Studies investigating bevacizumab in metastatic colorectal cancer in the first line.
\\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:"webinar-introduction-to-open-science-wednesday-18-may-1-pm-cest-20220518",title:"Webinar: Introduction to Open Science | Wednesday 18 May, 1 PM CEST"},{slug:"step-in-the-right-direction-intechopen-launches-a-portfolio-of-open-science-journals-20220414",title:"Step in the Right Direction: IntechOpen Launches a Portfolio of Open Science Journals"},{slug:"let-s-meet-at-london-book-fair-5-7-april-2022-olympia-london-20220321",title:"Let’s meet at London Book Fair, 5-7 April 2022, Olympia London"},{slug:"50-books-published-as-part-of-intechopen-and-knowledge-unlatched-ku-collaboration-20220316",title:"50 Books published as part of IntechOpen and Knowledge Unlatched (KU) Collaboration"},{slug:"intechopen-joins-the-united-nations-sustainable-development-goals-publishers-compact-20221702",title:"IntechOpen joins the United Nations Sustainable Development Goals Publishers Compact"},{slug:"intechopen-signs-exclusive-representation-agreement-with-lsr-libros-servicios-y-representaciones-s-a-de-c-v-20211123",title:"IntechOpen Signs Exclusive Representation Agreement with LSR Libros Servicios y Representaciones S.A. de C.V"},{slug:"intechopen-expands-partnership-with-research4life-20211110",title:"IntechOpen Expands Partnership with Research4Life"},{slug:"introducing-intechopen-book-series-a-new-publishing-format-for-oa-books-20210915",title:"Introducing IntechOpen Book Series - A New Publishing Format for OA Books"}]},book:{item:{type:"book",id:"9923",leadTitle:null,fullTitle:"Modeling and Simulation in Engineering - Selected Problems",title:"Modeling and Simulation in Engineering",subtitle:"Selected Problems",reviewType:"peer-reviewed",abstract:'The general aim of this book is to present selected chapters of the following types: chapters with more focus on modeling with some necessary simulation details and chapters with less focus on modeling but with more simulation details. This book contains eleven chapters divided into two sections: Modeling in Continuum Mechanics and Modeling in Electronics and Engineering. We hope our book entitled "Modeling and Simulation in Engineering - Selected Problems" will serve as a useful reference to students, scientists, and engineers.',isbn:"978-1-83968-250-6",printIsbn:"978-1-83968-249-0",pdfIsbn:"978-1-83968-251-3",doi:"10.5772/intechopen.87734",price:119,priceEur:129,priceUsd:155,slug:"modeling-and-simulation-in-engineering-selected-problems",numberOfPages:240,isOpenForSubmission:!1,isInWos:null,isInBkci:!1,hash:"4b0bacd0e1184b17d25ee58e03fadb6a",bookSignature:"Jan Valdman and Leszek Marcinkowski",publishedDate:"December 9th 2020",coverURL:"https://cdn.intechopen.com/books/images_new/9923.jpg",numberOfDownloads:5938,numberOfWosCitations:1,numberOfCrossrefCitations:4,numberOfCrossrefCitationsByBook:0,numberOfDimensionsCitations:7,numberOfDimensionsCitationsByBook:1,hasAltmetrics:1,numberOfTotalCitations:12,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"November 19th 2019",dateEndSecondStepPublish:"February 26th 2020",dateEndThirdStepPublish:"April 26th 2020",dateEndFourthStepPublish:"July 15th 2020",dateEndFifthStepPublish:"September 13th 2020",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6,7",editedByType:"Edited by",kuFlag:!1,featuredMarkup:null,editors:[{id:"177759",title:"Associate Prof.",name:"Jan",middleName:null,surname:"Valdman",slug:"jan-valdman",fullName:"Jan Valdman",profilePictureURL:"https://mts.intechopen.com/storage/users/177759/images/system/177759.jpg",biography:"Dr. Jan Valdman is an associate professor of applied mathematics at the Faculty of Science, University of South Bohemia in České Budějovice and a researcher at the Institute of Information Theory and Automation of the Czech Academy of Sciences in Prague. He obtained his MSc degrees from the Mathematical Research Institute in Utrecht, the Netherlands, and the University of West Bohemia in Pilsen, Czech Republic in 1998. He graduated from the University of Kiel, Germany with his PhD thesis on modeling of elastoplasticity in 2002. After spending further years at several foreign institutions (Linz, Bergen, Reykjavik, and Leipzig), he returned to Czech Republic and finished his habilitation at the Technical University of Ostrava in 2011. His areas of interest include computational nonlinear mechanics of solids and aposteriori error estimates for nonlinear problems. He has published several vectorized finite element codes in MATLAB.",institutionString:"University of South Bohemia in České Budějovice",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"0",totalChapterViews:"0",totalEditedBooks:"3",institution:{name:"University of South Bohemia in České Budějovice",institutionURL:null,country:{name:"Czech Republic"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:{id:"311809",title:"Dr.",name:"Leszek",middleName:null,surname:"Marcinkowski",slug:"leszek-marcinkowski",fullName:"Leszek Marcinkowski",profilePictureURL:"https://mts.intechopen.com/storage/users/311809/images/10147_n.jpg",biography:"Dr. Leszek Marcinkowski is an associate professor of applied mathematics at the Faculty of Mathematics, Informatics, and Mechanics, University of Warsaw. He obtained his MSc degree in 1994, his Ph.D. degree in 2000, and his habilitation in 2010 from the University of Warsaw. All degrees were obtained with distinctions. His Ph.D. thesis was on parallel solvers for partial differential equations discretizations. Later he was a post-doctoral fellow in the Department of Computer Science of the University of Colorado at Boulder, USA. He visited many foreign institutions, including the University of Colorado, Lawrence Livermore National Laboratory, and the University of Bergen, for shorter research visits. His research areas are focused on discretization methods and parallel solvers for partial differential equations. In particular, he is interested in discretizations built on nonmatching grids and domain decomposition methods.",institutionString:"University of Warsaw",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"0",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"University of Warsaw",institutionURL:null,country:{name:"Poland"}}},coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"607",title:"Mathematical Modeling",slug:"numerical-analysis-and-scientific-computing-mathematical-modeling"}],chapters:[{id:"72052",title:"Cohesive Elements or Phase-Field Fracture: Which Method Is Better for Dynamic Fracture Analyses?",doi:"10.5772/intechopen.92180",slug:"cohesive-elements-or-phase-field-fracture-which-method-is-better-for-dynamic-fracture-analyses-",totalDownloads:643,totalCrossrefCites:0,totalDimensionsCites:1,hasAltmetrics:0,abstract:"Numerical techniques to simulate crack propagation can roughly be divided into sharp and diffuse interface methods. Two prominent approaches to quantitative dynamic fracture analysis are compared here. Specifically, an adaptive cohesive element technique and a phase-field fracture approach are applied to simulate Hopkinson bar experiments on the fracture toughness of high-performance concrete. The experimental results are validated numerically in the sense of an inverse analysis. Both methods allow predictive numerical simulations of crack growth with an a priori unknown path and determine the related material parameter in a quantitative manner. Reliability, precision, and numerical costs differ however.",signatures:"Tim Dally, Carola Bilgen, Marek Werner and Kerstin Weinberg",downloadPdfUrl:"/chapter/pdf-download/72052",previewPdfUrl:"/chapter/pdf-preview/72052",authors:[null],corrections:null},{id:"72784",title:"Methods of Nonequilibrium Statistical Mechanics in Models for Mixing Bulk Components",doi:"10.5772/intechopen.93137",slug:"methods-of-nonequilibrium-statistical-mechanics-in-models-for-mixing-bulk-components",totalDownloads:390,totalCrossrefCites:2,totalDimensionsCites:2,hasAltmetrics:0,abstract:"When describing the mechanics of the behavior of bulk materials during their mixing, a theoretical basis for the design of the specified equipment is formed. In recent years, the most well-known methods of modeling this process include the stochastic approach, in the framework of which models of the following types are actively developing: cell, managerial, with time series, energy, etc. Moreover, as a rule, predicting the quality of the finished mixture according to the selected criterion is achieved by using numerical calculation methods based on the generated cyber system. Of particular interest is the use of the energy method from the statistical mechanics of nonequilibrium processes due to the possibility of obtaining analytical simulation results. The paper describes the motion models of bulk components in rarefied flows, which are built on the basis of the energy method and take into account the main characteristics of the studied mixing process.",signatures:"Anna Kapranova, Daria Bahaeva, Dmitry Stenko, Ivan Verloka, Anton Lebedev and Mikhail Tarshis",downloadPdfUrl:"/chapter/pdf-download/72784",previewPdfUrl:"/chapter/pdf-preview/72784",authors:[null],corrections:null},{id:"73480",title:"Mathematical Modelling and Numerical Simulation of Diffusive Processes in Slow Changing Domains",doi:"10.5772/intechopen.93788",slug:"mathematical-modelling-and-numerical-simulation-of-diffusive-processes-in-slow-changing-domains",totalDownloads:331,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Nowadays, diffusion and heat conduction processes in slow changing domains attract great attention. Slow-phase transitions and growth of biological structures can be considered as examples of such processes. The main difficulty in numerical solutions of correspondent problems is connected with the presence of two time scales. The first one is time scale describing diffusion or heat conduction. The second time scale is connected with the mentioned slow domain evolution. If there is sufficient difference in order of the listed time scale, strong computational difficulties in application of time-stepping algorithms are observed. To overcome the mentioned difficulties, it is proposed to apply a small parameter method for obtaining a new mathematical model, in which the starting parabolic initial-boundary-value problem is replaced by a sequence of elliptic boundary-value problems. Application of the boundary element method for numerical solution of the obtained sequence of problems gives an opportunity to solve the whole considered problem in slow time with high accuracy specific to the mentioned algorithm. Besides that, questions about convergence of the obtained asymptotic expansion and correspondence between initial and obtained formulations of the problem are considered separately. The proposed numerical approach is illustrated by several examples of numerical calculations for relevant problems.",signatures:"Dmytro V. Yevdokymov and Yuri L. Menshikov",downloadPdfUrl:"/chapter/pdf-download/73480",previewPdfUrl:"/chapter/pdf-preview/73480",authors:[null],corrections:null},{id:"72770",title:"Modeling of the Two-Dimensional Thawing of Logs in an Air Environment",doi:"10.5772/intechopen.93177",slug:"modeling-of-the-two-dimensional-thawing-of-logs-in-an-air-environment",totalDownloads:387,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"A two-dimensional mathematical model has been created, solved, and verified for the transient nonlinear heat conduction in logs during their thawing in an air environment. For the numerical solution of the model, an explicit form of the finite-difference method in the computing medium of Visual FORTRAN Professional has been used. The chapter presents solutions of the model and its validation towards own experimental studies. During the validation of the model, the inverse task of the heat transfer has been solved for the determination of the logs’ heat transfer coefficients in radial and longitudinal directions. This task has been solved also in regard to the logs’ surface temperature, which depends on the mentioned coefficients. The results from the experimental and simulative investigation of 2D nonstationary temperature distribution in the longitudinal section of poplar logs with a diameter of 0.24 m, length of 0.48 m, and an initial temperature of approximately –30°C during their many hours thawing in an air environment at room temperature are presented, visualized, and analyzed.",signatures:"Nencho Deliiski, Ladislav Dzurenda and Natalia Tumbarkova",downloadPdfUrl:"/chapter/pdf-download/72770",previewPdfUrl:"/chapter/pdf-preview/72770",authors:[{id:"43040",title:"Prof.",name:"Nencho",surname:"Deliiski",slug:"nencho-deliiski",fullName:"Nencho Deliiski"},{id:"184902",title:"Prof.",name:"Ladislav",surname:"Dzuranda",slug:"ladislav-dzuranda",fullName:"Ladislav Dzuranda"},{id:"284649",title:"Dr.",name:"Natalia",surname:"Tumbarkova",slug:"natalia-tumbarkova",fullName:"Natalia Tumbarkova"}],corrections:null},{id:"72997",title:"Innovations in Heat Pump Design Using Computational Fluid Dynamics with Control Volume Method",doi:"10.5772/intechopen.93191",slug:"innovations-in-heat-pump-design-using-computational-fluid-dynamics-with-control-volume-method",totalDownloads:463,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Mathematical modeling of the heat pump as a result of continuity, momentum, and energy equations is obtained. To solve these equations numerically, the problem is divided by a finite number of control volumes. Then the differential equations in these control volumes integrated and converted into algebraic equations. The importance of computational fluid dynamics in Industry 4.0 applications is to make current applications more efficient in heat pump applications. In this study, the book section is composed of the application of computational fluid dynamics by the control volume method using Ansys fluent program, which will benefit readers from industry 4.0 perspective, especially in energy efficiency issues according to the volume method of controlling correct heat pump designs.",signatures:"Cemil Koyunoğlu",downloadPdfUrl:"/chapter/pdf-download/72997",previewPdfUrl:"/chapter/pdf-preview/72997",authors:[{id:"282057",title:"Dr.",name:"Cemil",surname:"Koyunoğlu",slug:"cemil-koyunoglu",fullName:"Cemil Koyunoğlu"}],corrections:null},{id:"73385",title:"A Robust and Oblivious Watermarking Method Using Maximum Wavelet Coefficient Modulation and Genetic Algorithm",doi:"10.5772/intechopen.93832",slug:"a-robust-and-oblivious-watermarking-method-using-maximum-wavelet-coefficient-modulation-and-genetic-",totalDownloads:373,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"An image watermarking method using Discrete Wavelet Transform (DWT) and Genetic Algorithm (GA) is presented for applications like content authentication and copyright protection. This method is robust to various image attacks. For watermark detection/extraction, the cover image is not essential. Gray scale images of size 512 × 512 as cover image and binary images of size 64 × 64 as watermark are used in the simulation of the proposed method. Watermark embedding is done in the DWT domain. 3rd and 2nd level detail sub-band coefficients are selected for further processing. Selected coefficients are arranged in different blocks. The size of the block and the number blocks depends on the size of the watermark. One watermark bit is embedded in each block. Then, inverse DWT operation is performed to get the required watermarked image. This watermarked image is used for transmission and distribution purposes. In case of any dispute over the ownership, the hidden watermark is decoded to solve the problem. Threshold-based method is used for watermark extraction. Control parameters are identified and optimized based on GA for targeted performance in terms of PSNR and NCC. Performance comparison is done with the existing works and substantial improvement is witnessed.",signatures:"Surya Prasada Rao Borra, Kongara Ramanjaneyulu and K. Raja Rajeswari",downloadPdfUrl:"/chapter/pdf-download/73385",previewPdfUrl:"/chapter/pdf-preview/73385",authors:[null],corrections:null},{id:"72991",title:"A New BEM for Modeling and Simulation of Laser Generated Ultrasound Waves in 3T Fractional Nonlinear Generalized Micropolar Poro-Thermoelastic FGA Structures",doi:"10.5772/intechopen.93376",slug:"a-new-bem-for-modeling-and-simulation-of-laser-generated-ultrasound-waves-in-3t-fractional-nonlinear",totalDownloads:362,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"In this chapter, we introduce a new theory called acoustic wave propagation of three-temperature fractional nonlinear generalized micropolar poro-thermoelasticity and we propose a new boundary element technique for modeling and simulation of laser-generated ultrasonic wave propagation problems of functionally graded anisotropic (FGA) structures which are linked with the proposed theory. Since it is very difficult to solve general acoustic problems of this theory analytically, we need to develop and use new computational modeling techniques. So, we propose a new boundary element technique for solving such problems. The numerical results are shown graphically to depict the effects of three temperatures on the thermal stress waves propagation. The validity, accuracy, and efficiency of our proposed theory and the technique are examined and demonstrated by comparing the obtained outcomes with those previously reported in the literature as special cases of our general study.",signatures:"Mohamed Abdelsabour Fahmy",downloadPdfUrl:"/chapter/pdf-download/72991",previewPdfUrl:"/chapter/pdf-preview/72991",authors:[{id:"233766",title:"Prof.",name:"Mohamed Abdelsabour",surname:"Fahmy",slug:"mohamed-abdelsabour-fahmy",fullName:"Mohamed Abdelsabour Fahmy"}],corrections:null},{id:"72532",title:"Interactions between Terrestrial Cosmic-Ray Neutrons and III–V Compound Semiconductors",doi:"10.5772/intechopen.92774",slug:"interactions-between-terrestrial-cosmic-ray-neutrons-and-iii-v-compound-semiconductors",totalDownloads:525,totalCrossrefCites:1,totalDimensionsCites:2,hasAltmetrics:1,abstract:"This work explores by numerical simulation the impact of high-energy atmospheric neutrons and their interactions with III–V binary compound semiconductors. The efforts have focused on eight III–V semiconductors: GaAs, AlAs, InP, InAs, GaSb, InSb, GaN, and GaP. For each material, extensive Geant4 numerical simulations have been performed considering a bulk target exposed to a neutron source emulating the atmospheric neutron spectrum at terrestrial level. Results emphasize in detail the reaction rates per type of reaction (elastic, inelastic, nonelastic) and offer a classification of all the neutron-induced secondary products as a function of their atomic number, kinetic energy, initial stopping power, and range. Implications for single-event effects (SEEs) are analyzed and discussed, notably in terms of energy and charge deposited in the bulk material and in the first nanometers of particle range with respect to the critical charge for modern complementary metal oxide semiconductor (CMOS) technologies.",signatures:"Daniela Munteanu and Jean-Luc Autran",downloadPdfUrl:"/chapter/pdf-download/72532",previewPdfUrl:"/chapter/pdf-preview/72532",authors:[{id:"14152",title:"Prof.",name:"Jean-Luc",surname:"Autran",slug:"jean-luc-autran",fullName:"Jean-Luc Autran"},{id:"14602",title:"Dr.",name:"Daniela",surname:"Munteanu",slug:"daniela-munteanu",fullName:"Daniela Munteanu"}],corrections:null},{id:"71601",title:"Modeling and Simulation in Microwave-Photonics Applications",doi:"10.5772/intechopen.91940",slug:"modeling-and-simulation-in-microwave-photonics-applications",totalDownloads:695,totalCrossrefCites:0,totalDimensionsCites:1,hasAltmetrics:0,abstract:"In this chapter, with the goal to recover an optimal mean for computer-aided modeling and simulating a newer class of microwave-photonics-based radio electronic apparatuses, a number of comparative simulation experiments for the basic microwave band electronic devices and systems using well-known software tools referred to photonic design automation or upgraded electronic design automation platforms are carried out. As a result, it is shown that exploiting the software of upgraded electronic design automation platform provides significantly better accuracy of calculations for the devices and systems of this class.",signatures:"Mikhail E. Belkin, Tatiana Bakhvalova, Vladislav Golovin, Yuriy Tyschuk and Alexander S. Sigov",downloadPdfUrl:"/chapter/pdf-download/71601",previewPdfUrl:"/chapter/pdf-preview/71601",authors:[null],corrections:null},{id:"71801",title:"Machine Health Monitoring and Fault Diagnosis Techniques Review in Industrial Power-Line Network",doi:"10.5772/intechopen.92044",slug:"machine-health-monitoring-and-fault-diagnosis-techniques-review-in-industrial-power-line-network",totalDownloads:732,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"The machinery arrangements in industrial environment normally consist of motors of diverse sizes and specifications that are provided power and connected with common power-bus. The power-line could be act as a good source for travelling the signal through power-line network and this can be leave a faulty symptom while inspection of motors. This influence on other neighbouring motors with noisy signal that may present some type of fault condition in healthy motors. Further intricacy arises when this type of signal is propagated on power-line network by motors at different slip speeds, power rating and many faulty motors within the network. This sort of convolution and diversification of signals from multiple motors makes it challenging to measure and accurately relate to a certain motor or specific fault. This chapter presents a critical literature review analysis on machine-fault diagnosis and its related topics. The review covers a wide range of recent literature in this problem domain. A significant related research development and contribution of different areas regarding fault diagnosis and traceability within power-line networks will be discussed in detail throughout this chapter.",signatures:"Saud Altaf and Shafiq Ahmad",downloadPdfUrl:"/chapter/pdf-download/71801",previewPdfUrl:"/chapter/pdf-preview/71801",authors:[null],corrections:null},{id:"71973",title:"Semiconductor Device Modeling and Simulation for Electronic Circuit Design",doi:"10.5772/intechopen.92037",slug:"semiconductor-device-modeling-and-simulation-for-electronic-circuit-design",totalDownloads:1038,totalCrossrefCites:1,totalDimensionsCites:1,hasAltmetrics:0,abstract:"This chapter covers different methods of semiconductor device modeling for electronic circuit simulation. It presents a discussion on physics-based analytical modeling approach to predict device operation at specific conditions such as applied bias (e.g., voltages and currents); environment (e.g., temperature, noise); and physical characteristics (e.g., geometry, doping levels). However, formulation of device model involves trade-off between accuracy and computational speed and for most practical operation such as for SPICE-based circuit simulator, empirical modeling approach is often preferred. Thus, this chapter also covers empirical modeling approaches to predict device operation by implementing mathematically fitted equations. In addition, it includes numerical device modeling approaches, which involve numerical device simulation using different types of commercial computer-based tools. Numerical models are used as virtual environment for device optimization under different conditions and the results can be used to validate the simulation models for other operating conditions.",signatures:"Samira Shamsir, Md Sakib Hasan, Omiya Hassan, Partha Sarathi Paul, Md Razuan Hossain and Syed K. Islam",downloadPdfUrl:"/chapter/pdf-download/71973",previewPdfUrl:"/chapter/pdf-preview/71973",authors:[null],corrections:null}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},subseries:null,tags:null},relatedBooks:[{type:"book",id:"5141",title:"Applications from Engineering with MATLAB Concepts",subtitle:null,isOpenForSubmission:!1,hash:"bdc44a3ab8aa8a9b5d9a2b62b6e09c67",slug:"applications-from-engineering-with-matlab-concepts",bookSignature:"Jan Valdman",coverURL:"https://cdn.intechopen.com/books/images_new/5141.jpg",editedByType:"Edited by",editors:[{id:"177759",title:"Associate Prof.",name:"Jan",surname:"Valdman",slug:"jan-valdman",fullName:"Jan Valdman"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"6577",title:"Optimization 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It refers to when new blood vessels sprout from existing ones. This multi-step process is imperative to the physiological maintenance of the body such as tissue repair [1]. It is also thought to be a critical process that tumours depend on for the delivery of oxygen and nutrients, in order to facilitate growth and progression [2]. Both pro-angiogenic factors and anti-angiogenic factors play a role in modulating tumour neovascularisation. Notably, vascular endothelial growth factors (VEGF) and catecholaminergic signalling pathways have been shown to be key factors in angiogenesis, invasion and metastases [3]. Investigations into catecholaminergic signalling from the sympathetic nervous system have shown to increase VEGF and matrix metalloprotease (MMP) levels, promoting tumour growth, invasion and metastasis [4]. Since tumour angiogenesis requires the up-regulation of these factors, anti-angiogenic agents have now been developed. A multitude of trials have investigated the effect of anti-angiogenic agents on the progression of cancer as well as combination therapies to improve the current standard of care. However, not all patients respond to these, leading to studies that aim at elucidating the mechanisms of resistance.
