Summary
\\n\\n
IntechOpen was founded by scientists, for scientists, in order to make book publishing accessible around the globe. Over the last two decades, this has driven Open Access (OA) book publishing whilst levelling the playing field for global academics. Through our innovative publishing model and the support of the research community, we have now published over 5,700 Open Access books and are visited online by over three million academics every month. These researchers are increasingly working in broad technology-based subjects, driving multidisciplinary academic endeavours into human health, environment, and technology.
\\n\\nBy listening to our community, and in order to serve these rapidly growing areas which lie at the core of IntechOpen's expertise, we are launching a portfolio of Open Science journals:
\\n\\nAll three journals will publish under an Open Access model and embrace Open Science policies to help support the changing needs of academics in these fast-moving research areas. There will be direct links to preprint servers and data repositories, allowing full reproducibility and rapid dissemination of published papers to help accelerate the pace of research. Each journal has renowned Editors in Chief who will work alongside a global Editorial Board, delivering robust single-blind peer review. Supported by our internal editorial teams, this will ensure our authors will receive a quick, user-friendly, and personalised publishing experience.
\\n\\n"By launching our journals portfolio we are introducing new, dedicated homes for interdisciplinary technology-focused researchers to publish their work, whilst embracing Open Science and creating a unique global home for academics to disseminate their work. We are taking a leap toward Open Science continuing and expanding our fundamental commitment to openly sharing scientific research across the world, making it available for the benefit of all." Dr. Sara Uhac, IntechOpen CEO
\\n\\n"Our aim is to promote and create better science for a better world by increasing access to information and the latest scientific developments to all scientists, innovators, entrepreneurs and students and give them the opportunity to learn, observe and contribute to knowledge creation. Open Science promotes a swifter path from research to innovation to produce new products and services." Alex Lazinica, IntechOpen founder
\\n\\nIn conclusion, Natalia Reinic Babic, Head of Journal Publishing and Open Science at IntechOpen adds:
\\n\\n“On behalf of the journal team I’d like to thank all our Editors in Chief, Editorial Boards, internal supporting teams, and our scientific community for their continuous support in making this portfolio a reality - we couldn’t have done it without you! With your support in place, we are confident these journals will become as impactful and successful as our book publishing program and bring us closer to a more open (science) future.”
\\n\\nWe invite you to visit the journals homepage and learn more about the journal’s Editorial Boards, scope and vision as all three journals are now open for submissions.
\\n\\nFeel free to share this news on social media and help us mark this memorable moment!
\\n\\n\\n"}]',published:!0,mainMedia:{caption:"",originalUrl:"/media/original/237"}},components:[{type:"htmlEditorComponent",content:'
After years of being acknowledged as the world's leading publisher of Open Access books, today, we are proud to announce we’ve successfully launched a portfolio of Open Science journals covering rapidly expanding areas of interdisciplinary research.
\n\n\n\nIntechOpen was founded by scientists, for scientists, in order to make book publishing accessible around the globe. Over the last two decades, this has driven Open Access (OA) book publishing whilst levelling the playing field for global academics. Through our innovative publishing model and the support of the research community, we have now published over 5,700 Open Access books and are visited online by over three million academics every month. These researchers are increasingly working in broad technology-based subjects, driving multidisciplinary academic endeavours into human health, environment, and technology.
\n\nBy listening to our community, and in order to serve these rapidly growing areas which lie at the core of IntechOpen's expertise, we are launching a portfolio of Open Science journals:
\n\nAll three journals will publish under an Open Access model and embrace Open Science policies to help support the changing needs of academics in these fast-moving research areas. There will be direct links to preprint servers and data repositories, allowing full reproducibility and rapid dissemination of published papers to help accelerate the pace of research. Each journal has renowned Editors in Chief who will work alongside a global Editorial Board, delivering robust single-blind peer review. Supported by our internal editorial teams, this will ensure our authors will receive a quick, user-friendly, and personalised publishing experience.
\n\n"By launching our journals portfolio we are introducing new, dedicated homes for interdisciplinary technology-focused researchers to publish their work, whilst embracing Open Science and creating a unique global home for academics to disseminate their work. We are taking a leap toward Open Science continuing and expanding our fundamental commitment to openly sharing scientific research across the world, making it available for the benefit of all." Dr. Sara Uhac, IntechOpen CEO
\n\n"Our aim is to promote and create better science for a better world by increasing access to information and the latest scientific developments to all scientists, innovators, entrepreneurs and students and give them the opportunity to learn, observe and contribute to knowledge creation. Open Science promotes a swifter path from research to innovation to produce new products and services." Alex Lazinica, IntechOpen founder
\n\nIn conclusion, Natalia Reinic Babic, Head of Journal Publishing and Open Science at IntechOpen adds:
\n\n“On behalf of the journal team I’d like to thank all our Editors in Chief, Editorial Boards, internal supporting teams, and our scientific community for their continuous support in making this portfolio a reality - we couldn’t have done it without you! With your support in place, we are confident these journals will become as impactful and successful as our book publishing program and bring us closer to a more open (science) future.”
\n\nWe invite you to visit the journals homepage and learn more about the journal’s Editorial Boards, scope and vision as all three journals are now open for submissions.
\n\nFeel free to share this news on social media and help us mark this memorable moment!
\n\n\n'}],latestNews:[{slug:"webinar-introduction-to-open-science-wednesday-18-may-1-pm-cest-20220518",title:"Webinar: Introduction to Open Science | Wednesday 18 May, 1 PM CEST"},{slug:"step-in-the-right-direction-intechopen-launches-a-portfolio-of-open-science-journals-20220414",title:"Step in the Right Direction: IntechOpen Launches a Portfolio of Open Science Journals"},{slug:"let-s-meet-at-london-book-fair-5-7-april-2022-olympia-london-20220321",title:"Let’s meet at London Book Fair, 5-7 April 2022, Olympia London"},{slug:"50-books-published-as-part-of-intechopen-and-knowledge-unlatched-ku-collaboration-20220316",title:"50 Books published as part of IntechOpen and Knowledge Unlatched (KU) Collaboration"},{slug:"intechopen-joins-the-united-nations-sustainable-development-goals-publishers-compact-20221702",title:"IntechOpen joins the United Nations Sustainable Development Goals Publishers Compact"},{slug:"intechopen-signs-exclusive-representation-agreement-with-lsr-libros-servicios-y-representaciones-s-a-de-c-v-20211123",title:"IntechOpen Signs Exclusive Representation Agreement with LSR Libros Servicios y Representaciones S.A. de C.V"},{slug:"intechopen-expands-partnership-with-research4life-20211110",title:"IntechOpen Expands Partnership with Research4Life"},{slug:"introducing-intechopen-book-series-a-new-publishing-format-for-oa-books-20210915",title:"Introducing IntechOpen Book Series - A New Publishing Format for OA Books"}]},book:{item:{type:"book",id:"462",leadTitle:null,fullTitle:"Autism - A Neurodevelopmental Journey from Genes to Behaviour",title:"Autism",subtitle:"A Neurodevelopmental Journey from Genes to Behaviour",reviewType:"peer-reviewed",abstract:"The book covers some of the key research developments in autism and brings together the current state of evidence on the neurobiologic understanding of this intriguing disorder. The pathogenetic mechanisms are explored by contributors from diverse perspectives including genetics, neuroimaging, neuroanatomy, neurophysiology, neurochemistry, neuroimmunology, neuroendocrinology, functional organization of the brain and clinical applications from the role of diet to vaccines. It is hoped that understanding these interconnected neurobiological systems, the programming of which is genetically modulated during neurodevelopment and mediated through a range of neuropeptides and interacting neurotransmitter systems, would no doubt assist in developing interventions that accommodate the way the brains of individuals with autism function. In keeping with the multimodal and diverse origins of the disorder, a wide range of topics is covered and these include genetic underpinnings and environmental modulation leading to epigenetic changes in the aetiology; neural substrates, potential biomarkers and endophenotypes that underlie clinical characteristics; as well as neurochemical pathways and pathophysiological mechanisms that pave the way for therapeutic interventions.",isbn:null,printIsbn:"978-953-307-493-1",pdfIsbn:"978-953-51-6448-7",doi:"10.5772/974",price:139,priceEur:155,priceUsd:179,slug:"autism-a-neurodevelopmental-journey-from-genes-to-behaviour",numberOfPages:500,isOpenForSubmission:!1,isInWos:null,isInBkci:!1,hash:null,bookSignature:"Valsamma Eapen",publishedDate:"August 17th 2011",coverURL:"https://cdn.intechopen.com/books/images_new/462.jpg",numberOfDownloads:61368,numberOfWosCitations:37,numberOfCrossrefCitations:17,numberOfCrossrefCitationsByBook:1,numberOfDimensionsCitations:49,numberOfDimensionsCitationsByBook:1,hasAltmetrics:1,numberOfTotalCitations:103,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"October 20th 2010",dateEndSecondStepPublish:"November 17th 2010",dateEndThirdStepPublish:"March 24th 2011",dateEndFourthStepPublish:"April 23rd 2011",dateEndFifthStepPublish:"June 22nd 2011",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6",editedByType:"Edited by",kuFlag:!1,featuredMarkup:null,editors:[{id:"62816",title:"Dr.",name:"Valsamma",middleName:null,surname:"Eapen",slug:"valsamma-eapen",fullName:"Valsamma Eapen",profilePictureURL:"https://mts.intechopen.com/storage/users/62816/images/1685_n.jpg",biography:"Valsamma Eapen is Professor & Chair of Infant, Child and Adolescent Psychiatry at the University of New South Wales (UNSW) and Head of the Academic Unit of Child Psychiatry, South West Sydney (AUCS), Australia. Professor Eapen graduated from Kerala, India and continued her postgraduate training in India (NIMHANS) and the UK. She completed her Child Psychiatry training through the Great Ormond Street Hospital Scheme, and PhD work at the National Hospital for Neurology and Neurosurgery, Queen Square, London. She started her academic career at the University College London, UK and then moved to the UAE University, where she was Professor of Child Psychiatry prior to taking up her current position in 2008. As a Child Psychiatrist with special expertise in neurodevelopmental disorders, her research interests include Tourette Syndrome, Autism, and ADHD, and her research has included epidemiological, genetic and clinical aspects of these disorders. Her other areas of research include neurobiology of attachment and separation anxiety disorder as well as developmental trajectory in normal and abnormal development.",institutionString:"University of New South Wales, Australia",position:null,outsideEditionCount:null,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"1",institution:null}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"1054",title:"Neurobiology",slug:"mental-and-behavioural-disorders-and-diseases-of-the-nervous-system-neurobiology"}],chapters:[{id:"18059",title:"Abnormal Developmental Trajectories of White Matter in Autism - The Contribution of MRI",doi:"10.5772/18518",slug:"abnormal-developmental-trajectories-of-white-matter-in-autism-the-contribution-of-mri",totalDownloads:2144,totalCrossrefCites:0,totalDimensionsCites:4,hasAltmetrics:0,abstract:null,signatures:"Dafna Ben Bashat",downloadPdfUrl:"/chapter/pdf-download/18059",previewPdfUrl:"/chapter/pdf-preview/18059",authors:[{id:"31741",title:"Dr.",name:"Dafna",surname:"Ben Bashat",slug:"dafna-ben-bashat",fullName:"Dafna Ben Bashat"}],corrections:null},{id:"18060",title:"GABAergic Dysfunction in Autism and Epilepsy",doi:"10.5772/17387",slug:"gabaergic-dysfunction-in-autism-and-epilepsy",totalDownloads:2579,totalCrossrefCites:1,totalDimensionsCites:3,hasAltmetrics:0,abstract:null,signatures:"Sacha Genovesi, Giovanni Provenzano, Mark Dunleavy, Paola Sgadò and Yuri Bozzi",downloadPdfUrl:"/chapter/pdf-download/18060",previewPdfUrl:"/chapter/pdf-preview/18060",authors:[{id:"28191",title:"Prof.",name:"Yuri",surname:"Bozzi",slug:"yuri-bozzi",fullName:"Yuri Bozzi"},{id:"44429",title:"Dr.",name:"Paola",surname:"Sgadò",slug:"paola-sgado",fullName:"Paola Sgadò"},{id:"44430",title:"Dr.",name:"Sacha",surname:"Genovesi",slug:"sacha-genovesi",fullName:"Sacha Genovesi"},{id:"44431",title:"Prof.",name:"Giovanni",surname:"Provenzano",slug:"giovanni-provenzano",fullName:"Giovanni Provenzano"},{id:"44432",title:"Dr.",name:"Mark John",surname:"Dunleavy",slug:"mark-john-dunleavy",fullName:"Mark John Dunleavy"}],corrections:null},{id:"18061",title:"GABA and Glutamate Receptors of the Autistic Brain",doi:"10.5772/20304",slug:"gaba-and-glutamate-receptors-of-the-autistic-brain",totalDownloads:3604,totalCrossrefCites:1,totalDimensionsCites:2,hasAltmetrics:1,abstract:null,signatures:"Agenor Limon, Jorge M. 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\r\n\tMicrofluidics and Nanofluidics referred to a technology where fluid flows are from the macroscale down to the nanoscale traditionally used as key components of control and sensing systems. Nowadays, the research and application areas of Microfluidics and Nanofluidics have been greatly expanded to advanced materials, biochemistry, new energy, single-cell/single-molecule studies, human health, and so forth. Microfluidics and Nanofluidics deal with transport phenomena, i.e., mass, momentum, and heat transfer, in the micrometer or nanometer range, and conventional fluid dynamics cannot be directly used in this area. The possible challenge in fluid properties must be considered. Thus, in the last two decades, the fundamental theories, as well as their application, have been rapidly in Microfluidics and Nanofluidics. Therefore, this book aims to host original research or review works addressing the fundamentals and applications of any functional flow in Microfluidics and Nanofluidics. The potential topics include all aspects of microfluidics, nanofluidics, and lab-on-a-chip science and technology, it might be (but are not limited to) fundamental principles of micro-and nanoscale phenomena like flow, mass transport and reactions, theoretical models, and numerical simulation with experimental and/or analytical proof, micromixer device, and particle manipulation. Experimental and numerical studies are welcome.
\r\n\t
Objective: Neuronal and Mixed Neuronal-glial Tumors of the Central Nervous System are frequently encountered in the neurosurgical practice.
Ganglioglioma and gangliocytoma are well-differentiated, slowly growing benign neuroepithelial tumors. with World Health Organization (WHO) grade I. higher grade is based on the degree of malignancy in the glial-cell component. They represent around 1% of all central nervous system (CNS) tumors, However it is frequently oencountered in children and young adults between age 8 and 25 years. Gangliogliomas contain mature neoplastic neuronal cells, neoplastic glial cells, astrocytic cells, and ganglion cells, and may display mitotic activity. These lesions are curable by total removal.
Central neurocytoma and extraventricular neurocytoma are WHO grade II tumors composed of regular rounded cells that have undergone neuronal differentiation. Central neurocytomas are typicaly located within the lateral ventricles just next to the foramen of Monro, whereas extraventricular neurocytomas are located within the brain parenchyma. Both characteristically occur in young adults. The outcome is favorable after complete resectioning.
Dysembryoplastic neuroepithelial tumor (DNT) is frequently a benign, supratentorial glial-neuronal WHO grade I tumor. DNT occur mainly in children or young adults, who usually present with intractable partial complex seizure. Characterized by a predominantly cortical location, DNT histopathologically exhibits a complex columnar and multinodular architecture, and is often associated with cortical dysplasia.
Desmoplastic infantile astrocytomas (DIAs) and desmoplastic infantile gangliogliomas (DIGs) are almost WHO grade I tumors that are often cystic and commonly occur in infants. Composed of a prominent desmoplastic stroma with neuroepithelial components, mainly neoplastic astrocytes in DIAs or astrocytes together with variable neuronal components in DIGs, they involve the cerebral cortex and leptomeninges, and are often adherent to the dura. The natural course is benign.
Rosette-forming glioneuronal tumor of the fourth ventricle (RGNT) is a usually rare and slowly growing WHO grade I tumor. It is commonly affecting young adults, RGNT is composed of two distinct histological cells types; uniform neurocytes which form rosettes and/or perivascular pseudorosettes and astrocytic cells similar to pilocytic astrocytomas. The prognosis is good upon surgical removal.
This rare type of cerebellar tumors is WHO grade II tumor that typically occurs in adults. It is Composed of neuronal, astrocytic, and some lipomatous cells, they tend to recur after initial treatment.
Papillary glio-neuronal tumors is a well defined and benign with WHO grade I. the natural course is insidius. It is composed of flat to cuboidal, GFAP-positive astrocytes lining hyalinized vascular pseudo-papillae and synaptophysin-positive interpapillary sheets of neuronal cells. Upon microscopy, it exhibits different sizes of large and intermediate neuron “ganglioid” cells.
Spinal paraganglioma is encapsulated, benign, neuro-endocrine WHO grade I tumor. Arising from neural crest cells and composed of segmental or collateral autonomic ganglia (paraganglia), It is primarily involving the cauda equine and filum terminale region. The uniform main cells exhibit neuronal differentiation and forming compact nests (Zellballen) surrounded by cells and a delicate capillary network within the CNS.
Gangliogliomas and gangliocytomas are well-differentiated, slowly growing benign neuroepithelial neoplasms that consist of neoplastic, mature ganglion cells. Both gangliogliomas and gangliocytomas are a type of neuroepithelial tumor that is the most frequent pathology observed in patients with long-term epilepsy. A gangliocytoma in the absence of neoplastic glial-cell development and a ganglioglioma in the presence of neoplastic glial-cell development. [1]
Gangliocytomas and most gangliogliomas are categorized as WHO grade I tumors [1].
