Dr. Pletser’s experience includes 30 years of working with the European Space Agency as a Senior Physicist/Engineer and coordinating their parabolic flight campaigns, and he is the Guinness World Record holder for the most number of aircraft flown (12) in parabolas, personally logging more than 7,300 parabolas.
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Seeing the 5,000th book published makes us at the same time proud, happy, humble, and grateful. This is a great opportunity to stop and celebrate what we have done so far, but is also an opportunity to engage even more, grow, and succeed. It wouldn't be possible to get here without the synergy of team members’ hard work and authors and editors who devote time and their expertise into Open Access book publishing with us.
\\n\\n
Over these years, we have gone from pioneering the scientific Open Access book publishing field to being the world’s largest Open Access book publisher. Nonetheless, our vision has remained the same: to meet the challenges of making relevant knowledge available to the worldwide community under the Open Access model.
\\n\\n
We are excited about the present, and we look forward to sharing many more successes in the future.
\\n\\n
Thank you all for being part of the journey. 5,000 times thank you!
\\n\\n
Now with 5,000 titles available Open Access, which one will you read next?
Preparation of Space Experiments edited by international leading expert Dr. Vladimir Pletser, Director of Space Training Operations at Blue Abyss is the 5,000th Open Access book published by IntechOpen and our milestone publication!
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"This book presents some of the current trends in space microgravity research. The eleven chapters introduce various facets of space research in physical sciences, human physiology and technology developed using the microgravity environment not only to improve our fundamental understanding in these domains but also to adapt this new knowledge for application on earth." says the editor. Listen what else Dr. Pletser has to say...
\n\n\n\n
Dr. Pletser’s experience includes 30 years of working with the European Space Agency as a Senior Physicist/Engineer and coordinating their parabolic flight campaigns, and he is the Guinness World Record holder for the most number of aircraft flown (12) in parabolas, personally logging more than 7,300 parabolas.
\n\n
Seeing the 5,000th book published makes us at the same time proud, happy, humble, and grateful. This is a great opportunity to stop and celebrate what we have done so far, but is also an opportunity to engage even more, grow, and succeed. It wouldn't be possible to get here without the synergy of team members’ hard work and authors and editors who devote time and their expertise into Open Access book publishing with us.
\n\n
Over these years, we have gone from pioneering the scientific Open Access book publishing field to being the world’s largest Open Access book publisher. Nonetheless, our vision has remained the same: to meet the challenges of making relevant knowledge available to the worldwide community under the Open Access model.
\n\n
We are excited about the present, and we look forward to sharing many more successes in the future.
\n\n
Thank you all for being part of the journey. 5,000 times thank you!
\n\n
Now with 5,000 titles available Open Access, which one will you read next?
\n'}],latestNews:[{slug:"webinar-introduction-to-open-science-wednesday-18-may-1-pm-cest-20220518",title:"Webinar: Introduction to Open Science | Wednesday 18 May, 1 PM CEST"},{slug:"step-in-the-right-direction-intechopen-launches-a-portfolio-of-open-science-journals-20220414",title:"Step in the Right Direction: IntechOpen Launches a Portfolio of Open Science Journals"},{slug:"let-s-meet-at-london-book-fair-5-7-april-2022-olympia-london-20220321",title:"Let’s meet at London Book Fair, 5-7 April 2022, Olympia London"},{slug:"50-books-published-as-part-of-intechopen-and-knowledge-unlatched-ku-collaboration-20220316",title:"50 Books published as part of IntechOpen and Knowledge Unlatched (KU) Collaboration"},{slug:"intechopen-joins-the-united-nations-sustainable-development-goals-publishers-compact-20221702",title:"IntechOpen joins the United Nations Sustainable Development Goals Publishers Compact"},{slug:"intechopen-signs-exclusive-representation-agreement-with-lsr-libros-servicios-y-representaciones-s-a-de-c-v-20211123",title:"IntechOpen Signs Exclusive Representation Agreement with LSR Libros Servicios y Representaciones S.A. de C.V"},{slug:"intechopen-expands-partnership-with-research4life-20211110",title:"IntechOpen Expands Partnership with Research4Life"},{slug:"introducing-intechopen-book-series-a-new-publishing-format-for-oa-books-20210915",title:"Introducing IntechOpen Book Series - A New Publishing Format for OA Books"}]},book:{item:{type:"book",id:"6145",leadTitle:null,fullTitle:"Primary Total Knee Arthroplasty",title:"Primary Total Knee Arthroplasty",subtitle:null,reviewType:"peer-reviewed",abstract:'This book presents a compilation of topics related to primary total knee arthroplasty. The chapters cover, in a clear and didactic way, the current themes, written by experts from the area, from different parts of the world. Topics related to the three surgical phases (before surgery, during surgery, and after surgery) are discussed here. This is very important because the surgeon is not a "factory worker." First of all, it is a medicine doctor who has to feel and understand the particularities of each patient. Demographic studies show an aging population. Osteoarthritis and inflammatory diseases are becoming much more prevalent. In addition, a worldwide epidemic of trauma has led to the need for arthroplasties much more frequently. Therefore, total knee arthroplasty will be an increasingly important subject.',isbn:"978-1-78923-143-4",printIsbn:"978-1-78923-142-7",pdfIsbn:"978-1-83881-302-4",doi:"10.5772/intechopen.68269",price:119,priceEur:129,priceUsd:155,slug:"primary-total-knee-arthroplasty",numberOfPages:134,isOpenForSubmission:!1,isInWos:1,isInBkci:!1,hash:"18df110af120b1a8e88e0a1ded2aba75",bookSignature:"Alessandro Rozim Zorzi and João Batista de Miranda",publishedDate:"May 23rd 2018",coverURL:"https://cdn.intechopen.com/books/images_new/6145.jpg",numberOfDownloads:7857,numberOfWosCitations:1,numberOfCrossrefCitations:1,numberOfCrossrefCitationsByBook:0,numberOfDimensionsCitations:2,numberOfDimensionsCitationsByBook:0,hasAltmetrics:0,numberOfTotalCitations:4,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"June 28th 2017",dateEndSecondStepPublish:"July 19th 2017",dateEndThirdStepPublish:"December 2nd 2017",dateEndFourthStepPublish:"January 13th 2018",dateEndFifthStepPublish:"March 14th 2018",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6",editedByType:"Edited by",kuFlag:!1,featuredMarkup:null,editors:[{id:"80871",title:"M.D.",name:"Alessandro Rozim",middleName:null,surname:"Zorzi",slug:"alessandro-rozim-zorzi",fullName:"Alessandro Rozim Zorzi",profilePictureURL:"https://mts.intechopen.com/storage/users/80871/images/system/80871.jpeg",biography:'Prof. Dr. Alessandro Rozim Zorzi (M.D., M.Sc., Ph.D.) is the Supervisor of Orthopedic Surgery Medical Residency Program at the State University of Campinas, Researcher and Lecturer of graduation and post graduation at São Leopoldo Mandic Medical School in Brazil. He is the author of dozens of international publications such as original articles, review articles, and book chapters. He is also the editor of the scientific blog "Femur Distal" (http://www.blogs.unicamp.br/femurdistal) and editor of five previous books with IntechOpen since 2014: "Bone Grafting"; "Osteonecrosis"; "Advanced Techniques in Bone Regeneration"; "Primary Total Knee Arthroplasty"; and "Cartilage Repair and Regeneration".',institutionString:"State University of Campinas",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"2",totalChapterViews:"0",totalEditedBooks:"5",institution:{name:"State University of Campinas",institutionURL:null,country:{name:"Brazil"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:{id:"84386",title:"Prof.",name:"João",middleName:null,surname:"Batista de Miranda",slug:"joao-batista-de-miranda",fullName:"João Batista de Miranda",profilePictureURL:"https://mts.intechopen.com/storage/users/84386/images/system/84386.jpg",biography:"Professor João Batista de Miranda is the chairman of the Division of Knee Surgery and Inflammatory Diseases, at the Department of Orthopedic Surgery, Campinas State University (Unicamp), Brazil. He performs teaching activities with medical students, orthopedic fellows, and postgraduating researchers. He also develops research and clinical care. He is currently the superintendent of the Unicamp Teaching Hospital. Prof. Miranda obtained PhD with an experimental study on bone regeneration and on allografts. He has published several scientific articles in international journals and is coeditor of the book Bone Grafting of InTechOpen.",institutionString:"University of Campinas",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"State University of Campinas",institutionURL:null,country:{name:"Brazil"}}},coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"1150",title:"Orthopedics",slug:"orthopedics"}],chapters:[{id:"58841",title:"Planning Primary Total Knee Arthroplasties",doi:"10.5772/intechopen.72775",slug:"planning-primary-total-knee-arthroplasties",totalDownloads:1082,totalCrossrefCites:1,totalDimensionsCites:1,hasAltmetrics:0,abstract:"Preoperative planning is routinely recommended prior to total knee arthroplasty (TKA). We introduce a methodology for planning TKA based on mechanical alignment. A methodology for planning total knee arthroplasty was discussed among experienced knee surgeons. A rational methodology for planning TKA was stablished and it was setted to an application for mobile devices. It has proved to be useful and revealed accuracy compared to the manual form of preoperative planning. It was able to reduce planning time by more than a half and it was still reliable in measuring the anatomical-mechanical femoral angle (MAFÂ). This chapter introduces a TKA planning method based on mechanical alignment and GAP balancing principles. Kinematic alignment and strategies for soft-tissue balancing in special situations are cited as well.",signatures:"João Bosco Sales Nogueira, Leonardo Heráclio do Carmo Araújo\nand Marcelo José Cortez Bezerra",downloadPdfUrl:"/chapter/pdf-download/58841",previewPdfUrl:"/chapter/pdf-preview/58841",authors:[{id:"215718",title:"M.Sc.",name:"João Bosco Sales",surname:"Nogueira",slug:"joao-bosco-sales-nogueira",fullName:"João Bosco Sales Nogueira"}],corrections:null},{id:"59498",title:"Cruciate-Retaining Total Knee Arthroplasty",doi:"10.5772/intechopen.74024",slug:"cruciate-retaining-total-knee-arthroplasty",totalDownloads:1318,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"The debate over the relative merits of substituting or retaining the posterior cruciate ligament (PCL) in total knee arthroplasty is still ongoing. The potential advantages of PCL preservation are a more natural femoral rollback, the presence of a structure critical for the proprioception, the maintenance of a native central stabilizer of the joint, and low shear stress on the bone-cement interface of the tibial component. Numerous retrospective studies of cruciate-retaining (CR) total knee arthroplasties have demonstrated consistently good clinical results and excellent intermediate and long-term survival. The main criticisms of the surgical technique are that the distal attachment of the PCL is vulnerable to injury and that balancing the PCL can be difficult; based on our experience, surgical tricks will be described to avoid the avulsion of the ligament and they will be discussed the main points to consider when you can find a discrepancy between flexion and extension stability. Based on the current evidence, we conclude that with a standardized technique, this type of implant should be preferred even in those cases where the sacrifice of the cruciate ligament seems to be the easiest way.",signatures:"Vittorio Calvisi, Alessandro Paglia, Norman Ciprietti and Remo\nGoderecci",downloadPdfUrl:"/chapter/pdf-download/59498",previewPdfUrl:"/chapter/pdf-preview/59498",authors:[{id:"218908",title:"Prof.",name:"Vittorio",surname:"Calvisi",slug:"vittorio-calvisi",fullName:"Vittorio Calvisi"},{id:"218967",title:"Dr.",name:"Remo",surname:"Goderecci",slug:"remo-goderecci",fullName:"Remo Goderecci"},{id:"218968",title:"Dr.",name:"Alessandro",surname:"Paglia",slug:"alessandro-paglia",fullName:"Alessandro Paglia"},{id:"218970",title:"Dr.",name:"Norman",surname:"Ciprietti",slug:"norman-ciprietti",fullName:"Norman Ciprietti"}],corrections:null},{id:"59238",title:"Methods of DVT Prophylaxis after Total Knee Arthroplasty",doi:"10.5772/intechopen.73645",slug:"methods-of-dvt-prophylaxis-after-total-knee-arthroplasty",totalDownloads:1120,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Postoperative deep-vein thrombosis (DVT), venous thromboembolism (VTE), and pulmonary embolism are few of the most serious complications following total joint arthroplasty. Identification of risk factors and initiation of prophylactic measures are the most important measures to prevent the occurrence of DVT. Several protocols and guidelines are published for DVT prophylaxis in TKA, leaving the surgeon still perplexed. Pharmacological and mechanical prophylaxis methods are used to reduce the risk of postoperative symptomatic deep-vein thrombosis and pulmonary embolism. The use of pharmacological methods is based on a fine balance between their efficacy and the adverse effects associated with them. Each of these agents has their own advantages and disadvantages. Several newer agents are getting approved by FDA for the same. Hence, the choice should be carefully made based on the patient characteristics and risk stratification, and the onset of side effects has to be carefully monitored.",signatures:"Melvin J. George",downloadPdfUrl:"/chapter/pdf-download/59238",previewPdfUrl:"/chapter/pdf-preview/59238",authors:[{id:"210622",title:"Dr.",name:"Melvin",surname:"George",slug:"melvin-george",fullName:"Melvin George"}],corrections:null},{id:"59367",title:"Primary Total Knee Arthroplasty in Valgus Deformity",doi:"10.5772/intechopen.74114",slug:"primary-total-knee-arthroplasty-in-valgus-deformity",totalDownloads:1405,totalCrossrefCites:0,totalDimensionsCites:1,hasAltmetrics:0,abstract:"Proper limb and component alignments as well as soft tissue balance are vital for the longevity and optimal long-term outcomes of total knee arthroplasty (TKA). The majority of orthopedic surgeons agree that the total arthroplasty procedure in valgus knees with a deformity of more than 10° is technically demanding and may prove challenging. At the time of operation, the bone and soft tissue abnormalities that should be corrected make accurate axis restoration, correct component positioning and joint stability attaining a difficult task. Specific pathologic anatomic changes associated with valgus knee should be understood preoperatively and estimated so as to select the proper surgical method, to enhance component position and to restore soft-tissue balancing. The purpose of this chapter is to consider all the valgus knee anatomical variations, to analyze the best preoperative planning and to evaluate the type of implant, constrained or not. Lastly, it will also be underlying the current main approaches and techniques to be proposed in the literature for both bone cuts and soft tissue management of valgus knees and if minimally invasive techniques can be performed in severe deformed knees.",signatures:"Nikolopoulos Dimitrios, Sagos George and Michos Ioannis",downloadPdfUrl:"/chapter/pdf-download/59367",previewPdfUrl:"/chapter/pdf-preview/59367",authors:[{id:"228477",title:"Dr.",name:"Dimitrios D.",surname:"Nikolopoulos",slug:"dimitrios-d.-nikolopoulos",fullName:"Dimitrios D. Nikolopoulos"},{id:"228550",title:"Dr.",name:"John",surname:"Michos",slug:"john-michos",fullName:"John Michos"},{id:"228551",title:"Dr.",name:"George K.",surname:"Safos",slug:"george-k.