkov, StockholmTie-Qiang Li, Stockholm

Switzerland

Nicolau Beckmann, BaselChristian Boy, BernGiorgio Treglia, Bellinzona

Stephan Ulmer, Kiel

Thailand

Sirianong Namwongprom, Chiang Mai

Turkey

Kubilay Aydin, IstanbulRamazan Akdemir, SakaryaSerhat Avcu, Ankara Ayse Aralasmak, IstanbulOktay Algin, AnkaraNevbahar Akcar, MeselikBilal Battal, AnkaraZulkif Bozgeyik, ElazigNazan Ciledag, AakaraFuldem Y Donmez, AnkaraGulgun Engin, IstanbulAhmet Y Goktay, IzmirOguzhan G Gumustas, BursaKaan Gunduz, AnkaraPelin Ozcan Kara, MersinKivanc Kamburoglu, AnkaraOzgur Kilickesmez, IstanbulFuruzan Numan, IstanbulCem Onal, AdanaOzgur Oztekin, IzmirSeda Ozbek (Boruban), KonyaSelda Sarikaya, ZonguldakFigen Taser, KutahyaBaran Tokar, EskisehirEnder Uysal, IstanbulEnsar Yekeler, Istanbul

United Kingdom

Indran Davagnanam, LondonM DC Valdés Hernández, EdinburghAlan Jackson, ManchesterSuneil Jain, BelfastLong R Jiao, LondonMiltiadis Krokidis, CambridgePradesh Kumar, LiverpoolPeter D Kuzmich, DerbyGeorgios Plataniotis, BrightonVanessa Sluming, Liverpool

United States

Garima Agrawal, Saint LouisJames R Brasic, BaltimoreRajendra D Badgaiyan, BuffaloUlas Bagci, BethesdaAnat Biegon, Stony Brook Ramon Casanova, Winston SalemWenli Cai, BostonZheng Chang, DurhamCorey J Chakarun, Long BeachKai Chen, Los AngelesHyun-Soon Chong, ChicagoMarco Cura, DallasRavi R Desai, BensalemDelia DeBuc, MiamiCarlo N De Cecco, Charleston

Timm-Michael L Dickfeld, BaltimoreSubba R Digumarthy, BostonHuy M Do, StanfordTodd A Faasse, Grand RapidsSalomao Faintuch, BostonGirish M Fatterpekar, New YorkDhakshinamoorthy Ganeshan, HoustonRobert J Griffin, Little RockAndrew J Gunn, BostonSandeep S Hedgire, BostonTimothy J Hoffman, ColumbiaMai-Lan Ho, San FranciscoJuebin Huang, JacksonAbid Irshad, CharlestonMatilde Inglese, New YorkEl-Sayed H Ibrahim, JacksonvillePaul R Julsrud, RochesterPamela T Johnson, BaltimoreMing-Hung Kao, TempeSunil Krishnan, HoustonRichard A Komoroski, CincinnatiSandi A Kwee, HonoluluKing Kim, Ft. LauderdaleGuozheng Liu, WorcesterYiyan Liu, NewarkVenkatesh Mani, New YorkLian-Sheng Ma, PleasantonRachna Madan, BostonZeyad A Metwalli, HoustonYilong Ma, ManhassetHui Mao, AtlantaFeroze B Mohamed, PhiladelphiaGul Moonis, BostonJohn L Nosher, New BrunswickRahmi Oklu, BostonAytekin Oto, ChicagoBishnuhari Paudyal, PhiladelphiaRajul Pandya, YoungstownChong-Xian Pan, SacramentoJay J Pillai, BaltimoreNeal Prakash, DuarteReza Rahbar, BostonAli S Raja, BostonGustavo J Rodriguez, El PasoDavid J Sahn, Portlsand Steven Schild, ScottsdaleAli R Sepahdari, Los AngelesLi Shen, IndianapolisJP Sheehan, CharlottesvilleAtul B Shinagare, BostonSarabjeet Singh, BostonCharles J Smith, ColumbiaKenji Suzuki, ChicagoMonvadi Srichai-Parsia, WashingtonSree H Tirumani, BostonHebert A Vargas, New YorkSachit Verma, PhiladelphiaYoichi Watanabe, MinneapolisLi Wang, Chapel HillCarol C Wu, BostonShoujun Xu, HoustonMin Yao, ClevelandXiaofeng Yang, AtlantaQingbao Yu, AlbuquerqueAifeng Zhang, ChicagoChao Zhou, BethlehemHongming Zhuang, Philadelphia

III January 28, 2014WJR|www.wjgnet.com

EDITORIAL91 Laserablationoflivertumors:Anancillarytechnique,oranalternativetoradiofrequencyandmicrowave?

Sartori S, Di Vece F, Ermili F, Tombesi P

REVIEW97 Complementaryrolesofinterventionalradiologyandtherapeuticendoscopyingastroenterology

Ray DM, Srinivasan I, Tang SJ, Vilmann AS, Vilmann P, McCowan TC, Patel AM

112 Three-dimensionalradiationdosimetryusingpolymergelandsolidradiochromicpolymer:Frombasicsto

clinicalapplications

Watanabe Y, Warmington L, Gopishankar N

ORIGINAL ARTICLE

Retrospective Study

126 ReportingrotatorcufftearsonmagneticresonancearthrographyusingtheSnyder’sarthroscopic

classification

Aliprandi A, Messina C, Arrigoni P, Bandirali M, Di Leo G, Longo S, Magnani S, Mattiuz C, Randelli F, Sdao S, Sardanelli F,

Sconfienza LM, Randelli P

Observational Study

134 Multimodalityimagingusingprotonmagneticresonancespectroscopicimagingand18F-fluorodeoxyglucose-

positronemissiontomographyinlocalprostatecancer

Shukla-Dave A, Wassberg C, Pucar D, Schöder H, Goldman DA, Mazaheri Y, Reuter VE, Eastham J, Scardino PT, Hricak H

143 Computedtomographypulmonaryangiographyusinga20%reductionincontrastmediumdosedelivered

inamultiphasicinjection

Chen M, Mattar G, Abdulkarim JA


Contents Monthly Volume 9 Number 3 March 28, 2017

� March 28, 2017|Volume 9|�ssue 3|WJR|www.wjgnet.com

Contents

NAMEOFJOURNALWorld Journal of Radiology

ISSNISSN 1949-8470 (online)

LAUNCHDATEJanuary 31, 2009

FREQUENCYMonthly

EDITORS-IN-CHIEFKai U Juergens, MD, Associate Professor, MRT und PET/CT, Nuklearmedizin Bremen Mitte, ZE-MODI - Zentrum für morphologische und moleku-lare Diagnostik, Bremen 28177, Germany

Edwin JR van Beek, MD, PhD, Professor, Clinical Research Imaging Centre and Department of Medi-cal Radiology, University of Edinburgh, Edinburgh EH16 4TJ, United Kingdom

Thomas J Vogl, MD, Professor, Reader in Health Technology Assessment, Department of Diagnos-tic and Interventional Radiology, Johann Wolfgang Goethe University of Frankfurt, Frankfurt 60590,

FLYLEAF

EDITORS FOR THIS ISSUE

Responsible Assistant Editor: Xiang Li Responsible Science Editor: Fang-Fang JiResponsible Electronic Editor: Dan Li Proofing Editorial Office Director: Xiu-Xia SongProofing Editor-in-Chief: Lian-Sheng Ma

Germany

EDITORIALBOARDMEMBERSAll editorial board members resources online at http://www.wjgnet.com/1949-8470/editorialboard.htm

EDITORIALOFFICEXiu-Xia Song, DirectorWorld Journal of RadiologyBaishideng Publishing Group Inc8226 Regency Drive, Pleasanton, CA 94588, USATelephone: +1-925-2238242Fax: +1-925-2238243E-mail: [email protected] Desk: http://www.wjgnet.com/esps/helpdesk.aspxhttp://www.wjgnet.com

PUBLISHERBaishideng Publishing Group Inc8226 Regency Drive, Pleasanton, CA 94588, USATelephone: +1-925-2238242Fax: +1-925-2238243E-mail: [email protected] Desk: http://www.wjgnet.com/esps/helpdesk.aspxhttp://www.wjgnet.com

PUBLICATIONDATEMarch 28, 2017

COPYRIGHT© 2017 Baishideng Publishing Group Inc. Articles published by this Open-Access journal are distributed under the terms of the Creative Commons Attribu-tion Non-commercial License, which permits use, dis-tribution, and reproduction in any medium, provided the original work is properly cited, the use is non commercial and is otherwise in compliance with the license.

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ABOUT COVER EditorialBoardMemberofWorldJournalofRadiology ,SamerEzziddin,MD,PhD,Professor,KlinikfürNuklearmedizin,UniversitätsklinikumdesSaarlandes,66421Homburg,Germany

World Journal of Radiology (World J Radiol, WJR, online ISSN 1949-8470, DOI: 10.4329) is a peer-reviewed open access academic journal that aims to guide clinical practice and improve diagnostic and therapeutic skills of clinicians.

WJR covers topics concerning diagnostic radiology, radiation oncology, radiologic physics, neuroradiology, nuclear radiology, pediatric radiology, vascular/interventional radiology, medical imaging achieved by various modalities and related methods analysis. The current columns of WJR include editorial, frontier, diagnostic advances, therapeutics advances, field of vision, mini-reviews, review, topic highlight, medical ethics, original articles, case report, clinical case conference (clinicopathological conference), and autobi-ography.

We encourage authors to submit their manuscripts to WJR. We will give priority to manuscripts that are supported by major national and international foundations and those that are of great basic and clinical significance.

World Journal of Radiology is now indexed in PubMed, PubMed Central.

I-III EditorialBoard

AIM AND SCOPE

��

World Journal of RadiologyVolume 9 Number 3 March 28, 2017

INDEXING/ABSTRACTING

�� March 28, 2017|Volume 9|�ssue 3|WJR|www.wjgnet.com

Sergio Sartori, Francesca Di Vece, Francesca Ermili, Paola Tombesi

EDITORIAL

91 March 28, 2017|Volume 9|Issue 3|WJR|www.wjgnet.com

Laser ablation of liver tumors: An ancillary technique, or an alternative to radiofrequency and microwave?

Sergio Sartori, Francesca Di Vece, Francesca Ermili, Paola Tombesi, Section of Interventional Ultrasound, St Anna Hospital, 44100 Ferrara, Italy

Author contributions: Sartori S, Di Vece F, Ermili F and Tombesi P contributed equally to this paper with conception and design of the study, literature review and analysis, drafting and critical revision and editing, and final approval of the final version.

Conflict-of-interest statement: The authors declare no conflict of interest.

Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/

Manuscript source: Invited manuscript

Correspondence to: Sergio Sartori, MD, Section of Inter-ventional Ultrasound, St Anna Hospital, via A. Moro 8, 44100 Ferrara, Italy. [email protected]: +39-0532-239480Fax: +39-0532-239613

Received: July 31, 2016Peer-review started: August 2, 2016First decision: September 28, 2016Revised: December 23, 2016Accepted: January 11, 2017Article in press: January 14, 2017Published online: March 28, 2017

AbstractRadiofrequency ablation (RFA) is currently the most popular and used ablation modality for the treatment of

non surgical patients with primary and secondary liver tumors, but in the last years microwave ablation (MWA) is being technically improved and widely rediscovered for clinical use. Laser thermal ablation (LTA) is by far less investigated and used than RFA and MWA, but the available data on its effectiveness and safety are quite good and comparable to those of RFA and MWA. All the three hyperthermia-based ablative techniques, when performed by skilled operators, can successfully treat all liver tumors eligible for thermal ablation, and to date in most centers of interventional oncology or interventional radiology the choice of the technique usually depends on the physician’s preference and experience, or tech-nical availability. However, RFA, MWA, and LTA have peculiar advantages and limitations that can make each of them more suitable than the other ones to treat patients and tumors with different characteristics. When all the three thermal ablation techniques are available, the choice among RFA, MWA, and LTA should be guided by their advantages and disadvantages, number, size, and location of the liver nodules, and cost-saving con-siderations, in order to give patients the best treatment option.

Key words: Radiofrequency ablation; Liver neoplasm; Laser ablation; Microwave ablation; Hepatocellular carcinoma; Liver metastases

© The Author(s) 2017. Published by Baishideng Publishing Group Inc. All rights reserved.

Core tip: Radiofrequency ablation, microwave ablation, and laser thermal ablation, when performed by skilled operators, can successfully treat all liver tumors eligible for thermal ablation. However, each of them has pecu-liar advantages and limitations that can make one technique more suitable than the other ones to treat patients and tumors with different characteristics. When all the three techniques are available, the choice should be guided by their advantages and disadvantages, number, size and location of the liver nodules, and cost-


Submit a Manuscript: http://www.wjgnet.com/esps/

DOI: 10.4329/wjr.v9.i3.91

World J Radiol 2017 March 28; 9(3): 91-96



Sartori S et al . Laser ablation of liver tumors

saving considerations, in order to give patients the best treatment option.

Sartori S, Di Vece F, Ermili F, Tombesi P. Laser ablation of liver tumors: An ancillary technique, or an alternative to radiofrequency and microwave? World J Radiol 2017; 9(3): 91-96 Available from: URL: http://www.wjgnet.com/1949-8470/full/v9/i3/91.htm DOI: http://dx.doi.org/10.4329/wjr.v9.i3.91

INTRODUCTIONTemperatures in excess of 60 ℃ are known to cause relatively instantaneous cell death, and thermal ablation by heating neoplastic tissue to cytotoxic temperatures is becoming increasingly important for treating primary and secondary liver cancer[1]. Radiofrequency ablation (RFA) is currently the most popular and used ablation modality, but in the last years microwave ablation (MWA) is being technically improved and widely rediscovered for clinical use[2-6]. RFA energy is delivered as an alternating current at a frequency of about 400 MHz, resulting in molecular frictional agitation and heat generation known as the joule effect[1,7]. Tissues nearest to the electrode are heated directly, while more peripheral areas are less effectively heated by thermal conduction[8]. MWA is a special case of dielectric heating where the dielectric material is tissue containing water. MWA induces a high-speed (between 900 and 2450 MHz) alternating electric field, causing the rotation of water molecules and generating heat[1,7,9,10]. In contrast to RFA, energy radiates into the tissue with direct heating of the lesion, and charring and vaporization in the proximity of the needle are not obstacles to the delivery of energy[10,11].

The effectiveness and limits of RFA have widely and extensively been reported worldwide. Due to the physical limitations in energy deposition, the effectiveness of RFA in local tumor control decreases with the increase of tumor size[10]. Local control rates over 90% have been reported for nodules up to 3 cm in diameter, and only 6%-10% for tumors greater than 5 cm[12]. Moreover, tumor location close to large vessels can also influence ablation success, because thermal energy is partially shunted away by the cooler blood (the so-called heat-sink effect)[13,14].

The recent technical developments of MWA tech-nology, such as the introduction of a cooling jacket around the MWA antenna and a miniaturized device for MW confinement into the distal portion of the antenna, have minimized the main limits of the earlier MWA systems, allowing for the reduction of back heating effects, increase of the ablation time, and amount of power that can be safely delivered[2,6]. Due to these technical improvements and the characteristics of heat production and energy delivery[9-11], MWA has recently been reported to achieve larger ablation areas than RFA[3,4,15], and appears to be less susceptible to the heat-sink effect[10,11].

Most studies investigating the effectiveness of MWA were conducted before the introduction into clinical practice of the most recent advancements in MWA technology, and at present the best available evidence suggests similar outcomes for RFA and MWA. Reported three- and 5-year survival rates of Child’s class A patients with single hepatocellular carcinoma (HCC) less than 5 cm, or up to three HCC less than 3 cm, range from 60% to 78%, and from 50% to 64%, respectively, for RFA[16-18], and from 72% to 73%, and 51%-57%, respectively, for MWA[19,20]. The outcomes of RFA and MWA in patients with up to 6 metastases from colorectal cancer with a maximum diameter of 6 cm are also comparable, with 3-year survival rates of 28%-46% and 46%-51%, respectively, and 5-year survival rates of 25%-46% and 17%-32%, respectively[21-24].

LASER THERMAL ABLATION - WHY CINDERELLA?However, there is a third hyperthermia-based ablation technique, which uses laser optical fibers to deliver high-energy laser radiation to the tissue. Because of light absorption, temperatures of up to 150 ℃ are reached, leading to coagulative necrosis[7,9,11]. Neodymium:Yttrium Aluminum Garnet (Nd:YAG, wavelength of 1064 nm) and diode (wavelength of 800-980 nm) lasers are most commonly used, as penetration of light is optimal in the near infrared spectrum. Light is delivered via flexible quartz fibers with a diameter from 300 to 600 µm. Conventional bare-tip fibers provide an almost spherical thermal lesion of 12-15 mm in diameter, and a beam-splitting device or a multi-source device allow for the use of up to four fibers, simultaneously delivering the light into each single fiber[11,25,26]. Moreover, interstitial quartz fibers with flat or cylindrical diffusing tips have been reported to achieve larger ablation areas[9]. Laser-induced interstitial thermotherapy is a special form of laser technique that uses a unique saline-cooled power laser application system to increase the volume of coagulative necrosis while preventing carbonization at the tip of the laser applicator[10]. The device consists of a 9 French catheter with centimetre markings and a 7 French sheathed catheter with irrigated double lumina. Room temperature saline is used as the irrigation fluid, and a pump is integrated with the laser. This permits reliable cooling of the applicator and expansion of the laser-induced necrosis zone, resulting particularly useful for the treatment of liver metastases that require large safety margins to take care of microscopic disease around the lesions[27].

Laser thermal ablation (LTA) is by far less investigated and used than RFA and MWA, but the available data on its effectiveness and safety are quite good. Most of the studies on LTA are focused on the treatment of HCC. Complete response rates ranging from 82% to 97%, and cumulative 3-year survival rates up to 73% were reported in Child’s class A patients with single HCC ≤ 5


cm or up to three nodules ≤ 3 cm treated with multiple bare fibers[28,29]. Moreover, median survival of 3.5 years was achieved in patients with nodules ≤ 5 cm located at high-risk sites by using water-cooled higher power LTA[30]. To date, there are in literature just two randomized trials comparing LTA and RFA in the treatment of HCC, and both of them did not find any significant difference between the two techniques in terms of local tumor control, overall survival, and safety[31,32]. A multicenter study investigating the safety of LTA in five hundred-twenty patients with 647 HCC treated by 1004 LTA sessions reported mortality and major complication rates of 0.8% and 1.5%, respectively[33]. Likewise, also the outcomes of patients with liver metastases from colorectal cancer with diameter up to 5 cm treated with LTA appear comparable to those reported for RFA and MWA, with 3- and 5-year survival rates ranging from 28% to 72.4%, and from 10% to 37%, respectively[9,34-36].

Despite these excellent results, LTA is frequently not considered an effective ablation technique, and the vast majority of reviews, consensus, or position papers dealing with the efficacy or safety of thermal ablation of liver tumors does not even mention LTA among the ablative techniques that are to date available[1,10,37-41].

We do not agree with such an attitude. Although it is true that LTA has been investigated less vigorously than the other ablation techniques, it is also true that the relatively low number of published studies dealing with LTA seems to be due to an unjustified prejudice, rather than to an actual lower efficacy of LTA in comparison with RFA or MWA. All the three hyperthermia-based ablative techniques, when performed by skilled operators, can successfully treat all liver tumors eligible for thermal ablation, and to date in most centers of interventional oncology or interventional radiology the choice of the technique usually depends on the physician’s preference and experience, or technical availability. However, in our opinion RFA, MWA and LTA have peculiar advantages and limitations that can make each of them more suitable than the other ones to treat patients and tumors with different characteristics. For instance, RFA is surely the best established thermal technique, and its efficacy has been largely proven, but lesions larger than 2-2.5 cm require multiple overlapping ablations to create an adequate safety margin, and sub-capsular or high-risk location of the tumors is considered a relative contraindication to RFA, even though some reports documented its feasibility[42,43]. Moreover, tumors strictly close to large vessels can be incompletely treated because of the heat-sink effect. MWA has less sensitivity to the heat-sink effect, deeper penetration of energy and better propagation across the poorly conductive tissue than RFA, and can achieve larger ablation volumes. On the other hand, microwave energy is more difficult to distribute than RF energy, is carried in wavelengths which are more cumbersome than the small wires used to feed energy to RF electrodes, and are prone to heating when carrying large amount of power[11]. Consequently, MWA appears less feasible than RFA in the treatment of high-

risk located and sub-capsular nodules. Moreover, the latest versions of MWA devices provided with the most recent technical advances are more expensive than RFA.

As regards LTA, the technique proposed by Pacella et al[28] and improved by Di Costanzo et al[44] uses 300-µm bare optical fibers introduced into the tumor through 21-gauge needles. The diameter of the needles is considerably smaller than RFA electrodes and MWA antennas, making LTA safer and more suitable for ablating lesions in at-risk location or in locations that are difficult to reach[11,45]. Moreover, a multisource device allows to use from one to four fibers at once, enabling to achieve ablation areas from one to 4-5 cm in diameter, and consequently to treat tumors ranging from 5-6 mm to 3 cm in diameter obtaining an acceptable safety margin. Furthermore, in western countries LTA has been reported to be the cheapest ablation technique when up to three fibers are used, and cheaper than MWA when four fibers are used[11]. For these characteristics, LTA has been proposed as a valid alternative to RFA for lesions up to 2 cm[46], and it has been suggested as the technique of choice in presence of multiple small and variably sized liver tumors[45]. On the other hand, the correct placement of the fibers can be challenging, particularly if more than two fibers are needed, and should be performed by very skill operators[11]. Moreover, like RFA, also the efficacy of LTA can be limited by the heat-sink effect.

FINAL CONSIDERATIONSIn the last years, multimodality anti-tumor strategies including surgery, chemotherapy, radiotherapy, ablation techniques, and catheter-based treatments are being more and more advocated, to tailor the best treatment options to patient and tumor characteristics[45,47-49]. Such an approach is often adopted not only to choose the most suitable treatment options, but also to choose the most suitable technique available for each treatment option. For instance, patients candidate to catheter-based treatments can undergo bland embolization, transarterial chemoembolization with lipiodol or with drug-eluting beads, or radioembolization, according to the type of tumor, liver function, and presence or absence of portal venous thrombosis. Likewise, patients candidate to liver surgery can undergo wedge resection, segmentectomy, lobectomy, or transplantation according to the liver function, and number, size, and location of the tumors.

In our opinion, the choice among the thermal ablation techniques should also be based on the same criteria whenever possible. Some authors suggested that the reference centers for thermal ablation should be equipped with all the available techniques so as to be able to use the best and the most suitable one for each type of tumor[26]. Recently, an algorithm has been proposed to tailor thermal ablation on each single patient, according to advantages and disadvantages of RFA, MWA and LTA, number, size, and location of the liver nodules, and cost-saving considerations (Figures 1 and 2)[11]. On the basis of this algorithm, all the three ablation techniques have



a preferential role in some specific circumstances. For instance, a single nodule 2 cm or smaller in size can be

efficaciously treated using all the thermal modalities, but RFA and LTA are cheaper than MWA and should

Single nodule

≤ 2 cm 2-3 cm ≥ 3 cm

HCC LM Consider combined treatments

Close to

large vessels?MWA

Yes No

MWAHigh risk location?

