The Cutolo classification criteria [22].
\\n\\n
Released this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\\n\\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
Note: Edited in March 2021
\\n"}]',published:!0,mainMedia:{caption:"Highly Cited",originalUrl:"/media/original/117"}},components:[{type:"htmlEditorComponent",content:'IntechOpen is proud to announce that 191 of our authors have made the Clarivate™ Highly Cited Researchers List for 2020, ranking them among the top 1% most-cited.
\n\nThroughout the years, the list has named a total of 261 IntechOpen authors as Highly Cited. Of those researchers, 69 have been featured on the list multiple times.
\n\n\n\nReleased this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\n\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
Note: Edited in March 2021
\n'}],latestNews:[{slug:"intechopen-supports-asapbio-s-new-initiative-publish-your-reviews-20220729",title:"IntechOpen Supports ASAPbio’s New Initiative Publish Your Reviews"},{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"}]},book:{item:{type:"book",id:"7121",leadTitle:null,fullTitle:"Cell Growth",title:"Cell Growth",subtitle:null,reviewType:"peer-reviewed",abstract:"This book on cell growth is the ideal resource for a scientist who wishes to learn more about cell growth topics. It provides information on plant growth hormones, kinetic studies on cell growth, growth of fungal cells and production, cell growth measurement, ion homeostasis response to nutrient deficiency stress in plants, intracellular lipid homeostasis in eukaryotes, and cell-based assays in cancer research. Each topic begins with a summary of the essential facts. Chapters were carefully edited to maintain consistent use of terminology and approach of covering topics in a uniform, systematic format.",isbn:"978-1-78984-557-0",printIsbn:"978-1-78923-806-8",pdfIsbn:"978-1-78985-311-7",doi:"10.5772/intechopen.73916",price:119,priceEur:129,priceUsd:155,slug:"cell-growth",numberOfPages:128,isOpenForSubmission:!1,isInWos:null,isInBkci:!1,hash:"9845b4d66ecca197908bcbfe4fd89321",bookSignature:"Biba Vikas and Michael Fasullo",publishedDate:"March 4th 2020",coverURL:"https://cdn.intechopen.com/books/images_new/7121.jpg",numberOfDownloads:12685,numberOfWosCitations:1,numberOfCrossrefCitations:15,numberOfCrossrefCitationsByBook:0,numberOfDimensionsCitations:28,numberOfDimensionsCitationsByBook:0,hasAltmetrics:0,numberOfTotalCitations:44,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"July 9th 2018",dateEndSecondStepPublish:"September 10th 2018",dateEndThirdStepPublish:"November 9th 2018",dateEndFourthStepPublish:"January 28th 2019",dateEndFifthStepPublish:"March 29th 2019",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6",editedByType:"Edited by",kuFlag:!1,featuredMarkup:null,editors:[{id:"241658",title:"Dr.",name:"Biba",middleName:null,surname:"Vikas",slug:"biba-vikas",fullName:"Biba Vikas",profilePictureURL:"https://mts.intechopen.com/storage/users/241658/images/7704_n.jpg",biography:"Dr. Biba Vikas carried out her Post Doctorate in Cancer Biology, KSCSTE, Jawaharlal Nehru Tropical Botanic Garden and Research Institute, Trivandrum, India. Ph. D in Cancer Biology at Regional Cancer Centre, Thiruvananthapuram, India. She worked as a Post- Doctoral Research Associate in CSIR National Institute for Interdisciplinary Science and Technology, Trivandrum, India. She started working as a Research Fellow in Regional Cancer Centre, Thiruvananthapuram, India. Her Expertise areas are: Cancer Research, Microbiology, Molecular Biology, Tissue Culture, Drug Delivery, Cell Based Assays, Phytochemical analysis.",institutionString:"KSCSTE",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"1",institution:{name:"Malabar Institute of Medical Sciences",institutionURL:null,country:{name:"India"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:{id:"258231",title:"Dr.",name:"Michael",middleName:"Thomas",surname:"Fasullo",slug:"michael-fasullo",fullName:"Michael Fasullo",profilePictureURL:"https://mts.intechopen.com/storage/users/258231/images/system/258231.jpg",biography:"Michael Fasullo, Ph.D., is an associate professor at SUNY Polytechnic University, New York. He earned a BSc at the Massachusetts Institute of Technology and a Ph.D. at the Department of Biochemistry, Stanford University, California. He was an American Cancer Society fellow at Columbia University, New York, and held faculty positions at Loyola University Chicago and Albany Medical College, New York. He has authored more than forty peer-reviewed publications, book chapters, and review articles in the field of yeast genetics, DNA recombination and repair, oncolytic viruses, and toxicology. His present work focuses on profiling the yeast and mammalian genome for resistance to P450-activated mycotoxins and heterocyclic amines. His research has been funded by the National Institutes of Health, Department of Defense, March of Dimes, and Leukemia Research Foundation.",institutionString:"State University of New York Polytechnic Institute",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"2",totalChapterViews:"0",totalEditedBooks:"1",institution:{name:"State University of New York Polytechnic Institute",institutionURL:null,country:{name:"United States of America"}}},coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"47",title:"Cell Biology",slug:"biochemistry-genetics-and-molecular-biology-cell-biology"}],chapters:[{id:"65617",title:"Plant Growth Hormones",doi:"10.5772/intechopen.84350",slug:"plant-growth-hormones",totalDownloads:1487,totalCrossrefCites:3,totalDimensionsCites:3,hasAltmetrics:0,abstract:"Many factors can cause and affect cell growth in the plant such as external (environmental) and internal factors; one of the most important internal factors is plant growth hormones. Many hormones required for cell growth, such as auxins, gibberellins, brassinosteroids, ethylene, jasmonates, salicylic acid, strigolactones and cytokinins which able to accelerate or promote growth, but, some hormone-like abscisic acid has an adverse effect on growth which increases seed dormancy by inhibiting cell growth. Also, plant hormones are able to breakdowns dormancy for many plants and can alleviate abiotic stress (salinity, extreme temperatures and, drought,…) which led to enhance germination and improve growth for many plants, whether naturally occurring in the plant or by adding it to the plant in its artificially formed or in the form of bio- or nano-fertilization in order to increase the productivity and improve its efficiency under extreme conditions. Therefore, this chapter will highlight and will provide data for the positive or/and negative effect of these hormones on many plants to achieve a rapid germination method. It will also shed light on the relationship of these hormones to some enzymes to accelerate growth.",signatures:"Amira Shawky Soliman",downloadPdfUrl:"/chapter/pdf-download/65617",previewPdfUrl:"/chapter/pdf-preview/65617",authors:[{id:"273877",title:"Prof.",name:"Amira",surname:"Soliman",slug:"amira-soliman",fullName:"Amira Soliman"}],corrections:null},{id:"67793",title:"Kinetic Studies on Cell Growth",doi:"10.5772/intechopen.84353",slug:"kinetic-studies-on-cell-growth",totalDownloads:3883,totalCrossrefCites:4,totalDimensionsCites:9,hasAltmetrics:0,abstract:"The kinetic model of cell growth is substantially capable to predict product formation. Mathematical models provide a strategy for solving problems encountered in fermentation process. A biochemical engineering approach to address this problem could be to develop a mathematical model which not only helps in the understanding of the system but also predicts various cultivation strategies to facilitate the optimization of a fermentation process, saving much of the time and cost for performing experiments. The presented overview indicates that many of the environmentally relevant aspects in growth kinetics are still waiting to be discovered, established, and exploited. A kinetic model that describes microbial growth, product formation and substrate consumption and the experimental data were fitted with modified logistic equation.",signatures:"Punniavan Sakthiselvan, Setti Sudharsan Meenambiga and Ramasamy Madhumathi",downloadPdfUrl:"/chapter/pdf-download/67793",previewPdfUrl:"/chapter/pdf-preview/67793",authors:[{id:"268626",title:"Dr.",name:"Punniavan",surname:"Sakthiselvan",slug:"punniavan-sakthiselvan",fullName:"Punniavan Sakthiselvan"},{id:"269591",title:"Dr.",name:"Madhumathi",surname:"Ramasamy",slug:"madhumathi-ramasamy",fullName:"Madhumathi Ramasamy"},{id:"279920",title:"Dr.",name:"S S",surname:"Meenambiga",slug:"s-s-meenambiga",fullName:"S S Meenambiga"}],corrections:null},{id:"67599",title:"Growth of Fungal Cells and the Production of Mycotoxins",doi:"10.5772/intechopen.86533",slug:"growth-of-fungal-cells-and-the-production-of-mycotoxins",totalDownloads:1151,totalCrossrefCites:3,totalDimensionsCites:5,hasAltmetrics:0,abstract:"Some filamentous fungi are able to grow in food and produce toxic metabolites. It occurs mainly in grains, cereals, oilseeds and some by-products. The growth of fungi in a particular food is governed largely by a series of physical and chemical parameters. The production of toxic metabolites is not confined to a single group of molds irrespective of whether they are grouped according to structure, ecology, or phylogenetic relationships. Mycotoxins can be carcinogenic and cause several harmful effects to both human and animal organisms, in addition to generating large economic losses. The major mycotoxins found in food are the aflatoxins, fumonisins, ochratoxins, patulin, zearalenone, and trichothecenes, generally stable at high temperatures and long storage periods. Considering the difficult prevention and control, international organizations for food safety establish safe levels of these toxins in food destined for both human and animal consumption. Good agricultural practices and control of temperature and moisture during storage are factors which contribute significantly to inhibit the production of mycotoxins. The use of some fungistatic products, such as essential oils and antioxidants, as well as physical, mechanical, chemical, or thermal processing, represents important methods to have the concentration of mycotoxins reduced in food.",signatures:"Márcia Regina Ferreira Geraldo Perdoncini, Maria Josiane Sereia, Fabio Henrique Poliseli Scopel, Maysa Formigoni, Eliane Sloboda Rigobello, Stéfani Caroline Beneti, Flavia Aparecida Reitz Cardoso, Livia Benossi Marchi, Claudio Gomes da Silva Junior, Paula Gimenez Milani Fernandes, Tuan Henrique Smielevski de Souza, Priscila Wielewski, Erica Gomes de Lima, Angelivia Gregório, Maria Rosa Trentin Zorzenon, Juliana Cristina Castro, Vanessa de Cássia Mendes Del Bel, Magali Soares dos Santos Pozza and Leila Larisa Medeiros Marques",downloadPdfUrl:"/chapter/pdf-download/67599",previewPdfUrl:"/chapter/pdf-preview/67599",authors:[{id:"192188",title:"Dr.",name:"Maria",surname:"Sereia",slug:"maria-sereia",fullName:"Maria Sereia"},{id:"192847",title:"Dr.",name:"Márcia",surname:"Perdoncini",slug:"marcia-perdoncini",fullName:"Márcia Perdoncini"},{id:"241270",title:"M.Sc.",name:"Cláudio",surname:"Silva Júnior",slug:"claudio-silva-junior",fullName:"Cláudio Silva Júnior"},{id:"289317",title:"Dr.",name:"Leila Larissa",surname:"Medeiros Marques",slug:"leila-larissa-medeiros-marques",fullName:"Leila Larissa Medeiros Marques"},{id:"289318",title:"Dr.",name:"Livia",surname:"Benossi Marchi",slug:"livia-benossi-marchi",fullName:"Livia Benossi Marchi"},{id:"289319",title:"Dr.",name:"Flavia Aparecida",surname:"Reitz Cardoso",slug:"flavia-aparecida-reitz-cardoso",fullName:"Flavia Aparecida Reitz Cardoso"},{id:"289320",title:"Dr.",name:"Eliane",surname:"Sloboda Rigobello",slug:"eliane-sloboda-rigobello",fullName:"Eliane Sloboda Rigobello"},{id:"289321",title:"Dr.",name:"Fabio Henrique",surname:"Poliseli Scopel",slug:"fabio-henrique-poliseli-scopel",fullName:"Fabio Henrique Poliseli Scopel"},{id:"289322",title:"MSc.",name:"Maysa",surname:"Formigone",slug:"maysa-formigone",fullName:"Maysa Formigone"},{id:"289324",title:"Dr.",name:"Erica",surname:"Gomes De Lima",slug:"erica-gomes-de-lima",fullName:"Erica Gomes De Lima"},{id:"289325",title:"MSc.",name:"Angelivia",surname:"Gregório",slug:"angelivia-gregorio",fullName:"Angelivia Gregório"},{id:"289326",title:"BSc.",name:"Vanessa De Cássia",surname:"Mendes Del Bel",slug:"vanessa-de-cassia-mendes-del-bel",fullName:"Vanessa De Cássia Mendes Del Bel"},{id:"289327",title:"BSc.",name:"Tuan Henrique",surname:"Smielevski De Souza",slug:"tuan-henrique-smielevski-de-souza",fullName:"Tuan Henrique Smielevski De Souza"},{id:"289329",title:"Dr.",name:"Priscila",surname:"Wielewski",slug:"priscila-wielewski",fullName:"Priscila Wielewski"},{id:"289330",title:"MSc.",name:"Paula",surname:"Gimenez Milani",slug:"paula-gimenez-milani",fullName:"Paula Gimenez Milani"},{id:"289338",title:"Dr.",name:"Magali Soares",surname:"Santos Pozza",slug:"magali-soares-santos-pozza",fullName:"Magali Soares Santos Pozza"}],corrections:null},{id:"69854",title:"Cell Growth Measurement",doi:"10.5772/intechopen.86835",slug:"cell-growth-measurement",totalDownloads:1354,totalCrossrefCites:1,totalDimensionsCites:2,hasAltmetrics:0,abstract:"The cell is the basic structural and functional unit of all living organisms. As the smallest unit and building blocks of life, cells differ in size, shape, metabolism, reproduction, and growth requirements. Cells reproduce through cell division involving a four-phase (G1, S, G2, M) cell cycle, which is tightly regulated at multiple checkpoints. The resulting growth curve demonstrates that cell population increases in three sequential steps: incubation, exponential hyperplasia, and stagnation/death phases. Cell growth is subject to changes in disease state and/or environmental conditions. This chapter will focus on methods for cell growth measurement, which are grouped into five sections: cell cycle, apoptosis, growth curve, drug-induced proliferation (DIP), and continuous assays. Among the continuous assays, the EZMTT dye allows for long-term tracking of cell growth under various conditions and shows promise in precision medicine by early detection of drug resistance.",signatures:"Ning Xu, Xingrou Chen, Jingjing Rui, Yan Yu, Dongshi Gu, Jennifer Jin Ruan and Benfang Helen Ruan",downloadPdfUrl:"/chapter/pdf-download/69854",previewPdfUrl:"/chapter/pdf-preview/69854",authors:[{id:"269973",title:"Prof.",name:"Benfang",surname:"Ruan",slug:"benfang-ruan",fullName:"Benfang Ruan"},{id:"292947",title:"Dr.",name:"Ning",surname:"Xu",slug:"ning-xu",fullName:"Ning Xu"},{id:"292949",title:"Mr.",name:"Yan",surname:"Yu",slug:"yan-yu",fullName:"Yan Yu"},{id:"292950",title:"BSc.",name:"Jingjing",surname:"Rui",slug:"jingjing-rui",fullName:"Jingjing Rui"},{id:"292951",title:"BSc.",name:"Xingrou",surname:"Chen",slug:"xingrou-chen",fullName:"Xingrou Chen"},{id:"292953",title:"BSc.",name:"Dongshi",surname:"Gu",slug:"dongshi-gu",fullName:"Dongshi Gu"},{id:"292955",title:"BSc.",name:"Jennifer",surname:"Ruan",slug:"jennifer-ruan",fullName:"Jennifer Ruan"}],corrections:null},{id:"69690",title:"Ion Homeostasis Response to Nutrient-Deficiency Stress in Plants",doi:"10.5772/intechopen.89398",slug:"ion-homeostasis-response-to-nutrient-deficiency-stress-in-plants",totalDownloads:2669,totalCrossrefCites:3,totalDimensionsCites:6,hasAltmetrics:0,abstract:"A crucial feature of plant performance is its strong dependence on the availability of essential mineral nutrients, affecting multiple vital functions. Indeed, mineral-nutrient deficiency is one of the major stress factors affecting plant growth and development. Thereby, nitrogen and potassium represent the most abundant mineral contributors, critical for plant survival. While studying plant responses to nutrient deficiency, one should keep in mind that mineral nutrients, along with their specific metabolic roles, are directly involved in maintaining cell ion homeostasis, which relies on a finely tuned equilibrium between cytosolic and vacuolar ion pools. Therefore, in this chapter we briefly summarize the role of the ion homeostasis system in cell responses to environmental deficiency of nitrate and potassium ions. Special attention is paid to the implementation of plant responses via NO3− and K+ root transport and regulation of ion distribution in cell compartments. These responses are strongly dependent on plant species, as well as severity and duration of nutrient deficiency.",signatures:"Natalia Osmolovskaya, Julia Shumilina, Ksenia Bureiko, Veronika Chantseva, Tatiana Bilova, Ludmila Kuchaeva, Nikolai Laman, Ludger A. Wessjohann and Andrej Frolov",downloadPdfUrl:"/chapter/pdf-download/69690",previewPdfUrl:"/chapter/pdf-preview/69690",authors:[{id:"177609",title:"Dr.",name:"Natalia",surname:"Osmolovskaya",slug:"natalia-osmolovskaya",fullName:"Natalia Osmolovskaya"},{id:"309520",title:"Ms.",name:"Julia",surname:"Shumilina",slug:"julia-shumilina",fullName:"Julia Shumilina"},{id:"309521",title:"Ms.",name:"Ksenia",surname:"Bureiko",slug:"ksenia-bureiko",fullName:"Ksenia Bureiko"},{id:"309522",title:"Ms.",name:"Veronika",surname:"Chantseva",slug:"veronika-chantseva",fullName:"Veronika Chantseva"},{id:"309523",title:"Dr.",name:"Tatiana",surname:"Bilova",slug:"tatiana-bilova",fullName:"Tatiana Bilova"},{id:"309524",title:"Mrs.",name:"Ludmila",surname:"Kuchaeva",slug:"ludmila-kuchaeva",fullName:"Ludmila Kuchaeva"},{id:"309525",title:"Prof.",name:"Ludger A.",surname:"Wessjohann",slug:"ludger-a.-wessjohann",fullName:"Ludger A. Wessjohann"},{id:"309526",title:"Dr.",name:"Andrej",surname:"Frolov",slug:"andrej-frolov",fullName:"Andrej Frolov"}],corrections:null},{id:"69404",title:"Intracellular Lipid Homeostasis and Trafficking in Autophagy",doi:"10.5772/intechopen.89683",slug:"intracellular-lipid-homeostasis-and-trafficking-in-autophagy",totalDownloads:1089,totalCrossrefCites:1,totalDimensionsCites:3,hasAltmetrics:0,abstract:"In eukaryotes, lipids are not only an important constituent of the plasma membrane but also used to generate specialized membrane-bound organelles, including temporary compartments with critical functions. As such, lipids play a key role in intracellular homeostasis—the ability of a cell to maintain stable internal conditions upon changes in its extracellular environment. Autophagy, one of the cellular processes through which eukaryotic cells strive for survival under stress, is heavily dependent on lipid and membrane trafficking through the de novo formation of autophagosomes—temporary, large, and double-bilayered organelles in which materials are encapsulated for recycling. This chapter discusses what we know about lipid homeostasis and trafficking during autophagy and autophagosome formation and comments on future directions of the field.",signatures:"Shreya Goyal, Meaghan R. Robinson, Verónica A. Segarra and Richard J. Chi",downloadPdfUrl:"/chapter/pdf-download/69404",previewPdfUrl:"/chapter/pdf-preview/69404",authors:[{id:"299107",title:"Ms.",name:"Shreya",surname:"Goyal",slug:"shreya-goyal",fullName:"Shreya Goyal"},{id:"299593",title:"Dr.",name:"Richard",surname:"Chi",slug:"richard-chi",fullName:"Richard Chi"},{id:"309458",title:"Dr.",name:"Veronica",surname:"Segarra",slug:"veronica-segarra",fullName:"Veronica Segarra"},{id:"311231",title:"Ms.",name:"Meaghan",surname:"Robinson",slug:"meaghan-robinson",fullName:"Meaghan Robinson"}],corrections:null},{id:"70241",title:"Cell-Based Assays in Cancer Research",doi:"10.5772/intechopen.90226",slug:"cell-based-assays-in-cancer-research",totalDownloads:1056,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:1,abstract:"Cell growth is referred to as cell proliferation, that is, the increase in cell numbers during repeated cell division. Cell growth can be defined as the enlargement of cell volume, which might take place in the absence of cell division. Growth and reproduction are features of cells in all living organisms. All cells reproduce by dividing into two, with each parental cell giving rise to two daughter cells each time they divide. Various genes are involved in the control of cell division and growth. Reproduction in unicellular organisms are referred to cell division and in multicellular organisms it is tissue growth and maintenance. Survival of the eukaryotes depends upon interactions between various cell types, that helps in the balanced distribution. This is achieved through the highly regulated process of cell proliferation. Knowledge in cell cycle is necessary to determine the best time to collect cells, to harvest cell products, or to move cells to a new growth environment. Cancer cells do not die at the natural point in a cell’s life cycle. Cancer cells occur as the results of cellular changes caused by the uncontrolled growth and division of cells. The chapter focuses on cancer cell maintenance, apoptosis, and its detection assays.",signatures:"Biba Vikas and Sukumaran Anil",downloadPdfUrl:"/chapter/pdf-download/70241",previewPdfUrl:"/chapter/pdf-preview/70241",authors:[{id:"241658",title:"Dr.",name:"Biba",surname:"Vikas",slug:"biba-vikas",fullName:"Biba Vikas"},{id:"25232",title:"Prof.",name:"Sukumaran",surname:"Anil",slug:"sukumaran-anil",fullName:"Sukumaran Anil"}],corrections:null}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},subseries:null,tags:null},relatedBooks:[{type:"book",id:"6964",title:"Cell Culture",subtitle:null,isOpenForSubmission:!1,hash:"045f3a964a9628162956abc06ef5777d",slug:"cell-culture",bookSignature:"Radwa Ali Mehanna",coverURL:"https://cdn.intechopen.com/books/images_new/6964.jpg",editedByType:"Edited by",editors:[{id:"182118",title:"Dr.",name:"Radwa Ali",surname:"Mehanna",slug:"radwa-ali-mehanna",fullName:"Radwa Ali Mehanna"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"6820",title:"Keratin",subtitle:null,isOpenForSubmission:!1,hash:"6def75cd4b6b5324a02b6dc0359896d0",slug:"keratin",bookSignature:"Miroslav Blumenberg",coverURL:"https://cdn.intechopen.com/books/images_new/6820.jpg",editedByType:"Edited by",editors:[{id:"31610",title:"Dr.",name:"Miroslav",surname:"Blumenberg",slug:"miroslav-blumenberg",fullName:"Miroslav Blumenberg"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"7264",title:"Calcium and Signal Transduction",subtitle:null,isOpenForSubmission:!1,hash:"e373a3d1123dbd45fddf75d90e3e7c38",slug:"calcium-and-signal-transduction",bookSignature:"John N. Buchholz and Erik J. Behringer",coverURL:"https://cdn.intechopen.com/books/images_new/7264.jpg",editedByType:"Edited by",editors:[{id:"89438",title:"Dr.",name:"John N.",surname:"Buchholz",slug:"john-n.