Physical characteristics of the main isotopes positron emitters used in positron emission tomography (PET).
\r\n\tFood insecurity results in fear of hunger and starvation that ultimately affects one’s ability to work for sustainability and economic growth of the country. In addition to this, food insecurity results in various chronic diseases due to reduce immunity that ultimately, a burned on the county economy. Therefore, this book will intend to discuss in detail about the food insecurity challenges and their effect on the quality of life. This book will also aim to provide an overview about the new trends and future prospective that help to resolve the food security issues.
",isbn:"978-1-80356-942-0",printIsbn:"978-1-80356-941-3",pdfIsbn:"978-1-80356-943-7",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!0,isSalesforceBook:!1,isNomenclature:!1,hash:"090302a30e461cee643ec49675c811ec",bookSignature:"Dr. Muhammad Haseeb Ahmad, Dr. Muhammad Imran and Dr. Muhammad Kamran Khan",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/11475.jpg",keywords:"Nutrition, Poverty, Hunger, Food Waste Utilization, Innovative Technologies, Food Processing, Genetically Modified Food, Policy Making, Trade Reforms, Climate Change, Agriculture Productivity, Disease Resistant Crops",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"April 7th 2022",dateEndSecondStepPublish:"May 5th 2022",dateEndThirdStepPublish:"July 4th 2022",dateEndFourthStepPublish:"September 22nd 2022",dateEndFifthStepPublish:"November 21st 2022",dateConfirmationOfParticipation:null,remainingDaysToSecondStep:"2 months",secondStepPassed:!0,areRegistrationsClosed:!1,currentStepOfPublishingProcess:3,editedByType:null,kuFlag:!1,biosketch:"An emerging scientist in the field of food science and technology with special expertise in development of rapid and nondestructive technologies, chemometrics and data mining.",coeditorOneBiosketch:"Muhammad Imran has expertise in extrusion technology, microencapsulation, lipids chemistry, sensory evaluation and food process engineering.",coeditorTwoBiosketch:"A renowned scientist with expertise in Novel food processing technologies.",coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"292145",title:"Dr.",name:"Muhammad",middleName:null,surname:"Haseeb Ahmad",slug:"muhammad-haseeb-ahmad",fullName:"Muhammad Haseeb Ahmad",profilePictureURL:"https://mts.intechopen.com/storage/users/292145/images/system/292145.png",biography:"Dr. Muhammad Haseeb Ahmad is currently an assistant professor in the Department of Food Science, Government College University Faisalabad, Pakistan. He also served as an assistant professor for one year at the National Institute of Food Science and Technology, University of Agriculture Faisalabad, Pakistan. He received his doctoral degree from Hohenheim University, Stuttgart, Germany, in 2016. During his stay there, he also worked as a research associate for research projects relevant to various food disciplines. Dr. Ahmad is the author of about thirty five research publications and twelve book chapters. He has also presented his research work at various national and international conferences (25). His area of research is food science with special expertise in process analytics and data mining.",institutionString:"Government College University, Faisalabad",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"2",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"Government College University, Faisalabad",institutionURL:null,country:{name:"Pakistan"}}}],coeditorOne:{id:"208646",title:"Dr.",name:"Muhammad",middleName:null,surname:"Imran",slug:"muhammad-imran",fullName:"Muhammad Imran",profilePictureURL:"https://mts.intechopen.com/storage/users/208646/images/system/208646.jpg",biography:"Dr. Muhammad Imran, is an Assistant Professor in the Department of Food Science, Faculty of Life Sciences, Government College University, Faisalabad–Pakistan since September 03, 2012. Dr. Muhammad Imran completed his Doctorate (Food Technology) from the National Institute of Food Science and Technology, University of Agriculture, Faisalabad. He won the Indigenous and IRSIP (Department of Food Science and Human Nutrition, Michigan State University, East Lansing, USA) Fellowships for completion of doctorate research funded by HEC, Islamabad, Pakistan. Dr. Muhammad Imran has expertise in extrusion technology, microencapsulation, lipids chemistry, sensory evaluation, and food process engineering. Until today, Dr. Muhammad Imran has authored 80 publications (International & National) in various Impact Journals of Scientific repute and written 15 Book Chapters as principal author and co-author. Dr. Muhammad Imran has attended several International Conferences (held nationally and locally) as an Invited and Keynote Speaker and also participated as an organizing member to conduct International Conferences, Seminars Workshops, etc. Dr. Muhammad Imran is a Life Time Member of PSFST.",institutionString:"Government College University, Faisalabad",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"2",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"Government College University, Faisalabad",institutionURL:null,country:{name:"Pakistan"}}},coeditorTwo:{id:"208645",title:"Dr.",name:"Muhammad",middleName:null,surname:"Kamran Khan",slug:"muhammad-kamran-khan",fullName:"Muhammad Kamran Khan",profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:"Government College University Faisalabad",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"2",totalChapterViews:"0",totalEditedBooks:"0",institution:null},coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"5",title:"Agricultural and Biological Sciences",slug:"agricultural-and-biological-sciences"}],chapters:null,productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"429339",firstName:"Jelena",lastName:"Vrdoljak",middleName:null,title:"Ms.",imageUrl:"https://mts.intechopen.com/storage/users/429339/images/20012_n.jpg",email:"jelena.v@intechopen.com",biography:"As an Author Service Manager, my responsibilities include monitoring and facilitating all publishing activities for authors and editors. From chapter submission and review to approval and revision, copyediting and design, until final publication, I work closely with authors and editors to ensure a simple and easy publishing process. I maintain constant and effective communication with authors, editors and reviewers, which allows for a level of personal support that enables contributors to fully commit and concentrate on the chapters they are writing, editing, or reviewing. I assist authors in the preparation of their full chapter submissions and track important deadlines and ensure they are met. I help to coordinate internal processes such as linguistic review, and monitor the technical aspects of the process. As an ASM I am also involved in the acquisition of editors. Whether that be identifying an exceptional author and proposing an editorship collaboration, or contacting researchers who would like the opportunity to work with IntechOpen, I establish and help manage author and editor acquisition and contact."}},relatedBooks:[{type:"book",id:"6418",title:"Hyperspectral Imaging in Agriculture, Food and Environment",subtitle:null,isOpenForSubmission:!1,hash:"9005c36534a5dc065577a011aea13d4d",slug:"hyperspectral-imaging-in-agriculture-food-and-environment",bookSignature:"Alejandro Isabel Luna Maldonado, Humberto Rodríguez Fuentes and Juan Antonio Vidales Contreras",coverURL:"https://cdn.intechopen.com/books/images_new/6418.jpg",editedByType:"Edited by",editors:[{id:"105774",title:"Prof.",name:"Alejandro Isabel",surname:"Luna Maldonado",slug:"alejandro-isabel-luna-maldonado",fullName:"Alejandro Isabel Luna Maldonado"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10359",title:"Landraces",subtitle:"Traditional Variety and Natural Breed",isOpenForSubmission:!1,hash:"0600836fb2c422f7b624363d1e854f68",slug:"landraces-traditional-variety-and-natural-breed",bookSignature:"Amr Elkelish",coverURL:"https://cdn.intechopen.com/books/images_new/10359.jpg",editedByType:"Edited by",editors:[{id:"231337",title:"Dr.",name:"Amr",surname:"Elkelish",slug:"amr-elkelish",fullName:"Amr Elkelish"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1591",title:"Infrared Spectroscopy",subtitle:"Materials Science, Engineering and Technology",isOpenForSubmission:!1,hash:"99b4b7b71a8caeb693ed762b40b017f4",slug:"infrared-spectroscopy-materials-science-engineering-and-technology",bookSignature:"Theophile Theophanides",coverURL:"https://cdn.intechopen.com/books/images_new/1591.jpg",editedByType:"Edited by",editors:[{id:"37194",title:"Dr.",name:"Theophile",surname:"Theophanides",slug:"theophile-theophanides",fullName:"Theophile Theophanides"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3161",title:"Frontiers in Guided Wave Optics and Optoelectronics",subtitle:null,isOpenForSubmission:!1,hash:"deb44e9c99f82bbce1083abea743146c",slug:"frontiers-in-guided-wave-optics-and-optoelectronics",bookSignature:"Bishnu Pal",coverURL:"https://cdn.intechopen.com/books/images_new/3161.jpg",editedByType:"Edited by",editors:[{id:"4782",title:"Prof.",name:"Bishnu",surname:"Pal",slug:"bishnu-pal",fullName:"Bishnu Pal"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3092",title:"Anopheles mosquitoes",subtitle:"New insights into malaria vectors",isOpenForSubmission:!1,hash:"c9e622485316d5e296288bf24d2b0d64",slug:"anopheles-mosquitoes-new-insights-into-malaria-vectors",bookSignature:"Sylvie Manguin",coverURL:"https://cdn.intechopen.com/books/images_new/3092.jpg",editedByType:"Edited by",editors:[{id:"50017",title:"Prof.",name:"Sylvie",surname:"Manguin",slug:"sylvie-manguin",fullName:"Sylvie Manguin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"371",title:"Abiotic Stress in Plants",subtitle:"Mechanisms and Adaptations",isOpenForSubmission:!1,hash:"588466f487e307619849d72389178a74",slug:"abiotic-stress-in-plants-mechanisms-and-adaptations",bookSignature:"Arun Shanker and B. Venkateswarlu",coverURL:"https://cdn.intechopen.com/books/images_new/371.jpg",editedByType:"Edited by",editors:[{id:"58592",title:"Dr.",name:"Arun",surname:"Shanker",slug:"arun-shanker",fullName:"Arun Shanker"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"72",title:"Ionic Liquids",subtitle:"Theory, Properties, New Approaches",isOpenForSubmission:!1,hash:"d94ffa3cfa10505e3b1d676d46fcd3f5",slug:"ionic-liquids-theory-properties-new-approaches",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/72.jpg",editedByType:"Edited by",editors:[{id:"19816",title:"Prof.",name:"Alexander",surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"314",title:"Regenerative Medicine and Tissue Engineering",subtitle:"Cells and Biomaterials",isOpenForSubmission:!1,hash:"bb67e80e480c86bb8315458012d65686",slug:"regenerative-medicine-and-tissue-engineering-cells-and-biomaterials",bookSignature:"Daniel Eberli",coverURL:"https://cdn.intechopen.com/books/images_new/314.jpg",editedByType:"Edited by",editors:[{id:"6495",title:"Dr.",name:"Daniel",surname:"Eberli",slug:"daniel-eberli",fullName:"Daniel Eberli"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"57",title:"Physics and Applications of Graphene",subtitle:"Experiments",isOpenForSubmission:!1,hash:"0e6622a71cf4f02f45bfdd5691e1189a",slug:"physics-and-applications-of-graphene-experiments",bookSignature:"Sergey Mikhailov",coverURL:"https://cdn.intechopen.com/books/images_new/57.jpg",editedByType:"Edited by",editors:[{id:"16042",title:"Dr.",name:"Sergey",surname:"Mikhailov",slug:"sergey-mikhailov",fullName:"Sergey Mikhailov"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1373",title:"Ionic Liquids",subtitle:"Applications and Perspectives",isOpenForSubmission:!1,hash:"5e9ae5ae9167cde4b344e499a792c41c",slug:"ionic-liquids-applications-and-perspectives",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/1373.jpg",editedByType:"Edited by",editors:[{id:"19816",title:"Prof.",name:"Alexander",surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"43519",title:"Principles and Applications of Nuclear Medical Imaging: A Survey on Recent Developments",doi:"10.5772/54884",slug:"principles-and-applications-of-nuclear-medical-imaging-a-survey-on-recent-developments",body:'The main difference between nuclear imaging and other radiologic tests is that nuclear imaging assesses how organs function, whereas other imaging methods assess anatomy, or how the organs look. The advantage of assessing the function of an organ is that it helps physicians make a diagnosis and plan present or future treatments for the part of the body being evaluated. Fast improvements in engineering and computing technologies have made it possible to acquire high-resolution multidimensional nuclear images of complex organs to analyze structural and functional information of human physiology for computer-assisted diagnosis, treatment evaluation, and intervention. Technological inventions and developments have created new possibilities and breakthroughs in nuclear medical diagnostics. The classic example is the discovery of Anger, fifty six years ago. The application and commercial success of new nuclear imaging methods depends mainly on three primary factors: sensitivity, specificity and cost effectiveness. The first two determine the added clinical value, in comparison with existing medical imaging methods. Nowadays, much greater importance is attached to cost effectiveness than in the past. This also holds true for diagnostic equipment where, for example, one of the consequences is that price erosion will occur where the functionality of an instrument is not open to further development. Cost effectiveness is enhanced by more efficient data handling in the hospitals, which has become possible through the digitization of diagnostic information. The inevitable integration of medical data also offers other new possibilities, such as the use of pre-operatively acquired images during surgical procedures.
This chapter presents the principles of nuclear imaging methods and some cases studies and future trends of nuclear imaging. It discusses too the recent developments in image analysis and the possible impact of some important current technological progression on nuclear medical imaging. The survey is limited to developments for hospitals, mainly within the product range of some famous and emerging international companies.
In addition to conventional gamma scintigraphic imaging, the two major nuclear imaging techniques developed are Positron Emission Tomography (PET) and Single Photon Emission Computed Tomography (SCECT). Both imaging modalities are now standard in the major nuclear medicine services.
The principle of radiation detection is based on the interaction of these radiations with the matter. When a gamma photon enters in interaction with a detector material, it loses its energy mainly in the form of ionizations or excitations. The excited atoms return to their ground state through the emission of secondary low energy gamma photons. The incident gamma photon can be partially or totally absorbed (photoelectric effect). In the first case, the energy loss is accompanied by a deviation of the photon (Compton scattering). The photon loses "memory" of its initial place of issue. So the photoelectric effect is the right phenomenon which must be considered when we interest to the gamma-ray emission site.
In the gamma camera, the detection medium is historically a NaI scintillation crystal typically doped with thallium. This crystal is able to emit light especially through a fluorescence process after the excitation of its molecules by a charged particle (electron). The density of NaI is 3.67 g/cm3 and its atomic number 50. Its time of scintillation (fluorescence) is 230 nm and the maximum light emission is at 4150 Angstroms wave length. Its refractive index is 1.85, and it is relatively transparent to its own light; about 30% of emitted light is transmitted to the detection chain [1]. The energy resolution can reach 7-8% at 1 MeV and the constant time of their pulse is equal to ~10-7 sec. The detection efficiency of NaI is quite large, of the order of 40 photons/keV. Indeed, gamma-ray energy of 100 keV transferring all its energy in the crystal results in the creation of approximately 4000 fluorescence light photons. These photons are collected by the photocathode of a photomultiplier tube (Figure 1).
Main components of Gamma-camera.
For the detection of the secondary light photons generated in the crystal by the interaction with the incident gamma radiations, a photomultiplier tube (PMT) located behind the scintillator is used (Figure 1). At the level of the PMT photocathode, each light photon is converted to electrons. These electrons are then accelerated and multiplied by ten dynodes polarized by a gradually increasing voltage, and finally collected by an anode placed at the other side of the PMT where they give birth to an electrical impulse. This pulse has an amplitude proportional to the energy of the detected gamma-ray.
The output signal is amplified by the PMT. Its amplitude is measured, digitized and stored. Numerical analysis enables to obtain a spectrum (number of photons detected as a function of their energy) characteristic of the detected gamma-rays. Detection time (acquisition) should be sufficient to obtain good counting statistics. The theoretical gamma-rays spectrum reaching the crystal is a line spectrum; the spectrum is continuous (Figure 2). The spectrum includes the total energy peak corresponding to gamma directly emitted by the radioactive source without any interaction before reaching the crystal and a background of lower energies due to the partial absorption of gamma by Compton scattering. Compton scattering in the path of the photon is changed making it impossible to locate its transmitter site. It is therefore necessary to take into account only the events corresponding to the photoelectric interactions at the level of the crystal with the total emission energy. This is achieved by the intermediate of a "window" for selecting the double-threshold energy (pulse height analyzer).
Gamma-rays spectrum at the level of the crystal detector (ideal (top) and real (bottom) cases).
The width of the peak of total absorption depends essentially of the random statistical fluctuations of the gain of the PMT. The width at half maximum ΔE relative to an average energy E0 defines the energy resolution ΔE/E0. The energy resolution of PMT is about 10% at 140 keV (emission peak of technetium-99m). The pulses selected by the pulse analyzer (maximum intensity) are directed to a time scaling circuit having a time integrator which then delivers a count rate in counts per second (cps). This count rate can be correlated to the real activity of the source after a number of corrections taking into account in particular the geometric efficiency and the detection performance of the detection chain. For very high source activity, the detector response is no longer linear so that a number of events are not taken into account. The lapse of time in which these events are lost (not counted by the detector) is called the dead time. In practice, it is usual, to work under conditions such that the detection dead time correction is not necessary (medium activity source).
The Anger gamma scintillation camera (Figure 3) uses the information provided by the amplitude of the electrical pulse not only to measure the energy of the detected radiation, but also to locate in the space the emission site of this radiation.
The camera developed by Anger in 1953 has a crystal of sodium iodide (NaI) thallium activated. It can take single crystal of large dimensions, up to 60x50 cm2 with a thickness ranging from 1/4 inch to 1 inch [1]. These crystals are fragile and are highly sensitive to shocks and moisture. The surface of the crystal is covered with a large number of PMTs (between 50 and 100). When scintillation occurs, the sum of the output signals of all the MPTs provides the energy lost in the volume of the scintillator (Z coordinate). The large number of PMTs ensures the collection of maximum light. Moreover, the amplitude of the output signal of PMT varies with the distance between the centre of the photocathode and the place where the scintilaltion is produced is in the crystal. The amplitude distribution of the output pulses of the PMT then provides the location information (X and Y coordinates) by means of a computer listing. For each photon interacting with the detector is thus obtained location coordinates (X and Y) and a value of the energy given or lost in the crystal (Z coordinate). An amplitude analysis allows selecting only the photon energy characteristic of the radionuclide used (eg. 140 keV for 99mTc) having lost all their energy in the crystal (photoelectric peak).
Gamma-camera called also Anger camera.
The scintillation Gamma-camera was used originally for planer projection imaging is mainly composed by the following components:
The scintigraphic image corresponds to the projection of the distribution of radioactivity on the crystal detector. Gamma rays cannot be focused using lenses as in the case of light. The use of a special kind of collimator can permit just to one direction gamma rays to reach the crystal, the most common being perpendicular to the crystal. A collimator is a wafer usually lead wherein cylindrical or conical holes are drilled along a system axes determined. Gamma-ray where the path does not borrow these directions is absorbed by the collimator before reaching the crystal. The partition (wall) separating two adjacent holes i called "septa". The thickness of lead is calculated to cause an attenuation of at least 95% of the energy of the photons passing through the septa. The most commonly used collimator is the parallel holes. It retains the dimensions of the image. For non-parallel collimators, the dimensions of the image depend on the geometrical disposition and the divergence or convergence nature of the collimator. This leads to a geometric distortion must be taken into account. The efficiency of a collimator is the fraction of radiation passing through the collimator (without any interaction), reaching the crystal and effectively participating in the image formation. The collimator resolution corresponds to the accuracy of the image formed in the detector. Resolution improves with increasing thickness of the septa at the expense of collimator efficiency. A good compromise is to find the realization of a collimator performance depends on the intrinsic characteristics of the detector and the use we want to make [2].
The
Their role is to convert light energy emitted by the crystal to an electrical signal that can be exploited in electronic circuits [3, 5]. This is achieved by the combination of several elements, placed in a vacuum to allow the flow of electrons. The first element, placed in contact with the crystal is the photocathode, metal foil on which the light photons are able to extract electrons. These electrons are attracted to the first dynode by the application of a high voltage between it (positively charged) and the photocathode. The electrons acceleration allows them to extract a much larger number of electrons from the dynode. Then there are several cascading dynodes, on which the same phenomenon is repeated. The successive dynodes are submitted to potentials higher and higher. From a dynode to another, we obtain a cascade of electrons more intense (amplification phenomenon), which ultimately results in a measurable electric current. This current is collected by the last element called anode and a real electrical signal is generated (Figure 4).
PMTs disposition in a Gamma-camera. Generally a hexagonal shape of PTM is preferred then a circular because it well cover the detection area. Additional very small PMT can also be used between principal PMT for best detection area covering (CEM, Rennes, France).
Scintigraphy is a method designed to reproduce the shape or to measure the activity of an organ by administering a product which contains an element which emits radioactivity, an isotope. The radioactivity emitted by the isotope is picked up by special detectors called gamma-cameras counters described above. Generally, the dose is administered to a patient in need of scintigraphy is safe for the body (except for pregnancy). The data acquisition principle is illustrated on the diagram of Figure 5.
Illustration of data acquisition in planer gamma scintigraphy.
The use of radioactive tracers that are introduced in the living system to study its metabolism dates from 1923 when de Hevesy and Paneth studied the transport of radioactive lead in plants [6]. In 1935, de Hevesy and Chiewitz were the first to apply the method to the study of the distribution of a radiotracer (P-32) in rats [7]. The major development of scintigraphic imaging started with the invention of the gamma camera by Anger in 1956 [1]. In parallel, positron imaging was developed. Both imaging modalities are now standard in the major nuclear medicine departments.