Some gangliogliomas with anaplastic features of the glial component are categorized as WHO grade III tumors (anaplastic gangliogliomas). Criteria for grade II types has also been suggested [2, 3].
These uncommon neoplastic lesions represent only 0.4% of all CNS tumors and 1.3% of all brain tumors [3,4]. The age of patients is variable, ranging from 2 months to 70 years. Data from 5 large series of a total of 626 patients indicate an average age at diagnosis ranging from 8.5 to 25 years and a male: female ratio ranging from 1.1:1 to 1.9:1 [5,6,7,8]. In one study, the mean age in children at diagnosis is 9.5 years, with a slight female prevalence [9].
The vast majority of gangliogliomas (>70%) occur in the temporal lobe. However, Gangliocytomas and most gangliogliomas may occur throughout the CNS, including in the cerebrum, brain stem, cerebellum, spinal cord, optic nerves, and pituitary and pineal glands. [2, 6, 7, 8, 10].
Variable clinical symptoms of gangliocytomas and most gangliogliomas are encountered and related to tumor size and site. Seizure is usually the initial presenting symptoms. Gangliocytomas and gangliogliomas are the most common tumors associated with chronic and intractable temporal lobe epilepsy and observed in 15% to 25% of patients undergoing epilepsy surgery [11,12].duration of symptoms ranging from 1 month to 50 years before diagnosis, with a median interval of 6 to 25 years [6,7,8]. Tumors affecting the brain stem or spinal cord frequently present with crossed paresis or long-tract lesion and sphincteric disorder of a mean duration of 1.25 and 1.4 years, respectively [6].
Computed tomography (CT) of a ganglioglioma or gangliocytoma may indicate a well-circumscribed solid mass or cyst with a mural nodule and some calcification, and slight or absent contrast enhancement. Skull scalloping may be noted adjacent to superficial cerebral tumors. These lesions appear hypointense on T1-weighted and hyperintense on T2-weighted magnetic resonance imaging (MRI), with well-defined masses showing enhancement absorption that can range from none to vivid and may be solid or only on the rim or nodular [13,14]. Figure 1
MRI
Gangliogliomas are solid or cystic lesions, characteristically with little mass effect. Calcification may be observed, whilst hemorrhage and necrosis are rare [8]
A primary characteristic of gangliogliomas is a mixture of neuronal and glial-cell elements that may display a striking heterogeneity. Gangliocytomas consist of clusters of large, multipolar neurons with immature features. The matrix contains non-neoplastic glial components and a network of reticulin fibers. Immature neurons are characterized by the loss of cyto-architectural arrangement of subcortical localization, a grouped appearance, enlargement of cells, and aggregation of Nissl bodies. Multinucleated neurons may present in 50% of cases. On the other hand, the glial element in gangliogliomas, which comprises the proliferation part of the tumor, shows considerable inconsistency, and may include any glial-cell type with Rosenthal fibers and eosinophilic granular bodies. Thestroma is typically fibrillary and may contain a microcystic component with mucous material. Occasional mitotic activity may be noted, and is typically compatible with the diagnosis of ganglioglioma, whereas necrosis is absent unless the glial component is undergoing malignant transformation. Other histopathological features that may be seen in gangliogliomas are calcifications, extensive lymphatic infiltrates with perivascular spaces or within the tumor substance or brain tissue, and a capillary network that forms an angiomatous constituent. In high-grade (anaplastic) gangliogliomas, malignant changes almost always involve the glial component and may be seen at the site of a previously removed ganglioglioma [2, 3, 5, 7, 8]. Figure 2A
No specific marker is available to differentiate dysplastic and neoplastic neurons from normal and mature neurons. Neuronal protein markers, such as synaptophysin, neurofilaments, MAP2, and Neu N, are used to reveal the neuronal component in gangliogliomas.. However, use of the onco-fetal CD34 antigen can be positive, as CD34 is absent in neural cells of the adult brain but consistently expressed in 70% to 80% of gangliogliomas, especially those arising from the temporal lobe [15]. Staining for GFAP reveals the astrocytic component the neoplastic glial element of gangliogliomas. Contrary to that seen in diffuse gliomas, MAP2 immunoreactivity is usually weak or absent in the astrocytic component of gangliogliomas [16]. Figure 2B
The presence of neurons with dense core granules is a characteristic feature of gangliogliomas and gangliocytomas. Neuronal synaptic junctions may be few or completely absent [5,17]. Observation of round protein bodies in gangliogliomas has also been mentioned [18].
A and B
Ki-67/MIB-1 labeling the glial component has shown values ranging from 1.1 to 2.7%. Mitotic activity is low [5,7].
Genetic vulnerability to the development of gangliogliomas and gangliocytomas has not been well established. Previous studies reported a ganglioglioma of the optic nerve in a patient with neurofibromatosis type 1 [19] and a ganglioglioma in a Peutz-Jeghers patient [20]. Mutational analysis of the tuberous sclerosis 1 (TSC1] and TSC2 genes revealed significant sequence alterations in the TSC2 gene, including polymorphisms in intron 4 and exon 41, in patients with gangliogliomas. In a further study of ezrin and radixin genes, coding for the interaction partners of TSC1 and TSC2 was not observed [30,31,32].
Chromosomal abnormalities have been recorded in one-third of cases, in the approximately 30 cases of gangliogliomas that have been studied cytogenetically, a change in chromosome 7 was the most one observed. The karyotype was found to be abnormal in 3 cases with unfavorable outcomes. [21,22,23,24,25,26]. Chromosomal imbalances have been detected in 5/5 gangliogliomas by comparative genomic hybridization. Although partial loss of chromosome 9p and gain of chromosome 7 has been observed in several patients, abnormal epidermal growth factor receptor (EGFR) expression was not observed in these cases [27]. A study of 14 cases [11 WHO grade I and 3 WHO grade III) failed to show TP53 mutation, PTEN mutation, or CDK4 and EGFR amplification, whereas CDKN2A deletion was observed in two-thirds of cases of anaplastic ganglioglioma [28]. However, TP53 mutation was only noted in the recurrence of a WHO grade I ganglioglioma [29].
The histogenesis of gangliogliomas and gangliocytomas still not understood. However, evolution from a dysplastic, abnormal glio-neuronal precursor with subsequent neoplastic transformation of the glial element has been proposed [33].
Favorable prognosis is observed in patients with long-standing epilepsy with temporal localization and complete surgical resectioning. These lesions are typically benign tumors with a 7.5-year recurrence-free survival rate of 94%.. Anaplastic changes, such as mitotic activity and microvascular proliferation and necrosis, in the glial component similar to those observed in high-grade gliomas.
Central neurocytomas and extraventricular neurocytomas are neoplasms composed of uniform round cells with neuronal differentiation. Central neurocytomas are typically located in the lateral ventricles in the region of the foramen of Monro and extraventricular neurocytomas in the brain parenchyma. These tumors are usually seen in young adults and have a favorable prognosis.
Central neurocytomas correspond histologically to WHO grade II tumors [1].
“Central neurocytoma” expression was used by Hassoun et al. [34] to describe a neuronal tumor with pathological features to differentiate it from cerebral neuroblastomas that occurs in young adults, it is commonly located in the third ventricle, and histologically may resemble oligodendrogliomas. They were also reported in other locations. The term central neurocytoma should be restricted to neoplasms located within the intracerebral ventricles. Tumors similar to central neurocytomas but occurring within the cerebral hemispheres (“cerebral neurocytomas”) or the spinal cord [35, 36,37] have subsequently been mentioned and described as “extraventricular neurocytoma” these tumours are now given to neoplasms that arise within the CNS parenchyma and have histological features with the more common central neurocytomas but exhibit a wider morphological spectrum. Neurocytic differentiation has been reported in an increasing number of tumors with specific morphological characteristics, some of these have been categorized as new entities, such as cerebellar liponeurocytomas, papillary glioneuronal tumors, or their variants [38, 39, 40].
The incidence ranged from 0.25% to 0.5% of all intracranial tumors. In an analysis of 243 cases, age at clinical manifestation is almost variable ranging from 8 days to 67 years (mean age, 29 years), with 69% between the ages of 20 and 40 year. Both sexes are equally affected [40, 34].
Central neurocytomas are usually located supratentorially in the lateral or the third ventricle. With most common site is the anterior part of the lateral ventricles [50%), more frequently on the left, followed by combined extension into the lateral and third ventricles and a bilateral intraventricular location. Attachment to the septum pellucidum is common, but isolated third-ventricular occurrence is rare. [40, 41]
The majority of patients present with symptoms of increased intracranial pressure rather than with other neurological deficit. The clinical history is short (mean 3.2 months). Central neurocytomas may present as acute hemorrhage or as an incidental finding on imaging [41].
On CT scans, mass is typically isodense or slightly hyperdense. Enhancement is common. Calcifications and cystic changes may be observed. MRI scan shows heterogeneous hypointensity on T1-weighted images and fluid- attenuated inversion recovery (FLAIR) and hyperintensity on T2-weighted images and FLAIR, with a well-defined margin mild to strong enhancement after gadolinum injection [42]. Figure 3
Figure 3
Intraventricular tumors are typically grey in color and friable with varying calcifications, these tumours are vascular and with occasional hemorrhage. ( 43,44]
Central neurocytomas have a benign histological appearance and may display various architectural patterns, even within the same specimen, including an oligodendroglioma-like honeycomb appearance, large fibrillary areas mimicking the irregular “rosettes” in pineocytomas. These lesions are neuroepithelial tumors composed of uniform round cells that show immunohistochemical and ultrastructural features of neuronal differentiation, fibrillary areas mimicking neuropils, and a low proliferation rate. Cells are isomorphous, having a round or oval nucleus with a finely speckled chromatin and an occasional nucleolus, cells arranged in straight lines, or perivascular pseudorosettes similar to those noted in ependymoma tumours. Calcifications are usually seen in around 50% of cases, normally distributed throughout the tumor. Blood vessels, classically arranged in a linear architecture pattern, giving an endocrine appearance. Rarer findings may include Homer Wright rosettes and ganglioid cells [43,44].
These tumour may mimic, and must be distinguished from, oligodendroglioma, ependymoma, pineocytoma, and dysembryoplastic neuroepithelial. In rare cases, anaplastic histological features, including high mitotic activity and microvascular proliferation, have been observed. In some conditions, necrosis was associated with anaplastic features. Necrosis may also be observed in rare cases that are otherwise without malignant features, may be s as a vascular effect ( 41, 44, 46, 47, 48,49]. Figure 4A
A and B
Synaptophysin is the most suitable and reliable diagnostic marker, with immunoreactivity diffusely present in neuropils, especially in fibrillary zones and perivascular nuclei-free cuffs [48]. A significant number of nuclei are immunopositive for NeuN in almost all cases [50]. The mean labeling index was 74% in one series of 11 cases, with a significantly lower Ki-67 staining rate for cells expressing NeuN [51]. In extraventricular lesions, intracytoplasmic and para-nuclear immunolabeling must be cautiously inferred whenever other histological, immunohistochemical, or ultrastructural data of neuronal differentiation is lacking. Of particular interest is the anti-Hu antibody because it labels the nuclei of neurocytes [52]. Chromogranin A and neurofilament staining are typically absent except when ganglion cells are present Although most studies found that GFAP was expressed only in trapped reactive astrocytes, the antigen has been detected by some studies in tumor cells ( 44, 45, 53,54]. Figure 4B
Electron microscopy may be required when expression of specific neuronal markers (synaptophysin, NeuN) is questionable and in other extraventricular neoplasms mimicking central neurocytomas. The central neurocytoma cells show uniform round nuclei with a finely discreted chromatin and a small nucleolus in a few cells. The cytoplasm contains mitochondria, a prominent Golgi apparatus, and several rough endoplasmic reticulum cisternae, often arranged in concentric lamellae. copious thin and combined cell processes containing microtubules and dense core and clear vesicles are always observed [41,55].
MIB-1 labeling indices are classically low, usually less than 2%. However, Tumors with indices greater than 2%, as in one series in which they were found to be 3%, are referred to as “atypical neurocytomas” and associated with a significantly shorter recurrence-free interval [53, 56, 57].
Unclear, but central neurocytoma was observedin patients with von Hippel-Lindau disease [58]. The molecular pathogenesis of central neurocytomas remains unknown, the observation of several genetic alterations, mainly chromosomal gains, has been reported. In one study, gain on chromosome 7 was observed in 3 of 9 neurocytomas [59]. However, another study found no EGFR amplification in central neurocytomas [60]. In related studies, gains on chromosomes 2p, 10q, 18q, and 13q were found in over 20% of tumors in one study ; an isochromosome 17 and complex karyotype were observed in 2 studies [61, 62, 63]; and TP53 mutations and MYCN amplification were reported to be rare or absent in several studies [45, 60, 63, 64, 65].there are two studies that reported loss of 1p and 19q, 1 study reported allelic loss on 1p as well as an inability to detect 19q [64], whereas the other study reported 6 of 9 tumors showed loss at 1 or more loci on 1p and that 5 tumors showed 19q loss. These data suggest that central neurocytomas are genetically distinct from oligodendrogliomas. Although the expression profiles of cerebellar liponeurocytomas appear to have a closer relationship to those of central neurocytomas, the lack of TP53 mutations in central neurocytomas suggests the involvement of different genetic pathways [60, 66,67].
Central neurocytomas were previously thought to be derived from precurssor cells of the septum pellucidum [34]. Still, the indication of both astrocytic and neuronal differentiation in some tumor cells by various approaches in vivo and in vitro has suggested that they are derived from neuroglial precursor cells with a potential to undergo dual differentiation. These precursor cells might arise from the subependymal layer of the lateral ventricle or from the ventricular region. [45,54, 68].
The natural course of central neurocytoma is classically benign. Total surgical resection is the most important prognostic factor. recurrence is frequent with incomplete removal, but the residual tumor growth can be treated with radiotherapy. CNS dissemination is rare. [57, 66, 69, 70]. central neurocytomas is rarely aggressive [44,47]. Patients with central neurocytomas and a MIB-1 labeling index (LI) >2% or >3% have significantly shorter recurrence-free intervals. Involvement of the periventricular parenchyma involvement may be associated with poor outcome ( 71, 72].
Extraventricular neurocytomas are usually well-defined and contrast-enhancing lesions that often have a cyst–mural nodule complex which is usually useful in distinguishing them from histologically similar neoplasms, such as oligodendrogliomas. Histologically, extraventricular neurocytomas may be identical to central lesions, but are often more complex, less cellular, and more likely to contain ganglion cells or ganglioid cells with nuclei that are larger than those of neurocytes. Lower cellularity, in combination with the presence of perinuclear haloes, may give these lesions the appearance of oligodendrogliomas. Although GFAP-positive glial cells have been observed, it has been difficult to identify them as clearly neoplastic. Hyalinized vessels and dense calcification are common [73].
Dysembryoplastic neuroepithelial tumors (DNTs) are usually benign. They are supratentorial glio- neuronal neoplasms that seen in children or young adults. Characterized by a cortical location and intractable partial complex seizures, they ideally demonstrate a complex columnar and multinodular structural design and are often associated with cortical dysplasia [74].
DNTs correspond histologically to WHO grade I tumors. [1]
DNTs were first recognized as lesions in patients who had undergone epilepsy surgery for the treatment of longstanding, drug-resistant partial seizure sand showed unusual morphological features, including cortical topography, multinodular architecture, a “specific glioneuronal component” with a columnar structure. No recurrence with long term follow up even in patients with incomplete partia resection. Several factors strongly suggested a dysembryoplastic origin, the term “dysembryoplastic neuroepithelial tumor” was proposed for these lesions [74].
In the 1993 WHO Classification of Tumors Affecting the Central Nervous System [36], DNTs were included in the category of “neuronal and mixed neuronal-glial tumors.” With “complex form,” and “simple type” [75]. Later, “non-specific histological forms” were addedd. Furthermore, it has been indicated that DNTs may be seen in the infratentorial location [76, 77, 78,79].
Incidence is variable. In a study of patients who were treated surgically for epilepsy, the incidence of “typical” DNTs was reported to be 12% in adults and 13.5% in children [80], whereas it was reported to be 19% to 22% in all patients in a series that included “non-specific” histological variants [78,81,82]. Among all neuroepithelial tumors diagnosed in a single institution, DNTs were identified in about 0.2% among patients aged more than 20 years and in 1.2% of the patients under the age of 20 years [83].
In about 90% of cases, the first seizure attack occurs before 20 years of age, but it may present from 3 weeks to 38 years [84,85]. though patients are often diagnosed in the 2ed or 3rd decade of life, detection of DNTs by imaging in children or young adults with recent onset seizures has become more common, leading to more surgical intervention for treatment of DNTs in pediatric neurosurgery. It was observe that males are more slightly affected. [86, 87, 88, 89,90].
There is a predilection for the temporal lobe and for involvement with mesial structures although DNTs may be located in any part of the supratentorial cortex, [80, 81,82,83,84]. In one series of patients treated in a general practice, temporal lobe involvement was found in 50% or fewer of cases [85,86]. DNTs have also been found in the area of the caudate nucleus [76,77] or lateral ventricle, the septum pellucidum, the trigonoseptal region [88], the midbrain and tectum, and the cerebellum or cerebellum and brain stem [89,90,91,92]. In total, 25 extracortical cases have been reported. In addition, 4 cases of multifocal DNTs have been reported, indicating that these tumors may arise in the region of the third ventricle, the basal ganglia, and the pons [93, 94,95].
Drug -resistant partial complex seizure is the typical presentation with or without secondary generalization, and no focal neurological deficit. The duration of seizures prior to surgical resection can vary from weeks to many years, leading to variability in patient age at pathologic diagnosis[79, 73,74, 97,98].
