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Barely three months into the new year and we are happy to announce a monumental milestone reached - 150 million downloads.
\n\nThis achievement solidifies IntechOpen’s place as a pioneer in Open Access publishing and the home to some of the most relevant scientific research available through Open Access.
\n\nWe are so proud to have worked with so many bright minds throughout the years who have helped us spread knowledge through the power of Open Access and we look forward to continuing to support some of the greatest thinkers of our day.
\n\nThank you for making IntechOpen your place of learning, sharing, and discovery, and here’s to 150 million more!
\n\n\n\n\n'}],latestNews:[{slug:"intechopen-supports-asapbio-s-new-initiative-publish-your-reviews-20220729",title:"IntechOpen Supports ASAPbio’s New Initiative Publish Your Reviews"},{slug:"webinar-introduction-to-open-science-wednesday-18-may-1-pm-cest-20220518",title:"Webinar: Introduction to Open Science | Wednesday 18 May, 1 PM CEST"},{slug:"step-in-the-right-direction-intechopen-launches-a-portfolio-of-open-science-journals-20220414",title:"Step in the Right Direction: IntechOpen Launches a Portfolio of Open Science Journals"},{slug:"let-s-meet-at-london-book-fair-5-7-april-2022-olympia-london-20220321",title:"Let’s meet at London Book Fair, 5-7 April 2022, Olympia London"},{slug:"50-books-published-as-part-of-intechopen-and-knowledge-unlatched-ku-collaboration-20220316",title:"50 Books published as part of IntechOpen and Knowledge Unlatched (KU) Collaboration"},{slug:"intechopen-joins-the-united-nations-sustainable-development-goals-publishers-compact-20221702",title:"IntechOpen joins the United Nations Sustainable Development Goals Publishers Compact"},{slug:"intechopen-signs-exclusive-representation-agreement-with-lsr-libros-servicios-y-representaciones-s-a-de-c-v-20211123",title:"IntechOpen Signs Exclusive Representation Agreement with LSR Libros Servicios y Representaciones S.A. de C.V"},{slug:"intechopen-expands-partnership-with-research4life-20211110",title:"IntechOpen Expands Partnership with Research4Life"}]},book:{item:{type:"book",id:"6251",leadTitle:null,fullTitle:"Difficulties in Cataract Surgery",title:"Difficulties in Cataract Surgery",subtitle:null,reviewType:"peer-reviewed",abstract:'For thousands of years, cataract surgery continues to be the "pearl" of ophthalmic surgery. It is explained by the fact that cataract removal always leads to an increase in visual acuity of patients. A new technology of cataract removal, phacoemulsification, was introduced by Charles Kelman in 1967. Despite this, it was difficult for the surgeons to transform from extracapsular cataract extraction to the new method - phacoemulsification. Recently, in the ophthalmological practice, the method of femtolaser cataract surgery (FLACS) has been introduced. This method allows you to automatically perform the basic stages of cataract surgery - corneal incisions, capsulorhexis, nucleus fracture. At the same time, to apply the various techniques of cataract surgery, the surgeon must possess virtually all the necessary techniques. This is dictated by the fact that, as a rule, cataract itself is rarely isolated - senile. Knowledge of the basic rules of cataract surgery, the use of pupillary rings and iris retractors in narrow pupils, the use of capsular rings in subluxations of the lens, the use of special modes of phaco in severe late cataracts, and a comprehensive clinical way of thinking can undoubtedly reduce the complications of cataract surgery.',isbn:"978-1-78923-257-8",printIsbn:"978-1-78923-256-1",pdfIsbn:"978-1-83881-360-4",doi:"10.5772/intechopen.68878",price:119,priceEur:129,priceUsd:155,slug:"difficulties-in-cataract-surgery",numberOfPages:154,isOpenForSubmission:!1,isInWos:null,isInBkci:!1,hash:"16adb188451fd4f0e63c07ffa24b2b14",bookSignature:"Artashes Zilfyan",publishedDate:"June 13th 2018",coverURL:"https://cdn.intechopen.com/books/images_new/6251.jpg",numberOfDownloads:7694,numberOfWosCitations:0,numberOfCrossrefCitations:6,numberOfCrossrefCitationsByBook:0,numberOfDimensionsCitations:10,numberOfDimensionsCitationsByBook:0,hasAltmetrics:0,numberOfTotalCitations:16,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"May 22nd 2017",dateEndSecondStepPublish:"June 12th 2017",dateEndThirdStepPublish:"October 28th 2017",dateEndFourthStepPublish:"December 28th 2017",dateEndFifthStepPublish:"February 28th 2018",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6",editedByType:"Edited by",kuFlag:!1,featuredMarkup:null,editors:[{id:"157235",title:"Dr.",name:"Artashes",middleName:"Arto",surname:"Zilfyan",slug:"artashes-zilfyan",fullName:"Artashes Zilfyan",profilePictureURL:"https://mts.intechopen.com/storage/users/157235/images/3864_n.jpg",biography:"Professor Artashes Zilfyan, MBA, PhD, is a chief ophthalmologist of Yerevan City. He is the founder and president of Association of Young Ophthalmologists in Armenia. He is the director of Eye Laser Center at MC “Shengavit.” He is also a professor of Ophthalmology.\nHis areas of specialization are minimally invasive cataract surgery—microcoaxial phacoemulsification—glaucoma nonpenetrating and penetrating surgery, using drains and shunts; treatment of keratoconus by crosslinking, keraring, and keratoplasty; and treatment of myopia, hyperopia, and astigmatism using Excimer laser Femto-LASIK.\n\nHe is the author of more than 75 publications and more than 45 scientific articles in international conferences and journals (mainly in ophthalmology on the subject ACAID syndrome of immune deviation of the eye for complicated and senile cataracts). He is the author and inventor of a new method of keratoconus diagnosis MMP9 as a main factor.",institutionString:null,position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"2",totalChapterViews:"0",totalEditedBooks:"1",institution:{name:"Yerevan State Medical University",institutionURL:null,country:{name:"Armenia"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"191",title:"Ophthalmology",slug:"medicine-ophthalmology"}],chapters:[{id:"58217",title:"Cataract Surgery in Patients with Uveitis: Preoperative and Surgical Considerations",doi:"10.5772/intechopen.71031",slug:"cataract-surgery-in-patients-with-uveitis-preoperative-and-surgical-considerations",totalDownloads:1428,totalCrossrefCites:0,totalDimensionsCites:1,hasAltmetrics:0,abstract:"Cataract is one of the most frequent visual impairment complications of uveitis, accounting for up to 40% of the visual loss seen in these patients. In general, uveitis patients differ from the general cataract population in that they are younger and have a higher rate of comorbidities, however the rates of inflammatory sequelae vary markedly among uveitic entities. Cataract development may be influenced by the cause and duration of uveitis, the degree of inflammation control, and the use of corticosteroid therapy. Cataract surgery in patients with uveitis represents a serious challenge due to pre-existing ocular comorbidities that may limit the visual outcome and difficult the surgical procedure; the need for preoperative control of inflammation; and the efficacy of postoperative management to avoid immediate and late ocular complications. A detailed ophthalmologic exam prior to surgery is essential to know the status of pre-existing pathologic changes, adjust the medical therapy to achieve absolute control of inflammation, establish a surgical plan, and deliver an objective visual prognosis to the patient or the relatives. The key point to surgical success is the absolute control of inflammation, meaning no cells in the anterior chamber for at least 3 months prior to surgery. Today, minimally invasive phacoemulsification with acrylic foldable intraocular lens implantation is the standard of care for most patients with uveitis. It must be taken into consideration that higher rates of intraoperative and postoperative complications may occur. Vision-limiting pathology related to pre-existing uveitis complications are the major contributing factors for limited postoperative visual outcome.",signatures:"Alejandro Rodriguez-Garcia and C. Stephen Foster",downloadPdfUrl:"/chapter/pdf-download/58217",previewPdfUrl:"/chapter/pdf-preview/58217",authors:[{id:"209514",title:"Dr.",name:"Alejandro",surname:"Rodriguez-Garcia",slug:"alejandro-rodriguez-garcia",fullName:"Alejandro Rodriguez-Garcia"},{id:"221323",title:"Dr.",name:"C. Stephen",surname:"Foster",slug:"c.-stephen-foster",fullName:"C. Stephen Foster"}],corrections:null},{id:"58941",title:"Strategies for Managing Difficult Cases",doi:"10.5772/intechopen.72477",slug:"strategies-for-managing-difficult-cases",totalDownloads:905,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Standard cataract surgery is considered as low-risk surgery for both patients and the surgeon, but some eyes have higher risk of complication due to some reasons that are generally known or can be predicted preoperatively. Knowing risky eyes and management of possible complications is important point for achieving good visual outcome after cataract surgery. We issued most encountered problems during surgery and some solutions to manage these difficult cases.",signatures:"Baris Komur",downloadPdfUrl:"/chapter/pdf-download/58941",previewPdfUrl:"/chapter/pdf-preview/58941",authors:[{id:"209512",title:"Dr.",name:"Baris",surname:"Komur",slug:"baris-komur",fullName:"Baris Komur"}],corrections:null},{id:"58035",title:"Analysis of the Disturbances Caused by Intraocular Forced Convection Mechanism Failure",doi:"10.5772/intechopen.72248",slug:"analysis-of-the-disturbances-caused-by-intraocular-forced-convection-mechanism-failure",totalDownloads:911,totalCrossrefCites:3,totalDimensionsCites:3,hasAltmetrics:0,abstract:"In this chapter, we show the refractive error treatment result of a patient, the first author, who restarted in 2000, after a 4-year break, at the study start. According to previous publications, the treatment consists of rehydration and elimination of agglutinated, dehydrated and deposited metabolic residues in the cornea, the trabecular meshwork, the crystalline lens and the retina, as a consequence of the failure in the mechanism of intraocular mass transfer by forced convection. However, the forced movement of the metabolic mass to rehydrate one region can cause dehydration in another region. Therefore, the patient developed posterior and capsular cataract in their respective eyes, right and left. This dehydration, during the treatment, increases the difficulties for the success of the treatment. The first part is a chronological record of the most important components of the treatment. Then, the research method and the material used are discussed. The main symptoms and signs are analyzed and correlated with the failure of the mass transfer process and the accumulation of metabolic residues. The anatomy of binocular vision is analyzed as a part of the forced convection mechanism, and in conclusion, the report shows the main oculomotor functions, topographic mapping of corneas over an interval of 17 months.",signatures:"Humberto D. Silva, Eduardo D. Silva, Maria Tamires D. Silva,\nCristiana P. Dória and Cristiane P. Dória",downloadPdfUrl:"/chapter/pdf-download/58035",previewPdfUrl:"/chapter/pdf-preview/58035",authors:[{id:"210547",title:"Dr.",name:"Humberto",surname:"Dória Silva",slug:"humberto-doria-silva",fullName:"Humberto Dória Silva"},{id:"210592",title:"Dr.",name:"Eduardo",surname:"Dória Silva",slug:"eduardo-doria-silva",fullName:"Eduardo Dória Silva"},{id:"210614",title:"B.Sc.",name:"Maria Tamires",surname:"Dória Silva",slug:"maria-tamires-doria-silva",fullName:"Maria Tamires Dória Silva"},{id:"210615",title:"M.Sc.",name:"Cristiana",surname:"Pereira Dória",slug:"cristiana-pereira-doria",fullName:"Cristiana Pereira Dória"},{id:"210616",title:"Prof.",name:"Cristiane",surname:"Pereira Dória",slug:"cristiane-pereira-doria",fullName:"Cristiane Pereira Dória"}],corrections:null},{id:"61499",title:"Combined Glaucoma and Cataract: An Overview",doi:"10.5772/intechopen.73584",slug:"combined-glaucoma-and-cataract-an-overview",totalDownloads:1152,totalCrossrefCites:1,totalDimensionsCites:1,hasAltmetrics:0,abstract:"Glaucoma and cataract frequently coexist in our elderly population regardless of geographical location or ethnicity. Cataract extraction alone has demonstrated to reduce intraocular pressure in eyes either with or without glaucoma. However, this chapter focuses on how cataract surgery might be combined with different glaucoma surgical procedures, such as trabeculectomy, non-penetrating procedures and minimally invasive procedures (MIGS), as well as implantation of drainage devices like the Trabectome® and the iStent®, both used for trabecular flow increase; the CyPass® implant, which acts by increasing the uveoscleral flow; the XEN® implant that facilitates the drainage of the aqueous humor from the anterior chamber to the subconjunctival space and finally the endocyclophotocoagulation that decreases the aqueous humor production. Current surgical options will be discussed, focusing on recently reported studies, analyzing the clinical aspects that influence the choice for each surgical treatment.",signatures:"Jesús Jiménez-Román, Carolina Prado-Larrea, Luis Laneri-Pusineri\nand Roberto Gonzalez-Salinas",downloadPdfUrl:"/chapter/pdf-download/61499",previewPdfUrl:"/chapter/pdf-preview/61499",authors:[{id:"215560",title:"M.D.",name:"Jesus",surname:"Jiménez Roman",slug:"jesus-jimenez-roman",fullName:"Jesus Jiménez Roman"},{id:"215563",title:"MSc.",name:"Roberto",surname:"González Salinas",slug:"roberto-gonzalez-salinas",fullName:"Roberto González Salinas"},{id:"215564",title:"Dr.",name:"Carolina",surname:"Prado Larrea",slug:"carolina-prado-larrea",fullName:"Carolina Prado Larrea"},{id:"215565",title:"Dr.",name:"Luis",surname:"Laneri Pusineri",slug:"luis-laneri-pusineri",fullName:"Luis Laneri Pusineri"}],corrections:null},{id:"57886",title:"Phacoemulsification Cataract Surgery without Viscoelastic Substance: Bianchi’s Method",doi:"10.5772/intechopen.72084",slug:"phacoemulsification-cataract-surgery-without-viscoelastic-substance-bianchi-s-method",totalDownloads:1300,totalCrossrefCites:2,totalDimensionsCites:5,hasAltmetrics:0,abstract:"Life expectancy of the population increase and cataract development will affect all the people with aging. Cataract surgery, a worldwide performed procedure, evolves and progresses. However, different techniques exist, which could be selected for different cases. Any ideal technique should be safe, simple, fast, and easy to learn with good clinical outcome. This chapter will describe one technique to operate cataracts with those characteristics and to perform phacoemulsification cataract surgery without viscoelastic substance. Some advantages of this technique are related to avoiding viscoelastic potential problems, as postoperative intraocular pressure elevation or anterior chamber inflammation associated with viscoelastic. Moreover, a fundamental factor to remark is the difference between work into the anterior chamber with negative pressure or positive pressure. Because the anterior chamber is maintained by the balanced salt solution with the continuous irrigation without viscoelastic. Performing the capsulorhexis is easier. Other advantages are shorten surgical time, fewer economical cost, and potentially fewer complications. Some limitations are as follows: intraocular lens must be one piece foldable, and principally, patients with corneal endothelial pathology must be excluded. Tips, step-by-step surgery, recommendations, and evolution of the technique will be described, with the wish that many surgeons will try to perform Bianchi’s method (bimanual, microincision phacoemulsification cataract surgery without viscoelastic substance) for your next patient.",signatures:"Germán R. Bianchi",downloadPdfUrl:"/chapter/pdf-download/57886",previewPdfUrl:"/chapter/pdf-preview/57886",authors:[{id:"220509",title:"Dr.",name:"Germán",surname:"Bianchi",slug:"german-bianchi",fullName:"Germán Bianchi"}],corrections:null},{id:"58106",title:"Optimizing Outcome of Cataract Surgery in Resource Scarce Sub-Saharan Africa",doi:"10.5772/intechopen.71799",slug:"optimizing-outcome-of-cataract-surgery-in-resource-scarce-sub-saharan-africa",totalDownloads:941,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Background: Sub-Saharan Africa disproportionately accounts for high number of avoidably blind largely caused by cataracts.",signatures:"Lawan Abdu",downloadPdfUrl:"/chapter/pdf-download/58106",previewPdfUrl:"/chapter/pdf-preview/58106",authors:[{id:"30695",title:"Prof.",name:"Lawan",surname:"Abdu",slug:"lawan-abdu",fullName:"Lawan Abdu"}],corrections:null},{id:"58058",title:"Presbyopia Correction During Cataract Surgery with Multifocal Intraocular Lenses",doi:"10.5772/intechopen.71969",slug:"presbyopia-correction-during-cataract-surgery-with-multifocal-intraocular-lenses",totalDownloads:1058,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Introduction: The first generations of multifocal intraocular lenses (MFIOLs) were designed to provide patients good distance and near vision, but intermediate was not satisfactory. Trifocal, a bifocal of low-add and quadrifocal MFIOLs were invented, offering possibility to correct vision for distance, near, and intermediate tasks. The novel IOL, extended range of vision (EROV), is covering mostly intermediate and distance vision, with lower level of photic phenomena.",signatures:"Iva Dekaris, Nikica Gabrić, Ante Barišić and Adis Pašalić",downloadPdfUrl:"/chapter/pdf-download/58058",previewPdfUrl:"/chapter/pdf-preview/58058",authors:[{id:"212359",title:"Prof.",name:"Iva",surname:"Dekaris",slug:"iva-dekaris",fullName:"Iva Dekaris"},{id:"213121",title:"Prof.",name:"Nikica",surname:"Gabrić",slug:"nikica-gabric",fullName:"Nikica Gabrić"},{id:"213122",title:"Dr.",name:"Ante",surname:"Barišić",slug:"ante-barisic",fullName:"Ante Barišić"}],corrections:null}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},subseries:null,tags:null},relatedBooks:[{type:"book",id:"8855",title:"Retinoblastoma",subtitle:"Past, Present and Future",isOpenForSubmission:!1,hash:"1686b2f1d697de9d4bc2005a5fa9b998",slug:"retinoblastoma-past-present-and-future",bookSignature:"Hind Manaa Alkatan",coverURL:"https://cdn.intechopen.com/books/images_new/8855.jpg",editedByType:"Edited by",editors:[{id:"223782",title:"Dr.",name:"Hind",surname:"Alkatan",slug:"hind-alkatan",fullName:"Hind Alkatan"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"5917",title:"Causes and Coping with Visual Impairment and Blindness",subtitle:null,isOpenForSubmission:!1,hash:"59fe032e3de5e150eab8bf47bd2d8fdd",slug:"causes-and-coping-with-visual-impairment-and-blindness",bookSignature:"Shimon Rumelt",coverURL:"https://cdn.intechopen.com/books/images_new/5917.jpg",editedByType:"Edited by",editors:[{id:"54335",title:"Dr.",name:"Shimon",surname:"Rumelt",slug:"shimon-rumelt",fullName:"Shimon Rumelt"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"6372",title:"Early Events in Diabetic Retinopathy and Intervention Strategies",subtitle:null,isOpenForSubmission:!1,hash:"46ff48bdb1bac8a69372566fff0e2f6d",slug:"early-events-in-diabetic-retinopathy-and-intervention-strategies",bookSignature:"Andrew T.C. 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It is promising novel research that has received a lot of interest over the last few decades. It covers advanced topics on optical, physical, medicinal, and biological applications of AuNPs. Development of green nanotechnology is generating the interest of researchers towards the synthesis of eco-friendly, safe, non-toxic applications, which can be used for manufacture at a large scale. These are simple, cost-effective, stable, enduring, and reproducible aqueous room temperature synthesis applications to obtain the self-assembly of AuNPs. This potentially unique work offers various approaches to R&D with AuNP materials in aqueous or non-aqueous phases through fully modified or unmodified states as hybrids. Nanotechnology and nanoscience can regulate substances at the nanoscale, and nanodimension substances of a few nanometers allow us to control the novel practical applications of AuNPs. This book presents an overview of current AuNP fundamental and substantial applications and research worldwide, which investigates the techniques of AuNP preparation, various types of characterization, and possible applications related to AuNP research. 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The word “melanoma” was first used by
The incidence of cutaneous malignant melanoma has increased significantly among all Caucasian populations over the last several decades. The rate of incidence of cutaneous melanoma continues to rise almost inexorably in populations of European origin worldwide. Diagnosis of melanoma at an early stage is almost curable but there is currently no effective treatment for advanced melanoma. Probably a large proportion of melanomas can be ascribed to a single (modifiable) risk factor-sun exposure. It has not been established whether medical intervention of any kind influences the outcome in the case of melanoma. Major initiatives in recent years have concentrated on education about sun avoidance, the importance of skin awareness and skin examination, and the screening of populations at high risk for melanoma. However, it is unclear whether any of the latter measures have had any significant influence on mortality from melanoma. The annual increase in incidence rate varies between populations, but in general has been in the order of 3–7% per year for fair-skinned Caucasian populations. CMM represents a significant and growing public health burden because of the increase in incidence and the consequent mortality [3].