The tracer principle, which forms the basis of nuclear imaging, is the following: a radioactive biologically active substance is chosen in such a way that its spatial and temporal distribution in the body reflects a particular body function or metabolism. In order to study the distribution without disturbing the body function, only traces of the substance are administered to the patient [8, 9].
The radiotracer decays by emitting gamma rays or positrons (followed by annihilation gamma rays).The distribution of the radioactive tracer is inferred from the detected gamma rays and mapped as a function of time and/or space.
The most often used radio-nuclides are Tc-99m in \'single photon\' imaging and F-18 in \'positron\' imaging. Tc-99m is the decay daughter of Mo-99 which itself is a fission product of U. The half-life of Tc-99m is 6h, which is optimal for most metabolic studies but too short to allow for long time storage. Mo-99 has a half-life of 65h. This allows a Mo-99 generator (a \'cow\') to be stored and Tc-99m to be \'milked\' when required. Tc-99m decays to Tc-99 by emitting a gamma ray with an energy output of 14O keV. This energy is optimal for detection by scintillator detectors. Tc-99 itself has a half-life of 211100 years and is therefore a negligible burden to the patient [8, 9].
F-18 is cyclotron produced and has a half-life of 110 minutes. It decays to stable O-18 by emitting a positron. The positron loses its kinetic energy through Coulomb interactions with surrounding nuclei. When it is nearly at rest, which in tissue occurs after an average range of less than 1 mm, the probability of a collision with an electron greatly increases and becomes one. During the collision matter-antimatter annihilation occurs in which the rest mass of the electron and the positron is transformed into two gamma rays of 511 keV. The two gamma rays originate at exactly the same time (they are “coincident”) and leave the point of collision in almost opposite directions [9].
Different modalities of scintigraphic acquisition are possible:
Static acquisition with a detector in a fixed position relative the patient: examination of thyroid, kidney....
Scanning of the whole body: succession of static images joined: the detector move simultaneously and scan the patient\'s body from head to foot. The bone scan is a routine application.
Tomographic acquisition: The Positron Emission Single Photon (SPECT): detectors rotate around the patient to obtain in a digital representation of a 3D radioactive distribution of the body: chest, pelvis, skull....
Dynamic acquisition as a function of time: a number of successive static images used to reconstruct a video to study some interesting dynamic biological processes. Interesting applications are: kidney and bone phase’s vascular scans and scintigraphy of the heart ventricle.
ECG ECG : Electrocardiogram.
This medical imaging method was introduced in 1963 by Kuhl and Edwards [10]. Known by the acronym SPECT (Single Photon Emission Computerized Tomography), this imaging method is equivalent in scintigraphy to Computed Tomography (CT) in radiology. The injected radioactive tracers emit during their disintegration gamma photons which are detected by an external detector, after passing through the surrounding tissue. Because the gamma photons emission is isotropic, a collimator is placed before the detector to select the direction of the photons to be detected. Thus, if we call f(x, y, z) the distribution of radioactivity emitted point {x, y, z} per unit solid angle, the number of photons detected at the point {x\',y\'} of the detector is equal to (Figure 6) [11]:
Where L is the line given by the direction of the channel’s collimator and passing through the point (x\',y\'). As in CT, the various projections are obtained by rotating the detector around the object (patient).
Detection principle in SPECT imaging.
In SPECT, the main radioactive isotopes are technetium-99m, Iodine and Thallium-201, which is used primarily for studies on the heart. At the opposite of PET system, the collimator is an indispensable component in a SPECT machine. The first collimators used were two-dimensional parallel channels (Figure 7, a). By rotating the detector & collimator assembly around the patient, two-dimensional projections are obtained, and the distribution of radioactivity may be 3D reconstructed slice by slice. These parallel collimators are used in the vast majority of SPECT systems used in Nuclear Medicine services. The resolution of these systems varied from 10 to 15 mm.
To increase the sensitivity and resolution of SPECT systems, converging channels collimators were developed (Figure 7, b). The first proposed included a series of converging channels to a focal line which is parallel to the rotation axis of the system [12]. This system is therefore equivalent to a scanner used in X-ray fan beam tomography where 3D image is reconstructed slice by slice. For imaging small organs such as heart and brain, a converging cone collimators is used [13, 14]. This last collimator allows obtaining magnification of the object in all directions (cross and longitudinal). This kind of collimators can be used only for small field tests, so for small structures, the size of the detectors has not increased. With these systems, image data registration is completely 3D as well as in cone beam X-ray tomography, and therefore reconstruction is not performed slice by slice. In these systems, it is important to be able to shift the head of the detector relatively to the rotation axis, thereby to perform trajectories other than circular. In addition to the fact that this shift allow to complete the set of projections, such a shift is interesting to avoid obstacles, such as shoulders brain imaging. Finally, other kinds of collimators are also available for SPECT such as diverging and pinhole collimators. Diverging collimator (Figure 7, c) is reserved to large structure imaging. Pin-hole collimator (Figure 7, d) allows obtaining a mirror image with a variable magnification function of collimator depth and object to collimator distance. This collimator is suitable for small structures imaging such as thyroid and hip.
Different kinds of collimators used with SPECT imaging system (O: object, I: image).
Positron emission tomography (PET) is a medical imaging modality that measures the three-dimensional distribution of a molecule labelled with a positron emitter. The acquisition is carried out by a set of detectors arranged around the patient. The detectors consist of a scintillator which is selected according to many properties, to improve the efficiency and the signal on noise. The coincidence circuit measures the two 511 keV gamma photons emitted in opposite directions resulting from the annihilation of the positron. The sections were reconstructed by algorithms, the same but more complex than those used for conventional CT, to accommodate the three-dimensional acquisition geometries. Correction by considering the physical phenomena provides an image representative of the distribution of the tracer. In PET scan an effective dose of the order of 8 mSv is delivered to the patient. This technique is in permanent evolution, both from the point of view of the detector and that of the used image reconstruction algorithms. A new generation of hybrid scanner “PET-CT” provides additional information for correcting the attenuation, localize lesions and to optimize therapeutic procedures. All these developments make one PET fully operational tool that has its place in medical imaging.
Positron emitters are radioactive isotopes (11C, 13N, 15O, 18F) which can easily be incorporated molecules without altering their biological properties [15-22]. The first 18F labelled molecules were synthesized to late 1970s. At the same time, were built the first emission tomography scanners (PET cameras) used in a clinical setting. Since the 1970, many studies conducted by research centres and industrialists have allowed the development of PET to perform tests whole body, in conditions of resolution and adapted sensitivity. Until the last decade, PET was available only in centres equipped with a cyclotron capable of producing the different isotopes. However, today\'s growing role PET in oncology is reflected in the rapid spread of this medical imaging modality in hospitals. The operation of these structures is based on the installation of PET machine, and the implementation a network distribution radio-pharmaceutical marked by 18F, characterized by a half life of 110 minutes. The most widely used molecule is the Fluorodeoxyglucose (FDG) labelled with fluorine 18 (18F-FDG) due to its many properties and advantages. Generally to find the right tracer molecule, a close look into the designated processes and the related biochemistry is necessary, the following gives a short overview:
Metabolism and general biochemical function;
Receptor-ligand biochemistry;
Enzyme function and inhibition;
Immune reaction and response;
Pharmaceutical effects.
Toxicology (carcinogen and mutagenic substances).
The realization of a PET scan is the result of a set of operations, since the production of the isotope, the synthesis of the molecule, the injection of the radioactive tracer, the detection of radiation, the tomographic reconstruction, and finally the application of a series of corrections to provide image representative of the distribution of the tracer within the patient.
The main physical characteristics of isotopes used in PET are summarized in Table 1.
\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t
Maximum kinetic energy of β+ (MeV) | \n\t\t\t0.98 | \n\t\t\t1.19 | \n\t\t\t1.72 | \n\t\t\t0.63 | \n\t\t\t3.98 | \n\t\t
Period (mn) | \n\t\t\t20.4 | \n\t\t\t10.0 | \n\t\t\t2.1 | \n\t\t\t109.8 | \n\t\t\t972 | \n\t\t
Maximum Free path in water (mm) | \n\t\t\t3,9 | \n\t\t\t5 | \n\t\t\t7,9 | \n\t\t\t2,3 | \n\t\t\t20 | \n\t\t
Physical characteristics of the main isotopes positron emitters used in positron emission tomography (PET).
The principle of PET is based coincidence 511 keV Gamma-photons detection (created by positron annihilation) by considering the parallelepiped joining any two detector elements as a volume of response (Figure 8, a). In the absence of physical effects such as attenuation, scattered and accidental coincidences, detector efficiency variations, or count-rate dependent effects, the total number of coincidence events detected will be proportional to the total amount of tracer contained in the tube or volume of response. Both Two and three dimensional modalities are available for one scan and it depends on the collimator-Detector system used. In two dimensional PET imaging, only lines of response lying within a specified imaging plane are considered (Figure 8, b). The lines of response are then organized into sets of projections. The collection of all projections obtained by rotation around the patient forms a two dimensional function called a sonogram which will be used for 2D image reconstruction. Multiple 2-D planes are can be stacked to form a 3-D volume. In fully three-dimensional PET imaging, the acquisition is performed both in the direct planes as well as the line-integral data lying on \'oblique\' imaging planes that cross the direct planes, as shown in figure 8 c. PET scanners operating in fully 3-D mode increase sensitivity, and thus reduce the statistical noise associated with photon counting and improve the signal-to-noise ratio in the reconstructed image.
Principle of PET imaging and 2D and full 3D image acquisition modes.
Tomographic slices are reconstructed from the acquired projection data using either analytic or iterative algorithms. Analytic reconstructions represent an exact mathematic solution, and there is a general solution for true projection data: filtered backprojection. Although filtered backprojection is a relatively efficient operation, it does not always perform well on noisy projections and, as is the case with SPECT and PET data, it generates artifacts when the projections are not line integrals of the internal activity. Iterative algorithms are a preferred alternate method for performing SPECT reconstruction, and over the past 10 years there has been a shift from filtered backprojection to iterative reconstruction in most clinics [23-26]. The big advantage of the iterative approach is that accurate corrections can be made for all physical properties of the imaging system and the transport of γ-rays that can be mathematically modeled. This includes attenuation, scatter, septal penetration in the case of SPECT, and spatial resolution. In addition, streak artifacts common to filtered backprojection are largely eliminated with iterative algorithms. A major advance was the introduction of the ordered-subset expectation maximization approach, which produces usable results with a small number of iterations.
In each study, the PET or SPECT images selected for statistical analysis are registered, smoothed and intensity normalized and this because of the following objectives:
Registration is required to align the data sets, which is an important step for any kind of voxel-by-voxel-based image analysis.
Smoothing effectively reduces differences in the data, which cannot be compensated for by registration alone, such as intrapatient variations in pathology, and the resolution of the reconstruction of scans. Another reason for smoothing is the reduction of noise.
Intensity values of the data sets may vary significantly, depending on the individual physiology of the patient (e.g., injected dose, body mass, washout rate, metabolic rate). These factors are not relevant in the study of the disease, and need to be eliminated using intensity normalization, to obtain meaningful statistical comparisons during multivariate analysis.
Key PET and SPECT image processing parameters include also the following:
Filtering: improve image quality by removing noise and blur;
Reconstruction: by analytical or iterative methods;
Motion correction: recommended to reduce motion blur due to object motion;
Attenuation correction: identifying source of attenuation for image correction;
Quantification: assessment by image quantification of the affected area;
Normal database: reference used for calculation of extent and severity of defect;
Segmentation: process of partitioning a digital image into multiple segments to simplify and/or change the representation of an image into something that is more meaningful and easier to analyze;
Volume fraction calculation.
In addition to these pre-processing methods which have an impact on the interpretation of the results, there are other processing methods that must be applied to SPECT image to extract essential information according to the studied pathologic case. Thus, SPECT images can be processed by various methods such as: 1) “Principal Components Analysis (PCA) which is a multivariate analysis method that aims at revealing the trends in the data by representing the data in a dimensionally lower space[27], 2) “Discrimination Analysis (DA)” used to identify a discrimination vector such that projecting each data set onto this vector provides the best possible separation between population groups subject to SPECT study and 3) Bootstrap Resampling which is applied to evaluate the robustness and the predictive accuracy of the PCA and DA approach [28].
The key technology in the development of SPECT and PET systems for static or dynamic image acquisition is embodied in the development of the detector, or rather, the detector chain. Although it has already reached a high degree of perfection, continuous improvements are still increasing the performance of, for example, the scintillator material, which is a critical component in the chain. The time of flight camera, introduced by Philips Medical Systems in the 1980s, is replacing the conventional Anger camera and offers significant improvements in image quality. The trend here is towards higher resolution where, for certain applications, 2048 x 2048 pixel matrices will be used. In addition to continuous improvements in the detector chain, there are also radically novel approaches which dispense with the need for a semiconductor detector. A detector based on scintillator crystals coupled to hybrid photodetectors that provides full 3D reconstruction in PET imaging with high resolution and avoiding parallax errors developed during last ten years are actually available [29, 30].
Another improvement is SPECT systems provision on a single stand of rotation of several (two or three) detecting heads, allowing examination time reduction and detection sensitivity increasing. In addition, one of the heads can record a transmission coefficient image induced by a radioactive external gamma source photons of the same energy as those issued by the tracer during the examination. These acquisitions are then used to correct the effect of self-absorption.
Development of SPECT and PET systems much more efficient enable major advances in the clinical use of these techniques with very widespread applications field. Additional development may include research on more efficient scintillators, the use of more adequate recording geometries, such as the conical geometry for example, accompanied sure with the development of robust reconstruction algorithms.
Time-of-Flight technology has always held the promise of better PET imaging. Philips delivered on that promise with its innovative Astonish TF technology. Now with 4D TOF, Philips continues to push the envelope of PET imaging performance. See how 4D TOF Innovation is making an impact on PET imaging.
Design of Hybrid machines has been a very interesting research and technologic development axe in nuclear imaging during last fifteen years. Indeed, many hybrid PET-CT, SPECT-CT and PET-MRI machines were manufactured offering a variety of very interesting diagnostic applications by the combination of results of two imaging methods allowing the revelation of a very interesting pathologic information that cannot be revealed by a single technique alone. PET-CT is creating a new benchmark in imaging and analysis of cardiovascular disease. PET-CT enables the combination of PET myocardial perfusion and viability imaging with CT coronary angiography and calcium scoring in a single integrated environment. In oncology, it provides the integration of metabolic data from PET and anatomical data from CT.
SPECT-CT is a system designed entirely for nuclear medicine and has particular value in the cardiology cycle of care. This hybrid machine allows table to remain stationary in many cases, eliminating complexities inherent in table indexing, acquires the entire heart volume in just one rotation and permits patients to breathe normally during SPECT and CT acquisitions. In oncology, it plays an important role in diagnosis, treatment, and follow-up in the oncology cycle of care, including the use of low-dose localization and aids better visualization that is especially valuable during studies and in bone imaging.
Researchers continue to develop new ways of using PET. One recent development has been the combination of PET and MRI MRI: MagneticResonance Imaging.
Actually, the main hybrid machines routinely used in hospitals are the following:
The first machine was created by University of Pittsburgh physicist David Townsend and engineer Ronald Nutt; the PET-CT machine was called the “Medical Science Invention of the Year” by
GE offers a variation in its range of PET-CT “Discovery ST” machine to meet the specific clinical needs. After the Discovery ST oriented oncology and cardiology, the GE Discovery VCT sells dedicated cardiology is associated with a 64-slice scanner. The latest version offers a higher spatial resolution responding to neurological applications. GE ST machines are available in versions scanner 4, 8 or 16 cups. The 2D acquisition abandoned by other manufacturers is optional and defended by GE to obtain less noisy images (useful for some advanced applications or for overweight patients) and for new applications mostly outside the scope FDG. GE believes that the increase of activity of PET-CT will be around 50% in the next three years and examines the association of PET and MRI modalities. The contribution of MRI compared to CT is questionable, except perhaps in functional imaging.
PHILIPS GEMINI PET/CT scanners combine the Brilliance CT technology, that is well-suited to cardiac imaging with its wide-coverage submillimeter imaging, ultra fast acquisition times and Rate Responsive image acquisition technology that adapts to the patient’s heart rate and rhythm during acquisition. GEMINI PET/CT scanners deliver high spatial resolution and high sensitivity PET imaging resulting in improved image quality when imaging the short-lived radiopharmaceuticals used with cardiac PET. Philips PET-CT hybrid machines ALLEGRO maintain in the range GEMINI.
SIEMENS works to upgrade the install PET-CT around the world. The range of PET-CT, BIOGRAPH marketed since 2000 continues to benefit from developments. After improving the sensitivity BGO crystals by replacing the LSO crystals, SIEMENS in 2004 increased the detection speed by introducing a new channel detection (PICO 3D) with the coincidence window is only 4.5 ns and improved spatial resolution due to detector Hi-Rez (block 13 x 13 x 8 against 8 elements far). Note that BIOGRAPH have a tunnel of 70 cm diameter field used in whole to acquire PET scanner. This criterion is important for obese patients.
Example of commercially PET-CT scanners.
A variety of SPECT-CT scanners are nowadays available in many hospitals and oncology centres (Figure 10). GE proposes a robust SPECT-CT hybrid machine called “Infinia” which is a dual-head, large field for general applications. The Infinia has an open stand. It is available with SPECT thick crystals (5/8th) or thin (3/8th) depending on the intended application. It is available in solo or in combination with a scanner. The Infinia Hawkeye 4 SPECT/CT from GE Healthcare builds upon its performance with a wealth of innovations, from enabling low dosage and improved acquisition times to enhancing imaging results through scatter correction modeling and reduction, motion detection and correction, and accurate attenuation correction. Hawkeye 4 should respond to all applications except exams angio CT or cardiology.
PHILIPS approaches the market hybrid machines by combining existing methods in its range. The hybrid machine called PRECEDENCE. Precedence SPECT/CT system offers the combination of functional data from SPECT with high-resolution anatomical detail from a multi-slice diagnostic CT scanner to give clinicians a new standard of diagnostic confidence.
When SPECT functional data is fused with CT, the location and extent of disease may be better visualized and treated.
SEIMENS “Symbia” SPECT-CT hybrid machine is integrated SPECT and diagnostic multislice-CT bring a whole new dimension to nuclear medicine. With the ability to provide precise localization of tumors and other pathologies before disease reveals itself, Symbia has the potential to revolutionize treatment planning for cancer, heart disease, and neurological disorders. Symbia has enormous potential for cardiac imaging, revealing even the hard-to-detect conditions that carry the highest risk for patients.
Examples of SPECT-CT hybrid scanners.
Simultaneous PET and MRI scans eliminate the need to move patients from one imaging unit to another, making it easier to combine data from both scans to produce enhanced details. The scanner also exposes patients to significantly lower radiation levels than an older combined scanning technique, PET-computed tomography (CT). PET-MRI scanner is used in understanding certain types of malignancies, such as cancers of the brain, neck and pelvis because the anatomy is very complex in those areas, and combined PET-MRI should produce a more detailed reading of the intricate boundaries between disease and healthy tissue. The integration of PET and MRI for simultaneous scanning was a complex task because powerful MRI magnets interfered with the imaging detectors on the PET scanner. But scientists overcome this problem and PET-MRI scanners are nowadays available for research and patient care (Figure 11).
In 2010, Philips unveiled its own solution which involves a 3T MR and a high resolution PET scanner with an integrated rotating table that passes the patient from one machine immediately into the other. Philips Ingenuity TF PET/MR is a new modality so original and resourceful that it offers Astonish Time-of-Flight technology combined with the superior soft tissue imaging of Achieva 3.0T MRI in a whole-body footprint.
In 2011, Siemens Healthcare said that its hybrid PET-MRI scanner received USA Food and Drug Administration clearance. The device, the Biograph mMR, is the first integrated PET-MR device capable of doing simultaneous whole-body magnetic resonance imaging and positron emission tomography scans. It combines a 3-Tesla MR system with PET detectors, giving doctors the morphological and soft tissue information from MR with the cellular and metabolic activity data from PET.
Actually available PET-MRI hybrid scanners.
In addition to conventional nuclear image processing methods described above, Registration and Validation are also a very important research axes in nuclear imaging. In this section, we present the state-of-the-art and research topics regarding only these two axes.
There is increasing interest in being able to automatically register medical images from either the same or different modalities. Registered images are proving useful in a range of applications, not only providing more correlative information to aid in diagnosis, but also assisting with the planning and monitoring of therapy, both surgery and radiotherapy. The classification of registration methods is classically based on the criteria formulated by van den Elsen, Pol & and Viergever [31]. Many basic criteria can be used, which each can be developed and subdivided again [32, 33]. The main are the following:
Dimensionality: 2D or 3D only spatial dimensions or time series with spatial dimensions;
Nature of registration basis: Extrinsic, Intrinsic or Non-image based (calibrated coordinate systems);
Nature of transformation: rigid, affine, projective, or curved;
Doman of transformation: local, global or interaction;
Interaction: interactive, semi-automatic or automatic;
Optimization procedure: parameters computed or parameters searched for;
Modalities involved: mono-modal, multi-modals, modality to model or patient to modality;
Subject: intrasubject; intersubject or atlas;
Object: head, abdomen, limbs, thorax…
Although great advances have been made in basic nuclear medicine imaging in both the detection and estimation tasks, personalized medicine is a challenging goal. It requires the ability to detect many different signals that are specific to a patient’s disease. That requirement has led to the increasing development of hybrid imaging systems.