The cortical location of the lesion in the absence of both mass effect and peritumoral edema are important criteria in differentiating between DNTs and gliomas. DNTs typically encompass the thickness of the normal cortex and, in a minority of the cases, have an area of signal abnormality that extends into the subcortical white matter. The cortical location of the lesion is easily identified on MRI than on CT. DNTs appear hyperintense on T2-weighted images and hypointense or iso-intense on T1-weighted images. They often have a pseudo-cystic or multi-cystic appearance although true cyst formations are rare and small [91]. In tumors located at the convexity, scalloping of the overlying bone is often observed on scans, a finding supports the diagnosis of DNT(, 77, 99,100, 101,102]. Calcifications are rare. Contrast enhancement on CT or MRI is not common, it is often appearing as rings rather than homogeneous enhancement. Such ring-shaped contrast enhancement may be observed on a previously non-enhancing tumor on scans [96, 102]. Increased tumour size, without peritumoral edema, may also be observed on imaging follow-up. However, these changes are naturally not signs of malignant transformation but rather as a result of ischemic or hemorrhagic changes [103,104].
DNTs vary in size from several millimeters to several centimeters. In their typical location, they are often easily identified superficially at the cortical, and may show exophytic development, but indicate no involvement of leptomeninges. The most typical feature is viscous consistency of the glioneuronal component, which may be associated with multiple or single firmer nodules, and spreading out of the affected cortex [68].
The histological hallmark of a classical DNT is the presence of a “specific glio-neuronal constituent.” This element is characterized by columns formed by bundles of axons lined by small oligodendroglia-like cells that are oriented perpendicularly to the cortical surface between which neurons with normal cytology appear to float in a pale, eosinophilic medium. There are also elements of scattered GFAP-positive stellate astrocytes. Depending on the amount of fluid extravasation, subtle variation from a columnar to o a more packed in structure may be observed. Several histological forms of DNTs have been mentioned, but their subclassification has no clinical or therapeutic implications [76,77]. Figure 5A.B
In the complex form of a DNT, glial nodules, which give the tumor a feature of multinodular pattern, are seen in association with a specific glio-neuronal element. The variable appearance of these tumors is due to the presence of multiple cells of astrocytic, oligodendrocytic, and neuronal components. The glial components seen in the complex forms of DNTs have a highly variable form due to many causes : 1- they may form typical nodules with diffuse pattern; 2- they may mimic usual categories of gliomas and may illustrate unusual features; 3- they usually resemble low-grade gliomas, but may demonstrate nuclear atypia, some mitotic activity, or microvascular-like proliferation and ischemic necrosis; 4- they display a microvascular network. Within the glial components, typically calcified vessels are frequent that may behave as vascular malformations and be responsible for bleeding [65,66,86, 99,101,103, 104,105].
A and B
“Non-specific” histological variants of DNTs, identified according to clinical presentation as well as their cortical location, neuroimaging features, and steadiness on long-term preoperative imaging follow-up, have been described [77]. Due to lackness the specific glioneuronal element and multinodular architecture, these variants are often histologically indistinguishable from low-grade gliomas. The diagnosis of these tumors thus requires that the clinical presentation and neuro-imaging appearance of the lesion be taken into consideration. Non-specific histological types account for 20% to 50% of DNTs in many studies [79,106,). Although gliomas identified in patients with long-term epilepsy during epilepsy surgery are typically associated with a distinctly benign course the diagnosis of “non-specific” histological variants of DNTs still debatable ( 107,108,110].
Morphologically, the simple form of a DNT consists of a unique glioneuronal component it shows a patchy pattern owing to the proximity of foci of tumor and a well-defined cortex [76],.
Dysplastic disorganization of the cortex has been observed in up to 80% of DNT cases in studies with adequate sampling [111,112]. Supratentorial cortical DNTs contain mature neurons that, both in the tumor itself and in the area of cortical dysplasia, may show different degrees of cytological anomaly. Thoug, DNTs do not have atypical or immature neurons that look like dysplastic ganglion cells as observed in gangliogliomas. Some tumor cells with an oligodendrocytic appearance have been found to occasionally express neuronal markers and display axo-somatic synapses suggesting that what is called “oligodendroglial-like cells” of DNTs and it may undergo early neuronal differentiation. However, using in-situ hybridization indicates that oligodendro-glial-like cells copy myelin genes and express myelin oligodendrocyte glycoprotein protein, indicating oligodendro-glial demarcation [113, 114,115, 116].
The borders of the tumor often match with those of the cortex to a very large degree. it also appears to involve the adjoining white matter. However, as neurons are typically found in even the deeper parts of the tumor and in the neighboring white matter, such association is high likely indicates disordered neuronal migration [117].
The diagnosis of DNT should be taken into consideration in every case in which all of the following criteria [76, 77, 80. 81] are present:
the presence of partial complex seizures with/ without secondary generalization beginning before age 20
the absence of progressive neurological deficit.
the presence of a supratentorial lesion with a predominantly cortical topography, best indicated on MRI
the absence of mass effect on CT or MRI, except if related to a cyst
the absence of peritumoral edema on the scans
Differential diagnosis of DNTs and gangliogliomas may be tricky on account of several factors: 1- the clinical presentation of gangliogliomas is often similar to that of DNTs. 2- the immature ganglion cells of gangliogliomas may not be present in a small or inadequate sample. 3- Gangliogliomas may show a multinodular arrangement, 4- small gangliogliomas may show a predominant cortical topography.
A ganglioglioma is suspected when a tumor shows perivascular lymphocytic infiltration, a network of reticulin fibers, and a large cystic component. as gangliogliomas may undergo malignant transformation, their distinction from DNTs is important from a prognostic point of view. ( 118, 119, 120,121].
The above clinical and radiological criteria help in distinguishing benign DNTs from diffuse gliomas. In diagnosis, it is important to consider that 1- in diffuse gliomas, so-called “floating” neurons may be present, 2- in low-grade diffuse gliomas, infiltrative microcystic activity may cause to the formation of a construction that mimics a “specific glio-neuronal element”; 3- some oligodendrogliomas, a nodular pattern may be seen, 4- in diffuse gliomas, secondary architectural changes in the cortex caused by the expansion of gliomas into the cortex may be not easy to differentiate from the presence of dysplastic cortical disorganization [76,77,80.81]..
DNTs have reported in patients with neurofibromatosis type 1 (NF1] and with XYY syndrome [122,123,124].
Variable MIB-1 labeling indices of DNTs have been reported from 0% to 8% focally [79, 81, 84].
Many factors have suggested that DNTs are a malformative origin, including the presence of focal cortical dysplasia and migrated neurons in the adjacent white matter, young age of symptom onset, and bone deformity adjacent to the tumor. Some observations indicate that they may be derived from secondary germinal layers. the histogenesis of DNTs remains unknown [74,77,81, 125]
DNTs are benign lesions. Their stability was indicated in a study of 53 patients for whom successive pre-operative CT or MRI was available with a mean duration of follow-up of 4.5 years [102]. Long-term clinical follow-up typically shows no evidence of recurrence, even in patients with incomplete surgical resection ( 76, 97,99, 102, 107, 126]. Risk factors for post operative recurrent seizures at long-term follow-up include longer pre-operative history of seizures, cortical dysplasia next to DNT and residual tumour ( 85, 100, 127, 128]. Malignant transformation is extremely rare, only 2 cases reported from 700 cases of DNTs [129].
Desmoplastic infantile astrocytomas (DIAs) and desmoplastic infantile gangliogliomas (DIGs) are usually large cystic tumors occurring in infantile period that typically affect the cerebral cortex and leptomeninges and are often attached to the dura. DIGs contain neoplastic astrocytes and neuronal components while DIAs contain only neoplastic astrocytes.
Histologically, DIAs and DIGs correspond to WHO grade I tumors.
DIAs were originally described by Taratuto et al in 1982. [130] as meningocerebral astrocytomas attached to the dura displaying a desmoplastic reaction. Their subsequent description as superficial cerebral astrocytomas attached to the dura [131] led to the delineation of a previously unknown entity. In 1993, this entity was included in the WHO Classification of Tumors Affecting the Central Nervous System [132] under the term “desmoplastic cerebral astrocytoma of infancy.” In 1987, VandenBerg et al reported observation of desmoplastic supratentorial neuroepithelial tumors of infancy with diverse differentiation (“desmoplastic infantile gangliogliomas”) in the same clinical setting. They described the histopathology of DIGs as differing from that of DIAs due to the presence of a neuronal component with variable differentiation in the former. [133]. Since both types of lesions have similar clinical and neuroimaging features they have been currently categorized together as DIAs or DIGs in the WHO Classification.
DIAs and DIGs are rare tumours and only observed in childhood whose rate can only be estimated from their reported frequency in institutional series. One series of 6500 CNS tumors in patients of all ages reported only 22 cases of DIG at a rate of 0.3% [134]. In a series of CNS intracranial tumors limited only to the pediatric age group reported 6 cases of DIA, accounting for 1.25% of all childhood brain neoplasm. While, reports limited to brain tumors of infancy have found that DIAs and DIGs account for 16% of intracranial tumors [131,135].
In a study, the age range for 84 reported cases of DIA and DIG was found to be 1 to 24 months. Males ae more commonly affected, with Male:female ratio is 1.5:1. The large majority of infantile cases present within the first year of life. However, several non-infantile DIA, DIG between 5 to 25 years have been reported [136, 137].
DIAs and DIGs invariably arise in the supratentorial region and commonly involve more than one lobe, most frequently the frontal and parietal lobes, followed by the temporal and less commom the occipital lobe [137].
The clinical features of DIAs and DIGs are of short duration and include increasing head circumference, tense and bulging fontanelles, lethargy, and sun set sign. Patients may also present with seizuresor focal motor signs, calvarial bulging over the tumor may also be observed [136].
On CT, these lesions are seen as large, hypodense cystic masses with a solid isodense or slightly hyperdense superficial portion that extends into the overlying meninges and shows contrast enhancement. The cystic portion is typically located deep within the tumor, where the solid portion is peripheral. The MRI T1-weighted images are characterized by a hypointense cystic component with an isointense peripheral solid component that takes contrast. On T2-weighted images, the cystic component is hyperintense and the solid portion is heterogeneous. Edema is usually absent or light [138]. Figure 6
A and B
DIAs and DIGs are typically large tumors, measuring up to 13 cm in diameter, with deep multiloculated cysts filled with clear or xanthochromic fluid. The solid superficial portion is primarily extracerebral, attached to leptomeninges and the superficial cortex, it is firm or rubbery in consistency, and grey or white in color.
The DIA or DIG composed of neuroepithelial tumor with 3 characteristic components: a main desmoplastic leptomeningeal component, a poorly differentiated neuroepithelial component, and a cortical component. The desmoplastic leptomeningeal component consists of a mixture of fibroblast-like spindle-shaped cells and pleomorphic, neoplastic, and neuroepithelial cells with eosinophilic cytoplasm, both of which are arranged in fascicles or in a whorled pattern. Reticulin impregnations show a prominent reticulin-positive network surrounding almost every cell and mimicking that of a mesenchymal tumor. Astrocytes are the main tumor-cell feature in DIAs or the predominant neoplastic population associated with immature neurons in DIGs. The type of neoplastic neuron may range from atypical ganglionic cell to a small polygonal cell [133,139].
In addition to this desmoplastic leptomeningeal component, both DIAs and DIGs contain a group of poorly differentiated neuroepithelial cells with small, round, deeply basophilic nuclei and minimal surrounding perikarya. Such an immature component lacking desmoplasia may predominate in some areas. A cortical component devoid of desmoplasia may also be seen that is often multinodular, with some nodules being microcystic [139].There is a sharp delineation between the cortical surface and the desmoplastic neoplasm, Virchow-Robin spaces in the underlying cortex are often occupied with tumor cells. Calcifications are frequent. Mitotic activity and necrosis are rare. Some tumors may be slightly vascular [137, 140, 141, 142]. Figure 7A.B
Figure 7
In the desmoplastic leptomeningeal component, fibroblast-like cells express vimentin. As most other neuroepithelial tumor cells react with GFAP, astrocytes predominate in this component. Antibodies to collagen typr VI react in a reticulin-like pattern around tumor cells [143,144]. Expression of neuronal markers (synaptophysin, NF-H, and class III ß-tubulin) has been observed in both the neoplastic neuronal cells as well as cells lacking apparent neuronal differentiation [145]. In the poorly differentiated neuroepithelial component, cells react with not only GFAP and vimentin but also with neuronal markers and MAP2 Desmin expression may be present [134,145, 146, 148]; but epithelial markers (CAM 5.2, AE1/AE3, and EMA) are usually absent [145]. Figure 8A.B
Astrocytic tumor cells are characterized by intermediate filaments typically arranged in bundles as well as scattered cisternae of rough endoplasmic reticulum and mitochondria with extensive basal lamina. Fibroblasts containing granular endoplasmic reticulum and well-developed Golgi complexes [141, 142]. The neuronal cells of DIGs contain dense core secretory granules and neurofilaments. Immunoelectron microscopy has shown filamentous reactivity to NF-H in these neuronal cell bodies as well as processes lacking involvement of the basal lamina. [149].
Mitotic activity is rare and, when present, is mostly restricted to the undifferentiated, small-cells in DIGs [134,139]. Ki-67 labeling indices reported in the literature range from less than 0.5% to 5%, with the majority of studies reporting them as less than 2% [150]. Proliferation does not appear to be related to clinical behavior in completely resected tumors but may expect more aggressive nature in subtotally resected cases. In 3 cases analyzed by flow cytometry, the S-phase fraction ranged from 3.7% to 12%, with a mean of 6.6% [151, 152, 153].
The cellular origins of DIAs and DIGs is yet to be known. The presence of primitive small-cell populations that express both glial and neuronal proteins suggest that these cells are progenitor cells to the more differentiated neuroepithelial components and supports the contention that DIAs and DIGs are embryonal neoplasms programmed to progressive maturation [42,155]. Origination from the specialized subpial astrocytes that form a continuous, limiting basal lamina providing their terminal processes could account for a comparable phenomenon occurring in desmoplastic infantile tumors and for their superficial localization. The lack of genetic alterationsas observed in most diffuse astrocytomas suggests they are not related to these neoplasms [142,143].
A and B
A comparative genomic hybridization study of 3 cases of DIA and DIG revealed no consistent chromosomal gains or losses [150]. Molecular studies of DIAs revealed no loss of heterozygosity on chromosomes 10 and 17 and the absence of TP53 mutations [142,152]. One case of DIG showed a loss on 8p22-pter, whereas one case of DIA showed a gain on 13q21. [154].
Follow-up studies indicate that gross total removal is the treatment of choice. In a study 14 of patients with DIGs (median follow-up, 8.7 years), no mortality or evidence of tumor recurrence was observed [134].. In cases of subtotal resectioning or biopsy, most tumors are stable or recurre slowly. In 1 study, 2 tumors showed radiologic evidence of tumor regression following incomplete resectioning. Dissemination of these tumors through the CSF has been reported but rare,[151,156] Long-term tumor control in cases of DIA and DIG can be achieved by total surgical resectioning despite the presence of primitive-appearing cellular aggregates with mitotic activity or foci of necrosis.. However, tumor evolution has been reported in cases of DIG that underwent subtotal removal, including those with high proliferative indices and anaplastic features [149,157,158]
This type of posterior fossa tumours is a rare and slowly growing neoplasm in the fourth ventricular region, predominantly affecting young adults, and composed of uniform neurocytes forming rosettes or perivascular pseudorosettes and astrocytes mimic pilocytic astrocytoma.
The rosette-forming glioneuronal tumor (RGNT) corresponds to WHO grade I [1].
A neoplasm displaying features of RGNT was early reported as a “dysembryoplastic neuroepithelial tumor (DNT) of the cerebellum”. However, Komori et al. described RGNT as a distinct entity as a variant of mixed glio-neuronal tumor [159,160]. Wheares, Preusser et al. confirmed RGNT as a tumor entity [161].
The age range at disease presentation is 12–59 years (mean, 33 years). With a slight female preference.
RGNT is a rare brain tumor. In five different studies, only 17 cases were reported. These lesions arise in the midline and occupy the fourth ventricle and may be the aqueduct, it may extend to involve the adjacent brain stem, cerebellar vermis, pineal gland, or thalamus( 160,161, 163, 164,165].
MR imaging reveals a relatively circumscribed, solid tumor in the fourth ventricular region, showing low intensity on T1-weighted images and high intensity on T2-weighted images,, and focal or heterogenous gadolinium enhancement. Secondary hydrocephalus is common ( 164,165].
The clinical presentation of RGNT is most often with headache due to of obstructive hydrocephalus, and unsteadiness. Cervical pain is occasionally experienced. Rarely discovered incidentally. Figure 9.
Figure 9
RGNTs are well demarcated, but some infiltration into the brain stem and cerebellar parenchyma may be observed. They are characterized by a biphasic neurocytic and glial architecture. The neurocytic component consists of a uniform group of neurocytes. these cells have spherical nuclei with finely granular chromatin, inconspicuous nucleoli, scant cytoplasm, and delicate cytoplasmic processes forming neurocytic rosettes and/or perivascular pseudorosettes. Neurocytic rosettes feature ring-like arrays of neurocytic nuclei surrounding delicate eosinophilic neuropil cores. While the perivascular pseudorosettes feature delicate cell processes radiating toward vessels. The neurocytic rosettes and perivascular pseudorosettes when viewed longitudinally, may show a columnar arrangement.. These neurocytic structures may lie in a partly microcystic, mucinous matrix.