Yes No

LTA RF/LTA

Figure 1 Algorythm proposed by Tombesi et al[11] for thermal ablation of single liver tumor. HCC: Hepatocellular carcinoma; MWA: Microwave ablation; LTA: Laser thermal ablation; RF: Radiofrequency.

Multiple nodules

Close to large vessels?

Yes No

MWA1-2 nodules

≤ 2 cm

≥ 3 nodules≤ 2 cm

≥ 3 nodules2-3 cm

≥ 3 nodules≥ 3 cm

High risk location? LTA HCC LM MWA

Yes No LTA MWA

LTA LTA (RFA)

Consider combined treatments

Figure 2 Algorythm proposed by Tombesi et al[11] for thermal ablation of multiple liver tumors. HCC: Hepatocellular carcinoma; MWA: Microwave ablation; LTA: Laser thermal ablation; RFA: Radiofrequency ablation.



be preferred. Conversely, MWA should be considered the technique of choice when the tumor is ≥ 3 cm in diameter or is close to large vessels independently of its size, as MWA can achieve larger ablation volumes and is not affected by the heat-sink effect. Multiple small and variably sized lesions should be treated with LTA, and so on (Figures 1 and 2). This algorithm reflects the personal experience and opinion of the authors, and it can surely be modified and improved. However, it is also based on objective considerations that can largely be shared, and in our opinion it could represent the basis for a consensus on the optimal and reasoned use of the thermal ablation modalities.

In conclusion, at present there is no ideal ablation technique that outclasses the other ones. There are ablation techniques that share some main technical aspects and are usually comparable, but each of them has peculiar characteristics that make it the “ideal” technique in some particular settings. We believe we should exploit such peculiarities to give patients the best treatment option.

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P- Reviewer: Oto A, Vogl TJ S- Editor: Kong JX L- Editor: A E- Editor: Li D


David M Ray, Indu Srinivasan, Shou-jiang Tang, Andreas S Vilmann, Peter Vilmann, Timothy C McCowan, Akash M Patel

REVIEW


Complementary roles of interventional radiology and therapeutic endoscopy in gastroenterology

David M Ray, Timothy C McCowan, Akash M Patel, Department of Radiology, Division of Interventional Radiology, University of Mississippi Medical Center, Jackson, MS 39216, United States

Indu Srinivasan, Shou-jiang Tang, Division of Digestive Diseases, Department of Medicine, University of Mississippi Medical Center, Jackson, MS 39216, United States

Andreas S Vilmann, Peter Vilmann, GastroUnit, Division of Endoscopy, Copenhagen University Hospital Herlev, 2730 Herlev, Denmark

Author contributions: All authors were involved in the planning the design and conduct of the review paper, and equally in revising the manuscript and approving the final version; the initial research was conducted by Ray DM and Srinivasan I; Ray DM, Srinivasan I, Patel AM and Tang SJ were involved in drafting the manuscript.

Conflict-of-interest statement: Drs. David M Ray, Indu Srinivasan, ShouJiang Tang, Andreass S Vilmann, Timothy C McCowan, and Akash M Patel have no conflict of interest or financial to disclose related to this review. Peter Vilmann is a consultant at MediGlobe GmbH, Grassau, Germany.

Open-Access: This article is an openaccess article which was selected by an inhouse editor and fully peerreviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BYNC 4.0) license, which permits others to distribute, remix, adapt, build upon this work noncommercially, and license their derivative works on different terms, provided the original work is properly cited and the use is noncommercial. See: http://creativecommons.org/licenses/bync/4.0/


Correspondence to: Akash M Patel, MD, Department of Radiology, Division of Interventional Radiology, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS 39216, United States. [email protected]: +16019840454

Received: July 28, 2016 Peer-review started: July 31, 2016First decision: September 2, 2016Revised: November 12, 2016Accepted: January 11, 2017Article in press: January 14, 2017Published online: March 28, 2017

AbstractAcute upper and lower gastrointestinal bleeding, enteral feeding, cecostomy tubes and luminal strictures are some of the common reasons for gastroenterology service. While surgery was initially considered the main treatment modality, the advent of both therapeutic endoscopy and interventional radiology have resulted in the paradigm shift in the management of these conditions. In this paper, we discuss the patient’s work up, indications, and complementary roles of endoscopic and angiographic management in the settings of gastrointestinal bleeding, enteral feeding, cecostomy tube placement and luminal strictures. These conditions often require multidisciplinary approaches involving a team of interventional radio-logists, gastroenterologists and surgeons. Further, the authors also aim to describe how the fields of inter-ventional radiology and gastrointestinal endoscopy are overlapping and complementary in the management of these complex conditions.

Key words: Gastrointestinal hemorrhage; Enteral nutrition; Interventional radiology; Gastroenterology; Endoscopy


Core tip: This paper reviews the current information and dissects the similarities, differences, and complementary roles of gastroenterologists and interventional radiologists



DOI: 10.4329/wjr.v9.i3.97




Ray DM et al . Complementary roles of IR and GI

in the management of various luminal gastrointestinal conditions such as gastrointestinal bleeding, enteral feeding, placement of cecostomy tubes and strictures. We discuss the multidisciplinary approach, indications, contraindications and management of these conditions in an attempt to provide an educational experience for all your esteemed readers.

Ray DM, Srinivasan I, Tang SJ, Vilmann AS, Vilmann P, McCowan TC, Patel AM. Complementary roles of interventional radiology and therapeutic endoscopy in gastroenterology. World J Radiol 2017; 9(3): 97111 Available from: URL: http://www.wjgnet.com/19498470/full/v9/i3/97.htm DOI: http://dx.doi.org/10.4329/wjr.v9.i3.97

INTRODUCTIONVarious gastrointestinal (GI) diseases such as acute GI bleeding, esophageal strictures, strictures associated with inflammatory bowel disease and enteral feedings were traditionally managed by the surgeons alone. However, surgery has been associated with high morbidity and mortality rates, thus leading on to a search for other modalities that were less invasive and equally or better efficacious. Though the first endoluminal visualization of the stomach was performed by Kussmaul in 1868, it was not until 1958 that the first fiberscope was introduced by Hirschowitz et al[1]. From then, the field of endoscopy has evolved rapidly with various innovations such as charged couple devices, video chip to hemostatic clips, biopsy forceps, snares, banding kit, etc. These innovations have expanded the horizons of endoscopy, changing it from a mere diagnostic tool to one of therapeutics. Endoscopists are now able to treat GI bleeding, perform biopsies, remove polyps, dilate strictures, place stents and feeding tubes. Similar to gastroenterology, the field of interventional radiology (IR) has had its share of technological advances. Fluoroscopy advanced during the early 1900s. The first angioplasty by Dotter in 1964 was a landmark in vascular interventions[2]. Embolization, angioplasty, and other fluoroscopic guided techniques significantly advanced have also decreased the need for first line surgery in many patients[2,3].

Interventional endoscopy and radiology are two minimally invasive disciplines that overlap and complement one another in the care of multiple complex GI disease processes. Acute GI bleeding is a common presentation to the emergency room which can be life threatening. Management of this often times requires a collaboration between a gastroenterologist, radiologist, and a surgeon. However, with the advent of therapeutic endoscopy and interventional radiology, in many cases, the role of surgery is now limited to technically challenging cases not amenable to endoscopic or radiological intervention. Though few articles addressing the need for multidisciplinary approach in treating GI bleeding have been published, there is a paucity of literature for other

above mentioned conditions. Thus, in this article we hope to not only outline the role of endoscopists and radiologists in managing various GI conditions but also their complementary roles to overcome their individual short comings. Since this is an expansive topic we will be only focusing on endoluminal conditions such as GI bleeding, access for enteral nutrition, cecostomy tube placement and strictures. Hepatobiliary pathology including variceal bleeding, portal hypertensive gastropathy, biliary drainage, endoscopic ultrasound (EUS) guided internal drainage, EUS guided celiac block and tissue biopsy will be described elsewhere.

lITeRaTURe ReSeaRCHWe conducted an English literature review of the various GI topics. Searches were performed for GI hemorrhage with respect to management, endoscopy and interventional radiology. Searches for hemorrhage were further subdivided into upper and lower GI bleeding. Similar review was performed for enteral feeding, cecostomy tubes, and stricture management. Further literature was reviewed by evaluating references. Also, since many patients are complex and require the opinion of several specialists in the outpatient and emergent setting, the authors added the opinion of our institution when appropriate.

Acute upper GI bleedAcute life threatening GI bleeding once considered a surgical emergency with significant mortality continues to have a high mortality rate despite tremendous advances made in endoscopic and radiographic techniques. The incidence of GI bleeding tends to increase with age and ranges between 37 and 172/100000 adults[4,5]. It has been reported to account for approximately 350000 hospital admissions per year in the United States alone[6]. Rebleeding following interventions remains relatively high at reported rates of 7%16%[4]. It is a frequent presenting symptom to the hospital and requires management by a multidisciplinary team comprising of gastroenterologists, surgeons, interventional radiologists, and anesthesiologists[7].

GI bleeding is usually arbitrarily divided between upper and lower bleeds. Upper GI bleed constitutes any bleed that originates in the GI tract proximal to ligament of Treitz while anything distal constitutes a lower GI bleed. Upper GI hemorrhage may manifest as hematemesis, coffee ground emesis, bloody return through nasogastric tube or feeding tube, melena or as brisk hematochezia with hemodynamic compromise. Lower GI bleeding usually presents as melena (if from the right colon or distal small bowel) or hematochezia. The most common cause of nonvariceal upper GI bleed is peptic ulcer disease[8]. Other etiologies include neoplasms, inflammation, iatrogenic, trauma, ischemia, and vascular malformations (such as Dieulafoy’s lesions and angioectasis) with more than one diagnosis noted in 16%20% of cases[4].

When a patient presents to the emergency room with


GI bleeding, initial assessment must be made to ensure hemodynamic stability of the patient and determine the need for urgent intervention. Resuscitation with crystalloids and blood transfusion must be performed. In patients suspected with nonvariceal upper GI bleed, proton pump inhibitors must be initiated as they reduce the chances of finding high risk stigmata during endoscopy[9]. If the patient is stable enough to undergo upper endoscopy, then it must be performed next as it can be both diagnostic and therapeutic. The patient is placed in a left lateral position with head bend forward to facilitate the insertion of the endoscope. At the time of upper endoscopy, there are various endoscopic treatment modalities available to help achieve hemostasis. Traditionally, endoscopic therapy has been broadly categorized into injection, thermal and mechanical methods.

Injection therapyInjection therapy includes administration of epinephrine (1:10000) around the bleeding vessel. This was first described by Soehendra et al[10]. In 1988, Chung et al[11] presented the first randomized trial comparing injection therapy to medical therapy in 68 patients and reported reduced surgery, transfusion requirements and shorter hospital stay in the group with injection therapy. This is performed by placing multiple aliquots of 0.5 to 1 mL of diluted epinephrine (1:10000) 1 to 2 mm away from the bleeding vessel. This technique works by a combination of tamponade and transient vasoconstriction. Typically, 5 mL can be administered in one setting but on occasion as high as 25 mL have also been administered with no significant side effects except transient tachycardia. However, it should be avoided in patients with active ongoing cardiac ischemia. After injection of epinephrine blanching of the surrounding mucosa is noticed. Studies[12,13] have demonstrated that epinephrine alone is effective, but epinephrine in combination with another endoscopic modality is superior to epinephrine alone. This is most likely due to its transient duration of action.

More recently hemostatic powders have gained popularity. These are designed to be delivered via a catheter passed through the accessory channel of the endoscope. Hemospray is an inorganic powder that is metabolically inert and nontoxic. This acts in two ways; the first is upon coming in contact with water it forms a stable mechanical barrier over the vessel and stops the bleeding. Secondly, it acts by increasing the local concentration of clotting factors and promoting clot formation[14]. The adherent clot that it forms sloughs off within 24-72 h and is eliminated from the GI tract[15]. In 2011, Sung et al[15] conducted a pilot study in 20 patients with active peptic ulcer bleeding. Hemostasis was achieved in all but one patient (95%). It has also proven to be efficacious in tumor related bleeding[16] given its ease of application to large surfaces even in difficult positions. In a small study, Holster et al[17] evaluated the efficacy of this novel technique in patients on antithrombotic agents and concluded that endoscopic hemostasis by Hemospray is not decreased by systemic antithrombotic effects such

as Plavix, aspirin, or vitamin K antagonists. Thus, though initial reports are fascinating, further trials with larger populations are needed.

THeRMal MeTHODSThermal devices can be divided into contact devices such as heater probe and bipolar probe and noncontact devices such as argon plasma coagulation (APC). Contact probes are ideal for bleeding vessels that are less than 2 to 3 mm in size. The goal of a contact probe is to apply firm pressure on the visible vessel to interrupt the blood flow and then to apply enough heat to weld the walls of the vessel together[18]. Heater probes contain a nonstick Teflon coated heating element directly delivering heat to the vessel. It also contains three irrigation ports on the sides to wash out the clots and allow better visualization of the vessel. The heat is then delivered for a preset amount of time by tapping the coagulation pedal. For the treatment of actively bleeding ulcer four pulses of 30 Joules must be applied[18].

Bipolar probes work by delivering electrical current from an electrosurgical generator to electrodes situated at the tip of the probe. Tissue coagulation is obtained indirectly by conversion of electrical energy to heat energy. Similar to heater probes they also contain a water channel which is, however, centrally located. Unlike the heater probe coagulation time is determined by the amount of time the endoscopist presses the coagulation foot pedal. For bleeding peptic ulcers, a setting of 20 watts for a contact period of 7 to 10 s is suggested[19]. APC is a noncontact monopolar thermal method which acts by delivering high frequency electrical current conducted via argon gas (that has been ionized) to the tissue. This method, however, produces superficial coagulation only, and once the tissue gets desiccated, it loses its electrical conductivity. Hence, the maximum depth is about 3 mm to 4 mm which is a safety feature to prevent deep tissue injury. The probe can be circu-mferential, end or side fearing, and should be held 12 mm away from the target. However, owing to its superficial effect it is not routinely used for peptic ulcer disease.

MeCHaNICal MeTHODSMechanical hemostasis can be achieved by causing a physical tamponade of the bleeding site. Currently two types of instruments are widely used: Clips and banding kits. The use of through-the-scope clips was first reported in 1975 by Hayashi et al[20] for endoscopic hemostasis. Since then, tremendous improvements have been made in both the clip designs and their deployment devices. They are either single use clips or reusable clips which can be rotated, closed and reopened multiple times. They are deployed over the bleeding vessel and act by clamping the bleeding point. They slough off within few days to weeks. They are most beneficial for accessible lesions that do not have a hard fibrotic base. Based on



historical data, the vessel should be ≤ 2 mm in size. Recently, overthescope clipping devices have become available and can be applied to larger vessels. Banding devices are mostly used for esophageal varices, which will not be discussed in this review.

EtiologiesThe two most common etiologies for peptic ulcers include nonsteroidal antiinflammatory drugs and helicobacter pylori infection. These are easily visualized at the time of endoscopy, and certain endoscopic features such as active bleeding, spurting arterial vessel, adherent clot and nonbleeding visible vessel, predict high rate of rebleeding and hence require endoscopic therapy and/or interventional embolization therapy[21]. While treating a high risk stigmata ulcer, it is recommended that injection therapy should not be used alone as studies[12,13] demonstrated that the combination therapy of epinephrine with clips or thermal devices was superior to injection alone. APC have not been demonstrated to be useful in peptic ulcer bleeding. Through-the-scope Hemoclips and contact thermal devices have found to be equally efficacious in treating vessels less than 2 mm in size[22]. Placing a clip may be challenging in difficult to access locations such as the posterior wall of the duodenal bulb where contact thermocoagulation should be attempted. In cases with oozing without a visible vessel monotherapy is adequate. Treating ulcers with adherent clots is challenging as metaanalysis[22] has shown conflicting results regarding endoscopic treatment vs medical management.

Dieulafoy’s lesions which are characterized by a large submucosal vessel eroding through the mucosa and then rupturing were first described almost a hundred years ago. Endoscopically it is identified when there is visible or an active bleeding vessel with no ulcer. Treatment is usually similar to actively bleeding vessel in peptic ulcer disease and includes injection therapy, clips, banding devices, heater probe and bipolar probe. Studies have shown that monotherapy with injection should not be attempted. Bipolar probes should be set at 20 watts and applied for 10 to 12 s, and heater probes should be set

at 30 joules and 4 pulse should be administered.Mallory Weiss tears are usually selflimited bleeds

and do not need endoscopic therapy. However, in the presence of ongoing active bleeding clips are preferred, though other devices such as band devices and electrocautery have also been reported[23,24]. The settings for bipolar and heater probes include 15-20 watts for 4 s and 1520 joules for 3 pulses respectively. However, there are no trials comparing the various treatment modalities.

Angioectasias and gastric antral vascular ectasias (GAVE) usually cause chronic and obscure GI bleeding. These are usually treated with APC. The probe should be set at 45 watts with 1 L/min argon flow rate for vascular ectasia; whereas for GAVE, 60 watts with 1 L/min is applied for deeper tissue penetration. Though other previously mentioned methods have been used, there are again no prospective comparison trials.

However, despite the advances made in therapeutic endoscopies there are still certain instances where we fail to achieve hemostasis endoscopically. Thus, it is important to realize the limitations of various modalities and be aware of other options that we may have. Large bleeding vessels more than 2 mm to 3 mm in size, or high stigmata ulcer in posterior wall of the duodenal bulb may not be amenable to endoscopic intervention. Rarely interventions in such instances may fuel a massive GI bleed requiring IR intervention (Figures 13).

Pre-intervention imagingIf a patient is stable enough during presentation and plans are not made for immediate endoscopy, preprocedure imaging can be performed to attempt localization of the culprit vessel or other underlying etiologies. Computerized tomography (CT) scanning is readily available in many centers and can tolerate patients with a tenuous clinical picture due to the speed of image acquisition. Multiphasic CT is usually performed without contrast followed by three contrasted series of images in the arterial, venous, and delayed phases to assist in localizing the bleed. A positive study occurs when there is contrast extravasation into the bowel lumen or identification of an abnormal vessel, mass, or other underlying etiology; the same is true for conventional catheter based angiography[8,25]. CT angiography can detect bleeds with a reported sensitivity of 0.5 cc/min of active extravasation which is compared to the sensitivity of catheter arteriography rate of detection of at least 1 cc/min[25].

Another imaging modality for patients is technetium labeled red blood cell scintigraphy. In this study, patient’s red blood cells are tagged with technetium and imaged for 6090 min. Pooling of radiotracer is considered to be positive. Typical rates of bleeding required for detection of bleeding have been reported between 0.050.5 cc/min[25]. A benefit of this study is the ability to detect arterial or venous bleeding; a disadvantage, in turn, becomes the lack of precisely identifying the location of the bleed. Sensitivity and specificity of this study are 91% and 95%

Figure 1 Endoscopic image showing a large ulcer in the superior wall of the bulb with a large visible vessel. Attempted endoclip placement after epinephrine injection resulted in major bleeding and a loss of endoscopic view and patient was then emergently transferred to interventional radiology.



respectively and are improved with increasing volume of extravasation[25].

As mentioned earlier, if endoscopy is unsuccessful at either identifying or stopping the bleeding source, transcatheter arteriography is the next step at intervention. Typically, the femoral artery is used as the site for arterial access unless other factors prevent this approach; however, radial approach is an alternative which has been gaining interest at some centers[26]. If upper GI bleeding is suspected, the celiac artery is usually cannulated first[8]. Superselective evaluations are performed based on any prior studies used to help localize the location of the bleed. If a culprit vessel is identified, multiple methods of embolization have been described[8,27]. Patient breathing causes motion which can make visualization of bleeding difficult on angiography. Also, bowel gas and bowel movement can cause further limitations during catheter angiography.

There are many different techniques for embolization and controlling active hemorrhage. These include placing covered stents, endovascular coils/plugs, and embolic glue. In some instances, the microcatheter used to evaluate the culprit vessel will occlude and stop the hemorrhage temporarily. This can be utilized in temporary situations to spasm an artery to achieve hemostasis without per

manently occluding an artery. Care must be taken to evaluate the vasculature in the region of bleeding as many sites in the GI tract have collateral blood flow. In sites that have collateral flow, a sandwich technique can be utilized; this requires identifying the bleeding site and embolizing the distal and proximal side branches to provide occlusion ensuring no distal reconstitution and decreasing chances of rebleeding[8].

In some instances, patients are too hemodynamically unstable to obtain imaging and may need to go directly to the angiography suite or the endoscopy lab. Close communication between the emergency room physicians, anesthesiologists, surgeons, gastroenterologists, and interventional radiologists must be encouraged in order to provide optimal care for these critically ill patients. One important caveat to consider regarding angiography over endoscopy as a first line intervention is that angio-graphy will only be positive if there is active bleeding, an abnormal vessel, or tumor blush. Also, active bleeding with high clinical suspicion of the approximate location of a bleed can be an appropriate indication of taking the patient directly to angiography in order to identify and treat the site of bleeding as active bleeding may terminate during the time taken to obtain imaging[28]. Hyperemia can be identified by angiography but subtle

A B

Figure 2 During interventional angiography, selected fluoroscopic images showing a pseudoaneurysm of the gastroduodenal artery (A, red arrow) that was successfully coiled with subsequent hemostasis via the sandwich technique (B). Previously placed Endoclip is visible and can act as a fluoroscopic marker during angiography.

A B

Figure 3 Fluoroscopic images of a case of 2-3 cm bleeding duodenal ulcer that failed endoscopic hemostasis with Endoclip application. A: Fluoroscopic image following contrast injection to the right gastric artery showing active extravasation into the lumen. The bleeding vessel (red arrow) is identified which is near the endoscopically placed clip; B: Digital subtraction angiography post coiling of the right gastric artery (green arrow).



mucosal abnormalities will be more readily identified with endoscopic management. Additionally, in cases of high risk ulcers which have had either successful or unsuccessful endoscopy, catheter arteriography has been shown to play a key role in preventing rebleeding by performing prophylactic embolization[29]. Surgical consultation is always recommended and performed at our hospital.

aCUTe lOweR GI bleeDINGAcute lower gastrointestinal bleeding is defined as bleed-ing of recent duration (< 3 d), hemodynamic instability, anemia or requirement of blood transfusion[30]. Though most lower GI bleeds resolve spontaneously, mortality and morbidity is increased in elderly patients and those with comorbid medical conditions[31]. Bleeding rate and total blood loss become a critical factor in determining correct patient management. Initial management and assessment is similar to upper GI bleeds. A multidisciplinary approach is crucial for providing the best care for these critically ill patients.

Lower GI bleeding accounts for approximately 30% of all GI hemorrhage and has many etiologies[32]. The most common causes of lower GI bleeding are diverticula, angiodysplasia, anorectal neoplasm, and colitis[32,33]. The incidence increases with age with mean age of presentation ranging from 63 to 77 years of age. It has been estimated that lower GI bleeding is 200 times more likely in an 80 years old than a 20 years old[32]. Although bleeding can be life threatening, unlike upper GI bleeding, most cases of lower bleeding tend to be selflimited. Of the cases considered a lower bleed, the colon is the source in approximately 80% of cases[28]. Many patients with bleeding associated with diverticulosis can stop spontaneously in up to 80% of patients[32,33]. Mortality rates have been reported at less than 5%[34].