-buchholz",fullName:"John N. Buchholz"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"6683",title:"Ion Channels in Health and Sickness",subtitle:null,isOpenForSubmission:!1,hash:"8b02f45497488912833ba5b8e7cdaae8",slug:"ion-channels-in-health-and-sickness",bookSignature:"Kaneez Fatima Shad",coverURL:"https://cdn.intechopen.com/books/images_new/6683.jpg",editedByType:"Edited by",editors:[{id:"31988",title:"Prof.",name:"Kaneez",surname:"Fatima Shad",slug:"kaneez-fatima-shad",fullName:"Kaneez Fatima Shad"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"5907",title:"Stem Cells in Clinical Practice and Tissue Engineering",subtitle:null,isOpenForSubmission:!1,hash:"968012935832c68c09da71ccb81ca420",slug:"stem-cells-in-clinical-practice-and-tissue-engineering",bookSignature:"Rakesh Sharma",coverURL:"https://cdn.intechopen.com/books/images_new/5907.jpg",editedByType:"Edited by",editors:[{id:"98263",title:"Prof.",name:"Rakesh",surname:"Sharma",slug:"rakesh-sharma",fullName:"Rakesh Sharma"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"6925",title:"Endoplasmic Reticulum",subtitle:null,isOpenForSubmission:!1,hash:"a9e90d2dbdbc46128dfe7dac9f87c6b4",slug:"endoplasmic-reticulum",bookSignature:"Angel Català",coverURL:"https://cdn.intechopen.com/books/images_new/6925.jpg",editedByType:"Edited by",editors:[{id:"196544",title:"Prof.",name:"Angel",surname:"Catala",slug:"angel-catala",fullName:"Angel Catala"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"8498",title:"Extracellular Vesicles and Their Importance in Human Health",subtitle:null,isOpenForSubmission:!1,hash:"eb168770441543e33da9325f16197fb4",slug:"extracellular-vesicles-and-their-importance-in-human-health",bookSignature:"Ana Gil De Bona and Jose Antonio Reales Calderon",coverURL:"https://cdn.intechopen.com/books/images_new/8498.jpg",editedByType:"Edited by",editors:[{id:"203919",title:"Dr.",name:"Ana",surname:"Gil De Bona",slug:"ana-gil-de-bona",fullName:"Ana Gil De Bona"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"8774",title:"Programmed Cell Death",subtitle:null,isOpenForSubmission:!1,hash:"0459d0c7a518f61817a48fd4709c35bd",slug:"programmed-cell-death",bookSignature:"Hala Gali-Muhtasib and Omar Nasser Rahal",coverURL:"https://cdn.intechopen.com/books/images_new/8774.jpg",editedByType:"Edited by",editors:[{id:"57145",title:"Prof.",name:"Hala",surname:"Gali-Muhtasib",slug:"hala-gali-muhtasib",fullName:"Hala Gali-Muhtasib"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"6883",title:"Cell Signalling",subtitle:"Thermodynamics and Molecular Control",isOpenForSubmission:!1,hash:"e4e17d85c0643c7f4d274fa9adbcc628",slug:"cell-signalling-thermodynamics-and-molecular-control",bookSignature:"Sajal Ray",coverURL:"https://cdn.intechopen.com/books/images_new/6883.jpg",editedByType:"Edited by",editors:[{id:"173697",title:"Prof.",name:"Sajal",surname:"Ray",slug:"sajal-ray",fullName:"Sajal Ray"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"7999",title:"Free Radical Medicine and Biology",subtitle:null,isOpenForSubmission:!1,hash:"083e5d427097d368a3f8a02bd6c76bf8",slug:"free-radical-medicine-and-biology",bookSignature:"Kusal Das, Swastika Das, Mallanagouda Shivanagouda Biradar, Varaprasad Bobbarala and S. Subba Tata",coverURL:"https://cdn.intechopen.com/books/images_new/7999.jpg",editedByType:"Edited by",editors:[{id:"187859",title:"Prof.",name:"Kusal",surname:"Das",slug:"kusal-das",fullName:"Kusal Das"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}],ofsBooks:[]},correction:{item:{id:"79356",slug:"corrigendum-to-analytical-study-of-environmental-impacts-and-their-effects-on-groundwater-hydrology",title:"Corrigendum to: Analytical Study of Environmental Impacts and Their Effects on Groundwater Hydrology",doi:null,correctionPDFUrl:"https://cdn.intechopen.com/pdfs/72413.pdf",downloadPdfUrl:"/chapter/pdf-download/72413",previewPdfUrl:"/chapter/pdf-preview/72413",totalDownloads:null,totalCrossrefCites:null,bibtexUrl:"/chapter/bibtex/72413",risUrl:"/chapter/ris/72413",chapter:{id:"68077",slug:"analytical-study-of-environmental-impacts-and-their-effects-on-groundwater-hydrology",signatures:"Muhammad Salik Javaid, Laila Khalid and Muhammad Zeshan Khalid",dateSubmitted:"April 29th 2019",dateReviewed:"June 12th 2019",datePrePublished:null,datePublished:"March 4th 2020",book:{id:"8602",title:"Groundwater Hydrology",subtitle:null,fullTitle:"Groundwater Hydrology",slug:"groundwater-hydrology",publishedDate:"March 4th 2020",bookSignature:"Muhammad Salik Javaid",coverURL:"https://cdn.intechopen.com/books/images_new/8602.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",editors:[{id:"208759",title:"Dr.",name:"Muhammad Salik",middleName:null,surname:"Javaid",slug:"muhammad-salik-javaid",fullName:"Muhammad Salik Javaid"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:[{id:"208759",title:"Dr.",name:"Muhammad Salik",middleName:null,surname:"Javaid",fullName:"Muhammad Salik Javaid",slug:"muhammad-salik-javaid",email:"msalikj@hotmail.com",position:null,institution:{name:"Abasyn University",institutionURL:null,country:{name:"Pakistan"}}}]}},chapter:{id:"68077",slug:"analytical-study-of-environmental-impacts-and-their-effects-on-groundwater-hydrology",signatures:"Muhammad Salik Javaid, Laila Khalid and Muhammad Zeshan Khalid",dateSubmitted:"April 29th 2019",dateReviewed:"June 12th 2019",datePrePublished:null,datePublished:"March 4th 2020",book:{id:"8602",title:"Groundwater Hydrology",subtitle:null,fullTitle:"Groundwater Hydrology",slug:"groundwater-hydrology",publishedDate:"March 4th 2020",bookSignature:"Muhammad Salik Javaid",coverURL:"https://cdn.intechopen.com/books/images_new/8602.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",editors:[{id:"208759",title:"Dr.",name:"Muhammad Salik",middleName:null,surname:"Javaid",slug:"muhammad-salik-javaid",fullName:"Muhammad Salik Javaid"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:[{id:"208759",title:"Dr.",name:"Muhammad Salik",middleName:null,surname:"Javaid",fullName:"Muhammad Salik Javaid",slug:"muhammad-salik-javaid",email:"msalikj@hotmail.com",position:null,institution:{name:"Abasyn University",institutionURL:null,country:{name:"Pakistan"}}}]},book:{id:"8602",title:"Groundwater Hydrology",subtitle:null,fullTitle:"Groundwater Hydrology",slug:"groundwater-hydrology",publishedDate:"March 4th 2020",bookSignature:"Muhammad Salik Javaid",coverURL:"https://cdn.intechopen.com/books/images_new/8602.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",editors:[{id:"208759",title:"Dr.",name:"Muhammad Salik",middleName:null,surname:"Javaid",slug:"muhammad-salik-javaid",fullName:"Muhammad Salik Javaid"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}}},ofsBook:{item:{type:"book",id:"11773",leadTitle:null,title:"Archaeology - Challenges and Updates",subtitle:null,reviewType:"peer-reviewed",abstract:"This book will be a self-contained collection of scholarly papers targeting an audience of practicing researchers, academics, PhD students and other scientists. The contents of the book will be written by multiple authors and edited by experts in the field.",isbn:null,printIsbn:null,pdfIsbn:null,doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!0,isSalesforceBook:!1,isNomenclature:!1,hash:"17d91462fa926279f65164ac0d5641cd",bookSignature:"",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/11773.jpg",keywords:null,numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"December 20th 2021",dateEndSecondStepPublish:"January 10th 2022",dateEndThirdStepPublish:"March 11th 2022",dateEndFourthStepPublish:"May 30th 2022",dateEndFifthStepPublish:"July 29th 2022",dateConfirmationOfParticipation:null,remainingDaysToSecondStep:"7 months",secondStepPassed:!0,areRegistrationsClosed:!0,currentStepOfPublishingProcess:1,editedByType:null,kuFlag:!1,biosketch:null,coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:null,coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"23",title:"Social Sciences",slug:"social-sciences"}],chapters:null,productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:null},relatedBooks:[{type:"book",id:"6942",title:"Global Social Work",subtitle:"Cutting Edge Issues and Critical Reflections",isOpenForSubmission:!1,hash:"222c8a66edfc7a4a6537af7565bcb3de",slug:"global-social-work-cutting-edge-issues-and-critical-reflections",bookSignature:"Bala Raju Nikku",coverURL:"https://cdn.intechopen.com/books/images_new/6942.jpg",editedByType:"Edited by",editors:[{id:"263576",title:"Dr.",name:"Bala",surname:"Nikku",slug:"bala-nikku",fullName:"Bala Nikku"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"6926",title:"Biological Anthropology",subtitle:"Applications and Case Studies",isOpenForSubmission:!1,hash:"5bbb192dffd37a257febf4acfde73bb8",slug:"biological-anthropology-applications-and-case-studies",bookSignature:"Alessio Vovlas",coverURL:"https://cdn.intechopen.com/books/images_new/6926.jpg",editedByType:"Edited by",editors:[{id:"313084",title:"Dr.",name:"Alessio",surname:"Vovlas",slug:"alessio-vovlas",fullName:"Alessio Vovlas"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1591",title:"Infrared Spectroscopy",subtitle:"Materials Science, Engineering and Technology",isOpenForSubmission:!1,hash:"99b4b7b71a8caeb693ed762b40b017f4",slug:"infrared-spectroscopy-materials-science-engineering-and-technology",bookSignature:"Theophile Theophanides",coverURL:"https://cdn.intechopen.com/books/images_new/1591.jpg",editedByType:"Edited by",editors:[{id:"37194",title:"Dr.",name:"Theophile",surname:"Theophanides",slug:"theophile-theophanides",fullName:"Theophile Theophanides"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3161",title:"Frontiers in Guided Wave Optics and Optoelectronics",subtitle:null,isOpenForSubmission:!1,hash:"deb44e9c99f82bbce1083abea743146c",slug:"frontiers-in-guided-wave-optics-and-optoelectronics",bookSignature:"Bishnu Pal",coverURL:"https://cdn.intechopen.com/books/images_new/3161.jpg",editedByType:"Edited by",editors:[{id:"4782",title:"Prof.",name:"Bishnu",surname:"Pal",slug:"bishnu-pal",fullName:"Bishnu Pal"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"371",title:"Abiotic Stress in Plants",subtitle:"Mechanisms and Adaptations",isOpenForSubmission:!1,hash:"588466f487e307619849d72389178a74",slug:"abiotic-stress-in-plants-mechanisms-and-adaptations",bookSignature:"Arun Shanker and B. Venkateswarlu",coverURL:"https://cdn.intechopen.com/books/images_new/371.jpg",editedByType:"Edited by",editors:[{id:"58592",title:"Dr.",name:"Arun",surname:"Shanker",slug:"arun-shanker",fullName:"Arun Shanker"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3092",title:"Anopheles mosquitoes",subtitle:"New insights into malaria vectors",isOpenForSubmission:!1,hash:"c9e622485316d5e296288bf24d2b0d64",slug:"anopheles-mosquitoes-new-insights-into-malaria-vectors",bookSignature:"Sylvie Manguin",coverURL:"https://cdn.intechopen.com/books/images_new/3092.jpg",editedByType:"Edited by",editors:[{id:"50017",title:"Prof.",name:"Sylvie",surname:"Manguin",slug:"sylvie-manguin",fullName:"Sylvie Manguin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"72",title:"Ionic Liquids",subtitle:"Theory, Properties, New Approaches",isOpenForSubmission:!1,hash:"d94ffa3cfa10505e3b1d676d46fcd3f5",slug:"ionic-liquids-theory-properties-new-approaches",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/72.jpg",editedByType:"Edited by",editors:[{id:"19816",title:"Prof.",name:"Alexander",surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"2270",title:"Fourier Transform",subtitle:"Materials Analysis",isOpenForSubmission:!1,hash:"5e094b066da527193e878e160b4772af",slug:"fourier-transform-materials-analysis",bookSignature:"Salih Mohammed Salih",coverURL:"https://cdn.intechopen.com/books/images_new/2270.jpg",editedByType:"Edited by",editors:[{id:"111691",title:"Dr.Ing.",name:"Salih",surname:"Salih",slug:"salih-salih",fullName:"Salih Salih"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"117",title:"Artificial Neural Networks",subtitle:"Methodological Advances and Biomedical Applications",isOpenForSubmission:!1,hash:null,slug:"artificial-neural-networks-methodological-advances-and-biomedical-applications",bookSignature:"Kenji Suzuki",coverURL:"https://cdn.intechopen.com/books/images_new/117.jpg",editedByType:"Edited by",editors:[{id:"3095",title:"Prof.",name:"Kenji",surname:"Suzuki",slug:"kenji-suzuki",fullName:"Kenji Suzuki"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3828",title:"Application of Nanotechnology in Drug Delivery",subtitle:null,isOpenForSubmission:!1,hash:"51a27e7adbfafcfedb6e9683f209cba4",slug:"application-of-nanotechnology-in-drug-delivery",bookSignature:"Ali Demir Sezer",coverURL:"https://cdn.intechopen.com/books/images_new/3828.jpg",editedByType:"Edited by",editors:[{id:"62389",title:"PhD.",name:"Ali Demir",surname:"Sezer",slug:"ali-demir-sezer",fullName:"Ali Demir Sezer"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"65046",title:"The Established and Evolving Role of Nailfold Capillaroscopy in Connective-Tissue Disease",doi:"10.5772/intechopen.82386",slug:"the-established-and-evolving-role-of-nailfold-capillaroscopy-in-connective-tissue-disease",body:'The technique of nailfold capillaroscopy (NFC) was first described almost 100 years ago by Brown and O’Leary, but its utility in connective tissue disease was first truly recognised and demonstrated through the work of Maricq et al. in the 1970s and 1980s [1, 2, 3]. It is now established as a low-cost, non-invasive, highly specific, reproducible, and rapid investigation in the diagnostic workup of scleroderma-spectrum disorders and, tellingly, was included in the most recent ACR/EULAR systemic sclerosis classification criteria [4]. As a consequence, there has never been more interest in capillaroscopy and contemporary research is actively evaluating both the additional utility of NFC within scleroderma-spectrum disorders as well as in other diseases characterised by microvasculopathy. This chapter will summarise the techniques and principles of NFC, its established role, and explore the emerging roles for NFC with a focus on connective-tissue diseases.
As the name implies, NFC involves visualising the nailfold capillaries. Capillaries are the smallest blood vessels, with a size that normally allows the passage of a single red blood cell at a time. They form a complex network of “loops” (U-shaped structures commonly compared to hairpins) with an afferent (arterial) and efferent (venous) limb and an apex connecting the two (see Figure 1). These small vessels aid the diffusion of gases and the movement of substrates for and non-essential by-products of cellular respiration. The skin has a rich network of capillaries which are usually orientated vertically, distributing blood from the deep cutaneous arterioles to the surface skin and then back down again to the venous plexus. In contrast, at the nailfolds, these capillary loops lie horizontally which allows a visualisation along the length of their course. To be strictly accurate, we are not able to visualise the capillaries themselves, the thin walls of which are essentially transparent, but instead the column of red blood cells. Over many years researchers have identified abnormalities in the structure and arrangement of these capillaries present in certain diseases characterised by microvasculopathy. These abnormalities are discussed in more detail later.
Normal nailfold capillaries. The typical appearance of capillary “loops”.
NFC consists of two interrelated elements, image acquisition and image interpretation, and these will be discussed in turn in this and the following sections.
For all techniques, there are a number of general principles that should be observed. Firstly, to minimise the potential for variability in findings due to vasoconstriction and altered digital perfusion, capillaroscopy should be performed in a warm environment, with most studies suggesting a 15–30 minute period of acclimatisation to “room temperature”, usually around 20°C. Subjects should be advised to avoid smoking, caffeine or medications (where possible) that could cause peripheral vasoconstriction immediately prior to the investigation. Secondly, visualisation of the nailfold capillaries is aided by the use of a gel or oil interface to reduce surface reflection from the device light source. The more commonly used substances are clear or lightly coloured oils (such as paraffin or light olive oil) or lubricant jellies, applied in the region of the nailbed and cuticle immediately prior to visualisation. There are an increasing number of differing techniques for acquiring images and we will discuss the most frequently employed.
Widefield stereomicroscopy (WSM; see Figure 2a) is the original technique pioneered by Maricq et al. and is still considered one of the two “gold-standard” techniques [2, 3, 5]. Each nailfold (usually of just the index-little finger of each hand, as thumbs can be difficult to orientate under the microscope) is examined at around 20-fold magnification which allows for a panoramic view of the entire nailfold. The microscope allows close control of depth of focus. The microscope can be combined with a camera and other digital equipment to allow recording of images and assist real-time explanation of investigation findings. The technique typically takes around 5 minutes to complete.
The different techniques for performing nailfold capillaroscopy. (a) Widefield microscopy; (b) videocapillaroscopy; (c) dermoscopy (with a smartphone attachment).
Nailfold videocapillaroscopy (NVC; see Figure 2b) is the other “gold-standard” technique and is now the most frequent technique used in capillaroscopy research. Either a fixed or handheld imaging device is used which, when combined with computer software, affords a highly magnified view of the nailfold at 200–300-fold. This technique allows for very detailed images but an important consequence is that not all the nailfold can be visualised at the same time. The impact of this can be particularly relevant to studies looking at longitudinal nailfold changes (see later), as it can be difficult at subsequent study visits to visualise the exact same region of the nailfold. There is software that can ‘stitch’ together images using digital picture recognition and therefore produce a panoramic nailfold image made up of smaller high magnification images, first used by Herrick et al., which can mitigate this issue [6]. NVC can take substantially longer than other techniques if all fingers are studied (20–30 minutes), and consequently many studies restrict image acquisition to a single finger in both hands (most commonly the ring finger). An important potential downside of this compromise is that nailfold changes can vary markedly between even adjacent fingers. NVC has been shown in multiple studies to have good intra- and inter-observer variability and/or concordance and correlates well with WSM [6, 7, 8, 9].
Two important factors that have limited accessibility to NFC and its use in the broader rheumatology community are the relative (expensive) cost and the lack of portability of the two gold-standard techniques. There are clear advantages to being able to take a test to the “bedside” rather than having to bring a patient to the test, which is often only currently available at a small number of specialist institutions. Fortuitously, there are a number of low cost and handheld devices such as dermatoscopes and ophthalmoscopes which achieve a good visualisation of the nailfolds at around 10–20-fold magnification (see Figure 2c). A number of studies directly comparing these techniques with WSM and NVC have found a reassuring concordance [10, 11, 12]. In particular, although the rate of “unclassifiable” images is higher, ample diagnostically relevant findings can be elicited, even if more subtle changes can be missed. Rapidly improving technology, particularly with the availability of USB microscopes or attachments for smartphones, can already achieve similar magnification to NVC and record images. This infers that these devices are going to become more commonplace [11]. An additional advantage with the handheld devices is that they can be easier to use in patients with finger deformities and in thumbs (or even toes) which are often not visualised in other techniques, although the additional information gleaned from these is not yet of clear clinical utility.
