WJRV 4 I 8

ISSN 1949-8470 (online)
World Journal of Radiology

World J Radiol 2012 August 28; 4(8): 345-390
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Editorial Board
2009-2013
The World Journal of Radiology Editorial Board consists of 319 members, representing a team of worldwide experts in radiology. They are from 40 countries, including Australia (3), Austria (4), Belgium (5), Brazil (3), Canada (9), Chile (1), China (25), Czech (1), Denmark (1), Egypt (4), Estonia (1), Finland (1), France (6), Germany (17), Greece (8), Hungary (1), India (9), Iran (5), Ireland (1), Israel (4), Italy (28), Japan (14), Lebanon (1), Libya (1), Malaysia (2), Mexico (1), Netherlands (4), New Zealand (1), Norway (1), Saudi Arabia (3), Serbia (1), Singapore (2), Slovakia (1), South Korea (16), Spain (8), Switzerland (5), Thailand (1), Turkey (20), United Kingdom (16), and United States (82).
EDITOR-IN-CHIEF Filippo Cademartiri, Monastier di Treviso STRATEGY ASSOCIATE EDITORS-IN-CHIEF Ritesh Agarwal, Chandigarh Kenneth Coenegrachts, Bruges Mannudeep K Kalra, Boston Meng Law, Lost Angeles Ewald Moser, Vienna Aytekin Oto, Chicago AAK Abdel Razek, Mansoura lex Rovira, Barcelona Yi-Xiang Wang, Hong Kong Hui-Xiong Xu, Guangzhou GUEST EDITORIAL BOARD MEMBERS Wing P Chan, Taipei Wen-Chen Huang, Taipei Shi-Long Lian, Kaohsiung Chao-Bao Luo, Taipei Shu-Hang Ng, Taoyuan Pao-Sheng Yen, Haulien MEMBERS OF THE EDITORIAL BOARD
Siegfried Trattnig, Vienna
Belgium Piet R Dirix, Leuven Yicheng Ni, Leuven Piet Vanhoenacker, Aalst Jean-Louis Vincent, Brussels
Brazil Emerson L Gasparetto, Rio de Janeiro Edson Marchiori, Petrpolis Wellington P Martins, So Paulo
Shen Fu, Shanghai Gang Jin, Beijing Tak Yeung Leung, Hong Kong Wen-Bin Li, Shanghai Rico Liu, Hong Kong Yi-Yao Liu, Chengdu Wei Lu, Guangdong Fu-Hua Peng, Guangzhou Liang Wang, Wuhan Li-Jun Wu, Hefei Zhi-Gang Yang, Chengdu Xiao-Ming Zhang, Nanchong Chun-Jiu Zhong, Shanghai
Czech Canada Sriharsha Athreya, Hamilton Mark Otto Baerlocher, Toronto Martin Charron, Toronto James Chow, Toronto John Martin Kirby, Hamilton Piyush Kumar, Edmonton Catherine Limperpoulos, Quebec Ernest K Osei, Kitchener Weiguang Yao, Sudbury Vlastimil Vlek, Brno
Denmark Poul Erik Andersen, Odense
Egypt Mohamed Abou El-Ghar, Mansoura Mohamed Ragab Nouh, Alexandria Ahmed A Shokeir, Mansoura
Australia Karol Miller, Perth Tomas Kron, Melbourne Zhonghua Sun, Perth
Chile Masami Yamamoto, Santiago
Estonia China Tiina Talvik, Tartu
Austria Herwig R Cerwenka, Graz Daniela Prayer,Vienna
Feng Chen, Nanjing Ying-Sheng Cheng, Shanghai Woei-Chyn Chu, Taipei Guo-Guang Fan, Shenyang
Finland Tove J Grnroos, Turku
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France Alain Chapel, Fontenay-Aux-Roses Nathalie Lassau, Villejuif Youlia M Kirova, Paris Graldine Le Duc, Grenoble Cedex Laurent Pierot, Reims Frank Pilleul, Lyon Pascal Pommier, Lyon
Ireland Joseph Simon Butler, Dublin
Malaysia R Logeswaran, Cyberjaya Kwan-Hoong Ng, Kuala Lumpur
Israel Amit Gefen, Tel Aviv Eyal Sheiner, Beer-Sheva Jacob Sosna, Jerusalem Simcha Yagel, Jerusalem
Mexico Heriberto Medina-Franco, Mexico City
Germany Ambros J Beer, Mnchen Thomas Deserno, Aachen Frederik L Giesel, Heidelberg Ulf Jensen, Kiel Markus Sebastian Juchems, Ulm Kai U Juergens, Bremen Melanie Kettering, Jena Jennifer Linn, Munich Christian Lohrmann, Freiburg David Maintz, Mnster Henrik J Michaely, Mannheim Oliver Micke, Bielefeld Thoralf Niendorf, Berlin-Buch Silvia Obenauer, Duesseldorf Steffen Rickes, Halberstadt Lars V Baron von Engelhardt, Bochum Goetz H Welsch, Erlangen Italy Mohssen Ansarin, Milan Stefano Arcangeli, Rome Tommaso Bartalena, Imola Sergio Casciaro, Lecce Laura Crocetti, Pisa Alberto Cuocolo, Napoli Mirko DOnofrio, Verona Massimo Filippi, Milan Claudio Fiorino, Milano Alessandro Franchello, Turin Roberto Grassi, Naples Stefano Guerriero, Cagliari Francesco Lassandro, Napoli Nicola Limbucci, L'Aquila Raffaele Lodi, Bologna Francesca Maccioni, Rome Laura Martincich, Candiolo Mario Mascalchi, Florence Roberto Miraglia, Palermo Eugenio Picano, Pisa Antonio Pinto, Naples Stefania Romano, Naples Luca Saba, Cagliari Sergio Sartori, Ferrara Mariano Scaglione, Castel Volturno Lidia Strigari, Rome Vincenzo Valentini, Rome
Netherlands Jurgen J Ftterer, Nijmegen Raffaella Rossin, Eindhoven Paul E Sijens, Groningen
New Zealand W Howell Round, Hamilton
Norway Arne Sigmund Borthne, Lrenskog
Saudi Arabia Mohammed Al-Omran, Riyadh Ragab Hani Donkol, Abha Volker Rudat, Al Khobar
Greece Panagiotis Antoniou, Alexandroupolis George C Kagadis, Rion Dimitris Karacostas, Thessaloniki George Panayiotakis, Patras Alexander D Rapidis, Athens C Triantopoulou, Athens Ioannis Tsalafoutas, Athens Virginia Tsapaki, Anixi Ioannis Valais, Athens
Serbia Djordjije Saranovic, Belgrade
Singapore Uei Pua, Singapore Lim CC Tchoyoson, Singapore
Hungary Peter Laszlo Lakatos, Budapest
India Anil Kumar Anand, New Delhi Surendra Babu, Tamilnadu Sandip Basu, Bombay Kundan Singh Chufal, New Delhi Shivanand Gamanagatti, New Delhi Vimoj J Nair, Haryana R Prabhakar, New Delhi Sanjeeb Kumar Sahoo, Orissa
Japan Shigeru Ehara, Morioka Nobuyuki Hamada, Chiba Takao Hiraki, Okayama Akio Hiwatashi, Fukuoka Masahiro Jinzaki, Tokyo Hiroshi Matsuda, Saitama Yasunori Minami, Osaka Jun-Ichi Nishizawa, Tokyo Tetsu Niwa, Yokohama Kazushi Numata, Kanagawa Kazuhiko Ogawa, Okinawa Hitoshi Shibuya, Tokyo Akira Uchino, Saitama Haiquan Yang, Kanagawa
Slovakia Frantiek Dubeck, Bratislava
South Korea Bo-Young Choe, Seoul Joon Koo Han, Seoul Seung Jae Huh, Seoul Chan Kyo Kim, Seoul Myeong-Jin Kim, Seoul Seung Hyup Kim, Seoul Kyoung Ho Lee, Gyeonggi-do Won-Jin Moon, Seoul Wazir Muhammad, Daegu Jai Soung Park, Bucheon Noh Hyuck Park, Kyunggi Sang-Hyun Park, Daejeon Joon Beom Seo, Seoul Ji-Hoon Shin, Seoul Jin-Suck Suh, Seoul Hong-Gyun Wu, Seoul
Iran Vahid Reza Dabbagh Kakhki, Mashhad Mehran Karimi, Shiraz Farideh Nejat, Tehran Alireza Shirazi, Tehran Hadi Rokni Yazdi, Tehran
Lebanon Aghiad Al-Kutoubi, Beirut
Libya Anuj Mishra, Tripoli
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Spain Eduardo J Aguilar, Valencia Miguel Alcaraz, Murcia Juan Luis Alcazar, Pamplona Gorka Bastarrika, Pamplona Rafael Martnez-Monge, Pamplona Alberto Muoz, Madrid Joan C Vilanova, Girona
United Kingdom K Faulkner, Wallsend Peter Gaines, Sheffield Balaji Ganeshan, Brighton Nagy Habib, London Alan Jackson, Manchester Pradesh Kumar, Portsmouth Tarik F Massoud, Cambridge Igor Meglinski, Bedfordshire Robert Morgan, London Ian Negus, Bristol Georgios A Plataniotis, Aberdeen N J Raine-Fenning, Nottingham Manuchehr Soleimani, Bath MY Tseng, Nottingham Edwin JR van Beek, Edinburgh Feng Wu, Oxford
Switzerland Nicolau Beckmann, Basel Silke Grabherr, Lausanne Karl-Olof Lvblad, Geneva Tilo Niemann, Basel Martin A Walter, Basel
United States Thailand Sudsriluk Sampatchalit, Bangkok Athanassios Argiris, Pittsburgh Stephen R Baker, Newark Lia Bartella, New York Charles Bellows, New Orleans Walter L Biffl, Denver Homer S Black, Houston Wessam Bou-Assaly, Ann Arbor Owen Carmichael, Davis Shelton D Caruthers, St Louis Yuhchyau Chen, Rochester Melvin E Clouse, Boston Ezra Eddy Wyssam Cohen, Chicago Aaron Cohen-Gadol, Indianapolis Patrick M Colletti, Los Angeles Kassa Darge, Philadelphia Abhijit P Datir, Miami Delia C DeBuc, Miami Russell L Deter, Houston Adam P Dicker, Phil Khaled M Elsayes, Ann Arbor Steven Feigenberg, Baltimore Christopher G Filippi, Burlington Victor Frenkel, Bethesda Thomas J George Jr, Gainesville Patrick K Ha, Baltimore Robert I Haddad, Boston Walter A Hall, Syracuse Mary S Hammes, Chicago
Turkey Olus Api, Istanbul Kubilay Aydin, stanbul Il Bilgen, Izmir Zulkif Bozgeyik, Elazig Barbaros E il, Ankara Gulgun Engin, Istanbul M Fatih Evcimik, Malatya Ahmet Kaan Gndz, Ankara Tayfun Hakan, Istanbul Adnan Kabaalioglu, Antalya Fehmi Kamaz, Ankara Musturay Karcaaltincaba, Ankara Osman Kizilkilic, Istanbul Zafer Koc, Adana Cem Onal, Adana Yahya Paksoy, Konya Bunyamin Sahin, Samsun Ercument Unlu, Edirne Ahmet Tuncay Turgut, Ankara Ender Uysal, Istanbul
John Hart Jr, Dallas Randall T Higashida, San Francisco Juebin Huang, Jackson Andrei Iagaru, Stanford Craig Johnson, Milwaukee Ella F Jones, San Francisco Csaba Juhasz, Detroit Riyad Karmy-Jones, Vancouver Daniel J Kelley, Madison Amir Khan, Longview Euishin Edmund Kim, Houston Vikas Kundra, Houston Kennith F Layton, Dallas Rui Liao, Princeton CM Charlie Ma, Philadelphia Nina A Mayr, Columbus Thomas J Meade, Evanston Steven R Mess, Philadelphia Nathan Olivier Mewton, Baltimore Feroze B Mohamed, Philadelphia Koenraad J Mortele, Boston Mohan Natarajan, San Antonio John L Nosher, New Brunswick Chong-Xian Pan, Sacramento Dipanjan Pan, St Louis Martin R Prince, New York Reza Rahbar, Boston Carlos S Restrepo, San Antonio Veronica Rooks, Honolulu Maythem Saeed, San Francisco Edgar A Samaniego, Palo Alto Kohkan Shamsi, Doylestown Jason P Sheehan, Charlottesville William P Sheehan, Willmar Charles Jeffrey Smith, Columbia Monvadi B Srichai-Parsia, New York Dan Stoianovici, Baltimore Janio Szklaruk, Houston Dian Wang, Milwaukee Jian Z Wang, Columbus Shougang Wang, Santa Clara Wenbao Wang, New York Aaron H Wolfson, Miami Gayle E Woloschak, Chicago Ying Xiao, Philadelphia Juan Xu, Pittsburgh Benjamin M Yeh, San Francisco Terry T Yoshizumi, Durham Jinxing Yu, Richmond Jianhui Zhong, Rochester
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Contents
EDITORIAL
345

Monthly Volume 4 Number 8 August 28, 2012
Extrahepatic biliary cancer: New staging classification
Ganeshan D, Moron FE, Szklaruk J
REVIEW
353
Progress in atherosclerotic plaque imaging

Soloperto G, Casciaro S
BRIEF ARTICLES
372
Imaging investigation of pancreatic cystic lesions and proposal for therapeutic guidelines
Hilendarov AD, Deenichin GP, Velkova KG
379
Hepatocellular carcinoma treated with transarterial chemoembolization: Evaluation with parametric contrast-enhanced ultrasonography
Moschouris H, Malagari K, Marinis A, Kornezos I, Stamatiou K, Nikas G, Papadaki MG, Gkoutzios P
CASE REPORT
387
Inferior pancreaticoduodenal artery aneurysm treated with coil packing and stent placement
Ikoma A, Nakai M, Sato M, Kawai N, Tanaka T, Sanda H, Nakata K, Minamiguchi H, Sonomura T
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August 28, 2012|Volume 4|Issue 8|
Contents
ACKNOWLEDGMENTS APPENDIX
I I I-V
Volume 4 Number 8 August 28, 2012

Acknowledgments to reviewers of World Journal of Radiology Meetings Instructions to authors Editorial Board Member of World Journal of Radiology , Ewald Moser, PhD, Associate Professor of Medical Physics and Biophysics, MR Center of Excellence, Center for Medical Physics and Biomedical Engineering, Medical University of Vienna, Lazarettgasse 14, A-1090 Vienna, Austria World Journal of Radiology (World J Radiol, WJR, online ISSN 1949-8470, DOI: 10.4329) is a monthly peer-reviewed, online, open-access, journal supported by an editorial board consisting of 319 experts in radiology from 40 countries. The major task of WJR is to rapidly report the most recent improvement in the research of medical imaging and radiation therapy by the radiologists. WJR accepts papers on the following aspects related to radiology: Abdominal radiology, women health radiology, cardiovascular radiology, chest radiology, genitourinary radiology, neuroradiology, head and neck radiology, interventional radiology, musculoskeletal radiology, molecular imaging, pediatric radiology, experimental radiology, radiological technology, nuclear medicine, PACS and radiology informatics, and ultrasound. We also encourage papers that cover all other areas of radiology as well as basic research. I-III Editorial Board
ABOUT COVER
AIM AND SCOPE
FLYLEAF
EDITORS FOR THIS ISSUE

NAME OF JOURNAL World Journal of Radiology ISSN ISSN 1949-8470 (online) LAUNCH DATE December 31, 2009 FREQUENCY Monthly
Responsible Assistant Editor: Jian-Xia Cheng Responsible Electronic Editor: Li Xiong Proofing Editor-in-Chief: Lian-Sheng Ma
Responsible Science Editor: Jian-Xia Cheng
EDITOR-IN-CHIEF Filippo Cademartiri, MD, PhD, FESC, FSCCT, Professor, Cardio-Vascular Imaging Unit-Giovanni XXIII Hospital, Via Giovanni XXIII, 7-31050-Monastier di Treviso (TV), Italy EDITORIAL OFFICE Jian-Xia Cheng, Director Jin-Lei Wang, Vice Director World Journal of Radiology Room 903, Building D, Ocean International Center, No. 62 Dongsihuan Zhonglu, Chaoyang District, Beijing 100025, China Telephone: +86-10-59080039 Fax: +86-10-85381893 E-mail: wjr@wjgnet.com http://www.wjgnet.com PUBLISHING Baishideng Publishing Group Co., Limited Room 1701, 17/F, Henan Building, No.90 Jaffe Road, Wanchai, Hong Kong, China Fax: +852-31158812 Telephone: +852-58042046
PUBLICATION DATE August 28, 2012 COPYRIGHT 2012 Baishideng. Articles published by this OpenAccess journal are distributed under the terms of the Creative Commons Attribution Non-commercial License, which permits use, distribution, 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. SPECIAL STATEMENT All articles published in this journal represent the viewpoints of the authors except where indicated otherwise. INSTRUCTIONS TO AUTHORS Full instructions are available online at http://www. wjgnet.com/1949-8470/g_info_20100316162358.htm. ONLINE SUBMISSION http://www.wjgnet.com/esps/
EDITING Editorial Board of World Journal of Radiology, Room 903, Building D, Ocean International Center, No. 62 Dongsihuan Zhonglu, Chaoyang District, Beijing 100025, China Telephone: +86-10-59080039 Fax: +86-10-85381893 E-mail: wjr@wjgnet.com http://www.wjgnet.com
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World J Radiol 2012 August 28; 4(8): 345-352 ISSN 1949-8470 (online) 2012 Baishideng. All rights reserved.
Online Submissions: http://www.wjgnet.com/1949-8470office wjr@wjgnet.com doi:10.4329/wjr.v4.i8.345
EDITORIAL
Extrahepatic biliary cancer: New staging classification

Dhakshinamoorthy Ganeshan, Fanny E Moron, Janio Szklaruk
Dhakshinamoorthy Ganeshan, Janio Szklaruk, Department of Diagnostic Radiology, Division of Diagnostic Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, United States Fanny E Moron, Department of Diagnostic Radiology, Baylor College of Medicine, Houston, TX 77030, United States Author contributions: Szklaruk J, Ganeshan D and Moron FE contributes to drafting the article, critical revision of the article and final approval of the version to be published; Szklaruk J participates in conception and design, acquisition of data, analysis and interpretation of data. Correspondence to: Dr. Janio Szklaruk, Professor of Radiology, Department of Diagnostic Radiology, Division of Diagnostic Imaging, The University of Texas MD Anderson Cancer Center, 1400 Pressler Street, Unit 1473, Houston, TX 77030, United States. jszklaru@mdanderson.org Telephone: +1-713-7451453 Fax: +1-713-7451302 Received: January 30, 2012 Revised: July 19, 2012 Accepted: July 26, 2012 Published online: August 28, 2012
Abstract
Tumor staging defines the point in the natural history of the malignancy when the diagnosis is made. The most common staging system for cancer is the tumor, node, metastases classification. Staging of cancers provides useful parameters in the determination of the extent of disease and prognosis. Cholangiocarcinoma are rare and refers to cancers that arise from the biliary epithelium. These tumors can occur anywhere along the biliary tree. These tumors have been previously divided into extrahepatic and intrahepatic lesions. Until recently the extrahepatic bile duct tumors have been considered as a single entity per American Joint Commission on Cancer (AJCC) staging classification. The most recent changes to the AJCC classification of bile duct cancers divide the tumors into two major categories: proximal and distal tumors. This practical classification is based on anatomy and surgical management. High quality cross-sectional computed tomography (CT) and/or magnetic resonance (MR) imaging of the abdomen are essential information to accurately stage this tumors. Imaging plays an important role in diag-
nosis, localization, staging and optimal management of cholangiocarcinoma. For example, it helps to localize the tumor to either perihilar or distal bile duct, both of which have different management. Further, it helps to accurately stage the disease and identify the presence of significant nodal and distant metastasis, which may preclude surgery. Also, it helps to identify the extent of local invasion, which has a major impact on the management. For example, extensive involvement of hepatic duct reaching up to second-order biliary radicals or major vascular encasement of portal vein or hepatic arteries precludes curative surgery and patient may be managed by palliative therapy. Further, imaging helps to identify any anatomical variations in the hepatic arterial or venous circulation and biliary ductal system, which is vital information for surgical planning. This review presents relevant clinical presentation and imaging acquisition and presentation for the accurate staging classification of bile duct tumors based on the new AJCC criteria. This will be performed with the assistance of anatomical diagrams and representative CT and MR images. The image interpretation must include all relevant imaging information for optimum staging. Detailed recommendations on the items required on the radiology report will be presented.
2012 Baishideng. All rights reserved.
Key words: American Joint Commission on Cancer; Staging; Bile duct tumors; Computed tomography; Magnetic resonance Peer reviewers: Shu-Hang Ng, MD, Professor, Department of
Diagnostic Radiology, Chang Gung Medical Center at Linkou, 5 Fuhsing St. Kueisan Hsiang, Taoyuan Hsien 333, Taiwan, China; Ahmed Abdel Razek, MD, Professor, Department of Diagnostic Radiology, 62 El Nokri St, Meet Hadr, Mansoura Faculty of Medicine, Mansoura 35111, Egypt Ganeshan D, Moron FE, Szklaruk J. Extrahepatic biliary cancer: New staging classification. World J Radiol 2012; 4(8): 345-352 Available from: URL: http://www.wjgnet.com/1949-8470/full/ v4/i8/345.htm DOI: http://dx.doi.org/10.4329/wjr.v4.i8.345
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Ganeshan D et al . Extrahepatic biliary cancer
INTRODUCTION
Staging of cancers provides useful parameters in the determination of the extent of disease and prognosis. The most recent changes to the American Joint Commission on Cancer (AJCC) classification of bile duct cancers divide the tumors into two major categories: proximal and distal tumors and this has major implications in the management of these tumors. In this review, the anatomy, epidemiology, clinical presentations, imaging presentation, staging, and managements of bile duct tumors will be presented with the assistance of anatomical diagrams and radiological imaging.
EPIDEMIOLOGY
The tumors of the bile duct are rare, estimated at 2% of all cancers with an incidence of 0.01%-0.046 % in autopsy series. This percentage includes intrahepatic and extrahepatic tumors. There are countries with a higher incidence of malignancy such as Israel and Japan[1] . And in certain populations such as the United States Native American there is a higher incidence of bile duct tumors[2]. The patients present mostly in the 6th to 7th decade of life. The risk factors for extrahepatic bile duct tumors are (1) congenital cystic changes as seen secondary to Carolis disease or polycystic liver disease; (2) primary sclerosing cholangitis; (3) ulcerative colitis; (4) exposure to chemicals (i.e. thorotrast); and (5) medication such as oral contraceptives and methyldopa[3,4]. These are shared with other cholangiocarcinoma (bile duct, intrahepatic cholangiocarcinoma, and gallbladder cancers, Figure 1). The method for tumor development is unknown and various possible pathways has been proposed. For example, it is has been proposed that these tumors may developed as a result of (1) chronic inflammatory process in the bile ducts[4]; (2) mutations; and (3) parasite induced DNA damage[5].
Figure 1 Anatomical distribution of cholangiocarcinoma. The intrahepatic cholangiocarcinoma present most as solid masses in the liver (blue arrow), gallbladder (GB) cancer present as solid mass in the GB (yellow arrow), proximal bile duct tumors present mostly as infiltrating masses (red arrow), middle bile duct tumors (green arrow), and distal bile duct tumors (black arrow). The cystic duct is labeled with a white arrow.
CLINICAL PRESENTATION
The clinical presentation of bile ducts tumors may mimic the signs and symptoms of pancreatic head cancer (i.e., painless jaundice). The degree of jaundice is dependent on the extent of biliary involvement. The sparing of disease in segments of the biliary tree can compensate in the excretion of bile ducts and result in a delay in the clinical presentation. Other symptoms associated with biliary cancer include diarrhea, weight loss and fever. In the setting of distal bile duct tumors, the tumor may present with symptoms of cholecystitis secondary to Mirizzis -like presentation, obstruction of the cystic duct. In contrast, the proximal bile duct tumor will not present with obstruction of the gallbladder. The blood work for suspected bile duct tumors may demonstrate elevated levels of CA 19-9 serum markers and abnormal liver function tests[6,7].
hepatic and extrahepatic bile ducts. The extrahepatic bile ducts can be further divided into proximal, middle, and distal bile ducts (Figure 1). The proximal extrahepatic bile duct extends from the confluence of the right and left hepatic bile ducts to the level of the cystic duct. The middle portion of the extrahepatic bile ducts extends from the cystic duct to the level of the duodenum. The distal ducts are composed of the bile duct that extends to the level of the ampulla (Figure 1). A more detail classification of hilar tumors is provided by the Bismouth-Corlette classification (Figure 2). This classification is based on tumors that are within 1 cm of the common hepatic duct (Klatskin tumors)[8,9]. These are divided into five types of tumors: the tumors that do not extend to the bifurcation of the right and left extrahepatic bile ducts (Type), tumors that extend to the bifurcation (Type ), tumors that extend to either the right (Type a) or the left (Type b) intrahepatic bile ducts, and tumors that extend to both the right and left (Type ) intrahepatic bile duct tumors.
IMAGING
Various invasive and noninvasive imaging techniques are used in the diagnosis and staging of cholangiocarcinoma. The invasive tests include endoscopic retrograde cholangiopancreatography, endoscopic ultrasound, optical coherence tomography and spy glass endoscopy. The noninvasive imaging tests include ultrasound, multidetector computed tomography (MDCT), magnetic resonance imaging (MRI) and positron emission tomography-com puted tomography (PET-CT). However, MDCT and magnetic resonance imaging (MRI) are the most common imaging modalities used in the primary staging of these malignancies. Standard techniques of MDCT and MRI used for imaging extrahepatic cholangiocarcinoma have been described before and we have tabulated the technique used in our institute[10](Tables 1-3). The pre-surgical evaluation of the bile tumor requires high quality cross sectional imaging (CT and MR). An
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PATHOLOGICAL CLASSIFICATION OF CHOLANGIOCARCINOMA