The glial component of RGNT typically dominates, and in some areas may resemble pilocytic astrocytoma. Astrocytic tumor cells are spindle to stellate in shape, with elongated to oval nuclei and moderately dense chromatin. Cytoplasmic processes often form a compact to loosely textured fibrillary background. Rosenthal fibers, eosinophilic granular bodies, microcalcifications, and hemosiderin deposits may be observed. In some areas, the glial component may be microcystic, containing round, oligodendroglia-like cells with some perinuclear halos. Vessels may be thin-walled and dilated or hyalinized. Thrombosed vessels and glomeruloid vasculature may also be noted. The adjacent cerebellar cortex has no features of dysplasia ( 160,162, 164, 165]. Figure 10A
A and B
Immunoreactivity for synaptophysin is present at the centers of neurocytic rosettes and in the neuropil of perivascular pseudorosettes.furthermore, the cytoplasm and processes of neurocytic tumor cells may express MAP-2 and neuron-specific enolase. GFAP and S-100 immunoreactivity is shown in the glial part, but absent in the rosettes and pseudorosettes. [160, 162, 164]. Figure 10 B.
Ki-67 labeling indices are low, being less than 3% in reported cases, Mitosis is absent [165].
One reported patient with RGNT had a Chiari type I malformation [160]. No other evidence of an underlying neurological disorder or association with a familial tumor syndrome has been reported.
The histological investigations indicate that RGNTs arise from the brain tissue surrounding the infratentorial ventricular system. An origin of RGNT from the subependymal plate; the remnants of the periventricular germinal matrix has been suggested [160].
The clinical outcome of these primary benign neoplasm is favorable in terms of survival, but disabling cerebellar features postoperatively have been reported in approximately half the cases [160].
A well circumscribed, clinically insidius and histologically biphasic cerebral neoplasm composed of flat to cuboidal, GFAP-positive astrocytes lining hyalinized vascular pseudopapillae and synaptophysin-positive interpapillary collections of sheets of neurocytes, large neurons, and ganglioid cells.
Papillary glioneuronal tumors is corresponding to WHO grade I. late aggressive behavior has been reported [1,165].
The papillary glioneuronal tumor, was first established as a distinct clinicopathological entity by Komori et al. in 1998 and listed in the 2000 WHO classification as a variant of ganglioglioma, [166]. Some tumors were previously described under a variety of names, including pseudopapillary ganglioglioneurocytoma and pseudopapillary neurocytoma with glial differentiation ( 167,168].
They are very rare neoplasms; and only a few cases have been reported [169.170]. These tumors may occur at any age. There is no gender preference. The mean age at presentation is 27 years; the oldest and youngest patient reported was 75 and 4 years, respectively [171,172]..
These tumors are generally seen in the cerebral hemispheres, with a predilection for the temporal lobe.
On MRI and CT imaging, the tumors appear as well defined, solid and/ or cystic, with some contrast-enhancement there is usually little mass effect. A cyst-mural nodule architecture may be observed [166, 169.173].
Mainly headache and seizures. Focal deficits, cognition, and emotional disorder may also be encountered. [174].
Papillary glioneuronal neoplasms is characterized by a prominent pseudopapillary manner in which a single or pseudostratified layer of small, cuboidal glial cells with rounded nuclei and scant cytoplasm covers hyalinized blood vessels, as well as interpapillary sheets or focal collections of neurocytes, and occasionally ganglion cells or medium-sized ganglioid cells with accompanying neuropil.
At the immunohistochemical level, vessels with mural hyalinization are ensheathed by a layer of small, uniform, GFAP-positive cells with rounded nuclei and scant cytoplasm. In some cases, OLIG2-positive, GFAP-negative glial cells surround this layer. These glial elements lack both nuclear atypia and mitotic activity. Interpapillary neuronal elements show considerable variation in size and shape. all get stained with antisera to synaptophysin, NSE, and class III-tubulin. The majority of neuronal cells are positive for NeuN, but NFP expression is mostly confined to larger ganglioid and ganglion cells. Membranous immunoreactivity for NCAM is also found ( 166, 172, 175], but chromogranin-A expression is lacking. Minigemistocytes which show intense GFAP immunoreactivity, are occasionally noted in the interpapillary spaces. Microvascular proliferation or necrosis is rare. Even in cases with increased proliferative activity. At the periphery of the lesion, scattered tumor cells are mixed with gliotic brain tissue containing Rosenthal fibers, eosinophilic granular bodies, hemosiderin, and microcalcifications are encountered; this results in a a blurred tumor edge ( 165, 175]. Figure 11 A.B
The ultrastructure of few papillary glioneuronal tumors has been studied. Three cell types have been reported: astrocytic; neuronal; and poorly differentiated neurons. Neurons vary in size: large forms with abundant organelles lie between the papillae; their neuronal processes filled with parallel microtubules showed terminations containing clear vesicles and occasional synapses. The poorly differentiated cells contain mitochondria, ribosomes, occasional dense bodies, intermediate filaments and microtubules, but no well-formed dense core granules. Astrocytes contain bundles of intermediate filaments, and are separated from vessels by a basal lamina. Minigemistocytes and OLIG-2-expressing oligodendrocyte-like cells may also be present ( 165, 166, 171].
MIB-1 labeling indices are usually low, in the range of 1–2%. Only 1 tumor featuring minigemistocytes showed an increased [10%) labeling index in that unusual element [165].
A and B
Papillary glioneuronal tumors reported to date have been sporadic in occurrence. [175].
The histogenesis of papillary glioneuronal tumors is uncertain, but an origin from multipotent precursors capable of divergent glioneuronal differentiation is supposed. [166].
The cystic formation, indolent course and low proliferative activity are given a favorable clinical outcome. In most cases, gross total resection without adjuvant therapy is curable with long-term survival. [165].
A very rare cerebellar neoplasm with variable neuronal, astrocytic, and focal lipomatous differentiation, and low proliferative potential; the tumor usually has a favorable clinical course.
Data available advocate that this tumor typically corresponded to WHO grade I [1]. However, recurrences have been reported in almost 50% cases, typically without the histological features of malignant transformation. [176].
Bechtel et al. Reported a case of lipomatous medulloblastoma in a 44-year-old man. in 1978 [177]. Subsequently 28 more cases were reported. The terms neurolipocytoma [178], medullocytoma [179], lipomatous glioneurocytoma [180], and lipidized mature neuroectodermal tumor of the cerebellum [181]. The WHO Classification in 2000 [1] included the term “cerebellar liponeurocytoma”. However, This term is now widely accepted, and is supported by genetic analyses indicating that this lesion is not a variant of medulloblastoma [170]. Clinical, histopathological, immunohistochemical, and genetic data strongly suggest that the cerebellar liponeurocytoma comprise a rare but distinct clinico-pathological entity. Some tumors with features of liponeurocytoma have also been observed in supratentorial locations. [182, 183, 184]..
In the 29 patients with cerebellar liponeurocytoma reported ( 182, 185, 186, 187,188,189], the mean age was around 50 years (range, 24–77 years), with a peak in the third to sixth decade of life. This is in contrast with the age distribution of cerebellar medulloblastomas, more than 70% of which occur in children [178]. There is no significant gender predilection [13 men and 16 women) in patients with cerebellar Liponeurocytoma [186, 187,188,189].
Non specific symptoms such as Headache and signs of raised intracranial pressure may be the initial presentation, resulting from either the lesion itself or obstructive hydrocephalus. Cerebellar signs are also frequent [188].
MRI appearance is variable, and may be related to the distribution and proportion of lipidized tissue. On T1-weighted MRI, the mass is generally hyperintense but heterogeneous. Hyperintense streaks on T2-weighted images have been associated with the macroscopic appearance of adipose tissue at surgery. Enhancement with gadolinium is usually irregular. Peritumoral edema is usually absent (,190, 191].
These neoplasms are predominantly located in the cerebellar hemispheres, followed by in the vermis. And rarely in the cerebellopontine angle. Raely, liponeurocytomas have been diagnosed in the supratentorial ventricular system at a rate to approximately 3% of central neurocytomas. There are 2 cases of cerebellar neurocytomas without adipose tissue have been reported [182, 185, 192, 193]. In 1 case, it was shown that the lipid vacuoles progressively accumulate and coalesce within cells, maintaining neurocytic features, and indicating tumoral lipidization rather than true adipose metaplasia. These observations justify the description of central liponeurocytoma as a separate entity, and these lesions contribute to histogenetic and biological characteristics with cerebellar liponeurocytoma [194, 195,196].
Biphasic in appearance, the tumor consists of small neuronal cells with the cytology of neurocytes and focal lipomatous differentiation, characterized by lipidized cells resembling mature adipose tissue. Tumor cells have round or oval nuclei, and often show a clear cytoplasm resembling neoplastic oligodendrocytes, but also have many morphological similarities to medulloblastoma and clear cell ependymoma. Despite the cellularity of the lesion, tumor cells have a uniform cytological appearance, with absent or very few mitotic figures and aggressive features. No malignant transformation noted [194, 195,196]. Figure 12A
Neuronal differentiation is observed by a reliable, diffuse expression of NSE, synaptophysin, and MAP-2. Accordingly, several reported cases were diagnosed as neurocytoma or neuroblastoma, rather than medulloblastoma. Focal GFAP expression by tumor is also seen, indicating astrocytic differentiation [184]. Immunoreactivity for neuronal markers and GFAP is also seen in the adipose cells, indicating an abnormal differentiation of tumor cells rather than an entrapped adipocytes. It is crucial to note that xanthomatous histiocytes, as are occasionally observed in ordinary medulloblastomas, are not considered evidence of lipomatous differentiation. Two reports mention additional immunoreactivity to desmin, and morphological features of incipient myogenic differentiation [177,181]. Figure 12 B
The most important differential diagnosis is medulloblastoma with lipidized cells. The distinction between these 2 lesions is crucial, since medulloblastomas with lipidized cells require adjuvant radio/chemotherapy. Most importantly, the growth fraction is in the range of 15–40%, which is incompatible with a diagnosis of liponeurocytoma. Cerebellar liponeurocytoma is a neoplasm of adults, while lipidized medulloblastomas also occur in children [186, 188, 197, 198, 199]. The liponeurocytomas may also mimic neoplastic oligodendrocytes and clear cell ependymoma [199].
Figure 12
The Ki-67/ MIB-1 labeling index, is usually in the range of 1–3%, but may be as high as 6%, with a mean value of 2.5%. In the adipose component, the MIB-1 labeling index is even lower [184, 200].
An origin from the external granular layer of the cerebellum cannot be ruled out, Immunoreactivity to neuronal antigens and GFAP includes cell bodies embracing fat globules. This suggests that the fat-containing cells result from lipomatous differentiation of tumor cells. The cell of origin is most likely a precursor cell with a preferential commitment to neuronal differentiation. [184,185,200].
Genetic analysis of 20 cerebellar liponeurocytomas revealed TP53 missense mutations in 4 cases [20%), a frequency significantly higher than that in medulloblastomas [6%). There was no case with a PTCH, APC, or ß-catenin mutation, each of which can be present in subsets of medulloblastomas. FISH analysis showed that isochromosome 17q, a genetic hallmark present in 40% of cerebellar medulloblastomas, was not enountered in any of the cases investigated. This finding supports the view that the cerebellar liponeurocytoma is a distinct entity and not a variant of medulloblastoma. cDNA expression profiles showed a relationship to central neurocytoma, but the presence of TP53 mutations, which are absent in central neurocytomas, suggests that they develop through different genetic pathways [182].
A review of published cases indicates that this lesion generally carries a favorable prognosis. Because of the rarity of this tumor and the lack of systematic follow-up data, survival and recurrence rates must be interpreted with some caution [182, 185].
Of 21 patients with follow-up data, 6 [29%) died within 6 months to 2 years, 5 [24%) died after 2–4 years and 10 [48%) survived 5–16 years after surgical intervention. The 5-year survival rate was 48% and the mean overall survival was 5.8 years. However, 62% of patients developed a recurrence from 1 to 12 years, and in 3 patients there was a second relapse 1 to 5 years later. Despite its aggressive course there is no malignant transformation observed. [176].
A distinctive neuroendocrine neoplasm, usually encapsulated, slowgrowing, and benign, arising from specialized neural crest cells associated with segmental autonomic ganglia (paraganglia); it is composed of uniform chief cells displaying neuronal differentiation and forming compact nests (Zellballen), surrounded by sustentacular cells and a delicate capillary network. This type of neoplasm is mostly affecting the cauda equine and filum terminale
Paragangliomas of the cauda equine/filum terminale correspond histologically to WHO grade I [1].
The early terminology of paragangliomas is not well known. Early authors divided them into chromaffin and nonchromaffin on the basis of their reaction with chromic acid. However, since this reaction does not reliably reflect their functional activity, current terminology is based upon anatomical location as seen in carotid body paraganglioma (chemodectoma), jugulotympanic paraganglioma (glomus jugulare tumor).
Paragangliomas of the CNS are infrequent, the vast majority present as lumber spinal intradural tumors in the cauda equina region. Since the first description of cauda equina region paraganglioma in 1970 [201], more than 210 cases have been reported. And 174 cases reported prior to 2003 [202]. Paragangliomas of the cauda equine region comprise 3.4% to 3.8% of all tumors affecting this region [203, 204]. Other spinal levels are involved far less often; 14 paragangliomas were reported in the thoracic region, most being extradural with an intravertebral and paraspinal component [205, 206], and 2 tumors involved the cervical region [207, 208].
Intracranial paragangliomas are usually located in the posterior fossa; jugulotympanic paragangliomas [209]. However, intracranial tumors have also been described. These locations include sellar region, the cerebellopontine angle, cerebellar parenchyma, and the fronto-temporal lobes [210, 211, 212, 213].
Cauda equina paragangliomas generally affect adults. Patient age ranges from 9 to 74 years (mean, 46 years), with a slight predominance in males with Male:Female ratio at 1.4:1. Jugulotympanic paragangliomas are more common in Caucasians, with a strong female preference, and occur mainly in the fifth and sixth decades [209].
The most common presenting symptoms include a long standing history of low-back pain and sciatica. Sensory deficit, paraparesis, and sphincter disturbances are common in the later stage, while complete cauda equina syndrome is rare. An intracranial hypertension symptoms and signs was reported in 8 cases. Only 3 endocrinologically functional paragangliomas of the cauda equine region have been reported [214, 215, 216]. The few reported paragangliomas of the thoracic spine presented with short term of signs of spinal cord compression [217]. About 36% of glomus jugulare paragangliomas extend into the cranial cavity and produce headache, pulsatile tinnitus and lower cranial nerve involvement; rarely, signs of catecholamine secretion may be seen [209].
Cauda equina paragangliomas has no specific features. Most appear as isodense, homogeneously enhancing masses on CT. However, since CT without contrast may miss the lesion, MRI is the investigation of choice. MRI images typically show a well marked, may be with cystic component mass that is hypo- or isointense to spinal cord on T1-weighted images, with a vivd contrast enhancemnet. It appears as hyperintense on T2-weighted images. The presence of ecstatic and dilated vessels and a low signal intensity rim (“cap sign”) on T2-weighted images are considered diagnostically important feature. Plain radiographs are usually helpful, and show some scalloping of the vertebral bod y due to chronic bone compression [204, 218]. Figure 13
Tumors are well differentiated, mimicking normal paraganglia, nearly half of cauda equina paragangliomas contain mature ganglion cells, as well as cells transitional between chief and ganglion cells. These lesions are composed of chief (type I) cells disposed in nests or lobules (Zellballen pattern), and surrounded by a single layer of sustentacular (type II) cells. The Zellballen are surrounded by a delicate capillary network that may undergo sclerosis. The uniform round or polygonal chief cells possess central, round-to-oval nuclei, with finely stippled chromatin and inconspicuous nucleoli. Cytoplasm varies somewhat in quantity and is usually eosinophilic and finely granular. In some conditions, it is amphophilic or clear. Sustentacular cells are spindle-shaped. Encompassing the lobules, their long processes are often so attenuated that they are undetectable by routine light microscopy, and visible only on immunostains for S-100 protein. [219]. Such “gangliocytic paragangliomas” are also found in other sites such as the duodenum and are analogous to phaeochromocytoma with neuronal differentiation. Some paragangliomas of the cauda equina region show architectural features similar to carcinoid tumors, including angiomatous, adenomatous, and pseudorosette patterns. Tumors composed predominantly of spindle and melanin-containing cells (melanotic paragangliomas) have also been described at this site, as has oncocytic paraganglioma [220, 221, 222]. hemorrhagic necrosis may also occur, and scattered mitotic figures can be seen. these features are not of prognostic implication [223]. Figure 14A
Chief and sustentacular cells can be identified by biomarkers. Chief cells are marked with Neuron-specific enolase (NSE), synaptophysin and chromogranin [228, 229]. Chromogranin A reactivity parallels the Grimelius (argyrophil) reaction [219, 223,224]. Neurofilament proteins are also useful markers of chief cells. Expression of serotonin [5H-T) and of various neuropeptides (somatostatin, leu, and metenkephalin) has been demonstrated in paraganglioma of the cauda equina region. Paranuclear cytkeokeratin immunoreactivity is particularly prominent in cauda equina examples. Sustentacular cells are uniformly reactive for S-100 protein, and usually show staining for glial fibrillary acidic protein (GFAP). Chief cells may also show variable S-100 immunoreactivity [220, 223, 225]. Figure 14B
The characteristic ultrastructural features of chief cells is the presence of dense core (neurosecretory) granules measuring 100 to 400 nm (mean, 140 nm). Depending on their cytoplasmic electron density, “light” and “dark” chief cells are recognized. A layer of basal lamina is present at the interface of Zellballen and surrounding stroma. In addition to well-developed Golgi, extensive smooth endoplasmic reticulum, and lysosomes, chief cells may contain numerous atypical mitochondria, as well as paranuclear whorls of intermediate filaments [223, 226]. Sustentacular cells are characterized by an elongated nucleus with marginal chromatin, increased cytoplasmic electron density, relative profusion of intermediate filaments, and low core granules [225, 226, 227].