Initial management includes determination of the need for urgent evaluation and resuscitation with crystalloids and blood products and correction of coagulation factors in applicable. If stable, imaging plays a key role in

identifying the source and etiology of the bleeding. As stated previously, CT and tagged red blood cell scintigraphy are excellent noninvasive options to assist with acute management decisions (Figures 4 and 5). Other useful tools in the management of patients with small bowel bleeding distal to the ligament of Treitz include capsule endoscopy and CT enterography to evaluate for a specific lesion or site of bleeding. Though diagnostic testing helps to localize the lesion, studies have shown that the diagnostic yield of colonoscopy ranges from 45% to 100%[34] which is higher than radiological evaluation. If stable enough, patients should undergo urgent colonoscopy within 8 to 24 h of admission as that improves diagnostic yield and likelihood of therapeutic intervention. This was also demonstrated by Strate and Syngal[35] in 2003 where they studied 144 patients and concluded that endoscopic therapy was successful in 29% of colonoscopies performed within 12 h and this dropped to 4% when performed between 24 to 48 h. These patients need to undergo rapid purge prep which involves drinking 1L of Golytely every 30 to 45 min until no fecal matter is noted in the effluent[36]. However, performing a colonoscopy at the time of active significant bleeding is often not useful as the bleeding impairs visualization in the colon; this is in contrast to angiography, which usually requires active extravasation to detect the hemorrhage. The various hemostatic devices are similar to the one discussed in the upper GI bleeding section. In cases of intermittent scant hematochezia, if hemodynamically stable, healthy individual less than 40 years of age can be considered for flexible sigmoidoscopy[37].

Diverticular bleeding accounts for 20% to 65% of acute lower GI bleeds[32] and causes significant bleeding in 3% to 15%[38] of the cases (Figure 6). The bleeding is characterized as painless hematochezia which stops simultaneously in 75% to 80% of the cases but recurs in about 25% to 40% of the cases within 4 years[38]. Endoscopic management involves using clipping or thermal

Figure 4 A male patient presented with massive bright red blood per rectum which was unresponsive to transfusions. A representative computed tomography scan image demonstrates active contrast extravasation in the rectum (white arrow).

Figure 5 During interventional angiography, contrast extravasation is visualized into the colon via a distal branch artery from the internal iliac artery (white arrow). The culprit vessel was occluded by spasm or dissection at the ostium with no residual active bleeding. During follow-up lower endoscopy, an endoscopic image showed no active bleeding with discrete large sized clean based ulcers, consistent with ischemic colitis.



contact modalities either alone or in conjugation with injection technique. Due to thinner walls of the right sided colon, perforation is a concern. Endoclip placement is often preferred to treat the bleeding or visible vessel at the neck or bottom of the diverticulum. If thermal methods are used care should be taken to apply lower setting for short periods of time only. Typically 10-15 joules (heater probe) or 10 to 16 watts (bipolar) should be applied for 2 to 3 second pulse contacts and mild pressure[39,40]. Endoscopic clips can be either deployed over the bleeding vessel or use to oppose the walls to act as a tamponade effect and prevent bleeding[41]. Kaltenbach et al[42] described using EndoCap to evert the diverticulum and placing the clip.

Ischemic colitis affects about 1% to 19% of the cases[35] and typically presents as painful hematochezia[43] affecting the water shed areas of the colon: Splenic flexure and rectosigmoid junction. The majority of patients respond to conservative management and treatment of the underlying condition. Angiography is recommended in patients with severe ischemic colitis, right sided colitis or suspicion of underlying thromboembolism or concurrent mesenteric ischemia[44]. Radiation proctitis is caused by radiation induced endarteritis obliterans with resultant telangiectasia and neovascularization in the rectum[45]. Effective treatment includes serial management with APC.

The other etiologies for colitis such as Clostridium difficile colitis, inflammatory bowel disease, viral, bacterial and parasitic infections, diversion colitis can also present with hematochezia and usually managed by treating the underlying conditions.

Angioectasias account for 3% to 15% of cases with lower GI bleeding[30], and their incidence also increase with age[46]. They range from 2 mm to several centimeters and are characterized by ectatic blood vessels radiating from a central feeding vessel[46]. Though both contact and non-contact thermal methods are used for its treatment, APC is the preferred treatment modality[47]. Owing to thin walls of the right side of the colon power settings of 15 W to 30 W at 1 L/min argon flow rate is utilized. Short pulses of 1 to 2 s are applied and the probe is held 1 to 3 mm

away from the mucosa[40]. Lee et al[48] in 2010 described application of Hemoclips in conjugation with APC to control bleeding.

Hemorrhoids are present in 75% of colonoscopies[46] but are indicated in only 2% to 10% of acute lower GI bleeds[49]. Bleeding hemorrhoids are usually managed with banding devices. Like esophageal varices they are also conducted in series with no more than 3 bands placed in one setting.

Management of rectal ulcers and Dieulafoy’s lesion are similar to upper GI bleeds and achieved by thermal or mechanical methods or dual therapy, including injection technique. Hence, as stated above most cases of lower GI bleeding are selflimited, but occasionally patients may present with massive GI bleeding where they are too unstable to undergo colonoscopy or despite drinking the prep the colon is still filled with blood obscuring endoscopic evaluation. In such cases, it is IR that can prove invaluable. Surgery is typically reserved as a last resort since even with location identified mortality is high, and mortality increases when the bleed cannot be localized.

Angiography is similar regarding lower GI bleeds compared to upper bleeds. A major advantage compared to colonoscopy is that no bowel prep is needed. Typically, the interventional radiologist will begin with the superior mesenteric artery (SMA) as this will be the major supply to the distal small bowel, ascending and transverse colon. The inferior mesenteric artery (IMA) supplies the descending sigmoid colon as well as the rectum and anus. Branches of the internal iliac artery also supply the rectosigmoid colon and anus and become the main supply in cases of an occluded or diminutive IMA. Many collaterals and normal anatomic variants exist which must be evaluated prior to any interventions[28]. For instance, the SMA may provide arterial supply to the entire colon in the event the IMA is occluded via the arc of Riolan or marginal artery of Drummond which are arterioarterio anastomoses between the superior and inferior mesenteric arteries[50].

Ideally, a selective embolization is performed if the etiology is discovered by angiography. When distal

A B C

Figure 6 Fluoroscopic images of a case of colon diverticular bleeding that failed endoscopic hemostasis with Endoclip application. A: Active extravasation at the site of the clip (red arrow); B: Ongoing extravasation superior to the clip after initial coils placed in the inferior branch of the middle colic artery; C: Digital subtraction angiography following additional coils with no extravasation.



branches are able to be cannulated, the risk of developing colonic ischemia is low and perhaps subclinical. Other methods such as vasospasm can prove useful to maintain normal blood flow while clot and hemostasis develop as demonstrated in Figures 4 and 5.

GaSTROSTOMY TUbeThough feeding tubes have been in place for over 400 years it was not until 1980 that the first description of percutaneous endoscopic gastrostomy tube was attempted by Gauderer et al[51]. Subsequently, in 1981 the first percutaneous gastrostomy tube was placed under radiological guidance[52]. This was initially developed for cases where endoscopy could not be performed or was too risky to be attempted[52,53]. Since then, these two approaches have widely replaced surgical open gastrostomy owing to its minimally invasive nature, reduced cost and ease of tube placement[54]. These tubes are not only used for feeding but can also be used for decompression. Typical indications for gastrostomy tube are for providing nutrition in patients with an inability to obtain adequate nutrition but with intact and functional GI tract. Impaired swallowing mechanism associated with neurological conditions and neoplastic conditions of the oropharynx, larynx and esophagus are some of the common indications[55,56]. It can also be performed to attain gastric decompression in patients with gastroparesis or obstruction such as peritoneal carcinomatosis.

Absolute contraindications to this procedure are an uncorrectable coagulopathy, thrombocytopenia, peritonitis, or bowel ischemia. Large gastric varices, if known, can pose an increased risk of internal hemorrhage. Ascites or peritoneal dialysis is a relative contraindication given potential for pericatheter leakage and life threatening peritonitis respectively. In these patients, paracentesis can provide assistance to make the procedure safe[57]. In peritoneal dialysis patients, the procedure should be discussed with patient’s nephrologist. Contraindications specific for endoscopic placement include inability to bring the gastric wall in apposition with the anterior abdominal wall, facial fractures, skull fractures and upper GI obstruction[58]. In these cases, radiologically placed gastrostomy tube is preferred. Specific contraindications to radiologically placed feeding tubes include inability to travel to the radiology suite in patients with hemodynamic instability[58]. Also, prior gastric surgery can make the anatomical window smaller and more challenging suggesting the need for CT guidance[55,56].

For percutaneous endoscopic gastrostomy tube placement, there are currently three techniques: (1) “pull” or PomskyGauderer technique[51]: This involves insufflating the stomach and selecting an appropriate site by indenting the abdominal wall with a finger. Sterile precautions should then be followed and the site anesthetized with lidocaine. Subsequently the needle is advanced in to the stomach while withdrawing the plunger. The endoscopist confirms that the gastric puncture of

the needle corresponds to the air in the syringe. This is essential to ensure the absence of any intervening bowel. A small skin incision is made and trocar is introduced into the stomach. A guidewire is then fed through the trocar and grasped endoscopically and pulled out through the mouth along with the endoscope. The feeding tube is then attached to the guidewire and pulled through the esophagus, stomach and abdominal wall and held in place by both internal and external bumper; (2) “push” or Sacksvine technique[59]. This technique is similar to pull technique till the guidewire is placed. Then an introducer tube is threaded over the guidewire and pushed till it emerges through the abdominal wall and then is grasped manually and secured in position; and (3) introducer technique or Russell technique[60], this was developed in 1984 and has recently gained popularity to be used in cases with head and neck cancer to avoid seeding of the gastrostomy tract[61]. This uses a transabdominal approach. In this technique once the access to stomach is obtained endoscopically, gastropexy is performed next using either T fasteners[62] or gastropexy sutures[63]. Subsequently, the stomach is accessed with a needle and a guidewire. The tract is then dilated with a dilating catheter and finally a balloon tip gastrostomy catheter is placed into the stomach through the peel away sheath.

Interventional radiological gastrostomy tube can be placed with either fluoroscopic, CT, or ultrasound guidance. These procedures can be performed with excellent success rates[55]. Success typically depends on the appropriate anatomic window in order to make a percutaneous approach into the stomach. Previous cross sectional imaging is utilized to evaluate for appropriate anatomical window for gastrostomy tube placement. Patients are administered barium orally or via nasogastric/orogastric tube at least 12 h prior to the procedure in order to opacify the transverse colon. Upon the patient entering the IR suite, a nasogastric tube is inserted if not already present. At our institution, we then use ultrasound to evaluate the liver margin and outline prior to the procedure. The insertion site is chosen below the costal margin, above the transverse colon, and to the left of midline. Some institutions, including ours, will administer 0.51 mg of intravenous glucagon to inhibit gastric motility during the procedure. The stomach is then insufflated with air. Gastropexy is next performed with T-fasteners in order to apply the stomach to the abdominal wall. An incision is then made between the gastropexy sutures. A needle is inserted into the stomach which is confirmed by aspirating air at an angle directed towards the pylorus. Care must be taken during these next steps to ensure the stomach remains insufflated with air; typically, a technologist will assist with insufflating air as needed. A wire is then inserted and the tract is dilated to the appropriate tube size. The gastrostomy tube is then inserted by using a peelaway sheath. Gastrostomy tubes may have a pigtail or balloon to secure within the stomach; we use tubes with balloons for securing the tube location. Contrast is then injected and both AP and lateral fluoroscopic views obtained to ensure the tube has been placed into the



stomach only and is secured to the abdominal wall. This procedure is illustrated in Figure 7. Occasionally, this method will be adjusted and performed under CT guidance for patients with a narrow anatomic window. Percutaneous sonographic gastrostomy which was initially described by Gebel et al[64] in 1991 for patients with upper GI tract obstruction is yet another technique. This procedure is currently not widely performed in United States, though is still popular in Europe. This process involves passage of a nasogastric tube into the stomach, followed by instillation 500 to 1500 cc of water. The stomach is then localized by ultrasound. The puncture site into the stomach is identified after establishing absence of vessels and colon or small intestine interposition with ultrasound and Doppler. A small skin incision is made, and a needle is introduced into the stomach. A wire is then passed through the stomach into the duodenum. The puncture site is then dilated with serial dilators and gastrostomy tube placed. In 1998 Bleck et al[65], reported successful placement of feeding tube in 38 patients via this method with no major complications reported in a 4 mo follow-up period. Major complications can include internal hemorrhage, catheter dislodgement, peritonitis/sepsis, or death. Minor complications are catheter leakage and clogging requiring exchange.

Thus, though studies have proven them to have equal success rates with both endoscopic and radiological tube placement, each procedure has a distinct advantage over the other[66]. With endoscopic placement, the procedure can be performed at the bed side and have diagnostic capabilities. In a study published in 1990, 10%71%

of patients were found to have abnormal endoscopy findings out of which management had to be altered in 36% of patients[67]. Also the endoscopic procedure reduces the radiation exposure. Meanwhile, radiological placement is possible in patients who fail endoscopic management such as those who are morbidly obese or have severe upper GI luminal narrowing[68]. Hence it is of utmost importance that practitioners are aware of these indications so that the patient can be sent to appropriate discipline for gastrostomy tube placement.

CeCOSTOMY TUbeSCecostomy tubes can be placed surgically or percutaneously with endoscopic or image guidance[69]. These tubes are mainly indicated in patients with neurological disorder with resultant fecal incontinence to facilitate cleansing enemas[70], in the assistance of bowel training in the pediatric population, neurogenic bowel due to any issue, chronic colonic pseudo obstruction and colonic obstruction[71]. The contraindications are similar to ga-strostomy tube[72,73].

Placement of a percutaneous endoscopic cecostomy tube is similar to endoscopic percutaneous gastrostomy tube placement[74]. The night before the procedure 4 liters of Golytely is administered to clean the colon. In patients with chronic constipation more prolonged prep may be needed[75]. The colonoscope is then advanced all the way to the cecum which is insufflated. An appropriate site is selected by finger indentation in the right lower

A B

C D

Figure 7 Selected fluoroscopic images demonstrating fluoroscopically guided gastrostomy placement. A: Contrast seen throughout the transverse colon; B: The first T-tac (white arrow) is deployed following needle insertion into the gastric lumen; C: Two more T-tacs placed; D: Static lateral image of the gastrostomy tube against abdominal wall and not in the colon. The contrast is injected into the tube to demonstrate intraluminal placement.



quadrant and transillumination is performed. The rest of the procedure is similar to percutaneous endoscopic gastrostomy tube placement via the “pull” technique. The cecum needs to be fixed to the abdominal wall with the help of a “fixation” device to prevent leakage of the fecal content[69].

IR can perform these procedures either under fluoroscopic or CT guidance. The bowel will be prepped prior to the procedure similar to endoscopic procedures. Similar to gastrostomy tubes, the colon is insufflated with air and glucagon administered to decrease bowel contractions. A needle is inserted, T-tacks used to secure the position of the cecum, a wire inserted with subsequent dilation, and a tube is then inserted. This has been reported as a safe procedure although not commonly performed at our institution[72]. Though only small case series have been described, the procedure is easily performed and has a good success rate. However, the complication rate has been reported to be as high as 42% and includes wound infection, bleeding, perforation leading to peritonitis and buried bumper syndrome[76]. Buried bumper syndrome (BBS) which is a wellknown complication of gastrostomy tube placement, occurs due to excessive outward traction on the tube. In 2011 Rao et al[77] described its occurrence in a patient who had undergone percutaneous endoscopic cecostomy tube placement about 1.5 years prior to the presentation. BBS usually presents with peristomal cellulitis owing to the presence of intraluminal stool. If the tract is immature, BBS can lead to fecal peritonitis and intraabdominal sepsis. Management involves antibiotics and removal of the tube. Cecostomy tubes should not be removed by external traction as it can lead to colonic laceration. Instead, the tube should be cut externally and removed endoscopically with the help of a snare. This complication can potentially be prevented with the usage of balloon tube or by avoiding excessive traction. In 2006, Uno[78], described the introducer technique to reduce the incidence of wound infection. In 2015, Duchalais et al[79] published a prospective trial to evaluate the efficacy of constipation in patients undergoing percutaneous endoscopic cecostomy tube placement and reported successful results in three quarters of the patient population. However, chronic wound pain prompted the removal in the other one fourth of the patient population. Currently there are no trials comparing the efficacy of endoscopic and fluoro-scopically placed percutaneous cecostomy tubes.

STRICTUReSEsophageal strictures are routinely seen in practice. The common causes include peptic strictures which develop as a sequel to GERD and account for almost 80% of benign strictures[80]. Their incidence seems to be decreasing in recent years with the more widespread use of proton pump inhibitors. Other causes include: Schatzki’s ring, radiation, caustic injury, anastomotic stricture, pill induced esophagitis, esophageal web, eosinophilic esophagitis

and malignancy[81]. They can be further divided into simple and complex strictures[82]. Simple strictures are symmetric, < 2 cm in length, with a diameter of greater than equal to 12 mm, and allow easy passage of an upper endoscope. Complex strictures, however, are asymmetric, have a diameter < 12 mm, more than > 2 cm long, and do not allow the passage of the scope. Most of these strictures are amenable to treatment with dilation and stent placement which can be done both endoscopically and radiographically.

These patients present with dysphagia and should undergo initial endoscopic evaluation as that not only helps in diagnosis but can also aid in performing possible therapeutic intervention such as dilation[83]. Further, they can also assess to see if they are any predisposing factors such as angulated stricture, diverticula, and hiatal hernia which may increase the risk of complications. Most benign strictures respond to dilation unlike malignant strictures which have a greater risk of complications[84]. Active esophageal perforation is an absolute contraindication to dilation[85]. There are currently three types of dilators: Maloney bougie (without a guidewire), savoryGilliard (passed over a guidewire) and through the scope (TTS) balloon dilators[86]. Prior to dilation, the endoscopist should consider the method of dilation, the diameter to which the obstruction should be dilated, need for wire guidance and need for radiographic screening[85]. Benign esophageal strictures are usually dilated to about 13 to 15 mm. However Schatzki’s ring can be dilated to about 16 to 20 mm[85]. Maloney dilators range from 16F to 60F and exert both longitudinal and radial force. This can be done blindly or under fluoroscopic guidance. These dilators can also be used for self-dilation without sedation[82]. Patients with benign esophageal stricture requiring frequent dilations are ideal candidates for self-dilation. The Maloney dilator is usually marked at two points: 20 cm from the entry site and 10 cm beyond the distal end of the stricture. The procedure is performed with the patient in sitting position. The dilator is lubricated with water and introduced over the tongue into the oropharynx. Once the patient visualizes the 20 cm marking, the tube is in the esophagus. The dilator is then advanced until the second marking is seen at the level of incisors, which confirms the passage of maximal diameter of the dilator across the stricture. Lastly, the dilator is carefully withdrawn.

Similarly, Savory dilators also range from 16F to 60F and have the same mechanism of action. The rigid tip is passed over a guidewire. They are also marked with radiopaque band at their maximal diameter. The guidewire is usually passed to the antrum and can be done endoscopically or fluoroscopically. Subsequently, the dilator is passed over the guidewire till the maximal diameter is beyond the stricture. If no force is experienced, then the dilator is slowly removed in one to one exchange manner to ensure the positioning of the guidewire. This uses tactile perception to determine the amount of resistance encountered. Sequential dilation is performed but usually in one setting no greater than



3 dilators are passed though studies have shown no increased risks with passing > 3 dilators in cases of a benign simple esophageal stricture[87]. TTS balloons work by exerting only radial force. They can usually increase up to 3 diameters and are useful for serial dilations with a single balloon. The endoscope is usually positioned proximal to the stricture and the balloon dilator is advanced through the stricture. The balloon is then inflated under direct endoscopic visualization and the pressure is held for 30 to 60 s.

Studies have shown similar efficacy in treating peptic strictures via any of the above mentioned methods[88,89]. In the treatment of postesophagectomy anastomotic strictures these methods show a similar efficacy of 93%; however, they have a high recurrence rate and need multiple sessions[90,91]. Though most procedures are performed under endoscopic guidance, fluoroscopy is important in the setting of complex strictures as it aids in dilation[85]. Further in cases where an endoscope is unable to cross proximal lesions, fluoroscopic dilation must be performed.

Fluoroscopic or other image guided balloon dilatation has been described in the literature as a safe method for stricture treatment of the esophagus in various disease states[92,93]. However, this has not been a common procedure in our IR department. In cases of refractory benign strictures, steroid injection into the stricture prior to dilation has shown to be effective in increasing post dilation diameter, reducing the need for repeat dilation and increasing the interval between dilations. Temporary esophageal stenting is also an option. A systemic review published regarding the use of plastic stents in benign esophageal strictures reported successful dilation in 52% of the cases. However, stent migration was reported in 24% of the population[94]. Song et al[95] in 2000 published a study where fully covered metal stents were placed in 25 patients, but migration was noted in 80% while 48% of them developed a new stricture. Few studies[96,97] have also been published regarding the use of biodegradable stents without promising results.

Similar to the upper GI tract, patients with inflammatory bowel disease are known to develop strictures. This is more common in Crohn’s disease where 40% of patients with ileal disease develop strictures[98]. Further studies demonstrate that 60% of patients with strictures would undergo surgery within the next 20 years[99]. Strictures in Crohn’s disease can occur de novo, at the site of bowel anastomosis, or at the ileal pouch. They can be divided into inflammatory vs fibrotic[100]. Inflammatory strictures can be treated with medical management. However, fibrotic strictures were traditionally treated with only surgical management[101]. Studies have shown that stricturoplasty tends to preserve bowel length and is associated with high recurrence rate leading to frequent operations. In younger adults, the course tends to be more aggressive leading to frequent operations and finally short bowel syndrome[102]. Endoscopic managements have been devised in an attempt to reduce this dreaded complication. Prior to any therapy

endoscopic evaluation and biopsy, assessment of the stricture must be performed to rule out malignancy especially in the setting of ulcerative colitis. Endoscopic management includes dilation therapy, local injection of steroids, needleknife stricturotomy and stent placement[103]. The technique of balloon dilation (TTS) is similar to the one described for esophageal stricture. Endoscopic balloon dilation has shown to both avoid or delay the need for surgery, though frequent dilations may be needed. In a systemic review published by Hassan et al[104] in patients with Crohn’s disease related strictures, endoscopic dilation achieved success in 86% of the patients with long term clinical efficacy obtained in 56% of them. In a multivariate analysis, stricture length of < 4 cm was the only predictor for surgery free follow up period. The mean adverse events (perforation and bleeding) were less than 2%. In 2010, Mueller et al[105] published a prospective single center study of 55 patients. They reported an initial success rate of 95% with 76% of those patients not requiring surgery during the followup period. Given the high relapsing rate, addition of steroid injection to the stricture at the time of dilation has been studied. However, currently the data is conflicting[106,107]. More recently stent placement at the time of endoscopy in this patient population has been evaluated. However, studies using selfexpandable metallic stents (SEMS)[108] and biodegradable stents[109] have reported high rates of stent migration and other adverse events. In 2012 Loras et al[110] published a small series of 25 SEMS placement with technical success obtained in 92% of the stent placements that was maintained for a 4 wk follow-up period.