Angiogenesis is considered to be a fundamental event in tumour progression and metastatic dissemination and is [2] regulated by numerous endogenous factors that stimulate or inhibit neovascularisation [3]. One of the most studied pathways is the vascular endothelial growth factor (VEGF) family of ligands and their receptors [5]. In humans and mice, the VEGF family consists of 5 members: VEGF-A, -B, -C, -D and placental growth factor (PIGF). These ligands demonstrate variable specificity for the three VEGF receptors (VEGFR1, VEGFR2, VEGFR3) [3, 5]. The predominant member of the VEGF family involved in tumourigenesis is VEGF-A and will be referred to as simply ‘VEGF’ from herein.
One of the most important stimuli for tumour angiogenesis is hypoxia, which can occur when a rapidly growing tumour exceeds the ability of the local vasculature to supply its needs. Hypoxia-inducible factor 1 (HIF-1) is a heterodimeric transcription factor, made up of two DNA binding proteins (HIF-1
Binding of VEGF to the extracellular domain of VEGFR2 causes receptor dimerisation and phosphorylation of the receptor on tyrosine residues within the intracellular domain (Figure 1) [11]. The Y1054 and Y1059 residues, which lie within the kinase domain, become phosphorylated in response to VEGF stimulation. These positively regulate the intrinsic kinase activity of the intracellular domain and signal to phospholipase-Cγ (PLCγ), which in turn leads to VEGFR2 internalisation [12]. The Y1175 and Y1214 residues lie in the carboxyl terminal tail. These residues become highly phosphorylated in response to VEGF. Y1214 signalling leads to endothelial cell migration and Y1175 signalling leads to PLCγ and extracellular related kinase 1/2 (ERK1/2) activation that is required for DNA synthesis and cell proliferation [13]. Activation of ERK1/2 requires the Ras-Raf-MEK-ERK1/2 signalling cascade but may also require the PLCγ/PKC/PKD pathway [14]. The roles of Y951 and Y996 residues, which lie in the kinase insert region, have not been definitively determined, but Y951 phosphorylation has been shown to increase endothelial cell migration and proliferation via both the PLC-γ and PI3K pathways [15].
Signalling from VEGFR2. The signalling cascades downstream of VEGFR2 have been the best studied and are illustrated here. VEGF binding to VEGFR2 induces dimerisation of VEGFR2 and phosphorylation of tyrosine residues (indicated by the four-digit numbers in the illustration). Pathways activated include the Ras-Raf-MEK-ERK pathway, PLCγ/PKC pathway and the PI3K/Akt pathway. Activation of downstream signalling from VEGF receptors exerts control over multiple processes required for angiogenesis including endothelial cell proliferation, migration, tube formation and vascular permeability.
According to the established dogma, VEGF released by tumours stimulates the growth of new vessels in the following way. The VEGF diffuses through the tissue and activates endothelial cells located in local blood vessels. Firstly, VEGF receptor activation induces the selection of sprouting endothelial cells. Proteinases such as urokinase-type plasminogen activator, uPA, and members of the matrix metalloproteinase (MMP) family mediates the dissolution of the vascular basement membrane and extracellular matrix to facilitate the infiltration of sprouting endothelial cells into the surrounding tissue [16]. Next, endothelial proliferation, migration and branching allows for the formation of new vessels. This is followed by sprout fusion and lumen formation where vessels fuse together to form a network. Finally, there is perfusion and maturation. This is where the stabilisation of new blood vessels forms a functionally perfused system, which is mediated by the recruitment of pericytes to surround the newly formed endothelial tubes; recruitment of pericytes prevents further endothelial cell proliferation and migration and also suppresses vessel leakage [17].
Multiple possible mechanisms exist regarding immunosuppressive effects of VEGF on the tumour microenvironment. Firstly, due to the effect of VEGF on tumour vasculature, T cell migration from lymph nodes to the microenvironment may be impaired. Furthermore, the ability of T cells to migrate through vessels is negatively affected by VEGF through the down regulation of vascular endothelial selectins, adhesion molecules and promotion of Fas ligand expression. Secondly, VEGF binding to its receptor on myeloid derived suppressor cells within the tumour microenvironment results in STAT 3 signalling, with subsequent promotion of Treg cells and the down regulation of tumour specific T cells [18]. Additionally, the binding of VEGF to VEGFR2 has effects including reduced activation of cytotoxic CD8+ and CD4+ T cells, as well as the upregulation of inhibitory receptors including PD1 and CTLA4 [19]. The interaction of VEGF with VEGFR may also upregulate the programmed death ligand 1 (PDL1) on dendritic cells (DCs) [20]. Furthermore, the binding of VEGF to VEGFR1 on dendritic cells has the effect of inhibiting dendritic cell maturation [20].
Given the key role VEGF is proposed to play in tumour angiogenesis, it is unsurprising that it has become a major drug target. Various drugs designed to inhibit VEGF signalling have been developed, including VEGF neutralising antibodies (e.g. bevacizumab), novel fusion proteins which bind pro-angiogenic growth factors (e.g. aflibercept) and VEGF receptor tyrosine kinase inhibitors (e.g. sunitinib) [5, 21]. Such agents have shown promise in the treatment of several malignancies, including mCRC, metastatic renal cell carcinoma (mRCC), metastatic lung cancer, hepatocellular carcinoma (HCC) and pancreatic neuroendocrine tumours (PNET) [22].
Bevacizumab (Avastin®) is a recombinant humanised monoclonal antibody that binds to the VEGF-A isoform of human VEGF specifically and prevents the VEGF from activating the VEGF receptor [23].
Trials with bevacizumab as a single agent in metastatic colorectal cancer (mCRC) failed to demonstrate activity, but early Phase I trials demonstrated that it has the potential to be combined with many chemotherapy agents [24]. In the advanced setting, several randomised Phase II and III clinical trials clearly demonstrated that bevacizumab improves response rates (ORR), progression free survival (PFS) and overall survival (OS) in mCRC, when added to standard chemotherapy in the first line setting [25, 26], and the second line setting [27] (Table 1). In February 2004, the US Food and Drug Administration (FDA) approved bevacizumab for the treatment of mCRC in combination with 5-fluorouracil-based chemotherapy regimens based on a pivotal Phase III study which demonstrated significant PFS and OS survival benefit [25]. Of clinical importance, bevacizumab in combination with a fluoropyrimidine has also demonstrated efficacy in elderly patients with mCRC [26].
Studies investigating bevacizumab in metastatic colorectal cancer in the first line.
Despite these data, only a small proportion of patients benefit from the addition of bevacizumab, and furthermore, some studies have demonstrated only an increase in PFS, with no increase in ORR or OS (Table 1) [28]. Additionally, even those who respond initially to bevacizumab combined with chemotherapy will inevitably develop resistance and relapse [29].
In the setting of colorectal liver-only metastasis (CRLM), it has been well demonstrated that preoperative chemotherapy improves outcome and metastatectomy rates [30]. With this in mind, and on the basis that bevacizumab can improve ORR, several groups set out to evaluate its role in the preoperative CRLM setting. Findings from a small non-randomised controlled trial of neoadjuvant conventional chemotherapy with bevacizumab in high-risk CRLM patients alluded to an improvement of CRC liver metastasis rate to 40% [31]. Data from retrospective, inter-trial studies have also suggested that the addition of bevacizumab to chemotherapy significantly improves pathological response in CRLM compared to when chemotherapy is administered alone [32]. Subgroup post hoc analyses extracted from large randomised controlled trials of unselected patients have failed to show significant improvements in resection rates with the addition of bevacizumab [33]. Without prospective randomised trials however, it is difficult to make conclusions regarding the efficacy of chemotherapy versus chemotherapy combined with bevacizumab in the CRLM setting.
The role of continuing bevacizumab beyond first progression in advanced colorectal cancer has also been examined. The results of two non-randomised observational cohort studies (BRiTE and ARIES) demonstrated a significant correlation between the use of bevacizumab beyond progression and substantial improvement in OS [34, 35]. Benefit of treatment beyond progression following first line treatment was later confirmed in a prospective randomised trial [36].
The efficacy of bevacizumab has also been evaluated in the adjuvant setting in CRC patients. Two large randomised studies compared survival between the following arms: adjuvant chemotherapy alone for 6 months versus adjuvant chemotherapy in combination with bevacizumab for 6 months (followed by bevacizumab alone for 6 months). Both studies demonstrated that at 1 year there was an improvement in PFS in the bevacizumab arm. However, no significant difference in OS was observed between treatment arms when assessed at 3 or 5 years [37, 38]. In fact, an analysis at 5 years in the AVANT study demonstrated a possible detrimental effect on survival with the addition of bevacizumab, documenting a higher number of relapses and deaths due to disease progression [37].
Bevacizumab in combination with cytotoxic chemotherapy has also shown significant clinical efficacy in other tumour types.
In advanced non-squamous non-small cell lung cancer (NSCLC), two randomised controlled phase III trials demonstrated significant benefit in PFS when bevacizumab was added to platinum-based doublet chemotherapy [39, 40], but only one study reported an increase in OS [40]. To further understand this discrepancy, a recent meta-analysis pooling data from several studies including the aforementioned two, deduced a modest but significant improvement in OS [41]. More recently in metastatic non-squamous NSCLC, the Impower150 phase 3 clinical trial investigated treatment with bevacizumab plus platinum doublet chemotherapy with or without the PDL1 inhibitor atezolizumab. Treatment with atezolizumab, bevacizumab and chemotherapy compared with bevacizumab and chemotherapy resulted in a significant improvement in PFS at 6 months (66.9% vs. 36.5%) and at 12 months (56.1% vs. 18%) [42]. In an interim analysis of OS, an improvement was again seen (Table 2) [42].
Studies investigating anti-VEGF agents in NSCLC and RCC.
In advanced ovarian cancer, in the first- and second-line settings, the efficacy of bevacizumab has been assessed when added to platinum-based chemotherapy doublets. Two pivotal first line phase III studies utilising the same chemotherapy doublet (ICON7/AGO-OVAR and GOG-0218 trials) demonstrated a significant improvement in PFS [43]. An updated survival analysis failed to show a significant survival benefit [43].
Bevacizumab has been investigated in glioblastoma multiforme (GBM), in the recurrent setting following first line treatment with temozolamide and radiation therapy. In this setting bevacizumab monotherapy is ineffective, however in combination with lomustine it has resulted in improvement in PFS but not OS [44]. Bevacizumab has also been investigated in the first line setting with chemoradiation in a large randomised placebo controlled trial, but failed to improve outcomes [45].
Earlier phase III trials in RCC have demonstrated efficacy of bevacizumab in combination with sorafenib, sunitinib and interferon alpha (Table 2). More recently, bevacizumab has been combined with atezolizumab in metastatic RCC. A phase III randomised trial confirmed significant improvement in PFS for bevacizumab combined with atezolizumab compared with sunitinib monotherapy but mature OS data are still awaited [46].
Despite such encouraging results, bevacizumab has thus far failed to make a significant impact in several other indications, including metastatic breast cancer (mBC), melanoma, pancreatic cancer and prostate cancer. Interestingly, in breast cancer, pooled data from four large clinical trials demonstrated that it neither prolonged OS, nor delayed disease progression significantly, leading the FDA to revoke its initial approval of bevacizumab for mBC [47]. The variation in impact that bevacizumab has, not only across tumour types, but also within a single tumour type, is curious and needs to be better understood.
Ramucirumab is a fully human IgG1 monoclonal antibody that binds to the extracellular domain of VEGFR-2, blocking VEGF from activating the receptor [48]. Clinical efficacy and tolerability have been demonstrated in a number of preclinical studies and more recently in phase III trials. In the refractory metastatic gastric and gastro-oesophageal junction (GOJ) adenocarcinoma setting, ramucirumab significantly improved median OS compared with placebo but this only represented an absolute improvement of 1.4 months [49]. In the second line setting of advanced gastric and GOJ adenocarcinoma, the combination of ramucirumab and paclitaxel has become standard treatment based on the results of the pivotal RAINBOW trial showing significant improvement in OS compared with paclitaxel and placebo [50]. Ramucirumab has not shown benefit in the first line setting including combination with chemotherapy [51].
Ramucirumab has also been investigated in metastatic NSCLC but does not yet have an established role for this indication. After progression on first line platinum based chemotherapy, there was a small but statistically significant benefit in median OS of ramucirumab added to docetaxel [52]. Early results of the RELAY phase 3 clinical trial investigating ramucirumab in combination with erlotinib in the first line setting of metastatic EGFR mutated NSCLC have indicated an improvement in PFS however formal publication of the study findings are awaited.
Ramucirumab has also been investigated in urothelial cancers. In a phase III trial of ramucirumab plus docetaxel compared with docetaxel plus placebo in patients with advanced urothelial carcinoma who had received platinum-based chemotherapy, there was a statistically significant improvement in median PFS (4.07 months vs. 2.76 months) [53].
Aflibercept is a recombinant fusion protein that binds to VEGF-A, VEGF-B and placental growth factor (PLGF), all of which have been implicated in angiogenesis and/or the survival of newly formed blood vessels [54]. As it binds to additional pro-angiogenic targets (compared to bevacizumab which binds only VEGF-A), aflibercept may provide further anti-angiogenic effects compared to targeting VEGF-A alone. In preclinical studies, it demonstrated a broad range of anti-tumour and anti-angiogenic activity both alone and in combination with chemotherapy, which was also observed in phase I clinical trials [55]. Recently, a large randomised phase III clinical trial (VELOUR) in advanced CRC patients, receiving second line therapy, demonstrated that the addition of aflibercept to systemic chemotherapy significantly improved outcomes compared to chemotherapy alone [56]. Based on this data, aflibercept was recently approved for use in the second line setting in mCRC when given in combination with chemotherapy. Importantly, results from a subanalysis of VELOUR showed that there was no significant impact of prior exposure to bevacizumab, illustrating the benefit that it provides as a multiple angiogenic factor trap, in a setting where resistance to bevacizumab may have developed [57].
Several small molecule inhibitors of VEGF receptor tyrosine kinase activity now have an established role in the treatment of certain tumour types, including mRCC, HCC and advanced CRC. These small molecule inhibitors readily diffuse through the cell membrane to compete for ATP binding to the intracellular tyrosine kinase domain of VEGF receptor 2.
Sunitinib is an orally active multi-kinase inhibitor, which targets VEGFR1–3, PDGFR
In terms of outcome in the clinical setting, sunitinib initially showed efficacy, as a single agent, for second-line therapy in single-arm, Phase II studies in mRCC [61]. Patients treated with sunitinib showed promising outcomes in terms of ORR, response duration, PFS and OS. A pivotal Phase III study was subsequently conducted comparing sunitinib with interferon-α as a first-line treatment in mRCC, which demonstrated improved OS, PFS and ORR in the sunitinib arm [62]. Based on such data, sunitinib was approved by the FDA in 2006 for the first line treatment of mRCC. Other TKI’s, with similar target specificity (sorafenib, pazopanib, cabozantinib and axitinib) also have activity in mRCC. Combination with immunotherapeutic agents has also shown promising results and we are seeing the treatment algorithm for mRCC change rapidly. In a recent landmark phase 3 trial of advanced RCC in the first line setting, axitinib was combined with the PD1 inihibitor pembrolizumab and compared with sunitinib monotherapy (KEYNOTE-426). The results are promising with a significant improvement in PFS and ORR with axitinib and pembrolizumab, however more mature OS data are awaited [63].
The role of such TKIs has also being evaluated in mCRC. The anti-tumour and anti-angiogenic effects of sunitinib have been well documented in a series of CRC xenograft tumour models [64]. In the clinical setting, however, sunitinib employed either as a single agent or with combination chemotherapy, has failed to demonstrate favourable outcome, both for ORR and PFS [65].
Recently, another TKI called regorafenib has created a lot of interest in advanced CRC. This agent inhibits VEGFR1-3, PDGFR
Regorafenib also has clinical utility in gastrointestinal stromal tumours (GIST) where it is currently employed in the third line setting after imatinib and sunitinib. This indication followed from a phase 3 randomised trial, demonstrating significantly improved PFS for regorafenib compared with placebo (4.8 months vs. 0.9 months) [69]. There was no significant difference in OS, however this trial did allow for crossover which likely impacted on this finding [69].
Regorafenib has FDA approval for second line treatment of HCC following the positive results of the phase 3 RESORCE clinical trial. Compared with placebo, regorafenib demonstrated survival benefit [70].
Early phase clinical trials have demonstrated that bevacizumab, in combination with systemic cytotoxic chemotherapy, can potentiate treatment efficacy when given concomitantly [71]. In fact, in most clinical settings, with the exception of ovarian cancer where bevacizumab has been observed to have single agent activity [72], bevacizumab has only shown significant activity when it is combined with cytotoxic chemotherapy and the same is true for aflibercept [21].
It has been well-established that the tumour vasculature is dysfunctional and leaky, resulting in enhanced interstitial fluid pressure and thus preventing effective delivery of chemotherapy [73]. Evidence from preclinical studies showed that bevacizumab can ‘normalise’ the chaotic tumour vasculature, achieving reduced vessel tortuosity, reduced leakiness and reduced interstitial fluid pressure. Based on these studies, it was proposed that bevacizumab works in combination with chemotherapy to improve chemotherapy delivery [71, 73], which is now a widely accepted notion amongst many clinicians.
However, this concept is also highly controversial, with some work even refuting the normalisation hypothesis. For example, one group demonstrated that bevacizumab persistently reduced both tumour perfusion and chemotherapy delivery when NSCLC patients were treated with bevacizumab-containing chemotherapy [74]. Therefore, other potential explanations for synergy between bevacizumab and chemotherapy must be considered. Current alternative theories based mostly on preclinical data include: (1) direct synergy between the anti-angiogenic effects of bevacizumab and potential anti-angiogenic effects of chemotherapy [75], (2) targeting of VEGF signalling directly in cancer cells by bevacizumab [21], (3) chemotherapy may inhibit resistance to bevacizumab, because chemotherapy suppresses the tumour recruitment of myeloid cells that have been implicated in resistance to bevacizumab [76], (4) bevacizumab may prevent tumour rebound that may occur during breaks in chemotherapy [76].
It should be noted that vessel normalisation facilitated by anti-angiogenic agents may provide therapeutic benefit through other mechanisms, which are independent of chemotherapy delivery. For example, in glioblastoma patients, vessel normalisation induced by single agent VEGF-targeted therapy may prolong survival due to other effects, such as oedema control or improved tumour oxygenation [77].
There are two other curious observations that have yet to be properly explained. Firstly, the synergistic effect of adding bevacizumab to chemotherapy does not occur in all tumour types. For example, the addition of bevacizumab does not lead to improvements in outcome in advanced breast cancer [78]. Secondly, VEGFR TKIs show single agent activity without the need for co-administration of chemotherapy [21].
Recent insight into these two curious observations has been reported. A study examining both clinical and mouse tumour tissue specimens demonstrated that tumour types utilising a vasculature surrounded by a well-developed stroma (e.g. mCRC, NSCLC) respond better to bevacizumab when it is added to chemotherapy as opposed to tumour types that utilise a vasculature without a well-developed intervening stromal component (e.g. mRCC, PNET) which respond better to VEGF TKIs alone [79]. This suggests that tumour cell interactions with different stromal components may influence response to different anti-angiogenic agents and how they synergise with concomitant drugs. However, there is still much work to be done in order to understand the mechanisms involved.
A series of pre-clinical studies have shown that the use of anti-angiogenic agents along with immune checkpoint inhibitors (ICI) as a combination therapy has a synergistic and enhanced effect on the tumour when compared to either ICI therapy or anti-angiogenic therapy alone. Immunotherapy has emerged as a promising treatment option for many cancer types, offering hope for patients with the demonstration of improved outcomes including durable responses in some. Unfortunately, there are still many patients that either have short lived responses to such therapies or none at all. To overcome resistance mechanisms, combinations of immunotherapy with other treatments including VEGF inhibitors are being explored.
Since 2013, pre-clinical investigations in mice with various tumours have indicated that the combination of ICI and anti-angiogenic agents results in prolonged overall survival [80]. It has been observed that the VEGF can cause the upregulation of immune checkpoint molecules such as PD-1 and as a result, the use of anti-VEGF agents has been seen to reduce the expression of PD-1 on cytotoxic T lymphocytes [81]. Thus, the combination of using both anti-VEGF agents as well as anti-PD-1 agents could have a synergistic effect on inhibiting further tumour development [81]. Through the encouraging findings of pre-clinical investigations, many clinical studies have recently or are still in the process of investigating this.