The development of image reconstruction algorithms, simulation tools, and techniques for kinetic model analysis plays an important role in the right interpretation of the generated image signals. Development of these software tools is essential to accurately model the data and thereby quantify the radiotracer uptake in nuclear medicine studies. The ability to perform this task in practice has benefited from the increased availability of powerful computing resources. For example, an iterative image reconstruction algorithm with data corrections built into the system model was considered to be impractical a decade ago. Yet, this type of algorithm can now be used to generate images in a practical amount of time in both the research laboratory and the clinic Leaders in instrumentation and computational development in nuclear medicine from universities, national laboratories, and industry were solicited for commentary and analysis.
The ability of nuclear imaging devices to provide anatomical images and physiological information has provided unparalleled opportunities for biomedical and clinical research, and has the potential for important improvements in the diagnosis and treatment of a wide range of diseases. However, all nuclear imaging devices suffer from various limitations that can restrict their general applicability. Some major limitations are sensitivity, spatial resolution, temporal resolution, and ease of interpretation of data. To overcome these limitations, scientists have worked particularly on: on: 1) Development of technological and methodological advances that improve the sensitivity, spatial resolution and temporal resolution, 2) Development of multi-modality approaches that combine two (or more) biomedical imaging techniques. In addition to these two research areas, validation of nuclear imaging technologies and methodologies is uncontainable to develop nuclear imaging and medicine. Development of "multi-modality" approaches could be used to combine information that might not be available from a single imaging technique or to compare and validate results obtained with one imaging technique with results obtained using another imaging technique. Thus, development and improving approaches for analysis and optimization of complex multi-component biomedical imaging devices is highly required. The validation methods are classified in the following main categories:
Statistical validation methods;
Validation with phantoms;
Clinical validation.
To date there is very little in terms of validation and standardizing the validation process in nuclear image processing. Further research is needed in validation for nuclear image-processing as issues concerning validation are numerous. Clinically relevant validation criteria need to be developed. Mathematical and statistical tools are required for quantitative evaluation or for estimating performances in the absence of a suitable reference standard. The diversity of problems and approaches in medical imaging contributes significantly to this. Validation data sets with available accuracy reference are required. Comprehension of clinical issues and establishment of robust therapy protocols is also required. Indeed, validation is by itself a research topic where methodological innovation and research are required [34].
Current clinical applications of nuclear medicine include the ability to:
diagnose diseases such as cancer, neurological disorders (e.g., Alzheimer’s and Parkinson’s diseases), and cardiovascular disease in their initial stages through use of imaging devices including PET-MRI, PET-CT and SPECT-CT;
provide molecularly targeted treatment of cancer, and certain endocrine disorders (including thyroid disease and neuroendocrine tumors);
Non-invasively assess a patient’s response to therapies, reducing the patient’s exposure to the toxicity of ineffective treatments, and allowing alternative treatments to be started earlier.
The use of nuclear hybrid imaging, particularly PET-CT, is expanding rapidly. More recently, positron emission tomography (PET) has increased its applications in total body imaging to include the postoperative orthopedic patient. PET and PET-CT scanning for postoperative infection has also been investigated in the spine, also showing good results, with increased specificity for infection in contrast to routine three-phase bone scan or combination radiotracers [35]. The increasing specificity of nuclear medicine agents continues to broaden nuclear medicine applications in the postoperative musculoskeletal imaging setting.
The development of SPECT and SPECT-CT is a logical consequence of the previous success of PET-CT, the first of these hybrid imaging techniques. The introduction of this technique, about 10 years ago, meant a final advanced nuclear medicine in the field of oncology. Pushed forward by the scientific and commercial success of these PET-CT, the industry developed the SPECT-CT, a technology similar to the exams conventional (= non-PET) nuclear medicine. Here too, the SPECT functional information is supplemented by information from CT coupled thereto. Within a single examination, SPECT-CT is able give the correct diagnosis of bone lesion corresponded to metastatic disease. In a general hospital, the SPECT-CT is also used in the development of pain syndromes of orthopedic or rheumatic origin, for example at the lumbar level ("back pain") or a knee. The success of SPECT-CT is that the bone scan shows osteoblastic lesions selectively cause pain and coupling with the CT image interpretation makes-SPECT abnormalities more accurately [36]. SPECT-CT is also successively used for the detection of sentinel lymph node scintigraphy. It allows the visualization of the effect or lymph vessels in which they lead and are thus likely to be the site of métastastiques cells. In principle (and in practice), if such individual nodes called "sentinel" are not found with the tumor cells, while cleaning, any additional node excision is unnecessary [36]. Among other undesirable side effects, thus avoiding impairment of lymphatic drainage of the upper limb and the onset postoperative thugs. SPECT-CT allows more accurate localization by this or these nodes but also give information on their volume, shape and density, all useful information for surgeons in their quest intraoperative these nodes. SPECT-CT in this area still has other potential applications, such as cancers of the prostate, cervix of the uterus and of the head and neck. Patients with thyroid cancer who develop recurrent disease is suspected are often subjected to whole body scintigraphic imaging after administration of a small activity of an isotope of iodine (iodine-123 or iodine-131). With SPECT-CT, better diagnosis of pulmonary embolism is also possible. Pulmonary embolism (PE) is indeed a common problem in cancer. Planar scintigraphic imaging of the normal, the diagnosis of PE is typically established by the demonstration of a mismatch, a defect of pulmonary perfusion with preserved ventilation, normal in the same territory. Here SPECT acquisitions of pulmonary ventilation (after inhalation aerosol technetium) and pulmonary perfusion (after injection of macro-aggregates of albumin technetium) will be combined with a CT scan of the lungs. The classically observed mismatches between ventilation (preserved) and perfusion (altered) will be confronted with anomalies of the CT scan in the corresponding regions [36]”.
A review of applications of PET, PET-CT, SEPCT and SPECT-CT and their clinical benefits with an emphasis on oncologic applications is given below (Figures 12-18).
Thyroid scan with planar scintigraphy (99mTc04). Source: CEM, Rennes.
A SPECT slice of a patient\'s heart. SPECT is generally indicated for evaluation of coronary perfusion and myocardial viability. (a): showing anterior ischemia, (b): demonstration of a myocardial infarction. Source: CEM, Rennes.
Larynx cancer demonstration and imaging with PET and CT images combination. Source: CEM, Rennes.
Bone SPECT Scan (Phosphonates -99m-Tc), (a): depicting bone metabolism in whole body: abnormal osteogenesis zones screening and surveillance (bone lesions carcinoma and other primary or metastatic bone lesions (Paget\'s disease, Osteomyelitis and fractures)), (b): SPECT bone scan showing left femoral neck fracture. Source: CEM, Rennes.
SPECT and PET applications in Neurology. These techniques are indicated in the diagnosis of Regional brain abnormalities (Cerebral perfusion) in and in vitro leukocyte marking (99mTc). (a) Epilepsy: SPECT can be very helpful in the localization of the epileptogenic zone and for mapping functional areas of the brain, such as those for language and motor function, (b) Parkinson: image from of a normal healthy case (left) and abnormal image in the case of early Parkinson\'s disease untreated, and (c) Alzheimer: PET scan of a normal volunteer (left) and a patient with Alzheimer’s disease (right). Nuclear imaging devices help doctors diagnose such diseases in their initial stages. Sources: CEM, Rennes and Daniel Silverman, UCLA.
PET and SPECT neuro-receptors and neuro-transporters imaging with specific radio-marker molecules. (a): dopamine transporter, (b): dopamine receptor, (c): Nicotine receptor, and (d): Opioid receptor. Source: CEM, Rennes.
During radiotherapy planning FDG-PET-CT has been shown to be useful to better delineate the biologically active tumor volume and to distinguish between viable tumor tissue and non-specific changes due to previous surgical and/or radio therapeutic treatments. The figure present a planning for radiotherapy fields based on images from PET-CT in a patient with advanced stage lung carcinoma. Source: www.IAEA.org/.../gc54inf-3-att1_en.pdf.
In conclusion, PET and SPECT nuclear medical imaging have a clinical role in the evaluation of the postoperative oncologic patient, provided that the modalities are protocoled for the anticipated clinical concern and prescribed by the musculoskeletal physicians. Parameters and protocols include appropriate scintigraphic agent selection. These imaging techniques are also required to optimally visualize as much of the wide diversity of anatomical structures, and physiological and pathological processes, as possible. The success of nuclear imaging is due to the modality’s ability to supply new clinical information which is useful for the routine care of large numbers of patients. The demand for more effective and less invasive therapy increases the need for real-time nuclear imaging. The choice of an imaging modality for a given procedure is determined by its ability to display both the patient’s anatomy and the operator’s instruments. Patient access and the safety of both patient and operator are also of major concern. Multi-modality (SPECT-CT, PET-CT and PET-MRI) imaging can often enhance medical decisions. Indeed, combining images from different origins in a workstation can facilitate this process to the benefit of the radiologist, referring physician and, ultimately, the patient.
The development of new technology platforms can contribute to accelerate, diversify, and lower the cost of discovering and validating new nuclear imaging probes, biomarkers, radiotracers, and labeled drugs, as well as new radiotherapeutic agents. The wide implementation of nuclear imaging techniques for local use in research and clinical programs requires the invention of new, small and low-cost miniaturized particle-accelerators and generators for producing short-lived radioisotopes. The invention of new detector technologies for PET and SPECT would contribute to enhance sensitivity as well as spatial and temporal resolution. Finally, the development of new iterative algorithms and high-speed/high-capacity computational systems for rapid image reconstruction; would allow image data to be converted to quantitative parametric images pertaining to biological and pharmacological processes in disease.
Data and statements expressed in this paper are those from the author and published bibliography cited in this work, and do not necessarily reflect organizations, laboratories and the firms which the author has mentioned as examples. The author does not endorse any equipment or material cited herein.
About 7% of the population >65 years suffer from a painful heel, even though younger people are often affected, too [1]. The most common cause of this symptom is the so‐called “plantar fasciitis” [2]. This term is widely used, although “plantar fasciopathy” or “plantar fasciosis” would be a better description to point out the degenerative nature of the disease. However, as more than 1100 citations in Pubmed quote “plantar fasciitis” (in comparison with only 50), we will use the traditional term in the following.
Plantar fasciitis has been associated with obesity, with acute or chronic work overload, or with work on hard surfaces [2, 3]. It seems that physiological degeneration of the fascia at the calcaneal insertion exacerbates due to repetitive microtraumas caused by vertical compression [4]. This causes inflammatory tissue reactions. As a result, the fascia is thickened with an associated fluid collection to 4.0 mm and more in ultrasonography [5]. Furthermore, this inflammation may trigger bone formation, the so‐called “plantar heel spur.” This process has been studied intensively by Kumai and Benjamin [6]. They proposed three stages of spur growth: “(a) an initial formation of cartilage cell clusters and fissures at the plantar fascia enthesis; (b) thickening of the subchondral bone plate at the enthesis as small spurs form; and (c) development of vertically oriented trabeculae buttressing the proximal end of larger spurs” [6]. The first description of this spur formation and correlation with the clinical symptoms was carried out by Plettner in 1900 [7]. However, not every heel spur is associated with heel pain, as these spurs are found in 11–16% of the normal asymptomatic population [4]. On the other hand, some patients with painful plantar fasciitis do not have a radiographic confirmation of a spur formation.
A similar mechanism (although caused by longitudinal traction and not by vertical compression) of bone formation has been described at the insertion of the Achilles tendon [8].
According to the American clinical practice guidelines from 2010, diagnosis is established by the typical anamnesis and the characteristic localizations of tenderness. Still, weight‐bearing radiographs are also recommended [9].
Single doses of external beam radiotherapy (EBRT) in the range of 0.3–1 Gy are called “low dose EBRT” (LD‐EBRT). These single fractions are applied two or three times a week until a total dose of about 3–6 Gy is reached. Such radiotherapeutic concepts are used for diverse nonmalignant conditions, e.g., osteoarthrosis, tendinopathy, epicondylitis, or bursitis. A comprehensive review of the historical developments in LD‐EBRT for benign diseases is given by Trott [10].
In contrast, EBRT in oncology is characterized by much higher single and total doses. “Normofractionation” describes single doses of 1.8–2 Gy, applied about five times a week. To treat breast cancer, the total doses of about 62 Gy are necessary, in prostate cancer even more than 72 Gy. From a radiobiological point of view, these high cumulative doses are used to induce DNA double strand breaks. Due to errors in a repair mechanism (nonhomologous end joining), dicentric chromosomes can occur. These can result in unfinished mitoses, the so‐called “mitotic catastrophe,” the main mechanism to reduce clonogenic survival in tumor cells [11]. High doses of EBRT induce local inflammation and tissue reactions.
The much lower doses of LD‐EBRT act via different mechanisms. In the last two decades, several anti‐inflammatory effects have been discovered, contrary to the effects of the above‐mentioned high EBRT doses.
Furthermore, doses between 0.1 and 0.5 Gy reduced the adhesion of PBMC significantly to endothelial cells (ECs)
A third mechanism was the suppression of nitric oxide (NO) production in activated macrophages by LD‐EBRT between 0.3 and 1.25 Gy [18]. As the expression of inducible nitric oxide synthases (iNOS) proteins was not altered, the LD‐EBRT seemed to act at the translational or posttranslational level. Furthermore, a dose of 0.5 Gy significantly reduced oxidative burst and superoxide production of stimulated macrophages [19]. A diminished release of reactive oxygen species (ROS) can also contribute to the anti‐inflammatory effects of LD‐EBRT.
Taken together, all of these pathways and mechanisms showed a similar dose dependence with a maximum effect between 0.3 and 0.7 Gy regarding a discontinuous dose‐effect relation [20].
There are several
Since 1937 [21] for decades, large retrospective studies on the efficacy of LD‐EBRT in calcaneodynia have been published (overview in 22). In 1970, one negative randomized trial was reported and heavily criticized but had not been repeated [23]. Starting in the 1980s, patients were systematically clinically examined and interrogated in a structured manner to try to control for diverse risk factors and to compare the efficacy of different fractionation schemes and total doses [24].
It took until the past decade to perform and report prospectively randomized trials to proof the efficacy of LD‐EBRT and to identify the optimal dose fractionation schedule. In the following, we report the design and the results of these trials. Table 1 gives a short overview of the studied dose concepts and the results. Due to methodological reasons, we will describe the studies not following their publications dates, but according to a systematic order.
Since the publication of the first randomized trial on LD-EBRT in 1970, the efficacy of LD‐EBRT was questioned [23]. Goldie et al. randomized 399 patients, however, only nine patients suffered from calcaneodynia. This is why these results cannot be extrapolated to LD‐EBRT of a painful heel spur. Furthermore, endpoints were not clearly defined, and therapy was started in an acute stage of the disease [25].
The landmark study to prove the efficacy of LD‐EBRT was performed by the German cooperative group on the radiotherapy for benign diseases (GCGBD) under the responsibility of Niewald et al. [26]. A very low dose EBRT (6 × 0.1 Gy applied twice a week up to a total dose of 0.6 Gy) was randomized to a standard dose LD‐EBRT (6 × 1 Gy twice a week up to a total dose of 6 Gy). In the case of an unfavorable response after 3 months, the patient was offered a second treatment series (“reirradiation”) applying a standard dose. The dosage of the experimental arm was chosen to examine if very low doses are effective at all. Second, it acted as a placebo irradiation, as a sham irradiation was regarded unethical. LD‐EBRT was applied using a linear accelerator (4‐ to 6‐MV photons) using lateral parallel opposing fields.
Inclusion criteria were tenderness of the calcaneus with a limitation of the painless walking distance and duration of the symptoms for more than 6 months. Furthermore, a radiological proof of a heel spur was required, and the patients had to be least 40 years of age. Patients with previous traumata to the foot, rheumatic or vascular diseases, lymphatic edema, pregnancy, or breastfeeding were excluded. Concomitant therapy with oral analgesics was not limited. However, local injections with steroids during the study period were not permitted.
Initially, 200 patients were planned [27] to detect a difference of 10% in the quality of life (QOL) sum score (SF‐12) [28] and calcaneodynia sum score (CS) [29] (Table 2) with a power of 80% and an error probability of 5%. Furthermore, the visual analogue scale (VAS) to evaluate pain intensity was used. However, after randomization of 66 patients and interim analysis of 62 patients (4 had to be excluded due to a withdrawal of informed consent or violation of the inclusion criteria), the differences in efficacy between the two treatment arms were so pronounced, that the trial was closed early.
Author | Year | N | Standard arm | Experimental arm | Results | Conclusions |
---|---|---|---|---|---|---|
2012 | 66 | 6 × 1 Gy twice a week | 6 × 0.1 Gy | 3 months: VAS/CS/SF12 sig. better with standard | 1. Dose‐response relationship | |
1 year: less second treatment series with standard | 2. Proof of therapeutic effect of LD‐EBRT | |||||
2007 | 130 | 6 × 1 Gy twice a week | 6 × 0.5 Gy | 6 months: CS no sig. differences | 6 × 0.5 Gy as standard fractionation | |
2014 | 457 | 6 × 1 Gy twice a week | 6 × 0.5 Gy | 6 weeks, 2.5 years: VAS/CS no sig. differences | 6 × 0.5 Gy as standard confirmed | |
2015 | 127 | 6 × 1 Gy twice a week | 12 × 0.5 Gy thrice a week | 3 months: VAS/CS/SF12 no sig. differences | Efficacy not increased with 12 × 0.5 Gy standard still 6 × 0.5 Gy |
Summary of contemporary randomized trials on LD‐EBRT of painful heel spurs: tested schedules, results, and conclusions.
Criteria | Extent of symptoms/alteration | Points |
---|---|---|
S = Pain at | 6 / 4 / 2 / 0 | |
(total: 30%) | N = Pain during D = Pain during R = Pain at I = Pain at none = 6 ; slight = 4 ; moderate = 2 ; severe = 0 points ⇨ | 6 / 4 / 2 / 0 6 / 4 / 2 / 0 6 / 4 / 2 / 0 6 / 4 / 2 / 0 |
per single criterion | ||
(total: 15%) | None Orthopedic shoe, insoles, heel cushion One cane or crutch Two canes or crutches ⇨ | 15 10 5 0 |
(total: 20%) | No limitation, maximum professional strain possible Slight limitation, normal professional work possible Moderate limitation, reduced professional activity Severe limitation, daily professional work impossible ⇨ | 20 10 5 0 |
(total: 15%) | No limitation of daily and leisure activities and sports Slightly limitation/reduced leisure activities and sports Moderate limitation/no leisure activities and sports Complete limitation of any daily and leisure activities ⇨ | 15 10 5 0 |
(total: 20%) | No limp, normal walking is possible without a limitation Slightly altered, limp after walking Moderately altered, limp after walking Severely altered, normal walking is impossible ⇨ | 20 10 5 0 |
The mean age of patients was 54 years in the standard dose group and 58 years in the 6 × 0.1 Gy group. Sixty‐one patients had a plantar, one patient a dorsal heel spur. In mean, patients in the standard dose group suffered for 15.3 months before the start of LD‐EBRT, in the 6 × 0.1 Gy group for 18.8 months. Twenty‐one patients had symptoms on both sides. In 28 patients the pain irradiated into the calf, only in 18 patients it was localized to the sole of the foot. Two patients had received surgery for LD‐EBRT.
Three months after therapy VAS values, CS‐ and QOL‐scores were significantly better after the standard dose in comparison with the very low dose treatment arm. The higher pain relief resulted in a better QOL. Twelve months after therapy about 64% of the patients after 6 × 0.1 Gy had to receive a second treatment series due to insufficient treatment results, in comparison with only 17% of the patients in the standard dose treatment group. As the second series was applied with a standard dose (6 × 1 Gy), patients in the 6 × 0.1 Gy group who were reirradiated showed equally favorable results compared with those in the standard‐dose group who did not receive a second course [26]. This is why the second treatment series in this clinical setting acted as a “salvage therapy.” Another interesting finding was that patients with a good response already at 3 months remained stable or even improved at 12 months. Furthermore, this underlines the long‐lasting efficacy of LD‐EBRT.
Acute side effects or long‐term toxicity did not occur.
In conclusion, this randomized trial established a dose‐response‐relationship of the analgesic effect of LD‐EBRT, thus providing a clinical and methodological proof of the efficacy of 6 × 1 Gy LD‐EBRT on the clinical course of painful heel spurs. The early termination of the study was justified due the interim analysis showing significant differences in the clinical outcome between both treatment arms. Still, the trial was not blinded, so both the patients and the staff were aware of the received dose. With modern linear accelerators, a complete blinding of the staff is nearly impossible. The only option would be a shame irradiation with closed collimator jaws, reducing the dose to the unavoidable “leakage” radiation. A much easier and straight forward way was used in the above‐mentioned study by application of a minimal physical dose with 0.1 Gy. Another critical point might be that only half of the patients were examined 12 months after therapy (
Another potential confounder not only in this study but also in all other published prospective and retrospective case series might be that a lot of the patients had received diverse and other conservative therapies before being referred to LD‐EBRT. An interaction between one of these other treatments and LD‐EBRT cannot be ruled out due to methodological reasons. This reflects clinical reality. Still, an interaction between one of these therapies and LD‐EBRT is rather unlikely and counter‐intuitive, as patients were referred to LD‐EBRT after the clinical failure of all the other conservative treatments.
