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1 ISSN (online) World Journal of Gastrointestinal Oncology World J Gastrointest Oncol 2017 December 15; 9(12): Published by Baishideng Publishing Group Inc

2 W J G O World Journal of Gastrointestinal Oncology Editorial Board The World Journal of Gastrointestinal Oncology Editorial Board consists of 420 members, representing a team of worldwide experts in gastrointestinal oncology. They are from 42 countries, including Argentina (2), Australia (11), Austria (1), Belgium (5), Brazil (2), Canada (5), Chile (2), China (55), Czech Republic (1), Denmark (1), Finland (2), France (8), Germany (23), Greece (13), Hungary (2), India (9), Iran (3), Ireland (2), Israel (4), Italy (39), Japan (44), Kuwait (2), Mexico (1), Netherlands (8), New Zealand (2), Norway (1), Poland (3), Portugal (4), Romania (1), Saudi Arabia (1), Serbia (2), Singapore (4), South Korea (29), Spain (10), Sweden (5), Switzerland (2), Syria (1), Thailand (1), Turkey (6), United Arab Emirates(1), United Kingdom (12), and United States (90). EDITORS-IN-CHIEF Hsin-Chen Lee, Taipei Dimitrios H Roukos, Ioannina ASSOCIATE EDITORS Jianyuan Chai, Long Beach Dietrich Doll, Vechta Sukru Mehmet Erturk, Istanbul Haiyong Han, Phoenix Saeed Khan, Silver Spring Antonio Macrì, Messina Tomoyuki Nishizaki, Nishinomiya Jong Park, Tampa Uwe Pelzer, Berlin Godefridus J Peters, Amsterdam Ondrej Slaby, Brno Vicki Whitehall, Brisbane Takeharu Yamanaka, Yokohama Shu-Yu Zhang, Suzhou GUEST EDITORIAL BOARD MEMBERS Da-Tian Bau, Taichung Chiao-Yun Chen, Kaohsiung Joanne Jeou-Yuan Chen, Taipei Shih-Hwa Chiou, Taipei Tzeon-Jye Chiou, Taipei Jing-Gung Chung, Taichung Yih-Gang Goan, Kaohsiung Tsann-Long Hwang, Taoyuan Long-Bin Jeng, Taichung Kwang-Huei Lin, Taoyuan Joseph T Tseng, Tainan Jaw-Yuan Wang, Kaohsiung Tzu-Chen Yen, Taoyuan MEMBERS OF THE EDITORIAL BOARD Argentina María Eugenia Pasqualini, Córdoba Lydia Inés Puricelli, Buenos Aires Australia Ned Abraham, Coffs Harbour Stephen John Clarke, Concord Marco Falasca, Perth Michael A McGuckin, Qld Muhammed Ashraf Memon, Queensland Liang Qiao, Westmead Rodney Scott, Newcastle Joanne Patricia Young, Qld Xue-Qin Yu, NSW Xu Dong Zhang, Newcastle Austria Michael Gnant, Concord Belgium Wim Peter Ceelen, Ghent Suriano Gianpaolo, Brussels Xavier Sagaert, Leuven Eric Van Cutsem, Louvain Jan B Vermorken, Edegem Brazil Raul Balbinotti, Caxias do Sul RS Sonia M Oliani, Colombo Canada Alan Graham Casson, Saskatoon Hans Tse-Kan Chung, Toronto Rami Kotb, Sherbrooke Sai Yi Pan, Ontario Shawn Ritchie, Saskatoon Chile Alejandro H Corvalan, Santiago Juan Carlos Roa, Temuco China Dong Chang, Beijing George G Chen, Hong Kong Xin-Zu Chen, Chengdu Yong-Chang Chen, Zhenjiang Chi-Hin Cho, Hong Kong Ming-Xu Da, Lanzhou Xiang-Wu Ding, Wuhan Yan-Qing Ding, Guangzhou Jin Gu, Beijing Qin-Long Gu, Shanghai Hai-Tao Guan, Xi an Chun-Yi Hao, Beijing I February 29, 2016

3 Li-Sung Hsu, Taichung Huang-Xian Ju, Nanjing Wai-Lun Law, Hong Kong Shao Li, Beijing Yu-Min Li, Lanzhou Bing-Ya Liu, Shanghai Ka Ho Lok, Hong Kong Maria Li Lung, Hong Kong Simon SM Ng, Hong Kong Li-Zong Shen, Nanjing Wei-Hao Sun, Nanjing Qian Tao, Hong Kong Bin Wang, Nanjing Chun-You Wang, Wuhan Kai-Juan Wang, Zhengzhou Wei-Hong Wang, Beijing Ya-Ping Wang, Nanjing Ai-Wen Wu, Beijing Zhao-Lin Xia, Shanghai Xue-Yuan Xiao, Beijing Guo-Qiang Xu, Hangzhou Yi-Zhuang Xu, Beijing Win-Nei Yeo, Hong Kong Ying-Yan Yu, Shanghai Siu Tsan Yuen, Hong Kong Wei-Hui Zhang, Harbin Li Zhou, Beijing Yong-Ning Zhou, Lanzhou Denmark HJ Nielson, Hvidovre Finland Pentti Sipponen, ESPOO Markku Voutilainen, Lappeenranta France Stéphane Benoist, Boulogne Paolo Boffetta, Lyon Anne-Marie Bouvier, Dijon Mehdi Ouaissi, Marseille Jean-Franois Rey, St Laurent du Var Karem Slim, Clermont Ferrand David Tougeron, Poitiers Cedex Isabelle Van Seuningen, Lille cedex Germany Han-Xiang An, Marburg Karl-Friedrich Becker, Munich Stefan Boeck, Munich Joachim Drevs, Freiburg Volker Ellenrieder, Marburg Amor Hajri, Freiburg Jakob R Izbicki, Hamburg Gisela Keller, Munich Jorg Kleeff, Munich Axel Kleespies, Munich Markus Menges, Schwaebisch Hall Hans-Joachim Meyer, Solingen Lars Müller, Kiel Joachim Pfannschmidt, Heidelberg Marc André Reymond, Bielefeld Robert Rosenberg, Munich Ralph Schneider, Marburg Helmut K Seitz, Heidelberg NH Stoecklein, Dusseldorf Oliver Stoeltzing, Mainz Ludwig Strauss, Heidelberg Greece Ekaterini Chatzaki, Alexandroupolis Eelco de Bree, Heraklion Maria Gazouli, Athens Vassilis Georgoulias, Iraklion John Griniatsos, Athens Ioannis Kanellos, Thessaloniki Viaos Karanikas, Larissa Michael I Koukourakis, Alexandroupolis Georgios V Koukourakis, Athens Gregory Kouraklis, Athens Konstantinos N Syrigos, Athens Ioannis A Voutsadakis, Lausanne Hungary László Herszényi, Budapest Zsuzsa Schaff, Budapest India Uday C Ghoshal, Lucknow R Gupta, New Delhi Kalpesh Jani, Vadodara Ashwani Koul, Chandigarh Balraj Mittal, Lucknow Rama Mittal, Lucknow Susanta Roychoudhury, Kolkata Yogeshwer Shukla, Lucknow Imtiaz Ahmed Wani, Kashmir Iran Mohammad Reza Abbaszadegan, Mashhad M Mohamadnejad, Tehran Mohamad Amin Pourhoseingholi, Tehran Ireland Aileen Houston, Cork C O'Morain, Dublin Israel Nadir Arber, Tel Aviv Eytan Domany, Rehovot Dan David Hershko, Haifa Yaron Niv, Petah Tiqwa Italy Massimo Aglietta, Candiolo Domenico Alvaro, Rome Amalia Azzariti, Bari Marco Braga, Milan Federico Cappuzzo, Rozzano Lorenzo Capussotti, Turin Fabio Carboni, Rome Vincenzo Cardinale, Rome Luigi Cavanna, Piacenza Valli De Re, Aviano Ferdinando De Vita, Naples Riccardo Dolcetti, Aviano Pier Francesco Ferrucci, Milano Natale Figura, Siena Francesco Fiorica, Ferrara Gennaro Galizia, Naples Silvano Gallus, Milan Milena Gusella, Rovigo Massimo Libra, Catania Gabriele Masselli, Rome Simone Mocellin, Padova Gianni Mura, Arezzo Gerardo Nardone, Naples Gabriella Nesi, Florence Francesco Perri, San Giovanni Rotondo Francesco Recchia, Avezzano Vittorio Ricci, Pavia Fabrizio Romano, Monza Antonio Russo, Palermo Daniele Santini, Rome Claudio Sorio, Verona Cosimo Sperti, Padua Gianni Testino, Genoa Giuseppe Tonini, Rome Carlo Vecchia, Milano Bruno Vincenzi, Rome Wainer Zoli, Forli Angelo Zullo, Rome Japan Suminori Akiba, Kagoshima Keishiro Aoyagi, Kurume Narikazu Boku, Shizuoka Yataro Daigo, Tokyo Miyoshi Eiji, Suita Itaru Endo, Yokohama Mitsuhiro Fujishiro, Tokyo Osamu Handa, Kyoto Kenji Hibi, Kanagawa Asahi Hishida, Aichi Eiso Hiyama, Hiroshima Atsushi Imagawa, Kagawa Johji Inazawa, Tokyo Terumi Kamisawa, Tokyo Tatsuo Kanda, Niigata Masaru Katoh, Tokyo Takayoshi Kiba, Ishikawa II February 29, 2016

4 Hiroki Kuniyasu, Kashihara Yukinori Kurokawa, Osaka Chihaya Maesawa, Iwate Yoshinori Marunaka, Kyoto Osam Mazda, Kyoto Shinichi Miyagawa, Matumoto Toshiyuki Nakayama, Fukuoka Masahiko Nishiyama, Saitama Koji Oba, Kyoto Masayuki Ohtsuka, Chiba Tomoyuki Shibata, Toyoake Mitsugi Shimoda, Tochigi Haruhiko Sugimura, Hamamatsu Tomomitsu Tahara, Aichi Shinji Takai, Takatsuki Satoru Takayama, Aichi Akio Tomoda, Tokyo Akihiko Tsuchida, Tokyo Yasuo Tsuchiya, Niigata Takuya Watanabe, Niigata Toshiaki Watanabe, Tokyo Hiroki Yamaue, Wakayama Hiroshi Yasuda, Kumamoto Yutaka Yonemura, Oosaka Reigetsu Yoshikawa, Osaka Kuwait Fahd Al-Mulla, Safat Salem Alshemmari, Safat Portugal Celso Albuquerque Reis, Oporto Lucio Lara Santos, Porto Maria Raquel Campos Seruca, Porto Manuel Rodrigues Teixeira, Oporto Romania Marius Raica, Timisoara Saudi Arabia Ragab Hani Donkol, Abha Serbia Milos M Bjelovic, Belgrade Goran Z Stanojevic, Nish Singapore Peh Yean Cheah, Singapore Si-Shen Feng, Singapore Zhi-Wei Huang, Singapore Qi Zeng, Singapore Spain Manuel Benito, Madrid JI Casal, Madrid Antoni Castells, Barcelona E Folch-Puy, Barcelona Jose JG Marin, Salamanca Joan Maurel, Barcelona Jose M Ramia, Madrid Margarita Sanchez-Beato, Madrid Laura Valle, Barcelona Jesus Vioque, Alacant Sweden Nils Albiin, Stockholm Samuel Lundin, Goteborg Haile Mahteme, Uppsala Richard Palmqvist, Umea Ning Xu, Lund Switzerland Paul M Schneider, Zurich Luigi Tornillo, Basel Syria Zuhir Alshehabi, Lattakia Mexico O Arrieta, Mexico City Netherlands Elisabeth Bloemena, Amsterdam JP De Boer, Amsterdam Peter JK Kuppen, Leiden Gerrit Albert Meijer, Amsterdam Anya N Milne, Utrecht M Muller, Groningen Cornelis FM Sier, Leiden New Zealand Lynnette Robin Ferguson, Auckland Jonathan Barnes Koea, Auckland Norway Kjetil Soreide, Stavanger Poland Andrzej Szkaradkiewicz, Poznań Michal Tenderenda, Polskiego Jerzy Wydmanski, Gliwice South Korea Seungmin Bang, Seoul Daeho Cho, Seoul Byung I Choi, Seoul Hyun Cheol Chung, Seoul Sang-Uk Han, Suwon Jun-Hyeog Jang, Inchon Seong Woo Jeon, Taegu Dae Hwan Kang, Inchon Gyeong Hoon Kang, Seoul Dong Yi Kim, Kwangju Jae J Kim, Seoul Jin Cheon Kim, Seoul Jong Gwang Kim, Daegu Min Chan Kim, Pusan Samyong Kim, Daegu Tae IL Kim, Seoul Young-Woo Kim, Goyang-si Inchul Lee, Seoul Jung Weon Lee, Seoul Kyu Taek Lee, Seoul Kyung Hee Lee, Daegu Na Gyong Lee, Seoul Suk Kyeong Lee, Seoul Jong-Baeck Lim, Seoul Young Joo Min, Ulsan Sung-Soo Park, Seoul Young Kee Shin, Seoul Hee Jung Son, Seoul Si Young Song, Seoul Thailand Sopit Wongkham, Khon Kaen Turkey Ugur Coskun, Ankara Vedat Goral, Izmir Yavuz Selim Sari, YeniLevent Mesut Tez, Ankara Murat H Yener, Tekirdag United Arab Emirates Riyad Bendardaf, Sharjah United Kingdom Runjan Chetty, Glasgow Chris Deans, Edinburgh Dipok Kumar Dhar, London Giuseppe Garcea, Leicester Oleg Gerasimenko, Liverpool Neena Kalia, Birmingham Anthony Maraveyas, East Yorkshire Andrew Maw, North Wales Kymberley Thorne, Swansea Chris Tselepis, Birmingham III February 29, 2016

5 Nicholas FS Watson, Nottingham Ling-Sen Wong, Coventry United States Shrikant Anant, Oklahoma Seung Joon Baek, Knoxville Jamie S Barkin, Miami Beach H Bernstein, Tucson Kimberly Maureen Brown, Kansas City Weibiao Cao, Providence Deliang Cao, Springfield Chris N Conteas, Los Angeles Pelayo Correa, New Orleans JJ John Cullen, Lowa James C Cusack, Boston Ananya Das, Scottsdale Juan Dominguez-Bendala, Miami Wafik S El-Deiry, Philadelphia Laura Elnitski, Rockville Thomas Joseph Fahey, New York James W Freeman, San Antonio Bruce Joseph Giantonio, Philadelphia Ajay Goel, Dallas Karen Gould, Omaha GA Nagana Gowda, Lafayette Stephen Randolph Grobmyer, Gainesville Young S Hahn, Charlottesville John W Harmon, Baltimore Paul J Higgins, Albany Steven Norbit Hochwald, Gainesville Su-Yun Huang, Houston Qin Huang, Duarte Jamal A Ibdah, Columbia Yihong Jiang-Cao Kaufmann, Little Rock Temitope Olubunmilayo Keku, Chapel Hill Vijay P Khatri, Sacramento Peter Sean Kozuch, New York Sunil Krishnan, Houston Robert R Langley, Houston Otto Schiueh-Tzang Lin, Seattle Ke-Bin Liu, Augusta Rui-Hai Liu, Ithaca Deryk Thomas Loo, South San Francisco Andrew M Lowy, La Jolla Bo Lu, Nashville David M Lubman, Ann Arbor James David Luketich, Pittsburgh Ju-Hua Luo, Morgantown Henry Thomson Lynch, Omaha Shelli R McAlpine, San Diego Ellen Darcy McPhail, Rochester Anil Mishra, Cincinnati Priyabrata Mukherjee, Rochester Steffan Todd Nawrocki, Memphis Shuji Ogino, Boston Macaulay Onuigbo, Eau Claire Philip Agop Philip, Detriot Blase N Polite, Chicago James A Radosevich, Chicago Robert Raffaniello, New York Jasti S Rao, Peoria Srinevas Kadumpalli Reddy, Durham Stephen H Safe, Houston Muhammad Wasif Saif, New Haven Prateek Sharma, Kansas City Eric Tatsuo Shinohara, Philadelphia Liviu Andrei Sicinschi, New Orleans Pankaj K Singh, Omaha Seema Singh, Mobile William Small, Chicago Sanjay Srivastava, Amarillo Gloria H Su, New York Sujha Subramanian, Waltham David W Townsend, Boothbay Harbor Asad Umar, Rockville Ji-Ping Wang, Buffalo Zheng-He Wang, Cleveland Michael J Wargovich, Charleston Neal W Wilkinson, Iowa City Siu-Fun Wong, Pomona Shen-Hong Wu, New York Ke-Ping Xie, Houston Dong Xie, Los Angeles Hao-Dong Xu, Rochester Xiao-Chun Xu, Houston Zeng-Quan Yang, Detroit Gary Y Yang, Buffalo Wan-Cai Yang, Chicago Zuo-Feng Zhang, South Los Angeles Andrew X Zhu, Boston IV February 29, 2016

6 S Contents Monthly Volume 9 Number 12 December 15, 2017 MINIREVIEWS 457 Neoadjuvant therapy for resectable pancreatic cancer Rahman SH, Urquhart R, Molinari M ORIGINAL ARTICLE Retrospective Cohort Study 466 Tumor-stroma ratio as prognostic factor for survival in rectal adenocarcinoma: A retrospective cohort study Scheer R, Baidoshvili A, Zoidze S, Elferink MAG, Berkel AEM, Klaase JM, van Diest PJ META-ANALYSIS 475 Laparoscopic vs open complete mesocolic excision with central vascular ligation for colon cancer: A systematic review and meta-analysis Negoi I, Hostiuc S, Negoi RI, Beuran M CASE REPORT 492 Cystic metastasis from a mucinous adenocarcinoma of duodenum mimicking type II choledochal cyst: A case report Kim YN, Song JS 497 Extrapancreatic solid pseudopapillary neoplasm followed by multiple metastases: Case report Wu H, Huang YF, Liu XH, Xu MH December 15, 2017 Volume 9 Issue 12

7 Contents World Journal of Gastrointestinal Oncology Volume 9 Number 12 December 15, 2017 ABOUT COVER Editorial Board Member of World Journal of Gastrointestinal Oncology, Wei-Hao Sun, PhD, Professor, Department of Geriatric Gastroenterology, the First Affiliated Hospital of Nanjing Medical University, Nanjing , Jiangsu Province, China AIM AND SCOPE World Journal of Gastrointestinal Oncology (World J Gastrointest Oncol, WJGO, online ISSN , DOI: ) is a peer-reviewed open access academic journal that aims to guide clinical practice and improve diagnostic and therapeutic skills of clinicians. WJGO covers topics concerning carcinogenesis, tumorigenesis, metastasis, diagnosis, prevention, prognosis, clinical manifestations, nutritional support, molecular mechanisms, and therapy of benign and malignant tumors of the digestive tract. The current columns of WJGO include editorial, frontier, diagnostic advances, therapeutics advances, field of vision, mini-reviews, review, topic highlight, medical ethics, original articles, case report, clinical case conference (Clinicopathological conference), and autobiography. Priority publication will be given to articles concerning diagnosis and treatment of gastrointestinal oncology diseases. The following aspects are covered: Clinical diagnosis, laboratory diagnosis, differential diagnosis, imaging tests, pathological diagnosis, molecular biological diagnosis, immunological diagnosis, genetic diagnosis, functional diagnostics, and physical diagnosis; and comprehensive therapy, drug therapy, surgical therapy, interventional treatment, minimally invasive therapy, and robot-assisted therapy. We encourage authors to submit their manuscripts to WJGO. We will give priority to manuscripts that are supported by major national and international foundations and those that are of great clinical significance. INDEXING/ABSTRACTING World Journal of Gastrointestinal Oncology is now indexed in Science Citation Index Expanded (also known as SciSearch ), PubMed, and PubMed Central. FLYLEAF I-IV Editorial Board EDITORS FOR THIS ISSUE Responsible Assistant Editor: Xiang Li Responsible Electronic Editor: Ya-Jing Lu Proofing Editor-in-Chief: Lian-Sheng Ma Responsible Science Editor: Fang-Fang Ji Proofing Editorial Office Director: Xiu-Xia Song NAME OF JOURNAL World Journal of Gastrointestinal Oncology ISSN ISSN (online) LAUNCH DATE February 15, 2009 FREQUENCY Monthly EDITORS-IN-CHIEF Hsin-Chen Lee, PhD, Professor, Institute of Pharmacology, School of Medicine, National Yang-Ming University, Taipei 112, Taiwan Dimitrios H Roukos, MD, PhD, Professor, Personalized Cancer Genomic Medicine, Human Cancer Biobank Center, Ioannina University, Metabatiko Ktirio Panepistimiou Ioanninon, Office 229, Ioannina, TK 45110, Greece EDITORIAL BOARD MEMBERS All editorial board members resources online at EDITORIAL OFFICE Xiu-Xia Song, Director World Journal of Gastrointestinal Oncology Baishideng Publishing Group Inc 7901 Stoneridge Drive, Suite 501, Pleasanton, CA 94588, USA Telephone: Fax: Help Desk: PUBLISHER Baishideng Publishing Group Inc 7901 Stoneridge Drive, Suite 501, Pleasanton, CA 94588, USA Telephone: Fax: Help Desk: PUBLICATION DATE December 15, 2017 COPYRIGHT 2017 Baishideng Publishing Group Inc. Articles published by this Open-Access 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 journals owned by the Baishideng Publishing Group (BPG) represent the views and opinions of their authors, and not the views, opinions or policies of the BPG, except where otherwise explicitly indicated. INSTRUCTIONS TO AUTHORS ONLINE SUBMISSION II December 15, 2017 Volume 9 Issue 12