The anatomy of the biliary tree can be divided into intraWJR|www.wjgnet.com
Figure 2 Hilar tumor classification. A: Typehilar tumors are proximal bile duct tumors that do not extend to the bifurcation; B: Type tumors extend to the bifurcation without extension into the intrahepatic bile ducts; C:Type a proximal bile duct tumors correspond to tumors that extend to the right intrahepatic bile ducts; D: Type b proximal bile duct tumors correspond to tumors that extend to the left intrahepatic bile ducts; E: Type tumors extend to the right and left intrahepatic bile ducts.
Table 1 Multidetector computed tomography parameters

Parameter Detector collimation Pitch kVp Contrast Value 0.5 to 0.75 0.984 120 125 cc of intravenous optiray 350
optimal protocol will provide the required information to properly staged the tumor, selection of surgical candidates and for surgical planning[11]. The imaging protocol is a multiphasic post-contrast examination with very thin slices and multiplanar reconstructions. The CT exam is obtained at 2.5 mm slice thickness with 0.625 mm reconstructions following the intravenous administration of iodinated contrast[12,13]. On CT, the tumor has soft tissue attenuation and enhances on delayed imaging. The MR exams are obtained with a combination of pre- and postcontrast imaging. The pre-contrast exam combines T1 and T2 weighted images. These include very fluid sensitive sequence - T2 weighted images[11]. This series provide a magnetic resonance cholangiopancreatography (MRCP; Figure 3). The MRCP provides a map of the biliary tree similar to that seen on endoscopic retrograde cholangiopancreatography (ERCP) (Figure 3). The CT images can generate similar CT cholangiopancreatography (CTCP) utilizing minimum intensity projection to visualize the bile ducts (Figure 4). The post-Gd MR exams are obtained at 4mm slice thickness with a 2 mm overlap. A
post-contrast multiphasic exam is performed. On MR, the tumor has low signal on T1 weighted images, slightly intense on T2 weighted images (less than fluid), and show delayed enhancement (Figure 5). Hepatocyte specific contrast agent have been used to generate post-contrast images of the biliary tree[14]. The image presentation of malignant tumors on CT and MR include: (1) abrupt termination of the ducts; (2) thickened and enhancing bile duct wall; (3) atrophy of the liver segments; (4) crowding of the vessels; and (5) intrahepatic bile duct dilatation[11]. The tumors may present as an infiltrative process with thickening of the bile duct wall, mostly seen in the proximal tumors. The tumors may also present as papillary or nodular masses. The latter are more common in the distal bile duct tumors[15]. The papillary bile duct tumor may mimic bile duct stones[16]. The CT and MR examination not only provides anatomical information of location of the primary bile duct tumor but essential anatomic information such as any evidence of hepatic artery, portal vein, and biliary variant anatomy. The presence of these variants has major implications of selection of surgical candidates and surgical planning.
STAGING
The AJCC has recently published new staging criteria for extrahepatic bile duct tumors[17]. These tumors were previously grouped into proximal, middle and distal tumors
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Table 2 Multidetector computed tomography multiphasic acquisition
Phase of image acquisition Unenhanced liver images Arterial phase liver images Portal venous phase abdomen and pelvis Delayed phase Time of acquisition Bolus tracking technique or manually at 30-35 s after the onset of contrast material injection Acquired 60-65 s after the start of injection Acquired 3-5 min after the start of injection Section thickness (mm) Milliamperage (mA) 5 1-2.5 2.5-5 5 250 500 500 250
2.5-mm thick coronal and sagittal reformats are reconstructed with images of the portal venous phase.
Table 3 Magnetic resonance imaging protocol

Entry Coil type Series desc Scan plane Image mode Pulse seq TE1/TE2 (ms) TR/#R-R (ms) Flip angle ETL (echo train length) RCV BW1 (kHz) FOV (cm) SCAN THK (mm) Spacing/#Loc Freq phase NEX Phase FOV Freq dir Feet first 8 cardiac or 8 body upper (1) Axial T2 Axial 2D FSE-XL 85 4000-6000 16 41.67 34-44 6 0 256 192 3-4 0.75-1.0 R/L Position 8 cardiac or 8 cardiac or 8 body upper 8 body upper (3) Axial T1 asset (4) 3D LAVA XV Dyn Axial pre Axial 2D in/out phase 3D Fast SPGR Fast SPGR FWIP/FWOP Min Full 150-220 85 15 62.50 34-44 5 0 256 192 1 0.9-1.0 R/L 83.33 34-42 4 -2.0 320 (160-192) 0.75-1.0 R/L Supine 8 cardiac or 8 body upper (5) Diffusion Axial 2D DW EPI Min (~ 50-60) 1200-1800 NA (125) 38-44 5 0/36 slices 100 160 6 1.0 R/L
8 cardiac or 8 body upper (2) ASSET calib Axial 2D Fast SPGR
8 cardiac or 8 body upper (6) 3D 5 min LAVA XV Axial 3D Fast SPGR
8 cardiac or 8 body upper (7) Fiesta Coronal 2D Fiesta Min 50-75 83-125 34-44 5 0 or -1 192 356 2 0.75 1.0 S/I
15 83.33 34-44 4 -2.0 320 (160-192) 0.70-0.90 R/L
48 10 0 1 1.0 A/P
Figure 3 Bile duct tumor. A: Magnetic resonance cholangiopancreatography (MRCP) of a 57-year-old female with a proximal bile duct tumor (dash arrow). There is dilatation of the right intrahepatic bile ducts (solid arrow); B: Corresponding endoscopic cholangiopancreatography of 57-year-old female with proximal bile duct tumor (arrowhead). This is a type a tumor as per BismouthCorlette classification.
Figure 4 Computed tomography cholangiopancreatography utilizing minimum intensity projection. The common bile duct (dash arrow), the pancreatic duct (arrowhead), and the gallbladder (solid arrow) are visualized and are normal in appearance.
but were considered as a single entity and had single TNM classification. Now, the middle group of extrahepatic bile duct tumors have been removed as the treatment of this group is similar to either proximal or distal group. Currently, extrahepatic bile duct tumors are simply classified as perihilar and distal bile duct tumors (Figure 1). Further, these two subgroups have different TNM stag-
ing as their pathology, treatment and prognosis is variable (Tables 4-6). Perihilar tumors refer to those located in the extrahepatic biliary tree proximal to the origin of the cystic duct. The early stage (T1) tumor for the extrahepatic bile duct cancers is described as tumor confined to the bile duct wall (Figure 5). On imaging this tumor presents as wall thickening of the bile duct. The low (fat) attenuation of the periductal fat is preserved. The T2 tumors are can-
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Figure 5 T-staging for proximal bile duct tumors. A: T1 tumors are confined to the bile duct wall without extension to the periductal fat; B: The T2 tumors extend to the periductal fat or the liver; C: T3 tumors have unilateral extension to the portal vein (arrow) or hepatic artery; D: T4 tumors extend to the main portal vein (arrow), common hepatic artery, secondary biliary radicles, or contralateral vascular extension.
Figure 6 Proximal bile tumor T2 stage. Post-contrast computed tomography exam at the level of the common hepatic duct in a 62-year-old male with biliary cancer. There is enhancement and thickening of the bile duct wall (solid arrow). The fat around the duct is not preserved but the portal vein (dash arrow) and hepatic artery (arrowhead) are spared. Radiologically, this is a T2 tumor due to involvement of periductal fat.
Figure 7 T4 - proximal bile tumor. Post-contrast computed tomography exam at the level of the intrahepatic bile duct in a 58-year-old female with biliary cancer. There is enhancement and thickening of the right intrahepatic bile duct wall (arrowheads). There is abrupt termination of the left intrahepatic bile ducts (arrow) in keeping with tumor extension). Radiologically, this is a T4 tumor due to bilateral involvement of secondary biliary radicles
cers that invade the periductal fat (T2a) or the liver (T2b) (Figures 5 and 6). The proximal extrahepatic bile duct tumors may extend to the portal vein or hepatic artery. The unilateral vascular extension is considered T3 (Figure 7), whereas more advanced extension is considered T4. The latter (T4) includes extension into the main portal vein, common hepatic artery, contralateral vascular extension, and involvement of secondary biliary radical (Figure 7). Hepatic parenchymal involvement is now classified as T2 instead of T3 as patients with hepatic parenchymal involvement alone have a better prognosis compared to those with unilateral vascular involvement[18]. Distal bile duct tumors refer to those located between the junction of the cystic duct-bile duct and the ampulla of Vater. Previously these had the same AJCC classification as the proximal tumors but it has been recognized that these tumors have significant differences in the anatomy compared to the proximal lesions, which affect their resectability. Hence, these lesions have a separate TNM classification. The TNM staging of the distal bile duct tumors shares some of the features of the proximal bile duct
tumors. For example, in both tumors, the T1 and T2 are confined to the bile duct wall (T1) or invade the bile duct without invasion of adjacent organs (T2) (Figures 8 and 9). The invasion of adjacent organs (pancreas, stomach, and duodenum) is considered T3 for distal bile duct tumors (Figure 10). The invasion of celiac artery and superior mesenteric artery are considered T4 (Figure 10). The T-classification of the distal bile duct cancers shares features with pancreatic cancer. The nodal staging of bile ducts tumors is also different for the proximal and distal bile duct tumors. The proximal bile duct tumors have three classifications (N0, N1 and N2). N1 nodes refer to regional nodes such as hilar, cystic, pericholedochal, hepatic artery, portal, and posterior pancreaticoduodenal. The N2 nodes refer to distant nodes such as celiac, superior mesenteric artery, and para-aortic nodes. The presence of N2 nodes may disqualify the patient from potential curative surgery. The nodal staging of distal bile duct tumors has two classifications (N0, N1). In contrast to proximal bile duct tumors, the nodal staging is performed at the time of surgery with sampling of at least 12 nodes. This is analog to the
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Table 4 Extrahepatic bile duct tumors (American Joint Commission on Cancer staging 6th edition)
Tumor T1 T2 T3 T4 TNM classification Tumor confined to bile duct histologically Tumor beyond the wall of bile duct Tumor invades liver, GB, pancreas, and/or ipsilateral PV (R or L) or hepatic artery (R or L) Tumor invades main portal vein or its branches bilaterally, common hepatic artery, or adjacent structures (colon, stomach, duodenum, abdominal wall) No regional lymph node metastasis Regional lymph node metastasis (including hilar, celiac, superior mesenteric, periduodenal and peripancreatic) No distant metastasis Distant metastasis AJCC staging 6th edition T1, N0, M0 T2, N0, M0 T3, N0, M0 T1 or T2 or T3, N1, M0 T4, any N, M0 Any T, any N, M1 Node N0 N1
Table 5 Perihilar bile duct tumors (American Joint Commission on Cancer staging 7th edition)
Tumor T1 T2a T2b T3 T4 TNM classification Tumor confined to bile duct histologically Tumor beyond the wall of bile duct into adjacent fat Tumor beyond the wall of bile duct into liver parenchyma Tumor invades ipsilateral portal vein (R or L) or hepatic artery (R or L) Tumor invades (1) Main portal vein or its branches bilaterally (or) (2) Common hepatic artery (or) (3) The second-order biliary radicals bilaterally (4) Unilateral second-order biliary radicals with contralateral portal vein or hepatic artery involvement No regional lymph node metastasis Regional lymph node metastasis (including nodes along the cystic duct, common bile duct, hepatic artery, and portal vein) Metastasis to periaortic, pericaval, superior mesenteric artery, and/or celiac artery lymph nodes No distant metastasis Distant metastasis AJCC staging 6th edition T1, N0, M0 T2a-b, N0, M0 T3, N0, M0 T1 or T2 or T3, N1, M0 T4, N0 or N1, M0 Any T, N2, M0 or any T, any N, M1
Node N0 N1 Metastasis M0 M1 Tumor stage StageA StageB Stage A Stage B Stage Stage
N2 Metastasis M0 M1 Tumor stage Stage Stage Stage A Stage B Stage a Stage b
T: Tumor; N: Node; M: Metastases; GB: Gallbladder; PV: Pulmonary vein; AJCC: American Joint Commission on Cancer.
Table 6 Distal bile duct tumors (American Joint Commission on Cancer staging 7th edition)
Tumor T1 T2 T3 T4 Node N0 N1 Metastasis M0 M1 Tumor stage StageA StageB Stage A Stage B Stage Stage TNM classification Tumor confined to bile duct histologically Tumor beyond the wall of bile duct Tumor invades liver, GB, pancreas, but no involvement of celiac axis, or the superior mesenteric artery Tumor involves the celiac axis, or the superior mesenteric artery No regional lymph node metastasis Regional lymph node metastasis (including hilar, celiac, superior mesenteric, periduodenal and peripancreatic) No distant metastasis Distant metastasis AJCC staging 6th edition T1, N0, M0 T2, N0, M0 T3, N0, M0 T1 or T2 or T3, N1, M0 T4, any N, M0 Any T, any N, M1
background anatomy. The M-staging for the extrahepatic biliary tumors is the similar for proximal and distal bile duct tumors. Metastases may be seen of CT and MR as soft tissue masses in the peritoneum, lungs, adrenals, liver and other sites.
MANAGEMENT
Curative surgery is the best hope for the treatment of bile duct cancers. Depending on the local extent of the tumors, the proximal and distal bile duct tumors resections can involve major en-bloc removal of multiple organs with the goal to achieve an R0 resection. The surgical approach differs for proximal and distal bile duct tumors[20-22]. The resection for proximal bile cancers may include cholecystectomy, resection of extrahepatic bile ducts, regional lymphadenectomy, hepatic lobar resection, caudate lobe resection, Roux-en-Y hepaticojejunostomy, and vascular reconstruction or resection[21-23]. Liver transplantation is also a consideration in the management of proximal bile duct tumors[24]. The resection of distal bile duct tumors includes pancreaticoduodenectomy and may include resection of the duodenum, stomach, and colon. In the distal bile duct cancer, the resection includes sampling of at least 12 regional nodes is performed.
management of pancreatic cancer. On imaging, there are no definite criteria for the diagnosis of malignant nodes[19]. A node that is larger than 1cm in minimum diameter, round in morphology and heterogeneous in attenuation is likely to be malignant. Proximity to the primary mass also increases the likelihood of malignancy. The MR diffusion weighted images provide optimum contrast between lymph nodes and
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Figure 8 T-Staging for distal bile duct tumors. A: T1 tumors are confined to the bile duct wall without extension to the periductal fat; B: T2 tumors extend to the periductal fat or the liver; C: T3 tumors have adjacent organs without celiac axis or superior mesenteric artery invasion; D:T4 tumors extend to the superior mesenteric artery (arrow) or celiac artery.
Figure 9 Distal bile duct tumors. Post-contrast computed tomography (CT) examination of the abdomen in a 58-year-old female with cholangiocarcinoma of the bile duct; A: CT image at a cranial location shows dilatation of the bile duct and bile duct enhancement (green arrow); B: CT image at a caudal location shows enhancement of the distal bile duct. There is a small regional lymph node (yellow arrow). The hepatic artery (white arrow), portal vein (blue arrow), and superior mesenteric artery (red arrow) are spared. Radiologically, appearances are consistent with a T1 tumor (periductal fat not involved) and this was confirmed by pathology.
ment of portal vein, common or proper hepatic artery or both the right and left hepatic arteries (16951395).
CONCLUSION
The radiological report may be the only tangible contribution provided to the patient and clinician by the radiologists. A complete report is required to properly managed and stage oncologic patients. In the setting of biliary cancers, the report should include anatomical information such as location of tumors (proximal vs distal; segmental involvement), local extent of tumor (fat/organ/vascular invasion), nodal disease location (proximal vs distal nodes), and comments on any evidence of metastatic disease. Ancillary but important information such as vascular (arterial, venous, portal) variants to the liver and biliary variants should be carefully evaluated and included in the radiology report. MRCP and CTCP images are also complementary to the report in providing a visual representation of the primary tumor. The knowledge of tumor staging and management should be the guide to image interpretation by the radiologists. Imaging should help to accurately localize and stage the tumor, highlight presence of features
Figure 10 Distal bile duct tumors. Post-contrast computed tomography (CT) examination of the abdomen in a 65-year-old female with cholangiocarcinoma of the bile duct. CT image of the distal bile at the level of the pancreas shows a soft tissue tumor (yellow arrow) in keeping with the tumor. The tumor extends to the superior mesenteric artery (red arrow). There is a biliary stent in place (blue arrow). Radiologically, appearances are consistent with a T4 tumor due to involvement of superior mesenteric artery.
An important role of imaging is to identify features that may preclude surgery - such as marked nodal or distant metastases, involvement of hepatic duct reaching up to second-order biliary radicals, or major vascular encase-
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which may preclude surgery and warn the surgeons about any surgically relevant anatomical variations. Imaging should help to identify if the tumor is an early stage lesion involving the duct alone (T1) or has advanced such that the periductal fat (T2), major vessels and extensive biliary ductal (T3 and T4) are involved. Current classification has down staged hepatic parenchymal involvement from T3 to T2, which has major implications for prognosis and treatment. The new AJCC classification provides a distinct clinical picture of patients with distal and proximal bile ducts that was absent in the prior classifications with major management implications.
11 12
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REFERENCES
1 van Gulik TM, Ruys AT, Busch OR, Rauws EA, Gouma DJ. Extent of liver resection for hilar cholangiocarcinoma (Klatskin tumor): how much is enough? Dig Surg 2011; 28: 141-147 Fraumeni JF. Cancers of the pancreas and biliary tract: epidemiological considerations. Cancer Res 1975; 35: 3437-3446 Szendri M, Nmeth L, Vajta G. Asbestos bodies in a bile duct cancer after occupational exposure. Environ Res 1983; 30: 270-280 Parkin DM , Ohshima H, Srivatanakul P, Vatanasapt V. Cholangiocarcinoma: epidemiology, mechanisms of carcinogenesis and prevention. Cancer Epidemiol Biomarkers Prev 1993; 2: 537-544 Nault JC, Zucman-Rossi J. Genetics of hepatobiliary carcinogenesis. Semin Liver Dis 2011; 31: 173-187 Heimbach JK, Gores GJ, Haddock MG, Alberts SR, Pedersen R, Kremers W, Nyberg SL, Ishitani MB, Rosen CB. Predictors of disease recurrence following neoadjuvant chemoradiotherapy and liver transplantation for unresectable perihilar cholangiocarcinoma. Transplantation 2006; 82: 1703-1707 Malaguarnera G, Giordano M, Paladina I, Rando A, Uccello M, Basile F, Biondi A, Carnazzo S, Alessandria I, Mazzarino C. Markers of bile duct tumors. World J Gastrointest Oncol 2011; 3: 49-59 Klatskin G. Adenocarcinoma of the hepatic duct at its bifurcation within the porta hepatis. An unusual tumor with distinctive clinical and pathological features. Am J Med 1965; 38: 241-256 Bismuth H, Castaing D. [Surgical treatment of hilus cancers]. Acta Chir Belg 1984; 84: 307-311 Sainani NI, Catalano OA, Holalkere NS, Zhu AX, Hahn PF, Sahani DV. Cholangiocarcinoma: current and novel imaging techniques. Radiographics 2008; 28: 1263-1287
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Szklaruk J, Tamm E, Charnsangavej C. Preoperative imaging of biliary tract cancers. Surg Oncol Clin N Am 2002; 11: 865-876 Aloia TA, Charnsangavej C, Faria S, Ribero D, Abdalla EK, Vauthey JN, Curley SA. High-resolution computed tomography accurately predicts resectability in hilar cholangiocarcinoma. Am J Surg 2007; 193: 702-706 Tamm EP, Loyer EM, Faria S, Raut CP, Evans DB, Wolff RA, Crane CH, Dubrow RA, Charnsangavej C. Staging of pancreatic cancer with multidetector CT in the setting of preoperative chemoradiation therapy. Abdom Imaging 2006; 31: 568-574 Koelblinger C, Schima W, Weber M, Mang T, Nemec S, Kulinna-Cosentini C, Bastati N, Ba-Ssalamah A. Gadoxateenhanced T 1-weighted MR cholangiography: comparison of 1.5 T and 3.0 T. Rofo 2009; 181: 587-592 Nakanishi Y, Zen Y, Kawakami H, Kubota K, Itoh T, Hirano S, Tanaka E, Nakanuma Y, Kondo S. Extrahepatic bile duct carcinoma with extensive intraepithelial spread: a clinicopathological study of 21 cases. Mod Pathol 2008; 21: 807-816 Lim JH, Kim MH, Kim TK, Lee MG, Lee SS, Lee JW, Lee KT, Lee JK, Lim HK. Papillary neoplasms of the bile duct that mimic biliary stone disease. Radiographics 2003; 23: 447-455 American Joint Committee on Cancer. AJCC cancer staging manual. 7th ed. New York/London: Springer, 2011 Ebata T , Nagino M, Kamiya J, Uesaka K, Nagasaka T, Nimura Y. Hepatectomy with portal vein resection for hilar cholangiocarcinoma: audit of 52 consecutive cases. Ann Surg 2003; 238: 720-727 Ruys AT, Kate FJ, Busch OR, Engelbrecht MR, Gouma DJ, van Gulik TM. Metastatic lymph nodes in hilar cholangiocarcinoma: does size matter? HPB (Oxford) 2011; 13: 881-886 Hidalgo E , Asthana S, Nishio H, Wyatt J, Toogood GJ, Prasad KR, Lodge JP. Surgery for hilar cholangiocarcinoma: the Leeds experience. Eur J Surg Oncol 2008; 34: 787-794 di Sebastiano P, Festa L, Bchler MW, di Mola FF. Surgical aspects in management of hepato-pancreatico-biliary tumours in the elderly. Best Pract Res Clin Gastroenterol 2009; 23: 919-923 van Gulik TM, Ruys AT, Busch OR, Rauws EA, Gouma DJ. Extent of liver resection for hilar cholangiocarcinoma (Klatskin tumor): how much is enough? Dig Surg 2011; 28: 141-147 Kondo S, Takada T, Miyazaki M, Miyakawa S, Tsukada K, Nagino M, Furuse J, Saito H, Tsuyuguchi T, Yamamoto M, Kayahara M, Kimura F, Yoshitomi H, Nozawa S, Yoshida M, Wada K, Hirano S, Amano H, Miura F. Guidelines for the management of biliary tract and ampullary carcinomas: surgical treatment. J Hepatobiliary Pancreat Surg 2008; 15: 41-54 Thelen A, Neuhaus P. Liver transplantation for hilar cholangiocarcinoma. J Hepatobiliary Pancreat Surg 2007; 14: 469-475 S- Editor Cheng JX L- Editor A E- Editor Xiong L
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Giulia Soloperto, Sergio Casciaro