Before proceeding to discuss nailfold capillary abnormalities, it is important to note that there is a surprisingly broad range of capillary appearances between or even within ‘normal’ subjects and the disease controls used in research settings [13]. It can sometimes be difficult to be certain whether subtle changes are of significance or not but with increasing experience this distinction becomes somewhat easier. In practice, most examinations will clearly fall into a normal or definitely abnormal category and for those that do not there is usually extra information from a history, examination and additional diagnostic tests that can help contextualise the capillaroscopy results.
The abnormal features that originally defined Maricq’s “scleroderma-dermatomyositis pattern (SD-pattern) remain the most important to examine for [2]. These consist of giant (significantly enlarged) capillaries, avascular areas (also referred to as capillary “drop-out”), and microhaemorrhages. Other abnormalities are recognised and include excessively tortuous capillaries, unusually shaped capillaries (“bushy” or “arborized” capillaries) and cuticular hypertrophy, but their clinical significance especially in isolation is less well established.
There is no universally agreed definition of a “giant capillary” but one is by and large accepted as a capillary that is that is enlarged over four-fold normal diameter (and often >ten-fold) (see Figure 3). A normal adult capillary is somewhere between 25-50um and therefore generally anything over 150um is considered pathologic. Enlarged capillaries are somewhere in between giant capillaries and normal. A useful clinical tip is to compare capillaries within the same patient to first establish the appearances and dimensions of their “normal” capillaries and use these to compare the enlarged capillaries against, if present. The presence of even a single giant capillary is very suggestive of an underlying connective tissue disease.
A single giant capillary, in this example associated with a microhaemorrhage in the distal cuticle.
Avascular areas or areas of capillary “drop-out” are regions where there are no capillaries and in the absence of local nailfold trauma are highly specific for systemic sclerosis in particular (see Figure 4). Again, there is no internationally ratified definition but a working definition is a 1 mm region of the distal nailfold with no capillaries present. Another definition is the absence of two or more sequential capillary loops [14]. It can be difficult if there is not adequate visualisation of the nailfold for technical reasons or if it is difficult to get the appropriate depth of focus to bring all capillaries in to view. A simple tip is to compare within the same patients nailfolds to see if the usual density of capillaries (number within a defined width or area) is regionally varied.
Avascular areas, demonstrating areas of capillary “drop-out”. Note in the right-hand image the extensive associated microhaemorrhages and cuticle hypertrophy.
These are evidenced by reddish-brown punctate lesions (haemosiderin staining) in the cuticle (see Figure 5). They are often associated with regional capillary architectural abnormalities (such as a giant capillary) and sometimes recurrent haemorrhage can be deduced from lesions “growing-out” along the cuticle over time.
Nailfold microhaemorrhages.
It is difficult to define “bushy”, “arborized” or excessively tortuous capillaries as these are qualitative judgements and experience dependent (see Figure 6). In addition, although cuticle hypertrophy is well recognised (although not that prevalent) there is no established definition for it and it is based upon a subjective assessment.
Other abnormal capillary shapes. (a) A tortuous capillary; (b) elongated capillaries.
Recently, the reliability of simple capillaroscopic definitions to describe the different morphologies that can be seen in rheumatic diseases has been published and widely accepted [15]. Although there are a range of potential abnormalities which may seem relatively complex, there is actually very good intra- and inter-observer concordance in most studies and even only a short amount of training (for example an hour) can help complete novices make accurate assessments [16]. There has been encouraging results when capillaroscopy has been used in a primary care setting as well [17]. Two prospective studies in particular have elegantly demonstrated the prognostic significance of these abnormalities in patients with Raynaud’s phenomenon. Koenig et al. showed that giant capillaries and capillary loss strongly predict the evolution to a diagnosis of systemic sclerosis (then using the 1980 ACR criteria) and, when combined with a relevant positive autoantibody, had a positive predictive value of 79% and negative predictive value of 93% [18]. A second study, by Ingegnoli et al., found that the three capillary abnormalities that correlated with a later diagnosis of systemic sclerosis were giant capillaries, capillary density and microhaemorrhages [19].
There is no universally adopted consensus on exactly how the varying combination of above potential capillary abnormalities should be classified and this is an ongoing research priority. Classification criteria have many discrete purposes from diagnostic criteria and we will cover only a few illustrative examples as our intended focus is on the use of capillaroscopy in the clinical rather than research setting.
The first proposed classification criteria was that of Maricq et al. who classified patient’s nailfold capillaries as having either “normal” appearances, “non-specific” abnormalities or the “Scleroderma-Dermatomyositis (or SD-) pattern” [2, 5]. This latter category was defined by the presence of giant capillaries or avascular areas and could include the other capillary abnormalities described above. It is this pattern that has now been shown in numerous publications to help differentiate primary from secondary Raynaud’s syndrome and as the pattern present in around 90% of systemic sclerosis patients, often very early in the course of their disease [20]. In essence, therefore, it is these features that are of primary clinical significance as they strongly suggest an associated underlying connective-tissue disease. The “non-specific” group consists of individuals who have some definite capillary abnormalities (such as microhaemorrhages, enlarged or tortuous capillaries), but neither of the more specific features of giant capillaries or avascular areas. From a clinical perspective, the significance of an investigation with these findings should usually be interpreted as normal but it may have some suggestive relevance when considered in the context of a patient’s history, examination and other investigations as supportive of a scleroderma-spectrum disorder.
Because of the intrinsic issues with purely qualitative classification systems, especially when trying to compare or reproduce different study methodologies and research findings, there have been many efforts to develop a more structured and systematic approach into criteria. A Brazilian group developed the Maricq scoring system and incorporated a count of the total number of enlarged or giant capillaries as well as a measure of mean capillary density (capillaries per mm) [21]. Other early efforts at moving towards a more quantitative classification included those by the research group of Lee et al. [14]. More recently, the most widely adopted criteria is that of Cutolo et al. who described “early”, “active” and “late” categories (see Table 1) for individuals with definite capillary abnormal features [23]. Several studies have shown that the Cutolo criteria are associated with disease activity and severity. The “early” and “active” patterns are more common in limited SSc, whereas the “late” category is present more frequently in patients with diffuse SSc [24]. In the same study, the severity of organ involvement progressively increased across groups from “early” towards “late”. Other studies have reported the “late” pattern in older patients, in those with a longer disease duration, and in those with diffuse disease [15, 16]. Several studies have shown that the “late” pattern in particular predicts digital ulcers as well as more severe cutaneous, cardiac and pulmonary disease [24, 25, 26, 27]. The initial Cutolo criteria was later simplified into a score ranging from 0 to 9, correlating to the average score for each of three variables in each of eight examined nailfolds [28].
Classification | Description |
---|---|
Early | Few giant capillaries, few haemorrhages and no capillary loss |
Active | Numerous giant capillaries and microhaemorrhages, mild capillary architecture disturbance and moderate capillary loss |
Late | Severe capillary loss with extensive avascular areas, disorganised capillaries and ramified capillaries. |
The Cutolo classification criteria [22].
Certain components of the capillaroscopic assessment are well suited to quantitative assessment. Capillary density (by convention the number of capillaries within a 1 mm region of the distal nailfold) is the best example of this, with anything less than 6 per mm being pathologically abnormal. A quantitative method was employed in a recent multicentre study and involved counting all the microhaemorrhages, normal capillaries, enlarged capillaries, giant capillaries and other abnormal capillary shapes in the distal row within two 1 mm fields per finger [29]. The study concluded that the simple count of capillaries (i.e. capillary density) was sufficient to monitor the progression of scleroderma. Recently, some groups have used computer technology to count capillaries and automate this quantitative process with good reproducibility and obvious potential advantages for future work [30, 31]. Reduced capillary density has been associated with disease complications such as pulmonary hypertension, interstitial lung disease and digital ulcers. Many other capillary features have been measured and investigated including, for example, capillary length, angle and loop diameter, but the clinical relevance of these measurements is not well established.
The first clearly established clinically relevant role for capillaroscopy was in the assessment of patients with Raynaud’s symptoms. Abnormal nailfold capillaroscopy is strongly predictive of an underlying connective tissue disease (synonymous with “secondary” Raynaud’s syndrome) and, conversely, normal nailfold capillaroscopy is reassuring that an underlying connective tissue disease is unlikely (“primary” Raynaud’s syndrome). The early work into the importance of nailfold capillary changes in identifying patients with secondary Raynaud’s syndrome is well summarised in a systematic review from 1998, where abnormal capillaries had the highest odds ratio (OR) of any variable studied for progression to secondary diseases [32]. These findings have been replicated and enhanced in the prospective study of Koenig et al. over 3000 patient years, who found abnormal capillaries and systemic sclerosis-specific autoantibodies were both independent predictors of an underlying connective tissue disease [18]. Twenty-six percent of patients with capillary abnormalities at baseline (and 36% with a specific autoantibody) developed systemic sclerosis within follow up, which increased to 80% in subjects with both features. Conversely, only 1.8% of patients with neither present at baseline developed a connective tissue disease during follow up. Similarly, a study from Pavlov-Dolijanovic et al. found 45% of their 3029 consecutive patients with Raynaud’s syndrome and abnormal NFC went on to develop a connective tissue disease. The OR for being diagnosed with systemic sclerosis in patients with abnormal NFC compared to those with Raynaud’s syndrome without capillary abnormalities was 183 (95% confidence intervals 97.9–271.5) [33].
Abnormal capillaroscopy features are particularly useful in the diagnosis of systemic sclerosis (SSc) and are present in up to 90% of patients [34]. The work of Leroy and Medsger highlighted the importance of NFC in detecting early SSc in particular and much subsequent work has helped include capillaroscopy in the most recent SSc classification criteria (see Table 2) [4, 35]. Abnormal capillaroscopic findings contribute 2 points towards the 9 points necessary to establish a diagnosis of SSc. If combined with Raynaud’s symptoms, a common indication for the investigation, it contributes a total of 4 points towards the diagnosis. The addition of capillaroscopy to the new criteria have helped improve their sensitivity for early and very early SSc which is an area of great interest to researchers seeking to find interventions and treatments to improve long-term outcomes [36, 37]. It could be argued on the basis of these criteria that access to NFC should be a pre-requisite for all clinicians and researchers evaluating patients with potential SSc.
Item | Sub-item | Weight/score |
---|---|---|
Skin thickening of fingers of both hands extending proximal to the MCPs | – | 9 |
Skin thickening (only count the higher score) | Puffy fingers | 2 |
Sclerodactyly | 4 | |
Finger tip lesions (only count the higher score) | Digital tip ulcers | 2 |
Finger tip pitting scars | 3 | |
Telangiectasia | – | 2 |
Abnormal nailfolds | – | 2 |
Pulmonary arterial hypertension and/or interstitial lung disease (maximum of 2) | Pulmonary arterial hypertension | 2 |
Interstitial lung disease | 2 | |
Raynaud’s phenomenon | – | 2 |
SSc-related autoantibodies (maximum score is 3) | Anti-Scl70 (anti-topoisomerase I) | 3 |
Anti-centromere | ||
Anti-RNA polymerase III |
The 2013 classification criteria for systemic sclerosis [4].
Patients with a score of ≥9 are classified as having definite systemic sclerosis.
There is an accumulating literature on the association between capillaroscopic findings and certain organ-specific complications of SSc. In general, the more severe morphological changes correlate with more severe disease [34, 38]. The converse is also true, where patients with less marked NFC abnormalities have less severe cutaneous and pulmonary involvement [39].
Digital ulcers (DU) are a visible representation of peripheral vasculopathy, occurring in up to 50% of patients at some point in their illness [40]. It stands to reason that capillaroscopic abnormalities would correlate with their presence and there has been considerable interest in applying capillaroscopy as a predictor of digital ulcers in systemic sclerosis. The association of capillary loss and digital ischaemia was first established almost a decade ago with work by Herrick et al. and Ennis et al. [37, 41]. The more recent video CAPillaroscopy (CAP) study showed the mean number of capillaries in the dominant hand middle finger (per mm) was one of three predictors of DU (the two others being number of DUs at enrolment and critical digital ischaemia at enrolment) [29]. The “late” NFC pattern (see Table 1) has been shown in a prospective longitudinal study to be an independent predictor for DU in patients both with and without a history of DUs [42]. NFC findings may help in future target high risk patients for vascular remodelling and protective strategies. Indeed, a prognostic tool, the capillaroscopic skin ulcer risk index (CSURI), has been developed and demonstrated to help predict ulcers in the 3 months following assessment [43]. Another similar tool to predict digital trophic lesions intended for day-to-day clinical used based upon a simple capillary count has also been described [44].
Pulmonary hypertension affects around 15% of patients with systemic sclerosis and despite advances in therapy still accounts for substantial morbidity and mortality [45]. Because of its relatively lower prevalence than other organ specific manifestations, it is more difficult to explore the role of NFC in predicting its presence or severity but some studies have already shown some intriguing results. In a recent Dutch cohort of over 200 patients, NFC changes were independently predictive of cardio-respiratory complications and, notably, all patients with pulmonary hypertension had abnormal NFC [46]. The “late” pattern and reduced capillary density have both been associated with the presence and severity of pulmonary hypertension in SSc [47, 48].
Interstitial lung disease (ILD) is present in up to 80% of patients with systemic sclerosis and, although only around 25% develop progressive disease, this again contributes to substantial morbidity and mortality [35]. In a retrospective observational study an association was found between abnormal NFC and the presence of ILD [49]. Capillaroscopic abnormalities were associated with a mean 15% reduction in forced vital capacity and DLCO compared to participants with normal capillaroscopy findings. Multiple other studies have also found an association between abnormal capillaroscopy and the presence or severity of ILD [27, 34, 46].
Abnormal NFC has been associated with an increased mortality. A study of almost 3000 patients with Raynaud’s symptoms but without an established diagnosis of a CTD was conducted for a mean of 9.3 years. An increased all-cause mortality rate was found for females (HR 1.10; 1.07–1.77) but this association was interestingly not found for males, although the substantially fewer males with Raynaud’s syndrome and relatively short follow up for this outcome measure may have impacted [50]. A more recent study also found an association between capillary loss and mortality, although this did not remain significant after multi-variant adjustment [51].
There has never been more activity and interest in capillaroscopy and its applications are only likely to expand over time. Although its role in the diagnosis of SSc is well established, it is emerging as having a role in a variety of other CTDs such as the idiopathic inflammatory myopathies (IIM) and mixed connective tissue disease (MCTD). Even within SSc there is much ongoing work into further understanding the potential role for capillaroscopy in more accurately screening and monitoring for disease complications and as a putative biomarker. Others are evaluating the potential role of capillaroscopy in monitoring the efficacy of new therapies and as a trial outcome measure. Finally, it is likely that capillaroscopy can be combined with complementary technologies or investigations to better serve the need for progress in the understanding and management of CTDs.
Implicit in Maricq’s initial qualitative classification of the “scleroderma-dermatomyositis” pattern was a recognition that dermatomyositis (DM) had similar nailfold capillary changes to SSc. This perhaps is not surprising given, like SSc, DM is a condition characterised by microvasculopathy and, along with other IIM subtypes such as the anti-synthetase syndrome and overlap myositis, it shares many clinical manifestations such as Raynaud’s syndrome, myositis and cutaneous involvement [52]. NFC has not been as thoroughly evaluated in this patient group as in SSc but there are some interesting findings. An Italian study of 52 patients with IIM found nailfold changes were significantly more common in patients with DM versus polymyositis (PM) and that disease duration seemed to have an impact on the features, as patients with longer disease duration had less of the “late” features [53]. This may seem counter-intuitive and the opposite of the findings in SSc where there is a trend towards more “late” pattern changes with increasing disease duration, but the study was not controlled for the impact of treatment on the capillary features. In an earlier study from Spain, the combination of microhaemorrhages and capillary enlargement was found more frequently in patients with DM
Many patients with MCTD, which again shares considerable clinical manifestation overlap with SSc, will have NFC abnormalities although this has not been studied in isolation [33]. The recent study by Markusse et al. found that the “early” pattern was associated with a positive anti-RNP antibody, a hint that, similar to NFC in the IIM, MCTD may have differing underlying microvascular pathophysiology with less avascular areas or capillary drop-out compared to patients with SSc [46].
In a recent systematic review, Cutolo et al. have helped summarise the limited existing literature of NFC in systemic lupus erythematosus (SLE) [57]. Although differences in the prevalence of capillary abnormalities in patients with SLE compared to normal controls have been found (especially with increased capillary tortuosity, prominent venous plexus and elongated capillaries), these are usually subtle compared to the more marked findings in SSc and IIM. An increased NFC score did correlate with disease activity in the majority of the few studies that reported on this, especially with the frequency of Raynaud’s symptoms or digital gangrene.
Although the role of NFC in diagnosis is well established, its role, if any, in established disease is less clear – could serial examinations be used to screen for complications in much the same way as an annual echocardiogram and pulmonary function tests would do? Prospective longitudinal studies are required to properly address this question, and some are already completed or underway. A recent study by Avouac et al. followed patients prospectively over three years and found that changes in NFC over time (in particular a loss of capillary density to <4 per mm), which occurred in almost half of patients, was a strong marker of organ progression [58]. As mentioned above numerous studies have linked the “late” NFC pattern with SSc disease activity, digital ulcers, cutaneous, cardiac and pulmonary involvement, which suggests an evolution of NFC changes over time [24, 26, 27]. A study from Brazil looked at overall mortality within a group of patients with SSc and found an increased mortality in those with more marked capillary loss [59]. Longitudinal NFC assessments in patients with systemic sclerosis could become feasibly become a part of routine care [60]. The comprehensive review by Ingegnoli & Gualtierotti also summarises the literature to date on the association between abnormalities of NFC and other serum biomarkers such as endothelin-1 and VEGF, which offers an insight into a potential future where biomarkers could be combined to stratify patients and personalise management [9].
Another area that is being researched intensively is in the arena of monitoring effects of drugs on nailfold changes. If, as has been largely established, the structural microvascular changes in CTDs can associate with disease activity, it would also make sense that a successful treatment may reverse the microvascular changes. NFC could therefore be used as a measure of treatment efficacy or even a trial outcome measure. There have been reports of significant improvements in microangiopathy paralleling the substantial clinical improvement in patients after autologous haematopoeitic stem cell transplant (HSCT) for SSc as well as in a patient with anti-synthetase syndrome [61, 62, 63]. In one report (of two patients with SSc and MCTD respectively), progressive improvements in NFC were seen with the cyclophosphamide used for stem cell mobilisation and then the subsequent HSCT [63]. Despite the evidence that endothelin-1 inhibitors reduce the incidence of digital ulcer recurrence and Raynaud’s symptoms [64, 65, 66], two studies have failed to find significant changes in structural microvascular changes [67, 68]. However, the follow up of these studies was relatively short and it has been argued that the true impact of endothelin-1 antagonists on structural microvascular change may take longer to establish. Similarly, intravenous prostanoid therapy was not associated with NFC improvements at 12 months despite a statistically significant improvement in Raynaud’s symptoms [69]. Some researchers are already postulating that making an early diagnosis of SSc in patients with NFC abnormalities may allow for the early instigation of preventative therapies (e.g. endothelin-1 antagonists to prevent pulmonary hypertension, antifibrotic therapies to prevent ILD) and therefore help change the natural history of the disease [70].
As technology rapidly advances there may become available a variety of novel techniques that allow for image acquisition. Inexpensive USB microscopes are already available as are accessory equipment allowing the digital camera of a smart phone to take diagnostically useful images [11]. Technology could also be harnessed to allow for quicker and more reproducible image assessment, as in the case of the recent publication of automated capillary counting [30]. NFC is an excellent measure of structural microvascular changes in disease, but the role and assessment of functional changes may also add clinically useful information. Thermography, where the skin surface temperature is measured using thermal cameras, is already well established at some expert centres [20]. The equipment is relatively expensive and requires regular calibration but technology is advancing and soon thermal cameras may be available as smartphone attachments. Several studies have shown thermography to be able to differentiate between healthy controls and primary Raynaud’s and between primary Raynaud’s and Raynaud’s secondary to systemic sclerosis based upon an abnormal pattern (a persistent “distal-dorsal difference”) of rewarming [71, 72]. Although thermography as a stand-alone test has some utility, further work may help establish that, in time, assessments of patients with potential CTD may include both a structural assessment in the form of NFC and a functional assessment. Developing a standardised protocol for thermography with a plan to validate the protocol to assist ongoing research in thermography is already underway [39]. Another novel strategy for functional perfusion assessment is to use Laser technology. Techniques such as laser Doppler flowmetry and laser speckle contrast analysis (LASCA) have shown good reliability in patients with SSc [73, 74, 75, 76, 77]. Advances are occurring in parallel with advances in other non-invasive imaging techniques such as optical coherence tomography and photoacoustic imaging which allow the opportunity to view the skin and cutaneous vessels in three dimensions [20].