It is not clear, there is no reported association of spinal paragangliomas with genetic abnormalit. However, Systemic paragangliomas may be multifocal, The association of spinal paraganglioma with brain tumors, spinal epidural haemangioma, syringomyelia, and intramedullary cysts are encountered [228, 229, 230, 231], but these associations may be coincidental. Several autosomal dominant inherited syndromes predispose to paraganglioma or phaeochromocytomaas noted in von Hippel- Lindau disease (VHL); multiple endocrine neoplasia type 2 (RET mutations); neurofibromatosis type 1 (NF1]. Multiple, benign, head and neck paragangliomas are often caused by SDHD mutations, while SDHB mutations are associated with phaeochromocytoma. There are only 4 families with the SDHC mutation have been identified. Spinal paragangliomas are considered non-familial, but a study of 22 spinal paragangliomas showed an SDHD germline mutation in 1 patient with recurrent spinal paraganglioma and a cerebellar metastasis [232].
The histogenesis is unknow. Some authors favor an origin from paraganglion cells associated with regional autonomic nerves and blood vessels [233]. Others have suggested that peripheral neuroblasts usually present in the adult filum terminale may undergo paraganglionic differentiation [229]. Jugulotympanic paragangliomas presumably arise from microscopic paraganglia within the temporal bone. Some interesting cases have reported the coexistence of a paraganglioma and myxopapillary ependymoma in the cauda equina region [234, 235].
Tumor location is the most important predictive prognostic factor rather than histology of paragangliomas. For instance, the metastasis rate of para-aortic paraganglioma is high (28 to 42%), whereas that of carotid body tumors is only 2 to 9% [236]. About 50% of the glomus jugulare tumors recur locally, but only 5% with distant metastastases [234, 237]. The tumor vascularity has no significant value. The vast majority of cauda equina paragangliomas are slowly growing and curable by total excision. Based on long-term follow-up, it is estimated that 4% will recur following gross total removal [238, 239]. Metastasis outside the CNS is rare [220]. CSF seeding of spinal paragangliomas has been reported [240].
CNS neuroepithelial and neuronal tumours are usually benign and slow growing neoplasms with WHO grade I-II. They comprise a low percentage of the whole CNS neoplasms and may affect any part of the CNS. These lesions present with non specific symptoms and signs; but tend to cause intractable epilepsy when affecting the cerebral cortex. Along with clinical presentation and neuroimaging; the histopathology and immunochemistry confirm the diagnosis. Surgical resctioning is the treatment of choice with favorable prognosis and long term cure; adjuvant treatment is preserved to recurrent tumours or to high grade lesions
Location | WHO | Type of cells | Specific features | prognosis | |
Ganglioglioma and Gangliocytoma | Throughout the CNS more common in Supratentorial. Temporal lobe predilection | Grade I Garde III | Immature ganglion cells and/ or astrocyte | Large neoplastic ganglion cells with/without glial components | Low grade favorable Higher grade : variable |
Central Neurocytoma and extraventricular Neurocytoma | Supratentorial. Paraventricular | Grade I-II | Uniform ferentiated neurocyte | Oligodendroglioma-like honeycomb appearance, irregular “rosettes” perivascular pseudorosettes | Favorable |
Dysembryoplastic Neuroepithelial tumour | Temporal lobe and mesial region | Grade I | glio-neuronal constituent | columns formed by bundles of axons lined by small oligodendroglia-like cells | Favorable |
DIA , DIG | Supratentorial with frontal and parietal lobes predilection | Grade I | desmoplastic leptomeningeal, poorly differentiated neuroepithelial cells | Astrocytes are the main tumor-cell in DIAs. immature neurons in DIGs | Favorable |
RGNT | 4th ventricle and aqueduct cerebellar and brain stem | Grade I | a biphasic neurocytic and glial architecture. | The neurocytic rosettes ,perivascular pseudorosettes. | Favorable |
Papillary Glio-neuronal tumour | Temporal lobe | Grade I | small, cuboidal glial cells,collections of neurocytes,and occasionally ganglion cells | pseudopapillary manner and pseudostratified layer of small, cuboidal glial cells, interpapillary sheets collections of neurocytes, ganglion cells. | Favorable |
Cerebellar Liponeurocytoma | Cerebellar hemisphere , vermis CP angle, rarely supratentorial | Grade I | small neuronal cells with focal lipomatous differentiation, | small neuronal cells with the cytology of neurocytes and focal lipomatous cella, resembling mature adipose tissue | Favorable |
Filum terminale and spinal paraganglioma | Cauda equine region. Jugulotympaniirial arely supratento | Grade I | mature ganglion cells, transitional cells between chief and ganglion cells | mature ganglion cells, cells transitional cells. Chief (type I) cells disposed in nests or lobules (Zellballen pattern) surrounded a delicate capillary network, and sustentacular (type II) cells. | Favorable |
Summary
The use of osteobiologics to improve the outcome of spinal fusion has contributed to an increase in spinal fusion surgical procedures worldwide [1]. There are many different types of bone graft fusion materials currently on the market, however there is still a need for a cost effective biological material to achieve a successful permanent arthrodesis [2]. Presently iliac crest autograft, used for spinal fusion surgeries, is desirable as it possess osteo-biological properties with reduced risk of diseases transmission and graft rejection [3]. However, according to some studies, autograft has been linked to longer surgery time, few donor site availability [4], and chronic donor site pain [5, 6]. These limitations and disadvantages have led to novel therapeutic bone graft options for spinal fusion surgery [5, 7], like BMPs.
Marshall Urist was the first to describe BMP in 1965. It belongs to the transforming growth factor-ß family. There are various types of BMP molecules that exist, however few of them have been associated with osteoblast differentiation and bone development [7]. Recombinant rhBMP-2 is the market available form of BMP-2 FDA approved for anterior lumbar interbody fusion (ALIF) [8]. There have been several clinical studies on the anterior lumbar interbody fusions and all have reported effective fusion rates, reduced operative time, reduced blood loss, and reduced hospital duration with the administration of rhBMP-2 when compared to iliac crest bone graft (ICBG) [9]. However, there have been conflicting reports as to whether rhBMP-2 is efficient in spinal fusion. A well-done study was performed by Papakostidis et al., who investigated the benefits of rhBMP-2 in promoting posterolateral fusion. They concluded in their report that rhBMP-2 significantly increases rates of fusion, reduced hospital stay with the administration of BMP-2, compared to autologous iliac crest bone graft [10]. Lee et al. also confirmed the efficacy of the administration of rhBMP-2 in elderly patients undergoing posterolateral lumbar fusion at a single operative level [11]. Similarly, researchers like Meisel and colleagues also reported a 95–100% successful arthrodesis with use of BMP-2 when performing posterior lumbar interbody fusion [12]. However, recent systematic reviews question the efficacy and use of BMP-2 over iliac crest bone graft as noted in the Yale University Open Data base (YODA) Project and FDA reports. Including 13 randomized-controlled and 31 cohort studies, the study reported that for spinal fusion, rhBMP and iliac crest bone graft have similar efficacy. However, incidence of adverse event might be greater in anterior lumbar-body fusion and anterior cervical spine fusion. Furthermore, rhBMP can increase 24-month cancer risk [8]. These reports concluded that there were no substantial clear benefits of the administration of BMP-2 in spine fusion over autologous bone graft, and in fact there were more complications linked with BMP-2 use [13] (Figure 1).
Lateral radiograph of the cervical spine demonstrating massive soft- tissue swelling (arrows) following anterior cervical diskectomy and fusion surgery using rhBMP-2. Image was culled from.
There are about 20 different BMPs, however only BMP-2 is presently FDA approved for human spinal surgery [14, 15]. In addition, BMP-7 has been investigated for human use but is not FDA approved.
Burkus and colleagues demonstrated that patients administered with recombinant rhBMP-2 inside a Lumbar Tapered Fusion Device (LT-CAGE) had statistically significant lower length of surgery, lower duration of hospitalization and higher fusion rates at 6 months, 1 year and 2 years, compared to patients administered with the conventional ICBG [16]. In another clinical study, Burkus and co-worker compared the administration effect of rhBMP-2 in ALIF with structural cortical allografts and the INTER FIX Threaded Fusion Device to ICBG [17]. They concluded that patients administered with rhBMP- 2 exhibited better clinical and radiographic results, compared to ICBG patients [18]. Furthermore Burkus and colleagues reported that they recorded a superior and higher rates of radiographic fusion compared to the control group, in addition they demonstrated that rhBMP- 2 resulted into an improved ODI outcomes, enhanced radiographic fusion rate, compared to the ICBG control group. Table 1 shows a summary of different available clinical studies demonstrating the potency of rhBMP-2 in increasing fusion rates of various spine surgeries.
Anatomical location of rhBMP-2 | Adverse events | % Of fusion | Reference |
---|---|---|---|
Posterolateral lumbar | None reported | 100% | [18] |
Anterior lumbar | None reported | 94.5% | [13] |
Posterolateral lumbar | None reported | 95% | [19] |
Posterolateral lumbar | None reported | 96% | [20] |
Posterolateral lumbar | None reported | 88% | [21] |
Anterior lumbar | There were reports of retrograde ejaculation | NA | [22] |
Posterior cervical | There were evidences of large seroma with recurrence after surgery | NA | [23] |
Posterior lumbar interbody | Osteolysis | 83% | [24] |
Posterior lumbar interbody | There were reports of increased incidence of radiculitis | 96.5% | [25] |
Posterior lumbar interbody | There were reports malignancy at 5 years | NA | [26] |
Showing the rates of fusion and adverse events associated with the application of rhBMP-2.
Culled from [27].
The efficacies of rhBMP-2 have been studied and reported over the past few years. Boden et al. in their prospective randomized multicenter clinical trials demonstrated that the administration of rhBMP-2 in posterolateral lumbar fusion (PLF) [19]. They compared the effect of rhBMP-2 in patients with suffering from degenerative disc disease following PLF [20]. The patients were divided into three groups: autograft with pedical screw fixation, rhBMP-2 with pedical screw fixation, and rhBMP-2 without pedical screw fixation [21]. They concluded that they recorded a 100% fusion rate in the rhBMP-2 groups compared to the 40% fusion rate in the autograft group was 40.
Carreon and colleagues in their study, compared the application of autograft and higher dose rhBMP-2 in single-level of PLF case was carried out [22]. They concluded in their study that they recorded an 89% and 96% fusion rate in the autograft group and rhBMP- 2/CRM group respectively at 2 years follow-up. However they also recorded no similar clinical outcome measures between the two compared groups [23]. There have also been few smaller studies that reported related results of high fusion rates with the use of rhBMP-2 in PLF compared to ICBG [24].
Haid and co-worker reported the efficiency of rhBMP-2 in posterior lumbar interbody fusion (PLIF), however there is a possibility for heterotopic bone formation. Haid and co-workers reported that they recorded 92.3% and 77.8% fusion rate with rhBMP-2 group and control group respectively, however there was an insignificant difference in clinical progress between the two compared groups [25]. They also reported via CT imaging that there was formation of ectopic bone around the PLIF [26].
Baskin and colleague reported that there was a 100% fusion rate with the administration rhBMP-2 when compared with autograft [28]. Furthermore, they reported that the efficiency of rhBMP-2 was further improved when collagen sponges, PEEK cages, bioab- sorbable spacers, and allograft rings were added to it [29]. However, the positive results have been marred by reports of the incidence of soft-tissue related complications including potentially life-threatening airway compromise from tissue swelling. Cole, Veeravagu [30] conducted a MarketScan database-based retrospective study regarding the use of rhBMP in anterior cervical discectomy and fusion procedure. The outcomes of the study indicated that the use of drug is associated with increased incidence of hematoma, seroma, dysphagia, and pulmonary complications. Low dose rhBMP is also not associated with reduced incidence of the postoperative complications [31]. The FDA has placed a black box warning on the use of rhBMP-2 in the anterior cervical spine indicating that the risk of use may outweigh the benefit and therefore, its use is not recommended in anterior cervical fusion.
There have been studies to investigate the efficiency of rhBMP-2 on transforaminal lumbar interbody fusion (TLIF, Figure 2). Villavicencio et al., in their clinical study on 74 patients, underwent single and multiple- level TLIF administered with rhBMP-2 and combined with auto- graft [33]. They recorded that there was radiographic evidence of fusion in all 74 patients after 10 months [34]. Furthermore, they recorded few adverse events in the rhBMP-2 group noting two patients developed postoperative radiculitis. In another similar study by Rihn et al., 48 patients underwent single-level TLIF administered with rhBMP-2 [35]. They concluded radiographic fusion, improved clinical outcomes and satisfaction with surgical results in 95.8%, 83% and 84% of the patients, respectively. However, 27.1% of their patients had complications like transient postoperative radiculitis and symptomatic ectopic bone formation (Table 2).
An axial CT scan of the lumbar spine demonstrating ectopic bone formation (arrow) in the left neural foramen impinging on the exiting nerve root in a patient who underwent a transforaminal lumbar interbody fusion with rhBMP-2. Culled from [
Type of fusion | Recommendations |
---|---|
Anterior Lumbar Interbody Fusion (ALIF) | There have been reports of insignificant difference between the administration of rhBMP-2 and ICBG. It is recommended that in the absence of an autograft procedure, rhBMP-2 administration can be opted for. |
Posterolateral Fusion (PLF) | There have been reports of no significant difference between the administration of rhBMP-2 and ICBG. It is recommended that in the absence of an autograft procedure, rhBMP-2 administration can be opted for. |
Posterior Interbody Lumbar Fusion (PLIF) | The use of rhBMP-2 has been linked with formation of ectopic bone resulting into neurological deficit, as such ICBG procedure is preferred. |
Transforaminal Interbody Fusion (TLIF) | The use of rhBMP-2 has been linked with seroma formation and neurological deficits. Judicious administration of rhBMP-2 is adviced |
The use of rhBMP-2 offers an alternative therapeutic option when iliac crest autograft is either unavailable or may result in severe side effects. There are various clinical studies investigating how the use of rhBMP-2 can be effective in achieving spinal fusion. However, though rhBMP-2 is effective at achieving spinal fusion patients need to be informed of the possible formation ectopic bone requiring additional surgery and seroma formation when preforming transforaminal lumbar interbody fusion. There is a need for further study to minimize or lower the rates of complication linked with the application of rhBMP-2.
The authors deny any conflict of interest in any terms or by any means during the study.
Informed consent was obtained from each participant.
No animals were used in this research. All human research procedures followed were in accordance with the ethical standards of the committee responsible for human experimentation (institutional and national), and with the Helsinki Declaration of 1975, as revised in 2013.
All relevant data and materials are provided with in manuscript.
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",metaTitle:"About Open Access",metaDescription:"Open access contributes to scientific excellence and integrity. It opens up research results to wider analysis. It allows research results to be reused for new discoveries. And it enables the multi-disciplinary research that is needed to solve global 21st century problems. Open access connects science with society. It allows the public to engage with research. To go behind the headlines. And look at the scientific evidence. And it enables policy makers to draw on innovative solutions to societal challenges.\n\nCarlos Moedas, the European Commissioner for Research Science and Innovation at the STM Annual Frankfurt Conference, October 2016.",metaKeywords:null,canonicalURL:"about-open-access",contentRaw:'[{"type":"htmlEditorComponent","content":"The Open Access publishing movement started in the early 2000s when academic leaders from around the world participated in the formation of the Budapest Initiative. They developed recommendations for an Open Access publishing process, “which has worked for the past decade to provide the public with unrestricted, free access to scholarly research—much of which is publicly funded. Making the research publicly available to everyone—free of charge and without most copyright and licensing restrictions—will accelerate scientific research efforts and allow authors to reach a larger number of readers” (reference: http://www.budapestopenaccessinitiative.org)
\\n\\nIntechOpen’s co-founders, both scientists themselves, created the company while undertaking research in robotics at Vienna University. Their goal was to spread research freely “for scientists, by scientists’ to the rest of the world via the Open Access publishing model. The company soon became a signatory of the Budapest Initiative, which currently has more than 1000 supporting organizations worldwide, ranging from universities to funders.
\\n\\nAt IntechOpen today, we are still as committed to working with organizations and people who care about scientific discovery, to putting the academic needs of the scientific community first, and to providing an Open Access environment where scientists can maximize their contribution to scientific advancement. By opening up access to the world’s scientific research articles and book chapters, we aim to facilitate greater opportunity for collaboration, scientific discovery and progress. We subscribe wholeheartedly to the Open Access definition:
\\n\\n“By “open access” to [peer-reviewed research literature], we mean its free availability on the public internet, permitting any users to read, download, copy, distribute, print, search, or link to the full texts of these articles, crawl them for indexing, pass them as data to software, or use them for any other lawful purpose, without financial, legal, or technical barriers other than those inseparable from gaining access to the internet itself. The only constraint on reproduction and distribution, and the only role for copyright in this domain, should be to give authors control over the integrity of their work and the right to be properly acknowledged and cited” (reference: http://www.budapestopenaccessinitiative.org)
\\n\\nOAI-PMH
\\n\\nAs a firm believer in the wider dissemination of knowledge, IntechOpen supports the Open Access Initiative Protocol for Metadata Harvesting (OAI-PMH Version 2.0). Read more
\\n\\nLicense
\\n\\nBook chapters published in edited volumes are distributed under the Creative Commons Attribution 3.0 Unported License (CC BY 3.0). IntechOpen upholds a very flexible Copyright Policy. There is no copyright transfer to the publisher and Authors retain exclusive copyright to their work. All Monographs/Compacts are distributed under the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0). Read more
\\n\\nPeer Review Policies
\\n\\nAll scientific works are Peer Reviewed prior to publishing. Read more
\\n\\nOA Publishing Fees
\\n\\nThe Open Access publishing model employed by IntechOpen eliminates subscription charges and pay-per-view fees, enabling readers to access research at no cost. In order to sustain operations and keep our publications freely accessible we levy an Open Access Publishing Fee for manuscripts, which helps us cover the costs of editorial work and the production of books. Read more
\\n\\nDigital Archiving Policy
\\n\\nIntechOpen is committed to ensuring the long-term preservation and the availability of all scholarly research we publish. We employ a variety of means to enable us to deliver on our commitments to the scientific community. Apart from preservation by the Croatian National Library (for publications prior to April 18, 2018) and the British Library (for publications after April 18, 2018), our entire catalogue is preserved in the CLOCKSS archive.