-safos",fullName:"George K. Safos"}],corrections:null},{id:"59316",title:"Tourniquet Use in Total Knee Arthroplasty",doi:"10.5772/intechopen.73644",slug:"tourniquet-use-in-total-knee-arthroplasty",totalDownloads:1008,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"The use of an intraoperative tourniquet for total knee arthroplasty (TKA) is a common practice. Although it provides clear filed and ideal cementation during surgery, issues regarding the effectiveness, drawbacks and complications are still investigated. This review was conducted to evaluate the role of tourniquet in TKA through a comprehensive literature search was done in PubMed Medicine, Embase, and other internet database. Debating issues, including the blood loss, operation time, alignment, compromised wound healing, quadriceps weakness and timing of release were furtherly examined. Based on our prior work and the general consensus that the tourniquet should be set with the lowest pressure and for the least ischemic time possible, we recommend early tourniquet release right after the closure of extensor mechanism in the TKAs without drainage.",signatures:"Kai-Lan Hsu, Chih-Wei Chang, Chyun-Yu Yang and Jou-Hua Wang",downloadPdfUrl:"/chapter/pdf-download/59316",previewPdfUrl:"/chapter/pdf-preview/59316",authors:[{id:"66952",title:"Prof.",name:"Chyun-Yu",surname:"Yang",slug:"chyun-yu-yang",fullName:"Chyun-Yu Yang"},{id:"70966",title:"Dr.",name:"Chih-Wei",surname:"Chang",slug:"chih-wei-chang",fullName:"Chih-Wei Chang"},{id:"231056",title:"Dr.",name:"Jou-Hwa",surname:"Wang",slug:"jou-hwa-wang",fullName:"Jou-Hwa Wang"},{id:"231057",title:"Dr.",name:"Kai-Lan",surname:"Hsu",slug:"kai-lan-hsu",fullName:"Kai-Lan Hsu"}],corrections:null},{id:"59480",title:"Pain Management",doi:"10.5772/intechopen.74296",slug:"pain-management",totalDownloads:920,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Postoperative pain is caused by neuronal damage that occurs during the surgical procedure and the stimulation of the nociceptors. In postoperative period, total knee arthroplasty (TKA) is painful, and pain management is quite difficult. The main purpose of postoperative pain relief is to reduce the pain of the patient, to contribute to the healing process, to shorten the length of hospital stay, and to reduce hospital costs. Techniques such as intravenous analgesia, epidural analgesia, and peripheral nerve blocks are used to prevent postoperative pain. In addition, oral and parenteral analgesics, patient-controlled analgesia (PCA), nerve blocks, and periarticular injection methods are used as multimodal analgesia methods. Pain scales such as visual analogue scale (VAS), verbal descriptive scale (VDS), and numerical rating scale (NRS) are used as the standard methods in the evaluation of pain of patients. Systemic opioids, nonsteroidal anti-inflammatory drugs, and local anesthetics are used for postoperative analgesia. Preemptive analgesia, defined as analgesia initiated prior to surgical incision, and multimodal analgesia have been shown to reduce opioid consumption associated with high complication rates. Postoperative pain management should be planned considering the clinical characteristics of the patient, experience of the anesthetist, and clinical facilities. Early postoperative analgesia reduces systemic complication rates and improves early rehabilitation, patient satisfaction, and quality of life.",signatures:"Yavuz Orak and Mahmut Arslan",downloadPdfUrl:"/chapter/pdf-download/59480",previewPdfUrl:"/chapter/pdf-preview/59480",authors:[{id:"211211",title:"M.D.",name:"Yavuz",surname:"Orak",slug:"yavuz-orak",fullName:"Yavuz Orak"},{id:"238247",title:"Dr.",name:"Mahmut",surname:"Arslan",slug:"mahmut-arslan",fullName:"Mahmut Arslan"}],corrections:null},{id:"59237",title:"Fast Track Surgery Program in Knee Replacement",doi:"10.5772/intechopen.74026",slug:"fast-track-surgery-program-in-knee-replacement",totalDownloads:1006,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"A Fast-track (FT) program, a well-established approach for patients undergoing selective operations, aims at enhanced post-operative recovery. It was first introduced by Professor Henrik Kehlet in 1990s and was applied in colorectal surgery. With the increasing elderly population as well as the increasing incidence of osteoarthritis, the rapid growth of requirement of joint arthroplasties is to be expected. Therefore, many orthopedic teams have applied related principles to their daily practice of total knee arthroplasty to accelerate rehabilitation with lower mortality and morbidity, and to optimize patient satisfaction. The program is a multimodal and multidisciplinary standardized care. Various caring specialties are involved to fulfill the goals of the fast-track program; the basic members include anesthetists, surgeons, pain specialist, physiotherapists, nurses and even medical physicians. In general, the strategy consists of five strands: careful patient selection, improving preoperative care, minimizing perioperative stresses, decreasing postoperative discomfort, and improving postoperative recovery. Through full understanding of these strands and concepts, a comprehensive, perioperative care is thus constructed. This review article gives reader an overall concept of fast track surgery in total knee replacement surgery. A comprehensive search in English literature, including case series, associate randomized controlled trials and systematic reviews were performed using the PubMed databases in 2017 December.",signatures:"Jou-Hua Wang, Chih-Wei Chang, Yi-Chen Chen, Chyun-yu Yang\nand Kai-Lan Hsu",downloadPdfUrl:"/chapter/pdf-download/59237",previewPdfUrl:"/chapter/pdf-preview/59237",authors:[{id:"66952",title:"Prof.",name:"Chyun-Yu",surname:"Yang",slug:"chyun-yu-yang",fullName:"Chyun-Yu Yang"},{id:"70966",title:"Dr.",name:"Chih-Wei",surname:"Chang",slug:"chih-wei-chang",fullName:"Chih-Wei Chang"},{id:"231056",title:"Dr.",name:"Jou-Hwa",surname:"Wang",slug:"jou-hwa-wang",fullName:"Jou-Hwa Wang"},{id:"231057",title:"Dr.",name:"Kai-Lan",surname:"Hsu",slug:"kai-lan-hsu",fullName:"Kai-Lan Hsu"}],corrections:null}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},subseries:null,tags:null},relatedBooks:[{type:"book",id:"5164",title:"Advanced Techniques in Bone Regeneration",subtitle:null,isOpenForSubmission:!1,hash:"e99f852544eefac23fb5fe0697c2096d",slug:"advanced-techniques-in-bone-regeneration",bookSignature:"Alessandro Rozim Zorzi and Joao Batista de Miranda",coverURL:"https://cdn.intechopen.com/books/images_new/5164.jpg",editedByType:"Edited by",editors:[{id:"80871",title:"M.D.",name:"Alessandro Rozim",surname:"Zorzi",slug:"alessandro-rozim-zorzi",fullName:"Alessandro Rozim Zorzi"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"5522",title:"Osteonecrosis",subtitle:null,isOpenForSubmission:!1,hash:"108218b008b3e8768c595a6ab363c331",slug:"osteonecrosis",bookSignature:"Alessandro R Zorzi and Joao Batista de Miranda",coverURL:"https://cdn.intechopen.com/books/images_new/5522.jpg",editedByType:"Edited by",editors:[{id:"80871",title:"M.D.",name:"Alessandro Rozim",surname:"Zorzi",slug:"alessandro-rozim-zorzi",fullName:"Alessandro Rozim Zorzi"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"943",title:"Bone Grafting",subtitle:null,isOpenForSubmission:!1,hash:"9afab8beeb4879b2751907783a3de842",slug:"bone-grafting",bookSignature:"Alessandro Zorzi and Joao Batista de Miranda",coverURL:"https://cdn.intechopen.com/books/images_new/943.jpg",editedByType:"Edited by",editors:[{id:"80871",title:"M.D.",name:"Alessandro Rozim",surname:"Zorzi",slug:"alessandro-rozim-zorzi",fullName:"Alessandro Rozim Zorzi"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"6052",title:"Cartilage Repair and Regeneration",subtitle:null,isOpenForSubmission:!1,hash:"e4881b3685ffd70f3f4d3d2c49b1d7f6",slug:"cartilage-repair-and-regeneration",bookSignature:"Alessandro R. 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1. Introduction
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Lung cancer is the leading cause of cancer mortality worldwide, with over 1.7 million deaths and over 2 million newly diagnosed cases annually [1]. More than a half of all new diagnosed patients with non-small cell lung cancer (NSCLC) presents in stage IV disease with a median overall survival (OS) of 10–12 months. Stage IV NSCLC is generally considered incurable disease with a 5-year survival ranged from 0 to 10% [2]. However, the sub segment of patients in stage IV was recognized years ago with different clinical presentation and prolonged survival that overcomes expected for metastatic disease [3]. Oligometastatic disease was first described in 1995 as a state of limited systemic metastatic burden in which treatment of oligometastases with radical local therapies could be curative in selected patients [3, 4]. For decades, no high-level evidence has been introduced for management of these patients subset. Moreover, no uniform definition and staging requirements for usage the term oligometastatic NSCLC have been accepted until recently. Clinical data indicate that the number of patients with oligometastatic disease that undergo ablative local treatment is increasing at a great rate [5]. With the extension of imaging diagnostic methods like 2-deoxy-2-[fluorine-18]fluoro-D-glucose positron emission tomography/computed tomography (18F-FDG PET/CT) and magnetic resonance imaging (MRI), oligometastatic NSCLC patients who benefit most from radical treatment could be selected precisely [6]. On the other hand, development in technical improvement of modern local treatment approaches and advances in new systemic treatment options for NSCLC patients offer new hope for improvement of outcomes in oligometastatic NSCLC. In this chapter, we present most relevant scientific evidence regarding oligometastatic NSCLC and discuss future perspectives in treatment of these patients in the era of molecular targeted treatment and immunotherapy.
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2. Definition
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Even the oligometastatic disease was first described in 1995, no uniform and clear definition has been accepted for years [3]. Most past clinical trial protocols have used an upper limit of metastases between one and eight as inclusion criteria; however, 90% of included patients actually had one metastasis [5, 7].
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The concept of oligometastatic NSCLC include different clinical scenarios of limited number of metastatic lesions that are feasible to local ablative treatment. Regarding the time of presentation, in synchronous oligometastatic disease metastatic lesions are detected at the time of diagnosis of the primary tumor. In metachronous oligometastatic disease new metastatic lesions not present at the time of the primary diagnosis develop [8, 9]. Other related terms are currently used, like oligorecurrence, in which limited number of metastatic lesions develop in otherwise controlled primary tumor site followed radical treatment. Oligoprogression describes metastatic disease with controlled primary tumor and most metastases due to systemic therapy followed by progression of one or few metastatic lesions. Oligoressistance follows systemic therapy of patients with widespread metastases who have a near complete response but limited number of persistent lesions remains. First attempt to unify the oligometastatic state was inclusion oligometastatic disease in the 8th edition of the Tumor, Node, Metastasis (TNM) published by the International Association for the Study of Lung Cancer (IASLC). In the assessment for M descriptor, 225 (22%) of the 1025 metastatic patients were reported with a single metastasis in a single organ that had significantly better prognosis than those with multiple metastases in one or several organs [10]. Accordingly, single metastatic lesion in a single distant organ was assigned to the new M1b category [2, 10].
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Recently, a pan-European multidisciplinary consensus statement on the definition and staging of synchronous oligometastatic NSCLC was formulated [11]. As it was concluded, the definition is relevant when a radical treatment is technically feasible with acceptable toxicity, with all sites being amenable to local treatment modality that may result in long-term disease control. A maximum of 5 metastases and 3 organs is proposed for definition of oligometastatic NSCLC. The presence of diffuse serosal metastases (meningeal, pericardial, pleural, and mesenteric) or bone marrow involvement excludes cases from the definition, as these cannot be treated with radical intent. For pulmonary metastases, the eight TNM classification should be followed. Metastasis in the same lobe (T3) or in the same lung (T4) should not be counted as a metastatic site, but it can influence the possibility of treatment with radical intent. Mediastinal lymph nodes must be considered as regional disease, but their involvements are of importance in the decision of feasibility for radical treatment of locoregional disease. The recommendations for staging include 18F-FDG PET/CT and brain imaging, preferably magnetic resonance imaging (MRI), that are mandatory. Besides mediastinal lymph node staging with 18F-FDG PET/CT, pathological confirmation is required if this influences the treatment decision. In addition, pathological confirmation at least of one metastasis is required unless the risk outweighs the benefit.
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3. Incidence
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Oligometastatic disease used to be reported sporadically [12]; however, with the improvement in diagnostic imaging, mainly 18F-FDG PET/CT and MRI, oligometastases appear relatively frequent. While available data on incidence of oligometastatic NSCLC at diagnosis remains limited, even when published mostly in retrospective reports, the diversity of inclusion criteria about the maximum number of metastatic lesions accepted for study, makes it more difficult to compare. However, it has been estimated that aproximatelly 20–50% patients with metastatic NSCLC at diagnosis present with oligometastatic disease [10, 13, 14]. As mentioned before, in the IASLC TNM classification of lung cancer, 22% of all metastatic patients had a single metastatic lesion [10]. The most frequent site of a single lesion was bone, followed by brain, adrenals and liver. In an analysis of 725 NSCLC patients with metastatic disease at diagnosis, 186 (26%) were recognized with oligometastatic disease defined as ≤5 lesions [13]. Of those, 51% of the patients had a single metastatic lesion and in 81% of patients, metastases were limited to one organ site. As in previous analysis, the most common site of a single lesion appearance was brain, bone and adrenal glands. In the group of oligorecurrent NSCLC patients after treatment of the primary site, 50–60% were reported to present with only one to three metastatic sites [4, 15]. The majority of patients who have been treated with surgery, at recurrence presented with metastases in the brain, contralateral lung or adrenal gland. The pattern of oligoprogression in advanced or metastatic NSCLC patients after first-line chemotherapy has been barely reported. In a study of Rusthoven et al., local progression only, was the predominant pattern of failure in 64% of patients after systemic therapy, mostly platinum-based chemotherapy, suggesting that consolidation local therapy after first-line systemic treatment could potentially alter the patterns of failure and prolong time to progression in a substantial proportion of those patients [14]. With the introduction of new systemic treatment possibilities that prolong survival, like tyrosine kinase inhibitors (TKI) in patients with epidermal growth factor receptor (EGFR) mutation/anaplastic lymphoma kinase (ALK) rearrangement, oligoprogression has been reported more often. Molecular targeted therapy with TKI enable higher response rates and better progression-free survival (PFS), however, progression inevitably develops in most cases after 1 to 2 years of molecular targeted treatment due to acquired resistance [16]. Data from literature reveals that the proportion of patients progressing with an oligoprogressive pattern of disease ranges from 15 to 47% during EGFR TKI treatment [17, 18, 19]. Few series also suggest that as many as 25% of patient treated with TKI progress with single metastases and 50% with four or less lesions [17, 20]. For those patients with oligoprogressive or oligoresistance disease, local ablative therapy and continuation of molecular targeted therapy could result in more than 6 months of additional clinical benefits [20].
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4. Prognostic factors
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Oligometastatic disease is highly divers in prognosis, ranged from rapid progression with demise during treatment to long-term survivals. It is assumed that about 25% of oligometastatic patients will have prolonged disease-free interval [7, 12, 21]. Therefore, the identification of oligometastatic patients that will benefit most from aggressive local treatment is of the crucial importance.
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As already mentioned, results from IASLC 8th TNM classification validation study revealed significantly longer OS in patients with a single extrathoracic metastasis than in those with multiple metastases [10]. In the individual patients data meta-analysis of Ashworth et al. 757 oligometastatic NSCLC patients were included from 1985 to 2012 and managed with ablative treatments to all sites of disease, however, half of the patients had only a single metastasis [7]. Surgery was the most commonly used treatment for the primary tumor (83.9%) and metastases (62.3%). Factors predictive for OS were synchronous versus metachronous metastases (P < .001), N-stage (P = .002), and adenocarcinoma histology (P = .036). In recursive partitioning analysis, three risk groups were identified: low-risk, metachronous metastases (5-year OS, 47.8%); intermediate risk, synchronous metastases and N0 disease (5-year OS, 36.2%); and high risk, synchronous metastases and N1/N2 disease (5-year OS, 13.8%). In the analysis of Parikh et al., 186 patients with five or fewer distant metastatic lesions at diagnosis were included, of whom 52% patients had a single metastatic lesion [13]. On multivariable analysis, Eastern Cooperate Oncology Group (ECOG PS) performance status, nodal status N2–3, squamous pathology, and metastases to multiple organs were associated with a greater hazard of death (all P < .01). However, the number of metastatic lesions and radiologic size of the primary tumor were not associated with OS. Definitive local therapy to the primary tumor was associated with prolonged survival. Data from twenty-four studies that included altogether 1935 patients with oligometastatic NSCLC were analyzed in a meta-analysis by Li et al. [22]. Among patients with oligometastatic disease, defined as 5 or fewer lesions, they identified several factors associated with improved survival, including aggressive treatment to the primary lung tumor, female gender, lower nodal stage, adenocarcinoma histology and thoracic stage. Other retrospective publications reported importance of aggressive local treatment [23, 24]; moreover, the major predictors of OS were the extent of intra-thoracic disease including nodal status and possibilities for resection or radical radiotherapy [25, 26, 27]. In the trial by Gomez et al. besides treatment type (local treatment versus no local treatment) presence of driver mutations were associated with improved PFS [28, 29]. Aside of the number of metastases, mediastinal node involvement, time until onset of metastases, histology, PS, T stage, treatment of the primary and metastatic lesions, diagnosis-specific graded prognostic assessment (DS-GPA classification, and Lung-molGPA) is well known for patients with brain metastasis.
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Additionally, a specific genetic or epigenetic alterations (“initiation,” “progression,” and “virulence” genes) have been described so far that together with failures in immunosurveillance impact patients‘clinical outcomes. The oligometastatic tumors are believed to have more indolent biology [3]. Initial investigations of the mechanisms running occurrence of oligometastases identified a central role of microRNAs (miRNAs). Lussier and colleagues evaluated miRNA profiles in an analysis of patients with five metastases manageable for RT. They found that overexpression of the miR-200 family was correlated with polymetastatic progression [30]. Moreover, they observed a specific microRNA expression that identified the patients most likely to remain oligometastatic after metastases directed treatment and therefore associated with a better prognosis.
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5. Treatment
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Since oligometastatic NSCLC is considered as intermediate state between localized lung cancer and widespread metastatic disease, the therapeutic approaches used for treatment of these patients besides standard systemic therapy include aggressive local therapy.