Despite the great progress made by research into NFC over the last 50 years there is much work that is still required to be done. There is a great need for a widely-accepted consensus classification criteria. Work needs to continue to improve awareness of and access to the investigation which will be aided by more convenient and cheaper technologies. Prospective longitudinal studies will allow for a better understanding of certain nailfold capillary abnormalities and their link with organ-specific complications, disease severity, disease activity and hopefully, in time, the efficacy of certain treatments. Further work will also target other related CTDs.
Nailfold capillaroscopy is a simple, non-invasive, and non-expensive investigation with established roles in the diagnosis of scleroderma-spectrum disorders as well as being linked to the presence and severity of a variety of serious organ-specific manifestations which account for substantial morbidity and mortality. Access to the investigation is likely to increase as technology makes equipment more user friendly, reproducible and inexpensive. Demand for the investigation is similarly going to increase substantially as it has been included in recent classification criteria for SSc and the potential clinical applications are only increasing in a wide range of conditions characterised by microangiopathy. Because microvascular change is often present very early in the clinical disease course, nailfold capillaroscopy may be a tool to identify a “window of opportunity”, in conditions which to date have proven largely refractory to the therapies employed with much greater success in other rheumatic and autoimmune disease. It may usher in a new era of preventative rather than reactionary therapy and may become a part of disease management decisions, perhaps in a similar way to the use of clinical ultrasound in patients with rheumatoid arthritis. It is of relevance to all clinicians seeing patients with suspected connective tissue diseases to stay abreast of the progress being made in nailfold capillaroscopy and the related investigations.
The authors would like to thank the patients of Royal Prince Alfred Hospital.
The authors declare no conflict of interests.
Squamous cell carcinoma (SCC) of the eye is an invasive epithelial malignancy and involves the periocular skin, ocular surface and lacrimal apparatus [1]. Over the past four decades, there has been a progressive rise in the global incidence of SCC on account of increased exposure to carcinogens such as ultraviolet (UV) radiation, cigarette smoking, immunosuppressive drugs or human papillomavirus (HPV) infection [1, 2, 3]. The tumor comprises a large and diverse spectrum of conditions and threatens both vision and life. Diagnosis and management of patients with such malignant ophthalmic tumors present additional challenges.
Eyelid SCC is the second most common periocular skin malignancy, far exceeded by basal cell carcinoma (BCC) which is 10–13 times more common [4, 5]. The reported incidence of SCC of the eyelid is 0.09 to 2.42 cases per 100,000 persons per year, representing 3.4–12.6% of all types of malignant eyelid neoplasms [6]. A longitudinal study in England has shown that the age-standardized incidence of SCC has increased approximately 2% per year between 2000 and 2014 [3]. It mainly presents in the seventh decade of life with a male predominance (1.83:1) [7].
Ocular surface SCC is the most common primary ocular neoplasm with reported incidence from 0.3 to 1.9 per 100,000 persons per year, accounting 4–29% of all oculo-orbital tumors [8, 9, 10].
Primary lacrimal sac/duct malignancies are very rare with SCC being the most frequently reported neoplasm [11]. In one study, only 38 out of 3865 (0.98%) specimens of lacrimal sac biopsy showed malignant [12].
SCC is prevalent in the elderly and more frequent among men than women [1, 3]. Typically, SCC affects individuals with a fair complexion and a history of chronic sunlight exposure, which is reflected in an increased risk in white populations [3]. Advanced age and cumulative UV radiation are the major risk factors for SCC formation [6, 13, 14]. There is a doubling in the incidence of SCC with each 10-degree reduction in latitude and every decade increase over the age of sixty [3, 15]. Ionizing radiation, exposure to chemicals (arsenic, polycyclic hydrocarbons and psoralen), high fat diet, cigarette smoking, and infection of HPV also contribute to the formation of SCC [5]. Higher rate of SCC development has been observed in those with immunosuppression secondary to organ transplantation and acquired immunodeficiency syndrome (AIDS) [16, 17]. Studies have shown that the risk of developing SCC varies with the types of transplants and the time intervals following transplantation [17, 18, 19]. Other intrinsic factors predisposing to SCC include preexisting skin neoplasms, chronic cutaneous inflammatory lesions (such as nonhealing wounds, ulcers, burns, scars and sinus tracts), and genetic skin disorders (such as xeroderma pigmentosum, epidermodysplasia verruciformis and albinism) [1, 7, 20].
SCC may arise de novo or from preexisting actinic keratosis or carcinoma in situ (Bowen disease) [1, 7, 21]. Conjunctival intraepithelial neoplasia (CIN) refers to varying degrees of conjunctival epithelial dysplasia. CIN that involves the entire epithelium is referred to as carcinoma in situ. In some cases of squamous cell papilloma, they have been found to grow quite large, covering the surface of the cornea and simulating a squamous cell carcinoma. Most cases of squamous cell papilloma are benign tumor, but its potential for malignant transformation has yet to be studied (Figures 1 and 2). Development of such malignancy undergoes a multi-step process of carcinogenesis involving mutations of genes (such as TP53, CDKN2A, NOTCH1 and NOTCH2, EGFR and TERT) and molecular pathways (RAS–RAF–MEK–ERK and PI3K-AKT–mTOR), epigenetic modifications, viral oncogenesis, and microenvironmental changes [18, 22]. Inactivation of the p53 tumor suppressor gene results in altered apoptosis and clonal proliferation of keratinocytes [1, 18]. Moreover, upregulation of matrix metalloproteinases (MMPs) and other factors account for the invasive activity associated with tumor progression [22].
Periocular squamous cell papilloma with focal mild dysplasia.
Diffused type of conjunctival squamous cell carcinoma (conjunctival intraepithelial neoplasm). a, gross view. b, high magnification (X2 original).
Histologically, SCC is characterized by full-thickness atypia of squamous cells with increased mitotic activity, pleomorphism, and prominent nuclei. The tumor is classified as carcinoma in situ when it is confined to the basement membrane, and as invasive SCC when it extends deep to the dermis or stroma. In a well-differentiated tumor, the cells form nests and strands and exhibit polygonal with abundant eosinophilic cytoplasm and hyperchromatic nuclei. Dyskeratosis, keratin pearls, intercellular bridges are more prominent. Poorly differentiated SCC presents high pleomorphism with anaplastic cells, little keratinization and loss of intercellular bridges. Other variants include spindle and adenoid SCC [1]. Immunohistochemical studies may be useful in diagnosis as cells are positive for epithelial membrane antigen (EMA), cytokeratin, prekeratin, AE1/AE3, MNF16, p63 [5, 23, 24]. Stains for CAM5.2, Ber-EP4, adipophilin, lysozyme, S100 protein and desmin are negative [5, 24, 25].
The appearance of cutaneous SCC (cSCC) has a broad spectrum and may be indistinguishable from various benign and malignant lesions. Collision tumor, a neoplastic lesion comprised of two or more distinct cell populations that maintain distinct borders, which is rare but well documented in the eyelid (Figure 3) [23]. Studies had reported that the accuracy of preoperative clinical diagnosis of cSCC is 51–62.7% [6, 7, 26]. The tumor has a predilection for the lower eyelid and medial can thus, similar to basal cell carcinomas (BCCs). However, cSCC is more likely to involve the upper eyelid than is BCC (Figure 4). SCC of the eyelids grows more rapidly and aggressively than does BCC. The tumor typically appears as a slightly raised nodule or plaque with irregular margins and overlying scaling, crusting, induration, keratinization, or ulceration. Some may feature cutaneous horn, papillomatous lesion, and large fungating growth. The periocular architecture may be distorted and madarotic. The surface vascularization or telangiectasia is usually absent.
Collision tumor of squamous cell carcinoma and sebaceous cell carcinoma coincident in a single mass. a, preoperative photograph. b, postoperative status with reconstruction.
Cutaneous SCC of the eyelid. a, preoperative photograph. b, postoperative status with reconstruction.
Eyelid SCC has potential for local extension with tissue destruction and perineural infiltration which may facilitate intraorbital and intracranial spread with associated cranial neuropathies. This occurs in 4–8% of cases [7, 27]. Unlike BCC, SCC tends to metastasize to regional lymph nodes and distant sites through lymphatic and haematogenous routes. The rate of metastasis ranges from 1–24% depending on tumor size, length of follow up and underlying risk factors [28, 29].
Conjunctival or corneal SCC belongs to the disease spectrum of ocular surface squamous neoplasia (OSSN). It appears as a fleshy, elevated plaque-like lesion usually at the limbus and bulbar conjunctiva within the interpalpebral fissure zone [30]. There are three common morphologic patterns: leukoplakic, papillomatous and gelatinous [31]. Superficial feeder vasculature and pigmentation of the lesion may be prominent, but some tumors may appear avascular. The tumor may cause ocular irritation, foreign body sensation, pruritus, conjunctival congestion, decreased vision and even diplopia.
Although, the metastatic disease is rare, local invasion through corneoscleral lamella into the anterior chamber occurs in about 40% of cases [32, 33]. Mucoepidermoid carcinoma and spindle cell carcinoma (Figure 5) are other rare variants of conjunctival SCC which tend to be more aggressive and more likely to invade the globe or orbit [30, 34]. The incidence of intraocular spread by conjunctival SCC is reported up to 13% and orbital invasion about 12–16% [35, 36, 37].
Advanced spindle squamous cell carcinoma. A, primary site. B, after one year without treatment. C, submandibular lymph node metastasis.
The clinical manifestations of lacrimal sac tumors are featureless such as chronic epiphora and recurrent dacryocystitis. However, a firm, nonreducible, nontender mass with insidious growth above the medial canthal tendon should prompt the suspicion of possible malignancy [38, 39]. The tumor may invade the skin and produce ulceration and spontaneous bleeding.
Metastasis to regional lymph nodes may also occur. When regional or distant metastases are present in all types of ophthalmic SCC, the prognosis is poor, and the mortality is high [1].
To achieve minimizing the rate of recurrence, a complete pre-op assessment must be made, including a highly precise clinical approach to the diagnostic: whether the lesion is circumscribed or diffuse, bilateral or unilateral, suspected to be pre-cancerous or malign. The extension of the tumor must also be assessed, determining the existence of intra-ocular and/or intra-orbital invasion, carrying out palpation of regional lymphatics and, when considered appropriate, a systemic extension study for detecting metastasis.
Clinical staging is based on the assessment of cancer by inspection; slit-lamp examination, palpation of regional nodes, and clinical photography are used, as well as preoperative ultrasound biomicroscopy (UBM) and (Optical Coherence Tomograph) OCT when the intraocular invasion is suspected. Radiological examination (CT, magnetic resonance imaging [MRI], and PET/CT) can be used to examine regional node status, paranasal sinuses, orbit, brain, and chest. Ongoing studies are designed to clarify the role of sentinel node biopsy in the accurate staging of invasive squamous cell carcinoma [40].
TNM staging also includes clinical classification and pathological classification as outlined by the American Joint Committee on Cancer (AJCC), this staging applies to squamous carcinomas with the natural history of lymphatic spread to regional nodes, the possibility of hematogenous metastases, as well as subsequent locoregional disease and metastatic disease. Tables 1 and 2 are the staging of eyelid SCC and ocular surface SCC, respectively.
Category | Definition | |
---|---|---|
TX | Primary tumor cannot be assessed | |
T0 | No evidence of primary tumor | |
Tis | Carcinoma in situ | |
T1 | Tumor ≤10 mm in greatest dimension | |
T1a | Tumor does not invade the tarsal plate or eyelid margin | |
T1b | Tumor invades the tarsal plate or eyelid margin | |
T1c | Tumor involves full thickness of the eyelid | |
T2 | Tumor >10 mm but ≤20 mm in greatest dimension | |
T2a | Tumor does not invade the tarsal plate or eyelid margin | |
T2b | Tumor invades the tarsal plate or eyelid margin | |
T2c | Tumor involves full thickness of the eyelid | |
T3 | Tumor >20 mm but ≤30 mm in greatest dimension | |
T3a | Tumor does not invade the tarsal plate or eyelid margin | |
T3b | Tumor invades the tarsal plate or eyelid margin | |
T3c | Tumor involves full thickness of the eyelid | |
T4 | Any eyelid tumor that invades adjacent ocular, orbital, or facial structures | |
T4a | Tumor invades ocular or intraorbital structures | |
T4b | Tumor invades (or erodes through) the bony walls of the orbit or extends to the paranasal sinuses or invades the lacrimal sac / nasolacrimal duct or brain | |
NX | Regional lymph nodes cannot be assessed | |
N0 | No evidence of lymph node involvement | |
N1 | Metastasis in a single ipsilateral regional lymph node, ≤ 3 cm in greatest dimension | |
N1a | Metastasis in a single ipsilateral regional lymph node based on clinical evaluation or imaging findings | |
N1b | Metastasis in a single ipsilateral regional lymph node based on lymph node biopsy | |
N2 | Metastasis in a single ipsilateral regional lymph node, > 3 cm in greatest dimension, or in bilateral or contralateral lymph nodes | |
N2a | Metastasis documented based on clinical evaluation or imaging findings | |
N2b | Metastasis documented based on microscopic findings on lymph node biopsy | |
M0 | No distant metastasis | |
M1 | Distant metastasis | |
AJCC, American Joint Committee on Cancer. |
Staging for eyelid carcinoma according to AJCC 8th edition.
Category | Definition | |
---|---|---|
TX | Primary tumor cannot be assessed | |
T0 | No evidence of primary tumor | |
Tis | Carcinoma in situ | |
T1 | Tumor ≤5 mm. Or less in greatest dimension | |
T2 | Tumor >5 mm. In greatest dimension, without invasion of adjacent structures | |
T3 | Tumor invades adjacent structures (excluding the orbit) | |
T4 | Tumor invades the orbit with or without further extension | |
T4a | Tumor invades the orbital soft tissues, without bone invasion | |
T4b | Tumor invades bone | |
T4c | Tumor invades adjacent paranasal sinuses | |
T4d | Tumor invades brain | |
NX | Regional lymph nodes cannot be assessed | |
N0 | No regional lymph node metastasis | |
N1 | Regional lymph node metastasis | |
M0 | No distant metastasis | |
M1 | Distant metastasis | |
AJCC, American Joint Committee on Cancer. |
Staging for conjunctival carcinoma according to AJCC 7th edition.
The management of CIN or SCC in the ocular surface varies with the extent or recurrence of the lesion. To completely destroy or extirpate the tumor through surgery and adjuvating treatments (cryotherapy, topical chemotherapy, radiotherapy) remains the widely accepted treatment strategy for primary lesion after precise histopathological confirmation.
Most of the primary conjunctival squamous cell carcinoma arises in the interpalpebral area near the limbus and the surgical technique for limbal tumors is different than that for forniceal tumors [41, 42, 43, 44].
In general, for tumors that are circumscribed, limbar or conjunctival bulbar, complete extirpation (excisional biopsy) with the smallest possible amount of manipulation and a resection margin of 3–5 mm could be sufficient treatment. Limbal neoplasms possibly can invade through the corneal epithelium and sclera into the anterior chamber and through the soft tissues into the orbit. Thus, it is often necessary to remove a thin lamella of the cornea or sclera to achieve tumor-free margins and to decrease the chance for tumor recurrence. The management of limbal lesions could involve alcohol epitheliectomy or corneal epitheliectomy with a beaver blade for the corneal component and partial lamellar scleroconjunctivectomy with wide margins for the conjunctival component followed by freeze–thaw cryotherapy to the remaining adjacent bulbar conjunctiva. Bowman’s layer should be respected because its removal would facilitate the intraocular penetration of any recurrence [43, 44].
In all cases, the full conjunctival component along with the underlying Tenon’s fascia should be excised totally. Those tumors in the forniceal region can be managed by wide local resection and cryotherapy. In diffuse and extended lesions where complete resection is difficult, the largest possible extirpation must be made which must also allow for a precise histopathological diagnostic.
Because cells from these friable tumors can seed into adjacent tissues, a gentle technique without touching the tumor (no-touch technique) is advised. Additionally, the operative field should be left dry to minimize the seeding of cells. In some cases, microscopically controlled excision (Mohs surgery) is performed at the time of surgery to ensure tumor-free margins [45].
An extensive suspicious tumor that is symptomatic or suspected to be malignant can be approached by incisional wedge biopsy or punch biopsy. In general, it should be concerned if tumors occupy 4 clock hours or less on the bulbar conjunctiva, excisional biopsy is preferable to incisional biopsy. Incisional biopsy is also appropriate for lesions that are ideally treated with radiotherapy, chemotherapy, or other topical medications. These include metastatic tumors, and some cases of squamous cell carcinoma that are unsuitable for surgical management [44].
Primary excisional biopsy is appropriate for relatively smaller tumors (≦4 clock hours limbal tumor or≦15 mm basal dimension) that are symptomatic or suspected to be malignant. In these situations, excisional biopsy is preferred over incisional biopsy to avoid inadvertent tumor seeding [44].
Surgery remains the main modality for the management of periocular cancer. Unlike other treatment modalities, it allows histological confirmation of the diagnosis. Furthermore, examination of the excision margin assesses the adequacy of tumor clearance. To minimize the risk of incomplete excision, the larger safe margin of excision with at least 4–6 mm for SCC was recommended [46, 47].
Margin control can be achieved using frozen sections, but there are inherent inaccuracies in frozen-section techniques, and it is not unusual for frozen sections to be clear with involved margins on paraffin-fixed specimens. Confirmation of tumor clearance is essential before undertaking periocular reconstruction. Routine paraffin fixed specimens take several days to be processed, but the specimens can be processed within 24–48 h by prior arrangement with the local pathologist, allowing delayed reconstruction.
As it allows three-dimensional assessment of the tumor margins, Mos micrographic surgery (MMS) has excellent cure rates for non-melanoma skin cancers and is widely regarded as the gold standard for tumor excision [27].
Supplemental cryotherapy, topical chemotherapy and irradiation should be applied if the tumor margin is unclear or if there is residual involvement of bulbar conjunctiva.
Eyelid or periocular malignancies require different considerations from other cutaneous malignancies of the same pathohistological cell type. It needs unique anatomic considerations to preserve the functional impact of ocular protection and vision after wide excision and reconstruction.
For a small conjunctival lesion, double layers closure with Tenon’s fascia first and then conjunctiva over wound by primary suture may be enough. In cases where excessive conjunctiva is sacrificed, autologous conjunctival or buccal mucosa grafts, or amniotic membrane graft may be employed for reconstruction. For eyelid lesion, the primary suture is suitable for a small lesion, but an autologous graft or rotational flap may be needed for the extensive lesion.
Mitomycin C (MMC) is an antineoplastic and antibiotic agent. 5-fluorouracil (5FU) is an anticancer drug that interrupts DNA replication and cell growth. These agents are often used by an ophthalmologist in glaucoma and pterygium surgery to prevent inappropriate scar formation, especially MMC.
In cases with positive margins related to inadequate surgical excision, extensive tumors, higher recurrence, or more local invasion especially those with the extensive corneal component, treatment with topical MMC, 5FU, or interferon α (IFNα) and interferon 2b (IFN2b) as an adjuvant after surgical removal have been employed [48, 49, 50, 51].
Topical chemotherapy enables to treat the entire ocular surface and is not dependent upon surgical margins. It may be preferred as primary treatment over the surgery by some patients who are inadequate to surgery or refuse surgery.
Subconjunctival and perilesional injections to treat OSSN have also been proposed, however, the evidence is limited and requires more studies [52].
In general, the adverse effects are minimal and tolerance in 5FU and IFN. The ocular surface toxicity and other serious adverse effects are much greater in MMC than in 5FU or IFN-b. It is the main drawback of MMC. To relieve the side effects, preservative-free artificial tears, or short-term use of the topical steroid to minimize ocular surface irritation could be used as needed. Applying petroleum jelly to the lower eyelid skin is recommended to reduce skin irritation and toxicity. Additionally, it may be instructed to occlude the punctum briefly after applying the medication to minimize the risk of punctal stenosis [53].
Using topical 0.02–0.04% MMC eyedrops are very effective which show high-resolution rates ranging from 76–100% and low recurrence rates ranging from 0–20% [54, 55, 56, 57, 58]. Alvarez had recommended MMC in 4 week cycles of 0.04% four times a day for 1 week, followed by 3 weeks of no treatment, with cycles repeated until resolution [53]. Others may use MMC with shorter breaks, such as topically 4 times daily for a 1-week period followed by a 1-week hiatus to allow the ocular surface to recover, and this cycle is repeated once again.
Its propensity for causing ocular surface toxicity and other serious adverse effects is much greater than 5FU or IFN-b. These include allergy, itching, pain, conjunctival hyperaemia, punctate staining of the cornea, punctal stenosis corneal-scleral melting, disturbance of tear film stability, goblet cell loss, squamous metaplasia and limbal stem cells deficiency [53, 59, 60, 61].
Chemoreduction with topical MMC followed by interferon alfa 2b (1 million IU/mL) 4 times daily, or topical Cyclosporine A (0,05%) combined with a topical low dose of MMC (0,01%) had also been prescribed as the effective treatments in extensive CIN cases where surgical resection with safety margins is infeasible and corneal extension resection and the repetitive cycles of MMC adjunctive could cause a depletion of limbal stem cells and other commented side effects on the ocular surface [62].
1% of 5FU used as topical eye-drops shows very effective in treating OSSN with high-resolution rates of 82–100% and low recurrence rates of 10–14% [58, 62, 63, 64, 65].
It is recommended four times a day for 1 week, and then stop the drug for 3 weeks. This protocol could continue until resolution [62, 63, 64].