REVIEW
Progress in atherosclerotic plaque imaging
Giulia Soloperto, Sergio Casciaro, Biomedical Engineering Science and Technology Division and Nanoimaging Ultrasound Lab at National Research Council, Institute of Clinical Physiology (CNR-IFC), 73100 Lecce, Italy Author contributions: Soloperto G and Casciaro S contributed to this paper equally. Correspondence to: Sergio Casciaro, PhD, Biomedical Engineering Science and Technology Division and Nanoimaging Ultrasound LAB at National Research Council, Institute of Clinical Physiology (CNR-IFC), 73100 Lecce, Italy. sergio.casciaro@cnr.it Telephone: +39-0832-422310 Fax: +39-0832-422341 Received: March 14, 2012 Revised: May 14, 2012 Accepted: May 21, 2012 Published online: August 28, 2012
Biophysics, School of Life Science and Technology, University of Electronic Science and Technology of China, Northern Jianshe Road 2-4, Chengdu 610054, Sichuan Province, China Soloperto G, Casciaro S. Progress in atherosclerotic plaque imaging. World J Radiol 2012; 4(8): 353-371 Available from: URL: http://www.wjgnet.com/1949-8470/full/v4/i8/353.htm DOI: http://dx.doi.org/10.4329/wjr.v4.i8.353
INTRODUCTION
In 2007, more than 2200 Americans died of cardiovascular diseases each day; in particular, stroke accounted for 1 in every 18 deaths, while an estimated 1 person per minute died from myocardial infarction, as reported by the latest statistics of the American Heart Association[1]. The major cause of stroke is cerebral blood vessel blockage as a consequence of atherosclerotic plaque rupture in carotid arteries; similarly, myocardial infarction is strongly related to coronary artery narrowing as a consequence of atherosclerosis[2]. Pathogenesis of the atherosclerotic plaque: Biological and functional key features Atherosclerosis is a systemic arterial inflammatory disease initiated by the accumulation of fatty streaks within the arterial wall, which may evolve into a cholesterol-rich lesion hardened by the presence of proliferating smooth muscle cells (SMCs); these types of lesions are called atheromas[3]. Physiologically, the arterial wall consists of three layers, starting from the exterior: tunica adventitia (collagen and fibres), tunica media (SMCs and elastic fibres), and tunica intima [endothelial cells (ECs), lining the lumen of all vessels]. Mechanoreceptors on the surface of ECs sense bloodflow-induced shear stress on the arterial lumen and tran smit a stimulus to the nuclei through the cytoskeleton, inducing the intracellular signalling cascade[4-6] that eventually leads to alteration in the physical properties of ECs[7]. Consequently, intravascular low density lipopro-
Abstract
Cardiovascular diseases are the primary cause of mortality in the industrialized world, and arterial obstruction, triggered by rupture-prone atherosclerotic plaques, lead to myocardial infarction and cerebral stroke. Vulnerable plaques do not necessarily occur with flow-limiting stenosis, thus conventional luminographic assessment of the pathology fails to identify unstable lesions. In this review we discuss the currently available imaging modalities used to investigate morphological features and biological characteristics of the atherosclerotic plaque. The different imaging modalities such as ultrasound, magnetic resonance imaging, computed tomography, nuclear imaging and their intravascular applications are illustrated, highlighting their specific diagnostic potential. Clinically available and upcoming methodologies are also reviewed along with the related challenges in their clinical translation, concerning the specific invasiveness, accuracy and cost-effectiveness of these methods.
Key words: Atherosclerosis; Diagnostic imaging; Plaque characterization Peer reviewer: Yi-Yao Liu, PhD, Professor, Department of
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Soloperto G et al . Progress in atherosclerotic plaque imaging
teins (LDL) and circulating monocytes can migrate below the intimal layer and may coalesce to form larger beds of fatty streaks, rich in cholesterol crystals. Additionally, fibres and SMCs, physiologically present where cholesterol accumulates can proliferate leading to plaque formation and growth[3]. A plaque could then develop into a fibrous cap atheroma, consisting of a large necrotic core rich in extracellular lipid, cholesterol crystals and necrotic debris covered by a fibrous cap. The cap is constituted by SMCs in a collagen-pro teoglycan matrix, with infiltrated macrophages and T lymphocytes[3]. Inflammatory cells are also present in the shoulder of the plaque, at the interface with the underlying necrotic core. Highly calcified stable lesions or the development of mural haemorrhage are possible evolutions of the fibrous cap atheroma[3]. Moreover, T cells encountering antigens, such as Oxidized LDL and cytokines, induce macrophage activation, superoxide production, up-regulation of vascular cell adhesion molecule (VCAM)-1 and protease activity, via up-regulation of matrix metalloproteases (MMPs) expression, favouring matrix degradation, hence the transition from stable plaque to thin fibrous cap atheroma (TFCA), which is unstable and at risk of rupture[8]. Because atherosclerosis is a systemic disease, diagnostic imaging can be used to study arteries outside the heart such as the carotid artery and aorta, which are more accessible and suitable for the limited spatial resolution of most imaging techniques; for instance, cap thickness of the TFCA is usually lower than 200 m when it occurs in the carotid artery bifurcation and is 65 m when found in the coronary artery[9]. Increased neovascularisation within the atherosclerotic plaque and fibrous cap is a further marker of symptomatic carotid disease. The newly formed vasculature has larger and more irregular microvessels then the physiologic vasa vasorum and may contribute to plaque instability and to the onset of thromboembolic sequelae[10]. Immature and dysmorphic microvessels are recognized as sites of vascular leakage and inflammation; nonetheless these vessels may be therapeutic targets for promoting plaque stabilization[11]. However, the vessels exhibiting TFCA do not necessarily show severe narrowing, but do have positive external remodelling[9] (Figure 1). The latter represents a compensation strategy to restore physiological levels of blood flow velocity when intima thickness occurs. Conventionally, low shear stress regions, such as arterial bifurcations and bends, are associated with plaque formation, whereas localized high shear stress has been linked to plaque rupture[12,13]. Nonetheless, evidence of plaque rupture occurring in a region of extremely low wall shear stress located downstream of the throat of a stenotic carotid bifurcation[14,15] contributes to undermine the consensus regarding the conventional association between shear stress values and plaque vulnerability; recent studies converge on the hypothesis that vulnerability is related to the mechanical Von Mises stress (typically five orders of magnitude larger than wall
shear stress) borne by the fibrous cap, to its thickness, to arterial remodelling and to the morphological distribution of the necrotic core and other plaque components[16]. Moreover, biomechanical studies have shown that intimal tears in coronary arteries often occur at the interface of calcified and adjacent to non-calcified arterial tissues[17], thus it is likely that calcification plays an active role in plaque rupture. Different methodologies have been developed to directly image atherosclerosis, either invasively or noninvasively. In 1959, Sones et al[18,19] performed the first selective coronary angiography, and this rapidly became the technique of choice for enabling the operator to observe narrowing in the arterial lumen and clinically assess the effects of atherosclerosis. However, angiography is an exclusively luminographic technique, providing no information on the extent of the disease in the arterial wall. For this reason, computed tomography (CT) and positron emission tomography (PET) are required to investigate the lesion composition. Both techniques involve ionizing radiation, potentially producing biological side effects with different classes of clinical features. Later developments in diagnostic imaging techniques, such as B-mode Ultrasound and magnetic resonance imaging (MRI), allow non-ionizing imaging of the arterial wall and eventually the assessment of its pathological status. The diagnostic imaging techniques employed for atherosclerotic plaque analysis can be graded on their level of invasiveness (Figure 2), and in this review, they are presented from the less hazardous to the most health threatening.
NON INVASIVE ATHEROSCLEROTIC PLAQUE ASSESSMENT

Non-invasive assessment of atherosclerosis targets populations at risk of cardiovascular disease and asymptomatic patients who have not yet presented with an acute cardiovascular event. Completely non-invasive diagnostic imaging modalities are those examinations performed without percutaneous access to the vessel and employing nonionizing radiation. Non-ionizing radiation is described as a series of energy waves of different nature, such as oscillating electric or magnetic fields, sound waves and includes the spectrum of ultraviolet, visible light, infrared, microwave, radio frequency (RF), and extremely low frequency. The crucial morphological and biological features that characterize atherosclerotic plaques can be specifically addressed by non-ionizing diagnostic criteria using non-invasive imaging modalities (Table 1). Conventional and IB ultrasound In modern clinical practice, vessel outline reconstruction is one of the most validated and employed applications of ultrasonography (US), also supported by optimized tracking devices; in particular, because of their accessibility, carotid arteries represent the ideal site for clinical examinations[20]. In addition, the increase in intima-media thickness (IMT) of the common carotid artery can be a
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Table 1 Plaque feature identification through non-invasive diagnostic imaging (without using ionizing radiation)
US Morphology features Outward remodelling Plaque burden Lipid pool Necrotic core Composition Fibro-fatty Fibrous plaque Dense calcium Biological features Inflammation Macrophage infiltration Neo-angiogenesis TFCA TFCA + MI
1
CE-US -1 [39]1 -2 -2 -2 -2 -2 [39]1 [36]1 -2 -2
MRI -1 -1 [50]1 [53]1 [50]1 -1 [50]1 [57]1 -2 -2 [50]1 -2
CE-MRI -1 -1 [57]1
Lipid rich necrotic core
-1 -2 [32]1 [30]1 -2 [32]1 [32]1 -2 -2 -2 -2
[57]1 -1 [58]1 [60]1 [59]1 [142]1 -2
Lumen Fibrous cap SMCs Foam cells Calcification Inflammatory cells LDL infiltration Secretion of MMPs and cytokine Neovessel Hemorrhage Thrombus
Limited clinical experience; 2research in progress. US: Ultrasound; CE-US: Contrast-enhanced ultrasound; MRI: Magnetic resonance imaging; CEMRI: Contrast-enhanced magnetic resonance imaging; MI: Macrophage infiltration; TFCA: Thin fibrous cap atheroma.
Figure 1 Scheme of the thin fibrous cap atheroma. Main cellular components characterizing atherosclerotic plaque formation and destabilization are illustrated as well as biological and morphological features occurring in vulnerable plaque. SMCs: Smooth muscle cells; LDL: Low density lipoprotein; MMPs: Matrix metalloproteases.
consequence of arterial aging and hypertension and may identify with one of the earliest stages of atherosclerosis, as large IMT is associated with cardiovascular and total mortality risk[21] and could predict cardiovascular events in patients with coronary artery disease[22] as well as in asymptomatic patients[23]. IMT is usually measured manually on longitudinal B-mode ultrasound images, but many computer-based techniques for IMT measurement have been proposed to overcome the limits of manual segmentation and measurements, most requiring a certain degree of user interaction[24-26]. Despite the widespread use of carotid IMT, it provides only limited information about the atherosclerotic process occurring distally, i.e. at the bifurcation or at the internal carotid, under different hemodynamic conditions. The latter are evaluated using Multigate Doppler systems in order to provide accurate estimates of the distribution of spectral Doppler components within human arteries, and real-time processing of all the echo signals produced along an M-line is also possible[27,28]. M-mode ultrasound records motion of the interfaces toward and away from the transducer, hence real-time measurement of arterial wall distension can be analysed through specific 2-D autocorrelation algorithms, whose results can be displayed in real-time to enhance the accuracy of diagnosis even over long acquisitions[29]. Although preliminary attempts at tissue characterisation from conventional B-mode US were conducted with encouraging high retrospective accuracy[30], the introduction of advanced analysis of the backscattered US signal, namely integrated backscatter (IB) analysis, enabled the different plaque components to be distinguished based on their specific spectral content[31]. Integrated backscatter ul-
trasonography (IB-US) methodologies allow non-invasive evaluation of the tissue substructure in human plaques by means of offline data processing techniques, that improve the poor spatial resolution on conventional US up to 300 m. Compared with histology, the sensitivity and specificity for detecting thrombi, lipid pools and fibrous tissue ranged between 80%-85% and 78%-91%, respectively, with peak accuracy in the detection of calcified regions (sensitivity: 89%; specificity: 91%) (Figure 3)[32]. Contrast-enhanced ultrasound Based on clinical observations and published reports, the presence of neovascularisation, characterized by high permeability, appears to be a distinct marker of plaque instability and vulnerability[10,33]. Contrast-enhanced ultrasonography (CE-US) relies on the detection of acoustic signals produced by microbubbles that are targeted to the sites of disease. Because they contain gas and are smaller than the wavelength of ultrasound, these agents undergo volumetric oscillation in an acoustic field, thereby compressing and expanding according to the acoustic pressure peaks and nadirs, respectively[34]. To improve in vivo stability, ultrasound contrast agents commonly contain inert gases that have low diffusion and low solubility coefficients in blood. CE-US techniques may serve to characterize intra-plaque angiogenesis[35], which is unrelated to the degree of stenosis[36]. Specifically, a retrospective study of 147 patients with symptomatic carotid atherosclerosis demonstrated how the presence and degree of adventitial vasa vasorum and plaque neovascularisation were directly associated with cardiovascular diseases and events, and could be assessed by means of contrast-enhanced ultrasound[37] down to the scale of the microvessel[38]. Additionally, a preliminary report suggests that microbubbles may also be useful in quantifying plaque inflammation within the plaque[39].
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Contrast medium injection Lonizing radiation Angiographic localization of the probe Endovascular acces
IB-US MRI
CE-US CE-MRI
CT
CE-CT
SPECT PET
PET-MRI
PET-CT
Invasiveness
US-E IVMRI OCT VH IVUS
Figure 2 Illustration of the invasiveness of the possible plaque imaging modalities along with the reasons of their grading. MRI: Magnetic resonance imaging; IB-US: Integrated backscatter ultrasound; CE-US: Contrast enhanced ultrasound; CE-MRI: Contrast enhanced magnetic resonance imaging; CT: Computed tomography; CE-CT: Contrast enhanced computed tomography; SPECT: Single proton emission computed tomography; PET: Positron emission tomography; US-E: Ultrasound elastography; IVMRI: Intravascular magnetic resonance imaging; OCT: Optical coherence tomography; VH: Virtual histology; IVUS: Intravascular ultrasound.
A1
A2
A3
Calcification
Mixed lesion
Fibrosis
Lipid pool
B1
B2
B3
Hyperpiasia
Thrombus
Intima
Media
C1
C2
C3
Figure 3 Example of plaque characterization trough integrated backscatter ultrasonography. A: Large plaque (arrow); A1: An integrated backscatter (IB) image at autopsy; A2: A color-coded map constructed from A1, based on the five IB categories and conventional 2D echo findings; A3: van Gieson staining of the same segment as the IB measurement (bar = 1 mm); B: Intimal fibrosis (arrow); B1: An IB image during life; B2: A color-coded map constructed from B1; B3: Massons trichrome staining of the same segment; C: Intimal hyperplasia consisting of smooth muscle cells (arrow); C1: An integrated backscatter image during life; C2: A colorcoded map constructed from C1; C3: Massons trichrome staining of the same segment (reprint with permission)[32].
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T2W
PDW
T1W
TOF
HE
HE
Mallory's trichrome
Figure 4 Example of histological validation of magnetic resonance imaging at four consecutive locations spanning the bifurcation. Multiple histological sections (at 0.5-1.0 mm-separation) generally correspond to each 2-mm thick image. Contours have been drawn for lumen (red), outer wall (cyan), lipid-rich/necrotic core (yellow), calcification (black), loose fibrous matrix (pink/white) and hemorrhage (orange)[49]. TOF: Time-of flight; HE: Hematoxylin and eosin; PDW: Proton density weighted; T2W: T2-weighted; T1W: T1-weighted.
Different US contrast agents, such as echogenic immunoliposomes (ELIP) conjugated with different proteases, have also been employed for the in vivo imaging of specific molecular expression in swine with induced endothelial lesions. The selective enhancement of endothelial injury/atheroma components in the presence of the functionalized ELIPs was confirmed by immunohistochemistry staining[11]. Thrombus-targeted microbubbles for CE-US conjugated with tirofiban - a glycoprotein b/ a antagonist - can specifically bind to activated platelets in the thrombus; the capability of enhancing both the image contrast and thrombolysis, obtained as an effect of microbubble US cavitation, has been investigated with good results compared to the non-bound contrast agent[40]. Recent developments in nanoparticles (NPs) have demonstrated their potential higher safety, due to their physical stability, and the same molecular specificity; in particular, low dose silica NPs are detectable with high sensitivity in experimental studies[41,42]. MRI MRI of atherosclerosis can provide information on both plaque volume and composition in the different arterial districts. Recent developments in coil and MRI sequence design[42,43] allow in vivo imaging of carotid artery plaques with a spatial resolution of 300 m at 1.5 Tesla[44,45]. Additionally, the introduction of multispectral imaging
allowed the characterisation of pathological plaque components (Figure 4), discrimination of the lipid core, the fibrous cap, calcification, haemorrhage and thrombus with sensitivity and specificity values of 76%-92% and 65%-86%, respectively[46-50]. Direct thrombus imaging is possible with specially optimized T1 weighted magnetization-prepared 3-dimensional rapid acquisition gradient echo (MP-RAGE) sequences, that comprise an inversion recovery RF pulse for magnetization preparation and a fast gradient echo acquisition sequence[51]. With the inversion time properly selected, a strong T1 weighting can be achieved, effectively detecting haemorrhage as proved in clinical studies[52]. A new slab-selective phase-sensitive inversion-reco very (SPI) technique is also promising improvements in the imaging of intraplaque haemorrhage[53]. SPI sequences were compared with MP-RAGE and evaluated both ex vivo and in vivo for discriminating intraplaque haemorrhage and arterial wall; SPI had better intraplaque haemorrhage identification accuracy (P < 0.01) and a significantly higher intraplaque haemorrhage-wall contrastto-noise ratio than MP-RAGE[53]. Further examples of clinical results of MRI plaque imaging application in symptomatic patients with different degrees of carotid stenosis were provided in a study of the association bet ween plaque characteristics, cardiovascular risk factors and statin use by means of plaque 1.5-T MRI (sequences
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used were: 3-dimensional T1-weighted turbo field echo, 3-dimensional time-of-flight, 2-dimensional T2-weighted turbo spin-echo, and pre- and postcontrast 2-dimensional T1-weighted turbo spin-echo images). Statin use was positively associated with the percentage of fibrous tissue within the plaque, and evidence suggests that symptomatic patients with moderate stenosis have a higher prevalence of complicated plaques than patients with mild stenosis[54]. The use of higher magnetic field strength for evaluating possible atherosclerotic plaque progression is also documented. In particular, a cohort of patients with symptomatic and asymptomatic carotid plaques, presenting with recent intraplaque haemorrhage, underwent 3.0-Tesla MRI over a period of 18 mo[55]. MR sequences included three-dimensional time-of flight (3DTOF), quadruple-inversion-recovery T1WI (QIR-T1WI), proton density-weighted imaging (PDWI), and T2-wei ghted imaging (T2WI). The contrast-to-noise ratio of intraplaque haemorrhage showed a significant difference between the haemorrhages found in symptomatic and asymptomatic carotid plaques on 3D-TOF (P = 0.029), QIR-T1WI (P = 0.005), and PDWI (P = 0.028), but not on T2WI (P = 0.362). Symptomatic intraplaque haemorrhage displayed no significant change in signal intensity, whilst asymptomatic intraplaque haemorrhage contrastto-noise ratios exhibited a gradual decreasing trend on all contrast weighted images (P < 0.05). Repeat carotid intraplaque haemorrhage may be more common in patients with symptomatic than asymptomatic plaques and could represent a possible stimulus for progression of atherosclerosis which is stronger than one-time carotid intraplaque haemorrhage[55]. Contrast-enhanced MRI Contrast-enhanced MRI (CE-MRI) is typically used to perform magnetic resonance angiography (CE-MRA); CE-MRA can be supplemented with time-resolved angiography, flow measurement, vessel wall imaging, and plaque characterisation for a more comprehensive assessment of vascular diseases[56]. The two types of contrast agent suitable for CE-MRI are the paramagnetic gadolinium chelates and ultra-small super paramagnetic iron oxide (USPIO) particles; however, some patients exhibit adverse reactions to these agents. The standard contrast agent is Gadolinium bound to a chelate in order to obtain a biocompatible compound. Gadolinium is a rare earth metal; it has a short T1 time constant, which promotes relaxation of water molecules in its proximity, leading to high signal intensity on T1 weighted sequence. After injection, the contrast agent initially remains in the vascular space; subsequently Gadolinium-chelate moves into the extracellular space, becoming more concentrated in areas where the extravascular space is expanded, such as in scar tissue, or the fibrous cap. Intravenous Gadolinium contrast can be used to improve tissue characterisation between the fibrous cap and the lipid core (correlation coefficient: 0.87)[57,58] and to identify sites of neoangiogenesis (correlation coefficient: 0.67)[59]. Moreover, lipoproteins have been adopted for use as
effective molecular imaging probes, as ApoA-I has been extracted from human plasma and reconstituted with a Gadolinium chelate; when injected into ApoE knockout mice, a significant accumulation of this particle was seen in the aorta[60]. Further potential of diagnostic imaging of plaque biological activity includes the visualisation of MMPs expression, as they contribute to destabilizing plaques by segmental remodelling; protease expression can be studied by employing an activated near-infrared fluorescence probe (99mTc-labelled annexin A5)[61] and a Gadolinium-coupled matrix metalloprotease inhibitor (MPI) (99mTc-MPI)[62]. Investigations conducted on apoE null mice of different ages, which were administered 2 tracers, demonstrated that between 20 and 40 wk the aortic lesion area increased, the disease extended into the carotids and the MMP expression was greater than apoptosis as the disease progressed. Thus, differences found in the histology correlated with differences in tracer uptake, and the results supported the premise that radiolabeled MPI is better than annexin A5 for the imaging of more advanced disease[63]. USPIO particles are iron-based blood pool agents with a strong T1 and T2 shortening effect. USPIOs have the combined property of being taken up by macrophages, and of being visible by CMR, as iron particles cause low signal intensity on CMR images. High sensitivity and specificity of CMR to USPIOs have been demonstrated by a surgical trial in which USPIOs were administered before and after endarterectomy (P < 0.001, sensitivity: 92.5%; specificity: 64%)[64], and USPIO-related signal drop out was concordant with plaque inflammation, as visualised by 18FDG PET (see section below), but not necessarily unlinked to the degree of stenosis[65]. Additionally, USPIOs have been used to show a reduction in carotid plaque morphology in response to intensive cholesterol lowering with statin treatment[66]; nonetheless, this agent (Sinerem 20 mg/mL) has now been withdrawn. Larger microparticles of iron oxide (4.5 m diameter) have also been constructed to target endothelial P-selectin and VCAM-1 adhesion molecules, which allow binding to the arterial wall in the early stages of plaque development[67].
IONIZING IMAGING TECHNIQUES

CT and PET are imaging techniques that have to compromise with the radioactivity induced by X-ray and radionuclides, respectively. Ionizing radiation may interfere with molecule binding and alter DNA and RNA transcription, generating free radicals. For instance, radiation doses associated with commonly used CT examinations resemble doses received by individuals in whom an increased risk of cancer was documented[68,69]. In Table 2, the possibilities of biological/morphological target identification of each ionizing diagnostic criterion are presented, according to the relevant literature. Electron-beam CT and multiple detector CT Two types of CT scanner can be used to assess athero-
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Table 2 Plaque feature identification through non-invasive diagnostic imaging (using ionizing radiation)
MDCT Morphology features Outward Remodelling Plaque Burden Lipid pool Necrotic core Composition Fibro-fatty Fibrous plaque Dense calcium Biological features Inflammation Macrophage infiltration Neo-angiogenesis
1
CE-CT [79]2 -2 -2 -2 [80]2