There are a multitude of clinical studies supporting the role of bevacizumab in the positive immune modulation of the tumour microenvironment and its beneficial effects when combined with the immune checkpoint PD1/PDL1 and CTLA4 inhibitors. In a study investigating melanoma patients treated with ipilimumab plus bevacizumab versus ipilimumab alone, the results showed that the combination therapy increased circulating CD4+ and CD8+ T cells compared with ipilimumab monotherapy [82]. The investigation showed that there was a greater median overall survival in patients undergoing combination therapy (25.1 months) compared to those who underwent the ipilimumab alone treatment (10.1 months) [82]. Furthermore, a separate study of patients with RCC investigating the effect that bevacizumab plus atezolizumab had versus bevacizumab alone found that the combination therapy demonstrated a reduction in neovasulature-related gene expression and decreased microvascular density. The treatment was also associated with an increased tumour infiltration of CD8+ T cells as demonstrated by immunohistochemical staining of cells [83]. This study also demonstrated that MHC Class I is upregulated as a result of the treatment and that both intratumoural CD8+ T cells and macrophages increased as well.
In a phase II study involving patients with RCC, as compared with sunitinib monotherapy, atezolizumab and bevacizumab demonstrated improvements in PFS in patients with an immunosuppressive tumour microenvironment [84]. Whilst it was also discovered that the use of atezolizumab failed to generate an anti-tumour immune response (possibly due to myeloid-induced immune suppression), the addition of bevacizumab to atezolizumab was found to be able to overcome this suppression [84].
Both pre-clinical and clinical studies have shown that anti-angiogenic agents and immunomodulatory therapies have a synergistic affect in reducing tumour growth and a multitude of clinical trials are currently investigating this synergy further. Thus, there is promise in the use of a combination therapy with anti-angiogenic agents and immunomodulatory agents to improve on patient prognosis.
In view of the variable outcomes seen in the clinic, there is a need for the development of validated predictive biomarkers of response for anti-angiogenic therapy. In this way, patients who will derive benefit from such agents could be appropriately selected, whilst those that will not derive benefit (either at the outset or during therapy) could be selected for alternative, more effective therapy. Such a strategy would not only improve clinical outcomes but would also reduce the unnecessary burden of (a) toxicity to the patient, and (b) cost to the economy. Despite extensive international research in this field, there is currently no biomarker which predicts benefit or resistance to anti-angiogenic agents that is approved for routine clinical practice. The following are amongst several which have been investigated in the clinical setting.
Circulating biomarkers are an attractive tool for patients and clinicians as ‘liquid biopsies’ are relatively non-invasive and easy to perform, as compared with tissue biopsies of tumour with associated risks and potential technical difficulties depending on tumour site. VEGF levels have been studied as a potential biomarker with high levels associated with poorer outcomes [85]. Findings regarding its utility as a predictive biomarker have been more inconsistent [85]. An analysis of four randomised phase 3 trials investigated circulating VEGF level as a prognostic and predictive biomarker in mCRC, lung cancer and RCC which included bevacizumab in the treatment regimen. Tumour specimens were also tested for VEGF level. This found that higher baseline circulating VEGF levels were associated with poorer clinical outcomes but levels did not predict response to bevacizumab [86]. There is early evidence from small and exploratory studies to suggest soluble VEGFR-1, with higher levels being associated with poorer outcomes with anti-angiogenic treatments, however larger studies are required to confirm these findings [87].
Other potential circulating biomarkers have also been investigated. In mCRC, elevated IL-8 levels at baseline were associated with a shorter PFS in patients treated with chemotherapy (FOLFIRI) and bevacizumab [88]. Elevated LDH and neutrophil levels have been found to independently predict poorer survival in patients treated with chemotherapy plus bevacizumab [89]. A promising predictive biomarker for response to bevacizumab based therapy in CRC appears to be circulating endothelial cells, with studies showing that patients with lower circulating endothelial cells at baseline undergoing treatment with bevacizumab based therapy had improved PFS [90].
Levels of VEGF expression in a tumour could be a determinant of responsiveness to anti-VEGF therapy. Some small studies have demonstrated a relationship between baseline VEGF expression and response, however these findings have not been consistently replicated in large clinical trials and are often more informative as prognostic rather than predictive biomarkers [91]. Data from more recent prospective studies, however, have shown more consistency in the use of VEGF as a biomarker. A large randomised trial in patients with advanced breast cancer treated with bevacizumab demonstrated a significant association between high circulating levels of VEGF and survival benefit [78]. VEGF expression in tumours was investigated in the large phase III clinical trial of bevacizumab plus chemotherapy in mCRC, but this failed to predict outcomes [92].
There are multiple reasons why using VEGF expression as a biomarker could be problematic: (1) advanced tumours express numerous pro-angiogenic factors in addition to VEGF which could confer resistance to bevacizumab irrespective of the amount of VEGF produced [93], (2) differences in the intensity of VEGF expression might be too small to be clinically relevant, (3) hypoxia, which is promoted by anti-angiogenic therapy, is an important inducer of VEGF expression and might, therefore, lead to increased VEGF production in the presence of bevacizumab treatment; indeed, anti-angiogenic agents have been shown to induce expression of VEGF even in tumour naïve hosts [94], (4) variations in methodology across centres (including sample handling, the use of different scoring systems and non-validated antibodies) have a significant effect on biomarker trial results [95], (5) it is very challenging to standardise cut-offs for low and high VEGF levels, due to: (a) different methods used to measure VEGF at different centres and (b) differences in biology that occur between racial groups, tumour types and different stages of disease [95].
Studies which have investigated other single circulating factors (such as FGF2, and r soluble VEGFR2) have also yielded contradictory and unsatisfactory conclusions [96]. Interestingly, however, recent clinical work in mRCC patients treated with anti-angiogenic TKIs suggests that profiling multiple circulating factors in the blood could have a more powerful prognostic and predictive role than assessing levels of single factors alone [97]. In this study, when patients with mRCC were treated with the TKI pazopanib, a biomarker signature of six factors (HGF, interleukin 6 and interleukin 8, osteopontin, VEGF and TIMP1) was able to distinguish a sub-group of patients that derived a significantly greater overall survival benefit from this agent.
Polymorphisms in VEGF or VEGF receptors have been proposed to predict outcome from anti-angiogenic therapy. As these are generally binary in nature, they are attractive biomarkers since they may be easier to measure and apply prospectively. In metastatic breast cancer, polymorphisms in VEGF and VEGFR2 were analysed in several retrospective subset analyses in patients treated with chemotherapy, with or without bevacizumab. Two polymorphisms within the VEGF promoter/5′ untranslated region, VEGF alleles −2578AA and −1154AA, were significantly associated with improved OS in the bevacizumab plus paclitaxel group when compared to the −2578CA/−2578CC and −1154GA/−1154GG alleles. In contrast, they did not have prognostic power for OS in the chemotherapy-only arm [98]. The predictive power of the −2578AA and −1154AA VEGF alleles was also reported in a retrospective subset analysis of patients with metastatic colorectal cancer that received either FOLFIRI (leucovorin, fluorouracil, and irinotecan) plus bevacizumab or XELIRI (capecitabine and irinotecan) plus bevacizumab [99].
More recently, the role of VEGFR1 polymorphisms was studied in a large meta-analysis pooling DNA data from two phase III trials in patients with advanced pancreatic cancer treated with bevacizumab. VEGFR1 −1213AC/−1213CC alleles were significantly associated with poor outcome in patients receiving bevacizumab when compared to VEGFR1 −1213AA alleles [100]. To understand how this VEGFR1 polymorphism functionally affects VEGFR1 expression and how it might explain its correlation with poor outcome in patients receiving bevacizumab, Lambrechts and colleagues performed an
Functional clinical imaging, taking into account tumour vasculature or metabolic activity by utilising CT, MRI or PET scanning, either prior to commencing treatment or following brief exposure of patients to therapy, may be a useful tool for predicting response or resistance to anti-angiogenic therapy [102]. For conventional cytotoxic chemotherapy, imaging has been employed to assess therapy response based on change in tumour size, as defined by RECIST (Response Evaluation Criteria In Solid Tumours). However, biological agents, such as bevacizumab and TKIs, may be cytostatic in terms of their mechanism of action, thus size may not be the only parameter that needs to be considered when assessing response and outcome. Examination of various parameters such as blood flow and tumour morphology may provide additional important predictive information.
Several studies have examined pre-treatment levels of tumour perfusion and whether they can predict outcome. For example, enhanced levels of vessel perfusion at baseline (measured by contrast-assisted tumour enhancement) in mRCC patients treated with VEGF TKIs has been shown to predict for response and survival [103].
Early alterations in features of the tumour vasculature on imaging after a short period of therapy have also been shown to be associated with response and outcome. For example, in studies of mRCC patients treated with anti-angiogenic TKIs, response criteria that measured both a significant reduction in tumour vascular perfusion and a significant reduction in tumour size were more predictive of outcome compared to change in lesion size alone [104].
Although the use of the above radiological criteria may seem promising as predictors of response and outcome, there are associated challenges that need to be considered before incorporating them into clinical practice. These include, (a) diversity in the methodologies used to assess potential surrogate radiological biomarkers of response between studies and across centres, and (b) insufficient comprehension of how certain radiological features correlate with the underlying tumour biology.
Currently, the efficacy of any anti-neoplastic therapy is assessed by several outcome measures, which include (a) effective downsizing of tumours on clinical imaging (to facilitate curative surgery or consolidative radiotherapy for localised disease and to reduce the symptomatic burden of disease in the metastatic setting), (b) prolongation of the interval where a patient is either disease-free or progression-free, and (c) prolongation of survival.
Conventional assessment of residual tumour volume after cytotoxic chemotherapy has traditionally been performed with the use of size-based criteria (overall response rate, ORR, by RECIST). This was based on evidence that there is good correlation between radiological information and residual viable tumour (pathological response) and good correlation with progression-free (PFS) and overall survival (OS) in patients treated with cytotoxic chemotherapy [105]. However, with the advent of biological therapies, such as bevacizumab, the value of utilising RECIST on its own as a surrogate for outcome has been questioned and new imaging criteria have been proposed [102].
For anti-angiogenic therapy employed in advanced malignant disease, retrospective clinical meta-analyses have (a) highlighted the pitfalls and limitations of using RECIST alone in the assessment of response and progression, and (b) highlighted a disassociation of RECIST from time-related endpoints of PFS and OS [105].
This curiosity was provoked by several large randomised clinical trials investigating the effect of adding bevacizumab to conventional chemotherapy in different tumour types. These have consistently demonstrated that significant improvements in PFS and OS were incongruent with modest increases in ORRs [25, 28, 40]. In their CRC meta-analysis, Grothey and colleagues specifically examined the impact of tumour response to bevacizumab (ORR) on treatment benefit (PFS, OS) and concluded that patients who did not attain a positive response according to RECIST (i.e. stable disease) in fact showed significant benefit from bevacizumab, which was of the same magnitude as responding patients (i.e. complete or partial response) [105].
Moreover, similar concepts have consistently featured in several Phase I and II clinical trials employing antiangiogenic agents, and other molecular targeted therapies. These studies corroborate that there is little value in utilising ORR alone, particularly in predicting whether an agent will ultimately have truly meaningful effects on pathological response or in prolonging survival [106]. The underlying reason for these incongruent observations with bevacizumab and other molecular targeted therapies may be because such agents are cytostatic rather than cytotoxic [107].
There has been growing interest in how the appearance of lesions on clinical imaging can be utilised to accurately assess the effect of bevacizumab on tumour volume and how this appearance may correlate with other clinical end-points. In a small retrospective colorectal liver only metastasis (CRLM) patient cohort treated with bevacizumab and chemotherapy, Chun and colleagues demonstrated that novel morphological response criteria predicted more accurately for OS and pathological response than RECIST (Figure 2) [108]. This was subsequently validated in a larger patient population which included patients who were treated with and without bevacizumab [109]. Not only were the morphological response criteria superior to RECIST in predicting major pathological response and OS, further analyses confirmed that the morphological response criteria did not correlate with responses measured according to RECIST. Moreover, there was a significantly higher incidence of optimal responses (measured by morphological response criteria) in the patient cohort receiving bevacizumab with chemotherapy compared to the chemotherapy alone cohort [109]. These data suggest that (a) morphological response criteria and RECIST measure different biological parameters, and (b) the use of morphological response criteria represents a more sensitive tool for measuring tumour response and time-related endpoints of survival for bevacizumab. Similar findings were reported in a retrospective study of non-small cell lung cancer patients treated with bevacizumab and concomitant chemotherapy [110].
Morphological response criteria on contrast-enhanced CT (CECT) scans as a predictor of outcome (i) and (ii) CECT performed in a 43-year old patient before and after 10 cycles of bevacizumab containing chemotherapy demonstrating an optimal response (OR). (i) Before therapy, the liver metastasis presented with profound heterogeneous attenuation, a hyperattenuated peripheral rim and a thick, poorly defined tumour-liver interface (‘group 3’ metastasis). (ii) After therapy, the same liver metastasis shows complete resolution of these features (i.e. it is homogeneous, of low attenuation, with a thin, sharply defined tumor-liver interface). Change in size of lesion is minimal. (iii) and (iv) CECT of the liver performed in a 67-year old patient before and after 2 cycles of bevacizumab-containing chemotherapy demonstrating a partial response (PR). (iii) Before therapy, the liver metastas is presented with features of a ‘group 3’ metastasis. (iv) After therapy, the same liver metastasis shows moderate resolution of these features (i.e. it has a moderate degree of heterogeneous attenuation, a moderately defined tumor-liver interface with a slight hyperattenuating peripheralrim (‘group 2’ metastasis)). (v) and (vi) CECT of the liver performed in a 56-year old patient before and after 2 cycles of bevacizumab-containing chemotherapy demonstrating an absent response (AR). (v) Before therapy, the liver metastasis presented with features of a ‘group 3’ metastasis. (vi) After therapy, the same liver metastas is shows a decrease in tumour size without change in attenuation or tumour-liver interface (‘group 3’ metastasis). Changes in tumour morphology on CECT have been shown to correlate more significantly with survival than the use of RECIST citeria in CRLM patients treated with bevacizumab-containing chemotherapy.
Radiological assessment alone may not accurately reflect response to therapy because simple, unidimensional imaging parameters may overestimate or underestimate downstaging of tumour burden [111]. Furthermore, in the case of adding anti-angiogenic therapy to chemotherapy, although it has been suggested that proposed morphological imaging characteristics can accurately predict tumour response and clinical outcome, such scoring methods have not yet been validated for conventional use in clinical practice and may also be too subjective. Scoring of pathological response may therefore be a better alternative or perhaps an adjunct in assessing residual viable tumour. Moreover, in the case of preoperative chemotherapy or radiotherapy in settings such as rectal cancer and oesophageal cancer, pathological response has also been shown to correlate significantly to disease-free survival (DFS) and OS [112].
Several methodologies incorporating various parameters for scoring pathological response in resected CRLMs, treated with and without bevacizumab, have been proposed. It is still not clear from the current literature which of these classification methods may be superior.
Microscopic assessment of the percentage residual viable tumour on haematoxylin & eosin-stained sections of resected tissue has been employed as a predominant parameter in assessing the efficacy of different pre-operative chemotherapy regimens in tumour types such as oesophageal, gastric and rectal adenocarcinomas [113]. Based on this methodology, Ribero and colleagues modified this scoring system for application in CRLMs treated preoperatively, with or without bevacizumab [114]. A semi-quantitative estimation of the percentage area of residual viable tumour cells relative to total tumour surface area within each CRLM metastasis was made with the analysis of four tumour cell viability subsets (<25%, 25–49%, 50–75%, >75%). This retrospective study confirmed that the addition of bevacizumab to chemotherapy yielded an incrementally greater decrease in residual viable cells within these CRLMs in comparison to those treated with chemotherapy alone but no correlation with imaging, or other clinical end-points, was made [114].
Mandard and colleagues were one of the first to establish a five-point histological scoring system for pathological response. This was based on cytological and stromal changes on haematoxylin & eosin-stained sections of primary oesophageal squamous cell carcinomas treated with chemoradiotherapy prior to resection [115]. Tumour response was scored according to five tumour regression grades (TRG1-5) based on the proportion of fibrosis to viable tumour cells. Later, this TRG scoring system was modified for its application in CRLMs receiving different chemotherapy backbones prior to liver resection (Figure 3A–E) [116]. Correlation analyses have demonstrated a significant association of major histological responders with increased survival.
Tumour regression grade (TRG) scoring system as a component of measuring pathological response in treated CRLMs. (A–E) TRG as scored on haematoxylin and eosin sections of CRLMs based on the proportion of fibrosis to viable tumour cells. The five TRGs shown in this cartoon roughly illustrate the different proportions of fibrosis (fibrils) to tumour cells (black areas). (A) TRG1. There is an absence of viable tumour cells and large amounts of fibrosis. (B) TRG2. The presence of viable tumour cells is rare and they are scattered throughout the fibrosis. (C) TRG3. There is the presence of more residual tumour cells but fibrosis predominates. (D) TRG4. Residual cancer cells predominate over fibrosis. (E) TRG5. There are no signs of tumour regression. The percentage of the CRLM surface area occupied by necrosis is also incorporated as a parameter for pathological response (grey areas). 3 main pathological response groups: TRG1-2: major response (MjHR), TRG3: partial response (PHR), TRG4-5: no histological response (NHR).
Similar retrospective studies using the TRG in CRLMs were undertaken to see whether adding bevacizumab to chemotherapy would further increase pathological response rate, without necessarily increasing radiographic response rate, after liver resection. Indeed, several retrospective analyses demonstrated that a significantly increased percentage of patients treated with bevacizumab achieved a major pathological response and a significantly higher percentage area of tumour necrosis compared to chemotherapy-only treated patients [117]. Furthermore, the extent of pathological response correlated significantly with long-term-outcomes such as 3- and 5-year overall survival.
As is the case with most cancer therapeutics, drug resistance is considered to be a major factor that limits the efficacy of anti-angiogenic agents. Two ‘modes’ of resistance to anti-angiogenic therapy are currently recognised: intrinsic resistance, whereby the tumour fails to respond to the therapy from the outset, and acquired resistance, whereby the tumour develops means to evade the therapy after a period of response [21, 29, 118]. It is important to realise that resistance to anti-angiogenic therapy may be attributable to either the tumour cells themselves or due to interactions with their microenvironment. In terms of specific mechanisms mediating resistance to anti-angiogenic therapy, several have been proposed.
Pre-clinical work has demonstrated that although anti-angiogenic agents thwart the growth of newly established tumour vessels, they are less effective against more mature blood vessels, indicating that they may be less dependent on VEGF (Figure 4A) [29]. This may be due to PDGF secretion mediating pericyte recruitment, allowing young vessels to mature and survive [119]. Co-inhibition of VEGF and PDGF has been shown to generate significant anti-angiogenic and anti-tumour effects than with VEGF inhibition alone [120].
Proposed mechanisms of resistance to anti-angiogenic therapy. (A–F) The potential mechanisms that tumours can utilise to evade anti-angiogenic therapy. (A) Vessel heterogeneity. Tumours can contain vessels that are at different stages of maturation making some more sensitive to therapy than others. For example, here the top vessel is immature and is abolished by therapy (grey), whilst the bottom one is mature and remains viable (red). (B) Alternative proangiogenic signalling pathway scan affect the susceptibility of vessels to therapy. Here, tumour cells (blue) have up-regulated an alternative pro-angiogenic growth factor to facilitate persistent blood vessel growth and survival despite VEGF blockade. (C) Stromal cells infiltrating into of the tumour, such as myeloid progenitors (black) or fibroblasts (green), can also mediate resistance by releasing pro-angiogenic growth factors or by physically incorporating into vessels. (D) Tumour cell adaptation to stress. Subpopulations of cancer cells in the tumour (blue) can survive the hypoxic conditions and nutrient shortage resulting from vascular destruction by employing different adaptation mechanisms. (E) Alternative tumour vascularisation mechanisms. Apart from sprouting angiogenesis, tumours may utilise alternative mechanisms to recruit a vascular supply. In intussusceptive microvascular growth, new vessels are generated by the fission of pre-existing vessels. Glomeruloid angiogenesis is where tight nests of vessels, resembling the renal glomerulus, are formed. Vasculogenic mimicry is a process whereby tumour cells can create vascular-like structures themselves (blue) which are perfused as they become continuous with the host vasculature (red). In looping angiogenesis, contractile myofibroblasts (green) pull host vessels (red) out of the surrounding parenchymal tissue (pink region). Vessel co-option is a process whereby invading tumour cells engulf pre-existing vessels (red) in the normal parenchyma (pink region). (F) Selection of aggressive cells. Therapy alters the biology of the tumour cells in that they become more invasive and/or facilitate accelerated growth of metastases.
Alternative pro-angiogenic signalling pathways may allow tumour vascularisation to proceed when VEGF signalling is blocked (Figure 4B) [29]. A large body of preclinical work has identified candidate pathways that may provide such an alternative pro-angiogenic stimulus. These include fibroblast growth factors 1 and 2 (FGF1 and FGF2) [121], hepatocyte growth factor (HGF) [122] and epidermal growth factor (EGF) [123]. Most of the above preclinical work suggests that, by inhibiting both VEGF signalling and the candidate pathway, improvements in the anti-tumour efficacy can be seen. Therefore, targeting multiple pro-angiogenic pathways may prove more beneficial than employing agents that inhibit VEGF signalling alone.
Preclinical data suggest that cells in the tumour stroma, including fibroblasts, neutrophils, macrophages and myeloid progenitors, mediate resistance to VEGF-targeted agents (Figure 4C) [124]. For example, tumour-derived granulocyte-colony stimulating factor (G-CSF) mobilises myeloid cells from bone marrow, and is believed to promote pro-angiogenic Bv8 signalling by myeloid cells, which in tumours may confer resistance to anti-VEGF treatment [125]. Immunohistochemistry studies in human tumours showed expression of Bv8 in tumour-infiltrating neutrophils, which were seen in around 15% of breast carcinomas [126].