\\n\\nOpen Science is transparent and accessible knowledge that is shared and developed through collaborative networks.
\\n\\nOpen Science is about increased rigour, accountability, and reproducibility for research. It is based on the principles of inclusion, fairness, equity, and sharing, and ultimately seeks to change the way research is done, who is involved and how it is valued. It aims to make research more open to participation, review/refutation, improvement and (re)use for the world to benefit.
\\n\\nOpen Science refers to doing traditional science with more transparency involved at various stages, for example by openly sharing code and data. It implies a growing set of practices - within different disciplines - aiming at:
\\n\\nWe aim at improving the quality and availability of scholarly communication by promoting and practicing:
\\n\\n\\n"}]'},components:[{type:"htmlEditorComponent",content:'
The Open Access publishing movement started in the early 2000s when academic leaders from around the world participated in the formation of the Budapest Initiative. They developed recommendations for an Open Access publishing process, “which has worked for the past decade to provide the public with unrestricted, free access to scholarly research—much of which is publicly funded. Making the research publicly available to everyone—free of charge and without most copyright and licensing restrictions—will accelerate scientific research efforts and allow authors to reach a larger number of readers” (reference: http://www.budapestopenaccessinitiative.org)
\n\nIntechOpen’s co-founders, both scientists themselves, created the company while undertaking research in robotics at Vienna University. Their goal was to spread research freely “for scientists, by scientists’ to the rest of the world via the Open Access publishing model. The company soon became a signatory of the Budapest Initiative, which currently has more than 1000 supporting organizations worldwide, ranging from universities to funders.
\n\nAt IntechOpen today, we are still as committed to working with organizations and people who care about scientific discovery, to putting the academic needs of the scientific community first, and to providing an Open Access environment where scientists can maximize their contribution to scientific advancement. By opening up access to the world’s scientific research articles and book chapters, we aim to facilitate greater opportunity for collaboration, scientific discovery and progress. We subscribe wholeheartedly to the Open Access definition:
\n\n“By “open access” to [peer-reviewed research literature], we mean its free availability on the public internet, permitting any users to read, download, copy, distribute, print, search, or link to the full texts of these articles, crawl them for indexing, pass them as data to software, or use them for any other lawful purpose, without financial, legal, or technical barriers other than those inseparable from gaining access to the internet itself. The only constraint on reproduction and distribution, and the only role for copyright in this domain, should be to give authors control over the integrity of their work and the right to be properly acknowledged and cited” (reference: http://www.budapestopenaccessinitiative.org)
\n\nOAI-PMH
\n\nAs a firm believer in the wider dissemination of knowledge, IntechOpen supports the Open Access Initiative Protocol for Metadata Harvesting (OAI-PMH Version 2.0). Read more
\n\nLicense
\n\nBook chapters published in edited volumes are distributed under the Creative Commons Attribution 3.0 Unported License (CC BY 3.0). IntechOpen upholds a very flexible Copyright Policy. There is no copyright transfer to the publisher and Authors retain exclusive copyright to their work. All Monographs/Compacts are distributed under the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0). Read more
\n\nPeer Review Policies
\n\nAll scientific works are Peer Reviewed prior to publishing. Read more
\n\nOA Publishing Fees
\n\nThe Open Access publishing model employed by IntechOpen eliminates subscription charges and pay-per-view fees, enabling readers to access research at no cost. In order to sustain operations and keep our publications freely accessible we levy an Open Access Publishing Fee for manuscripts, which helps us cover the costs of editorial work and the production of books. Read more
\n\nDigital Archiving Policy
\n\nIntechOpen is committed to ensuring the long-term preservation and the availability of all scholarly research we publish. We employ a variety of means to enable us to deliver on our commitments to the scientific community. Apart from preservation by the Croatian National Library (for publications prior to April 18, 2018) and the British Library (for publications after April 18, 2018), our entire catalogue is preserved in the CLOCKSS archive.
\n\nOpen Science is transparent and accessible knowledge that is shared and developed through collaborative networks.
\n\nOpen Science is about increased rigour, accountability, and reproducibility for research. It is based on the principles of inclusion, fairness, equity, and sharing, and ultimately seeks to change the way research is done, who is involved and how it is valued. It aims to make research more open to participation, review/refutation, improvement and (re)use for the world to benefit.
\n\nOpen Science refers to doing traditional science with more transparency involved at various stages, for example by openly sharing code and data. It implies a growing set of practices - within different disciplines - aiming at:
\n\nWe aim at improving the quality and availability of scholarly communication by promoting and practicing:
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On September, 29th 2006 he has won a post PhD fellowship from the university of Bologna (from October 2006 to October 2008), at the competitive examination he was ranked first in the industrial engineering area. He extensively served as referee for several international journals. He is author/coauthor of more than 100 research papers. He has been involved in some projects supported by MURST and European Community. 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After finishing his P. hD degree in 1992, he served in the Industry as a Scientific Officer and continued his academic career as a visiting scholar for a number of educational institutions. In 1996 he joined National University of Science & Technology Pakistan (NUST) as an Associate Professor; NUST is one of the top few universities in Pakistan. In 1999 he joined an International Company Lineo Inc, Canada as Manager Compiler Group, where he headed the group for developing Compiler Tool Chain and Porting of Operating Systems for the BLACKfin processor. The processor development was a joint venture by Intel and Analog Devices. In 2002 Lineo Inc., was taken over by another company, so he joined Aalborg University Denmark as an Assistant Professor.\nProfessor Akbar has truly a multi-disciplined career and he continued his legacy and making progress in many areas of his interests both in teaching and research. 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Liposuction is a procedure to improve the body contour and not a surgery to reduce weight, although recently people who have failed in their plans to lose weight look at liposuction as a means to contour their body figure. Tumescent liposuction of large volumes requires a meticulous selection of each patient; their preoperative evaluation and perioperative management are essential to obtain the expected results. The various techniques of general anesthesia are the most recommended and should be monitored in the usual way, as well as monitoring the total doses of infiltrated local anesthetics to avoid systemic toxicity. The management of intravenous fluids is controversial, but the current trend is the restricted use of hydrosaline solutions. The most feared complications are deep vein thrombosis, pulmonary thromboembolism, fat embolism, lung edema, hypothermia, infections and even death. The adherence to the management guidelines and prophylaxis of venous thrombosis/thromboembolism is mandatory.",book:{id:"6221",slug:"anesthesia-topics-for-plastic-and-reconstructive-surgery",title:"Anesthesia Topics for Plastic and Reconstructive Surgery",fullTitle:"Anesthesia Topics for Plastic and Reconstructive Surgery"},signatures:"Sergio Granados-Tinajero, Carlos Buenrostro-Vásquez, Cecilia\nCárdenas-Maytorena and Marcela Contreras-López",authors:[{id:"273532",title:"Dr.",name:"Sergio Octavio",middleName:null,surname:"Granados Tinajero",slug:"sergio-octavio-granados-tinajero",fullName:"Sergio Octavio Granados Tinajero"}]},{id:"30178",title:"Chest Mobilization Techniques for Improving Ventilation and Gas Exchange in Chronic Lung Disease",slug:"chest-mobilization-techniques-for-improving-ventilation-and-gas-exchange-in-chronic-lung-disease",totalDownloads:31193,totalCrossrefCites:0,totalDimensionsCites:5,abstract:null,book:{id:"648",slug:"chronic-obstructive-pulmonary-disease-current-concepts-and-practice",title:"Chronic Obstructive Pulmonary Disease",fullTitle:"Chronic Obstructive Pulmonary Disease - Current Concepts and Practice"},signatures:"Donrawee Leelarungrayub",authors:[{id:"73709",title:"Associate Prof.",name:"Jirakrit",middleName:null,surname:"Leelarungrayub",slug:"jirakrit-leelarungrayub",fullName:"Jirakrit Leelarungrayub"}]}],onlineFirstChaptersFilter:{topicId:"3",limit:6,offset:0},onlineFirstChaptersCollection:[{id:"82399",title:"Geriatric Care in Africa",slug:"geriatric-care-in-africa",totalDownloads:1,totalDimensionsCites:0,doi:"10.5772/intechopen.105614",abstract:"There are an increasing number of people that are aging. This is also common in Africa. Therefore, they need specialist care from various categories of health care workers and other professionals on geriatric medicine and gerontology. There are few geriatricians in Africans. This is because there are few training centres in the continents. Also, most of the geriatricians are trained on the other side of the continent overseas.",book:{id:"11226",title:"Geriatric Medicine and Healthy Aging",coverURL:"https://cdn.intechopen.com/books/images_new/11226.jpg"},signatures:"Dabota Yvonne Buowari"},{id:"82376",title:"Mechanical Thrombectomy for Acute Pulmonary Ischemia",slug:"mechanical-thrombectomy-for-acute-pulmonary-ischemia",totalDownloads:1,totalDimensionsCites:0,doi:"10.5772/intechopen.102548",abstract:"Acute pulmonary embolism (PE) is a restrictive pulmonary vascular compromise with devastating complications depending on size and location. Massive and sub-massive classifications reflect hemodynamic compromise and cardiac dysfunction due to right ventricular strain, respectively. In addition to cardiac dysfunction, pulmonary ischemia and infarction play a key clinical factor. Mainstay management is with anticoagulation to prevent further clot propagation. Recent technological advances have revolutionized treatment modalities. Mechanical thrombectomy, catheter-based clot retrieval, is an effective way to eliminate emboli, restore cardiopulmonary function, and prevent ischemic injury. One such device, the FlowTriever System, has emerged as a way interventionalists can proceed with embolectomy and provide high level, life-saving care for acutely decompensated patients.",book:{id:"10712",title:"Thrombectomy - Recent Advances in Ischaemic Damage Treatment",coverURL:"https://cdn.intechopen.com/books/images_new/10712.jpg"},signatures:"Adam Raskin, Anil Verma and Kofi Ansah"},{id:"82402",title:"Diagnosis and Treatment of Venous Leg Ulcer",slug:"diagnosis-and-treatment-of-venous-leg-ulcer",totalDownloads:1,totalDimensionsCites:0,doi:"10.5772/intechopen.105676",abstract:"Venous leg ulcer (VLU) represent a pathological tissue change in the form of a defect in the lower leg which occurs as a complication of chronic venous insufficiency. The prevalence of VLUs varies between 1.5–3% in the total population and 4–5% in persons over the age of 80. Venous ulcer is usually localized on the inner side of the lower third of the leg, oval, circular or irregular in shape. It is usually fibrous or covered with fresh granules that bleed heavily to the touch. It is very important to have a comprehensive clinical examination at the very beginning. Subsequent non-invasive and sometimes invasive tests may be indicated for diagnosis and treatment planning. Inadequate diagnosis results in inadequate therapy. The goal of therapy is complete restitution of the tissue defect and prevention of recurrence. The three basic elements of VLUs therapy are: local therapy, compression therapy and surgical treatment. If VLUs do not heal despite the application of standard therapeutic modalities, there are opportunities to apply new treatment technologies. The modern approach to the treatment of VLUs is based on the application of various biophysical interventions and medical devices.",book:{id:"11723",title:"Wound Healing - Recent Advances and Future Opportunities",coverURL:"https://cdn.intechopen.com/books/images_new/11723.jpg"},signatures:"Karanikolic Vesna and Karanikolic Aleksandar"},{id:"82398",title:"Computer-Aided Drug Design and Development: An Integrated Approach",slug:"computer-aided-drug-design-and-development-an-integrated-approach",totalDownloads:0,totalDimensionsCites:null,doi:"10.5772/intechopen.105003",abstract:"Drug discovery and development is a very time- and resource-consuming process. Comprehensive knowledge of chemistry has been integrated with information technology to streamline drug discovery, design, development, and optimization. Computer-aided drug design is being utilized to expedite and facilitate hit identification, hit-to-lead selection, and optimize the absorption, distribution, metabolism, excretion, and toxicity profile. Regulatory organizations and the pharmaceutical industry are continuously involved in the development of computational techniques that will improve the effectiveness and efficiency of the drug discovery process while decreasing the use of animals, cost, and time and increasing predictability. The present chapter will provide an overview of computational tools, such as structure-based and receptor-based drug designing, and how the coupling of these tools with a rational drug design process has led to the discovery of small molecules as therapeutic agents for numerous human disease conditions duly approved by the Food and Drug Administration. It is expected that the power of CADD will grow as the technology continues to evolve.",book:{id:"11091",title:"Drug Development Life Cycle",coverURL:"https://cdn.intechopen.com/books/images_new/11091.jpg"},signatures:"Neelima Dhingra"},{id:"82393",title:"Pathogenicity, Characterisation and Impact of Ambient Bio-Aerosols on the Climatic Processes: With a Special Emphasis on the Indian Subcontinent",slug:"pathogenicity-characterisation-and-impact-of-ambient-bio-aerosols-on-the-climatic-processes-with-a-s",totalDownloads:3,totalDimensionsCites:0,doi:"10.5772/intechopen.104750",abstract:"Airborne particulate matter contains biological entities from various anthropogenic/biogenic activities. Within 1 nm–100 μm size, these are carried to long distances through various external agents. Identified as potential pathogens, they bring forth substantial economic losses in many parts of the world. Despite these shortcomings, bio-aerosols play a vital role in cloud condensation, ice nucleation, precipitation and various atmospheric processes affecting the hydrological cycle in general. Furthermore, bio-aerosols play a decisive role in the dispersal of reproductive plant parts and fungal spores, which play important roles in the evolution and sustenance of ecosystems. However, there remains substantial knowledge on air micro-biome with respect to their occurrence, transformation, role in climate change, interaction and impact on living organisms, agriculture and ecosystem. The current COVID-19 pandemic is a wakeup call for retrospective analysis of airborne particles to reduce their emission, transmission and health risk hazards while understanding their impact on various atmospheric processes. This chapter identifies the various types of bio-aerosols and systematically includes their prime role in the climatic processes, pathogenicity to the exposed flora and fauna along with an exclusive interrogation into their types and characterisation over the Indian subcontinent with a hugely diverging population and pollution panorama.",book:{id:"11231",title:"Air Quality and Health",coverURL:"https://cdn.intechopen.com/books/images_new/11231.jpg"},signatures:"Minati Behera, Jyotishree Nath, Sony Pandey, Ramasamy Boopathy and Trupti Das"},{id:"82384",title:"Phytochemicals from Solanaceae Family and Their Anticancer Properties",slug:"phytochemicals-from-solanaceae-family-and-their-anticancer-properties",totalDownloads:3,totalDimensionsCites:0,doi:"10.5772/intechopen.104462",abstract:"Cancer is one of the most dreadful disease conditions all over the world. With the side effects and cost of conventional treatment, there is a demand for new therapies to prevent cancer. Research studies proved many plant products possess anticancer properties. Currently, a few plant-based drugs are used to treat it. The phytochemicals are investigated by in vitro and in vivo to assess their mechanism of action against cancer. This chapter is an overview of anticancer compounds extracted from plants of Solanaceae family with the potentials results. Many research has confirmed the anticancer efficiency of the biomolecules, such as solanine, solamargine, tomatidine, Withanolides, scopoletin, capsaicin found in Solanaceae, and their mode of action, such as cell cycle arrest, inhibiting signaling pathways, autophagy, suppression of enzymes in various human cancer cell lines of breast, pancreas, colorectal, liver, and cervical and also in animal models. This chapter seeks to provide an outline of key examples of anticancer activity of phytochemicals from the Solanaceae family, which offers a track for the development of novel medicines for cancer treatment as a single drug or in combinational drug. This chapter helps to identify the novel bioactive molecule for cancer treatment as lead molecule with less side effects in future.",book:{id:"11299",title:"Medicinal Plants",coverURL:"https://cdn.intechopen.com/books/images_new/11299.jpg"},signatures:"Sangilimuthu Alagar Yadav and Feba Sara Koshi"}],onlineFirstChaptersTotal:791},preDownload:{success:null,errors:{}},subscriptionForm:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[],offset:8,limit:8,total:0},allSeries:{pteSeriesList:[{id:"14",title:"Artificial