8 Submit a Manuscript: DOI: /wjgo.v9.i World J Gastrointest Oncol 2017 December 15; 9(12): ISSN (online) Neoadjuvant therapy for resectable pancreatic cancer MINIREVIEWS Sheikh Hasibur Rahman, Robin Urquhart, Michele Molinari Sheikh Hasibur Rahman, Robin Urquhart, Department of Surgery, Dalhousie University, Halifax B3H 2Y9, Nova Scotia, Canada Michele Molinari, Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, United States ORCID number: Sheikh Hasibur Rahman ( ); Robin Urquhart ( ); Michele Molinari ( ). Author contributions: Rahman SH participated in the concept, design and search of the scientific literature, extracted the data and wrote the manuscript including the tables; Urquhart R participated in the concept and design and participated in revising the manuscript; Molinari M formulated the research question, designed the literature search, supervised and co-authored the manuscript with Rahman SH. Conflict-of-interest statement: The authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest (such as honoraria; educational grants; participation in speakers bureaus; membership, employment, consultancies, stock ownership, or other equity interest; and expert testimony or patent-licensing arrangements), or non-financial interest (such as personal or professional relationships, affiliations, knowledge or beliefs) in the subject matter or materials discussed in this manuscript. Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: licenses/by-nc/4.0/ Manuscript source: Unsolicited manuscript Correspondence to: Michele Molinari, MD, MSc, Senior Scientist, Surgeon, Associate Professor, Department of Surgery, University of Pittsburgh Medical Center, 3459 Fifth Avenue, N758, Pittsburgh, PA 15213, United States. Telephone: Fax: Received: June 25, 2017 Peer-review started: June 27, 2017 First decision: August 7, 2017 Revised: August 24, 2017 Accepted: September 15, 2017 Article in press: September 15, 2017 Published online: December 15, 2017 Abstract The use of neoadjuvant therapies has played a major role for borderline resectable and locally advanced pancreatic cancers (PCs). For this group of patients, preoperative chemotherapy or chemoradiation has increased the likelihood of surgery with negative resection margins and overall survival. On the other hand, for patients with resectable PC, the main rationale for neoadjuvant therapy is that the overall survival with current strategies is unsatisfactory. There is a consensus that we need new treatments to improve the overall survival and quality of life of patients with PC. However, without strong scientific evidence supporting the theoretical advantages of neoadjuvant therapies, these potential benefits might turn out not to be worth the risk of tumors progression while waiting for surgery. The focus of this paper is to provide the readers an overview of the most recent evidence on this subject. Key words: Pancreatic adenocarcinoma; Neoadjuvant chemotherapy; Neoadjuvant chemoradiation therapy; Metaanalysis; Decision analysis; Borderline resectable; Locally advanced; Randomized controlled trial; Phase Ⅰ trial; Phase Ⅱ trial; Phase Ⅲ trial The Author(s) Published by Baishideng Publishing Group Inc. All rights reserved. Core tip: The use of neoadjuvant therapy for patients with resectable pancreatic cancer (PC) has been used by an increasing number of cancer centers around 457 December 15, 2017 Volume 9 Issue 12

9 Rahman SH et al. Neoadjuvant therapy for resectable pancreatic cancer the world. The main rationale of using neoadjuvant therapies in resectable PC is the hope that patients likelihood of long-term overall survival will benefit from the chemo or chemoradiation therapy administered when their overall conditions allow them to tolerate the treatment. At this time, there is no phase Ⅲ trial to support the use of neoadjuvant therapies in resectable PC. Without strong scientific evidence supporting the theoretical advantages of neoadjuvant therapies, these potential benefits might turn out not to be worth the risk of tumors progression while waiting for surgery. Rahman SH, Urquhart R, Molinari M. Neoadjuvant therapy for resectable pancreatic cancer. World J Gastrointest Oncol 2017; 9(12): Available from: URL: wjgnet.com/ /full/v9/i12/457.htm DOI: org/ /wjgo.v9.i INTRODUCTION The most common form of pancreatic cancers (PCs) originates from the ductal cells of the exocrine gland [1,2]. In the United States, it represents the fourth leading cause of cancer-related deaths with new cases per year [2,3]. The prognosis of patients with PC remains poor with only 5%-10% of patients alive after five years [4]. Their outcome is significantly improved if they undergo surgery; however, even in this case, 5-year survival is only 25%-40% [1,4]. PC is a difficult tumor to cure as it behaves as a systemic disease even in its early stages. Although surgery remains the only potential cure, it is still inadequate for most of the patients who will develop recurrent disease within five years. The use of multimodality therapy (surgery, chemotherapy and radiation therapy) provides the best chance for long-term survival [5], but the ideal sequence and duration of these treatments remain unknown due to the lack of scientific evidence. Despite these limitations, there is a consensus that, because of the poor outcomes observed with old treatment modalities, new strategies are necessary [6]. Among them, the use of neoadjuvant chemotherapy has gained traction and, in recent years, an increasing number of oncologists and surgeons are recommending it [7,8]. For borderline resectable and locally advanced PC, there is evidence that neoadjuvant therapy increases the probability of negative resection margins and the number of patients who can undergo surgery [8,9]. On the other hand, for resectable PC, neoadjuvant chemotherapy or chemoradiation remains debatable because of the conflicting data on its effectiveness, and because there is no phase Ⅲ trial to support their use [10-12]. The focus of this publication is to provide an overview of the most recent evidence on this topic, appraise the potential benefits and disadvantages of neoadjuvant vs surgery first approach, and finally, to review the ongoing phase Ⅲ trials that might address some of the questions that are still unanswered. RESECTABILITY Surgery remains the only potential cure for patients with PC. Determining if the disease is resectable or not at the time of diagnosis is crucial, but often subjective to the interpretation of preoperative imaging tests. Resectability is usually determined using a combination of imaging tests and laparoscopic assessment of the peritoneal cavity to rule out small hepatic or peritoneal metastases that might be missed even with highquality contrast enhanced computerized tomography (CT scans) or magnetic resonance imaging (MRI) studies [2,13]. There are several definitions of tumor resectability that are summarized in Table 1 [13-16]. All criteria currently used to identify patients with resectable disease are based on the degree of contact between the tumor and blood vessels adjacent to the pancreas in the absence of distant disease. TREATMENT STRATEGIES Until recently, the most accepted treatment paradigm for resectable PC was surgery followed by postoperative systemic chemotherapy or chemoradiation. In recent years, the use of systemic pre-operative chemotherapy alone or in combination with radiation therapy has been offered to an increasing number of patients with the main intent of reducing the size of the tumor, increase the likelihood of negative resection margins, and test the effects of cytotoxic medications in vivo [9]. Most patients who are treated with neoadjuvant chemotherapy or chemoradiation receive oral or intravenous medications for the duration of three to six months before undergoing surgery [17]. ADVANTAGES AND DISADVANTAGES OF NEOADJUVANT THERAPY Neoadjuvant therapy has several theoretical benefits but also drawbacks (Table 2). It is usually well tolerated, does not increase the perioperative morbidity, reduces the interval between diagnosis and the initiation of systemic treatment [17] and has the potential benefit of facilitating radical resections by lessening the size of the tumors before surgery. Despite these advantages, postponing surgery for neoadjuvant treatment might give enough time for the tumor to progress and become unresectable [17,18]. RECENT STUDIES Table 3 summarizes details of the latest phase Ⅰ and Ⅱ trials reporting the outcomes of patients treated with neoadjuvant chemotherapy or chemoradiation for radiologically resectable PC. In all these studies, tumor 458 December 15, 2017 Volume 9 Issue 12

10 Rahman SH et al. Neoadjuvant therapy for resectable pancreatic cancer Table 1 Operational definitions of resectability of pancreatic cancer Classification of resectability of pancreatic cancer Definition by AHPBA/SSO/SSAT Definition by MD Anderson Cancer Centre Resectable Borderline resectable Locally advanced The tumor does not abut or encase any of the following The tumor abuts or encases the superior mesenteric vein or vascular structures: the superior mesenteric vein or portal portal vein without occluding the lumen. Absence of abutment vein, superior mesenteric artery or common hepatic artery or encasement of the superior mesenteric artery, common hepatic or celiac trunk artery or celiac trunk Abutment, encasement or occlusion of the superior mesenteric vein or portal vein. Abutment of the superior mesenteric artery. Abutment or short segment encasement of the common hepatic artery. Absence or abutment or encasement of the celiac trunk Tumor located in the proximity of the superior mesenteric vein or portal vein and the superior mesenteric vein or portal vein are unable to be resected and reconstructed. Tumor encasing the superior mesenteric artery, or longsegment encasement of the common hepatic artery, or abutment of the celiac trunk Tumor causing a short-segment occlusion of the superior mesenteric vein or portal vein. Presence of abutment of the superior mesenteric artery, abutment or encasement of a short segment of the common hepatic artery, absence of abutment or encasement of the celiac trunk Tumor located in the proximity of the superior mesenteric vein or portal vein that are not reconstructible. Presence of tumor encasement of the superior mesenteric artery, long-segment encasement of the common hepatic artery and encasement of the celiac trunk AHPBA: Americas Hepato-Pancreato-Biliary Association; SSO: Society of Surgical Oncology; SSAT: Society for Surgery of the Alimentary Tract. Table 2 Summary of the benefits and drawbacks of neo-adjuvant and adjuvant therapies for the treatment of patients with resectable pancreatic cancer Neo-adjuvant therapy Adjuvant therapy Advantages Disadvantages Advantages Disadvantages In comparison to the strategy of adjuvant chemotherapy or chemoradiation therapy where up to 50% of patients who undergo surgery cannot complete their therapy due to complications or decline of their function, neoadjuvant strategy has been shown to be well tolerated by the majority of patients and therefore a greater proportion receive systemic therapy The use of neo-adjuvant therapy might sterilize the presence of small metastatic disease and reduce the size of the primary tumor. Downsizing the primary tumor might increase the likelihood of negative resection margins Treating patients before surgery, gives physicians some time to identify the tumors with poor prognosis that do not respond to the therapy. The identification of those patients who are likely to experience early metastases is very important because prevents them to undergo unnecessary surgery One of the advantages of using chemotherapy or chemoradiation therapy before surgery is that the blood supply to the pancreatic tumor is not compromised by the ligation of vessels. Therefore, chemotherapy agents can be delivered to the pancreatic tumor in higher concentrations Neoadjuvant therapy requires the placement of biliary stents to decompress the biliary obstruction prior to surgery of patients with jaundice. The placement of biliary stents before surgery increases the risk of infections in the perioperative period Pre-operative therapy delays surgery and increases the risk of progression of the disease to the point of becoming unresectable The use of neoadjuvant therapies might increase the risk of perioperative morbidity and mortality due to the side effects of chemotherapy or chemoradiation One of the advantages of surgery About 20%-50% of first approach is that patients have a short period of time between when they are diagnosed and when they undergo resections of their tumor. This might have some benefits on patients and their families anxiety Since patients undergo surgery as soon as possible after their diagnosis, their risk of tumor progression is smaller than patients who wait a longer time before being operated on Patients who undergo surgery first do not routinely need the placement of biliary stents to release their jaundice before undergoing resection patients will not be able to complete their postoperative therapy due to surgical complications or overall decline of their performance status One of the risk of undergoing surgery first for pancreatic cancer is that, some patients will undergo a major operation without the benefit of being cured as they might already have micrometastases Patients who undergo surgery first have a higher risk of positive resection margins response was evaluated differently as some investigators reported radiographic or clinical response before surgical exploration and others the histopathological response observed in the surgical specimen. Gillen et al [17] published the first systematic metaanalysis on the effects of preoperative therapy in PC. The authors reviewed 515 studies, but only 111 trials were included with a total of 4394 patients. Among these studies, 15 were a phase I, 13 were a phase Ⅰ/Ⅱ, 28 were phase Ⅱ, 14 were cohort studies, and 41 were case series. Most the studies were prospective (No. 78). Chemotherapy was used as neoadjuvant therapy in 459 December 15, 2017 Volume 9 Issue 12

11 Rahman SH et al. Neoadjuvant therapy for resectable pancreatic cancer Table 3 Phase Ⅰ and Phase Ⅱ studies assessing the outcomes of patients with resectable pancreatic cancer treated with neoadjuvant therapies Author (yr)/ journal/trial/ institution No. of patients Clinical stage/ duration of neoadjuvant therapy Study design Chemotherapy/ chemoradiation Radiological response Resection rate (%) Negative resection margins (%) Median overall survival (mo) Hoffman (1998)/J 53 Resectable Clin Oncol/ECOG PC/2.8 mo PistersPister (2002)/J Clin Oncol/MD Anderson Cancer Centre Joensuu (2004)/ Int J Radiat Oncol Biol Phys/Helsinki University Talamonti (2006)/ Ann Surg Oncol/ Northwestern University Palmer (2007)/ Ann Surg Oncol/ University of Birmingham Palmer (2007)/ Ann Surg Oncol/ University of Birmingham 35 Resectable PC/1.8 mo 28 Resectable PC/3.5 mo 20 Resectable PC/3.8 mo 24 Resectable PC/4 mo 26 Resectable PC/4 mo Le Scodan (2009)/ 41 Resectable Ann Oncol/SFRO- PC/3 mo FFCD Heinrich (2008)/Ann Surg/University Hospital of Zurich 28 Resectable PC/2 mo Evans (2008)/J Clin Oncol/MD Anderson Cancer Centre Varadhachari (2008)/J Clin Oncol/MD Anderson Cancer Centre Turrini (2009)/ Oncology /University Mediterranean 80 Resectable PC/3 mo 90 Resectable PC/4.3 mo 34 Resectable PC/2.1 mo Phase Ⅱ, prospective study, November 1991 to September 1993 Phase Ⅱ, prospective study, timeframe not specified Phase Ⅰ-Ⅱ prospective study, November 1999 to December FU (1000 mg/m 2 ) per day + Mitomycin C (10 mg/m 2 ) + RT (50 Gy) Paclitaxel (60 mg/m 2 ) weekly, RT (30 Gy) Gemcitabine (20 mg/m 2 vs 50 mg/m 2 vs 100 mg/m 2 ) twice a week + RT (50 GY) Phase Ⅱ Gemcitabine prospective, multiinstitutional study, weekly) + RT (1000 mg/m 2 April 2002 to (36 Gy) October 2003 Phase Ⅱ, prospective study, November 1999 to May 2003 Phase Ⅱ, prospective study, November 1999 to May 2003 Phase Ⅱ, prospective study, January 1998 to March 2003 Phase Ⅱ, prospective study, August 2001 to April 2007 Phase Ⅱ, prospective study, July 1998 to October 2001 Phase Ⅱ, prospective study, October 2002 to February 2006 Phase Ⅱ, prospective study, May 2003 to July 2005 Gemcitabine (1000 mg/m 2 weekly) Gemcitabine (1000 mg/m 2 weekly) + Cisplatin (25 mg/m 2 ) RT (50 Gy) + 5-FU (300 mg/m 2 daily) + Cisplatin (20 mg/m 2 ) Gemcitabine (1000 mg/m 2 twice weekly) + Cisplatin (50 mg/m 2 ) Gemcitabine (400 mg/m 2 weekly) + RT (30 Gy) Gemcitabine (750 mg/m 2 weekly) + Cisplatin (30 mg/m 2 ) every 2 wk + RT (30 Gy) Docetazel (30 mg/m 2 ) weekly + RT (45 GY) Partial response 8%; Stable disease 78%; Progression 16% Partial response 4%; Stable disease 23%; Progression 20% with surgery; without surgery 8; 10.9 for the entire cohort for the entire cohort; 19 with surgery; 10 without surgery NA 71 NA 13.6 for the entire cohort Partial response 15%; Stable disease 80%; Progression 5% Partial Response 0%; Stable Disease 29%; Progression 4%; Unable to measure 4% Partial Response 0%; Stable Disease 66%; Progression 21%; Unable to measure 4% Partial response 10%; Stable Disease 65%; Progression 25% mo with surgery with surgery; 9.9 for the entire cohort with surgery; 9.9 for the entire cohort with surgery; 9.4 for the entire cohort Partial response mo with 4%; Stable Disease 61%; Progression 13% surgery NA mo with surgery; 22.7 mo for the entire cohort; 7 mo without surgery NA mo with surgery; 17.4 mo for the entire cohort; 10.5 mo without surgery Partial response 9%; Stable disease 59%; Progression 32% mo with surgery; 15.5 mo for entire cohort; 11 mo without surgery 460 December 15, 2017 Volume 9 Issue 12

12 Rahman SH et al. Neoadjuvant therapy for resectable pancreatic cancer Landry (2010)/J Surg Oncol/Emory University/ Multicenter ECOG Wo (2014)/ Radiother Oncol/ Multicentric Shinoto (2013)/ Cancer/Japan O'Reilly (2014)/Ann Surg/Memorial Sloan Kettering Cancer Centre Golcher (2015)/ Strahlenther Onkol/ Germany Van Buren (2013)/Ann Surg Oncol/ Multicenter/ United States 21 Resectable PC/3 mo 10 Resectable PC 26 Resetable PC 38 Resectable PC 66 (33 patients Resectable allocated to PC surgery + 33 patients allocated to chemoradiation followed by surgery) 59 Resectable PC Phase Ⅱ, Arm A: prospective twoarm study, October 2013 to June 2015 Phase Ⅰ, prospective study Phase Ⅰ, prospective study, April 2003 to December 2010 Phase Ⅱ, prospective study, July 2007 to December 2011 Phase Ⅱ, prospective randomized trial with two arms: Primary surgery vs preoperative chemoradiation followed by surgery. June 2003 to December 2009 Phase Ⅱ, prospective study, February 2007 to February 2011 Gemcitabine (500 mg/m 2 ) weekly + RT (50 Gy) Arm B: Gemcitabine (175 mg/m 2 ) + Cisplatin (20 mg/m 2 ) + 5-FU (600 mg/m 2 ) + RT (50 Gy) Capecitabine (1650 mg/m 2 ) over 10 d + RT (30 Gy) RT (30 Gy) Gemcitabine (1000 mg/m 2 ) + Oxaliplatin (80 mg/m 2 ) every 2 wk Gemcitabine NA (300 mg/m 2 ) + Cisplatin (30 mg /m 2 ) + RT (50.4 Gy) (Preoperative for patients enrolled in Arm A) Gemcitabine (1500 mg/m 2 ) ever 2 wk + Bevacizumab (10 mg/kg) + RT (30 Gy) Arm A: Partial response 10%, Arm B: Partial response 18.2% NA NA Arm A: Entire cohort 19.4 mo. Arm B: entire cohort 13.4 mo mo with surgery NA 80 NA NA Partial response 3.8%; Stable disease 96.1% Partial response 10.5%; Stable disease 73.7%; Progression 7.9%; NA 7.9% Partial response 8.4%; Stable disease 73.7%; Progression 7.9% mo for entire cohort; NA for patients who underwent surgery mo for the enire cohort; 22 mo progression free survival with surgery Preoperative chemoradiation: 69% Surgery first: 57% Arm A Arm A (preoperative (preoperative chemoradition): 48. Arm B (surgery first): 51 chemoradiation): 18.9 mo. Arm B (surgery first): 25.0 mo mo with surgery; 16.8 mo for the entire cohort NA: Not available. 107 (96%) and radiotherapy in 104 (94%) with doses ranging from 24 to 63 Gy. In 13 trials, patients received intraoperative radiation therapy with doses between 10 and 30 Gy. Six studies stated that the RECIST criteria were used to assess the preoperative radiological response to neoadjuvant therapy. The criteria used to evaluate tumor response were clearly stated in 44 studies, while in 61 studies the criteria used were not adequately reported. Pooled results of patients with resectable cancers at the time of diagnosis showed a complete response in 3.6%, partial response in 30.6%, progression in 20.9% and stable disease in 42.1%. Resections were performed in 73.6% (95%CI: 65.9%-80.6%) of patients. Perioperative morbidity occurred in 26.7% (95%CI: 20.7%-33.3%) and mortality in 3.9% (95%CI: 2.2%-6.0%) which were comparable to the outcomes of patients undergoing surgery first. Negative resection margins (R0) were observed in 82.1% of patients (95%CI: 73.1%-89.6%) with a median survival of 23.3 mo (range 12-54). Analysis of trials with monotherapy vs poly-chemotherapy revealed higher rates of complete or partial response when multiple chemotherapy agents were used. Higher response rates, however, did not translate into higher resection rates. One year later, Assifi et al [19], published a second systematic review and meta-analysis of only phase Ⅱ neoadjuvant therapy trials. Out of 397 studies published from 1993 to 2010, 14 trials were included with a total of 536 patients. All studies were prospective, with 12 out of 14 (86%) being a single arm. Patients who had resectable tumors were 402 (75% of the sample). Gemcitabine was used in 8 trials, while the remaining 6 used 5-FU. Radiotherapy was given in 12 of 14 studies 461 December 15, 2017 Volume 9 Issue 12

13 Rahman SH et al. Neoadjuvant therapy for resectable pancreatic cancer (85%) with doses ranging between 30 and 50.4 Gy. In patients with resectable disease at diagnosis, complete radiological response was observed in 0.8% (95%CI: 0.0%-2.6%), partial response in 9.5% (95%CI: 2.9%-19.4%), stable disease in 73.9% (95%CI: 63.2%-83.3%) and progression in 17.0% (95%CI: 11.9%-22.7%). After neoadjuvant therapy, the resection rate was 65.8% (95%CI: 55.4%-75.6%) and negative resection margins were observed in 85.1% (95%CI: 76.8%-91.9%). Median survival was 23.0 mo (range ). The most significant finding of these two meta-analyses was that even if safe, neoadjuvant therapy did not seem to add any substantial survival advantage [18]. Due to the heterogeneity of these studies, no conclusion can be drawn regarding the overall impact on survival and what are the most effective chemotherapy agents or the best combination of chemotherapy agents for resectable PC. More recently, D Angelo et al [20] completed another systematic review of randomized controlled trials on adjuvant and neoadjuvant therapies for resectable PC. Fifteen studies were included covering a period of 30 years (1985 to 2015). Their analysis suggested that despite all the best efforts, the question whether neoadjuvant therapy provides a better overall survival than adjuvant therapy remains unanswered. DECISION ANALYSES VanHouten et al [21] used a decision analysis model to assess what is the best treatment strategy for resectable PC. A survival advantage of 7 mo was found in patients who underwent neoadjuvant therapy in comparison to surgery first (27.2 mo vs 19.9 mo). Another Markov decision analysis by de Geus et al [22] supported the use of neoadjuvant chemotherapy that provided longer overall survival (32 mo vs 27 mo) and quality-adjusted life expectancy (25 mo vs 21 mo) in comparison to surgery followed by adjuvant chemotherapy. Sensitivity analysis of the model showed that if the probability of surgical resection after neoadjuvant therapy was lower than 57%, upfront surgery was the best treatment option. Another group led by Sharma et al [23] compared the efficacy of neoadjuvant-based chemotherapy with adjuvant treatment with an intention-to-treat analysis using a two-arms Markov model. In the neoadjuvant group, patients were treated with an average of 3 mo of neoadjuvant therapy followed by surgery. After surgery, patients who received preoperative chemotherapy did not receive any adjuvant treatment. On the other hand, patients who underwent surgery first, underwent chemotherapy after they recovered from their operations. In this model, the median overall survival was longer for the neoadjuvant cohort (22 mo) in comparison to the adjuvant group (20 mo), and the cumulative quality-adjusted survival for patients who underwent the neoadjuvant strategy was 19.8 mo compared to 18.4 mo for patients who had adjuvant therapy. One-way sensitivity analysis showed that surgery first provided higher quality-adjusted survival rates if more than 44% of patients treated with neoadjuvant therapy experienced progression of their disease and failed to undergo surgical resection. All these models provided evidence that neoadjuvant therapies have better overall survival and quality of life in comparison to surgery first, although the differences were clinically quite small. PERSISTENT CONTROVERSY For borderline or locally advanced PC, the use of neoadjuvant therapy makes sense, and it is desirable for both patients and physicians. For patients perspective, neoadjuvant treatments might decrease the tumor burden and give them the chance of becoming resectable. Similarly, for the surgeons perspective, any reduction of the tumor size is welcome as it facilitates the technical aspect of the resection around critical vascular structures such as the superior mesentericportal vein junction or superior mesenteric artery. However, this is not the case for resectable PC. Neoadjuvant therapy does not facilitate surgery, as the tumor is resectable at the time of diagnosis. Preoperative therapy might increase the rate of negative margins; however, this needs to be proven in randomized controlled trials, as the current evidence is not sufficient. Furthermore, for patients perspective, there is a considerable risk of missing out the only opportunity of being cured with surgery as the tumor might progress to become unresectable while neoadjuvant therapies are delivered. Because the current evidence is inadequate, there are no unequivocal criteria able to assist health-care providers to select the strategy with the best long-term survival for resectable PC. Physicians are left to decide whether to use neoadjuvant therapy and whether to use of one or multiple pre-operative chemotherapeutic agents or chemoradiation is worth the risk of toxicities and the possibility of disease progression. In theory, neoadjuvant treatments would be unanimously recommended for patients at high risk of positive resection margins, as their surgery would not be curative. The selection of these patients is not easy. To overcome this concerns, Bao et al [24] developed a predictive module to maximize the probability of identifying patients with true resectable tumors by using commonly available preoperative imaging modalities. With this model, the authors could classify patients with low-risk and high-risk for noncurative resections and concluded that until better evidence is available, patients who are unlikely to have R0 margins should be treated with neoadjuvant therapy. FUTURE DIRECTIONS D Angelo et al [20] pointed out that the current literature is biased because the likelihood that radiologically 462 December 15, 2017 Volume 9 Issue 12