2 2
PET -2 -2 -2 -2 -1 -2 -2 [105]1 [99]1
SPECT -2 -2 -2
[72]1 -2 [77]1
plicability of CT in the future. Progressive improvements introduced in MDCT imaging include the reduction of the potential for cardiac and respiratory motion artefact, as well as the introduction of 256- and 512-slice scanners aiming to significantly improve the spatial resolution[76,77] with potential for fibro-fatty plaque identification[78]. Contrast-enhanced MDCT Detailed imaging of plaque morphology can also be performed when an appropriate contrast medium is used: a good correlation between contrast-enhanced MDCT (Solutrast 300, 300 mgI/mL1, Altana, Konstanz, Germany) and IVUS has been demonstrated in terms of plaque characterisation and volumetric analysis. The mean crosssectional areas of plaque, lumen and external elastic membrane, and the degree of vessel obstruction (percentage of the external elastic membrane cross-sectional area occupied by the plaque) determined by IVUS and 64-slice contrast-enhanced MDCT were highly correlated (r = 0.73, r = 0.81, r = 0.88, and r = 0.61, respectively)[79]. Additionally, these findings are supported by a study investigating the possibility of constructing a MDCT based plaque map from a series of 0.4 mm thick crosssectional images of the coronary artery obtained at intervals of 5 mm. Compared with the results for IVUS in the analysis of 662 slices of 78 vessels, the plaque map showed sensitivities of 92%, 87% and 89% in the identification of soft, intermediate and calcified lesions, respectively[80]. Macrophage accumulation can also be detected by means of iodine-based contrast agent (N1177) in combination with MDCT. The intensity of the enhancement detected with CT in the aortic wall of rabbits injected with N1177 correlated with inflammatory activity evaluated with 18F-FDG PET/CT and macrophage density on histology[81]. Newly developed contrast media can also be employed in the assessment of plaques using an experimental CT scanner, such as the spectral CT system, in which incident X-rays are divided into six different energy bins to achieve multicolour CT imaging. Different compounds were imaged in a variety of phantoms: gold high-density lipoprotein nanoparticle contrast agent (Au-HDL) targeting atherosclerosis, an iodine-based contrast agent and calcium phosphate[82]. Au-HDL was intravenously injected at baseline; the calcium phosphate contrast material was injected 24 h later and the CT imaging was then performed. Multicolour CT imaging, conducted with the spectral CT scanner, allowed differentiation of Au-HDL, iodine-based contrast material, and calcium phosphate in the phantoms. Multicolour CT, used in combination with Au-HDL, was further studied to evaluate its potential in characterising macrophage burden, calcification, and plaque stenosis in an apolipoprotein E knockout (apo E-KO) mouse in vitro model of atherosclerosis and validated against transmission electron microscopy and confocal microscopy of aorta sections[82]. Au-HDL accumulated in the aortas of the apo E-KO mice, while the
[77]1 [77]1 [72]1 -2 -2 -2
-2 -2 -2 [103]2 [99,100]2 -2
[81]2
2
-2
Limited clinical experience; 2research in progress. MDCT: Multidetector computed tomography; CE-CT: Contrast-enhanced computed tomography; PET: Positron emission tomography; SPECT: Single proton emission tomography.
sclerosis: electron-beam CT and multiple detector CT (MDCT). The former uses tungsten rings to generate X-ray images at 3-mm slice thickness and is used to calculate coronary artery calcium score in the assessment and prediction of cardiovascular risk[70]. Conversely, the latter uses a continuously rotating X-ray source able to obtain 0.5-mm slices during a single patient breath-hold. Intravenous contrast can be used to perform coronary angiographic (CTA) imaging in order to extract information on atherosclerotic plaques in the coronary arterial wall. Analyses of CT imaging revealed how the amount of coronary calcium detected was correlated with the amount of coronary atherosclerosis present on histology[71], thus artery calcium scoring has been the predominant method of risk assessment using CT to date. However, the imperative to image the vessel wall, has led to an improvement in the use of CT to perform CTA in order to identify Glagov-type outward arterial remodelling (P < 0.01; sensitivity: 100% specificity: 90% compared to intravascular ultrasound (IVUS)[72] and to assess soft (non-calcium containing) atherosclerotic plaques. A recent study found that patients affected by plaques accompanied by positively remodelled coronary segments and characterised by CT low attenuation were at higher risk of acute coronary syndrome than were patients without these findings[73]. In younger patients, CTA can detect both calcium- and lipid-rich plaques; in elderly patients, it allows exclusion of the presence of a flow-limiting stenosis even if the calcium burden is high[74]. In addition to exquisite delineation of arterial wall calcium, CT can potentially differentiate between lipid-rich and fibrous plaque, although the overall specificity is lowered by the large overlap in the attenuation values of these plaque components[75]. However, the majority of clinical research to date has been performed employing 64-slice CT scanners; ongoing technical developments are likely to increase the ap-
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Conventional
Gold
Overlay
Figure 5 Example of gold high-density lipoprotein nanoparticle contrast agent detection through spectral computed tomography. A-C: Spectral computed tomography (CT) images of thorax and abdomen in apolipoprotein E knockout (apo E-KO) mouse injected 24 h earlier with gold high-density lipoprotein nanoparticle contrast agent (Au-HDL); D, E: Spectral CT images near bifurcation of aorta in apo E-KO mouse injected with Au-HDL and an iodinated emulsion contrast agent (Fenestra VC) for vascular imaging (reprint with permission)[82].
Conventional CT image
Overlay of gold, iodine, photoelectric and compton image
Aorta
iodine-based contrast agent and calcium-rich tissue were also co-localized with the vasculature and bones (skeleton) (Figure 5). Microscopic analysis of the samples revealed that Au-HDL is primarily found in the macrophages; hence, multicolour CT was able to image the macrophage burden. An independent review on the above study showed that if the translation of these studies to humans were successful, complete plaque characterisation would be possible by means of a one-in-all scan able to detect, simultaneously, plaque stenosis, calcification and inflammation [83]. Although multispectral CT imaging could be extremely valuable in addressing inflamed areas, the major challenge to be overcome is the high dose of gold particles administered. Specifically, tracer doses, around 35 g of Au-HDL for an adult, raise issues regarding the safety, bio-disposition, costs and consequent availability of a clinical spectral CT scanner. However, the main concern in employing CT-based modalities is the radiation dose, which is currently between 9 and 1 mSv for a retrospectively gated MDCT coronary angiogram[84]. Recent technical advances, such as the use of volume scanning (as opposed to helical scanning) allowed a reduction in the effective radiation dose by 90% for the average examination[85]. Furthermore, the investigative use of serial MDCT plaque imaging in clinical practice is currently under optimization. Despite plaque progression being shown in the clinical setting[86], it is still unclear how this relates to patient prognosis. Conversely, a negative CT coronary angiogram has a predictive value for coronary artery disease and can avoid further invasive coronary angiography for patients at low or intermediate risk of coronary artery disease[87].
PET PET and single photon emission CT (SPECT) are able to trace tissue metabolic activity by means of positron emitting isotopes, typically glucose isotopes bind to a tracer molecule injected into the subject. The consensus is that 18-fluorodeoxyglucose (18FDG), the most commonly used tracer, uptake is generally greater in symptomatic atheromatous plaques than in asymptomatic lesions[88] and the arterial 18FDG signal was found to be linked to levels of inflammatory biomarkers[89] and to factors of the metabolic syndrome[90]. SPECT and PET differ in several ways; given its better spatial resolution (4 to 5 mm vs 1 to 1.6 cm)[91,92] and its intrinsic capability to quantify biological processes in absolute terms, PET has been used, with 18FDG or translocator protein ligands and choline ligands, in most of the human studies on nuclear imaging of atherosclerosis. Nonetheless, specific SPECT ligands have been used in order to investigate their capabilities of probing various processes of atherosclerosis progression and rupture, including chemotaxis[93], angiogenesis[94], lipoprotein accumulation[95], proteolysis[96] and thrombogenicity[97]. For these reasons, PET and SPECT have been established as important tools for identifying vascular inflammation in the inflammatory vasculitides, and for monitoring patients with inflammatory diseases[98,99]. Specifically, the possibility of imaging in vivo early and developing plaque-like lesions by means of a C-type atrial natriuretic factor (C-ANF) has been investigated[100]. Vulnerable lesions are indeed often characterised by vascular remodelling and manifest the up-regulation of natriuretic peptide clearance receptors (NPR-Cs) expression both in the endothelium and in vascular SMCs (VSMCs); natri-
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Table 3 Plaque feature identification through invasive diagnostic imaging
IVUS Morphology features Outward remodelling Plaque burden Lipid pool Necrotic core Composition Fibro-fatty Fibrous plaque Dense calcium Biological features Inflammation Macrophage infiltration Neo-angiogenesis TFCA TFCA + MI
1
VH -1 -1 [130]1 [131]1 [131]1 [131]1 [131]1 [57]1 -2 -2 -1 -2
US-E [137]1 [137]1 -2 -2 [141]1 [141]1 [138]1
OCT [116]1 [116]1 -1 -1 [116]1 [116]1 [116]1 [122]1 [119]1 -2 [116]1 -2
IVMRI -1 -1 -1 -1 [146,147]1
-1 [124]1 [126]1 [124]1
[128]1 -2 -2 -2 -1 -2
[141]1 -2 -1 [137]1
-2 -2 -2 -2 -2
Limited clinical experience; 2research in progress. IVUS: Intravascular ultrasound; VH: Virtual histology; OCT: Optical coherence tomography; US-E: Elastography; IVMRI: Intravascular magnetic resonance imaging; MI: Macrophage infiltration; TFCA: Thin fibrous cap atheroma.
uretic peptides have strong antiproliferative and antimigratory effects on VSMCs. C-ANF was functionalised with 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) and labelled with copper-64 (64Cu) then, prior to PET scanning, injected in a hypercholesterolaemic rabbit bearing atherosclerotic-like lesions. Histopathology and immunohistochemistry analyses were performed to assess plaque development and NPR-C localisation. 64CuDOTA-C-ANF uptake in the atherosclerotic region was imaged by PET, with the highest target-to-background ratio (3.59 0.94). PET and immunohistochemistry competitive blocking studies confirmed receptor-mediated 64Cu-DOTA-C-ANF uptake in the plaque, concluding that the tracer may be a promising candidate for in vivo PET imaging of NPR-Cs on atherosclerotic plaques[100]. Furthermore, monocyte recruitment can be imaged by means of a radiolabelled peptide (18F-4V), which can be internalized by the endothelial cells through VCAM-1mediated binding[101]. MMPs are also believed to play a crucial role in plaque destabilization; hence the feasibility of in vivo imaging of MMP expression has also been investigated. In particular, the results from radiolabelled broad-based MPI administered to apoE null and LDLR null mice described the in vivo uptake of a 99mTc-labelled MPI RP805 in aortic atherosclerotic plaque; uptake of the tracer correlated with immunohistochemical staining for macrophages and with MMP-2 and MMP-9[102,103]. Furthermore, modifications in the signal from the 99mTc-MPI within the lesion can be used to tailor therapies, usually statin-based, to reduce MMP expression[104]. However, the main limitation of PET is poor spatial resolution; nonetheless, this difficulty has, to a large extent, been overcome by advances in imaging hardware and software that allow PET images to be co-registered with another imaging modality with much higher spatial
resolution (most commonly CT, often in combined PETCT scanners)[105]. The first clinical study using PET-CT to assess atheromas in vivo included 8 patients presenting with angiographic carotid artery stenosis and reporting a recent transient ischemic attack (TIA). PET was coregistered with CT, and plaques were found ipsilaterally with respect to the ischemic symptoms in all patients; furthermore, 18FDG accumulated in the ipsilateral plaque, significantly more than in the plaque on the contralateral side. On the basis of the histological analysis following carotid endarterectomy, areas of 18FDG uptake were found to correspond to dense macrophage infiltration within the plaque[106]. A subsequent larger study confirmed these findings and correlated the degree of 18FDG uptake with the degree of macrophage staining in the corresponding histological sections[107]. PET can also be co-registered with CMR (Figure 6), which provides better plaque imaging; requiring two separate scans, co-registration using anatomical landmarks is needed in this case. In the past, the combination of the two modalities has revealed, for patients with recent TIA and an ipsilateral high-grade carotid stenosis, an additional ipsilateral lesion with a high level of 18FDG uptake, but without high-grade stenosis[108]. PET-CT has also been used to assess the effectiveness of statin therapy in reducing the level of inflammation[109]. More challenging is the imaging of inflamed atheroma in the coronary vasculature with 18F-FDG due to myocardial uptake of 18F-FDG and the smaller size of the coronary arteries. Nonetheless, the feasibility of PET-CT imaging of inflamed lesions in the coronary vessels has been recently demonstrated, suppressing the myocardial 18FDG uptake by administering a high-fat, low-carbohydrate diet to the patients[110]. Alternatively, 18F-labelled fluorocholine (FCH) can be used to elude 18FDG myocardial uptake[111]. FCH is a tracer usually employed to image prostate cancer on the basis that activity of the choline-specific transporter increases in proliferating cells. Activated macrophages, similar to tumour cells, show enhanced FCH uptake[112], and a study conducted on mice demonstrated, for the first time, that FCH has a greater sensitivity in detecting plaques with respect to FDG (84% vs 64%)[113].
INVASIVE IMAGING TECHNIQUES

Diagnostic imaging can be used to closely investigate the atherosclerotic lesion due to probe miniaturization which allows intravascular imaging of symptomatic patients, undergoing invasive angiography, in order to detect morphological and biological markers of unstable and vulnerable plaques, as listed in Table 3. Intravascular optical coherence tomography Studies have revealed that optical coherence tomography (OCT) is capable of differentiating lipid tissue from water-based tissues[114]. Furthermore, the thickness of the fibrous cap overlying an atheroma can be demarcated by OCT, as demonstrated in the in vitro analysis of aortic tis-
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Figure 6 Co-registered fluorodeoxyglucose positron emission tomography and lowresolution magnetic resonance images in the neck region (arrows). Right carotid is indicated (courtesy of Dr. Rudd).
Coronal
Axial
Sagittal
1 mm
geting endothelial markers, such as VCAM-1 which is a critical component of the leukocyte-endothelial adhesion cascade regulating the atherogenic process[121]. Cathepsin B activated NPs were also used within optical imaging methodologies to monitor plaque inflammation in small animal in vivo studies[122]. Clearly, the major limitation of OCT is its invasiveness, limiting its application to patients who have already been referred for X-ray angiography. Nonetheless, OCT remains the imaging technique with the highest spatial resolution, suitable for assessing the thickness of the fibrous cap. Intravascular ultrasound US imaging of arterial disease with magnified detail of the plaque has been made possible only since the recent expansion of endovascular techniques and ultrasound probe miniaturization, which has led to the rapidly evolving diagnostic imaging modality known as IVUS [123]. IVUS provides real-time, as opposed to offline IB-US processing, with cross-sectional images of the examined vessel perpendicular to the longitudinal axis of the catheter. Previous studies on the applicability of IVUS in conjunction with coronary angiography demonstrated the feasibility of 3D reconstruction of coronary arteries via IVUS, with the motion of the catheter being tracked from bi-planar angiographic images[124]. The latest IVUS probes use phased array transducers sited around the tip of a catheter, allowing coaxial and fast exchange catheter configurations with a guide wire. Phased array US employs an electronically-controlled current that travels around the transducer firing US signals, which are sent out in a rotating sweep[125]. An IVUS examination can discriminate all three layers of the arterial wall[126], detect the presence of plaque[127], and can assess atherosclerotic disease[128] as well as plaque features, by identifying vulnerable or ruptured plaques, Glagov-type outward arterial remodelling[129,130] and the extent of calcified nodules, with variable accuracy depending on the regularity of lumen surface (sensitivity 94.1%, specificity 90.3% for convex lumen; sensitivity 64.7%, specificity 88.4% for irregular lumen)[128]. Monitoring changes in the extent of coronary atherosclerosis with IVUS has been increasingly employed in clinical trials to assess progression of the pathology, as IVUS is able to generate high-resolution
Figure 7 Measurement of fibrous cap thickness in ruptured plaque using optical coherence tomography. Residual fibrous cap was identified as a flap between the lumen of the coronary artery and the cavity of plaque, and its thickness was measured at the thinnest part (arrows). Scale bar = 1 mm (courtesy of Dr. Kubo).
sue[114]. The potential for intravascular assessment of culprit lesions in the coronary arteries has also been investigated. This procedure could enable detailed measurement of fibrous cap thickness as well as identification of erosive processes and thrombus formation, as achievements in post mortem samples have suggested (Figure 7)[115]. Usually performed only qualitatively via OCT[116], iden tification of plaque components amongst fibrous, calcified and lipid-rich tissues is intended to be supported quantitatively by targeting specific optical coefficients, such as optical attenuation t[117], backscatter and extinction coefficients[118]. OCT can also evaluate the presence and quantity of cellular species typically found in atherosclerotic plaques such as macrophages and smooth muscle actin[119]. The feasibility and accuracy of OCT for detecting the frequency and spatial distribution of TFCA has been investigated on coronary arterial segments ex vivo; OCT accurately detected TFCA with 90% sensitivity and 79% specificity[116]. The use of OCT, which has a resolution between 4 and 20 m, may be advantageous in measuring vulnerable cap thickness, usually thinner than 65 m, and recent findings demonstrated that quantitative assessment of plaque components could be feasible in vivo[120]. The further diagnostic potential of OCT imaging can be seen in the use of functionalized magnetofluorescent NPs tar-
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Figure 8 Example of intravascular ultrasound imaging (left), virtual histology (center) and movat pentachrome histology (courtesy of Dr. Nair).
imaging of the entire thickness of the coronary artery wall permitting evaluation of the entire burden of atherosclerotic plaque[131]. The resolution of IVUS (150 to 300 m) may be insufficient to detect thin fibrous caps in coronary (50 to 75 m) or carotid arteries (200 [129] m) . However, virtual histology (VH) could be realized through IVUS, implementing the spectral analysis of the backscattering US signal to model plaque in three dimensions. This approach has been validated in ex vivo coronary arteries, and was successful in identifying lipidrich necrotic cores, fibro-fatty plaques, and regions of calcification (Figure 8) with high accuracy[132-134]; additionally, its application in vivo demonstrated that the angiographic and clinical outcome up to 12 mo after long stent placement guided by IVUS was superior to guidance by angiography[135]. Despite its invasiveness, IVUS facilitates the in vivo delineation of the relative contributions of the necrotic core and fibrous atheroma in unstable lesions. Its clinical potential lies in it being used prior to percutaneous intervention in order to inspect and measure vessel size, evaluate side-branch anatomy, plaque length and assess calcification. Recent studies demonstrated that IVUS employed in conjunction with carotid artery stenting provided precise disease assessment and efficient surgery planning with no adverse events[136]. Although showing satisfactory inter-operator reproducibility, the classification of VH still relies on manual border detection and needs an improved automatic border detection algorithm for the use of VH IVUS as a diagnostic tool for surgical assessment[137]. IVUS can also be employed in elastography (US-E) to determine mechanical properties of the plaque. Elastography reflects the rate of deformation (strain) of the tissue and can be employed as an index of mechanical stiffness. The lumen is strained between pairs of US detectors that acquire the signal at a certain intraluminal pressure and at a slightly different pressure value ( 3 mmHg)[138,139]. Displacement of the signals of the two IVUS images is estimated and the strain of the tissue can be calculated by dividing the differential displacement (displacement of proximal layer - displacement of distal layer) by the undeformed distance between the
two layers. The strain can then be calculated for multiple layers and colour-coded into a so-called elastogram. The elastogram images the radial strain on the arterial wall and plaque deformability can be derived for the entire volume (Figure 9). Specifically, US-E showed a high sensitivity and specificity (88% and 89%) in identifying vulnerable plaques from excised human coronary arteries[140]. Moreover, animal studies demonstrated that elastography is capable of identifying fibro-fatty and fibrous plaques and macrophage infiltration, with high sensitivity (93%, 96% and 92%, respectively) and specificity (89%, 76% and 66%, respectively)[141]. Although US-E is able to differentiate fatty from fibrous plaques, compared with VH-IVUS, it remains an emerging imaging modality, thus prospective studies correlating vulnerable plaques identified by US-E and cardiac events are underway[142]. Intravascular MRI Similar to IVUS, probe miniaturization allowed the development of intravascular MRI (IVMRI) catheters capable of imaging the arterial wall of the aorta or the coronary arteries without external magnets or coils, and the resulting signal enabled the differentiation of lipid-rich and fibrotic-rich areas of the atherosclerotic plaque on the basis of differential water diffusion[143-145]. Preliminary ex vivo studies demonstrated good agreement between IVMRI and histology, with a specificity of 89% and a sensitivity of 100%, with spatial resolution of IVMRI as low as 100 [146] m . Regardless of the limitations due to the necessary use of an occluding balloon and to the mechanical rotation of the catheter, in vivo data obtained in human iliac arteries indicate that IVMRI might be superior to IVUS in identifying lipid, fibrous and calcified areas within the plaque burden[147].
CONCLUSION
Clinical results obtained by exploiting the capabilities derived from efficient plaque imaging show how current guidelines for atherosclerosis therapy planning, based purely on percentage stenosis, fail to address a significant proportion of culprit lesions. Therefore, medical imag-
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Strain (%) 2
Figure 9 In vitro intravascular echogram and elastogram of a human femoral artery. The elastogram reveals that the plaque at 12 oclock contains a soft core that is covered from the lumen by a stiff cap. At 9 oclock a soft tissue is present at the lumen vessel-wall boundary. A different strain was found at 9 and 3 oclock and this difference was not present in the echogram[140].
Calcium score Degree of luminal stenosis Plaque burden Lipid rich necrotic core Calcification Thrombus
Thin fibrous cap
4-10 mm SPECT
2 mm PET
6 mm CT
300 mm MRI
130-300 mm IB-US
120 mm IVMRI
150 mm IVUS
200-400 mm US-E
100-200 mm VH
4-20 mm OCT
Spatial resolution Inflammatory cells FDG, F-4V Neovascularization FDG Gadolinum Optison (GE healthcare)
CatB-agent
USPIO, Au-HDL
SonoVue (Bracco)
Matrix remodelling/degradation (MMPs) Protease annexin ED-B fibronectin USPIO Au-HDL Optison (GE health care) SonoVue (Bracco)
Adhesion molecules (antiVCAM-1 binding) FDG, F-4V Fluo NPs
MPIO
nmolar PET SPECT OCT CE-MRI
mmolar CE-CT
mmolar CE-US
Tracer dosage
Figure 10 Spatial resolution and dose-effectiveness of different diagnostic imaging modalities. Minimum spatial resolution required for the identification of the indicated morphological feature of vulnerable atherosclerotic plaque (top); dose effectiveness in the identification of specific biological processes and compound; specific target and respective tracer are indicated (bottom). SPECT: Single photon emission computed tomography; PET: Positron emission tomography; CT: Computed tomography; MRI: Magnetic resonance imaging; IB-US: Integrated backscatter ultrasonography; IVMRI: Intravascular magnetic resonance imaging; IVUS: Intravascular ultrasound; US-E: Intravascular ultrasound employed in elastography; VH: Virtual histology; OCT: Optical coherence tomography; CE-MRI: Contrast-enhanced magnetic resonance imaging; CE-CT: Contrast-enhanced computed tomography; CE-US: Contrast-enhanced ultrasonography; FDG: Fluorodeoxyglucose; USPIO: Ultra-small super paramagnetic iron oxide; Au-HDL: High-density lipoprotein nanoparticle contrast agent; VCAM: Vascular cell adhesion molecule; NP: Nanoparticle; MPIO: Microparticles of iron oxide.
ing is continuously improving towards higher accuracy in recognizing in vivo morphological and molecular features related to vulnerability. Specifically, identification of morphological features is more effective with higher spatial
resolved imaging modalities (Figure 10, top), whereas precise biological processes and compound detection is achievable independent of the spatial resolution of imaging modalities able to trace the specific contrast agent and
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Clinically available US PET CT MRI OCT IVUS
Preclinical stage CE-US IB-US Experimental stage PETMRI Novel PET tracer PET-CT CE-MRI CE-CT VH US-E
IVMRI
Figure 11 Clinical implementation and research status of diagnostic imaging modalities for atherosclerotic plaque characterization. US: Ultrasonography; PET: Positron emission tomography; CT: Computed tomography; MRI: Magnetic resonance imaging; OCT: Optical coherence tomography; IVUS: Intravascular ultrasound; VH: Virtual histology; US-E: Intravascular ultrasound employed in elastography; CE-US: Contrast-enhanced ultrasonography; IB-US: Integrated backscatter ultrasonography; CE-CT: Contrast-enhanced computed tomography; PET-MRI: Positron emission tomography-magnetic resonance imaging; PET-CT: Positron emission tomographycomputed tomography; CE-MRI: Contrast-enhanced-magnetic resonance imaging; IVMRI: Intravascular magnetic resonance imaging.
is considered highly efficient for minimum agent dose administration (Figure 10, bottom). Current challenges for atherosclerosis plaque imaging The in vivo detection of plaque vulnerability has the potential to become a reality soon, due to the various techniques described in this review, when they are translated into the clinical routine. However, their implementation is currently limited by the difficulty in resolving minute regions of interest within a much larger field of view, for instance when small coronary vessel diameter is below PET and SPECT spatial resolution. Presentation of the information in a quantifiable and easy-to-read manner also needs further improvements to achieve effective employment in the diagnostic paradigm. Moreover, the correlation between imaging data, the risk of rupture and, eventually, the outcome of patients needs to be reinforced, broadening what was recently addressed by VH and IVUS based clinical trials[148,149] through the collection of blood-based markers and diverse imaging data. Therefore, novel techniques need to be widely available and affordable to allow the success of ongoing prospective studies[150] and to provide standardized high-quality image sets for quantitative reference, as well as new integrated risk markers for low-risk and intermediate-risk population management. Future perspective A summary of the clinical implementation and research stage of the different imaging modalities is illustrated in Figure 11. Potential advances in image based plaque morphology assessment can be seen from the application of 3T and 7T MR scanners in clinical practice, as documented in a recent study[151] as well as from the implementation in real-time of IB-US methodologies and RF spectral analyses. Furthermore, implementation of micro and nanostructured contrast agents, developed to selectively
enhance specific biological compounds at a molecular level, could lead to a substantial reduction in contrast agent dose to achieve satisfactory examinations[11,43]. Further improvements in available imaging modalities should take account of the costs that would be incurred once implemented and the trade-off in terms of diagnostic accuracy (Figure 12); those requiring a catheterization procedure are not only highly invasive, hence useful for a niche of symptomatic cases already referred for arterial angiography, but are extremely expensive as the catheterization intervention increases the cost of these imaging modalities to 20 times more than US and double that of the most expensive non-invasive imaging modality[152]. The latter, PET, is a concern due to the radioactive nature of 18FDG, as each examination has a radiation exposure of approximately 5 mSv (250 chest X ray equivalents)[153]. Therefore, clinical translation of novel contrast media for CT and MRI as well as the development of innovative sequencing may allow a similar level of accuracy with limited costs; additionally, improvements in CE-US and further optimization towards real-time implementation of IB-US analysis will result not only in a drastic reduction in costs associated with plaque characterisation, but also an important reduction in the invasiveness of such diagnostic procedures. For example, although their human application is still limited, the optical properties of contrast media suitable for US imaging are being extensively studied[154-156] aimed at a hybrid imaging modality, namely optoacoustic imaging, which could obtain images with high optical contrast at high ultrasonic resolution in relatively large volumes of biological tissue[15,157]. The use of NPs combined with a site specific drug delivery system is extremely promising for pharmacological and gene therapy applications[158] or molecular guided LASER or US based interventions[40]. Finally, implementation of nanostructured contrast agents will reduce the health hazards due to ionizing radiation or radioactive tracers and of those derived from surgical treatments and from
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100 95 90 85 80 75 70 65 Catheterization costs 60 0 5 10 15 20 Average cost (x-fold echo cost) 25 30 CEUS CE-CT CE-MRI PET VH US CT MRI SPECT OCT US-E IVMRI Low Medium High
Sensitivity (%)
IVUS
Figure 12 Cost-effectiveness of diagnostic imaging modalities for atherosclerotic plaque characterization. The range of sensitivity is used for accuracy quantification. Echocardiography is the cost comparator where costs of other modalities are a ratio of x-fold higher costs. Indicated intravascular imaging costs add-up catheterization costs (costs are unit operating costs, not charges). CE-US: Contrast-enhanced ultrasonography; CE-CT: Contrast-enhanced computed tomography; CE-MRI: Contrast-enhanced magnetic resonance imaging; CT: Computed tomography; US: Ultrasound; SPECT: Single photon emission computed tomography; MRI: Magnetic resonance imaging; OCT: Optical coherence tomography; IVUS: Intravascular ultrasound; IVMRI: Intravascular magnetic resonance imaging.
traditional high dose pharmacological therapies. Translating in vivo the possibility of performing high resolution imaging and highly accurate reconstruction of plaque components distribution, traditionally performed on histological specimens, may lead to a completely different approach to atherosclerosis assessment and therapeutic planning.
8 9 10
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BRIEF ARTICLE
Imaging investigation of pancreatic cystic lesions and proposal for therapeutic guidelines
Atanas D Hilendarov, Georgi Petrov Deenichin, Kichka Georgieva Velkova
Atanas D Hilendarov, Department of Diagnostic Imaging, Medical University Faculty of Medicne, 4001 Plovdiv, Bulgaria Georgi Petrov Deenichin, Department of Sergery III, Medical University, 66 Pestersko Shose str., Plovdiv 4001, Bulgaria Kichka Georgieva Velkova, Department of Diagnostic Imaging, Medical University, Plovdiv 4001, Bulgaria Author contributions: Hilendarov AD contributes to the practical performing of the invasive diagnostic procedures under imdging control, collected and analyzed data; Velkova KG contributes to the diagnostic process, analysis and interpretation of data; Deenitchin GP participates to therapeutic process and critical revision of the article. Correspondence to: Dr. Atanas D Hilendarov, PhD, Associate Professor Atanas Hilendarov, Department of Diagnostic Imaging, Medical University Faculty of Medicne, 66 Pestersko Shose str., 4001 Plovdiv, Bulgaria. dr_hill@abv.bg Telephone: +35-9-888332642 Fax: +35-9-32625696 Received: January 30, 2012 Revised: May 30, 2012 Accepted: April 7, 2012 Published online: August 28, 2012
methods of guiding the interventional procedures: (1) free-hand biopsy and puncture method under ultrasound (US) or computed tomography (CT) control; (2) guiding method using biopsical transducer. RESULTS: All 56 patients in this study underwent at least two cuts imaging survey methods, such as US, CT or magnetic resonance imaging (MRI). The most common preoperative diagnostic examination was US scan - 56 patients (100%). MDCT studies were conducted in 49 (87.50%) and MRI in 13 (23.21%). More than half of patients surveyed (37) underwent some type of interventional procedure: 25-fine-needle aspiration and 29-fine needle aspiration biopsy (FNAB), as part of the examination. Thirty-four patients of all 56 patients underwent surgery because of histological evidence of malignancy after the FNAB for cystic lesions of the pancreas. Distal pancreatectomy with splenectomy was the most common operative approach in 13 patients, followed by Whipple resection in 11 and distal pancreatectomy without splenectomy in 7. Three patients were treated with total pancreatectomy due to the presence of a multifocal mucinous neoplasm. Comparing the diagnostic results of US examination with those of MDCT examination and histological verification true positive results were found in 31 patients, true negative in 11 patients, false positive in 5 and false negative in 9 patients. Accordingly we estimated the power of the diagnostic imaging methods for cystic lesions of the pancreas. A specificity of 68.75%, sensitivity of 79.48%, accuracy of 75.00%, positive predictive value of 86.11% and negative predictive value of 55% were obtained. The power increased after applying invasive procedures with immunohistochemical analysis of CEA and P-53 (Fig. 4). In 15 patients with cytological feature of malignant tumour cells, the tumour markers were positive. In our opinion the higher the percentage of reacting cells the higher the percent of malignancy. In patients with clear symptoms and/or clear imaging features of malignant or premalignant cystic neoplasm, the need for surgery was confirmed by histological verification in 34 (60.71%) of cases.
Abstract
AIM: To propose a diagnostic algorithm for preoperatively predicting the need for surgical intervention. METHODS: The study included 56 patients (27 men and 29 women) with a final diagnosis of cystic pancreatic lesions. The following materials were used: ultrasonic equipment with 3.5 and 7 MHz linear, convex and biopsical transducers. Multidetector computed tomography (MDCT) investigations were performed using a 16-slice scanner. Images were obtained following the oral administration of 200 mL water and 100 mL intravenous iopamidol (300 mg/mL) administered by pump injector at a rate of 3 mL/s (40 and 60 s post-injection, respectively) using 0.5 mm detectors, reconstructed at 1 mm (pancreatic phase) or 2 mm (portal venous phase) increments. The table feed was 10 mm per rotation. Images were acquired in the pancreatic and portal venous phases of contrast enhancement. The Chiba needles 18, 20, 22, 23 G and an automatic aspiration system were used in conjunction with the following
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Hilendarov AD. Imaging investigation of pancreatic cystic lesions
CONCLUSION: By using the proposed algorithm, cystic mucinous tumors of the pancreas were detected and proper operative interventions would have been rendered with fewer diagnostic examinations.
MATERIALS AND METHODS