Similar to upper GI strictures, fluoroscopic guided balloon dilatation and/or stent placement has also been described for the lower GI tract for patients as a presurgical or palliative relief[111,112]. Typically, the procedure involves placing the patient supine on the fluoroscopy table. A wire is then inserted through the anus retrograde to the level of the obstruction. Once the wire passes the obstruction and is proximal, a catheter is inserted for the purpose of water soluble contrast injection. This step is critical to evaluate the dimensions of the stent and type of delivery system used. Appropriate stents should cover the lesion with 12 cm extension beyond the obstruction. Covered stents are not recommended due to risk of migration[111]. Watersoluble contrasted enema can be repeated immediately or any time after the procedure to evaluate placement. However, this is also another procedure not commonly performed in our IR department.

CONClUSIONAdvances in the medical field have been to the advantage of the patient in many disease processes as discussed above. In today’s era of minimally invasive procedures, surgery as a first choice of management is getting less popular. Therapeutic endoscopy and interventional radiology have come a long way from their



initial inception to being main modalities of treatment. Treatment modality of choice is often based on avail-ability of the services, clinical stability of the patients and their presentation. However, these are complex patients that often require close collaboration between gastroenterologists, radiologists and surgeons.

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P- Reviewer: Andersen PE, Francica G, Lassandro F S- Editor: Kong JX L- Editor: A E- Editor: Li D


Yoichi Watanabe, Leighton Warmington, N Gopishankar

REVIEW


Three-dimensional radiation dosimetry using polymer gel and solid radiochromic polymer: From basics to clinical applications

Yoichi Watanabe, Leighton Warmington, Department of Radiation Oncology, University of Minnesota, Minneapolis, MN 55455, United States

N Gopishankar, All India Institutes of Medical Sciences, Delhi 110029, India

Author contributions: Watanabe Y wrote the article; Warmington L provided the data and reviewed the manuscript; Gopishankar N reviewed the manuscript and made suggestions for improvement.

Conflict-of-interest statement: Authors declare no conflict of interests for this article.



Correspondence to: Yoichi Watanabe, PhD, Department of Radiation Oncology, University of Minnesota, 420 Delaware St. SE, MMC494, Minneapolis, MN 55455, United States. [email protected]: +1-612-6266708Fax: +1-612-6267060

Received: October 10, 2016 Peer-review started: October 13, 2016First decision: November 30, 2016Revised: December 31, 2016 Accepted: January 16, 2017Article in press: January 18, 2017Published online: March 28, 2017

AbstractAccurate dose measurement tools are needed to evaluate the radiation dose delivered to patients by using modern and sophisticated radiation therapy techniques. However, the adequate tools which enable us to directly measure the dose distributions in three-dimensional (3D) space are not commonly available. One such 3D dose measurement device is the polymer-based dosimeter, which changes the material property in response to radiation. These are available in the gel form as polymer gel dosimeter (PGD) and ferrous gel dosimeter (FGD) and in the solid form as solid plastic dosimeter (SPD). Those are made of a continuous uniform medium which polymerizes upon irradiation. Hence, the intrinsic spatial resolution of those dosimeters is very high, and it is only limited by the method by which one converts the dose information recorded by the medium to the absorbed dose. The current standard methods of the dose quantification are magnetic resonance imaging, optical computed tomography, and X-ray computed tomography. In particular, magnetic resonance imaging is well established as a method for obtaining clinically relevant dosimetric data by PGD and FGD. Despite the likely possibility of doing 3D dosimetry by PGD, FGD or SPD, the tools are still lacking wider usages for clinical applications. In this review article, we summarize the current status of PGD, FGD, and SPD and discuss the issue faced by these for wider acceptance in radiation oncology clinic and propose some directions for future development.

Key words: Optical computed tomography; Three-dimensional dose measurement; Solid radiochromic polymer; Magnetic resonance imaging; Polymer gel




DOI: 10.4329/wjr.v9.i3.112




Watanabe Y et al . Three-dimensional radiation dosimetry

Core tip: Polymer gel and solid radiochromic polymer dosimeters are promising tools for measuring the radiation dose distributions in three-dimensional space. The techniques have been studied for last 20 years, but are not used for routine clinical applications to im-prove the radiation delivery quality. In this review, we summarize the current status and discuss the necessary development to make these tools more accessible for wider usages.

Watanabe Y, Warmington L, Gopishankar N. Three-dimensional radiation dosimetry using polymer gel and solid radiochromic polymer: From basics to clinical applications. World J Radiol 2017; 9(3): 112-125 Available from: URL: http://www.wjgnet.com/1949-8470/full/v9/i3/112.htm DOI: http://dx.doi.org/10.4329/wjr.v9.i3.112

INTRODUCTIONThe accurate quantification of radiation dose absorbed by the medium is the fundamental requirement in radiation physics. Particularly, when the radiation is used for medical purpose, the high accuracy of dose determination delivered to a patient is mandatory. In radiation therapy, the amount of the radiation dose absorbed by the tissue strongly correlates to the killing probability of both cancer cells and healthy cells[1]. Hence, the radiation must be delivered precisely to the planned location. The absolute dose can be very accurately measured by ion-chambers[2]; hence, it serves as a starting point for evaluating the overall accuracy of dose delivery methods. With the introduction of sophisticated technologies, for example, the intensity modulated radiation therapy (IMRT), the volumetrically modulated arc therapy (VMAT), and the stereotactic ablative radiation therapy, we can deliver the radiation dose distributed in an ideal three-dimensional (3D) shape with the maximum dose delivered to the cancer cells and the minimum dose to the healthy cells[3]. Many factors make the delivered dose very different from the ideal dose distributions. Therefore, the validation of the dose delivered to the patient in comparison to the planned dose is the most important task which one needs to perform before the actual application of the new technologies to patients.

A modern treatment planning requires sophisticated software, which can reproduce the actual radiation delivery and compute the radiation dose to the patient. The treatment planning system (TPS) uses the 3D model of the beam for the dose calculations. The beam data necessary for this process must be supplied by the users, who collect the data by using a 3D water scanning system consisting of a water phantom and an appropriate dosimeter. Hence, the main application of 3D dosimeters is the validation of the dose delivery technique through the comparison of the 3D dose distributions calculated by the TPS with the actual dose delivered to the patient or in a phantom that mimics the patient as a surrogate of the

patient.There are many measurement tools available for

characterizing the dose distribution in multi-dimensional space. One can move a point detector, such as an ionization chamber and a silicon diode in a 3D space to cover a volume of interest. An extension of this line of thought is to place many point detectors such as ionization chambers, silicon diodes, thermoluminescent detectors (TLD), in a line, or in the one dimension, and on a flat plane or curved surface in the two dimensions (2D). One of the limitations of this approach is the achievable spatial resolution. Note that the moving point detector method may be able to remedy this problem to some extent with longer measurement time.

The spatial resolution problem can be solved by using a real multi-dimensional detector such as radiographic and radiochromic films. The films can record the dose on a microscopic scale, but it requires specialized equipment to decipher the recorded dose information. The concept of these 2D dose measurement tools can be easily extended into the 3D space. Some materials change its material characteristics when they are irradiated. Hence, if we can build an appropriate instrument to convert the changes to the absorbed dose, we can measure the dose in 3D.

The Fricke ferrous sulfate dosimeter, a type of chemical dosimeters, was developed in early 20th century and was capable of recording the dose in a 3D space[4]. Besides the lack of adequate dose quantification method, the dosimeter suffered a major drawback because the recorded dose distribution quickly fades out due to the diffusion of the ferrous ions. The problem was finally solved by the invention of a non-ferrous solution such as the acrylamide-based polymer gel in the mid-1990s. The first of such material was the BANANA gel manufactured and sold by the MGS Research (now 3D Dosimetry Inc., Madison, CT, United States). Later the dosimeter went through a few cycles of improvement, and it is now available commercially as BANG from the same company. A major drawback of the first polymer gel dosimeter (PGD) was its high sensitivity to the oxygen contamination, which necessitated a hypoxic environment for the manufacturing, for example, in a glove box, and often lead to an incorrect radiation response in the area where the oxygen interacted with the gel. A solution to this problem was the introduction of polymer gels with much-reduced sensitivity to oxygen. The first of these was called MAGIC (Methacrylic and Ascorbic acid in Gelatin Initiated by Copper)[5]. Subsequently, many other groups developed variations of MAGIC. In the same time period, a 3D dosimeter in the solid form, the solid plastic dosimeter (SPD), was commercialized as PRESAGE (Heuris Inc., Skillman, NJ, United States)[6]. For the last 20 years, there have been very active research and development in the field of 3D dosimetry. In this review article, we summarize the current status of the 3D dosimeters and discuss the issue faced by these for wider acceptance in radiation oncology clinic and propose some directions for future development.


3D DOSIMETERHere we define 3D dosimeter as a dose measurement device, which can record the 3D dose distribution in a continuous medium. Consequently, the spatial resolution of this dosimeter is mostly determined by the read-out technique used with this dosimeter. In contrast, a dosimeter which is made of many point-like detectors at discrete points and a non-negligible distance among those can be called as pseudo 3D dosimeter. In this review, we will minimize the discussion on the pseudo 3D dosimeter. The following 3D dosimeters are currently available commercially or in research laboratories: The PGD; the Fricke gel dosimeter (FGD); the SPD.

Furthermore, we cannot ignore two other 3D do-simeters, scintillators, and Cherenkov-radiation detectors. The former is a rather old technology, but it has not gained much attention as a 3D dosimetry tool mostly because the material has mass density and effective atomic number very different from those of the water[7]. The Cherenkov detector has been studied by one group for last few years and has a potential to be an excellent 3D dosimeter[8], but it needs further extensive studies by many different investigators before clinical applications. Therefore, we focus on PGD, FGD and SPD in the rest of this article.

PGDPGD is composed of five chemical components: water, gelatin, monomer, catalyzer, and oxygen scavenger[9]. Note that the oxygen scavenger is added to make PGD more resistant to oxygen contamination. Such a PGD is called normoxic PGD or nPGD. Usually, we can group PGD/nPGD into two groups. Those with methacrylic as a monomer are called MAGAT/nMAG and those with acrylamide are called PAGAT/nPAG. There are many variations of those depending on the chemical agents. We summarized the MAGAT/nMAG and PAGAT/nPAG in Table 1. Notably, Vandecasteele et al[10] recently developed the radiochromic gel dosimeter (RGD), which is composed of 92% weight of water, gelatin, sodium dodecyl sulfate, trichloroacetic acid (CCl3COOH) and leuco-malachite green (LMG). The RGD was mainly developed to be used with an optical computed tomography (OCT) scanner as a read-out method[10]. The list is certainly incomplete, but can show a significant contribution from many investigators in many countries and demonstrate the international nature of this field. The photo in Figure 1 shows the PAGAT dosimeter. The white cloud in the center of the clear PAGAT gel contained in a cylindrical plastic container indicates the high radiation dose volume generated by a 6MV photon beam.

Dosimeter name Type Base Monomer Crosslinker Catalyzer/stabilizer

Scavenger/antioxidant

Key investigator

Country Ref.

BANANA PAG Agarose Acrylamide BIS Nitrous oxide Maryanski United States [58]BANG PAG Gelatin Acrylamide BIS Ammonium-

persulphate, TEMED

Maryanski United States [59,60]

BANG-2 PAG Gelatin MAA BIS Sodium Hydroxide

AA Maryanski United States [42]

BANG-3 MAG Gelatin MAA CuSO4-5H2O AA Maryanski United States [61]MAGIC MAG Gelatin MAA CuSO4-5H2O,

HydroquinoneAA Gore United States [5]

MAGAT MAG Gelatin MAA THPC Baldock Australia [62]nPAG PAG Gelatin Acrylamide BIS THPS De Deene Belgium [63]nMAG MAG Gelatin MAA THPS De Deene Belgium [63]nMAG MAG Gelatin MAA THP Ceberg Sweden [64]MAGIC-f MAG Gelatin MAA Formaldehyde CuSO4-5H2O AA Baffa Brazil [65]HEA Gelatin HEA BIS Baldock Australia [66]VIPAR Gelatin VIPAR BIS Pappas Greece [67]NIPAM Gelatin NIPAM BIS THPC Schreiner Canada [68]Genipin gel MAG Gelatin MAA, genipin Sulfuric acid Jordan Canada [69]LCV micelle radiochromic gel

Gelatin LCV, surfactant-Triton, TCAA

Formaldehyde Jordan Canada [70]

PAG PAG Gelatin Acrylamide BIS NaI THPC Elleaume France [71]nMAG nMAG Agarose,

GelatinMAA THPC Yoshioka Japan [72]

nMAG nMAG Gelatin HEMA, TGMEMA, 9G

THPC Hiroki Japan [73]

Radiochromic gel RGD Gelatin SDS, Chloroform, TCAA

LMG dye De Deene Australia [10]

Table 1 Summary of polymer gel dosimeter

BIS: N,N’-methylene-bis-acrylamide; MAA: Methacrylic acid; AA: Ascorbic acid; THPC: Tetrakis (hydroxymethyl) phosphonium chloride; THPS: Tetrakis (hydroxymethyl) phosphonium sulfate; NIPAM: N-isopropylacrylamide; LCV: Leuco crystal violet; TCAA: TriChloro Acetic Acid (CCl3COOH); VIPAR: N-vinylpyrrolidone argon; HEA: 2-hydroxyethylacrylate; HEMA: 2-hydroxyethyl methacrylate; TGMEMA: Triethylene glycol monoethyl ether monomethacrylate; 9G: Polyethylene glycol 400 dimethacrylate; SDS: Sodium dodecyl sulfate.



FGDFricke ferrous sulfate dosimeter is a type of chemical dosimeter. The radiation induces a chemical change as Fe2+ ions convert to Fe3+ ions[11]. The concentration of the ferric ions can be measured by absorption photo-spectrometry. Since the ferric ion concentration strongly affects its magnetic property, magnetic resonance imaging (MRI) is an ideal tool to determine the ferric ion distribution. Later, to prevent the diffusive motion of the ferric ions, which blurs the dose distribution, hydrogels were introduced as the background material[12,13]. Babic et al[13] used radiochromic ferrous xylenol orange with the Fricke gel so that it changes the color upon irradiation, allowing the utilization of an optical technique for 3D dose quantification. FGD is summarized in Table 2.

SPDThe SPD, often called a solid radiochromic dosimeter, is a new type of 3D dosimeters. Some plastic material such as polydiacetylene polymerizes when it interacts with photons. The characteristic of the photopolymerization can be amplified by adding coloring dye to produce a radiation responding medium. Radiochromic or gafchro-mic films were developed from this material. Those are commercially available as EBT series products (Ashland Inc., Covington, KY, United States). The same chemical principle can be realized in a 3D material. Adamovics et al[6] produced the first 3D radiochromic dosimeter based on polyurethane with LMG. The radiation sensitivity

was enhanced by adding chemical catalyzer such as chloroform[6]. This dosimeter is available commercially as PRESAGE and may contain proprietary ingredients. As shown in Table 3, there are only a few investigators who currently produce SPD in-house. Fortunately, the production of SPD is rather straightforward since there is a commercial product which was developed for artwork. A mixture of Clear Poly A and B (Smooth-On Inc., Easton, PA) can cast in any shape. By adding LMG, this material can be quickly turned into SPD[14]. Figure 2 shows the SPD manufactured in-house. The green bar vertically running in the middle of the cylindrical phantom indicates the beam path of 18 MV photons with 1 cm × 1 cm field size.

Water equivalencyOne of the requirements for a dosimeter is its ability to measure the dose absorbed by water in water[4]. The detectors, therefore, must be placed in a water equivalent medium, which includes the actual water, such as the 3D water scanning system, and a solid phantom that is equivalent to water such as the white water and solid water[15]. The equivalency, however, needs a special con-sideration when the atomic composition of the material is different from that of water. The actual equivalency of radiological characteristics means that the photon and electron scattering cross sections are the same as those of water for all energy of photons and electrons. This definition of water equivalency also applies to heavier charged particles such as protons and heavy ions. It is

Figure 1 The photo of PAGAT polymer gel dosimeter. Figure 2 The photo of solid plastic dosimeter.

Dosimeter Type Base Monomer Key investigator Country Ref.

Fricke Fluid None Ammonium ferrous sulfate Gore United States [11]FeMRI FGD Agarose Seaplaque, seagel Olsson Sweden [74]PVA-FX FGD Hydrogel PVA, FBX Chu Canada [75]FAX FGD Agarose XO, ferrous Leong Malaysia [76]FX FGD Gelatin Ferrous ammonium sulfate, XO, sulfuric acid Jordan Canada [70]PVA cryogel FGD Hydrogel FBX, PVA, dimethyl sulfoxide Eyadeh Canada [77]XO-PVA FGD Hydrogel PVA, XO, ferrous sulfate, sulfuric acid Trapp Australia [78]NC-FG FGD Gelatin Nano-clay, ammonium iron (Ⅱ) sulfate, Perchloric acid Maeyama Japan [41]

Table 2 Summary of ferrous gel dosimeter

PVA: Polyvinyl alcohol; XO: Xylenol orange; FBX: Ferrous benzoic xylenol orange (= ferrous ammonium sulfate, XO, H2SOF4); FGD: Ferrous gel dosimeter; MRI: Magnetic resonance imaging; NC-FG: Nano-composite Fricke gel.



important to remember that the radiological quantity often depends on the radiation energy.

To simplify the discussion, we focus on the photons and electrons in this section. Then, the cross sections can be replaced by the photon attenuation coefficients and electron stopping power. To quantify the radiological quantity of the materials, we can use the effective atomic number, mass density, and electron density. We use the photon energy above the energy of gamma rays produced by Cobalt-60, or. 1.25 MeV, and below 20 MeV, which is the maximum photon and electron energy currently clinically in use. For this range of energy, we might assume three quantities mentioned above can be evaluated for one energy, say, at 6 MeV. In Table 4 we summarized those for some of the standard 3D dosimeters. Note that the genipin PGD has the radiological quantities the closest to those of water.

DOSE QUANTIFICATION TECHNIQUESAll 3D dosimeters under review are not absolute dosimeters in the sense of calorimeter or ionization chambers since those do not quantify either energy absorbed by a medium or the number of ion-electron pairs produced in a medium. Those rather rely on a monotonic relationship between the expected absorbed dose and the amount of the quantitative changes of the characteristic of the dosimeter material. PGD material polymerizes when the radiation interacts with the material. The polymerization occurs among the monomers which are suspended in the gelatin matrix. This process, in turn, causes a change in the

molecular structure and the mass density. Consequently, these changes lead to an alteration of the mechanical, optical, and magnetic properties. FGD relies on a mecha-nism different from PGD. In FGD, new ferrous ions are produced by radiation. The change in the concentration of ferrous ions is closely related to the absorbed dose. In SPD, the radiation causes copolymerization of the monomers and the change of color at the same time. It is noteworthy that we always need to obtain a calibration relationship between the dose absorbed by the 3D dosimeter and the amount of quantitative changes measured by the dose quantification tool for the dose measurement.

Here, we discuss three dose quantification techniques; MRI, OCT, and X-ray computed tomography (XCT). There are other techniques such as the ultrasound device, but those will not be considered in this review because they are not readily available in clinics or their unproven measurement accuracy. Each system has its advantages and disadvantages. In Table 5, we summarized the cons and pros of those systems. Note that since the technology keeps changing and improving, some of the disadvantages may disappear in the future.

MRIThe most common method of the dose quantification of PGD and FGD is MRI. MRI can measure the changes of the transverse (or spin-lattice) relaxation time (T1), the lateral (or spin-spin) relaxation time (T2), the magnetization transfer, the susceptibility, and radio-frequency spectra. Because of the solid nature, MRI cannot be used with SPD.

Dosimeter Type A B Initiator Dye Key investigator Country Ref.

SPD SPD Diacetylene Ethyl trichloroacetate, heptachloropropane, etc.

Radiochromic (fuschin cyanide, etc.)

Leuco crystal violet, or LMG

Patel United States [79]

PRESAGE SPD Polyol_A,diasocyanate

Polyol_B Carbon tetrachloride, methylene chloride, tetra-chloroethane, Chloroform

LMG Adamovics United States [6]

PRESAGE SPD Crystal clear A Crystal clear B Carbon tetrachloride LMG Hashemi Iran [80]PRESAGE SPD Crystal clear A Crystal clear B Chloroform, bromoform, or

iodoformLMG Geso Australia [81]

PRESAGE SPD Crystal clear A Crystal clear B Bromoform LMG Watanabe United States [14]

Table 3 Summary of solid plastic dosimeter

LMG: Leuco-malachite green; SPD: Solid plastic dosimeter.

Dosimeter Type Relative effective atomic number Relative mass density Relative electron density

PAGAT PGD 1.0131 1.0264 0.9284

MAGAT PGD 1.0141, 0.9843 1.0323 0.9933

nMAG PGD 1.0181

MAGIC PGD 1.0181, 0.9873 1.0373 0.9903

Genipin gel PGD 1.0142 1.0012 0.99822

PRESAGE-A SPD 1.0372 1.0542 0.9772

Water 1.00 (Zeff = 7.42) 1.000 1.0 (3.343 x 1023 Electrons/g)

Table 4 Water equivalency of three-dimensional dosimeters

The numbers in parentheses indicate the references. 1Ref. [82] (for 18MeV photon energy); 2Ref. [83]; 3Ref. [84]; 4Ref. [85]. PGD: Polymer gel dosimeter; SPD: Solid plastic dosimeter.



The T2 change is most noticeable in PGD; hence, it is the most important parameter. The 3D distribution of T2 or the inverse of T2, the spin-spin relaxation rate (R2), can be measured by using a multiple spin echo pulse sequence such as Car-Purcell-Meiboom-Gill[16]. The T1 change is quantified for FGD since the ions strongly influence the spin-lattice relaxation[17].

OCTThe change in the mass density in PGD and the color change of SPD naturally lead to an optical method for the dose quantification. By borrowing the ideas from both the optical densitometer used for radiographic and radiochromic films and the X-ray CT, the 3D distribution of the change in the optical properties can be measured by OCT. There are three types of OCT systems. The first generation OCT uses the line of laser light with a pair of a light source and a point photon detector. The entire 3D volume can be covered by moving the laser light and the sensor together both in the transverse and longitudinal directions while the sample is rotated. The standard image reconstruction algorithm can be used to obtain full 3D dose distribution data. The second generation scanner uses a mirror to sweep the light ray along the transverse direction to speed up the scanning time. For an even quicker scan, the third generation OCT uses a broad cone beam of laser light, either parallel beam or a divergent beam in the object, and a charge coupled detector camera as the sensor. Some researchers proposed a fan-beam type scanning system by generating a horizontal fan beam[14,18]. OCT measures the attenuation of photons, and this is represented by the optical density (OD). Hence, the dose must be estimated by using an appropriate calibration relationship between OD and the dose.

XCTXCT relies on the photon attenuation by the object. Since the radiation changes the density of PGD, the dose pattern can be visualized by using XCT. This approach might be the most attractive method for routine appli-cations of the 3D dosimetry because of the wide-spread use of the XCT in the radiation therapy clinic. However,

the practicality of XCT as the readout tool yet needs to be proven.

Comparison of dose quantification methodsImportant factors which determine the quality of the dose quantification methods are the accuracy, the precision, the spatial resolution, the speed, and the cost. The accuracy depends on the quality of the calibration data which are used to convert the measured physical parameters to dose to the dosimeter (or often to the water). Hence, a parameter more important than the accuracy is the uncertainty or the precision of the measurement. We compare these parameters of MRI, OCT and XCT, based on the published results. The scanning speed and the precision are strongly correlated for MRI, to some extent, for both OCT and XCT. For example, the repeated acqui-sition of MR images decreases the image noise, though the noise only decreases with the square root of the number of image acquisition, resulting in a significant increase in the scanning time or slower scanning speed. Note that among these, only OCT is not used in radiation oncology clinics as a standard imaging tool for routine clinical work and needs to be purchased specifically for the 3D dosimetry purpose.