Two randomized studies investigated the efficacy of 0.5 Gy single dose in comparison to 1 Gy.
The first trial was conducted by Heyd et al. [30]. They randomized 130 patients between 6 × 0.5 Gy twice weekly (low dose) and 6 × 1 Gy (standard dose). A linear accelerator was used, applying a single field technique.
Inclusion criteria were clinical signs of a painful heel spur, radiological evidence of spur formation, patient age ≥30 years and a relapse after previous conservative treatments, in patients >45 years LD‐EBRT could be used as the primary treatment. Endpoints of the study were changes in the “original” calcaneodynia score [31], that was documented before LD‐EBRT, at the end of the course, and 6 weeks and 6 months afterward.
One hundred and thirty patients were randomized. Mean age was 58.4 years. A 102 patients suffered from a plantar, one patient from a dorsal, and 27 patients from combined spurs. In mean, patients had been suffering from symptoms for 9.8 months. The symptoms had been present in 58 patients for less than 6 months, in 72 patients for a longer time. In 7 heels LD‐EBRT was the first therapeutic approach.
At the end of LD‐EBRT, 66% in the low dose group vs. 59% in the standard dose experienced an improvement in symptoms, 6 weeks later 80 vs. 85%. At this time point, 1.5% in each group reported an increase in symptoms, 19 vs. 14% no change. No statistically significant differences were noted. In case of insufficient treatment results patients were offered a second EBRT series. Thus 26 vs. 37% were treated a second time. Six weeks after that, 71 vs. 79% of these patients reported a further improvement. Six months after LD‐EBRT 88% of the patients in both groups had an amelioration of their symptoms, the remaining patients reported no change. During the EBRT series a slight increase in pain was reported by 26 vs. 29% of the patients. No other acute or late toxicity occurred.
In conclusion, 6 × 0.5 Gy twice weekly was as effective as 6 × 1 Gy.
These results were confirmed by a second randomized trial [32, 33]. Ott et al. randomized 457 patients between 6 × 0.5 Gy (low dose) and 6 × 1 Gy (standard dose). In contrast to the above‐cited “Heyd‐study” [30] an X‐ray unit (orthovoltage) and not linear accelerators was used. Patients received a single field (6 × 8 cm on the plantar calcaneus) with 150 kV, 15 mA, 1 mm Cu‐filter, with source‐to‐skin distance (SSD) of 40 cm. Six weeks after the LD‐EBRT a second series was offered to patients with an insufficient response. The endpoint was pain reduction. CS score and VAS values were measured before and at the end of LD‐EBRT (early response), 6 weeks (delayed), and 2.5 years (long‐term) afterward.
With a median follow‐up of 32 months the mean VAS values before treatment, for early, delayed, and long‐term response for the 0.5 and 1.0 Gy groups were 65.5 ± 22.1 and 64.0 ± 20.5 (
Taken together, the above‐mentioned studies proofed an equivalent clinical efficacy of 6 × 0.5 Gy in comparison to 6 × 1 Gy, thus defining a new clinical treatment standard with six times 0.5 Gy twice weekly as the minimum effective dose.
Before proofing 0.5 Gy as the new standard single dose, another randomized study tried to increase efficacy in reaching the “old” cumulative dose of 6 Gy with a single dose of 0.5 Gy. Niewald et al. randomized between 6 × 1 Gy twice a week (old “standard dose”) and 12 × 0.5 Gy three times a week (“experimental dose”) [25]. The aim was not just to get comparable results, but to further improve the analgesic effects. Linear accelerators (6 MV photons) applying a lateral opposing field technique were used.
Inclusion and exclusion criteria were quite similar to the ones used in the landmark study [26]: Clinical evidence of a painful heel spur, and duration of the symptoms for more than 6 months; radiological proof of a spur formation; age at least 40 years; Karnofsky‐Index at least 70%. Patients with previous radiotherapy or previous trauma to the foot, rheumatic or vascular diseases, lymphatic edema, pregnancy, breastfeeding, or severe psychiatric disorders were excluded. Concomitant therapy with analgesics was allowed. However, patients receiving surgery or shock wave therapy after randomization were excluded.
Endpoints were the SF‐12 sum score, the CS sum score (Table 2), and VAS. Follow‐up was scheduled every 6 weeks for 1 year.
Two‐hundred and forty patients were calculated to detect a difference of 15% in the VAS and CS score, with a power of 80%, and an error probability of 5%. After randomization of 127 patients and an interim analysis of 107 patients, the study was closed early, as the intended increase in analgesic efficacy by the experimental treatment was very unlikely to be achieved.
The mean age of the patients in the standard group was 56.1 Gy in comparison with 58.1 Gy in the experimental group. The mean duration of symptoms before initiation of LD‐EBRT was 17 vs. 16 months. In 98% of the standard group and 93% of the experimental group a plantar spur was treated, in 2 and 7% a combined (plantar and dorsal) spur.
Results after 3 months have been issued so far [25], longer follow‐up has yet to be published. After 3 months, there were no significant differences neither in the VAS (standard 42.3 vs. experimental 44.4) nor the CS sum score (28 vs. 28.4) nor in the QOL (SF‐12) scores. Although longer follow‐up has to be awaited, a further increase in the analgesic effect by applying 12 × 0.5 Gy three times a week is unlikely. This is why this fractionation schedule is currently not recommended, as it does not follow the “as low as reasonable achievable” principle of radiation protection.
Further reduced single doses in LD‐EBRT (with the exception of 0.1 Gy [26]) have never been tested in a prospectively randomized clinical trial. In radiotherapy of degenerative joint disorders, single doses of about 0.3–0.4 Gy were established by von Pannewitz in the late 1920s and published in 1933 and 1970 [34, 35]. However, two studies on calcaneodynia have raised serious concerns on single doses as low as 0.3 Gy.
Seegenschmiedt et al. analyzed treatment efficacy in 141 patients (170 irradiated heels), who were treated from 1984–1994 with X‐ray units (250 kV/200 kV, 20 mA, 40 cm SSD), applying a single field of 6 × 8 cm [24]. Seventy‐two heels received 12 Gy with 6 × 1 Gy (three times a week) –6 weeks break – 6 × 1 Gy (group A), 50 heels were treated with 10 × 0.3 Gy every day (group B1), and 38 heels 10 × 0.5 Gy every day (group B2). The endpoint was the value of a semiquantitative pain score 3 months and in mean 4 years after LD‐EBRT.
The median age of patients was 55 years in group A and 59 years in group B1/B2. The mean duration of symptoms before LD‐EBRT was 8 months, in one‐third, the symptoms persisted for more than 6 months.
Complete pain remission was achieved in 68–71% of the patients without significant differences between the treatment groups. However, there were differences in the clinical course of patients with partial remission of the symptoms: The best results in these patients were achieved during longer follow‐up in group B1 (10 × 0.5 Gy), followed by group A (6 × 1–6 × 1 Gy), followed by group B2 (10 × 0.3 Gy). The latter group showed a significantly worse amelioration of symptoms than the other groups.
A reduced efficacy was also reported in another retrospective case series, comprising 673 heels treated with a single dose of 0.3 Gy three times weekly up to 1.5 Gy (X‐ray) [36]. In case of insufficient treatment results the patients were offered a second course. After the first treatment, only 13% reported CR, nearly all patients had undergone a second LD‐EBRT.
Taken together, to the best of our current knowledge a single dose of 0.5 Gy is standard of care and should only be modified in controlled clinical trials.
In Table 3 selected contemporary randomized trials and patient series are shown broken down into several factors that might be correlated with treatment efficacy. For a better overview, we did not differentiate between univariate and multivariate analyses. We did not try to collect all ever published data.
Duration of symptoms before start of LD‐EBRT has been shown to be correlated with treatment efficacy in numerous studies.
Muecke et al. analyzed in a retrospective multicenter study 502 patients [22]. Duration of symptoms ≤6 months was associated with 76% treatment success vs. 44% after a history >6 months. Also Seegenschmiedt et al. found in their large collectives a correlation between the duration of heel pain and treatment outcome [24]. A significant influence of duration of symptoms before LD‐EBRT was also reported in 73 heels by Schneider et al. [37]. With a history of 3–6 months, the VAS value was reduced by 85%, 28 months after LD‐EBRT in comparison with a reduction of 58% with a history > 6 months. Similar results were obtained by Hermann et al. in 285 heels comparing <12 month history of pain vs. >12 months [38].
In contrary, another study could not confirm these results [30].
To the best of our knowledge, in no study, an influence of gender on treatment outcome has been confirmed [22, 24, 30, 38, 39]. In contrast to radiotherapy for oncological indications with high doses, efficacy and tolerability of LD‐EBRT seems to be the same concerning gender.
Several studies described a correlation between older age and better treatment results, at least 6 weeks after LD‐EBRT [37]. Age somewhat over 50 years seems to be important: >50 years [40], > 53 [38], or > 58 [22]. For a possible explanation see Section 2.3.7.
However, other studies found no influence of this patient characteristic on treatment outcome [24, 30, 39].
A very precise registration of changes in pain intensity (VAS) was done by Schneider at al. [37]. Sixty‐two patients (73 treated heels) were prospectively scored every week during LD‐EBRT, at the end of therapy, 6 weeks, 28 months, and 40 months later. Additionally, subjective mechanical heel stress during LD‐EBRT was estimated. A linear accelerator (10 MV) was used, applying one single field with a size of 12 × 17 cm. Patients were treated twice a week to a total dose of 5 Gy, with increasing single fraction doses (0.25 – 0.25 – 0.5 – 1 – 1 – 1 – 1 Gy). Mean patient age was 54 years, and all had a radiologically proven plantar spurn, mean symptom duration before LD‐EBRT was 6.5 months. Nearly all patients had received other conservative therapies before LD‐EBRT with insufficient results.
Interestingly, VAS scores decreased continuously during LD‐EBRT: before treatment the mean value was 6.3 ± 1.5, after the first week of LD‐EBRT 6.2 ± 1.8, after the second week 5.5 ± 2 (
In standard schedules with fixed single doses a slight increase in pain during the treatment series was reported by 26% (during 6 × 0.5 Gy) vs. 29% (6 × 1 Gy) of the patients [30]. Unfortunately, a possible correlation of this phenomenon with definite treatment results was not investigated.
Without further quantification, another study (6 × 1 vs. 6 × 0.1 Gy) stated, that this initial increase in symptoms “had no influence on the final pain relief 3 and 12 months after treatment” [26]. Older studies postulated a temporary reduction of the pH value in the irradiated tissues at the beginning of the treatment series, without consequences for the long‐term efficacy of LD‐EBRT [41].
This is contrasted by observations of LD‐EBRT in peritendinitis humeroscapularis [42]. In 73 patients (86 shoulders) initial increase of pain during the treatment course was significantly associated with a good response.
Muecke et al. analyzed in a retrospective multicenter study the influence of different treatment techniques in 502 patients [22]. Treatment failure was defined as pain persistence after LD‐EBRT and recurrence of pain during follow‐up. Treatment with MV (6–10 MV) was a significant prognostic factor for pain relief in multivariate analysis, as MV was associated with an eight‐year event‐free probability of 68 vs. 61% after X‐ray beams (175 kV). There are two possible explanations for this finding: besides the possibility of a random result, the authors postulate a more homogenous dose distribution with MV treatment in comparison with KV [22].
Schneider et al. reported an efficacy of just one‐third after a second LD‐EBRT course (so‐called “re‐irradiation”) in comparison with the effects of the first course [37]. Out of 73 heels treated with 5 Gy LD‐EBRT 18 heels received reirradiation due to insufficient treatment response. However, pain reduction measured by means of changes in VAS shortly after the second course and during long‐term follow‐up was significantly diminished in comparison with the efficacy of the first course (about 30% reduction in pain at the last evaluation vs. 86%).
Similar results were obtained in the large retrospective series (502 patients) by Muecke et al. [22]. Treatment failure was significantly associated with the number of treatment series: eight‐year event‐free probability was about 70% after the first course in comparison with just about 30% after reirradiation.
A systematic study on the efficacy of a reirradiation has been published by Hautmann et al. [43]. Eighty‐three patients (101 heels) with insufficient response to the first course or recurrent pain afterward due to plantar fasciitis (83 heels), or achillodynia (28 heels) received a second LD‐EBRT course in median 10 weeks (range 4 weeks to 63 months) after the first LD‐EBRT. About 75% of the patients were treated with 6 × 1 Gy, the others 6 × 0.5 Gy. The pain was assessed using the numeric rating scale (NRS) before and at the end of LD‐EBRT, 6, and 12 weeks, and 6, 12, and 24 months thereafter.
Before reirradiation NRS values were 6 (interquartile range 5–8), at the end of LD‐EBRT 5 (2–6), 6 weeks later 2 (1–4), at 12 weeks 1 (0–3), at 6 months 0 (0–2), at 12 and 24 months 0 (0–1). Interestingly, not only the patients with recurrent pain after the first course but also patients with insufficient responses to the first course experienced a profound and long‐lasting amelioration of their symptoms after the second course.
This is why a second treatment course should be recommended in case of insufficient efficacy of the first course.
A significant correlation between avoidance of heel stress during LD‐EBRT and efficacy of LD‐EBRT 6 weeks after therapy was reported by Schneider et al. in 73 heels [37]. With a Pearson\'s correlation coefficient of -0.467 (
An intuitive explanation is given by the authors [37]: As patient age was associated with positive treatment results, too, they proposed that older patients are often retired, thus being able to take more care of their heels.
Interestingly, all randomized trials required the radiological proof of a heel spur before including patients into the studies. Furthermore, most of the prospective and retrospective series warranted such an objective sign. However, as a substantial part of the patients suffers from plantar heel pain without having developed a heel spur, LD‐EBRT should be effective in these patients, too.
Hermann et al. analyzed treatment efficacy in 250 patients (285 heels), who received LD‐EBRT predominantly with 6 × 1 Gy [38]. In this series, 33% of the treated heels were without radiological evidence of a spur. In 185 patients a spur was confirmed with a mean length of 6.5 mm (range 0.6–25 mm). Patients without evidence of a plantar heel spur had a significantly higher chance of CR after LD‐EBRT (43 vs. 35%). Furthermore, the length of the spurs correlated directly with treatment outcome. Spurs >6.5 mm had just a 30% chance of experiencing CR in comparison with shorter ones. No statistical differences were found between treatment results of heels without spurs and those with spurs ≤6.5 mm.
Miszczyk et al. reported on 327 patients (623 LD‐EBRT series) mostly treated with X‐ray (180 kV, usually 1mm Cu filters) with single doses of 1.5 Gy (range 1–3 Gy) up to a total dose between 9 and 12 Gy (range 1–45 Gy) [39]. Mean spur size was 9 mm (range 1–30 mm). With a mean follow‐up of 74 months, no correlation between spur size and duration of pain relief was found. Analysis concerning spur length and treatment outcome in itself were unfortunately not reported.
Multivariate logistic regression enables the identification of factors independently predicting treatment outcome. By combining these factors, models can be calculated, that predict treatment outcome with a high probability. An example from the study of Hermann et al. is given in Table 4: in 285 heels treated with 6 × 1 Gy/6 × 0.5 Gy the influences of the patient characteristics age, spur length, and duration of symptoms before LD-EBRT alone and in combination were calculated [38]. The best results were obtained for patients > 53 years, spur length <6 mm, and a duration of symptoms <12 months with a probability for CR of 55% (CI 36–73%) and PR of 38% (CI 22–58%). Without these characteristics, the chance for CR was just 18% (CI 9–33%), for PR 31% (17–48%).
Study (citation) | [30] | [26] | [24] | [37] | [39] | [22] | [38] | [40] | [83] |
---|---|---|---|---|---|---|---|---|---|
Rand | Rand | Prospect | Prospect | Retrospect | Retrospect | Retrospect | Retrospect | Retrospect | |
130 | 66 | 170 | 73 | 623 | 502 | 285 | 161 | 7947 | |
MV | MV | KV | MV | KV | MV, KV | MV | KV | MV, KV | |
calcaneus | calcaneus | calcaneus | entire dorsal and middle foot | insertion of plantar fascia | calcaneus | calcaneus vs. insertion of calcaneus | calcaneus | entire dorsal foot vs. calcaneus vs. insertion of plantar fascia | |
6 × 1 vs. 6 × 0.5 Gy | 6 × 1 Gy vs. 6 × 0.1 Gy | 12, 3, 5 Gy | 5 Gy (increasing single dose) | 1.5 (1–3) up to 9–12 Gy (1–45) | 5–10 × 0.5–1 Gy | 6 × 1 Gy6 × 0.5 Gy | 6 × 1 Gy | 0.3–1.5 Gy; 2–3x weekly 2.5–18.76 Gy | |
History of symptoms | 0 | n.i. | + | + | 0 | + | + | + | + |
Gender | 0 | n.i. | 0 | n.i. | 0 | 0 | 0 | n.i. | n.i. |
Patient\'s age | 0 | n.i. | 0 | + | 0 | + | + | + | n.i. |
Initial worsening of pain during LD‐EBRT | n.i. | n.i. | n.i. | n.i. | n.i. | n.i. | n.i. | n.i. | n.i. |
MV vs. KV | n.i. | n.i. | n.i. | n.i. | n.i. | + | n.i. | n.i. | 0 |
Number of therapy series | n.i. | n.i. | n.i. | + | n.i. | + | n.i. | n.i. | + |
Heel stress during LD‐EBRT | n.i. | 0 | n.i. | + | n.i. | n.i. | n.i. | n.i. | n.i. |
Factors associated with treatment efficacy in contemporary studies.
Patient\'s age >53 | No spur or spur ≤6.5 mm | Duration of symptoms <12 months | Probability of | ||
---|---|---|---|---|---|
No change | Partial remission | Complete remission | |||
1 | 1 | 1 | 0.07 (0.03–0.14) | 0.38 (0.22–0.58) | 0.55 (0.36–0.73) |
1 | 1 | 0 | 0.13 (0.07–0.28) | 0.37 (0.21–0.57) | 0.50 (0.30–0.70) |
1 | 0 | 1 | 0.15 (0.06–0.24) | 0.53 (0.33–0.72) | 0.32 (0.17–0.53) |
1 | 0 | 0 | 0.25 (0.13–0.45) | 0.48 (0.27–0.69) | 0.27 (0.13–0.48) |
0 | 1 | 1 | 0.17 (0.10–0.31) | 0.33 (0.19–0.50) | 0.50 (0.33–0.66) |
0 | 1 | 0 | 0.34 (0.20–0.53) | 0.40 (0.24–0.59) | 0.26 (0.13–0.45) |
0 | 0 | 1 | 0.30 (0.20–0.46) | 0.29 (0.18–0.43) | 0.41 (0.27–0.56) |
0 | 0 | 0 | 0.51 (0.35–0.69) | 0.31 (0.17–0.48) | 0.18 (0.09–0.33) |
Probabilities (95%‐CI) for NC, PR and CR calculated by polytomous logistic regression in dependence of the risk factors age, spur length, and duration of symptoms before LD‐EBRT according to Hermann et al. in a collective of 285 heels treated with 6 × 1/6 × 0.5 Gy (taken from [38]).
In modern radiotherapeutic departments, X‐ray sources are less and less available. This is why nowadays most patients are treated with linear accelerators, which were initially developed for the treatment of oncological diseases. However, these machines can be used in the treatment of benign diseases without any modifications or problems. Due to the high efforts in physical, technical, and organizational quality assurances for the operation of an accelerator or an X-ray source, the concentration on accelerators and their use for all indications is recommended.
For irradiation of the heel, the patient has to be placed on the treatment couch with the feet toward the gantry of the accelerator (so‐called “feet first”). Two different patient positions are widely used. He can be placed in supine position, with the irradiated leg is stretched out, while the other leg is angled. Another option is to place the patient in a lateral decubitus position on the side of the involved heel. Again, the symptomatic leg is stretched, while the contralateral leg is bent, with a cushion placed beneath the knee. Using X‐rays, the ipsilateral knee is bent by 90% and the foot is positioned on the treatment table. One anterior‐posterior (AP) beam is usually applied in this technique.
For the treatment itself, there are also two different options. Irradiation may be given as a single stationary field (SSD 100cm by convention). Alternatively, parallel opposing fields from 0° and 180° gantry position (in decubitus position) or lateral opposing fields (90° and 270° in supine position) are also applicable but take a little bit longer in daily clinical practice. The hypothetical advantage of using two opposing fields is a uniform dose distribution in the entire beam path in the calcaneus (Figure 1). However, there has never been a clinical proof, whether this theoretical assumption translates into any clinical advantage for the patient. When applying opposing fields, the dose is specified according to the ICRU 50 report, normally in the center of the calcaneus.
Dose distribution of two different treatment techniques generated in a treatment planning system (XIO®). In A and B just one single 6 MV photon field (8 × 8 cm) is applied, while C and D shows the dose distribution with two opposing fields from 0 and 180°. In the upper row, the so‐called “beams eye views” are given, while in the lower row the respective dose distributions on an axial CT scan directly at the calcaneal insertion are shown. Note the more uniform dose distribution with opposing fields. The 95% isodose is given as a green line (2.85 Gy). This dose encompasses larger parts of the calcaneal bone in D (opposing fields) than in B (single field). More information is given in Section 2.4.