The cancer statistic in the United States was reported to be 6 cases per 100.000 inhabitants at the beginning of the 1970s and 18 cases per 100.000 and year at the beginning of 2000, thus demonstrating a threefold increase in incidence rates. Incidence rates in central Europe increased in the same time period, from 3 to 4 cases to 10 to 15 cases per 100.000 inhabitants and year, which is very similar to the increase in the United States. The highest incidence rates were reported in Australia and New Zealand, with 30 to 60 cases per 100.000 inhabitants and year [4]. Cutaneous melanoma ranks as the sixth most common cancer in American men and women, the second most common cancer in patients between the ages of 20 and 35, and the leading cause of cancer death in women ages 25 to 30 years [5]. Although melanoma accounts for 5% of all skin cancers in the United States, it is responsible for the most common skin cancer-related deaths (it accounts for 79 percent of all skin cancer deaths) because of its high mortality when identified at an advanced stage [6, 7]. The number of deaths due to CMM has also increased in most fair-skinned populations throughout the world in the past few decades. However, melanoma mortality rates have been rising at a rate of increase lower than that for melanoma incidence. Between 1955 and 1984, mortality from CMM had been rising both in young adults (20–44 years) and in middle-aged populations (45–64 years) in most European countries, North America, Australia and New Zealand, with a rate of increase of 2–4% annually. In Australia in 1985–1999 the mean age-standardized mortality rates were 4.8 and 2.5 per 100.000 in men and women, respectively. In 1990–1994 the rate rose by 3.7% in men to 5.0 per 100.000 and in women it fell by 5.2% to 2.4 per 100.000 [3]. Although mortality rates have increased, 5-year survival has steadily improved over recent decades, and is now greater than 85%, but melanoma causes disproportionate mortality in those of young and middle age, such that an average of 18.6 years of potential life are lost for each melanoma death in the USA, one of the highest rates for adult-onset cancers [8]. Predicted 1-year survival for stage IV disease ranges between 41% and 59% [5].
The etiology of melanoma is multifactorial that environmental, host, and genetic factors contribute to its development. The most important environmental risk factor is ultraviolet radiation (UVR) exposure [6]. Most melanomas are thought to be caused by periodic, intense sun exposure (particularly during the critical time period of childhood and adolescence), termed the
Cutaneous malignant melanoma is currently classified into four major clinical subtypes: Superficial spreading, nodular, acral lentiginous, and lentigo maligna, of which superficial spreading melanoma is by far the most common form (approximately 70%) of CMM [10]. CMM that is less invasive and locally defined at diagnosis has a five-year survival rate of more than 95% after treatment by surgical excision alone. Fortunately, the vast majority of CMM (approximately 80%) are diagnosed at this early stage. If the cancer is more advanced, however, survival rates drop substantially to 30% to 60% after five years, depending on the tumor thickness in millimeters (
The prognosis for a patient with a newly diagnosed cutaneous melanoma depends mainly on two factors— the thickness of the primary tumour and the presence or absence of metastasis to regional lymph nodes. However, other prognostic factors are very important, including tumour ulceration, mitotic rate, and presence of regression, as well as sex and age of the patient, and tumour site [8].
For the primary prevention, physical protection from exposure to sunlight is generally accepted as the most important element of melanoma risk reduction. It seems particularly meaningful to prevent multiple erythemas during childhood, convincing parents and care takers not to let children stay too long under the sun. Sun-protective clothing and hats should be worn and peak hours of sun intensity should be avoided. For these purposes, mass media campaigns and widespread public education programmes would be most effective to make changes in attitude and behaviour towards sun protection [8,11]. The wavelength of light that is causal for melanoma is still not known and therefore sunscreens should be broad-spectrum types, providing protection across both UVB and UVA ranges. Advice should be to use sunscreens that are water proof, and sunscreens must be applied regularly and in sufficient quantities [12]. Regular screening of the total population for CMM does not seem useful and is not propagated in any country in the world. However, it seems likely that people with a familial risk of developing melanomas (those with familial or sporadic dysplastic naevus syndrome, xeroderma pigmentosum and large congenital naevi, representing approximately 10% of all melanoma patients) can benefit from regular check-ups. Screening in these populations, and regular checks (every 6–12 months) lead to earlier detection [11].
The etiology of melanoma is multifactorial, with environmental, host, and genetic factors contributing to its development. Ultraviolet radiation exposure is the most important environmental risk factor [6]. The precise type of sun exposure that is causal has been controversial but the data are now strong that the dominant cause is intermittent sun exposure [12]. Periodic and intense sun exposure rather than long, heavy sun exposure especially during childhood and adolescence is the feature of intermittent sun exposure. Also, sunburn history particularly blistering and peeling burns are important indicators for intermittent sun exposure [7].
In a meta-analysis by
The geographic distribution of melanoma supports the importance of UVR exposure in its pathogenesis. Living closer to the equator, where there is the greatest ambient solar radiation, is consistently associated with increased melanoma risk [6]. When the incidence and mortality rates of melanoma compared between Europe and Australia it was reported 5 to 10 times higher incidence rates in Australia [4]. Melanoma incidence and mortality among Caucasians correlate inversely with latitude of residence and dose of UV radiation, termed
The anatomic distribution of melanoma also offers insight into the pathogenesis of the disease and the role of UVR. The most common sites for melanoma are the trunk in men and the lower legs in women which are areas of high levels of acute, intermittent sun exposure. In older people, there is a greater incidence of melanomas located on chronically sun exposed areas with maximal cumulative sun exposure that the face is the most common location [6,7].
Weaker phenotypic risk factors are related to; the presence of skin that burns easily in the sun such as: skin phototype I-II, high density of freckles, fair complexion/sun sensitivity, an increased number of common or atypical/dysplastic nevi (moles), blue eye colour and red hair colour [12].
The strongest phenotypic risk factor for melanoma is the presence of increased numbers of melanocytic naevi [12]. With growing numbers of melanocytic nevi, the melanoma risk increases nearly linearly. In addition, the presence of atypical melanocytic nevi was found to be an independent risk factor [4]. Adults with more than 100 clinically typical-appearing nevi, children with more than 50 typical-appearing, and any patient with atypical nevi are at risk. Large congenital nevi are recognized potential precursors of melanoma, although the degree of risk varies depending on the size of the lesion [7]. Twin studies have provided strong evidence that naevus number is predominantly genetically determined with a smaller effect of environmental factors, particularly sun exposure. It is theorized, therefore, that the genes that determine naevus number are also common melanoma susceptibility genes [12]. Many of the oncogenic mutations initially identified in melanomas have also been detected in benign melanocytic proliferations [5].
Any family history increases the risk of melanoma. Familial melanoma comprises 10-15% of all patients with melanoma [7,12]. The presence of more than one case of melanoma in a family may occur by chance alone, or may be due to low penetrance alleles and/or sun exposure habits common to affected relatives. However, an estimated 25% of familial melanoma is associated with germline mutations of the CDKN2A gene on chromosome 9 (which codes for the cell cycle inhibitor protein, p16) and often presents with an autosomal dominant pattern of transmission [17].
Melanoma develops as a result of accumulated abnormalities in genetic pathways within the melanocyte. These abnormalities promote cell proliferation and prevent normal pathways of apoptosis in response to DNA damage [8]. The driving force behind the initiation and progression of melanoma development is the acquisition of somatic mutations in key regulatory genes. The first gene found to be specifically altered in melanoma was
BRAF is a serine/threonine kinase, which is a major player in the Ras-Raf-Mek-Erk mitogen-activated protein kinase (MAPK) signaling transduction pathway that regulates cell growth, proliferation, and differentiation in response to various stimuli [7]. Mutations in
The two recognized major melanoma susceptibility genes,
The
Generally, an individual\'s risk for developing melanoma depends on two groups of factors; intrinsic and extrinsic that is environmental. "Intrinsic" factors are generally an individual\'s family history and inherited genotype, while the most relevant environmental factor is sun exposure. Epidemiologic studies suggest that exposure to ultraviolet radiation (UVA and UVB) is one of the major contributors to the development of melanoma. UV radiation causes damage to the DNA of cells, typically thymine dimerization, which when unrepaired can create mutations in the cell\'s genes. When the cell divides, these mutations are propagated to new generations of cells. If the mutations occur in protooncogenes or tumor suppressor genes, the rate of mitosis in the mutation-bearing cells can become uncontrolled, leading to the formation of a tumor [26].
Cutaneous malignant melanoma is the most serious form of skin cancer. In general, cutaneous melanoma most commonly affects adult Caucasians and is rarely observed before puberty. Melanoma may occur at any age, although children younger than age 10 years rarely develop a de novo melanoma. It was reported that in 2002 there were 53.600 new cases, and 7.400 deaths from cutaneous malignant melanoma in the United States. The incidence rate of MM has increased 4% per year since 1973 [27]. This epidemic of MM is also evident in other parts of the industrialized world, including Australia and southern Europe. It is predicted that the incidence of MM will continue to increase as a result of the continuing decrease in the concentration of stratospheric ozone and increasing leisure time for sunlight-related recreation, including sunbathing, which increases exposure to solar UV radiation [28].
Sunlight and most particularly the ultraviolet spectrum of sunlight is the only environmental factor that has been compellingly implicated as a cause of melanoma [29].
Possible significant elements in determining risk include the intensity and duration of sun exposure, the age at which sun exposure occurs, and the degree of skin pigmentation. Exposure during childhood is a more important risk factor than exposure in adulthood [30, 31].
Individuals with blistering or peeling sunburns (especially in the first twenty years of life) have a significantly greater risk for melanoma. This does not mean that sunburn is the cause of melanoma. Instead it is merely statistically correlated [32].
Fair and red-headed people, individuals with multiple atypical nevi or dysplastic nevi and people born with giant congenital melanocytic nevi are at increased risk [33]. Melanoma incidence is 10–20-fold higher among the fair-skinned than the dark-skinned people. Among fair-skinned people, melanoma incidence generally increases with proximity to the equator (some exceptions occur, particularly in continental Europe, where the association is confounded by pigmentation). Fair-skinned migrants from high- (e.g. the UK) to low-latitude countries (e.g. Australia) have lower melanoma rates than native-born residents, and vice versa [29].
History of melanoma in melanoma-prone families due to mutations in some genes were found to greatly increase the risk of a person. (e.g. CDKN2A and CDK4). Patients with a history of melanoma are at risk of developing a second primary tumor [34, 35].
Looking at the geographical distribution of the incidence of malignant melanoma in Europe has increased in Northern Europe, especially Scandinavian countries (20.7 per 100.000 person-year). Incidence rates were lowest in Southern and Eastern Europe for both males and females, with rates between 5-10 per 100.000 person-year. mortality rates in studies conducted in Europe (5.1 per 100 000 person-years ranging from 2.5) was found to be different in a lot less. Death rates lower in women than men had been established. In the 1990s compared the incidence and mortality rates in southern and eastern Europe, northern and western Europes have been identified as the highest and lowest [36].
Between the years 1970-2009, a study conducted among young adults in the United States the incidence of cutaneous melanoma is increasing rapidly, especially among women. This high-risk population should be closely monitored constantly [37]. The incidence may be higher due to melanoma underreporting to cancer registries, particularly for tumors that are diagnosed and managed in the outpatient setting [38].
While melanoma accounts for roughly 4% of all skin cancers, it causes more than 75% of skin cancer deaths. Treatment of melanoma in its early stages provides the best opportunity for cure. In the United States, an estimated approximately 9.000 deaths will occur in 2012. Melanoma incidence has continued to increase worldwide, with the highest incidence in Australia and New Zealand. The most recent analysis of global cancer statistics for melanoma, from 2002, demonstrated a prevalence of 37.7 cases per 100.000 men and 29.4 cases per 100.000 women in Australia and New Zealand, compared with 6.4 cases per 100,000 men and 11.7 cases per 100.000 women in North America [39].
Differing melanoma incidence between males and females, and the tendency for females to develop excess melanin pigmentation during periods of hormonal stimulation such as pregnancy, has led to a number of studies investigating the role of pregnancy, oral contraceptives and hormone replacement therapy both as risk factors for melanoma and also as events that may affect prognosis. Cumulative data from publications on these topics provide no evidence that prior pregnancy is a risk factor for melanoma. Similarly, there is no evidence to indicate that oral contraceptive or hormone replacement use contributes to melanoma risk, nor that either factor alters the prognosis for those in whom melanoma has already been diagnosed [40, 41].
Airline crews, particularly pilots, have been recorded in a number of studies as having a higher-than-expected incidence of melanoma. It is suggested that this may be due to greater opportunities for recreational sun exposure during regulation breaks between flights in areas of the world with a high solar exposure [42].
A number of publications show conflicting results concerning the risk of melanoma developing after renal transplantation and the necessary immunosuppression. Studies from Sweden and the Netherlands show no increase in melanoma incidence over that expected in these countries [43], while studies from the USA and UK show a significantly increased risk, 3.6- and 8-fold higher for USA and UK patients, respectively. While some of these differences may relate to time frames of studies and changes in immunosuppressive regimes over time, further large long-term contemporary studies are required to determine the degree of increased cutaneous surveillance required for transplant patients [44].
A case–control study comparing melanoma on the palms and soles in both the UK and Australia observed that melanoma patients reported greater exposure to pesticides than that reported by controls, and recently, an Italian case–control study has confirmed higher use of pesticides in a residential setting in melanoma patients compared with that in controls. Interpretation of these data is complex, as over the past decade there have been many regulatory changes in
Xeroderma pigmentosum (XPD) is a genetic disorder with a mutation of the XPD gene leading to nucleotide excision repair defects. Patients experience 1000-fold greater risk of melanoma as they are unable to repair UV-induced DNA damage. The relative ability to repair DNA modifies the risk in the presence of other host factors such as age, poor tanning ability and dysplastic naevi. Two polymorphisms of the XPD gene are associated with a decreased risk of melanoma among women with five or more severe sunburns or high cumulative sun exposure.
Mutations of the melanocortin-1 receptor gene variants are more common among fair-skinned and red-haired people. Polymorphism of this gene is associated with melanoma. The risky factors are the phenotype of pigmentation of the individual, the presence of atypical naevi, >50 melanocytic naevi, high recreational and occupational sun exposures [45]. People with a past history of other types of skin cancer (basal cell carcinomas and squamous cell carcinomas) caused by high doses of solar UV radiation have threefold higher risks of melanoma than the average population [46].
Several forms of artificial light have been associated with the development of melanoma in some studies: fluorescent lighting and suntan beds and parlors. Although exposure to fluorescent lighting was hypothesized to increase risk for developing melanoma, there have been no studies to support this idea. On the other hand, the use of tanning lamps and tanning parlors may increase risk for melanoma [47, 48].
Differing melanoma incidence between males and females, and the tendency for females to develop excess melanin pigmentation during periods of hormonal stimulation like pregnancy, have led to a number of studies investigating the role of pregnancy, oral contraceptives and hormone replacement therapy both as risk factors for melanoma and also as events that may affect prognosis. Cumulative data from publications on these topics provide no evidence that prior pregnancy is a risk factor for melanoma. Similarly, there is no evidence to indicate that oral contraceptive or hormone replacement use contributes to melanoma risk, nor that either factor alters the prognosis for those in whom melanoma has already been diagnosed [41, 49, 50].
The most common sites that melanomas are found include the trunk (back) followed by the upper extremities, and head and neck for men; and the lower extremities followed by the back, upper extremities, and head and neck for women. Amelanotic melanoma and those resembling keratoses are particularly difficult to diagnose without a high index of suspicion. Acral melanoma is the most frequent form of melanoma among Asians, Africans, and other ethnic groups of color. Subungual melanoma (SM) is a distinctive variant of acral melanoma that most often involves the nail bed of the great toe or thumb. Clinical types include;
Lentigo maligna melanoma is one of the 4 main subtypes of invasive melanoma and constitutes 10 to 15% of cutaneous melanomas. Generally, patients with lentigo maligna are older than 40 years, with a mean age of 65 years. The peak incidence occurs in the seventh to eighth decades of life [51]. The incidence of lentigo maligna subtypes (in situ and invasive) appears to be rising in the United States [52].
Sir
Lentigo maligna melanoma has evolved from a lentigo maligna.They are usually found on chronically sun damaged skin such as the face and the forearms of the elderly people. The risk increases as the number of years spent in sunny districts increases, as well as with increased hours of exposure to sunlight. The incidence of melanoma is highest in Australia, where lentigo maligna accounts for 10-15% of all melanomas. Approximately 10-30% of all cutaneous melanoma arise in head and neck regions. The other risk factors for lentigo malign melanoma are large or giant congenital naevi, fair skin and history of severe sunburn [53].
Many authors consider lentigo maligna to be a preinvasive lesion induced by long-term cumulative ultraviolet injury. Conceptually, the term melanoma is used when atypical melanocytes invade the rich vascular and lymphatic networks of the dermis, thereby establishing metastatic potential [12, 51, 53].
Most malignant melanomas arise as superficial tumors confined to the epidermis, which is often known as horizontal growth. At some point, a stepwise accumulation of genetic abnormalities leads to proliferation and progression to the vertical growth phase, which leads to dermal and deeper involvement and subsequently nodal metastases [54].
Initially the lentigo maligna is a flat, brown or black, irregularly shaped lesion. These lesions will grow very slowly, over months or years, and there may be central regression while the peripheral margin continues to extend. In time, a raised central nodule will develop, indicating transition to the vertical growth phase [12, 51, 53, 54].
