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Personalized Management of Gastric Cancer Translational and Precision Medicine Jia Wei Baorui Liu Editors 123 Personalized Management of Gastric Cancer Jia Wei • Baorui Liu Editors Personalized Management of Gastric Cancer Translational and Precision Medicine Editors Jia Wei Baorui Liu The Comprehensive Cancer Center The Comprehensive Cancer Center Drum Tower Hospital Drum Tower Hospital Medical School of Nanjing University Medical School of Nanjing University Nanjing Nanjing Jiangsu Jiangsu China China ISBN 978-981-10-3977-5 ISBN 978-981-10-3978-2 (eBook) DOI 10.1007/978-981-10-3978-2 Library of Congress Control Number: 2017940425 © Springer Nature Singapore Pte Ltd. 2017 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifcally the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microflms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specifc statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, express or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affliations. Printed on acid-free paper This Springer imprint is published by Springer Nature The registered company is Springer Nature Singapore Pte Ltd. The registered company address is: 152 Beach Road, #21-01/04 Gateway East, Singapore 189721, Singapore Preface We are on the precipice of entering a stage of rapid development in the treat- ment of gastric cancer. For quite a long time, treatment progress was slow and stood in sharp contrast to the advances seen in lung cancer, colon cancer, and melanoma. However, a large reason for this slow progression was the reluc- tance of researchers to boldly apply the most advanced scientifc concepts and technology to its treatment. With the vision of an emerging era of precise medicine, this book is based on the author’s perception of both clinical expe- rience and the most up-to-date scientifc research. In so doing, the book describes and comments on the four felds most likely to signifcantly improve the therapeutic effcacy of gastric cancer treatment: personalized therapy, pre- cision regional therapy, immunotherapy, and nanomedicine. The frst part of the book elaborates on personalized therapy in the treat- ment of gastric cancer. A comprehensive review is made from relevant aspects of molecular pathology, genetics and molecular signatures, circulating tumor cells, customized chemotherapy, and targeted gastric cancer therapy, thereby providing the latest research results for precise medication in the treatment of gastric cancer. The second part details precision regional therapy in gastric cancer. It is discussed through the following lenses: laparoscopic and robotic surgical approaches, radiotherapy, and personalized intraperitoneal strate- gies. The third part is focused on current “hotspots” in immunotherapy and is presented from the perspectives of checkpoint therapy, therapeutic vaccines, adoptive cell therapy, as well as combinational strategies. All of these approaches are explored with regard to their prospective applications in gas- tric cancer treatment. The fnal part is based on current research and focuses on nanomedicine and their delivery systems in the diagnosis and treatment of cancer. It has a specifc focus on the translational signifcance of biomaterials and clinical medicine. Collectively, these four parts seek to tackle the current hotspots in gastric cancer treatment as well as the remaining diffculties faced in the feld. This is accomplished by combining translational research and clinical explora- tions, which together hold great promise in helping doctors and research fel- lows engaged in the necessary goal of gastric cancer treatment. Nanjing, China Jia Wei Baorui Liu v Contents Part I Personalized Therapy in Gastric Cancer 1 M olecular Pathology of Heredity Gastric Cancer . . . . . . . . . . . . 3 Lin Li and Xiangshan Fan 2 G enetics and Molecular Signature of Gastric Cancer . . . . . . . . . 15 Meng Zhu and Guangfu Jin 3 C irculating Tumor Cells in Gastric Cancer . . . . . . . . . . . . . . . . . 35 Jie Shen and Lifeng Wang 4 C ustomized Chemotherapy in Advanced Gastric Cancer . . . . . 45 Jia Wei and Nandie Wu 5 T argeted Therapy in Advanced Gastric Cancer . . . . . . . . . . . . . 