Side effects of 5FU are generally mild and well-tolerated. These may include pain, tearing, redness, eyelid edema and keratopathy [63]. It is reported that short-term complications include lid toxicity in 52% of patients, keratopathy in 11% and epiphora in 5% [66].
IFN can be used as topical eye-drops, subconjunctival perilesional injections, or both [67, 68]. Both forms have shown great success in treating OSSN.
In cases of CIN, the combination of subconjunctival and topical treatment of IFN α-2b showed the average time to complete tumor response at mean of 5.5 weeks (range 2–12). For INF α-2b topical treatment, the average time to complete tumor response is 11 weeks (range 2–59). Injection treatment had the benefit of rapid tumor resolution [67].
Topical IFN α-2b, 1 million IU/ ml, four times daily, until resolution following with at least 1–3 months have been recommended. Weekly subconjunvtival injection of 3 million IU in 0.5ml of IFN α-2b until tumor resolution is an alternative [69].
The resolution rates showed 81–100% in topical administration and 87–100% in injections [68, 70, 71, 72]. IFN eye-drops also have remarkably low recurrence rates ranging from 0–4% [58, 71, 72].
Topical IFN eye-drops are very well tolerated by patients and nearly without side effects or discomfortable. Some follicular conjunctivitis was found [71]. Injections of IFN are also well-tolerated, but patients typically experience mild flu-like symptoms for about 24 hours following the injection [71].
Intraoperative cryotherapy by a double freeze-slow thaw method applied on conjunctival margins of the excised area has proved to diminish recurrences significantly after surgical excision in pre-cancerous and SCC in situ, but not suitable for invasive cancers [73].
The advantages of cryotherapy include the elimination of subclinical or microscopic malignant tumor cells and the prevention of recurrence. The adverse effects include conjunctival chemosis, cataract formation, uveitis, thinning scleral and corneal. Frozen globe and risk of phthisis bulbi could unexpectedly develop if cryotherapy had been excessively used [74].
It is also safe and useful for cutaneous SCC in situ in patients who refuse surgery, poor surgical candidates or with bleeding disorders.
Radiotherapeutic treatment has been limited to brachytherapy techniques either alone for whom surgery is risky, or as adjuvant therapy after surgical resection for whom the disease has spread to nerves/lymph nodes or with poorly defined margins.
When conjunctival SCC invades deeply into the sclera or into the globe, topical chemotherapeutic agents and cryotherapy might be ineffective due to not penetrating the sclera or into the eye, and enucleation is often necessary [68, 75]. To preserve vision and salvage eyeball, plaque radiotherapy had been reported as reliable alternative treatment without globe removal for conjunctival SCC demonstrating scleral invasion and/or intraocular involvement.
Using Beta radiation with strontium-90 source as adjunctive therapy to control residual microscopic tumor following surgical resection of conjunctival SCC had been reported. It revealed excellent control rates with only 3 in total 131 patients indicating recurrent after a 30-Gy dose [76], Similar results have been observed with ruthenium-106 after a total 320-Gy dose delivered at the surface without recurrence at 22 months [77]. Gamma radiotherapy using I125 has also been explored as an adjunctive treatment to excision for invasive conjunctival SCC because it has a deeper penetrability compared with beta radiation [78].
Arepalli and Shields had explored an alternative to enucleation using plaque radiotherapy with a gamma source of I125 for invasive conjunctival SCC. Plaque radiotherapy can be an effective alternative to enucleation for residual scleral-invasive conjunctival SCC following resection. In final, total globe salvage was achieved in 10 cases from their total 15 SCC patients with scleral (all cases) and anterior chamber invasion (3 cases). However, 4 cases showed further distant conjunctival tumor recurrence (remote of the radiotherapy site) with orbital involvement at 5 months after plaque radiotherapy, necessitating enucleation (n = 2) or orbital exenteration (n = 2). Complications included cataract (n = 13), iris telangiectasia (n = 5), corneal epithelial defect (n = 4), corneal edema (n = 3), and glaucoma (n = 1). One patient required enucleation due to a nonhealing epithelial defect and chronic ocular irritation [79].
In the management of eyelid malignancies, adjuvant radiotherapy has been recommended for eyelid malignancies with aggressive histologic subtype, perineural invasion, or nodal metastasis at presentation [80]. Radiotherapy is used as an adjunct to surgery in cases of incomplete tumor excision and/or perineural invasion [81, 82]. Although, radiotherapy alone is also an alternative to surgery for patients who are not candidates for surgery, there are several drawbacks. The recurrence rates are higher after radiotherapy alone than surgery [83]. Furthermore, when recurrence occurs, it is usually difficult to manage and definitively diagnose [84]. Unlike surgery, radiation therapy does not readily demonstrate histological evidence of tumor clearance. It is also noted that a large dose of radiotherapy may cause ocular complications leading to visual disturbance.
Systemic chemotherapy is recommended for patients in the advanced stage with distant metastasis and can be considered for patients with extensive nodal disease.
Other treatment modalities currently with favorable outcomes include radiotherapy, surgical excision in combination with absolute alcohol, vitamin A, excimer laser, topical imiquimod 5% cream, and adjuvant topical or perilesional chemotherapy [50].
Orbital invasion by eyelid SCC occurs in 4–8% of cases [7, 27]. Conjunctival SCC can represent 0 ~ 13% of intraocular and/or 1–6% of orbital local invasion. The orbital invasion should be suspected if a patient with a current or previously treated periocular malignancy presents with a palpable orbital mass, globe displacement, limitation of eye movement, numbness, or pain in the distribution of the trigeminal nerve (Figure 6) [85, 86]. If Intraocular or/and infraorbital invasion occurs, it has devastating visual consequences [32, 33, 35].
A patient with squamous cell carcinoma of the right eyelid with orbital metastasis: Periocular mass, proptosis, facial numbness and palsy.
The intraocular spread tends to follow recurrence of the conjunctival lesion after attempted excision. Modes of invasion may include direct invasion through the sclera, along the tract of the anterior ciliary vessels, or inoculation through intraocular surgery incision [87].
Although, there have been reports of local control achieved with globe-sparing surgeries [79, 88], enucleation or exenteration is usually required to manage intraocular or/and intra-orbital invasion with or without adjunctive radiotherapy.
Local tumor clearance is usually possible by orbital exenteration with or without adjunctive radiotherapy. However, the perineural invasion occurs commonly in such cases, and increases the risk of incomplete excision even after exenteration [85]. Furthermore, perineural invasion worsens the prognosis because of extensive orbital, and sometimes intracranial involvement. A meta-analysis of 9 publications on large series of exenterations between 1954 and 2005 indicated that 89/559 (16%) cases were for conjunctival SCC and required exenteration for advanced disease [89].
Orbital exenteration rates are 6% at 5 years in the US, but are higher in HIV endemic areas, with 13/23 cases (56%) reported in a case series in Zimbabwe [33]. Risk factors predictive of orbital exenteration were positive margins at primary resection, perineural invasion, positive nodal status, and medial canthal tumor location [89].
The discovery of overexpression of the epidermal growth factor receptor (EGFR, a transmembrane tyrosine kinase receptor in the ErbB family) in SCC has opened the door to consideration of targeted therapy in inoperable cases of advanced BCC or cutaneous SCC of the orbit and periocular region [90].
Recently, both Yin’s group and El-Sawy’s group show successful outcomes after oral erlotinib (EGFR inhibitor) treatment in some patients who have advanced SCC with orbital invasion and regional lymph nodes metastasis [91, 92]. However, several reports also show that patients often acquire resistance. Several publications point out that despite EGFR inhibition, there are multiple downstream signaling pathways that serve as alternatives and that are found to be persistently activated, thus permitting cancer resistance to EGFR-inhibitors [93, 94]. Additionally, less than 5% of head and neck cancers contain EGFR mutations, which may partially explain the limited efficacy in using EGFR inhibitors and the current lack of FDA-approved for HNSCC [93, 95]. For the efficacy of EGFR inhibitor in the treatment of cutaneous SCC, more studies are needed to further conform.
In 2018, designated by the FDA as a breakthrough therapy, cemiplimab-rwlc, a PD-1–blocking antibody, became the first drug to receive FDA approval for the treatment of patients with advanced cutaneous SCC. Of the 75 patients with metastatic CSCC, 46.7% achieved an objective response; of the 33 patients with locally advanced CSCC, 48.5% achieved an objective response. Furthermore, 60% of patients with metastatic CSCC and 63% of patients with locally advanced CSCC maintained a response to treatment for ≥6 months [96].
With the Libtayo approval, the FDA has approved six immune checkpoint inhibitors targeting the PD-1/PD-L1 pathway for treating a variety of tumors, from the bladder to head and neck cancer, and now advanced cutaneous squamous-cell carcinoma.
Early diagnosis and adequate treatment of the eyelid SCC is very important, because of its ability to invade the orbital and intracranial legions and metastasis to the lymph nodes and distant organs. Regional lymph nodes are generally believed to be the most common first site of metastasis for SCC of the eyelid. The incidence of regional lymph node metastasis of eyelid SCC varies widely from 10% to 24.3% [97]. with most regional metastases occurring in the parotid, preauricular, and submandibular nodes. Distant metastasis is much less common, reported in 6.2% of cases [28].
Radical dissection with sentinel lymph node biopsy for patients with extensive lesions especially with perineurial invasion and recurrent lesions may get benefit if there is a ruling out distant metastasis. A high degree of suspicion for the orbital invasion along sensory nerves should be maintained. Perineural spread of cutaneous SCC is associated with an increased risk of local recurrence and distant metastasis, but may also be the direct cause of death when the primary tumor on the head and face gains access to the intracranial cavity via the cranial nerves [98, 99]. Risk factors have been found to correlate with the increased death and poor prognosis for cutaneous SCC, including prior treatments, lesion size ≥2 cm, increased depth, poor histopathological differentiation and immunosuppression [100]. In Nasser’s study, patients who had a lymph node metastasis at presentation or during follow-up had tumors that were stage T2C (according to AJCC, 9th edition; or T2b in AJCC, 8th edition) or higher at and ≥ 18 mm in greatest dimension at presentation. This finding will help practitioners select patients for closer surveillance for nodal metastasis or possibly for SLN biopsy [101].
Recurrence rates in OSCC range from 5–50% [33, 102, 103, 104, 105]. Galor et al. found that the 1-year recurrence rate was 10% and the 5-year recurrence rate was 21%, with a mean time to recurrence of 2.5 years when analyzing 389 excised OSSN lesions [73]. In Savino’s study, the overall recurrence rate was significantly higher (64%) in their advanced ocular surface squamous cell carcinoma (OSSC, T3 and T4 stage) cases series after long-term follow-up (median: 31 months, range: 6–120 months) [106].
In advanced, OSCC involving periocular tissues and/or orbit is an aggressive disease with a high recurrence rate. Multicentric disease, positive surgical margins, inferior tarsus localization, and surgery without adjuvant therapies are strong predictors of recurrence and are the main factors affecting prognosis [105].
The type of treatment is also correlated with the recurrence rate. Sudesh et al. reported a recurrence rate of 28.5% with surgical excision alone and 7.7% with surgical excision and cryotherapy [107]. Adjuvant topical therapy showed effectiveness in decreasing recurrence rates, particularly in patients with positive margins, histological high-risk SCC, tarsal, and multicentric pattern anatomical involvement. [73, 108].
The presence of positive margins can increase the risk of recurrence by as much as 10-fold, from 5–50% [35].
The microscopic and histologic information of cutaneous and periocular SCC is helpful to evaluate the recurrence, perineural invasion, local invasion, and metastasis. Histological well-differentiated tumors are associated with a lower risk of subclinical tumor extension, recurrence, and orbital invasion [27, 100]. Histologic specimens should be carefully examined for evidence of perineural invasion when facing cases of particularly aggressive tumors or in patients with symptoms of trigeminal pain, trigeminal-distribution sensory deficit, facial palsy, orbital pain, or biopsy of the supraorbital orbital nerve [28, 109]. Perineural invasion is associated with high local invasion, recurrence, and distant metastasis [98, 99].
The local recurrence rates for SCC range from 2.4% to 36.9% at 5 years [7, 28]. The perineural invasion has been found to be present in approximately 8–14% of cases of facial and periorbital SCC [7, 110].
Squamous cell carcinoma of the eyelid and ocular surface is an aggressive malignancy and maybe vision- and life-threatening although it grows slowly. Precise diagnosis along with appropriate management is a prerequisite.
The authors declare no conflict of interest.
The Internet has irrevocably changed the dynamics of scholarly communication and publishing. Consequently, we find it necessary to indicate, unambiguously, our definition of what we consider to be a published scientific work.
",metaTitle:"Prior Publication Policy",metaDescription:"Prior Publication Policy",metaKeywords:null,canonicalURL:"/page/prior-publication-policy",contentRaw:'[{"type":"htmlEditorComponent","content":"A significant number of working papers, early drafts, and similar work in progress are openly shared online between members of the scientific community. It has become common to announce one’s own research on a personal website or a blog to gather comments and suggestions from other researchers. Such works and online postings are, indeed, published in the sense that they are made publicly available. However, this does not mean that if submitted for publication by IntechOpen they are not original works. We differentiate between reviewed and non-reviewed works when determining whether a work is original and has been published in a scholarly sense or not.
\\n\\nThe significance of Peer Review cannot be overstated when it comes to defining, in our terms, what constitutes a published scientific work. Peer Review is widely considered to be the cornerstone of modern publishing processes and the key value-adding contribution to a scholarly manuscript that a publisher can make.
\\n\\nOther than the issue of originality, research misconduct is another major issue that all publishers have to address. IntechOpen’s Retraction & Correction Policy and various publication ethics guidelines identify both redundant publication and (self)plagiarism to fall within the definition of research misconduct, thus constituting grounds for rejection or the issue of a Retraction if the work has already been published.
\\n\\nIn order to facilitate the tracking of a manuscript’s publishing history and its development from its earliest draft to the manuscript submitted, we encourage Authors to disclose any instances of a manuscript’s prior publication, whether it be through a conference presentation, a newspaper article, a working paper publicly available in a repository or a blog post.
\\n\\nA note to the Academic Editor containing detailed information about a submitted manuscript’s previous public availability is the preferred means of reporting prior publication. This helps us determine if there are any earlier versions of a manuscript that should be disclosed to our readers or if any of those earlier versions should be cited and listed in a manuscript’s references.
\\n\\nSome basic information about the editorial treatment of different varieties of prior publication is laid out below:
\\n\\n1. CONFERENCE PAPERS & PRESENTATIONS
\\n\\nGiven that conference papers and presentations generally pass through some sort of peer or editorial review, we consider them to be published in the accepted scholarly sense, particularly if they are published as a part of conference proceedings.
\\n\\nAll submitted manuscripts originating from a previously published conference paper must contain at least 50% of new original content to be accepted for review and considered for publication.
\\n\\nAuthors are required to report any links their manuscript might have with their earlier conference papers and presentations in a note to the Academic Editor, as well as in the manuscript itself. Additionally, Authors should obtain any necessary permissions from the publisher of their conference paper if copyright transfer occurred during the publishing process. Failure to do so may prevent Us from publishing an otherwise worthy work.
\\n\\n2. NEWSPAPER & MAGAZINE ARTICLES
\\n\\nNewspaper and magazine articles usually do not pass through any extensive peer or editorial review and we do not consider them to be published in the scholarly sense. Articles appearing in newspapers and magazines rarely possess the depth and structure characteristic of scholarly articles.
\\n\\nSubmitted manuscripts stemming from a previous newspaper or magazine article will be accepted for review and considered for publication. However, Authors are strongly advised to report any such publication in an accompanying note to the External Editor.
\\n\\nAs with the conference papers and presentations, Authors should obtain any necessary permissions from the newspaper or magazine that published the work, and indicate that they have done so in a note to the External Editor.
\\n\\n3. GREY LITERATURE
\\n\\nWhite papers, working papers, technical reports and all other forms of papers which fall within the scope of the ‘Luxembourg definition’ of grey literature do not pass through any extensive peer or editorial review and we do not consider them to be published in the scholarly sense.
\\n\\nAlthough such papers are regularly made publicly available via personal websites and institutional repositories, their general purpose is to gather comments and feedback from Authors’ colleagues in order to further improve a manuscript intended for future publication.
\\n\\nWhen submitting their work, Authors are required to disclose the existence of any publicly available earlier drafts in a note to the Academic Editor. In cases where earlier drafts of the submitted version of the manuscript are publicly available, any overlap between the versions will generally not be considered an instance of self-plagiarism.
\\n\\n4. SOCIAL MEDIA, BLOG & MESSAGE BOARD POSTINGS
\\n\\nWe feel that social media, blogs and message boards are generally used with the same intention as grey literature, to formulate ideas for a manuscript and gather early feedback from like-minded researchers in order to improve a particular piece of work before submitting it for publication. Therefore, we do not consider such internet postings to be publication in the scholarly sense.
\\n\\nNevertheless, Authors are encouraged to disclose the existence of any internet postings in which they outline and describe their research or posted passages of their manuscripts in a note to the Academic Editor. Please note that we will not strictly enforce this request in the same way that we would instructions we consider to be part of our conditions of acceptance for publication. We understand that it may be difficult to keep track of all one’s internet postings in which the researcher´s current work might be mentioned.
\\n\\nIn cases where there is any overlap between the Author´s submitted manuscript and related internet postings, we will generally not consider it to be an instance of self-plagiarism. This also holds true for any co-Author as well.
\\n\\nFor more information on this policy please contact permissions@intechopen.com.
\\n\\nPolicy last updated: 2017-03-20
\\n"}]'},components:[{type:"htmlEditorComponent",content:'A significant number of working papers, early drafts, and similar work in progress are openly shared online between members of the scientific community. It has become common to announce one’s own research on a personal website or a blog to gather comments and suggestions from other researchers. Such works and online postings are, indeed, published in the sense that they are made publicly available. However, this does not mean that if submitted for publication by IntechOpen they are not original works. We differentiate between reviewed and non-reviewed works when determining whether a work is original and has been published in a scholarly sense or not.
\n\nThe significance of Peer Review cannot be overstated when it comes to defining, in our terms, what constitutes a published scientific work. Peer Review is widely considered to be the cornerstone of modern publishing processes and the key value-adding contribution to a scholarly manuscript that a publisher can make.
\n\nOther than the issue of originality, research misconduct is another major issue that all publishers have to address. IntechOpen’s Retraction & Correction Policy and various publication ethics guidelines identify both redundant publication and (self)plagiarism to fall within the definition of research misconduct, thus constituting grounds for rejection or the issue of a Retraction if the work has already been published.
\n\nIn order to facilitate the tracking of a manuscript’s publishing history and its development from its earliest draft to the manuscript submitted, we encourage Authors to disclose any instances of a manuscript’s prior publication, whether it be through a conference presentation, a newspaper article, a working paper publicly available in a repository or a blog post.
\n\nA note to the Academic Editor containing detailed information about a submitted manuscript’s previous public availability is the preferred means of reporting prior publication. This helps us determine if there are any earlier versions of a manuscript that should be disclosed to our readers or if any of those earlier versions should be cited and listed in a manuscript’s references.
\n\nSome basic information about the editorial treatment of different varieties of prior publication is laid out below:
\n\n1. CONFERENCE PAPERS & PRESENTATIONS
\n\nGiven that conference papers and presentations generally pass through some sort of peer or editorial review, we consider them to be published in the accepted scholarly sense, particularly if they are published as a part of conference proceedings.
\n\nAll submitted manuscripts originating from a previously published conference paper must contain at least 50% of new original content to be accepted for review and considered for publication.
\n\nAuthors are required to report any links their manuscript might have with their earlier conference papers and presentations in a note to the Academic Editor, as well as in the manuscript itself. Additionally, Authors should obtain any necessary permissions from the publisher of their conference paper if copyright transfer occurred during the publishing process. Failure to do so may prevent Us from publishing an otherwise worthy work.
\n\n2. NEWSPAPER & MAGAZINE ARTICLES
\n\nNewspaper and magazine articles usually do not pass through any extensive peer or editorial review and we do not consider them to be published in the scholarly sense. Articles appearing in newspapers and magazines rarely possess the depth and structure characteristic of scholarly articles.
\n\nSubmitted manuscripts stemming from a previous newspaper or magazine article will be accepted for review and considered for publication. However, Authors are strongly advised to report any such publication in an accompanying note to the External Editor.
\n\nAs with the conference papers and presentations, Authors should obtain any necessary permissions from the newspaper or magazine that published the work, and indicate that they have done so in a note to the External Editor.
\n\n3. GREY LITERATURE
\n\nWhite papers, working papers, technical reports and all other forms of papers which fall within the scope of the ‘Luxembourg definition’ of grey literature do not pass through any extensive peer or editorial review and we do not consider them to be published in the scholarly sense.
\n\nAlthough such papers are regularly made publicly available via personal websites and institutional repositories, their general purpose is to gather comments and feedback from Authors’ colleagues in order to further improve a manuscript intended for future publication.
\n\nWhen submitting their work, Authors are required to disclose the existence of any publicly available earlier drafts in a note to the Academic Editor. In cases where earlier drafts of the submitted version of the manuscript are publicly available, any overlap between the versions will generally not be considered an instance of self-plagiarism.
\n\n4. SOCIAL MEDIA, BLOG & MESSAGE BOARD POSTINGS
\n\nWe feel that social media, blogs and message boards are generally used with the same intention as grey literature, to formulate ideas for a manuscript and gather early feedback from like-minded researchers in order to improve a particular piece of work before submitting it for publication. Therefore, we do not consider such internet postings to be publication in the scholarly sense.