It is presumed that the inhibition of tumour vascularisation by anti-angiogenic agents will lead to a reduction in oxygen and nutrients available to the tumour thus causing retardation of tumour growth. However, tumours may develop a number of survival mechanisms enabling them to adapt to such hostile conditions (Figure 4D).
Some studies have suggested that anti-angiogenic therapy leads to metabolic reprogramming of tumour cells, allowing them to adapt to reduced vascular supply. Preclinical studies have demonstrated that treatment with anti-VEGF antibodies can lead to tumour cells relying on anaerobic metabolism and the glycolytic pathway for ATP [127]. Furthermore, the withdrawal of anti-angiogenic therapy has been shown to cause an increase in lipid metabolism, leading to a rebound in tumour growth [127].
Tumours treated with anti-angiogenic agents may also adapt to survive by activation of autophagy. Autophagy can occur in response to treatment related stressors such as hypoxia and occurs when organelles and proteins in the cell are degraded and recycled by lysosomes [128]. Autophagy-mediating molecules such as BNIP3 have been identified in GBM tumour cells after exposure (a) to hypoxic conditions in vitro, (b) to bevacizumab therapy in vivo or (c) to bevacizumab therapy in human tumours [129]. Furthermore, a recent study has reported that when MDA-MB-231 breast cancer cells were treated with an agent that induced autophagy, they exhibited increased invasiveness [130].
It is becoming clear that many solid tumours contain relatively rare subpopulations of cancer stem cells. These are clones of tumour cells that are able to sustain self-renewal and can tolerate hostile environments [131]. Furthermore, it has been proposed that hypoxia induced by anti-angiogenic therapy can (a) select for CSCs, and (b) maintain the niche that supports the survival of CSCs [132]. Conceivably, these persistent clones of CSCs may render the tumour more invasive and metastatic and may also lead to antiangiogenic therapy resistance [133].
Anti-angiogenic therapy has been proposed to induce hypoxic tumour microenvironments, enhancing the aggressiveness of tumour cells (Figure 4F) [134]. This may help explain why the response to anti-angiogenic therapy is often transient as anti-angiogenic agents can cause initial reductions in tumour burden and a prolonged PFS, but with minimal or no improvement in OS [118]. Anti-angiogenic agents have demonstrated an ability to select for more aggressive cancer cells and enhance tumour cell invasion, growth and metastasis [135]. Moreover, it is now well accepted that some GBM patients with tumours treated with bevacizumab show an increase in tumour invasiveness [136].
Despite the dogma that tumours primarily employ VEGF-dependent sprouting angiogenesis, emerging evidence now exists for alternative tumour vascularisation mechanisms, including: intussusceptive microvascular growth (IMG) (sometimes known merely as ‘intussusception’), glomeruloid angiogenesis, vascular mimicry (also sometimes called ‘vasculogenic mimicry’), looping angiogenesis, and vessel co-option (also sometimes called ‘vascular co-option’) (Figure 4E) [21]. These mechanisms may occur by alternative signalling pathways that may not be inhibited by VEGF-targeted therapies.
Intussusception is a mechanism whereby pre-existing vessels split into two daughter vessels without the need for endothelial cell proliferation and sprouting (Figure 4E). It has been observed in embryonic development and within experimental tumours recovering from anti-angiogenic therapy and radiotherapy [137]. The molecular mechanisms that control this process are still not well understood.
Vascular mimicry (VM) is a process observed in clinical and preclinical studies whereby tumour cells differentiate into vascular-like structures themselves [138] (Figure 4E). It has been shown that basic fibroblast growth factor (bFGF) and VEGF, are incapable of inducing VM channels and networks in poorly aggressive melanoma cell lines, suggesting that VM channel formation maybe be independent of these classical pro-angiogenic growth factors [139]. However, further mechanistic detail is lacking.
Vessel co-option is the process whereby, when a tumour invades, existing local vessels become directly incorporated into the tumour (Figure 4E). Histopathological studies have indicated that colorectal and breast cancer liver metastases may utilise vessel co-option [140, 141].
Vessel co-option has been shown to mediate resistance to VEGF inhibitors in mouse models of melanoma metastasis to the brain and in mouse models of glioblastoma multiforme, and has been observed in glioblastoma patients who have progressed on anti-VEGF therapy [142, 143, 144]. Recently, it has been demonstrated that vessel co-option plays a role in mediating resistance to anti-angiogenic therapy in colorectal cancer liver metastases [145].
In tumour samples obtained from primary lung cancer patients, gene expression arrays have been utilised to identify pathways differentially expressed between angiogenic tumours and vessel co-opting tumours [146]. Stromal expression of thrombospondin-1 appeared to be up regulated in angiogenic tumours, whilst in vessel co-option tumours, there was increased expression of genes involved in oxidative phosphorylation in primary [146]. Surprisingly, no differences in classic hypoxia or angiogenesis related genes were found between angiogenic and non-angiogenic tumours.
In a glioma rat model of breast cancer brain and lung metastasis, co-opted blood vessels were seen in early-stage tumours and these vessels were found to overexpress angiopoietin-2, a natural antagonist of angiopoietin-1 [147]. As these tumours grew to become more hypoxic, VEGF was upregulated at the hypoxic tumour periphery and stimulated angiogenesis [147]. These observations suggest that a transition from vessel co-option to angiogenesis, or vice versa, may be dependent on the relative expression of pro-angiogenic growth factors (angiopoeitin-1, VEGF) and anti-angiogenic factors (angiopoeitin-2).
Cell adhesion molecules have been implicated in facilitating the process of vessel co-option. In a preclinical brain metastasis model, Carbonell et al. demonstrated that the β1 integrin subunit in breast cancer and lymphoma cells facilitates (a) tumour cell adhesion to the vascular basement membrane of existing brain vessels, (b) tumour cell invasion and (c) the process of vessel co-option [148]. When the function of the β1 integrin subunit was blocked, adhesion to vessels was attenuated and brain metastasis colonies failed to become established and grow [148].
Furthermore, the L1 cell adhesion molecule (L1CAM) has been shown to be involved in vessel co-option in the brain [149]. The ability of cancer cells to co-opt blood vessels was suppressed when L1CAM expression was depleted using shRNA. Conversely, when L1CAM was overexpressed, tumour cells demonstrated enhanced adherence to the outer surface of vessels and tumour growth alongside them. Although such mechanisms are likely to be more specific for vessel co-option in the brain, similar mechanisms may be at work during vessel co-option at other anatomical sites.
Tumour vascularisation is modulated by the complex interplay of several endogenous factors and processes that can be up-regulated or downregulated, depending on the tumour microenvironment and the treatment pressures that are imposed on it. A multitude of studies have shown that the majority of solid tumours exhibit an overexpression of VEGF, one of the key drivers of sprouting angiogenesis. As a result, various anti-angiogenic therapies targeting VEGF or VEGFR have now been developed and are used conventionally in the clinic. Compellingly, recent pre-clinical and clinical studies using anti-angiogenic agents in combination with immunotherapies (e.g. ICI’s), have demonstrated a synergistic effect in reducing tumour growth. This highlights that there is promise, not only in incorporating anti-angiogenic therapy in the management of most cancers, but also in combining such agents with immunomodulatory agents.
However, as is the case with many cancer treatments, drug resistance can limit the efficacy of these agents. Trials of VEGF-targeted therapies in advanced malignancies have not consistently demonstrated beneficial outcomes in terms of tumour response and survival. Importantly, only a proportion of patients benefit from anti-angiogenic therapy, control of tumour growth is generally transient, there remains significant risk for therapeutic toxicity and we are still challenged by the burden of health costs.
Limited clinical outcomes with anti-angiogenic therapies are felt to be driven by either intrinsic or acquired resistance mechanisms, and several of these have now been proposed. In this chapter, we have reviewed the most commonly used anti-angiogenic agents in the clinic and have highlighted the spectrum of mechanisms that may be involved in therapeutic resistance. However, despite the plethora of pre-clinical and clinical studies that have been undertaken, these mechanisms are yet to be entirely elucidated. Importantly, the clinically relevant mechanisms that mediate such resistance to anti-angiogenic therapy are poorly understood and we still do not have means to select patients who will benefit from these agents. Furthermore, there has been a rapid expansion in the development of multiple next generation anti-vascular agents, but there is still little clarity regarding important biological pathways that may affect their efficacy.
The data supporting the role of candidate biomarkers for response and resistance to anti-angiogenic therapies thus far have been generated from basic research, retrospective studies and limited prospective correlative studies. As such there remains a crucial need for substantial research of clinically relevant predictive biomarkers with the use of large, prospective randomised trials. This could also provide a platform for longitudinal and frequent biospecimen collection in order to further interrogate the mechanisms involved in tumour vascularisation and therapeutic resistance over time.
Golf participation has exploded in the past 2 decades. In the early part of the century, it was calculated that Golf is played by over 55 million people throughout the world. In 2018 there were 38,864 golf courses in 290 of the world’s 449 countries [1]. Golf has a particular traditional home in Great Britain and Ireland with 494 courses populating the island of Ireland. The majority of golfers reside in America, where over 23.4 million golfers were recorded in the USA in 2018. This had risen to 34.2 million by January 2021, with 9 million participating in golf at ranges and using indoor simulators. There are approximately one million individuals playing golf twice a week in England and have done so for the past five years [1, 6].
The Golf Industry is an $84 billion economic engine that drives nearly 2 million jobs in the USA producing a total economic output in California alone of $15.1bn in 2019.
Golf is both a recreational pastime and a competitive sporting pursuit. Golf started to thrive as a spectator sport in the 1920’s and boomed in earnest in the 1960’s with the arrival of live golf on TV. Its charm and allure might be the lack of age and gender barriers. Fundamentally, it is a game of skill and guile requiring some athletic ability.
The rise in popularity of golf is multifactorial. Golf as a sport has a dedicated viewing population unlike many sports and many non-golfers happily enjoy the trials and travails of professional golfers which appear on TV channels on a weekly basis. In many ways a 4 day professional sporting event is like a drama or soap opera with villains and heroes in equal measure performing on perfectly manicured fairways. Golf is peculiar in spawning a dedicated TV channel, The Golf Channel, watched by millions of viewers on a weekly basis. The recent pandemic delayed Masters played in Augusta, Georgia, USA in the Autumn of 2020 which had a viewership of over 15 million. The exercise associated with golf is of great health benefit [2] providing the perfect physiological work out to sustain health and longevity [3].
Golf too may be considered the perfect exercise for improving health and longevity. Recent recommendations have suggested that the perfect exercise would involve aerobic activity intermingled with resistance activity and anaerobic activity [3]. It is reported that this exercise prescription positively affects all cause and specific cause mortality in American adults. It appears that carrying or pushing golf clubs around an 18-hole course provides an almost perfect exercise prescription [2]. The association of golf participation and improved physical health and mental well-being and the contribution to increased life expectancy has prompted a number of experts to recommend policy makers encourage golf as a beneficial pastime [4].
The worldwide reach of golf and its ability to transcend barriers of age, race and gender and its general appeal has seen the reintroduction of golf to the 2016 Olympic Games.
In parallel with increased participation, injury rates among golfers have also increased. Research has suggested that almost 7 in 10 amateurs and 9 in 10 professionals will suffer a golf-related injury at least once in a lifetime of golf participation [5].
Increased participation, just short of a million people play golf twice a month in England for the past 5 years [6] has resulted in increased injury rates more frequently in elite golfers. [7] Annual Injury incidences of between 2 and 4% are reported among golfers. Put more simply a golfer can expect to sustain an injury for every 100 hours of golf participation with an overall incidence rate of injury of 15.8 injuries per 100 golfers and with a range of 0.36 to 0.60 injuries per 1,000 hours per person. 46.2% of injuries are reportedly sustained during the golf swing, and injury is most likely to occur at the point of ball impact (23.7%) [8]. Golf carries a significant injury rate with levels exceeding other non- contact sports. Perhaps golf is in fact a contact sport, with contact being made with turf and ball through a metal implement, frequently in a ferocious and repetitive manner.
There is a significant variation in the incidence and type of injury suffered by amateur or recreational golfers in comparison to their professional counterparts. In a review of over a thousand amateur golfers, the survey confirmed that more than 60% of amateur golfers sustained one or more golf related injuries over the course of their playing career. The injury rate was higher in the over 50 year old amateur with a 65% injury rate in comparison to the under 50 group, which had an injury incidence of 58% [9]. There was a slightly higher incidence of injury at 67.5% among single figure handicappers rather than their double-digit colleagues. A typical injury resulted in the amateur golfer missing five weeks of playing time [5, 6, 7].
More than 80% of professional golfers report a golf-related injury at some point in their career. It is estimated that between 10% and 33% of professional golfers are actually playing while they are carrying an injury during their professional career. Most professional golfers will experience 2 significant golf-related injuries during their career. Over a career, 9 weeks for professional men and 3 weeks for professional women are lost due to injury. On returning from injury more than 50% of professional golfers are compromised by their injury and often play through pain [10, 11, 12].
Recent research has indicated that general exercise has an injury rate of 5.3 per 1,000 persons, golf having a similar injury rate to rugby at 1.5 per 1000 persons [13]. The injury rate is significant but the over-arching benefits of playing golf outweigh the risks, particularly to physical and mental well-being [2, 3].
All golfers are prone to injury. Amateur golfers have a lifetime incidence of injury ranging from 25.2% to 67.7%. Professionals golfers have higher rates between 31% to 88.5% over a lifetime.
Many studies on golf injuries have found that low back injuries account for 15.2% to 34% of all golf injuries, followed by injuries to the elbow (7% to 27%) and shoulder (4% to 19%). The wrist accounts for 10% of all golf injuries. In professional golf, wrist injury incidence has been reported to be up to 54% (
The change in the injury profile is associated with increased playing hours as well as the nature of golf. Newer golf clubs with composite heads and lighter shafts have allowed the golfer to swing faster in the constant and increasing race by club manufacturers to achieve greater distance.
The majority of golf injuries are referred to as “over-use injuries” caused by the repeated action of swinging the golf club and hitting the golf ball and turf. This activity not only takes place on the golf course where the average long shot golf rate is 40 to 50 swings per round but also on the practice tee and driving range where 100’s of balls are hit. Lighter clubs and the availability of golfing practice facilities have also impacted the increased injury rate. Specific risk factors for overuse golf injuries are age, ability, and swing mechanics [15].
Overuse injuries affecting the musculoskeletal system are caused by repetitive trauma which result in micro trauma to soft tissue structures such as tendons, muscles ligaments as well as bones. The factors pertaining to these overuse injuries can be divided simply into: 1) Intrinsic causes; 2) Extrinsic causes.
Swing mechanic and alteration in technique on the quest for greater distance off the tee are probably the greatest causes of overuse injuries in the modern golfing population.
The golf swing is a means of transferring energy to a stationary ball. The energy is transferred to the ball which then travels down the fairway.
The modern golf swing can be broken up into a number of components (Figure 1):
Set-up
Back swing
Transition
Down swing
Impact
Follow-through
The phases of a golf swing.
The function of the golf swing is to apply the face of the golf club in a consistent, stable and square fashion allowing force to be impacted onto the golf ball from the club face producing linear momentum which is transmitted to the ball. The force applied to the ball is a function of the mass of the object (golf club) and its velocity (mass × velocity = momentum). The rules of golf remove the first variable [the mass of the club), the second element has amused and exercised golf teachers and technologists for centuries.
At first look the conundrum of a golf swing appears simple. However, it involves a number of complex laws of physics:
Newtons 3rd Laws of Motion
Potential and Kinetic Energy Transfer
Circular motion and its constituent parts
In the first instance energy is transmitted from the golf club to the golf ball based on Newton’s 3rd Law of Motion i.e. The Law of Action and Reaction.
One object exerts a force on a second object, the second object exerts an equal opposite force on the first object. As club hits ball it applies force causing it to go in motion. In return, the ball also applies a reciprocal and equal force back to the club. This force slows your club down. The interplay of these actions and reactions result in a golf ball flying towards a target. Not all the energy is transmitted to the ball, with some being diverted up the club to the wrist. This is further increased by imperfect or missed shots.
During a golf swing energy is transferred between both potential and kinetic. The back swing creates kinetic energy which is converted into stored or potential energy at the top of the swing and then converted back to kinetic energy on the down swing. This happens because of the law of conservation of energy.
Potential Energy (PE) is stored energy. It is energy an object possesses due to its position or the arrangements of its parts. This potential or stored energy is created at the top of the golf swing.
Hence the higher the hands and the club head from the ball the greater the stored energy in the swing.
Kinetic Energy (KE) is energy that occurs when an object is in motion.
This is the energy created by the golf club descending towards the golf ball.
The Law of Conservation of Energy states that: Energy is neither created nor destroyed, it is conserved. Hence the back swing creates kinetic energy at the top of the swing. This is stored as Potential energy during the transition phase and then transferred back to kinetic energy on the down swing before it is transmitted to the golf ball at impact.
Unlike other ball hitting sports such as cricket, hurling, tennis and baseball the golf swing is a circular motion attacking a stationary object, the golf ball.
The circular motion is subject to other physic parameters:
Double pendulum Effect
Centipedal forces
Torque
A physical pendulum is a solid object that swings back and forth on a pivot under the influence of gravity. The golfer has 2 anchors, the shoulder and the wrists. In a golf swing, the connection between arms and club creates a double pendulum effect. The arms make up one pendulum that pivots around the shoulders, while the club makes a second pendulum that pivots around the wrists, which acts as the pivot. The two pendulums can swing independently but work together to make the swing feel effortless.
Centripetal Force is a force that makes an object move in a curved motion, like a rollercoaster hugging the curve around a loop. The golf club swinging in an arc from the shoulder to the ball. The hands hold the club and prevent it flying off in a straight line, in a centrifugal fashion. In essence the golfer pulls the wrists and club handle inward while swinging the golf club and golf head outward.
The faster the club curves and the bigger the arc in a golf swing (radius) the greater the force of the club on the ball, and the farther the golfer should be able to hit the ball.
The mass and velocity are also a function of gravity.
In physics Torque is a measure of the force that can cause an object to rotate about an axis. It is a rotating force in a circular motion as opposed to a simple force which causes an object to accelerate linearly. Torque is the force that causes an object to acquire angular acceleration in a golf swing.
Torque is the rotating force in circular motion as you swing back, coiling your body, and then start the downswing. This creates the stored or potential energy at the top of the swing. If you hold the club and prevent it releasing on the down swing you increase this stored energy. The hands and wrists are resisting the angular acceleration of the golf club. Increased torque and stored energy are ultimately released by the club face at the bottom of the swing.
These elements of classical physics have fascinated golfers who seek greater distance in their golf shots. The mass dynamics and weight of golf clubs and their structure are subject to the rules of golf (1) and can be considered a constant. Velocity is the variable element.
Golfers have pondered on this singular element for centuries. Swinging faster or manipulating the club in the down swing through releasing the club later will add greater speed. Similarly firing the right side of the body or manipulating the club face through the hands remain the other options available to the golfer seeking greater distance. Each augmentation compromises the leading wrist and are associated with injury.
Modern biomechanics techniques have allowed a clear understanding of the physical requirements of the body for the execution of a golf swing. Simply put, a golf club made up of a stick or shaft attached to a heavier head hits a ball towards a target by swinging the stick.
The motion involves a complex manipulation of shaft and club by the golfer to promote maximum force on the ball in an effort to propel the ball towards a target. Once described by Winston Churchill as” a game whose aim is to hit a very small ball into an even smaller hole with weapons singularly ill-designed for the purpose”.
The golf club exerts a force on the golf ball by creating a greater force on the down swing which is transferred to the ball. This force is a function on the mass of the club and the speed it is travelling at. This in turn is a function of the distance travelled to the ball and gravity. Extra speed can be generated by the double pendulum affect. Holding the wrist angle for a long as possible in the down swing increases stored energy by a concept referred to as lag. As the stored energy is released in the down swing at 30 degrees the club is released towards the ball greater speed is created. This results in a greater force being applied to the ball.
Newton’s second law of motion, the acceleration of an object is dependent upon both force and mass. Thus, if the colliding objects have unequal mass, they will have unequal accelerations as a result of the contact force that results during the collision.
Newton’s laws of motion are naturally applied to collisions between the golf club and the golf ball. In this collision both ball and club experience forces that are equal in magnitude and opposite in direction.
The force experienced by the club head is equal to the force experienced by the golf ball.
The forces upon the ball and club head are equal, but accelerations are unequal due to the size of the two objects at the moment of contact or collision. In simple terms club head and ball experience equal forces, yet the ball experiences a greater acceleration due to its smaller mass.
Golfers are well aware of this and refer to it as the “Smash Factor”. This relates to the amount of energy transferred from the club head to the golf ball. The more efficiently energy is transferred the greater the acceleration. Smash Factor is ball speed divided by club speed.
The higher the smash factor the better the energy transfer. A golf swing of 100mph and a smash factor of 1.5 would create a ball speed of 150 mph. This can be affected by a number of other elements such as club lift and grip size, but ultimately the greater the club head speed the greater the Smash Factor and the further the ball travels. Hence for the same 100 mph club, a ball speed of 10mph speed difference will affect ball distance. A 10 mph in ball speed equates to a 20-yard increase in distance hitting a driver.
The upshot of Newton’s laws of motion and the golf swing are simple. The greater the force applied to the smaller golf ball by the bigger golf club, the greater the acceleration, and the further a ball will travel. The acceleration of the club is produced by two pendulums working in concert i.e. the shoulder element and the wrist element.
The leading wrist is placed on the upper golf grip and the trailing wrist on the lower element. Both hands are joined together by either interlocking or overlapping the index finger of the leading and small fifth finger of the trailing hand.
The leading wrist is placed in different anatomical positions to achieve a consistent contact on the golf ball. Each phase of the golf swing puts specific stresses and strains on the leading wrist and hand, which can result in different types of injuries [16, 17, 18].