For dosimetric applications, the precision must be high, and it should be smaller than 5%. In Table 6, we summarize the precision quoted in literature. It is, however, worth mentioning that those values are a combination of the precision stemming from the dosimeter itself and the dose quantification tool. Furthermore, many items in Table 6 are not known, and systematic studies are needed to quantify those uncertainty values.

Long scanning time is acceptable if the scanning system is used solely for the 3D dosimetry such as a dedicated OCT system. Otherwise, the system should be capable of acquiring 3D dose data in a reasonable time frame, i.e., shorter than one hour and at most 2 h.

The cost of the dose data quantification is user fees for MRI and XCT. Usually, the fee is about $500 per hour at the most institutions in the United States if any payment is needed. Note that in this review the cost is estimated at the United States dollars. The cost of OCT, if purchased, could range from $10000 to $50000. Hence, for repeated uses, OCT could be the most economical system unless the MRI and XCT are available for free.

ACCURACY AND PRECISIONAccuracy of absolute dose measurementThe primary purpose of 3D dose measurements is not the absolute quantification of the absorbed dose, but rather it is often a measurement of the relative 3D dis-tribution of the dose produced by a radiation delivery technique. Hence, the capability of the absolute dose measurement is not the most important requirement for the 3D dosimeters. However, the 3D dosimeters can be used as an absolute dosimeter if the radiation response is adequately characterized.

Method Pros Cons

MRI Commonly available at a hospitalEasily accessible scan protocolKnown accuracy and precision

Linear dose response

Low SNRImage artifacts

Limited spatial resolutionLong scan time

OCT High spatial resolutionSmall physical size or compactEasy and free access if owned

Optical artifactsNeeds refractive index

matchingXCT Easy access at hospital

High SNRVery fast scan

Low image contrast

Table 5 Comparison of dose quantification techniques

SNR: Signal-to-noise ratio; MRI: Magnetic resonance imaging; OCT: Optical computer tomography; XCT: X-ray computed tomography.



The accuracy of the dose measured by a detector depends on the accuracy of the original signal recorded inside the 3D dosimeter medium and the precision of the dose-response data or the calibration equation, which is used to convert the raw signal data to the absorbed dose[16,19]. To study this more quantitatively, let us assume the calibration equation represented by a second order polynomial, which is the most common response characteristics of the 3D dosimeters. For the raw data X recorded by the 3D dosimeter, the absolute dose D can be now expressed by

D = aX2 + bX + c (1)

It is well known that the uncertainty of D can be given as the function of the uncertainties of the raw data X, and the three coefficients, a, b and c, in Eq.(1):

δD = {(X2δa)2 + (Xδb)2 + (δc)2 + [(2aX + b)δX]2}1/2 (2)

If the calibration equation (1) is exact, i.e., δa = δb = δc = 0, Eq.(2) can be modified as

δD/D = (X/D) × (dD/dX) (δX/X) = {[(2aX + b)X]/D} × (δX/X) (3)

Eq.(3) implies that the relative uncertainty of D is proportional to the relative uncertainty of X; in other words, the smaller the uncertainty of X the smaller the uncertainty of the dose. In reality, however, the uncertainty of the coefficients, a, b and c, is not negligible; hence, the uncertainty of D can be much larger than the uncertainty given by Eq.(3). Another point which is often forgotten is that the uncertainty of dose also depends on the dose

itself because the proportional constant in Eq.(3) is a function of X and D.

PrecisionThe precision or the uncertainty of the measured dose is a summation of the uncertainty due to the random errors (or Type A) and systematic errors (Type B). The Type A uncertainty can be estimated by Eq.(2) or a similar equation derived for a particular calibration equation. It is not simple, however, to characterize the Type B errors.

MacDougall et al[20] attempted to estimate the measurement uncertainty of PGD and FGD in 2002. They gave a rather pessimistic estimate of the accuracy obtainable, i.e., 10% for PGD and 5% for FGD, and the estimated uncertainty was 1.5% for FGD only. Since that time, the dose read-out technique and the quality of 3D dosimeter have improved. The issues of the measurement uncertainty with the 3D dosimeters were, again, reviewed by De Deene and Andrew[21] in 2015. The nominal uncertainty values from this article are summarized in Table 6. The data are still sparse mainly because the uncertainty is unique to every measurement and dosimeter quality and there is a significant variation in the quality of both measurements and the dosimeters. It is important to note that there are many boxes which are not filled in Table 6. Those are not easily measurable and not well characterized yet. However, eventually, all those uncertainty factors must be estimated to provide a reliable 3D dosimetry tool to the medical community.

PRECLINICAL APPLICATIONSBesides the highly 3D nature of the dose distribution delivered by modern radiation therapy devices, three

Uncertainty type Source Factor PGD FGD SPD

A Physicochemical Chemical composition < 2% < 2%Temperature variation

Temporal and spatial integrityIrradiation Dose rate

EnergyTemperature 2%

Phantom position setup 1 mmMRI Image noise < 0.4% (3 mm3)OCT Image noiseXCT The standard deviation of CT number 2% to 8%

B MRI B0 non-uniformity < 3%B1 non-uniformity

Gradient non-uniformityTemperature during scanning

Medium Non-uniform refractive indexOCT Refractive index matching

Unstable light sourceAmbient stray light

Desynchronization between galvanic mirror and detectorMisalignment of light, subject, and detector

XCT Image processing 5%Calibration equation

Table 6 Precision (or uncertainty) of three-dimensional dosimetry[22]

MRI: Magnetic resonance imaging; OCT: Optical computer tomography; XCT: X-ray computed tomography; FGD: Ferrous gel dosimeter; PGD: Polymer gel dosimeter; SPD: Solid plastic dosimeter.



factors affect the dose, consequently the treatment effectiveness. The human body is mostly made of water, or about 50%-65% with the rest composed of higher density tissue, such as bone and lower density material such as lung or air cavity. Furthermore, some patients receive implants often made of high-density material for medical reasons. The dose distribution drastically changes in the vicinity of or near the interface between media with different mass density. The heterogeneity of the medium generates the highly complex dosage patterns and often the current dose calculation algorithms used by the TPS system cannot handle this circumstance accurately. Hence, the effect of tissue heterogeneity must be studied through experimental measurements. Another factor significantly impacting the dose to the tissue is that the temporal change of the human body, consequently the changes in the shape and the material density distribution during a radiation therapy. Such a temporal change is more important when more fractions are used. Note that radiotherapy for the treatment may last for even longer than two months. The effect on the 3D dose distributions can be studied by taking many CT scans. However, what is not known is that the motion of specific points in 3D space and the accumulated dose at that point. We cannot figure out where a tissue volume at a point A on day 1 is on day 2 when the body is deformed. Perhaps, this problem could be solved by creating a mechanical model of the inside of the human body. Alternatively, we can measure the exact accumulated 3D dose distribution to the volume at the end of the treatment with an appropriate dosimetric tool. The third factor is the size of the volume in which the dose must be measured. If the volume is less than 1 cm3 and we need to obtain the 3D dose distribution in this volume, there is a lack of adequate dosimetry tools, currently.

Heterogeneity effectsThe interface dosimetry in which one addresses the dose distribution near the tissue and non-tissue interface is well studied at least in a simple geometry such as in the vicinity of a planar heterogeneous material. When we move to heterogeneous materials with more complex 3D shape, the standard dose measurement tools such as ionization chambers, TLD, silicon diodes, radiographic and radiochromic films, are not useful because those cannot provide a real 3D dose distribution with high spatial resolution and add extra heterogeneity due to the measurement tool itself. For this type of measurements, the 3D dosimeters, PGD, FGD and SPD, are ideal dosimeters. There are only a few studies addressing the 3D interface dosimetry by the 3D dosimeters. Since the current deterministic dose calculation methods may not be accurate for this problem, one need to use Monte Carlo simulation methods to create a reference data, to which the measured data are compared to the evaluation of the measurements[22,23].

Deformable object There is commercially available software such as Velocity

(Varian Medical Systems, Palo Alto, CA, United States) and MIM Maestro (MIM Software Inc., Cleveland, OH, United States), which can deform the shape of the body image and provide the sum of the doses delivered to many differently deformed objects. Experimental measurements should validate the algorithms of this software. The shape of soft material can be easily deformed. Hence, by implanting many small detectors, i.e., silicon diodes or MOSFET, in the material, we can track the dose to points. At the end of such a study, we can obtain the accumulated dose. The more attractive approach is to use a deformable material which can measure 3D dose distributions. PGD and FGD are ideal for this study because of their flexible nature of the material and the ability to record the dose in 3D space. Applications of PGD in this area of research are not ad-vanced at all, and only a few researchers are currently working on this topic, including the De Deene’s group[24].

Small fieldWhen the size of the radiation beam is small, e.g., less than 1 cm, the only currently available measurement tool is either radiographic/radiochromic films or the 3D dosimeters. There are a few publications on applications of PGD/FGD/SPD[25-30], and more studies on this topic are needed.

CLINICAL APPLICATIONS3D dosimeters can be used in clinical practice in radiation oncology. Currently, it is used for evaluation of new tools and radiation delivery techniques. It is also being used as an external QA auditing tool to monitor the quality of dose delivery[31]. In Figure 3, we present a standard measurement and analysis procedure when we use the 3D dosimeter for evaluation of the delivered dose in comparison to the dose predicted by the TPS.

3D dosimetry productsBANG series dosimeter (nMAG-type PGD) is manu-factured and sold by 3D Dosimetry Inc. The same com-pany recently introduced the RGD as CrystalBall™[32]. PRESAGE SPD is available from Heuris Inc., owned by Dr. Adamovic. The most common imaging device for the dose quantification of PGD/FGD is the MRI system, and it is readily available at most medical facilities. There are only two companies which supply OCT systems for PGD/FGD/SPD. The 3D Dosimetry, Inc. sells its OCTOPUS series system. Modus Medical, Inc. (London, ON, Canada) manufactures two types of cone-beam-based OCT systems, named as Vista.

Analysis softwareThe analysis software should be able to process the raw image data acquired by the imaging device and convert the raw data to the 3D dose. Also, it is desirable for the software to be able to perform the evaluation of the measured dose in comparison to the reference data from



TPS, Monte Carlo code, or other 3D dose measurement tools. The gamma index analysis capability in addition to volumetric analysis, such as generation of dose volume histograms (DVH) using the contour data from TPS is the desired function.

The commercial OCT systems, OCTOPUS and Vista, come with the analysis software. The OCTOPUS system from the 3D Dosimetry Inc. comes with built-in VOLQA™ software. A commercial software PolyGeVero is available from the GeVero Co (Lotz, Poland). Additionally, RTSafe, P.C. (Athens, Greece) and 3D Dosimetry Inc. provide the dosimetry analysis service.

Most research groups in this field developed own data analysis software. Those cannot be used for the work directly related to routine patient treatments, but are excellent tools for research related to new equipment and delivery techniques. These can be easily available for free from the developers[33].

Routine quality assuranceThe regular quality assurance (QA) involves the measure-ments of beam output and the evaluation of mechanical and dosimetric accuracy[34]. Other regular QA includes the dosimetric validation of the treatment plans for every IMRT/VMAT treatment[34]. Thorough dosimetric measure-ments performed at the acquisition of the new accelerator, or the annual QA can be included in this category. The 3D dosimeters are not used for this purpose currently.

Testing new dosimetry equipmentPseudo 3D dosimetry tools are being introduced into clinics for routine applications. The device must be tested, and its accuracy must be evaluated before actual applications for patients. PGD/FGD/SPD are ideal tools for such evaluation studies. One example in this area is the assessment of the ArcCHECK device (SUN NUCLEAR, Melbourne, FL, United States). This device contains 1383 small silicon detectors arranged helically on the cylindrical surface. The device measures the radiation dose deposited by both incident and exiting beams. The device is specifically designed for QA of VMAT. Furthermore, special software

3DVH can be used to reconstruct the radiation dose distribution inside the cylinder where there is no detector or in the patient by using the dose data measured by ArcCHECK. The 3D dose data can be mathematically reconstructed from the available fluence data. Hence, this device can provide the users a 3D dose distribution data in a phantom or a patient. Since the device is based on a new idea and its design is very innovative, the evaluation of its performance is essential. Watanabe and Nakaguchi, hence, undertook an assessment study by using BANG3[33]. They measured the 3D dose distribution generated by VMAT and compared the results with those obtained by ArcCHECK. Their results demonstrated a satisfactory agreement between those two measure-ment techniques, hence, confirming the measurement accuracy of the new device as a pseudo-3D dosimeter. This application of PGD is a critical step to demonstrate its value and suggests that the PGD should be invaluable. PGD may become the standard tool for evaluation of psedo-3D dosimeters which will be developed in the future.

End-to-end QAA task group of AAPM, TG-142, recommends the end-to-end test of a new dose delivery system such as SRS and IMRT/VMAT[34]. Such a test can be accomplished the most adequately by using the 3D dosimeter because the shape of a patient can be simulated easily by using these tools. The earliest application of PGD was made to the end-to-end QA of Gamma Knife stereotactic radiosurgery (GKSRS). One of the studies could, in fact, point out a non-negligible geometric error associated with the imaging, which was not considered or quantified before[35]. As a matter of fact, all the MRI-based PGD of GKSRS is considered as an end-to-end test of the dose delivered when the dose delivery is planned on the MR image which was taken before planning and radiation delivery.

SRSThe application of 3D dosimeters for GKSRS is well established as discussed before. Applications of 3D dosimeters to other types of SRS technique have not been performed as often as GKSRS for an unknown reason. Björeland et al[36] used nMAG for the dosimetric evaluation of a linac-based hypofractionated SRS system. PAGAT was used for QA of SRS by multi-leaf collimator (MLC), m3 (BrainLab)[37].

IMRT/VMAT/tomotherapyThe dose delivery technique of IMRT and VMAT (including tomotherapy) requires very sophisticated mechanical maneuver of the MLC, jaws, and the angles of gantry and collimator. The radiation delivery is, in essence, four-dimensional because the positions of all these components move during a single delivery of treatment. Hence, the precision of delivering dose is affected by the composite of many factors. An individual test of this element is not sufficient. Hence, the actual 3D dose evaluation of these technologies should be performed at least once before the introduction to clinical usages.

Process flow diagram for 3D validation of radiation delivery thechniques

3D dosimeter manufacturing

Treatment planning

Irradiate

Calibration phantoms

Main phantom

Irradiate

Data readout (MRI, OCT, XCT)

Convert to 3D dose

3D dose comparison

Figure 3 The process flow for dose evaluation using the three-dimensional dosimeters. MRI: Magnetic resonance imaging; OCT: Optical computer tomography; XCT: X-ray computed tomography; 3D: Three-dimensional.



The 3D dosimetry tools can be used effectively for this purpose.

The major goal of the 3D dosimetry, hence, is the validation of the 3D dose distribution predicted by TPS by comparing with the measured dose which reflects the performance of the radiation delivery system. There are many studies on this topic. In Table 7, we summarize the published studies, which provide the gamma index passing rates. There are many other studies, most of which are earlier publications without the gamma analysis.

Proton/heavy ionsBecause of its unique depth dose generated by ion beams such as protons and heavy ions, i.e., carbon-12, a tremendous interest in those technologies exists. In fact, the use of protons for radiation therapy is rapidly expanding. The desirable depth-dose characteristics, mainly due to the existence of the Bragg peak at a particular range, however, suffers from a significant uncertainty of the actual location of the sharp peak in the dose. This issue is sometimes called as range uncertainty. The measurement of the depth dose of particle beams, hence, is an important task, which every new facility should perform. The 3D dosimeter can be a good can-didate for this type of applications if those materials are tailored to adequately simulate the linear energy transfer (LET) of particles in water or tissue.

Gustavsson et al[38] used BANG3 for the measurement of the central axis depth dose curve of a 68MeV proton beam. They found that the dose at the Bragg peak was underestimated by a factor of two by BANG3 because of the “quenching”. The quenching or under-response of the BANG3 occurred because the proton energy changes as those travel into deeper locations. LET depends on the proton energy. Thus, calibration data obtained by a specific energy at a shallow depth cannot be applied to the depth dose measurement. We can solve this problem by using the estimated proton energy as the function of depth theoretically, for example, by Monte Carlo simulation[38]. The introduction of BANG3-Pro eventually solved the issue of PGD due to the LET dependence of its

radiation response. The new PGD had gelatin matrix with higher viscosity than the original BANG3[39]. PGD was also tested with heavy ion beams[40]. Recently, Maeyama et al. used the nano-composite Fricke gel (NC-FG), a type of FGD, with carbon and argon ion beams, whose LET ranged from 10 to 3000 eV/μm[41]. NC-FG showed a consistent dose response for the range of LET tested in their study.

BrachytherapyBrachytherapy uses the small size of the radioactive material as radiation sources for radiation therapy. It is easy to expect, hence, that the dose distributions generated by single brachytherapy source or multiple sources are highly three-dimensional. Because of the large dose gradient, the 3D dosimeters are potentially an ideal dose measurement device. Therefore, 3D dosimeters were widely used with radioactive sources. The primary application is in the 3D dose distribution measurement of the single radioactive source. The results can be compared with the standard data of TG53 which are clinically in use. The measurements were done with various types of radioactive sources: Iridium-192 high dose rate (HDR) source[42-48], low dose rate (LDR) Iodine-125 seed[49,50], and LDR Cesium-137 source[51]. Additionally, the 3D dosimeters were used for the dosimetry of beta-emitting radioactive sources such as Ruthenium-103[52], Renium-188[53], and Ytirium-90[54]. The SPD was also used with a radioactive source[55,56].

For many brachytherapy procedures using LDR and HDR sources, the high dose is delivered to a large volume by placing many sources or moving a single HDR source over the volume. There is a lack of 3D dosimetry study in this more clinically useful source configuration.

DISCUSSION AND SUMMARYCurrent technical issuesAn ultimate goal of the 3D dosimeter study is to produce a tool for 3D dosimetry, which can be routinely used in all radiation therapy clinics all over the world. This goal

Ref. Dosimeter Read-out method Treatment site Delivery type Photon energy/number of

fields

Comparison on the plane or in volume

Gamma index criteria % dose difference (global/

local)/DTA (mm)/threshold (%)

Gamma index passing rate

[86] MAGIC MRI/T2 Model IMRT/GKSRS 6MV/Co-60 Volume 3/3/ 50.3%[87] FX gel OCT/Vista Head and Neck IMRT 6MV Volume 3/3/none 84.1%[88] BANG3 MRI/T2 Prostate Tomotherapy 6MV/Arc Volume 3/3 53%[89] PRESAGE DLOS Brain IMRT 6MV Volume 3/3 95%[90] MAGIC-f MRI/T2 Prostate Tomotherapy 6MV/Arc Plane 3/3 88.4%[91] nPAG OCTOPUS-IQ Prostate IMRT /7fields Volume 95.3%[10] PAGAT MRI/T2 Pituitary IMRT 6MV/7fields Volume 2/2 99.4%[33] BANG3 MRI/T2 Prostate VMAT (Elekta) 6MV/Arc Volume 3 (global)/3/25 95.7%[92] BANG3 MRI/T2 Prostate VMAT (Varian) 6MV/Arc Volume 3 (global)/3/50 90.0%[93] PRESAGE DMOS Brain IMRT 6MV/5fields Volume 3 (global)/3/10 99.4%[94] NIPAM MRI/T2 Eye IMRT 6MV/5fields Plane 3/3/ 98.5%

Table 7 IMRT/VMAT/tomotherapy three-dimensional dosimetry

MRI: Magnetic resonance imaging; DTA: Distance to agreement; DMOS: Duke Mid-Sized Optical-CT Scanner; DLOS: Duke Large field-of-view Optical-CT Scanner.



is yet to be reached. It seems that even institutions with sufficient expertise in this field are not using the tool routinely except occasional applications, mostly, for research purpose or evaluation of new devices or software. There are two major factors for this somewhat depressing situation after over 20 years of extensive research. The first factor is the precision of the measurements in comparison to the existing tools. As discussed in the precision section, the state-of-art methods in PGD, FGD, and SPD can achieve ± 5% uncertainty with 95% confidence if the measurements and instruments are well prepared and managed. This accuracy is still less than that of other more standard tools such as a 3D water scanning system with an ionization chamber, which can provide a 3D dose distribution, but with coarser measurement grids than PGD and SPD. Note that the 3D water scanning is faster than PGD and SPD when the measurement time includes the preparation and the data analysis. Hence, the current 3D dosimeters cannot replace the 3D water scanning system, which is always used for commissioning and annual QA of the accelerator.

Therefore, the improvement of the measurement precision should be the primary goal of the 3D dosimetry community. The uncertainty is composed of the random errors (Type A), which are caused by the random nature of the signal acquired by the measurement device, and the uncertainty of the calibration data, which is again strongly affected by the random errors during the calibration. However, a larger uncertainty stems from other factors (Table 6): (1) the non-uniformity of the detector medium; (2) the reproducibility of dosimetric properties; and (3) the uncertainty associated with the dose quantification device.

The issues (1) and (2) can be overcome by improving the manufacturing process and the distribution (or delivery of the product to the customer) system. The issue (3) can be solved by using an imaging device specifically designed for the 3D dosimetry. MRI cannot be easily made just for the 3D dosimetry. Since MRI is a diagnostic tool, it is not suited for the quantitative measurement. However, the situation will improve because the community is now more interested in the “quantitative” imaging. On the other hand, OCTs are designed for the 3D dosimetry to provide the most accurate result, although the current system still requires further improvement.

The cost of the 3D dosimetry is another obstacle preventing its widespread acceptance as a routine mea-surement tool. Let us examine this issue further by using an example. Suppose we would like to use PGD for the regular patient specific IMRT/VMAT QA. Assume that the current standard is the use of ArcCHECK and the price of the ArcCHECK system is $50000. Now, then we purchase a commercial PGD, whose price is $500 for an 18-cm diameter 20-cm long cylindrical phantom containing PGD. The cost of the dose quantification device is zero if MRI is used or $30000 if a commercial OCT system is purchased. Assume we use an OCT system. Then, the difference of the device costs between the ArcCHECK and PGD approach is $20000 by excluding the cost of PGD.

This difference can cover 40 PGD phantoms, which are the number needed for one year of patient specific QA at a typical radiation oncology department. If we assume that we use these systems for five years, the total cost of the ArcCHECK approach is still $50000. However, the total cost of PGD is $130000. Hence, there is a tremendous disadvantage of the PGD over the ArcCHECK regarding the cost. However, this cost analysis does not diminish the value of the 3D dosimeter approach as we discuss next. It is evident from this analysis, furthermore, that the development of reusable 3D dosimeters could lead to significant cost saving[57].

Now, let us consider the information obtained by these tools. The information is quantified by the number of pixels and voxels, which record the dose data, for PGD, and the number of diode detectors in ArcCHECK, which is 1386. The voxel size of typical OCT scan is 1 mm × 1 mm × 1 mm or 1 mm3 (= 0.001 cm3). The volume of dose measurement is a 20-cm diameter and 20-cm long; hence, this volume is 833 cm3 and contains 833000 voxels. Assume we use the system for 40 × 5 = 200 times in five years. The dollar per the data point or information is 18 cents for the ArcCHECK method; whereas it is 0.08 cents for PGD. Therefore, PGD is much more cost effective if all the acquired data can be utilized to improve the treatment quality.