14 Rahman SH et al. Neoadjuvant therapy for resectable pancreatic cancer Table 4 List of ongoing phase Ⅱ and phase Ⅲ trials comparing neoadjuvant therapies vs adjuvant strategies for resectable pancreatic adenocarcinoma Study Design No. of patients needed Therapy Primary outcome NEOPAC (NCT ) NEOPAC (NCT ) Phase Ⅲ Enrollment Phase Ⅲ Initiated in Neoadjuvant gemcitabineoxaliplatin + adjuvant gemcitabine vs Adjuvant gemcitabine 310 Preoperative FOLFIRINOX, followed by adjuvant gemcitabine after surgery vs adjuvant gemcitabine after resection Progression free survival Five-year progression free survival NCT Phase Ⅲ 410 Neoadjuvant gemcitabine-based chemoradiation therapy followed Three-year overall survival by adjuvant gemcitabine vs adjuvant gemcitabine NCT Phase Ⅱ 100 Neoadjuvant FOLFIRINOX Progression free survival NEONAX (NCT ) NCT ACOSOG-Z5041 (NCT ) Randomized phase Ⅱ 166 Neoadjuvant gemcitabine + nab-paclitaxel followed by adjuvant gemcitabine + nab-paclitaxel vs adjuvant gemcitabine + nabpaclitaxel 370 Adjuvant PEXG vs adjuvant gemcitabine vs neoadjuvant PEXG - followed by surgery and then adjuvant PEXG Disease-free survival at 18 mo Randomized One year event-free survival phase Ⅱ/Ⅲ Phase Ⅱ 123 Neoadjuvant gemcitabine + erlotinib (completed; results pending) Two-year overall survival NCT Phase Ⅱ 87 Neoadjuvant GVAX +/- IV or oral cyclophosphamide followed by adjuvant gemcitabine + CRT Safety, feasibility, and immune response NCT Phase Ⅱ 48 Neoadjuvant FOLFIRINOX Pathologic complete response GEMCAD1003 Phase Ⅱ 24 Neoadjuvant gemcitabine + erlotinib R0 resection rate (NCT ) NCT Phase Ⅱ 112 Neoadjuvant and adjuvant mfolfirinox vs neoadjuvant and Overall survival Enrollment adjuvant Nab-paclitaxel and gemcitabine NCT Randomized 112 Neoadjuvant FOLFIRINOX vs gemcitabine + nab-paclitaxel 18-mo overall survival phase Ⅱ NCT Pilot 15 Neoadjuvant gemcitabine + nab-paclitaxel ± paricalcitol Number of adverse events NCT Randomized phase Ⅰb/Ⅱ 56 Neoadjuvant capecitabine-based CRT ± pembrolizumab (MK-3745) Safety and immune response CRT: Chemoradiation therapy; GVAX: Granulocyte-macrophage colony-stimulating factor gene-transfected tumor cell vaccine; PEXG: Cisplatin, epirubicin, capecitabine, gemcitabine; R0: Margin-negative surgical resection. resectable PCs is indeed unresectable at the time of surgery is only about 40% [25]. Therefore, the only way to find out if there is any benefit from neoadjuvant therapy is to complete an intention to treat randomized controlled trial where one arm entails surgery followed by adjuvant therapy (current standard of care) and the second arm involves neoadjuvant therapy followed by surgery followed by adjuvant therapy (experimental group). Recent chemotherapy regimens, such as FOLFI RINOX [folinic acid (leucovorin)/5-fu/irinotecan/ Oxaliplatin], have already demonstrated promising results in a small group of patients with borderline resectable tumors [26,27]. Given these findings, several ongoing prospective studies are examining the role of FOLFIRINOX in a neoadjuvant setting for resectable disease (Table 4). Other studies include NEOPAC, NEONAX, NCT , and NCT NEOPAC (Adjuvant vs Neoadjuvant Plus Adjuvant Chemotherapy in Resectable Pancreatic Cancer) will compare neoadjuvant gemcitabine and oxaliplatin plus adjuvant gemcitabine vs adjuvant gemcitabine alone. NEONAX, (Neoadjuvant Plus Adjuvant or Only Adjuvant Nab- Paclitaxel Plus Gemcitabine for Resectable Pancreatic Cancer) will assess the effects of neoadjuvant plus adjuvant Nab-Paclitaxel plus gemcitabine vs adjuvant only Nab-Paclitaxel plus gemcitabine. Other ongoing trials are a single-arm nonrandomized trial evaluating preoperative and postoperative FOLFIRINOX in patients with resectable disease (NCT ) and the multicenter German randomized trial investigating adjuvant gemcitabine compared with neoadjuvant and adjuvant FOLFIRINOX (NCT ). CONCLUSION Based on the current literature, there is still insufficient evidence to fully support the use of neoadjuvant therapy for all patients with radiologically resectable PC. Randomized controlled trials are urgently needed to address many of the questions that are still unanswered. Until then, clinicians need to weigh the pros and cons of the two treatment strategies and guide their patients. Ideally, patients should be educated on the advantages, and detrimental effects associated with each of the two possible therapies and their preferences should be elicited. Since each patient is unique, proposing neoadjuvant therapy with one-sizefits-all approach should be discouraged, and patients should become active participants and share with their 463 December 15, 2017 Volume 9 Issue 12

15 Rahman SH et al. Neoadjuvant therapy for resectable pancreatic cancer physicians the responsibility of selecting the treatment strategy that fits best with their goals and values. ACKNOWLEDGMENTS The authors would like to acknowledge: Stefanie Condon-Oldreive founder and director of Craig s Cause Pancreatic Cancer Society ( for the research scholarship that supported Dr. Sheikh Hasibur Raman while working on this project. The authors thank Melissa Connell for her administrative support and technical and language editing that helped improving the quality of the manuscript and the quality of the audio file. REFERENCES 1 Cameron JL, He J. Two thousand consecutive pancreaticoduodenectomies. J Am Coll Surg 2015; 220: [PMID: DOI: /j.jamcollsurg ] 2 Sharma C, Eltawil KM, Renfrew PD, Walsh MJ, Molinari M. Advances in diagnosis, treatment and palliation of pancreatic carcinoma: World J Gastroenterol 2011; 17: [PMID: DOI: /wjg.v17.i7.867] 3 Yeo TP. Demographics, epidemiology, and inheritance of pancreatic ductal adenocarcinoma. Semin Oncol 2015; 42: 8-18 [PMID: DOI: /j.seminoncol ] 4 Hurton S, MacDonald F, Porter G, Walsh M, Molinari M. The current state of pancreatic cancer in Canada: incidence, mortality, and surgical therapy. Pancreas 2014; 43: [PMID: DOI: /MPA ] 5 Bilimoria KY, Bentrem DJ, Ko CY, Stewart AK, Winchester DP, Talamonti MS. National failure to operate on early stage pancreatic cancer. Ann Surg 2007; 246: [PMID: DOI: /SLA.0b013e ] 6 Raval MV, Bilimoria KY, Talamonti MS. Quality improvement for pancreatic cancer care: is regionalization a feasible and effective mechanism? Surg Oncol Clin N Am 2010; 19: [PMID: DOI: /j.soc ] 7 Roland CL, Yang AD, Katz MH, Chatterjee D, Wang H, Lin H, Vauthey JN, Pisters PW, Varadhachary GR, Wolff RA, Crane CH, Lee JE, Fleming JB. Neoadjuvant therapy is associated with a reduced lymph node ratio in patients with potentially resectable pancreatic cancer. Ann Surg Oncol 2015; 22: [PMID: DOI: /s ] 8 Cloyd JM, Katz MH, Prakash L, Varadhachary GR, Wolff RA, Shroff RT, Javle M, Fogelman D, Overman M, Crane CH, Koay EJ, Das P, Krishnan S, Minsky BD, Lee JH, Bhutani MS, Weston B, Ross W, Bhosale P, Tamm EP, Wang H, Maitra A, Kim MP, Aloia TA, Vauthey JN, Fleming JB, Abbruzzese JL, Pisters PW, Evans DB, Lee JE. Preoperative Therapy and Pancreatoduodenectomy for Pancreatic Ductal Adenocarcinoma: a 25-Year Single-Institution Experience. J Gastrointest Surg 2017; 21: [PMID: DOI: / s ] 9 Sutton JM, Abbott DE. Neoadjuvant therapy for pancreas cancer: past lessons and future therapies. World J Gastroenterol 2014; 20: [PMID: DOI: /wjg.v20.i ] 10 Wilkowski R, Wolf M, Heinemann V. Primary advanced unresectable pancreatic cancer. Recent Results Cancer Res 2008; 177: [PMID: DOI: / _10] 11 Valeri S, Borzomati D, Nappo G, Perrone G, Santini D, Coppola R. Complete pathological response after FOLFIRINOX for locally advanced pancreatic cancer. The beginning of a new era? Case report and review of the literature. Pancreatology 2014; 14: [PMID: DOI: /j.pan ] 12 Springett GM, Hoffe SE. Borderline resectable pancreatic cancer: on the edge of survival. Cancer Control 2008; 15: [PMID: DOI: / ] 13 Murakami Y, Satoi S, Sho M, Motoi F, Matsumoto I, Kawai M, Honda G, Uemura K, Yanagimoto H, Shinzeki M, Kurata M, Kinoshita S, Yamaue H, Unno M. National Comprehensive Cancer Network Resectability Status for Pancreatic Carcinoma Predicts Overall Survival. World J Surg 2015; 39: [PMID: DOI: /s ] 14 Katz MH, Landry J, Kindler HL. Current controversies in the stagespecific multidisciplinary management of pancreatic cancer. Am Soc Clin Oncol Educ Book 2014: e157-e164 [PMID: DOI: /EdBook_AM e157] 15 Katz MH, Merchant NB, Brower S, Branda M, Posner MC, William Traverso L, Abrams RA, Picozzi VJ, Pisters PW; American College of Surgeons Oncology Group. Standardization of surgical and pathologic variables is needed in multicenter trials of adjuvant therapy for pancreatic cancer: results from the ACOSOG Z5031 trial. Ann Surg Oncol 2011; 18: [PMID: DOI: /s y] 16 Katz MH, Varadhachary GR, Fleming JB, Wolff RA, Lee JE, Pisters PW, Vauthey JN, Abdalla EK, Sun CC, Wang H, Crane CH, Lee JH, Tamm EP, Abbruzzese JL, Evans DB. Serum CA 19-9 as a marker of resectability and survival in patients with potentially resectable pancreatic cancer treated with neoadjuvant chemoradiation. Ann Surg Oncol 2010; 17: [PMID: DOI: / s ] 17 Gillen S, Schuster T, Meyer Zum Büschenfelde C, Friess H, Kleeff J. Preoperative/neoadjuvant therapy in pancreatic cancer: a systematic review and meta-analysis of response and resection percentages. PLoS Med 2010; 7: e [PMID: DOI: /journal. pmed ] 18 Verma V, Li J, Lin C. Neoadjuvant Therapy for Pancreatic Cancer: Systematic Review of Postoperative Morbidity, Mortality, and Complications. Am J Clin Oncol 2016; 39: [PMID: DOI: /COC ] 19 Assifi MM, Lu X, Eibl G, Reber HA, Li G, Hines OJ. Neoadjuvant therapy in pancreatic adenocarcinoma: a meta-analysis of phase II trials. Surgery 2011; 150: [PMID: DOI: / j.surg ] 20 D Angelo FA, Antolino L, La Rocca M, Petrucciani N, Magistri P, Aurello P, Ramacciato G. Adjuvant and neoadjuvant therapies in resectable pancreatic cancer: a systematic review of randomized controlled trials. Med Oncol 2016; 33: 28 [PMID: DOI: /s z] 21 VanHouten JP, White RR, Jackson GP. A decision model of therapy for potentially resectable pancreatic cancer. J Surg Res 2012; 174: [PMID: DOI: /j.jss ] 22 de Geus SW, Evans DB, Bliss LA, Eskander MF, Smith JK, Wolff RA, Miksad RA, Weinstein MC, Tseng JF. Neoadjuvant therapy versus upfront surgical strategies in resectable pancreatic cancer: A Markov decision analysis. Eur J Surg Oncol 2016; 42: [PMID: DOI: /j.ejso ] 23 Sharma G, Whang EE, Ruan DT, Ito H. Efficacy of Neoadjuvant Versus Adjuvant Therapy for Resectable Pancreatic Adenocarcinoma: A Decision Analysis. Ann Surg Oncol 2015; 22 Suppl 3: S1229-S1237 [PMID: DOI: /s ] 24 Bao P, Potter D, Eisenberg DP, Lenzner D, Zeh HJ, Lee Iii KK, Hughes SJ, Sanders MK, Young JL, Moser AJ. Validation of a prediction rule to maximize curative (R0) resection of early-stage pancreatic adenocarcinoma. HPB (Oxford) 2009; 11: [PMID: DOI: /j x] 25 Allen VB, Gurusamy KS, Takwoingi Y, Kalia A, Davidson BR. Diagnostic accuracy of laparoscopy following computed tomography (CT) scanning for assessing the resectability with curative intent in pancreatic and periampullary cancer. Cochrane Database Syst Rev 2013; (11): CD [DOI: / CD pub2] 26 Denost Q, Laurent C, Adam JP, Capdepont M, Vendrely V, Collet D, Cunha AS. Pancreaticoduodenectomy following chemoradiotherapy for locally advanced adenocarcinoma of the pancreatic head. 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16 Rahman SH et al. Neoadjuvant therapy for resectable pancreatic cancer 27 Ducreux M, Cuhna AS, Caramella C, Hollebecque A, Burtin P, Goéré D, Seufferlein T, Haustermans K, Van Laethem JL, Conroy T, Arnold D; ESMO Guidelines Committee. Cancer of the pancreas: ESMO Clinical Practice Guidelines for diagnosis, treatment and followup. Ann Oncol 2015; 26 Suppl 5: v56-v68 [PMID: DOI: /annonc/mdv295] P- Reviewer: Kim SM, Munoz M, Nakai Y, Sun XT S- Editor: Ji FF L- Editor: A E- Editor: Lu YJ 465 December 15, 2017 Volume 9 Issue 12

17 Submit a Manuscript: DOI: /wjgo.v9.i World J Gastrointest Oncol 2017 December 15; 9(12): ISSN (online) Retrospective Cohort Study ORIGINAL ARTICLE Tumor-stroma ratio as prognostic factor for survival in rectal adenocarcinoma: A retrospective cohort study René Scheer, Alexi Baidoshvili, Shorena Zoidze, Marloes AG Elferink, Annefleur EM Berkel, Joost M Klaase, Paul J van Diest René Scheer, Annefleur EM Berkel, Joost M Klaase, Department of Surgery, Medisch Spectrum Twente, Enschede 7500 KA, The Netherlands Alexi Baidoshvili, Shorena Zoidze, Laboratory for Pathology East-Netherlands, Hengelo 7550 AM, The Netherlands Marloes AG Elferink, Netherlands Comprehensive Cancer Organization, Location Enschede, Enschede 7511 JP, The Netherlands Paul J van Diest, Department of Pathology, University Medical Center Utrecht, Utrecht 3508 GA, The Netherlands ORCID number: René Scheer ( ); Alexi Baidoshvili ( ); Shorena Zoidze ( ); Marloes AG Elferink ( ); Annefleur EM Berkel ( ); Joost M Klaase ( ); Paul J van Diest ( ). Author contributions: Scheer R and Klaase JM designed the research; Scheer R and Zoidze S performed the research; Baidoshvili A supervised the histological scoring and took final decisions in case of discrepancy in scores between Scheer R and Zoidze S; Elferink MAG collected data from the populationbased The Netherlands Cancer Registy and analyzed the data; Berkel AEM, Klaase JM and van Diest PJ supervised and interpreted the results; Scheer R and Zoidze S wrote the paper; all authors critically reviewed and accepted the final version of the manuscript. Institutional review board statement: The requirement for informed consent and ethical approval was waived because of the retrospective study design. The study is conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines. Conflict-of-interest statement: The authors declare no conflict of interests. Data sharing statement: Technical appendix, statistical code, and dataset available from the corresponding author at mst.nl. Participants informed consent was not obtained, but the presented data are anonymized and risk of identification is low. Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: licenses/by-nc/4.0/ Manuscript source: Invited manuscript Correspondence to: Joost M Klaase, MD, PhD, Surgical- Oncologist, Department of Surgery, Medisch Spectrum Twente, PO Box , Enschede 7500 KA, The Netherlands. Telephone: Fax: Received: June 22, 2017 Peer-review started: July 14, 2017 First decision: August 7, 2017 Revised: September 17, 2017 Accepted: October 15, 2017 Article in press: October 15, 2017 Published online: December 15, 2017 Abstract AIM To evaluate the prognostic value of the tumor-stroma ratio (TSR) in rectal cancer. METHODS TSR was determined on hematoxylin and eosin stained histological sections of 154 patients treated for rectal adenocarcinoma without prior neoadjuvant treatment in the period by two observers to assess 466 December 15, 2017 Volume 9 Issue 12

18 Scheer R et al. Tumor-stroma ratio in rectal cancer reproducibility. Patients were categorized into three categories: TSR-high [carcinoma percentage (CP) 70%], TSR-intermediate (CP 40%, 50% and 60%) and TSR-low (CP 30%). The relation between categorized TSR and survival was analyzed using Cox proportional hazards model. RESULTS Thirty-six (23.4%) patients were scored as TSR-low, 70 (45.4%) as TSR-intermediate and 48 (31.2%) as TSRhigh. TSR had a good interobserver agreement (κ = 0.724, concordance 82.5%). Overall survival (OS) and disease free survival (DFS) were significantly better for patients with a high TSR (P = 0.01 and P = 0.02, respectively). A similar association existed for disease specific survival (P = 0.06). In multivariate analysis, patients without lymph node metastasis and an intermediate TSR had a higher risk of dying from rectal cancer (HR = 5.27, 95%CI: ), compared to lymph node metastasis negative patients with a high TSR. This group also had a worse DFS (HR = 6.41, 95%CI: ). An identical association was seen for OS. These relations were not seen in lymph node metastasis positive patients. CONCLUSION The TSR has potential as a prognostic factor for survival in surgically treated rectal cancer patients, especially in lymph node negative cases. Key words: Rectal cancer; Adenocarcinoma; Prognosis; Recurrence; Pathology; Tumor-stroma ratio The Author(s) Published by Baishideng Publishing Group Inc. All rights reserved. Core tip: The tumor-stroma ratio (TSR) can be determined accurately on routine histopathological sections by different observers. The TSR has potential as a prognostic factor for survival in surgically treated rectal cancer patients, especially in lymph node negative cases. It could therefore be useful in decision making regarding adjuvant treatment in individual patients. Scheer R, Baidoshvili A, Zoidze S, Elferink MAG, Berkel AEM, Klaase JM, van Diest PJ. Tumor-stroma ratio as prognostic factor for survival in rectal adenocarcinoma: A retrospective cohort study. World J Gastrointest Oncol 2017; 9(12): Available from: URL: htm DOI: INTRODUCTION Colorectal cancer (CRC) is a common form of cancer in both men and women. More than new patients with a colorectal carcinoma were diagnosed in The Netherlands in 2016 [1]. The common form to stage this type of cancer is the TNM staging system of the Union Internationale Contre le Cancer/American Joint Cancer Committee (UICC/AJCC) [2]. This system is also used in decision making about the appliance of (neo)adjuvant (chemo)radiotherapy. Although the TNM staging system is still regarded as the most important prognostic factor [3], it seems insufficiently able to predict the prognosis of the individual patient. This applies in particular to patients with stage II rectal cancer [4]. A part of the patients is overtreated and consequently exposed to a higher risk on therapy related complications, indicating a need for additional prognostic factors. More recently, some studies have focused on the tumor-host interaction in relation to metastatic invasion. This interaction is enacted in an environment including cancer cells, the stromal tissue, consisting of different cell types like fibroblasts, myofibroblasts, endothelial cells and immune cells, and the extracellular matrix [5]. Mesker et al [6] showed that a high tumor-stroma ratio (TSR), the proportion of carcinoma relative to the proportion of tumor stroma in the histopathological section through the tumor, is an indicator of a better outcome of disease in colon cancer. This is more outspoken for right sided tumors [6]. Similar results were seen in breast cancer, oral squamous cell carcinoma and prostate cancer [7-9]. A high TSR is possibly related to both a longer disease free and overall survival (OS) according to a study on a small number of rectal cancer patients [10]. In this respect, it is meaningful to explore the relevance of the TSR in a larger cohort of patients with rectal adenocarcinoma. MATERIALS AND METHODS Patients Patients with rectal adenocarcinomas under the peritoneal reflection were identified out of all patients, who underwent surgery for left sided colorectal malignancies at our hospital between 1996 and 2006, by analyzing the histopathological reports. Only patients treated with curative intent were included, i.e., patients without known distant metastases at surgery and radically resected tumors (M0, R0 resections). Patients who received neoadjuvant therapy, with malignancies in the past, other than radically excised basal cell carcinoma of the skin, and cases where no tumor was found in the resected specimen, despite preoperative adenocarcinoma in the biopsy of a suspected abnormality, were excluded. Other exclusion criteria were the presence of synchronous colorectal tumors, Lynch syndrome, familial adenomatous polyposis, and inflammatory bowel diseases. Patients who died within thirty days after surgery, with incomplete follow-up or unavailable histopathological material were also excluded (Figure 1). Data concerning local recurrences, distant metastases, death, and cause of death were collected from the patient records and by consultation of general practitioners. Furthermore, dates of death were retrieved from the population-based Netherlands Cancer Registry. All data were handled in a coded anonymous 467 December 15, 2017 Volume 9 Issue 12