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Several early case and retrospective reports showed that a subset of NSCLC patients with mostly solitary metastasis that were radically treated to all known metastatic sites, could achieve long-term survival [31, 32, 33]. Following years, more retrospective reports of oligometastatic patients treated with radical intent were published that demonstrating better-than-expected prolonged survival with median OS between 13.5 to 26 months and 5-year survival between 10 to 36% [13, 23, 24, 25, 34, 35, 36, 37]. In an individual patient data meta-analysis on 757 oligometastatic NSCLC treated between 1985 and 2012 with surgical metastasectomy, stereotactic radiotherapy/radiosurgery, or radical external-beam radiotherapy for metastases and with curative treatment of the primary lung cancer, median OS was 26 months, 1-year OS 70.2%, and 5-year OS 29.4% [7].
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While the last decade use of effective local treatment with minimally invasive surgery or advanced radiation technics for oligometastatic lesions in NSCLC patients has risen, the evidence from prospective studies has been lacking. The first prospective single-arm phase II trial of oligometastatic NSCLC patient with up to five metastases at primary diagnosis amendable for radical local treatment was published in 2012 [27]. Forty patients were enrolled with brain, bone and adrenal gland metastases. Of all included, 87% had a single metastatic lesion and 95% of all received chemotherapy as part of their primary treatment. Median OS was 13.5 months and two- and three- year survival rates were 23.3% and 17.5%, respectively. In 2016, Gomez et al. published the results of a prospective multicentre randomized phase 2 trial that enrolled 74 oligometastatic NSCLC patients with the maximum of 3 metastatic lesion [28]. All patients received standard first-line systemic therapy including platinum-based chemotherapy or TKI in patients with EGFR mutations or ALK rearrangements. Patients were randomly assigned to either local consolidative therapy consisting of resection or (chemo) radiotherapy or to maintenance treatment alone. The study was terminated early after randomization of 49 patients as part of the annual analyses due to substantial efficacy improvement in the local consolidative group compared with the maintenance group. At a median follow-up time of 12.39 months, the median PFS in the consolidative group was significantly longer with 11.9 months versus 3.9 months in the maintenance group. Importantly, time to appearance of a new lesion was longer in the consolidative group arm (11.9 months vs. 5.7 months) suggesting that local consolidative treatment may have altered the natural course of the disease, either by limiting the potential for subsequent dissemination or by altering systemic anticancer immune response. In 2018, the updated survival data at a median follow-up of 38.8 month, confirmed the PFS benefit in consolidative group with 14.2 months compared to 4.4 months in the maintenance group and median OS of 41.2 months in the consolidative arm versus 17.0 months in the maintenance arm [29].
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In a phase II randomized clinical trial conducted by Iyengar et al., a total of 29 patients with oligometastatic NSCLC were included [38]. Inclusion criteria allowed up to six sites of extra cranial lesions (including primary) and exclude patients receiving first-line molecular targeted therapy with EGFR/ALK TKI. Fourteen patients were assign to the stereotactic body radiation therapy (SBRT)-plus-maintenance chemotherapy arm, and 15 patients to the maintenance chemotherapy–alone arm. In the SBRT group, all residual disease sites were treated with SBRT. A total of 31 lesions were treated in 14 patients with intrathoracic sites the most common locations of SBRT treatment. Likewise, the trial was stopped to accrual early after an interim analysis found a significant improvement in PFS in the SBRT-plus-maintenance chemotherapy arm with 9.7 months vs. 3.5 months in the maintenance chemotherapy–alone arm (P = .01).
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A third completed randomized phase II trial, SABR (stereotactic ablative radiotherapy)-COMET international trial included patients with a controlled primary malignancy of different solid cancers and 1–5 metastatic lesions manageable for SABR treated between 2012 and 2016 [39]. Ninety-nine patients, of those 18% NSCLC patients, were randomly assigned in a 1:2 ratio between standard-of-care treatments and standard-of-care treatments plus SABR. Median OS was 28 months in the control group versus 41 months in the SABR group. Adverse events of grade 2 or worse were significantly higher in SABR group (29% vs. 9%) with three deaths after SABR. Recently, results of extended follow-up were published [40]. With the median follow-up of 51 months, median OS was 28 months in the control arm versus 50 months in the SABR group. Five-year OS rates were 17.7% versus 42.3%, respectively. There were no new grade 2–5 adverse events.
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All three randomized studies have contributed increasingly in the evidence that radical local treatment approach added to standard therapy may yield prolonged survival in selected oligometastatic NSCLC. However, last decade most studies have still been retrospective in nature and biased with respect to definition of oligometastatic disease. Systematic review by Schanne et al. included 54 studies that were published between 1987 and 2018 with altogether 1994 patients with oligometastatic NSCLC [5]. Even with a wide range of oligometastatic definitions, 90% of patients were treated for a single metastasis. 60% of patients were diagnosed with adenocarcinoma and 55% of the metastases were located in the brain, 17% in the lung, 11% in the adrenal gland and 17% in other organs. Systemic therapy was used in 68% of patients in a variety of settings, mostly adjuvant/maintenance or neoadjuvant but also combined with RT. Molecular targeted therapy was used in 5% of cases; however, immunotherapy was not used treatment modality in any of analyzed studies. Surgical resection was the most common local treatment modality used in 76% of patients for primary tumor and in 65% of patients for distant metastases. RT was used as neoadjuvant/adjuvant or definitive treatment of primary tumor in 9% and 22%, respectively. Adjuvant RT after surgical resection for metastatic lesions was used in 27% of patients, mostly after resection of brain metastases. Radiation as primary treatment modality was more common for treatment of metastases than for primary tumors (69% vs. 35%). Median OS in the analyzed studies was 19.6 months (6.2–52.9 months) with an observed plateau and possible long-term survival of 20%. Importantly, this analysis also gives us insight in time trends of management oligometastatic NSCLC patients for the last three decades. Relating to time analysis, in the studies published after 2011 radiotherapy has almost surpassed surgical approaches. Local treatment changed in favor to wider use of radiotherapy for primary tumors from 23 to 41%. Moreover, wider adoption of SBRT instead of conventionally fractionated RT with an increase from 0 to 23% for primary tumors and from 15 to 60% for distant metastases was reported. Additionally, the number of patients receiving no systemic therapies was reduced from 45% before 2011 to 24% afterwards. Notably, a trend for improved median OS over time was observed: patients from reports published after 2011 revealed better OS compared to the earlier period: 28.1 months versus 17.2 months, respectively. Comparing the effect of different type of local treatment, when only studies after 2011 were included, no significant effect on median OS was detected neither for primary tumor nor for metastases.
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Despite the lack of evidence for optimal treatment of patients with oligometastatic NSCLC, the concept of delivering local radical treatment in patients with oligometastatic NSCLC was incorporated in NSCLC guidelines. The European Society for Medical Oncology (ESMO) Clinical Practice Guidelines due to the limited available evidence propose preferred inclusion in clinical trials [41, 42]. The National Comprehensive Cancer Network (NCCN) guidelines state that patients with NSCLC with limited metastases can receive local radical treatment [43].
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6. Challenges in the era of molecular targeted and immunotherapy
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The management of oligometastatic NSCLC has changed significantly over the past decades. While surgery, radiotherapy, stereotactic radiotherapy and systemic therapy are the cornerstones of current treatment strategies, treatment modalities have varied over time with respect to the advantages of local treatment techniques as introduction of new systemic treatment possibilities. According to the literature, surgery has been mostly used in oligometastatic NSCLC patients for resection of brain, contralateral lung and adrenal gland metastases [5, 23, 35, 44] Considering the significant morbidity associated with surgical resection of multiple sites of metastatic disease, SBRT has become an alternative treatment approach for achieving local ablation. The highest level of evidence for incorporation of local treatment in oligometastatic NSCLC patients based on small randomize phase II clinical trials, which regularly reported higher PFS and OS with the use of SBRT compared with no SBRT [28, 29, 38, 39, 40]. However, the efficacy of SBRT in potentially curable patients with the stage I NSCLC is already confirmed [45]. The broader adoption of SBRT in clinical practice reflects its non-invasive nature, ability to simultaneous treatment of multiple sites in a short time, feasibility of concurrent local and systemic treatment, utility to treatment in the outpatient setting and relatively low toxicity profile [46, 47]. Moreover, SBRT to the progressing lesions may delay the need to start or change systemic therapy that might reflect in prolonged PFS, OS and quality of life for the patients [48, 49, 50]. In a systematic review by Tsao et al., reported median OS ranged from 13.5 to 55 months and PFS from 4.4 to 14.7 months. [50] SBRT has currently become a treatment option for tumors in almost any body site, with many publications documenting its efficacy for lung, liver, adrenal, and bone/spine metastases, achieving high as much as 70–90% of local control [51].
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Systemic therapy is the backbone treatment for metastatic NSCLC patients; though it is not well defined in management for oligometastatic NSCLC [41, 42, 43]. Despite potentially successful local treatment, the majority of oligometastatic NSCLC patients will develop distant progression due to undetectable micrometastases at the time of diagnosis. Therefore, all recent prospective trials combined local treatment with addition of systemic therapy standardly used at the time of the study. However, the therapeutic sequence of systemic therapy might be important for oligometastatic disease, as usually only the patients who do not progress with induction systemic treatment were capable for aggressive local treatment. We are currently not able to reliably predict the course of oligometastatic disease at the time of diagnosis, therefore upfront local therapy colud represent an overtreatment due to rapid progression to multimetastatic disease. Although studies with oligometastatic NSCLC have included patients treated with systemic therapy, mostly chemotherapy and minority molecular targeted therapies, current clinical practice and guidelines for treatment of metastatic NSCLC include molecular targeted agents, immunotherapy or combination of immunotherapy and chemotherapy in first-line setting [52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64]. The introduction of new agents as molecular targeted and immunotherapy has resulted in the improved survival in patients with metastatic and locally advanced NSCLC. As a result, the first line systemic therapies used in most retrospective and prospective studies of oligometastatic NSCLC do not reflect those currently used. With onset of new systemic therapies in the management of NSCLC patients, great interest has risen in exploring the safety and efficacy of combined SBRT with new agents to improve the therapeutic outcomes in metastatic NSCLC as well as in oligometastatic disease.
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6.1 Molecular targeted therapy in oligometastatic NSCLC
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Patients with actionable tumor mutations have high response rates and long PFS times when treated with molecular targeted therapy [54, 55, 56, 57, 58, 59, 60, 61, 62]. However, progression inevitably occurs due to either insufficient CNS passage of the drug in some cases of CNS progression, or to acquired resistance with biological change in the tumor cells. The concept of oligoprogression supports the idea of disease progression due to the development of TKI-resistant clones with subsequent distant progression [65]. Different scenarios of progression in patients with actionable tumor mutations including oligoressistance, oligoreccurence or oligoprogression requiring consideration for local treatment. In the analysis of Guo et al. the majority of progressive disease on osimertinib was reported within residual lesions in initially involved sites, thus consolidative SBRT may prolong time to progression in a selected subgroup of patients [66]. In a retrospective study of Xu et al., 145 patients with oligometastatic EGFR-mutant NSCLC diagnosed from 2010 to 2016 were enrolled [67]. According to consolidative local treatment with surgery or radiotherapy, patients were grouped in three category, 51 in the all-local therapy group (consolidative to all residual disease, including primary tumor, lymph nodes, and metastatic sites), 55 in the part-local therapy group (consolidative to either primary tumor or oligometastatic sites), and 39 in the non-local therapy group (not receive any local therapy). Radiotherapy included standard-fractionation radiotherapy (60 Gy in 2-Gy fractions), aggressive palliation radiotherapy (45 Gy in 3-Gy fractions, a biologically equivalent dose of approximately 60 Gy) or stereotactic radiosurgery (SRS), with curative intent when possible. The median PFS in all-local, part-local, and non-local groups were 20.6, 15.6, and 13.9 months, respectively (p < 0.001). The median OS in all-local, part-local, and non-local groups were 40.9, 34.1, and 30.8 months, respectively (p < 0.001). The difference was significant between the all-local group and part-local or non-local group. The median OS was significantly better with consolidative local therapy for primary tumor (40.5 versus 31.5 months, p < 0.001), brain metastases (38.2 versus 29.2 months, p < 0.002), and adrenal metastases (37.1 versus 29.2 months, p < 0.032). Radiation toxicity was acceptable, included grade ≥ 3 pneumonitis (7.7%) and esophagitis (16.9%). No grade 5 toxicity was reported. A retrospective multi-institutional analysis by Magnuson et al. explored the optimal management of patients with EGFR-mutant NSCLC who developed brain metastases and have not received EGFR TKI [68]. A total of 351 patients from six institutions were included. Patients were treated with SRS followed by EGFR-TKI, WBRT followed by EGFR-TKI, or EGFR-TKI followed by SRS or WBRT at intracranial progression. The median OS for the SRS, WBRT, and EGFR-TKI cohorts was 46, 30 and 25 months, respectively (P < .001). On multivariable analysis, SRS versus EGFR-TKI, WBRT versus EGFR-TKI, age, performance status, EGFR exon 19 mutation, and absence of extracranial metastases were associated with improved OS. SRS followed by EGFR-TKI resulted in the longest OS and allowed patients to avoid the potential neurocognitive sequelae of WBRT.
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In a retrospective analysis of Elamin et al. 129 patients with EGFR-mutant NSCLC who were treated with first-line TKI and 12 that were treated with TKI followed by local consolidation therapy were included [69]. Among the 12 patients treated with TKI plus local consolidative treatment, 8 patients had oligometastatic disease (defined as 3 metastases), and 4 patients had >3 metastases. Local consolidative treatment regimens were hypofractionated radiotherapy or SBRT for 11 patients and surgery for 1 patient. TKI followed by local consolidative treatment resulted in a significantly longer PFS (36 months) compared with TKI alone (14 months). Recently, Wang et al. presented an interim result of a randomized phase III, open-label clinical trial of first-line tyrosine kinase inhibitor with or without upfront local RT in patients with EGFR oligometastatic NSCLC [70]. From January 2016 to January 2019, 133 participants were enrolled, including 65 in the TKI arm who received standard of care TKI alone and 68 in the SBRT arm who received SBRT and TKI. At a median follow-up of 19.6 months, the median PFS for TKI alone was 12.5 months, and for TKI and SBRT was 20.20 months, respectively (P < .001). The median OS in the TKI alone arm was 17.40 months, and for TKI and SBRT arm was 25.50 months, respectively (P < .001).
\n
Concerning the safety profile for combining EGFR or ALK TKI inhibitors and high dose RT, treatment was well tolerated and none of the available studies reported a significant increase in side effects [66, 67, 68, 69]. To conclude, SBRT in combination with molecular targeted agents in actionable mutations NSCLC patients seem rationale for improving long-lasting disease control in synchronous oligometastatic oncogene addicted NSCLC patients; however no prospective data are available to confirm this.
\n
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6.2 Combining immunotherapy and radiotherapy
\n
Immunotherapy with immune checkpoint inhibitors has revolutionized the management of stage IV NSCLC. In recent years, the blockade of programmed cell death 1 (PD-1) / programmed cell death ligand 1 (PD-L1) axis which served as a mechanism for tumor evasion of host tumor antigen-specific T-cell immunity, has demonstrated evident benefit in PFS and OS in metastatic and locally advanced NSCLC [61, 62, 63, 64, 71, 72]. The indications for PD-1/PD-L1 blockade with immune checkpoint inhibitors (ICI) currently include most metastatic NSCLC patients without actionable tumor mutations, either as a single agent or combined with cytotoxic chemotherapy. The anti-PD-1/PD-L1 drugs approved at the moment for NSCLC are pembrolizumab, nivolumab, atezolizumab and durvalumab. Despite this paradigm shift, most patients present some kind of resistance to ICI, therefore arise the interest of researchers to combine multiple therapies. According to growing preclinical data describing mechanistic synergy between radiotherapy and immunotherapy, the most promising investigated combination is ICI with RT [73, 74]. Rational for combining radiotherapy and immunotherapy arises from the significant immune-stimulatory effects they both possess increasing the natural antitumor immune response through synergistic potentiation of an immunomodulatory effect [75, 76]. Increasing evidence indicates that cancer cells killed by radiation release tumor-associated antigens and immunoregulatory cytokines that serve as a kind of in situ vaccine against cancer [77, 78]. Cytokines also activate systemic tumor-specific immune response to eliminate tumor cells even outside the radiation field, so called abscopal effect [79]. This radiation-induced immune-mediated systemic antitumor phenomenon has high therapeutic potential, but is rare and relating to preclinical data more probable induced by high ablative doses, combined with checkpoint inhibitors [80, 81]. SBRT, through released neo-antigens and consequent maturation and proliferation of naive T-cells, and immunotherapy through activation and amplification of naive T-cells, may reciprocally potentiate each other amplification of T-cells-mediated tumoricidal effects [82, 83, 84]. Due to the lack of evidence, most “immunogenic” time sequencing of radio-immunotherapy and radiation dose-fractionation is not determined. Some data indicate that concurrent treatment or close sequencing of immunotherapy following radiotherapy may be the most effective [82]. However, according to data the radiation dose for the optimal antitumor immune response should be sub-tumoricidal. Several preclinical studies suggested that 8 to 10 Gy per fraction in 1–3 fractions represent optimal immunogenic dose [82, 83, 84].