Differantial diagnosis of lentigo malign melanom are solar lentigo, pigmented actinic keratosis, seborrheic keratosis, common acquired nevi and dysplastic nevi [12].
Lentigo maligna is basically in situ melanoma and is characterized by epidermal atrophy, extensive solar, lentiginous, and back-to-back proliferation of melanoma cells. Only 5% of patients with lentigo maligna progress to lentigo maligna melanoma, and it usually takes several years. Several methods of therapy can be used to treat lentigo maligna including cryotherapy, superficial radiation therapy, and surgical excision with mapping and modified
Some imaging methods before proceeding to the treatment of lentigo maligna melanoma can be made. Especially, in patients with suspected metastatic disease, PET scan, CT scan and MR can be made to detect lymph node and internal organ metastases [57].
The treatment of the melanoma is as for other sites in that the margin of excision for tumours thinner than 2 mm is 1 cm minimum and for thicker tumours should be 2 to 3 cm. It is recognized, however, that on the face these margins may not be attainable without unacceptable cosmetic deficit. The surgery is also subject to the same constraints as described above for lentigo maligna, in that there is a high local recurrence rate of the in situ component [12, 58].
Superficial spreading melanoma is the most common type of cutaneous melanoma. It accounts for nearly 70% of cutaneous melanoma. The mean age at diagnosis is in the fifth decade. The commonest sites are the female leg and the male back (Figure 1), but every site may be affected [12].
Superficial spreading melanoma with characteristic asymmetry, irregular borders.
Superficial spreading melanoma occurs in two phases: At first, superficial spreading melanoma grows horizontally on the skin surface (radial growth phase). The lesion constitutes as a slowly-enlarging flat area of discoloured skin. At second, superficial spreading melanoma becomes invasive, the melanoma cells cross the basal membrane of the epidermis. A rapidly-growing nodular melanoma can start to proliferate more deeply within the skin [59].
The main risk factors for superficial spreading melanoma are: age, previous invasive melanoma or melanoma in situ, nonmelanoma skin cancer, many melanocytic moles, multiple atypical naevi, family history of melanoma, fair skin and sun damage. Other risk factors include blue or green eyes and red or blond hair [60, 61].
Superficial spreading melanoma presents as a slowly growing or changing flat patch of discoloured skin. At first, it often resembles a mole or freckle. It becomes more distinctive in time, often growing over months to years or even decades before it is detected. Like other flat forms of cutaneous melanoma, it can be detected by the ABCDE rule: Asymmetry, border irregularity, colour variation, large diameter and evolving [51].
The characteristics of superficial spreading melanoma are larger size, irregular shape, variable pigmentation (colours may include light brown, dark brown, black, blue, grey) and irregular surface. It is generally greater than 6 mm in diameter. Irregular asymmetric borders are characteristic [12, 51, 59, 60].
Dermoscopy can be very helpful in distinguishing superficial spreading melanoma from other skin lesions, such as melanocytic naevi, solar lentigines, seborrhoeic keratoses and pigmented basal cell carcinoma (Figure 2) [62].
Macroscopic view of a superficial spreading melanoma (A), dermoscopic view characterized by blue-white veil (B).
The initial treatment of a primary melanoma is to cut it out; the lesion should be completely excised with a 2-3 cm margin of normal tissue. Further treatment depends mainly on the
Acral lentiginous melanoma (ALM) is a rare variant occuring exclusively on the sole, with the palm and subungual locations [7, 63]. Subungual melanomas often are mistaken for subungual hematomas (splinter hemorrhages). Subungual melanoma may show itself as a longitudinal pigmented band (melanonychia striata) within the nail plate. This variant of melanoma may also affect the oral and nasal mucosa and involve the anogenital area [64]. This is the least common subtype of melanoma in white people (2-8% of melanoma cases). It is the most common subtype of melanoma in dark skinned patients (ie, Afro-American, Asian, and Hispanic people), representing 29-72% of melanoma cases [65, 66]. Not all palmo-plantar melanomas are ALMs; a minority are superficial spreading or nodular melanomas [7]. ALM shows typically as an asymmetric, brown to black macule with variegations in colour and irregular borders [67]. They usually arise from the nail matrix or, less often, from the nail bed or nail fold. ALM is similar to lentigo maligna melanoma in that an irregular pigmented macule is present for a long time [68].
Although the pathogenesis of ALM remains unknown, it has been theorized that the more intense and chronic trauma experienced in acral locations may be a predisposing factor [69].
ALM has key demographic and life-style differences to differentiate ALM from other melanoma subtypes: it occurs in an older patient population, and is associated with a lower number of common and atypical nevi, a lower incidence of familial melanoma, and a lower incidence of sunburn but a higher personal and family history of noncutaneous cancers [69].
There is often a delay in the diagnosis of ALM.The presence of invasion can be deceptive and may be present in entirely flat lesions [63]. The clinical differential diagnosis of ALM include a planter wart, which is common reason of delayed diagnosis, black heel (talon noir), lentigines, melanocytic nevi, tinea nigra, traumatic haemorrhage and tattoos such as by silver nitrate. Any growing, tender nodule, or an “ulcer” won’t heal, on the sole of the foot, should give rise to concern that the lesion is a melanoma and biopsy should be considered [12, 70].
Subungual melanoma, considered a variant of ALM, generally arises from the nail matrix. They are the most common on the thumb or great toe. It may manifest as diffuse nail discoloration, a longitidunal pigmented band (melanonychia striata) within the nail plate or growth in the nail bed. Furthermore, 20% of subungual malignant melanomas may present with amelanocytic lesions rather than melanonychia [7, 71].
Pigment spread to the proximal or lateral nail folds is termed the
Overall 5 year survival is disproportionately poor (25-51%) compared to other histological subtypes [71].
Longitidunal melanonychia: longitudinal pigmented band within the nail plate.
Nodular melanoma (NM) is the second most common subtype after superficial spreading melanoma and accounts for approximately 15% to 30% of all melanomas. It is diagnosed most frequently in patients in their sixth decade of life [63, 67]. NM tends to affect men more than women. The most common locations are head, neck, the trunk in men (Figure 4) and legs in women [70].
Nodular melanoma manifests as a dark brown-to-black dome-shaped nodule.
NM clinically lacks an apparent radial growth phase. It is more common for NM to begin de novo than to arise in a pre-existing nevus. Typically, it presents as a black or blue-black nodule, but 5 percent are amelanotic and often misdiagnosed clinically. Thus, any rapidly growing flesh-colored lesion that persists after 1 month or ulcerates or bleeds should prompt medical evaluation [7].
It tends to lack the typical ABCDE melanoma warning signs and thus, may elude early detection. Histologically, it is believed to lack a preceding radial or in situ growth phase. The prognosis of NM is generally worse than other forms of melanoma because there is involvement of the dermis and the lesion is in the “vertical growth phase” at the time of diagnosis.
The clinical differential diagnosis includes hemangioma, pyogenic granuloma, blue nevi, dermatofibroma, pigmented basal cell carcinoma, as well as other cutaneous neoplasms (Figure 5). As a general rule, a firm papule or nodule should never be subjected to any form of monitoring-biopsy if the diagnosis is in doubt [63, 70].
Nodular melanoma must be differentiated from pyogenic granuloma, blue nevi, and pigmented basal cell carcinoma.
Mucosal melanoma is a rare cancer that is clearly distinct from its cutaneous counterpart in biology, clinical course, and prognosis. It accounts for 1.3%-1.4% of all melanomas; that they tend to occur near the mucocutaneous junctions of squamous and columnar epithelia. The most common sites are the head and neck region (conjuctival, intranasal, sinus and oral cavities), vulva, anorectal, or even urethral melanoma. Activating mutations in the c-KIT gene are detected in a significant number of patients with mucosal melanoma [72].
Sun exposure does not play a role in the pathogenesis of these lesions. Irritants and carcinogenic compounds in the air, such as tobacco smoke and formaldehyde, have been implicated in the devolepment of head and neck melanoma, the potential role of these compounds is not clear. The most common presenting trait of mucosal melanoma is the presence of extensive, irreguler macular pigmentation. Most mucosal melanomas are lentiginous (mucosal lentiginous melanoma), followed in incidence by superficial spreading and nodular types.
Because of its hidden location and rich vascularization, mucosal melanoma usually presents at a more advanced stage and is therefore associated with a higher mortality rate than cutaneous melanoma [7, 12, 73].
Childhood melanoma is very rare, particularly before puberty. Approximately 1% to 4% occur in patients younger than 20 years of age, and only 0.3 to 0.4% occur in pubertal children. After puberty the incidence of melanoma starts to rise slowly.
As in adults, childhood melanomas mainly affect the white population. Previous surveys have shown slight female predominance of melanoma in children. The most common primary tumor sites are the extremities, followed by trunk. Location in head and neck and trunk has been related to poor prognosis. The risk factors for melanoma in children are parallel those in adults. There are three known predispositions in childhood melanoma: congenital naevi, the atypical mole syndrome, familial melanoma and other family cancer syndromes such as xeroderma pigmentosum and retinoblastoma. Increasing age, UV exposure, and
Histologically, childhood melanomas may resemble those of adults, but small cell melanomas and melanomas with features of
Congenital melanoma is extremely rare; most melanomas in children are acquired after birth. In addition, a mother with visceral metastases can transfer tumor cells transplacentally, giving birth to a newborn with disseminated metastases.
Although, it seems that pediatric patients with melanoma may have a better prognosis than adults showing the same type of lesions, a number of children will still develop metastasis and die of their disease, especially when melanoma is diagnosed after puberty. Treatment follows the same rationale as in adults, with the aim of early detection and appropriate resection of the primary melanoma [12, 67, 68, 74, 75].
Desmoplastic melanoma (DM) is a rare sub-type melanoma that provokes a scar-like tissue reaction and is frequently associated with neurotropism. It makes up <1% of all melanomas. It is most commonly develops in older persons and has a male predominance 2:1. The head and neck are the most frequently involved sites, although lesions may develop on the trunk and extremities, palate, gingiva, lip, vulva, anus, and conjunctiva. DMs usually arise on the skin that has been severely damaged by long-standing sun exposure, although they have been reported to develop on skin damaged by ionizing radiation and in burn scars [63, 70, 76-78].
Its clinical features are similar to nonmelanoma (keratinocytic) skin cancer. It may occur in association with macular, lentigo maligna-type pigmentation, or it may present de novo as a firm, amelanotic nodule or scar. Fifty percent of the time it is amelanotic and may be mistaken for something as innocent as a scar. In the other 50% of cases it is associated with an overlying lentigo maligna or superficial spreading melanoma [64, 78]. Lack of pigmentation and clinical features more suggestive of keratinocytic skin cancer may result in delay in detection and thicker tumors at diagnosis [39].
Histologically, the tumor is composed of collections of spindle cells diffusely infiltrating the dermis and often the subcutis, associated with abundant stromal collagen. Many DMs are deeply invasive at diagnosis and have a tendency to infiltrate perineurally, otherwise called neurotropic melanoma. Neurotropism is related to increase the frequency of local recurrences. Also, it seems that neurotropism is associated with a signifiant decrease in survival in patients with DM. Occasionally, there are some lesions with prominent perineural invasion and no evidence of an intraepidermal component. These lesions are designated neurotropic melanoma. This seen particularly in lesions on the head and neck area, and may cause severe, relentless pain. In the recent studies, the percentage of desmoplastic melanomas with neurotropism ranged from 16.7 to 77.8% [7, 79].
The clinical differential diagnosis is broad, because these lesions often do not have features that suggest melanoma. Some of the clinical diagnoses that may be rendered include, scar, basal cell carcinoma, squamous cell carcinoma, fibroma, recurrent nevus, and metastatic carcinoma. Deep tissue samples are necessary to establish the diagnosis. The use of immunochemistry (testing for S100 antigen) is suggested as a useful tool in establishing the diagnosis. This sub-type of melanoma usually lacks any valuable dermoscopic features [12, 76-78].
Local recurrence is common, in 22% to 70% of cases, largely because of the tendency of DM to exhibit neurotropism. Although deeply invasive, DM is associated with lower metastatic rates than other sub-types of melanoma when matched for depth of invasion. When they metastasize, these tumors, unlike most melanomas may by-pass regional lymph nodes and spread hematogenously [7, 64, 70].
Angiotropic melanoma is defined by cuffing of (close apposition to) the external surfaces of either blood microvessels or lymphatic channels by melanoma cells in a pericytic location without evidence of intravasation in at least two or more foci. Angiotropic metastasis is not synonymous with vascular invasion. The mechanism of angiotropism of melanoma is not clear. There may be a special affinity between the tumor cells and the vascular wall. Angiotropism is seen with greater frequency in melanomas also showing desmoplasia and neurotropism. Angiotropism has been suggested to be a prognostic factor strongly predicting risk for metastasis of melanoma [77, 80].
Nevoid melanoma describes a heterogeneous grup of rare lesions that they may resemble a
Histologically, the architectural pattern appears very similar to that of a compound or intradermal nevus with an overall symmetry, well-defined lateral margins, minimal or no intraepidermal pagetoid spread. Histological features mentioning melanoma include the absence of maturation of dermal tumor cells, slight cytological atypia with some mitoses in the dermal component [77, 78].
The differential diagnosis includes
Clinically, verrucous melanomas are usually small hyperkeratotic papules without areas of regression and mimic either a verruca, seborrheic keratosis, or a compound or congenital naevus. Some studies reported a greater frequency on the extremities of women, but this has not been confirmed. The back of men also frequently is involved. Histologically, the verrucous component is represented by marked epithelial hyperplasia. It has the same prognosis as conventional melanoma [68, 77, 82].
Small cell melanoma describes a heterogeneous group of melanomas arising in different settings whose common denominator is a population of small cells. A first type, developing particularly in adults, is comprised of small cells with roundish, hyperchromatic nuclei, slight cytoplasm, and numerous mitoses resembling
A recent report suggested that a small-cell morphology in melanomas is significantly associated with positive sentinel lymph node involvement. Melanomas manifesting this morphology are invariably in vertical growth phase and have an aggressive course [77, 78, 83].
Spitzoid melanoma is a rare sub-type of melanoma that resembles clinically and histologically a
Some spitzoid melanomas can evolve from a preexisting
The prognosis of spitzoid melanoma in adults is the same as that for other variants of melanoma of equal
Balloon cell malignant melanoma (BCMM) is the rarest histological type of primary cutaneous melanoma and is composed of large, polyhedral, foamy cells with abundant cytoplasmic vacuoles. Clinically, lesions appear as soft, rubbery, or firm nodules with a polypoid or papillomatous contour whose cut surfaces are grayish white or brown. The differential diagnosis includes balloon cell change in benign nevi including blue nevi and common acquired nevi, with which balloon cell melanoma may coexist, as well as other malignant clear cell neoplasms. The presence of cytological atypia, nuclear pleomorphism, and mitoses are important for its distinction from the more common balloon-cell nevus. The expression of the usual immunohistochemical markers such as S-100 protein and HMB-54 helps to distinguish this lesion from other clear cell tumors of the skin. The prognosis is similar to that of other types of melanoma matched for depth of invasion [70, 77, 78, 85].
Clear-cell sarcoma (CCS) is a perplexing tumor considered by some authors as a soft tissue sarcoma derived from the neural crest and by others as an unusual variant or subtype of melanoma. CCS shows a predilection for the deep soft tissues of the lower extremities close to the tendon, fascia, or aponeuroses. The tumor presents as a slowly growing deep-seated mass in close relation with tendons and aponeuroses associated with tenderness and pain. It generally appears in young adults between the ages of 20 and 40 years.
Histologically, the tumor has a multilobulated apperance made by nests and fascicles of uniform plump spindle cells seperated by fine to coarse fibrous septa. CCS is an aggressive neoplasm with a poor prognosis similar to that of sarcomas, with a high rate of local recurrences and metastases to lymph nodes and lungs. Both survival and distant metastases seem to correlate with the tumor size more than the histological parameters [12, 67, 77, 86].
Melanoma must be distinguished from a variety of several cutaneous and mucosal lesions. The differential diagnosis change according to the subtype of melanoma.
This is the most common type of melanoma. It is usually seen on sun-exposed areas, mostly on the lower extremities of women, and the upper back of men. Superficial spreading melanoma can present as an irregular macule with variation in color and texture. A papule or nodule may arise from the macule as the tumor progresses from radial to vertical growth. Superficial spreading melanoma can present de novo or within a preexisting nevus. Atypical nevus, melanocytic nevus, lentigo, seborrheic keratosis,
There are several features that can aid in distinguishing the common melanocytic nevus from melanoma. The “ABCD” rule, which has been expanded to the “ABCDE” rule, provides a helpful aid in the diagnosis of pigmented lesions:
A = Asymmetry
B = Border irregularity
C = Color variegation
D = Diameter greater than 6 mm/Difference
E = Elevation/Evolving
Atypical nevus may be misdiagnosed as melanoma because of focal or minimal pagetoid spread, confluence of cellular aggregates along the dermal-epidermal junction, prominent variation in nesting pattern, significant cytologic atypia, entrapment of nests of dermal nevus cells in the papillary dermis, and dense mononuclear cell infiltrates. On occasion, the distinction of atypical nevus from melanoma is exceedingly difficult. The discrimination of melanoma from atypical nevus is usually possible because of the larger size, greater asymmetry, disorder, cellularity, and cytologic atypia encountered in melanoma. Usually atypical nevus will maintain an overall symmetry, a nevic appearance as exemplified by fairly organized junctional nesting, a basilar proliferation of melanocytes that is still concentrated along the epidermal rete and with greater density toward the lower poles of the rete [89-91]. Melanoma may mimic seborrheic keratoses but also may arise within the seborrheic keratosis.
Nodular melanoma is the second common subtype of melanoma. It is mostly seen on trunk. This type grows rapidly and enlarge. Instead of arising from the nevus, nodular melanoma begins de novo. Pigmented nodules may be mistaken with blue nevus, pigmented
Metastatic melanoma is often fairly monomorphous with little stromal response while nodular melanoma are often polymorphous and exhibits greater stromal response.
The blue nevus is a dark blue or black, hairless, dome-shaped nodule, ranging in diameter from a few millimeters to several centimeters, but usually measuring about 5 mm. Its color results from the
The keratoacanthoma, in common with the spindle and epithelioid nevus of
When there is a doubt in clinically; dermoscopic images and histopathological examination must be done and the exact decision must be made by that.
Lentigo maligna (LM) has a long radial growth phase that may progress to invasive lentigo malign melanoma. Some authors consider LM as in situ melanoma. Both subtypes are seen in older population. The most common locations are cheeks, nose, neck and scalp. It is related to cumulative sun exposure. Most cases presenting as LM remain in situ lesions; these lesions commonly occur in cosmetically sensitive areas on the head and neck and can abut critical anatomic sites, such as the eyelids, ears, nose, and lips [7, 87, 88]. In dermoscopic examination; hyperpigmented follicular opening, annular-granular pattern, pigmented rhomboidal structures, obliterated hair follicles are seen. Classical dermoscopic features of extrafacial melanoma (atypical pigment network, irregularly distributed globules, dots, streaks and pseudopods) and vertical growth phase-associated dermoscopic criteria (ulceration, blue papular areas and black structureless areas) can also be seen. [99-101].