A third option is the so‐called “plantar field” with the patient lying in prone position. A single field is positioned directly over the plantar insertion/calcaneus, potentially with rotations of the patient table and the gantry to compensate for inclinations of the patients surface in the irradiated field. However, this technique is regarded problematic when using linear accelerators due to the dose build‐up effect in the critical tissue depth. This problem is illustrated in Figure 2: photons with 6 MV reach just the half of the prescribed dose at the skin level, 100% is reached at 1.5 cm tissue depth. This would result in an insufficient dose in the critical structures (plantar fascia and heel spur). To overcome this problem, a silicone flap of about 1 cm diameter must be positioned on the skin before radiation.
Depth curves of different megavoltage energies. Blue 6 MV photons, red 15 MV photons. At the surface of the body/skin (depth 0 mm), only half (or even less with 15 MV) of the prescribed dose is applied. By physical interactions between photons and the tissue/water, there is a steep increase in dose. A 100% is reached at 1.5 cm depth with 6 MV and at about 3 cm depth with 15 MV. KV‐radiation reaches the maximum dose directly under the surface/skin (not shown). More information is given in Section 2.4.
Patients are often sent to the radiotherapist after a long unsuccessful history of diverse conservative treatments. The reason for this is a widespread fear among general practitioners that LD‐EBRT might be associated with severe side effects and risks. These fears are not substantiated, as reactions of the nerves or vessels require much higher doses than used for LD‐EBRT. For example, a dose of 45 Gy in normofractionated oncological therapy is considered to be safe for the spinal cord and therefore daily clinical practice [44]. Peripheral nerves are even more radioresistant. Acute or chronic side‐effects have never been reported in all contemporary studies on LD‐EBRT.
Acute side effects are negligible, as very low doses of ionizing radiation (in comparison with oncological treatments) are applied to a distal extremity. The total dose of LD‐EBRT with 3 or 6 Gy is far too low to cause any acute or late reactions on the skin overlaying the calcaneus. During normofractionated EBRT (single doses of 1.8–2 Gy, treatment on 5 days a week) erythema and mild edema develop at about 30 Gy [45]. Hyperpigmentation occurs at about 45 Gy, moist epitheliolyses at about 50 Gy. A 50–60 Gy might cause telangiectasias years after the therapy. This is why there is no report on acute treatment side effects in LD‐EBRT until now to the best of our knowledge.
About one‐third of the patients might experience a slight increase in pain during LD‐EBRT. In the randomized trial by Heydt et al. this phenomenon was seen in 26% (during 6 × 0.5 Gy) vs. 29% (6 × 1 Gy) [30]. It does not seem to be correlated with treatment outcome; further detailed information is given in Section 2.3.4.
The dose scattered to the male gonads is somewhat higher than to the ovaries. Jansen et al. calculated for 6 × 0.5 Gy about 1.5 mSv received by the testes and 0.75 mSv to the ovaries [46]. Comparable results have repeatedly been measured in the past [47, 48].
Taken together, the dose received by the gonads is insignificant. As the distal extremity is irradiated, scattered dose to the gonads is comparable to normal diagnostic radiological imaging [49]. The hereditary effects of these doses are very small and very likely negligible [46].
Although spermatogonial cells are very radiosensitive, a single dose of at least 100 mSv is needed to induce a temporary failure of spermatogenesis [50]. A single dose of 1000 mSv (equivalent to 1 Gy photon irradiation) results in an azoospermia for 9–18 months [51]. Interestingly, fractionated doses harm these cells even more. A temporary oligospermia is reported after receiving several fractions up to a cumulative dose of 160 mSv [52]. An azoospermia lasting for 14–22 months has been reported for fractionated doses of 620–860 mSv [53]. The actually during LD‐EBRT received testicular dose is about 100 times smaller than the lowest dose causing temporary changes in testicular tissues.
The dose to the testicles can be further reduced by utilizing a special testicular shielding. However, clinically meaningful dose reductions have been only measured in MV treatment of subdiaphragmatic/pelvine lymphatic regions or tumors [54, 55].
The mean lethal dose for human oocytes has been estimated at 2 Gy (2000 mSv) [56]. Permanent ovarian failure after radiotherapy is age dependent: in perimenopausal women, a dose of 6 Gy is sufficient [57], while in younger women up to 20 Gy are tolerated. The dose scattered to the ovaries during LD‐EBRT for calcaneodynia cannot cause such sequelae (0.75 mSv).
Naturally, pregnancy has to be excluded in all premenopausal women before beginning with LD‐EBRT, to avoid any risk to the fetus.
So far, no studies with long‐term observation periods have been published, describing a case of malignancy induced by LD‐EBRT for calcaneodynia. However, induction of malignancies is a stochastic effect of ionizing radiation. This means that there is no threshold dose—in contrast for example to the above‐mentioned reactions of the skin. A photon can accidentally trigger a mutation, which in turn leads to tumor formation many years later. The higher the radiation dose, the higher the probability of such an event occurring.
The best available data on tumor induction of full dose EBRT in oncology has been collected in patients treated with breast cancer. Almost 11,000 patients have been followed for over 20 years. The risk of a radiation‐induced tumor was approx. 1% per decade after radiotherapy [58].
To estimate the risk associated with much lower doses of LD‐EBRT, mathematical models on the basis of epidemiological long‐term observations of atomic bomb victims have been developed by the ICRP [59].
Jansen et al. applied the ICRP model on LD‐EBRT of a painful heel spur [46]. Assumed was a single field entering at the foot sole with a size of 8 × 10 cm, 200 kV photons, SSD 40 cm. For an LD‐EBRT series with 6 × 1 Gy the average attributable lifetime risk for induction of a fatal tumor was calculated to be about 0.5 in a thousand patients. An important risk factor for radiogenic‐induced cancer is the patient\'s age by the time the radiation exposure occurs. The risk is already reduced in the 3rd decade of the patient\'s life, it starts to decrease steadily from the age of 40 [60]. Applying these calculations, the estimated lifetime risk per one thousand patients for a fatal tumor accounts for the age of 25 0.6 (male)/0.8 (female), for the age of 50 0.2/0.3, for the age of 75 0.07/0.1 [46].
However, it must be critically noted that this mathematical model was developed for radiation protection and relates to the exposure of complete organ systems with approx. 1 Gy. Therefore, other groups argue that a significantly lower risk of radiogenic cancer induction— approx. ten times less—should be adopted [49, 61]. Furthermore, taken the new standard scheme with 6 × 0.5 Gy into account, these risks are additionally halved.
This risk (max. 1/1000, very likely much lower) must be seen in relation to the tumor risk of the not additionally radiotherapeutical‐treated population. In 2008, the lifetime risk of a man in Germany to suffer from cancer was 50.7% (25.9% to die from malignancy), in women 42.8% and 20.2% respectively [62].
By limiting the application of LD‐EBRT treatment to patients > 30 years of age, an exposure of the juvenile “relatively higher risk” patient population is avoided.
Traditionally target volume definition has been quite large. Field sizes of 12 × 17cm were treated, including the entire dorsal and middle foot, and not just the calcaneus [37, 82] (Figure 3A).
Field definitions in LD‐EBRT of a painful plantar heel spur/fasciitis. (A) traditional field definition including the entire dorsal and middle foot. (B) In randomized trials and large prospective series commonly used field definition encompassing the entire calcaneus, including insertion of the plantar fascia and the Achilles tendon. (C) Proposed small field definition for localized painful plantar fasciitis/plantar spur, encompassing only the painful area with 2 cm margins extending into the neighboring areas (calcaneus, fascia, fat pad).
In the recent randomized trials and prospective observational studies target volume definition was more restricted and confined to the calcaneus (Figure 3B). “The target volume consisted of the calcaneus and the region of the plantar aponeurosis” [26]. “The ventral margin is corresponding to the ventral surface of the calcaneus, the plantar and dorsal margins are surrounding the soft‐tissue border, and the cranial margin is below the ankle” [30]. “Target volume is the calcaneus, normally with a field size of 6 cm × 8 cm” [32]. “The calcaneus and the plantar aponeurosis were included in the target volume” [25].
In a German national survey 2001 on LD‐EBRT of painful heel spurs the target volume definition “large” (dorsal and middle foot) vs. “small” (entire calcaneus) was not correlated with treatment outcome [83]. Consequently, very large field definitions should be regarded as obsolete.
However, as the pathophysiological cause of calcaneodynia is thought to be a localized inflammatory process (see Section 1), it is questionable, whether the entire calcaneus has to be irradiated (as long as there are not a plantar as well as a painful dorsal spurs). There are some clinical data that support a further restriction of target volume definition.
Field sizes have been given in the study by Miszczyk et al. on 327 patients treated with X‐ray beams [39]. Target volume was “… the insertion of the plantar fascia with a calcaneal spur and a reasonable margin. The field size varied from 27 to 150 cm2 (mean 47 cm2).” However, although not explicitly stated, no correlation was found between field size and duration of pain relief after LD‐EBRT. Treatment efficacy in itself was apparently not investigated.
In the above‐mentioned series of 285 heels Hermann et al. analyzed treatment efficacy in dependence of field sizes, too [38]. The mean field size was 74 cm2. No correlation between field size (smaller vs. larger than 74 cm2) with treatment efficacy was found. Further analyses of small fields (< 6 × 6 cm), medium‐sized fields (36–64 cm2) and larger fields revealed no significant differences.
This is why it seems to suffice to encompass the painful region with 2 cm margins extending into the neighboring areas (calcaneus, fascia, fat pad; Figure 3C). However, this recommendation is deducted from pathophysiological considerations and the above‐mentioned case series. A randomized trial is necessary to proof clinical equivalence of a field definition “entire calcaneus” (Figure 3B) vs. “insertion of the plantar fascia” (Figure 3C).
The optimal fractionation schedule has not been elucidated yet. All randomized trial used twice weekly treatments. Only one experimental arm was scheduled three times a week [25]. In a National Survey in Germany with 146 answering institutions, about 45% applied two fractions and 37.5% three fractions weekly [83].
Interestingly, in the landmark study by von Pannewitz a fractionation schedule of only once per week was established [34]. Until now, there is no proof of a higher efficacy applying LD‐EBRT twice or three times per week.
In radiotherapy of another benign disease (endocrine orbitopathy) a 1 Gy per week over 20 weeks schedule was more effective than the standard schedules (10 × 2 Gy or 10 × 1 Gy every working day) [84]. Although other immunological mechanisms cause endocrine orbitopathy in comparison with plantar fasciitis, there is sufficient clinical evidence to test in a randomized trial different fractionation schedules (twice a week vs. once a week, possibly thrice a week).
Other therapies than LD‐EBRT have been applied in painful heel spur. In the following, just a rough overview can be given.
Different kinds of insoles and foot orthoses have been developed. The goal was to reduce plantar contact pressure and to distribute the pressure uniformly over the whole rearfoot [63]. Magnetic insoles do not seem to provide additional benefit [64]. As a short‐term treatment, low‐Dye taping techniques are often used. However, in a randomized trial only a modest improvement in ‘first‐step’ pain was seen in comparison with sham‐intervention [65].
Manual stretching is often recommended. A systematic review of six studies found only statistically significant differences in comparison with the control in one study combining calf muscle and plantar fascia stretches [66].
Several trials have investigated acupuncture. A systematic review from 2010 showed (limited) evidence for the effectiveness [67]. A randomized trial published in 2014 recruited 84 patients [68]. The authors concluded, that “dry needling provided statistically significant reductions in plantar heel pain, but the magnitude of this effect should be considered against the frequency of minor transitory adverse events.”
Ultrasound therapy has led to questionable results [69], but a randomized trial on cryo‐ultrasound with about 100 patients published in 2014 showed good effectiveness [70].
Low‐level laser light (635 nm), given twice a week for a total of six applications, reduced in a randomized trial VAS scores significantly after 8 weeks in comparison with placebo [71]. However, the study comprised of just 69 patients; other similar studies have not been reported so far.
Extracorporeal shock waves are widely applied. Three metaanalyses comprising at least five randomized trials found significant short‐term pain relief and improved functional outcomes for this therapeutic option [72–74]. Another study compared the analgesic efficacy of ultrasound and shock wave therapy in 47 patients [75]. The results suggested that the shock wave therapy had greater analgesic efficacy.
Another basic approach is the oral administration of nonsteroidal anti‐inflammatory drugs (NSAID) to achieve a symptomatic relief. Injections into the painful area are also recommended. A recent review summarized ten randomized trials on corticosteroid injections into the plantar fascia [76]. A significant effect of the steroids on the pain has been shown. However, it was usually short‐term, lasting 4–12 weeks in duration. No advantage of ultrasound‐guided injection techniques in comparison with palpation guidance was found, and no superiority of one type of corticosteroid over another was seen. A longer lasting pain relief has been suggested by a small randomized trial of botulinum toxin injections [77]. Another option is the injection of autologous platelet‐rich plasma. A recent review identified three randomized trials, all showing promising results [78]. However, a very small trial challenged this method of plasma preparation, as the same clinical effectivity was observed after the injection of whole blood [79].
Different surgical approaches have been developed. Releases of the plantar fascia are done, in some studies combined with a spur resection [80]. Due to a probably faster recovery after surgery with comparable functional results endoscopic procedures are recommended nowadays [81]. Surgery is usually indicated after failure of conservative therapies as the ultimate “salvage‐therapy.”
There is only a limited amount of studies randomizing patients between LD‐EBRT and the above‐mentioned alternative therapies.
Canyilmaz et al. randomized 123 patients between LD‐EBRT (6 × 1 Gy, three times a week) and 1 ml injection of 40 mg methylprednisolone and 0.5 ml 60 mg 1% lidocaine under the guidance of palpation [85]. After 3 and 6 months, VAS values and CS‐scores were compared between both groups. After 3 months, the results in the radiotherapy arm were significantly superior compared with those after injections.
To corroborate these findings, similar studies should be conducted. Furthermore, more studies randomizing LD‐EBRT against other therapies (e.g. extracorporeal shock waves) are needed. A minimum size of 50 patients per treatment arm should be assured to gain more statistically relevant results. Recruiting patients without prior excessive other therapies for these studies would be optimal.
The goal must be an evidence‐based algorithm defining the therapeutic sequence of the different conservative treatment modalities for plantar fasciitis.
LD‐EBRT for painful plantar fasciitis/heel spur is an effective and safe treatment option for patients over 30 years of age and after exclusion of pregnancy. A fractionation of 6 × 0.5 Gy twice weekly up to a total dose of 3 Gy is currently recommended. In the case of an insufficient response a second course can be offered to the patient.
Randomized trials on target volume definition and further optimization of LD‐EBRT fractionation are currently in the process of planning. Further trials to compare the different conservative therapies for plantar fasciitis with each other are necessary to allow the development of an evidence‐based treatment algorithm.
This chapter is dedicated to Professor Gisela Hermann‐Brennecke on the occasion of her 70th birthday.
AP | anterior‐posterior |
CI | confidence interval |
CR | complete remission |
CS | Calcaneodynia score |
Cu | chemical element symbol for copper |
EC | endothelial cells |
GCG‐BD | German Cooperative Group on Radiotherapy for Benign Diseases |
Gy | Gray |
ICRP | International Commission on Radiological Protection |
IL | interleukin |
iNOS | inducible nitric oxide synthases |
KV | kilovoltage |
LD‐EBRT | low dose external beam radiotherapy |
mA | milliampere |
mRNA | messenger ribonuclein acid |
mSv | milliSievert |
MV | megavoltage |
NC | no change |
NF‐κB | nuclear factor kappa B |
NO | nitric oxide |
NSAID | non‐steroidal anti‐inflammatory drug |
PBMC | peripheral blood mononuclear cells |
PR | partial remission |
QOL | quality of life |
ROS | reactive oxygen species |
SSD | skin‐to‐source distance |
TGF‐β1 | transforming growth factor β1 |
VAS | visual analogue scale |
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On September, 29th 2006 he has won a post PhD fellowship from the university of Bologna (from October 2006 to October 2008), at the competitive examination he was ranked first in the industrial engineering area. He extensively served as referee for several international journals. He is author/coauthor of more than 100 research papers. He has been involved in some projects supported by MURST and European Community. His research interests include pattern recognition, bioinformatics, and biometric systems (fingerprint classification and recognition, signature verification, face recognition).",institutionString:null,institution:null},{id:"496",title:"Dr.",name:"Carlos",middleName:null,surname:"Leon",slug:"carlos-leon",fullName:"Carlos Leon",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Seville",country:{name:"Spain"}}},{id:"512",title:"Dr.",name:"Dayang",middleName:null,surname:"Jawawi",slug:"dayang-jawawi",fullName:"Dayang Jawawi",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Technology Malaysia",country:{name:"Malaysia"}}},{id:"528",title:"Dr.",name:"Kresimir",middleName:null,surname:"Delac",slug:"kresimir-delac",fullName:"Kresimir Delac",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/528/images/system/528.jpg",biography:"K. 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Aalborg University has Two Satellite Campuses, one in Copenhagen (Aalborg University Copenhagen) and the other in Esbjerg (Aalborg University Esbjerg).\n· He is a member of prestigious IEEE (Institute of Electrical and Electronics Engineers), and IAENG (International Association of Engineers) organizations. \n· He is the chief Editor of the Journal of Software Engineering.\n· He is the member of the Editorial Board of International Journal of Computer Science and Software Technology (IJCSST) and International Journal of Computer Engineering and Information Technology. \n· He is also the Editor of Communication in Computer and Information Science CCIS-20 by Springer.\n· Reviewer For Many Conferences\nHe is the lead person in making collaboration agreements between Aalborg University and many universities of Pakistan, for which the MOU’s (Memorandum of Understanding) have been signed.\nProfessor Akbar is working in Academia since 1990, he started his career as a Lab demonstrator/TA at the University of Sussex. After finishing his P. hD degree in 1992, he served in the Industry as a Scientific Officer and continued his academic career as a visiting scholar for a number of educational institutions. In 1996 he joined National University of Science & Technology Pakistan (NUST) as an Associate Professor; NUST is one of the top few universities in Pakistan. In 1999 he joined an International Company Lineo Inc, Canada as Manager Compiler Group, where he headed the group for developing Compiler Tool Chain and Porting of Operating Systems for the BLACKfin processor. The processor development was a joint venture by Intel and Analog Devices. In 2002 Lineo Inc., was taken over by another company, so he joined Aalborg University Denmark as an Assistant Professor.\nProfessor Akbar has truly a multi-disciplined career and he continued his legacy and making progress in many areas of his interests both in teaching and research. 