\n
Clinical interest for the combination of ICI and RT in NSCLC started to arise after the results of the KEYNOTE-001 study that enrolled progressive locally advanced or metastatic NSCLC [85]. A secondary analysis of the phase I trial revealed that of 97 included patients, 43% had been treated with RT prior to the administration of pembrolizumab. Those patients had significantly longer PFS (4.4 vs. 2.1 months) and OS (11.6 vs. 5.3 months) comparing patients with no RT. A single-arm phase 2 study of Bauml et al. included 45 patients with oligometastatic NSCLC with up to 4 metastatic sites [86]. Pembrolizumab was administered 4 to 12 weeks after prior comprehensive locally ablative therapy consisting of radiotherapy, chemoradiotherapy, surgery, or radiofrequency ablation, but most received ablative radiotherapy. Median PFS was 19.1 months, significantly greater than the historical median of 6.6 months (P = .005). OS at 12 months was 90.9% and at 24 months 77.5%. Even not conducted in oligometastatic NSCLC patients, the results of a multicetre, randomized phase 2 study (PEMBRO-RT) are interested. 92 patients were enrolled with advanced NSCLC after at least one regiment of chemotherapy with at least two metastases but upper limit was not specified [87]. Altogether, 76 patients were randomized to the pembrolizumab alone (control, 40 patients) or pembrolizumab after radiotherapy (3 fraction of 8 Gy) that was applied to a single metastatic site (experimental, 36 patients) to increase the likelihood of abscopal effect. The overall response rate at 12 weeks was 18% in the control arm vs. 36% in the experimental arm (P = .07). Median PFS was 1.9 months vs. 6.6 months (P = .19), and median OS was 7.6 months vs. 15.9 months (P = .16). Although a doubling of overall response rate was observed, the results did not meet the study’s prespecified end point criteria for meaningful clinical benefit. Interestingly, subgroup analyses showed the largest benefit of radiotherapy in patients with PD-L1 – negative tumors. In a retrospective study of Samstein et al. 758 patients treated with ICI and RT were analyzed [88]. Median OS was 9 months in the entire cohort. Subanalysis regarding sequencing ICI and RT revealed increased OS in patients who received ICI and RT simultaneously. Median OS was 20 months for patients who started with ICI for at least 1 month before RT and continued throughout RT compared with 11 months for those that started ICI less than 30 days prior to RT and continued ICI throughout RT. In the cohort of patients who received concurrent therapy, hypofractionated radiotherapy (dose >4.00 Gy per fraction) and ICI greater than 30 days before RT was associated with improved OS.
\n
Prospective data for management of patients with oligometastatic NSCLC in the era of immunooncology is scarce. Most of the available data on combining ICI and SBRT has been retrospective experiences on patients with metastatic NSCLC; however the benefit of combined treatment has been persistently demonstrated [89, 90, 91]. Importantly, the available data suggest that toxicity profile from the combination treatment has not increased in comparison to immunotherapy alone in the metastatic setting. A recent systematic review from prospective studies revealed grade ≥ 3 median toxicity rates of 14.5% with anti-PD-1/L1 plus SABR and 26% with anti-CTLA-4 plus SABR [92]. Concerning toxicity, no increased rates of immune-related adverse events using SBRT in the different organs or tissue types have been reported. However, reports from the studies that combined dual ICI therapy with SBRT in different cancers in prospective trials detected more toxicity.
\n
In the future management of oligometastatic NSCLC patients, more questions should be answered. In the era of immunooncology, local treatment still presents the backbone of management with adding ICI to improve outcome of oligometastatic NSCLC patients. However, future prospective studies should give us answers to what sequence of local treatment and ICI is the most optimal combination, which radiation technique and fractionation would offer the best results, which patients should be selected for radical-intent treatment regarding biomarkers. A great number of trials combining ICI and RT are ongoing. Regarding oligometastatic NSCLC, one is of particular interest, a randomized trial of consolidative immunotherapy with vs. without thoracic radiotherapy and/or SBRT after first-line systemic therapy for metastatic NSCLC comparing PFS as primary objective (NCT03867175).
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\n
\n
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7. Beyond progression: oligoprogression in NSCLC patients
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An important growing subsegment of NSCLC patients is a group with oligoprogressive disease. With more effective systemic therapies that offer high response rates and long PFS times in patients with metastatic NSCLC, the oligoprogressive disease has become more and more common clinical scenario. Oligoprogressive disease, presented in oncogene driven NSCLC mostly occur due to the isolated emergence of well-described resistance mutations [65]. According to the literature, the occurrence of oligoprogression during TKI treatment seems to be quite frequent, reported in the range of 32–49% [17, 19, 20]. However, the optimal therapeutic approach in these patients is still unclear. Three main treatment options include changing systemic therapy, continuing the same systemic therapy beyond progression or using local therapy for eradicate the resistant clones while continuing the same systemic therapy [41]. The evidence supporting local treatment is limited to small retrospective reports. Weckhard et al. reported that 49% of ALK or EGFR positive metastatic NSCLC patients are treated with TKI presented with intracranial or extracranial oligoprogression suitable for local treatment [20]. Of 25 patients, 24 were treated with RT and one underwent surgery; however, 19 of 25 locally treated patients progressed again with PFS of 6.2 months. Yu et al. reported on 184 patients with EGFR mutation, of these 42 progressed with intracranial and 18 with extracranial oligometastases. These 18 were treated with local therapy, including surgery, radiofrequency ablation or RT with the median TTP of 10 months. Gan et al. reported on 33 ALK+NSCLC patients treated with crizotinib that had extracranial oligoprogression. Of these, 14 were suitable for local treatment with SBRT. Median overall time on crizotinib among those treated with SBRT versus those who progressed but were not suitable for SBRT was 28 and 10.1 months, respectively. Patients remaining on crizotinib for >12 months vs. ≤12 months had a 2 year OS of 72% vs. 12%, respectively (p < 0.0001) [93]. Xu et al. reported on 206 EGFR-mutant NSCLC patients included in the analysis of the survival benefit of adding local ablative therapy after oligoprogression during first-line TKI. With the median follow-up time of 42 months, the median PFS1, median PFS2 and median OS were 10.7 months, 18.3 months and 37.4 months, respectively. Survival rates of 1 year, 2 years and 3 years were 94.1%, 78.9%, and 54.7%, respectively. Altogether, the data suggest that local ablative treatment of progressive lesions in actionable mutations NSCLC patients can prolong treatment with first-line TKI without reported unacceptable excess toxicity. Moreover, despite the paucity and the heterogeneity of clinical data the use of local therapy in oligoprogressive oncogene driven NSCLC is already considered as standard clinical practice [94].
\n
Currently, a few prospective randomized clinical trials are ongoing researching the benefit of local ablative treatment in oligoprogressive NSCLC. A Canadian trial, the STOP-NSCLC (NCT02756793) is a randomized phase II trial with estimated enrolment of 54 patients with oligoprogressive NSCLC during TKI or maintenance chemotherapy that evaluate either SBRT with continuation of current systemic agents or standard of care that may include continuation of current systemic agent, observation or switch to next-line treatment. Primary end-point will be PFS, while secondary end-points will be OS, local control, toxicity, quality of life and patterns of further progression. Similarly, European HALT study (NCT03256981) is a phase II/III, randomized study with question whether the use of SBRT to ≤3 sites of oligoprogressive disease in mutation positive advanced NSCLC patients with continuation of TKI improves PFS compared to continuation of TKI alone. The study aims to recruit 110 patients with oligoprogressive mutation positive advanced NSCLC following initial response to TKI. Third ongoing randomized trial is PROMISE-004 (NCT03808662) study with heterogeneous cohort including breast and NSCLC patients and estimated enrolment of 160 patients with either no targetable mutations upfront or targetable mutations after progression on first-line TKI. The purpose of the study is to evaluate the role of SBRT when metastatic lesions have just begun to grow with PFS as primary end-point.
\n
In the context of immunotherapy in NSCLC patients, which includes the majority of lung cancer patients currently, tumor escape is not uncommon, but studies of oligoprogression are lacking. According to mechanism, oligoprogression might represent local immune tolerance due to stromal or tumor changes. Recently, in order to specify oligoprogression in NSCLC patients treated with immunotherapy, the results of a retrospective analysis of the failure pattern of 297 on ICI and 75 patients treated combined with chemotherapy and ICI were published [95]. Under ICI monotherapy in the first-line treatment, oligoprogression was more frequent (20% vs. 10%, p < .05), occurred later (median 11 vs. 5 months, p < .01) and affected fewer sites (mean 1.1 vs. 1.5, p < .05) compared to oligoprogression in patients treated with ICI monotherapy in later lines. Lymph nodes (42%, manly mediastinal) and the brain (39%) were mostly affected, followed by the lung (24%) and other organs. Compared to multifocal progression, oligoprogression occurred later (11 vs. 4 months, p < .001) and was associated with longer survival (26 vs. 13 months, p < .001) and higher tumor PD-L1 expression (p < .001). Chemoimmunotherapy showed a similar incidence of oligoprogression as ICI monotherapy (13% vs. 11% at 2 years). Local treatments were applied regularly for brain but only in 50% for extracranial lesions. However, oligoprogression in NSCLC patients is less common under ICI treatmnet than under TKI and its frequency descent with time. Few prospective trials evaluate the value of RT in oligoprogressive NSCLC treated with ICI, with one randomized phase II study designed to evaluate the effect of local consolidative RT to all sites of oligoprogressive disease in patients with metastatic NSCLC who have progressed through first-line systemic therapy containing an ICI (NCT04485026).
\n
\n
\n
8. Conclusion
\n
The number of patients with oligometastatic NSCLC has increased significantly over the last decade as well as the use of the locally ablative therapy to treat these patients. The evidence supporting this approach includes three randomized phase II clinical trials and substantial retrospective data; however, the inclusion criteria in these trials were mostly incomparable. Oligometastatic NSCLC has recently been defined by a consensus of multidisciplinary group of European thoracic oncology experts and this was the first step to unify future researching regarding diagnostic procedures and inclusion criteria. Recently, the therapeutic landscape of metastatic NSCLC has dramatically changed with the introduction of new systemic agents as molecular targeted and immunotherapy resulting in the prolonged survival and changing the field of oligometastatic framework significantly. A new concept that emerged with more effective systemic therapy is oligoprogression, frequently presents in patients treated with TKI. Additionally, combining radiotherapy and immunotherapy represent an increasing filed of interest due to synergistic potentiation of an immunomodulatory effect as a way to overcome the resistance of immunotherapy that exist in a substantial part of metastatic NSCLC patients. Especially for oligometastatic NSCLC patients, this integration might be meaningful due to a low tumor burden that seems to be one of the most important predictive factors for the benefit of SBRT-immunotherapy combination. In the future, further studies are needed to assess different treatment variables in order to optimize management of oligometastatic NSCLC in the way that the intent of treatment might not be just prolonged survival but cure.
\n
\n\n',keywords:"oligometastases, non-small cell lung cancer, ablative treatment, stereotactic body radiation therapy, immunotherapy, molecular targeted therapy",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/73888.pdf",chapterXML:"https://mts.intechopen.com/source/xml/73888.xml",downloadPdfUrl:"/chapter/pdf-download/73888",previewPdfUrl:"/chapter/pdf-preview/73888",totalDownloads:330,totalViews:0,totalCrossrefCites:0,dateSubmitted:"July 22nd 2020",dateReviewed:"October 20th 2020",datePrePublished:"December 1st 2020",datePublished:"June 2nd 2021",dateFinished:"November 3rd 2020",readingETA:"0",abstract:"Since 1995, when the concept of oligometastatic non-small cell lung cancer was first described, no high-level evidence has been introduced for management of those patients subset. Data from retrospective reports and analysis and from every-day clinical practice revealed that some of the non-small cell lung cancer patients with a few metastases could benefit significantly with local radical treatment approach of primary and metastatic lesions. Recent advances in modern local treatment approaches with minimally invasive surgery and stereotactic radiotherapy, as well as introduction of immunotherapy, open new field of interest for personalized treatment of limited metastatic non-small cell lung cancer. In this report, we are summarizing limited data of case reports, retrospective studies and few randomized studies of patients with oligometastatic non-small cell lung cancer and discuss challenges of treatment in the era of molecular targeted therapy and immunotherapy.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/73888",risUrl:"/chapter/ris/73888",signatures:"Martina Vrankar",book:{id:"10437",type:"book",title:"Lung Cancer",subtitle:"Modern Multidisciplinary Management",fullTitle:"Lung Cancer - Modern Multidisciplinary Management",slug:"lung-cancer-modern-multidisciplinary-management",publishedDate:"June 2nd 2021",bookSignature:"Henry S. Park",coverURL:"https://cdn.intechopen.com/books/images_new/10437.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",isbn:"978-1-78985-576-0",printIsbn:"978-1-78985-575-3",pdfIsbn:"978-1-78985-638-5",isAvailableForWebshopOrdering:!0,editors:[{id:"96610",title:"Dr.",name:"Henry S.",middleName:null,surname:"Park",slug:"henry-s.-park",fullName:"Henry S. Park"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:[{id:"327889",title:"Assistant Prof.",name:"Martina",middleName:null,surname:"Vrankar",fullName:"Martina Vrankar",slug:"martina-vrankar",email:"mvrankar@onko-i.si",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Definition",level:"1"},{id:"sec_3",title:"3. Incidence",level:"1"},{id:"sec_4",title:"4. Prognostic factors",level:"1"},{id:"sec_5",title:"5. Treatment",level:"1"},{id:"sec_6",title:"6. Challenges in the era of molecular targeted and immunotherapy",level:"1"},{id:"sec_6_2",title:"6.1 Molecular targeted therapy in oligometastatic NSCLC",level:"2"},{id:"sec_7_2",title:"6.2 Combining immunotherapy and radiotherapy",level:"2"},{id:"sec_9",title:"7. Beyond progression: oligoprogression in NSCLC patients",level:"1"},{id:"sec_10",title:"8. Conclusion",level:"1"}],chapterReferences:[{id:"B1",body:'\nBray F, Ferlay J, Soerjomataram I, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018; 68: 394-424.\n'},{id:"B2",body:'\nGoldstraw P, Chansky K, Crowley J,et al. The IASLC Lung Cancer Staging Project: Proposal for Revision of the TNM Stage Groupings in the Forthcoming (Eight) Edition of the TNM Classification for Lung Cancer. J Thorac Oncol. 2016;11(1):39-51.\n'},{id:"B3",body:'\nHellman S, Weichselbaum RR. Oligometastases. 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J Thorac Oncol. 2012;7(12):1807-1814.\n'},{id:"B21",body:'\nHendriks LE, Derks JL, Postmus PE, et al. Single organ metastatic disease and local disease status, prognostic factors for overall survival in stage IV non-small cell lung cancer: Results from a population-based study. Eur J Cancer. 2015;51(17):2534-44.\n'},{id:"B22",body:'\nLi S, Zhu R, Li D, et al. Prognostic factors of oligometastatic non-small cell lung cancer: a meta-analysis. J Thorac Dis. 2018;10(6):3701-3713.