There are 3 basic wrist motions during the golf swing. They are subtle and subject to significant variation [19] of motions from player to player (Figure 2).
Ulnar/Radial Deviation
Flexion/Extension
Supination/Pronation
Directions of leading wrist motion during a golf swing.
At address the leading wrist is positioned in an ulnar deviated flexed position. It is pronated in strong grips (showing 3 or more knuckles), supinated in weak grips (showing one or less knuckles), (Figure 3) Classical teaching advises a neutral grip showing 1.5 or 2 knuckles.
Classic left-hand grip showing less than one and a half knuckles (left) and a strong left-hand grip showing 3 or more knuckles (right).
In the back swing the leading wrist travels into a radial deviated, flexed and pronated position.
In the down swing the leading wrist travels into an ulnar deviated, supinated and extended position.
At address, the leading wrist is usually held in ulnar deviation of the order of 17%.
During the backswing, the left wrist transitions to a radial deviated position and then travels back to the ball transitioning again from radial to a predominant ulnar deviated position at impact (Figure 4).
Leading wrist ulnar deviation at address and impact (right) and radial deviation at the top of the back swing (left).
Modern golf coaches often teach their pupils to hold the wrist in a radial deviated position for as long as possible on the down swing. This is referred to as a cocked position (Figure 5). When held in this position stored energy is increased. This cocked or radial deviated wrist position is created by maintaining an angle between the shaft and the left forearm in the downswing. The longer the wrists can maintain this angle, the greater the lag and resulting stored energy. This referred to “lag” as the club head is lagging behind the shaft caused by the wrist position, which is called wrist torque by golf teachers (Figure 6).
The angle between the shoulder, wrist and club head is maintained close to a right angle in the down swing to 30 degrees below the horizontal line through the shoulder joint, at which point the hands are released.
The leading wrist in a flexed and radial deviated position maintains the angle between club shaft and arm to the bottom of the down swing, resulting in the head of the club “lagging” behind the hands storing energy.
This manoeuvre is based on research which has shown that greater club head speed is achieved if an active wrist torque is applied to the club during the latter stages of the downswing [19]. To produce a club head speed of 100 miles per hour, the optimal timing of the activation of wrist torque occurs when the arm segment is at approximately 30° below the horizontal line through the shoulder joint [20].
Therefore, significant timing of the shot is required to manoeuvre in releasing club head back square to the ball. This requires a careful return of the leading wrist from radial to ulnar deviation prior to impact.
Flexion/Extension motion of the leading wrist is a significantly individual watermark of every swing. Elite golfers also vary dramatically from player to player.
Classical golf swing teaching suggests that the wrist is placed in a neutral or slightly extended position at address (Figure 7).
Wrist positions at the top of the Back swing.
At the top of the back swing it stays in a neutral flexion/extension pattern. This referred to as” square at the top”.
In classical teaching the leading wrist descends in the down swing to the ball in a flexed position in which it impacts the ball. Not everyone follows this teaching.
Consistent players such as Jack Nicklaus was “square at the top” for most of his career. Ben Hogan placed his leading wrist in an extended or “cupped “position (Figure 7) at the top of his swing before transitioning to a flexed position at impact. This has been replicated by current touring pro Mathew Perry and is seen as a way of avoiding placing hook spin on the ball. Dustin Johnson is in a more extreme flexed or “bowed” position (Figure 7) at the top of the swing and maintains that position on the down swing using the large trunk muscles to return the club face square to the ball at impact. This move has been followed by many golfers looking for extra distance.
Classical golf teaching used the wrist and hands to generate club head speed at impact. In the back swing the leading wrist pronated turning the back of the leading wrist and forearm to face towards the sky at the top of the backswing. At the top of the back swing the 1st row of carpal bones are held in a pronated position at the top of the swing. During this downswing phase the leading wrist is adjusting back towards a neutral position, with the 1st carpal row of bones traversing from a bowed, pronated position towards supination. The leading wrist rotates towards supination and continues in this motion through impact where the palm of the leading wrist motions to face towards the sky in the follow through phase.
At impact the club head makes contact with the ball and the leading wrist accelerates allowing the leading wrist to unhinge into further supination in a whip-like motion, the right hand frequently rolling over the left hand and wrist thus creating extra club head speed at impact. This move is referred to as “rolling the wrists” at impact.
These pronation and supination motions are not commonly seen in modern golfers. These “handsy” moves are considered to be inconsistent. They are regularly seen in good wind players who need to manipulate the face of the golf club in relation to changing wind directions. The majority of modern elite players and coaches tend to manipulate the radial, ulnar and flexion and extension motions.
There are many versions of the wrist flexion/extension pattern in modern golf swings, ultimately returning the leading wrist to a flexed position at impact. Each technique creates greater swing speeds and allows individual players square the club face at impact. All place varying degrees of stress on the leading wrist. These can be summarised into 3 patterns employed by leading professional golfers [21]. All have one thing in common; a flexed wrist at square club face at impact, the body moving at speed providing the acceleration to square the club face.
John Rahm has a weaker grip or neutral grip at address showing 1 and ½ knuckles in his leading hand. He flexes his wrist at the top of the swing and maintains that flexed position on the down swing and rotates his body to square up the club face at impact.
Dustin Johnson has a stronger grip at address showing 3 knuckles with his wrist held in flexion. At the top of the swing he further flexes his leading wrist. On the way down he turns his body aggressively to square up the club face at impact.
Matt Wolff has a weak to neutral grip at address, extends his wrist at the top of the swing and with great skill and co-ordination rapidly converts his lead wrist to a flexed position on the down swing before he releases the club face into a square position at impact.
Bryson De Chambeau who is considered the longest hitter on the PGA tour has very specific statistics [22].
13 degree of flexion at address, 11 degrees of extension at the top of the swing and 20 degrees of flexion at impact.
20 degrees of ulnar deviation at address, 14 degrees of radial deviation at the top of the swing and 15 degrees of ulnar deviation at impact.
At impact the golf ball, club and ground collide resulting in a counter force that is transmitted up the shaft of the club to the wrist and hands which are on the golf club grip. The majority of golf injuries occur on the downswing and at impact [23].
The golf swing requires complex movement of many components of the body. The co-ordination of muscle sequencing is particularly important and is noted to be the most efficient in the elite golfer. The manipulation of the leading wrist has been a source of a crusade for many golfers as they seek the perfect golf swing. The leading wrist has the ability of storing the kinetic energy which is released at impact, thus resulting in greater power delivery to the ball and greater accuracy [20, 21, 22, 23, 24], but it comes at a cost.
With a late hit, skilful golfers apply torque to the leading wrist in an effort to store more energy prior to impact with the golf ball. This stored energy by holding the leading wrist in a forced flexed and ulnar deviated position throughout the first part of the down swing could be considered a compensatory methodology and an effort to compensate for faulty swing mechanics. This may be a purist view, however, the manipulation of the wrist to improve stored energy prior to impact places further extreme pressure onto the leading wrist and particularly the lateral aspect of the wrist. The rapid transitions from a radial deviated, flexed pronated position through a relatively neutral position at impact and onwards to a supinated and ulnar deviated position is the cause of trauma to this anatomical location.
Many skilled golfers manipulate the club face with the hand and wrists as the face of the club impacts with the golf ball. These subtle variations impart different spins onto the golf ball affecting its flight and trajectory as it seeks it target on the green. A “hold off “shot imparts a left to right spin on the ball in a right-handed golfer. This is achieved by holding the left wrist firm (holding it off) at impact, preventing the natural supination of the left wrist as it transitions to impact and the follow through phase of the swing. Resisting this natural movement places great stresses on the medial structures of the left wrist which are activated to resist this natural anatomical motion.
Golfers who have quiet hands and wrists during the golf swing rarely sustain wrist injuries. Wrist manipulation may be a trade off between distance and injury.
The anatomical site and specific location also varies between professional and elite golfers and their amateur counterparts. There are also gender differences. For professional male golfers, the most frequently injured site is the low back at 25% of injuries, with the left wrist accounting for 16% and the left shoulder accounting for 11%. Among female professionals, the most commonly injured site is the left wrist (in 31% of cases) and the low back in 22% of cases. In general terms, therefore, the leading wrist is the most commonly affected structure among professional and elite golfers with a combined incidence of 37%, the low back at 24%, the shoulder at 10%, the elbow at 7%, the knee at 7%, the ankle and foot at 5% and the neck at 3% [25].
In amateur golfers, the low back is the most commonly injured site with an incidence in males of 36%, the elbow causing injuries in 33% of cases, the wrist or hand 21% and the shoulder 11% with the knee accounting for only 9% of injuries. In female amateur golfers, the elbow is the most commonly injured anatomical site at 36% of all female injuries, the low back accounts for 27% of injuries, the shoulder 16% and the wrist and hand 15%, the knee accounting for only 11% of injuries. When combining the data, it suggests that the most commonly injured site for amateur golfers is the lumbar spine accounting for 35% of all injuries, whereas the wrist or hand is the most common location for elite or professional golf injuries.
There is also a difference between amateur and professional golf injury aetiology. In amateur golfers, excessive play or practice, direct trauma from hitting the ground or an object during a golf swing are common causes. The most common cause, however, in amateur golfers, and particularly high handicap golfers, is injuries that result from poor swing mechanics [24, 25, 26]. Professional and elite golfers are particularly prone to overuse injuries due to repeated and repetitive swinging of a golf club. This can be further complicated by alteration in swing techniques. The changes and improvement in golf equipment, with lighter shafts and composite heads on drivers and fairway metals, have also contributed to increased swing speeds. This, in association with alteration in swing techniques, can make the elite golfer more prone to injuries. In simple terms, the sheer number of swings that an elite golfer takes every week is a multiple of that of an amateur golfer. It would not be uncommon for a professional golfer to hit two or three hundred golf balls on a daily basis. This is a combination of practice, warm up and almost daily playing schedule.
The upper limb is the most commonly injured anatomical site in elite golfers. An injury site can be devastating for the competitive amateur golfer, or the professional golfer, as it can result in time away from the game, as damage to shoulder, elbow or wrist makes coordinated swinging of a golf club difficult and occasionally impossible The majority of golf injuries are overuse injuries of the wrist flexor or extensor tendons. However, the reminder of the shoulder joint accounts for between 4% and 19% of all golf injuries with similar rates among the professional and amateur players. Elbow injuries account for 7% to 27% of all golf injuries. Amateur golfers frequently injure this structure with reports as high as 33% in comparison to professionals whose injury rate for the elbow is 7% injuries [25, 26, 27, 28].
The shoulder itself is made up of three bones, namely the humerus, the scapula and the clavicle. The rotator cuff is made up of four different muscles: the supraspinatus, infraspinatus, subscapularis and biceps muscles. Each muscle is intimately involved in the golf swing and is liable to injury. Outside of the rotator cuff, the strong deltoid muscle stabilises the shoulder and is an essential component in creating normal shoulder abduction during the golf swing. The pectoral muscles are also particularly involved in the golf swing in both the takeaway and downswing motion. The latissimus dorsi muscle is also a critical muscle for the initiation of the downswing. Each structure can be injured directly or in combination during the golf swing and this joint accounts for 10% of professional injuries and 12% of amateur golf-related injuries.
Elbow injuries are particularly common among amateur golfers where they account for a third of all injuries but less than 10% in the professional ranks. The elbow joint is a hinge joint formed between the humerus, the radius and the ulna. It can only be flexed and extended. During the golf swing it also pronates and supinates. Extensor and flexor tendons are inserted to the elbow. The extensor apparatus is located on the outside or lateral aspect of the elbow and the extensor tendon can frequently be injured. This injury is known as a tennis elbow but is in fact more common in the golfing population than its counterpart, the golfer’s elbow. The flexor tendon is inserted into the inside or medial aspect of the elbow and inflammation of this area is referred to as a medial epicondylitis or Golfer’s elbow. Unusually, a tennis elbow is more common than a golfer’s elbow in the golfing population.
Other tendons can also be injured around the elbow and the triceps tendon can be injured directly due to trauma from poor impact with the ground or from overuse. In cases of chronic medial epicondylitis, the ulnar nerve can be compromised resulting in pins and needles into the 4th and 5th digit of the hand. In cases of poor playing technique, the supinator muscle can become inflamed. This lies just below the elbow joint. The radial nerve runs through this structure and if the muscle becomes hypertrophied or injured it can result in local entrapment of the radial nerve. This often results in sensory alteration in the 1st webspace of the hand and weakness in wrist extension. When the radial nerve and its branch (the posterior interosseous nerve) become involved the condition can mimic tennis elbow. In these instances, surgical release of the nerve is often required. This condition is often referred to as “resistant tennis elbow” as the symptoms mimic the classical tennis elbow which is inflammation of the extensor tendon.
The bony wrist joint (Figure 8) is made up of the articulation of the distal radius and ulna bones with the carpal bones. The carpal bones are arranged in two rows, the 1st or proximal row and the second or distal row.
Bony anatomy of the wrist, showing the 2 carpal rows.
The proximal row comprises of the scaphoid, lunate triquetrum and trapezoid bones.
The second carpal row consists of the pisiform, trapezium capitate and hamate bones.
The first row of bones is a more mobile articulation in comparison to the second row which acts as one. The scaphoid communicates through both rows.
There are 3 axes of motion at the wrist joint; Flexion/Extension; Ulnar/Radial deviation; Pronation/Supination (see Figure 2). According to the “link” concept of wrist biomechanics a chain of communication exists between the radius, lunate and capitate bones, with the head of the capitate bone acting as the centre of rotation. The proximal row in the form of the lunate can act as an intercalated unit as it has no direct tendon attachment. The distal row of carpal bones act as a complete unit. The scaphoid bridges both rows. When the wrist is in ulnar deviation the scaphoid is pushed into extension, and radial deviation pushes it into flexion.
The bones are held together in a lattice of extrinsic and intrinsic wrist ligaments.
The extensor tendons at the level of the wrist are divided into six extensor compartments (Figure 9) that are designated by Roman numerals from lateral to medial:
Extensor pollicis brevis, abductor pollicis longus.
Extensor carpi radialis longus, extensor carpi radialis brevis.
Extensor pollicis longus.
Extensor digitorum, extensor indicis
Extensor digiti minimi
Extensor Carpi Ulnaris
The 6 extensor compartment of the wrist joint.
The 6th compartment is the most compromised during the golf swing. The first extensor compartment is most affected in skiing, fishing and racket sports with a common occurrence of De Quervain’s Tenosynovitis.
The flexor tendons of the wrist are divided into two main structures: 1) the flexor digitorum profundus (FDP) and the flexor digitorum superficialis (FDS) tendons.
FDP tendons help bend the index, middle, ring, and small fingers at the fingertip joint. FDS tendons help flexes the index, middle, ring, and small fingers at the middle finger joint. 9 of these flexor tendons travel into the wrist through the carpal tunnel. Each of the flexor tendons perform an important function in gripping the golf club in a consistent fashion to allow a natural swing of the club.
Wrist injuries are common [25, 26, 27] and particularly prevalent in elite golfers [28, 64].
Golfers who sustain injuries to their wrist regularly fail to rest after practice sessions and do not allow adequate time for soft tissue recovery and adaptation after a heavy practice session. It is not uncommon for an elite golfer to hit balls every day. Enthusiastic amateurs can be seen hitting “buckets” of balls in an effort to groove a repetitive swing. A standard bucket of balls in a driving range contains 50 to 60 balls when a round of golf rarely exceeds 40 full shots. This simple training error often under pins wrist injuries.
These wrist injuries are often extended and exacerbated by “playing through the pain” which must always be discouraged. This behaviour is most prevalent in men who outweigh injuries in female golfers by 2 to 1 [12, 27]. This area is also more frequently affected in the professional ranks as the golf swing is a means of income, much in the same way as other manual occupations such as painters and decorators [29] suffer from overuse injuries to the upper limb (11). In a 30-person cohort 43% of hairdressers reported overuse injury symptoms to hands and wrists form their work activity [30].
In golf it is almost impossible to consistently hit a golf ball with an injury to the wrist or hand which is the second most common site for golf injuries and a result of impacting the ball incorrectly due to poor swing mechanics [8, 9, 10].
Patterns of injury differ based on level of play and time spent playing or practicing golf. Among golf professionals, the hand/wrist is the most commonly injured upper extremity structure. The elbow is more commonly injured than the wrist in amateur golfers [31].
The medial aspect of the leading wrist in a golfer is particularly prone to injury due to the forces and stress applied to this location during the modern golf swing. The most common structure to be injured is the Extensor Carpi Ulnaris tendon and its tendon sheath and sub-sheath.
Extensor Carpi Ulnaris (ECU) tendinitis & tendinosis.
ECU tendon Subluxation.
Triangular Fibro-cartilage injury.
Hook of Hamate injury.
Guyon’s Canal Syndrome.
Carpal Tunnel Syndrome.
Dupuytren’s contracture.
Flexor Carpi Ulnaris tendon.
Proximal entrapment of the ulnar nerve.
Proximal entrapment of the median nerve.
The extensor carpi ulnaris tendon (Figure 10) originates from the lateral epicondyle of the humerus and the dorsal surface of the ulna, passes through the groove dorsally at the ulnar head within a fibro-osseous tunnel of extensor retinaculum in the 6th compartment (Figure 11). It has its own tendon sub-sheath for its stabilisation there and inserts on the base of the 5th metacarpal medially angled to its position in the groove of ulnar head. It acts to adduct (or ulnar deviate) and extend the wrist joint.
ECU muscle and tendon origin and insertion.
The double pendulum effect of the golf swing. The first pendulum is the arm acting around the pivot of the shoulder joint and torso. The second pendulum is the golf club acting around the wrist joint.
The Extensor Carpi Ulnaris tendon (ECU) is particularly vulnerable to injury in the golfing population because of the complex nature of the golf swing. During the golf swing the leading wrist goes through a complex motion involving ulnar and radial deviation i.e. extension and flexion and pronation and supination. These manoeuvres send forces through the wrist joint culminating with the impact of club on ball (Figure 1). The anatomical location of the ECU tendon in the 6th extensor compartment (Figure 12) held in a tendon sheath makes it liable to injury due to the excessive tensile loading and subsequent breakdown of the loaded tendon [32, 33]. ECU Tendinopathies, and tendon injuries account for significant time away from sport and lost time in practice and competition [9, 10, 11, 34, 35].
ECU tendon, tendon sheath and sub sheath in the 6th extensor compartment of the wrist.
ECU tendon injuries come in many varieties and severities but can be simply divided in to 3 major categories of injury.
There are 3 types of injury that occur to the ECU tendon in the golfing population. Each is associated with overuse caused by excessive play and practice accompanied by poor swing technique [36].
ECU tenosynovitis or tendinitis
ECU Tendinosis
ECU Subluxation, (of which there are 3 varieties)
Injury to the ECU tendon in the leading wrist of a golfer is common due to the forceful return of the ball as the leading wrist travels from a radial deviated position at the top of the backswing to an ulnar deviated position at impact with the second carpal row transitioning into a supinate position. Injury and subluxation of the ECU tendon are exacerbated by ulnar deviation and supination [37], which is the classical position of the leading wrist at impact during a golf swing. Hence the frequency of this injury in golfers.
Tendinopathy or tendinosis refers to the breakdown of collagen in a tendon. Tendinopathy is often the long consequence of long-term inflammation caused by tendinitis. This causes burning pain in addition to reduced flexibility and range of motion. The collagen loss being a function of tenocyte malfunction secondary to chronic and reoccurring inflammation and injury. ECU tendinopathy occurs over time due to repetitive insults. The Tendinopathy is a pathological adaptive response resulting in degeneration due to the tendon’s collagen loss in response to chronic overuse. Loss of function as well as pain on activity are cardinal complaints.
Tendinitis is the inflammation of the tendon and results from micro-tears that happen when the musculotendinous unit is acutely overloaded with a tensile force that is too heavy and/or too sudden. ECU tenosynovitis can occur when the extensor retinaculum tears. It can result in mechanical friction between the ECU tendon and the ulnar groove [36, 37]. It usually starts as tendon irritation manifesting as pain and can progress to friction between the tendon and the ulnar grove. In the golf swing the ECU is irritated by the motion to and from ulnar and radial deviation with the wrist in a supinated position. Symptoms include wrist pain and loss of grip strength.
If the tendon sheath and sub sheath rupture or stretch, the ECU tendon can then migrate to the medial or ulnar side of the wrist. This is caused by a rupture on the ulnar or radial side of the tendon sub-sheath, or if the sub-sheath is stretched due to stripping of the periosteum (Figure 13). Each type results in subluxation and relocation producing a snapping sensation at the wrist during the golf swing. There are 3 types of ECU tendon sub-sheath injury.
Axial MR and graphic image of split ECU tendon tear with partial rupture of sub-sheath with medial subluxation of the tendon.
Type 1 (Figure 14) rupture occurs on the lateral side of the sub sheath. The tendon subluxes through the radial side of the sheath and returns to rest on the ulnar grove on top of the remaining sheath.
The 3 types of ECU sub sheath injury resulting in tendon subluxation.
Type 2 (Figure 14) rupture occurs on the medial side resulting in a tendon subluxing in an ulnar direction before returning to the ulnar groove without resting on top of the sheath.
Type3 (Figure 14) subluxation occurs if the ECU sheath does not rupture but the force causes ulnar periosteum stripping: The ECU sheath pulls the periosteum off the ulna on the ulnar side and forms a false pouch into which the tendon dislocates before relocating back onto the ulnar groove (Figure 15).
Coronal MR image showing ECU tear and tenosynovitis.