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Lakka and Chandrasekar Kuppan",authors:[{id:"304950",title:"Prof.",name:"Chandrasekar",middleName:null,surname:"Kuppan",slug:"chandrasekar-kuppan",fullName:"Chandrasekar Kuppan"},{id:"309984",title:"Mr.",name:"Narasimha S",middleName:null,surname:"Lakka",slug:"narasimha-s-lakka",fullName:"Narasimha S Lakka"}]},{id:"33046",title:"Affinity Chromatography: Principles and Applications",slug:"affinity-chromatography-principles-and-applications",totalDownloads:48609,totalCrossrefCites:8,totalDimensionsCites:21,abstract:null,book:{id:"1490",slug:"affinity-chromatography",title:"Affinity Chromatography",fullTitle:"Affinity Chromatography"},signatures:"Sameh Magdeldin and Annette Moser",authors:[{id:"123648",title:"Dr.",name:"Sameh",middleName:null,surname:"Magdeldin",slug:"sameh-magdeldin",fullName:"Sameh Magdeldin"},{id:"136483",title:"Dr.",name:"Annette",middleName:"C.",surname:"Moser",slug:"annette-moser",fullName:"Annette Moser"}]},{id:"50574",title:"Bioinformatics for RNA‐Seq Data Analysis",slug:"bioinformatics-for-rna-seq-data-analysis",totalDownloads:5930,totalCrossrefCites:6,totalDimensionsCites:7,abstract:"While RNA sequencing (RNA‐seq) has become increasingly popular for transcriptome profiling, the analysis of the massive amount of data generated by large‐scale RNA‐seq still remains a challenge. RNA‐seq data analyses typically consist of (1) accurate mapping of millions of short sequencing reads to a reference genome, including the identification of splicing events; (2) quantifying expression levels of genes, transcripts, and exons; (3) differential analysis of gene expression among different biological conditions; and (4) biological interpretation of differentially expressed genes. Despite the fact that multiple algorithms pertinent to basic analyses have been developed, there are still a variety of unresolved questions. In this chapter, we review the main tools and algorithms currently available for RNA‐seq data analyses, and our goal is to help RNA‐seq data analysts to make an informed choice of tools in practical RNA‐seq data analysis. In the meantime, RNA‐seq is evolving rapidly, and newer sequencing technologies are briefly introduced, including stranded RNA‐seq, targeted RNA‐seq, and single‐cell RNA‐seq.",book:{id:"5160",slug:"bioinformatics-updated-features-and-applications",title:"Bioinformatics",fullTitle:"Bioinformatics - Updated Features and Applications"},signatures:"Shanrong Zhao, Baohong Zhang, Ying Zhang, William Gordon,\nSarah Du, Theresa Paradis, Michael Vincent and David von Schack",authors:[{id:"176364",title:"Dr.",name:"Shanrong",middleName:null,surname:"Zhao",slug:"shanrong-zhao",fullName:"Shanrong Zhao"}]},{id:"49873",title:"An Introduction to Actinobacteria",slug:"an-introduction-to-actinobacteria",totalDownloads:8089,totalCrossrefCites:29,totalDimensionsCites:101,abstract:"Actinobacteria, which share the characteristics of both bacteria and fungi, are widely distributed in both terrestrial and aquatic ecosystems, mainly in soil, where they play an essential role in recycling refractory biomaterials by decomposing complex mixtures of polymers in dead plants and animals and fungal materials. They are considered as the biotechnologically valuable bacteria that are exploited for its secondary metabolite production. Approximately, 10,000 bioactive metabolites are produced by Actinobacteria, which is 45% of all bioactive microbial metabolites discovered. Especially Streptomyces species produce industrially important microorganisms as they are a rich source of several useful bioactive natural products with potential applications. Though it has various applications, some Actinobacteria have its own negative effect against plants, animals, and humans. On this context, this chapter summarizes the general characteristics of Actinobacteria, its habitat, systematic classification, various biotechnological applications, and negative impact on plants and animals.",book:{id:"5056",slug:"actinobacteria-basics-and-biotechnological-applications",title:"Actinobacteria",fullTitle:"Actinobacteria - Basics and Biotechnological Applications"},signatures:"Ranjani Anandan, Dhanasekaran Dharumadurai and Gopinath\nPonnusamy Manogaran",authors:[{id:"48914",title:"Dr.",name:"Dharumadurai",middleName:null,surname:"Dhanasekaran",slug:"dharumadurai-dhanasekaran",fullName:"Dharumadurai Dhanasekaran"}]},{id:"72074",title:"The Chemistry Behind Plant DNA Isolation Protocols",slug:"the-chemistry-behind-plant-dna-isolation-protocols",totalDownloads:3691,totalCrossrefCites:3,totalDimensionsCites:5,abstract:"Various plant species are biochemically heterogeneous in nature, a single deoxyribose nucleic acid (DNA) isolation protocol may not be suitable. There have been continuous modification and standardization in DNA isolation protocols. Most of the plant DNA isolation protocols used today are modified versions of hexadecyltrimethyl-ammonium bromide (CTAB) extraction procedure. Modification is usually performed in the concentration of chemicals used during the extraction procedure according to the plant species and plant part used. Thus, understanding the role of each chemical (viz. CTAB, NaCl, PVP, ethanol, and isopropanol) used during the DNA extraction procedure will benefit to set or modify protocols for more precisions. A review of the chemicals used in the CTAB method of DNA extraction and their probable functions on the highly evolved yet complex to students and researchers has been summarized.",book:{id:"8912",slug:"biochemical-analysis-tools-methods-for-bio-molecules-studies",title:"Biochemical Analysis Tools",fullTitle:"Biochemical Analysis Tools - Methods for Bio-Molecules Studies"},signatures:"Jina Heikrujam, Rajkumar Kishor and Pranab Behari Mazumder",authors:[{id:"74521",title:"Dr.",name:"Rajkumar",middleName:null,surname:"Kishor",slug:"rajkumar-kishor",fullName:"Rajkumar Kishor"},{id:"309357",title:"Prof.",name:"Pranab Behari",middleName:null,surname:"Mazumder",slug:"pranab-behari-mazumder",fullName:"Pranab Behari Mazumder"},{id:"318351",title:"Ph.D. Student",name:"Jina",middleName:null,surname:"Heikrujam",slug:"jina-heikrujam",fullName:"Jina Heikrujam"}]}],onlineFirstChaptersFilter:{topicId:"6",limit:6,offset:0},onlineFirstChaptersCollection:[{id:"82409",title:"Purinergic Signaling in Covid-19 Disease",slug:"purinergic-signaling-in-covid-19-disease",totalDownloads:2,totalDimensionsCites:0,doi:"10.5772/intechopen.105008",abstract:"SARS-CoV-2 virus infection causes the Covid-19 disease pandemic. Purinergic signaling is a form of extracellular signaling. Purinergic signaling plays significant role in the pathology of Covid-19. Purinergic system includes extracellular nucleotides, nucleosides, ectonucleotidases, and purinergic receptors. ATP, ADP, and adenosine are the main nucleotides, nucleosides. CD39 and CD73 are the main ectonucleotidases. There are two classes of purinergic receptors, P1 and P2. Each of them can be further divided, P1 into A1, A2A, A2B, and A3, P2 into P2X, and P2Y. In Covid-19, the purinergic system is disordered. SARS-CoV-2 viruses invading leads to extracellular ATP and ADP accumulation, purinergic receptor abnormally activation, tissue homeostasis balance is broken, which lead to inflammation even hyperinflammation with cytokine storm and thrombosis et al. symptoms. Currently, Covid-19 therapeutic medicine is still in shortage. Target purinergic system components is a promising way to treat Covid-19, which will help inhibit inflammation and prevent thrombosis. Currently, many relevant preclinical and clinical trials are ongoing. Some are very promising.",book:{id:"10801",title:"Purinergic System",coverURL:"https://cdn.intechopen.com/books/images_new/10801.jpg"},signatures:"Hailian Shen"},{id:"81708",title:"High Throughput Methods to Transfer DNA in Cells and Perspectives",slug:"high-throughput-methods-to-transfer-dna-in-cells-and-perspectives",totalDownloads:2,totalDimensionsCites:0,doi:"10.5772/intechopen.104542",abstract:"Genome sequencing led to thousands of genes to study and their molecular cloning to provide ORF collection plasmids. The main approach to study their function involves analysis of the biological consequences of their expression or knockdown, in a cellular context. Given that, the starting point of such experiments is the delivery of the exogenous material, including plasmid DNA in cells. During the last decades, efforts were made to develop efficient methods and protocols to achieve this goal. The present chapter will first give a rapid overview of the main DNA transfer methods described so far: physical, chemical, and biological. Secondly, it will focus on the different methods having reached high-throughput nowadays. Finally, it will discuss the perspectives of this field in terms of future enhancements.",book:{id:"11356",title:"Molecular Cloning",coverURL:"https://cdn.intechopen.com/books/images_new/11356.jpg"},signatures:"Colin Béatrice and Couturier Cyril"},{id:"82374",title:"The Potential of the Purinergic System as a Therapeutic Target of Natural Compounds in Cutaneous Melanoma",slug:"the-potential-of-the-purinergic-system-as-a-therapeutic-target-of-natural-compounds-in-cutaneous-mel",totalDownloads:4,totalDimensionsCites:0,doi:"10.5772/intechopen.105457",abstract:"Cutaneous melanoma is an aggressive and difficult-to-treat disease that has rapidly grown worldwide. The pharmacotherapy available in so many cases results in low response and undesirable side effects, which impair the life quality of those affected. Several studies have been shown that the purinergic system is involved in cancer context, such as in cutaneous melanoma. With technological advances, several bioactive compounds from nature are studied and presented as promising adjuvant therapies against cancer, as phenolic compounds and related action by purinergic system modulations. Thus, phenolic compounds such as rosmarinic acid, resveratrol, tannic acid, as well as vitamin D may be promising substances in a therapeutic perspective to treat cutaneous melanoma via purinergic system pathway. More research needs to be done to open up new horizons in the treatment of melanoma by the purinergic signaling.",book:{id:"10801",title:"Purinergic System",coverURL:"https://cdn.intechopen.com/books/images_new/10801.jpg"},signatures:"Gilnei Bruno da Silva, Daiane Manica, Marcelo Moreno and Margarete Dulce Bagatini"},{id:"82338",title:"Advantages of Noncoding RNAs in Molecular Diagnosis",slug:"advantages-of-noncoding-rnas-in-molecular-diagnosis",totalDownloads:7,totalDimensionsCites:0,doi:"10.5772/intechopen.105525",abstract:"Noncoding RNAs contribute to physiological processes by regulating many intracellular molecules participating in the life-supporting mechanisms of development, differentiation, and regeneration as well as by disrupting various signaling mechanisms such as disease development and progression and tumor growth. Because microRNAs (miRNAs) target and regulate the functions of key proteins, it is very useful to identify specific miRNAs that contribute to cellular functions and to clarify the roles of their target molecules as diagnostic and therapeutic strategies for cancer prognosis and treatment. In this section, the roles of miRNAs in various cancers and the processes leading to the identification of their target molecules are described, and the latest diagnostic strategies using miRNAs are discussed with specific examples.",book:{id:"11353",title:"Recent Advances in Non-Coding RNAs",coverURL:"https://cdn.intechopen.com/books/images_new/11353.jpg"},signatures:"Tomomi Fujii, Tomoko Uchiyama and Maiko Takeda"},{id:"82298",title:"Predicting SNPs in Mature MicroRNAs Dysregulated in Breast Cancer",slug:"predicting-snps-in-mature-micrornas-dysregulated-in-breast-cancer",totalDownloads:8,totalDimensionsCites:0,doi:"10.5772/intechopen.105514",abstract:"Breast cancer (BC) is the leading type of cancer among women. Findings have revolutionized current knowledge of microRNA (miRNA) in breast tumorigenesis. The seed region of miRNA regulates the process of gene expression negatively. The presence of SNPs in the seed regions of miRNA dramatically alters the mature miRNA function. Additionally, SNPs in the out-seed region of miRNAs have a significant impact on miRNA targeting. This study focuses on the in silico analysis procedure of mature miRNA SNPs and their impact on BC risk. The database annotated SNPs on mature miRNAs was used. Also, target gene alterations, miRNAs function in BC, and the interaction of miRNAs with targets were predicted. A list of 101 SNPs in 100 miRNAs with functional targets in BC was indicated. Under the SNPs allele variation, 10 miRNAs changed function, 6 miRNAs lost targets, 15 miRNAs gained targets, 48 onco-miRNAs remained unchanged, and 21 tumor suppressor miRNAs remained unchanged. At last, a list of 89 SNPs, which alter miRNA function and miRNA-mRNA interaction, were shown to be potentially associated with BC risk. This research theoretically generated a list of possible causative SNPs in the mature miRNA gene that might be used in future BC management studies.",book:{id:"11353",title:"Recent Advances in Non-Coding RNAs",coverURL:"https://cdn.intechopen.com/books/images_new/11353.jpg"},signatures:"Thanh Thi Ngoc Nguyen, Thu Huynh Ngoc Nguyen, Luan Huu Huynh, Hoang Ngo Phan and Hue Thi Nguyen"},{id:"82103",title:"The Role of Endoplasmic Reticulum Stress and Its Regulation in the Progression of Neurological and Infectious Diseases",slug:"the-role-of-endoplasmic-reticulum-stress-and-its-regulation-in-the-progression-of-neurological-and-i",totalDownloads:6,totalDimensionsCites:0,doi:"10.5772/intechopen.105543",abstract:"The unfolded protein response (UPR) is a cellular mechanism activated by endoplasmic reticulum (ER) stress, which ranges from inhibition of protein synthesis to apoptosis. ER stress is induced in general by aggregated autologous or foreign (e.g. viral) proteins, oxidative stress, mitochondrial dysfunction, disruption of intracellular calcium, or inflammation. In patients with Alzheimer’s disease (AD) and amyotrophic lateral sclerosis (ALS), the known stressors are aggregated amyloid-beta and superoxide dismutase (SOD-1), respectively, but autologous DNA released by trauma into the cytoplasm may also be involved in ALS. In HIV-1-associated neurocognitive disorders (HAND), ER stress is induced by HIV-1 and antiretroviral therapy. Additionally, in cases of epilepsy, ER stress has been implicated in neuronal dysfunction. In this chapter, we examine a clinical and immunologic approach to ER stress in the progression of neurological and infectious diseases. In addition, we will briefly discuss emerging treatments including omega fatty acids, progesterone, and DHA, which repair and favorably regulate UPR in some patients with neurological diseases.",book:{id:"11674",title:"Updates on Endoplasmic Reticulum",coverURL:"https://cdn.intechopen.com/books/images_new/11674.jpg"},signatures:"Mary Dover, Michael Kishek, Miranda Eddins, Naneeta Desar, Ketema Paul and Milan Fiala"}],onlineFirstChaptersTotal:58},preDownload:{success:null,errors:{}},subscriptionForm:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[],offset:0,limit:8,total:null},allSeries:{pteSeriesList:[{id:"14",title:"Artificial Intelligence",numberOfPublishedBooks:9,numberOfPublishedChapters: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:317,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:129,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:105,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:2,numberOfUpcomingTopics:1,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:"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"}}}},{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"}}}}]},series:{item:{id:"14",title:"Artificial Intelligence",doi:"10.5772/intechopen.79920",issn:"2633-1403",scope:"Artificial Intelligence (AI) is a rapidly developing multidisciplinary research area that aims to solve increasingly complex problems. In today's highly integrated world, AI promises to become a robust and powerful means for obtaining solutions to previously unsolvable problems. This Series is intended for researchers and students alike interested in this fascinating field and its many applications.",coverUrl:"https://cdn.intechopen.com/series/covers/14.jpg",latestPublicationDate:"June 11th, 2022",hasOnlineFirst:!0,numberOfPublishedBooks:9,editor:{id:"218714",title:"Prof.",name:"Andries",middleName:null,surname:"Engelbrecht",slug:"andries-engelbrecht",fullName:"Andries Engelbrecht",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRNR8QAO/Profile_Picture_1622640468300",biography:"Andries Engelbrecht received the Masters and PhD degrees in Computer Science from the University of Stellenbosch, South Africa, in 1994 and 1999 respectively. He is currently appointed as the Voigt Chair in Data Science in the Department of Industrial Engineering, with a joint appointment as Professor in the Computer Science Division, Stellenbosch University. Prior to his appointment at Stellenbosch University, he has been at the University of Pretoria, Department of Computer Science (1998-2018), where he was appointed as South Africa Research Chair in Artifical Intelligence (2007-2018), the head of the Department of Computer Science (2008-2017), and Director of the Institute for Big Data and Data Science (2017-2018). In addition to a number of research articles, he has written two books, Computational Intelligence: An Introduction and Fundamentals of Computational Swarm Intelligence.",institutionString:null,institution:{name:"Stellenbosch University",institutionURL:null,country:{name:"South Africa"}}},editorTwo:null,editorThree:null},subseries:{paginationCount:6,paginationItems:[{id:"22",title:"Applied Intelligence",coverUrl:"https://cdn.intechopen.com/series_topics/covers/22.jpg",isOpenForSubmission:!0,editor:{id:"27170",title:"Prof.",name:"Carlos",middleName:"M.",surname:"Travieso-Gonzalez",slug:"carlos-travieso-gonzalez",fullName:"Carlos Travieso-Gonzalez",profilePictureURL:"https://mts.intechopen.com/storage/users/27170/images/system/27170.jpeg",biography:"Carlos M. Travieso-González received his MSc degree in Telecommunication Engineering at Polytechnic University of Catalonia (UPC), Spain in 1997, and his Ph.D. degree in 2002 at the University of Las Palmas de Gran Canaria (ULPGC-Spain). He is a full professor of signal processing and pattern recognition and is head of the Signals and Communications Department at ULPGC, teaching from 2001 on subjects on signal processing and learning theory. His research lines are biometrics, biomedical signals and images, data mining, classification system, signal and image processing, machine learning, and environmental intelligence. He has researched in 52 international and Spanish research projects, some of them as head researcher. He is co-author of 4 books, co-editor of 27 proceedings books, guest editor for 8 JCR-ISI international journals, and up to 24 book chapters. He has over 450 papers published in international journals and conferences (81 of them indexed on JCR – ISI - Web of Science). He has published seven patents in the Spanish Patent and Trademark Office. He has been a supervisor on 8 Ph.D. theses (11 more are under supervision), and 130 master theses. He is the founder of The IEEE IWOBI conference series and the president of its Steering Committee, as well as the founder of both the InnoEducaTIC and APPIS conference series. He is an evaluator of project proposals for the European Union (H2020), Medical Research Council (MRC, UK), Spanish Government (ANECA, Spain), Research National Agency (ANR, France), DAAD (Germany), Argentinian Government, and the Colombian Institutions. He has been a reviewer in different indexed international journals (<70) and conferences (<250) since 2001. He has been a member of the IASTED Technical Committee on Image Processing from 2007 and a member of the IASTED Technical Committee on Artificial Intelligence and Expert Systems from 2011. \n\nHe has held the general chair position for the following: ACM-APPIS (2020, 2021), IEEE-IWOBI (2019, 2020 and 2020), A PPIS (2018, 2019), IEEE-IWOBI (2014, 2015, 2017, 2018), InnoEducaTIC (2014, 2017), IEEE-INES (2013), NoLISP (2011), JRBP (2012), and IEEE-ICCST (2005)\n\nHe is an associate editor of the Computational Intelligence and Neuroscience Journal (Hindawi – Q2 JCR-ISI). He was vice dean from 2004 to 2010 in the Higher Technical School of Telecommunication Engineers at ULPGC and the vice dean of Graduate and Postgraduate Studies from March 2013 to November 2017. He won the “Catedra Telefonica” Awards in Modality of Knowledge Transfer, 2017, 2018, and 2019 editions, and awards in Modality of COVID Research in 2020.\n\nPublic References:\nResearcher ID http://www.researcherid.com/rid/N-5967-2014\nORCID https://orcid.org/0000-0002-4621-2768 \nScopus Author ID https://www.scopus.com/authid/detail.uri?authorId=6602376272\nScholar Google https://scholar.google.es/citations?user=G1ks9nIAAAAJ&hl=en \nResearchGate https://www.researchgate.net/profile/Carlos_Travieso",institutionString:null,institution:{name:"University of Las Palmas de Gran Canaria",institutionURL:null,country:{name:"Spain"}}},editorTwo:null,editorThree:null},{id:"23",title:"Computational Neuroscience",coverUrl:"https://cdn.intechopen.com/series_topics/covers/23.jpg",isOpenForSubmission:!0,editor:{id:"14004",title:"Dr.",name:"Magnus",middleName:null,surname:"Johnsson",slug:"magnus-johnsson",fullName:"Magnus Johnsson",profilePictureURL:"https://mts.intechopen.com/storage/users/14004/images/system/14004.png",biography:"Dr Magnus Johnsson is a cross-disciplinary scientist, lecturer, scientific editor and AI/machine learning consultant from Sweden. \n\nHe is currently at Malmö University in Sweden, but also held positions at Lund University in Sweden and at Moscow Engineering Physics Institute. \nHe holds editorial positions at several international scientific journals and has served as a scientific editor for books and special journal issues. \nHis research interests are wide and include, but are not limited to, autonomous systems, computer modeling, artificial neural networks, artificial intelligence, cognitive neuroscience, cognitive robotics, cognitive architectures, cognitive aids and the philosophy of mind. \n\nDr. Johnsson has experience from working in the industry and he has a keen interest in the application of neural networks and artificial intelligence to fields like industry, finance, and medicine. \n\nWeb page: www.magnusjohnsson.se",institutionString:null,institution:{name:"Malmö University",institutionURL:null,country:{name:"Sweden"}}},editorTwo:null,editorThree:null},{id:"24",title:"Computer Vision",coverUrl:"https://cdn.intechopen.com/series_topics/covers/24.jpg",isOpenForSubmission:!0,editor:{id:"294154",title:"Prof.",name:"George",middleName:null,surname:"Papakostas",slug:"george-papakostas",fullName:"George Papakostas",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002hYaGbQAK/Profile_Picture_1624519712088",biography:"George A. Papakostas has received a diploma in Electrical and Computer Engineering in 1999 and the M.Sc. and Ph.D. degrees in Electrical and Computer Engineering in 2002 and 2007, respectively, from the Democritus University of Thrace (DUTH), Greece. Dr. Papakostas serves as a Tenured Full Professor at the Department of Computer Science, International Hellenic University, Greece. Dr. Papakostas has 10 years of experience in large-scale systems design as a senior software engineer and technical manager, and 20 years of research experience in the field of Artificial Intelligence. Currently, he is the Head of the “Visual Computing” division of HUman-MAchines INteraction Laboratory (HUMAIN-Lab) and the Director of the MPhil program “Advanced Technologies in Informatics and Computers” hosted by the Department of Computer Science, International Hellenic University. He has (co)authored more than 150 publications in indexed journals, international conferences and book chapters, 1 book (in Greek), 3 edited books, and 5 journal special issues. His publications have more than 2100 citations with h-index 27 (GoogleScholar). His research interests include computer/machine vision, machine learning, pattern recognition, computational intelligence. \nDr. Papakostas served as a reviewer in numerous journals, as a program\ncommittee member in international conferences and he is a member of the IAENG, MIR Labs, EUCogIII, INSTICC and the Technical Chamber of Greece (TEE).",institutionString:null,institution:{name:"International Hellenic University",institutionURL:null,country:{name:"Greece"}}},editorTwo:null,editorThree:null},{id:"25",title:"Evolutionary Computation",coverUrl:"https://cdn.intechopen.com/series_topics/covers/25.jpg",isOpenForSubmission:!0,editor:{id:"136112",title:"Dr.",name:"Sebastian",middleName:null,surname:"Ventura Soto",slug:"sebastian-ventura-soto",fullName:"Sebastian Ventura Soto",profilePictureURL:"https://mts.intechopen.com/storage/users/136112/images/system/136112.png",biography:"Sebastian Ventura is a Spanish researcher, a full professor with the Department of Computer Science and Numerical Analysis, University of Córdoba. Dr Ventura also holds the positions of Affiliated Professor at Virginia Commonwealth University (Richmond, USA) and Distinguished Adjunct Professor at King Abdulaziz University (Jeddah, Saudi Arabia). Additionally, he is deputy director of the Andalusian Research Institute in Data Science and Computational Intelligence (DaSCI) and heads the Knowledge Discovery and Intelligent Systems Research Laboratory. He has published more than ten books and over 300 articles in journals and scientific conferences. Currently, his work has received over 18,000 citations according to Google Scholar, including more than 2200 citations in 2020. In the last five years, he has published more than 60 papers in international journals indexed in the JCR (around 70% of them belonging to first quartile journals) and he has edited some Springer books “Supervised Descriptive Pattern Mining” (2018), “Multiple Instance Learning - Foundations and Algorithms” (2016), and “Pattern Mining with Evolutionary Algorithms” (2016). He has also been involved in more than 20 research projects supported by the Spanish and Andalusian governments and the European Union. He currently belongs to the editorial board of PeerJ Computer Science, Information Fusion and Engineering Applications of Artificial Intelligence journals, being also associate editor of Applied Computational Intelligence and Soft Computing and IEEE Transactions on Cybernetics. Finally, he is editor-in-chief of Progress in Artificial Intelligence. 