19 Scheer R et al. Tumor-stroma ratio in rectal cancer All patients treated by surgery for left sided colorectal malignancies at our hospital between 1996 and 2006 n = 516 Pre-operative exclusion Malignancy in history n = 59 Familial adenomatous polyposis n = 1 Inflammatory bowel disease n = 2 Neo-adjuvant chemo- or (chemo)radiotherapy n = 55 Surgery with palliative intention n = 1 Synchronous colorectal tumors n = 10 Tumor in resected specimen after preoperative biopsy with adenocarcinoma? Yes n = 371 No n = 17 Position tumor relative to PR Under PR n = 181 Above PR n = 62 On PR n = 39 Unknown n = 89 Pre- or peroperative M-status M0 n = 170 M1 n = 11 Radicality R0 n = 162 R1 n = 8 Post-operative exclusion Death <30 d after surgery n = 5 Missing data/incomplete follow up n = 3 Included patients n = 154 Figure 1 Flowchart of exclusion criteria applied to the dataset of all patients. PR: Peritoneal reflection. fashion according to the Code for proper secondary use of human tissue from the Dutch Federation of Medical Scientific Societies and with respect to the Helsinki Declaration. TSR assessment TSR was determined on hematoxylin and eosin (H and E) stained histological sections. The section with the most invasive part of the tumor was identified to semiquantitatively assess the carcinoma percentage (CP) in 10% steps. The CP is a derivative of the TSR and is complementary to the percentage of stroma and other components, like mucus. For example, a CP of 20% corresponds to a stroma percentage of 80%, which coincides with a low TSR. The section was viewed with a 5 objective (50 times magnification). The CPs were determined on all image fields of the entire section with tumor cells in all sides of it (North- East-South-West). Areas with the lowest CP were given more weight in rating the mean CP of the total assessed area, as is common practice in routine pathology in determining tumor differentiation. All sections were assessed separately by two observers (René Scheer and Shorena Zoidze) to allow assessment of reproducibility. The absolute CPs were categorized for a good clinical reproducibility and clarity reasons into three categories, finally. TSR-low including the CP-values 30%, TSRintermediate including the CP-values 40%, 50% and 60%, and TSR-high including the CP-values 70% (Figure 2). In the results only the categorized TSR are shown for clarity. In case of a difference of 10% in determined CPs, which lead to a different TSR category, the lowest CP was used for the determination of the final TSR. The sections were reviewed by a third observer (AB) in case of > 10% difference in determined CPs leading 468 December 15, 2017 Volume 9 Issue 12

20 Scheer R et al. Tumor-stroma ratio in rectal cancer TSR-high (10 ) TSR-intermediate (10 ) TSR-Low (10 ) Figure 2 Examples of different categories of the tumor-stroma ratio. H and E stained 2 µm paraffin sections of primary rectal adenocarcinoma. TSR-high (carcinoma percentage 70%), TSR-intermediate (carcinoma percentage 40%, 50% and 60%), and TSR-low (carcinoma percentage 30%). TSR: Tumor-stroma ratio. to different TSR categories. This third opinion was considered as decisive. Statistical analysis Data were analyzed using SPSS, version 19.0 (SPSS Inc., Chicago, IL, United States) and Stata, version 12.0 (StataCorp LP, College Station, Texas, United States). The statistical methods of this study were reviewed by Elferink MA, from the Netherlands Comprehensive Cancer Organization. Patient characteristics were compared using Pearson χ 2 tests and one-way ANOVA. Interobserver reproducibility for the absolute and categorized CPs was analyzed by using Cohen s Kappa (κ) coefficient. A κ-value of 0.0 or less was considered to represent poor agreement, slight agreement, fair, moderate, sufficient to good, and near-perfect agreement [11]. Survival analyses based on categorized CPs included comparison of OS, disease free survival (DFS), and disease specific survival (DSS) by Kaplan-Meier survival analysis and log-rank statistics. Follow-up time in OS analyses was defined as the period between the date of primary surgery and the date of death from any cause, or the date of last followup. The DSS was restricted to death from rectal cancer only. Follow-up time in DFS analyses was defined as the time from the date of primary surgery until the date of a local recurrence or distant metastasis (irrespective of site). In DFS analyses, cases were censored in case of a second primary tumor (colorectal or other types) or death. The date of last follow-up was used as endpoint to calculate follow-up time, if none of these events occurred. The relation between categorized TSR and survival (OS, DFS, and DSS) was analyzed, and adjusted for confounders (age, gender, grading, pathological T- and N-stage, and adjuvant treatment), using Cox proportional hazards model. Probability values < 0.05 (2-sided) were considered statistically significant. RESULTS Patient characteristics A total of 154 patients met the inclusion criteria for this study. Three types of resections were used: Abdominoperineal resection in 67 (43.5%), low anterior resection in 63 (40.9%), and Hartmann resection, a modulated low anterior resection without construction of an anastomosis, in 24 patients (15.6%). The median follow-up of all patients was 5.3 years. Out of the analyzed samples, 36 (23.4%) were scored as TSR-low, 70 (45.4%) as TSR-intermediate, and 48 (31.2%) as TSR-high. There were more lymph node metastasis positive patients with a low TSR in comparison with patients with a higher TSR (P = 0.029), who consequently received adjuvant treatment. Radiotherapy was the most common form of adjuvant therapy. Detailed patient characteristics are shown by categorized TSR in Table December 15, 2017 Volume 9 Issue 12

21 Scheer R et al. Tumor-stroma ratio in rectal cancer Table 1 Patient characteristics by categorized tumor-stroma ratio TSR-low (n = 36) TSR-intermediate (n = 70) TSR-high (n = 48) P -value 1 n % n % n % Gender NS Male Female Age (yr) M 68.0 SD 8.0 M 67.3 SD 10.3 M 65.7 SD 10.3 NS 2 (range ) (range ) (range ) Treatment NS APR LAR Hartmann T-status NS pt pt pt pt N-status pn N N Stage NS Ⅰ Ⅱ Ⅲ Grading NS Well Moderate Poor Adjuvant treatment Radiotherapy Chemoradiotherapy Chemotherapy Pearson c 2 test; 2 One-Way ANOVA; 3 P-value for adjuvant treatment in general. Significant P-values are shown bold. n: Number of patients; %: Percentage; Age defined as period from birth until date of primary surgery; LAR: Low anterior resection; APR: Abdominoperineal resection; pt: Pathological tumor status; pn: Pathological nodal status; Stage according to UICC/AJCC TNM staging system, 5 th edition; TSR: Tumor-stroma ratio; UICC/AJCC: Union Internationale Contre le Cancer/American Joint Cancer Committee. Interobserver reproducibility A third opinion about a final TSR in case of interobserver disagreement about CPs with > 10% difference in determined CPs leading to different TSR categories was needed in 12 patients (7.8%). Mainly strong heterogeneity of the tumor complicated the determination of the CP for the total section. CPs were scored in a range between 10 and 90 percent. Lower CPs were found in mucinous adenocarcinomas. Cohen s Kappa (κ) coefficient for interobserver agreement of the absolute CP showed a moderate agreement (κ = 0.522, concordance 59.1%). By categorizing the CP into three categories TSR (TSR-low, TSRintermediate, and TSR-high) the κ-value improved and showed a good agreement (κ = 0.724, concordance 82.5%). Prognostic impact on outcome The 5-year survival rate for OS was 64.6% in the TSRhigh population, vs 50.0% and 55.6% in the TSRintermediate and TSR-low population, respectively. For the DFS, the 5-year survival rates for TSR-high, TSRintermediate, and TSR-low were 77.2%, 51.8%, and 55.2%, respectively. The OS and DFS were significant different between the three TSR categories (P = 0.01 and P = 0.02, respectively). The 5-year survival rates for DSS were 81.6% for TSR-high, 60.3% for TSRintermediate, and 63.9% for TSR-low. Although a higher DSS for the TSR-high population was thereby seen, the differences between the three TSR categories were just not significant (P = 0.06). The Kaplan-Meier survival curves are shown in Figure 3. After adjusting for known prognostic factors (age, grading, and the use of adjuvant therapy), an intermediate TSR in lymph node metastasis negative patients showed a trend to a lower OS rate (HR = 2.04, 95%CI: ) in comparison with a high TSR. There were no statistical differences between the TSR categories in OS among lymph node metastasis positive patients (Table 2). A statistically significant worse DFS was seen among the lymph node metastasis negative patients with an intermediate TSR (HR = 6.41, 95%CI: ) compared to patients with a high TSR. Among lymph node metastasis positive patients, no statistically significant differences were seen between TSR categories for DFS (Table 3). Lymph node meta- 470 December 15, 2017 Volume 9 Issue 12

22 Scheer R et al. Tumor-stroma ratio in rectal cancer A 1.00 P = 0.01 B 1.00 P = 0.02 Cumulative overall survival TSR-high TSR-intermediate TSR-low Years after resection Cumulative disease-free survival TSR-high TSR-intermediate TSR-low Years after resection C 1.00 P = 0.06 Cumulative disease-specific survival TSR-high TSR-intermediate TSR-low Years after resection Figure 3 Kaplan-Meier survival curves of overall survival, disease free survival and disease specific survival by categorized tumor-stroma ratio. A: Overall survival; B: Disease free survival; C: Disease specific survival. P-values of Log-rank statistics. TSR-high (carcinoma percentage 70%), TSR-intermediate (carcinoma percentage 40%, 50% and 60%), and TSR-low (carcinoma percentage 30%). TSR: Tumor-stroma ratio. stasis negative patients with an intermediate TSR had a higher risk of dying from rectal cancer (HR 5.27, 95%CI: ) in comparison with patients with a high TSR. These differences were not seen in lymph node metastasis positive patients (Table 4). DISCUSSION This study, analyzing data of 154 patients with rectal adenocarcinoma diagnosed in the period , showed that the TSR is a prognostic factor for patients without lymph node metastasis. In such cases, a high TSR had a longer local recurrence and distant metastasis free period, and a lower risk of death from rectal adenocarcinoma. Besides, a high TSR was associated with a lower risk of death from any cause. The determination of the TSR may therefore contribute to stratify patients for prognosis. Determination of the TSR turned out to be feasible and reproducible among observers on routinely made sections of rectal cancers. The TSR therefore has the potential to contribute to decision making regarding the individual treatment policy in rectal cancer. The relation between the prognosis and the TSR may be explained pathophysiologically. A dual effect of the tumor stroma in the tumor-host interaction has been described. The tumor stroma is able to exert inhibitory effects on the malignant cells at first. With ongoing tumor growth, the tumor can exploit its stroma, for example by changing its composition (e.g., vasculature), to promote tumor growth and metastasis. A process called stromagenesis, which occurs parallel with tumor progression. Stromagenesis is characterized by bidirectional communication between the tumor and its stroma. The interactional pathways are multiple and complex [12-14]. Despite this complexity it is justifiable to conclude that the stromal tissue is not a passive component surrounding the tumor. A sufficient amount of stroma contributes to a more aggressive phenotype of tumor, as is shown in this study as well. Indeed, the poor prognosis for lymph node negative patients with an intermediate TSR is remarkable. The survival rates for death from all causes, death from rectal cancer, and the occurrence of local recurrences and distant metastasis are the lowest for this group of patients. This may be explained by a favorable balance between the tumor and its stroma. In this way, the tumor may be able to exploit the surrounding tumor stroma very efficiently. The concept of a balance between pro- and antitumor factors had been hypothesized earlier. For example, there is a relation between the degree of the peritumoral inflammatory 471 December 15, 2017 Volume 9 Issue 12

23 Scheer R et al. Tumor-stroma ratio in rectal cancer Table 2 Cox multivariate analysis for overall survival Table 4 Cox multivariate analysis for disease specific survival N0 N+ HR 95%CI HR 95%CI Age < 70 yr 1 Ref. 1 Ref. > 70 yr 3.32 a a Grading Poor 1 Ref. 1 Ref. Moderate Well Adjuvant treatment No 1 Ref. 1 Ref. Yes TSR TSR-high 1 Ref. 1 Ref. TSR-intermediate TSR-low a P < Age defined as period from birth until date of primary surgery. N0: Lymph node metastasis negative patients; N+: Lymph node metastasis positive patients; TSR: Tumor-stroma ratio. N0 N+ HR 95%CI HR 95%CI Age < 70 yr 1.00 Ref Ref. > 70 yr pt-status T Ref Ref. T T T Grading Poor 1.00 Ref Ref. Moderate Well 1 1 Adjuvant treatment No 1.00 Ref Ref. Yes TSR TSR-high 1.00 Ref Ref. TSR-intermediate 5.27 a TSR-low Table 3 Cox multivariate analysis for disease free survival N0 N+ HR 95%CI HR 95%CI Age < 70 yr 1.00 Ref Ref. > 70 yr pt-status T Ref Ref. T T T Grading Poor 1.00 Ref Ref. Moderate Well 1 1 Adjuvant treatment No 1.00 Ref Ref. Yes TSR TSR-high 1.00 Ref Ref. TSR-intermediate 6.41 a TSR-low a P < 0.05; 1 Too small numbers to analyze. Age defined as period from birth until date of primary surgery. N0: Lymph node metastasis negative patients; N+: Lymph node metastasis positive patients; pt: Pathological tumor status; TSR: Tumor-stroma ratio. reaction and its ability to destroy invading colorectal malignant cells [15]. Lymph node metastasis can be seen as an expression of a developed tumor that has exploited its environment successfully. When lymph node metastasis has occurred, the effect of the tumor micro-environment may be negligible. This statement may explain why we did not find differences in survival in lymph node metastasis positive patients survival based on the TSR. The effect of a high TSR on survival demonstrated in this study is in line with other studies on the prognostic impact of the TSR in colorectal carcinomas (CRCs) and a P < 0.05; 1 Too small numbers to analyze. Age defined as period from birth until date of primary surgery. N0: Lymph node metastasis negative patients; N+: Lymph node metastasis positive patients; pt: Pathological tumor status; TSR: Tumor-stroma ratio. other malignancies [6-10,16]. The present study is however the first that has identified a subgroup of patients with rectal cancer, namely lymph node metastasis negative patients with an intermediate TSR, whereby the TSR is a strong prognostic factor. The interobserver agreement for absolute scores was moderate. The correlation coefficient improved to good, when grouping as TSR-low, TSR-intermediate, and TSR-high. The categorization into these categories was performed with the aim of generating enhanced prognostic information based on the TSR, which had been executed earlier in a previous study on the TSR in oesophageal adenocarcinomas [17]. Other studies concerning the TSR used an arbitrary cut-off value of 50%. No differences in the given survival rates were found at this and other cut-off values in our population (Appendix 1). The rate of agreement of the present study is slightly lower compared to these studies [7,8], which may be attributed to the determination of absolute CPs before the categorization and the addition of an extra CP-category. This study has some shortcomings to be noted. Neo-adjuvant radiotherapy for rectal malignancies was applied more frequently at our hospital relatively late in the study period and consequentially patients received adjuvant therapy frequently. Neoadjuvant treated patients were excluded, while in most cases a neoadjuvant (chemo)radiotherapy regimen is given nowadays. Though, it remains valuable to investigate tissue based prognostic factors in non-pretreated patients. There is a tendency to treat elderly, for whom there is an increasing incidence of rectal cancer, without neoadjuvant radiotherapy due to postoperative 472 December 15, 2017 Volume 9 Issue 12

24 Scheer R et al. Tumor-stroma ratio in rectal cancer wound complications in The Netherlands. According to the Dutch Surgical Colorectal Audit, no neoadjuvant therapy was used in 26% of ct2 patients aged > 75 years with rectal carcinoma in comparison with 14% in younger patients [18]. Furthermore, there is still a debate about adjuvant chemotherapy for rectal cancer. Future research about the balance between the oncological benefit, i.e., relative risk reduction of 50% in local recurrences and the side effects, i.e., relative risk increase of 50% in acute treatment-relate toxicity, and long-term anorectal and sexual dysfunction [19-21] of neoadjuvant radiotherapy will help to determine the position of pretreatment dependent tissue-based markers like the TSR in predicting an individual prognosis. It would be of interest to analyze the TSR and its prognostic value in biopsy specimens of well described areas of a rectal tumor. Prognostic information could then be provided before the use of neoadjuvant therapy. The visual estimation of the TSR could be made more accurate by the use of tumor or stroma specific stainings. Besides, it would be desirable to develop a more objective instrument to determine the TSR than the visual estimation in this study. This could be provided by the use of tumor specific staining and the development of computer software in the growing field of digital pathology. Determination of the TSR has the potential to identify patients without lymph node metastasis with a good and a poor clinical outcome and can thereby help in decision making on (neo)adjuvant treatment policy in individual cases. Determination of the TSR in routine sections is feasible and can be done with a good concordance by different observers. COMMENTS Background Colorectal cancer is one of the most common form of cancer in both men and women. The TNM staging system, the most common system to stage colorectal tumors, is used to discriminate between patients with a better and a poor prognosis, but it seems insufficiently able to predict the prognosis of the individual patient. Additional prognostic factors are desirable, because a part of the patients is overtreated and consequently exposed to a higher risk on therapy related complications. The tumor-stroma ratio (TSR), the proportion of carcinoma relative to the proportion of tumor stroma in the histopathological section through the tumor, has proven to be of prognostic value in several malignancies. Research frontiers A previous study, on a small number of rectal cancer patients, showed that a high TSR is possibly related to both a longer disease free and overall survival. In this respect, it is meaningful to explore the relevance of the TSR in a larger cohort of patients with rectal adenocarcinoma, as the authors did. Innovations and breakthroughs This paper showed that the TSR has potential as a prognostic factor for survival in surgically treated rectal cancer patients, especially in lymph node negative cases. The effect of a high TSR on survival demonstrated in this study is in line with other studies on the prognostic impact of the TSR in colorectal carcinomas and other malignancies. The present study is however the first that has identified a subgroup of patients with rectal cancer, namely lymph node metastasis negative patients with an intermediate TSR, whereby the TSR is a strong prognostic factor. Applications The determination of the TSR may contribute to stratify patients for prognosis and has the potential to contribute to decision making regarding the individual treatment policy in rectal cancer. Terminology The TSR is the proportion of carcinoma relative to the proportion of tumor stroma in the histopathological section through the tumor. The carcinoma percentage (CP) is a derivative of the TSR and is complementary to the percentage of stroma and other components, like mucus. TSR-low including the CP-values 30%, TSR-intermediate including the CP-values 40%, 50% and 60%, and TSR-high including the CP-values 70%. Peer-review The study is well designed and clearly presented and the topic of high interest for oncologists that should decide after surgery what patients will benefit more from an adjuvant treatment. REFERENCES 1 Utrecht: IKNL. Nederlandse Kankerregistratie, beheerd door IKNL Accessed April 10, Available from: URL: Sobin LH, Fleming ID. TNM Classification of Malignant Tumors, fifth edition (1997). Union Internationale Contre le Cancer and the American Joint Committee on Cancer. Cancer 1997; 80: [PMID: DOI: /(SICI) ( ) 80:93.0.CO;2-9] 3 Zlobec I, Lugli A. Prognostic and predictive factors in colorectal cancer. J Clin Pathol 2008; 61: [PMID: DOI: /jcp ] 4 Figueredo A, Coombes ME, Mukherjee S. Adjuvant therapy for completely resected stage II colon cancer. Cochrane Database Syst Rev 2008; (3): CD [PMID: DOI: / CD pub2] 5 Witz IP, Levy-Nissenbaum O. The tumor microenvironment in the post-paget era. Cancer Lett 2006; 242: 1-10 [PMID: DOI: /j.canlet ] 6 Mesker WE, Junggeburt JM, Szuhai K, de Heer P, Morreau H, Tanke HJ, Tollenaar RA. The carcinoma-stromal ratio of colon carcinoma is an independent factor for survival compared to lymph node status and tumor stage. Cell Oncol 2007; 29: [PMID: ] 7 de Kruijf EM, van Nes JG, van de Velde CJ, Putter H, Smit VT, Liefers GJ, Kuppen PJ, Tollenaar RA, Mesker WE. Tumor-stroma ratio in the primary tumor is a prognostic factor in early breast cancer patients, especially in triple-negative carcinoma patients. Breast Cancer Res Treat 2011; 125: [PMID: DOI: /s ] 8 Marsh D, Suchak K, Moutasim KA, Vallath S, Hopper C, Jerjes W, Upile T, Kalavrezos N, Violette SM, Weinreb PH, Chester KA, Chana JS, Marshall JF, Hart IR, Hackshaw AK, Piper K, Thomas GJ. Stromal features are predictive of disease mortality in oral cancer patients. J Pathol 2011; 223: [PMID: DOI: / path.2830] 9 Yanagisawa N, Li R, Rowley D, Liu H, Kadmon D, Miles BJ, Wheeler TM, Ayala GE. Stromogenic prostatic carcinoma pattern (carcinomas with reactive stromal grade 3) in needle biopsies predicts biochemical recurrence-free survival in patients after radical prostatectomy. Hum Pathol 2007; 38: [PMID: DOI: /j.humpath ] 10 West NP, Dattani M, McShane P, Hutchins G, Grabsch J, Mueller W, Treanor D, Quirke P, Grabsch H. The proportion of tumour cells is an independent predictor for survival in colorectal cancer patients. Br J Cancer 2010; 102: [PMID: DOI: / sj.bjc ] 11 Koch GG, Landis JR, Freeman JL, Freeman DH Jr, Lehnen RC. 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25 Scheer R et al. Tumor-stroma ratio in rectal cancer general methodology for the analysis of experiments with repeated measurement of categorical data. Biometrics 1977; 33: [PMID: ] 12 Joyce JA, Pollard JW. Microenvironmental regulation of metastasis. Nat Rev Cancer 2009; 9: [PMID: DOI: / nrc2618] 13 Bissell MJ, Radisky D. Putting tumours in context. Nat Rev Cancer 2001; 1: [PMID: DOI: / ] 14 Beacham DA, Cukierman E. Stromagenesis: the changing face of fibroblastic microenvironments during tumor progression. Semin Cancer Biol 2005; 15: [PMID: DOI: / j.semcancer ] 15 Zlobec I, Lugli A, Baker K, Roth S, Minoo P, Hayashi S, Terracciano L, Jass JR. Role of APAF-1, E-cadherin and peritumoral lymphocytic infiltration in tumour budding in colorectal cancer. J Pathol 2007; 212: [PMID: DOI: /path.2164] 16 Courrech Staal EF, Wouters MW, van Sandick JW, Takkenberg MM, Smit VT, Junggeburt JM, Spitzer-Naaykens JM, Karsten T, Hartgrink HH, Mesker WE, Tollenaar RA. The stromal part of adenocarcinomas of the oesophagus: does it conceal targets for therapy? Eur J Cancer 2010; 46: [PMID: DOI: /j.ejca ] 17 Courrech Staal EF, Smit VT, van Velthuysen ML, Spitzer-Naaykens JM, Wouters MW, Mesker WE, Tollenaar RA, van Sandick JW. Reproducibility and validation of tumour stroma ratio scoring on oesophageal adenocarcinoma biopsies. Eur J Cancer 2011; 47: [PMID: DOI: /j.ejca ] 18 Dutch Surgical Colorectal Audit. Jaarrapportage Accessed April 10, Available from: URL: documenten/2012/jaarrapportage% pdf 19 Marijnen CA, van de Velde CJ, Putter H, van den Brink M, Maas CP, Martijn H, Rutten HJ, Wiggers T, Kranenbarg EK, Leer JW, Stiggelbout AM. Impact of short-term preoperative radiotherapy on health-related quality of life and sexual functioning in primary rectal cancer: report of a multicenter randomized trial. J Clin Oncol 2005; 23: [PMID: DOI: /JCO ] 20 Peeters KC, Marijnen CA, Nagtegaal ID, Kranenbarg EK, Putter H, Wiggers T, Rutten H, Pahlman L, Glimelius B, Leer JW, van de Velde CJ; Dutch Colorectal Cancer Group. The TME trial after a median follow-up of 6 years: increased local control but no survival benefit in irradiated patients with resectable rectal carcinoma. Ann Surg 2007; 246: [PMID: DOI: /01. sla ce] 21 Fleming FJ, Påhlman L, Monson JR. Neoadjuvant therapy in rectal cancer. Dis Colon Rectum 2011; 54: [PMID: DOI: /DCR.0b013e31820eeb37] P- Reviewer: Cecchin E, Fogli L, Velenik V S- Editor: Ji FF L- Editor: A E- Editor: Lu YJ 474 December 15, 2017 Volume 9 Issue 12