Lentigo malign melanoma is confused with solar lentigo, ephelids, pigmented actinic keratosis, solar melanocytic hyperplasia, flat seborrheic keratosis and superficial pigmented basal cell carcinoma. Solar lentigines and its amount in excess are predisposed to LMM [7, 99]. Ephelids appear early in childhood. They darken in the summer in response to UV irradiation and lighten in the winter. LM develops irregularities of color, margins, and surface characteristics and enlarges progressively, unlike a common ephelid. Benign lentigines are usually tan to brown, flat, and oval, measuring 5 to 10 mm in diameter. Lentigines, whether benign or lentigo maligna, do not fade when shielded from light. Histologically, they are characterized by an increased number of normal dendritic melanocytes along the dermo-epidermal junction. The solar lentigo appears on sun-exposed surfaces during middle to late life, in common with lentigo maligna, and may closely resemble lentigo maligna [87, 94, 102].
The frequency of this subtype in various ethnic groups is different from each other. ALM represents the most common type in darker-pigmented individuals (in blacks 60-72 %, in Asians 29-46 %). ALM is diagnosed in fifth or sixth decades. The most common sites for ALM are the soles, palms and subungual locations. Subungual melanoma may be first evident as a split nail, a swelling of part of the nail bed, an ulceration with a bloody crust, or a longitudinal black or brown streak in the nail bed. The great toe and thumb are most often affected. ALM may be confused with plantar wart, hematoma, palmoplantar nevus and pyogenic granuloma. Subungual melanoma must be differentiated from glomus tumor, hemorrhage, infection, onychomycosis,
Acral lentiginous melanoma, the most common clinicohistologic type of acral melanoma, shares some histologic features with LMM but differs from LMM in its younger age at onset, its anatomic site, the absence of chronic sun exposure, and the greater depth of penetration at diagnosis [71].
The differential diagnosis for acral melanoma primarily includes lentigines and lentiginous melanocytic nevi of acral skin. Lentigines of acral skin usually do not exhibit the frequency of melanocytic proliferation or cytologic atypia that is typical of acral melanoma [7, 97].
Mucosal melanomas can arise on the head, neck, vulva, anorectal region and even urethra. With the exception of conjunctiva, patients present with delayed diagnosis. Because of a radial growth phase manifesting as a macular pigmentation any suspicious area in these locations must be biopsied. It can be mistaken with melanotic macules, amalgam tattoo, venous lake,
Melanoma of the vulva is really mistaken with vulvar melanosis. Lesions of vulvar melanosis manifest irregular pigmentation with skip areas up to several centimeters in size, but the borders are regular and sharp. Histologically, vulvar melanosis manifests prominent basal layer keratinocytic pigmentation with either a normal or slightly increased density of cytologically basal melanocytes having prominent elongated dendrites. Pigmented
This subtype is rare and locally aggressive. Commonly it arise in the sixth or seventh decades. The sun-exposed head and neck regions are most effected parts. The lesions have typically have a firm, sclerotic, or indurated. One half of these melanomas are amelanotic. Desmoplastic melanoma is usually diagnosed at an advanced stage, because of the difficulty of its diagnosis.
Sclerosing blue nevus, desmoplastic
Nevoid melanoma describes a heterogeneous group of rare lesions that histologically resembles benign nevus by their symmetry and apparent maturation with descent in the dermis. Histopathologic features include marked hyperchromasia of the nuclei of tumor cells, the presence of mitoses, and an expansile growth of the dermal cells with effacement of the adventitia in affected area. It may be seen as a papule or nodule that is more than 1 cm in diameter. Minimal deviation melanoma, nodular melanoma, and melanoma arising in dermal nevus must be considered in the differential diagnosis [51, 87].
Dermoscopy, dermatoscopy, epiluminescence microscopy, diascopy, surface microscopy and incident light microscopy are all synonym. Dermoscopy is a noninvasive technique in which a handheld device is used to examine a lesion through a film of liquid, mainly immersion oil, using nonpolarized light, or the lesion is examined under polarized light without a contact medium. Digital dermoscopy permits computerized digital dermoscopic images to be retrieved and examined at a later date so that comparisons could be made and changes detected over time. Confocal scanning laser microscopy and multispectral digital dermatoscopy are new imaging instruments used for early detection of cutaneous melanomas. Dermoscopy improves sensitivity up to 30% and specificity of melanoma diagnosis compared with clinical diagnosis. Morphologic features which are invisible to the naked eye, could be seen with the help of this technique.
Various diagnostic dermoscopic algorithms such as the ABCD rule, the seven-point checklist, pattern analysis,
Melanomas are multicolored in brown colors and other colors such as black, blue, and pink.
Usually a multicomponent pattern of three or more distinctive features can be seen. Atypical pigment network (Figure 6), irregular dots and globules, irregular streaks (pseudopods, radial streaming), irregular blotches, blue-white veil, abrupt cut-off of the trabeculae (Figure 7), regression structures (peppering), and atypical vascular architecture are common in invasive melanomas.
Irregular pigment network is seen (By the courtesy of Prof. Dr. Oya Oğuz).
Notice the abrupt cut-off of the trabeculae (By the courtesy of Prof. Dr. Oya Oğuz).
Highly specific surface microscopic features of cutaneous malignant melanoma metastases are as follows: saccular pattern (red-blue, red-light brown, reddish-brownish-gray, blue-gray, dark brown to black); gray streaks surrounding the lesion (melanoma cell infarcts); red-brown globules irregular in size and color; polymorphic angiectatic base pattern and/or aneurysms; areas of polymorphic ectatic vessels running parallel to the skin surface; peripheral erythema (red corona); microscopic ovoid blood lakes; and homogeneous pattern (brown or blue to black) [12, 51, 87].
Essentially all melanomas begin as a proliferation of melanocytes initially confined to the epidermis. Increasing cytologic atypia of melanocytes accompanies the aberrant architectural appearance of melanomas. After the period of intraepidermal proliferation, there is often invasion of the papillary dermis, primarily as single cells and small aggregates of cells.
Lentigomaligna (known as
Lentigo maligna: in this in situ lesion, tumor cells are hyperchromatic and distributed in a lentiginous pattern (By the courtesy of Dr. Ahmet Cemil Kaur).
Superficial spreading melanoma is also known as pagetoid melanoma which characterized by a proliferation of atypical melanocytes singly and in nests in all layers of the epidermis [114]. Atypical melanocytes sometimes show “buckshot scatter” within the epidermis (Figure 9) [113]. The large tumor cells contain dark, atypical nuclei and abundant, pale cytoplasm [118]. The epidermis may have normal or hyperplastic appearance [119]. There is a continuous spread of tumor growth from one rete ridge to another [114]. If the tumor progresses to vertical growth phase, microinvasive tumor which contains nested and dispersed cells is seen within the dermis [109].
Superficial spreading melanoma: atypical melanocytes are scattered throughout the epidermis. Tumor cells compose cell groups at basal layer, The melanocytes have abundant eosinophilic cytoplasm and pleomorphic vesicular nuclei. Nucleoli are prominent (By the courtesy of Dr. Ahmet Cemil Kaur).
Nodular melanoma has no concomitant or preexisting radial growth phase [109]. It grows vertically from the beginning and thus may invade the epidermis [113, 114]. Cellular features include a large nucleoli and frequent mitosis [118]. Epidermal melanocytic proliferation is so minimal which typically extending less than three epidermal ridges on both sides of tumor [120]. The tumor mass contains small nests and aggregates of atypical melanocytes (Figure 10, 11, 12) [117].
Histological changes are not fully clear in the early stages which may be seen irregular epidermal hyperplasia and dispersed, localized to the basal layer, atypical melanocytes [114]. Atypical cells proliferate as diffuse along to dermoepidermal junction in the radial growth phase. These cells create a lentiginous pattern by scattered severally [121]. Atypical melanocytes have marked nuclear atypia and also seen around the adnexal structures [109]. In contrast to acral nevi, pigment is seen throughout the stratum corneum [105]. Other changes in the epidermis include acanthosis and elongation of the rete ridges.Tumor infiltration of lymphocytes and tumor regression are common findings in ALM. Kim et al. observed that the frequencies of these findings are 75% and 25% of ALM cases, respectively [122]. The dermal invasive component is predominantly spindle cell type, but epitheloid or nevoid cells may be seen. The presence of small nevus cells may indicate a worse prognosis. Additionally lack of elastosis in dermis is prominent [105, 113, 123].
Nodular melanoma: characteristic melanoma morphology, the tumor is composed of cell groups (By the courtesy of Dr. Ahmet Cemil Kaur).
Nodular melanoma: close view, the tumor cells are pleomorphic with abundant cytoplasm, large vesicular nuclei and prominent nucleoli (By the courtesy of Dr. Ahmet Cemil Kaur).
Nodular melanoma: in this example there is heavy melanin pigmentation (By the courtesy of Dr. Ahmet Cemil Kaur).
Desmoplastic melanoma is characterized by intensive atypical spindle-shape melanocytes within dense collagen bundles [124]. Tumor cells have hyperchromatic, elongated nuclei but usually no contain pigment in their cytoplasm [125, 126]. There are often nodular lymphocytic aggregates that are helpful in diagnosis [114, 127]. Perineural invasion has been reported in some studies. In a study by Lens et al., the percentage of desmoplastic melanoma with nuerotropism ranged from 16.7% to 77.8% [76].
Minimal deviation melanoma is a variant of invasive melanoma that characterized by a nodule with minimal histologic deviation compared to ordinary nevus. It may be confined into the papillary dermis or may invade into the reticular dermis or beyond. This melanoma variant is divided into 6 subtypes according to cytological features (Spitz, halo-nevus like, pigmented spindle cell, desmoplastic, small cell and dermal variant). The average thickness is 3, 40 mm. The infiltration into the subcutaneous fat tissue is not often seen. Necrosis is absent while perineural invasion, mitoses and inflammation with desmoplasia can be seen. Mitotic activity is usually quite low [78, 114, 130, 131].
This rare variant is characterized by a deep-seated follicular structure in which atypical melanocytic cells extend downward along the follicular epithelium and mainly involves follicular unit as well as adjacent dermal layer [113, 132, 133].
Primary tumor thickness is the most powerful predictor of melanoma survival. The
Melanomas confined to the | \n\t\t|
Penetration by melanomas into the papillary dermis | \n\t\t|
Tumor cells fill and expand the papillary dermis | \n\t\t|
Spreading into the reticular dermis | \n\t\t|
Penetration into the subcutaneous fat | \n\t\t
If Clark’s level increases, the mean life span is decreased [119, 134-137].
Ulceration is defined as disappearance of the all layers of epidermis (including basement membrane), evidence of host response, and thinning, effacement or reactive hyperplasia of adjacent epidermis. The presence of ulceration shows that the lesion has aggressive feature. Ulceration due to trauma should be excluded. The presence of ulceration is associated with a higher risk of metastases. According to the presence or absence of ulceration, each T category is divided into two as “a” and “b” in the AJCC cutaneous melanoma classification 2009 (Table 2). This system classifies melanomas on the basis of their local, regional, and distant characteristics, as follows: [39, 51, 135, 138]
Stage I and II - Localized primary melanoma
Stage III - Metastasis to single regional lymph node basin (with or without in-transit metastases)
Stage IV – Distant metastatic disease.
The mitotic rate is important prognostic indicator that is determined by the number of mitotic figures/1 mm2 of tumor in the most mitotically active area. The increased mitotic activity is associated with poor prognosis [51, 114].
Microsatellites are defined as discrete tumor aggregates separated from the main body of the tumor mass. These deposites settled to 0,05 mm or more away from the main tumor mass are associated with an increased risk of local recurrence, regional lymph node metastases and diminished survival [114, 134].
\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
0 | \n\t\t\tTis | \n\t\t\tN0 | \n\t\t\tM0 | \n\t\t\tIn situ melanoma (ıntraepithelial) | \n\t\t
IA | \n\t\t\tT1a | \n\t\t\tN0 | \n\t\t\tM0 | \n\t\t\t≤1 mm without ulceration | \n\t\t
IB | \n\t\t\tT1b | \n\t\t\tN0 | \n\t\t\tM0 | \n\t\t\t≤1 mm with ulceration | \n\t\t
T2a | \n\t\t\tN0 | \n\t\t\tM0 | \n\t\t\t1.01-2 mm without ulceration | \n\t\t|
IIA | \n\t\t\tT2b | \n\t\t\tN0 | \n\t\t\tM0 | \n\t\t\t1.01-2 mm with ulceration | \n\t\t
T3a | \n\t\t\tN0 | \n\t\t\tM0 | \n\t\t\t2.01-4 mm without ulceration | \n\t\t|
IIB | \n\t\t\tT3b | \n\t\t\tN0 | \n\t\t\tM0 | \n\t\t\t2.01-4 mm with ulceration | \n\t\t
T4a | \n\t\t\tN0 | \n\t\t\tM0 | \n\t\t\t4 mm without ulceration | \n\t\t|
IIC | \n\t\t\tT4b | \n\t\t\tN0 | \n\t\t\tM0 | \n\t\t\t"/>4 mm with ulceration | \n
IIIA | \n\tT1-4a | \n\tN1a | \n\tM0 | \n\tSingle regional nodal micrometastasis, without ulceration | \n
T1-4a | \n\tN2a | \n\tM0 | \n\t2-3 microscopic positive regional nodes, without ulceration | \n|
IIIB | \n\tT1-4b | \n\tN1a | \n\tM0 | \n\tSingle regional nodal micrometastasis, with ulceration | \n
T1-4b | \n\tN2a | \n\tM0 | \n\t2-3 microscopic positive regional nodes, with ulceration | \n|
T1-4a | \n\tN1b | \n\tM0 | \n\tSingle regional nodal macrometastasis, without ulceration | \n|
T1-4a | \n\tN2b | \n\tM0 | \n\t2-3 macroscopic regional nodes, without ulceration | \n|
T1-4a/b | \n\tN2c | \n\tM0 | \n\tIn-transit met(s)/ satellite lesion(s) without metastatic lymph nodes | \n|
IIIC | \n\tT1-4b | \n\tN1b | \n\tM0 | \n\tSingle regional nodal macrometastasis, with ulceration | \n
T1-4b | \n\tN2b | \n\tM0 | \n\t2-3 macroscopic regional nodes, with ulceration | \n|
Any T | \n\tN3 | \n\tM0 | \n\t4 or more metastatic nodes, matted nodes, or in-transit met(s)/satellite lesion(s) with metastatic nodes | \n|
IV | \n\tAny T | \n\tAny N | \n\tAny M1 | \n\tM1a: Distant skin, subcutaneous, or nodal mets with normal LDH levels M1b: Lung metastases with normal LDH M1c: All other visceral metastases with normal LDH or any distant metastasis with elevated LDH | \n
Cutaneous Melanoma Staging
T=tumor size; N=node status; M=metastasis; Ta=without ulceration; Tb=with ulceration;
Tumor-infiltrating lymphocytes are an important indicator of host immune response against melanoma. This response is divided into 3 categories and should be reported as brisk, non-brisk and absent. Although the presence of host inflammatory response is generally associated with a better prognosis in melanoma, there are also studies reporting that no significant correlation between lymphocytic infiltration and prognosis [119].
There is no survival difference among three histological subtypes (superficial spreading, nodular and acral lentiginous) when these are corrected for thickness. But lentigo malign melanoma, particularly in woman, has been reported to have a better prognosis, independent of thickness [51].
Regression is caused by the interaction between melanoma cells and host immune system. Tumor tissue replaced with degenerative melanoma cells, melanophages, lymphocytic proliferation, haphazard fibrosis and telangiectasias. Complete regression is characterized by total absence of malignant melanoma cells in both dermis and epidermis. The correlation between regression and prognosis is still controversial [119, 134].
Tumor cells may invade the vessel lumen. It correlates with the development of in-transit metastases, when the presence of blood vessel and lymphatic invasion should be reported. Vascular invasion is associated with poor prognosis and decreased survival in thick cutaneous malignant melanomas [109, 119]. Angiogenesis is a distinct histological prognostic indicator that is defined as the increasing development of new blood vessels at the base of the tumor mass. Increasing angiogenesis is associated with thick tumors, surface ulceration, relapse and tumor related death [114].
Immunohistochemical staining is often used for differentiate melanomas from tumors that they mimic in conventionally stained sections [139].
S-100 is a commonly used sensitive marker for melanoma. But its positivity appears some tumors such as nerve sheath and granular cell tumors and myoepitheliomas. Although its sensitivity is 97-100%, its specificity for melanocytic lesions is limited. The specificity of S-100 is ranged from 75% to 87%. S-100 A6 is one of the subtypes of S-100 protein, expressed in both benign and malignant melanocytic lesions. S-100 A6 has been reported that it is expressed in approximately 62-100% of metastatic and primary melanomas [140, 141].
HMB-45 is an antibody formed against the cytoplasmic premelanosomal glycoprotein gp100 while its sensitivity is lower than S-100, its specificity is greater. HMB-45 expression is maximal (77-100%) in primary melanomas. This rate is lower (58-83%) in patients with metastatic lesions [139].
Melan-A, also known as melanoma antigen recognized by T cells-1 (MART-1), is an important melanocytic marker. Sensitivity and specificity of Melan-A are similar to HMB-45 that ranged from 75-92% and 95-100%, respectively. It is less positive in lesions with metastatic melanomas than primary melanoma [139].
MIB-1, also known as Ki-67, is a proliferation marker that is expressed by proliferating cells. It provides guidance about presence or absence of “maturation”. MIB-1 has an important role in distinguishing between melanocytic nevi and melanoma. While less than 5% of nuclei is positive in melanocytic nevi, this ratio is greater (25% or more) in melanoma [114, 141].
Tyrosinase is an enzyme that plays a role in hydroxylation of tyrosine in the synthesis of melanin. Its sensitivity for melanoma is slightly better than HMB-45 at 84-94%. The sensitivity is reduced in advanced diseases and metastatic lesions (79-93%). The specificity is very high for melanoma (97-100%) [139].
Microphthalmic transcription factor (MITF) is expressed in most benign melanocytic nevi and melanomas. Nuclear staining occurs with MITF unlike cytoplasmic markers. MITF expression has been reported in 81-100% of melanomas [51, 113].
There are also numerous immunohistochemical markers such as epithelial markers (keratin, EMA, CEA), histiocytic markers (eg. CD68, Mac 378, alpha-1 antitrypsin), Bcl-2, Cyclin D1, p16, CD40, CD44, melanoma cell adhesion molecule (Mel-CAM) [114].
Any lesion that is clinically suspicious for melanoma should ideally undergo an complete elliptical excisional biopsy with narrow margins (such as 2 mm) [12]. Wide excisions should be avoided for obtaining an accurate result of the subsequent sentinel lymph node biopsy, if necessary. Examination of the entire pigmented lesion allows for the greatest chance of accurate diagnosis and also for the measurement of
Although cutaneous melanoma is rare in children and young adults, the incidence is rising annually in this population. Staging work up is almost similar, in children and adults [143].