CONCLUSIONThe 3D dosimeters have been under development for many years and were studied by researchers all over the world. It seems that the lack of the acceptance for wider radiation oncology applications stems from the inherent or unknown uncertainty of the tools and the cost needed for everyday usages. These issues should be addressed in the future. More focused studies are needed to resolve these problems.

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P- Reviewer: Arisan V, Tomizawa M, Tsalafoutas IA S- Editor: Ji FF L- Editor: A E- Editor: Li D


Alberto Aliprandi, Carmelo Messina, Paolo Arrigoni, Michele Bandirali, Giovanni Di Leo, Stefano Longo, Sandro Magnani, Chiara Mattiuz, Filippo Randelli, Silvana Sdao, Francesco Sardanelli, Luca Maria Sconfienza, Pietro Randelli

ORIGINAL ARTICLE


Reporting rotator cuff tears on magnetic resonance arthrography using the Snyder’s arthroscopic classification

Retrospective Study

Alberto Aliprandi, Michele Bandirali, Giovanni Di Leo, Silvana Sdao, Francesco Sardanelli, Servizio di Radiologia, IRCCS Policlinico San Donato, 20097 San Donato Milanese, Italy

Carmelo Messina, Sandro Magnani, Chiara Mattiuz, Scuola di Specializzazione in Radiodiagnostica, Università degli Studi di Milano, 20122 Milano, Italy

Paolo Arrigoni, Unità Operativa di Ortopedia e Traumatologia II, IRCCS Policlinico San Donato, 20097 San Donato Milanese, Italy

Stefano Longo, Francesco Sardanelli, Luca Maria Sconfienza, Pietro Randelli, Dipartimento di Scienze Biomediche per la Salute, Università degli Studi di Milano, 20139 Milano, Italy

Filippo Randelli, Unità Operativa di Ortopedia e Traumatologia V, IRCCS Policlinico San Donato, 20097 San Donato Milanese, Italy

Luca Maria Sconfienza, Unità Operativa di Radiologia/Diagnostica per Immagini con Servizio di Radiologia Interventistica, IRCCS Istituto Ortopedico Galeazzi, 20161 Milano, Italy

Pietro Randelli, Unità Operativa Complessa, I Divisione, Istituto Ortopedico Gaetano Pini, 20122 Milano, Italy

Author contributions: Aliprandi A, Arrigoni P, Randelli F, Sardanelli F and Randelli P designed the research and substantially contributed to study conception; Messina C, Bandirali M, Magnani S, Mattiuz C and Sdao S acquired the data and performed the research; Di Leo G and Longo S contributed to study design and data interpretation/analysis; Messina C, Bandirali M, Magnani S, Mattiuz C and Sdao S drafted the article; Aliprandi A, Arrigoni P, Randelli F, Sardanelli F and Sconfienza LM made critical revision related to important content of the manuscript; all authors approved the final version of the manuscript to be published.

Institutional review board statement: The study was

reviewed and approved by the Comitato Etico ASL Milano Due Institutional Review Board.

Informed consent statement: Informed consent was waived from Institutional Review Board.

Conflict-of-interest statement: All authors declare no conflicts of interest.

Data sharing statement: Technical appendix, statistical code, and dataset available from the corresponding author at ([email protected]). Consent was not obtained but the presented data are anonymized and risk of identification is low.

Open-Access: This article is an openaccess article which was selected by an inhouse editor and fully peerreviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BYNC 4.0) license, which permits others to distribute, remix, adapt, build upon this work noncommercially, and license their derivative works on different terms, provided the original work is properly cited and the use is noncommercial. See: http://creativecommons.org/licenses/bync/4.0/


Correspondence to: Dr. Luca Maria Sconfienza, Dipartimento di Scienze Biomediche per la Salute, Università degli Studi di Milano, Via Mangiagalli 31, 20139 Milano, Italy. [email protected]: +390266214497

Received: August 24, 2016Peer-review started: August 24, 2016First decision: October 20, 2016Revised: December 12, 2016Accepted: January 2, 2017Article in press: January 3, 2017Published online: March 28, 2017



DOI: 10.4329/wjr.v9.i3.126




Aliprandi A et al . Snyder’s classification and magnetic resonance arthrography

AbstractAIMTo determine diagnostic performance of magnetic re-sonance arthrography (MRA) in evaluating rotator cuff tears (RCTs) using Snyder’s classification for reporting.

METHODSOne hundred and twenty-six patients (64 males, 62 females; median age 55 years) underwent shoulder MRA and arthroscopy, which represented our reference standard. Surgical arthroscopic reports were reviewed and the reported Snyder’s classification was recorded. MRA examinations were evaluated by two independent radiologists (14 and 5 years’ experience) using Snyder’s classification system, blinded to arthroscopy. Agreement between arthroscopy and MRA on partial- and full-thickness tears was calculated, first regardless of their extent. Then, analysis took into account also the extent of the tear. Interobserver agreement was also calculated the quadratically-weighted Cohen kappa statistics.

RESULTSOn arthroscopy, 71/126 patients (56%) had a full-thickness RCT. The remaining 55/126 patients (44%) had a partial-thickness RCT. Regardless of tear extent, out of 71 patients with arthroscopically-confirmed full-thickness RCTs, 66 (93%) were correctly scored by both readers. All 55 patients with arthroscopic diagnosis of partial-thickness RCT were correctly assigned as having a partial-thickness RCT at MRA by both readers. Interobserver reproducibility analysis showed total agreement between the two readers in distinguishing partial-thickness from full-thickness RCTs, regardless of tear extent (k = 1.000). With regard to tear extent, in patients in whom a complete tear was correctly diagnosed, correct tear extent was detected in 61/66 cases (92%); in the remaining 5/66 cases (8%), tear extent was underestimated. Agreement was k = 0.955. Interobserver agreement was total (k = 1.000).

CONCLUSIONMRA shows high diagnostic accuracy and reproducibility in evaluating RCTs using the Snyder’s classification for reporting. Snyder’s classification may be adopted for routine reporting of MRA.

Key words: Arthroscopy; Magnetic resonance imaging; Shoulder; Arthrography; Supraspinatus tendon; Rotator cuff tear


Core tip: In the present study we determined the diagnostic performance of magnetic resonance arthro-graphy (MRA) in evaluating rotator cuff tears (RCTs) using Snyder’s classification for reporting. One hundred and twenty-six patients underwent MRA and arthroscopy, which represented our reference standard. Agreement between arthroscopy and MRA on partial- and full-

thickness tears was calculated. Arthroscopy findings: 71/126 patients (56%) had a full-thickness RCTs, while 55/126 patients (44%) had a partial-thickness RCTs. MRA showed high diagnostic accuracy and reproducibility in evaluating RCTs using the Snyder’s classification for reporting. Snyder’s classification may be adopted for routine reporting of MRA.

Aliprandi A, Messina C, Arrigoni P, Bandirali M, Di Leo G, Longo S, Magnani S, Mattiuz C, Randelli F, Sdao S, Sardanelli F, Sconfienza LM, Randelli P. Reporting rotator cuff tears on magnetic resonance arthrography using the Snyder’s arthroscopic classification. World J Radiol 2017; 9(3): 126133 Available from: URL: http://www.wjgnet.com/19498470/full/v9/i3/126.htm DOI: http://dx.doi.org/10.4329/wjr.v9.i3.126

INTRODUCTIONThe shoulder joint is a complex anatomic structure consisting of static and dynamic stabilizers, which confers functional stability and high degree of mobility at the same time[1]. Rotator cuff (RC) acts as a dynamic stabilizer contributing to shoulder stability: It consists of four muscles (supraspinatus, subscapularis, infraspinatus and teres minor), which tendons fuse to form a continuous structure near their insertions. Together with long head of biceps tendon, RC tendons create an ideal configuration to actively compress the humeral head into the glenoid’s cavity[2]. Nevertheless, due to the glenohumeral joint highgrade of mobility, RC tears (RCTs) are commonly encountered, implying shoulder pain and dysfunction, often associated with loss of biomechanical balance and instability and subacromial impingement[3,4]. The prevalence of fullthickness RCTs is almost 25% of individuals in their 60s and 50% of individuals in their 80s, with the supraspinatus being the most frequently involved tendon[5].

Both ultrasound and magnetic resonance imaging (MRI) are accurate techniques in identifying shoulder pathologic conditions and RCTs[6,7]. Magnetic resonance arthrography (MRA) has been shown to improve diagnostic performance of conventional MRI, as contrast material distends the joint capsule and outlines intraarticular structures; thus, MRA is particularly useful for RC partialthickness tears as well as labrum and glenohumeral ligament tears and degeneration[7,8].

Several orthopaedic classifications of RCTs were proposed throughout years. In 1934, Codman[9] described the development of supraspinatus partialthickness tears. In 1983, Neer[10] classified RCTs into three progressive stages of impingement. In 1984, DeOrio and Cofield[11] used the length of the greatest diameter of the tear to categorize the tear in four degrees. In 1990, Ellman[12] further developed the classification of Neer, popularizing for the first time a system to classify partial thickness tears based on intra-operative findings. Recently, Davidson and Burkhart[13] developed a geometric classification system


based on preoperative (MRI)[14]. At our institution, shoulder orthopaedic surgeons use the Snyder’s arthroscopic classification of RCTs, which includes three parameters: The location of the lesion, the extent of the lesion, i.e., partialthickness or fullthickness and the number of involved tendons (Table 1)[15,16]. In particular, Snyder’s classification separates RCTs into articular-sided, bursalsided, and complete tears.

Despite many orthopaedic classifications, these never entered into radiological practice and radiologists still descriptively report tears of the RC[17]. A recent study from Bosmans et al[18] showed that, although radiology report remains an indispensable tool for medical practice, there is still a consistent percentage of referring physicians that remains unsatisfied with them. In fact, communication is a critical aspect when providing medical care, and a discrepancy in the language used between physicians (i.e., radiologists and orthopaedic surgeons) may not convey the correct message and generate confusion[19]. Thus, the aim of our study was to evaluate the diagnostic performance of MRA in evaluating RCTs using the Snyder’s classification system for reporting MRA findings, having arthroscopy as reference standard.

MATERIALS AND METHODSStudy population and designThis retrospective study was reviewed and approved by the Institutional Review Board (Comitato Etico ASL Milano Due) and patients’ informed consent was waived. Between June 2006 and December 2013, a series of 1324 consecutive shoulder MRA were performed at our institution in patients presenting with pain and functional limitation of the shoulder. From this database, we selected all patients who underwent arthroscopic surgery at our Institution, for a total of 126 patients (64 males and 62 females; age range 1579 years; median age 55

years; 25th75th percentile 3863 years). Inclusion criteria for the study were: (1) MRA performed at our Institution following a standardised protocol; and (2) surgery performed at our Institution.

MRA - ultrasound-guided intra-articular injection of contrast materialIntraarticular injection of contrast agent was performed under ultrasoundguidance using a high frequency probe with anterior approach, as described by Sconfienza et al[20] and Messina et al[21]. Patients were positioned supine with the shoulder under investigation slightly extrarotated, with the arm outstretched along the body. After careful skin disinfection, a 19G needle was introduced in the joint and contrast material was injected. The procedure ended after injection of up to 20 mL of 0.0025 mmol/mL of gadoterate meglumine (GdDOTA, Dotarem pre-filled syringes; Guerbet, Paris, France). After injection, patient’s arm was gently intra and extrarotated for better contrast distribution into the joint capsule.

MRA - image acquisitionMRA was performed within 10 min from contrast agent injection using a 1.5T system (Magnetom Sonata Maestro Class, Siemens Medical Solution, Erlangen, Germany) equipped with a 40 mT/m gradient power and a dedicated phasedarray surface coil. The following imaging protocol was acquired: 3 plane (axial, coronal oblique and sagittal oblique) turbo spinecho T1weighted fatsaturated sequences (TR/TE = 763/15 ms; slice thickness = 4 mm; FOV = 190 mm × 190 mm; matrix = 256 × 256); oblique coronal turbo spinecho T2weighted fatsaturated sequences (TR/TE = 4000/74 ms; slice thickness = 4 mm with 0.8mm interslice gap; FOV = 240 mm × 240 mm; matrix = 256 × 256); threetimensional dual echo steady state (3DDESS, TR/TE = 17/6 ms, slice thickness = 0.8 mm, voxel = 0.8 mm × 0.8

LocationA Articular sideB Bursal sideC Full-thickness tears, connecting A and B sidesSeverity of partial tears (A and B side)0 Normal cuff, with smooth coverings of synovium and bursa1 Minimal, superficial bursal or synovial irritation or slight capsular fraying in a small, localized area; usually < 1 cm2 Actually fraying and failure of some rotator cuff fibres in addition to synovial, bursal, or capsular injury; usually < 2 cm3 More severe rotator cuff injury, including fraying and fragmentation of tendons fibers, often involving the whole surface of a cuff

tendon; usually < 3 cm4 Very severe partial rotator cuff tear that usually contains, in addition to fraying and fragmentation of tendon tissue, a sizable flap tear

and often encompasses more than a single tendonSeverity of complete tears (C)1 Small, complete tear, such as a puncture wound2 Moderate tear, (usually < 2 cm) that still encompasses only one of the rotator cuff tendons with no retraction of the torn ends3 Large, complete tear involving an entire tendon with minimal retraction of the torn edge; usually 3 to 4 cm4 Massive rotator cuff tear involving two or more rotator cuff tendons, frequently with associated retraction and scarring of the

remaining tendon

Table 1 Snyder’s classification of rotator cuff tears

Modified from Millstein and Snyder[16].



mm × 0.8 mm).

Imaging evaluation and RCTs classification As a pilot attempt to classify RCTs using Snyder’s classification, in the present study we only considered RCTs involving the supraspinatus tendon. The Snyder’s arthroscopic classification (Table 1) was used as reference for evaluating complete tears. For partialthickness tears, the Snyder’s classification was modified according to what reported in Table 2. Images were reviewed by two independent radiologists with 14 (reader 1) and 5 years’ (reader 2) experience in musculoskeletal MRA, respectively, blinded to arthroscopic findings.

Surgical classification of RCTsArthroscopy was performed by one of three orthopaedic surgeons with 5 to 17 years’ experience in shoulder arthroscopy. Surgical reports were reviewed and the reported Snyder’s classification was recorded.

Statistical analysisFor analysis of lesion extent accuracy, data obtained by the most experiences reader (reader 1) was used and compared to reference standard. We calculated first the agreement between arthroscopy and MRA on partial and fullthickness tears, regardless of their extent. Then, we performed a deeper analysis taking into account also the extent of the tear, still separately for partial and fullthickness tears. Interobserver agreement was also calculated the quadraticallyweighted Cohen kappa statistics was used.

RESULTSReference standardArthroscopy was performed after a median of 137 d

from MRA (25th75th percentile 72211 d). At arthroscopic assessment, 71/126 patients (56%) had a fullthickness RCT with different severity grade: C1, n = 27; C2, n = 25; C3, n = 15; C4, n = 4. The remaining 55/126 patients (44%) had a partialthickness RCT. Distribution of the articular and bursal location of the tear is reported in Table 3 according to the most experienced reader (reader 1).

Accuracy vs the reference standard regardless of tear extentOut of 71 patients with arthroscopically-confirmed full-thickness RCTs, 66 (93%) were correctly scored by both readers; in the remaining 5 patients (7%), both readers assigned a partialthickness tear instead of a fullthickness tear. Table 4 shows data about the 5 patients with a complete tear at arthroscopy who were assigned with a partial score by the most experienced reader (reader 1). Figures 1-3 show MRA findings and corresponding arthroscopic confirmation.

All 55 patients with arthroscopic diagnosis of partialthickness tear were correctly assigned as having a partialthickness tear at MRA by both readers (Figure 3).

Interobserver reproducibility analysis showed total agreement between the two readers in distinguishing partialthickness from fullthickness RCTs, regardless of tear extent (k = 1.000).

Accuracy vs the reference standard considering tear extentIn patients in whom a complete tear was correctly diagnosed, correct tear extent was detected in 61/66 cases (92%); in the remaining 5/66 cases (8%), tear extent was underestimated, as both readers assigned C1 instead of C2. Agreement with arthroscopy was k = 0.955.

Lesion's grade Severity of partial tears (A or B lesion)

1 Subtle irregularities of the tendon surface with preserved thickness2 Major irregularities of the tendon surface with preserved thickness3 Lesions involve less than 50% of tendon diameter and lesion extension is less than 3 cm4 Lesions involve more than 50% of tendon's diameter with an extension of more than 3 cm or the lesion involves two tendons

Table 2 Adaptation to magnetic resonance arthrography of arthroscopic Snyder’s classification of rotator cuff partial tears

A: Articular side; B: Bursal side.

Articular side tearA0 A1 A2 A3 A4

Bursal side tear

B0 - 1 1 2 1B1 3 8 0 0 0B2 4 5 5 3 1B3 0 0 1 5 2B4 0 0 0 1 12

Table 3 Distribution of lesion severity degree on articular and bursal sides of 55 patients with a partial rotator cuff tear at the arthroscopic assessment


Reader 1 Reference standard

Articular side Bursal side Complete tearA 2 B 1 C 1A 3 B 4 C 1A 2 B 3 C 1A 4 B 4 C 1A 4 B 4 C 1

Table 4 Data regarding the 5 patients with a complete tear at the reference standard assigned with a partial score at the magnetic resonance arthrography by the most experienced reader (reader 1)




Interobserver agreement was total (k = 1.000).In 55 patients in whom a partialthickness tear was

diagnosed, agreement in terms of tear extent was k = 0.878 for the articular side and k = 0.837 for the bursal side, respectively. Full data are reported in Tables 5 and 6, respectively. Regarding interobserver agreement, the two readers disagreed at maximum for 1 degree

for either articular or bursal side of the supraspinatus tendon, with k = 0.947 and k = 0.969, respectively.

DISCUSSIONWhen managing a patient affected with a RCT, both clinical and imaging evaluation play a crucial role[22].

A B

Figure 1 Magnetic resonance arthrography of a C2 lesion of the supraspinatus tendon. A: MRA, coronal TSE T1w fat sat. Full tear with fiber retraction of supraspinatus tendon. Yellow arrows show the bare area of foot print lesion (C2 lesion according to Snyder classification); B: Arthroscopic view. Dotted line shows the crescent shape lesion. MRA: Magnetic resonance arthrography.

17.26 mm

A B C

Figure 2 Magnetic resonance arthrography of a C1 tear of the supraspinatus tendon. A: MRA coronal, double echo steady state. Viewfinder shows the hyperintense signal in supraspinatus tendon, expression of full tear (C1 lesion according to Snyder classification); B: MRA Sagittal TSE T1w. Yellow arrows show the full tear (C1 lesion according to Snyder classification). White arrows show the degenerative tendon matrix, later removed by the surgeon; C: Arthroscopic view. White dotted line show a full, V-shape, tear of supraspinatus tendon completed to C2 according to Snyder classification by the surgeon. MRA: Magnetic resonance arthrography.

A B

Figure 3 Magnetic resonance arthrography and arthroscopy of an A4 tear of the supraspinatus tendon. A: MRA, coronal TSE T1w fat sat. The yellow arrows show the articular asymmetric profile, expression of erosion and partial tear of supraspinatus tendon (A4 lesion according to Snyder classification). White arrows show the regular bursal profile; B: Arthroscopic view. The black arrows show the mangy and flap of supraspinatus tendon. MAR: Magnetic resonance arthrography.



The role of diagnostic imaging is to help in the choice between surgical or nonsurgical treatment. Ultrasound, unenhanced MR and MRA have become the most common imaging techniques by which a RCT is diagnosed. Ultrasound is as accurate as unenhanced MR, but MRA remains the most sensitive and specific technique and is generally performed in cases in which ultrasound and unenhanced MR are not definitive[7].

The use of a common RCTs classification by radiologists and orthopaedists may allow for a more direct comparison, leading to better clinical diagnosis and letting the patient to decide a treatment option with clearer information. Snyder proposed a classification system for the evaluation of RCTs measuring both their extent and number of tendons involved, providing indications for surgery or conservative treatment on the basis of the obtained score[16]. In the present study we adopted the Snyder’s classification as it was already successfully used by orthopaedics surgeons at our Institution, as a tentative to achieve a better communication with them.

In our study we found a high agreement in diagnosing RCTs for both radiologists having arthroscopy as reference standards. These results are in line with what is already reported in a recent systematic review about the accuracy of MRA in diagnosing RCTs using conventional descriptive reporting systems[23]. Moreover, we found a very high interobserver reproducibility between the two readers, with a perfect agreement for fullthickness RCTs; regarding partialthickness RCTs, the two readers rarely disagreed. This means that also the less experienced reader showed a very good diagnostic performance. As a consequence, we can think that the Snyder’s classification system may have a value also when used in reporting MRA, even though originally created for arthroscopy.

A deeper analysis of the results showed that radiologists tend to underestimate the damage of the tendon, for both fullthickness and partialthickness RCTs. This data deserves some considerations. The margins of a tendon tear are usually made by degenerated tendon matrix. During arthroscopy, the orthopaedic surgeon debrides the degenerated area to have more consistent margins for repair[24]. Thus, final evaluation of tear extent by the orthopaedic surgeon may be larger compared to

what previously seen on MRA.Regarding partialthickness RCTs, reproducibility of

MRA is still high but lower than for fullthickness RCTs. This was expected, as it is known that both MRI and MRA have higher performance in assessing the fullthickness RCTs rather than partialthickness RCTs[2527]. However, the difference between the radiologist and the arthroscopy was only 1 degree in the majority of cases and 2 degrees in a few patients: These discrepancies are expected to not affect significantly the patients’ management[28]. Moreover, similarly to what happens for fullthickness RCTs, the radiologist always tends to underestimate the lesion degree of partial RCTs. Again, the main reason for this underestimation may be related to the fact that partialtear tendon debridement procedure could be performed by the surgeon on wider area of the tendon, with a consequent extension of the Snyder’s arthroscopic score[28]. Overall, we should also consider the time elapsed from MRA to surgery (median delay 137 d) which could represent a factor for progression of mild damage of the tendon. It is known that tendon injuries, if left untreated, can progress by determining the transition from small partial injury to a greater degree and from partial to complete tears[29].

This study has some limitations. First, it was performed retrospectively. Second, arthroscopy was performed by several orthopaedic surgeons with different experience in RCTs repair. Thus, certain degree of variability in RCTs scoring at the reference standard may be expected and may have slightly influenced our results. The same can be said for the delay between MRA and arthroscopy, which limited the reliability of the reference standard. In fact, the median delay of 137 d between MRA and arthroscopy could be seen as a long time between the two exams; nevertheless, this kind of delays may be common in everyday hospital practice, as patients usually attempt conservative treatments before undergoing surgery.

In conclusion, our study demonstrates high reproducibility of MRA in evaluating RCTs using the Snyder’s classification as a method for reporting. This allows to conclude that not only MRA but also the Snyder’s classification has an intrinsic high diagnostic value. Even though originally created for arthroscopy, Snyder’s classification is well suitable and may be adopted for routine reporting of

Reader 1A0 A1 A2 A3 A4

Arthroscopy

A0 7 0 0 0 0A1 8 6 0 0 0A2 2 2 3 0 0A3 0 0 4 7 0A4 0 0 0 8 8

Table 5 Data on agreement of the severity degree assigned on the articular side for partial tear between magnetic resonance arthrography (according to the most experienced reader) and arthroscopy

Quadratically weighted Cohen kappa = 0.878. A: Articular side.