Data of imaging research methods and the disease history of patients with cystic lesions of the pancreas diagnosed and treated in the Surgical Clinics of the University Hospital St. George for the period 2007-2010 year were collected in a retrospective study. Patients with a clear history of acute pancreatitis and subsequent development of pseudocyst also were confirmed histologically. The study included 56 patients (27 men and 29 women) with cystic lesions of the pancreas. The information collected included medical records, demographic data, disease symptoms and diagnostic tests. Operational protocols were reviewed with respect to the type of resection and the need for extended resection of neighboring structures. Histological reports were reviewed to confirm the diagnosis and detect abnormal variants. The latter included tumor location and size, histological type and degree of invasion. Lesions were categorized into five histologic subtypes: mucinous tumor, serous cystadenomas, pseudocysts, solid and papillary cystic tumor and mesothelial cysts. Mucinous tumors were subdivided into mucinous cystadenomas (benign and border), intraductal papillary mucinous tumor and mucinous cystadenocarcinoma. In addition to routine laboratory specific behavior the examination of pancreatic cystic lesions was followed using imaging studies. Diagnostic examinations are divided into invasive and non-invasive. Non-invasive examinations included abdominal US, CT scan and MRI study. Invasive procedures were fine-needle aspiration biopsy (FNAB) and FNA under imaging (US and CT) control. In some cases immunocytochemical examination of CEA and P-53 as malignant markers was performed[3,5]. In all patients at least two diagnostic imaging methods were applied to characterize the cystic pancreatic lesions. All patients with cystic pancreatic lesions (regardless of treatment) were followed by diagnostic imaging methods for a period of 3 years to search for suspected malignant features. In case of malignancy additional invasive (FNAB) diagnostic procedures were applied for histological verification. The following materials and methods were used: (1) ultrasonic equipment with 3.5 and 7 MHz linear, convex and biopsical transducers for guidance of the interventional procedures; (2) MDCT investigations and guidance were done with a 16-slice scanner. Images were obtained after oral administration of 200 mL water and 100 mL intravenous iopamidol (300 mg/mL) administered by pump injector at a rate of 3 mL/s. Images were acquired in the pancreatic and portal venous phases of contrast enhancement; (3) the Chiba needles 18, 20, 22, 23 G catheters pig-tail 7, 8 F were used; and (4) cytopathologic preparations were either air-dried for Diff-Quik staining or fixed in alcohol for Papanicolaou staining. Serial sections of the prepared from aspirates blocks were stained with hematoxylin-eosin. Immunostaining with antibodies against the following antigens was performed: cytokeratin (AE1, AE3), vimentin, CEA and P-53.
Key words: Pancreatic cystic neoplasm; Diagnostic intervention; Fine-needle biopsy Peer reviewer: Wenbao Wang, MD, Department of Orthopaedic, Columbia University Medical Center, 106 Fort Washington Avenue, Apt 3H, New York, NY 10032, United States
Hilendarov AD, Deenichin GP, Velkova KG. Imaging investigation of pancreatic cystic lesions and proposal for therapeutic guidelines. World J Radiol 2012; 4(8): 372-378 Available from: URL: http://www.wjgnet.com/1949-8470/full/v4/i8/372.htm DOI: http:// dx.doi.org/10.4329/wjr.v4.i8.372
INTRODUCTION
Although the clinical, radiological and pathologic features of cystic pancreatic lesions are well known, preoperative diagnosis is difficult. Before the widespread use of modern ultrasound (US), computed tomography (CT) and magnetic resonance imaging (MRI) methods, cystic neoplasms of the pancreas were considered very rare, and were thought to constitute 10%-15% of all cystic pancreatic lesions and 1%-5% of pancreatic neoplasms[1]. With the increasing use of advanced imaging technology significantly increased accidental openings of asymptomatic cystic lesions have occurred. In some medical centers more than one third of patients with cystic neoplasms of the pancreas are asymptomatic and neoplasms are discovered incidentally on imaging studies[2]. The problem that surgeons face is how to differentiate benign lesions such as serous cystadenomas and pseudocysts from malignant lesions and premalignant mucinous neoplasms. With increasing incidental detection of these cystic neoplasms, especially in light of the understanding that most of these lesions are benign in nature, resection in all cases is unnecessary[2,3]. No optimal test distinguishing benign from malignant cystic tumors has been provided so far. CT is also accurate in identifying vascular involvement, which complements multidetector computed tomography (MDCT) in predicting resectability[4]. In cases of diagnostic uncertainty, US or CT-guided fine-needle aspiration (FNA) were used to obtain tissue samples from solid lesions and fluid aspirates from cystic lesions, allowing histological, cytological, and biochemical analysis to determine the nature of the lesion. The aim of this study is to propose a diagnostic algorithm for differentiating cystic pancreatic lesions and define criteria for surgical intervention. At our institution the proposed algorithm was the method of choice for all of the patients with cystic pancreatic lesions.
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+ +2 +1
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Figure 1 Computed tomography and ultrasound images of microcystic pancreatic lesions/serous cystic neoplasm.
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Figure 2 Ultrasound and computed tomography image of septated macrocyst-mucinous cystic neoplasm/mucinous cystic neoplasm.
Table 1 Demographics, symptomatology and surgical interventions

Magnitude Sex Men Women Symptoms Pain Loss of weight (kg) Asymptomatic Vomiting Reflux Anorexia Jaundice Operations Whipple Distal pancreatectomy with splenectomy Distal pancreatectomy without splenectomy Total pancreatectomy All
n (%)
27 (48.21) 29 (51.78) 39 (69.64) 14 (25.00) 11 (19.64) 3 (5.35) 6 (10.71) 3 (5.35) 1 (1.78) 11 (19.64) 13 (23.21) 7 (12.50) 3 (5.35) 34 (60.71)
other complaints (Table 1). Thirty-four (60.71%) of all 56 patients underwent surgery because of histological features of malignancy after the FNAB. Distal pancreatectomy with splenectomy was the most common operative approach in 13 patients, followed by Whipple resection in 11 and distal pancreatectomy without splenectomy in 7 of the patients with pancreatic cystic lesions. Three patients were treated with total pancreatectomy due to the presence of multifocal mucinous neoplasm. Imaging features In the process of US and CT diagnostic examination for cystic lesions of the pancreas and their differential diagnostic clarification characteristic images were seen in various neoplasms: in 9 (83.33%) of the cases with serous cystic neoplasm (SCN) the cystic entity presented as multiple cavities (up to 2 cm in diameter) alluding to the so-called honeycomb with polycyclic borders (Figure 1). Five (41.66%) of the patients with SCN presented with a central scar of fibrous tissue, forming a typical star image. In 18 (69.23%) of 26 cases with mucinous cystic neoplasm (MCN) presented on US and CT images as a large cyst, rarely multicavitary. These neoplasms developed mainly in the body-tail of the pancreas and although it has no communication with the pancreatic duct can cause its obstruction. Usually the lesions presented with an image of a cyst with thick, irregular walls with papillary
RESULTS
Forty-two (75%) patients were symptomatic at the time of presentation. The most common symptom was abdominal pain observed in 39 patients, followed by weight loss in 14 and nausea with vomiting in 3 patients. Twelve patients presented without symptoms. In those patients, cysts were found during preliminary examination for
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Figure 3 Multidetector computed tomography coronal reconstruction and ultrasound images of multiple branch duct type of intraductal papillary mucinous tumors. Note the dilated pancreatic duct on ultrasound image.
Table 2 Histological characteristics, location and size of cystic lesions

Histology Serous cystadenoma Mucinous cystadenoma-benign Mucinous cystadenoma -borderline Mucinous cystadenocarcinoma Intraductal papillary mucinous neoplasm Adenocarcinoma Solid and papillary cystic U Lymphoepithelial cyst Pseudocyst All
n (%)
12 (21.42) 15 (26.78) 5 (8.92) 6 (10.71) 9 (16.07) 1 (1.78) 1 (1.78) 3 (5.35) 4 (7.14) 56 (100)
Figure 4 Cytological preparation with immuno-reactivity to P-53 in 80%-95% of the cells.
growths or septation (Figure 2). In 5 (55.55%) patients with intraductal mucinous cystic neoplasm (IPMN) cystic lesions located in the processus uncinatus presented with images of echogenic/hypodense lesions with papillary defects and cystic dilation of the main pancreatic duct (Figure 3). Histological features The distribution of the lesions by their location was as follows: in the head/processus uncinatus - 15; in the body/neck - 11; and in the tail - 30. The average size of lesions was 4.3 cm with a range of 0.5-22 cm. Histological analysis showed that the most common neoplasm in this patient group was mucinous tumor - 34, followed by serous cystadenoma - 12 ( Table 2). Of mucinous tumors, mucinous cystadenomas with benign features were the most frequent (15 cases); in 11 patients the lesions were with both borderline and malignant signs and 9 lesions were intraductal papillary mucinous neoplasms. In 4 patients without a clear prior history of acute pancreatitis or pseudocyst a final diagnosis of pseudocyst was made. Comparing the diagnostic results of US examination with those of MDCT examination and histological verification true positive results were found in 31 patients, true negative in 11 patients, false positive in 5 and false nega-
tive in 9 patients. Accordingly we estimated the power of the diagnostic imaging methods for cystic lesions of the pancreas. A specificity of 68.75%, sensitivity of 79.48%, accuracy of 75.00%, positive predictive value of 86.11% and negative predictive value of 55% were obtained. The power increased after applying invasive procedures with immunohistochemical analysis of CEA and P-53 (Figure 4). Thirty-five true positive results, true negative in 13 patients, false positive in 3 and false negative in 5 patients were found. A specificity of 81.25%, sensitivity of 87.50%, accuracy of 85.71%, positive predictive value of 92.10% and negative predictive value of 72.22% was obtained. In 15 patients with cytological features of malignant tumour cells the tumour markers were positive. In our opinion the higher the percentage of reacting cells the higher the percent of malignancy. In patients with clear symptoms and/or clear imaging features of malignant or premalignant cystic neoplasm, the need for surgery was confirmed by histological verification in 34 (60.71%) of cases. Adding the results of invasive procedures this percentage increased to 46 (82.14%) because the high expression of P-53 antigen and CEA combined with degenerative cells and intra/extracellular mucin provided almost certain diagnosis of malignant cystic lesions. Algorithm Based on the presence or absence of clinical symptoms,
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Cystic pancreatic lesions
Imaging examination US, CT or MRI
TU formation Jaundice
Imaging features of mucinous neoplasm or malignant TU expanding lesion
Imaging features of dilated main pancreatic duct/MPD
Cystic lesions Without symptoms No dilated MPD No malign features
Operative intervention
ERCP
US, CT and FNAB Analysis of cystic content
Features of IPMN
Cytology Mucinous cells Mucin
Positive
Negative Positive Negative
Imaging control
CEA, P-53
Positive
Figure 5 Proposed diagnostic algorithm and therapeutic behavior of suspected pancreatic cystic neoplasms. US: Ultrasound; CT: Computed tomography; MRI: Magnetic resonance imaging; ERCP: Endoscopic retrograde cholangiopancreatography; FNAB: fine needle aspiration biopsy.
clear and reliable imaging of MCNs, and high specificity of the criteria of invasive manipulations, we proposed a diagnostic-therapeutic algorithm for cystic lesions of the pancreas (Figure 5). The algorithm proposed and used routinely in our institution allowed us to detect mucinous tumors and perform proper operative interventions at low risk of missing malignant lesions.
DISCUSSION
The use of multiple imaging methods significantly increases the reports of accidental detection of cystic lesions of the pancreas. In some centres, the increase in operational interventions is almost 50% in cystic lesions of the pancreas[6]. With a growing body of information about the biological behavior of the pancreatic cystic lesions the necessity of performing resections in all cases with cystic lesions is changing[7-9]. These lesions should be resected only in the presence of significant symptomatology related to their increase[8-10]. In our study, the average number of tests performed for diagnostic clarification of cystic lesions of the pancreas was two. After the first clinical application of CT in 1973, a growing development in technology and related innovations has been observed[11]. There is a large range of variations in CT sensitivity in cystic pancreatic neoplasm (20%-70%)[12-14]. Some authors recommend CEUS, as a better method for identification of vascularization of pancreatic tumors when the pancreatic gland is optimally
visualized[15]. CT is recommended as the primary method in the study of cystic pancreatic neoplasms[16,17]. Typical serous cystadenoma is characterized by numerous small cysts usually more than 6 mm up to 2-3 cm in diameter. The central star feature of fibrotic changes and calcifications is a pathognomonic scar[10,12,17]. Our algorithm proposed imaging features highly suspicious of mucinous or malignant tumor, including CT and MRI signs of thick walls with septations with or without calcifications and adjacent mass. Performing FNAB and obtaining mucin containing cells eliminates the need for further examination because of the necessity of surgical intervention. One exception may be the suspicion of IPMN on MDCT and MRI examination. Dilation of the main pancreatic duct over 10 mm could then be secondary to chronic pancreatitis, obstruction of lumen and tumor IPMN[17,18]. ERCP preoperatively allows the distribution and localization of pancreatic duct involvement. Very important information on the needs and volume of operative intervention can be obtained using these techniques. US morphological diagnosis with FNAB and analysis of cystic fluid have the same restrictions as other scanning methods. Many studies show that this is less sensitive than CT[19-21]. To increase the accuracy of diagnostic imaging methods we offer a combination of FNAB and FNA[22]. Biopsy findings of mucinous columnar cells, atypical cytology or malignant cells clearly require operation[23]. Many authors recommend examination of the fluid with cytological preparations and examination for P-53 and CEA antigens[22,24-26].
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Cystic tumors of the pancreas represent a diagnostic challenge for both radiologists and surgeons because of their overlapping clinical, radiological and pathologic features. In patients with cystic lesions of the pancreas presenting with clinical symptoms, imaging signs or malignant mucinous cells from FNA additional tests and examinations are not necessary. Cytological preparations of FNA and FNAB are sufficient to differentiate mucinous neoplasms of the pancreas. The algorithm presented, based on symptomatology, imaging features and examination of cytology FNA and FNAB, enables satisfactory basis for an adequate therapeutic behavior in cystic lesions of the pancreas. Based on the results obtained and our understanding of the limited possibilities of accurate diagnosis of cystic pancreatic neoplasms, we believe that all cystic lesions should be suspected and biopsied in search of early signs of malignant changes.
5 6
COMMENTS COMMENTS
Background
Cystic tumours comprise 10%-15% of all cystic masses and 1%-5% of all pancreatic malignancies. The clinical, radiologic and pathologic features of cystic pancreatic lesions are well known, but still preoperative diagnosis is difficult. With advancements in diagnostic imaging, cystic lesions of the pancreas are being detected with increasing frequency and this requires looking for signs of malignancy.
8 9
10
Research frontiers
With increasing incidental detection of these cystic neoplasms, especially in light of the understanding that most of these lesions are benign in nature, resection in all cases is unnecessary. No optimal test distinguishing benign from malignant cystic tumors has been provided so far. Computed tomography (CT) is also accurate in identifying vascular involvement, which complements multidetector computed tomography (MDCT) in predicting resectability.
11 12
Innovations and breakthroughs
Contrast-enhanced, single-section, helical CT is almost 100% accurate in determining unresectability, but is less accurate in predicting resectability. However, the latest MDCT technology provides three-dimensional multiplanar reconstruction techniques enabling accurate determination of tumour involvement of the pancreatic duct, and peripancreatic vasculature. This has improved the preoperative determination of surgical respectability.
13 14
Applications
The study proposes a diagnostic algorithm for differentiating cystic neoplasms and to define criteria for preoperatively predicting the need for surgical intervention. The power increased after applying invasive procedures with immunohistochemical analysis of CEA and P-53.
15
Terminology
Cystic tumors of the pancreas represent a diagnostic challenge for both radiologists and surgeons because of their overlapping clinical, radiological and pathologic features. The algorithm presented, based on symptomatology, imaging features and examination of cytology fine-needle aspiration and fine needle aspiration biopsy enables satisfactory basis for an adequate therapeutic behavior in cystic lesions of the pancreas.
16 17 18
Peer review
This is a very interesting paper addressing a common clinical condition. The authors reported an algorithm to guide the diagnostic and treatment approach for cystic pancreatic lesion, which was not reported before. However, the manuscript needs revision
19
REFERENCES
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Fernndez-del Castillo C, Targarona J, Thayer SP, Rattner DW, Brugge WR, Warshaw AL. Incidental pancreatic cysts: clinicopathologic characteristics and comparison with symptomatic patients. Arch Surg 2003; 138: 427-437; discussion 427-437 Warshaw AL, Compton CC, Lewandrowski K, Cardenosa G, Mueller PR. Cystic tumors of the pancreas. New clinical, radiologic, and pathologic observations in 67 patients. Ann Surg 1990; 212: 432-443; discussion 444-445 Rafique A, Freeman S, Carroll N. A clinical algorithm for the assessment of pancreatic lesions: utilization of 16- and 64-section multidetector CT and endoscopic ultrasound. Clin Radiol 2007; 62: 1142-1153 Brugge WR. Management and outcomes of pancreatic cystic lesions. Digestive and Liver Disease 2008; 40: 854-859 Balcom JH, Rattner DW, Warshaw AL, Chang Y, Fernandezdel Castillo C. Ten-year experience with 733 pancreatic resections: changing indications, older patients, and decreasing length of hospitalization. Arch Surg 2001; 136: 391-398 Sarr MG, Murr M, Smyrk TC, Yeo CJ, Fernandez-del-Castillo C, Hawes RH, Freeny PC. Primary cystic neoplasms of the pancreas. Neoplastic disorders of emerging importance-current state-of-the-art and unanswered questions. J Gastrointest Surg 2003; 7: 417-428 Brugge WR, Lauwers GY, Sahani D, Fernandez-del Castillo C, Warshaw AL. Cystic neoplasms of the pancreas. N Engl J Med 2004; 351: 1218-1226 Spinelli KS, Fromwiller TE, Daniel RA, Kiely JM, Nakeeb A, Komorowski RA, Wilson SD, Pitt HA. Cystic pancreatic neoplasms: observe or operate. Ann Surg 2004; 239: 651-657; discussion 651-657 Allen PJ, Jaques DP, DAngelica M, Bowne WB, Conlon KC, Brennan MF. Cystic lesions of the pancreas: selection criteria for operative and nonoperative management in 209 patients. J Gastrointest Surg 2003; 7: 970-977 Stockburger WT. CT imaging, then and now: a 30-year review of the economics of computed tomography. Radiol Manage 2004; 26: 20-22, 24-27; quiz 28-30 Procacci C, Biasiutti C, Carbognin G, Accordini S, Bicego E, Guarise A, Spoto E, Andreis IA, De Marco R, Megibow AJ. Characterization of cystic tumors of the pancreas: CT accuracy. J Comput Assist Tomogr 1999; 23: 906-912 Scott J, Martin I, Redhead D, Hammond P, Garden OJ. Mucinous cystic neoplasms of the pancreas: imaging features and diagnostic difficulties. Clin Radiol 2000; 55: 187-192 Curry CA, Eng J, Horton KM, Urban B, Siegelman S, Kuszyk BS, Fishman EK. CT of primary cystic pancreatic neoplasms: can CT be used for patient triage and treatment? AJR Am J Roentgenol 2000; 175: 99-103 DOnofrio M, Malag R, Zamboni G, Vasori S, Falconi M, Capelli P, Mansueto G. Contrast-enhanced ultrasonography better identifies pancreatic tumor vascularization than helical CT. Pancreatology 2005; 5: 398-402 Minami M, Itai Y, Ohtomo K, Yoshida H, Yoshikawa K, Iio M. Cystic neoplasms of the pancreas: comparison of MR imaging with CT. Radiology 1989; 171: 53-56 Hashimoto L, Walsh RM, Vogt D, Henderson JM, Mayes J, Hermann R. Presentation and management of cystic neoplasms of the pancreas. J Gastrointest Surg 1998; 2: 504-508 Adsay NV, Conlon KC, Zee SY, Brennan MF, Klimstra DS. Intraductal papillary-mucinous neoplasms of the pancreas: an analysis of in situ and invasive carcinomas in 28 patients. Cancer 2002; 94: 62-77 Madura JA, Wiebke EA, Howard TJ, Cummings OW, Hull MT, Sherman S, Lehman GA. Mucin-hypersecreting intraductal neoplasms of the pancreas: a precursor to cystic pancreatic malignancies. Surgery 1997; 122: 786-792; discussion 792-793 Sedlack R, Affi A, Vazquez-Sequeiros E, Norton ID, Clain JE, Wiersema MJ. Utility of EUS in the evaluation of cystic pan-
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creatic lesions. Gastrointest Endosc 2002; 56: 543-547 Brandwein SL, Farrell JJ, Centeno BA, Brugge WR. Detection and tumor staging of malignancy in cystic, intraductal, and solid tumors of the pancreas by EUS. Gastrointest Endosc 2001; 53: 722-727 Wiersema MJ, Vilmann P, Giovannini M, Chang KJ, Wiersema LM. Endosonography-guided fine-needle aspiration biopsy: diagnostic accuracy and complication assessment. Gastroenterology 1997; 112: 1087-1095 Jones EC, Suen KC, Grant DR, Chan NH. Fine-needle aspiration cytology of neoplastic cysts of the pancreas. Diagn Cytopathol 1987; 3: 238-243 Lewandrowski KB, Southern JF, Pins MR, Compton CC, Warshaw AL. Cyst fluid analysis in the differential diagnosis of pancreatic cysts. A comparison of pseudocysts, serous cystadenomas, mucinous cystic neoplasms, and mucinous cystadenocarcinoma. Ann Surg 1993; 217: 41-47 Sand JA, Hyoty MK, Mattila J, Dagorn JC, Nordback IH. Clinical assessment compared with cyst fluid analysis in the differential diagnosis of cystic lesions in the pancreas. Surgery 1996; 119: 275-280 Hammel P, Levy P, Voitot H, Levy M, Vilgrain V, Zins M, Flejou JF, Molas G, Ruszniewski P, Bernades P. Preoperative cyst fluid analysis is useful for the differential diagnosis of cystic lesions of the pancreas. Gastroenterology 1995; 108: 1230-1235 L- Editor ONeill M E- Editor Xiong L
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BRIEF ARTICLE
Hepatocellular carcinoma treated with transarterial chemoembolization: Evaluation with parametric contrastenhanced ultrasonography
Hippocrates Moschouris, Katerina Malagari, Athanasios Marinis, Ioannis Kornezos, Konstantinos Stamatiou, Georgios Nikas, Marina Georgiou Papadaki, Panagiotis Gkoutzios
Hippocrates Moschouris, Ioannis Kornezos, Georgios Nikas, Marina Georgiou Papadaki, Department of Radiology, Tzaneion General Hospital, 18536 Piraeus, Greece Katerina Malagari, Second Department of Radiology, University of Athens, Attikon Hospital, Chaidari, 12462 Athens, Greece Athanasios Marinis, First Department of General Surgery, Tzaneion General Hospital,18536 Piraeus, Greece Konstantinos Stamatiou, Department of Urology, General Hospital Tzanio, 18536 Piraeus, Greece Panagiotis Gkoutzios, Department of Interventional Radiology, Guys and St. Thomas Hospital, NHS Foundation Trust, SE17EH London, United Kingdom Author contributions: Moschouris H, Malagari K, Kornezos I performed the chemoembolizations and evaluation with CEUS; Moschouris H, Marinis A and Stamatiou K drafted the manuscript and revised it according to reviewers comments; Moschouris H, Kornezos I and Nikas G gathered all clinical and radiological data from the patients, organized and analyzed them; Papadaki MG and Gkoutzios P critically revised the manuscript; and all authors read and approved the final and the revised form of this manuscript. Correspondence to: Athanasios Marinis, Consultant General Surgeon, First Department of General Surgery, Tzaneion General Hospital, Zanni and Afentouli 1 str, 18536 Piraeus, Greece. drmarinis@gmail.com Telephone: +30-21-04592493 Fax: +30-21-04592491 Received: January 30, 2012 Revised: August 20, 2012 Accepted: August 27, 2012 Published online: August 28, 2012
and 20 d after TACE. The distribution and morphology of TACE-induced necrosis in these tumors precluded accurate evaluation by visual assessment or by simple measurements. For pCEUS, a 4.8 mL bolus of SonoVue (Bracco, Milan, Italy) was intravenously administered and analysis of tumor perfusion during the initial phase of enhancement (0-30 s post injection) was performed with dedicated software (Qontrast, Bracco, Milan, Italy). Time-intensity curves were plotted and three parameters were calculated: peak intensity (PI, in percentage %), time to peak (TTP in seconds, s) and area under the curve during wash-in (AUC-WI, in arbitrary units, a.u). Magnetic resonance imaging was the standard imaging modality for post-treatment evaluation. Changes in tumor size were recorded and response was assessed according to response evaluation criteria in solid tumors criteria. RESULTS: A statistically significant decrease in PI and AUC-WI was observed in the treated tumors post TACE; PIpre: 21.5% 8.7% (mean SD), PIpost: 12.7% 6.7%, P < 0.001, AUC-WI pre: 17493 9563 a.u, AUCWI post: 9585 5494 a.u, P < 0.001. A slight increase in TTP was noted post TACE, but this was not statistically significant; TTP pre: 13.1 4.3 s, TTP post: 13.6 4.2 s , P = 0.058). The changes in the aforementioned parameters were not accompanied by significant tumor shrinkage. CONCLUSION: pCEUS, even when limited to the study of the arterial phase of tumoral enhancement, can detect and quantify early perfusional changes in HCC post TACE.
Abstract
AIM: To evaluate the response of hepatocellular carcinoma (HCC) to transarterial chemoembolization (TACE) using a simplified protocol of parametric contrastenhanced ultrasound (pCEUS). METHODS: Eighteen patients with HCC (18 target tumors, diameter: 2.8-12 cm) were evaluated before,
Key words: Contrast-enhanced ultrasonography; Hepatocellular carcinoma; Parametric imaging; Transarterial chemoembolization
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Moschouris H et al . Parametric CEUS evaluation of TACE
Peer reviewers: Rajasvaran Logeswaran, PhD, Associate Professor, Faculty of Engineering, Multimedia University, 63100 Cyberjaya, Malaysia; Dr. Charikleia Triantopoulou, Konstantopouleion Hospital, 3-5, Agias Olgas street, 14233 Athens, Greece Moschouris H, Malagari K, Marinis A, Kornezos I, Stamatiou K, Nikas G, Papadaki MG, Gkoutzios P. Hepatocellular carcinoma treated with transarterial chemoembolization: Evaluation with parametric contrast-enhanced ultrasonography. World J Radiol 2012; 4(8): 379-386 Available from: URL: http://www. wjgnet.com/1949-8470/full/v4/i8/379.htm DOI: http://dx.doi. org/10.4329/wjr.v4.i8.379
INTRODUCTION
One of the many evolving roles of contrast-enhanced ultrasonography (CEUS) in oncologic imaging is in the evaluation of the efficacy of transarterial chemoembolization (TACE) of liver tumors[1-3]. CEUS has been proved to be efficient in differentiating residual (enhancing) from necrotic (non-enhancing) tumor after TACE, and the therapeutic effect can be assessed by subjective, visual evaluation or by simple calculations (for example, by uni- or bi-dimensional measurements of the residual enhancing tumor at a representative section). In order to achieve a more accurate and quantitative assessment of the enhancement of liver tumors using CEUS, dedicated software has been developed, which allows for pixel-by-pixel analysis of the changes in signal intensity (SI) of CEUS images acquired at a defined plane over a selected period of time and for calculation of several perfusion parameters[4]. Quantitative (parametric) CEUS has already been used to assess the effect of antiangiogenetic agents on liver tumors; however, this technique could also be applied for the study of liver tumors post-TACE, particularly in cases in which the chemoembolic effect cannot be easily estimated with the aforementioned simple methods.
of the residual enhancing tumor tissue. The 18 patients in this study were a subgroup of a total of 63 patients who were eligible for, and underwent TACE in our institution during a period of 21 mo. Fortyfive out of sixty-three patients were not included in the study for the following reasons: (1) Twenty-one patients (33.3%) were unsuitable for an optimal and reproducible CEUS study. Thirteen of those patients had deep-seated lesions (> 10 cm from the skin surface). The remaining 8 patients showed poor co-operation, regarding breathholding; (2) in 20 patients, TACE had caused a welldefined, easily measurable enhancement defect, and parametric analysis was deemed unnecessary; and (3) four patients showed complete disappearance of tumoral enhancement indicative of complete necrosis. TACE TACE was performed using a technique similar to that described in previous studies[1,2]. All patients were treated with subsegmental and/or segmental TACE. TACE was performed with drug-eluting microspheres (DC-Beads Biocompatibles Ltd, Surrey, United Kingdom). Each patient received 2-4 mL of DC beads (diameters: 100-300 m and 300-500 m) preloaded with doxorubicin (Adriblastina, Pfizer Italia S.r.L., Nerviano, Milano, Italy, dose: 25-37.5 mg drug/mL of hydrated beads). Additional bland embolization was performed in 7 cases (Embozene microspheres, CeloNova BioSciences Inc., Newnan, GA, United States). Post-embolization angiogram showed partial devascularization in all 18 target tumors. CEUS CEUS examination consisted of two phases, the second phase being performed 15 min after the first. Each phase required the intravenous administration of a 4.8 mL bolus of second generation echo-enhancer based on sulfur hexafluoride (SonoVue, Bracco S.p.A., Milan, Italy), followed by 10 mL of sterile solution. A Philips HD11 XE (Philips Ultrasound, Andover, MA, United States) ultrasononographic unit equipped with dedicated, contrast specific, low mechanical index software and a convex probe (frequency: 2.5-5 MHz) were utilized. The first phase was a non-parametric study (npCEUS), during which the entire target tumor and the surrounding liver parenchyma were scanned for approximately 120 s (i.e. during the arterial, portal and parenchymal phases of enhancement). During this phase, an overall impression of the tumor enhancement was provided and the imaging plane, which depicted the target tumor at its largest diameter, was defined. This was the reference imaging plane for the subsequent, parametric study. During npCEUS, scan parameters (depth, focus, pulse repetition frequency, mechanical index, gain, depth-gain compensation) were optimized for a clear, artifact-free depiction of tumoral enhancement at the reference plane. The second phase was exclusively focused on the study of tumoral enhancement at the reference plane for the first 30 s after injection of the echo enhancer. The probe was manually stabilized at the reference plane and
MATERIALS AND METHODS