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Radiotherapy and Nuclear Medicine Technology has always been my aspiration and my life. As years passed I accumulated a tremendous amount of skills and knowledge in Radiotherapy and Nuclear Medicine, Conventional Radiology, Radiation Protection, Bioinformatics Technology, PACS, Image processing, clinically and lecturing that will enable me to provide a valuable service to the community as a Researcher and Consultant in this field. My method of translating this into day to day in clinical practice is non-exhaustible and my habit of exchanging knowledge and expertise with others in those fields is the code and secret of success.",institutionString:null,institution:{name:"Majmaah University",country:{name:"Saudi Arabia"}}},{id:"313277",title:"Dr.",name:"Bartłomiej",middleName:null,surname:"Płaczek",slug:"bartlomiej-placzek",fullName:"Bartłomiej Płaczek",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/313277/images/system/313277.jpg",biography:"Bartłomiej Płaczek, MSc (2002), Ph.D. (2005), Habilitation (2016), is a professor at the University of Silesia, Institute of Computer Science, Poland, and an expert from the National Centre for Research and Development. His research interests include sensor networks, smart sensors, intelligent systems, and image processing with applications in healthcare and medicine. He is the author or co-author of more than seventy papers in peer-reviewed journals and conferences as well as the co-author of several books. He serves as a reviewer for many scientific journals, international conferences, and research foundations. Since 2010, Dr. Placzek has been a reviewer of grants and projects (including EU projects) in the field of information technologies.",institutionString:"University of Silesia",institution:{name:"University of Silesia",country:{name:"Poland"}}},{id:"35000",title:"Prof.",name:"Ulrich H.P",middleName:"H.P.",surname:"Fischer",slug:"ulrich-h.p-fischer",fullName:"Ulrich H.P Fischer",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/35000/images/3052_n.jpg",biography:"Academic and Professional Background\nUlrich H. P. has Diploma and PhD degrees in Physics from the Free University Berlin, Germany. He has been working on research positions in the Heinrich-Hertz-Institute in Germany. Several international research projects has been performed with European partners from France, Netherlands, Norway and the UK. He is currently Professor of Communications Systems at the Harz University of Applied Sciences, Germany.\n\nPublications and Publishing\nHe has edited one book, a special interest book about ‘Optoelectronic Packaging’ (VDE, Berlin, Germany), and has published over 100 papers and is owner of several international patents for WDM over POF key elements.\n\nKey Research and Consulting Interests\nUlrich’s research activity has always been related to Spectroscopy and Optical Communications Technology. Specific current interests include the validation of complex instruments, and the application of VR technology to the development and testing of measurement systems. He has been reviewer for several publications of the Optical Society of America\\'s including Photonics Technology Letters and Applied Optics.\n\nPersonal Interests\nThese include motor cycling in a very relaxed manner and performing martial arts.",institutionString:null,institution:{name:"Charité",country:{name:"Germany"}}},{id:"341622",title:"Ph.D.",name:"Eduardo",middleName:null,surname:"Rojas Alvarez",slug:"eduardo-rojas-alvarez",fullName:"Eduardo Rojas Alvarez",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/341622/images/15892_n.jpg",biography:null,institutionString:null,institution:{name:"University of Cuenca",country:{name:"Ecuador"}}},{id:"215610",title:"Prof.",name:"Muhammad",middleName:null,surname:"Sarfraz",slug:"muhammad-sarfraz",fullName:"Muhammad Sarfraz",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/215610/images/system/215610.jpeg",biography:"Muhammad Sarfraz is a professor in the Department of Information Science, Kuwait University. His research interests include computer graphics, computer vision, image processing, machine learning, pattern recognition, soft computing, data science, intelligent systems, information technology, and information systems. Prof. Sarfraz has been a keynote/invited speaker on various platforms around the globe. He has advised various students for their MSc and Ph.D. theses. He has published more than 400 publications as books, journal articles, and conference papers. He is a member of various professional societies and a chair and member of the International Advisory Committees and Organizing Committees of various international conferences. Prof. Sarfraz is also an editor-in-chief and editor of various international journals.",institutionString:"Kuwait University",institution:{name:"Kuwait University",country:{name:"Kuwait"}}},{id:"32650",title:"Prof.",name:"Lukas",middleName:"Willem",surname:"Snyman",slug:"lukas-snyman",fullName:"Lukas Snyman",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/32650/images/4136_n.jpg",biography:"Lukas Willem Snyman received his basic education at primary and high schools in South Africa, Eastern Cape. He enrolled at today's Nelson Metropolitan University and graduated from this university with a BSc in Physics and Mathematics, B.Sc Honors in Physics, MSc in Semiconductor Physics, and a Ph.D. in Semiconductor Physics in 1987. After his studies, he chose an academic career and devoted his energy to the teaching of physics to first, second, and third-year students. After positions as a lecturer at the University of Port Elizabeth, he accepted a position as Associate Professor at the University of Pretoria, South Africa.\r\n\r\nIn 1992, he motivates the concept of 'television and computer-based education” as means to reach large student numbers with only the best of teaching expertise and publishes an article on the concept in the SA Journal of Higher Education of 1993 (and later in 2003). The University of Pretoria subsequently approved a series of test projects on the concept with outreach to Mamelodi and Eerste Rust in 1993. In 1994, the University established a 'Unit for Telematic Education ' as a support section for multiple faculties at the University of Pretoria. In subsequent years, the concept of 'telematic education” subsequently becomes well established in academic circles in South Africa, grew in popularity, and is adopted by many universities and colleges throughout South Africa as a medium of enhancing education and training, as a method to reaching out to far out communities, and as a means to enhance study from the home environment.\r\n\r\nProfessor Snyman in subsequent years pursued research in semiconductor physics, semiconductor devices, microelectronics, and optoelectronics.\r\n\r\nIn 2000 he joined the TUT as a full professor. Here served for a period as head of the Department of Electronic Engineering. Here he makes contributions to solar energy development, microwave and optoelectronic device development, silicon photonics, as well as contributions to new mobile telecommunication systems and network planning in SA.\r\n\r\nCurrently, he teaches electronics and telecommunications at the TUT to audiences ranging from first-year students to Ph.D. level.\r\n\r\nFor his research in the field of 'Silicon Photonics” since 1990, he has published (as author and co-author) about thirty internationally reviewed articles in scientific journals, contributed to more than forty international conferences, about 25 South African provisional patents (as inventor and co-inventor), 8 PCT international patent applications until now. Of these, two USA patents applications, two European Patents, two Korean patents, and ten SA patents have been granted. A further 4 USA patents, 5 European patents, 3 Korean patents, 3 Chinese patents, and 3 Japanese patents are currently under consideration.\r\n\r\nRecently he has also published an extensive scholarly chapter in an internet open access book on 'Integrating Microphotonic Systems and MOEMS into standard Silicon CMOS Integrated circuitry”.\r\n\r\nFurthermore, Professor Snyman recently steered a new initiative at the TUT by introducing a 'Laboratory for Innovative Electronic Systems ' at the Department of Electrical Engineering. The model of this laboratory or center is to primarily combine outputs as achieved by high-level research with lower-level system development and entrepreneurship in a technical university environment. Students are allocated to projects at different levels with PhDs and Master students allocated to the generation of new knowledge and new technologies, while students at the diploma and Baccalaureus level are allocated to electronic systems development with a direct and a near application for application in industry or the commercial and public sectors in South Africa.\r\n\r\nProfessor Snyman received the WIRSAM Award of 1983 and the WIRSAM Award in 1985 in South Africa for best research papers by a young scientist at two international conferences on electron microscopy in South Africa. He subsequently received the SA Microelectronics Award for the best dissertation emanating from studies executed at a South African university in the field of Physics and Microelectronics in South Africa in 1987. In October of 2011, Professor Snyman received the prestigious Institutional Award for 'Innovator of the Year” for 2010 at the Tshwane University of Technology, South Africa. This award was based on the number of patents recognized and granted by local and international institutions as well as for his contributions concerning innovation at the TUT.",institutionString:null,institution:{name:"University of South Africa",country:{name:"South Africa"}}},{id:"317279",title:"Mr.",name:"Ali",middleName:"Usama",surname:"Syed",slug:"ali-syed",fullName:"Ali Syed",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/317279/images/16024_n.png",biography:"A creative, talented, and innovative young professional who is dedicated, well organized, and capable research fellow with two years of experience in graduate-level research, published in engineering journals and book, with related expertise in Bio-robotics, equally passionate about the aesthetics of the mechanical and electronic system, obtained expertise in the use of MS Office, MATLAB, SolidWorks, LabVIEW, Proteus, Fusion 360, having a grasp on python, C++ and assembly language, possess proven ability in acquiring research grants, previous appointments with social and educational societies with experience in administration, current affiliations with IEEE and Web of Science, a confident presenter at conferences and teacher in classrooms, able to explain complex information to audiences of all levels.",institutionString:null,institution:{name:"Air University",country:{name:"Pakistan"}}},{id:"75526",title:"Ph.D.",name:"Zihni Onur",middleName:null,surname:"Uygun",slug:"zihni-onur-uygun",fullName:"Zihni Onur Uygun",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/75526/images/12_n.jpg",biography:"My undergraduate education and my Master of Science educations at Ege University and at Çanakkale Onsekiz Mart University have given me a firm foundation in Biochemistry, Analytical Chemistry, Biosensors, Bioelectronics, Physical Chemistry and Medicine. After obtaining my degree as a MSc in analytical chemistry, I started working as a research assistant in Ege University Medical Faculty in 2014. In parallel, I enrolled to the MSc program at the Department of Medical Biochemistry at Ege University to gain deeper knowledge on medical and biochemical sciences as well as clinical chemistry in 2014. In my PhD I deeply researched on biosensors and bioelectronics and finished in 2020. Now I have eleven SCI-Expanded Index published papers, 6 international book chapters, referee assignments for different SCIE journals, one international patent pending, several international awards, projects and bursaries. In parallel to my research assistant position at Ege University Medical Faculty, Department of Medical Biochemistry, in April 2016, I also founded a Start-Up Company (Denosens Biotechnology LTD) by the support of The Scientific and Technological Research Council of Turkey. Currently, I am also working as a CEO in Denosens Biotechnology. The main purposes of the company, which carries out R&D as a research center, are to develop new generation biosensors and sensors for both point-of-care diagnostics; such as glucose, lactate, cholesterol and cancer biomarker detections. My specific experimental and instrumental skills are Biochemistry, Biosensor, Analytical Chemistry, Electrochemistry, Mobile phone based point-of-care diagnostic device, POCTs and Patient interface designs, HPLC, Tandem Mass Spectrometry, Spectrophotometry, ELISA.",institutionString:null,institution:{name:"Ege University",country:{name:"Turkey"}}},{id:"267434",title:"Dr.",name:"Rohit",middleName:null,surname:"Raja",slug:"rohit-raja",fullName:"Rohit Raja",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/267434/images/system/267434.jpg",biography:"Dr. Rohit Raja received Ph.D. in Computer Science and Engineering from Dr. CVRAMAN University in 2016. His main research interest includes Face recognition and Identification, Digital Image Processing, Signal Processing, and Networking. Presently he is working as Associate Professor in IT Department, Guru Ghasidas Vishwavidyalaya (A Central University), Bilaspur (CG), India. He has authored several Journal and Conference Papers. He has good Academics & Research experience in various areas of CSE and IT. He has filed and successfully published 27 Patents. He has received many time invitations to be a Guest at IEEE Conferences. He has published 100 research papers in various International/National Journals (including IEEE, Springer, etc.) and Proceedings of the reputed International/ National Conferences (including Springer and IEEE). He has been nominated to the board of editors/reviewers of many peer-reviewed and refereed Journals (including IEEE, Springer).",institutionString:"Guru Ghasidas Vishwavidyalaya",institution:{name:"Guru Ghasidas Vishwavidyalaya",country:{name:"India"}}},{id:"246502",title:"Dr.",name:"Jaya T.",middleName:"T",surname:"Varkey",slug:"jaya-t.-varkey",fullName:"Jaya T. Varkey",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/246502/images/11160_n.jpg",biography:"Jaya T. Varkey, PhD, graduated with a degree in Chemistry from Cochin University of Science and Technology, Kerala, India. She obtained a PhD in Chemistry from the School of Chemical Sciences, Mahatma Gandhi University, Kerala, India, and completed a post-doctoral fellowship at the University of Minnesota, USA. She is a research guide at Mahatma Gandhi University and Associate Professor in Chemistry, St. Teresa’s College, Kochi, Kerala, India.\nDr. Varkey received a National Young Scientist award from the Indian Science Congress (1995), a UGC Research award (2016–2018), an Indian National Science Academy (INSA) Visiting Scientist award (2018–2019), and a Best Innovative Faculty award from the All India Association for Christian Higher Education (AIACHE) (2019). She Hashas received the Sr. Mary Cecil prize for best research paper three times. She was also awarded a start-up to develop a tea bag water filter. \nDr. Varkey has published two international books and twenty-seven international journal publications. She is an editorial board member for five international journals.",institutionString:"St. Teresa’s College",institution:null},{id:"250668",title:"Dr.",name:"Ali",middleName:null,surname:"Nabipour Chakoli",slug:"ali-nabipour-chakoli",fullName:"Ali Nabipour Chakoli",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/250668/images/system/250668.jpg",biography:"Academic Qualification:\r\n•\tPhD in Materials Physics and Chemistry, From: Sep. 2006, to: Sep. 2010, School of Materials Science and Engineering, Harbin Institute of Technology, Thesis: Structure and Shape Memory Effect of Functionalized MWCNTs/poly (L-lactide-co-ε-caprolactone) Nanocomposites. Supervisor: Prof. Wei Cai,\r\n•\tM.Sc in Applied Physics, From: 1996, to: 1998, Faculty of Physics & Nuclear Science, Amirkabir Uni. of Technology, Tehran, Iran, Thesis: Determination of Boron in Micro alloy Steels with solid state nuclear track detectors by neutron induced auto radiography, Supervisors: Dr. M. Hosseini Ashrafi and Dr. A. Hosseini.\r\n•\tB.Sc. in Applied Physics, From: 1991, to: 1996, Faculty of Physics & Nuclear Science, Amirkabir Uni. of Technology, Tehran, Iran, Thesis: Design of shielding for Am-Be neutron sources for In Vivo neutron activation analysis, Supervisor: Dr. M. Hosseini Ashrafi.\r\n\r\nResearch Experiences:\r\n1.\tNanomaterials, Carbon Nanotubes, Graphene: Synthesis, Functionalization and Characterization,\r\n2.\tMWCNTs/Polymer Composites: Fabrication and Characterization, \r\n3.\tShape Memory Polymers, Biodegradable Polymers, ORC, Collagen,\r\n4.\tMaterials Analysis and Characterizations: TEM, SEM, XPS, FT-IR, Raman, DSC, DMA, TGA, XRD, GPC, Fluoroscopy, \r\n5.\tInteraction of Radiation with Mater, Nuclear Safety and Security, NDT(RT),\r\n6.\tRadiation Detectors, Calibration (SSDL),\r\n7.\tCompleted IAEA e-learning Courses:\r\nNuclear Security (15 Modules),\r\nNuclear Safety:\r\nTSA 2: Regulatory Protection in Occupational Exposure,\r\nTips & Tricks: Radiation Protection in Radiography,\r\nSafety and Quality in Radiotherapy,\r\nCourse on Sealed Radioactive Sources,\r\nCourse on Fundamentals of Environmental Remediation,\r\nCourse on Planning for Environmental Remediation,\r\nKnowledge Management Orientation Course,\r\nFood Irradiation - Technology, Applications and Good Practices,\r\nEmployment:\r\nFrom 2010 to now: Academic staff, Nuclear Science and Technology Research Institute, Kargar Shomali, Tehran, Iran, P.O. Box: 14395-836.