\n\nNevertheless, Authors are encouraged to disclose the existence of any internet postings in which they outline and describe their research or posted passages of their manuscripts in a note to the Academic Editor. Please note that we will not strictly enforce this request in the same way that we would instructions we consider to be part of our conditions of acceptance for publication. We understand that it may be difficult to keep track of all one’s internet postings in which the researcher´s current work might be mentioned.
\n\nIn cases where there is any overlap between the Author´s submitted manuscript and related internet postings, we will generally not consider it to be an instance of self-plagiarism. This also holds true for any co-Author as well.
\n\nFor more information on this policy please contact permissions@intechopen.com.
\n\nPolicy last updated: 2017-03-20
\n'}]},successStories:{items:[]},authorsAndEditors:{filterParams:{},profiles:[{id:"6700",title:"Dr.",name:"Abbass A.",middleName:null,surname:"Hashim",slug:"abbass-a.-hashim",fullName:"Abbass A. Hashim",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/6700/images/1864_n.jpg",biography:"Currently I am carrying out research in several areas of interest, mainly covering work on chemical and bio-sensors, semiconductor thin film device fabrication and characterisation.\nAt the moment I have very strong interest in radiation environmental pollution and bacteriology treatment. The teams of researchers are working very hard to bring novel results in this field. I am also a member of the team in charge for the supervision of Ph.D. students in the fields of development of silicon based planar waveguide sensor devices, study of inelastic electron tunnelling in planar tunnelling nanostructures for sensing applications and development of organotellurium(IV) compounds for semiconductor applications. I am a specialist in data analysis techniques and nanosurface structure. I have served as the editor for many books, been a member of the editorial board in science journals, have published many papers and hold many patents.",institutionString:null,institution:{name:"Sheffield Hallam University",country:{name:"United Kingdom"}}},{id:"54525",title:"Prof.",name:"Abdul Latif",middleName:null,surname:"Ahmad",slug:"abdul-latif-ahmad",fullName:"Abdul Latif Ahmad",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"20567",title:"Prof.",name:"Ado",middleName:null,surname:"Jorio",slug:"ado-jorio",fullName:"Ado Jorio",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Universidade Federal de Minas Gerais",country:{name:"Brazil"}}},{id:"47940",title:"Dr.",name:"Alberto",middleName:null,surname:"Mantovani",slug:"alberto-mantovani",fullName:"Alberto Mantovani",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Istituto Superiore di Sanità",country:{name:"Italy"}}},{id:"12392",title:"Mr.",name:"Alex",middleName:null,surname:"Lazinica",slug:"alex-lazinica",fullName:"Alex Lazinica",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/12392/images/7282_n.png",biography:"Alex Lazinica is the founder and CEO of IntechOpen. After obtaining a Master's degree in Mechanical Engineering, he continued his PhD studies in Robotics at the Vienna University of Technology. Here he worked as a robotic researcher with the university's Intelligent Manufacturing Systems Group as well as a guest researcher at various European universities, including the Swiss Federal Institute of Technology Lausanne (EPFL). During this time he published more than 20 scientific papers, gave presentations, served as a reviewer for major robotic journals and conferences and most importantly he co-founded and built the International Journal of Advanced Robotic Systems- world's first Open Access journal in the field of robotics. Starting this journal was a pivotal point in his career, since it was a pathway to founding IntechOpen - Open Access publisher focused on addressing academic researchers needs. Alex is a personification of IntechOpen key values being trusted, open and entrepreneurial. Today his focus is on defining the growth and development strategy for the company.",institutionString:null,institution:{name:"TU Wien",country:{name:"Austria"}}},{id:"19816",title:"Prof.",name:"Alexander",middleName:null,surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/19816/images/1607_n.jpg",biography:"Alexander I. Kokorin: born: 1947, Moscow; DSc., PhD; Principal Research Fellow (Research Professor) of Department of Kinetics and Catalysis, N. Semenov Institute of Chemical Physics, Russian Academy of Sciences, Moscow.\r\nArea of research interests: physical chemistry of complex-organized molecular and nanosized systems, including polymer-metal complexes; the surface of doped oxide semiconductors. He is an expert in structural, absorptive, catalytic and photocatalytic properties, in structural organization and dynamic features of ionic liquids, in magnetic interactions between paramagnetic centers. The author or co-author of 3 books, over 200 articles and reviews in scientific journals and books. He is an actual member of the International EPR/ESR Society, European Society on Quantum Solar Energy Conversion, Moscow House of Scientists, of the Board of Moscow Physical Society.",institutionString:null,institution:{name:"Semenov Institute of Chemical Physics",country:{name:"Russia"}}},{id:"62389",title:"PhD.",name:"Ali Demir",middleName:null,surname:"Sezer",slug:"ali-demir-sezer",fullName:"Ali Demir Sezer",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/62389/images/3413_n.jpg",biography:"Dr. Ali Demir Sezer has a Ph.D. from Pharmaceutical Biotechnology at the Faculty of Pharmacy, University of Marmara (Turkey). He is the member of many Pharmaceutical Associations and acts as a reviewer of scientific journals and European projects under different research areas such as: drug delivery systems, nanotechnology and pharmaceutical biotechnology. Dr. Sezer is the author of many scientific publications in peer-reviewed journals and poster communications. Focus of his research activity is drug delivery, physico-chemical characterization and biological evaluation of biopolymers micro and nanoparticles as modified drug delivery system, and colloidal drug carriers (liposomes, nanoparticles etc.).",institutionString:null,institution:{name:"Marmara University",country:{name:"Turkey"}}},{id:"61051",title:"Prof.",name:"Andrea",middleName:null,surname:"Natale",slug:"andrea-natale",fullName:"Andrea Natale",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"100762",title:"Prof.",name:"Andrea",middleName:null,surname:"Natale",slug:"andrea-natale",fullName:"Andrea Natale",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"St David's Medical Center",country:{name:"United States of America"}}},{id:"107416",title:"Dr.",name:"Andrea",middleName:null,surname:"Natale",slug:"andrea-natale",fullName:"Andrea Natale",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Texas Cardiac Arrhythmia",country:{name:"United States of America"}}},{id:"64434",title:"Dr.",name:"Angkoon",middleName:null,surname:"Phinyomark",slug:"angkoon-phinyomark",fullName:"Angkoon Phinyomark",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/64434/images/2619_n.jpg",biography:"My name is Angkoon Phinyomark. I received a B.Eng. degree in Computer Engineering with First Class Honors in 2008 from Prince of Songkla University, Songkhla, Thailand, where I received a Ph.D. degree in Electrical Engineering. My research interests are primarily in the area of biomedical signal processing and classification notably EMG (electromyography signal), EOG (electrooculography signal), and EEG (electroencephalography signal), image analysis notably breast cancer analysis and optical coherence tomography, and rehabilitation engineering. I became a student member of IEEE in 2008. During October 2011-March 2012, I had worked at School of Computer Science and Electronic Engineering, University of Essex, Colchester, Essex, United Kingdom. In addition, during a B.Eng. I had been a visiting research student at Faculty of Computer Science, University of Murcia, Murcia, Spain for three months.\n\nI have published over 40 papers during 5 years in refereed journals, books, and conference proceedings in the areas of electro-physiological signals processing and classification, notably EMG and EOG signals, fractal analysis, wavelet analysis, texture analysis, feature extraction and machine learning algorithms, and assistive and rehabilitative devices. I have several computer programming language certificates, i.e. Sun Certified Programmer for the Java 2 Platform 1.4 (SCJP), Microsoft Certified Professional Developer, Web Developer (MCPD), Microsoft Certified Technology Specialist, .NET Framework 2.0 Web (MCTS). I am a Reviewer for several refereed journals and international conferences, such as IEEE Transactions on Biomedical Engineering, IEEE Transactions on Industrial Electronics, Optic Letters, Measurement Science Review, and also a member of the International Advisory Committee for 2012 IEEE Business Engineering and Industrial Applications and 2012 IEEE Symposium on Business, Engineering and Industrial Applications.",institutionString:null,institution:{name:"Joseph Fourier University",country:{name:"France"}}},{id:"55578",title:"Dr.",name:"Antonio",middleName:null,surname:"Jurado-Navas",slug:"antonio-jurado-navas",fullName:"Antonio Jurado-Navas",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRisIQAS/Profile_Picture_1626166543950",biography:"Antonio Jurado-Navas received the M.S. degree (2002) and the Ph.D. degree (2009) in Telecommunication Engineering, both from the University of Málaga (Spain). He first worked as a consultant at Vodafone-Spain. From 2004 to 2011, he was a Research Assistant with the Communications Engineering Department at the University of Málaga. In 2011, he became an Assistant Professor in the same department. From 2012 to 2015, he was with Ericsson Spain, where he was working on geo-location\ntools for third generation mobile networks. Since 2015, he is a Marie-Curie fellow at the Denmark Technical University. His current research interests include the areas of mobile communication systems and channel modeling in addition to atmospheric optical communications, adaptive optics and statistics",institutionString:null,institution:{name:"University of Malaga",country:{name:"Spain"}}}],filtersByRegion:[{group:"region",caption:"North America",value:1,count:13389},{group:"region",caption:"Middle and South America",value:2,count:11661},{group:"region",caption:"Africa",value:3,count:4168},{group:"region",caption:"Asia",value:4,count:22334},{group:"region",caption:"Australia and Oceania",value:5,count:2019},{group:"region",caption:"Europe",value:6,count:33642}],offset:12,limit:12,total:135275},chapterEmbeded:{data:{}},editorApplication:{success:null,errors:{}},ofsBooks:{filterParams:{hasNoEditors:"0",sort:"-dateEndThirdStepPublish"},books:[{type:"book",id:"9985",title:"Geostatistics",subtitle:null,isOpenForSubmission:!0,hash:"423cb3896195a618c4acb493ce4fd23d",slug:null,bookSignature:"Prof. Jeffrey M. Yarus, Dr. Marko Maucec, Dr. Timothy C. Coburn and Associate Prof. Michael Pyrcz",coverURL:"https://cdn.intechopen.com/books/images_new/9985.jpg",editedByType:null,editors:[{id:"78011",title:"Prof.",name:"Jeffrey M.",surname:"Yarus",slug:"jeffrey-m.-yarus",fullName:"Jeffrey M. Yarus"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"12112",title:"The Colorectal Surgery",subtitle:null,isOpenForSubmission:!0,hash:"21c65e742d31d5b69fb681ef78cfa0be",slug:null,bookSignature:"Dr. Muhammad Shamim",coverURL:"https://cdn.intechopen.com/books/images_new/12112.jpg",editedByType:null,editors:[{id:"235128",title:"Dr.",name:"Muhammad",surname:"Shamim",slug:"muhammad-shamim",fullName:"Muhammad Shamim"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"12079",title:"Strategies Towards the Synthesis of Heterocycles and Their Applications",subtitle:null,isOpenForSubmission:!0,hash:"bc4022af925c0883636e0819008971ee",slug:null,bookSignature:"Dr. Premlata Kumari and Dr. Amit B Patel",coverURL:"https://cdn.intechopen.com/books/images_new/12079.jpg",editedByType:null,editors:[{id:"177041",title:"Dr.",name:"Premlata",surname:"Kumari",slug:"premlata-kumari",fullName:"Premlata Kumari"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"11998",title:"Biocomposites - Recent Advances",subtitle:null,isOpenForSubmission:!0,hash:"8bc7ffd7544fff1901301c787e64fada",slug:null,bookSignature:"Prof. Magdy Elnashar",coverURL:"https://cdn.intechopen.com/books/images_new/11998.jpg",editedByType:null,editors:[{id:"12075",title:"Prof.",name:"Magdy",surname:"Elnashar",slug:"magdy-elnashar",fullName:"Magdy Elnashar"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"11999",title:"Earthquakes - Recent Advances, New Perspectives and Applications",subtitle:null,isOpenForSubmission:!0,hash:"b2af07109b13b76e5af9583532ab5bee",slug:null,bookSignature:"Dr. Walter Salazar",coverURL:"https://cdn.intechopen.com/books/images_new/11999.jpg",editedByType:null,editors:[{id:"236461",title:"Dr.",name:"Walter",surname:"Salazar",slug:"walter-salazar",fullName:"Walter Salazar"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"12058",title:"Future Housing",subtitle:null,isOpenForSubmission:!0,hash:"e7f4a1e57fab392b61156956c1247b9e",slug:null,bookSignature:"Dr. Ivan Oropeza-Perez and Dr. Astrid Helena Petzold-Rodríguez",coverURL:"https://cdn.intechopen.com/books/images_new/12058.jpg",editedByType:null,editors:[{id:"282172",title:"Dr.",name:"Ivan",surname:"Oropeza-Perez",slug:"ivan-oropeza-perez",fullName:"Ivan Oropeza-Perez"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"12215",title:"Cell Death and Disease",subtitle:null,isOpenForSubmission:!0,hash:"dfd456a29478fccf4ebd3294137eb1e3",slug:null,bookSignature:"Dr. Ke Xu",coverURL:"https://cdn.intechopen.com/books/images_new/12215.jpg",editedByType:null,editors:[{id:"59529",title:"Dr.",name:"Ke",surname:"Xu",slug:"ke-xu",fullName:"Ke Xu"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"12113",title:"Tendons - Trauma, Inflammation, Degeneration, and Treatment",subtitle:null,isOpenForSubmission:!0,hash:"2387a4e0d2a76883b16dcccd452281ab",slug:null,bookSignature:"Dr. Nahum Rosenberg",coverURL:"https://cdn.intechopen.com/books/images_new/12113.jpg",editedByType:null,editors:[{id:"68911",title:"Dr.",name:"Nahum",surname:"Rosenberg",slug:"nahum-rosenberg",fullName:"Nahum Rosenberg"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"11500",title:"Multi-Objective Optimization - Recent Advances, New Perspectives and Applications",subtitle:null,isOpenForSubmission:!0,hash:"842f84f308439c0a55c4e8e6a8fd9c01",slug:null,bookSignature:"Dr. Adel El-Shahat",coverURL:"https://cdn.intechopen.com/books/images_new/11500.jpg",editedByType:null,editors:[{id:"193331",title:"Dr.",name:"Adel",surname:"El-Shahat",slug:"adel-el-shahat",fullName:"Adel El-Shahat"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"12196",title:"Sepsis - New Perspectives",subtitle:null,isOpenForSubmission:!0,hash:"3590e6f6047122bd96d1d57da29c4054",slug:null,bookSignature:"Dr. Lixing Huang, Dr. Youyu Zhang and Dr. Lingbin Sun",coverURL:"https://cdn.intechopen.com/books/images_new/12196.jpg",editedByType:null,editors:[{id:"333148",title:"Dr.",name:"Lixing",surname:"Huang",slug:"lixing-huang",fullName:"Lixing Huang"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"12102",title:"Current Trends in Ambulatory Care",subtitle:null,isOpenForSubmission:!0,hash:"fa37d79f81893fd0a9ab346ae1c3e4a9",slug:null,bookSignature:"Dr. Xin-Nong Li",coverURL:"https://cdn.intechopen.com/books/images_new/12102.jpg",editedByType:null,editors:[{id:"345917",title:"Dr.",name:"Xin-Nong",surname:"Li",slug:"xin-nong-li",fullName:"Xin-Nong Li"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"12050",title:"Advanced Biodiesel - Technological Advances, Challenges, and Sustainability Considerations",subtitle:null,isOpenForSubmission:!0,hash:"bb86ab5c5ca0dab95f01941eb350f920",slug:null,bookSignature:"Dr. IMR Fattah",coverURL:"https://cdn.intechopen.com/books/images_new/12050.jpg",editedByType:null,editors:[{id:"463663",title:"Dr.",name:"IMR",surname:"Fattah",slug:"imr-fattah",fullName:"IMR Fattah"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}],filtersByTopic:[{group:"topic",caption:"Agricultural and Biological Sciences",value:5,count:24},{group:"topic",caption:"Biochemistry, Genetics and Molecular Biology",value:6,count:7},{group:"topic",caption:"Business, Management and Economics",value:7,count:4},{group:"topic",caption:"Chemistry",value:8,count:16},{group:"topic",caption:"Computer and Information Science",value:9,count:18},{group:"topic",caption:"Earth and Planetary Sciences",value:10,count:8},{group:"topic",caption:"Engineering",value:11,count:39},{group:"topic",caption:"Environmental Sciences",value:12,count:5},{group:"topic",caption:"Immunology and Microbiology",value:13,count:8},{group:"topic",caption:"Materials Science",value:14,count:15},{group:"topic",caption:"Mathematics",value:15,count:9},{group:"topic",caption:"Medicine",value:16,count:64},{group:"topic",caption:"Nanotechnology and Nanomaterials",value:17,count:2},{group:"topic",caption:"Neuroscience",value:18,count:3},{group:"topic",caption:"Pharmacology, Toxicology and Pharmaceutical Science",value:19,count:7},{group:"topic",caption:"Physics",value:20,count:5},{group:"topic",caption:"Psychology",value:21,count:5},{group:"topic",caption:"Robotics",value:22,count:2},{group:"topic",caption:"Social Sciences",value:23,count:8},{group:"topic",caption:"Veterinary Medicine and Science",value:25,count:2}],offset:12,limit:12,total:251},popularBooks:{featuredBooks:[{type:"book",id:"7827",title:"Interpersonal Relationships",subtitle:null,isOpenForSubmission:!1,hash:"ebf41f4d17c75010eb3294cc8cac3d47",slug:"interpersonal-relationships",bookSignature:"Martha Peaslee Levine",coverURL:"https://cdn.intechopen.com/books/images_new/7827.jpg",editors:[{id:"186919",title:"Dr.",name:"Martha",middleName:null,surname:"Peaslee Levine",slug:"martha-peaslee-levine",fullName:"Martha Peaslee Levine"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"10808",title:"Current Concepts in Dental Implantology",subtitle:"From Science to Clinical Research",isOpenForSubmission:!1,hash:"4af8830e463f89c57515c2da2b9777b0",slug:"current-concepts-in-dental-implantology-from-science-to-clinical-research",bookSignature:"Dragana Gabrić and Marko Vuletić",coverURL:"https://cdn.intechopen.com/books/images_new/10808.jpg",editors:[{id:"26946",title:"Prof.",name:"Dragana",middleName:null,surname:"Gabrić",slug:"dragana-gabric",fullName:"Dragana Gabrić"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"10796",title:"Extracellular Vesicles",subtitle:"Role in Diseases, Pathogenesis and Therapy",isOpenForSubmission:!1,hash:"eb5407fcf93baff7bca3fae5640153a2",slug:"extracellular-vesicles-role-in-diseases-pathogenesis-and-therapy",bookSignature:"Manash K. Paul",coverURL:"https://cdn.intechopen.com/books/images_new/10796.jpg",editors:[{id:"319365",title:"Assistant Prof.",name:"Manash K.",middleName:null,surname:"Paul",slug:"manash-k.