Intelligence",numberOfPublishedBooks:9,numberOfPublishedChapters:89,numberOfOpenTopics:6,numberOfUpcomingTopics:0,issn:"2633-1403",doi:"10.5772/intechopen.79920",isOpenForSubmission:!0},{id:"7",title:"Biomedical Engineering",numberOfPublishedBooks:12,numberOfPublishedChapters:104,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2631-5343",doi:"10.5772/intechopen.71985",isOpenForSubmission:!0}],lsSeriesList:[{id:"11",title:"Biochemistry",numberOfPublishedBooks:31,numberOfPublishedChapters:314,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2632-0983",doi:"10.5772/intechopen.72877",isOpenForSubmission:!0},{id:"25",title:"Environmental Sciences",numberOfPublishedBooks:1,numberOfPublishedChapters:11,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2754-6713",doi:"10.5772/intechopen.100362",isOpenForSubmission:!0},{id:"10",title:"Physiology",numberOfPublishedBooks:11,numberOfPublishedChapters:141,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-8261",doi:"10.5772/intechopen.72796",isOpenForSubmission:!0}],hsSeriesList:[{id:"3",title:"Dentistry",numberOfPublishedBooks:8,numberOfPublishedChapters:129,numberOfOpenTopics:2,numberOfUpcomingTopics:0,issn:"2631-6218",doi:"10.5772/intechopen.71199",isOpenForSubmission:!0},{id:"6",title:"Infectious Diseases",numberOfPublishedBooks:13,numberOfPublishedChapters:113,numberOfOpenTopics:3,numberOfUpcomingTopics:1,issn:"2631-6188",doi:"10.5772/intechopen.71852",isOpenForSubmission:!0},{id:"13",title:"Veterinary Medicine and Science",numberOfPublishedBooks:11,numberOfPublishedChapters:105,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2632-0517",doi:"10.5772/intechopen.73681",isOpenForSubmission:!0}],sshSeriesList:[{id:"22",title:"Business, Management and Economics",numberOfPublishedBooks:1,numberOfPublishedChapters:18,numberOfOpenTopics:2,numberOfUpcomingTopics:1,issn:"2753-894X",doi:"10.5772/intechopen.100359",isOpenForSubmission:!0},{id:"23",title:"Education and Human Development",numberOfPublishedBooks:0,numberOfPublishedChapters:5,numberOfOpenTopics:1,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100360",isOpenForSubmission:!0},{id:"24",title:"Sustainable Development",numberOfPublishedBooks:0,numberOfPublishedChapters:14,numberOfOpenTopics:5,numberOfUpcomingTopics:0,issn:null,doi:"10.5772/intechopen.100361",isOpenForSubmission:!0}],testimonialsList:[{id:"6",text:"It is great to work with the IntechOpen to produce a worthwhile collection of research that also becomes a great educational resource and guide for future research endeavors.",author:{id:"259298",name:"Edward",surname:"Narayan",institutionString:null,profilePictureURL:"https://mts.intechopen.com/storage/users/259298/images/system/259298.jpeg",slug:"edward-narayan",institution:{id:"3",name:"University of Queensland",country:{id:null,name:"Australia"}}}},{id:"13",text:"The collaboration with and support of the technical staff of IntechOpen is fantastic. The whole process of submitting an article and editing of the submitted article goes extremely smooth and fast, the number of reads and downloads of chapters is high, and the contributions are also frequently cited.",author:{id:"55578",name:"Antonio",surname:"Jurado-Navas",institutionString:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRisIQAS/Profile_Picture_1626166543950",slug:"antonio-jurado-navas",institution:{id:"720",name:"University of Malaga",country:{id:null,name:"Spain"}}}}]},series:{item:{id:"7",title:"Biomedical Engineering",doi:"10.5772/intechopen.71985",issn:"2631-5343",scope:"Biomedical Engineering is one of the fastest-growing interdisciplinary branches of science and industry. The combination of electronics and computer science with biology and medicine has improved patient diagnosis, reduced rehabilitation time, and helped to facilitate a better quality of life. 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Dr. Koprowski has authored more than a hundred research papers with dozens in impact factor (IF) journals and has authored or co-authored six books. Additionally, he is the author of several national and international patents in the field of biomedical devices and imaging. Since 2011, he has been a reviewer of grants and projects (including EU projects) in biomedical engineering.",institutionString:null,institution:{name:"University of Silesia",institutionURL:null,country:{name:"Poland"}}},editorTwo:null,editorThree:null},subseries:{paginationCount:3,paginationItems:[{id:"7",title:"Bioinformatics and Medical Informatics",coverUrl:"https://cdn.intechopen.com/series_topics/covers/7.jpg",isOpenForSubmission:!0,editor:{id:"351533",title:"Dr.",name:"Slawomir",middleName:null,surname:"Wilczynski",slug:"slawomir-wilczynski",fullName:"Slawomir Wilczynski",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000035U1loQAC/Profile_Picture_1630074514792",biography:"Professor Sławomir Wilczyński, Head of the Chair of Department of Basic Biomedical Sciences, Faculty of Pharmaceutical Sciences, Medical University of Silesia in Katowice, Poland. His research interests are focused on modern imaging methods used in medicine and pharmacy, including in particular hyperspectral imaging, dynamic thermovision analysis, high-resolution ultrasound, as well as other techniques such as EPR, NMR and hemispheric directional reflectance. Author of over 100 scientific works, patents and industrial designs. Expert of the Polish National Center for Research and Development, Member of the Investment Committee in the Bridge Alfa NCBiR program, expert of the Polish Ministry of Funds and Regional Policy, Polish Medical Research Agency. 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He completed a one-year Post-Doctoral Fellowship awarded by the DFAIT (Foreign Affairs and International Trade Canada) at the Institute of Biomedical Engineering of the University of New Brunswick (Canada) in 2010. Currently, he is Professor in the Faculty of Electrical Engineering (UFU). He has authored and co-authored more than 200 peer-reviewed publications in Biomedical Engineering. He has been a researcher of The National Council for Scientific and Technological Development (CNPq-Brazil) since 2009. He has served as an ad-hoc consultant for CNPq, CAPES (Coordination for the Improvement of Higher Education Personnel), FINEP (Brazilian Innovation Agency), and other funding bodies on several occasions. He was the Secretary of the Brazilian Society of Biomedical Engineering (SBEB) from 2015 to 2016, President of SBEB (2017-2018) and Vice-President of SBEB (2019-2020). He was the head of the undergraduate program in Biomedical Engineering of the Federal University of Uberlândia (2015 - June/2019) and the head of the Centre for Innovation and Technology Assessment in Health (NIATS/UFU) since 2010. He is the head of the Postgraduate Program in Biomedical Engineering (UFU, July/2019 - to date). He was the secretary of the Parkinson's Disease Association of Uberlândia (2018-2019). Dr. Andrade's primary area of research is focused towards getting information from the neuromuscular system to understand its strategies of organization, adaptation and controlling in the context of motor neuron diseases. His research interests include Biomedical Signal Processing and Modelling, Assistive Technology, Rehabilitation Engineering, Neuroengineering and Parkinson's Disease.",institutionString:null,institution:{name:"Federal University of Uberlândia",institutionURL:null,country:{name:"Brazil"}}},editorTwo:null,editorThree:null},{id:"9",title:"Biotechnology - Biosensors, Biomaterials and Tissue Engineering",coverUrl:"https://cdn.intechopen.com/series_topics/covers/9.jpg",isOpenForSubmission:!0,editor:{id:"126286",title:"Dr.",name:"Luis",middleName:"Jesús",surname:"Villarreal-Gómez",slug:"luis-villarreal-gomez",fullName:"Luis Villarreal-Gómez",profilePictureURL:"https://mts.intechopen.com/storage/users/126286/images/system/126286.jpg",biography:"Dr. Luis Villarreal is a research professor from the Facultad de Ciencias de la Ingeniería y Tecnología, Universidad Autónoma de Baja California, Tijuana, Baja California, México. Dr. Villarreal is the editor in chief and founder of the Revista de Ciencias Tecnológicas (RECIT) (https://recit.uabc.mx/) and is a member of several editorial and reviewer boards for numerous international journals. He has published more than thirty international papers and reviewed more than ninety-two manuscripts. His research interests include biomaterials, nanomaterials, bioengineering, biosensors, drug delivery systems, and tissue engineering.",institutionString:null,institution:{name:"Autonomous University of Baja California",institutionURL:null,country:{name:"Mexico"}}},editorTwo:null,editorThree:null}]},overviewPageOFChapters:{paginationCount:23,paginationItems:[{id:"82392",title:"Nanomaterials as Novel Biomarkers for Cancer Nanotheranostics: State of the Art",doi:"10.5772/intechopen.105700",signatures:"Hao Yu, Zhihai Han, Cunrong Chen and Leisheng Zhang",slug:"nanomaterials-as-novel-biomarkers-for-cancer-nanotheranostics-state-of-the-art",totalDownloads:0,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Biotechnology - Biosensors, Biomaterials and Tissue Engineering - Annual Volume 2022",coverURL:"https://cdn.intechopen.com/books/images_new/11405.jpg",subseries:{id:"9",title:"Biotechnology - Biosensors, Biomaterials and Tissue Engineering"}}},{id:"82184",title:"Biological Sensing Using Infrared SPR Devices Based on ZnO",doi:"10.5772/intechopen.104562",signatures:"Hiroaki Matsui",slug:"biological-sensing-using-infrared-spr-devices-based-on-zno",totalDownloads:3,totalCrossrefCites:0,totalDimensionsCites:0,authors:[{name:"Hiroaki",surname:"Matsui"}],book:{title:"Biosignal Processing",coverURL:"https://cdn.intechopen.com/books/images_new/11153.jpg",subseries:{id:"7",title:"Bioinformatics and Medical Informatics"}}},{id:"82122",title:"Recent Advances in Biosensing in Tissue Engineering and Regenerative Medicine",doi:"10.5772/intechopen.104922",signatures:"Alma T. Banigo, Chigozie A. Nnadiekwe and Emmanuel M. 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For 20 years, he has studied the analysis and processing of biomedical images, emphasizing the full automation of measurement for a large inter-individual variability of patients. Dr. Koprowski has authored more than a hundred research papers with dozens in impact factor (IF) journals and has authored or co-authored six books. Additionally, he is the author of several national and international patents in the field of biomedical devices and imaging. Since 2011, he has been a reviewer of grants and projects (including EU projects) in biomedical engineering.",institutionString:null,institution:{name:"University of Silesia",institutionURL:null,country:{name:"Poland"}}}]},{type:"book",id:"7218",title:"OCT",subtitle:"Applications in Ophthalmology",coverURL:"https://cdn.intechopen.com/books/images_new/7218.jpg",slug:"oct-applications-in-ophthalmology",publishedDate:"September 19th 2018",editedByType:"Edited by",bookSignature:"Michele Lanza",hash:"e3a3430cdfd6999caccac933e4613885",volumeInSeries:2,fullTitle:"OCT - Applications in Ophthalmology",editors:[{id:"240088",title:"Prof.",name:"Michele",middleName:null,surname:"Lanza",slug:"michele-lanza",fullName:"Michele Lanza",profilePictureURL:"https://mts.intechopen.com/storage/users/240088/images/system/240088.png",biography:"Michele Lanza is Associate Professor of Ophthalmology at Università della Campania, Luigi Vanvitelli, Napoli, Italy. His fields of interest are anterior segment disease, keratoconus, glaucoma, corneal dystrophies, and cataracts. His research topics include\nintraocular lens power calculation, eye modification induced by refractive surgery, glaucoma progression, and validation of new diagnostic devices in ophthalmology. \nHe has published more than 100 papers in international and Italian scientific journals, more than 60 in journals with impact factors, and chapters in international and Italian books. He has also edited two international books and authored more than 150 communications or posters for the most important international and Italian ophthalmology conferences.",institutionString:'University of Campania "Luigi Vanvitelli"',institution:{name:'University of Campania "Luigi Vanvitelli"',institutionURL:null,country:{name:"Italy"}}}]},{type:"book",id:"7560",title:"Non-Invasive Diagnostic Methods",subtitle:"Image Processing",coverURL:"https://cdn.intechopen.com/books/images_new/7560.jpg",slug:"non-invasive-diagnostic-methods-image-processing",publishedDate:"December 19th 2018",editedByType:"Edited by",bookSignature:"Mariusz Marzec and Robert Koprowski",hash:"d92fd8cf5a90a47f2b8a310837a5600e",volumeInSeries:3,fullTitle:"Non-Invasive Diagnostic Methods - Image Processing",editors:[{id:"253468",title:"Dr.",name:"Mariusz",middleName:null,surname:"Marzec",slug:"mariusz-marzec",fullName:"Mariusz Marzec",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. 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His research interests include root canal morphology, functionally graded concept, dental biomaterials, epidemiology and dental education, biomimetic restoration, finite element analysis and endodontic regeneration. Dr. Madfa has numerous international publications, full articles, two patents, a book and a book chapter. Furthermore, he won 14 international scientific awards. Furthermore, he is involved in many academic activities ranging from editorial board member, reviewer for many international journals and postgraduate students' supervisor. Besides, I deliver many courses and training workshops at various scientific events. Dr. Madfa also regularly attends international conferences and holds administrative positions (Deputy Dean of the Faculty for Students’ & Academic Affairs and Deputy Head of Research Unit).",institutionString:"Thamar University",institution:null},{id:"210472",title:"Dr.",name:"Nermin",middleName:"Mohammed Ahmed",surname:"Yussif",slug:"nermin-yussif",fullName:"Nermin Yussif",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/210472/images/system/210472.jpg",biography:"Dr. Nermin Mohammed Ahmed Yussif is working at the Faculty of dentistry, University for October university for modern sciences and arts (MSA). Her areas of expertise include: periodontology, dental laserology, oral implantology, periodontal plastic surgeries, oral mesotherapy, nutrition, dental pharmacology. She is an editor and reviewer in numerous international journals.",institutionString:"MSA University",institution:null},{id:"204606",title:"Dr.",name:"Serdar",middleName:null,surname:"Gözler",slug:"serdar-gozler",fullName:"Serdar Gözler",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/204606/images/system/204606.jpeg",biography:"Dr. Serdar Gözler has completed his undergraduate studies at the Marmara University Faculty of Dentistry in 1978, followed by an assistantship in the Prosthesis Department of Dicle University Faculty of Dentistry. Starting his PhD work on non-resilient overdentures with Assoc. Prof. Hüsnü Yavuzyılmaz, he continued his studies with Prof. Dr. Gürbüz Öztürk of Istanbul University Faculty of Dentistry Department of Prosthodontics, this time on Gnatology. He attended training programs on occlusion, neurology, neurophysiology, EMG, radiology and biostatistics. In 1982, he presented his PhD thesis \\Gerber and Lauritzen Occlusion Analysis Techniques: Diagnosis Values,\\ at Istanbul University School of Dentistry, Department of Prosthodontics. As he was also working with Prof. Senih Çalıkkocaoğlu on The Physiology of Chewing at the same time, Gözler has written a chapter in Çalıkkocaoğlu\\'s book \\Complete Prostheses\\ entitled \\The Place of Neuromuscular Mechanism in Prosthetic Dentistry.\\ The book was published five times since by the Istanbul University Publications. Having presented in various conferences about occlusion analysis until 1998, Dr. Gözler has also decided to use the T-Scan II occlusion analysis method. Having been personally trained by Dr. Robert Kerstein on this method, Dr. Gözler has been lecturing on the T-Scan Occlusion Analysis Method in conferences both in Turkey and abroad. Dr. Gözler has various articles and presentations on Digital Occlusion Analysis methods. He is now Head of the TMD Clinic at Prosthodontic Department of Faculty of Dentistry , Istanbul Aydın University , Turkey.",institutionString:"Istanbul Aydin University",institution:{name:"Istanbul Aydın University",country:{name:"Turkey"}}},{id:"240870",title:"Ph.D.",name:"Alaa Eddin Omar",middleName:null,surname:"Al Ostwani",slug:"alaa-eddin-omar-al-ostwani",fullName:"Alaa Eddin Omar Al Ostwani",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/240870/images/system/240870.jpeg",biography:"Dr. Al Ostwani Alaa Eddin Omar received his Master in dentistry from Damascus University in 2010, and his Ph.D. in Pediatric Dentistry from Damascus University in 2014. Dr. Al Ostwani is an assistant professor and faculty member at IUST University since 2014. \nDuring his academic experience, he has received several awards including the scientific research award from the Union of Arab Universities, the Syrian gold medal and the international gold medal for invention and creativity. Dr. Al Ostwani is a Member of the International Association of Dental Traumatology and the Syrian Society for Research and Preventive Dentistry since 2017. He is also a Member of the Reviewer Board of International Journal of Dental Medicine (IJDM), and the Indian Journal of Conservative and Endodontics since 2016.",institutionString:"International University for Science and Technology.",institution:{name:"Islamic University of Science and Technology",country:{name:"India"}}},{id:"42847",title:"Dr.",name:"Belma",middleName:null,surname:"Işik Aslan",slug:"belma-isik-aslan",fullName:"Belma Işik Aslan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/42847/images/system/42847.jpg",biography:"Dr. Belma IşIk Aslan was born in 1976 in Ankara-TURKEY. After graduating from TED Ankara College in 1994, she attended to Gazi University, Faculty of Dentistry in Ankara. She completed her PhD in orthodontic education at Gazi University between 1999-2005. Dr. Işık Aslan stayed at the Providence Hospital Craniofacial Institude and Reconstructive Surgery in Michigan, USA for three months as an observer. She worked as a specialist doctor at Gazi University, Dentistry Faculty, Department of Orthodontics between 2005-2014. She was appointed as associate professor in January, 2014 and as professor in 2021. Dr. Işık Aslan still works as an instructor at the same faculty. She has published a total of 35 articles, 10 book chapters, 39 conference proceedings both internationally and nationally. Also she was the academic editor of the international book 'Current Advances in Orthodontics'. She is a member of the Turkish Orthodontic Society and Turkish Cleft