61 Li Xie, Jia Wei, Lijing Zhu, and Wenjing Hu Part II Precision Regional Therapy in Gastric Cancer 6 L aparoscopic Surgery and Robotic Surgery . . . . . . . . . . . . . . . . 79 Meng Wang and Wenxian Guan 7 R adiotherapy in Gastric Cancer with Peritoneal Carcinomatosis . . . . . . . . . . . . . . . . . . . . . . . . . . . 87 Yang Yang, Ju Yang, and Jing Yan 8 P ersonalized Intraperitoneal Strategies in Gastric Cancer . . . 103 Yang Yang, Nandie Wu, and Jia Wei Part III Immunotherapy 9 I mmune Checkpoint Blockade and Gastric Cancer . . . . . . . . . 115 Shu Su and Baorui Liu 1 0 T herapeutic Vaccine of Gastric Cancer . . . . . . . . . . . . . . . . . . . 131 Fangjun Chen and Fanyan Meng vii viii Contents 1 1 A doptive Cell Therapy of Gastric Cancer . . . . . . . . . . . . . . . . . 149 Zhengyun Zou, Lianjun Zhao, Yu Ren, and Shiyao Du 1 2 C ombinational Immunotherapy of Gastric Cancer . . . . . . . . . . 163 Juan Du and Baorui Liu Part IV U se of Nanomedicine in the Diagnosis and Treatment of Gastric Cancer 1 3 U se of Nanomedicine in the Diagnosis of Gastric Cancer . . . . . 179 Rutian Li and Xiaoping Qian 1 4 S ystemic Drug Delivery in Gastric Cancer . . . . . . . . . . . . . . . . . 189 Rutian Li and Mi Yang 1 5 L ocal Drug Delivery Strategies for Gastric Cancer Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 203 Qin Liu and Baorui Liu 1 6 D rug Delivery in Synergistic Combination with Other Treatments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 215 Hanqing Qian and Baorui Liu Part I Personalized Therapy in Gastric Cancer Moleclu ar Patoh log y of Heredit y 1 Gastric Cancer Lin Li and Xiangshan Fan 1.1 nI trodcu tion inherited factors among patients with family his- tories of GC, in order to diagnose early and man- Gastric cancer (GC) affects nearly one million age effectively. We usually use symptoms, such individuals every year, and most of them are as different family individuals are diagnosed from China, Japan, and Korea. It is the ffth most with cancer, the histological types are diffused common malignant tumor worldwide and the adenocarcinoma, and the patients are young and third leading cause of malignant tumor mortality with multiple cancer syndromes, to identify with more than 723,000 deaths [1]. About HDGC. Some cases of other hereditary tumor 70–85% of individuals with GC die within syndromes may also present GC, and thus the 5 years of diagnosis, and the high mortality asso- risk of GC should be taken into account in these ciated with GC is mainly a result of limited ther- patients. The hereditary cancer syndromes apeutic methods and lacking of early diagnosis. include the gastric adenocarcinoma and proxi- Aggregation within families occurs in almost mal polyposis of the stomach (GAPPS), familial 10% of patients (5–30%), although most GCs intestinal gastric cancer (FIGC), Lynch syn- are sporadic. Now we know that hereditary drome (LS) caused by germline mutations in germline mutations lead to half of these familial DNA mismatch repair genes and microsatellite cases [2, 3]. In regions where the incidence of instability, familial adenomatous polyposis GC is low, heritable pathogenic mutations, (FAP) associated with germline APC mutations, which leads to most familial cases, increase risk MUTYH-associated polyposis (MAP) associ- from birth. Truly hereditary cases, as some stud- ated with MUTYH mutation, Peutz-Jeghers syn- ies pointed out, account for 1–3% of the global drome (PJS) caused by germline STK11 burden of GC [4], and most of those are heredi- mutations , juvenile polyposis syndrome (JPS) tary diffuse gastric cancer (HDGC). It is reported associated with germline mutations in the that, in about 40% of families affected by HDGC, BMPR1A and SMAD4 genes, hereditary breast- the E-cadherin/CDH1 germline mutations can ovarian cancer syndromes (HBCS) related to been found. It is very important to identify the germline mutations of BRCA1 and BRCA2, Li-Fraumeni syndrome (LFS) due to germline p53 mutations, and so on [5]. L. Li • X. Fan (*) Screening for familial gastric cancer (FGC) is Department of Pathology of Drum Tower Hospital, an especially important procedure. Because it has Medical School of Nanjing University, a higher risk of GC incidence, to the individuals Nanjing 210008, China who have inherited