Injury to the ECU tendon is a challenging diagnosis and great care is needed in confirming the pathology. This is in part due to the symptomatology and presentation of injury with players reporting pain on the ulnar aspect of the wrist and hand accompanied by a loss of dexterity and occasionally sensory alteration affecting the fingers. Other conditions to consider in the differential diagnosis include:
Triangular Fibro-cartilage injury
Hook of Hamate injury
Guyon’s Canal Syndrome
Carpal Tunnel Syndrome
The diagnosis of ECU tendon pathology in a golfer requires a high index of suspicion as many patients battle on through the pain thereby worsening the pathology. Excluding the other common injuries can be achieved by a combination of careful history, clinical examination and the use of special tests such as Electrodiagnostic Medicine and radiology.
Dynamic ultrasound is very useful in diagnosing and differentiating the type of tendon pathology. It is the ideal tool to confirm a subduing tendon as it observes the subluxation during ulnar and radial deviation and in flexion and extension motion [38]. The direction of subluxation and the type of sub-sheath injury being confirmed by dynamic imaging. In cases of significant subluxation in professional golfers, surgery is often warranted to repair ECU and its supporting structures.
Treatment for these varieties of ECU tendon injury should initially follow the normal treatment for tendinitis such as rest NSAID medication and splinting. Deep Oscillation Therapy has also been shown to be a promising treatment in swelling and symptom reduction] [39]. Ultrasound guided injections may also be required in resistant cases. In cases of tendinosis a similar approach is made with the addition of Platelet-Rich Plasma (PRP) injections in resistant cases. This is a minimally invasive surgical alternative that uses components from a patient’s own blood to regrow tissue and relieve pain and promotes tendon regeneration by reducing inflammation and promoting the expression of anabolic genes and proteins [40].
Rest and splinting are the cornerstone for treating a subluxing ECU tendon, with regular revaluations with Ultrasound. If the subluxing ECU tendon fails to respond to conservative therapy, surgical reconstruction of the roof of the 6th dorsal extensor compartment using a portion of the flexor carpi ulnaris is performed [41]. Type I subluxation frequently requires surgery.
Return to play will require appropriate alteration in golf grip and swing biomechanics. Therefore, the return to play protocol for this injury in the golfing population should always include an assessment from a registered golf professional. In some instances, customised splinting of the wrist will prevent reoccurrence and allow a golfer return to a bespoke practice regimen. The message of qualitative rather than quantitative practice should be reinforced to avoid a training error reoccurrence, with 30–40 balls a good rule of thumb per practice session.
Wrist injuries in golf are common and significantly interfere with a player’s ability to play and enjoy this common sporting pursuit. The ECU tendon is a frequent cause of wrist pain in the golfer. The sports medicine physician should have a high index of suspicion when dealing with this patient population. A combination of detailed history of injury and golf activity coupled with ultrasound, radiology and electrophysiological evaluation will result in a high diagnostic yield. Treatment should encompass alteration and improvement in golf swing and grip biomechanics as well as any practice or training errors.
The triangular fibrocartilage complex (TFCC) (Figure 16) is a load-bearing structure between the lunate, triquetrum, and ulnar head. It is a hammock-like structure made up of cartilage and ligaments. It stabilises the bones in the wrist, acts as a shock absorber and enables smooth movements. Forced ulnar deviation and positive ulnar variation are associated with injuries to the TFCC. A “weak” golf grip and swing biomechanics abnormalities makes injury to this structure more common.
Triangular fibrocartilage (TFCC).
The TFCC complex is prone to degeneration and wear-and-tear injuries. Injury occurs when compressive loads are placed on the TFCC during marked ulnar deviation. This occurs in the golf swing when the radial deviation of the wrist at the top of the back swing converts into ulnar deviation under significant force at impact. The triangular fibrocartilage disc attachment on the radial side is to hyaline cartilage. This makes the area vulnerable to injury as it is weaker when compared to the ulnar side whose attachment is bony.
Injury to the TFCC can lead to pain, weakness and instability. Patients with TFCC injury will present with ulnar-sided wrist pain that may present with clicking or point tenderness between the pisiform and the ulnar head.
The TFCC can be strained or torn from over-swinging or from “hitting down on the ball”. Hitting out of heavy rough or on hard practice matts are also extrinsic culprits in the development of this injury in the golfing population.
Diagnosis is confirmed by assessment of the sixth extensor compartment. At this location, the TFCC is examined in combination with the ECU tendon. The ECU relies on the TFCC for movement and hence both structures can be injured in combination.
Radiology may reveal avulsion of ulnar styloid, and ulnar variance in cases of the TFCC injury. High-resolution dynamic ultrasound (US) has emerged as a useful and valid tool for the diagnosis of this disorders [36, 37, 38].
The hamate bone (Figure 17) is one of the largest carpal bones and is located on the ulnar side of the palm of the hand and forms part of the distal carpal row. It has a protrusion called the “hook of hamate” which with the pisiform bones form the bony boundaries of Guyon’s Canal through which the ulnar nerve enters the wrist joint. Hook fractures can occur from a direct injury to the bone or from an indirect blow that occurs most commonly in sports [42].
Hook of the hamate bone.
In golf, most hook of hamate fractures occur because of the position of the golf club resting on the hook when hitting “down” on the ball, when it is buried in rough or embedded in a divot. These injuries are also common when hitting buckets of balls from a mat at the driving range. Many of the older ranges are built on concrete and injuries occur when the club head stops abruptly on the matt covering the concrete. The force of the impact is conducted through the club shaft and grip into the base of the hand and hamate bone, resulting in injury. That force is transmitted directly to the wrist and can cause a fracture of the hook of the hamate. These injuries occur more commonly in the following wrist [right hand in a right-handed golfer]. While fractures are rare and underreported, they are also frequently misdiagnosed as the initial trauma may seem trivial and present with a working diagnosis of a wrist sprain. Palpation of the hamate with or without ulnar nerve symptoms are cardinal findings. Plain radiology will confirm the diagnosis and conservative treatment such as rest and splinting usually resolves the problem.
Carpal Tunnel Syndrome (Figure 18) is the entrapment of the median nerve and repetitive use of the hands and wrists seen in golf contribute to the development of CTS. Repetitive activity such as golf swinging and practicing can result in flexor tenosynovitis as one or more of the 9 flexor tendons that travel through the Carpal Tunnel in the company of the median nerve become inflamed. Inflammation in the affected tendons in the wrist result in swelling of the sheath. This fluid will compromise the function of the nerve resulting in the symptoms of distal median neuropathy.
Carpal tunnel syndrome.
Golfers can be difficult to convince that the tingling fingers, numb hands or aching thumb or wrist pain is a result of Carpal Tunnel Syndrome. CTS is considered a disorder that only affects those who do intense repetitive activities all day long at work [43, 44], such as block laying, hairdressing [26] or computer keyboard work. However, in modern society golf driving ranges and facilities are readily available and frequently recreational golfers work harder on their golf than many other vocational pursuits.
Sports, pastimes and hobbies can play a major role in contributing to this repetitive strain induced hand and wrist condition. The repetitive activity causes inflammation to some of the 9 flexor tendons that travel through the Carpal Tunnel. This inflammation results in swelling which ultimately affects the function of the median nerve. CTS diagnosis is made by a combination of electrodiagnostic nerve conduction studies and ultrasound examinations. Treatment of this common condition which affects between 5% and 21% of the population [43, 44, 45, 46, 47, 48, 49] involves a combination of treatments including splinting the wrist, injection therapy and surgery. In the golfer, correction of golf biomechanics and golf club customization are helpful in preventing reoccurrence.
Guyon’s canal syndrome (Figure 19) is a condition where there is compression and irritation of the ulnar nerve at the wrist. The ulnar nerve is responsible for strength and sensation on the little finger’s side of the fourth finger and the entire fifth finger. Golfers with this condition may present with pain at the base of the wrist, loss of finger function and grip pressure as well as sensory alteration in the 4th and 5th fingers.
Guyon’s canal syndrome.
The hand may become clumsy when the muscles controlled by the ulnar nerve become weak. Weakness can affect the small muscles in the palm of the hand and the muscle that pulls the thumb into the palm.
Golfers are prone to irritation at Guyon’s canal from local trauma to the nerve associated with an improper golf grip and trauma from the butt of the golf club impacting at the base of the wrist [50].
Hard playing surfaces and hitting down on the ball are risk factors.
Diagnosis is made by Electrodiagnostic testing of the distal ulnar nerve. Ultrasound is also used to out rule other space occupying lesions such as a ganglion cyst or schwannoma.
This syndrome is much less common than carpal tunnel syndrome (CTS), yet both conditions can occur at the same time. The numbness by Guyon’s syndrome usually spares the thumb, index and long fingers.
Dupuytren contracture (Figure 20b) is a benign, myeloproliferative progressive disease of the palmar fascia which results in shortening, thickening, and fibrosis of the fascia and aponeurosis of the palm. It results in nodular formation on the palmar fascia which creates fibrosis resulting in one or more fingers become permanently bent in a flexed position. Dupuytrens contracture is caused by progressive thickening and shorting of the palmar fascia. This occurs due to slowly progressing fibrosis in the fascia that results in a flexion deformity at slowly the metacarpophalangeal (MCP) and proximal interphalangeal (PIP) joints usually affecting the 4th and 5th digits. The disease begins in the palm as painless nodules that form along longitudinal lines of tension. The nodules form cords that produce contracture deformities within fascial bands and tissues of the hand.
Dupuytren’s contracture caused by shortening, thickening, and fibrosis of the fascia and aponeurosis of the palm, results in nodular formation and a flexion deformity at the 4th and 5th digits, making a consistent grip of a golf club difficult.
The disorder has varying pattern of genetic predisposition across different regions and populations and is also known as the Viking disease, and Celtic hand, with 30% of the over 60-year-old male Norwegian population and 20% of a similar British population suffering from this condition [51].
It is expressed in an autosomal dominant fashion. This
The condition is associated with diabetes, seizure disorders, smoking, alcoholism, HIV, and vascular disease Ectopic manifestations beyond the hand can be seen in Ledderhose disease of the plantar fascia Peyronie disease (Dartos fascia of the penis), and Garrod disease (dorsal knuckle pads) [51, 52, 53].
Numerous authors going back as far as the 17th century have noted the association between traumatic events and the appearance of Dupuytren’s contracture. Initially by Plater in 1614, Goyrand in1835 and, Guillaume. Dupuytren, a French Surgeon in 1833 who the condition is named after [53, 54, 55, 56].
Golf has never specifically been cited as a caused of the condition but is a common disability encountered in the older golfer population. The disability causes technical issues gripping and swinging a golf club due to its anatomical location at the base of the wrist and the role of the 4th and 5th digit in gripping a club. Fatigue and hand pain has been reported in elite golfers with this condition and an inability to grip the club consistently.
In a 2017 survey of 504 Dupuytren’s sufferers, the Dupuytren’s society reported a significant proportion described difficulty golfing due to the pathology. In this observational study 8% of sufferers without a contracture reported a difficulty, 11% of single hand contracture and 23% of bilateral contracture suffers reported disfunction while golfing [57].
Up to one-fifth of patients seeking treatment for primary Dupuytren’s contracture were reported to suffer from an injury-induced Dupuytren’s contracture. It was noted that the injury to the wrist and hand seems to trigger the development of less progressive form Dupuytren’s contracture in younger age group [58].
In diagnosing Dupuytren Contracture the clinician needs to distinguish the condition from other diseases of the hand including stenosing flexor tenosynovitis, ganglion cysts, ECU tendon subluxation, Guyon’s Canal Syndrome and soft tissue masses. Diabetes, seizure disorders, smoking, alcoholism, HIV, and vascular disease should be considered during a careful history due their association with this condition.
Clinically the condition usually progresses at a slow rate over the course of several years and individuals may not be aware of the condition until it starts to cause functional disability. Pits and grooves in the palm of the hand are an early sign followed by the development of nodules in the medial palm. These nodules are often painless. Pain may be present distally at the knuckles pads of the proximal interphalangeal (PIP) as contracture evolve. The disorder is not always progressive and in at least 50–70% of patients, it may stabilise or even regress.
Investigations include radiology, which is usually normal and serology to out-rule metabolic or infective pathologies which are associated such as Diabetes Mellitus, Alcoholism and HIV infection, if there is a clinical suspicion.
Ultrasound [38] is the diagnostic tool with the highest yield as it confirms the presence of thickening of the palmar fascia and nodule formation.
Treatment includes physical therapy during the early stage of the disease. Some patients may also benefit from a brace to stretch the digits and maintaining range of motion of the fingers is necessary to prevent adhesions. This is particularly important in the golfing population. Corticosteroid injections may be beneficial and should be performed using Ultrasound guidance. Needle aponeurotomy is typically reserved for mild contractures. Collagenase injection which is a relatively new, minimally invasive treatment derived from Clostridium histolyticum has shown good initial results. The treatment is not available in all jurisdictions and should only be performed by a hand surgeon who can deal with any potential side effects of this treatment. Surgical fasciectomy is reserved for those cases who have failed conservative therapy and have a persisting disability.
A significant proportion of older golfers suffer from this disability that causes pain, discomfort and impairs the player’s ability to consistently grip a golf club, and regularly interferes with the enjoyment of the game. Golf due to trauma may provoke the injury and once present exacerbates the condition. Early identification, finger stretching, as well as the use of topical anti-inflammatory medication assist in reducing symptoms in golfers with mild or non- progressive disease.
Golfers frequently continue to play with this condition. In these instances, the Dupuytren’s sufferer should undergo a careful assessment of equipment. Golf shaft weight and grips should be reviewed by a PGA golf professional. In particular, correct or augmented golf grips can facilitate safe and enjoyable golf for the Celtic Hand golfer. Thickening grips can help mitigate overactive hands through the hitting zone thus reducing stress on the palmar aponeurosis. Golf grips come in 4 basic diameters and can be refined by a golf professional by the addition of wraps under the grip, further customising the all-important handle of the golf club. Larger grips also improve shock absorption and reduce transition of force to an already compromised palmar fascia. Small grips result in an increase in grip pressure and a propensity to grip the club in the palm. Holding the club too high across the palm increases the risk of hand injury or the exacerbation of an existing condition. The golfer should ensure his grip is biomechanically correct and the club is held in the fingers rather than the palm of the hand. This can be achieved by regripping the club in the last three fingers of the leading hand at address, prior to swinging. This helps to stabilises the club at impact and limits the stress on the palm of the hand. These small manageable changes will contribute to lessening the affect that this condition has on recreational and elite golfers.
Rare causes of leading wrist injury in golfers include damage to the Flexor Carpi Ulnaris tendon and proximal entrapment of the ulnar and median nerves, these are rare in golf but are commonly encountered in the general sporting population and among gym users (Figure 21).
Proximal entrapment of the median nerve by the pronator Teres muscle.
The Flexor Carpi Ulnaris (FCU) muscle has its origin at the medial epicondyle and it is inserted on the medial side of the wrist into the pisiform, hamate and the base of the 5th metacarpal bone. 5th carpal by a tendinous attachment. The FCU acts as a flexor and ulnar deviator of the wrist. Injury therefore can occur at impact with the ball during the golf swing as the wrist converts into a flexed and ulnar deviated position at impact. In cases of acute trauma, the injury is usually located distally at the level of the pisiform bone insertion. In cases of overuse injuries, the injury is usually proximal to the wrist at the level of the musculotendinous junction. Diagnosis is confirmed by careful palpation of the full length of the tendon. Pain is exacerbated by resisted wrist flexion and ulnar deviation. Ultrasound of the full length of the nerve confirms the diagnosis. The FCU tendon can be also compromised in injuries to the hook pf the hamate bone.
The ulnar nerve can be compromised at the elbow in cases of medial epicondylitis or “golfers elbow”. The ulnar nerve travels through the cubital tunnel prior to entering the ulnar groove as it travels caudally. The cubital tunnel is formed by bone, ligament and muscle.
The tunnel’s ceiling is formed by the cubital retinaculum, a ligament spanning from the medial epicondyle to the olecranon process that is continuous with the fascia connecting the humeral and ulnar heads of the flexor carpi ulnaris (FCU). Injury to these structures or to the flexor tendon insertion at the medial epicondyle can compromise the ulnar nerve resulting in a local irritation or compression of the ulnar nerve, known as Cubital Tunnel Syndrome. Golfers elbow is associated with golf and racket sports. Repetitive activity and holding the elbow in flexion at impact can be aetiological elements in the development of the tendon injury which may be a prequel to the local ulnar nerve irritation. The increased in elbow flexion causes the arcuate ligament to tighten, the FCU to tighten and the ulnar collateral ligament to buckle and encroach into the tunnel compromising the ulnar nerve [59, 60].
This can cause numbness and tingling in the hand and/or ring and little finger, especially when the elbow is bent. Occasionally a player will describe hand pain in the hypothermal eminence when swinging a golf club and weakness when gripping a club and a lack of consistency in golf grip due to muscle weakness in the intrinsic muscles of the hand which receive their innervation from the ulnar nerve.
Diagnosis is made by identifying the clinical signs of an ulnar neuropathy. Electrodiagnostic evaluation with Nerve Conduction Studies and needle EMG. Conservative treatment includes rest and Ultrasound guided injection therapy at the cubital tunnel. In chronic cases surgical release may be required.
Distal median neuropathies can also occur in the golfing population. It is well recognised in racket players [61]. This is referred to as pronator syndrome. The nerve can be compromised at 4 sites in the flexor aspect of the forearm.
The Ligament of Struthers is present in up to 2.7% of the population [62, 63]. Entrapment of the nerve at this site is exacerbated by elbow flexion and extension [63] which is a common manoeuvre in the leading arm of a golfer.
The median nerve travels through the 2 heads of the Pronator muscle just below the elbow joint, and can be compromised at this site. The nerve can also be entrapped by thickening of the bicipital aponeurosis, and finally by the flexor digitorum superficialis. These flexor and pronator muscles are frequently hypertrophied from overuse activities such as repeated golf swinging and practice, particularly in golfers with strong grips (pronated flexed wrists). With this grip the pronator testes muscle has to fire quickly at impact in an effort to square up the club face. The median nerve becoming entrapped at this proximal site. Symptoms are often vague and can suggest a mixed pattern of median and ulnar nerve symptoms. Diagnosis involves electrodiagnostic assessment. Treatment requires rest and alteration in technique and practice protocols. In resistant cases surgery is indicated.
Golf is a centuries old game whose popularity as a sport and entertainment grows exponentially internationally year on year. Increased golf facilities and accessibility have resulted in a world-wide explosion of golf participation. With this, golf related injuries have increased dramatically [64] as experienced and novice golfers alike attempt to imitate the extraordinary feats of distance power and accuracy exhibited by elite golfers who are beamed to out TVs week on week. These players now include 9 million participating at ranges and using indoor simulators [65] who hit “buckets “of balls in a finite period of time without the natural break between shots which occurs in a conventional game of golf. Golf teaching has mirrored these changes as golf is no longer considered a game but a sport, where improvement in performance is an essential component rather than the simple pleasures of walking in the countryside while hitting a ball towards a target in the fresh air. These natural changes in society to become better at this activity have spawned a multitude of teaching facilities in the real world and the cyber world where golfers strive for greater distance and accuracy through strength and conditioning and biomechanics. Humans are not machines and stress placed on human tissue frequently results in trauma and injury. In the case of the golf swing, sports science and biomechanical advances have improved the performance of golf with the side effect of increased injury, the leading wrist being particularly vulnerable to injury and pathology. The ECU tendon is the most commonly injured leading wrist structure particularly among elite golfers [36, 64]. The sports medicine physician should be aware of this potential and address swing mechanics and the risk reward nature of un-natural motions to the leading wrist in a golfing population to avoid chronic injury, time away from the game [66] and long-term disability.