Patients-lesions Eighteen non-consecutive patients (14 men and 4 women; mean age: 70.3 years; range: 54-84 years) with hepatocellular carcinoma (HCC), were included in this study. 10 of the studied patients had solitary lesions and 8 had multifocal involvement. In the latter, one tumor (superficial and lacking significant necrosis at baseline) was selected as the target lesion for the subsequent CEUS study. The longest diameter (sonographic measurement) of the target tumors ranged from 2.8-12 cm (mean: 7.5 2.6 cm). All target tumors were suitable for a detailed and reproducible sonographic study. Moreover, after TACE, all target tumors exhibited multiple, ill-defined necrotic (non-enhancing) areas as well as islets of viable tissue with varying degrees of enhancement; this complex appearance precluded accurate evaluation of the therapeutic effect by simple (uni- or bi-dimensional) measurements
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34 27 20 PI 14 7 SI (%) s. 3.740 7.480 11.220 14.960 18.700 22.440 26.180 29.920 AUC-WI
Curves history
TTP
Figure 1 Graph showing the time-intensity curve, which depicts the changes in signal intensity within the selected region of interest during the 30-s acquisition and the three derived parameters: Peak intensity, area under the curve during wash-in phase and time to peak. PI: Peak intensity; AUC-WI: Area under the curve during wash-in; SI: Signal intensity; TTP: oTime to peak.
the patient was instructed to hold his breath for 30 s, or to take very shallow breaths for the same period. Care was taken to avoid any change in imaging plane and in scan parameters that were defined from the first phase. The second phase of CEUS examination resulted in a cineloop of 399 frames, which depicted the initial phase of the enhancement of each studied tumor at the plane of its largest diameter. This cineloop was stored as a digital archive (Audio Video Interleave) in the hard disc of the sonographic unit and was transferred to a personal computer for off-line parametric analysis. The second phase of CEUS along with the subsequent analysis was referred to as parametric CEUS (pCEUS). Each of the 18 patients underwent the above-described biphasic CEUS examination 1-2 d prior to TACE, as well as 18-22 d post TACE, using the same imaging plane and the same scan parameters. We did not evaluate the patients early (i.e. 1-2 d) post TACE; it has been observed, that increased tumor echogenicity shortly after TACE may interfere with detection of tumoral enhancement on CEUS[3]. One session of TACE was studied per patient. All npCEUS and pCEUS studies were performed by the same consultant radiologist with 7 years experience in CEUS and 20 mo experience in utilization of pCEUS software. The presented study was approved by the institutional review board of our hospital. Off-line parametric analysis pCEUS digital archives were processed with dedicated software (Qontrast 4.00, Bracco, Milan, Italy) that evaluated tumoral perfusion using the video intensity data (i.e. non-linearized, compressed data)[4]. A region of interest (ROI) that encompassed the whole area of the tumor at the reference plane was manually drawn, and the software processed, pixel-by-pixel, the changes in SI, which occurred within the ROI over the selected 30 s period of initial enhancement. A time-intensity curve (TIC) and parametric graphs were produced. Since perfusion analy-
sis was limited to the initial 30 s of tumoral enhancement, only the following semi-quantitative parameters were calculated (Figure 1): (1) peak intensity (PI, in percentage %): defined as the increase in SI, from baseline SI to maximal SI measured in the selected ROI during the selected period of enhancement; (2) time to peak (TTP, in seconds): defined as the time period from the onset of tumoral enhancement until the moment maximal SI was reached; and (3) area under the curve during wash-in (AUC-WI, in arbitrary units, a.u): defined as the area under TIC from the onset of tumoral enhancement until the moment maximal SI was reached. Of note, Qontrast software can compensate for minor changes in imaging plane (caused, for example, by very shallow breathing). In case of more pronounced changes in imaging plane, frame-by-frame editing can be performed, and the respective frames can be manually selected and characterized as wrong. These are ignored during parametric analysis[4]. If wrong frames exceeded 10% of the total number of frames of the video clip, we rejected the respective pCEUS study as technically inadequate. Standard pre-and post TACE imaging Contrast-enhanced magnetic resonance (MR) performed 2-5 d prior to intervention and approximately 2 mo (55-68 d) post intervention was used as the standard imaging modality for the evaluation of TACE in all patients. The longest diameter of the target tumor and the sum of the longest diameters of the tumors were measured on axial MR sections prior to, and post TACE; changes were recorded and tumor response was estimated according to response evaluation criteria in solid tumors (RECIST). Moreover, similar to CEUS, a decrease in tumoral enhancement was visually appreciated in all target tumors on dynamic MR images post TACE; however, the distribution, borders definition and varying intensity of enhancement reduction precluded accurate measurement of the TACE-induced necrosis.
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50 40 30 20 10 0 Pre-TACE Post-TACE AUC-WI (a.u) 40.000 25
30.000 TTP (s) Pre-TACE Post-TACE
20
PI (%)
20.000
15
10.000
10
5 Pre-TACE Post-TACE
Figure 2 Box and whisker plots showing the statistically significant changes observed after transarterial chemoembolization in peak intensity and area under the curve during wash-in, while changes in time to peak were not statistically significant (the upper and lower end of each box corresponds to the 1st and 3rd quartile, respectively, and the horizontal line inside the box corresponds to the median value). PI: peak intensity; AUC-WI: area under the curve during wash-in; a.u: Arbitrary units; TACE: Transarterial chemoembolization.
Statistical analysis Descriptive statistics were produced for continuous variables. The normality of distribution of the studied parameters (PI, AUC-WI, TTP) was evaluated with the Kolmogorov-Smirnov test. The statistical significance of the changes in PI, AUC-WI and TTP was evaluated with the paired t-test. The Pearsons correlation coefficient between changes in longest tumor diameter and changes in perfusion parameters was calculated. A P value of < 0.05 was considered significant. Statistical calculations were performed with SPSS 19.0 (233 South Walker Drive Chicago, IL 60606-6412, United States).
Based on axial MR images, the change in the longest tumor diameters caused by TACE was not statistically significant (longest diameter pre-TACE: 77 27 mm, longest diameter 2 mo post-TACE: 75 26 mm, P = 0.09). Moreover, this change had no significant correlation with the aforementioned changes in PI (r = -0.27, P = 0.28), AUC-WI (r = -0.14, P = 0.56) and TTP (r = -0.18, P = 0.47). All patients were classified as stable disease according to RECIST criteria. The time required to perform a pCEUS study (including parametric analysis) did not exceed 20 min.
RESULTS
Prior to TACE, PI ranged from 10.8%-43.8% (mean: 21.5% 8.7%). Post TACE, PI ranged from 4.8-31.3% (mean: 12.7% 6.7%). The decrease in PI after TACE was statistically significant (P < 0.001). A decrease in PI was observed in all patients after TACE. The ratio of the decrease in PI [(PIpre-PIpost/PIpre) 100%] ranged from 12.3%-64.4% (mean: 40.9% 16.1%). All tumors reached their PI within the studied period of 30 s after injection of the echo-enhancer. Prior to TACE, TTP ranged from 7.8-22.4 s (mean: 13.1 4.3 s). Post TACE, TTP ranged from 8.1-22.1 s (mean: 13.6 4.2 s). The increase in TTP caused by TACE failed to reach statistical significance (P = 0.058). Post TACE, TTP was reduced (0.2-0.7 s shorter) in 6 patients, was prolonged (0.1-3.5 s) in 11 patients and remained unchanged in one patient. Prior to TACE, AUC-WI ranged from 4152-38489 a.u (mean: 17493 9563 a.u). Post TACE, AUC-WI ranged from 2635-21701 a.u (mean: 9585 5494 a.u). The decrease in AUC-WI after TACE was statistically significant (P < 0.001). A decrease in AUC-WI was observed in all patients after TACE, the ratio of the decrease [(AUC-WI pre- AUC-WI post/AUC-WI pre) 100%] ranged from 12.5%-70.3% (mean: 42.5% 17.4%). TACE-induced changes in the aforementioned parameters are schematically shown in Figure 2. Representative cases of pCEUS assessment of TACE are shown in Figures 3 and 4.
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DISCUSSION
This work was based on a simplified protocol of pCEUS, in which only the initial period (practically, the arterial phase) of tumoral enhancement was studied. Arterialphase pCEUS was originally proposed by Yoshida et al[5], who used this technique to study the effect of the antiangiogenetic agent, sorafenib, on liver tumors implanted in rabbits. Compared to a complete perfusional study (lasting at least 120 s), arterial-phase pCEUS seems to be simpler and less time-consuming. Moreover, it is much easier to maintain constant and favorable imaging conditions for 30 s than for 120 s. On the other hand, significantly more parameters can be derived from a complete perfusional study. Additionally, arterial-phase pCEUS might not be suitable for the study of tumors with a slower wash-in phase, which require more than 30 s to reach their peak enhancement. In our study, pCEUS revealed a statistically significant decrease in PI and in AUC-WI of the target tumors after TACE, indicating a potential value of these parameters for the quantification of the therapeutic effect of TACE. Parametric imaging is probably not necessary in tumors with total necrosis, or when TACE has caused a well-defined, easily measurable, enhancement defect. In contrast, pCEUS could be applied when simple measurements of the residual enhancing tissue cannot be performed (i.e. when TACE has caused multiple, ill-defined enhancement defects, or hypoperfused areas, instead of clear-cut necrosis).
30 24 18 12 6
Curves history
AUC-WI
SI (%)
s.
3.730 Curves history
7.460
11.190
14.920
18.650
22.380
26.110
29.840
30 24 18 12 6
AUC-WI s. 3.730 7.460 11.190 14.920 18.650 22.380 26.110 29.840
SI (%)
Figure 3 A case of hepatocellular carcinoma studied with non-parametric contrast-enhanced ultrasonography and parametric contrast-enhanced ultrasound before and after the first session of transarterial chemoembolization. A, B: Digital subtraction angiography of the tumor prior to (A) and post transarterial chemoembolization (TACE) (B), shows significant reduction in the angiographically detectable neovascularity after chemoembolization; C, D: Non-parametric contrast-enhanced ultrasonography (npCEUS) at the plane of longest tumor diameter prior to (C) and post TACE (D), shows post-therapeutic reduction in tumoral enhancement with non-enhanced, as well as hypoenhanced areas; E, F: Parametric images produced by analysis of tumor perfusion prior to (E) and post TACE (F), at the same plane as npCEUS. Lighter tones of gray represent areas with higher peak intensity (PI), while darker tones of gray represent hypoperfused areas, with lower PI; G, H: Time-intensity curves prior to (G) and post TACE (H) show an obvious reduction in PI and area under the curve during wash-in (AUC-WI) after TACE. SI: Signal intensity.
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55 Curves history 44 33 22 11 AUC-WI
SI (%)
s.
3.810 Curves history
7.620
11.430
15.240
19.050
22.860
26.670
30.480
55 44 33 22 11
AUC-WI s. 3.800 7.600 11.400 15.200 19.000 22.800 26.600 30.400
SI (%)
Figure 4 Another case of hepatocellular carcinoma studied with non-parametric contrast-enhanced ultrasonography and parametric contrast-enhanced ultrasound before and after the first session of transarterial chemoembolization. A, B: Non-parametric contrast-enhanced ultrasonography (npCEUS) at the plane of longest tumor diameter prior to (A) and post transarterial chemoembolization (TACE) (B), shows non-enhancing (necrotic) areas post-TACE as well as multiple residual enhancing components; C, D: parametric images prior to (C) and post TACE (D) depict well-perfused areas with red and yellow tones, while hypoperfused areas are depicted with tones of blue; E, F: Time-intensity curves prior to (E) and post TACE (F), confirm a reduction in peak intensity (PI) and area under the curve during wash-in (AUC-WI) after TACE; G, H: Corresponding coronal, T1-weighted, gadolinium-enhanced magnetic resonance images of the same tumor, prior to (G) and post TACE (H) correlate favorably with contrast-enhanced ultrasonography images and confirm the significant reduction in lesional enhancement, but no tumor shrinkage. SI: Signal intensity.
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Our results showed a large variability in the studied parameters and of their changes after TACE. This could be attributed to the small number of patients studied. It could also reflect the varying efficacy of TACE and the varying degrees of vascularity of the studied tumors; HCC is typically considered a hypervascular, arterially en hancing tumor, however, the degree of arterial hyperenhancement is not expected to be constant, depending, for example, on the degree of tumor differentiation and on the extent of spontaneous (pretreatment) necrosis. No significant correlation was found between posttherapeutic changes in PI and AUC-WI and changes in longest tumor diameter. We do not consider that this reduces the value of our observations; it rather reflects the insensitivity of size-based criteria in evaluating the therapeutic effect, at least for the first weeks after TACE. On the contrary, we recognize as a major limitation of our work, the fact that we did not correlate our results with overall survival or with another valid response criterion; all of our patients were alive upon completion of this study and all had received additional TACE sessions. In this first attempt to assess TACE using pCEUS, we focused on the description of the technique and on the evaluation of the feasibility of pCEUS; it is clear that the prognostic value of CEUS parameters require further research. Experience regarding post-therapeutic parametric evaluation with CEUS is primarily based on the assessment of antiangiogenetic agents[5-8], and a significant proportion of the relevant studies have been performed on animals. It is not clear which parameter better reflects the therapeutic effect. In the aforementioned study by Yoshida et al[5], the treated tumors exhibited a delay in TTP, but no significant change in PI. However, these authors included not the entire tumoral area, but only viable tumor components in their ROIs. A significant increase in TTP (and not in other parameters) was also associated with good response in the study by Schirin-Sokhan et al[6], who evaluated liver metastases treated with chemotherapeutic and antiangiogenic agents. In another study[7], a delay in TTP as well as a decrease in PI was observed post treatment with a vascular disruptive agent (AVE8062). In a third animal study[8], reduction in PI correlated well with immunohistochemically proven necrosis after administration of pazopanib. Another study[9] showed that perfusion indices, which were equivalent to our PI and AUC-WI, correlated positively with segmental blood flow and microcirculatory perfusion. Based on the last 2 observations, we can hypothesize that the reduction in PI and AUC-WI in our study reflects the TACE-induced necrosis and reduction in tumoral blood flow. Although we found a slight increase in TTP post TACE, we could not establish a statistical significance for this observation. Methodological (i.e. small patient number) and technical factors could account for this result. We also hypothesize that TACE may not necessarily have the same effect on TTP as antiangiogenic treatment; TACE causes tumor ischemia and devascularization with different mechanisms to those of antiangiogenetic agents.
Several factors (site and degree of vessel occlusion, diameter of target vessel, additional administration of bland embolic agents) could be responsible for the variability in our results; however, the analysis of these factors was beyond the scope of this preliminary work. The clinical application of pCEUS seems to be more challenging and more demanding compared to pCEUS of experimental tumors; a significant disadvantage of this method is that it can be applied only in selected patients, who are fit for a detailed, high-quality CEUS study and who can undergo follow-up under fully reproducible conditions. In another work[10], motion artifacts caused technical failure of pCEUS in 30% of the studied patients. An additional limitation of pCEUS is that it provides perfusional information only for the selected section of the tumor and not for the entire lesion. We conclude that a simplified protocol of pCEUS could be a useful adjunct to standard pre- and post-interventional imaging in selected cases of liver tumors, in which the efficacy of TACE cannot be adequately evaluated by visual assessment and by simple measurements. Additional studies are required, in order to define which parameters optimally estimate the therapeutic effect and to correlate these parameters with established response criteria.
COMMENTS COMMENTS
Background
One of the many evolving roles of contrast-enhanced ultrasonography (CEUS) in oncologic imaging is in the evaluation of the efficacy of transarterial chemoembolization (TACE) of liver tumors. CEUS has been proved to be efficient in differentiating residual (enhancing) from necrotic (non-enhancing) tumor after TACE, and therapeutic effect can be assessed by subjective, visual evaluation or by simple calculations.
Research frontiers
Quantitative (parametric) CEUS has already been used to assess the effect of antiangiogenetic agents on liver tumors. In this study, the authors used this technique for the study of liver tumors post-TACE.
Innovations and breakthroughs
In this study, pCEUS revealed a statistically significant decrease in higher peak intensity and in area under the curve during wash-in of the target tumors after TACE, indicating the potential value of these parameters for the quantification of the therapeutic effect of TACE.
Applications
A simplified protocol of pCEUS could be a useful adjunct to standard pre- and post-interventional imaging in selected cases of liver tumors, in which the efficacy of TACE cannot be adequately evaluated by visual assessment and by simple measurements.
Peer review
It is a well written paper with important results. Some clarifications on the methodology are needed.
REFERENCES
1 Malagari K, Chatzimichael K, Alexopoulou E, Kelekis A, Hall B, Dourakis S, Delis S, Gouliamos A, Kelekis D. Transarterial chemoembolization of unresectable hepatocellular carcinoma with drug eluting beads: results of an open-label study of 62 patients. Cardiovasc Intervent Radiol 2008; 31: 269-280 Moschouris H, Malagari K, Papadaki MG, Kornezos I, Ma tsaidonis D. Contrast-enhanced ultrasonography of hepa-
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tocellular carcinoma after chemoembolisation using drugeluting beads: a pilot study focused on sustained tumor necrosis. Cardiovasc Intervent Radiol 2010; 33: 1022-1027 Kono Y, Lucidarme O, Choi SH, Rose SC, Hassanein TI, Alpert E, Mattrey RF. Contrast-enhanced ultrasound as a predictor of treatment efficacy within 2 weeks after transarterial chemoembolization of hepatocellular carcinoma. J Vasc Interv Radiol 2007; 18: 57-65 Operators Manual of the parametric software (Qontrast). Greece: Esaote SpA, 2006: 8-17 Yoshida K, Hirokawa T, Moriyasu F, Liu L, Liu GJ, Yamada M, Imai Y. Arterial-phase contrast-enhanced ultrasonography for evaluating anti-angiogenesis treatment: a pilot study. World J Gastroenterol 2011; 17: 1045-1050 Schirin-Sokhan R, Winograd R, Roderburg C, Bubenzer J, do NC, Guggenberger D, Hecker H, Trautwein C, Tischendorf JJ. Response evaluation of chemotherapy in metastatic colorectal cancer by contrast enhanced ultrasound. World J Gastroenterol 2012; 18: 541-545 7 Lavisse S, Lejeune P, Rouffiac V, Elie N, Bribes E, Demers B, Vrignaud P, Bissery MC, Brul A, Koscielny S, Pronneau P, Lassau N. Early quantitative evaluation of a tumor vasculature disruptive agent AVE8062 using dynamic contrastenhanced ultrasonography. Invest Radiol 2008; 43: 100-111 Zhu XD, Zhang JB, Fan PL, Xiong YQ, Zhuang PY, Zhang W, Xu HX, Gao DM, Kong LQ, Wang L, Wu WZ, Tang ZY, Ding H, Sun HC. Antiangiogenic effects of pazopanib in xenograft hepatocellular carcinoma models: evaluation by quantitative contrast-enhanced ultrasonography. BMC Cancer 2011; 11: 28 Eichhorn ME, Klotz LV, Luedemann S, Strieth S, Kleespies A, Preissler G, Lindner M, Jauch KW, Reiser MF, Clevert DA. Vascular targeting tumor therapy: non-invasive contrast enhanced ultrasound for quantitative assessment of tumor microcirculation. Cancer Biol Ther 2010; 9: 794-802 Goetti R, Reiner CS, Knuth A, Klotz E, Stenner F, Samaras P, Alkadhi H. Quantitative perfusion analysis of malignant liver tumors: dynamic computed tomography and contrastenhanced ultrasound. Invest Radiol 2012; 47: 18-24
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CASE REPORT
Inferior pancreaticoduodenal artery aneurysm treated with coil packing and stent placement
Akira Ikoma, Motoki Nakai, Morio Sato, Nobuyuki Kawai, Takami Tanaka, Hiroki Sanda, Kouhei Nakata, Hiroki Minamiguchi, Tetsuo Sonomura
Akira Ikoma, Motoki Nakai, Morio Sato, Nobuyuki Kawai, Takami Tanaka, Hiroki Sanda, Kouhei Nakata, Hiroki Minamiguchi, Tetsuo Sonomura, Department of Radiology, Wakayama Medical University, 811-1 Kimiidera, Wakayamashi, Wakayama 641-8510, Japan Author contributions: Ikoma A, Nakai M performed the treatment; Sato M wrote this manuscript; Kawai N, Tanaka T and Sanda H researched the references; Nakata K and Minamiguchi H took care of the patient following treatment; and Sonomura T edited the paper. Correspondence to: Morio Sato, MD, Professor of Department of Radiology, Wakayama Medical University, 811-1 Kimiidera, Wakayamashi, Wakayama 641-8510, Japan. morisato@mail.wakayama-med.ac.jp Telephone: + 81-73-4443110 Fax: +81-73-4410604 Received: February 21, 2012 Revised: April 16, 2012 Accepted: April 23, 2012 Published online: August 28, 2012
Key words: Pancreaticoduodenal arterial aneurysm; Superior mesenteric artery stenosis; Balloon angioplasty; Stent placement; Coil packing; Pull-through technique Peer reviewer: Stefania Romano, MD, Department of Diagnostic Imaging, Section of General and Emergency Radiology, Cardarelli Hospital, Viale Cardarelli, 9, 80131 Naples, Italy
Ikoma A, Nakai M, Sato M, Kawai N, Tanaka T, Sanda H, Nakata K, Minamiguchi H, Sonomura T. Inferior pancreaticoduodenal artery aneurysm treated with coil packing and stent placement. World J Radiol 2012; 4(8): 387-390 Available from: URL: http:// www.wjgnet.com/1949-8470/full/v4/i8/387.htm DOI: http:// dx.doi.org/10.4329/wjr.v4.i8.387
INTRODUCTION Abstract
Two cases with a pancreaticoduodenal arterial aneurysm accompanied with superior mesenteric artery (SMA) stenosis were previously described and both were treated surgically. However, for interventional treatment, securing a sufficient blood supply to the SMA should be a priority of treatment. We present the case of a 71-year-old male with a 20 mm diameter pancreaticoduodenal arterial aneurysm accompanied by SMA stenosis at its origin. The guidewire traverse from SMA to the aneurysm was difficult because of the tight SMA stenosis; however, the guidewire traverse from the celiac artery was finally successful and was followed by balloon angioplasty using a pull-through technique, leading to stent placement. Thereafter, coil packing through the SMA achieved eradication of the aneurysm without bowel ischemia. At the last follow-up computed tomography 8 mo later, no recurrence of the aneurysm was confirmed. The pull-through technique was useful for angioplasty for tight SMA stenosis in this case.
Of the different types of systemic aneurysm, a visceral aneurysm is rare and occurs with a frequency of 0.1%-0.2%[1]. Splenic artery aneurysm accounts for more than half of all visceral aneurysms, followed by hepatic artery aneurysm, superior mesenteric artery (SMA) aneurysm, celiac artery aneurysm, and pancreaticoduodenal artery aneurysm, with frequencies of 20%, 8%, 4% and 2%, respectively[2]. A pancreaticoduodenal artery aneurysm is often accompanied by celiac artery axis stenosis but it is rare for it to occur with SMA stenosis[3,4]. Embolization of a pancreaticoduodenal artery aneurysm under SMA stenosis might induce ischemia to the bowel. Then, before embolization, it is crucial to secure sufficient blood flow of SMA. We present a case of pancreaticoduodenal artery aneurysm accompanied by a SMA stenosis treated with coil embolization following stent placement using a pullthrough technique.
CASE REPORT
A 71-year-old male presented to our hospital suffering
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Ikoma A et al . IPDA aneurysm with SMA stenosis