\n'},{id:"B23",body:'\nCollaud S, Stahel R, Inci I, et al. Survival of patients treated surgically for synchronous single-organ metastatic NSCLC and advanced pathologic TN stage. Lung Cancer. 2012;78(3):234-8.\n'},{id:"B24",body:'\nSheu T, Heymach JV, Swisher SG, et al. Propensity score-matched analysis of comprehensive local therapy for oligometastatic non-small-cell lung cancer that did not progress after front-line chemotherapy. Int J Radiat Oncol Biol Phys. 2014;90(4):850-7.\n'},{id:"B25",body:'\nGriffioen GH, Toguri D, Dahele M, et al. Radical treatment of synchronous oligometastatic non-small cell lung carcinoma (NSCLC): patient outcomes and prognostic factors. Lung Cancer. 2013;82(1):95-102.\n'},{id:"B26",body:'\nLopez Guerra JL, Gomez D, Zhuang Y, et al. Prognostic impact of radiation therapy to the primary tumor in patients with non-small cell lung cancer and oligometastasis at diagnosis. Int J Radiat Oncol Biol Phys. 2012;84(1):e61-7.\n'},{id:"B27",body:'\nDe Ruysscher D, Wanders R, van Baardwijk A, et al. Radical treatment of non-small-cell lung cancer patients with synchronous oligometastases: long-term results of a prospective phase II trial (Nct01282450). J Thorac Oncol. 2012;7(10);1547-55.\n'},{id:"B28",body:'\nGomez DR, Blumenschein GR Jr, Lee JJ, et al. Local consolidative therapy versus maintenance therapy or observation for patients with oligometastatic non-small-cell lung cancer without progression after first-line systemic therapy: a multicentre, randomised, controlled, phase 2 study. The Lancet Oncol. 2016;17(12):1672-1682.\n'},{id:"B29",body:'\nGomez DR, Tang C, Zhang J, et al. Local Consolidative Therapy Vs. Maintenance Therapy or Observation for Patients With Oligometastatic Non-Small-Cell Lung Cancer: Long-Term Results of a Multi-Institutional, Phase II, Randomized Study. J Clin Oncol. 2019;37(18):1558-1565.\n'},{id:"B30",body:'\nLussier YA, Khodarev NN, Regan K, et al. Oligo- and polymetastatic progression in lung metastasis (es) patients is associated with specific microRNAs. PLoS One. 2012;7(12):e50141.\n'},{id:"B31",body:'\nTanvetyanon T, Robinson LA, Schell MJ, et al. Outcomes of adrenalectomy for isolated synchronous versus metachronous adrenal metastases in non-small-cell lung cancer: a systematic review and pooled analysis. J Clin Oncol. 2008;26(7):1142-7.\n'},{id:"B32",body:'\nPorte H, Siat J, Guibert B, et al. Resection of adrenal metastases from non-small-cell lung cancer: a multicentre study. Ann Thorac Surg. 2001;71(3):981-5.\n'},{id:"B33",body:'\nAmbrogi V, Tonini G, Mineo TC. Prolonged survival after extracranial metastasectomy from synchronous resectable lung cancer. Ann Surg Oncol. 2001;8(8):663-6.\n'},{id:"B34",body:'\nCollen C, Christian N, Schallier D, et al. Phase II study of stereotactic body radiotherapy to primary tumor and metastatic locations in oligometastatic non-small-cell lung cancer patients. Ann Oncol. 2014;25(10):1954-1959.\n'},{id:"B35",body:'\nCongedo MT, Cesario A, Lococo F, et al. Surgery for oligometastatic non-small cell lung cancer: long-term results from a single center experience. J Thorac Cardiovasc Surg. 2012;144(2):444-52.\n'},{id:"B36",body:'\nFleckenstein J, Petroff A, Schäfers HJ, et al. Long-term outcomes in radically treated synchronous vs. metachronous oligometastatic non-small-cell lung cancer. BMC Cancer. 2016;16:348.\n'},{id:"B37",body:'\nInoue T, Katoh N, Aoyama H, et al. Clinical outcomes of stereotactic brain and/or body radiotherapy for patients with oligometastatic lesions. Jpn J Clin Oncol. 2010;40(8):788-94.\n'},{id:"B38",body:'\nIyengar P, Wardak Z, Gerber DE, et al. Consolidative Radiotherapy for Limited Metastatic Non-Small-Cell Lung Cancer: A Phase 2 Randomized Clinical Trial. JAMA Oncol. 2018;4(1):e173501.\n'},{id:"B39",body:'\nPalma DA, Olson R, Harrow S, et al. Stereotactic ablative radiotherapy versus standard of care palliative treatment in patients with oligometastatic cancers (SABR-COMET): a randomised, phase 2, open-label trial. Lancet. 2019;393(10185):2051-2058.\n'},{id:"B40",body:'\nPalma DA, Olson R, Harrow S, et al. Stereotactic Ablative adiotherapy for the Comprehensive Treatment of Oligometastatic Cancers: Long-Term Results of the SABR-COMET Phase II Randomized Trial. J Clin Oncol. 2020;38(25):2830-2838.\n'},{id:"B41",body:'\nPlanchard D, Popat S, Kerr K, et al. Metastatic non-small cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Updated version published 15 September 2020 by the ESMO Guidelines Committee. Originally published in 2018 – Ann Oncol (2018) 29(Suppl 4): iv192–iv237.\n'},{id:"B42",body:'\nPostmus PE, Kerr KM, Oudkerk M, et al. Early and Locally Advanced Non-Small-Cell Lung Cancer (NSCLC) Treatment Recommendations. Updated version published 04 May 2020 by the ESMO Guidelines Committee. Originally published in 2017 – Ann Oncol 2017;28(suppl 4):iv1-iv21.\n'},{id:"B43",body:'\nNCCN Guidelines. NSCLC version 7.2019. Available at: https://www.nccn.org/professionls/physician_gls/pdf/nscl.pdf (Accessed September 2020)\n'},{id:"B44",body:'\nPlönes T, Osei-Agyemang T, Krohn A, et al. Surgical Treatment of Extrapulmonary Oligometastatic Non-Small Cell Lung Cancer. Indian J Surg. 2015;77(Suppl 2):216-220.\n'},{id:"B45",body:'\nVidetic GMM, Donington J, Giuliani M, et al. Stereotactic body radiation therapy for early-stage non-small cell lung cancer: Executive Summary of an ASTRO Evidence-Based Guideline. Pract Radiat Oncol. 2017;7(5):295-301.\n'},{id:"B46",body:'\nChmura SJ, Winter K, Salama JK, et al. Phase I trial of stereotactic body radiation therapy (SBRT) to multiple metastatic sites: a NRG oncology study. Int J Radiat Oncol Biol Phys. 2018;102(03):S68-S69.\n'},{id:"B47",body:'\nKlement RJ, Hoerner-Rieber J, Adebahr S, et al. Stereotactic body radiotherapy (SBRT) for multiple pulmonary oligometastases: Analysis of number and timing of repeat SBRT as impact factors on treatment safety and efficacy. Radiother Oncol. 2018;127(2):246-252.\n'},{id:"B48",body:'\nCheung P. Stereotactic body radiotherapy for oligoprogressive cancer. Br J Radiol. 2016;89(1066):20160251.\n'},{id:"B49",body:'\nMerino Lara T, Helou J, Poon I, et al. Multisite stereotactic body radiotherapy for metastatic non-small-cell lung cancer: Delaying the need to start or change systemic therapy? Lung cancer. 2018;124:219-226.\n'},{id:"B50",body:'\nTsao MN, Ven LI, Cheung P, et al. Stereotactic Body Radiation Therapy for Extracranial Oligometastatic Non-small-cell Lung Cancer: A Systematic Review. Clin Lung Cancer. 2020;21(2):95-105.e1\n'},{id:"B51",body:'\nTimmerman RD, Herman J, Cho LC. Emergence of stereotactic body radiation therapy and its impact on current and future clinical practice. J Clin Oncol. 2014;32(26):2847-54.\n'},{id:"B52",body:'\nMok TS, Wu YL, Thongprasert S, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009;361(10):947-57.\n'},{id:"B53",body:'\nHan JY, Park K, Kim SW, et al. First-SIGNAL: first-line single-agent iressa versus gemcitabine and cisplatin trial in never-smokers with adenocarcinoma of the lung. J Clin Oncol. 2012;30(10):1122-8.\n'},{id:"B54",body:'\nMaemondo M, Inoue A, Kobayashi K, et al. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med. 2010;362(25):2380-8.\n'},{id:"B55",body:'\nRosell R, Carcereny E, Gervais R, et al. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 2012;13(3):239-46.\n'},{id:"B56",body:'\nSequist LV, Yang JC, Yamamoto N, et al. Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol. 2013;31(27):3327-34.\n'},{id:"B57",body:'\nCamidge DR, Bang YJ, Kwak EL, et al. Activity and safety of crizotinib in patients with ALK-positive non-small-cell lung cancer: updated results from a phase 1 study. Lancet Oncol. 2012;13(10):1011-9.\n'},{id:"B58",body:'\nShaw AT, Yeap BY, Solomon BJ, et al. Effect of crizotinib on overall survival in patients with advanced non-small-cell lung cancer harbouring ALK gene rearrangement: a retrospective analysis. Lancet Oncol. 2011;12(11):1004-12.\n'},{id:"B59",body:'\nSolomon BJ, Mok T, Kim DW, et al. First-line crizotinib versus chemotherapy in ALK-positive lung cancer. N Engl J Med. 2014;371(23):2167-77.\n'},{id:"B60",body:'\nSoria JC, Tan DSW, Chiari R, et al. First-line ceritinib versus platinum-based chemotherapy in advanced ALK-rearranged non-small-cell lung cancer (ASCEND-4): a randomised, open-label, phase 3 study. Lancet. 2017;389(10072):917-929.\n'},{id:"B61",body:'\nReck M, Rodriguez-Abreu D, Robinson AG, et al. Updated Analysis of KEYNOTE-024: Pembrolizumab Versus Platinum-Based Chemotherapy for Advanced Non-Small-Cell Lung Cancer With PD-L1 Tumor Proportion Score of 50% or Greater. J Clin Oncol. 2019;37(7):537-546.\n'},{id:"B62",body:'\nGandhi L, Rodriguez-Abreu D, Gadgeel S, et al. Pembrolizumab plus Chemotherapy in Metastatic Non-Small-Cell Lung Cancer. N Engl J Med. 2018;378(22):2078-2092.\n'},{id:"B63",body:'\nPaz-Ares L, Luft A, Vicente D, et al. Pembrolizumab plus Chemotherapy for Squamous Non-Small-Cell Lung Cancer. N Engl J Med. 2018:379(21):2040-2051.\n'},{id:"B64",body:'\nHellmann MD, Ciuleanu TE, Pluzanski A, et al. Nivolumab plus Ipilimumab in Lung Cancer with a High Tumor Mutational Burden. N Engl J Med. 2018;378(22):2093-2104.\n'},{id:"B65",body:'\nBasler L, Kroeze SG, Guckenberger M. SBRT for oligoprogressive oncogene addicted NSCLC. Lung Cancer. 2017;106:50-57.\n'},{id:"B66",body:'\nGuo T, Ni J, Yang X, et al. Pattern of Recurrence Analysis in Metastatic EGFR-Mutant NSCLC Treated with Osimertinib: Implications for Consolidative Stereotactic Body Radiation Therapy. Int J Rad Oncol Biol Phys. 2020;107(1):62-71.\n'},{id:"B67",body:'\nXu Q , Zhou F, Liu H, et al. Consolidative Local Ablative Therapy Improves the Survival of Patients With Synchronous Oligometastatic NSCLC Harboring EGFR Activating Mutation Treated With First-Line EGFR-TKIs. J Thorac Oncol. 2018;13(9):1383-1392.\n'},{id:"B68",body:'\nMagnuson WJ, Lester-Coll NH, Wu AJ, et al. Management of Brain Metastases in Tyrosine Kinase Inhibitor-Naïve Epidermal Growth Factor Receptor-Mutant Non-Small-Cell Lung Cancer: A Retrospective Multi- Institutional Analysis. J Clin Oncol. 2017;35(10):1070-1077.\n'},{id:"B69",body:'\nElamin YY, Gomez DR, Antonoff MB, et al. Local Consolidation Therapy (LCT) After First Line Tyrosine Kinase Inhibitor (TKI) for Patients With EGFR Mutant Metastatic Mutant Non-small-cell Lung Cancer (NSCLC). Clin Lung Cancer. 2019;20(1):43-47.\n'},{id:"B70",body:'\nWang X, Zeng M. First-line tyrosine kinase inhibitor with or without aggressive upfront local radiation therapy in patients with EGFRm oligometastatic non-small cell lung cancer: interim results of a randomized phase III, open-label clinical trial (SINDAS) (NCT02893332). J Clin Oncol. 2020;38(suppl 15):9508.\n'},{id:"B71",body:'\nAntonia SJ, Villegas A, Daniel D, et al. Durvalumab after Chemoradiotherapy in Stage III Non-Small-Cell Lung Cancer. N Engl J Med. 2017;377(20):1919-1929.\n'},{id:"B72",body:'\nAntonia SJ, Villegas A, Daniel D, et al. Overall Survival with Durvalumab after Chemoradiotherapy in Stage III NSCLC. N Engl J Med. 2018;379(24):2342-2350.\n'},{id:"B73",body:'\nDeng L, Liang H, Burnette B, et al. Irradiation and anti-PD-L1 treatment synergistically promote antitumor immunity in mice. J Clin Invest. 2014;124(2):687-95.\n'},{id:"B74",body:'\nLugade AA, Moran JP, Gerber SA, et al. Local radiation therapy of B16 melanoma tumors increases the generation of tumor antigen-specific effector cells that traffic to the tumor. J Immunol. 2005;174(12):7516-23.\n'},{id:"B75",body:'\nGupta A, Probst HC, Vuong V, et al. Radiotherapy promotes tumor-specific effector CD8+ T cells via dendritic cell activation. J Immunol. 2012;189(2):558-66.\n'},{id:"B76",body:'\nDeng L, Liang H, Xu M, et al. STING-Dependent Cytosolic DNA Sensing Promotes Radiation-Induced Type I Interferon-Dependent Antitumor Immunity in Immunogenic Tumors. Immunity. 2014;41(5):843-52.\n'},{id:"B77",body:'\nTang C, Wang X, Soh H, et al. Combining radiation and immunotherapy: a new systemic therapy for solid tumors? Cancer Immunol Res. 2014;2(9):831-8.\n'},{id:"B78",body:'\nDemaria S, Golden EB, Formenti SC. Role of Local Radiation Therapy in Cancer Immunotherapy. JAMA Oncol. 2015;1(9):1325-32.\n'},{id:"B79",body:'\nAbuodeh Y, Venkat P, Kim S. Systematic review of case reports on the abscopal effect. Curr Probl Cancer. 2016;40(1):25-37\n'},{id:"B80",body:'\nWeichselbaum RR, Liang H, Deng L, et al. Radiotherapy and immunotherapy: a beneficial liaison? Nat Rev Clin Oncol. 2017;14(6);365-379.\n'},{id:"B81",body:'\nNgwa W, Irabor OC, Schoenfeld JD, et al. Using immunotherapy to boost the abscopal effect. Nat Rev Cancer. 2018;18(5):313-322.\n'},{id:"B82",body:'\nBuchwald ZS, Wynne J, Nasti TH, et al. Radiation, Immune Checkpoint Blockade and the Abscopal Effect: A Critical Review on Timing, Dose and Fractionation. Front Oncol. 2018;8:612.\n'},{id:"B83",body:'\nTwyman-Saint Victor C, Rech AJ, Maity A, et al. Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer. Nature. 2015;520(7547);373-7.\n'},{id:"B84",body:'\nDovedi SJ, Adlard AL, Lipowska-Bhalla G, et al. Acquired resistance to fractionated radiotherapy can be overcome by concurrent PD-L1 blockade. Cancer Res. 2014;74(19):5458-68.\n'},{id:"B85",body:'\nShaverdian N, Lisberg AE, Bornazyan K, et al. Previous radiotherapy and the clinical activity and toxicity of pembrolizumab in the treatment of non-small-cell lung cancer: a secondary analysis of the KEYNOTE-001 phase 1 trial. Lancet Oncol. 2017;18(7);895-903.\n'},{id:"B86",body:'\nBauml JM, Mick R, Ciunci C, et al. Pembrolizumab After Completion of Locally Ablative Therapy for Oligometastatic Non-Small Cell Lung Cancer: A Phase 2 Trial. JAMA Oncol. 2019;5(9):1283-90.\n'},{id:"B87",body:'\nTheelen WSME, Peulen HMU, Lalezari F, et al. Effect of Pembrolizumab After Stereotactic Body Radiotherapy vs Pembrolizumab Alone on Tumor Response in Patients With Advanced Non-Small Cell Lung Cancer: Results of the PEMBRO-RT Phase 2 Randomized Clinical Trial. JAMA Oncol. 2019;5(9):1276-82.\n'},{id:"B88",body:'\nSamstein R, Rimner A, Barker CA, et al. Combined Immune Checkpoint Blockade and Radiation Therapy: Timing and Dose Fractionation Associated with Greatest Survival Duration Among Over 750 Treated Patients. Int J Radiat Oncol Biol Phys. 2017;99(2):S129-S130.\n'},{id:"B89",body:'\nChen L, Douglass J, Kleinberg L, et al. Concurrent Immune Checkpoint Inhibitors and Stereotactic Radiosurgery for Brain Metastases in Non-Small Cell Lung Cancer, Melanoma, and Renal Cell Carcinoma. Int J Radiat Oncol Biol Phys. 2018;100(4):916-925.\n'},{id:"B90",body:'\nVerma V, Cushman TR, Selek U, et al. Safety of Combined Immunotherapy and Thoracic Radiation Therapy: Analysis of 3 Single-Institutional Phase I/II Trials. Int J Radiat Oncol Biol Phys. 2018;101(5):1141-1148.\n'},{id:"B91",body:'\nSchapira E, Hubbeling H, Yeap BY, et al. Improved Overall Survival and Locoregional Disease Control With Concurrent PD-1 Pathway Inhibitors and Stereotactic Radiosurgery for Lung Cancer Patients With Brain Metastases. Int J Radiat Oncol Biol Phys. 2018;101(3):624-629.\n'},{id:"B92",body:'\nChicas-Sett R, Morales-Orue I, Castilla-Martinez J, et al. Stereotactic Ablative Radiotherapy Combined with Immune Checkpoint Inhibitors Reboots the Immune Response Assisted by Immunotherapy in Metastatic Lung Cancer: A Systematic Review. Int J Mol Sci. 2019;20(9):2173.\n'},{id:"B93",body:'\nGan GN, Weickhardt AJ, Scheier B, et al. Stereotactic radiation therapy can safely and durably control sites of extra–central nervous system oligoprogressive disease in anaplastic lymphoma kinase-positive lung cancer patients receiving crizotinib. Ini J Radiat Oncol Biol Phys. 2014;88:892-898.\n'},{id:"B94",body:'\nFranceschini D, De Rose F, Cozzi S, et al. The use of radiation therapy for oligoprogressive/oligopersistant oncogene-driven non-small cell lung cancer: State of the art. Crit Rev Oncol Hematol. 2020;148:102894.\n'},{id:"B95",body:'\nRheinheimer S, Heussel CP, Mayer P, et al. Oligoprogressive Non-Small-Cell Lung Cancer under Treatment with PD-(L)1 Inhibitors. Cancers (Basel). 2020;12(4):1046.\n'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Martina Vrankar",address:"mvrankar@onko-i.si",affiliation:'
Institute of Oncology Ljubljana, Slovenia