Reader 1B0 B1 B2 B3 B4

Arthroscopy

B0 5 0 0 0 0B1 7 4 0 0 0B2 4 7 7 0 0B3 0 0 3 5 0B4 0 0 0 3 10

Table 6 Data on agreement of the severity degree assigned on the bursal side for partial lesions between magnetic resonance arthrography and arthroscopic assessment

Quadratically weighted Cohen kappa = 0.837. B: Bursal side.



MRA.

COMMENTSBackgroundThe shoulder joint is a complex anatomic structure consisting of static and dynamic stabilizers, which confers functional stability and high degree of mobility at the same time. Rotator cuff acts as a dynamic stabilizer contributing to shoulder stability. Rotator cuff tears (RCTs) are commonly encountered, implying shoulder pain and dysfunction, often associated with loss of biomechanical balance and instability and subacromial impingement.

Research frontiersMagnetic resonance arthrography (MRA) is particularly useful for rotator cuff partial-thickness tears as well as labrum and glenohumeral ligament tears and degeneration. Several orthopaedic classifications of RCTs were proposed throughout years; At the authors’ institution, shoulder orthopaedic surgeons use the Snyder’s arthroscopic classification of RCTs, which includes three parameters: The location of the lesion, the extent of the lesion - and the number of involved tendons.

Innovations and breakthroughsDespite many orthopaedic classifications, these never entered into radiological practice and radiologists still descriptively report tears of the RC, with referring physicians that may remains unsatisfied with them. The authors evaluated the diagnostic performance of MRA in evaluating RCTs using the Snyder’s classification system for reporting MRA findings, evaluating its accuracy using arthroscopy as reference standard.

ApplicationsMRA showed high diagnostic accuracy and reproducibility in evaluating RCTs using the Snyder’s classification for reporting. Snyder’s classification may be adopted for routine reporting of MRA.

TerminologyMRA is an examination of magnetic resonance imaging that is performed after the injection of contrast material (gadolinium) into the joint, with the aim to increase its diagnostic performance. RCTs may involve the articular or bursal side, and can be classified as partial or complete according to thickness tendon involvement.

Peer-reviewThe authors evaluate the diagnostic performance of MRA in evaluating RCTs using the Snyder’s classification system for reporting MRA findings, evaluating its accuracy using arthroscopy as reference standard. They demonstrated high reproducibility of MRA in evaluating RCTs using the Snyder’s classification as a method for reporting.

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P- Reviewer: Gao BL, Li YZ S- Editor: Gong XM L- Editor: A E- Editor: Li D


Amita Shukla-Dave, Cecilia Wassberg, Darko Pucar, Heiko Schöder, Debra A Goldman, Yousef Mazaheri, Victor E Reuter, James Eastham, Peter T Scardino, Hedvig Hricak

ORIGINAL ARTICLE


Multimodality imaging using proton magnetic resonance spectroscopic imaging and 18F-fluorodeoxyglucose-positron emission tomography in local prostate cancer

Observational Study

Amita Shukla-Dave, Heiko Schöder, Yousef Mazaheri, Hedvig Hricak, Department of Radiology, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, United States

Amita Shukla-Dave, Yousef Mazaheri, Department of Medical Physics, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, United States

Cecilia Wassberg, Department of Diagnostic Radiology, Karolinska University Hospital, 17176 Solna, Sweden

Darko Pucar, Department of Radiology, Augusta University, Augusta, GA 30912, United States

Debra A Goldman, Department of Epidemiology-Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, United States

Victor E Reuter, Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, United States

James Eastham, Peter T Scardino, Department of Urology, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, United States

Author contributions: Shukla-Dave A, Wassberg C, Pucar D, Schöder H, Mazaheri Y and Hricak H designed the study, performed MRI and PET research, analyzed the data and wrote the paper; Goldman DA performed the statistical analysis; Reuter VE performed the pathology assessment for the study; Eastham J and Scardino PT enrolled patients, and performed clinical assessment as per standard of care; all authors reviewed the final manuscript.

Supported by National Institutes of Health grant, No. #R01 CA76423; and in part through the NIH/NCI Cancer Center Support grant, No. P30 CA008748.

Institutional review board statement: Our study was compliant with the Health Insurance Portability and Accountability Act. Twenty-two patients who were referred from the Urology

department for endorectal MRI/MRSI examinations and 18F-FDG-PET/CT and then underwent prostatectomy as primary or salvage treatment were included in the study.

Informed consent statement: Patient data were collected and handled in accordance with institutional and federal guidelines.

Conflict-of-interest statement: All authors have no conflicts of interest with regard to this manuscript.

Data sharing statement: Upon formal request and with proper motivation, all original data in anonymized format is available from the corresponding author for local inspection, but cannot leave Memorial Sloan Kettering Cancer Center.



Correspondence to: Amita Shukla-Dave, PhD, Department of Medical Physics, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, United States. [email protected]: +1-212-6393184Fax: +1-212-7173010

Received: October 31, 2016 Peer-review started: November 2, 2016 First decision: December 15, 2016 Revised: December 22, 2016 Accepted: January 11, 2017Article in press: January 14, 2017Published online: March 28, 2017



DOI: 10.4329/wjr.v9.i3.134




Shukla-Dave A et al . Multimodality imaging in local prostate cancer

AbstractAIMTo assess the relationship using multimodality imaging between intermediary citrate/choline metabolism as seen on proton magnetic resonance spectroscopic imaging (1H-MRSI) and glycolysis as observed on 18F-fluorodeo-xyglucose positron emission tomography/computed tomography (18F-FDG-PET/CT) in prostate cancer (PCa) patients.

METHODSThe study included 22 patients with local PCa who were referred for endorectal magnetic resonance imaging/1H-MRSI (April 2002 to July 2007) and 18F-FDG-PET/CT and then underwent prostatectomy as primary or salvage treatment. Whole-mount step-section pathology was used as the standard of reference. We assessed the relationships between PET parameters [standardized uptake value (SUVmax and SUVmean)] and MRSI parameters [choline + creatine/citrate (CC/Cmax and CC/Cmean) and total number of suspicious voxels] using spearman’s rank correlation, and the relationships of PET and 1H-MRSI index lesion parameters to surgical Gleason score.

RESULTSAbnormal intermediary metabolism on 1H-MRSI was present in 21/22 patients, while abnormal glycolysis on 18F-FDG-PET/CT was detected in only 3/22 patients. Specifically, index tumor localization rates were 0.95 (95%CI: 0.77-1.00) for 1H-MRSI and 0.14 (95%CI: 0.03-0.35) for 18F-FDG-PET/CT. Spearman rank corre-lations indicated little relationship (ρ = -0.36-0.28) between 1H-MRSI parameters and 18F-FDG-PET/CT parameters. Both the total number of suspicious voxels (ρ = 0.55, P = 0.0099) and the SUVmax (ρ = 0.46, P = 0.0366) correlated weakly with the Gleason score. No significant relationship was found between the CC/Cmax, CC/Cmean or SUVmean and the Gleason score (P = 0.15-0.79).

CONCLUSIONThe concentration of intermediary metabolites detected by 1H MRSI and glycolytic flux measured 18F-FDG PET show little correlation. Furthermore, only few tumors were FDG avid on PET, possibly because increased glycolysis represents a late and rather ominous event in the progression of PCa.

Key words: Proton magnetic resonance spectroscopic imaging; 18F-fluorodeoxyglucose-positron emission tomography; Prostate cancer


Core tip: Although metabolic imaging is increasingly utilized in prostate cancer (PCa), the mechanisms leading to cancer-related metabolic rearrangements and consequent imaging findings remain poorly understood. This

study compared two modalities utilizing distinct metabolic pathways, proton magnetic resonance spectroscopic imaging (1H-MRSI) and 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG-PET/CT), in local PCa. Abnormal intermediary metabolism on 1H-MRSI was present in 21/22 patients, while abnormal glycolysis on 18F-FDG-PET/CT was detected in only 3/22 patients. This study provides an insight why metabolic PET agents promising for detection of PCa target intermediary metabolism. On the other hand, elevated glycolysis may have ominous prognostic implications in PCa.

Shukla-Dave A, Wassberg C, Pucar D, Schöder H, Goldman DA, Mazaheri Y, Reuter VE, Eastham J, Scardino PT, Hricak H. Multimodality imaging using proton magnetic resonance spectroscopic imaging and 18F-fluorodeoxyglucose-positron emission tomography in local prostate cancer. World J Radiol 2017; 9(3): 134-142 Available from: URL: http://www.wjgnet.com/1949-8470/full/v9/i3/134.htm DOI: http://dx.doi.org/10.4329/wjr.v9.i3.134

INTRODUCTIONMultimodality imaging is performed in patients with cancer to understand metabolism, however the mechanisms leading to metabolic rearrangements remains poorly understood. By decoding the connections between cancer signaling and metabolism, it may be possible to better understand the clinical implications of imaging findings and develop new imaging strategies.

In patients with prostate cancer (PCa), two key functional imaging modalities, proton magnetic resonance spectroscopic imaging (1H-MRSI) and 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG-PET/CT), are used to identify cancer-induced changes in cellular metabolism[1-3]. On 1H-MRSI, decreased levels of citrate (a Krebs cycle and fatty acid synthesis intermediate) and polyamines (amino acid metabolism intermediates) and elevated choline (a precursor of membrane synthesis) are a signature of PCa[2,4-7]. On 18F-FDG-PET, increased glucose uptake by glucose transporters and glucose phosphorylation to glucose-6-phosphate by hexokinase are used for identifying PCa and other cancers[3,8]. The indications for 1H-MRSI and 18F-FDG-PET/CT examinations in patients with PCa are very different[9,10]. 1H-MRSI adds incremental value to standard prostate magnetic resonance imaging (MRI) in the detection of primary or recurrent loco-regional PCa and in the evaluation of its aggressiveness (Gleason Grade)[9-14]. 1H-MRSI can also be used prior to treatment to predict biochemical relapse of PCa after radical prostatectomy or the presence of insignificant PCa[14-17]. In contrast, 18F-FDG-PET/CT is not recommended for the detection and initial evaluation of PCa or detection of early recurrence. Various other PET agents, such as 18F- or 11C-labeled choline or acetate, several various amino acids, and agents binding to the


transmembrane PSMA molecule are available for this purpose[18-24]. 18F-FDG plays a role in the characterization of advanced metastatic PCa[8,25]. The clinical significance of the current study lies in exploring the use of multimodality imaging in local PCa. In this study, we wanted to explore the relationship using multimodality imaging between concentrations of intermediary metabolites citrate and choline, measured by 1H-MRSI, and glycolysis as noted on 18F-FDG PET/CT in local PCa.

MATERIALS AND METHODSPatient demographicsOur study was compliant with the Health Insurance Portability and Accountability Act. Patient data were collected and handled in accordance with institutional and federal guidelines. Twenty-two patients who were referred from the Urology department for endorectal MRI/MRSI examinations (April 2002 to July 2007) and 18F-FDG-PET/CT and then underwent prostatectomy as primary or salvage treatment were included in the study. Whole-mount step-section pathology of the surgical specimen was available for all the patients. Of the 22 patients, 11 were imaged before treatment while 11 were imaged after external beam radiation therapy. The institutional review board approved our retrospective review of multimodality imaging using MRI/MRSI and 18F-FDG-PET/CT studies, pathology data (from surgical pathology), and clinical follow-up data and waived the informed consent requirement. The mean time between the MRSI and PET exams was 11 ± 37 d (± SD).

Endorectal MRI/MRSI data acquisition and processingData were acquired on a 1.5-Tesla GE Signa Horizon scanner. MRI was done using a pelvic phased-array coil and an expandable endorectal coil; T1- and T2-weighted spin-echo MR images were obtained using a previously described standard prostate imaging protocol (total time, approximately 30 min)[4]. MR image acquisition was followed by a standard MRSI protocol with point-resolved spectroscopic voxel excitation and water and lipid sup-pression (total time, 17 min) in a voxel array and the SI dimension zero filled to 16 slices (3-mm resolution) with a voxel size of 0.12 to 0.16 cm3[4]. MRSI data were overlaid on the corresponding T2-weighted images, including the raw spectra and the metabolic ratio [choline + creatine to citrate (CC/C)][4]. Tumors were identified by dedicated radiologists with > 5 years of experience in prostate imaging.

1H-MRSI data interpretationAn MRI physicist with > 10 years of experience in prostate MRSI retrospectively interpreted the 1H-MRSI studies using established metabolic criteria for the evaluation of PCa in the peripheral and transition zones[6,14,26,27]. The physicist, who was blinded to clinical data and surgical pathology, recorded the location and total number of suspicious voxels (tumor volume estimation), maximum

(max) CC/C, and mean CC/C for the index lesion[6,14,26,27].

18F-FDG-PET/CT data acquisition and processingDetails of the 18F-FDG-PET/CT imaging procedure have been described previously[28]. Briefly, a low-dose CT scan (120-140 kV, approximately 80 mA), which is used for attenuation correction of PET emission images as well as for anatomic localization of PET abnormalities, was acquired first. This was followed by acquisition of PET emission images of the lower pelvis including of the prostate for 5 min per bed position. Images were reconstructed using iterative algorithms with average slice thickness of 3 mm and a 128 × 128 matrix size. Patients were scanned in the supine position. Before the examination, patients fasted for at least 6 h, but liberal intake of water was allowed. Patients were injected intravenously with 444-555 MBq of 18F-FDG and a PET/CT scan started after an uptake period of approximately 60 min. Plasma glucose level was < 200 mg at the time of imaging in all patients.

18F-FDG-PET/CT data interpretationAll 18F-FDG-PET/CT data were available for retrospective review on a standard clinical workstation (PACS with Advance Work Station extension; General Electric). One board-certified radiologist/nuclear medicine physician, who had > 10 years of experience in PET and > 5 years of experience in prostate imaging, reviewed the 18F-FDG-PET/CT studies. PET images were analyzed in three orthogonal planes (transaxial, coronal, sagittal) both visually and quantitatively. For quantitative PET analysis, maximum standardized uptake value (SUVmax) and average SUV (SUVmean) of the index lesion were determined using a Volume of Interest with 40% threshold of SUVmax. All SUVs were normalized to body weight.

PathologyWhole-mount transverse serial sections of the prostate were prepared as described previously[29]. The distal 5-mm portion of the apex was amputated and coned. The remainder of the gland was serially sectioned from the apex to the base at 3-4-mm intervals and submitted in its entirety for paraffin-embedded whole mounts. Cancer foci were outlined in ink on whole-mount, apical, and seminal vesicle sections and photographed. The photographs constituted the tumor maps. The primary and secondary Gleason grades as well as the pathologic tumor node stage were also determined. The index lesion was identified in all cases as the tumor with the largest volume. Tissue sections stained with H and E were examined by one uro-pathologist blinded to imaging and clinical data.

Matching of MRI/MRSI data, 18F-FDG-PET/CT and pathology dataThe matching of imaging and pathology for the index lesion was performed in consensus by two dually-boarded radiologists/nuclear medicine physicians with



> 5 years and > 15 years of experience in prostate imaging. The histopathologic axial step sections were visually matched with corresponding axial T2-weighted transverse MR images with superimposed MRSI data and fused 18F-FDG PET/CT data with a precision of ± 1 slice based on established anatomic landmarks[12]. Because the spectroscopic data were acquired in the same position and with the same gradients as the imaging data, registration of the spectroscopic data with the T2-weighted images was automatic, and the spectroscopic data could be compared with the most closely corresponding histopathologic step section.

Statistical analysisClinical and pathological characteristics were described using medians and ranges for continuous variables and frequencies and percents or proportions for categorical variables. Gleason grades were summed into Gleason scores of 6, 7, 8 or 9.

The localization rates of 18F-FDG-PET/CT and 1H-MRSI were calculated along with exact 95% confidence intervals. The relationships between PET parameters (SUVmax and SUVmean) and MRSI parameters (CC/Cmax, CC/Cmean, Total # Voxels) were assessed using Spearman’s rank correlation and graphically displayed with scatter plots and 95% confidence bands. Additionally, the relationships of PET and MRSI parameters to surgical Gleason score were assessed with Spearman’s rank

correlation and, given the Gleason score’s ordinal nature, graphically illustrated with box plots. P-values less than 0.05 were considered statistically significant. All analyses were done using SAS 9.4 (The SAS Institute, Cary, NC).

RESULTSPatient characteristics are summarized in Table 1. The patients had a median age of 58 years (range: 47-70 years) and median PSA of 4.81 ng/mL (range: 0.11-96.53 ng/mL).

Index tumor localization rates were 0.95 (95%CI: 0.77-1.00) for 1H-MRSI and 0.14 (95%CI: 0.03-0.35) for 18F-FDG-PET/CT, with 21 out of 22 index tumors found on pathology identified on 1H-MRSI and only 3 of those 21 index lesions identified on 18F-FDG-PET/CT. Figure 1 shows 1H-MRSI, 18F-FDG-PET/CT and whole-mount step-section pathology from a patient in whom the tumor seen at pathology was observed by multimodality imaging. Figure 2 shows 1H-MRSI, 18F-FDG-PET/CT and whole-mount step-section pathology from a patient in whom the tumor seen at pathology was observed by 1H-MRSI only. In the 3 patients with positive PET findings, the total tumor volumes measured by PET were 10.9, 11.1 and 10.4 cc and the SUVmax values were 3.3, 3.5 and 4.5. On 1H-MRSI in the 21 positive patients, CC/Cmax (median 6.4, range: 0.5-37.4), CC/Cmean (median 2.0, range: 0.5-18.5) and number of suspicious voxels (median 9.0, range 2-32) showed more profound alterations for all patients. Both the scatter plots (Figure 3 and Table 2) and the Spearman rank correlations indicated little relationship between 1H-MRSI parameters and 18F-FDG-PET/CT. Spearman’s ρ ranged between -0.362 and 0.28 (P-values range: 0.10-0.66). No clear pattern of association was detected in the graphs.

Gleason scores ranged from 6 (8/22, 36%) to 9 (4/22, 18.1%) with one patient lacking a score due to treatment effect. This patient was excluded from further analysis. Both the total number of voxels (ρ = 0.55, P = 0.0099) and the SUVmax (ρ = 0.46, P = 0.0366) correlated with the Gleason score. No significant relationship was found between the CC/Cmax, CC/Cmean or SUVmean and the Gleason score (P = 0.15-0.79, Table 3). The box plots demonstrate an upward trend for total number of voxels and SUVmax with each subsequent Gleason score (Figure 4).

DISCUSSIONMultimodality imaging in PCa detection on 1H-MRSI is based on the detection of decreased citrate and polyamines with elevated choline[2,4]. This is reflected in the high CC/Cmax (median 9.0) and CC/Cmean (median: 2.0) for the prostate index lesions. On 18F-FDG-PET/CT, PCa is identified based on increased glucose uptake by glucose transporters (GLUT) and glucose phosphorylation to glucose-6-phosphate by hexokinase[3,8]. The present study adds to the literature for patients with local or loco-regional primary or recurrent PCa and shows that the

n (%)

Clinical stage1 T1c 10 (45.5)T2a 4 (18.2)T2b 4 (18.2)T2c 1 (4.5)T3 1 (4.5)T3a 2 (9.1)

Biopsy Gleason score 0 + 0 1 (4.5)3 + 3 3 (13.6)3 + 4 5 (22.7)4 + 3 5 (22.7)4 + 4 4 (18.2)4 + 5 4 (18.2)

Pathology stage pT2a 3 (13.6)pT2b 5 (22.7)pT3a 7 (31.8)pT3b 6 (27.3)pT4 1 (4.5)

Pathology Gleason score 3 + 3 1 (4.5)3 + 4 8 (36.4)4 + 3 4 (18.2)4 + 4 4 (18.2)4 + 5 3 (13.6)5 + 4 1 (4.5)Not Graded2 1 (4.5)

Prior radiation treatment EBRT 11 (50)Untreated 11 (50)

Table 1 Patient characteristics

1Clinical stage was determined prior to primary or salvage surgery; 2One index tumor was not graded due to treatment effect. EBRT: External beam radiation therapy.



citrate decrease in PCa was both much more frequent and pronounced than was the elevation in 18F-FDG uptake. This is in-line with the known low sensitivity of 18F-FDG-PET/CT for detecting localized primary PCa. Further research is needed to develop a clearer understanding of the underlying genomic and metabolic mechanisms and to confirm whether metabolic alterations progress stepwise from early abnormalities in citrate metabolism to late abnormalities in glucose metabolism. Since our

patients were imaged at only one time point, the data appear consistent with this understanding. Improved understanding of PCa metabolism could help in deter-mining the most appropriate imaging modalities (including imaging with radiotracers) for different clinical stages of PCa and possibly also in identifying and monitoring novel targeted therapies.

For instance, according to the “bioenergetic theory of prostate malignancy”[1,17], the normal prostate produces

5.00

0.03

L

146

CA B

Figure 1 Representative 1.5T magnetic resonance imaging/magnetic resonance spectroscopic imaging in a 58-year-old patient with prostate specific antigen 96.53 ng/mL, clinical stage T3 and surgical Gleason score 4 + 5. A: Axial T2-weighted image and overlaid point-resolved spectroscopic box indicating excitation region selected and 3D MRSI demonstrating three suspicious voxels marked with asterisks; B: 18F-FDG-PET/CT fusion image shows a focal uptake in the left prostate; C: Whole-mount step-section histopathology after radical prostatectomy shows a large cancer in the left prostate. MRSI: Magnetic resonance spectroscopic imaging; 18F-FDG-PET/CT: 18F-fluorodeoxyglucose positron emission tomography/computed tomography.

1H-MRSI 18F-FDG Rho (ρ) P -value

CC/Cmax SUVmax -0.281 0.21SUVmean -0.101 0.66

CC/Cmean SUVmax -0.362 0.10SUVmean -0.158 0.48

Total # Voxels SUVmax 0.2565 0.25SUVmean 0.2783 0.21

Table 2 Spearman correlations between proton magnetic resonance spectroscopic imaging and 18F-fluorodeoxyglucose data (n = 22)

1H-MRSI: Proton magnetic resonance spectroscopic imaging; 18F-FDG:

18F-fluorodeoxyglucose.

With Gleason score18F-FDG/1H-MRSI Rho (ρ) P -valueCC/Cmax 0.2165 0.35CC/Cmean 0.0624 0.79Total # Voxels 0.5493 0.0099SUVmean 0.3225 0.15SUVmax 0.4584 0.0366

Table 3 Spearman correlations between proton magnetic resonance spectroscopic imaging and 18F-fluorodeoxyglucose data and surgical Gleason score (n = 22)

1H-MRSI: Proton magnetic resonance spectroscopic imaging; 18F-FDG:

18F-fluorodeoxyglucose.