Figure 1 Volume-rendered threedimensional computed tomography demonstrates an aneurysm (arrow) supplied from inferior pancreaticoduodenal artery and the overt stenosis of superior mesenteric artery at origin (arrowhead).
from colon cancer. The patient had no symptoms and laboratory tests revealed no abnormal findings except elevated carcinoembryonic antigen of 6.5 ng/mL. Abdominal computed tomography (CT) using contrast medium for investigating metastases accidentally revealed visceral artery aneurysm of 2 cm in diameter from a branch of the SMA, namely the inferior panncreaticoduodenal artery. Further, it revealed overt stenosis of SMA at its origin (Figure 1). No celiac artery stenosis with median arcuate ligament thickening was observed. After the patient was informed of surgical and intravascular treatments from a team of surgeons and interventional radiologists, he gave consent for treatment with transcatheter arterial embolization (TAE). The celiac artery was catheterized using a 4 Fr RC2 (Rosch celiac, Medikit, Tokyo, Japan) through 6 Fr sheath (SuperSheath, Medikit) inserted from the right femoral artery. Celiac arteriography revealed that blood flow from the SMA came from the celiac artery via dilated communications from posterior and anterior superior pancreaticoduodenal arteries to the inferior pancreaticoduodenal artery (IPDA), and an aneurysm was observed at the communication site among the three arteries (Figure 2A). Ischemia to the small intestine should be avoided during embolization so we devised a treatment strategy to dilate the origin of the SMA with stent placement followed by embolization of the aneurysm. First, the 4 Fr RC2 catheter was withdrawn, a 6 Fr guiding catheter (Envoy, Cordis, Johnson and Johnson, Miami, FL) was inserted from the 6 Fr sheath and the 4 Fr RC2 catheter was reinserted through the guiding catheter to catheterize to the SMA inlet. However, direct catheterization to the SMA was difficult, probably because of tight stenosis. Then a 4 Fr sheath (SuperSheath, Medikit) was inserted from the left femoral artery and a 4 Fr RC2 catheter was advanced through the sheath to the gastroduodenal artery via the celiac artery and common hepatic artery using a guidewire (0.035, Radiofocus, Terumo, Tokyo, Japan). A 2.2 Fr microcatheter (Shirabe, Piolax, Yokohama, Japan) was inserted through the 4 Fr RC2 catheter and advanced to prior to the origin of SMA over the ASPD and the aneurysm using a microwire (GT, 0.016 inch, 180 cm in length, Terumo). The traverse of the microwire from the SMA origin to aorta was also very tough but finally successful (Figure 2B).
Thereafter, a 4 Fr Amplatz Goose neck snare catheter (EV3 Endovascular Inc., Plymoth, MN) was inserted through the guiding catheter and grasped the microwire in the aorta. The microwire was pulled into the guiding catheter and taken out from the right femoral sheath. Then the pull-through from the left femoral artery to the right femoral artery was completed via the celiac artery, pancreaticoduodenal arcade, aneurysm and superior mesenteric artery. Percutaneous transluminal angioplasty (PTA) for SMA stenosis at its origin was performed using a balloon catheter (Sterling, 4 mm in diameter and 2 cm in length, Boston Scientific, Natic, MA) from a right femoral approach under a pull-through guidewire tension. After balloon dilatation, the 6 Fr guiding catheter was re-inserted and advanced to the SMA over its origin. A balloon expandable stent device (6 Fr, Palmatz Genesis Stent, 5 mm in diameter, 18 mm in length) was inserted to the SMA origin over the micro-guidewire (0.014 inch microwire (Deja-vu, 0.014, 180 cm, Cordis, Endovascular/Johnson and Johnson, Waren, NJ) and the stent was deployed by balloon inflation at 10 atmospheric pressure. Superior mesenteric arteriography after the stent placement revealed the marked dilatation of the SMA at its origin (Figure 3A). The microcatheter and RC2 catheter were inserted into the guiding catheter and advanced to the aneurysm. After stent deployment, test injection from a microcatheter showed the stagnation of blood flow of anterior and posterior superior pancreaticoduodenal arteries (ASPDA and PSPDA). Taking into consideration that embolizations of ASPDA, PSPDA and IPDA for the isolation of the aneurysm were troublesome and might cause ischemic damage to the small intestine or the duodenum, we attempted to perform selective embolization of aneurysm with microcoils (packing). A microcatheter was placed in the aneurysm using the microwire. The aneurysm was finally packed with 11 guglielmi detachable coils (3; 20 mm in diameter 33 cm in length, 3; 18 mm in diameter 30 cm in length, 3; 16 mm in diameter 30 cm in length, 1; 15 mm in diameter 30 cm in length, 1; 14 mm in diameter 30 cm in length). Celiac arteriography revealed the eradication of the aneurysm (Figure 3B). The following day, no abnormal symptoms and laboratory test results were observed except slight fever and the mild elevation of c-reactive protein. At the last follow-up, 8 mo later, CT angiography revealed no recurrent stenosis of SMA and no increase in the aneurysm.
DISCUSSION
Once the peripancreatic artery aneurysm has been found, early eradication is reported to be crucial because the correlation between the size of the peripancreatic artery aneurysm and the incidence of the rupture is not assured[5]. Causes of pancreaticoduodenal artery aneurysm include infection, trauma, pancreatitis, collagen disease and iatrogenic procedures[6]. However, hemodynamic stress accompanied with occlusion or stenosis of the main trunk artery is reported to be the leading cause[6]. Namely, more
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A
GDA CHA DPA SMA PSPDA IPDA CA
ASPDA
Figure 2 Angiography and catheterization prior to treatment. A: Celiac arteriography demonstrates a superior mesenteric artery via the dilated posterior and anterior pancreaticoduodenal arcades with aneurysm (black arrow head); B: Successful catheterization was achieved using a microwire, a microcatheter and Roesch celiac (RC) catheter from celiac artery to superior mesenteric artery and abdominal aorta via anterior pancreaticoduodenal arcade and an aneurysm. CA: Celiac artery; CHA: Common hepatic artery; GDA: Gastroduodenal artery; DPA: Dorsal pancreatic artery; SMA: Superior mesenteric artery; IPDA: Inferior pancreaticoduodenal artery; PSPDA: Posterior superior pancreaticoduodenal artery; ASPDA: Anterior superior pancreaticoduodenal artery.
Figure 3 Angiography following stent placement and microcoils embolization. A: Superior mesenteric arteriography following stent placement demonstrates the dilated superior mesenteric artery at origin; B: Celiac arteriography following microcoils embolization via superior mesenteric artery demonstrates the eradication of the aneurysm. An arrow indicates a metallic stent placed at the origin of the superior mesenteric artery.
than half of peripancreatic artery aneurysms are caused by celiac axis stenosis due to a median arcuate ligament thickening[6-8]. Our case had no past history of pancreatitis, infection and collagen disease. As occlusion of the SMA was observed, the cause of the present pancreaticoduodenal artery is considered to be an increase of blood flow from the celiac artery to the SMA via anterior and posterior pancreaticoduodenal arteries[4]. The cause of SMA occlusion was not clarified in this case. To the best of our knowledge, two cases with a pancreaticoduodenal artery aneurysm with SMA stenosis were previously reported with no description about the causes and both of them were treated by surgical repair (aneurysm resection or bypass operation)[3,4]. As the treatment for visceral artery aneurysms, TAE is supplied as a safe and less invasive treatment[7-9]. Isolation[7] and packing[8] using microcoils are suggested as embolization procedures. However, TAE-unmanageable cases exist because of the difficulty of catheterization to the responsible artery, the complicated anastomosis or branching[9]. Further, we have to take into consideration the issue of aneurysm rupture during catheterization or
ischemia to visceral organs following embolization in advance[9]. TAE has not been used for treatment of pancreaticoduodenal artery aneurysm accompanied with SMA stenosis before, probably because of the anticipation of bowel ischemia following embolization and difficult catheterization. In our case, the SMA occlusion was too tight to recanalize by catheterization from the SMA origin. However, catheterization from the celiac artery via the pancreaticoduodenal arcade and SMA enabled the traverse of the tight occlusion of SMA origin to the abdominal aorta. A pull-through technique from the left femoral artery to the right femoral artery via the celiac artery, pancreaticoduodenal arcade, aneurysm and superior mesenteric artery enabled balloon PTA, leading to stent placement. Previously, there was one report of successful port-catheter implantation of celiac stenosis using a pullthrough technique from the femoral artery to the subclavian artery via the SMA, pancreaticoduodenal arcade and celiac axis artery[10]. When tight occlusion at the celiac axis artery or SMA exists, catheterization using a pull-through technique is considered to be an alternative procedure. In conclusion, we presented a rare case with pancre-
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aticoduodenal artery aneurysm accompanied by SMA occlusion treated by coil packing to the aneurysm following securing SMA blood flow with stent placement at the SMA origin. A pull-through technique was useful for a possible recanalization for tight SMA occlusion and a balloon PTA.
REFERENCES
1 2 3 Drescher R, Kster O, von Rothenburg T. Superior mesenteric artery aneurysm stent graft. Abdom Imaging 2006; 31: 113-116 Upchurch GR Jr, Zelenock GB, Stanley JC. Splanchnic artery aneurysms. In: Rutherford RB, editor. Vascular Surgery, 6th ed. Philadelphia, New York: WB Saunders, 2005:1565-1581 Ichinokawa M, Iwai K, Matsumura Y, Mega S, Kawasaki R, Takahashi T, Kondo S. [A case of the anterior superior pancreaticoduodenal artery aneurysm with complete occulusion of the superior mesenteric artery]. Jpn J Gastroenterol Surg 2006; 39: 1678-1682 Kimura C, Adachi H, Yamaguchi A, Ino T. [A case of an unruptured inferior pancreaticoduodenal artery aneurysm with celiac artery occulusion and superior mesenteric artery
stenosis]. Jpn J Vasc Surg 2009; 18: 691-694 Moore E, Matthews MR, Minion DJ, Quick R, Schwarcz TH, Loh FK, Endean ED. Surgical management of peripancreatic arterial aneurysms. J Vasc Surg 2004; 40: 247-253 6 Ducasse E , Roy F, Chevalier J, Massouille D, Smith M, Speziale F, Fiorani P, Puppinck P. Aneurysm of the pancreaticoduodenal arteries with a celiac trunk lesion: current management. J Vasc Surg 2004; 39: 906-911 7 Ogino H, Sato Y, Banno T, Arakawa T, Hara M. Embolization in a patient with ruptured anterior inferior pancreaticoduodenal arterial aneurysm with median arcuate ligament syndrome. Cardiovasc Intervent Radiol 2002; 25: 318-319 Ikeda O, Tamura Y, Nakasone Y, Kawanaka K, Yamashita Y. 8 Coil embolization of pancreaticoduodenal artery aneurysms associated with celiac artery stenosis: report of three cases. Cardiovasc Intervent Radiol 2007; 30: 504-507 9 Guijt M , van Delden OM, Koedam NA, van Keulen E, Reekers JA. Rupture of true aneurysms of the pancreaticoduodenal arcade: treatment with transcatheter arterial embolization. Cardiovasc Intervent Radiol 2004; 27: 166-168 10 Yamagami T, Kato T, Hirota T, Yoshimatsu R, Matsumoto T, Nishimura T. Use of a pull-through technique at the time of port-catheter implantation in cases of celiac arterial stenosis. 5 J Vasc Interv Radiol 2006; 17: 1839-1844 S- Editor Cheng JX L- Editor ONeill M E- Editor Xiong L
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ACKNOWLEDGMENTS
Acknowledgments to reviewers of World Journal of Radiology

We acknowledge our sincere thanks to our reviewers. Many reviewers have contributed their expertise and time to the peer review, a critical process to ensure the quality of our World Series Journals. Both the editors of the journals and authors of the manuscripts submitted to the journals are grateful to the following reviewers for reviewing the articles (either published or rejected) over the past period of time.
Kenneth Coenegrachts, MD, PhD, Department of Radiology, AZ St.-Jan AV, Ruddershove 10, B-8000 Bruges, Belgium Shigeru Ehara, MD, Professor, Chair, Iwate Medical University School of Medicine, Morioka 020-8505, Japan Jurgen J Ftterer, MD, PhD, Department of Radiology, Radboud University Nijmegen Medical Centre, Geert Grooteplein 10, 6500HB Nijmegen, The Netherlands Rafael Martnez-Monge, MD, Professor, Chair, Radiation Oncology Division, University Clinic of Navarre, 31080 Pamplona, Navarra, Spain Yi-Xiang Wang, MMed, PhD, Associate Professor, Department of Diagnostic Radiology and Organ Imaging, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, NT, Hong Kong , China
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January 3-7, 2012 Imaging at Bachelor Gulch Beaver Creek, CO 81620, United States January 12-14, 2012 IROS 2012: Interventionell Radiologischen Olbert Symposium Salzburg, Austria January 26-29, 2012 American Society of Neuroimaging 2012 35th Annual Meeting Miami, FL 33169, United States February 9-11, 2012 JIM joint interventional meeting 2012 Rome, Italy February 13-16, 2012 Emergency Radiology Palm Beach, FL 33480, United States February 16-19, 2012 ASSR 2012 Annual Symposium Miami Beach, FL 33169, United States February 19-23, 2012 Internal Derangements of Joints: Advanced and Intensive MR Imaging/With a Special Symposium on Ankle and Foot Coronado, CA 92118, United States February 21-24, 2012 MRI in Practice Oslo, Norway March 1-5, 2012 ECR 2012 Vienna, Austria March 7-10, 2012 ISCD's 18th Annual Meeting Los Angeles, CA 90001, United States