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Leafy types, which are called turnip greens and turnip tops, are popular crops in NW Spain, and they represent an important part of the diet. However, their cultivation is limited in southern areas or in the Mediterranean basin, probably due to a lack of adaptation. Still, they could occupy a prominent place in the Mediterranean diet, which is based on a high consumption of fruits and vegetables. In this review, we summarize the studies on the agronomical and nutritional value of these crops when grown under Mediterranean climate conditions. Data reported here might be useful for a deeper understanding of these crops for both nutritional quality and bioaccessibility, and for selecting varieties adapted to the two abovementioned Mediterranean conditions, as well as for organic farming systems, thus contributing to the diversification of traditional Brassica vegetable production systems.",signatures:"María Elena Cartea, Fernando Cámara-Martos, Sara Obregón, Francisco Rubén Badenes-Pérez and Antonio De Haro",authors:[{id:"142197",title:"Prof.",name:"Fernando",surname:"Cámara-Martos",fullName:"Fernando Cámara-Martos",slug:"fernando-camara-martos",email:"bt2camaf@uco.es"},{id:"229534",title:"Dr.",name:"Antonio",surname:"De Haro-Bailón",fullName:"Antonio De Haro-Bailón",slug:"antonio-de-haro-bailon",email:"adeharobailon@ias.csic.es"},{id:"334691",title:"Dr.",name:"María Elena",surname:"Cartea",fullName:"María Elena Cartea",slug:"maria-elena-cartea",email:"ecartea@mbg.csic.es"},{id:"335952",title:"Dr.",name:"Sara",surname:"Obregon-Cano",fullName:"Sara Obregon-Cano",slug:"sara-obregon-cano",email:"saraobregon@ias.csic.es"},{id:"342339",title:"Dr.",name:"Francisco",surname:"Badenes-Pérez",fullName:"Francisco Badenes-Pérez",slug:"francisco-badenes-perez",email:"fr.badenes@csic.es"}],book:{id:"9686",title:"Brassica Breeding and Biotechnology",slug:"brassica-breeding-and-biotechnology",productType:{id:"1",title:"Edited Volume"}}}],collaborators:[{id:"142197",title:"Prof.",name:"Fernando",surname:"Cámara-Martos",slug:"fernando-camara-martos",fullName:"Fernando Cámara-Martos",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"181036",title:"Dr.",name:"Mohammad",surname:"Akmal",slug:"mohammad-akmal",fullName:"Mohammad Akmal",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Jamia Millia Islamia",institutionURL:null,country:{name:"India"}}},{id:"233726",title:"Dr.",name:"Ryo",surname:"Fujimoto",slug:"ryo-fujimoto",fullName:"Ryo Fujimoto",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Kobe University",institutionURL:null,country:{name:"Japan"}}},{id:"233727",title:"Ms.",name:"Ayasha",surname:"Akter",slug:"ayasha-akter",fullName:"Ayasha Akter",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"245615",title:"Dr.",name:"Jogendra",surname:"Singh",slug:"jogendra-singh",fullName:"Jogendra Singh",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/245615/images/14590_n.jpg",biography:null,institutionString:null,institution:{name:"Central Soil Salinity Research Institute",institutionURL:null,country:{name:"India"}}},{id:"331114",title:"Assistant Prof.",name:"Bahaderjeet",surname:"Singh",slug:"bahaderjeet-singh",fullName:"Bahaderjeet Singh",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"334691",title:"Dr.",name:"María Elena",surname:"Cartea",slug:"maria-elena-cartea",fullName:"María Elena Cartea",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Spanish National Research Council",institutionURL:null,country:{name:"Spain"}}},{id:"335952",title:"Dr.",name:"Sara",surname:"Obregon-Cano",slug:"sara-obregon-cano",fullName:"Sara Obregon-Cano",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Spanish National Research Council",institutionURL:null,country:{name:"Spain"}}},{id:"342339",title:"Dr.",name:"Francisco",surname:"Badenes-Pérez",slug:"francisco-badenes-perez",fullName:"Francisco Badenes-Pérez",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Spanish National Research Council",institutionURL:null,country:{name:"Spain"}}},{id:"345922",title:"Ms.",name:"Mst Arjina",surname:"Akter",slug:"mst-arjina-akter",fullName:"Mst Arjina Akter",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Kobe University",institutionURL:null,country:{name:"Japan"}}}]},generic:{page:{slug:"WIS-cost",title:"What Does It Cost?",intro:"
Open Access publishing helps remove barriers and allows everyone to access valuable information, but article and book processing charges also exclude talented authors and editors who can’t afford to pay. The goal of our Women in Science program is to charge zero APCs, so none of our authors or editors have to pay for publication.
",metaTitle:"What Does It Cost?",metaDescription:"Open Access publishing helps remove barriers and allows everyone to access valuable information, but article and book processing charges also exclude talented authors and editors who can’t afford to pay. The goal of our Women in Science program is to charge zero APCs, so none of our authors or editors have to pay for publication.",metaKeywords:null,canonicalURL:null,contentRaw:'[{"type":"htmlEditorComponent","content":"
We are currently in the process of collecting sponsorship. If you have any ideas or would like to help sponsor this ambitious program, we’d love to hear from you. Contact us at info@intechopen.com.
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All of our IntechOpen sponsors are in good company! The research in past IntechOpen books and chapters have been funded by:
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Bill and Melinda Gates Foundation
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Algal biorefineries must valorize the entire crop to grow profitable microalgae-based economies. With massive growth and demand for novel sustainable ingredients, farmed salmonid feed sectors are highly promising areas to focus on. Microalgae-based ingredients for salmonid feeds may have market advantages in terms of lower input costs, aerial foot-print, wastewater remediation benefits and carbon credits for industrial CO2 conversion. A handful of microalgae-based ingredients have been proposed as candidates to supply well-balanced nutrients and immunostimulatory compounds. However, technical gaps exist and need addressing before the industry could economically incorporate microalgae-based ingredients into commercial feeds. Current knowledge on comprehensive biochemical composition is incomplete, highly heterogeneous, and information on their nutritional value is scattered and/or inconsistent. The aim of this chapter is to consolidate relatively fragmented data on biochemical composition and nutritional value of microalgae-based ingredients focusing on farmed salmonid feeds. Presented are discussions on the potential for such ‘next-generation’ ingredients, opportunities/challenges for their use and a compendium of studies evaluating their performance in feeds for economically relevant farmed salmonids, including rainbow trout (Oncorhynchus mykiss), Arctic charr (Salvelinus alpinus) and Atlantic salmon (Salmo salar).",book:{id:"6541",slug:"microalgal-biotechnology",title:"Microalgal Biotechnology",fullTitle:"Microalgal Biotechnology"},signatures:"Sean Michael Tibbetts",authors:[{id:"228874",title:"Dr.",name:"Sean",middleName:null,surname:"Tibbetts",slug:"sean-tibbetts",fullName:"Sean Tibbetts"}]},{id:"59210",doi:"10.5772/intechopen.73791",title:"Spirulina Phycobiliproteins as Food Components and Complements",slug:"spirulina-phycobiliproteins-as-food-components-and-complements",totalDownloads:2615,totalCrossrefCites:15,totalDimensionsCites:26,abstract:"Spirulina has a documented history of use as a food for more than 1000 years, and has been in production as a dietary supplement for 40 years. Among many of Spirulina bioactive components, blue protein C-phycocyanin and its linear tetrapyrrole chromophore phycocyanobilin occupy a special place due to broad possibilities for application in various areas of food technology. The subject of this chapter is up-to-date food applications of these Spirulina components, with a focus on their use as food colorants, additives, nutriceuticals, and dietary supplements. Their other actual and future food application possibilities will also be briefly presented and discussed.",book:{id:"6541",slug:"microalgal-biotechnology",title:"Microalgal Biotechnology",fullTitle:"Microalgal Biotechnology"},signatures:"Dragana Stanic-Vucinic, Simeon Minic, Milan R. 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This interest has been partially due to the fact that some strains of microalgae and cyanobacteria have demonstrated the ability to produce a variety of bioactive products. Both, primary and secondary metabolism of these microorganisms has been demonstrated to play a key role in the production of special chemicals. Antioxidants, for instance, can be produced by some algal strains to protect photosynthetic cells from oxidative stress. Microalgae can produce a variety of polyunsaturated and monounsaturated fatty acids with clear health benefits for human nutrition. Potential products obtained from cyanobacteria and microalgae exhibiting interesting medical properties include polysaccharides, glycerol, glycoproteins, and antibiotics. From the aforementioned products, especially relevant has become the search of new antibiotics. The potential spread of bacterial resistance and the foreseen decrease on efficiency on antibiotics, has largely stimulated the research on novel antibiotics sources. Among these sources, cyanobacteria and microalgae have demonstrated a vast and just barely explored potential.",book:{id:"6541",slug:"microalgal-biotechnology",title:"Microalgal Biotechnology",fullTitle:"Microalgal Biotechnology"},signatures:"Elena Martínez-Francés and Carlos Escudero-Oñate",authors:[{id:"188725",title:"Dr.",name:"Carlos",middleName:null,surname:"Escudero-Oñate",slug:"carlos-escudero-onate",fullName:"Carlos Escudero-Oñate"},{id:"228683",title:"MSc.",name:"Elena",middleName:null,surname:"Martínez-Francés",slug:"elena-martinez-frances",fullName:"Elena Martínez-Francés"}]},{id:"59257",doi:"10.5772/intechopen.73702",title:"Bioeconomic Assessment of Microalgal Production",slug:"bioeconomic-assessment-of-microalgal-production",totalDownloads:1476,totalCrossrefCites:7,totalDimensionsCites:14,abstract:"Today, microalgae play an important role for the worldwide biofuel demand, together with the production of high value-added products used in pharmaceutical, nutraceutical and cosmetic industries. In 2014, the European Union adopted a strategy for developing the bioeconomy, by utilizing microalgae which represent an emerging biological resource of great importance for its potential applications in different fields. Huge potential of tiny microalgae could support a microalgae-based biorefinery and microalgae-based bioeconomy opening up vast opportunities in the global algae business. Nevertheless, in spite of having been studied for over 50 years now, there are still only just a few corporations that are cultivating algae on a large or commercial scale due to operational and capital cost. Techno-economic modeling is a powerful tool for guiding research priorities and assessing the economics, environmental impact and sustainability of microalgal productions. In this chapter, microalgal productions are assessed within bioeconomical aspects and case-studies on microalgal biorefinery are discussed.",book:{id:"6541",slug:"microalgal-biotechnology",title:"Microalgal Biotechnology",fullTitle:"Microalgal Biotechnology"},signatures:"Didem Özçimen, Benan İnan, Anıl Tevfik Koçer and Meyrem Vehapi",authors:[{id:"32444",title:"Dr.",name:"Didem",middleName:null,surname:"Özçimen",slug:"didem-ozcimen",fullName:"Didem Özçimen"},{id:"228422",title:"MSc.",name:"Benan",middleName:null,surname:"İnan",slug:"benan-inan",fullName:"Benan İnan"},{id:"240583",title:"MSc.",name:"Anıl Tevfik",middleName:null,surname:"Koçer",slug:"anil-tevfik-kocer",fullName:"Anıl Tevfik Koçer"},{id:"240584",title:"MSc.",name:"Meyrem",middleName:null,surname:"Vehapi",slug:"meyrem-vehapi",fullName:"Meyrem Vehapi"}]},{id:"57981",doi:"10.5772/intechopen.72175",title:"Application of Electrochemical Methods in Biosensing Technologies",slug:"application-of-electrochemical-methods-in-biosensing-technologies",totalDownloads:2102,totalCrossrefCites:7,totalDimensionsCites:14,abstract:"Introducing biochemical factor to electronic devices have created a new branch of science. Recent development in biosensing technology enabled progress in pathogens detection. Currently, wide range of biomarkers (enzymes, peptides, DNA, microorganisms, etc. )recognize various target analytes, starting from basic metabolism changes to serious infections caused by pathogens. Improved sensitivity, selectivity and response time of sensors have instantly replaced traditional techniques. Easy handling, low production costs and miniaturization have met therapeutics need. Biosensing technologies are very strong point in telemedicine in public healthcare. This chapter will focus on electrochemical techniques for pathogens detection and show trending applications in biosensing technologies.",book:{id:"6319",slug:"biosensing-technologies-for-the-detection-of-pathogens-a-prospective-way-for-rapid-analysis",title:"Biosensing Technologies for the Detection of Pathogens",fullTitle:"Biosensing Technologies for the Detection of Pathogens - A Prospective Way for Rapid Analysis"},signatures:"Karolina Dziąbowska, Elżbieta Czaczyk and Dawid Nidzworski",authors:[{id:"212390",title:"B.Sc.",name:"Karolina",middleName:null,surname:"Dziąbowska",slug:"karolina-dziabowska",fullName:"Karolina Dziąbowska"},{id:"212521",title:"Dr.",name:"Elżbieta",middleName:null,surname:"Czaczyk",slug:"elzbieta-czaczyk",fullName:"Elżbieta Czaczyk"},{id:"212524",title:"Dr.",name:"Dawid",middleName:null,surname:"Nidzworski",slug:"dawid-nidzworski",fullName:"Dawid Nidzworski"}]}],mostDownloadedChaptersLast30Days:[{id:"58097",title:"Detection and Control of Indoor Airborne Pathogenic Bacteria by Biosensors Based on Quorum Sensing Chemical Language: Bio-Tools, Connectivity Apps and Intelligent Buildings",slug:"detection-and-control-of-indoor-airborne-pathogenic-bacteria-by-biosensors-based-on-quorum-sensing-c",totalDownloads:1790,totalCrossrefCites:1,totalDimensionsCites:3,abstract:"Nowadays, lifestyles and climate change lead people to spend long periods in indoors spaces, where reduced ventilation and artificial light favor the concentration and spread of airborne pathogenic microorganisms. Current procedures for microbiological air evaluation are based on air sampling coupled to traditional microbiological culture-dependent methods such as biochemical tests and molecular rDNA 16S sequencing. These techniques generate an important delay in the application of prevention and control measures. This chapter presents whole cell-based biosensors that are able to detect quorum sensing signaling molecules produced by airborne pathogenic bacteria as a tool for indoor air monitoring. Furthermore, a general biosensor model is proposed. In this model, in vivo biosensors technology can be connected to online applications (Apps), being part of intelligent buildings, in order to reduce airborne pathogenic bacteria concentration and dissemination.",book:{id:"6319",slug:"biosensing-technologies-for-the-detection-of-pathogens-a-prospective-way-for-rapid-analysis",title:"Biosensing Technologies for the Detection of Pathogens",fullTitle:"Biosensing Technologies for the Detection of Pathogens - A Prospective Way for Rapid Analysis"},signatures:"Claudia Ibacache-Quiroga, Natalia Romo, Rodrigo Díaz-Viciedo and\nM. Alejandro Dinamarca",authors:[{id:"211459",title:"Prof.",name:"Alejandro",middleName:null,surname:"Dinamarca",slug:"alejandro-dinamarca",fullName:"Alejandro Dinamarca"},{id:"211467",title:"Ms.",name:"Natalia",middleName:null,surname:"Romo",slug:"natalia-romo",fullName:"Natalia Romo"},{id:"211474",title:"Dr.",name:"Claudia",middleName:null,surname:"Ibacache-Quiroga",slug:"claudia-ibacache-quiroga",fullName:"Claudia Ibacache-Quiroga"},{id:"230663",title:"Dr.",name:"Rodrigo",middleName:null,surname:"Díaz-Viciedo",slug:"rodrigo-diaz-viciedo",fullName:"Rodrigo Díaz-Viciedo"}]},{id:"65478",title:"The Oleaginous Red Yeast Rhodotorula/Rhodosporidium: A Factory for Industrial Bioproducts",slug:"the-oleaginous-red-yeast-em-rhodotorula-rhodosporidium-em-a-factory-for-industrial-bioproducts",totalDownloads:1290,totalCrossrefCites:5,totalDimensionsCites:9,abstract:"Rhodotorula genus, amended in 2015, is polyphyletic and contains Rhodotorula species that grow as single-cell yeast (monomorphic) and reproduce asexually via budding/fission (anamorphic); it also contains Rhodosporidium species that reproduce sexually (teleomorphic) and alternate between a yeast phase and dikaryotic filamentous phase (dimorphic). Several species of these “red yeast” produce industrial bioproducts, namely biofuel feedstocks, carotenoids, enzymes, and biosurfactants. This chapter highlights the biotechnology areas that Rhodotorula/Rhodosporidium contributes to and the future market value of those industries. The primary yeast species to be discussed include Rhodosporidium toruloides, Rhodotorula glutinis, Rhodosporidium diobovatum, Rhodosporidium kratochvilovae, Rhodotorula graminis, Rhodotorula babjevae, and