26 Submit a Manuscript: DOI: /wjgo.v9.i World J Gastrointest Oncol 2017 December 15; 9(12): ISSN (online) META-ANALYSIS Laparoscopic vs open complete mesocolic excision with central vascular ligation for colon cancer: A systematic review and meta-analysis Ionut Negoi, Sorin Hostiuc, Ruxandra Irina Negoi, Mircea Beuran Ionut Negoi, Department of General Surgery, Emergency Hospital of Bucharest, Carol Davila University of Medicine and Pharmacy Bucharest, Bucharest , Romania Sorin Hostiuc, National Institute of Legal Medicine Mina Minovici, Carol Davila University of Medicine and Pharmacy Bucharest, Bucharest , Romania Ruxandra Irina Negoi, Department of Anatomy, Carol Davila University of Medicine and Pharmacy Bucharest, Bucharest , Romania Mircea Beuran, Emergency Hospital of Bucharest, Carol Davila University of Medicine and Pharmacy Bucharest, Bucharest , Romania Author contributions: Negoi I and Negoi RI acquisition of data; Negoi I analysis of data; Negoi I and Hostiuc S interpretation of data; Negoi I drafting the article; Hostiuc S and Negoi RI revising the article; Negoi I, Hostiuc S, Negoi RI and Beuran M final approval; Beuran M conception and design of the study, critical revision; all authors had equally contributed to this scientific paper. Conflict-of-interest statement: The authors have no conflicts to disclose. Data sharing statement: No additional data are available. Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: licenses/by-nc/4.0/ Manuscript source: Invited manuscript Correspondence to: Ionut Negoi, MD, PhD, Senior Lecturer, Department of General Surgery, Emergency Hospital of Bucharest, Carol Davila University of Medicine and Pharmacy Bucharest, No 8 Floreasca Street, Sector 1, Bucharest , Romania. Telephone: Fax: Received: May 29, 2017 Peer-review started: June 5, 2017 First decision: July 3, 2017 Revised: July 8, 2017 Accepted: September 4, 2017 Article in press: September 4, 2017 Published online: December 15, 2017 Abstract AIM To compare the effectiveness of laparoscopic complete mesocolic excision (CME) with central vascular ligation (L-CME) with its open (O-CME) counterpart. METHODS We conducted an electronic search of the PubMed/ MEDLINE, Excerpta Medica Database, Web of Science Core Collection, Cochrane Center Register of Controlled Trails, Cochrane Database of Systematic Reviews, SciELO, and Korean Journal databases from their inception until May We considered randomized controlled trials (RCTs) and controlled clinical trials (CCTs) that included patients with colonic cancer comparing L-CME and O-CME. Primary outcomes included the quality of the resected specimen (lymph nodes retrieved, complete mesocolic plane excision, tumor to arterial high tie, resected mesocolon surface). Secondary outcomes included the three-year and five-year overall and disease-free survival rates, recurrence of the disease, surgical data, and postoperative morbidity and mortality. Two authors of the review screened the methodological quality of the eligible trials and independently extracted data from individual 475 December 15, 2017 Volume 9 Issue 12

27 Negoi I et al. Laparoscopic vs open complete mesocolic excision studies. RESULTS A total of one RCT and eleven CCTs (four from Europe and seven from Asia) met the inclusion criteria for the current meta-analysis. These studies involved 1619 patients in L-CME and 1477 patients in O-CME. The L-CME was associated with the same quality of the resected specimen, with no differences regarding the retrieved lymphnodes (MD = -1.06, 95%CI: to 1.53, P = 0.42), and tumor to high tie distance (MD = cm, 95%CI: to 32.82, P = 0.13); the surface of the resected mesocolon was higher in the L-CME group (MD = cm 2, 95%CI: 9.50 to 13.99, P < 0.001). The L-CME was associated with a lower rate of blood transfusions (OR = 0.45, 95%CI: 0.27 to 0.75, P = 0.002), faster recovery of gastrointestinal function, and less postoperative overall complication rate. The L-CME approach was associated with a statistical significant better three-year overall (OR = 2.02, 95%CI: 1.31 to 3.12, P = 0.001, I 2 = 28%) and disease-free (OR = 1.45, 95% CI: 1.00 to 2.10, P = 0.05, I 2 = 0%) survival. CONCLUSION The laparoscopic approach offers the same quality of the resected specimen as the open approach in complete mesocolic excision with central vascular ligation for colon cancer. The laparoscopic complete mesocolic excision with central vascular ligation is superior in all perioperative results and at least non-inferior in long-term oncological outcomes. Key words: Colon cancer; Complete mesocolic excision; D3 lymphadenectomy; Central vascular ligation The Author(s) Published by Baishideng Publishing Group Inc. All rights reserved. Core tip: The laparoscopic complete mesocolic excision with central vascular ligation was associated with the same quality of the resected specimen, with no differences regarding the retrieved lymphnodes, and tumor to high tie distance; the surface of the resected mesocolon was higher in the laparoscopic group. Laparoscopy was associated with a lower rate of blood transfusions, faster recovery of gastrointestinal function, and less postoperative overall complication rate. The laparoscopic approach was associated with a statistical significant better three-year overall and disease-free survival. Negoi I, Hostiuc S, Negoi RI, Beuran M. Laparoscopic vs open complete mesocolic excision with central vascular ligation for colon cancer: A systematic review and meta-analysis. World J Gastrointest Oncol 2017; 9(12): Available from: URL: DOI: INTRODUCTION Complete mesocolic excision (CME) with central vascular ligation (CVL) represents an extension to the colonic cancer of the already standardized resection for rectal cancer. It adheres to the same guiding principle that sharp surgical dissection, following embryological planes, with central vascular ligation, should improve oncological outcomes [1]. Hohenberger et al [2] (2007) published the technical details of a new concept termed CME and central ligation for colonic cancer. During CME with CVL for right-sided tumors, the ileocolic and right colic vessels should be ligated at their origin from the superior mesenteric artery. Transverse colon tumors require transection of the middle colic artery at its origin. Left-sided tumors require transection of the inferior mesenteric artery (IMA) at its origin from the aorta [3]. Using CME and CVL, Hohenberger et al [4] reported a reduction of the local five-year recurrence rate from 6.5% to 3.6% and an increase in the cancer-related five-year survival rate from 82.1% to 89.1%. This specimen-oriented technique is associated with the removal of more tissue compared with standard surgery, a wider distance from the tumor to the high vascular tie (131 mm vs 90 mm, P < ), a longer length of large bowel (314 mm vs 206 mm, P < ), a wider area of removed mesentery (19657 mm 2 vs mm 2, P < ) and a greater lymph node yield (30 vs 18, P < ) [5]. These differences may partially explain the higher reported survival rates with CME and CVL. One should note the similarities between D3 lymphadenectomies, recommended as a standard of care for stage Ⅱ and Ⅲ colon cancer in Eastern countries, and Western CME [3,6]. The Japanese nomenclature includes D1 as pericolic (close to the bowel wall), D2 as intermediate (along the feeding artery), and D3 as main (at the origin of the feeding artery) lymph nodes. For right-sided tumors, a D3 lymphadenectomy requires the transection of the feeding arteries next to their origin from the superior mesenteric artery. In left-sided cancers, a D3 lymphadenectomy requires transection of the IMA close to its aortic origin [7]. Current evidence is consistent with a faster postoperative recovery for laparoscopic colectomies compared with the open approach; the former is not associated with any negative impact regarding local recurrence and survival rates. Therefore, according to the latest National Comprehensive Cancer Network guidelines, the laparoscopic approach is preferred given access to a surgeon with experience in advanced minimally invasive procedures [8]. The objective of this systematic review and metaanalysis is to summarize the current evidence regarding laparoscopic CME (L-CME) and to compare its effectiveness with its open (O-CME) counterpart. MATERIALS AND METHODS This systematic review and meta-analysis was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement [9]. 476 December 15, 2017 Volume 9 Issue 12

28 Negoi I et al. Laparoscopic vs open complete mesocolic excision Electronic search, study selection, data extraction, and quality assessment was performed independently by two reviewers. Data sources and search strategy We conducted an electronic search to identify all published randomized controlled trials (RCTs) and controlled clinical trials (CCTs) using the following databases: United States National Library of Medicine - National Institutes of Health PubMed/MEDLINE, EMBASE, Web of Science Core Collection, Cochrane Center Register of Controlled Trails (CENTRAL), Cochrane Database of Systematic Reviews, SciELO, and Korean Journal databases from their inception until May We did not use any language restrictions. The most recent search in PubMed was performed in May We constructed the search strategy using various combinations of terms related to CME or D3 lymphadenectomy using an open or laparoscopic approach to colon cancer. We used in different combinations the following key words: colon, cancer, complete mesocolic excision, central vascular ligation, D3 lymphadenectomy, minimally invasive, laparoscopy, open, surgery, colectomy and resection. These words were identified as truncated words in the title, abstract, or in the medical subject headings (MeSH). We additionally used electronic and manual cross-referencing to find other relevant sources. The search strategy used in PubMed/Medline was: [colon (MeSH Terms)] OR colonic (Title/Abstract) OR lower intestinal (Title/Abstract) OR large bowel (Title/Abstract) AND cancer (MeSH Terms) OR neoplasia (Title/Abstract) OR neoplasm (Title/Abstract) OR tumor (Title/Abstract) AND laparoscopy(mesh Terms) OR minimally invasive (Title/Abstract) OR laparoscopic (Title/Abstract) AND complete mesocolic excision (Title/ Abstract) OR central vascular ligation (Title/Abstract) OR D3 lymphadenectomy (Title/Abstract). Trial selection Study eligibility criteria: We considered RCTs and CCTs comparing open with laparoscopic CME or D3 lymphadenectomy as eligible for inclusion if they included patients with colonic cancer. Outcome measures Primary outcome: Quality of the resected specimen (lymph nodes retrieved, complete mesocolic plane excision, tumor to arterial high tie, resected mesocolon surface). Secondary outcomes: Three-year and five-year overall and disease-free survival rates, recurrence of the disease, surgical data (operation time, length of the abdominal incision, conversion rate), intraoperative complications, blood loss, postoperative complications (anastomotic leakage, wound infections, overall complications), length of hospital stay, thirty-day mortality, immunologic response, quality of life, and cost. Data extraction Two authors [10] (Negoi and Hostiuc) assessed the methodological quality of the eligible trials and independently extracted data from individual studies using a dataextraction form. We extracted the following data: Year of publication, source, title, first author, contact address, criteria for patient inclusion and exclusion, sample size, baseline characteristics, and patient characteristics including mean age, sex ratio, location of the tumor, number of patients assigned to each treatment group, and details of the intervention regimens. We registered the following outcomes: One-, three- and five-year overall and disease-free survival rates, number of removed lymph nodes, length of the resected colon, resection of the mesocolic plane, operation time, length of hospital stay, number and frequency of postoperative complications, and quality of life. Assessment of risk of bias To assess the risk of bias, we used the Cochrane Collaboration tool for RCTs. This tool grades the random sequence generation, allocation concealment, blinding of participant and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting, and other biases [11]. To evaluate the non-randomized trials, we used the methodological index of nonrandomized studies (MINORS) [12]. We scored all of the 12 methodological items for non-randomized comparative studies as follows: 0 - not reported; 1 - reported but inadequate; or 2 - reported and adequate. The global ideal score for comparative (non-comparative) studies was 24. Statistical analysis For statistical analysis, we used Review Manager Software (The Nordic Cochrane Centre, Copenhagen, Denmark) [11] provided by the Cochrane Collaboration and OpenMetaAnalyst [13] with metaphor package [14] as statitstical softwares. We selected the mean difference (MD) as an effect measure for continuous data and the odds ratio (OR) for dichotomous data; we also reported the 95%CI. In cases of continuous data presented as median and range, we estimated the mean and standard deviation according to the methods described by Hozo et al [15]. We used Chi-square and I 2 statistics to assess the studies heterogeneity and explain the total variation observed between the studies that be generated by the differences between the trials rather than the sampling error (chance). An I 2 value 25% indicates less heterogeneity, an I 2 value > 25% but 75% indicates a moderate heterogeneity, and I 2 values > 75% indicate higher heterogeneity [16]. We explored the reasons behind the statistical heterogeneity using sensitivity analyses and the exclusion of specific studies. We used fixed-effect model analysis for outcomes with low heterogeneity. If we found clinical heterogeneity between included studies due to differences with respect to eligibility criteria (study population), the type of surgical technique, and lacking or differing definitions of outcomes, we performed meta-analysis by applying a random- 477 December 15, 2017 Volume 9 Issue 12

29 Negoi I et al. Laparoscopic vs open complete mesocolic excision Identification Records identified through database searching (n = 1576) Additional records identified through other sources (n = 3) Records after duplicates removed (n = 1292) Screening Records screened (n = 1292) Records excluded (n = 1118) Eligibility Full-text articles assessed for eligibility (n = 174) Full-text articles excluded with reasons (n = 162) Studies included in qualitative synthesis (n = 12, 1 RCT and 11 CCTs) Included Studies included in qualitative synthesis (metaanalysis) (n = 12, 1 RCT and 11 CCTs) Figure 1 Flow diagram of the systematic literature search and study selection according to prisma statement. RCT: Randomized control trial; CCT: Controlled clinical trial. effect model (the DerSimonian-Laird method) [17]. We used Begg s funnel plot and Egger s test for assessing publication bias [18]. The statistical significance was defined as P < 0.1 in Egger s test and P < 0.05 for the other statistical tests. To correct possible publication bias, we performed trim and fill analysis [19]. The statistical methods of this study were reviewed by Sorin Hostiuc from the Department of Legal Medicine and Bioethics, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania. RESULTS Description of studies Results of the search: The initial electronic and manual literature searches revealed 174 full-text articles. A total of one RCT (from Japan) [20,21] and eleven CCTs (four from Europe and seven from Asia) [22-32] met the inclusion criteria for the qualitative and quantitative (meta-analysis) synthesis; these studies involved 1619 patients in L-CME and 1477 patients in O-CME. Eleven studies were published in English and one in Chinese. The reasons for exclusion in each stage of the process are shown in Figure 1. Included studies: The characteristics of the included studies are summarized in Table 1. All of the studies were published between 2012 and 2016, the RCT being published in The sample size of the studies ranged from 23 to 533 patients. The CME or D3 lymphadenectomy was defined as dissection along the Told s fascia space and a high (apical or central) ligation of the feeding vessel. Colonic mobilization was conducted using a medial-tolateral or a lateral-to-medial approach according to the surgeon s preference. For right-sided tumors, the vascular pedicles were divided at their origin together with removal of the draining lymph nodes along the border of the superior mesenteric vein. For left-sided tumors, removal of the central lymph nodes from the origin of the inferior mesenteric artery was performed with high ligation or with preservation of the left colic artery. In the JCOG 0404 study, the accredited surgeons had completed more than 30 laparoscopic and 30 open colorectal resections [20]. In all of the other studies, the procedures were performed or supervised by colorectal surgeons. Conversion to laparotomy was defined as the extension of the abdominal incision more than eight cm or as the inability to complete the dissection fully laparoscopically. The reported rate 478 December 15, 2017 Volume 9 Issue 12

30 Negoi I et al. Laparoscopic vs open complete mesocolic excision Table 1 Characteristics of the included studies Ref. Country of origin Study type Study period Female (number, L/O) Mean age (yr, L/O) Intervention (L-CME) right/ transverse/left location of the tumor Control (O-CME) right/transverse/ left location of the tumor Adjuvant chemotherapy Kim et al [23], 2016 Storli et al [22], 2016 Huang et al [24], 2015 Yamamoto et al [20], 2014 Munkedal et al [25], 2014 Bae et al [27], 2014 Han et al [26], 2014 Zhao et al [28], 2014 Cong et al [29], 2014 Storli et al [30], 2013 Gouvas et al [31], 2012 Sun et al [32], 2012 South Korea Norway China Japan Denmark South Korea China China China Norway Greece China Case control, unicentre, prospective database Prospective non RT, unicentre Case control, unicentre RCT, multicentre Prospective nonrt, unicentre Case control, unicentre Case control, unicentre Case control, multicentre Case control, unicentre Prospective nonrt, unicentre Prospective nonrt, multicentric Case control, unicentre /44 69/67 116/0/0 99/0/0 L-CME = 68 pts (58.62%), O-CME = 78 pts (78.78%), recommended to all stage Ⅱ and Ⅲ /13 73/23 0/33/0 0/23/0 L-CME = 8 (61.5%), O-CME = 5 (62.5%), all stage Ⅲ below 75 yr /21 56/55 53/0/0 49/0/0 NR /215 64/64 144/0/ /0/368 NR, recommended for all stage Ⅲ / / /0/53 41/0/38 NR /38 64/65 73/12/0 76/9/0 All stage Ⅲ and Ⅱ with poor prognosis /67 67/65 177/0/0 147/0/0 NR, recommended for high risk stage Ⅱ and stage Ⅲ / / /30/0 65/36/0 NR, recommended for high risk stage Ⅱ and stage Ⅲ / / /0/0 82/0/0 NR / / /18/60 2 pts - multiple 35/44/42 All stage Ⅲ below 75 yr / /66.3 7/9/33 9/9/23 NR / / /7/91 43/9/74 NR, according to stage L-CME: Laparoscopic complete mesocolic excision; O-CME: Open complete mesocolic excision; RT: Randomized control trial; Non RT: Non randomized control trial; L/O: Laparoscopy/open groups; NR: Not reported. of conversion to laparotomy was between 2.82% and 7.6% [20,22-32]. Transverse colon cancers were excluded from the JCOG 0404 study [20]. Storli et al [30] performed 9 (7.3%) transverse colectomies in the open approach but none in the laparoscopic group. In a second paper, Storli et al [22] published their experience regarding CME only in transverse colon cancer. Gouvas et al [31] managed all of the transverse colon cancers using an extended right hemicolectomy. Munkedal et al [25] excluded all cancers in the transverse colon or flexures from their analysis. Bae et al [26], Han et al [27], and Zhao et al [28] managed all cases by a right or extended right hemicolectomy. All studies exhibited remarkable similar exclusion criteria: Stage Ⅳ disease and emergency surgery. All of the studies described the technique of laparoscopic CME. Perioperative care was not described in most trials. The patient demographics and baseline clinical data were similar between the treatment groups; the L-CME group exhibited a mean age of years, and the O-CME group exhibited a mean age of years. Women comprised 46.20% and 41.23% of the L-CME and O-CME patients, respectively. None of the studies were blinded, and all of the studies were powered to demonstrate the non-inferiority of the laparoscopic approach. Excluded studies: We excluded all studies in which the surgical technique did not comply with CME or D3 lymphadenectomy principles [33-42]. We also excluded studies based on the hand-assisted laparoscopic technique [43,44]. Due to the probability of overlapping patients, we have excluded first report of Kim et al [45] which includes only T4 patients. Risk of bias in the included studies The risk of bias in the one Japanese RCT was low in all domains [20]. Although blinding of patients and medical personnel was not performed in either trial, the endpoints were considered to be objective, particularly when they were supported by photos. The prospective and 479 December 15, 2017 Volume 9 Issue 12

31 Negoi I et al. Laparoscopic vs open complete mesocolic excision Table 2 Quality assessment of included non-randomized controlled trials Quality evaluation criteria Kim et al [23], 2016 Storli et al [22], 2016 Storli et al [30], 2016 Huang et al [24], 2015 Munkedal et al [25], 2014 Bae et al [27], 2014 Han et al [26], 2014 Zhao et al [28], 2014 Cong et al [29], 2014 Gouvas et al [31], 2012 Sun et al [32], 2012 Clear stated aim Inclusion of consecutive patients Prospective data collection Endpoints appropriate to the study aim Unbiased assessment of study end-point Appropriate follow-up period Loss to follow-up less than 5% Prospective calculation of the study size Adequate group control Contemporary groups Baseline equivalence Adequate statistical analysis Total : Non-reported; 1: Reported but inadequate; 2: Reported and adequate. retrospective non-randomized studies had good MINORS scores, although the risk of selection, performance, and detection bias was high (Table 2). As expected, the prospective observational studies [22-23,25,30,31] had a higher methodological quality comparing with the retrospective studies [24,26-29]. Effects of intervention Overall survival: Three-year overall survival was reported by four studies, including 1010 patients (Table 3). The laparoscopic approach was associated with a statistical significant better three-year overall survival, with an OR of 2.02 (95%CI: 1.31 to 3.12, P = 0.001, I 2 = 28%). The five-year overall survival was reported by three studies, with a high heterogeneity between them (I 2 = 63%). The combined data revealed no statistical significant differences between the L-CME and O-CME (OR = 0.77, P = 0.38, 95%CI: 0.44 to 1.37) (Figure 2). Meta-regression of studies on three-year overall survival according to the number of included patients revealed a trend, although not statistical significant (omnibus P = 0.127), for decreasing of the size of the effect with increasing the number of patients (Figure 3A). The subgroup analysis of studies that include or not only right sided colon cancers, reveled statistical significant results irrespective of that (P = and P = 0.018, respectively) (Figure 3B). On the other hand, the cumulative meta-analysis showed a progressively increasing of the size effect while experience is accumulating (Figure 3C). Disease-free survival Three studies, with a total of 686 patients, reported the three-year DFS with a low heterogeneity between them (I 2 = 0%). However, to adjust for possible methodological differences we used the random-effects model, which revealed that the laparoscopic approach is associated with a statistical significant better threeyear DFS (OR = 1.45, 95%CI: 1.00 to 2.10, P = 0.05) (Figure 4). Meta-regression of studies on three-year overall survival according to the number of the included patients revealed a trend, although not statistical significant (Omnibus P = 0.718), for decreasing of the size of the effect with increasing the number of patients (Figure 5). Local and distant recurrences The local recurrence rate was presented by five studies, including 1233 patients. In the fixed-effect metaanalysis there were no statistical significant differences between L-CME and O-CME (OR = 0.67, 95%CI: 0.38 to 1.17, P = 0.16, I 2 = 0%) (Figure 6). The distant recurrence rate was presented by four studies, with a moderate heterogeneity between them (I 2 = 40%). In the random-effects meta-analysis there were no statistical significant differences between the two groups (OR = 0.98, 95%CI: 0.61 to 1.58, P = 0.94). Using Egger s test, no publication bias was found for local (t = 0.22, P = 0.42) or distant recurrences (t = 0.38, P = 0.36). The port size metastasis rate was reported by two studies including 494 patients, with a low heterogeneity between them (I 2 = 0%). In the fixed-effect analysis model there was no difference regarding the port size metastasis rate between laparoscopic and open CME (OR = 1.52, 95%CI: 0.20 to 11.42, P = 0.69). Quality of the resected specimen Standardized evaluation of the resected specimen and grading its quality are objective measures that predict recurrence rate and survival. These data are correlated with the accuracy of the surgical technique. Lymphnodes retrieved Ten studies reported the number of retrieved lymph nodes for 1376 L-CME patients and 1271 O-CME pa- 480 December 15, 2017 Volume 9 Issue 12