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However, the clamping force is quite important for PP IGBTs because too much clamping fore will cause mechanical damage to the silicon chips and too little clamping force will increase the junction temperature of the silicon chips due to the increased thermal contact resistance. And eventually it leads to thermal damage. Furthermore, the clamping force distribution within PP IGBTs is affected by many factors, and they can be divided into the internal and external factors. The finite element analysis model of the PP IGBTs is established based on the theory of elastic mechanics to obtain the influence of the affect factors, including the external clamping modes, spring design, thermal stress, the machining accuracy, and so on. The contribution of those affect factors to the clamping force distribution is ranked, and this can be a guideline not only for users but also for the manufacturers.",book:{id:"6695",slug:"design-simulation-and-construction-of-field-effect-transistors",title:"Design, Simulation and Construction of Field Effect Transistors",fullTitle:"Design, Simulation and Construction of Field Effect Transistors"},signatures:"Erping Deng, Zhibin Zhao, Jinyuan Li and Yongzhang Huang",authors:[{id:"234852",title:"Dr.",name:"Erping",middleName:null,surname:"Deng",slug:"erping-deng",fullName:"Erping Deng"}]}],mostDownloadedChaptersLast30Days:[{id:"60792",title:"TCAD Device Modelling and Simulation of Wide Bandgap Power Semiconductors",slug:"tcad-device-modelling-and-simulation-of-wide-bandgap-power-semiconductors",totalDownloads:2116,totalCrossrefCites:15,totalDimensionsCites:15,abstract:"Technology computer-aided Design (TCAD) is essential for devices technology development, including wide bandgap power semiconductors. 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This chapter reviews the property of GaN material, the advantage of GaN-based SBD, and the Schottky contact to GaN including current transporation theory, Schottky material selection, contact quality and thermal stability. The chapter also discusses about the GaN lateral, quasi-vertical and vertical SBDs, and AlGaN/GaN field effect SBDs: the evolution of the epitaxial structure, processing techniques and device structure. The chapter closes with challenges ahead and gives an outlook on the future development of the GaN SBDs.",book:{id:"6625",slug:"disruptive-wide-bandgap-semiconductors-related-technologies-and-their-applications",title:"Disruptive Wide Bandgap Semiconductors, Related Technologies, and Their Applications",fullTitle:"Disruptive Wide Bandgap Semiconductors, Related Technologies, and Their Applications"},signatures:"Yaqi Wang",authors:[{id:"237104",title:"Dr.",name:"Yaqi",middleName:null,surname:"Wang",slug:"yaqi-wang",fullName:"Yaqi Wang"}]},{id:"53537",title:"FPGA-Based Software-Defined Radio and Its Real-Time Implementation Using NI-USRP",slug:"fpga-based-software-defined-radio-and-its-real-time-implementation-using-ni-usrp",totalDownloads:2796,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"In this chapter, we propose a novel design of scalable and real-time data acquisition software architecture for software-defined radio (SDR) using universal software radio peripheral (USRP). The software has been designed and tested in multi-thread model, using LabVIEW, which guarantees real-time performance and efficiency. With the help of this design, we have been able to improve the stability of the system besides providing a reconfigurable and flexible architecture. Wireless transfer of sensitive data using communication is not a very safe option. In this chapter, we aim to provide a safe and private wireless transmission between two terminals using the SDR approach and verifying the results in real-world environment with the use of USRP. The novel design being presented here can be used to transfer (random data, text or an image) encoded with different forward error correction (FEC) codes, which is then verified at the receiving terminal and then decoded accordingly to produce the desired result.",book:{id:"5597",slug:"field-programmable-gate-array",title:"Field",fullTitle:"Field - Programmable Gate Array"},signatures:"Nikhil Marriwala, Om. Prakash. Sahu and Anil Vohra",authors:[{id:"192912",title:"Associate Prof.",name:"Nikhil",middleName:null,surname:"Marriwala",slug:"nikhil-marriwala",fullName:"Nikhil Marriwala"},{id:"198652",title:"Prof.",name:"O.P",middleName:null,surname:"Sahu",slug:"o.p-sahu",fullName:"O.P Sahu"},{id:"198654",title:"Prof.",name:"Anil",middleName:null,surname:"Vohra",slug:"anil-vohra",fullName:"Anil Vohra"}]},{id:"61186",title:"Graphene Field-Effect Transistor for Terahertz Modulation",slug:"graphene-field-effect-transistor-for-terahertz-modulation",totalDownloads:1286,totalCrossrefCites:2,totalDimensionsCites:3,abstract:"The real-world applications of terahertz (THz) technology necessitate versatile adaptive optical components, for example, modulators. In this chapter, we begin with a brief review on different techniques for THz modulation. After that, we introduce the extraordinary features of graphene along with its advantages and disadvantages as channel materials for field effect transistor (FET). We then discuss two types of graphene FET-based THz modulators, one is rigid and another is flexible. The feasibility of the high-quality THz modulators with different graphene FET structures has been successfully demonstrated. It is observed that by tuning the carrier concentration of graphene by electrical gating, the THz modulation can be obtained with relatively large modulation depth, broad width band, and moderate speed. This chapter helps the reader in obtaining guidelines for the proper choice of a specific structure for THz modulator with graphene FET.",book:{id:"6695",slug:"design-simulation-and-construction-of-field-effect-transistors",title:"Design, Simulation and Construction of Field Effect Transistors",fullTitle:"Design, Simulation and Construction of Field Effect Transistors"},signatures:"Qi-Ye Wen, Yu-Lian He, Jing-Bo Liu, Qi Mao, Qing-Hui Yang, Zhi\nChen and Huai-Wu Zhang",authors:[{id:"235512",title:"Prof.",name:"Qiye",middleName:null,surname:"Wen",slug:"qiye-wen",fullName:"Qiye Wen"},{id:"247833",title:"Ms.",name:"Yu-Lian",middleName:null,surname:"He",slug:"yu-lian-he",fullName:"Yu-Lian He"},{id:"247834",title:"Prof.",name:"Zhi",middleName:null,surname:"Chen",slug:"zhi-chen",fullName:"Zhi Chen"},{id:"247837",title:"Prof.",name:"Qing-Hui",middleName:null,surname:"Yang",slug:"qing-hui-yang",fullName:"Qing-Hui Yang"},{id:"247839",title:"Prof.",name:"Huai-Wu",middleName:null,surname:"Zhang",slug:"huai-wu-zhang",fullName:"Huai-Wu Zhang"}]},{id:"53730",title:"High‐Speed Deterministic‐Latency Serial IO",slug:"high-speed-deterministic-latency-serial-io",totalDownloads:1734,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"In digital systems, serial IO at speeds in the range from 1 to 20 Gbps is realized by means of dedicated transceivers, named serializer-deserializers (SerDeses). In general, due to their internal architecture, the data transfer delay, or the latency, may vary after a reset of the device. On the other hand, some applications, such as high-speed transfer protocols for analog-to-digital and digital-to-analog converters, trigger and data acquisition systems, clock distribution, synchronization and control of radio equipment need this delay to be constant at each reset. In this chapter, we focus on a serial IO architecture based on configurable transceivers embedded in field-programmable gate arrays (FPGAs). We will show how it is possible to achieve deterministic-latency operation in a line-code-independent way. As a case study, we will consider a synchronous 2.5-Gbps serial link based on an 8b10b line code.",book:{id:"5597",slug:"field-programmable-gate-array",title:"Field",fullTitle:"Field - Programmable Gate Array"},signatures:"Raffaele Giordano, Vincenzo Izzo and Alberto Aloisio",authors:[{id:"193125",title:"Prof.",name:"Raffaele",middleName:null,surname:"Giordano",slug:"raffaele-giordano",fullName:"Raffaele Giordano"}]}],onlineFirstChaptersFilter:{topicId:"957",limit:6,offset:0},onlineFirstChaptersCollection:[],onlineFirstChaptersTotal:0},preDownload:{success:null,errors:{}},subscriptionForm:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[],offset:8,limit:8,total:0},allSeries:{pteSeriesList:[{id:"14",title:"Artificial Intelligence",numberOfPublishedBooks:9,numberOfPublishedChapters:89,numberOfOpenTopics:6,numberOfUpcomingTopics:0,issn:"2633-1403",doi:"10.5772/intechopen.79920",isOpenForSubmission:!0},{id:"7",title:"Biomedical Engineering",numberOfPublishedBooks:12,numberOfPublishedChapters:104,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2631-5343",doi:"10.5772/intechopen.71985",isOpenForSubmission:!0}],lsSeriesList:[{id:"11",title:"Biochemistry",numberOfPublishedBooks:32,numberOfPublishedChapters:318,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2632-0983",doi:"10.5772/intechopen.72877",isOpenForSubmission:!0},{id:"25",title:"Environmental Sciences",numberOfPublishedBooks:1,numberOfPublishedChapters:12,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2754-6713",doi:"10.5772/intechopen.100362",isOpenForSubmission:!0},{id:"10",title:"Physiology",numberOfPublishedBooks:11,numberOfPublishedChapters:141,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-8261",doi:"10.5772/intechopen.72796",isOpenForSubmission:!0}],hsSeriesList:[{id:"3",title:"Dentistry",numberOfPublishedBooks:8,numberOfPublishedChapters:133,numberOfOpenTopics:2,numberOfUpcomingTopics:0,issn:"2631-6218",doi:"10.5772/intechopen.71199",isOpenForSubmission:!0},{id:"6",title:"Infectious Diseases",numberOfPublishedBooks:13,numberOfPublishedChapters:113,numberOfOpenTopics:3,numberOfUpcomingTopics:1,issn:"2631-6188",doi:"10.5772/intechopen.71852",isOpenForSubmission:!0},{id:"13",title:"Veterinary Medicine and Science",numberOfPublishedBooks:11,numberOfPublishedChapters:107,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:19,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2753-894X",doi:"10.5772/intechopen.100359",isOpenForSubmission:!0},{id:"23",title:"Education and Human Development",numberOfPublishedBooks:0,numberOfPublishedChapters:5,numberOfOpenTopics:1,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100360",isOpenForSubmission:!0},{id:"24",title:"Sustainable Development",numberOfPublishedBooks:0,numberOfPublishedChapters:15,numberOfOpenTopics:5,numberOfUpcomingTopics:0,issn:null,doi:"10.5772/intechopen.100361",isOpenForSubmission:!0}],testimonialsList:[{id:"13",text:"The collaboration with and support of the technical staff of IntechOpen is fantastic. The whole process of submitting an article and editing of the submitted article goes extremely smooth and fast, the number of reads and downloads of chapters is high, and the contributions are also frequently cited.",author:{id:"55578",name:"Antonio",surname:"Jurado-Navas",institutionString:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRisIQAS/Profile_Picture_1626166543950",slug:"antonio-jurado-navas",institution:{id:"720",name:"University of Malaga",country:{id:null,name:"Spain"}}}},{id:"6",text:"It is great to work with the IntechOpen to produce a worthwhile collection of research that also becomes a great educational resource and guide for future research endeavors.",author:{id:"259298",name:"Edward",surname:"Narayan",institutionString:null,profilePictureURL:"https://mts.intechopen.com/storage/users/259298/images/system/259298.jpeg",slug:"edward-narayan",institution:{id:"3",name:"University of Queensland",country:{id:null,name:"Australia"}}}}]},series:{item:{id:"6",title:"Infectious Diseases",doi:"10.5772/intechopen.71852",issn:"2631-6188",scope:"This series will provide a comprehensive overview of recent research trends in various Infectious Diseases (as per the most recent Baltimore classification). Topics will include general overviews of infections, immunopathology, diagnosis, treatment, epidemiology, etiology, and current clinical recommendations for managing infectious diseases. Ongoing issues, recent advances, and future diagnostic approaches and therapeutic strategies will also be discussed. This book series will focus on various aspects and properties of infectious diseases whose deep understanding is essential for safeguarding the human race from losing resources and economies due to pathogens.",coverUrl:"https://cdn.intechopen.com/series/covers/6.jpg",latestPublicationDate:"June 25th, 2022",hasOnlineFirst:!0,numberOfPublishedBooks:13,editor:{id:"131400",title:"Prof.",name:"Alfonso J.",middleName:null,surname:"Rodriguez-Morales",slug:"alfonso-j.-rodriguez-morales",fullName:"Alfonso J. 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He is an External Professor, Master in Research on Tropical Medicine and International Health, Universitat de Barcelona, Spain. He is also a professor at the Master in Clinical Epidemiology and Biostatistics, Universidad Científica del Sur, Lima, Peru. In 2021 he has been awarded the “Raul Isturiz Award” Medal of the API. Also, in 2021, he was awarded with the “Jose Felix Patiño” Asclepius Staff Medal of the Colombian Medical College, due to his scientific contributions to COVID-19 during the pandemic. He is currently the Editor in Chief of the journal Travel Medicine and Infectious Diseases. His Scopus H index is 47 (Google Scholar H index, 68).",institutionString:"Institución Universitaria Visión de las Américas, Colombia",institution:null},editorTwo:null,editorThree:null},subseries:{paginationCount:4,paginationItems:[{id:"3",title:"Bacterial Infectious Diseases",coverUrl:"https://cdn.intechopen.com/series_topics/covers/3.jpg",isOpenForSubmission:!1,annualVolume:null,editor:null,editorTwo:null,editorThree:null},{id:"4",title:"Fungal Infectious Diseases",coverUrl:"https://cdn.intechopen.com/series_topics/covers/4.jpg",isOpenForSubmission:!0,annualVolume:11400,editor:{id:"174134",title:"Dr.",name:"Yuping",middleName:null,surname:"Ran",slug:"yuping-ran",fullName:"Yuping Ran",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bS9d6QAC/Profile_Picture_1630330675373",biography:"Dr. Yuping Ran, Professor, Department of Dermatology, West China Hospital, Sichuan University, Chengdu, China. Completed the Course Medical Mycology, the Centraalbureau voor Schimmelcultures (CBS), Fungal Biodiversity Centre, Netherlands (2006). International Union of Microbiological Societies (IUMS) Fellow, and International Emerging Infectious Diseases (IEID) Fellow, Centers for Diseases Control and Prevention (CDC), Atlanta, USA. Diploma of Dermatological Scientist, Japanese Society for Investigative Dermatology. Ph.D. of Juntendo University, Japan. Bachelor’s and Master’s degree, Medicine, West China University of Medical Sciences. Chair of Sichuan Medical Association Dermatology Committee. General Secretary of The 19th Annual Meeting of Chinese Society of Dermatology and the Asia Pacific Society for Medical Mycology (2013). In charge of the Annual Medical Mycology Course over 20-years authorized by National Continue Medical Education Committee of China. Member of the board of directors of the Asia-Pacific Society for Medical Mycology (APSMM). Associate editor of Mycopathologia. Vice-chief of the editorial board of Chinses Journal of Mycology, China. Board Member and Chair of Mycology Group of Chinese Society of Dermatology.",institutionString:null,institution:{name:"Sichuan University",institutionURL:null,country:{name:"China"}}},editorTwo:null,editorThree:null},{id:"5",title:"Parasitic Infectious Diseases",coverUrl:"https://cdn.intechopen.com/series_topics/covers/5.jpg",isOpenForSubmission:!0,annualVolume:11401,editor:{id:"67907",title:"Dr.",name:"Amidou",middleName:null,surname:"Samie",slug:"amidou-samie",fullName:"Amidou Samie",profilePictureURL:"https://mts.intechopen.com/storage/users/67907/images/system/67907.jpg",biography:"Dr. Amidou Samie is an Associate Professor of Microbiology at the University of Venda, in South Africa, where he graduated for his PhD in May 2008. He joined the Department of Microbiology the same year and has been giving lectures on topics covering parasitology, immunology, molecular biology and industrial microbiology. He is currently a rated researcher by the National Research Foundation of South Africa at category C2. He has published widely in the field of infectious diseases and has overseen several MSc’s and PhDs. His research activities mostly cover topics on infectious diseases from epidemiology to control. His particular interest lies in the study of intestinal protozoan parasites and opportunistic infections among HIV patients as well as the potential impact of childhood diarrhoea on growth and child development. He also conducts research on water-borne diseases and water quality and is involved in the evaluation of point-of-use water treatment technologies using silver and copper nanoparticles in collaboration with the University of Virginia, USA. He also studies the use of medicinal plants for the control of infectious diseases as well as antimicrobial drug resistance.",institutionString:null,institution:{name:"University of Venda",institutionURL:null,country:{name:"South Africa"}}},editorTwo:null,editorThree:null},{id:"6",title:"Viral Infectious Diseases",coverUrl:"https://cdn.intechopen.com/series_topics/covers/6.jpg",isOpenForSubmission:!0,annualVolume:11402,editor:{id:"158026",title:"Prof.",name:"Shailendra K.",middleName:null,surname:"Saxena",slug:"shailendra-k.-saxena",fullName:"Shailendra K. Saxena",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRET3QAO/Profile_Picture_2022-05-10T10:10:26.jpeg",biography:"Professor Dr. Shailendra K. Saxena is a vice dean and professor at King George's Medical University, Lucknow, India. His research interests involve understanding the molecular mechanisms of host defense during human viral infections and developing new predictive, preventive, and therapeutic strategies for them using Japanese encephalitis virus (JEV), HIV, and emerging viruses as a model via stem cell and cell culture technologies. His research work has been published in various high-impact factor journals (Science, PNAS, Nature Medicine) with a high number of citations. He has received many awards and honors in India and abroad including various Young Scientist Awards, BBSRC India Partnering Award, and Dr. JC Bose National Award of Department of Biotechnology, Min. of Science and Technology, Govt. of India. Dr. Saxena is a fellow of various international societies/academies including the Royal College of Pathologists, United Kingdom; Royal Society of Medicine, London; Royal Society of Biology, United Kingdom; Royal Society of Chemistry, London; and Academy of Translational Medicine Professionals, Austria. He was named a Global Leader in Science by The Scientist. He is also an international opinion leader/expert in vaccination for Japanese encephalitis by IPIC (UK).",institutionString:"King George's Medical University",institution:{name:"King George's Medical University",institutionURL:null,country:{name:"India"}}},editorTwo:null,editorThree:null}]},overviewPageOFChapters:{paginationCount:58,paginationItems:[{id:"81961",title:"Antioxidants as an Adjuncts to Periodontal Therapy",doi:"10.5772/intechopen.105016",signatures:"Sura Dakhil Jassim and Ali Abbas Abdulkareem",slug:"antioxidants-as-an-adjuncts-to-periodontal-therapy",totalDownloads:3,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Dental Trauma",coverURL:"https://cdn.intechopen.com/books/images_new/11567.jpg",subseries:{id:"2",title:"Prosthodontics and Implant Dentistry"}}},{id:"82357",title:"Caries Management Aided by Fluorescence-Based Devices",doi:"10.5772/intechopen.105567",signatures:"Atena Galuscan, Daniela Jumanca and Aurora Doris Fratila",slug:"caries-management-aided-by-fluorescence-based-devices",totalDownloads:4,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Dental Caries - The Selection of Restoration Methods and Restorative Materials",coverURL:"https://cdn.intechopen.com/books/images_new/11565.jpg",subseries:{id:"1",title:"Oral Health"}}},{id:"81894",title:"Diet and Nutrition and Their Relationship with Early Childhood Dental Caries",doi:"10.5772/intechopen.105123",signatures:"Luanna Gonçalves Ferreira, Giuliana de Campos Chaves Lamarque and Francisco Wanderley Garcia Paula-Silva",slug:"diet-and-nutrition-and-their-relationship-with-early-childhood-dental-caries",totalDownloads:11,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Dental Caries - The Selection of Restoration Methods and Restorative Materials",coverURL:"https://cdn.intechopen.com/books/images_new/11565.jpg",subseries:{id:"1",title:"Oral Health"}}},{id:"81595",title:"Prosthetic Concepts in Dental Implantology",doi:"10.5772/intechopen.104725",signatures:"Ivica Pelivan",slug:"prosthetic-concepts-in-dental-implantology",totalDownloads:27,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Current Concepts in Dental Implantology - From Science to Clinical Research",coverURL:"https://cdn.intechopen.com/books/images_new/10808.jpg",subseries:{id:"2",title:"Prosthodontics and Implant Dentistry"}}}]},overviewPagePublishedBooks:{paginationCount:8,paginationItems:[{type:"book",id:"6668",title:"Dental Caries",subtitle:"Diagnosis, Prevention and Management",coverURL:"https://cdn.intechopen.com/books/images_new/6668.jpg",slug:"dental-caries-diagnosis-prevention-and-management",publishedDate:"September 19th 2018",editedByType:"Edited by",bookSignature:"Zühre Akarslan",hash:"b0f7667770a391f772726c3013c1b9ba",volumeInSeries:1,fullTitle:"Dental Caries - Diagnosis, Prevention and Management",editors:[{id:"171887",title:"Prof.",name:"Zühre",middleName:null,surname:"Akarslan",slug:"zuhre-akarslan",fullName:"Zühre Akarslan",profilePictureURL:"https://mts.intechopen.com/storage/users/171887/images/system/171887.jpg",biography:"Zühre Akarslan was born in 1977 in Cyprus. She graduated from Gazi University Faculty of Dentistry, Ankara, Turkey in 2000. \r\nLater she received her Ph.D. degree from the Oral Diagnosis and Radiology Department; which was recently renamed as Oral and Dentomaxillofacial Radiology, from the same university. \r\nShe is working as a full-time Associate Professor and is a lecturer and an academic researcher. \r\nHer expertise areas are dental caries, cancer, dental fear and anxiety, gag reflex in dentistry, oral medicine, and dentomaxillofacial radiology.",institutionString:"Gazi University",institution:{name:"Gazi University",institutionURL:null,country:{name:"Turkey"}}}]},{type:"book",id:"7139",title:"Current Approaches in Orthodontics",subtitle:null,coverURL:"https://cdn.intechopen.com/books/images_new/7139.jpg",slug:"current-approaches-in-orthodontics",publishedDate:"April 10th 2019",editedByType:"Edited by",bookSignature:"Belma Işık Aslan and Fatma Deniz Uzuner",hash:"2c77384eeb748cf05a898d65b9dcb48a",volumeInSeries:2,fullTitle:"Current Approaches in Orthodontics",editors:[{id:"42847",title:"Dr.",name:"Belma",middleName:null,surname:"Işik Aslan",slug:"belma-isik-aslan",fullName:"Belma Işik Aslan",profilePictureURL:"https://mts.intechopen.com/storage/users/42847/images/system/42847.jpg",biography:"Dr. Belma IşIk Aslan was born in 1976 in Ankara-TURKEY. After graduating from TED Ankara College in 1994, she attended to Gazi University, Faculty of Dentistry in Ankara. She completed her PhD in orthodontic education at Gazi University between 1999-2005. Dr. Işık Aslan stayed at the Providence Hospital Craniofacial Institude and Reconstructive Surgery in Michigan, USA for three months as an observer. She worked as a specialist doctor at Gazi University, Dentistry Faculty, Department of Orthodontics between 2005-2014. She was appointed as associate professor in January, 2014 and as professor in 2021. Dr. Işık Aslan still works as an instructor at the same faculty. She has published a total of 35 articles, 10 book chapters, 39 conference proceedings both internationally and nationally. Also she was the academic editor of the international book 'Current Advances in Orthodontics'. She is a member of the Turkish Orthodontic Society and Turkish Cleft Lip and Palate Society. She is married and has 2 children. Her knowledge of English is at an advanced level.",institutionString:"Gazi University Dentistry Faculty Department of Orthodontics",institution:null}]},{type:"book",id:"7572",title:"Trauma in Dentistry",subtitle:null,coverURL:"https://cdn.intechopen.com/books/images_new/7572.jpg",slug:"trauma-in-dentistry",publishedDate:"July 3rd 2019",editedByType:"Edited by",bookSignature:"Serdar Gözler",hash:"7cb94732cfb315f8d1e70ebf500eb8a9",volumeInSeries:3,fullTitle:"Trauma in Dentistry",editors:[{id:"204606",title:"Dr.",name:"Serdar",middleName:null,surname:"Gözler",slug:"serdar-gozler",fullName:"Serdar Gözler",profilePictureURL:"https://mts.intechopen.com/storage/users/204606/images/system/204606.jpeg",biography:"Dr. Serdar Gözler has completed his undergraduate studies at the Marmara University Faculty of Dentistry in 1978, followed by an assistantship in the Prosthesis Department of Dicle University Faculty of Dentistry. Starting his PhD work on non-resilient overdentures with Assoc. Prof. Hüsnü Yavuzyılmaz, he continued his studies with Prof. Dr. Gürbüz Öztürk of Istanbul University Faculty of Dentistry Department of Prosthodontics, this time on Gnatology. He attended training programs on occlusion, neurology, neurophysiology, EMG, radiology and biostatistics. In 1982, he presented his PhD thesis \\Gerber and Lauritzen Occlusion Analysis Techniques: Diagnosis Values,\\ at Istanbul University School of Dentistry, Department of Prosthodontics. As he was also working with Prof. Senih Çalıkkocaoğlu on The Physiology of Chewing at the same time, Gözler has written a chapter in Çalıkkocaoğlu\\'s book \\Complete Prostheses\\ entitled \\The Place of Neuromuscular Mechanism in Prosthetic Dentistry.