the mutant gene, prophylactic e-mail: 4 LL .a i n a n X d F . gastrectomy is worthy of consideration [6]. It is There was a renewed version for genetic test- an enormous fscal expenditure of society to ing in 2010 [10]. The families, which fulfll the manage and control FGC each year. Thus, screen- following criteria for HDGC, would be recom- ing for prevention for it is a crucial step to mended to consider genetic counseling and decrease cancer incidence and mortality [7]. It is genetic testing for CDH1 gene mutations. Firstly, necessary to interview with pedigree precisely to at least two patients of documented diffuse GC in fnd the familial syndromes, individuals at risk, frst-degree family members, with one or more and genotypes [8]. At present, it is in urgent need documented case of diffuse GC being diagnosed of guidelines for genetic detecting, counseling, younger than 50 years old. Secondly, at least and management of patients with HDGC. If we three documented patients of diffuse GC in frst- pay more attention on these syndromes, we may or second-degree family members, ignoring of increase opportunities to detect and prevent GCs age of diagnosis. Thirdly, the diffuse GC case, in these high-risk cases. with no family history, was diagnosed before the Hereditary gastric cancer syndromes are an age of 40 years. Fourthly, families with patients infrequent but characteristic etiology of GCs. So of both lobular breast cancer and diffuse GC, far, we haven’t clarifed the genetic mutations with at least one diagnosed younger than the age attacking most affected families. Up to date, of 50 years. there are at least three main hereditary GC syn- The age at onset of clinically signifcant dif- dromes that have been reported: HDGC, GAPPS, fuse GC may be extremely variable with the aver- and FIGC [5, 9]. In this chapter, we mainly dis- age onset in the fourth decade of life (14–85 years cuss the available knowledge on HDGC, GAPPS, old), and the distribution of lesions also varies, FIGC, and several other hereditary cancer syn- involving all the topographic regions within the dromes associated with GC, with the aim of clari- stomach. HDGC’s genetic susceptibility and the fying the molecular pathology and genesis of molecular basis were frst identifed and then these heredity GCs. reinforced in Maori families and other popula- tions, respectively, in 1998 [11, 12]. Heterozygous germline alterations in the 1.2 H ereditary Diffuse Gastric E-cadherin gene (CDH1) result in HDGC [11]. Cancer There are fve types of germline CDH1 muta- tions, including large rearrangements (4–8.7%), HDGC is an autosomal dominant disorder pre- nonsense (17.3%) and missense (17.3%) muta- disposition syndrome with obvious penetrance tions, splice site (23.1%), as well as small frame- (about 80%) and characterized by an enhancive shifts (37.5%). They affect the protein's functional risk of early-onset, multigenerational, and signet domains and the entire coding sequence [13–15]. ring cell GC (Lauren diffuse type) and lobular 141 probands harboring more than one hundred breast carcinoma. different pathogenic germline CDH1 alterations A diagnosis of families with the HDGC syn- have been described across multiple ethnicities drome can be established if one of the following so far [16, 17]. The production of this gene, clinical features are present. Firstly, at least two which locates at 16q22.1, is E-cadherin. patients of documented diffuse GC in frst- or E-cadherin is a calcium-dependent transmem- second-degree family members, with one or brane cellular adhesion protein. There are three more being diagnosed younger than 50 years parts of E-cadherin, including an intracellular old. Secondly, at least three documented patients domain which binds β-catenin and p120-catenin, of diffuse GC in frst- or second-degree family the transmembrane domain, and the extracellular members, ignoring of age of diagnosis. The domain with fve cadherin repeats (EC1–EC5). checklist above was defned by the International There is a highly phosphorylated region in the Gastric Cancer Linkage Consortium (IGCLC) intracellular domain. Binding β-catenin with the in 1999. intracellular domain is necessary for E-cadherin

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