32 Negoi I et al. Laparoscopic vs open complete mesocolic excision Table 3 Results of meta-analysis comparing laparoscopic with open complete mesocolic excision for colon cancer Outcome or subgroups No. of Studies Participants Statistical method (95%CI) Effect estimate (95%CI) P value Heterogeneity P, I2 (%) Survival and recurrences Overall survival OR (M-H, random) 1.32 (0.83, 2.10) , 70 Three-year OR (M-H, random) 2.02 (1.31, 3.12) , 28 Five-year OR (M-H, random) 0.77 (0.44, 1.37) , 63 Disease free survival OR (M-H, random) 1.15 (0.70, 1.87) , 54 Three-year OR (M-H, random) 1.45 (1.00, 2.10) , 0 Five-year OR (M-H, random) 0.50 (0.24, 1.05) 0.07 NA Local recurrences OR (M-H, fixed) 0.67 (0.38, 1.17) , 0 One-year OR (M-H, fixed) 0.52 (0.20, 1.35) , 7 Five-year OR (M-H, fixed) 0.77 (0.38, 1.54) , 0 Distant recurrences OR (M-H, random) 0.98 (0.61, 1.58) , 40 Three-year OR (M-H, random) 1.28 (0.54, 3.03) 0.58 NA Five-year OR (M-H, random) 0.90 (0.48, 1.69) , 57 Port site metastasis OR (M-H, fixed) 1.52 (0.20, 11.42) , 0 Quality of the resected specimen Lymphnodes retrieved MD (IV, random) (-3.65, 1.53) 0.42 < 0.001, 92 RCTs MD (IV, random) 1.00 (-0.34, 2.34) 0.14 NA NRCTs MD (IV, random) (-4.42, 1.78) 0.40 < 0.001, 92 Lymphnodes retrieved MD (IV, random) (-3.65, 1.53) 0.42 < 0.001, 92 < 100 patients MD (IV, random) (-8.69, 2.33) 0.26 < 0.001, 85 > 100 patients MD (IV, random) 0.29 (-1.64, 2.21) 0.77 < 0.001, 83 Lymphnodes retrieved MD (IV, random) (-3.65, 1.53) 0.42 < 0.001, 92 Europe MD (IV, random) (-8.31, 1.64) 0.19 < 0.001, 90 Asia MD (IV, random) 0.56 (-1.33, 2.46) 0.56 < 0.001, 77 Tumor to arterial high tie (mm) MD (IV, random) (-4.30, 32.82) 0.13 < 0.001, 92 Resected mesocolon surface (cm 2 ) MD (IV, fixed) (9.50, 13.99) < , 0 Complete mesocolic plane excision 1 90 OR (M-H, fixed) 0.77 (0.20, 2.96) 0.71 NA Operative data Duration of surgery MD (IV, random) (5.06, 47.46) 0.02 < 0.001, 94 Incision length (cm) MD (IV, random) (-14.35, ) < , 0 Blood loss (ml) MD (IV, random) (-78.57, ) < < 0.001, 89 Transfusion requirement OR (M-H, random) 0.45 (0.27, 0.75) , 0 Intraoperative morbidity OR (M-H, fixed) 2.12 (0.95, 4.72) 0.07 NA Postoperative course Time to first flatus (d) MD (IV, random) (-1.46, -0.34) < 0.001, 97 Time to liquid diet (d) MD (IV, random) (-2.93, -0.74) < 0.001, 98 Short-term morbidity and mortality Thirty-day overall morbidity OR (M-H, fixed) 0.57 (0.46, 0.71) < , 0 RCTs OR (M-H, fixed) 0.66 (0.49, 0.89) NA NRCTs OR (M-H, fixed) 0.49 (0.36, 0.68) < , 0 Wound complications OR (M-H, fixed) 0.43 (0.30, 0.61) < , 0 Postoperative bleeding OR (M-H, fixed) 1.20 (0.46, 3.12) , 0 Pneumonia OR (M-H, random) 0.61 (0.20, 1.84) , 32 Anastomotic leakage OR (M-H, fixed) 0.82 (0.54, 1.25) , 0 Need for reoperation OR (M-H, fixed) 0.59 (0.28, 1.23) , 0 Thirty-day mortality OR (M-H, fixed) 0.42 (0.16, 1.12) , 0 Hospital stay (d) MD (IV, random) (-5.87, -2.28) < < 0.001, 91 M-H: Mantel-haenszel analysis method; IV: Inverse variance analysis method; RCT: Randomized control trial; NRCs: Non-randomized control trials; MD: Mean difference; OR: Odds ratio; NA: Not applicable. tients. There was a high heterogeneity between the studies (I 2 = 92%). In the random-effects model, we found no statistically significant mean difference between L-CME and O-CME (MD = -1.06, 95%CI: to 1.53, P = 0.42) (Figure 7). In order to address the observed heterogeneity, we performed subgroup analysis according to the number of included patients (less or more than 100 patients in each group) and the geographical location of the study (Europe and Asia). The subgroup analysis revealed a high heterogeneity between studies with less than (I 2 = 85%) or more (I 2 = 83%) than 100 patients into laparoscopy or open group. The results remained with no statistical significance into the two subgroups. Studies coming from Europe showed a high heterogeneity (I 2 = 90%) and with no differences regarding the number of retrieved lymphnodes (P = 0.19). Studies published in Asia had also a high heterogeneity (I 2 = 77%), and no statistical significant difference between L-CME and O-CME (P = 0.56). Meta-regression of retrieved lymphnodes according to the number of patients revealed that the equivalence between laparoscopic and open approach is stronger with the increased experience in laparoscopic approach (number of the included patients - omnibus P 481 December 15, 2017 Volume 9 Issue 12

33 Negoi I et al. Laparoscopic vs open complete mesocolic excision Laparoscopy Open Odds ratio Odds ratio Study or subgroup Events Total Events Total Weight M-H, random, 95%CI M-H, random, 95%CI 3-year Han % 1.48 [0.85, 2.57] Kim % 4.64 [1.78, 12.09] Storli % 1.83 [0.91, 3.67] Zhao % 2.05 [0.89, 4.75] Subtotal (95%CI) % 2.02 [1.31, 3.12] Total events Heterogeneity: Tau 2 = 0.06; c 2 = 4.17, df = 3 (P = 0.24); I 2 = 28% Test for overall effect: Z = 3.19 (P = 0.001) 5-year Bae % 0.36 [0.15, 0.88] Han % 1.17 [0.73, 1.87] Sun % 0.80 [0.47, 1.37] Subtotal (95%CI) % 0.77 [0.44, 1.37] Total events Heterogeneity: Tau 2 = 0.16; c 2 = 5.37, df = 2 (P = 0.07); I 2 = 63% Test for overall effect: Z = 0.88 (P = 0.38) Total (95%CI) % 1.32 [0.83, 2.10] Total events Heterogeneity: Tau 2 = 0.26; c 2 = 20.27, df = 6 (P = 0.002); I 2 = 70% Test for overall effect: Z = 1.18 (P = 0.24) Test for subgroup differences: c 2 = 6.93, df = 1 (P = 0.008); I 2 = 85.6% Favours open Favours Laparoscopy Figure 2 Meta-analysis of studies on overall survival of patients undergoing laparoscopic vs open complete mesocolic excision with central vascular ligation excision for colon cancer. A 1.5 Log odds ratio B Studies Estimate (95%CI) Ev/Trt Ev/Ctrl Patients number Han (0.848, 2.575) 148/ /147 Kim (1.782, ) 110/116 79/99 Subgroup Yes (I 2 = NA, P = 0.042) (1.277, 3.258) 258/ /246 Storli (0.908, 3.675) 113/128 99/123 Zhao (0.886, 4.750) 109/119 85/101 Subgroup Yes (I 2 = NA, P = 0.835) (1.119, 3.278) 222/ /224 Overall (I 2 = NA, P = 0.243) (1.394, 2.825) 480/ /470 C Studies Estimate (95%CI) Ev/Trt Ev/Ctrl Han (0.908, 3.675) 113/128 99/123 Kim (0.848, 2.575) 148/ /147 Storli (0.886, 4.750) 109/119 85/101 Zhao (1.782, ) 110/116 79/99 Overall (I 2 = NA, P = 0.243) (1.394, 2.825) 480/ / Odds ratio (log scale) Odds ratio (log scale) Figure 3 Results of statistical analysis. A: Meta-regression on three-year overall survival according with the number of included patients in each study, of patients undergoing laparoscopic vs open complete mesocolic excision with central vascular ligation excision for colon cancer; B: Subgroup meta-analysis according with the selection of patients with only right colon cancers (Yes group) or all-localizations colon cancer (No group); C: Cumulative meta-analysis according to the year of publishing for each study. 482 December 15, 2017 Volume 9 Issue 12

34 Negoi I et al. Laparoscopic vs open complete mesocolic excision Laparoscopy Open Odds ratio Odds ratio Study or subgroup Events Total Events Total Weight M-H, random, 95%CI M-H, random, 95%CI 3-year Kim % 1.45 [0.75, 2.80] Storli % 1.32 [0.73, 2.39] Zhao % 1.64 [0.84, 3.21] Subtotal (95%CI) % 1.45 [1.00, 2.10] Total events Heterogeneity: Tau 2 = 0.00; c 2 = 0.22, df = 2 (P = 0.89); I 2 = 0% Test for overall effect: Z = 1.98 (P = 0.05) 5-year Bae % 0.50 [0.24, 1.05] Subtotal (95%CI) % 0.50 [0.24, 1.05] Total events Heterogeneity: Not applicable Test for overall effect: Z = 1.82 (P = 0.07) Total (95%CI) % 1.15 [0.70, 1.87] Total events Heterogeneity: Tau 2 = 0.14; c 2 = 6.55, df = 3 (P = 0.09); I 2 = 54% Test for overall effect: Z = 0.55 (P = 0.58) Test for subgroup differences: c 2 = 6.32, df = 1 (P = 0.01); I 2 = 84.2% Favours open Favours Laparoscopy Figure 4 Meta-analysis of studies on disease-free survival of patients undergoing laparoscopic vs open complete mesocolic excision with central vascular ligation excision for colon cancer Log odds ratio Patients number Figure 5 Meta-regression of studies on three-year disease-free survival of patients undergoing laparoscopic vs open complete mesocolic excision with central vascular ligation excision for colon cancer. = 0.314, Figure 8A; and year of publishing of the study, Figure 8B). Tumor to high tie distance The mean distance from the tumor to the arterial high tie was reported by two studies that included 132 patients in the L-CME group and 120 patients in the O-CME group; we noted high heterogeneity among the studies (I 2 = 92%). Using the random-effects model, we did not find any statistically significant difference between the L-CME and O-CME groups (MD = cm, 95%CI: to 32.82, P = 0.13) (Figure 9). Surface of the resected mesocolon The surface of the resected mesocolon was reported by two studies with 132 patients in the L-CME group and 120 patients in the O-CME group. The surface of the resected mesocolon was larger in the L-CME group (MD = cm 2, 95%CI: 9.50 to 13.99, P < 0.001) (Figure 10). Complete mesocolic plane excision rate One study reported the rate of complete mesocolic plane excision, with no statistically significant difference between the laparoscopic and open approach (OR = 0.77, 95%CI: 0.20 to 2.96). Duration of surgery The duration of surgery was reported by seven studies, with a high heterogeneity between data (I 2 = 94%). The L-CME group had a longer duration of surgery with a mean difference of min (95%CI: 5.06 to 47.46, P = 0.02). Using Egger s test, no publication bias was found (t = 0.71, P = 0.26). Incision length The incision length was reported by two studies, including 586 patients in the L-CME group and 573 patients in the 483 December 15, 2017 Volume 9 Issue 12

35 Negoi I et al. Laparoscopic vs open complete mesocolic excision Laparoscopy Open Odds ratio Odds ratio Study or subgroup Events Total Events Total Weight M-H, fixed, 95%CI M-H, fixed, 95%CI 3-year Kim % 0.27 [0.05, 1.38] Storli % 0.79 [0.24, 2.67] Subtotal (95%CI) % 0.52 [0.20, 1.35] Total events 7 12 Heterogeneity: c 2 = 1.07, df = 1 (P = 0.30); I 2 = 7% Test for overall effect: Z = 1.35 (P = 0.18) 5-year Bae % 0.39 [0.07, 2.04] Han % 1.40 [0.33, 5.94] Sun % 0.76 [0.30, 1.92] Subtotal (95%CI) % 0.77 [0.38, 1.54] Total events Heterogeneity: c 2 = 1.31, df = 2 (P = 0.52); I 2 = 0% Test for overall effect: Z = 0.74 (P = 0.46) Total (95%CI) % 0.67 [0.38, 1.17] Total events Heterogeneity: c 2 = 2.73, df = 4 (P = 0.60); I 2 = 0% Test for overall effect: Z = 1.41 (P = 0.16) Test for subgroup differences: c 2 = 0.42, df = 1 (P = 0.52); I 2 = 0% Favours laparoscopy Favours open Figure 6 Meta-analysis of studies local recurrence rate of patients undergoing laparoscopic vs open complete mesocolic excision with central vascular ligation excision for colon cancer. Laparoscopy Open Mean difference Mean difference Study or subgroup Mean SD Total Mean SD Total Weight IV, random, 95%CI IV, random, 95%CI RCTs JCOG % 1.00 [-0.34, 2.34] Subtotal (95%CI) % 1.00 [-0.34, 2.34] Heterogeneity: Not applicable Test for overall effect: Z = 1.46 (P = 0.14) NRCTs Bae % [-5.74, 3.74] Gouvas % [-11.08, -6.92] Han % 3.80 [2.17, 5.43] Huang % 1.00 [-1.14, 3.15] Kim % [-7.10, -0.90] Munkedal % [-8.43, 2.43] Storli % [-3.60, 0.20] Storli % 1.90 [-4.30, 8.10] Zhao % 0.50 [-1.90, 2.90] Subtotal (95%CI) % [-4.42, 1.78] Heterogeneity: Tau 2 = 19.39; c 2 = , df = 8 (P < ); I 2 = 92% Test for overall effect: Z = 0.84 (P = 0.40) Total (95%CI) % [-3.65, 1.53] Heterogeneity: Tau 2 = 14.75; c 2 = , df = 9 (P < ); I 2 = 92% Test for overall effect: Z = 0.80 (P = 0.42) Test for subgroup differences: c 2 = 1.82, df = 1 (P = 0.18); I 2 = 44.9% Favours open Favours laparoscopy Figure 7 Meta-analysis of studies on lymphnodes retrieved of the specimen of patients undergoing laparoscopic vs open complete mesocolic excision with central vascular ligation excision for colon cancer. O-CME group. Patients from the laparoscopic group had a shorter incision, with a mean difference of cm (95%CI: to , P < 0.001). Blood loss Intraoperative blood-loss data were presented by five studies, with 964 and 904 patients in the L-CME and O-CME, respectively. Due to the high heterogeneity of the data (I 2 = 89%) we have used the random-effect analysis. The laparoscopic approach was associated with statistical significant lower intraoperative bleeding, with a mean difference of ml (95%CI: to , P < 0.001). Using Egger s test, no publication bias was found (t = 0.17, P = 0.44). Should be noted the clinical significance of lower intraoperative blood loss associated with laparoscopic approach, which was translated in a lower need for transfusion rate (OR = 0.45, 95%CI: 0.27 to 0.75, P = 0.002). Two studies, 484 December 15, 2017 Volume 9 Issue 12

36 Negoi I et al. Laparoscopic vs open complete mesocolic excision A 5 Mean difference Patients B Cumulative studies Cumulative estimate Gouvas ( , ) + Storlin ( , 1.817) + JCOG (-8.865, 2.480) + Bae (-7.505, 2.068) + Han (-5.643, 2.925) + Huang (-4.519, 2.611) + Kim (-4.621, 1.880) + Munkedal (-4.576, 1.518) + Storli (-4.136, 1.640) + Zhao (-3.649, 1.529) Mean difference Figure 8 Results of statistical analysis. A: Meta-regression of studies on lymphnodes retrieved of the specimen according to the number of the included patients in each study; B: Cumulative meta-analysis according to the year of publishing of the article of patients undergoing laparoscopic vs open complete mesocolic excision with central vascular ligation excision for colon cancer. Laparoscopy Open Mean difference Mean difference Study or subgroup Mean SD Total Mean SD Total Weight IV, random, 95%CI IV, random, 95%CI NRCTs Gouvas % 4.00 [-6.58, 14.58] Munkedal % [21.84, 24.16] Subtotal (95%CI) % [-4.30, 32.82] Heterogeneity: Tau 2 = ; c 2 = 12.25, df = 1 (P = ); I 2 = 92% Test for overall effect: Z = 1.51 (P = 0.13) Total (95%CI) % [-4.30, 32.82] Heterogeneity: Tau 2 = ; c 2 = 12.25, df = 1 (P = ); I 2 = 92% Test for overall effect: Z = 1.51 (P = 0.13) Test for subgroup differences: Not applicable Favours open Favours laparoscopy Figure 9 Meta-analysis of studies on tumor to arterial high tie (mm) distance of the specimen of patients undergoing laparoscopic vs open complete mesocolic excision with central vascular ligation excision for colon cancer. Laparoscopy Open Mean difference Mean difference Study or subgroup Mean SD Total Mean SD Total Weight IV, fixed, 95%CI IV, fixed, 95%CI NRCTs Gouvas % [-68.69, 54.69] Munkedal % [9.52, 14.02] Subtotal (95%CI) % [9.50, 13.99] Heterogeneity: c 2 = 0.36, df = 1 (P = 0.55); I 2 = 0% Test for overall effect: Z = (P < ) Total (95%CI) % [9.50, 13.99] Heterogeneity: c 2 = 0.36, df = 1 (P = 0.55); I 2 = 0% Test for overall effect: Z = (P < ) Test for subgroup differences: Not applicable Favours open Favours laparoscopy Figure 10 Meta-analysis of studies on resected mesocolon surface (cm 2 ) of the specimen of patients undergoing laparoscopic vs open complete mesocolic excision with central vascular ligation excision for colon cancer. 485 December 15, 2017 Volume 9 Issue 12

37 Negoi I et al. Laparoscopic vs open complete mesocolic excision Laparoscopy Open Odds ratio Odds ratio Study or subgroup Events Total Events Total Weight M-H, random, 95%CI M-H, random, 95%CI JCOG % 0.65 [0.18, 2.33] Kim % 0.42 [0.24, 0.74] Subtotal (95%CI) % 0.45 [0.27, 0.75] Total events Heterogeneity: Tau 2 = 0.00; c 2 = 0.38, df = 1 (P = 0.54); I 2 = 0% Test for overall effect: Z = 3.06 (P = 0.002) Favours laparoscopy Favours open Figure 11 Meta-analysis of studies on transfusion requirements of patients undergoing laparoscopic vs open complete mesocolic excision with central vascular ligation excision for colon cancer. including a total of 1272 patients, reported the need for blood transfusions, with a low heterogeneity between them (I 2 = 0%) (Figure 11). Recovery of gastrointestinal function The time to first flatus was reported by four studies, including 914 and 857 patients in the L-CME and O-CME, respectively. In the random-effects meta-analysis the laparoscopic approach was associated with a shorter time interval to first flatus, with a mean difference of 0.90 d (95%CI: to -0.34, P = 0.002, I 2 = 97%). The time to liquid diet was reported by five studies, with a high heterogeneity between them (I 2 = 98%). The time to liquid diet was shorter for the L-CME patients, with a mean difference of 1.84 d (95%CI: to -0.74, P = 0.001). Short-term morbidity and mortality Seven studies presented the postoperative overall morbidity, and these studies included 1116 patients in the L-CME group and 1028 patients in the O-CME group. There was low statistical heterogeneity among the studies (I 2 = 0%). The L-CME procedure was associated with a lower postoperative morbidity (OR = 0.57, 95%CI: 0.46 to 0.71, P < 0.001) (Figure 12). Wound complications, reported by eight studies, were significantly less frequent in the L-CME group (OR = 0.43, 95%CI: 0.30 to 0.61, P < 0.001). There was no statistical heterogeneity among the studies (I 2 = 0%). There was no difference between the two groups regarding postoperative bleeding (OR = 1.20, 95%CI: 0.46 to 3.12, P = 0.71), anastomotic leakage (OR = 0.82, 95%CI: to 1.25, P = 0.36), need for reoperation (OR = 0.59, 95%CI: 0.28 to 1.23, P = 0.16), and pulmonary complications (OR = 0.61, 95%CI: 0.20 to 1.84, P = 0.38). The 30-d mortality was reported by six studies with 1158 patients in the L-CME group and 1079 patients in the O-CME group. There was low heterogeneity among the studies (I 2 = 0%). In the fixed-effects meta-analysis we observed no statistically significant difference between the L-CME and O-CME groups (OR = 0.42, 95%CI: 0.16 to 1.12). Nine studies, with 1340 and 1233 patients in the L-CME and O-CME, respectively reported the hospital stay. There was a high heterogeneity between the studies (I 2 = 91%). In the random-effects metaanalysis we found a statistical significant lower hospital stay for laparoscopic group, with a mean difference of 4.07 d (95%CI: to -2.28, P < 0.001). Risk of bias across studies We conducted sensitivity analysis to assess statistical heterogeneity based on excluding specific studies with a high risk of bias (Figure 13). There were no relevant changes in the overall effects of the quantitative synthesis. Our analysis of the funnel plots reveals no significant asymmetries for the studied outcomes (Figures 14 and 15). DISCUSSION Our meta-analysis revealed that laparoscopic CME with CVL for colon cancer offers the same quality of the resected specimen as the open approach, being superior in all perioperative results and at least non-inferior in long-term oncological outcomes. Although not addressed the complete mesocolic excision or D3 lymphadenectomy technique, the equivalence of laparoscopy in terms of resected lymphnodes was showed in four large, multicenter, studies-clinical Outcomes of Surgical Therapy (COST), Conventional vs Laparoscopic-Assisted Surgery in Colorectal Cancer (CLASSIC), Colon Cancer Laparoscopic or Open Resection I (COLOR I), and the Australasian Randomized Clinic Study Comparing Laparoscopic and Conventional Open Surgical Treatments for Colon Cancer (ALCCaS); the mean number of resected lymph nodes was in the laparoscopic group and in the open group [40-42]. An RCT from Taiwan comparing open with laparoscopic left-sided D2 resections for stage Ⅱ or Ⅲ colon cancer reported 16 ± 3 dissected lymph nodes in its laparoscopic group and 16 ± 6 in its open group [33]. The long-term oncological outcomes between the L-CME and O-CME groups were also comparable; there were no differences regarding the local and distant recurrence rate, the three- and five-year overall rates and the disease-free survival rates. In our study, the three-year overall and diseasefree survival were superior in the laparoscopic group; however, should be noted the extensive experience in laparoscopy of the reporting centers. In Barcelona study, the laparoscopic approach was associated with a slight increase in survival rate, a faster postoperative recovery, and a shorter in-hospital stay duration [38]. In the COLOR 486 December 15, 2017 Volume 9 Issue 12