First step should always be history taking and physical examination. A careful lymph node examination of the whole body should be made, particulary the regions close to the site of the primary lesion. Also because of the aberrant lymphatic drainage pathways to unexpected nodal basins and to interval nodes between the primary site and expected regional nodal basin, a search for clinically detectable nodal disease in unexpected locations is crucial. If there is a palpable lymph node during physical examination, first a fine needle aspiration biopsy should be performed to make a histological confirmation. If the result of the fine needle aspiration is inconclusive, an excisional biospy can be made. For the detection small nodal metastases, best noninvasive methods seem to be ultrasound imaging and positron emission tomography, with sensitivity and specificity being lower than tissue diagnosis [144].
Sentinel lymph node biopsy (SLNB) as elective lymph node dissection (ELND) does not offer a survival advantage to melanoma patients, a new approach, SLNB has become the choice of biopsy type.
For the evaluation of distant metastases, a thorough examination of the neurologic, psychiatric, musculoskeletal, skin, lymphatic, endocrine, cardiovascular, and respiratory systems is necessary. Patients with newly diagnosed melanoma require a complete cutaneous and physical examination with particular attention to lymphadenopathy and hepatomegaly, and a baseline chest radiograph. If the latter examinations fail to detect any evidence of metastatic disease and the patient has no other symptoms or signs, no further laboratory evaluation is indicated. Current imaging technics like computed tomography, magnetic resonance imaging, PET, chest X-ray and laboratory tests like LDH are not routinely indicated as their sensitivity ans specificity are low. According to current guidelines, no additional work up is necessary in stage 0 and 1A, optional chest X-ray may be performed in stage 1B and 2, optional chest X-ray and LDH for stage 3 and chest X-ray and/or chest CT and LDH for stage 4 can be done [146].
The Standard treatment for primary cutaneous melanoma is wide local excision. The aim of wide excision is to reach histopathologically confirmed tumor-free margins, as well as preventing local recurrence. Recommended clinical margins around the residual lesion or biopsy scar for melanoma in situ, non lentigo maligna pattern, is 0.5 to 1 cm; for melanoma <1 mm
Lentigo maligna and lentigo maligna melanoma have high potential for sub-clinical peripheral extension, as their clinical margins are usually poorly defined and obscured by background photo-damage. For lentigo maligna melanoma, the probability of a macular invasive desmoplastic component is increased. Thus, standard surgical safety margins recommended, are often insufficient for these two subtypes [12, 51].
One of the main causes of melanoma-related morbidity with an important negative effect on quality of life is the poor control of the nodal disease. Therefore, current standard of therapy for microscopic or macroscopic melanoma in lymph nodes is complete dissection of the node in the involved regional basin. According to the current guidelines, adequate lymphadenectomy is described as at least 10 nodes in the groin region, 15 lymph nodes in the axillary region and 15 lymph nodes in the neck area. There are also some complications, leading to significant morbidity, of the lymph node dissection, like wound infection, delayed wound healing, seroma, lymphedema and nerve damage. In the case of regional metastatic melanoma, complete lymph node dissection is associated with long-term survival rates [87].
For micrometastatic disease, elective lymph node dissection was the procedure of choice, historically. It is the dissection of regional lypmh nodes draining the site of a primary cutaneous melanoma, with no clinically palpable lymph nodes or overt metastatic disease. With today’s knowledge, according to multiple prospective randomized-controlled trials, survival rates of the patients undergoing elective lymph node dissection were found to be no higher than other patients. Thus there is no role for elective lypmh node dissection today, especially considering its significant morbidity and the availability of sentinel lypmh node biopsy [144]. For the identification of micrometastatic nodal disease, sentinel node biopsy is the tool of choice. The only handicap of sentinel node biopsy is that, it can not be classified as therapeutic yet. If the result of the sentinel lymph node biopsy returns as positive, always a complete lymph node dissection should be performed. According to current trials of investigations, immediate complete lymph node dissection has a higher survival rate than delayed dissection.
Adjuvant therapy is usually given after surgical resection of the primary lesion. It is preferred in patients with increased relapse risk. When thickness of the primary lesion is higher than 4 mm or when there is nodal involvement, adjuvant therapy is necessary. Up to now, interferon-α2b (IFN- α2b) is the only form of adjuvant therapy, which is approved by U.S. Food and Drug Administration. It has been shown that interferon-α2b improves disease-free survival for stage 2B and 3 melanoma, and it also improves overall survival. Interferon-α2b is used in high doses. There are two phases of treatment with interferon, first phase is induction phase. During induction, 20 million units per square meter of body surface area per day, are given intravenously, 5 days a week, for 4 weeks. After this high dose period, during the maintenance period, 10 million units per square meter per day, given subcutaneously three times a week for 48 weeks. During or after interferon treatment, autoantibodies like antithyroid, anti-nuclear, anti-DNA, anticardiolipin autoantibodies may appear in blood tests of the patients and some autoimmune diseases may develop. Both autoantibody positivity and development of autoimmune diseases are associated with increased survival in those patients. High dose interferon treatment may cause flu-like symptoms, fatigue, malaise, fever, nausea and headache, depression, elevated levels of transaminases and myelosupression [147].
Melanoma vaccines: Vaccines stimulate specific immune response against melanoma-associated antigens. They can be of autologous, allogenic or peptide type and also immunologic adjuvants like bacille Calmette-Guérin or DETOX are added. Target of the vacines can be autologous tumor cells, allogenic melanoma cells, or more specifically heat shock proteins and T cell defined antigens glycoprotein 100, tyrosinase, MART-1. Up to now, none of the trials showed increased survival for the patients using these vaccines but more research on this area should be done.
For localized disease, limited to one extremity only, first choice of treatment should ideally be surgical excision with clear margins if possible. But in case of multiple lesions, chance of performing an ideal excision may be low, so in that case, isolated limb perfusion can be considered. It is a simple and less invasive, yet more effective treatment. Main idea about isolated limb perfusion is giving high doses of chemotherapeutic agents locally, to avoid systemic toxicity, and obtain more therapeutic effect. The technique of this method involves perfusing an isolated arm or leg, in a hyperthermic environment, with cytotoxic agents. Conventinally chemotherapeutic agent used in this procedure is melphalan. Approximately in half of the patients, complete disappearance of the lesion is observed. Although systemic side effects of this method is fairly less, when compared to conventinal chemotherapy, local side effects can be serious. Significant tissue damage due to high concentrations of cytotoxic agent can be seen. Compartment syndrome is one of the most severe morbidities. Advanced age and patients with serious co-morbidities are usually not preferred for this type of treatment. A new approach is isolated limb infusion, which is a less invasive method, for appliance on patients with older age or worse general health conditions. Isolated limb infusion can be done with melphalan and actinomycin D [51, 67].
In case of stage 4 melanoma, with distant metastasis, mean survival is 6 to 8 months and there is currently no effective systemic treatment, to increase survival rate. For this reason, main treatment goal is the palliation of symptoms. For the patients with increased age and serious comorbidities, observation and conservative treatment may also be the option of choice [146]. If there are symptomatic visceral metastasis, surgical excision to perform metastasectomy can be tried. Also excision of skin metastasis or lymph node metastasis may improve the locoregional control of the disease and may help to decrease morbidity.
In one case report [148], a 44-year-old
Although melanoma is known to be radiotherapy resistant, for brain metastasis, spinal cord compression and painful bone metastasis, local radiation can be used.
Radiation therapy plays a role in the management of primary cutaneous melanoma in definitive, adjuvant, and palliative settings. The role for radiation therapy in early stage primary melanom is limited as the treatment is adequate excision. However desmoplastic melanoma and those with neurotropism invasion are exceptions, due to frequent local recurrence [149]. The greatest controversy regarding radiotherapy lies with its use in stage III disease, particularly as postoperative treatment after lymph node dissection. A recently completed randomized trial confirmed the benefit of adjuvant radiotherapy in improvement in nodal field control after nodal dissection for patients who are at moderate to high risk for regional relapse [150].
For primary melanoma, adequate surgery is usually the best option for local control and cure. Factors often considered indicative of the need for adjuvant radiation therapy include primary site in the head and neck region, close or positive margins not amenable to further excision, lymphatic space invasion, multiple recurrences, and desmoplastic neurotropic growth [149]. Apart from its use in an adjuvant setting, radiation therapy has been used as the definitive treatment of primary melanomas, locally advanced acral lentiginous melanoma, and as a substitute for wide excision after limited excision.
Radiation therapy has a well-established role in patients with metastatic melanoma. Symptoms of pressure, mass effect, and bleeding from metastases in a variety of locations may benefit from palliative radiation. The development of stereotactic techniques has improved the efficacy of radiation for brain metastases. Expansion of this methodology to stereotactic body radiation metastases has the potential to improve further palliation of unresectable metastases.
For systemic chemotherapy, first line chemotherapeutic agent is dacarbazine, an alkylating agent. It is an U.S. Food and Drug Administration (FDA) approved chemotherapy drug for metastatic melanoma. It is thought to be the most effective single agent therapy. Approximately 10 to 20% of the patients response to treatment and the mean duration of response is 4 to 6 months. Dose of the treatment does not affect the response rate. Major side effects of dacarbazine are nausea and vomiting. Temozolomide is also an alkylating agent. This chemotherapeutic agent can also be used orally. Another advantage is that, temozolomide can cross the blood-brain barrier. Thus for patients with central nervous system involvement, temozolomide can be preferred. According to a randomized phase 3 study, its efficacy is equal to dacarbazine. For metastatic melanoma to brain, a combination of temozolomide and thalidomide, along with radiation, can be benefical. For dacarbazine, increased response rates are reported, when combined with other cytotoxic agents like cisplatin, vinblastine, carmustine or tamoxifen [144].
Among immunotherapeutic agents, interleukin 2 (IL-2) is the only agent, which has an approval form FDA. Overall response rate of this agent is 16%, but a durable response rate is 5 to 8%. Approximately the time for the duration of response is 9 months. Of the 28% of the patients with metastatic melanoma who responded to IL-2 treatment, no progression was observed at a follow-up period of 62 months. Also patients who responded longer than 30 months, did not show any sign of relapse afterwards. On the other hand, there are some important side effects of IL-2 treatment. Most common side effect of IL-2 is hypotension. It can also cause capillary leak syndrome, supraventricular tachycardia, transient renal insufficiency, respiratory distress, increased susceptibility to infections. There are also newer investigations about combining IL-2 with tumor-infiltrating lymphocytes and lymphokine activated killer cells. These immunologically active cells are considered to be helpful in transferring and adoptive immune force, to generate an antitumor effect.
In a case study [151], patient with cutaneous metastasis with significant comorbidities, including advanced age, anticoagulation for a metallic valve, chronic anemia, macular degeneration, and history of hematopoietic malignancy (high-grade lymphoma,
In another case [152], 82-year-old man who presented with rapidly progressing cutaneous melanoma metastases, together with inguinal lymph nodes and bilateral pulmonary involvement, treated with topical immunotherapy with diphencyclopropenone (DPCP) in aqueous cream weekly to elicit moderate contact hypersensitivity. Larger lesions were also treated with intralesional 5-fluorouracil (50 mg/mL). One month later, cutaneous metastases began to regress, and during the following 4 months his inguinal lymphadenopathy and pulmonary lesions disappeared. He remains clinically disease free 18 months after his metastases began to regress. This can show the potential for some patients to overcome even widespread and extensive disease, presumably via immune-mediated regression, and raises the possibility that topical immunotherapy may play a role even in patients with bulky disease.
Biochemotherapy alone has not shown any increase in overall survival rate, but when compared to other systemic chemotherapeutic agents like dacarbazine, or interferon, vaccines, IL-2, it can show better results.
About the etiopathology of intrinsic resistance of malignant melanoma to chemotherapy, the anti-apoptotic protein B-cell lymphoma 2 (Bcl-2) is found to play an important role. A new antisense Bcl-2 oligonucleotide, Oblimersen, is targeting Bcl-2 messenger RNA selectively and this leads to the degradation of the Bcl-1, thus decreasing the levels of Bcl-2 in the body. Oblimersen can also be used in combination with conventional systemic chemotherapeutic agents, like dacarbazine.
Also in two-thirds of melanomas, there is a mutation in B-raf gene. A RAF inhibitor, Sorafenib, inhibits both B-raf and C-raf, and also used orally. Since the evaluation of sorafenib, a new generation of BRAF inhibitors has been developed. These drugs show higher potency against mutated BRAF and have fewer off-target effects; the list of those currently under preclinical investigation includes SB590885, dabrafenib (GSK2118436), AZ628, XL281, GDC-0879, and vemurafenib (RG704, PLX4032/4720) [153]. PLX4032 (and its analogue PLX4720) are adenosine triphosphate (ATP)-competitive RAF inhibitors (wild-type BRAF 50% inhibitory concentration [IC50]-100 nmol/L, mutated BRAF IC50-31 nmol/L) that selectively inhibit growth in melanoma cell lines harboring the BRAF V600E mutation in both in vitro and in vivo mouse xenograft models [154].
Much of the foundation for the development of these treatments is the realisation that melanoma growth and progression is driven by somatic activating mutations in signalling molecules such as BRAF, KIT, NRAS and GNAQ/GNA11 [147]. Active drugs targeting BRAF and KIT are available and and the anti-CTLA4 antibody ipilimumab has shown an overall survival benefit and the possibility of prolonged disease control in the metastatic setting.
Although there are many phase III trials in progress, about treatment of metastatic melanoma, up to now, no curative adjuvant or systemic therapies have been approved for stage 4 metastatic melanoma. Among these treatments some may have serious side effects. According to one study [7], patients with metastatic melanoma are treated with the selective BRAF inhibitor, dabrafenib. Keratinocyte proliferation is characteristic of BRAF inhibitor induced cutaneous toxicities, and the spectrum of lesions ranges from benign seborrhoreic keratoses,
In the future of metastatic melanoma treatment, molecular profiling of patient tumors will play an important role in the part of therapy selection for medical oncologists. Recent preclinical studies shows that inhibitors of BRAF paradoxically activate MAPK signaling in tumors that lack activating BRAF mutations [153]. Reports from six independent groups have shown that BRAF inhibition activates MAPK in cell lines with NRAS and KRAS mutations, as well as those cell lines where the MAPK pathway is activated through other oncogenes such as HER2. Studies showed that although vemurafenib and other BRAF inhibitors were able to profoundly inhibit the activity of BRAF V600E-containing complexes in melanoma cells, they instead promoted the activity of CRAF-CRAF dimers in cells with RAS mutations, leading in turn to MEK activation. There is also evidence that PLX4032 increases the invasive potential of NRAS-mutated melanoma cells through the activation of ERK and FAK signaling. Additional studies demonstrated that BRAF inhibitors may even contribute to the progression of NRAS-mutated melanomas in part by suppressing apoptosis through the modulation of Mcl-1 expression.
According to one study [155], data of 97 patients with melanoma show substantial clinical activity of trametinib, MEK inhibitor. Differences in response rates during this treatment, according to mutations indicate the importance of mutational analyses.
These studies are extremely important for approaching the development of new cancer therapies as they indicate that simple empiric evaluation of novel cancer therapeutics in patients could be associated with adverse outcomes. Instead they affirm the approach of rationally developing therapies in cancer patients based on strong preclinical data and individual patient molecular profiling.
Melanoma is considered as a rather “immunogenic” tumor. One can understand it by the spontaneous immune-mediated regression of primary tumors, association between infiltrating T lymphocytes and improved survival, response to nonspecific immunotherapy agents, including interferon-alpha, IL-2, and ipilimumab and identification of tumor-associated melanoma antigens and human leukocyte antigen (HLA)-restricted epitopes within these anti- gens [156].
A variety of strategies, including peptide and protein vaccines, recombinant DNA and viral vectors, and the use of autologous and allogeneic whole cell vaccines, have been tested in patients. Although many studies have not had significant clinical benefit, there are some important data that have emerged from these clinical trials. There also have been at least two randomized phase III vaccine trials that have shown a clinical benefit in melanoma [157].
There has been considerable interest in the identification of patient-specific and tumor-specific biomarkers that may predict therapeutic response and clinical outcomes. These studies would help select patients more likely to respond to a particular vaccine approach and might identify new strategies for improving the potency of individual vaccines so that more patients might benefit from immunotherapy.
Malignant melanoma is the most fatal type of the skin cancers. The best survival rates of melanoma arise if it is detected at the early stages, this is generally when the size of the tumours is small and treatable. After detection the prognosis of the melanoma can be determined by assessing a number of histopathological (morphological) factors such as the thickness of lesions, levels of invasion, presence of ulceration and the number of metastatic lymph nodes involved. Clinical prognostic factors such as age, sex, anatomical location of the tumour can also be used to determine the possible progression of the cancer and the likely survival rates of the patient. The thickness of the tumor is the dominant prognostic factor in determining risk of metastasis and prognosis for cutaneous melanoma [158, 159]. The American Joint Committee on Cancer (AJCC) tumor node metastasis committee has approved a new melanoma staging system, which was implemented in 2009 [160]. The prognostic factors included in AJCC staging system are tumor thickness, ulceration, level of invasion (
In the AJCC staging system, tumor thickness is the most powerful independent prognostic factor for patients with cutaneous melanoma. Melanoma thickness is measured from the granular layer of the epidermis to the greatest depth of tumor invasion, this was originally described by
\n\t\t\t | \n\t\t\n\t\t\t | \n\t
≤1 mm (T1) | \n\t\t95% to 100% | \n\t
1.01 to 2 mm (T2) | \n\t\t80% to 96% | \n\t
2.01 to 4 mm (T3) | \n\t\t60% to 75% | \n\t
>4 mm (T4) | \n37% to 50% | \n
The relation of
The depth of the tumor is most accurately measured by evaluating the entire tumor via an excisional biopsy. Determination from specimens obtained using other biopsy techniques, such as a wedge or punch biopsy, is less accurate. Tumor depth cannot be calculated from a shave biopsy that only contains a portion of the tumor because it leads to an underestimation of its thickness. Excisional biopsy should extend down to the subcutaneous fat tissue [163].
The
Ulceration is the second most powerful factor for poor prognosis. The presence of ulcerations on the surface of the tumour causes a reduction in the survival rate. Ulcerations appear when an intact epidermis is not present around the tumour and is usually a result of an aggressive tumour. The presence of ulceration in tumours less than 1mm, causes a reduction in survival rate by 4% compared to non-ulcerated tumour. Survival rates can be reduced by up to 22% if the tumour thickness is greater than 4mm.This therefore, indicates that tumour thickness and ulceration have strong relationship with survival rates and so the prognosis of thin non-ulcerated melanoma is excellent [51].