CA B

Figure 2 Representative 1.5T magnetic resonance imaging/magnetic resonance spectroscopic imaging in a 64-year-old patient with prostate specific antigen 4.9 ng/mL, clinical stage T3 and surgical Gleason score 4 + 3. A: Axial T2-weighted image and overlaid point-resolved spectroscopic box indicating excitation region selected and 3D MRSI demonstrating ten suspicious voxels marked with asterisks; B: 18F-FDG-PET/CT fusion image shows no focal uptake in the prostate; C: Whole-mount step-section histopathology after radical prostatectomy shows a large cancer extending from medial to right side of the prostate. MRSI: Magnetic resonance spectroscopic imaging; 18F-FDG-PET/CT: 18F-fluorodeoxyglucose positron emission tomography/computed tomography.


and secretes an enormous amount of citrate; this is achieved by zinc-induced inhibition of m-aconitase, a Krebs cycle enzyme that converts citrate to isocitrate. With this truncated Krebs cycle, the normal prostate sacrifices ATP production for citrate secretion[17]. Conversely, in PCa, down-regulation of multiple membrane zinc transporters and zinc decline lead to activation of the full Krebs cycle, oxidation and a consequent decrease in intracellular and secreted citrate and increase in ATP production supporting malignancy[30-32]. However, the decline of citrate in PCa could also be related to its conversion to AcCoA by cytosolic ATP citrate lyase (ACLY) and subsequent utilization for fatty acid synthesis[30,33,34]. Activation of ACLY seems to be critical for biosynthesis and growth in various cancer models[30,34]. Thus, based on this bioenergetic theory, two possible scenarios could explain the low 18F-FDG uptake in early, slow-growing PCa: (1) early PCa exhibits only a mildly increased

cellular energy demand that is matched by activation of the mitochondrial Krebs cycle (bioenergetic mode); or (2) early PCa exhibits an unchanged energy demand and retains a persistently truncated Krebs cycle, but it diverts cytosolic citrate from secretion to fatty acid synthesis (biosynthetic mode).

Biochemical alterations in PCa may be linked to signaling pathways implicated in PCa initiation and progression. For example, the PTEN/PI-3-Kinase pathway, one of the central pathways in early PCa, is closely linked to cellular metabolism[35]. PTEN tumor suppressor loss, with subsequent activation of the PI-3-Kinase pathway and downstream effectors such as AKT and mTOR[36,37], has anabolic effects leading to increased glucose and amino acid uptake for the purposes of protein, fatty acid, and membrane synthesis, as well as the expression and membrane localization of glucose transporters[38]. Other consequences of PTEN loss include hexokinase translocation to the mitochondrial membrane[39], FA synthesis via ACLY[40,41], steroid hormone-dependent FA synthesis[42], glycogen synthesis, membrane localization of amino-acid transporters, amino-acid uptake, and protein synthesis[43]. Other signaling alterations that typically occur later in PCa progression may also eventually upregulate glycolysis. Loss of p53, for example, is associated with increased glycolysis through GLUT3 expression[44]. We therefore summarize the following: In early PCa, citrate is diverted from secretion to AKT-dependent FA synthesis and/or to zinc-deficiency-induced oxidation in the Krebs cycle, leading to a decline in citrate signal on 1H-MRSI. While AKT-dependent stimulation of glycolysis alone is insufficient to produce a detectable increase in 18F-FDG uptake in PCa, the subsequent loss of p53 further promotes glycolysis, resulting in a detectable difference in 18F-FDG uptake between PCa and normal prostate tissue. We are hoping that future studies which include genomic and proteomic tissue analysis, may eventually link tumor biology and imaging in PCa. Such links have been made in other studies. For instance, the extent of changes in intermediary metabolism on 1H-MRSI has been shown to correlate with the Gleason grade[14]. Similarly, risk scoring based on metabolic changes on 1H-MRSI has been found to correlate with treatment outcome in patients with high-risk PCa who underwent neoadjuvant chemotherapy/hormone therapy before radical prostatectomy or radiation therapy[15]. Conversely, near-normal intermediary meta-bolism on pre-treatment 1H-MRSI has been found to predict very-low-risk PCa in radical prostatectomy specimens[16].

Certain PET tracers are superior to 18F-FDG in de-tecting early PCa and early recurrence after radical prostatectomy or radiation therapy[18-24]. In contrast, in the most-advanced form of PCa, castration-resistant disease, 18F-FDG-PET/CT is predictive of survival[28,45], supporting the statement that increased glycolysis represents a late and ominous event in the progression of PCa. Of note, 18F-FDG-PET/CT has been established as predictive of outcome in multiple other cancers, with high 18F-FDG avidity predicting poor outcome[46-49]. The present study

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Figure 3 Scatter plots demonstrating the relationships between proton magnetic resonance spectroscopic imaging and 18F-fluorodeoxyglucose positron emission tomography parameters (n = 22). PET: Positron emission tomography.



has a few limitations given its retrospective study design and the fact that we could not control for treatment. Also, due to a low sample size, it was not feasible to estimate survival. However, this study met its purpose of exploring the relationship using multimodality imaging between 1H-MRSI and 18F-FDG-PET/CT in PCa patients. To optimize PCa multimodality imaging, it is critical to understand how different metabolic imaging techniques interact and how they can be used to develop the most effective imaging protocols.

The present study suggests that the concentration of intermediary metabolites detected by 1H MRSI and glycolytic flux measured 18F-FDG PET show little correla-tion. Furthermore, only few tumors were FDG avid on PET, possibly because increased glycolysis represents a late and rather ominous event in the progression of PCa.

ACKNOWLEDGMENTSThe authors thank Ada Muellner, MS for editing the manuscript.

COMMENTSBackgroundAlthough metabolic imaging is increasingly utilized in prostate cancer (PCa), the mechanisms leading to cancer-related metabolic rearrangements and consequent imaging findings remain poorly understood. The aim of the study was to better understand the sequence of metabolic changes in localized PCa.

Research frontiersTo optimize PCa multimodality imaging, it is critical to understand how different metabolic imaging techniques interact and how they can be used to develop the most effective imaging protocols.

Innovations and breakthroughsComparison of proton magnetic resonance spectroscopic imaging (1H-MRSI) and 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG-PET/CT) findings in local PCa demonstrated that abnormal choline intermediary metabolism on 1H-MRSI precedes the changes in glycolysis on 18F-FDG-PET/CT.

ApplicationsIn principle, imaging analysis of distinct metabolic pathways in PCa can be utilized to predict patient outcome, optimize management, and plan future

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Figure 4 Box plots demonstrating the relationships between surgical Gleason score and imaging parameters (n = 22).

COMMENTS



diagnostic and therapeutic trials in PCa.

Terminology1H-MRSI: Proton magnetic resonance spectroscopic imaging; 18F-FDG-PET: 18F-FDG-positron emission tomography; PCa: Prostate cancer.

Peer-reviewThe topic is actual and interesting.

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P- Reviewer: Hekal IA, Huang SP, Simone G S- Editor: Ji FF L- Editor: A E- Editor: Li D


Mitchell Chen, Gaith Mattar, Jamal A Abdulkarim

ORIGINAL ARTICLE


Computed tomography pulmonary angiography using a 20% reduction in contrast medium dose delivered in a multiphasic injection

Observational Study

Mitchell Chen, Jamal A Abdulkarim, Department of Radiology, George Eliot Hospital NHS Trust, Nuneaton, Warwickshire CV10 7DJ, United Kingdom

Gaith Mattar, Department of Radiology, University Hospitals Birmingham NHS Trust, Birmingham B15 2TH, United Kingdom

Author contributions: Abdulkarim JA designed the experiment; Chen M and Abdulkarim JA conducted literature research; Mattar G and Abdulkarim JA performed the data collection; Chen M analysed the data; Chen M and Abdulkarim JA prepared the manuscript.

Institutional review board statement: The study was reviewed and approved by the George Eliot Hospital NHS Trust Directorate of Audit and Research.

Informed consent statement: Individual consent from patients was not obtained as this is retrospective observational study. All patient data were fully anonymised.

Conflict-of-interest statement: Chen M declares no conflict of interest. Mattar G declares no conflict of interest. Abdulkarim JA declares no conflict of interest.

Data sharing statement: Technical appendix, statistical code, and dataset available from the corresponding author at [email protected]. Consent was not obtained for data sharing but the presented data are anonymised and risk of identification is low.



Correspondence to: Jamal A Abdulkarim, FRCR, Consultant Radiologist, Department of Radiology, George Eliot Hospital NHS Trust, College Street, Nuneaton, Warwickshire CV10 7DJ, United Kingdom. [email protected]: +44-247-6351351Fax: +44-247-6865175

Received: October 5, 2016Peer-review started: October 9, 2016First decision: November 29, 2016Revised: December 30, 2016Accepted: January 16, 2017Article in press: January 18, 2017Published online: March 28, 2017

AbstractAIMTo evaluate the feasibility of reducing the dose of iodi-nated contrast agent in computed tomography pulmonary angiography (CTPA).

METHODSOne hundred and twenty-seven patients clinically suspected of having pulmonary embolism underwent spiral CTPA, out of whom fifty-seven received 75 mL and the remaining seventy a lower dose of 60 mL of contrast agent. Both doses were administered in a multiphasic injection. A minimum opacification threshold of 250 Houn-sfield units (HU) in the main pulmonary artery is used for assessing the technical adequacy of the scans.

RESULTSMean opacification was found to be positively correlated to patient age (Pearson’s correlation 0.4255, P < 0.0001) and independent of gender (male:female, 425.6 vs 450.4,



DOI: 10.4329/wjr.v9.i3.143




Chen M et al . CTPA with a reduced contrast dose

P = 0.34). When age is accounted for, the study and control groups did not differ significantly in their mean opacification in the main (436.8 vs 437.9, P = 0.48), left (416.6 vs 419.8, P = 0.45) or the right pulmonary arteries (417.3 vs 423.5, P = 0.40). The number of sub-optimally opacified scans (the mean opacification in the main pulmonary artery < 250 HU) did not differ sig-nificantly between the study and control groups (7 vs 10).

CONCLUSIONA lower dose of iodine contrast at 60 mL can be feasibly used in CTPA without resulting in a higher number of sub-optimally opacified scans.

Key words: Computed tomography pulmonary angio-graphy; Contrast dose; Contrast induced nephropathy; Acute kidney disease; Contrast safety; Contrast dose reduction; Multiphasic injection


Core tip: Computed tomography pulmonary angiography scanning using a lower dose of contrast agent (60 mL) is proposed. Comparisons were made to patients in a control group who have received a standard dose of contrast medium (75 mL) at our Trust. There is no statistical difference in the degree of opacification in the main pulmonary artery between the two groups. The rate of rejection due to inadequate opacification is not affected by the reduction in contrast dose. The feasibility of using a reduced contrast dose at 60 mL is clearly demonstrated.

Chen M, Mattar G, Abdulkarim JA. Computed tomography pulmonary angiography using a 20% reduction in contrast medium dose delivered in a multiphasic injection. World J Radiol 2017; 9(3): 143-147 Available from: URL: http://www.wjgnet.com/1949-8470/full/v9/i3/143.htm DOI: http://dx.doi.org/10.4329/wjr.v9.i3.143

INTRODUCTIONComputed tomography pulmonary angiography (CTPA) is the de facto gold standard investigation for detecting or ruling out the presence of pulmonary embolism (PE)[1]. The degree of pulmonary arterial opacification defines the technical adequacy of a CTPA scan. It is proportional to the rate and dose of contrast medium administration[2]. A good quality scan is essential for optimising its negative predictive value. However, using a high dose of contrast medium can lead to contrast induced-acute kidney injury (CI-AKI), formerly known as contrast-induced nephro-pathy, when there is a sudden rise in serum creatinine following the exposure to iodinated contrast media, that is not linked to another nephrotoxic event. The condition is normally self-limiting but can lead to increased mor-bidity and mortality[3]. Certain patient groups are at

an increased risk of developing CI-AKI; such as those affected by hypertension, chronic kidney disease (CKD), diabetes mellitus, congestive heart failure, reduced intravascular volume, advanced age and recent exposure to nephrotoxic drugs[4]. For this reason, the dose of contrast should be kept to a minimum provided that it does not affect the overall quality of the image.

Recent advances in computed tomography (CT) tech-nology have enabled faster image acquisition times, thus reducing the time required during which the pulmonary vasculature must be opacified. This has made it possible to consider reducing the dose of contrast medium used in CTPA[5]. At our Trust, the current protocol is to administer 75 mL of 350 mg/mL iodine/ioversol delivered via a multiphasic injection. In this study, we have tested the hypothesis that the scan is technically adequate using only a 60 mL dose of the contrast medium at the same concentration. The dose reduction is intended to enhance patient safety as well reducing the overall scanning cost.

MATERIALS AND METHODSPatient selectionOne hundred and twenty-seven patients clinically sus-pected of having PE underwent spiral CTPA between the months of January to April 2015; of these subjects, seventy received a higher dose of 75 mL (control group) and the remaining fifty-seven, 60 mL (study group) of 350 mg/mL iodine/ioversol contrast agent (Omnipaque 350, GE Healthcare, United States). The dose reduction of 20% was chosen in conjunction with the CT scanner manufacturer (Siemens AG). In this observational study, both patient cohorts were studied retrospectively. Patient cohort allocation was not randomised due to the nature of this study.

In the control group, there were 32 male and 38 female patients, whose mean age was 65.7 years [range (34-93)]. In the study group, there were 23 male and 34 female patients, with a mean age of 62.7 years [range (16-92)]. Characteristics of the study population are given in Table 1. Patient data were fully anonymised.

CTPA protocolScans were performed on a 128-slice CT scanner (Somatom Definition AS+, Siemens AG, Berlin and Munich, Germany), and acquired with a radiation dose of 120 kV and a tube output of a minimum of 666 mAs/80 kW for 5 s, 0.3 s rotation time, pitch 0.6, 0.6 mm slice thickness with 38.4 mm collimation.

The contrast medium was given via an 18G cannula, placed in the ante-cubital fossa and delivered via a power injector (Ulrich Inject CT Motion, Ulrich Medical, Buchbrunnenweg, Germany) at a rate of 5 mL/s, with a saline chaser of 25 mL at the same injection rate. The overall injection time is 12 s for 60 mL of contrast and 15 s for 75 mL of contrast.

We used a bolus tracking method to control the scan initiation. We first acquired an initial low-dose monitoring image six seconds after contrast injection and repeated


every 1.5 s thereafter. Upon reaching a threshold of 100 Hounsfield units (HU) in the main pulmonary artery, the scan was initiated. The scan table is then moved from the monitoring to the starting position; during which time patients were instructed to breath-hold for 4-6 s. CTPA scans were acquired in a cranio-caudal direction. The images were reconstructed using Siemens iterative reconstruction method, SAFIRE (Sinogram Affirmated Iterative Reconstruction, strength 3).

Patients’ age and gender were obtained retro-spectively from their medical notes. Patient weight was not examined in this study.

Image data assessmentA radiology registrar with 3 year of experience per-formed the image data analysis retrospectively on an Insignia Picture Achieving and Communication System workstation (Basingstoke, United Kingdom). We mea-sured image opacification in the main, left and right pulmonary arteries. An acceptance threshold of a 250 HU for main pulmonary artery opacification was adopted for our study, as it was the figure used widely in various literatures[6].

Statistical analysisWe used the χ2 test to analyse categorical variables such as gender and number of rejected scans and Pearson’s coefficient for the correlation studies. We performed all statistical tests with a significance level of P < 0.05. Statistical calculations were performed using Microsoft Excel 2010 (Microsoft Corp, United States).

RESULTSWe found no significant difference between the two groups in either age (P value: 0.35) or gender (P value: 0.42).

Sample axial images from the 60 and 75 mL groups are given in Figure 1, showing the good opacification of the main pulmonary arteries.

The mean opacification values in the main, right and left pulmonary arteries are shown in Table 2. Even though the reported degree of opacification was higher with 75 mL of contrast medium, the difference did not affect the overall image quality, as shown in the dis-cussion below.

We found the mean opacification to be positively correlated to patient age (Pearson’s correlation 0.426, P < 0.0001). When age is accounted for by introducing an age-dependent linear regression coefficient to the mean opacification measure, the two groups did not differ significantly in terms of their mean opacification in the main (437 vs 438, P = 0.48), left (417 vs 420, P = 0.45) or the right pulmonary arteries (417 vs 424, P = 0.40). Taking an acceptance threshold of 250 HU, the rate of rejected scans did not differ significantly between the two groups, as shown in Table 3.

DISCUSSIONVarious past literature have reported on the use of a smaller dose of contrast media in CTPA[7-9]. In a former study carried out at our centre[7], we have established the feasibility of using a 75 mL of contrast in a higher concentration (350 mg/mL Iodine/Ioversol), compared to 100 mL of a standard concentration (300 mg/mL Iodine/Ioversol). This finding was also reported in a Randomised Clinical Trial published in the same year[8], which further established the use of a lower energy tube (80 kVp vs 100 kVp) for a reduced dose of radiation. In a different single cohort study[9], the authors have evaluated the practicality of CTPA with 30 mL of contrast medium in patients with renal impairment. Although it was stated that only one out of 24 scans were non-diagnostic, the reported average opacification (247 HU) in the main

60 mL 75 mL (control)

Size 57 70Gender (M:F) 23:34 32:38Mean age (yr) 65.7 62.7Age range (yr) 34-93 16-92

Table 1 Characteristics of the study population

M: Male; F: Female.

A B

Figure 1 Sample axial image slices showing the good opacification in the main pulmonary artery with intravenous contrast in the two groups (red arrows). A: 60 mL; B: 75 mL.



pulmonary arteries is notably lower than that found in our study and is below the 250 HU threshold that we have used. Furthermore, their work was a single cohort study and reported no comparisons to a control group.

The risk of CI-AKI in the general population is low (less than 2%) but would greatly increase to up to 40% in patients with certain risk factors (diabetes mellitus, cardiac failure, CKD, older age and recent exposure to nephrotoxic drugs)[3]. Since the risk of CI-AKI is known to be dose-dependent[3], the goal would be to keep the dose of contrast medium to a minimum. Additionally, a reduction in contrast medium dose can lower the cost by about 15% per scan, which is in line with figures cited in a related study[10].

Our study utilised a lower dose (60 mL) of contrast agent compared to the normal dose (75 mL) currently used in clinical practice at our Trust. The study results show that a further reduction in contrast agent dose in CTPA is possible, without impairing pulmonary arterial enhancement.

To highlight sub-optimally opacified scans, we used an acceptance threshold of 250 HU. It is important to note that there is no overall consensus on this cut-off figure and various other figures have been quoted in past literature[5,11]. The threshold of 250 HU was chosen based on the authors’ own clinical experience: When reporting on CTPA scans, a single radiodensity measurement is made in the main pulmonary artery and as such, PE can not be confidently ruled out if the minimum opacification was less than 250 HU. With this figure, the experimental and control groups have yielded a scan acceptance rate of 89% and 86%, respectively. This is comparable to the 88.9% acceptance rate quoted in Nazaroglu et al[12]. We note that the Hounsfield Unit is not the optimal quality measure for indeterminate scans, such as those affected by flow or streak artefacts. Given these artefacts are more prominent at a lower contrast dose, alternative quality measures such as a visual grading system or reporter confidence can be employed to potentially better assess our data.

Some patient factors are known to influence the

degree of vascular opacification. Most notably, age has been demonstrated to have a positive correlation with the degree of opacification[11], which is reflected in our results. Body weight is yet another factor with a negative impact on image opacification[5], this was not assessed given the retrospective nature of our study.

Another limitation of our study is that the patients were not monitored for any change in their renal func-tion, as this was not routinely done in our hospital but only reserved for those with a clinical suspicion of CI-AKI. Therefore, we were not able to assess the impact of using a lower dose of contrast medium on the incidence of CI-AKI. Moreover, given the small study size and the low incidence of CI-AKI in the general population, it might have been difficult to establish compelling evidence on this even had such test results been available. A potential improvement can be achieved by prospectively recruiting patients who are at a higher risk of developing CI-AKI and monitor for any incidence difference of CIN in the low contrast dose group. However, even without this result, knowing the dose-dependent nature of CI-AKI, it would still be sensible to strive for any contrast dose reduction when possible, especially for patients more prone to developing this condition[13].

Finally, we have focused our measurements on the central pulmonary vasculature whereas pulmonary emboli can also be found in the peripheries. It should be noted that the isolation and sampling of smaller peripheral vessel would be technically challenging and potentially inaccurate, and it is therefore impractical to incorporate peripheral vessel measurements at this stage.

In summary, our study demonstrated that using a reduced dose of contrast medium (60 mL vs 75 mL) is a clinically feasible without adversely affecting the image quality and diagnostic value of CTPA for PE. We propose the lower contrast dose of 60 mL should be used as standard practice in all patients undergoing CTPA.

ACKNOWLEDGMENTSWe would like to thank Mr Adam Ryder and the rest of the CT team at the George Eliot Hospital for their help during this study.

COMMENTSBackgroundComputed tomography pulmonary angiography (CTPA) is the de facto gold standard for visualising the pulmonary arteries to detect the presence of

Mean opacification ± standard deviation

60 mL of contrast agent 75 mL of contrast agent Mean difference (95%CI)Main pulmonary artery 437 ± 121 438 ± 142 1 (-45 to 47)Right pulmonary artery 417 ± 115 420 ± 130 3 (-41 to 47)Left pulmonary artery 417 ± 110 424 ± 140 7 (-38 to 50)

Table 2 A comparison of mean opacification values in the pulmonary arteries between the two groups

All values are given in Hounsfield units.

Group Number of sub-optimal studies

75 mL 1060 mL 7

P = 0.96

Table 3 Number of sub-optimal studies in each group

COMMENTS



pulmonary emboli (PE). However, the use of contrast agent in this modality can lead to contrast-induced acute kidney injury (CI-AKI). To enhance the safety of CTPA for patients prone to developing CI-AKI, such as the elderly and those with diabetes mellitus, cardiac failure or chronic kidney disease, a dose reduction is desirable and has been rendered feasible with recent technological advancements in computed tomography image acquisition and multiphasic contrast injection.

Research frontiersThe focus in this research area has been on reducing the dose of contrast used in CTPA to achieve better patient safety, while still producing technically satisfactory imaging data for PE detection.

Innovations and breakthroughsThe authors have demonstrated the feasibility of using a lower dose (60 mL) of contrast agent compared to the normal dose (75 mL) currently used at this Trust. The study results have shown that CTPA can be performed at this reduced contrast dose level without rendering pulmonary arterial enhancement inadequate.

ApplicationsThe result can be applied to clinical radiology practice where a lower dose of contrast can be used to produce technically adequate imaging data. Future works include the inclusion of patient body weight, a large sample size and a study of the specific effect of contrast medium dose on patients’ kidney function. A further reduction in contrast dose can also be considered.

Peer-reviewThis study utilised a lower dose (60 mL) of contrast agent compared to the normal dose (75 mL) currently used in clinical practice. The experimental results have shown that a reduction in contrast agent dose can be achieved without adversely affecting pulmonary arterial enhancement in CTPA. They demonstrated that using a reduced dose of contrast medium (60 mL vs 75 mL) is a clinically feasible without adversely affecting the image quality and diagnostic value of CTPA for PE. They proposed the lower contrast dose of 60 mL should be used as standard practice in all patients undergoing CTPA. The dose reduction is intended to enhance patient safety as well reducing the overall scanning cost. The dose reduction is a hot issue at present. This is a useful paper for the patient’s health care.

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P- Reviewer: Chow J, Gao BL, Li YZ S- Editor: Song XX L- Editor: A E- Editor: Li D


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World Journal of - Microsoft · 2017-05-14 · World Journal of W J R Radiology The World Journal of Radiology Editorial Board consists of 365 members, representing a team of worldwide