38 Negoi I et al. Laparoscopic vs open complete mesocolic excision Laparoscopy Open Odds ratio Odds ratio Study or subgroup Events Total Events Total Weight M-H, fixed, 95%CI M-H, fixed, 95%CI RCTs JCOG % 0.66 [0.49, 0.89] Subtotal (95%CI) % 0.66 [0.49, 0.89] Total events Heterogeneity: Not applicable Test for overall effect: Z = 2.76 (P = 0.006) NRCTs Bae % 0.45 [0.20, 1.01] Han % 0.52 [0.29, 0.93] Huang % 0.28 [0.05, 1.46] Kim % 0.53 [0.29, 0.96] Storli % 0.28 [0.08, 0.99] Zhao % 0.61 [0.29, 1.31] Subtotal (95%CI) % 0.49 [0.36, 0.68] Total events Heterogeneity: Tau 2 = 1.69; df = 5 (P = 0.89); I 2 = 0% Test for overall effect: Z = 4.41 (P < ) Total (95%CI) % 0.57 [0.46, 0.71] Total events Heterogeneity: c 2 = 3.37, df = 6 (P = 0.76); I 2 = 0% Test for overall effect: Z = 5.04 (P < ) Test for subgroup differences: c 2 = 1.73, df = 1 (P = 0.19); I 2 = 42.3% Favours laparoscopy Favours open Figure 12 Meta-analysis of studies on postoperative overall morbidity of patients undergoing laparoscopic vs open complete mesocolic excision with central vascular ligation excision for colon cancer. Leave-one-out summary Continuous random-effects model Metric: Mean difference Model results Studies Estimate Lower bound Upper bound Std. error P -value Overall Han Kim Storlin Zhao JCOG Bae Gouvas Huang Munkedal Storli Figure 13 Leave-one-out meta-analysis for the endpoint number of retrieved lymphnodes of patients undergoing laparoscopic vs open complete mesocolic excision with central vascular ligation excision for colon cancer. study, 1248 patients were randomized for open or laparoscopic colon resection [46]. After a median follow-up of 53 mo, the combined three-year, disease-free survival rate was 74.2% in the laparoscopic group and 76.2% in the open group (P = 0.70). The combined threeyear overall survival rate was 81.8% in the laparoscopic group and 84.2% in the open group (P = 0.45). The authors concluded that a difference in the three-year, disease-free survival rate could not be ruled out due to limitations of the study [46]. In the CLASSIC trial, 794 patients with colorectal cancer were randomized for open or laparoscopic resection [47]. An analysis of the subgroup of patients with colon cancer, 140 in the open group and 273 in the laparoscopic group, did not reveal any differences in terms of three-year overall survival rates (P = 0.51). After a median follow-up of 62.9 mo, there were no statistically significant differences in overall survival and disease-free survival rates [48]. In the COST study, 872 patients were randomized to receive an open or laparoscopic colectomy [49]. The 3- and 5-year followups revealed no differences regarding recurrence rate and overall survival rates [49,50]. We found a longer duration of surgery in the laparoscopic group. However, all the perioperative outcomes, such as blood loss, need for transfusion, incision length, wound complications, and thirty-day overall morbidity were less frequent in the laparoscopic group. In the COST, CLASSIC, COLOR I, and ALCCaS trials, the mean duration of surgery was compared to min, the hospital stay was 5-10 vs 6-11 d, the 30-d morbidity was 21%-38% vs 20%-45%, and the 30-d mortality was 0.5%-4.0% vs 0.7%-5.0% in the 487 December 15, 2017 Volume 9 Issue 12

39 Negoi I et al. Laparoscopic vs open complete mesocolic excision 0 RCTs NRCTs year 5-year SE (MD) 2 3 SE (log[or]) MD OR Figure 14 Begg s funnel plot for the endpoint number of retrieved lymphnodes of patients undergoing laparoscopic vs open complete mesocolic excision with central vascular ligation excision for colon cancer. RCTs: Randomized control trial; NRCTs: Non-randomized clinical studies. laparoscopic and open groups, respectively [40-42,49]. Liang et al [33] found a longer operative time for left-sided resections (224.4 ± 44.8 min vs ± 30.6 min), less blood loss (54 ± 12 ml vs 240 ± 34 ml), a shorter wound incision (10.6 ± 1.6 cm vs 18 ± 3.1 cm) for the laparoscopic approach, but there were no statistically significant differences regarding total postoperative complications (20 vs 29, P = 0.15). Our meta-analysis showed that patients from the laparoscopic group had a shorter hospital stay and a shorter recovery time to regain gastrointestinal function. This result is consistent with the current evidence that supported earlier recovery of bowel functioning and oral diet with an in-hospital stay duration 1.7 d shorter in the laparoscopic group [51]. The studies included in the current meta-analysis did not evaluate how surgery affected immune functioning. According to Liang et al [33], the postoperative proinflammatory response, evaluated by C-reactive protein and the erythrocyte sedimentation rate and postoperative immunosuppression and assessed by alteration of lymphocyte counts and the CD4 + / CD8 + ratio, was significantly less in the laparoscopic group (P < 0.001). An important concern regarding laparoscopic colon surgery is the reproducibility of results given the nature of multicenter, specialized centers and the heterogeneity of general surgeons. All surgical procedures from the studies included in this meta-analysis were performed by highly experienced or accredited surgeons. An analysis of the short-term outcomes of colon and rectal laparoscopic resections in Sydney South West Area Health Service revealed a lower morbidity (28.8% vs 54.4%, P < 0.001), fewer transfusions (0.4 units vs 0.7 units, P = ), a longer operative time (24.1 min, P < ) and a shorter length of stay (7 vs 10 d, P = ) for laparoscopic procedures [52]. Dobbins et al [53] published the results of laparoscopic resections for colon and rectal cancer from all of the public and private hospitals in New South Wales, Australia. The laparoscopic colon resections were associated with a Figure 15 Begg s funnel plot for the endpoint overall survival of patients undergoing laparoscopic vs open complete mesocolic excision with central vascular ligation excision for colon cancer. reduced rate of extended stay (OR = 0.60, 95%CI: ) and 28-d readmissions (OR = 0.86, 95%CI: ). Survival benefits for laparoscopy, regarding cancer-specific survival, were observed in highercaseload hospitals but not in lower-caseload hospitals [53]. The current meta-analysis has as a main limitation the clinical heterogeneity of the included studies, and caution should be exercised when interpreting its results. This meta-analysis involves several types of study designs, including retrospective, prospective, and RCT. There is an increased heterogeneity of the tumor localization on the colon, with the transverse colon cancers being excluded from the analysis in two studies, while the others included them into the right/ extended right hemicolectomy group. Excepting the one randomized controlled trial, the experience in minimally invasive surgery of the surgeons from the laparoscopic group is not quantified, although all procedures were performed or supervised by trained colorectal surgeons. However, using random-effects meta-analysis, with subgroup analysis and meta-regression, we limited the variance of the included outcomes. In summary, the current data suggest that the laparoscopic approach offers the same quality of resected specimens as the open approach in CME with CVL for colon cancer while maintaining all of the short-term benefits of a minimally invasive approach. Although a specimen-oriented surgical dissection in colon cancer via a laparoscopic approach is challenging, the magnification and predisposition to details of a minimally invasive technique are associated with a lower postoperative morbidity. COMMENTS Background Complete mesocolic excision with central vascular ligation represents an extension to the colonic cancer of the already standardized resection for rectal cancer. It adheres to the same guiding principle that sharp surgical dissection, following embryological planes, with central vascular ligation, should improve oncological outcomes. The technical details of this new concept were published in December 15, 2017 Volume 9 Issue 12

40 Negoi I et al. Laparoscopic vs open complete mesocolic excision Research frontiers A high-level evidence that laparoscopic approach offers the same quality of the resected specimen as open surgery for complete mesocolic excision with central vascular ligation for colon cancer is lacking. Innovations and breakthroughs Current evidence is consistent with a faster postoperative recovery for laparoscopic colectomies compared with the open approach; the former is not associated with any negative impact regarding local recurrence and survival rates. This study reveals that laparoscopy offers the same quality of the resected specimen as the open approach in complete mesocolic excision with central vascular ligation for colon cancer. The laparoscopic complete mesocolic excision with central vascular ligation is superior in all perioperative results and at least non-inferior in long-term oncological outcomes. Applications Due to all advantages of laparoscopy, the teaching and mentoring of minimally invasive techniques for colon resections should be accentuated, in order to increase the proportion of laparoscopic over open procedures. Terminology During complete mesocolic excision with central vascular ligation for right-sided tumors, the ileocolic and right colic vessels should be ligated at their origin from the superior mesenteric artery, medial (patient left-hand side) to the superior mesenteric vein. Transverse colon tumors require transection of the middle colic artery at its origin. Left-sided tumors require transection of the inferior mesenteric artery at its origin from the aorta. Peer-review This is an interesting meta-analysis and review of a highly debatable topic in surgery, the consensus about laparoscopic vs open surgery in high ligation. REFERENCES 1 Negoi I, Hostiuc S, Runcanu A, Negoi RI, Beuran M. 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41 Negoi I et al. Laparoscopic vs open complete mesocolic excision excision for right colon cancer. Int J Surg 2015; 23: [PMID: DOI: /j.ijsu ] 25 Munkedal DL, West NP, Iversen LH, Hagemann-Madsen R, Quirke P, Laurberg S. Implementation of complete mesocolic excision at a university hospital in Denmark: An audit of consecutive, prospectively collected colon cancer specimens. Eur J Surg Oncol 2014; 40: [PMID: DOI: /j.ejso ] 26 Han DP, Lu AG, Feng H, Wang PX, Cao QF, Zong YP, Feng B, Zheng MH. Long-term outcome of laparoscopic-assisted righthemicolectomy with D3 lymphadenectomy versus open surgery for colon carcinoma. Surg Today 2014; 44: [PMID: DOI: /s z] 27 Bae SU, Saklani AP, Lim DR, Kim DW, Hur H, Min BS, Baik SH, Lee KY, Kim NK. Laparoscopic-assisted versus open complete mesocolic excision and central vascular ligation for right-sided colon cancer. Ann Surg Oncol 2014; 21: [PMID: DOI: /s ] 28 Zhao LY, Chi P, Ding WX, Huang SR, Zhang SF, Pan K, Hu YF, Liu H, Li GX. 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Survival after laparoscopic surgery versus open surgery for colon cancer: long-term outcome of a randomised clinical trial. Lancet Oncol 2009; 10: [PMID: DOI: / S (08) ] 47 Jayne DG, Guillou PJ, Thorpe H, Quirke P, Copeland J, Smith AM, Heath RM, Brown JM; UK MRC CLASICC Trial Group. Randomized trial of laparoscopic-assisted resection of colorectal carcinoma: 3-year results of the UK MRC CLASICC Trial Group. J Clin Oncol 2007; 25: [PMID: DOI: / JCO ] 48 Green BL, Marshall HC, Collinson F, Quirke P, Guillou P, Jayne DG, Brown JM. Long-term follow-up of the Medical Research Council CLASICC trial of conventional versus laparoscopically assisted resection in colorectal cancer. Br J Surg 2013; 100: [PMID: DOI: /bjs.8945] 49 Clinical Outcomes of Surgical Therapy Study Group., Nelson H, Sargent DJ, Wieand HS, Fleshman J, Anvari M, Stryker SJ, Beart RW Jr, Hellinger M, Flanagan R Jr, Peters W, Ota D. A comparison of laparoscopically assisted and open colectomy for colon cancer. N Engl J Med 2004; 350: [PMID: DOI: / NEJMoa032651] 50 Fleshman J, Sargent DJ, Green E, Anvari M, Stryker SJ, Beart RW Jr, Hellinger M, Flanagan R Jr, Peters W, Nelson H; Clinical Outcomes of Surgical Therapy Study Group. Laparoscopic colectomy for cancer is not inferior to open surgery based on 5-year data from the COST Study Group trial. Ann Surg 2007; 246: ; discussion [PMID: DOI: /SLA.0b013e318155a762] 51 Mathis KL, Nelson H. Controversies in laparoscopy for colon and rectal cancer. Surg Oncol Clin N Am 2014; 23: [PMID: DOI: /j.soc ] 52 McKay GD, Morgan MJ, Wong SK, Gatenby AH, Fulham SB, Ahmed KW, Toh JW, Hanna M, Hitos K. Improved short-term 490 December 15, 2017 Volume 9 Issue 12

42 Negoi I et al. Laparoscopic vs open complete mesocolic excision outcomes of laparoscopic versus open resection for colon and rectal cancer in an area health service: a multicenter study. Dis Colon Rectum 2012; 55: [PMID: DOI: / DCR.0b013e f] 53 Dobbins TA, Young JM, Solomon MJ. Uptake and outcomes of laparoscopically assisted resection for colon and rectal cancer in Australia: a population-based study. Dis Colon Rectum 2014; 57: [PMID: DOI: /DCR ] P- Reviewer: Horesh N, Gurkan A S- Editor: Cui LJ L- Editor: A E- Editor: Lu YJ 491 December 15, 2017 Volume 9 Issue 12

43 Submit a Manuscript: DOI: /wjgo.v9.i World J Gastrointest Oncol 2017 December 15; 9(12): ISSN (online) Cystic metastasis from a mucinous adenocarcinoma of duodenum mimicking type Ⅱ choledochal cyst: A case report CASE REPORT Yo Na Kim, Ji Soo Song Yo Na Kim, Department of Pathology, Chonbuk National University Medical School, Research Institute for Endocrine Sciences, Jeonju 54907, South Korea Ji Soo Song, Department of Radiology, Chonbuk National University Medical School and Hospital, Jeonju 54907, South Korea Ji Soo Song, Research Institute of Clinical Medicine of Chonbuk National University, Jeonju 54907, South Korea Ji Soo Song, Biomedical Research Institute of Chonbuk National University Hospital, Jeonju 54907, South Korea ORCID number: Yo Na Kim ( ); Ji Soo Song ( ). Author contributions: Kim YN and Song JS wrote the manuscript; Kim YN performed the pathological examination; Song JS edited the manuscript. Institutional review board statement: This study was reviewed and approved by the Institutional Review Board of Chonbuk National University Hospital. Informed consent statement: The study was performed after obtaining the patient s informed consent. The patient was treated according to the provisions of the Helsinki criteria. Conflict-of-interest statement: Kim YN and Song JS declare no conflicts of interests. Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: licenses/by-nc/4.0/ Manuscript source: Unsolicited Manuscript Correspondence to: Ji Soo Song, MD, PhD, Department of Radiology, Chonbuk National University Medical School and Hospital, 20 Geonji-ro, Deokjin-gu, Chonbuk, Jeonju 54907, South Korea. Telephone: Fax: Received: August 11, 2017 Peer-review started: August 12, 2017 First decision: August 30, 2017 Revised: August 31, 2017 Accepted: September 14, 2017 Article in press: September 14, 2017 Published online: December 15, 2017 Abstract A 51-year-old male patient was referred to our hospital because of an incidentally detected cystic mass near the common bile duct (CBD). Imaging studies demonstrated a cystic mass that was suspected to communicate with the CBD. Gastroscopy showed irregular mucosal thickening with hyperemic change in the second portion of the duodenum. A type Ⅱ choledochal cyst combined with duodenal malignancy was suspected. The patient underwent surgical resection and the histological diagnosis was mucinous adenocarcinoma of the duodenum with cystic metastasis. Although its incidence is extremely rare, care should be taken to check for other sites of malignancy when a pericholedochal cystic mass is detected. Key words: Duodenal cancer; Choledochal cyst; Cystic metastasis; Mucinous adenocarcinoma The Author(s) Published by Baishideng Publishing Group Inc. All rights reserved. Core tip: Mucinous adenocarcinoma is very rare in the 492 December 15, 2017 Volume 9 Issue 12

44 Kim YN et al. Cystic metastasis from a mucinous adenocarcinoma of duodenum duodenum, and a cystic metastasis from mucinous adenocarcinoma of duodenum has never been reported. This is the first report of primary mucinous adenocarcinoma of duodenum with cystic metastasis. Although rare, careful evaluation with a high suspicion for other sites of malignancy is needed when a pericholedochal cystic mass is detected. Kim YN, Song JS. Cystic metastasis from a mucinous adenocarcinoma of duodenum mimicking type Ⅱ choledochal cyst: A case report. World J Gastrointest Oncol 2017; 9(12): Available from: URL: i12/492.htm DOI: INTRODUCTION The small intestine is the longest gastrointestinal (GI) tract organ, reaching six to seven meters in average length. Despite its length and the large mucosal surface area of the small intestine, only 5% of malignant neoplasms of the GI tract occur in the small intestine [1]. Among them, primary adenocarcinoma of the duodenum represents approximately 25%-52% of malignant neoplasms of the small intestine and 4.6% were mucinous adenocarcinoma [2]. Choledochal cysts are rare, congenital dilatation of the extrahepatic or intrahepatic biliary tree. Among them, type Ⅱ choledochal cyst, a diverticulum of the common bile duct (CBD), is the rarest type. Here, we present a case of mucinous adenocarcinoma of the duodenum with cystic metastasis, which is extremely rare and was initially misinterpreted as a type Ⅱ choledochal cyst. CASE REPORT A 51-year-old male patient visited a local hospital because of dyspepsia and epigastric pain. Ultrasonography revealed a 4.5 cm sized cystic mass near the CBD and pancreatic head (Figure 1A). He was transferred to our hospital for further evaluation of the cystic mass. His medical history and laboratory findings were unremarkable. Tumor markers such as alpha-fetoprotein, carcinoembryonic antigen, and carbohydrate antigen 19-9 were within normal limits. Contrast-enhanced abdominal computed tomography (CT) showed a homogeneous low-density cystic mass with thin, smooth walls next to the CBD, and there were suspicions of a communication between the two structures (Figure 1B). Under the impression that the lesion was a type Ⅱ choledochal cyst, which is a discrete diverticulum of the extrahepatic bile duct, magnetic resonance (MR) imaging and endoscopic ultrasound (EUS) were done. The cystic mass showed low signal intensity on the T1- weighted MR image and high SI on the T2-weighted MR image with nearly imperceptible walls and there was no evidence of an enhancing solid portion in the cyst (Figure 1C). EUS also revealed a 4.5 cm sized cystic mass which seemed to be connected with the CBD, and gastroscopy showed irregular mucosal thickening with hyperemic change in the second portion of the duodenum (Figure 1D). Based on these findings, the patient underwent Whipple s operation under the impression the lesion was a type Ⅱ choledochal cyst with extrinsic compression of the duodenum, and the possibility of combined duodenal malignancy due to the mucosal lesion in the duodenum. An examination of the resected specimen revealed a duodenal cancer in the second portion of the duodenum 2.5 cm proximal to the ampulla of Vater, and the cystic mass did not show communication with the CBD (Figure 2A and B). The histological diagnosis was mucinous adenocarcinoma of the duodenum with cystic metastasis and subpyloric lymph node metastasis (Figure 2C and D). The postoperative course of the patient was uneventful. The patient was disease-free 12 mo after the initial diagnosis. However, the patient died 18 mo after the recurrence. DISCUSSION We initially suspected a type Ⅱ choledochal cyst combined with duodenal malignancy due to the mucosal lesion in the duodenum and the gastroscopic biopsy revealed a moderate degree of dysplasia. All of the imaging studies showed a well-marginated, homogeneously thin-walled cyst adjacent to the CBD which is regarded as a diverticulum of the extrahepatic bile duct, and the duodenal lesion was invisible. Since surgical resection is generally considered for the treatment of choledochal cysts, the patient underwent Whipple s operation, and the patient was confirmed to have mucinous adenocarcinoma of the duodenum with cystic metastasis and subpyloric lymph node metastasis. Mucinous adenocarcinoma is one of the histologic subtypes of carcinoma and is very rare in the duodenum. A recent study from South Korea by Chang et al [3]. revealed that 54.8% of small intestinal carcinomas were located in the duodenum and 4.6% were mucinous adenocarcinoma. Due to its rarity, to the best of our knowledge, this is the first case report of primary mucinous adenocarcinoma of duodenum with cystic metastasis. Although there are several studies in the literature describing the imaging findings of small bowel carcinoma including duodenal carcinoma [3-6], there are no previous reports reporting the imaging findings of mucinous adenocarcinoma of the duodenum. According to previous studies, duodenal cancer typically appears as an irregular thickening of the duodenal wall with regional lymph node enlargement on CT. Since the duodenal lesion of our patient was flat and small (2.0 cm), the primary lesion in the second portion of the duodenum and metastatic lymph node in the subpyloric area were missed on initial imaging studies including CT and magnetic resonance imaging (MRI). In a retrospective review of CT and MRI, the metastatic lymph node in the subpyloric area was identified. However, the primary lesion was invisible. 493 December 15, 2017 Volume 9 Issue 12