Rhodotorula taiwanensis.",book:{id:"8107",slug:"yeasts-in-biotechnology",title:"Yeasts in Biotechnology",fullTitle:"Yeasts in Biotechnology"},signatures:"Mathew Lyman, Salustra Urbin, Cheryl Strout and Bonnee Rubinfeld",authors:[{id:"282320",title:"Dr.",name:"Mathew",middleName:null,surname:"Lyman",slug:"mathew-lyman",fullName:"Mathew Lyman"},{id:"290955",title:"Dr.",name:"Salustra",middleName:null,surname:"Urbin",slug:"salustra-urbin",fullName:"Salustra Urbin"},{id:"295704",title:"Dr.",name:"Cheryl",middleName:null,surname:"Strout",slug:"cheryl-strout",fullName:"Cheryl Strout"},{id:"295705",title:"Dr.",name:"Bonnee",middleName:null,surname:"Rubinfeld",slug:"bonnee-rubinfeld",fullName:"Bonnee Rubinfeld"}]},{id:"60275",title:"The Influence of Microalgae Addition as Co-Substrate in Anaerobic Digestion Processes",slug:"the-influence-of-microalgae-addition-as-co-substrate-in-anaerobic-digestion-processes",totalDownloads:1376,totalCrossrefCites:2,totalDimensionsCites:7,abstract:"Growth microalgae could be used as co-substrates in anaerobic digestion processes to produce biogas of a high-calorific value, which could be expended as heat or electricity in cogeneration engines. Lignocellulosic and high-carbon content wastes, due to their characteristics, hinder anaerobic digestion processes. The use of microalgae as a co-substrate with high-carbon content residues can adjust the C/N ratio and thereby obtain, in some cases, a higher biogas production and greater biodegradability of wastes during anaerobic digestion than without co-digestion options. In addition, microalgae and cyanobacteria are photosynthetic microorganisms that can produce oxygen and oxidize the organic matter and NH4+ contained in wastewaters. The growth of microalgae in industrial effluents and wastewaters can considerably reduce the organic matter contained in them and their pollutant load. This growth can take advantage of the nutrients that still remain in industrial effluents, avoiding the use of clean water for the growth of biomass. The chapter will focus on an overview of microalgae anaerobic co-digestion with different wastes and the benefits of this option.",book:{id:"6541",slug:"microalgal-biotechnology",title:"Microalgal Biotechnology",fullTitle:"Microalgal Biotechnology"},signatures:"Bárbara Rincón, María José Fernández-Rodríguez, David de la\nLama-Calvente and Rafael Borja",authors:[{id:"74541",title:"Dr.",name:"Barbara",middleName:null,surname:"Rincon",slug:"barbara-rincon",fullName:"Barbara Rincon"},{id:"89771",title:"Dr.",name:"Rafael",middleName:null,surname:"Borja",slug:"rafael-borja",fullName:"Rafael Borja"},{id:"246719",title:"MSc.",name:"María José",middleName:null,surname:"Fernández-Rodríguez",slug:"maria-jose-fernandez-rodriguez",fullName:"María José Fernández-Rodríguez"},{id:"246720",title:"MSc.",name:"David",middleName:null,surname:"De La Lama-Calvente",slug:"david-de-la-lama-calvente",fullName:"David De La Lama-Calvente"}]},{id:"64889",title:"Common Methods to Understand and Develop Indigenous Probiotics Yeast for Ruminant",slug:"common-methods-to-understand-and-develop-indigenous-probiotics-yeast-for-ruminant",totalDownloads:1397,totalCrossrefCites:1,totalDimensionsCites:2,abstract:"Probiotic yeast enhanced the ruminal gut microbial balance by producing intercellular effectors and important metabolites. The impact of yeast addition on animal health is influenced by different interlinked factors including animal genomics, its gut microbiota, and environment. Therefore, all factors should be considered regarding achieving the maximum outputs from animal probiotic yeast. In the situation of a high feeding cost, microbial feed supplements provide a suitable nutritional approach, which allows increased nutrient digestion rate and accordingly improves animal performance. Many yeast products are commercially available, but their efficiency as probiotic dietary addition in a particular breed is mostly questionable. Therefore, identification of ideal probiotic yeast strain is of great interest in this context. Innovative methods in relation to develop new probiotic are mainly focused on the exploring novel microbial strains from indigenous sources. It has been noted that for the identification of best probiotic strain for the host, a linkage between culture-independent and culture-dependent methods is a functional step. In this chapter, we will discuss the mode of action of probiotic yeast on animal lower gut microbiota and identification of ideal probiotic yeast by using advanced molecular methods.",book:{id:"8107",slug:"yeasts-in-biotechnology",title:"Yeasts in Biotechnology",fullTitle:"Yeasts in Biotechnology"},signatures:"Shakira Ghazanfar, Aayesha Riaz, Ghulam Muhammad Ali, Saima Naveed, Irum Arif, Sidra Irshad, Naeem Riaz and Khanzadi Nazneen Manzoor",authors:[{id:"202370",title:"Dr.",name:"Shakira",middleName:null,surname:"Ghazanfar",slug:"shakira-ghazanfar",fullName:"Shakira Ghazanfar"},{id:"286878",title:"Dr.",name:"Ghulam",middleName:null,surname:"Muhammad Ali",slug:"ghulam-muhammad-ali",fullName:"Ghulam Muhammad Ali"},{id:"286879",title:"Ms.",name:"Irum",middleName:null,surname:"Arif",slug:"irum-arif",fullName:"Irum Arif"},{id:"286880",title:"Ms.",name:"Sidra",middleName:null,surname:"Irshad",slug:"sidra-irshad",fullName:"Sidra Irshad"},{id:"286881",title:"Ms.",name:"Khanzadi",middleName:null,surname:"Nazneen Manzoor",slug:"khanzadi-nazneen-manzoor",fullName:"Khanzadi Nazneen Manzoor"},{id:"297912",title:"Dr.",name:"Naeem",middleName:null,surname:"Riaz",slug:"naeem-riaz",fullName:"Naeem Riaz"},{id:"304921",title:"Dr.",name:"Aayesha",middleName:null,surname:"Riaz",slug:"aayesha-riaz",fullName:"Aayesha Riaz"},{id:"304923",title:"Dr.",name:"Saima",middleName:null,surname:"Naveed",slug:"saima-naveed",fullName:"Saima Naveed"}]},{id:"58181",title:"FRET-Based Enzyme Activity Reporter: Practical Hints for Kinases as Indicators of Virulence",slug:"fret-based-enzyme-activity-reporter-practical-hints-for-kinases-as-indicators-of-virulence",totalDownloads:1450,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"Modulation of protein kinases activity is often requested for pathogenicity or virulence. This chapter provides several hints for one who might be interested in using FRET-based kinase activity reporters. The archetypes of these reporters, which are now within the arsenal of biosensors, were devoted to the detection and characterization of the activity of the cAMP-Protein kinase A pathway. Based on the principle of this biosensor, other FRET-based kinase activity reporters emerged. Here, the choice of the kinase to be monitored, the artifacts that might be met, and the flexibility and amenability of the FRET-based kinase activity reporters both for high-throughput analysis and dissection of protein kinase functions are discussed.",book:{id:"6319",slug:"biosensing-technologies-for-the-detection-of-pathogens-a-prospective-way-for-rapid-analysis",title:"Biosensing Technologies for the Detection of Pathogens",fullTitle:"Biosensing Technologies for the Detection of Pathogens - A Prospective Way for Rapid Analysis"},signatures:"Corentin Spriet, Angelina Kasprowicz, Dave Trinel and Jean-\nFrançois Bodart",authors:[{id:"98539",title:"Prof.",name:"Jean-François",middleName:"Laurent",surname:"Bodart",slug:"jean-francois-bodart",fullName:"Jean-François Bodart"},{id:"226954",title:"Dr.",name:"Corentin",middleName:null,surname:"Spriet",slug:"corentin-spriet",fullName:"Corentin Spriet"},{id:"230593",title:"MSc.",name:"Angelina",middleName:null,surname:"Kasprowicz",slug:"angelina-kasprowicz",fullName:"Angelina Kasprowicz"},{id:"230594",title:"MSc.",name:"Dave",middleName:null,surname:"Trinel",slug:"dave-trinel",fullName:"Dave Trinel"}]}],onlineFirstChaptersFilter:{topicId:"893",limit:6,offset:0},onlineFirstChaptersCollection:[],onlineFirstChaptersTotal:0},preDownload:{success:null,errors:{}},subscriptionForm:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[],offset:0,limit:8,total:null},allSeries:{pteSeriesList:[{id:"14",title:"Artificial Intelligence",numberOfPublishedBooks:9,numberOfPublishedChapters:87,numberOfOpenTopics:6,numberOfUpcomingTopics:0,issn:"2633-1403",doi:"10.5772/intechopen.79920",isOpenForSubmission:!0},{id:"7",title:"Biomedical Engineering",numberOfPublishedBooks:12,numberOfPublishedChapters:98,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2631-5343",doi:"10.5772/intechopen.71985",isOpenForSubmission:!0}],lsSeriesList:[{id:"11",title:"Biochemistry",numberOfPublishedBooks:27,numberOfPublishedChapters:287,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2632-0983",doi:"10.5772/intechopen.72877",isOpenForSubmission:!0},{id:"25",title:"Environmental Sciences",numberOfPublishedBooks:1,numberOfPublishedChapters:9,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2754-6713",doi:"10.5772/intechopen.100362",isOpenForSubmission:!0},{id:"10",title:"Physiology",numberOfPublishedBooks:11,numberOfPublishedChapters:139,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-8261",doi:"10.5772/intechopen.72796",isOpenForSubmission:!0}],hsSeriesList:[{id:"3",title:"Dentistry",numberOfPublishedBooks:8,numberOfPublishedChapters:129,numberOfOpenTopics:0,numberOfUpcomingTopics:2,issn:"2631-6218",doi:"10.5772/intechopen.71199",isOpenForSubmission:!1},{id:"6",title:"Infectious Diseases",numberOfPublishedBooks:13,numberOfPublishedChapters:106,numberOfOpenTopics:3,numberOfUpcomingTopics:1,issn:"2631-6188",doi:"10.5772/intechopen.71852",isOpenForSubmission:!0},{id:"13",title:"Veterinary Medicine and Science",numberOfPublishedBooks:10,numberOfPublishedChapters:103,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2632-0517",doi:"10.5772/intechopen.73681",isOpenForSubmission:!0}],sshSeriesList:[{id:"22",title:"Business, Management and Economics",numberOfPublishedBooks:1,numberOfPublishedChapters:12,numberOfOpenTopics:2,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100359",isOpenForSubmission:!0},{id:"23",title:"Education and Human Development",numberOfPublishedBooks:0,numberOfPublishedChapters:0,numberOfOpenTopics:2,numberOfUpcomingTopics:0,issn:null,doi:"10.5772/intechopen.100360",isOpenForSubmission:!1},{id:"24",title:"Sustainable Development",numberOfPublishedBooks:0,numberOfPublishedChapters:9,numberOfOpenTopics:4,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100361",isOpenForSubmission:!0}],testimonialsList:[{id:"13",text:"The collaboration with and support of the technical staff of IntechOpen is fantastic. The whole process of submitting an article and editing of the submitted article goes extremely smooth and fast, the number of reads and downloads of chapters is high, and the contributions are also frequently cited.",author:{id:"55578",name:"Antonio",surname:"Jurado-Navas",institutionString:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRisIQAS/Profile_Picture_1626166543950",slug:"antonio-jurado-navas",institution:{id:"720",name:"University of Malaga",country:{id:null,name:"Spain"}}}},{id:"6",text:"It is great to work with the IntechOpen to produce a worthwhile collection of research that also becomes a great educational resource and guide for future research endeavors.",author:{id:"259298",name:"Edward",surname:"Narayan",institutionString:null,profilePictureURL:"https://mts.intechopen.com/storage/users/259298/images/system/259298.jpeg",slug:"edward-narayan",institution:{id:"3",name:"University of Queensland",country:{id:null,name:"Australia"}}}}]},series:{item:{id:"11",title:"Biochemistry",doi:"10.5772/intechopen.72877",issn:"2632-0983",scope:"Biochemistry, the study of chemical transformations occurring within living organisms, impacts all areas of life sciences, from molecular crystallography and genetics to ecology, medicine, and population biology. Biochemistry examines macromolecules - proteins, nucleic acids, carbohydrates, and lipids – and their building blocks, structures, functions, and interactions. Much of biochemistry is devoted to enzymes, proteins that catalyze chemical reactions, enzyme structures, mechanisms of action and their roles within cells. Biochemistry also studies small signaling molecules, coenzymes, inhibitors, vitamins, and hormones, which play roles in life processes. Biochemical experimentation, besides coopting classical chemistry methods, e.g., chromatography, adopted new techniques, e.g., X-ray diffraction, electron microscopy, NMR, radioisotopes, and developed sophisticated microbial genetic tools, e.g., auxotroph mutants and their revertants, fermentation, etc. More recently, biochemistry embraced the ‘big data’ omics systems. Initial biochemical studies have been exclusively analytic: dissecting, purifying, and examining individual components of a biological system; in the apt words of Efraim Racker (1913 –1991), “Don’t waste clean thinking on dirty enzymes.” Today, however, biochemistry is becoming more agglomerative and comprehensive, setting out to integrate and describe entirely particular biological systems. The ‘big data’ metabolomics can define the complement of small molecules, e.g., in a soil or biofilm sample; proteomics can distinguish all the comprising proteins, e.g., serum; metagenomics can identify all the genes in a complex environment, e.g., the bovine rumen. This Biochemistry Series will address the current research on biomolecules and the emerging trends with great promise.",coverUrl:"https://cdn.intechopen.com/series/covers/11.jpg",latestPublicationDate:"May 18th, 2022",hasOnlineFirst:!0,numberOfPublishedBooks:27,editor:{id:"31610",title:"Dr.",name:"Miroslav",middleName:null,surname:"Blumenberg",slug:"miroslav-blumenberg",fullName:"Miroslav Blumenberg",profilePictureURL:"https://mts.intechopen.com/storage/users/31610/images/system/31610.jpg",biography:"Miroslav Blumenberg, Ph.D., was born in Subotica and received his BSc in Belgrade, Yugoslavia. He completed his Ph.D. at MIT in Organic Chemistry; he followed up his Ph.D. with two postdoctoral study periods at Stanford University. Since 1983, he has been a faculty member of the RO Perelman Department of Dermatology, NYU School of Medicine, where he is codirector of a training grant in cutaneous biology. Dr. Blumenberg’s research is focused on the epidermis, expression of keratin genes, transcription profiling, keratinocyte differentiation, inflammatory diseases and cancers, and most recently the effects of the microbiome on the skin. He has published more than 100 peer-reviewed research articles and graduated numerous Ph.D. and postdoctoral students.",institutionString:null,institution:{name:"New York University Langone Medical Center",institutionURL:null,country:{name:"United States of America"}}},editorTwo:null,editorThree:null},subseries:{paginationCount:4,paginationItems:[{id:"14",title:"Cell and Molecular Biology",coverUrl:"https://cdn.intechopen.com/series_topics/covers/14.jpg",isOpenForSubmission:!0,editor:{id:"165627",title:"Dr.",name:"Rosa María",middleName:null,surname:"Martínez-Espinosa",slug:"rosa-maria-martinez-espinosa",fullName:"Rosa María Martínez-Espinosa",profilePictureURL:"https://mts.intechopen.com/storage/users/165627/images/system/165627.jpeg",biography:"Dr. Rosa María Martínez-Espinosa has been a Spanish Full Professor since 2020 (Biochemistry and Molecular Biology) and is currently Vice-President of International Relations and Cooperation development and leader of the research group 'Applied Biochemistry” (University of Alicante, Spain). Other positions she has held at the university include Vice-Dean of Master Programs, Vice-Dean of the Degree in Biology and Vice-Dean for Mobility and Enterprise and Engagement at the Faculty of Science (University of Alicante). She received her Bachelor in Biology in 1998 (University of Alicante) and her PhD in 2003 (Biochemistry, University of Alicante). She undertook post-doctoral research at the University of East Anglia (Norwich, U.K. 2004-2005; 2007-2008).\nHer multidisciplinary research focuses on investigating archaea and their potential applications in biotechnology. She has an H-index of 21. She has authored one patent and has published more than 70 indexed papers and around 60 book chapters.\nShe has contributed to more than 150 national and international meetings during the last 15 years. Her research interests include archaea metabolism, enzymes purification and characterization, gene regulation, carotenoids and bioplastics production, antioxidant\ncompounds, waste water treatments, and brines bioremediation.