\\ The book was published five times since by the Istanbul University Publications. Having presented in various conferences about occlusion analysis until 1998, Dr. Gözler has also decided to use the T-Scan II occlusion analysis method. Having been personally trained by Dr. Robert Kerstein on this method, Dr. Gözler has been lecturing on the T-Scan Occlusion Analysis Method in conferences both in Turkey and abroad. Dr. Gözler has various articles and presentations on Digital Occlusion Analysis methods. He is now Head of the TMD Clinic at Prosthodontic Department of Faculty of Dentistry , Istanbul Aydın University , Turkey.",institutionString:"Istanbul Aydin University",institution:{name:"Istanbul Aydın University",institutionURL:null,country:{name:"Turkey"}}}]},{type:"book",id:"7060",title:"Gingival Disease",subtitle:"A Professional Approach for Treatment and Prevention",coverURL:"https://cdn.intechopen.com/books/images_new/7060.jpg",slug:"gingival-disease-a-professional-approach-for-treatment-and-prevention",publishedDate:"October 23rd 2019",editedByType:"Edited by",bookSignature:"Alaa Eddin Omar Al Ostwani",hash:"b81d39988cba3a3cf746c1616912cf41",volumeInSeries:4,fullTitle:"Gingival Disease - A Professional Approach for Treatment and Prevention",editors:[{id:"240870",title:"Ph.D.",name:"Alaa Eddin Omar",middleName:null,surname:"Al Ostwani",slug:"alaa-eddin-omar-al-ostwani",fullName:"Alaa Eddin Omar Al Ostwani",profilePictureURL:"https://mts.intechopen.com/storage/users/240870/images/system/240870.jpeg",biography:"Dr. Al Ostwani Alaa Eddin Omar received his Master in dentistry from Damascus University in 2010, and his Ph.D. in Pediatric Dentistry from Damascus University in 2014. Dr. Al Ostwani is an assistant professor and faculty member at IUST University since 2014. \nDuring his academic experience, he has received several awards including the scientific research award from the Union of Arab Universities, the Syrian gold medal and the international gold medal for invention and creativity. Dr. Al Ostwani is a Member of the International Association of Dental Traumatology and the Syrian Society for Research and Preventive Dentistry since 2017. 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He also obtained an MSc in Molecular and Genetic Medicine, and a Ph.D. in Clinical Immunology and Human Genetics from the University of Sheffield, UK. He also completed a short-term fellowship in Pediatric Clinical Immunology and Bone Marrow Transplantation at Newcastle General Hospital, England. Dr. Rezaei is a Full Professor of Immunology and Vice Dean of International Affairs and Research, at the School of Medicine, Tehran University of Medical Sciences, and the co-founder and head of the Research Center for Immunodeficiencies. He is also the founding president of the Universal Scientific Education and Research Network (USERN). Dr. Rezaei has directed more than 100 research projects and has designed and participated in several international collaborative projects. He is an editor, editorial assistant, or editorial board member of more than forty international journals. He has edited more than 50 international books, presented more than 500 lectures/posters in congresses/meetings, and published more than 1,100 scientific papers in international journals.",institutionString:"Tehran University of Medical Sciences",institution:{name:"Tehran University of Medical Sciences",country:{name:"Iran"}}},{id:"180733",title:"Dr.",name:"Jean",middleName:null,surname:"Engohang-Ndong",slug:"jean-engohang-ndong",fullName:"Jean Engohang-Ndong",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/180733/images/system/180733.png",biography:"Dr. Jean Engohang-Ndong was born and raised in Gabon. After obtaining his Associate Degree of Science at the University of Science and Technology of Masuku, Gabon, he continued his education in France where he obtained his BS, MS, and Ph.D. in Medical Microbiology. He worked as a post-doctoral fellow at the Public Health Research Institute (PHRI), Newark, NJ for four years before accepting a three-year faculty position at Brigham Young University-Hawaii. Dr. Engohang-Ndong is a tenured faculty member with the academic rank of Full Professor at Kent State University, Ohio, where he teaches a wide range of biological science courses and pursues his research in medical and environmental microbiology. Recently, he expanded his research interest to epidemiology and biostatistics of chronic diseases in Gabon.",institutionString:"Kent State University",institution:{name:"Kent State University",country:{name:"United States of America"}}},{id:"188773",title:"Prof.",name:"Emmanuel",middleName:null,surname:"Drouet",slug:"emmanuel-drouet",fullName:"Emmanuel Drouet",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/188773/images/system/188773.png",biography:"Emmanuel Drouet, PharmD, is a Professor of Virology at the Faculty of Pharmacy, the University Grenoble-Alpes, France. As a head scientist at the Institute of Structural Biology in Grenoble, Dr. Drouet’s research investigates persisting viruses in humans (RNA and DNA viruses) and the balance with our host immune system. He focuses on these viruses’ effects on humans (both their impact on pathology and their symbiotic relationships in humans). He has an excellent track record in the herpesvirus field, and his group is engaged in clinical research in the field of Epstein-Barr virus diseases. He is the editor of the online Encyclopedia of Environment and he coordinates the Universal Health Coverage education program for the BioHealth Computing Schools of the European Institute of Science.",institutionString:null,institution:{name:"Grenoble Alpes University",country:{name:"France"}}},{id:"131400",title:"Prof.",name:"Alfonso J.",middleName:null,surname:"Rodriguez-Morales",slug:"alfonso-j.-rodriguez-morales",fullName:"Alfonso J. Rodriguez-Morales",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/131400/images/system/131400.png",biography:"Dr. Rodriguez-Morales is an expert in tropical and emerging diseases, particularly zoonotic and vector-borne diseases (especially arboviral diseases). He is the president of the Travel Medicine Committee of the Pan-American Infectious Diseases Association (API), as well as the president of the Colombian Association of Infectious Diseases (ACIN). He is a member of the Committee on Tropical Medicine, Zoonoses, and Travel Medicine of ACIN. He is a vice-president of the Latin American Society for Travel Medicine (SLAMVI) and a Member of the Council of the International Society for Infectious Diseases (ISID). Since 2014, he has been recognized as a Senior Researcher, at the Ministry of Science of Colombia. He is a professor at the Faculty of Medicine of the Fundacion Universitaria Autonoma de las Americas, in Pereira, Risaralda, Colombia. He is an External Professor, Master in Research on Tropical Medicine and International Health, Universitat de Barcelona, Spain. He is also a professor at the Master in Clinical Epidemiology and Biostatistics, Universidad Científica del Sur, Lima, Peru. In 2021 he has been awarded the “Raul Isturiz Award” Medal of the API. Also, in 2021, he was awarded with the “Jose Felix Patiño” Asclepius Staff Medal of the Colombian Medical College, due to his scientific contributions to COVID-19 during the pandemic. He is currently the Editor in Chief of the journal Travel Medicine and Infectious Diseases. His Scopus H index is 47 (Google Scholar H index, 68).",institutionString:"Institución Universitaria Visión de las Américas, Colombia",institution:null},{id:"332819",title:"Dr.",name:"Chukwudi Michael",middleName:"Michael",surname:"Egbuche",slug:"chukwudi-michael-egbuche",fullName:"Chukwudi Michael Egbuche",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/332819/images/14624_n.jpg",biography:"I an Dr. Chukwudi Michael Egbuche. I am a Senior Lecturer in the Department of Parasitology and Entomology, Nnamdi Azikiwe University, Awka.",institutionString:null,institution:{name:"Nnamdi Azikiwe University",country:{name:"Nigeria"}}},{id:"284232",title:"Mr.",name:"Nikunj",middleName:"U",surname:"Tandel",slug:"nikunj-tandel",fullName:"Nikunj Tandel",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/284232/images/8275_n.jpg",biography:'Mr. Nikunj Tandel has completed his Master\'s degree in Biotechnology from VIT University, India in the year of 2012. He is having 8 years of research experience especially in the field of malaria epidemiology, immunology, and nanoparticle-based drug delivery system against the infectious diseases, autoimmune disorders and cancer. He has worked for the NIH funded-International Center of Excellence in Malaria Research project "Center for the study of complex malaria in India (CSCMi)" in collaboration with New York University. The preliminary objectives of the study are to understand and develop the evidence-based tools and interventions for the control and prevention of malaria in different sites of the INDIA. Alongside, with the help of next-generation genomics study, the team has studied the antimalarial drug resistance in India. Further, he has extended his research in the development of Humanized mice for the study of liver-stage malaria and identification of molecular marker(s) for the Artemisinin resistance. At present, his research focuses on understanding the role of B cells in the activation of CD8+ T cells in malaria. Received the CSIR-SRF (Senior Research Fellow) award-2018, FIMSA (Federation of Immunological Societies of Asia-Oceania) Travel Bursary award to attend the IUIS-IIS-FIMSA Immunology course-2019',institutionString:"Nirma University",institution:{name:"Nirma University",country:{name:"India"}}},{id:"334383",title:"Ph.D.",name:"Simone",middleName:"Ulrich",surname:"Ulrich Picoli",slug:"simone-ulrich-picoli",fullName:"Simone Ulrich Picoli",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/334383/images/15919_n.jpg",biography:"Graduated in Pharmacy from Universidade Luterana do Brasil (1999), Master in Agricultural and Environmental Microbiology from Federal University of Rio Grande do Sul (2002), Specialization in Clinical Microbiology from Universidade de São Paulo, USP (2007) and PhD in Sciences in Gastroenterology and Hepatology (2012). She is currently an Adjunct Professor at Feevale University in Medicine and Biomedicine courses and a permanent professor of the Academic Master\\'s Degree in Virology. She has experience in the field of Microbiology, with an emphasis on Bacteriology, working mainly on the following topics: bacteriophages, bacterial resistance, clinical microbiology and food microbiology.",institutionString:null,institution:{name:"Universidade Feevale",country:{name:"Brazil"}}},{id:"229220",title:"Dr.",name:"Amjad",middleName:"Islam",surname:"Aqib",slug:"amjad-aqib",fullName:"Amjad Aqib",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/229220/images/system/229220.png",biography:"Dr. Amjad Islam Aqib obtained a DVM and MSc (Hons) from University of Agriculture Faisalabad (UAF), Pakistan, and a PhD from the University of Veterinary and Animal Sciences Lahore, Pakistan. Dr. Aqib joined the Department of Clinical Medicine and Surgery at UAF for one year as an assistant professor where he developed a research laboratory designated for pathogenic bacteria. Since 2018, he has been Assistant Professor/Officer in-charge, Department of Medicine, Manager Research Operations and Development-ORIC, and President One Health Club at Cholistan University of Veterinary and Animal Sciences, Bahawalpur, Pakistan. He has nearly 100 publications to his credit. His research interests include epidemiological patterns and molecular analysis of antimicrobial resistance and modulation and vaccine development against animal pathogens of public health concern.",institutionString:"Cholistan University of Veterinary and Animal Sciences",institution:null},{id:"62900",title:"Prof.",name:"Fethi",middleName:null,surname:"Derbel",slug:"fethi-derbel",fullName:"Fethi Derbel",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/62900/images/system/62900.jpeg",biography:"Professor Fethi Derbel was born in 1960 in Tunisia. He received his medical degree from the Sousse Faculty of Medicine at Sousse, University of Sousse, Tunisia. He completed his surgical residency in General Surgery at the University Hospital Farhat Hached of Sousse and was a member of the Unit of Liver Transplantation in the University of Rennes, France. He then worked in the Department of Surgery at the Sahloul University Hospital in Sousse. Professor Derbel is presently working at the Clinique les Oliviers, Sousse, Tunisia. His hospital activities are mostly concerned with laparoscopic, colorectal, pancreatic, hepatobiliary, and gastric surgery. He is also very interested in hernia surgery and performs ventral hernia repairs and inguinal hernia repairs. He has been a member of the GREPA and Tunisian Hernia Society (THS). During his residency, he managed patients suffering from diabetic foot, and he was very interested in this pathology. For this reason, he decided to coordinate a book project dealing with the diabetic foot. Professor Derbel has published many articles in journals and collaborates intensively with IntechOpen Access Publisher as an editor.",institutionString:"Clinique les Oliviers",institution:null},{id:"300144",title:"Dr.",name:"Meriem",middleName:null,surname:"Braiki",slug:"meriem-braiki",fullName:"Meriem Braiki",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/300144/images/system/300144.jpg",biography:"Dr. Meriem Braiki is a specialist in pediatric surgeon from Tunisia. She was born in 1985. She received her medical degree from the University of Medicine at Sousse, Tunisia. She achieved her surgical residency training periods in Pediatric Surgery departments at University Hospitals in Monastir, Tunis and France.\r\nShe is currently working at the Pediatric surgery department, Sidi Bouzid Hospital, Tunisia. Her hospital activities are mostly concerned with laparoscopic, parietal, urological and digestive surgery. She has published several articles in diffrent journals.",institutionString:"Sidi Bouzid Regional Hospital",institution:null},{id:"229481",title:"Dr.",name:"Erika M.",middleName:"Martins",surname:"de Carvalho",slug:"erika-m.-de-carvalho",fullName:"Erika M. de Carvalho",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/229481/images/6397_n.jpg",biography:null,institutionString:null,institution:{name:"Oswaldo Cruz Foundation",country:{name:"Brazil"}}},{id:"186537",title:"Prof.",name:"Tonay",middleName:null,surname:"Inceboz",slug:"tonay-inceboz",fullName:"Tonay Inceboz",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/186537/images/system/186537.jfif",biography:"I was graduated from Ege University of Medical Faculty (Turkey) in 1988 and completed his Med. PhD degree in Medical Parasitology at the same university. I became an Associate Professor in 2008 and Professor in 2014. I am currently working as a Professor at the Department of Medical Parasitology at Dokuz Eylul University, Izmir, Turkey.\n\nI have given many lectures, presentations in different academic meetings. I have more than 60 articles in peer-reviewed journals, 18 book chapters, 1 book editorship.\n\nMy research interests are Echinococcus granulosus, Echinococcus multilocularis (diagnosis, life cycle, in vitro and in vivo cultivation), and Trichomonas vaginalis (diagnosis, PCR, and in vitro cultivation).",institutionString:"Dokuz Eylül University",institution:{name:"Dokuz Eylül University",country:{name:"Turkey"}}},{id:"71812",title:"Prof.",name:"Hanem Fathy",middleName:"Fathy",surname:"Khater",slug:"hanem-fathy-khater",fullName:"Hanem Fathy Khater",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/71812/images/1167_n.jpg",biography:"Prof. Khater is a Professor of Parasitology at Benha University, Egypt. She studied for her doctoral degree, at the Department of Entomology, College of Agriculture, Food and Natural Resources, University of Missouri, Columbia, USA. She has completed her Ph.D. degrees in Parasitology in Egypt, from where she got the award for “the best scientific Ph.D. dissertation”. She worked at the School of Biological Sciences, Bristol, England, the UK in controlling insects of medical and veterinary importance as a grant from Newton Mosharafa, the British Council. Her research is focused on searching of pesticides against mosquitoes, house flies, lice, green bottle fly, camel nasal botfly, soft and hard ticks, mites, and the diamondback moth as well as control of several parasites using safe and natural materials to avoid drug resistances and environmental contamination.",institutionString:null,institution:{name:"Banha University",country:{name:"Egypt"}}},{id:"99780",title:"Prof.",name:"Omolade",middleName:"Olayinka",surname:"Okwa",slug:"omolade-okwa",fullName:"Omolade Okwa",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/99780/images/system/99780.jpg",biography:"Omolade Olayinka Okwa is presently a Professor of Parasitology at Lagos State University, Nigeria. She has a PhD in Parasitology (1997), an MSc in Cellular Parasitology (1992), and a BSc (Hons) Zoology (1990) all from the University of Ibadan, Nigeria. She teaches parasitology at the undergraduate and postgraduate levels. She was a recipient of a Commonwealth fellowship supported by British Council tenable at the Centre for Entomology and Parasitology (CAEP), Keele University, United Kingdom between 2004 and 2005. She was awarded an Honorary Visiting Research Fellow at the same university from 2005 to 2007. \nShe has been an external examiner to the Department of Veterinary Microbiology and Parasitology, University of Ibadan, MSc programme between 2010 and 2012. She is a member of the Nigerian Society of Experimental Biology (NISEB), Parasitology and Public Health Society of Nigeria (PPSN), Science Association of Nigeria (SAN), Zoological Society of Nigeria (ZSN), and is Vice Chairperson of the Organisation of Women in Science (OWSG), LASU chapter. She served as Head of Department of Zoology and Environmental Biology, Lagos State University from 2007 to 2010 and 2014 to 2016. She is a reviewer for several local and international journals such as Unilag Journal of Science, Libyan Journal of Medicine, Journal of Medicine and Medical Sciences, and Annual Research and Review in Science. \nShe has authored 45 scientific research publications in local and international journals, 8 scientific reviews, 4 books, and 3 book chapters, which includes the books “Malaria Parasites” and “Malaria” which are IntechOpen access publications.",institutionString:"Lagos State University",institution:{name:"Lagos State University",country:{name:"Nigeria"}}},{id:"273100",title:"Dr.",name:"Vijay",middleName:null,surname:"Gayam",slug:"vijay-gayam",fullName:"Vijay Gayam",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/273100/images/system/273100.jpeg",biography:"Dr. Vijay Bhaskar Reddy Gayam is currently practicing as an internist at Interfaith Medical Center in Brooklyn, New York, USA. He is also a Clinical Assistant Professor at the SUNY Downstate University Hospital and Adjunct Professor of Medicine at the American University of Antigua. He is a holder of an M.B.B.S. degree bestowed to him by Osmania Medical College and received his M.D. at Interfaith Medical Center. His career goals thus far have heavily focused on direct patient care, medical education, and clinical research. He currently serves in two leadership capacities; Assistant Program Director of Medicine at Interfaith Medical Center and as a Councilor for the American\r\nFederation for Medical Research. As a true academician and researcher, he has more than 50 papers indexed in international peer-reviewed journals. He has also presented numerous papers in multiple national and international scientific conferences. His areas of research interest include general internal medicine, gastroenterology and hepatology. He serves as an editor, editorial board member and reviewer for multiple international journals. His research on Hepatitis C has been very successful and has led to multiple research awards, including the 'Equity in Prevention and Treatment Award” from the New York Department of Health Viral Hepatitis Symposium (2018) and the 'Presidential Poster Award” awarded to him by the American College of Gastroenterology (2018). He was also awarded 'Outstanding Clinician in General Medicine” by Venus International Foundation for his extensive research expertise and services, perform over and above the standard expected in the advancement of healthcare, patient safety and quality of care.",institutionString:"Interfaith Medical Center",institution:{name:"Interfaith Medical Center",country:{name:"United States of America"}}},{id:"93517",title:"Dr.",name:"Clement",middleName:"Adebajo",surname:"Meseko",slug:"clement-meseko",fullName:"Clement Meseko",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/93517/images/system/93517.jpg",biography:"Dr. Clement Meseko obtained DVM and PhD degree in Veterinary Medicine and Virology respectively. He has worked for over 20 years in both private and public sectors including the academia, contributing to knowledge and control of infectious disease. Through the application of epidemiological skill, classical and molecular virological skills, he investigates viruses of economic and public health importance for the mitigation of the negative impact on people, animal and the environment in the context of Onehealth. \r\nDr. Meseko’s field experience on animal and zoonotic diseases and pathogen dynamics at the human-animal interface over the years shaped his carrier in research and scientific inquiries. He has been part of the investigation of Highly Pathogenic Avian Influenza incursions in sub Saharan Africa and monitors swine Influenza (Pandemic influenza Virus) agro-ecology and potential for interspecies transmission. 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His research work has been published in various high-impact factor journals (Science, PNAS, Nature Medicine) with a high number of citations. He has received many awards and honors in India and abroad including various Young Scientist Awards, BBSRC India Partnering Award, and Dr. JC Bose National Award of Department of Biotechnology, Min. of Science and Technology, Govt. of India. Dr. Saxena is a fellow of various international societies/academies including the Royal College of Pathologists, United Kingdom; Royal Society of Medicine, London; Royal Society of Biology, United Kingdom; Royal Society of Chemistry, London; and Academy of Translational Medicine Professionals, Austria. He was named a Global Leader in Science by The Scientist. 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Voyich",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Montana State University",country:{name:"United States of America"}}},{id:"330412",title:"Dr.",name:"Muhammad",middleName:null,surname:"Farhab",slug:"muhammad-farhab",fullName:"Muhammad Farhab",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Agriculture Faisalabad",country:{name:"Pakistan"}}},{id:"349495",title:"Dr.",name:"Muhammad",middleName:null,surname:"Ijaz",slug:"muhammad-ijaz",fullName:"Muhammad Ijaz",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Veterinary and Animal Sciences",country:{name:"Pakistan"}}}]}},subseries:{item:{id:"95",type:"subseries",title:"Urban Planning and Environmental Management",keywords:"Circular economy, Contingency planning and response to disasters, Ecosystem services, Integrated urban water management, Nature-based solutions, Sustainable urban development, Urban green spaces",scope:"