45 Kim YN et al. Cystic metastasis from a mucinous adenocarcinoma of duodenum A B C D Figure 1 Evaluation of clinical findings. A: Ultrasonography of upper abdomen shows a 4.5 cm sized anechoic cystic mass adjacent to the head of the pancreas and common bile duct; B: Coronal multiplanar reformatted image of contrast-enhanced abdominal computed tomograph shows a homogeneous low-density cystic mass with thin, smooth walls abutting the common bile duct, with possible communication between the two structures; C: Axial T2-weighted magnetic resonance image demonstrates the cystic mass as a homogeneously high signal intensity lesion with thin walls, and there was no evidence of mural nodularity in the cystic mass; D: Endoscopic image of the duodenum shows irregular mucosal thickening with hyperemic change in the second portion of the duodenum. A B C D Figure 2 Gross specimen and pathological findings. A: The ulcerofungating mass measuring 2.4 cm 2.0 cm (arrow), 2.5 cm distant from the ampulla of vater, is observed in the duodenum; B: The cut surface reveals a grey-white mass that abuts the head of the pancreas; C: Histologically, the duodenal mass proved to be an infiltrative adenocarcinoma with subserosal invasion, note the abundant extracellular mucin with floating neoplastic epithelium (Inset); D: Photomicrograph of the cystic mass shows invasive tumor cells in the lining of the cyst and the surrounding soft tissue which is a definite malignant feature (Inset). 494 December 15, 2017 Volume 9 Issue 12

46 Kim YN et al. Cystic metastasis from a mucinous adenocarcinoma of duodenum Choledochal cysts are a rare congenital anomaly of the intrahepatic or extrahepatic biliary tree and is known to occur in 1 in to 1 in live births [7]. Choledochal cysts occur more frequently in Asian populations, with more than two-thirds of all reported cases originating in Asia. Traditionally, choledochal cysts presented predominantly in young age with the triad of abdominal pain, palpable right upper quadrant mass, and intermittent jaundice. Nonetheless, recent analyses show increasing numbers of adults presenting with choledochal cysts [8]. According to Todani s classification, choledochal cyst can be divided into 5 types: Type Ⅰ, a cystic or fusiform dilatation of the CBD, which is subdivided into saccular, segmental, and diffuse types; type Ⅱ, a diverticulum arising from the CBD; type Ⅲ, choledochocele or a bulbous dilation of the terminal CBD within the ampulla of Vater; type Ⅳ, multiple intrahepatic and extrahepatic cysts; and type Ⅴ, intrahepatic bile duct cysts or Caroli disease [9]. Among them, type Ⅱ cysts are the most rare form of choledochal cysts, usually making up less than 2%-5% of cases [10]. They usually manifest as a pericholedochal cystic mass, of various shapes, some being gallbladder-like, and others being diverticulum-like. Choledochal cysts have been associated with an approximately 20 to 50-fold increase in biliary malignancies when compared with the general population [11]. The risk of malignancy in type Ⅱ choledochal cysts has been estimated to range from 7%-9%, which is a slightly lower than the risk for other types of choledochal cysts (14.3% in the third decade) [12]. Current recommendations for management of choledochal cysts is surgical resection regardless of cyst type, including hepaticojejunostomy, Whipple procedure, partial liver resection, or liver transplantation [13]. In conclusion, we have described the first case of a mucinous adenocarcinoma of the duodenum with cystic metastasis. Even though the incidence of this particular type of cancer is extremely low, careful evaluation with a high suspicion for other sites of malignancy must be done when a pericholedochal cystic mass is detected incidentally. ARTICLE HIGHLENGTHS Case characteristics A 51-year-old male patient was admitted because of incidentally detected cystic mass near the common bile duct (CBD). Clinical diagnosis About 4.5 cm sized cystic mass near the CBD, with irregular mucosal thickening in the second portion of the duodenum. Differential diagnosis Type Ⅱ choledochal cyst combined with duodenal malignancy. Laboratory diagnosis Laboratory findings were unremarkable, including tumor markers such as alphafetoprotein, carcinoembryonic antigen, and carbohydrate antigen Imaging diagnosis Findings from gastroscopy, ultrasonography, computed tomograph, and magnetic resonance imaging led to a diagnosis of type Ⅱ choledochal cyst with extrinsic compression of the duodenum, and the possibility of combined duodenal malignancy. Pathological diagnosis Mucinous adenocarcinoma of the duodenum with cystic metastasis and subpyloric lymph node metastasis. Treatment Whipple s operation. Related reports Mucinous adenocarcinoma of the duodenum is very rare, and this is the first case report of primary mucinous adenocarcinoma of duodenum with cystic metastasis. Experiences and lessons Although rare, careful evaluation with a high suspicion for other sites of malignancy is needed when a pericholedochal cystic mass is detected. REFERENCES 1 Jemal A, Siegel R, Ward E, Hao Y, Xu J, Murray T, Thun MJ. Cancer statistics, CA Cancer J Clin 2008; 58: [PMID: DOI: /CA ] 2 Ryder NM, Ko CY, Hines OJ, Gloor B, Reber HA. Primary duodenal adenocarcinoma: a 40-year experience. Arch Surg 2000; 135: ; discussion [PMID: DOI: / archsurg ] 3 Chang HK, Yu E, Kim J, Bae YK, Jang KT, Jung ES, Yoon GS, Kim JM, Oh YH, Bae HI, Kim GI, Jung SJ, Gu MJ, Kim JY, Jang KY, Jun SY, Eom DW, Kwon KW, Kang GH, Park JB, Hong S, Lee JS, Park JY, Hong SM; Korean Small Intestinal Cancer Study Group. Adenocarcinoma of the small intestine: a multi-institutional study of 197 surgically resected cases. Hum Pathol 2010; 41: [PMID: DOI: /j.humpath ] 4 Angelelli G, Macarini L, Giordano G, Di Giulio G. [The role of computerized tomography in the study of duodenal carcinoma]. Radiol Med 1991; 82: [PMID: ] 5 Blandino A, Scribano E, Gaeta M, Loria G, Pandolfo I. [Computerized tomography in gaseous hypotonic duodenography in the study of the pancreatico-duodenal area]. Radiol Med 1994; 88: [PMID: ] 6 Sailer J, Zacherl J, Schima W. MDCT of small bowel tumours. Cancer Imaging 2007; 7: [PMID: DOI: / ] 7 Dhupar R, Gulack B, Geller DA, Marsh JW, Gamblin TC. The changing presentation of choledochal cyst disease: an incidental diagnosis. HPB Surg 2009; 2009: [PMID: DOI: /2009/103739] 8 Lipsett PA, Pitt HA. Surgical treatment of choledochal cysts. J Hepatobiliary Pancreat Surg 2003; 10: [PMID: DOI: /s ] 9 Todani T, Watanabe Y, Narusue M, Tabuchi K, Okajima K. Congenital bile duct cysts: Classification, operative procedures, and review of thirty-seven cases including cancer arising from choledochal cyst. Am J Surg 1977; 134: [PMID: DOI: / (77) ] 10 Yamauchi S, Koga A, Matsumoto S, Tanaka M, Nakayama F. Anomalous junction of pancreaticobiliary duct without congenital choledochal cyst: a possible risk factor for gallbladder cancer. Am J Gastroenterol 1987; 82: [PMID: ] 11 Søreide K, Søreide JA. Bile duct cyst as precursor to biliary tract cancer. Ann Surg Oncol 2007; 14: [PMID: DOI: /s ] 495 December 15, 2017 Volume 9 Issue 12

47 Kim YN et al. Cystic metastasis from a mucinous adenocarcinoma of duodenum 12 Voyles CR, Smadja C, Shands WC, Blumgart LH. Carcinoma in choledochal cysts. Age-related incidence. Arch Surg 1983; 118: [PMID: DOI: /archsurg ] 13 Metcalfe MS, Wemyss-Holden SA, Maddern GJ. Management dilemmas with choledochal cysts. Arch Surg 2003; 138: [PMID: DOI: /archsurg ] P- Reviewer: Agrawal S, Espinel J, Sitarz R S- Editor: Chen K L- Editor: A E- Editor: Lu YJ 496 December 15, 2017 Volume 9 Issue 12

48 Submit a Manuscript: DOI: /wjgo.v9.i World J Gastrointest Oncol 2017 December 15; 9(12): ISSN (online) CASE REPORT Extrapancreatic solid pseudopapillary neoplasm followed by multiple metastases: Case report Hao Wu, Yan-Fen Huang, Xiang-Hong Liu, Mei-Hua Xu Hao Wu, Yan-Fen Huang, Xiang-Hong Liu, Mei-Hua Xu, Department of Gastroenterology, Xiangya Hospital of Central South University, Changsha , Hunan Province, China ORCID number: Hao Wu ( ); Yan- Fen Huang ( x); Xiang-Hong Liu ( ); Mei-Hua Xu ( ). Author contributions: All authors contributed to the acquisition of data, writing, and revision of this manuscript. Informed consent statement: Patients were not required to give informed consent to the study because the participant is deceased. Conflict-of-interest statement: We have no pertinent financial relationships to disclose. Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: licenses/by-nc/4.0/ Manuscript source: Unsolicited manuscript Correspondence to: Dr. Mei-Hua Xu, MD, PhD, Professor, Department of Gastroenterology, Xiangya Hospital of Central South University, No 87 Xiangya Road, Changsha , Hunan Province, China. Telephone: Received: June 24, 2017 Peer-review started: June 26, 2017 First decision: August 7, 2017 Revised: August 24, 2017 Accepted: November 3, 2017 Article in press: November 3, 2017 Published online: December 15, 2017 Abstract Solid pseudopapillary neoplasm (SPN), also known as Gruber-Frantz tumor, is a rare form of neoplasm that almost exclusively occurs in the pancreas and in young females. While the potential of malignancy is low for SPN, these tumors can mimic other diseases and require a meticulous investigation and a standard treatment by total surgical resection. We present an unusual case of SPN arising in the mesentery of a 40-year-old man with subsequent multiple metastases. Histopathological examination showed similar properties of the mesenteric neoplasm to those of SPN in pancreas. Although the mass was surgically removed, the patient died of recurrent disease 4 years after the initial presentation. We speculate that SPN originates from pancreatic progenitor cells. Further histopathological analyses are required for the prediction of SPN recurrence after resection. Key words: Solid pseudopapillary neoplasm; Mesentery; Metastasis The Author(s) Published by Baishideng Publishing Group Inc. All rights reserved. Core tip: Solid pseudopapillary neoplasm (SPN) has been recognized by World Health Organization since 2010, and classified as a low malignant potential neoplasm. Such neoplasm is characterized by the presence of a mutation in the gene that encodes β-catenin. β-catenin is an important factor in the Wnt signaling pathway (β-catenin-dependent Wnt signaling). The identification of extrapancreatic SPN, especially in the mesentery, indicates a possible endoderm link between pancreatic progenitor cells and SPN cells. Wu H, Huang YF, Liu XH, Xu MH. Extrapancreatic solid pseudopapillary neoplasm followed by multiple metastases: Case 497 December 15, 2017 Volume 9 Issue 12

49 Wu H et al. Extrapancreatic solid pseudopapillary neoplasm report. World J Gastrointest Oncol 2017; 9(12): Available from: URL: htm DOI: INTRODUCTION Solid pseudopapillary neoplasm (SPN) is a rare and indolent type of neoplasm that occurs in pancreas; SPN forms 0.3% to 2.7% of all pancreatic exocrine tumors. A large body of SPN indices are found in young female patients, and well-circumscribed. A margin negative surgical resection shows curative result in majority of cases [1-3] ; recurrence after surgical resection is reported in 2% to 10% of patients [4,5]. Patients with unresectable SPN may have a long-term survival (5 years), and require complex chemo- and radio-therapy treatments; the efficacy of adjuvant therapies in the SPN treatment remains largely unknown and a clinical challenge. Thus, it is important to differentiate the risk of recurrence in SPN patients. An extrapancreatic development of SPN is a rare incident; only 16 cases of extrapancreatic SPN have been reported so far worldwide (Table 1). In the present article, we report a patient, in whom SPN was found in the mesentery; no invasion or attachments to adjacent organs was observed. To the best of our knowledge, this article is the first to report a SPN case in the mesentery. CASE REPORT A 40-year-old Chinese male came to hospital on November 15, His main complaint was abdominal distention that lasted over 6 mo. His physical examination revealed a 30 cm soft mass in the abdomen. An abdominal computed tomography (CT) scan exhibited solid and mixed cystic lesions, measuring > 28 cm diameter (Figure 1). Patient s blood test results were unremarkable. On November 22, 2012, the patient underwent an exploratory laparotomy, and the tumor protruding from the mesentery was completely excised. At that time, no invasion or attachments to adjacent organs was observed. In addition, the postoperative course was uneventful. The resected specimen of the mesenteric tumor was 25 cm 15 cm 28 cm, and showed a multilobulated structure with rich microvasculature. Microscopic characterization of the tumor showed that the tumor formation was a mix of solid and pseudopapillary areas. There was no evidence of pancreatic tissue in the analyzed sample. Further, the specimen was positive for alpha-1-antitrypsin, vimentin, CD56 and β-catenin immunostaining, whereas negative for S-100, neuron-specific enolase, E-cadherin, calretinin, progesterone receptor, chromogranin, and pancytokeration (Figure 2). Such results led to the diagnosis of SPN in the mesentery. Following 3.5 years, the patient continued to complain about abdominal distention and occasional polypnea. An abdominal CT scan exhibited multiple tumors in peritoneum, greater omentum, and colonic wall (Figure 3). Meanwhile, cells in the pleural effusion were Figure 1 An abdominal computed tomography scan exhibited solid and mixed cystic lesions, measuring > 28 cm diameter (black arrow). The tumor was apart from the pancreas (white arrow). found positive for alpha-1-antitrypsin, vimentin, CD56 and β-catenin. It was clear that the patient was suffering from recurrence of the disease. Before the surgical operation to clean the recurrent tumors, the patient received the treatment of 60 mg cisplatin by hyperthermic intraperitoneal chemotherapy (HIPEC). Unfortunately, there was no response to the treatment, and the patient was transferred to the palliative care unit. Soon after the patient s physical conditions worsened, we lost the patient on November 2016, 4 years after the initial surgery. DISCUSSION SPN has been recognized by the WHO classification as a low malignant potential neoplasm in 2010 [3]. It was first named as Gruber-Frantz tumor and after that it had been called the pancreatic solid papillary epithelial neoplasm, pancreatic papillary cystic neoplasm, pancreatic solid cystic tumor and solid pseudopapillary tumor. The differential diagnosis of SPN may include: pseudocyst, pancreatic mucinous neoplasms, well-differentiated ductal adenocarcinoma, pancreatic endocrine neoplasm, and acinic cell carcinoma. The pathogenesis of SPN remains unclear. Likewise, genetic events that contribute to the development of SPN are yet to be discovered. There are two basic proposals for the SPN origin: (1) genital ridge-related cells and (2) pancreatic progenitor cells [1,6]. To note, an important proportion of SPN cases show mutations in the somatic β-catenin coding gene (CTNNB1) [7-9]. Such mutations can affect Wnt signaling pathways as well as self-renewal capability of stem cells [10]. SPN cells were reported to be positive for β-catenin, vimentin, alpha-1-anti-trypsin, CD10, CD56, and progesterone receptors by immunohistochemical analysis [11] ; however this staining pattern fails to reveal a clear phenotypic relationship between SPN and any of the defined cell lineages of the pancreas. Thereby, it can be speculated as SPN cells show multipotential differentiation. According to the study concerned with the embryonic development of the human pancreas, dorsal and ventral pancreatic buds were reported to proliferate 498 December 15, 2017 Volume 9 Issue 12

50 Wu H et al. Extrapancreatic solid pseudopapillary neoplasm Table 1 Review of extra-pancreatic solid pseudopapillary neoplasm Ref. Age Sex Location Size (cm) Procedure Follow-up Miyazaki et al [19] 22 F Retroperitoneum 7 Laparoscopy 6 mo NED Hibi et al [20] 45 M Omentum 15 Laparoscopy 96 mo DOD Deshpande et al [21] 17 F Left ovary 25.5 Open surgery 72 mo NED 57 F Right ovary 3 Open surgery NA 21 F Left ovary 14 Open surgery NA He et al [22] 39 F Right ovary 6 Laparoscopy 36 mo NED Fukunaga et al [23] 46 F Omentum 5 Laparoscopy 3 mo NED Ishikawa et al [24] 13 F Mesocolon 4 Open surgery 36 mo NED Guo et al [25] 47 F Retroperitoneum 16 Open surgery 14 mo NED Geng et al [26] 37 F Retroperitoneum 8 Open surgery NA Zhu et al [27] 22 F Retroperitoneum 6 Laparoscopy 14 mo NED Chen et al [28] 47 F Left ovary 6 Open surgery 18 mo NED Cheuk et al [29] 25 F Right ovary 16.5 Open surgery 144 mo NED Walter et al [30] 32 F Stomach 10 Open surgery 24 mo LWD 73 M Duodenum 14 Open surgery 3 mo DOD Stoll et al [31] 48 F Left ovary 8 Open surgery 9 mo NED Present case 40 M Mesentery 28 Open surgery 48 mo DOD NED: No evidence of disease; DOD: Dead of disease; LWD: Live with disease; NA: Not available; F: Female; M: Male. A B C D E F Figure 2 Histological and immunohistochemical findings of the tumor ( 200). The tumor cells are arranged in solid sheets, pseudopapillary and microcysts (A and B: Hematoxylin-eosin stain), and are immunohistochemically positive for alpha-1-antitrypsin (C), β-catenin (D: Cytoplasmic and nuclear staining), CD56 (E), whereas negative for chromogranin (F). 499 December 15, 2017 Volume 9 Issue 12

51 Wu H et al. Extrapancreatic solid pseudopapillary neoplasm Thus, a complete cytoreductive surgery combined with HIPEC stands as an important treatment solution for high-risk group of SPN. Further, another report concluded that SPN are radiosensitive, and can be successfully treated by using radiation therapy [18]. Future clinical and molecular studies are required to provide more precise tools to predict the biological behavior of SPN. ARTICLE HIGHLIGHTS Case characteristics Abdominal distension. Figure 3 An abdominal computed tomography scan exhibited multiple tumors in peritoneum, greater omentum, and colonic wall (white arrow). from gut epithelium of endoderm during the 4 th week of gestation. Dorsal pancreas fuses with ventral pancreas at the 7 th week of gestation due to the rotation of the stomach and duodenum development [12]. Identification of extrapancreatic SPN in the ovary, retroperitoneum and the omentum, as listed in Table 1, indicates a possible endoderm link, substantiated by the migration of pancreas during embryogenesis. We therefore believe that extrapancreatic SPN originates from pancreatic progenitor cells. In SPN patients, tumor resection confers an 8 year survival rate in 85% of cases; nevertheless, local recurrence or distant metastases can occur in some patients [13]. Histological and clinical parameters for prediction of disease recurrence after the initial surgical operation remain a challenge as there is still no consensus in the medical community. Many clinicians and researchers have been working to determine such criteria. For example, Kang et al [14] listed: (1) a tumor size larger than 8 cm; (2) cellular atypia; (3) vascular invasion; (4) perineural invasion; (5) systemic metastasis; and (6) peritoneal seeding as significant prognostic factors for tumor recurrence in a multicenter study. A case series study conducted by Yang et al [15] showed that vascular invasion, extra-pancreatic invasion, lymph node metastasis, and Ki-67 index 4% are associated with SPN recurrence. It is important to note that a rupture of the tumor or laparoscopic biopsy may seed the tumor cells into the peritoneal cavity, and could be an etiological factor responsible for the peritoneal recurrence [16]. Nonetheless, a recurrence prediction scoring model require more investigation. Such model will help clinicians to distinguish a high-risk group from low-risk group. Likewise, there is still no consensus on the treatment strategy in patients with SPN recurrence. A previous report described a 35 years old woman relapsing 8 mo after the resection of an SPN, which ruptured preoperatively. The patient firstly underwent a complete cytoreductive surgery, but relapsed within 8 mo, and received another cytoreductive surgery combined with HIPEC (oxaliplatin and irinotecan). At 31 mo of follow-up, the patient showed no evidence of disease recurrence [17]. Clinical diagnosis Abdominal mass. Differential diagnosis Pancreatic mucinous neoplasms. Laboratory diagnosis All labs were within normal limits. Imaging diagnosis Mesenchymal neoplasm. Pathological diagnosis Solid pseudopapillary neoplasm (SPN). Treatment Complete cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy. Related reports Grading and staging play an important role in treatment and prognosis. Term explanation SPN: Solid pseudopapillary neoplasm. Experiences and lessons Future clinical and molecular studies are required to provide more precise tools to predict the biological behavior of SPN. REFERENCES 1 Mao C, Guvendi M, Domenico DR, Kim K, Thomford NR, Howard JM. Papillary cystic and solid tumors of the pancreas: a pancreatic embryonic tumor? Studies of three cases and cumulative review of the world s literature. Surgery 1995; 118: [PMID: DOI: /s (05) ] 2 Yu PF, Hu ZH, Wang XB, Guo JM, Cheng XD, Zhang YL, Xu Q. Solid pseudopapillary tumor of the pancreas: a review of 553 cases in Chinese literature. World J Gastroenterol 2010; 16: [PMID: DOI: /wjg.v16.i ] 3 Bosman FT, World Health Organization, International Agency for Research on Cancer. WHO Classification of Tumors of the Digestive System. 4th edn. Lyon: International Agency for Research on Cancer, Lubezky N, Papoulas M, Lessing Y, Gitstein G, Brazowski E, Nachmany I, Lahat G, Goykhman Y, Ben-Yehuda A, Nakache R, Klausner JM. Solid pseudopapillary neoplasm of the pancreas: Management and long-term outcome. Eur J Surg Oncol 2017; 43: [PMID: DOI: /j.ejso ] 500 December 15, 2017 Volume 9 Issue 12

52 Wu H et al. Extrapancreatic solid pseudopapillary neoplasm 5 Marchegiani G, Andrianello S, Massignani M, Malleo G, Maggino L, Paiella S, Ferrone CR, Luchini C, Scarpa A, Capelli P, Mino- Kenudson M, Lillemoe KD, Bassi C, Castillo CF, Salvia R. Solid pseudopapillary tumors of the pancreas: Specific pathological features predict the likelihood of postoperative recurrence. J Surg Oncol 2016; 114: [PMID: DOI: /jso.24380] 6 Kosmahl M, Seada LS, Jänig U, Harms D, Klöppel G. Solidpseudopapillary tumor of the pancreas: its origin revisited. 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Int J Gynecol Pathol 2011; 30: [PMID: DOI: /PGP.0b013e fb] 30 Walter T, Hommell-Fontaine J, Hervieu V, Adham M, Poncet G, Dumortier J, Lombard-Bohas C, Scoazec JY. Primary malignant solid pseudopapillary tumors of the gastroduodenal area. Clin Res Hepatol Gastroenterol 2011; 35: [PMID: DOI: / j.clinre ] 31 Stoll LM, Parvataneni R, Johnson MW, Gui D, Dorigo O, Sullivan P. Solid pseudopapillary neoplasm, pancreas type, presenting as a primary ovarian neoplasm. Hum Pathol 2012; 43: [PMID: DOI: /j.humpath ] P- Reviewer: Ikura Y, Lin J, Ramia JM, Şendur MAN S- Editor: Ji FF L- Editor: A E- Editor: Lu YJ 501 December 15, 2017 Volume 9 Issue 12

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