-paul",fullName:"Manash K. Paul"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"10908",title:"Advances in Decision Making",subtitle:null,isOpenForSubmission:!1,hash:"126486f7f91e18e2e3539a32c38be7b1",slug:"advances-in-decision-making",bookSignature:"Fausto Pedro García Márquez",coverURL:"https://cdn.intechopen.com/books/images_new/10908.jpg",editors:[{id:"22844",title:"Prof.",name:"Fausto Pedro",middleName:null,surname:"García Márquez",slug:"fausto-pedro-garcia-marquez",fullName:"Fausto Pedro García Márquez"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"95",title:"Applications and Experiences of Quality Control",subtitle:null,isOpenForSubmission:!1,hash:"4bcb22b1eee68210a977a97d5a0f363a",slug:"applications-and-experiences-of-quality-control",bookSignature:"Ognyan Ivanov",coverURL:"https://cdn.intechopen.com/books/images_new/95.jpg",editors:[{id:"22230",title:"Prof.",name:"Ognyan",middleName:null,surname:"Ivanov",slug:"ognyan-ivanov",fullName:"Ognyan Ivanov"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"2160",title:"MATLAB",subtitle:"A Fundamental Tool for Scientific Computing and Engineering Applications - Volume 1",isOpenForSubmission:!1,hash:"dd9c658341fbd264ed4f8d9e6aa8ca29",slug:"matlab-a-fundamental-tool-for-scientific-computing-and-engineering-applications-volume-1",bookSignature:"Vasilios N. Katsikis",coverURL:"https://cdn.intechopen.com/books/images_new/2160.jpg",editors:[{id:"12289",title:"Prof.",name:"Vasilios",middleName:"N.",surname:"Katsikis",slug:"vasilios-katsikis",fullName:"Vasilios Katsikis"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"3560",title:"Advances in Landscape Architecture",subtitle:null,isOpenForSubmission:!1,hash:"a20614517ec5f7e91188fe8e42832138",slug:"advances-in-landscape-architecture",bookSignature:"Murat Özyavuz",coverURL:"https://cdn.intechopen.com/books/images_new/3560.jpg",editors:[{id:"93073",title:"Dr.",name:"Murat",middleName:null,surname:"Ozyavuz",slug:"murat-ozyavuz",fullName:"Murat Ozyavuz"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"10739",title:"Global Decline of Insects",subtitle:null,isOpenForSubmission:!1,hash:"543783652b9092962a8fa4bed38eeb17",slug:"global-decline-of-insects",bookSignature:"Hamadttu Abdel Farag El-Shafie",coverURL:"https://cdn.intechopen.com/books/images_new/10739.jpg",editors:[{id:"192142",title:"Dr.",name:"Hamadttu",middleName:null,surname:"Abdel Farag El-Shafie",slug:"hamadttu-abdel-farag-el-shafie",fullName:"Hamadttu Abdel Farag El-Shafie"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"10911",title:"Higher Education",subtitle:"New Approaches to Accreditation, Digitalization, and Globalization in the Age of Covid",isOpenForSubmission:!1,hash:"223a02337498e535e967174c1f648fbc",slug:"higher-education-new-approaches-to-accreditation-digitalization-and-globalization-in-the-age-of-covid",bookSignature:"Lee Waller and Sharon Waller",coverURL:"https://cdn.intechopen.com/books/images_new/10911.jpg",editors:[{id:"263301",title:"Dr.",name:"Lee",middleName:null,surname:"Waller",slug:"lee-waller",fullName:"Lee Waller"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"3568",title:"Recent Advances in Plant in vitro Culture",subtitle:null,isOpenForSubmission:!1,hash:"830bbb601742c85a3fb0eeafe1454c43",slug:"recent-advances-in-plant-in-vitro-culture",bookSignature:"Annarita Leva and Laura M. R. Rinaldi",coverURL:"https://cdn.intechopen.com/books/images_new/3568.jpg",editors:[{id:"142145",title:"Dr.",name:"Annarita",middleName:null,surname:"Leva",slug:"annarita-leva",fullName:"Annarita Leva"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"3737",title:"MATLAB",subtitle:"Modelling, Programming and Simulations",isOpenForSubmission:!1,hash:null,slug:"matlab-modelling-programming-and-simulations",bookSignature:"Emilson Pereira Leite",coverURL:"https://cdn.intechopen.com/books/images_new/3737.jpg",editors:[{id:"12051",title:"Prof.",name:"Emilson",middleName:null,surname:"Pereira Leite",slug:"emilson-pereira-leite",fullName:"Emilson Pereira Leite"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"1770",title:"Gel Electrophoresis",subtitle:"Principles and Basics",isOpenForSubmission:!1,hash:"279701f6c802cf02deef45103e0611ff",slug:"gel-electrophoresis-principles-and-basics",bookSignature:"Sameh Magdeldin",coverURL:"https://cdn.intechopen.com/books/images_new/1770.jpg",editors:[{id:"123648",title:"Dr.",name:"Sameh",middleName:null,surname:"Magdeldin",slug:"sameh-magdeldin",fullName:"Sameh Magdeldin"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}}],offset:12,limit:12,total:4797},hotBookTopics:{hotBooks:[],offset:0,limit:12,total:null},publish:{},publishingProposal:{success:null,errors:{}},books:{featuredBooks:[{type:"book",id:"7827",title:"Interpersonal Relationships",subtitle:null,isOpenForSubmission:!1,hash:"ebf41f4d17c75010eb3294cc8cac3d47",slug:"interpersonal-relationships",bookSignature:"Martha Peaslee Levine",coverURL:"https://cdn.intechopen.com/books/images_new/7827.jpg",publishedDate:"July 27th 2022",numberOfDownloads:7175,editors:[{id:"186919",title:"Dr.",name:"Martha",middleName:null,surname:"Peaslee Levine",slug:"martha-peaslee-levine",fullName:"Martha Peaslee Levine"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"10808",title:"Current Concepts in Dental Implantology",subtitle:"From Science to Clinical Research",isOpenForSubmission:!1,hash:"4af8830e463f89c57515c2da2b9777b0",slug:"current-concepts-in-dental-implantology-from-science-to-clinical-research",bookSignature:"Dragana Gabrić and Marko Vuletić",coverURL:"https://cdn.intechopen.com/books/images_new/10808.jpg",publishedDate:"July 27th 2022",numberOfDownloads:1981,editors:[{id:"26946",title:"Prof.",name:"Dragana",middleName:null,surname:"Gabrić",slug:"dragana-gabric",fullName:"Dragana Gabrić"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"10796",title:"Extracellular Vesicles",subtitle:"Role in Diseases, Pathogenesis and Therapy",isOpenForSubmission:!1,hash:"eb5407fcf93baff7bca3fae5640153a2",slug:"extracellular-vesicles-role-in-diseases-pathogenesis-and-therapy",bookSignature:"Manash K. Paul",coverURL:"https://cdn.intechopen.com/books/images_new/10796.jpg",publishedDate:"July 20th 2022",numberOfDownloads:2308,editors:[{id:"319365",title:"Assistant Prof.",name:"Manash K.",middleName:null,surname:"Paul",slug:"manash-k.-paul",fullName:"Manash K. Paul"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"10908",title:"Advances in Decision Making",subtitle:null,isOpenForSubmission:!1,hash:"126486f7f91e18e2e3539a32c38be7b1",slug:"advances-in-decision-making",bookSignature:"Fausto Pedro García Márquez",coverURL:"https://cdn.intechopen.com/books/images_new/10908.jpg",publishedDate:"July 27th 2022",numberOfDownloads:1473,editors:[{id:"22844",title:"Prof.",name:"Fausto Pedro",middleName:null,surname:"García Márquez",slug:"fausto-pedro-garcia-marquez",fullName:"Fausto Pedro García Márquez"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"95",title:"Applications and Experiences of Quality Control",subtitle:null,isOpenForSubmission:!1,hash:"4bcb22b1eee68210a977a97d5a0f363a",slug:"applications-and-experiences-of-quality-control",bookSignature:"Ognyan Ivanov",coverURL:"https://cdn.intechopen.com/books/images_new/95.jpg",publishedDate:"April 26th 2011",numberOfDownloads:318571,editors:[{id:"22230",title:"Prof.",name:"Ognyan",middleName:null,surname:"Ivanov",slug:"ognyan-ivanov",fullName:"Ognyan Ivanov"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"2160",title:"MATLAB",subtitle:"A Fundamental Tool for Scientific Computing and Engineering Applications - Volume 1",isOpenForSubmission:!1,hash:"dd9c658341fbd264ed4f8d9e6aa8ca29",slug:"matlab-a-fundamental-tool-for-scientific-computing-and-engineering-applications-volume-1",bookSignature:"Vasilios N. Katsikis",coverURL:"https://cdn.intechopen.com/books/images_new/2160.jpg",publishedDate:"September 26th 2012",numberOfDownloads:271836,editors:[{id:"12289",title:"Prof.",name:"Vasilios",middleName:"N.",surname:"Katsikis",slug:"vasilios-katsikis",fullName:"Vasilios Katsikis"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"3560",title:"Advances in Landscape Architecture",subtitle:null,isOpenForSubmission:!1,hash:"a20614517ec5f7e91188fe8e42832138",slug:"advances-in-landscape-architecture",bookSignature:"Murat Özyavuz",coverURL:"https://cdn.intechopen.com/books/images_new/3560.jpg",publishedDate:"July 1st 2013",numberOfDownloads:243450,editors:[{id:"93073",title:"Dr.",name:"Murat",middleName:null,surname:"Ozyavuz",slug:"murat-ozyavuz",fullName:"Murat Ozyavuz"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"10739",title:"Global Decline of Insects",subtitle:null,isOpenForSubmission:!1,hash:"543783652b9092962a8fa4bed38eeb17",slug:"global-decline-of-insects",bookSignature:"Hamadttu Abdel Farag El-Shafie",coverURL:"https://cdn.intechopen.com/books/images_new/10739.jpg",publishedDate:"July 20th 2022",numberOfDownloads:1582,editors:[{id:"192142",title:"Dr.",name:"Hamadttu",middleName:null,surname:"Abdel Farag El-Shafie",slug:"hamadttu-abdel-farag-el-shafie",fullName:"Hamadttu Abdel Farag El-Shafie"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"10911",title:"Higher Education",subtitle:"New Approaches to Accreditation, Digitalization, and Globalization in the Age of Covid",isOpenForSubmission:!1,hash:"223a02337498e535e967174c1f648fbc",slug:"higher-education-new-approaches-to-accreditation-digitalization-and-globalization-in-the-age-of-covid",bookSignature:"Lee Waller and Sharon Waller",coverURL:"https://cdn.intechopen.com/books/images_new/10911.jpg",publishedDate:"July 13th 2022",numberOfDownloads:2082,editors:[{id:"263301",title:"Dr.",name:"Lee",middleName:null,surname:"Waller",slug:"lee-waller",fullName:"Lee Waller"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"3568",title:"Recent Advances in Plant in vitro Culture",subtitle:null,isOpenForSubmission:!1,hash:"830bbb601742c85a3fb0eeafe1454c43",slug:"recent-advances-in-plant-in-vitro-culture",bookSignature:"Annarita Leva and Laura M. R. Rinaldi",coverURL:"https://cdn.intechopen.com/books/images_new/3568.jpg",publishedDate:"October 17th 2012",numberOfDownloads:256294,editors:[{id:"142145",title:"Dr.",name:"Annarita",middleName:null,surname:"Leva",slug:"annarita-leva",fullName:"Annarita Leva"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}}],latestBooks:[{type:"book",id:"10808",title:"Current Concepts in Dental Implantology",subtitle:"From Science to Clinical Research",isOpenForSubmission:!1,hash:"4af8830e463f89c57515c2da2b9777b0",slug:"current-concepts-in-dental-implantology-from-science-to-clinical-research",bookSignature:"Dragana Gabrić and Marko Vuletić",coverURL:"https://cdn.intechopen.com/books/images_new/10808.jpg",editedByType:"Edited by",publishedDate:"July 27th 2022",editors:[{id:"26946",title:"Prof.",name:"Dragana",middleName:null,surname:"Gabrić",slug:"dragana-gabric",fullName:"Dragana Gabrić"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"11328",title:"Botulinum Toxin",subtitle:"Recent Topics and Applications",isOpenForSubmission:!1,hash:"7dd05a316001cef143e209eda51387a7",slug:"botulinum-toxin-recent-topics-and-applications",bookSignature:"Suna Sabuncuoglu",coverURL:"https://cdn.intechopen.com/books/images_new/11328.jpg",editedByType:"Edited by",publishedDate:"July 27th 2022",editors:[{id:"270856",title:"Associate Prof.",name:"Suna",middleName:null,surname:"Sabuncuoglu",slug:"suna-sabuncuoglu",fullName:"Suna Sabuncuoglu"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"11085",title:"Polycystic Ovary Syndrome",subtitle:"Functional Investigation and Clinical Application",isOpenForSubmission:!1,hash:"3066dd3ff29e1fac072fd60b08d4d3e7",slug:"polycystic-ovary-syndrome-functional-investigation-and-clinical-application",bookSignature:"Zhengchao Wang",coverURL:"https://cdn.intechopen.com/books/images_new/11085.jpg",editedByType:"Edited by",publishedDate:"July 27th 2022",editors:[{id:"204883",title:"Dr.",name:"Zhengchao",middleName:null,surname:"Wang",slug:"zhengchao-wang",fullName:"Zhengchao Wang"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10833",title:"Tumor Angiogenesis and Modulators",subtitle:null,isOpenForSubmission:!1,hash:"f29b575c46128b2da061ef7f9bd1070b",slug:"tumor-angiogenesis-and-modulators",bookSignature:"Ke Xu",coverURL:"https://cdn.intechopen.com/books/images_new/10833.jpg",editedByType:"Edited by",publishedDate:"July 27th 2022",editors:[{id:"59529",title:"Dr.",name:"Ke",middleName:null,surname:"Xu",slug:"ke-xu",fullName:"Ke Xu"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"11356",title:"Molecular Cloning",subtitle:null,isOpenForSubmission:!1,hash:"671c629dd86e97f0fb467b9e70e92296",slug:"molecular-cloning",bookSignature:"Sadık Dincer, Hatice Aysun Mercimek Takcı and Melis Sumengen Ozdenef",coverURL:"https://cdn.intechopen.com/books/images_new/11356.jpg",editedByType:"Edited by",publishedDate:"July 27th 2022",editors:[{id:"188141",title:"Prof.",name:"Sadik",middleName:null,surname:"Dincer",slug:"sadik-dincer",fullName:"Sadik Dincer"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"7827",title:"Interpersonal Relationships",subtitle:null,isOpenForSubmission:!1,hash:"ebf41f4d17c75010eb3294cc8cac3d47",slug:"interpersonal-relationships",bookSignature:"Martha Peaslee Levine",coverURL:"https://cdn.intechopen.com/books/images_new/7827.jpg",editedByType:"Edited by",publishedDate:"July 27th 2022",editors:[{id:"186919",title:"Dr.",name:"Martha",middleName:null,surname:"Peaslee Levine",slug:"martha-peaslee-levine",fullName:"Martha Peaslee Levine"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10908",title:"Advances in Decision Making",subtitle:null,isOpenForSubmission:!1,hash:"126486f7f91e18e2e3539a32c38be7b1",slug:"advances-in-decision-making",bookSignature:"Fausto Pedro García Márquez",coverURL:"https://cdn.intechopen.com/books/images_new/10908.jpg",editedByType:"Edited by",publishedDate:"July 27th 2022",editors:[{id:"22844",title:"Prof.",name:"Fausto Pedro",middleName:null,surname:"García Márquez",slug:"fausto-pedro-garcia-marquez",fullName:"Fausto Pedro García Márquez"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10669",title:"Corrosion",subtitle:"Fundamentals and Protection Mechanisms",isOpenForSubmission:!1,hash:"4a76d54f8a40fc2e7002a8d13fd617c1",slug:"corrosion-fundamentals-and-protection-mechanisms",bookSignature:"Fahmina Zafar, Anujit Ghosal and Eram Sharmin",coverURL:"https://cdn.intechopen.com/books/images_new/10669.jpg",editedByType:"Edited by",publishedDate:"July 27th 2022",editors:[{id:"89672",title:"Dr.",name:"Fahmina",middleName:null,surname:"Zafar",slug:"fahmina-zafar",fullName:"Fahmina Zafar"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10677",title:"Advanced Topics of Topology",subtitle:null,isOpenForSubmission:!1,hash:"bf964c52f9e653fac20a7fcab58070e5",slug:"advanced-topics-of-topology",bookSignature:"Francisco Bulnes",coverURL:"https://cdn.intechopen.com/books/images_new/10677.jpg",editedByType:"Edited by",publishedDate:"July 27th 2022",editors:[{id:"92918",title:"Dr.",name:"Francisco",middleName:null,surname:"Bulnes",slug:"francisco-bulnes",fullName:"Francisco Bulnes"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"11195",title:"Recent Advances in Biometrics",subtitle:null,isOpenForSubmission:!1,hash:"2d32e33e0f499cb5241734bb75dd2a83",slug:"recent-advances-in-biometrics",bookSignature:"Muhammad Sarfraz",coverURL:"https://cdn.intechopen.com/books/images_new/11195.jpg",editedByType:"Edited by",publishedDate:"July 27th 2022",editors:[{id:"215610",title:"Prof.",name:"Muhammad",middleName:null,surname:"Sarfraz",slug:"muhammad-sarfraz",fullName:"Muhammad Sarfraz"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},subject:{topic:{id:"81",title:"Analytical Chemistry",slug:"chemistry-analytical-chemistry",parent:{id:"8",title:"Chemistry",slug:"chemistry"},numberOfBooks:36,numberOfSeries:0,numberOfAuthorsAndEditors:819,numberOfWosCitations:1350,numberOfCrossrefCitations:636,numberOfDimensionsCitations:1732,videoUrl:null,fallbackUrl:null,description:null},booksByTopicFilter:{topicId:"81",sort:"-publishedDate",limit:12,offset:0},booksByTopicCollection:[{type:"book",id:"10696",title:"Applications of Calorimetry",subtitle:null,isOpenForSubmission:!1,hash:"8c87f7e2199db33b5dd7181f56973a97",slug:"applications-of-calorimetry",bookSignature:"José Luis Rivera-Armenta and Cynthia Graciela Flores-Hernández",coverURL:"https://cdn.intechopen.com/books/images_new/10696.jpg",editedByType:"Edited by",editors:[{id:"107855",title:"Dr.",name:"Jose Luis",middleName:null,surname:"Rivera Armenta",slug:"jose-luis-rivera-armenta",fullName:"Jose Luis Rivera Armenta"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9937",title:"Recent Advances in Gas Chromatography",subtitle:null,isOpenForSubmission:!1,hash:"2d37a39be8412d39e729669c9c73ebb8",slug:"recent-advances-in-gas-chromatography",bookSignature:"Fabrice Mutelet",coverURL:"https://cdn.intechopen.com/books/images_new/9937.jpg",editedByType:"Edited by",editors:[{id:"186677",title:"Dr.",name:"Fabrice",middleName:null,surname:"Mutelet",slug:"fabrice-mutelet",fullName:"Fabrice Mutelet"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"11072",title:"Sample Preparation Techniques for Chemical Analysis",subtitle:null,isOpenForSubmission:!1,hash:"38fecf7570774c29c22a0cbca58ba570",slug:"sample-preparation-techniques-for-chemical-analysis",bookSignature:"Massoud Kaykhaii",coverURL:"https://cdn.intechopen.com/books/images_new/11072.jpg",editedByType:"Edited by",editors:[{id:"349151",title:"Prof.",name:"Massoud",middleName:null,surname:"Kaykhaii",slug:"massoud-kaykhaii",fullName:"Massoud Kaykhaii"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9932",title:"Analytical Chemistry",subtitle:"Advancement, Perspectives and Applications",isOpenForSubmission:!1,hash:"18f54a89cdbbafde70f56e55e122171a",slug:"analytical-chemistry-advancement-perspectives-and-applications",bookSignature:"Abhay Nanda Srivastva",coverURL:"https://cdn.intechopen.com/books/images_new/9932.jpg",editedByType:"Edited by",editors:[{id:"293623",title:"Dr.",name:"Abhay Nanda",middleName:null,surname:"Srivastva",slug:"abhay-nanda-srivastva",fullName:"Abhay Nanda Srivastva"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10387",title:"Mass Spectrometry in Life Sciences and Clinical Laboratory",subtitle:null,isOpenForSubmission:!1,hash:"5f2fa81e1939bbe34ac689fb983ca4c1",slug:"mass-spectrometry-in-life-sciences-and-clinical-laboratory",bookSignature:"Goran Mitulović",coverURL:"https://cdn.intechopen.com/books/images_new/10387.jpg",editedByType:"Edited by",editors:[{id:"212804",title:"Dr.",name:"Goran",middleName:null,surname:"Mitulović",slug:"goran-mitulovic",fullName:"Goran Mitulović"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"7319",title:"Color Detection",subtitle:null,isOpenForSubmission:!1,hash:"6c3c446db0a120cfd1f2697760e7d784",slug:"color-detection",bookSignature:"Ling-Wen Zeng and Shi-Lin Cao",coverURL:"https://cdn.intechopen.com/books/images_new/7319.jpg",editedByType:"Edited by",editors:[{id:"173972",title:"Dr.",name:"Lingwen",middleName:null,surname:"Zeng",slug:"lingwen-zeng",fullName:"Lingwen Zeng"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"8380",title:"Mass Spectrometry",subtitle:"Future Perceptions and Applications",isOpenForSubmission:!1,hash:"662bbebeab1942b6710f413e2b217004",slug:"mass-spectrometry-future-perceptions-and-applications",bookSignature:"Ganesh Shamrao Kamble",coverURL:"https://cdn.intechopen.com/books/images_new/8380.jpg",editedByType:"Edited by",editors:[{id:"236420",title:"Dr.",name:"Ganesh",middleName:"Shamrao",surname:"Kamble",slug:"ganesh-kamble",fullName:"Ganesh Kamble"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"6831",title:"Gas Chromatography",subtitle:"Derivatization, Sample Preparation, Application",isOpenForSubmission:!1,hash:"b9ef7d64ef66b65cb3245157db815577",slug:"gas-chromatography-derivatization-sample-preparation-application",bookSignature:"Peter Kusch",coverURL:"https://cdn.intechopen.com/books/images_new/6831.jpg",editedByType:"Edited by",editors:[{id:"254714",title:"Dr.",name:"Peter",middleName:null,surname:"Kusch",slug:"peter-kusch",fullName:"Peter Kusch"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"7348",title:"Voltammetry",subtitle:null,isOpenForSubmission:!1,hash:"27acad9579f166df001d24b28c720e55",slug:"voltammetry",bookSignature:"Nobanathi Wendy Maxakato, Sandile Surprise Gwebu and Gugu Hlengiwe Mhlongo",coverURL:"https://cdn.intechopen.com/books/images_new/7348.jpg",editedByType:"Edited by",editors:[{id:"259515",title:"Dr.",name:"Nobanathi Wendy",middleName:null,surname:"Maxakato",slug:"nobanathi-wendy-maxakato",fullName:"Nobanathi Wendy Maxakato"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"8637",title:"Recent Advances in Analytical Chemistry",subtitle:null,isOpenForSubmission:!1,hash:"9d61b693f14e24d81342f6c36fc5ba32",slug:"recent-advances-in-analytical-chemistry",bookSignature:"Muharrem Ince and Olcay Kaplan Ince",coverURL:"https://cdn.intechopen.com/books/images_new/8637.jpg",editedByType:"Edited by",editors:[{id:"258431",title:"Prof.",name:"Muharrem",middleName:null,surname:"Ince",slug:"muharrem-ince",fullName:"Muharrem Ince"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"6697",title:"Chemometrics and Data Analysis in Chromatography",subtitle:null,isOpenForSubmission:!1,hash:"513cf51c1f8851d3a5fde73daa281571",slug:"chemometrics-and-data-analysis-in-chromatography",bookSignature:"Vu Dang Hoang",coverURL:"https://cdn.intechopen.com/books/images_new/6697.jpg",editedByType:"Edited by",editors:[{id:"199907",title:"Associate Prof.",name:"Vu Dang",middleName:null,surname:"Hoang",slug:"vu-dang-hoang",fullName:"Vu Dang Hoang"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"7488",title:"Analytical Pyrolysis",subtitle:null,isOpenForSubmission:!1,hash:"30a667792c3a70b53d30fb6e9e1e7b4d",slug:"analytical-pyrolysis",bookSignature:"Peter Kusch",coverURL:"https://cdn.intechopen.com/books/images_new/7488.jpg",editedByType:"Edited by",editors:[{id:"254714",title:"Dr.",name:"Peter",middleName:null,surname:"Kusch",slug:"peter-kusch",fullName:"Peter Kusch"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}],booksByTopicTotal:36,seriesByTopicCollection:[],seriesByTopicTotal:0,mostCitedChapters:[{id:"32817",doi:"10.5772/33098",title:"Derivatization Reactions and Reagents for Gas Chromatography Analysis",slug:"derivatization-reactions-and-reagents-for-gas-chromatography-analysis",totalDownloads:70672,totalCrossrefCites:38,totalDimensionsCites:102,abstract:null,book:{id:"2114",slug:"advanced-gas-chromatography-progress-in-agricultural-biomedical-and-industrial-applications",title:"Advanced