\r\nFrom 1997 to 2006: Expert of Materials Analysis and Characterization. Research Center of Agriculture and Medicine. Rajaeeshahr, Karaj, Iran, P. O. Box: 31585-498.",institutionString:"Atomic Energy Organization of Iran",institution:{name:"Atomic Energy Organization of Iran",country:{name:"Iran"}}},{id:"248279",title:"Dr.",name:"Monika",middleName:"Elzbieta",surname:"Machoy",slug:"monika-machoy",fullName:"Monika Machoy",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/248279/images/system/248279.jpeg",biography:"Monika Elżbieta Machoy, MD, graduated with distinction from the Faculty of Medicine and Dentistry at the Pomeranian Medical University in 2009, defended her PhD thesis with summa cum laude in 2016 and is currently employed as a researcher at the Department of Orthodontics of the Pomeranian Medical University. She expanded her professional knowledge during a one-year scholarship program at the Ernst Moritz Arndt University in Greifswald, Germany and during a three-year internship at the Technical University in Dresden, Germany. She has been a speaker at numerous orthodontic conferences, among others, American Association of Orthodontics, European Orthodontic Symposium and numerous conferences of the Polish Orthodontic Society. She conducts research focusing on the effect of orthodontic treatment on dental and periodontal tissues and the causes of pain in orthodontic patients.",institutionString:"Pomeranian Medical University",institution:{name:"Pomeranian Medical University",country:{name:"Poland"}}},{id:"252743",title:"Prof.",name:"Aswini",middleName:"Kumar",surname:"Kar",slug:"aswini-kar",fullName:"Aswini Kar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/252743/images/10381_n.jpg",biography:"uploaded in cv",institutionString:null,institution:{name:"KIIT University",country:{name:"India"}}},{id:"204256",title:"Dr.",name:"Anil",middleName:"Kumar",surname:"Kumar Sahu",slug:"anil-kumar-sahu",fullName:"Anil Kumar Sahu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/204256/images/14201_n.jpg",biography:"I have nearly 11 years of research and teaching experience. I have done my master degree from University Institute of Pharmacy, Pt. Ravi Shankar Shukla University, Raipur, Chhattisgarh India. I have published 16 review and research articles in international and national journals and published 4 chapters in IntechOpen, the world’s leading publisher of Open access books. I have presented many papers at national and international conferences. I have received research award from Indian Drug Manufacturers Association in year 2015. My research interest extends from novel lymphatic drug delivery systems, oral delivery system for herbal bioactive to formulation optimization.",institutionString:null,institution:{name:"Chhattisgarh Swami Vivekanand Technical University",country:{name:"India"}}},{id:"253468",title:"Dr.",name:"Mariusz",middleName:null,surname:"Marzec",slug:"mariusz-marzec",fullName:"Mariusz Marzec",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/253468/images/system/253468.png",biography:"An assistant professor at Department of Biomedical Computer Systems, at Institute of Computer Science, Silesian University in Katowice. Scientific interests: computer analysis and processing of images, biomedical images, databases and programming languages. He is an author and co-author of scientific publications covering analysis and processing of biomedical images and development of database systems.",institutionString:"University of Silesia",institution:null},{id:"212432",title:"Prof.",name:"Hadi",middleName:null,surname:"Mohammadi",slug:"hadi-mohammadi",fullName:"Hadi Mohammadi",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/212432/images/system/212432.jpeg",biography:"Dr. Hadi Mohammadi is a biomedical engineer with hands-on experience in the design and development of many engineering structures and medical devices through various projects that he has been involved in over the past twenty years. Dr. Mohammadi received his BSc. and MSc. degrees in Mechanical Engineering from Sharif University of Technology, Tehran, Iran, and his PhD. degree in Biomedical Engineering (biomaterials) from the University of Western Ontario. He was a postdoctoral trainee for almost four years at University of Calgary and Harvard Medical School. He is an industry innovator having created the technology to produce lifelike synthetic platforms that can be used for the simulation of almost all cardiovascular reconstructive surgeries. He’s been heavily involved in the design and development of cardiovascular devices and technology for the past 10 years. He is currently an Assistant Professor with the University of British Colombia, Canada.",institutionString:"University of British Columbia",institution:{name:"University of British Columbia",country:{name:"Canada"}}},{id:"254463",title:"Prof.",name:"Haisheng",middleName:null,surname:"Yang",slug:"haisheng-yang",fullName:"Haisheng Yang",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/254463/images/system/254463.jpeg",biography:"Haisheng Yang, Ph.D., Professor and Director of the Department of Biomedical Engineering, College of Life Science and Bioengineering, Beijing University of Technology. He received his Ph.D. degree in Mechanics/Biomechanics from Harbin Institute of Technology (jointly with University of California, Berkeley). Afterwards, he worked as a Postdoctoral Research Associate in the Purdue Musculoskeletal Biology and Mechanics Lab at the Department of Basic Medical Sciences, Purdue University, USA. He also conducted research in the Research Centre of Shriners Hospitals for Children-Canada at McGill University, Canada. Dr. Yang has over 10 years research experience in orthopaedic biomechanics and mechanobiology of bone adaptation and regeneration. He earned an award from Beijing Overseas Talents Aggregation program in 2017 and serves as Beijing Distinguished Professor.",institutionString:null,institution:{name:"Beijing University of Technology",country:{name:"China"}}},{id:"89721",title:"Dr.",name:"Mehmet",middleName:"Cuneyt",surname:"Ozmen",slug:"mehmet-ozmen",fullName:"Mehmet Ozmen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/89721/images/7289_n.jpg",biography:null,institutionString:null,institution:{name:"Gazi University",country:{name:"Turkey"}}},{id:"243698",title:"M.D.",name:"Xiaogang",middleName:null,surname:"Wang",slug:"xiaogang-wang",fullName:"Xiaogang Wang",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/243698/images/system/243698.png",biography:"Dr. Xiaogang Wang, a faculty member of Shanxi Eye Hospital specializing in the treatment of cataract and retinal disease and a tutor for postgraduate students of Shanxi Medical University, worked in the COOL Lab as an international visiting scholar under the supervision of Dr. David Huang and Yali Jia from October 2012 through November 2013. Dr. Wang earned an MD from Shanxi Medical University and a Ph.D. from Shanghai Jiao Tong University. Dr. Wang was awarded two research project grants focused on multimodal optical coherence tomography imaging and deep learning in cataract and retinal disease, from the National Natural Science Foundation of China. He has published around 30 peer-reviewed journal papers and four book chapters and co-edited one book.",institutionString:"Shanxi Eye Hospital",institution:{name:"Shanxi Eye Hospital",country:{name:"China"}}},{id:"242893",title:"Ph.D. Student",name:"Joaquim",middleName:null,surname:"De Moura",slug:"joaquim-de-moura",fullName:"Joaquim De Moura",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/242893/images/7133_n.jpg",biography:"Joaquim de Moura received his degree in Computer Engineering in 2014 from the University of A Coruña (Spain). In 2016, he received his M.Sc degree in Computer Engineering from the same university. He is currently pursuing his Ph.D degree in Computer Science in a collaborative project between ophthalmology centers in Galicia and the University of A Coruña. His research interests include computer vision, machine learning algorithms and analysis and medical imaging processing of various kinds.",institutionString:null,institution:{name:"University of A Coruña",country:{name:"Spain"}}},{id:"294334",title:"B.Sc.",name:"Marc",middleName:null,surname:"Bruggeman",slug:"marc-bruggeman",fullName:"Marc Bruggeman",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/294334/images/8242_n.jpg",biography:"Chemical engineer graduate, with a passion for material science and specific interest in polymers - their near infinite applications intrigue me. \n\nI plan to continue my scientific career in the field of polymeric biomaterials as I am fascinated by intelligent, bioactive and biomimetic materials for use in both consumer and medical applications.",institutionString:null,institution:null},{id:"255757",title:"Dr.",name:"Igor",middleName:"Victorovich",surname:"Lakhno",slug:"igor-lakhno",fullName:"Igor Lakhno",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/255757/images/system/255757.jpg",biography:"Igor Victorovich Lakhno was born in 1971 in Kharkiv (Ukraine). \nMD – 1994, Kharkiv National Medical Univesity.\nOb&Gyn; – 1997, master courses in Kharkiv Medical Academy of Postgraduate Education.\nPh.D. – 1999, Kharkiv National Medical Univesity.\nDSC – 2019, PL Shupik National Academy of Postgraduate Education \nProfessor – 2021, Department of Obstetrics and Gynecology of VN Karazin Kharkiv National University\nHead of Department – 2021, Department of Perinatology, Obstetrics and gynecology of Kharkiv Medical Academy of Postgraduate Education\nIgor Lakhno has been graduated from international training courses on reproductive medicine and family planning held at Debrecen University (Hungary) in 1997. Since 1998 Lakhno Igor has worked as an associate professor in the department of obstetrics and gynecology of VN Karazin National University and an associate professor of the perinatology, obstetrics, and gynecology department of Kharkiv Medical Academy of Postgraduate Education. Since June 2019 he’s been a professor in the department of obstetrics and gynecology of VN Karazin National University and a professor of the perinatology, obstetrics, and gynecology department. He’s affiliated with Kharkiv Medical Academy of Postgraduate Education as a Head of Department from November 2021. Igor Lakhno has participated in several international projects on fetal non-invasive electrocardiography (with Dr. J. A. Behar (Technion), Prof. D. Hoyer (Jena University), and José Alejandro Díaz Méndez (National Institute of Astrophysics, Optics, and Electronics, Mexico). He’s an author of about 200 printed works and there are 31 of them in Scopus or Web of Science databases. Igor Lakhno is a member of the Editorial Board of Reproductive Health of Woman, Emergency Medicine, and Technology Transfer Innovative Solutions in Medicine (Estonia). He is a medical Editor of “Z turbotoyu pro zhinku”. Igor Lakhno is a reviewer of the Journal of Obstetrics and Gynaecology (Taylor and Francis), British Journal of Obstetrics and Gynecology (Wiley), Informatics in Medicine Unlocked (Elsevier), The Journal of Obstetrics and Gynecology Research (Wiley), Endocrine, Metabolic & Immune Disorders-Drug Targets (Bentham Open), The Open Biomedical Engineering Journal (Bentham Open), etc. He’s defended a dissertation for a DSc degree “Pre-eclampsia: prediction, prevention, and treatment”. Three years ago Igor Lakhno has participated in a training course on innovative technologies in medical education at Lublin Medical University (Poland). Lakhno Igor has participated as a speaker in several international conferences and congresses (International Conference on Biological Oscillations April 10th-14th 2016, Lancaster, UK, The 9th conference of the European Study Group on Cardiovascular Oscillations). His main scientific interests: are obstetrics, women’s health, fetal medicine, and cardiovascular medicine. \nIgor Lakhno is a consultant at Kharkiv municipal perinatal center. He’s graduated from training courses on endoscopy in gynecology. He has 28 years of practical experience in the field.",institutionString:null,institution:null},{id:"244950",title:"Dr.",name:"Salvatore",middleName:null,surname:"Di Lauro",slug:"salvatore-di-lauro",fullName:"Salvatore Di Lauro",position:null,profilePictureURL:"https://intech-files.s3.amazonaws.com/0030O00002bSF1HQAW/ProfilePicture%202021-12-20%2014%3A54%3A14.482",biography:"Name:\n\tSALVATORE DI LAURO\nAddress:\n\tHospital Clínico Universitario Valladolid\nAvda Ramón y Cajal 3\n47005, Valladolid\nSpain\nPhone number: \nFax\nE-mail:\n\t+34 983420000 ext 292\n+34 983420084\nsadilauro@live.it\nDate and place of Birth:\nID Number\nMedical Licence \nLanguages\t09-05-1985. Villaricca (Italy)\n\nY1281863H\n474707061\nItalian (native language)\nSpanish (read, written, spoken)\nEnglish (read, written, spoken)\nPortuguese (read, spoken)\nFrench (read)\n\t\t\nCurrent position (title and company)\tDate (Year)\nVitreo-Retinal consultant in ophthalmology. Hospital Clinico Universitario Valladolid. Sacyl. National Health System.\nVitreo-Retinal consultant in ophthalmology. Instituto Oftalmologico Recoletas. Red Hospitalaria Recoletas. Private practise.\t2017-today\n\n2019-today\n\t\n\t\nEducation (High school, university and postgraduate training > 3 months)\tDate (Year)\nDegree in Medicine and Surgery. University of Neaples 'Federico II”\nResident in Opthalmology. Hospital Clinico Universitario Valladolid\nMaster in Vitreo-Retina. IOBA. University of Valladolid\nFellow of the European Board of Ophthalmology. Paris\nMaster in Research in Ophthalmology. University of Valladolid\t2003-2009\n2012-2016\n2016-2017\n2016\n2012-2013\n\t\nEmployments (company and positions)\tDate (Year)\nResident in Ophthalmology. Hospital Clinico Universitario Valladolid. Sacyl.\nFellow in Vitreo-Retina. IOBA. University of Valladolid\nVitreo-Retinal consultant in ophthalmology. Hospital Clinico Universitario Valladolid. Sacyl. National Health System.\nVitreo-Retinal consultant in ophthalmology. Instituto Oftalmologico Recoletas. Red Hospitalaria Recoletas. \n\t2012-2016\n2016-2017\n2017-today\n\n2019-Today\n\n\n\t\nClinical Research Experience (tasks and role)\tDate (Year)\nAssociated investigator\n\n' FIS PI20/00740: DESARROLLO DE UNA CALCULADORA DE RIESGO DE\nAPARICION DE RETINOPATIA DIABETICA BASADA EN TECNICAS DE IMAGEN MULTIMODAL EN PACIENTES DIABETICOS TIPO 1. Grant by: Ministerio de Ciencia e Innovacion \n\n' (BIO/VA23/14) Estudio clínico multicéntrico y prospectivo para validar dos\nbiomarcadores ubicados en los genes p53 y MDM2 en la predicción de los resultados funcionales de la cirugía del desprendimiento de retina regmatógeno. Grant by: Gerencia Regional de Salud de la Junta de Castilla y León.\n' Estudio multicéntrico, aleatorizado, con enmascaramiento doble, en 2 grupos\nparalelos y de 52 semanas de duración para comparar la eficacia, seguridad e inmunogenicidad de SOK583A1 respecto a Eylea® en pacientes con degeneración macular neovascular asociada a la edad' (CSOK583A12301; N.EUDRA: 2019-004838-41; FASE III). Grant by Hexal AG\n\n' Estudio de fase III, aleatorizado, doble ciego, con grupos paralelos, multicéntrico para comparar la eficacia y la seguridad de QL1205 frente a Lucentis® en pacientes con degeneración macular neovascular asociada a la edad. (EUDRACT: 2018-004486-13). Grant by Qilu Pharmaceutical Co\n\n' Estudio NEUTON: Ensayo clinico en fase IV para evaluar la eficacia de aflibercept en pacientes Naive con Edema MacUlar secundario a Oclusion de Vena CenTral de la Retina (OVCR) en regimen de tratamientO iNdividualizado Treat and Extend (TAE)”, (2014-000975-21). Grant by Fundacion Retinaplus\n\n' Evaluación de la seguridad y bioactividad de anillos de tensión capsular en conejo. Proyecto Procusens. Grant by AJL, S.A.\n\n'Estudio epidemiológico, prospectivo, multicéntrico y abierto\\npara valorar la frecuencia de la conjuntivitis adenovírica diagnosticada mediante el test AdenoPlus®\\nTest en pacientes enfermos de conjuntivitis aguda”\\n. National, multicenter study. Grant by: NICOX.\n\nEuropean multicentric trial: 'Evaluation of clinical outcomes following the use of Systane Hydration in patients with dry eye”. Study Phase 4. Grant by: Alcon Labs'\n\nVLPs Injection and Activation in a Rabbit Model of Uveal Melanoma. Grant by Aura Bioscience\n\nUpdating and characterization of a rabbit model of uveal melanoma. Grant by Aura Bioscience\n\nEnsayo clínico en fase IV para evaluar las variantes genéticas de la vía del VEGF como biomarcadores de eficacia del tratamiento con aflibercept en pacientes con degeneración macular asociada a la edad (DMAE) neovascular. Estudio BIOIMAGE. IMO-AFLI-2013-01\n\nEstudio In-Eye:Ensayo clínico en fase IV, abierto, aleatorizado, de 2 brazos,\nmulticçentrico y de 12 meses de duración, para evaluar la eficacia y seguridad de un régimen de PRN flexible individualizado de 'esperar y extender' versus un régimen PRN según criterios de estabilización mediante evaluaciones mensuales de inyecciones intravítreas de ranibizumab 0,5 mg en pacientes naive con neovascularización coriodea secunaria a la degeneración macular relacionada con la edad. CP: CRFB002AES03T\n\nTREND: Estudio Fase IIIb multicéntrico, randomizado, de 12 meses de\nseguimiento con evaluador de la agudeza visual enmascarado, para evaluar la eficacia y la seguridad de ranibizumab 0.5mg en un régimen de tratar y extender comparado con un régimen mensual, en pacientes con degeneración macular neovascular asociada a la edad. CP: CRFB002A2411 Código Eudra CT:\n2013-002626-23\n\n\n\nPublications\t\n\n2021\n\n\n\n\n2015\n\n\n\n\n2021\n\n\n\n\n\n2021\n\n\n\n\n2015\n\n\n\n\n2015\n\n\n2014\n\n\n\n\n2015-16\n\n\n\n2015\n\n\n2014\n\n\n2014\n\n\n\n\n2014\n\n\n\n\n\n\n\n2014\n\nJose Carlos Pastor; Jimena Rojas; Salvador Pastor-Idoate; Salvatore Di Lauro; Lucia Gonzalez-Buendia; Santiago Delgado-Tirado. Proliferative vitreoretinopathy: A new concept of disease pathogenesis and practical\nconsequences. Progress in Retinal and Eye Research. 51, pp. 125 - 155. 03/2016. DOI: 10.1016/j.preteyeres.2015.07.005\n\n\nLabrador-Velandia S; Alonso-Alonso ML; Di Lauro S; García-Gutierrez MT; Srivastava GK; Pastor JC; Fernandez-Bueno I. Mesenchymal stem cells provide paracrine neuroprotective resources that delay degeneration of co-cultured organotypic neuroretinal cultures.Experimental Eye Research. 185, 17/05/2019. DOI: 10.1016/j.exer.2019.05.011\n\nSalvatore Di Lauro; Maria Teresa Garcia Gutierrez; Ivan Fernandez Bueno. Quantification of pigment epithelium-derived factor (PEDF) in an ex vivo coculture of retinal pigment epithelium cells and neuroretina.\nJournal of Allbiosolution. 2019. ISSN 2605-3535\n\nSonia Labrador Velandia; Salvatore Di Lauro; Alonso-Alonso ML; Tabera Bartolomé S; Srivastava GK; Pastor JC; Fernandez-Bueno I. Biocompatibility of intravitreal injection of human mesenchymal stem cells in immunocompetent rabbits. Graefe's archive for clinical and experimental ophthalmology. 256 - 1, pp. 125 - 134. 01/2018. DOI: 10.1007/s00417-017-3842-3\n\n\nSalvatore Di Lauro, David Rodriguez-Crespo, Manuel J Gayoso, Maria T Garcia-Gutierrez, J Carlos Pastor, Girish K Srivastava, Ivan Fernandez-Bueno. A novel coculture model of porcine central neuroretina explants and retinal pigment epithelium cells. Molecular Vision. 2016 - 22, pp. 243 - 253. 01/2016.\n\nSalvatore Di Lauro. Classifications for Proliferative Vitreoretinopathy ({PVR}): An Analysis of Their Use in Publications over the Last 15 Years. Journal of Ophthalmology. 2016, pp. 1 - 6. 01/2016. DOI: 10.1155/2016/7807596\n\nSalvatore Di Lauro; Rosa Maria Coco; Rosa Maria Sanabria; Enrique Rodriguez de la Rua; Jose Carlos Pastor. Loss of Visual Acuity after Successful Surgery for Macula-On Rhegmatogenous Retinal Detachment in a Prospective Multicentre Study. Journal of Ophthalmology. 2015:821864, 2015. DOI: 10.1155/2015/821864\n\nIvan Fernandez-Bueno; Salvatore Di Lauro; Ivan Alvarez; Jose Carlos Lopez; Maria Teresa Garcia-Gutierrez; Itziar Fernandez; Eva Larra; Jose Carlos Pastor. Safety and Biocompatibility of a New High-Density Polyethylene-Based\nSpherical Integrated Porous Orbital Implant: An Experimental Study in Rabbits. Journal of Ophthalmology. 2015:904096, 2015. DOI: 10.1155/2015/904096\n\nPastor JC; Pastor-Idoate S; Rodríguez-Hernandez I; Rojas J; Fernandez I; Gonzalez-Buendia L; Di Lauro S; Gonzalez-Sarmiento R. Genetics of PVR and RD. Ophthalmologica. 232 - Suppl 1, pp. 28 - 29. 2014\n\nRodriguez-Crespo D; Di Lauro S; Singh AK; Garcia-Gutierrez MT; Garrosa M; Pastor JC; Fernandez-Bueno I; Srivastava GK. Triple-layered mixed co-culture model of RPE cells with neuroretina for evaluating the neuroprotective effects of adipose-MSCs. Cell Tissue Res. 358 - 3, pp. 705 - 716. 2014.\nDOI: 10.1007/s00441-014-1987-5\n\nCarlo De Werra; Salvatore Condurro; Salvatore Tramontano; Mario Perone; Ivana Donzelli; Salvatore Di Lauro; Massimo Di Giuseppe; Rosa Di Micco; Annalisa Pascariello; Antonio Pastore; Giorgio Diamantis; Giuseppe Galloro. Hydatid disease of the liver: thirty years of surgical experience.Chirurgia italiana. 59 - 5, pp. 611 - 636.\n(Italia): 2007. ISSN 0009-4773\n\nChapters in books\n\t\n' Salvador Pastor Idoate; Salvatore Di Lauro; Jose Carlos Pastor Jimeno. PVR: Pathogenesis, Histopathology and Classification. Proliferative Vitreoretinopathy with Small Gauge Vitrectomy. Springer, 2018. ISBN 978-3-319-78445-8\nDOI: 10.1007/978-3-319-78446-5_2. \n\n' Salvatore Di Lauro; Maria Isabel Lopez Galvez. Quistes vítreos en una mujer joven. Problemas diagnósticos en patología retinocoroidea. Sociedad Española de Retina-Vitreo. 2018.\n\n' Salvatore Di Lauro; Salvador Pastor Idoate; Jose Carlos Pastor Jimeno. iOCT in PVR management. OCT Applications in Opthalmology. pp. 1 - 8. INTECH, 2018. DOI: 10.5772/intechopen.78774.\n\n' Rosa Coco Martin; Salvatore Di Lauro; Salvador Pastor Idoate; Jose Carlos Pastor. amponadores, manipuladores y tinciones en la cirugía del traumatismo ocular.Trauma Ocular. Ponencia de la SEO 2018..\n\n' LOPEZ GALVEZ; DI LAURO; CRESPO. OCT angiografia y complicaciones retinianas de la diabetes. PONENCIA SEO 2021, CAPITULO 20. (España): 2021.\n\n' Múltiples desprendimientos neurosensoriales bilaterales en paciente joven. Enfermedades Degenerativas De Retina Y Coroides. SERV 04/2016. \n' González-Buendía L; Di Lauro S; Pastor-Idoate S; Pastor Jimeno JC. Vitreorretinopatía proliferante (VRP) e inflamación: LA INFLAMACIÓN in «INMUNOMODULADORES Y ANTIINFLAMATORIOS: MÁS ALLÁ DE LOS CORTICOIDES. RELACION DE PONENCIAS DE LA SOCIEDAD ESPAÑOLA DE OFTALMOLOGIA. 10/2014.",institutionString:null,institution:null},{id:"265335",title:"Mr.",name:"Stefan",middleName:"Radnev",surname:"Stefanov",slug:"stefan-stefanov",fullName:"Stefan Stefanov",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/265335/images/7562_n.jpg",biography:null,institutionString:null,institution:null},{id:"7227",title:"Dr.",name:"Hiroaki",middleName:null,surname:"Matsui",slug:"hiroaki-matsui",fullName:"Hiroaki Matsui",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Tokyo",country:{name:"Japan"}}},{id:"318905",title:"Prof.",name:"Elvis",middleName:"Kwason",surname:"Tiburu",slug:"elvis-tiburu",fullName:"Elvis Tiburu",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Ghana",country:{name:"Ghana"}}},{id:"336193",title:"Dr.",name:"Abdullah",middleName:null,surname:"Alamoudi",slug:"abdullah-alamoudi",fullName:"Abdullah Alamoudi",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Majmaah University",country:{name:"Saudi Arabia"}}},{id:"318657",title:"MSc.",name:"Isabell",middleName:null,surname:"Steuding",slug:"isabell-steuding",fullName:"Isabell Steuding",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Harz University of Applied Sciences",country:{name:"Germany"}}},{id:"318656",title:"BSc.",name:"Peter",middleName:null,surname:"Kußmann",slug:"peter-kussmann",fullName:"Peter Kußmann",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Harz University of Applied Sciences",country:{name:"Germany"}}},{id:"338222",title:"Mrs.",name:"María José",middleName:null,surname:"Lucía Mudas",slug:"maria-jose-lucia-mudas",fullName:"María José Lucía Mudas",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Carlos III University of Madrid",country:{name:"Spain"}}}]}},subseries:{item:{id:"41",type:"subseries",title:"Water Science",keywords:"Water, Water resources, Freshwater, Hydrological processes, Utilization, Protection",scope:"