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GENERAL INFORMATION

World J Radiol 2012 August 28; 4(8): I-V ISSN 1949-8470 (online) 2012 Baishideng. All rights reserved.
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ticles, thereby realizing the maximization of the personal benefits of editorial board members, authors and readers, and yielding the greatest social and economic benefits. Aims and scope The major task of WJR is to rapidly report the most recent improvement in the research of medical imaging and radiation therapy by the radiologists. WJR accepts papers on the following aspects related to radiology: Abdominal radiology, women health radiology, cardiovascular radiology, chest radiology, genitourinary radiology, neuroradiology, head and neck radiology, interventional radiology, musculoskeletal radiology, molecular imaging, pediatric radiology, experimental radiology, radiological technology, nuclear medicine, PACS and radiology informatics, and ultrasound. We also encourage papers that cover all other areas of radiology as well as basic research. Columns The columns in the issues of WJR will include: (1) Editorial: To introduce and comment on major advances and developments in the field; (2) Frontier: To review representative achievements, comment on the state of current research, and propose directions for future research; (3) Topic Highlight: This column consists of three formats, including (A) 10 invited review articles on a hot topic, (B) a commentary on common issues of this hot topic, and (C) a commentary on the 10 individual articles; (4) Observation: To update the development of old and new questions, highlight unsolved problems, and provide strategies on how to solve the questions; (5) Guidelines for Basic Research: To provide guidelines for basic research; (6) Guidelines for Clinical Practice: To provide guidelines for clinical diagnosis and treatment; (7) Review: To review systemically progress and unresolved problems in the field, comment on the state of current research, and make suggestions for future work; (8) Original Articles: To report innovative and original findings in radiology; (9) Brief Articles: To briefly report the novel and innovative findings in radiology; (10) Case Report: To report a rare or typical case; (11) Letters to the Editor: To discuss and make reply to the contributions published in WJR, or to introduce and comment on a controversial issue of general interest; (12) Book Reviews: To introduce and comment on quality monographs of radiology; and (13) Guidelines: To introduce consensuses and guidelines reached by international and national academic authorities worldwide on the research in radiology. Name of journal World Journal of Radiology ISSN ISSN 1949-8470 (online) Editor-in-Chief Filippo Cademartiri, MD, PhD, FESC, FSCCT, Professor, Cardio-Vascular Imaging Unit-Giovanni XXIII Hospital, Via Giovanni XXIII, 7-31050-Monastier di Treviso (TV), Italy
World Journal of Radiology ( World J Radiol , WJR , online ISSN 1949-8470, DOI: 10.4329), is a monthly, open-access (OA), peerreviewed journal supported by an editorial board of 319 experts in Radiology from 40 countries. The biggest advantage of the OA model is that it provides free, full-text articles in PDF and other formats for experts and the public without registration, which eliminates the obstacle that traditional journals possess and usually delays the speed of the propagation and communication of scientific research results. The open access model has been proven to be a true approach that may achieve the ultimate goal of the journals, i.e. the maximization of the value to the readers, authors and society. Maximization of personal benefits The role of academic journals is to exhibit the scientific levels of a country, a university, a center, a department, and even a scientist, and build an important bridge for communication between scientists and the public. As we all know, the significance of the publication of scientific articles lies not only in disseminating and communicating innovative scientific achievements and academic views, as well as promoting the application of scientific achievements, but also in formally recognizing the priority and copyright of innovative achievements published, as well as evaluating research per formance and academic levels. So, to realize these desired attributes of WJR and create a well-recognized journal, the following four types of personal benefits should be maximized. The maximization of personal benefits refers to the pursuit of the maximum personal benefits in a well-considered optimal manner without violation of the laws, ethical rules and the benefits of others. (1) Maximization of the benefits of editorial board members: The primary task of editorial board members is to give a peer review of an unpublished scientific article via online office system to evaluate its innovativeness, scientific and practical values and determine whether it should be published or not. During peer review, editorial board members can also obtain cutting-edge information in that field at first hand. As leaders in their field, they have priority to be invited to write articles and publish commentary articles. We will put peer reviewers names and affiliations along with the article they reviewed in the journal to acknowledge their contribution; (2) Maximization of the benefits of authors: Since WJR is an open-access journal, readers around the world can immediately download and read, free of charge, high-quality, peer-reviewed articles from WJR official website, thereby realizing the goals and significance of the communication between authors and peers as well as public reading; (3) Maximization of the benefits of readers: Readers can read or use, free of charge, high-quality peer-reviewed articles without any limits, and cite the arguments, viewpoints, concepts, theories, methods, results, conclusion or facts and data of pertinent literature so as to validate the innovativeness, scientific and practical values of their own research achievements, thus ensuring that their articles have novel arguments or viewpoints, solid evidence and correct conclusion; and (4) Maximization of the benefits of employees: It is an iron law that a first-class journal is unable to exist without first-class editors, and only first-class editors can create a first-class academic journal. We insist on strengthening our team cultivation and construction so that every employee, in an open, fair and transparent environment, could contribute their wisdom to edit and publish high-quality ar-
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Instructions to authors E-mail: wjr@wjgnet.com http://www.wjgnet.com Telephone: +86-10-59080039 Fax: +86-10-85381893 Indexed and Abstracted in PubMed Central, PubMed, Digital Object Identifier, and Directory of Open Access Journals. Published by Baishideng Publishing Group Co., Limited. in accordance with the above standards, the authors must explain the rationale for their approach and demonstrate that the institutional review body explicitly approved the doubtful aspects of the study. Before submitting, authors should make their study approved by the relevant research ethics committee or institutional review board. If human participants were involved, manuscripts must be accompanied by a statement that the experiments were undertaken with the understanding and appropriate informed consent of each. Any personal item or information will not be published without explicit consents from the involved patients. If experimental animals were used, the materials and methods (experimental procedures) section must clearly indicate that appropriate measures were taken to minimize pain or discomfort, and details of animal care should be provided.
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All articles published in this journal represent the viewpoints of the authors except where indicated otherwise. Biostatistical editing Statisital review is performed after peer review. We invite an expert in Biomedical Statistics from to evaluate the statistical method used in the paper, including t-test (group or paired comparisons), chi-squared test, Ridit, probit, logit, regression (linear, curvilinear, or stepwise), correlation, analysis of variance, analysis of covariance, etc. The reviewing points include: (1) Statistical methods should be described when they are used to verify the results; (2) Whether the statistical techniques are suitable or correct; (3) Only homogeneous data can be averaged. Standard deviations are preferred to standard errors. Give the number of observations and subjects (n). Losses in observations, such as drop-outs from the study should be reported; (4) Values such as ED50, LD50, IC50 should have their 95% confidence limits calculated and compared by weighted probit analysis (Bliss and Finney); and (5) The word significantly should be replaced by its synonyms (if it indicates extent) or the P value (if it indicates statistical significance). Conflict-of-interest statement In the interests of transparency and to help reviewers assess any potential bias, WJR requires authors of all papers to declare any competing commercial, personal, political, intellectual, or religious interests in relation to the submitted work. Referees are also asked to indicate any potential conflict they might have reviewing a particular paper. Before submitting, authors are suggested to read Uniform Requirements for Manuscripts Submitted to Biomedical Journals: Ethical Considerations in the Conduct and Reporting of Research: Conflicts of Interest from International Committee of Medical Journal Editors (ICMJE), which is available at: http://www.icmje.org/ethical_4conflicts.html. Sample wording: [Name of individual] has received fees for serving as a speaker, a consultant and an advisory board member for [names of organizations], and has received research funding from [names of organization]. [Name of individual] is an employee of [name of organization]. [Name of individual] owns stocks and shares in [name of organization]. [Name of individual] owns patent [patent identification and brief description]. Statement of informed consent Manuscripts should contain a statement to the effect that all human studies have been reviewed by the appropriate ethics committee or it should be stated clearly in the text that all persons gave their informed consent prior to their inclusion in the study. Details that might disclose the identity of the subjects under study should be omitted. Authors should also draw attention to the Code of Ethics of the World Medical Association (Declaration of Helsinki, 1964, as revised in 2004). Statement of human and animal rights When reporting the results from experiments, authors should follow the highest standards and the trial should conform to Good Clinical Practice (for example, US Food and Drug Administration Good Clinical Practice in FDA-Regulated Clinical Trials; UK Medicines Research Council Guidelines for Good Clinical Practice in Clinical Trials) and/or the World Medical Association Declaration of Helsinki. Generally, we suggest authors follow the lead investigators national standard. If doubt exists whether the research was conducted
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Manuscripts should be typed in 1.5 line spacing and 12 pt. Book Antiqua with ample margins. Number all pages consecutively, and start each of the following sections on a new page: Title Page, Abstract, Introduction, Materials and Methods, Results, Discussion, Acknowledgements, References, Tables, Figures, and Figure Legends. Neither the editors nor the publisher are responsible for the opinions expressed by contributors. Manuscripts formally accepted for publication become the permanent property of Baishideng Publishing Group Co., Limited, and may not be reproduced by any means, in whole or in part, without the written permission of both the authors and the publisher. We reserve the right to copy-edit and put onto our website accepted manuscripts. Authors should follow the relevant guidelines for the care and use of laboratory animals of their institution or national animal welfare committee. For the sake of transparency in regard to the performance and reporting of clinical trials, we endorse the policy of the ICMJE to refuse to publish papers on clinical trial results if the trial was not recorded in a publicly-accessible registry at its outset. The only register now available, to our knowledge, is http://www.clinicaltrials.gov sponsored by the United States National Library of Medicine and we encourage all potential contributors to register with it. However, in the case that other registers become available you will be duly notified. A letter of recommendation from each authors organization should be provided with the contributed article to ensure the privacy and secrecy of research is protected. Authors should retain one copy of the text, tables, photographs and illustrations because rejected manuscripts will not be returned to the author(s) and the editors will not be responsible for loss or damage to photographs and illustrations sustained during mailing. Online submissions Manuscripts should be submitted through the Online Submission System at: http://www.wjgnet.com/esps/. Authors are highly recommended to consult the ONLINE INSTRUCTIONS TO AUTHORS (http://www.wjgnet.com/1949-8470/g_info_ 20100316162358.htm) before attempting to submit online. For assistance, authors encountering problems with the Online Submi ssion System may send an email describing the problem to wjr@ wjgnet.com, or by telephone: +86-10-85381892. If you submit your manuscript online, do not make a postal contribution. Repeated online submission for the same manuscript is strictly prohibited.
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All contributions should be written in English. All articles must be submitted using word-processing software. All submissions must be typed in 1.5 line spacing and 12 pt. Book Antiqua with ample margins. Style should conform to our house format. Required information for each of the manuscript sections is as follows: Title page Title: Title should be less than 12 words. Running title: A short running title of less than 6 words should be provided.
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Instructions to authors Authorship: Authorship credit should be in accordance with the standard proposed by International Committee of Medical Journal Editors, based on (1) substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data; (2) drafting the article or revising it critically for important intellectual content; and (3) final approval of the version to be published. Authors should meet conditions 1, 2, and 3. Institution: Author names should be given first, then the complete name of institution, city, province and postcode. For example, XuChen Zhang, Li-Xin Mei, Department of Pathology, Chengde Medical College, Chengde 067000, Hebei Province, China. One author may be represented from two institutions, for example, George Sgourakis, Department of General, Visceral, and Transplantation Surgery, Essen 45122, Germany; George Sgourakis, 2nd Surgical Department, Korgialenio-Benakio Red Cross Hospital, Athens 15451, Greece Author contributions: The format of this section should be: Author contributions: Wang CL and Liang L contributed equally to this work; Wang CL, Liang L, Fu JF, Zou CC, Hong F and Wu XM designed the research; Wang CL, Zou CC, Hong F and Wu XM performed the research; Xue JZ and Lu JR contributed new reagents/analytic tools; Wang CL, Liang L and Fu JF analyzed the data; and Wang CL, Liang L and Fu JF wrote the paper. Supportive foundations: The complete name and number of supportive foundations should be provided, e.g., Supported by National Natural Science Foundation of China, No. 30224801 Correspondence to: Only one corresponding address should be provided. Author names should be given first, then author title, affiliation, the complete name of institution, city, postcode, province, country, and email. All the letters in the email should be in lower case. A space interval should be inserted between country name and email address. For example, Montgomery Bissell, MD, Professor of Medicine, Chief, Liver Center, Gastroenterology Division, University of California, Box 0538, San Francisco, CA 94143, United States. montgomery.bissell@ucsf.edu Telephone and fax: Telephone and fax should consist of +, country number, district number and telephone or fax number, e.g., Telephone: +86-10-85381892 Fax: +86-10-85381893 Peer reviewers: All articles received are subject to peer review. Normally, three experts are invited for each article. Decision for acceptance is made only when at least two experts recommend an article for publication. Reviewers for accepted manuscripts are acknowledged in each manuscript, and reviewers of articles which were not accepted will be acknowledged at the end of each issue. To ensure the quality of the articles published in WJR, reviewers of accepted manuscripts will be announced by publishing the name, title/position and institution of the reviewer in the footnote accompanying the printed article. For example, reviewers: Professor Jing-Yuan Fang, Shanghai Institute of Digestive Disease, Shanghai, Affiliated Renji Hospital, Medical Faculty, Shanghai Jiaotong University, Shanghai, China; Professor Xin-Wei Han, Department of Radiology, The First Affiliated Hospital, Zhengzhou University, Zhengzhou, Henan Province, China; and Professor Anren Kuang, Department of Nuclear Medicine, Huaxi Hospital, Sichuan University, Chengdu, Sichuan Province, China. Abstract There are unstructured abstracts (no more than 256 words) and structured abstracts (no more than 480). The specific requirements for structured abstracts are as follows: An informative, structured abstracts of no more than 480 words should accompany each manuscript. Abstracts for original contributions should be structured into the following sections. AIM (no more than 20 words): Only the purpose should be included. Please write the aim as the form of To investigate/study/; MATERIALS AND METHODS (no more than 140 words); RESULTS (no more than 294 words): You should present P values where appropriate and must provide relevant data to illustrate how they were obtained, e.g. 6.92 3.86 vs 3.61 1.67, P < 0.001; CONCLUSION (no more than 26 words). Key words Please list 5-10 key words, selected mainly from Index Medicus, which reflect the content of the study. Text For articles of these sections, original articles and brief articles, the main text should be structured into the following sections: INTRODUCTION, MATERIALS AND METHODS, RESULTS and DISCUSSION, and should include appropriate Figures and Tables. Data should be presented in the main text or in Figures and Tables, but not in both. The main text format of these sections, editorial, topic highlight, case report, letters to the editors, can be found at: http://www.wjgnet.com/1949-8470/g_info_20100313183720.htm. Illustrations Figures should be numbered as 1, 2, 3, etc., and mentioned clearly in the main text. Provide a brief title for each figure on a separate page. Detailed legends should not be provided under the figures. This part should be added into the text where the figures are applicable. Figures should be either Photoshop or Illustrator files (in tiff, eps, jpeg formats) at high-resolution. Examples can be found at: http://www.wjgnet.com/1007-9327/13/4520. pdf; http://www.wjgnet.com/1007-9327/13/4554.pdf; http:// www.wjgnet.com/1007-9327/13/4891.pdf; http://www. wjgnet.com/1007-9327/13/4986.pdf; http://www.wjgnet. com/1007-9327/13/4498.pdf. Keeping all elements compiled is necessary in line-art image. Scale bars should be used rather than magnification factors, with the length of the bar defined in the legend rather than on the bar itself. File names should identify the figure and panel. Avoid layering type directly over shaded or textured areas. Please use uniform legends for the same subjects. For example: Figure 1 Pathological changes in atrophic gastritis after treatment. A: ...; B: ...; C: ...; D: ...; E: ...; F: ...; G: etc. It is our principle to publish high resolution-figures for the printed and E-versions. Tables Three-line tables should be numbered 1, 2, 3, etc., and mentioned clearly in the main text. Provide a brief title for each table. Detailed legends should not be included under tables, but rather added into the text where applicable. The information should complement, but not duplicate the text. Use one horizontal line under the title, a second under column heads, and a third below the Table, above any footnotes. Vertical and italic lines should be omitted. Notes in tables and illustrations Data that are not statistically significant should not be noted. aP < 0.05, bP < 0.01 should be noted (P > 0.05 should not be noted). If there are other series of P values, cP < 0.05 and dP < 0.01 are used. A third series of P values can be expressed as eP < 0.05 and fP < 0.01. Other notes in tables or under illustrations should be expressed as 1 F, 2F, 3F; or sometimes as other symbols with a superscript (Arabic numerals) in the upper left corner. In a multi-curve illustration, each curve should be labeled with , , , , , , etc., in a certain sequence. Acknowledgments Brief acknowledgments of persons who have made genuine contributions to the manuscript and who endorse the data and conclusions should be included. Authors are responsible for obtaining written permission to use any copyrighted text and/or illustrations.
REFERENCES
Coding system The author should number the references in Arabic numerals ac-
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Instructions to authors cording to the citation order in the text. Put reference numbers in square brackets in superscript at the end of citation content or after the cited authors name. For citation content which is part of the narration, the coding number and square brackets should be typeset normally. For example, Crohns disease (CD) is associated with increased intestinal permeability[1,2]. If references are cited directly in the text, they should be put together within the text, for example, From references[19,22-24], we know that... When the authors write the references, please ensure that the order in text is the same as in the references section, and also ensure the spelling accuracy of the first authors name. Do not list the same citation twice. PMID and DOI Pleased provide PubMed citation numbers to the reference list, e.g. PMID and DOI, which can be found at http://www.ncbi.nlm.nih. gov/sites/entrez?db=pubmed and http://www.crossref.org/SimpleTextQuery/, respectively. The numbers will be used in E-version of this journal. Style for journal references Authors: the name of the first author should be typed in bold-faced letters. The family name of all authors should be typed with the initial letter capitalized, followed by their abbreviated first and middle initials. (For example, Lian-Sheng Ma is abbreviated as Ma LS, BoRong Pan as Pan BR). The title of the cited article and italicized journal title (journal title should be in its abbreviated form as shown in PubMed), publication date, volume number (in black), start page, and end page [PMID: 11819634 DOI: 10.3748/wjg.13.5396]. Style for book references Authors: the name of the first author should be typed in bold-faced letters. The surname of all authors should be typed with the initial letter capitalized, followed by their abbreviated middle and first initials. (For example, Lian-Sheng Ma is abbreviated as Ma LS, BoRong Pan as Pan BR) Book title. Publication number. Publication place: Publication press, Year: start page and end page. Format Journals English journal article (list all authors and include the PMID where applicable) 1 Jung EM, Clevert DA, Schreyer AG, Schmitt S, Rennert J, Kubale R, Feuerbach S, Jung F. Evaluation of quantitative contrast harmonic imaging to assess malignancy of liver tumors: A prospective controlled two-center study. World J Gastroenterol 2007; 13: 6356-6364 [PMID: 18081224 DOI: 10.3748/wjg.13. 6356] Chinese journal article (list all authors and include the PMID where applicable) 2 Lin GZ, Wang XZ, Wang P, Lin J, Yang FD. Immunologic effect of Jianpi Yishen decoction in treatment of Pixu-diarrhoea. Shijie Huaren Xiaohua Zazhi 1999; 7: 285-287 In press 3 Tian D, Araki H, Stahl E, Bergelson J, Kreitman M. Signature of balancing selection in Arabidopsis. Proc Natl Acad Sci USA 2006; In press Organization as author 4 Diabetes Prevention Program Research Group. Hypertension, insulin, and proinsulin in participants with impaired glucose tolerance. Hypertension 2002; 40: 679-686 [PMID: 12411462 PMCID:2516377 DOI:10.1161/01.HYP.0000035706.28494. 09] Both personal authors and an organization as author 5 Vallancien G, Emberton M, Harving N, van Moorselaar RJ; Alf-One Study Group. Sexual dysfunction in 1, 274 European men suffering from lower urinary tract symptoms. J Urol 2003; 169: 2257-2261 [PMID: 12771764 DOI:10.1097/01.ju. 0000067940.76090.73] No author given 6 21st century heart solution may have a sting in the tail. BMJ 2002; 325: 184 [PMID: 12142303 DOI:10.1136/bmj.325. 7357.184] Volume with supplement 7 Geraud G, Spierings EL, Keywood C. Tolerability and safety of frovatriptan with short- and long-term use for treatment of migraine and in comparison with sumatriptan. Headache 2002; 42 Suppl 2: S93-99 [PMID: 12028325 DOI:10.1046/ j.1526-4610.42.s2.7.x] Issue with no volume 8 Banit DM, Kaufer H, Hartford JM. Intraoperative frozen section analysis in revision total joint arthroplasty. Clin Orthop Relat Res 2002; (401): 230-238 [PMID: 12151900 DOI:10.10 97/00003086-200208000-00026] No volume or issue 9 Outreach: Bringing HIV-positive individuals into care. HRSA Careaction 2002; 1-6 [PMID: 12154804] Books Personal author(s) 10 Sherlock S, Dooley J. Diseases of the liver and billiary system. 9th ed. Oxford: Blackwell Sci Pub, 1993: 258-296 Chapter in a book (list all authors) 11 Lam SK. Academic investigators perspectives of medical treatment for peptic ulcer. In: Swabb EA, Azabo S. Ulcer disease: investigation and basis for therapy. New York: Marcel Dekker, 1991: 431-450 Author(s) and editor(s) 12 Breedlove GK, Schorfheide AM. Adolescent pregnancy. 2nd ed. Wieczorek RR, editor. White Plains (NY): March of Dimes Education Services, 2001: 20-34 Conference proceedings 13 Harnden P, Joffe JK, Jones WG, editors. Germ cell tumours V. Proceedings of the 5th Germ cell tumours Conference; 2001 Sep 13-15; Leeds, UK. New York: Springer, 2002: 30-56 Conference paper 14 Christensen S, Oppacher F. An analysis of Koza's computational effort statistic for genetic programming. In: Foster JA, Lutton E, Miller J, Ryan C, Tettamanzi AG, editors. Genetic programming. EuroGP 2002: Proceedings of the 5th European Conference on Genetic Programming; 2002 Apr 3-5; Kinsdale, Ireland. Berlin: Springer, 2002: 182-191 Electronic journal (list all authors) 15 Morse SS. Factors in the emergence of infectious diseases. Emerg Infect Dis serial online, 1995-01-03, cited 1996-06-05; 1(1): 24 screens. Available from: URL: http://www.cdc.gov/ ncidod/eid/index.htm Patent (list all authors) 16 Pagedas AC, inventor; Ancel Surgical R&D Inc., assignee. Flexible endoscopic grasping and cutting device and positioning tool assembly. United States patent US 20020103498. 2002 Aug 1 Statistical data Write as mean SD or mean SE. Statistical expression Express t test as t (in italics), F test as F (in italics), chi square test as 2 (in Greek), related coefficient as r (in italics), degree of freedom as (in Greek), sample number as n (in italics), and probability as P (in italics). Units Use SI units. For example: body mass, m (B) = 78 kg; blood pressure, p (B) = 16.2/12.3 kPa; incubation time, t (incubation) = 96 h, blood glucose concentration, c (glucose) 6.4 2.1 mmol/L; blood CEA mass concentration, p (CEA) = 8.6 24.5 mg/L; CO2 volume fraction, 50 mL/L CO2, not 5% CO2; likewise for 40 g/L formaldehyde, not 10% formalin; and mass fraction, 8 ng/g, etc. Arabic numerals such as 23, 243, 641 should be read 23243641.
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Instructions to authors The format for how to accurately write common units and quantums can be found at: http://www.wjgnet.com/1949-8470/ g_info_20100313185816.htm. Abbreviations Standard abbreviations should be defined in the abstract and on first mention in the text. In general, terms should not be abbreviated unless they are used repeatedly and the abbreviation is helpful to the reader. Permissible abbreviations are listed in Units, Symbols and Abbreviations: A Guide for Biological and Medical Editors and Authors (Ed. Baron DN, 1988) published by The Royal Society of Medicine, London. Certain commonly used abbreviations, such as DNA, RNA, HIV, LD50, PCR, HBV, ECG, WBC, RBC, CT, ESR, CSF, IgG, ELISA, PBS, ATP, EDTA, mAb, can be used directly without further explanation. Italics Quantities: t time or temperature, c concentration, A area, l length, m mass, V volume. Genotypes: gyrA, arg 1, c myc, c fos, etc. Restriction enzymes: EcoRI, HindI, BamHI, Kbo I, Kpn I, etc. Biology: H. pylori, E coli, etc. Examples for paper writing Editorial: http://www.wjgnet.com/1949-8470/g_info_20100313 182341.htm Frontier: http://www.wjgnet.com/1949-8470/g_info_2010031318 2448.htm Topic highlight: http://www.wjgnet.com/1949-8470/g_info_201003 13182639.htm Observation: http://www.wjgnet.com/1949-8470/g_info_20100313 182834.htm Guidelines for basic research: http://www.wjgnet.com/1949-8470/ g_info_20100313183057.htm Guidelines for clinical practice: http://www.wjgnet.com/19498470/g_info_20100313183238.htm Review: http://www.wjgnet.com/1949-8470/g_info_20100313 183433.htm Original articles: http://www.wjgnet.com/1949-8470/g_info_2010 0313183720.htm Brief articles: http://www.wjgnet.com/1949-8470/g_info_201003 13184005.htm Case report: http://www.wjgnet.com/1949-8470/g_info_20100313 184149.htm Letters to the editor: http://www.wjgnet.com/1949-8470/g_info_20 100313184410.htm Book reviews: http://www.wjgnet.com/1949-8470/g_info_201003 13184803.htm Guidelines: http://www.wjgnet.com/1949-8470/g_info_20100313 185047.htm
Please revise your article according to the revision policies of WJR. The revised version including manuscript and high-resolution image figures (if any) should be re-submited online (http://www.wjgnet. com/1949-8470office/). The author should send the copyright transfer letter, responses to the reviewers, English language Grade B certificate (for non-native speakers of English) and final manuscript checklist to wjr@wjgnet.com. Language evaluation The language of a manuscript will be graded before it is sent for revision. (1) Grade A: priority publishing; (2) Grade B: minor language polishing; (3) Grade C: a great deal of language polishing needed; and (4) Grade D: rejected. Revised articles should reach Grade A or B. Copyright assignment form Please download a Copyright assignment form from http://www. wjgnet.com/1949-8470/g_info_20100313185522.htm. Responses to reviewers Please revise your article according to the comments/suggestions provided by the reviewers. The format for responses to the reviewers comments can be found at: http://www.wjgnet.com/1949-8470/ g_info_20100313185358.htm. Proof of financial support For paper supported by a foundation, authors should provide a copy of the document and serial number of the foundation. Links to documents related to the manuscript WJR will be initiating a platform to promote dynamic interactions between the editors, peer reviewers, readers and authors. After a manuscript is published online, links to the PDF version of the submitted manuscript, the peer-reviewers report and the revised manuscript will be put on-line. Readers can make comments on the peer reviewers report, authors responses to peer reviewers, and the revised manuscript. We hope that authors will benefit from this feedback and be able to revise the manuscript accordingly in a timely manner. Science news releases Authors of accepted manuscripts are suggested to write a science news item to promote their articles. The news will be released rapidly at EurekAlert/AAAS (http://www.eurekalert.org). The title for news items should be less than 90 characters; the summary should be less than 75 words; and main body less than 500 words. Science news items should be lawful, ethical, and strictly based on your original content with an attractive title and interesting pictures. Publication fee WJR is an international, peer-reviewed, Open-Access, online journal. Articles published by this journal are distributed under the terms of the Creative Commons Attribution Non-commercial License, which permits use, distribution, 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. Authors of accepted articles must pay a publication fee. Publication fee: 600 USD per article. Editorial, topic highlights, book reviews and letters to the editor are published free of charge.
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ISSN 1949-8470 (online)

World Journal of Radiology

World Journal of Radiology

Siegfried Trattnig, Vienna

Denmark Poul Erik Andersen, Odense

Chile Masami Yamamoto, Santiago

Estonia China Tiina Talvik, Tartu

Austria Herwig R Cerwenka, Graz Daniela Prayer,Vienna

Finland Tove J Grnroos, Turku

August 28, 2012

Ireland Joseph Simon Butler, Dublin

Malaysia R Logeswaran, Cyberjaya Kwan-Hoong Ng, Kuala Lumpur

Mexico Heriberto Medina-Franco, Mexico City

New Zealand W Howell Round, Hamilton

Norway Arne Sigmund Borthne, Lrenskog

Serbia Djordjije Saranovic, Belgrade

Singapore Uei Pua, Singapore Lim CC Tchoyoson, Singapore

Hungary Peter Laszlo Lakatos, Budapest

Slovakia Frantiek Dubeck, Bratislava

Lebanon Aghiad Al-Kutoubi, Beirut

Libya Anuj Mishra, Tripoli

August 28, 2012

August 28, 2012

World Journal of Radiology

Progress in atherosclerotic plaque imaging

August 28, 2012|Volume 4|Issue 8|

World Journal of Radiology

Volume 4 Number 8 August 28, 2012

AIM AND SCOPE

EDITORS FOR THIS ISSUE

Responsible Science Editor: Jian-Xia Cheng

August 28, 2012|Volume 4|Issue 8|

World Journal of Radiology

Online Submissions: http://www.wjgnet.com/1949-8470office wjr@wjgnet.com doi:10.4329/wjr.v4.i8.345

Extrahepatic biliary cancer: New staging classification

August 28, 2012|Volume 4|Issue 8|

Ganeshan D et al . Extrahepatic biliary cancer

PATHOLOGICAL CLASSIFICATION OF CHOLANGIOCARCINOMA

Ganeshan D et al . Extrahepatic biliary cancer

Table 1 Multidetector computed tomography parameters

August 28, 2012|Volume 4|Issue 8|

Ganeshan D et al . Extrahepatic biliary cancer

Table 3 Magnetic resonance imaging protocol

8 cardiac or 8 body upper (2) ASSET calib Axial 2D Fast SPGR

8 cardiac or 8 body upper (6) 3D 5 min LAVA XV Axial 3D Fast SPGR

15 83.33 34-44 4 -2.0 320 (160-192) 0.70-0.90 R/L

August 28, 2012|Volume 4|Issue 8|

Ganeshan D et al . Extrahepatic biliary cancer

August 28, 2012|Volume 4|Issue 8|

Ganeshan D et al . Extrahepatic biliary cancer

N2 Metastasis M0 M1 Tumor stage Stage Stage Stage A Stage B Stage a Stage b

August 28, 2012|Volume 4|Issue 8|

Ganeshan D et al . Extrahepatic biliary cancer

August 28, 2012|Volume 4|Issue 8|

Ganeshan D et al . Extrahepatic biliary cancer

August 28, 2012|Volume 4|Issue 8|

World Journal of Radiology

Online Submissions: http://www.wjgnet.com/1949-8470office wjr@wjgnet.com doi:10.4329/wjr.v4.i8.353

Progress in atherosclerotic plaque imaging

August 28, 2012|Volume 4|Issue 8|

Soloperto G et al . Progress in atherosclerotic plaque imaging

NON INVASIVE ATHEROSCLEROTIC PLAQUE ASSESSMENT

August 28, 2012|Volume 4|Issue 8|