Gas Chromatography",fullTitle:"Advanced Gas Chromatography - Progress in Agricultural, Biomedical and Industrial Applications"},signatures:"Francis Orata",authors:[{id:"94007",title:"Dr.",name:"Francis",middleName:null,surname:"Orata",slug:"francis-orata",fullName:"Francis Orata"}]},{id:"26356",doi:"10.5772/33411",title:"Drift Correction Methods for Gas Chemical Sensors in Artificial Olfaction Systems: Techniques and Challenges",slug:"drift-correction-methods-for-gas-chemical-sensors-in-artificial-olfaction-systems-techniques-and-cha",totalDownloads:4662,totalCrossrefCites:8,totalDimensionsCites:57,abstract:null,book:{id:"589",slug:"advances-in-chemical-sensors",title:"Advances in Chemical Sensors",fullTitle:"Advances in Chemical Sensors"},signatures:"S. Di Carlo and M. Falasconi",authors:[{id:"50412",title:"Prof.",name:"Stefano",middleName:null,surname:"Di Carlo",slug:"stefano-di-carlo",fullName:"Stefano Di Carlo"},{id:"95331",title:"Dr.",name:"Matteo",middleName:null,surname:"Falasconi",slug:"matteo-falasconi",fullName:"Matteo Falasconi"}]},{id:"29012",doi:"10.5772/32108",title:"Identifying and Overcoming Matrix Effects in Drug Discovery and Development",slug:"identifying-and-overcoming-matrix-effects-in-drug-discovery-and-development",totalDownloads:18700,totalCrossrefCites:7,totalDimensionsCites:47,abstract:null,book:{id:"818",slug:"tandem-mass-spectrometry-applications-and-principles",title:"Tandem Mass Spectrometry",fullTitle:"Tandem Mass Spectrometry - Applications and Principles"},signatures:"Terence G. Hall, Inese Smukste, Karen R. Bresciano, Yunxia Wang, David McKearn and Ronald E. Savage",authors:[{id:"90202",title:"Dr",name:"Ronald",middleName:null,surname:"Savage",slug:"ronald-savage",fullName:"Ronald Savage"},{id:"90209",title:"Dr.",name:"Terence",middleName:null,surname:"Hall",slug:"terence-hall",fullName:"Terence Hall"},{id:"136599",title:"BSc.",name:"Karen",middleName:null,surname:"Bresciano",slug:"karen-bresciano",fullName:"Karen Bresciano"}]},{id:"46058",doi:"10.5772/57341",title:"Limit of Detection and Limit of Quantification Determination in Gas Chromatography",slug:"limit-of-detection-and-limit-of-quantification-determination-in-gas-chromatography",totalDownloads:18533,totalCrossrefCites:16,totalDimensionsCites:45,abstract:null,book:{id:"3822",slug:"advances-in-gas-chromatography",title:"Advances in Gas Chromatography",fullTitle:"Advances in Gas Chromatography"},signatures:"Ernesto Bernal",authors:[{id:"88572",title:"MSc.",name:"Ernesto",middleName:null,surname:"Bernal",slug:"ernesto-bernal",fullName:"Ernesto Bernal"}]},{id:"58596",doi:"10.5772/intechopen.72932",title:"Linearity of Calibration Curves for Analytical Methods: A Review of Criteria for Assessment of Method Reliability",slug:"linearity-of-calibration-curves-for-analytical-methods-a-review-of-criteria-for-assessment-of-method",totalDownloads:8098,totalCrossrefCites:19,totalDimensionsCites:44,abstract:"Calibration curve is a regression model used to predict the unknown concentrations of analytes of interest based on the response of the instrument to the known standards. Some statistical analyses are required to choose the best model fitting to the experimental data and also evaluate the linearity and homoscedasticity of the calibration curve. Using an internal standard corrects for the loss of analyte during sample preparation and analysis provided that it is selected appropriately. After the best regression model is selected, the analytical method needs to be validated using quality control (QC) samples prepared and stored in the same temperature as intended for the study samples. Most of the international guidelines require that the parameters, including linearity, specificity, selectivity, accuracy, precision, lower limit of quantification (LLOQ), matrix effect and stability, be assessed during validation. Despite the highly regulated area, some challenges still exist regarding the validation of some analytical methods including methods when no analyte-free matrix is available.",book:{id:"6379",slug:"calibration-and-validation-of-analytical-methods-a-sampling-of-current-approaches",title:"Calibration and Validation of Analytical Methods",fullTitle:"Calibration and Validation of Analytical Methods - A Sampling of Current Approaches"},signatures:"Seyed Mojtaba Moosavi and Sussan Ghassabian",authors:[{id:"216099",title:"Dr.",name:"Sussan",middleName:null,surname:"Ghassabian",slug:"sussan-ghassabian",fullName:"Sussan Ghassabian"},{id:"216101",title:"Mr.",name:"Seyed Mojtaba",middleName:null,surname:"Moosavi",slug:"seyed-mojtaba-moosavi",fullName:"Seyed Mojtaba Moosavi"}]}],mostDownloadedChaptersLast30Days:[{id:"55500",title:"Interpretation of Mass Spectra",slug:"interpretation-of-mass-spectra",totalDownloads:12503,totalCrossrefCites:12,totalDimensionsCites:25,abstract:"The chapter includes an introduction to the main ionisation techniques in mass spectrometry and the way the resulting fragments can be analysed. First, the fundamental notions of mass spectrometry are explained, so that the reader can easily cover this chapter (graphs, main pick, molecular ion, illogical pick, nitrogen rule, etc.). Isotopic percentage and nominal mass calculation are also explained along with fragmentation mechanism. A paragraph emphasises the ionisation energy issues, the basics of ionisation voltage, the developing potential and the energy balance. A frame time of the main theoretical milestones in both theory and experimental mass spectrometry is highlighted here. In the second part of the chapter, the molecular fragmentation for alkanes, iso-alkanes, cycloalkanes, halogen, alcohols, phenols, ethers, carbonyl compounds, carboxylic acids and functional derivatives, nitrogen compounds (amines, nitro compounds), sulphur compounds, heterocycles and biomolecules (amino acids, steroids, triglycerides) is explained. Fragmentation schemes are followed by the simplified spectra, which help the understanding of such complex phenomena. At the end of the chapter, acquisition of mass spectrum is discussed. The chapter presented here is an introduction to mass spectrometry, which, we think, helps the understanding of the mechanism of fragmentation corroborating spectral data and molecular structures.",book:{id:"5735",slug:"mass-spectrometry",title:"Mass Spectrometry",fullTitle:"Mass Spectrometry"},signatures:"Teodor Octavian Nicolescu",authors:[{id:"196775",title:"Dr.",name:"Teodor Octavian",middleName:"Octavian",surname:"Nicolescu",slug:"teodor-octavian-nicolescu",fullName:"Teodor Octavian Nicolescu"}]},{id:"57909",title:"Validation of Analytical Methods",slug:"validation-of-analytical-methods",totalDownloads:6994,totalCrossrefCites:13,totalDimensionsCites:22,abstract:"Method validation is a key element in the establishment of reference methods and within the assessment of a laboratory’s competence in generating dependable analytical records. Validation has been placed within the context of the procedure, generating chemical data. Analytical method validation, thinking about the maximum relevant processes for checking the best parameters of analytical methods, using numerous relevant overall performance indicators inclusive of selectivity, specificity, accuracy, precision, linearity, range, limit of detection (LOD), limit of quantification (LOQ), ruggedness, and robustness are severely discussed in an effort to prevent their misguided utilization and ensure scientific correctness and consistency among publications.",book:{id:"6379",slug:"calibration-and-validation-of-analytical-methods-a-sampling-of-current-approaches",title:"Calibration and Validation of Analytical Methods",fullTitle:"Calibration and Validation of Analytical Methods - A Sampling of Current Approaches"},signatures:"Tentu Nageswara Rao",authors:[{id:"220824",title:"Dr.",name:"Tentu",middleName:null,surname:"Nageswara Rao",slug:"tentu-nageswara-rao",fullName:"Tentu Nageswara Rao"}]},{id:"58596",title:"Linearity of Calibration Curves for Analytical Methods: A Review of Criteria for Assessment of Method Reliability",slug:"linearity-of-calibration-curves-for-analytical-methods-a-review-of-criteria-for-assessment-of-method",totalDownloads:8095,totalCrossrefCites:19,totalDimensionsCites:44,abstract:"Calibration curve is a regression model used to predict the unknown concentrations of analytes of interest based on the response of the instrument to the known standards. Some statistical analyses are required to choose the best model fitting to the experimental data and also evaluate the linearity and homoscedasticity of the calibration curve. Using an internal standard corrects for the loss of analyte during sample preparation and analysis provided that it is selected appropriately. After the best regression model is selected, the analytical method needs to be validated using quality control (QC) samples prepared and stored in the same temperature as intended for the study samples. Most of the international guidelines require that the parameters, including linearity, specificity, selectivity, accuracy, precision, lower limit of quantification (LLOQ), matrix effect and stability, be assessed during validation. Despite the highly regulated area, some challenges still exist regarding the validation of some analytical methods including methods when no analyte-free matrix is available.",book:{id:"6379",slug:"calibration-and-validation-of-analytical-methods-a-sampling-of-current-approaches",title:"Calibration and Validation of Analytical Methods",fullTitle:"Calibration and Validation of Analytical Methods - A Sampling of Current Approaches"},signatures:"Seyed Mojtaba Moosavi and Sussan Ghassabian",authors:[{id:"216099",title:"Dr.",name:"Sussan",middleName:null,surname:"Ghassabian",slug:"sussan-ghassabian",fullName:"Sussan Ghassabian"},{id:"216101",title:"Mr.",name:"Seyed Mojtaba",middleName:null,surname:"Moosavi",slug:"seyed-mojtaba-moosavi",fullName:"Seyed Mojtaba Moosavi"}]},{id:"64643",title:"Derivatization Methods in GC and GC/MS",slug:"derivatization-methods-in-gc-and-gc-ms",totalDownloads:6041,totalCrossrefCites:19,totalDimensionsCites:35,abstract:"The first part of this chapter presents the main objectives for performing derivatization of a sample to be analyzed by gas chromatography (GC) or gas chromatography/mass spectrometry (GC/MS). The derivatization is typically done to change the analyte properties for a better separation and also for enhancing the method sensitivity. In GC/MS, derivatization may improve the capability of compound identification. Examples illustrating such improvements are included. The second part describes several types of derivatization that are more frequently used in analytical practice. These include alkylation (e.g., methylation), formation of aryl derivatives, silylation (e.g., formation of trimethylsilyl derivatives), acylation (e.g., reactions with acyl chlorides or with chloroformates), and several other types of derivatizations. The chapter also presents typical derivatizations for analytes with specific functional groups and discusses artifact formation in certain derivatization reactions.",book:{id:"6831",slug:"gas-chromatography-derivatization-sample-preparation-application",title:"Gas Chromatography",fullTitle:"Gas Chromatography - Derivatization, Sample Preparation, Application"},signatures:"Serban C. Moldoveanu and Victor David",authors:[{id:"91597",title:"Dr.",name:"Serban",middleName:null,surname:"Moldoveanu",slug:"serban-moldoveanu",fullName:"Serban Moldoveanu"},{id:"278733",title:"Prof.",name:"Victor",middleName:null,surname:"David",slug:"victor-david",fullName:"Victor David"}]},{id:"40712",title:"Analytical Chemistry Today and Tomorrow",slug:"analytical-chemistry-today-and-tomorrow",totalDownloads:9135,totalCrossrefCites:1,totalDimensionsCites:5,abstract:null,book:{id:"2717",slug:"analytical-chemistry",title:"Analytical Chemistry",fullTitle:"Analytical Chemistry"},signatures:"Miguel Valcárcel",authors:[{id:"149298",title:"Dr.",name:null,middleName:null,surname:"Valcarcel",slug:"valcarcel",fullName:"Valcarcel"}]}],onlineFirstChaptersFilter:{topicId:"81",limit:6,offset:0},onlineFirstChaptersCollection:[{id:"82536",title:"Perspective Chapter: Multi-Dimensional Liquid Chromatography - Principles and Applications",slug:"perspective-chapter-multi-dimensional-liquid-chromatography-principles-and-applications",totalDownloads:14,totalDimensionsCites:0,doi:"10.5772/intechopen.104767",abstract:"Many complex mixtures usually constitute hundreds or even thousands of individual components of interest. Such mixtures are much too complicated to be separated for analytical duties in a reasonable period of time using only a single-dimensional chromatographic method. However, if a complex mixture is separated by an initial dimension using multi-dimensional liquid chromatography, a simpler portion of that separation is collected and goes to the second dimension. Each of these fractions will be analyzed separately, allowing exceedingly complex mixtures to be resolved in a short period of time. This chapter explains the fundamental principles, theoretical discussions as well as various applications with typical examples of multi-dimensional liquid chromatography in different fields.",book:{id:"11204",title:"Analytical Liquid Chromatography - New Perspectives",coverURL:"https://cdn.intechopen.com/books/images_new/11204.jpg"},signatures:"Esayas Tesfaye, Tadele Eticha, Ariaya Hymete and Ayenew Ashenef"},{id:"81761",title:"Progress in Technology of the Chromatographic Columns in HPLC",slug:"progress-in-technology-of-the-chromatographic-columns-in-hplc",totalDownloads:15,totalDimensionsCites:0,doi:"10.5772/intechopen.104123",abstract:"Chromatographic column is an essential part of a any HPLC separation, and significant progress has been made in developing columns with better performance to provide better separation, a shorter separation time, resilience to a wider pH range of the mobile phase, longer lifetime, use of lower volumes of mobile phase, etc. All these characteristics were achieved by the introduction of novel technologies and improvements of the older ones. These include smaller particle used to fill the column, more homogeneous spherical particles, core-shell particles, monolithic columns, more pure silica as a stationary phase support, use of ethylene bridge silica, a wider variety of active phases, use of mixed mode stationary phases, use of polymers as stationary phase, use of various endcapping techniques, etc. Miniaturization and progress in the instrumentation played an important role for the chromatographic column development. All these aspects are summarized in the present chapter.",book:{id:"11204",title:"Analytical Liquid Chromatography - New Perspectives",coverURL:"https://cdn.intechopen.com/books/images_new/11204.jpg"},signatures:"Serban C. Moldoveanu and Victor David"},{id:"81479",title:"Perspective Chapter: Mixed-Mode Chromatography",slug:"perspective-chapter-mixed-mode-chromatography",totalDownloads:29,totalDimensionsCites:0,doi:"10.5772/intechopen.104545",abstract:"In this chapter, we present mixed-mode stationary phases and their applications in the determination of nonpolar, polar, and charged compounds, as well as larger molecules such as peptides or proteins using a single column. Mixed-mode chromatography (MMC) has been growing rapidly in recent years, owing to the new generation of mixed-mode stationary phases and a better understanding of multimode interactions. Mixed-mode chromatography provides a wide range of selectivities and adequate retention of a variety of compounds, especially polar and charged molecules. In summary, this technique is particularly useful in the pharmaceutical analysis of drugs, impurities, biopharmaceuticals, and polar compounds in natural products.",book:{id:"11204",title:"Analytical Liquid Chromatography - New Perspectives",coverURL:"https://cdn.intechopen.com/books/images_new/11204.jpg"},signatures:"Ngoc-Van Thi Nguyen"},{id:"81368",title:"Ionic Liquids in Liquid Chromatography",slug:"ionic-liquids-in-liquid-chromatography",totalDownloads:39,totalDimensionsCites:0,doi:"10.5772/intechopen.104122",abstract:"Ionic liquids (ILs) are salts of organic cations that are present in liquid state. They can be used as alternative to organic solvents for various analytical processes such as extracting solvents in sample preparation, or as mobile phase or components of the mobile phase in high performance liquid chromatography (HPLC). Also they can be used as stationary phase in gas chromatography (GC), or attached to a solid support as stationary phase in HPLC. Ils are typically more environmentally-friendly solvents than the classic organic solvents having low volatility, flammability and toxicity. The chapter presents various applications of ILs in liquid chromatography.",book:{id:"11204",title:"Analytical Liquid Chromatography - New Perspectives",coverURL:"https://cdn.intechopen.com/books/images_new/11204.jpg"},signatures:"Victor David and Serban C. Moldoveanu"},{id:"80336",title:"Perspective Chapter: Advantages of Ion Mobility Coupled with HPLC/UPLC",slug:"perspective-chapter-advantages-of-ion-mobility-coupled-with-hplc-uplc",totalDownloads:58,totalDimensionsCites:0,doi:"10.5772/intechopen.102380",abstract:"Ion mobility is a new separation technique that can be coupled with high performance liquid chromatography (HPLC) or ultra-performance liquid chromatography (UPLC). Variances in cross-sectional ionic areas of different molecules create differential speeds through a gas allowing for millisecond separations. Combining ion mobility with both liquid chromatography and mass spectrometry with fragmentation, separations can be achieved on the second (HPLC), millisecond (ion mobility), and microsecond (mass spectrometry) timescales. This orthogonal separation greatly cleans up mass spectral data of co-eluting peaks from the liquid chromatography and adds to the descriptive data of each ion. With descriptive data such as retention time, cross-sectional area, m/z ratio, and mass spectral fragmentation, many options become available for analytical analysis. Options ranging from descriptive data collation into instrument libraries to sensitivity enhancement for trace analysis will be explored in this chapter along with the description of different forms of ion mobility.",book:{id:"11204",title:"Analytical Liquid Chromatography - New Perspectives",coverURL:"https://cdn.intechopen.com/books/images_new/11204.jpg"},signatures:"Robert Owen Bussey III"}],onlineFirstChaptersTotal:5},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:90,numberOfOpenTopics:6,numberOfUpcomingTopics:0,issn:"2633-1403",doi:"10.5772/intechopen.79920",isOpenForSubmission:!0},{id:"7",title:"Biomedical Engineering",numberOfPublishedBooks:12,numberOfPublishedChapters:108,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2631-5343",doi:"10.5772/intechopen.71985",isOpenForSubmission:!0}],lsSeriesList:[{id:"11",title:"Biochemistry",numberOfPublishedBooks:33,numberOfPublishedChapters:330,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2632-0983",doi:"10.5772/intechopen.72877",isOpenForSubmission:!0},{id:"25",title:"Environmental Sciences",numberOfPublishedBooks:1,numberOfPublishedChapters:19,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2754-6713",doi:"10.5772/intechopen.100362",isOpenForSubmission:!0},{id:"10",title:"Physiology",numberOfPublishedBooks:14,numberOfPublishedChapters:145,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-8261",doi:"10.5772/intechopen.72796",isOpenForSubmission:!0}],hsSeriesList:[{id:"3",title:"Dentistry",numberOfPublishedBooks:9,numberOfPublishedChapters:141,numberOfOpenTopics:2,numberOfUpcomingTopics:0,issn:"2631-6218",doi:"10.5772/intechopen.71199",isOpenForSubmission:!0},{id:"6",title:"Infectious Diseases",numberOfPublishedBooks:13,numberOfPublishedChapters:123,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-6188",doi:"10.5772/intechopen.71852",isOpenForSubmission:!0},{id:"13",title:"Veterinary Medicine and Science",numberOfPublishedBooks:11,numberOfPublishedChapters:112,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:22,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2753-894X",doi:"10.5772/intechopen.100359",isOpenForSubmission:!0},{id:"23",title:"Education and Human Development",numberOfPublishedBooks:0,numberOfPublishedChapters:11,numberOfOpenTopics:1,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100360",isOpenForSubmission:!0},{id:"24",title:"Sustainable Development",numberOfPublishedBooks:1,numberOfPublishedChapters:19,numberOfOpenTopics:5,numberOfUpcomingTopics:0,issn:"2753-6580",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:"24",title:"Sustainable Development",doi:"10.5772/intechopen.100361",issn:"2753-6580",scope:"