\nRosa María’s other roles include editorial board member for several journals related\nto biochemistry, reviewer for more than 60 journals (biochemistry, molecular biology, biotechnology, chemistry and microbiology) and president of several organizing committees in international meetings related to the N-cycle or respiratory processes.",institutionString:null,institution:{name:"University of Alicante",institutionURL:null,country:{name:"Spain"}}},editorTwo:null,editorThree:null},{id:"15",title:"Chemical Biology",coverUrl:"https://cdn.intechopen.com/series_topics/covers/15.jpg",isOpenForSubmission:!0,editor:{id:"441442",title:"Dr.",name:"Şükrü",middleName:null,surname:"Beydemir",slug:"sukru-beydemir",fullName:"Şükrü Beydemir",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00003GsUoIQAV/Profile_Picture_1634557147521",biography:"Dr. Şükrü Beydemir obtained a BSc in Chemistry in 1995 from Yüzüncü Yıl University, MSc in Biochemistry in 1998, and PhD in Biochemistry in 2002 from Atatürk University, Turkey. He performed post-doctoral studies at Max-Planck Institute, Germany, and University of Florence, Italy in addition to making several scientific visits abroad. He currently works as a Full Professor of Biochemistry in the Faculty of Pharmacy, Anadolu University, Turkey. Dr. Beydemir has published over a hundred scientific papers spanning protein biochemistry, enzymology and medicinal chemistry, reviews, book chapters and presented several conferences to scientists worldwide. He has received numerous publication awards from various international scientific councils. He serves in the Editorial Board of several international journals. Dr. Beydemir is also Rector of Bilecik Şeyh Edebali University, Turkey.",institutionString:null,institution:{name:"Anadolu University",institutionURL:null,country:{name:"Turkey"}}},editorTwo:{id:"13652",title:"Prof.",name:"Deniz",middleName:null,surname:"Ekinci",slug:"deniz-ekinci",fullName:"Deniz Ekinci",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYLT1QAO/Profile_Picture_1634557223079",biography:"Dr. Deniz Ekinci obtained a BSc in Chemistry in 2004, MSc in Biochemistry in 2006, and PhD in Biochemistry in 2009 from Atatürk University, Turkey. He studied at Stetson University, USA, in 2007-2008 and at the Max Planck Institute of Molecular Cell Biology and Genetics, Germany, in 2009-2010. Dr. Ekinci currently works as a Full Professor of Biochemistry in the Faculty of Agriculture and is the Head of the Enzyme and Microbial Biotechnology Division, Ondokuz Mayıs University, Turkey. He is a member of the Turkish Biochemical Society, American Chemical Society, and German Genetics society. Dr. Ekinci published around ninety scientific papers, reviews and book chapters, and presented several conferences to scientists. He has received numerous publication awards from several scientific councils. Dr. Ekinci serves as the Editor in Chief of four international books and is involved in the Editorial Board of several international journals.",institutionString:null,institution:{name:"Ondokuz Mayıs University",institutionURL:null,country:{name:"Turkey"}}},editorThree:null},{id:"17",title:"Metabolism",coverUrl:"https://cdn.intechopen.com/series_topics/covers/17.jpg",isOpenForSubmission:!0,editor:{id:"138626",title:"Dr.",name:"Yannis",middleName:null,surname:"Karamanos",slug:"yannis-karamanos",fullName:"Yannis Karamanos",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002g6Jv2QAE/Profile_Picture_1629356660984",biography:"Yannis Karamanos, born in Greece in 1953, completed his pre-graduate studies at the Université Pierre et Marie Curie, Paris, then his Masters and Doctoral degree at the Université de Lille (1983). He was associate professor at the University of Limoges (1987) before becoming full professor of biochemistry at the Université d’Artois (1996). He worked on the structure-function relationships of glycoconjugates and his main project was the investigations on the biological roles of the de-N-glycosylation enzymes (Endo-N-acetyl-β-D-glucosaminidase and peptide-N4-(N-acetyl-β-glucosaminyl) asparagine amidase). From 2002 he contributes to the understanding of the Blood-brain barrier functioning using proteomics approaches. He has published more than 70 papers. 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Since then, he has been working as an Adjunct Professor in the same Department at the University of Pavia. His research activity during the first years was primarily focused on the purification and structural characterization of enzymes from animal and plant sources. During this period, Prof. Iadarola familiarized himself with the conventional techniques used in column chromatography, spectrophotometry, manual Edman degradation, and electrophoresis). Since 1995, he has been working on: i) the determination in biological fluids (serum, urine, bronchoalveolar lavage, sputum) of proteolytic activities involved in the degradation processes of connective tissue matrix, and ii) on the identification of biological markers of lung diseases. 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She gained considerable experience in developing and validating new methodologies whose applications allowed her to determine both the amount of biomarkers (Desmosine and Isodesmosine) in the urine of patients affected by COPD, and the activity of proteolytic enzymes (HNE, Cathepsin G, Pseudomonas aeruginosa elastase) in the sputa of these patients. Simona Viglio was also involved in research dealing with the supplementation of amino acids in patients with brain injury and chronic heart failure. She is presently engaged in the development of 2-DE and LC-MS techniques for the study of proteomics in biological fluids. The aim of this research is the identification of potential biomarkers of lung diseases. She is an author of about 90 publications (According to Scopus: H-Index: 23; According to WOS: H-Index: 20) on peer-reviewed journals, a member of the “Società Italiana di Biochimica e Biologia Molecolare,“ and a Consultant Reviewer for International Journal of Molecular Science, Journal of Chromatography A, COPD, Plos ONE and Nutritional Neuroscience.",institutionString:null,institution:{name:"University of Pavia",institutionURL:null,country:{name:"Italy"}}},editorThree:null}]},overviewPageOFChapters:{paginationCount:49,paginationItems:[{id:"80495",title:"Iron in Cell Metabolism and Disease",doi:"10.5772/intechopen.101908",signatures:"Eeka Prabhakar",slug:"iron-in-cell-metabolism-and-disease",totalDownloads:1,totalCrossrefCites:0,totalDimensionsCites:null,authors:null,book:{title:"Iron Metabolism - Iron a Double‐Edged Sword",coverURL:"https://cdn.intechopen.com/books/images_new/10842.jpg",subseries:{id:"17",title:"Metabolism"}}},{id:"81799",title:"Cross Talk of Purinergic and Immune Signaling: Implication in Inflammatory and Pathogenic Diseases",doi:"10.5772/intechopen.104978",signatures:"Richa Rai",slug:"cross-talk-of-purinergic-and-immune-signaling-implication-in-inflammatory-and-pathogenic-diseases",totalDownloads:7,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Purinergic System",coverURL:"https://cdn.intechopen.com/books/images_new/10801.jpg",subseries:{id:"17",title:"Metabolism"}}},{id:"81764",title:"Involvement of the Purinergic System in Cell Death in Models of Retinopathies",doi:"10.5772/intechopen.103935",signatures:"Douglas Penaforte Cruz, Marinna Garcia Repossi and Lucianne Fragel Madeira",slug:"involvement-of-the-purinergic-system-in-cell-death-in-models-of-retinopathies",totalDownloads:4,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Purinergic System",coverURL:"https://cdn.intechopen.com/books/images_new/10801.jpg",subseries:{id:"17",title:"Metabolism"}}},{id:"81756",title:"Alteration of Cytokines Level and Oxidative Stress Parameters in COVID-19",doi:"10.5772/intechopen.104950",signatures:"Marija Petrusevska, Emilija Atanasovska, Dragica Zendelovska, Aleksandar Eftimov and Katerina Spasovska",slug:"alteration-of-cytokines-level-and-oxidative-stress-parameters-in-covid-19",totalDownloads:8,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Chemokines Updates",coverURL:"https://cdn.intechopen.com/books/images_new/11672.jpg",subseries:{id:"18",title:"Proteomics"}}}]},overviewPagePublishedBooks:{paginationCount:27,paginationItems:[{type:"book",id:"7006",title:"Biochemistry and Health Benefits of Fatty Acids",subtitle:null,coverURL:"https://cdn.intechopen.com/books/images_new/7006.jpg",slug:"biochemistry-and-health-benefits-of-fatty-acids",publishedDate:"December 19th 2018",editedByType:"Edited by",bookSignature:"Viduranga Waisundara",hash:"c93a00abd68b5eba67e5e719f67fd20b",volumeInSeries:1,fullTitle:"Biochemistry and Health Benefits of Fatty Acids",editors:[{id:"194281",title:"Dr.",name:"Viduranga Y.",middleName:null,surname:"Waisundara",slug:"viduranga-y.-waisundara",fullName:"Viduranga Y. 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She is also the Global Harmonization Initiative (GHI) Ambassador to Sri Lanka.",institutionString:"Australian College of Business & Technology",institution:null}]},{type:"book",id:"6820",title:"Keratin",subtitle:null,coverURL:"https://cdn.intechopen.com/books/images_new/6820.jpg",slug:"keratin",publishedDate:"December 19th 2018",editedByType:"Edited by",bookSignature:"Miroslav Blumenberg",hash:"6def75cd4b6b5324a02b6dc0359896d0",volumeInSeries:2,fullTitle:"Keratin",editors:[{id:"31610",title:"Dr.",name:"Miroslav",middleName:null,surname:"Blumenberg",slug:"miroslav-blumenberg",fullName:"Miroslav Blumenberg",profilePictureURL:"https://mts.intechopen.com/storage/users/31610/images/system/31610.jpg",biography:"Miroslav Blumenberg, Ph.D., was born in Subotica and received his BSc in Belgrade, Yugoslavia. He completed his Ph.D. at MIT in Organic Chemistry; he followed up his Ph.D. with two postdoctoral study periods at Stanford University. Since 1983, he has been a faculty member of the RO Perelman Department of Dermatology, NYU School of Medicine, where he is codirector of a training grant in cutaneous biology. Dr. Blumenberg’s research is focused on the epidermis, expression of keratin genes, transcription profiling, keratinocyte differentiation, inflammatory diseases and cancers, and most recently the effects of the microbiome on the skin. He has published more than 100 peer-reviewed research articles and graduated numerous Ph.D. and postdoctoral students.",institutionString:null,institution:{name:"New York University Langone Medical Center",institutionURL:null,country:{name:"United States of America"}}}]},{type:"book",id:"7978",title:"Vitamin A",subtitle:null,coverURL:"https://cdn.intechopen.com/books/images_new/7978.jpg",slug:"vitamin-a",publishedDate:"May 15th 2019",editedByType:"Edited by",bookSignature:"Leila Queiroz Zepka, Veridiana Vera de Rosso and Eduardo Jacob-Lopes",hash:"dad04a658ab9e3d851d23705980a688b",volumeInSeries:3,fullTitle:"Vitamin A",editors:[{id:"261969",title:"Dr.",name:"Leila",middleName:null,surname:"Queiroz Zepka",slug:"leila-queiroz-zepka",fullName:"Leila Queiroz Zepka",profilePictureURL:"https://mts.intechopen.com/storage/users/261969/images/system/261969.png",biography:"Prof. Dr. Leila Queiroz Zepka is currently an associate professor in the Department of Food Technology and Science, Federal University of Santa Maria, Brazil. She has more than fifteen years of teaching and research experience. She has published more than 550 scientific publications/communications, including 15 books, 50 book chapters, 100 original research papers, 380 research communications in national and international conferences, and 12 patents. She is a member of the editorial board of five journals and acts as a reviewer for several national and international journals. Her research interests include microalgal biotechnology with an emphasis on microalgae-based products.",institutionString:"Universidade Federal de Santa Maria",institution:{name:"Universidade Federal de Santa Maria",institutionURL:null,country:{name:"Brazil"}}}]},{type:"book",id:"7953",title:"Bioluminescence",subtitle:"Analytical Applications and Basic Biology",coverURL:"https://cdn.intechopen.com/books/images_new/7953.jpg",slug:"bioluminescence-analytical-applications-and-basic-biology",publishedDate:"September 25th 2019",editedByType:"Edited by",bookSignature:"Hirobumi Suzuki",hash:"3a8efa00b71abea11bf01973dc589979",volumeInSeries:4,fullTitle:"Bioluminescence - Analytical Applications and Basic Biology",editors:[{id:"185746",title:"Dr.",name:"Hirobumi",middleName:null,surname:"Suzuki",slug:"hirobumi-suzuki",fullName:"Hirobumi Suzuki",profilePictureURL:"https://mts.intechopen.com/storage/users/185746/images/system/185746.png",biography:"Dr. Hirobumi Suzuki received his Ph.D. in 1997 from Tokyo Metropolitan University, Japan, where he studied firefly phylogeny and the evolution of mating systems. He is especially interested in the genetic differentiation pattern and speciation process that correlate to the flashing pattern and mating behavior of some fireflies in Japan. He then worked for Olympus Corporation, a Japanese manufacturer of optics and imaging products, where he was involved in the development of luminescence technology and produced a bioluminescence microscope that is currently being used for gene expression analysis in chronobiology, neurobiology, and developmental biology. Dr. Suzuki currently serves as a visiting researcher at Kogakuin University, Japan, and also a vice president of the Japan Firefly Society.",institutionString:"Kogakuin University",institution:null}]}]},openForSubmissionBooks:{},onlineFirstChapters:{},subseriesFiltersForOFChapters:[],publishedBooks:{},subseriesFiltersForPublishedBooks:[],publicationYearFilters:[],authors:{}},subseries:{item:{id:"40",type:"subseries",title:"Ecosystems and Biodiversity",keywords:"Ecosystems, Biodiversity, Fauna, Taxonomy, Invasive species, Destruction of habitats, Overexploitation of natural resources, Pollution, Global warming, Conservation of natural spaces, Bioremediation",scope:"
\r\n\tIn general, the harsher the environmental conditions in an ecosystem, the lower the biodiversity. Changes in the environment caused by human activity accelerate the impoverishment of biodiversity.
\r\n
\r\n\tBiodiversity refers to “the variability of living organisms from any source, including terrestrial, marine and other aquatic ecosystems and the ecological complexes of which they are part; it includes diversity within each species, between species, and that of ecosystems”.
\r\n
\r\n\tBiodiversity provides food security and constitutes a gene pool for biotechnology, especially in the field of agriculture and medicine, and promotes the development of ecotourism.
\r\n
\r\n\tCurrently, biologists admit that we are witnessing the first phases of the seventh mass extinction caused by human intervention. It is estimated that the current rate of extinction is between a hundred and a thousand times faster than it was when man first appeared. The disappearance of species is caused not only by an accelerated rate of extinction, but also by a decrease in the rate of emergence of new species as human activities degrade the natural environment. The conservation of biological diversity is "a common concern of humanity" and an integral part of the development process. Its objectives are “the conservation of biological diversity, the sustainable use of its components, and the fair and equitable sharing of the benefits resulting from the use of genetic resources”.
\r\n
\r\n\tThe following are the main causes of biodiversity loss:
\r\n
\r\n\t• The destruction of natural habitats to expand urban and agricultural areas and to obtain timber, minerals and other natural resources.
\r\n
\r\n\t• The introduction of alien species into a habitat, whether intentionally or unintentionally which has an impact on the fauna and flora of the area, and as a result, they are reduced or become extinct.
\r\n
\r\n\t• Pollution from industrial and agricultural products, which devastate the fauna and flora, especially those in fresh water.
\r\n
\r\n\t• Global warming, which is seen as a threat to biological diversity, and will become increasingly important in the future.
",coverUrl:"https://cdn.intechopen.com/series_topics/covers/40.jpg",hasOnlineFirst:!1,hasPublishedBooks:!1,annualVolume:11968,editor:{id:"209149",title:"Prof.",name:"Salustiano",middleName:null,surname:"Mato",slug:"salustiano-mato",fullName:"Salustiano Mato",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRLREQA4/Profile_Picture_2022-03-31T10:23:50.png",biography:"Salustiano Mato de la Iglesia (Santiago de Compostela, 1960) is a doctor in biology from the University of Santiago and a Professor of zoology at the Department of Ecology and Animal Biology at the University of Vigo. He has developed his research activity in the fields of fauna and soil ecology, and in the treatment of organic waste, having been the founder and principal investigator of the Environmental Biotechnology Group of the University of Vigo.\r\nHis research activity in the field of Environmental Biotechnology has been focused on the development of novel organic waste treatment systems through composting. 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