Current studies have shown that tumor mitotic rate is a powerful independent prognostic factor. But the prognostic importance of mitotic rate in melanoma recurrences is not known. A high mitotic rate also correlates with a greater likelihood of having a positive sentinel lymph node biopsy. The mitotic rate is measured by simply examining the excised tumor with a microscope and manually counting the number of cells exhibiting mitosis, an easily identifiable characteristic of dividing cells. Most often, the mitotic rate is reported as one of three categories :
less than 1 per square millimeter
1 to 4 per square millimeter
greater than 4 per square millimeter
The higher the mitotic count, the more likely the tumor is to have metastasized. The logic is that the more cells are dividing, the more likely they will invade the blood or lymphatic systems and thus spread around the body. Research has shown that the odds of survival for patients with stage I melanoma and a mitotic rate of 0 per square millimeter is twelve times better than that of patients with a mitotic rate of greater than 6 per square millimeter. Also, only 4% of lesions with low mitotic rate recur compared to 24% of those with a high mitotic rate. Mitotic rate can also help to predict that your sentinel lymph node biopsy will be positive or not. Although mitotic rate has no role in the current staging system for melanoma, research has demonstrated that it is a more important prognostic factor than ulceration, which does have an important role in staging. The American Academy of Dermatology argues that mitotic rate should be optional in biopsy reports or not. On the other hand, the National Comprehensive Cancer Center recommends that mitotic rate should be reported for all lesions in stage I to II patients. Still other experts argue that measuring the mitotic rate should only be done in large academic medical centers for future research purposes. Increasing mitotic rate is related with a decreasing survival [165, 166].
Tumor-infiltrating lymphocytes (TILs) describe the patient\'s immune response to the melanoma. One marker used to determine immune activity in melanoma is the presence in sentinel lymph node biopsy samples, which has been variably associated with a favorable prognosis. Some investigators assessed whether the presence of tumor-infiltrating lymphocytes was an independent predictor of sentinel lymph node biopsy status and survival or not [167, 168].
Microscopic satellites are defined as dermal or subcutaneous nodules. Microscopic satellites in primary melanomas are considered to be localized micrometastases developing in close proximity to the main tumoral portion of melanomas and show bad prognosis. In particular, the presence of angiotropism predicts the detection of microscopic satellites, and microscopic satellites probably develop as a result of extravascular migration. Consequently the linkage between microscopic satellites and angiotropism provides additional support for extravascular migratory metastasis as a mechanism of melanoma metastasis. Finally, ongoing investigations to develop a more specific biomarker for angiotropism and extravascular migratory metastasis are essential for the more precise recognition of extravascular migratory metastases and the explaining of its biological and prognostic significance. This pericytic angiotropism of melanoma cells, without any sign of intravasation, suggests that melanoma cells may migrate along the external surface of vessels, a mechanism we have termed extravascular migratory metastasis (EVMM), as distinct from intravascular dissemination [51, 169].
Common cell types are epithelioid and spindle cells, although mixed cells may also be seen. Generally, spindle cells are associated with better prognosis than other cell types.
The incidence of malignant melanoma appears to be increasing at an alarming rate throughout the world over the past 35-40 years and continues to increase in the USA, Canada, Asia, Australia, and Europe. The behavior of head and neck melanoma is aggressive, and it has an overall poorer prognosis than that of other skin sites. Correlations between different factors were found, e.g. tumour localisation predominating on the back in males and on the legs in female. In one study, 11.734 patients were analyzed, 49.3% were male. Between 1978 and 1992, most of the newly registered melanoma patients were female, but after 1992 there was a higher incidence of male patients. Men exhibited a disadvantaged distribution for almost all prognostic indicators being significantly older at diagnosis, having thicker melanomas, and having more melanomas localized on the trunk or head and neck. In analyses of histological subtypes, females had significantly more lentigo maligna melanomas and acral lentiginous melanomas, but the incidence of superficial spreading melanoma and nodular melanoma did not differ across gender. Males more often presented with lymph node metastases or distant metastases at the time of diagnosis than did females (5.2 vs. 3.0% and 1.7 vs. 1.1%, respectively). Whereas overall disease progression, lymph node metastasis, and distant metastasis occurred significantly more often in males than in females, local recurrence and in-transit/satellite metastases were equally common [170-172].
If we summarize, prognostic factors include tumor thickness (mm), levels of invasion, presence of ulceration, increased mitotic rate. Prognosis is better if there happens to be tumor-infiltrating lymphocytes around the lesion. There is stil controversy going on about regression. Some studies have shown an adverse outcome while others no effect, or a favorable outcome. Presence of microscopic satellites shows bad prognosis and also angiotropism is a bad prognostic marker. Vascular/lymphatic invasion, although seen very rarely, indicates unfavorable prognosis. Tumor cell type also has an effect on prognosis. Better prognosis with spindle cells versus other cell types. Prognosis worsens with increasing age and women have better prognosis than men. Extremity lesions have better prognosis than axial lesions (trunk, head and neck, palms and soles) [12, 173].
Melanoma is the most dangerous form of skin cancer [174]. The incidence of melanoma is increasing worldwide, more than other cancers. The clinicians has the greatest impact on reducing these cases. They educate patients about early detection, treatment and prevention methods [175]. UV light is the most important risk factor for melanoma development. The risk of developing melanom may be reduced by protecting from UV light exposure. We must educate others as to the importance of sun protection [174]. Patients should be educated to avoid intense intermittent sun exposure and minimize cumulative sun exposure [176]. Avoiding overexposure to direct sunlight during the peak daylight hours, wearing protective clothing, and applying sunscreen are the ways to protect the skin [177].
Clinicians must educate patients as to the importance of using sunscreens that protects against both UVA and UVB light and with an SPF 30 or greater [174, 175]. It is important to emphasize the correct application of the recommended amount of sunscreen and the need for reapplication of sunscreen [176]. Sunscreen should be applied to exposed dry skin 15 to 30 minutes before sun exposure. The standard amount of sunscreen used in SPF testing is 2 mg/cm2. Sunscreen should be reapplied every 2 hours or after swimming or heavy perspiration; many water-resistant sunscreens lose effectiveness after 40 minutes in the water [177]. Clinicians recommend patients sun protective clothing such as sunglasses, hats or long sleeve clothing. Patients should be avoided direct exposure to the sunlight between 9 AM - 3 PM and tanning beds [174]. There is great concern in regard to the total amount of sun exposure during infancy and early childhood [175]. The importance of sun protection in childhood should be emphasized [176].
Self-examination of skin by informed patients in terms of suspicious nevi is an important contributory factor in the early diagnosis of melanoma [178].
Skin self examination has the potential to significantly reduce melanoma mortality. One retrospective study concluded that skin self examination has the potential to reduce melanoma mortality by 63% [179]. One study found that 44% of diagnosed recurrent melanoma was initially detected by patients based on symptoms that raised suspicion of metastasis [180]. For this reason, patients shoul be educated about the skin self examination. Patient education in skin self examination includes information on the warning signs of melanoma. Also it includes directions on how to perform a thorough whole-body skin examination [176]. Patients at higher risk should carefully examine their own skin monthly and also be frequently examined by dermatologists professionally [174].
Older individuals are both more likely to acquire and to die from cutaneous melanoma; thus, elderly people should be a primary target for secondary melanoma prevention. We must be careful for the early detection and patient routine screening. Also secondary melanoma prevention should be focused on targeted education to older men and their spouses for early detection and reduction of mortality in this extremely high-risk group [181].
Following the diagnosis of cutaneous melanoma, all patients should be educated on the risks of developing a second primary melanoma. In addition, counselling on the common clinical characteristics of cutaneous melanomas and instruction on how to perform a skin self examination should be provided. In the event of the development of new pigmented lesions or changes in preexisting pigmented lesions, patients should be advised to seek medical attention. In addition, appropriate lifelong follow-up surveillance is critical for the detection of thinner, more curable melanomas [182].
Most of the studies suggested that many cancer patients want to get detailed information about their disease, treatment options and prognosis of the disease. The most common complaint of these patients is not to told what is wrong with them, during the treatment. Cancer care professionals are beginning to recognize that patients’ information needs and preferences [183].
With growing evidence that well-informed patients are more satisfied with their care and do better clinically. Efforts are needed to improve the information provision to melanoma patients. Exploration of the patients’ personal information needs must lead to a more patient-tailored approach of informing melanoma patients. A good opportunity would be the implementation of a survivorship care plan, which aims at providing a cancer survivor with a summary of their course of treatment, management of late effects, and strategies for health promotion [184].
The importance of malignant melanoma as a potentially fatal skin cancer among Caucasian populations worldwide has received critical attention in recent years. As compared to other life-threatening malignancies such as breast or prostate carcinoma, melanoma may be diagnosed by simple inspection of the skin surface with 80 to 90% accuracy. Sun avoidance, regular self-examination are important measures that can easily be applied. Future investigations is needed to establish whether education and modification of behavior such as reduced sun exposure and various methodologies of skin examination have a significant impact in reducing mortality from melanoma.
There is increasing focus on platelet functions in people living with HIV/AIDS. This is because of the high incidence of cardiovascular events in these individuals that is 10 times higher than general population [1] independent of traditional risk factors such as age, hyperlipidemia, and ethnic/racial differences. Acquired platelet dysfunctions are often observed in association with HIV/AIDS. Of the available tests for platelet functions [2, 3], none fully captures the complexity involved in this population group.
The results of the functional assays are modified by the viral count, CD4/CD8 ratio, and immunological response and whether or not on antiretroviral treatment. The effects of combined antiretroviral therapy (cART) on platelet functions are complex. Despite achieving viral suppression, these drugs have been demonstrated to have independent effects on platelet functions.
Complete blood count and microscopic examination of formed elements are often the first investigations in suspected hemostatic disorders in clinical situations. Platelet count and morphological changes have impact on bleeding or thrombosis.
Globally, the prevalence of HIV-associated thrombocytopenia is 4–40% [4] though there are geographical, racial as well as ethnic differences from the same locality [5] and stage of disease. Indeed, thrombocytopenia has been considered as a marker of disease progression and improvement [6]. Whereas platelet counts improve with initiation of combined antiretroviral therapy (cART) viral suppression [7], beneficial effect does not apply to zidovudin (AZT) [8].
Despite thrombocytopenia, very low rates of clinical hemorrhage have been reported, estimated at only 3.2% among HIV thrombocytopenic patients [9] even with platelet count as low as 50 × 109/L [10] casting doubt on the clinical relevance of the laboratory results. As a result of lack of clear correlation between HIV-associated thrombocytopenia and clinical significance, some authors have questioned benefit of treatments purely directed toward improvement of platelet count [11].
The prevalence of HIV-associated thrombocytosis, defined as platelet count of more than 400× 109/L [12], is low but depends on the population studied and concurrent medications. Reported prevalence of thrombocytosis in pediatric group who were also HIV-positive cART naive was found at 6% [13], though could be higher at 14% (more than thrombocytopenia at 7% in same cohort) for children on co-trimoxazole prophylaxis [14]. Whether these findings were independent or dependent on co-administered drugs remains undetermined.
Thrombocytosis is an emerging toxic complication accounting for 9% on stable cART depending on the regimen [7] up from 5.8% in treatment-naïve individuals [7]. It remains undetermined the relationship between HIV-associated thrombocytosis and accelerated thrombosis.
Despite the thrombocytopenia being associated with HIV, peripheral blood film smears of platelets are either unremarkable or hypogranular, which are of different sizes appearing as fragments [15].
Ultrastructure of platelets from HIV individuals, apart from showing normal features of hyperactivated aggregates having membrane pseudopodia/filopodia formation, in addition have shriveled aggregates with irregular and torn membrane surfaces, membrane blebbing and shedding of vesicles [16, 17]. The most distinctive features are alteration of granular structure though data are limited.
Most studies on platelet aggregation in HIV have used single or fewer than the recommended panel of agonists with conflicting results [18]. Application of escalating agonist concentrations has uncovered dose-response patterns [19]. In this study, while epinephrine demonstrated greater potency indicating hyperresponsiveness, responses with collagen, TRAP, and ADP showed lesser maximum aggregation indicating lesser efficacy and hyporesponsiveness. The agonist dose-response curve is, however, modified by cART viral suppression, especially abacavir-containing regimens [20] depending on agonist [21]. It must be remembered that although cART is a commonly mentioned modifier, the effects of fever associated with HIV are neither reported nor analyzed in these studies. Hyperthermic conditions such as fever are associated with reduced platelet aggregation [22].
A study comparing whole blood platelet aggregation using MEA found hyporeactivity in both HIV-treated and untreated individuals [23], similar to findings by impedance aggregometry [24]. It is worth noting that co-infection with HBV (6 vs. 4%) and HCV (0 vs. 2%) and low CRP levels [23] could have obscured the overall response. Co-infection with other viruses modulates platelet responses in HIV [25].
Few studies have been performed using thromboelastography (TEG) in HIV individuals. Of the few studies done, MA amplitude was low despite higher normal fibrinogen levels in both cART-treated [21] and untreated HIV subjects [23]. These study results of hypocoagulability are not in keeping with other tests, probably reflecting lack of sensitivity of TEG as a platelet function assay.
Activated platelets are characterized by surface expression of activation-specific molecules such as P-selectin or CD62P, active GPIIbIIIa (PAC-1), phosphatidyleserine (PS) externalization; platelet-leukocyte aggregates (PLA); platelet microparticle formation (PMP), in addition to granule secretion such as platelet factor 4(PF4), β-thromboglobulin, and intracellular calcium flux [26].
A number of studies have documented platelet hyperactivity in HIV characterized by increased plasma membrane surface expression of CD62P, PAC-1, PS, CD63, [27], but paradoxically decreased GPIbα [28]. The levels positively correlate with viral loads but not CD4 count [29].
Although activation markers are higher in HIV sero-positive individuals who are cART naïve compared to healthy controls [30], with cART treatment levels decrease but do not normalize to pre-treatment levels [20, 31]. The persistent levels are related to inflammatory markers in virally suppressed individuals [32].
There is evidence of altered signal transduction affecting protein synthesis, degranulation, and activation functioning in HIV platelets. Experimental data show that HIV platelets had upregulation of ABCC4 (ATP-binding cassette subfamily 4), increase in cAMP, decrease in vasodilator-stimulated phosphoprotein (VASP), which correlated with increased membrane expression of CD62P and integrin αIIbβ3 (GPIIbIIIa) [33]. It must be noted that VASP is only sensitive to PY12 inhibitors, and not much data are available from HIV patients.
People living with HIV have increased secretion of alpha granule contents such as RANTES, sP-selectin, and sCD40L [34], despite viral suppression [33]. The persistence of these chemokines, especially anomalous secretion of RANTES, despite cART treatment [28] remains unexplained to date.
HIV platelets have low basal dense granule content and diminished secretion response as evidenced by low mepacrine uptake and release [33]. Although platelet mepacrine uptake and release have been considered among dense granule assays, it is not as specific as serotonin and lummiaggregometry for ATP [35, 36]. Despite this knowledge, the measurements of platelet serotonin and ATP remain largely undescribed in people living with HIV.
Although HIV-associated platelets display increased baseline expression of surface activation markers compared to healthy controls [32], there is evidence of refractoriness to further agonist stimulation. This behavior has been referred to as “platelet exhaustion” in many publications [25, 28, 32, 37, 38].
Platelet “exhaustion” as a concept was postulated in references to previous observations, before HIV era, where activated platelets continued to circulate [39, 40] and were shown to be activated [41] but with decreased aggregation [42, 43]. They were considered refractory to further agonist stimulation [44] owing to acquired storage pool granule depletion [45, 46].
In HIV, stimulation with increased agonist concentration leads to lesser response at each corresponding dose [21]. Specifically, decreased thrombin dose-response curve for granule content and secretions for P-selectin, PFA/CXCL4,TXA and RANTES in HIV platelets less than healthy controls [32]. The decreased P-selectin and PAC-1 secretory responses correspond to impaired c-AMP, ABCC4 and VASP signal transduction mechanisms [33]. Furthermore, HIV platelets display decreased mepacrine uptake and release [33], and wheat germ agglutinin staining (WGA) [32] indicating reduction of dense and alpha granule contents respectively.
Despite many studies mentioning “platelet exhaustion” in HIV, however the results in support are neither consistent for all agonists nor confirmed by other tests. In patients who are cART naïve, stimulation with AA, ADP or collagen, the dose-response curves for CD62P are higher than the uninfected controls [30]. None of the LTA aggregation tests have been accompanied by corresponding Lummiaggregometry test which could have better characterized platelet ATP dense granule secretion [47, 48]. Platelet lumiaggregometry testing remains largely un-described in HIV. Furthermore, the studies are on people who are already infected by HIV, but platelet responses prior to HIV infection remains unknown.
From the foregoing, evidence in support for “platelet exhaustion” in HIV is suggestive but inconclusive. Although decreased dose-response to thrombin has been described, however response to epinephrine was enhanced in some studies. The maintained response to epinephrine casts doubt on granule exhaustion, since true storage pool disorder do not respond to epinephrine [49] or variable [50]. Indeed HIV platelets maintain both alpha and dense granule secretions to collagen and ADP agonists stimulation [51]. Perhaps a better term to use could be “anergy,” refractory or “tired” platelets.
HIV platelets have enhanced adherence to fibrinogen-coated surfaces [32, 33]. However, testing by this method is technically difficult and not available in clinical situations.
Although platelet PFA-100/200 testing is always recorded as aggregation in most studies, in actual fact it is marker of adhesion [2, 52]. The few tests of PFA-100 in HIV compared those on cART treatment with untreated [31], or in addition to [53] all of which showed shorter closure time in treatment-naïve individuals. The short closure times were neither normalized with aspirin nor with cART. The results are strongly indicative of influence of vWF as a third dimension in platelet function testing [54, 55].
People living with HIV (PLWHIV) despite having very low platelet counts do not have issues of bleeding [56, 57, 58]. Instead, HIV-associated thrombotic complications [59] are an emerging issue of concern [60]. Although congenital thrombotic thrombocytopenic purpura (TTP) is very rare, acquired TTP is on the increase and associated with HIV estimated to be 15–40 times than the HIV negative in the general population [61]. It has been reported that HIV is responsible for 80% of TTP cases [62].
TTP is characterized by reduced or absent ADAMTS-13 and elevated vWF antigen as well as activity [63] especially the Unusually Ultralarge vWF multimers [64]. Elevated vWF Ag and high-molecular-weight vWF multimers [65] with reduced ADAMTS-13 have been detected in acute and chronic HIV [66, 67] and those with confirmed thrombosis [68]. Unusually, ultralarge vWF multimers that have increased adhesion to platelet GPIbα-V-IX receptors [69] compensates for hemostasis in the presence of the low platelet count in HIV.
It has been demonstrated that blood from HIV individuals have abundant circulating platelet microparticles [70], and this is despite viral suppression [71, 72]. The levels were associated with increased cellular ROS, caspases, eNOS [72], and mitochondrial membrane depolarization [73] indicative of apoptosis [74] . Further, co-existence of platelet microparticles with increased LPS and platelet P-selectin and TF [29] are strong indicators that they are products of platelet activation.
Recently, in mice, HIV particles were shown to be endocytosed by platelets by binding to TLR-7&9 leading to increased secretion of alpha (PFA-4) and dense granules (serotonin), and membrane expression of P-selectin [75]. Additionally, HIV interacts directly with platelets CLEC-2 and DC-SIGN receptors [76]
HIV preferentially infects CD4-T lymphocytes present in the gut leading to reduction in number and function [79]. The consequence is loss of gut epithelial immune protection and disruption of gut epithelial barrier allowing luminal indigenous intestinal bacteria to translocate out of the mucosa and into circulation [80]. Once in circulation, bacterial products such as lipopolysaccharides (LPS) interact with platelet toll-like receptors 4 (TLR4) [81]. The microbial products induce signal transduction mechanisms that eventually lead to facilitating platelet membrane receptor expression [82, 83]. The phenomenon of gut microbial translocation has been used to explain enhanced platelet reactivity despite therapy with antiplatelets such as ticagrelor in myocardial infarction [84]. However, some studies have disputed the role of LPS in platelet activation instead of reporting attenuation of receptor expression and aggregation in the presence of agonists [85] contradicting earlier findings. The paradoxical result may be due to the absence or presence of other factors such as soluble CD14 that prime TLR4 sensing of LPS [86], extent of TLR expression [87] or the different LPS isoforms [88], and experimental conditions [89] as well as clinical condition [89].
HIV infection is associated with elaboration of cytokines from inflammatory cells, and these have been shown to induce platelet activation [90, 91] The platelet activation is not limited to interleukins only, since tumor necrosis factor in blood leads to dose- and time-dependent increase in platelet expression of GPIIbIIIa, PS, and mitochondrial dysfunction [92]. The role of TNF-α in platelet activation and apoptosis are well supported by empirical evidence [93].
Platelets express FcRIIA (CD32a) or simply FcR receptor that recognizes the constant region of IgG in immune complexes [94]. The consequence of platelet-immune complex binding leads to platelet activation [95], aggregation and release of contents from alpha and dense granules [94], and microparticle formation [96]. The platelet activation from immune complexes is dependent on membrane GP IIbIIIa [97]. However, the immune complex-induced platelet aggregation is dependent on dose and charge [98].
Cross-reactive antibodies between HIV epitopes and platelet receptors have been described [99, 100].
When neutrophils encounter viruses such as HIV, they respond by releasing reactive oxygen species and net-like structures called neutrophil extracellular traps [101, 102]. The NETs, composed of DNA, histones, myeloperoxidase, citrinulated histones, and elastases, are the potent inducers of platelet aggregation and activation [103, 104, 105].
There is often cross-talk between platelets and leukocytes associated with bidirectional priming and activation of each other [106, 107]. These two cells interact through platelets such as P-selecti-PSGL-1, GPIb-vWF-CD18, integrin IIaIIIb-fibrinogen-MAC-1 neutrophil linkages that lead to the formation of platelet-leukocyte aggregates (PLA) [108] linked by P-selectin-PSGL. These PLA conjugates have been found in HIV patients involving T-cells associated with CD42b and CD62P [109]. Elevated PLA together with other immune markers is positively correlated with increased platelet CD36, CD62P, and platelet aggregation but inversely with CD4 count [110].
There is evidence of endothelial damage [111] and increased vWF levels in HIV patients [66, 67, 68, 112, 113]. Apart from the high vWF Ag levels, of significant is the persistently high functionally active Ultralarge vWF multimers (ULvWFM) in HIV individuals [65] that causes adhesion even at low platelet counts [114]. Correspondingly, as HIV disease progresses, platelet expression of the integrin GPIbα decreases paradoxically unlike the other surface receptors indicating consumption [28].
There are similarities in markers of platelet activation and apoptosis [115]. In both processes, there is phosphatidyleserine (PS) exposure on the membrane [116] and microparticles [117]. However, specific features of platelet apoptosis include mitochondrial membrane leakage characterized by changes in membrane depolarization (Δψm) and increase in cytosolic caspases 3&8, [118, 119]. Indeed, features of platelet apoptosis and activation have been demonstrated in HIV patients [25, 32, 38]. It should be noted that the few studies demonstrating occurrence of full spectra of apoptosis in HIV individuals were confounded by cART viral suppression [32] and dengue co-infection [25] and therefore, whether results were specific to HIV in itself largely remains undetermined.
Some of the consequences of platelet apoptosis include thrombocytopenia [120, 121]. This is because, apart from the fact that apoptotic platelet eventually disintegrates [74], the surface exposure of PS acts as “eat me” signal for engulfment by the macrophages thus removing the altered cells from circulation shortening survival [122, 123, 124].
Despite the success attained by cART in viral suppression and recovery of platelet counts [125, 126], their effects on platelet function remain variable. In general, platelet surface markers such as CD62P, PAC-1 and CD40L, soluble sCD62P, sCD40L as well as platelet-secreted chemokines such as RANTES persist despite cART viral suppression [27] with some variations between the individual drugs and study designs.
Platelet signal transduction and secretory effects are enhanced by HIV, but these effects are accentuated by cART. This was demonstrated by Pastori et al.’s [78] study in which levels of sCD40L, platelet sNOX-dp, and 8-iso-PGF2-α were elevated, the effects of PIs greater than NNRTI. The mechanism appears to be induction of oxidative stress, ROS, and arachidonic pathways that synergistically augment AA platelet activation. cART causes mitochondrial toxicities [127]
Abacavir is unique among cART [51] since it is a guanosine analogue and induces platelet activation
Despite other studies reporting levels of platelets MP remaining unchanged [29] or increased [71] after initiating antiretrovirals, one study found MP TF levels decreased with cART treatment [133]. The difference could be attributed to monocyte phenotypes [134] and level of activation and attendant TF expression with cART [135]. This is because platelets undergo decryption [136] and transfer TF to monocytes using microparticles as vehicles [137, 138].
The effects of cART on platelets are complicated by other factors such as TNF-α, a known platelet activator and apoptosis inducer. Although TNF levels are often elevated in HIV infection, levels persist despite cART [139] even if used over 24-month period [34]. Whereas cART treatment decreases circulating bacterial LPS levels in HIV patients, platelet reactivity is increased instead [23] suggesting intrinsic effects of the drugs independent of bacterial translocation.
People living with HIV/AIDS are at increased risk of cardiovascular events [140, 141], especially coronary heart disease [142, 143] and ischemic stroke [144, 145], than the general population. The increased risk is due to HIV infection alone and accentuated by cART [146, 147].
Although there is evidence of enhanced platelet activation in association with HIV [27], studies of antiplatelet therapy in these patients have yielded inconsistent results, perhaps owing to drug interactions [148]. It should be noted that the studies so far done were on patients concurrently taking cART.
In a study of HIV-1 infected patients who had been on 6-month cART, it was found that 325 mg of oral aspirin-attenuated platelet aggregation to agonists, activation markers [37]. In the same study, although levels of urinary thromboxane were decreased in both HIV-positive cART untreated and treated, it was least responsive to aspirin. Furthermore, despite aspirin administration, suppression of platelet hyperactivity did not decline to baseline levels indicating the contributory effects of cART. Apart from the small sample size and short duration of therapy, other limitations of this pilot study are that it evaluated only one antiplatelet drug, and it did not perform subgroup analysis among the different cART drugs (NNRTI, PI, Raltegravir, and abacavir) as well as the racial and ethnic differences.
Although aspirin and R406 (thromboxane analogue) but not ticagrelor inhibits platelet engulfment, they do not inhibit CD62P expression or PMA complex formation [149]. Other studies have confirmed the suboptimal effects of aspirin on platelets agonist (collagen and epinephrine)-induced aggregation, surface expression of CD62P, CD40L, and PAC-1 from individuals with HIV taking ABC [53]. This study identified subjects taking abacavir-containing cART as poor responders. While cART is currently standard of care in the treatment of HIV, there are no data on effects of antiplatelets in PLWH before adoption of practice.
Clopidogrel reduces thrombogenicity and platelet hyperreactivity better than aspirin in PLWH on cART [21]. The question whether dual antiplatelet therapy compared to single agent may have a better reduction in platelet hyperreactivity in HIV concurrently taking cART was evaluated in the EVERE2ST-HIV [18]. This study evaluated the extent of platelet inhibition patients with acute coronary patients on dual antiplatelet therapy undergoing PCI utilizing various platelet function assays [18]. The findings were that P2Y12 inhibitors (clopidogrel, prasugrel, and ticagralor) and aspirin were all associated with residual platelet reactivity on light transmission aggregometry (LTA), VerifyNow, and VASP assays. Furthermore, HIV infection was an independent risk factor for the high on antiplatelet reactivity that was increased by combined antiretroviral therapy (cART). Of the cART, protease inhibitors had greater effects than the NNRTIs. The residual platelet reactivity in PLWHIV despite viral suppression and dual antiplatelet therapy can probably be accounted by the active immune mechanisms and drug interactions [148].
Overall, few studies have evaluated the effects of antiplatelets in persons living with HIV. The available studies suffer from small sample sizes and have not been performed in populations not taking cART. Furthermore, the different classes of antiplatelets have not been evaluated. Of the studies done so far, the results do demonstrate neither efficacy nor improved outcomes with either aspirin or clopidogrel.
Infection with HIV is associated with reduced platelet count; extent of thrombocytopenia inversely correlates with viral load and disease progression. Despite thrombocytopenia, cardiovascular events are on the increase. There is associated platelet hyperactivity, as evidenced by increased surface expression of CD62P, CD40L, platelet microparticles, and platelet leukocyte aggregates. There is enhanced secretion of chemokines such as RANTES. Combined antiretroviral drugs independently and synergistically with HIV enhance platelet hyperactivity that persists despite viral suppression. Data on the effects of antiplatelets in this population can at best be described as clinical equipoise.
Autor’s ORCID identifier: 0000-0001-6466-172X.
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Over two decades after the transition from apartheid to democracy, vast inequalities across race, class, gender and socio-economic status persist in South Africa, with the majority of the African people being the most affected. Demographically, the African people constitute about 80.8% of the country’s total population, compared to whites, who constitute a meagre 8.8%, yet African households carry the highest burden of poverty, living way below the official poverty line of $1.90/day as determined by the World Bank and other international agencies. This chapter explores these inequalities and ponders on the role of e-learning for this poorest section of society in a country where modern technological devises in the form of information and communication technologies (ICTs) and access to the Internet are perceived to be ubiquitous. South Africa’s Department of Higher Education and Training (DHET) commits to “an expansion of open and distance education and the establishment of more ‘satellite’ premises where universities or colleges provide classes at places and times convenient to students (including in rural areas)”. This chapter also explores the role of UNISA in the provision of distance learning through structured and sustainable e-learning.",book:{id:"6533",slug:"trends-in-e-learning",title:"Trends in E-learning",fullTitle:"Trends in E-learning"},signatures:"Moeketsi Letseka, Matsephe Martha Letseka and Victor Pitsoe",authors:[{id:"187812",title:"Prof.",name:"Victor",middleName:"Justice",surname:"Pitsoe",slug:"victor-pitsoe",fullName:"Victor Pitsoe"},{id:"195883",title:"Dr.",name:"Matsephe M.",middleName:null,surname:"Letseka",slug:"matsephe-m.-letseka",fullName:"Matsephe M. Letseka"},{id:"210131",title:"Dr.",name:"Moeketsi",middleName:null,surname:"Letseka",slug:"moeketsi-letseka",fullName:"Moeketsi Letseka"}]},{id:"59392",doi:"10.5772/intechopen.74287",title:"Fixing the ‘Ready’ in E-Learning Readiness",slug:"fixing-the-ready-in-e-learning-readiness",totalDownloads:1169,totalCrossrefCites:5,totalDimensionsCites:7,abstract:"Evaluating the effectiveness of e-learning systems (ELSs) for course delivery can be achieved by measuring the user’s level of readiness for the ELS. While e-learning readiness (e-readiness) is well researched using several models, studies generally provide recommendations for the institution or instructor. However, most students are typically not equipped for using the ELS. This chapter focuses on assisting students in online and face-to-face courses who have e-readiness challenges when accessing an ELS throughout a semester. A survey captures responses on their technological, lifestyle and learning preparedness for the ELS to produce an e-readiness score. A modified DeLone and McLean model evaluates the impact of their level of e-readiness during their use of the ELS. Identifying where and when students have difficulties, pinpointing their deficits or recommending the more appropriate modality could help students achieve a positive course outcome.",book:{id:"6533",slug:"trends-in-e-learning",title:"Trends in E-learning",fullTitle:"Trends in E-learning"},signatures:"Glenda H. E. Gay",authors:[{id:"225677",title:"Dr.",name:"Glenda",middleName:"H. E.",surname:"H.E. Gay",slug:"glenda-h.e.-gay",fullName:"Glenda H.E. Gay"}]},{id:"59762",doi:"10.5772/intechopen.74862",title:"Applying a Usability Technique in the Open Source Software Development Process: Experiences from the Trenches",slug:"applying-a-usability-technique-in-the-open-source-software-development-process-experiences-from-the-",totalDownloads:911,totalCrossrefCites:2,totalDimensionsCites:4,abstract:"The growth in the number of non-developer open source software (OSS) application users has drawn attention to usability in the OSS community. OSS communities do not generally know how to apply usability techniques and are unclear about which techniques to use in each activity of the development process. The aim of our research is to determine the feasibility of applying the focus groups technique in the OSS ERMaster project. To do this, we participated as project volunteers. We used the case study research method to investigate technique application and OSS community participation. As a result, we identified adverse conditions that were an obstacle to the application of the original technique. We then adapted the technique to make it applicable in an OSS project. We can conclude that was not easy to recruit OSS users and developers to participate in technique application.",book:{id:"6533",slug:"trends-in-e-learning",title:"Trends in E-learning",fullTitle:"Trends in E-learning"},signatures:"Lucrecia Llerena, Nancy Rodriguez, Mayra Llerena, John W. Castro\nand Silvia T. Acuña",authors:[{id:"231253",title:"M.Sc.",name:"Lucrecia",middleName:null,surname:"Llerena",slug:"lucrecia-llerena",fullName:"Lucrecia Llerena"},{id:"231767",title:"MSc.",name:"Nancy",middleName:null,surname:"Rodriguez",slug:"nancy-rodriguez",fullName:"Nancy Rodriguez"},{id:"231769",title:"Dr.",name:"John W.",middleName:null,surname:"Castro",slug:"john-w.-castro",fullName:"John W. Castro"},{id:"231770",title:"Dr.",name:"Silvia T.",middleName:null,surname:"Acuña",slug:"silvia-t.-acuna",fullName:"Silvia T. Acuña"},{id:"231771",title:"MSc.",name:"Rosa Mayra",middleName:null,surname:"Llerena",slug:"rosa-mayra-llerena",fullName:"Rosa Mayra Llerena"}]},{id:"60130",doi:"10.5772/intechopen.75617",title:"Moodle Platform: A Case of Flexible Corporate Learning in the Financial Sector in Sierra Leone",slug:"moodle-platform-a-case-of-flexible-corporate-learning-in-the-financial-sector-in-sierra-leone",totalDownloads:1108,totalCrossrefCites:2,totalDimensionsCites:3,abstract:"In the current age of technology, which is supported by flexible (hand-held) devices like iPad, the use of learning platforms such as Moodle can support virtual learning through synchronisation with available technologies like effective (fibre-optic) network system. In addition to it being a good platform for academic learning, its use is now becoming widespread in the corporate environment, more so for compliance training in areas like banking and insurance sectors. In developing countries like Sierra Leone where resources are limited, effective corporate governance can be addressed by ensuring that people are conversant with their organisational compliance policies through access to Moodle managed learning environment (MLE). There is a myth concerning Moodle’s confined use in the academic environment, but this work will explore its relevance in an environment not so common in the working practices of staff professional engagement and learning in the corporate environment. Discussion is focused in the financial sector where demand on work is preventing employees and even those charged with governance from engaging themselves in activities supposedly meant to enhance their understanding of professional working practices, for example, addressing risks and compliance measures.",book:{id:"6533",slug:"trends-in-e-learning",title:"Trends in E-learning",fullTitle:"Trends in E-learning"},signatures:"Emerson Abraham Jackson",authors:[{id:"223511",title:"Ph.D. Student",name:"Emerson Abraham",middleName:"Abraham",surname:"Jackson",slug:"emerson-abraham-jackson",fullName:"Emerson Abraham Jackson"}]}],mostDownloadedChaptersLast30Days:[{id:"60465",title:"The Good, the Bad, and the Ugly of Distance Learning in Higher Education",slug:"the-good-the-bad-and-the-ugly-of-distance-learning-in-higher-education",totalDownloads:5085,totalCrossrefCites:19,totalDimensionsCites:32,abstract:"The chapter deals with opportunities and challenges of distance learning in higher education. One challenge comes from the changing perceptions of what learning is all about. The second challenge comes from new learning opportunities that technology now affords. Constructivism, interpretivism, and computing technology, separately and often together, have redesigned the conception of the challenges and opportunities of learning, and brought about new learning possibilities for almost all teaching and learning situations, including traditional classroom teaching, distance learning, and self-learning. Computer-supported learning environments could have good problems that will stimulate students to explore and reflect on their knowledge construction. Students who cannot afford higher education are discouraged from seeking or completing a degree. Distance learning-based programs could increase access for students to higher education, whereas open and distance-learning programs may be difficult to implement in the laboratory sciences, but they have real potential to maximize the use of technology.",book:{id:"6533",slug:"trends-in-e-learning",title:"Trends in E-learning",fullTitle:"Trends in E-learning"},signatures:"Vimbi Petrus Mahlangu",authors:[{id:"196797",title:"Prof.",name:"Vimbi",middleName:"Petrus",surname:"Mahlangu",slug:"vimbi-mahlangu",fullName:"Vimbi Mahlangu"}]},{id:"59935",title:"The Challenges of E-learning in South Africa",slug:"the-challenges-of-e-learning-in-south-africa",totalDownloads:2659,totalCrossrefCites:11,totalDimensionsCites:19,abstract:"The University of South Africa (UNISA) is the largest open distance e-learning (ODeL) university in the continent of Africa, with a student headcount more than 300,000. Over two decades after the transition from apartheid to democracy, vast inequalities across race, class, gender and socio-economic status persist in South Africa, with the majority of the African people being the most affected. Demographically, the African people constitute about 80.8% of the country’s total population, compared to whites, who constitute a meagre 8.8%, yet African households carry the highest burden of poverty, living way below the official poverty line of $1.90/day as determined by the World Bank and other international agencies. This chapter explores these inequalities and ponders on the role of e-learning for this poorest section of society in a country where modern technological devises in the form of information and communication technologies (ICTs) and access to the Internet are perceived to be ubiquitous. South Africa’s Department of Higher Education and Training (DHET) commits to “an expansion of open and distance education and the establishment of more ‘satellite’ premises where universities or colleges provide classes at places and times convenient to students (including in rural areas)”. This chapter also explores the role of UNISA in the provision of distance learning through structured and sustainable e-learning.",book:{id:"6533",slug:"trends-in-e-learning",title:"Trends in E-learning",fullTitle:"Trends in E-learning"},signatures:"Moeketsi Letseka, Matsephe Martha Letseka and Victor Pitsoe",authors:[{id:"187812",title:"Prof.",name:"Victor",middleName:"Justice",surname:"Pitsoe",slug:"victor-pitsoe",fullName:"Victor Pitsoe"},{id:"195883",title:"Dr.",name:"Matsephe M.",middleName:null,surname:"Letseka",slug:"matsephe-m.-letseka",fullName:"Matsephe M. Letseka"},{id:"210131",title:"Dr.",name:"Moeketsi",middleName:null,surname:"Letseka",slug:"moeketsi-letseka",fullName:"Moeketsi Letseka"}]},{id:"60282",title:"New Trends in e-Learning",slug:"new-trends-in-e-learning",totalDownloads:1515,totalCrossrefCites:1,totalDimensionsCites:2,abstract:"Guidance work is needed to learn about the current state of e-learning and to guide future research. In recent studies, e-learning environments appear to be under different headings in recent years. These new topics are mainly aimed at providing an up-to-date explanation on e-learning in this section. New trends in e-learning will be covered under artificial intelligence (AI), micro credentials, big data, virtual and empowered reality, blended learning, cloud e-learning, gamification, mobile learning, Internet of things, and online video. With this study, it is aimed to shed light on the concept of e-learning. In addition, e-learning environments focus on new possibilities for learners. Everyday, e-learning environments bring out new antagonistic concepts. As these new concepts rapidly entered our lives, they began to become indispensable materials in the field of education. New e-learning environments are being used as platforms that are related to each other. They essentially support the concept of e-learning.",book:{id:"6533",slug:"trends-in-e-learning",title:"Trends in E-learning",fullTitle:"Trends in E-learning"},signatures:"Fatih Çağatay Baz",authors:[{id:"241866",title:"Dr.",name:"Fatih Çağatay",middleName:null,surname:"Baz",slug:"fatih-cagatay-baz",fullName:"Fatih Çağatay Baz"}]},{id:"66544",title:"Factors Affecting the Utilization and Adoption of Technology in Education",slug:"factors-affecting-the-utilization-and-adoption-of-technology-in-education",totalDownloads:1064,totalCrossrefCites:3,totalDimensionsCites:3,abstract:"Education is vital in any type of society for the conservation of lives of its associates and the preservation of the public formation. The rationale of this chapter is not only to reveal the role of technology in education but also to reveal the factors affecting the proper utilization and adoption of technology in education. Prior studies carried out by researchers confirm that technology utilization and adoption in education undeniably helps teachers and learners in the teaching and learning process. This chapter serves as a stepping stone to support teachers to do better in utilizing and adopting technology in education to a certain extent as an alternative of overlooking their thoughts, efforts and desires in blindly trying to vie with the swift change of technology in education in this epoch. Hence, this chapter discusses technology in education, the roles of technology in education, factors associated with technology utilization and adoption in education and the factors that limit the proper utilization and adoption of technology in education.",book:{id:"7803",slug:"the-role-of-technology-in-education",title:"The Role of Technology in Education",fullTitle:"The Role of Technology in Education"},signatures:"Aliyu Mustapha, Abdulkadir Mohammed, Abdullahi Raji Egigogo, Abdullahi Abubakar Kutiriko and Ahmed Haruna Dokoro",authors:[{id:"284060",title:"M.Sc.",name:"Aliyu",middleName:null,surname:"Mustapha",slug:"aliyu-mustapha",fullName:"Aliyu Mustapha"},{id:"294267",title:"Dr.",name:"Abdulkadir",middleName:null,surname:"Mohammed",slug:"abdulkadir-mohammed",fullName:"Abdulkadir Mohammed"},{id:"294268",title:"MSc.",name:"Abdullahi",middleName:null,surname:"Raji Egigogo",slug:"abdullahi-raji-egigogo",fullName:"Abdullahi Raji Egigogo"},{id:"294270",title:"MSc.",name:"Abdullahi",middleName:null,surname:"Abubakar Kutiriko",slug:"abdullahi-abubakar-kutiriko",fullName:"Abdullahi Abubakar Kutiriko"},{id:"294272",title:"MSc.",name:"Ahmed",middleName:null,surname:"Haruna Dokoro",slug:"ahmed-haruna-dokoro",fullName:"Ahmed Haruna Dokoro"}]},{id:"55358",title:"Electric Power System Simulator Tool in MATLAB",slug:"electric-power-system-simulator-tool-in-matlab",totalDownloads:1928,totalCrossrefCites:1,totalDimensionsCites:1,abstract:"An electric power system is a network of electrical components used to supply, transmit, and use electric power. An example of an electric power system is the network that supplies a region’s homes and industry with power. Due to the complexity and nonlinearity of the power system, hand calculations may be very complicated in some cases, especially when the number of buses or inputs is very large. Here comes the role of software for convergence, time saving, and accuracy. The “Electric Power System Simulator” focuses on three main concepts in power system analysis, the “Power Flow Calculation,” “Faults Calculation,” and “Economic Dispatch Calculation.”",book:{id:"5845",slug:"science-education-research-and-new-technologies",title:"Science Education",fullTitle:"Science Education - Research and New Technologies"},signatures:"Mohamad Arnaout, Rabih Rammal and Samih Abdulnabi",authors:[{id:"197142",title:"Dr.",name:"Mohamad",middleName:null,surname:"Arnaout",slug:"mohamad-arnaout",fullName:"Mohamad Arnaout"},{id:"197817",title:"Dr.",name:"Rabih",middleName:null,surname:"Rammal",slug:"rabih-rammal",fullName:"Rabih Rammal"},{id:"208244",title:"Dr.",name:"Samih",middleName:null,surname:"Abdulnabi",slug:"samih-abdulnabi",fullName:"Samih Abdulnabi"}]}],onlineFirstChaptersFilter:{topicId:"286",limit:6,offset:0},onlineFirstChaptersCollection:[],onlineFirstChaptersTotal:0},preDownload:{success:null,errors:{}},subscriptionForm:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[],offset:8,limit:8,total:0},allSeries:{pteSeriesList:[{id:"14",title:"Artificial Intelligence",numberOfPublishedBooks:11,numberOfPublishedChapters:91,numberOfOpenTopics:6,numberOfUpcomingTopics:0,issn:"2633-1403",doi:"10.5772/intechopen.79920",isOpenForSubmission:!0},{id:"7",title:"Biomedical Engineering",numberOfPublishedBooks:12,numberOfPublishedChapters:108,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2631-5343",doi:"10.5772/intechopen.71985",isOpenForSubmission:!0}],lsSeriesList:[{id:"11",title:"Biochemistry",numberOfPublishedBooks:33,numberOfPublishedChapters:333,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2632-0983",doi:"10.5772/intechopen.72877",isOpenForSubmission:!0},{id:"25",title:"Environmental Sciences",numberOfPublishedBooks:1,numberOfPublishedChapters:19,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2754-6713",doi:"10.5772/intechopen.100362",isOpenForSubmission:!0},{id:"10",title:"Physiology",numberOfPublishedBooks:14,numberOfPublishedChapters:145,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-8261",doi:"10.5772/intechopen.72796",isOpenForSubmission:!0}],hsSeriesList:[{id:"3",title:"Dentistry",numberOfPublishedBooks:11,numberOfPublishedChapters:144,numberOfOpenTopics:2,numberOfUpcomingTopics:0,issn:"2631-6218",doi:"10.5772/intechopen.71199",isOpenForSubmission:!0},{id:"6",title:"Infectious Diseases",numberOfPublishedBooks:13,numberOfPublishedChapters:126,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-6188",doi:"10.5772/intechopen.71852",isOpenForSubmission:!0},{id:"13",title:"Veterinary Medicine and Science",numberOfPublishedBooks:11,numberOfPublishedChapters:113,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:23,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2753-894X",doi:"10.5772/intechopen.100359",isOpenForSubmission:!0},{id:"23",title:"Education and Human Development",numberOfPublishedBooks:0,numberOfPublishedChapters:13,numberOfOpenTopics:1,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100360",isOpenForSubmission:!0},{id:"24",title:"Sustainable Development",numberOfPublishedBooks:1,numberOfPublishedChapters:19,numberOfOpenTopics:5,numberOfUpcomingTopics:0,issn:"2753-6580",doi:"10.5772/intechopen.100361",isOpenForSubmission:!0}],testimonialsList:[{id:"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:"11",title:"Biochemistry",doi:"10.5772/intechopen.72877",issn:"2632-0983",scope:"Biochemistry, the study of chemical transformations occurring within living organisms, impacts all areas of life sciences, from molecular crystallography and genetics to ecology, medicine, and population biology. Biochemistry examines macromolecules - proteins, nucleic acids, carbohydrates, and lipids – and their building blocks, structures, functions, and interactions. Much of biochemistry is devoted to enzymes, proteins that catalyze chemical reactions, enzyme structures, mechanisms of action and their roles within cells. Biochemistry also studies small signaling molecules, coenzymes, inhibitors, vitamins, and hormones, which play roles in life processes. Biochemical experimentation, besides coopting classical chemistry methods, e.g., chromatography, adopted new techniques, e.g., X-ray diffraction, electron microscopy, NMR, radioisotopes, and developed sophisticated microbial genetic tools, e.g., auxotroph mutants and their revertants, fermentation, etc. More recently, biochemistry embraced the ‘big data’ omics systems. Initial biochemical studies have been exclusively analytic: dissecting, purifying, and examining individual components of a biological system; in the apt words of Efraim Racker (1913 –1991), “Don’t waste clean thinking on dirty enzymes.” Today, however, biochemistry is becoming more agglomerative and comprehensive, setting out to integrate and describe entirely particular biological systems. The ‘big data’ metabolomics can define the complement of small molecules, e.g., in a soil or biofilm sample; proteomics can distinguish all the comprising proteins, e.g., serum; metagenomics can identify all the genes in a complex environment, e.g., the bovine rumen. This Biochemistry Series will address the current research on biomolecules and the emerging trends with great promise.",coverUrl:"https://cdn.intechopen.com/series/covers/11.jpg",latestPublicationDate:"August 17th, 2022",hasOnlineFirst:!0,numberOfPublishedBooks:33,editor:{id:"31610",title:"Dr.",name:"Miroslav",middleName:null,surname:"Blumenberg",slug:"miroslav-blumenberg",fullName:"Miroslav Blumenberg",profilePictureURL:"https://mts.intechopen.com/storage/users/31610/images/system/31610.jpg",biography:"Miroslav Blumenberg, Ph.D., was born in Subotica and received his BSc in Belgrade, Yugoslavia. He completed his Ph.D. at MIT in Organic Chemistry; he followed up his Ph.D. with two postdoctoral study periods at Stanford University. Since 1983, he has been a faculty member of the RO Perelman Department of Dermatology, NYU School of Medicine, where he is codirector of a training grant in cutaneous biology. Dr. Blumenberg’s research is focused on the epidermis, expression of keratin genes, transcription profiling, keratinocyte differentiation, inflammatory diseases and cancers, and most recently the effects of the microbiome on the skin. He has published more than 100 peer-reviewed research articles and graduated numerous Ph.D. and postdoctoral students.",institutionString:null,institution:{name:"New York University Langone Medical Center",institutionURL:null,country:{name:"United States of America"}}},editorTwo:null,editorThree:null},subseries:{paginationCount:4,paginationItems:[{id:"14",title:"Cell and Molecular Biology",coverUrl:"https://cdn.intechopen.com/series_topics/covers/14.jpg",isOpenForSubmission:!0,editor:{id:"165627",title:"Dr.",name:"Rosa María",middleName:null,surname:"Martínez-Espinosa",slug:"rosa-maria-martinez-espinosa",fullName:"Rosa María Martínez-Espinosa",profilePictureURL:"https://mts.intechopen.com/storage/users/165627/images/system/165627.jpeg",biography:"Rosa María Martínez-Espinosa is a Full Professor of Biochemistry and Molecular Biology at the University of Alicante, Spain, and has been the vice president of International Relations and Development Cooperation at this university since 2010. She created the research group in applied biochemistry in 2017 (https://web.ua.es/en/appbiochem/), and from 1999 to the present has made more than 200 contributions to Spanish and international conferences. Furthermore, she has around seventy-five scientific publications in indexed journals, eighty book chapters, and one patent to her credit. Her research work focuses on microbial metabolism (particularly on extremophile microorganisms), purification and characterization of enzymes with potential industrial and biotechnological applications, protocol optimization for genetically manipulating microorganisms, gene regulation characterization, carotenoid (pigment) production, and design and development of contaminated water and soil bioremediation processes by means of microorganisms. This research has received competitive public grants from the European Commission, the Spanish Ministry of Economy and Competitiveness, the Valencia Region Government, and the University of Alicante.",institutionString:"University of Alicante",institution:{name:"University of Alicante",institutionURL:null,country:{name:"Spain"}}},editorTwo:null,editorThree:null},{id:"15",title:"Chemical Biology",coverUrl:"https://cdn.intechopen.com/series_topics/covers/15.jpg",isOpenForSubmission:!0,editor:{id:"441442",title:"Dr.",name:"Şükrü",middleName:null,surname:"Beydemir",slug:"sukru-beydemir",fullName:"Şükrü Beydemir",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00003GsUoIQAV/Profile_Picture_1634557147521",biography:"Dr. Şükrü Beydemir obtained a BSc in Chemistry in 1995 from Yüzüncü Yıl University, MSc in Biochemistry in 1998, and PhD in Biochemistry in 2002 from Atatürk University, Turkey. He performed post-doctoral studies at Max-Planck Institute, Germany, and University of Florence, Italy in addition to making several scientific visits abroad. He currently works as a Full Professor of Biochemistry in the Faculty of Pharmacy, Anadolu University, Turkey. Dr. Beydemir has published over a hundred scientific papers spanning protein biochemistry, enzymology and medicinal chemistry, reviews, book chapters and presented several conferences to scientists worldwide. He has received numerous publication awards from various international scientific councils. He serves in the Editorial Board of several international journals. Dr. Beydemir is also Rector of Bilecik Şeyh Edebali University, Turkey.",institutionString:null,institution:{name:"Anadolu University",institutionURL:null,country:{name:"Turkey"}}},editorTwo:{id:"13652",title:"Prof.",name:"Deniz",middleName:null,surname:"Ekinci",slug:"deniz-ekinci",fullName:"Deniz Ekinci",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYLT1QAO/Profile_Picture_1634557223079",biography:"Dr. Deniz Ekinci obtained a BSc in Chemistry in 2004, MSc in Biochemistry in 2006, and PhD in Biochemistry in 2009 from Atatürk University, Turkey. He studied at Stetson University, USA, in 2007-2008 and at the Max Planck Institute of Molecular Cell Biology and Genetics, Germany, in 2009-2010. Dr. Ekinci currently works as a Full Professor of Biochemistry in the Faculty of Agriculture and is the Head of the Enzyme and Microbial Biotechnology Division, Ondokuz Mayıs University, Turkey. He is a member of the Turkish Biochemical Society, American Chemical Society, and German Genetics society. Dr. Ekinci published around ninety scientific papers, reviews and book chapters, and presented several conferences to scientists. He has received numerous publication awards from several scientific councils. Dr. Ekinci serves as the Editor in Chief of four international books and is involved in the Editorial Board of several international journals.",institutionString:null,institution:{name:"Ondokuz Mayıs University",institutionURL:null,country:{name:"Turkey"}}},editorThree:null},{id:"17",title:"Metabolism",coverUrl:"https://cdn.intechopen.com/series_topics/covers/17.jpg",isOpenForSubmission:!0,editor:{id:"138626",title:"Dr.",name:"Yannis",middleName:null,surname:"Karamanos",slug:"yannis-karamanos",fullName:"Yannis Karamanos",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002g6Jv2QAE/Profile_Picture_1629356660984",biography:"Yannis Karamanos, born in Greece in 1953, completed his pre-graduate studies at the Université Pierre et Marie Curie, Paris, then his Masters and Doctoral degree at the Université de Lille (1983). He was associate professor at the University of Limoges (1987) before becoming full professor of biochemistry at the Université d’Artois (1996). He worked on the structure-function relationships of glycoconjugates and his main project was the investigations on the biological roles of the de-N-glycosylation enzymes (Endo-N-acetyl-β-D-glucosaminidase and peptide-N4-(N-acetyl-β-glucosaminyl) asparagine amidase). From 2002 he contributes to the understanding of the Blood-brain barrier functioning using proteomics approaches. He has published more than 70 papers. 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Since then, he has been working as an Adjunct Professor in the same Department at the University of Pavia. His research activity during the first years was primarily focused on the purification and structural characterization of enzymes from animal and plant sources. During this period, Prof. Iadarola familiarized himself with the conventional techniques used in column chromatography, spectrophotometry, manual Edman degradation, and electrophoresis). Since 1995, he has been working on: i) the determination in biological fluids (serum, urine, bronchoalveolar lavage, sputum) of proteolytic activities involved in the degradation processes of connective tissue matrix, and ii) on the identification of biological markers of lung diseases. 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She gained considerable experience in developing and validating new methodologies whose applications allowed her to determine both the amount of biomarkers (Desmosine and Isodesmosine) in the urine of patients affected by COPD, and the activity of proteolytic enzymes (HNE, Cathepsin G, Pseudomonas aeruginosa elastase) in the sputa of these patients. Simona Viglio was also involved in research dealing with the supplementation of amino acids in patients with brain injury and chronic heart failure. She is presently engaged in the development of 2-DE and LC-MS techniques for the study of proteomics in biological fluids. The aim of this research is the identification of potential biomarkers of lung diseases. 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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:{name:"University of Silesia",country:{name:"Poland"}}},{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:"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:{name:"Medical University Plovdiv",country:{name:"Bulgaria"}}},{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:"243698",title:"Dr.",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: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:"312999",title:"Dr.",name:"Bernard O.",middleName:null,surname:"Asimeng",slug:"bernard-o.-asimeng",fullName:"Bernard O. Asimeng",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Ghana",country:{name:"Ghana"}}},{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"}}}]}},subseries:{item:{id:"23",type:"subseries",title:"Computational Neuroscience",keywords:"Single-Neuron Modeling, Sensory Processing, Motor Control, Memory and Synaptic Pasticity, Attention, Identification, Categorization, Discrimination, Learning, Development, Axonal Patterning and Guidance, Neural Architecture, Behaviours and Dynamics of Networks, Cognition and the Neuroscientific Basis of Consciousness",scope:"Computational neuroscience focuses on biologically realistic abstractions and models validated and solved through computational simulations to understand principles for the development, structure, physiology, and ability of the nervous system. This topic is dedicated to biologically plausible descriptions and computational models - at various abstraction levels - of neurons and neural systems. This includes, but is not limited to: single-neuron modeling, sensory processing, motor control, memory, and synaptic plasticity, attention, identification, categorization, discrimination, learning, development, axonal patterning, guidance, neural architecture, behaviors, and dynamics of networks, cognition and the neuroscientific basis of consciousness. Particularly interesting are models of various types of more compound functions and abilities, various and more general fundamental principles (e.g., regarding architecture, organization, learning, development, etc.) found at various spatial and temporal levels.",coverUrl:"https://cdn.intechopen.com/series_topics/covers/23.jpg",hasOnlineFirst:!1,hasPublishedBooks:!0,annualVolume:11419,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 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