Lip and Palate Society. She is married and has 2 children. Her knowledge of English is at an advanced level.",institutionString:"Gazi University Dentistry Faculty Department of Orthodontics",institution:null},{id:"178412",title:"Associate Prof.",name:"Guhan",middleName:null,surname:"Dergin",slug:"guhan-dergin",fullName:"Guhan Dergin",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/178412/images/6954_n.jpg",biography:"Assoc. Prof. Dr. Gühan Dergin was born in 1973 in Izmit. He graduated from Marmara University Faculty of Dentistry in 1999. He completed his specialty of OMFS surgery in Marmara University Faculty of Dentistry and obtained his PhD degree in 2006. In 2005, he was invited as a visiting doctor in the Oral and Maxillofacial Surgery Department of the University of North Carolina, USA, where he went on a scholarship. Dr. Dergin still continues his academic career as an associate professor in Marmara University Faculty of Dentistry. He has many articles in international and national scientific journals and chapters in books.",institutionString:null,institution:{name:"Marmara University",country:{name:"Turkey"}}},{id:"178414",title:"Prof.",name:"Yusuf",middleName:null,surname:"Emes",slug:"yusuf-emes",fullName:"Yusuf Emes",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/178414/images/6953_n.jpg",biography:"Born in Istanbul in 1974, Dr. Emes graduated from Istanbul University Faculty of Dentistry in 1997 and completed his PhD degree in Istanbul University faculty of Dentistry Department of Oral and Maxillofacial Surgery in 2005. He has papers published in international and national scientific journals, including research articles on implantology, oroantral fistulas, odontogenic cysts, and temporomandibular disorders. Dr. Emes is currently working as a full-time academic staff in Istanbul University faculty of Dentistry Department of Oral and Maxillofacial Surgery.",institutionString:null,institution:{name:"Istanbul University",country:{name:"Turkey"}}},{id:"192229",title:"Ph.D.",name:"Ana Luiza",middleName:null,surname:"De Carvalho Felippini",slug:"ana-luiza-de-carvalho-felippini",fullName:"Ana Luiza De Carvalho Felippini",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/192229/images/system/192229.jpg",biography:null,institutionString:"University of São Paulo",institution:{name:"University of Sao Paulo",country:{name:"Brazil"}}},{id:"256851",title:"Prof.",name:"Ayşe",middleName:null,surname:"Gülşen",slug:"ayse-gulsen",fullName:"Ayşe Gülşen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/256851/images/9696_n.jpg",biography:"Dr. Ayşe Gülşen graduated in 1990 from Faculty of Dentistry, University of Ankara and did a postgraduate program at University of Gazi. \nShe worked as an observer and research assistant in Craniofacial Surgery Departments in New York, Providence Hospital in Michigan and Chang Gung Memorial Hospital in Taiwan. \nShe works as Craniofacial Orthodontist in Department of Aesthetic, Plastic and Reconstructive Surgery, Faculty of Medicine, University of Gazi, Ankara Turkey since 2004.",institutionString:"Univeristy of Gazi",institution:null},{id:"255366",title:"Prof.",name:"Tosun",middleName:null,surname:"Tosun",slug:"tosun-tosun",fullName:"Tosun Tosun",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/255366/images/7347_n.jpg",biography:"Graduated at the Faculty of Dentistry, University of Istanbul, Turkey in 1989;\nVisitor Assistant at the University of Padua, Italy and Branemark Osseointegration Center of Treviso, Italy between 1993-94;\nPhD thesis on oral implantology in University of Istanbul and was awarded the academic title “Dr.med.dent.”, 1997;\nHe was awarded the academic title “Doç.Dr.” (Associated Professor) in 2003;\nProficiency in Botulinum Toxin Applications, Reading-UK in 2009;\nMastership, RWTH Certificate in Laser Therapy in Dentistry, AALZ-Aachen University, Germany 2009-11;\nMaster of Science (MSc) in Laser Dentistry, University of Genoa, Italy 2013-14.\n\nDr.Tosun worked as Research Assistant in the Department of Oral Implantology, Faculty of Dentistry, University of Istanbul between 1990-2002. \nHe worked part-time as Consultant surgeon in Harvard Medical International Hospitals and John Hopkins Medicine, Istanbul between years 2007-09.\u2028He was contract Professor in the Department of Surgical and Diagnostic Sciences (DI.S.C.), Medical School, University of Genova, Italy between years 2011-16. \nSince 2015 he is visiting Professor at Medical School, University of Plovdiv, Bulgaria. \nCurrently he is Associated Prof.Dr. at the Dental School, Oral Surgery Dept., Istanbul Aydin University and since 2003 he works in his own private clinic in Istanbul, Turkey.\u2028\nDr.Tosun is reviewer in journal ‘Laser in Medical Sciences’, reviewer in journal ‘Folia Medica\\', a Fellow of the International Team for Implantology, Clinical Lecturer of DGZI German Association of Oral Implantology, Expert Lecturer of Laser&Health Academy, Country Representative of World Federation for Laser Dentistry, member of European Federation of Periodontology, member of Academy of Laser Dentistry. Dr.Tosun presents papers in international and national congresses and has scientific publications in international and national journals. He speaks english, spanish, italian and french.",institutionString:null,institution:{name:"Istanbul Aydın University",country:{name:"Turkey"}}},{id:"171887",title:"Prof.",name:"Zühre",middleName:null,surname:"Akarslan",slug:"zuhre-akarslan",fullName:"Zühre Akarslan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/171887/images/system/171887.jpg",biography:"Zühre Akarslan was born in 1977 in Cyprus. She graduated from Gazi University Faculty of Dentistry, Ankara, Turkey in 2000. \r\nLater she received her Ph.D. degree from the Oral Diagnosis and Radiology Department; which was recently renamed as Oral and Dentomaxillofacial Radiology, from the same university. \r\nShe is working as a full-time Associate Professor and is a lecturer and an academic researcher. \r\nHer expertise areas are dental caries, cancer, dental fear and anxiety, gag reflex in dentistry, oral medicine, and dentomaxillofacial radiology.",institutionString:"Gazi University",institution:{name:"Gazi University",country:{name:"Turkey"}}},{id:"256417",title:"Associate Prof.",name:"Sanaz",middleName:null,surname:"Sadry",slug:"sanaz-sadry",fullName:"Sanaz Sadry",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/256417/images/8106_n.jpg",biography:null,institutionString:null,institution:null},{id:"272237",title:"Dr.",name:"Pinar",middleName:"Kiymet",surname:"Karataban",slug:"pinar-karataban",fullName:"Pinar Karataban",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/272237/images/8911_n.png",biography:"Assist.Prof.Dr.Pınar Kıymet Karataban, DDS PhD \n\nDr.Pınar Kıymet Karataban was born in Istanbul in 1975. After her graduation from Marmara University Faculty of Dentistry in 1998 she started her PhD in Paediatric Dentistry focused on children with special needs; mainly children with Cerebral Palsy. She finished her pHD thesis entitled \\'Investigation of occlusion via cast analysis and evaluation of dental caries prevalance, periodontal status and muscle dysfunctions in children with cerebral palsy” in 2008. She got her Assist. Proffessor degree in Istanbul Aydın University Paediatric Dentistry Department in 2015-2018. ın 2019 she started her new career in Bahcesehir University, Istanbul as Head of Department of Pediatric Dentistry. In 2020 she was accepted to BAU International University, Batumi as Professor of Pediatric Dentistry. She’s a lecturer in the same university meanwhile working part-time in private practice in Ege Dental Studio (https://www.egedisklinigi.com/) a multidisciplinary dental clinic in Istanbul. Her main interests are paleodontology, ancient and contemporary dentistry, oral microbiology, cerebral palsy and special care dentistry. She has national and international publications, scientific reports and is a member of IAPO (International Association for Paleodontology), IADH (International Association of Disability and Oral Health) and EAPD (European Association of Pediatric Dentistry).",institutionString:null,institution:null},{id:"202198",title:"Dr.",name:"Buket",middleName:null,surname:"Aybar",slug:"buket-aybar",fullName:"Buket Aybar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/202198/images/6955_n.jpg",biography:"Buket Aybar, DDS, PhD, was born in 1971. She graduated from Istanbul University, Faculty of Dentistry, in 1992 and completed her PhD degree on Oral and Maxillofacial Surgery in Istanbul University in 1997.\nDr. Aybar is currently a full-time professor in Istanbul University, Faculty of Dentistry Department of Oral and Maxillofacial Surgery. She has teaching responsibilities in graduate and postgraduate programs. Her clinical practice includes mainly dentoalveolar surgery.\nHer topics of interest are biomaterials science and cell culture studies. She has many articles in international and national scientific journals and chapters in books; she also has participated in several scientific projects supported by Istanbul University Research fund.",institutionString:null,institution:null},{id:"260116",title:"Dr.",name:"Mehmet",middleName:null,surname:"Yaltirik",slug:"mehmet-yaltirik",fullName:"Mehmet Yaltirik",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/260116/images/7413_n.jpg",biography:"Birth Date 25.09.1965\r\nBirth Place Adana- Turkey\r\nSex Male\r\nMarrial Status Bachelor\r\nDriving License Acquired\r\nMother Tongue Turkish\r\n\r\nAddress:\r\nWork:University of Istanbul,Faculty of Dentistry, Department of Oral Surgery and Oral Medicine 34093 Capa,Istanbul- TURKIYE",institutionString:null,institution:null},{id:"172009",title:"Dr.",name:"Fatma Deniz",middleName:null,surname:"Uzuner",slug:"fatma-deniz-uzuner",fullName:"Fatma Deniz Uzuner",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/172009/images/7122_n.jpg",biography:"Dr. Deniz Uzuner was born in 1969 in Kocaeli-TURKEY. After graduating from TED Ankara College in 1986, she attended the Hacettepe University, Faculty of Dentistry in Ankara. \nIn 1993 she attended the Gazi University, Faculty of Dentistry, Department of Orthodontics for her PhD education. After finishing the PhD education, she worked as orthodontist in Ankara Dental Hospital under the Turkish Government, Ministry of Health and in a special Orthodontic Clinic till 2011. Between 2011 and 2016, Dr. Deniz Uzuner worked as a specialist in the Department of Orthodontics, Faculty of Dentistry, Gazi University in Ankara/Turkey. In 2016, she was appointed associate professor. Dr. Deniz Uzuner has authored 23 Journal Papers, 3 Book Chapters and has had 39 oral/poster presentations. She is a member of the Turkish Orthodontic Society. Her knowledge of English is at an advanced level.",institutionString:null,institution:null},{id:"332914",title:"Dr.",name:"Muhammad Saad",middleName:null,surname:"Shaikh",slug:"muhammad-saad-shaikh",fullName:"Muhammad Saad Shaikh",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Jinnah Sindh Medical University",country:{name:"Pakistan"}}},{id:"315775",title:"Dr.",name:"Feng",middleName:null,surname:"Luo",slug:"feng-luo",fullName:"Feng Luo",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Sichuan University",country:{name:"China"}}},{id:"423519",title:"Dr.",name:"Sizakele",middleName:null,surname:"Ngwenya",slug:"sizakele-ngwenya",fullName:"Sizakele Ngwenya",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of the Witwatersrand",country:{name:"South Africa"}}},{id:"419270",title:"Dr.",name:"Ann",middleName:null,surname:"Chianchitlert",slug:"ann-chianchitlert",fullName:"Ann Chianchitlert",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Walailak University",country:{name:"Thailand"}}},{id:"419271",title:"Dr.",name:"Diane",middleName:null,surname:"Selvido",slug:"diane-selvido",fullName:"Diane Selvido",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Walailak University",country:{name:"Thailand"}}},{id:"419272",title:"Dr.",name:"Irin",middleName:null,surname:"Sirisoontorn",slug:"irin-sirisoontorn",fullName:"Irin Sirisoontorn",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Walailak University",country:{name:"Thailand"}}},{id:"355660",title:"Dr.",name:"Anitha",middleName:null,surname:"Mani",slug:"anitha-mani",fullName:"Anitha Mani",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"SRM Dental College",country:{name:"India"}}},{id:"355612",title:"Dr.",name:"Janani",middleName:null,surname:"Karthikeyan",slug:"janani-karthikeyan",fullName:"Janani Karthikeyan",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"SRM Dental College",country:{name:"India"}}},{id:"334400",title:"Dr.",name:"Suvetha",middleName:null,surname:"Siva",slug:"suvetha-siva",fullName:"Suvetha Siva",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"SRM Dental College",country:{name:"India"}}},{id:"334239",title:"Prof.",name:"Leung",middleName:null,surname:"Wai Keung",slug:"leung-wai-keung",fullName:"Leung Wai Keung",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Hong Kong",country:{name:"China"}}}]}},subseries:{item:{id:"27",type:"subseries",title:"Multi-Agent Systems",keywords:"Collaborative Intelligence, Learning, Distributed Control System, Swarm Robotics, Decision Science, Software Engineering",scope:"Multi-agent systems are recognised as a state of the art field in Artificial Intelligence studies, which is popular due to the usefulness in facilitation capabilities to handle real-world problem-solving in a distributed fashion. The area covers many techniques that offer solutions to emerging problems in robotics and enterprise-level software systems. Collaborative intelligence is highly and effectively achieved with multi-agent systems. Areas of application include swarms of robots, flocks of UAVs, collaborative software management. Given the level of technological enhancements, the popularity of machine learning in use has opened a new chapter in multi-agent studies alongside the practical challenges and long-lasting collaboration issues in the field. It has increased the urgency and the need for further studies in this field. We welcome chapters presenting research on the many applications of multi-agent studies including, but not limited to, the following key areas: machine learning for multi-agent systems; modeling swarms robots and flocks of UAVs with multi-agent systems; decision science and multi-agent systems; software engineering for and with multi-agent systems; tools and technologies of multi-agent systems.",coverUrl:"https://cdn.intechopen.com/series_topics/covers/27.jpg",hasOnlineFirst:!1,hasPublishedBooks:!1,annualVolume:11423,editor:{id:"148497",title:"Dr.",name:"Mehmet",middleName:"Emin",surname:"Aydin",slug:"mehmet-aydin",fullName:"Mehmet Aydin",profilePictureURL:"https://mts.intechopen.com/storage/users/148497/images/system/148497.jpg",biography:"Dr. Mehmet Emin Aydin is a Senior Lecturer with the Department of Computer Science and Creative Technology, the University of the West of England, Bristol, UK. His research interests include swarm intelligence, parallel and distributed metaheuristics, machine learning, intelligent agents and multi-agent systems, resource planning, scheduling and optimization, combinatorial optimization. Dr. Aydin is currently a Fellow of Higher Education Academy, UK, a member of EPSRC College, a senior member of IEEE and a senior member of ACM. In addition to being a member of advisory committees of many international conferences, he is an Editorial Board Member of various peer-reviewed international journals. He has served as guest editor for a number of special issues of peer-reviewed international journals.",institutionString:null,institution:{name:"University of the West of England",institutionURL:null,country:{name:"United Kingdom"}}},editorTwo:null,editorThree:null,series:{id:"14",title:"Artificial Intelligence",doi:"10.5772/intechopen.79920",issn:"2633-1403"},editorialBoard:[{id:"275140",title:"Dr.",name:"Dinh Hoa",middleName:null,surname:"Nguyen",slug:"dinh-hoa-nguyen",fullName:"Dinh Hoa Nguyen",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRbnKQAS/Profile_Picture_1622204093453",institutionString:null,institution:{name:"Kyushu University",institutionURL:null,country:{name:"Japan"}}},{id:"20259",title:"Dr.",name:"Hongbin",middleName:null,surname:"Ma",slug:"hongbin-ma",fullName:"Hongbin Ma",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRhDJQA0/Profile_Picture_2022-05-02T08:25:21.jpg",institutionString:null,institution:{name:"Beijing Institute of Technology",institutionURL:null,country:{name:"China"}}},{id:"28640",title:"Prof.",name:"Yasushi",middleName:null,surname:"Kambayashi",slug:"yasushi-kambayashi",fullName:"Yasushi Kambayashi",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYOQxQAO/Profile_Picture_1625660525470",institutionString:null,institution:{name:"Nippon Institute of Technology",institutionURL:null,country:{name:"Japan"}}}]},onlineFirstChapters:{paginationCount:14,paginationItems:[{id:"82103",title:"The Role of Endoplasmic Reticulum Stress and Its Regulation in the Progression of Neurological and Infectious Diseases",doi:"10.5772/intechopen.105543",signatures:"Mary Dover, Michael Kishek, Miranda Eddins, Naneeta Desar, Ketema Paul and Milan Fiala",slug:"the-role-of-endoplasmic-reticulum-stress-and-its-regulation-in-the-progression-of-neurological-and-i",totalDownloads:5,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Updates on Endoplasmic Reticulum",coverURL:"https://cdn.intechopen.com/books/images_new/11674.jpg",subseries:{id:"14",title:"Cell and Molecular Biology"}}},{id:"80954",title:"Ion Channels and Neurodegenerative Disease Aging Related",doi:"10.5772/intechopen.103074",signatures:"Marika Cordaro, Salvatore Cuzzocrea and Rosanna Di Paola",slug:"ion-channels-and-neurodegenerative-disease-aging-related",totalDownloads:6,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Ion Channels - From Basic Properties to Medical Treatment",coverURL:"https://cdn.intechopen.com/books/images_new/10838.jpg",subseries:{id:"14",title:"Cell and Molecular Biology"}}},{id:"81647",title:"Diabetes and Epigenetics",doi:"10.5772/intechopen.104653",signatures:"Rasha A. 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Thus proteomics, an area of research that detects all protein forms expressed in an organism, including splice isoforms and post-translational modifications, is more suitable than genomics for a comprehensive understanding of the biochemical processes that govern life. The most common proteomics applications are currently in the clinical field for the identification, in a variety of biological matrices, of biomarkers for diagnosis and therapeutic intervention of disorders. From the comparison of proteomic profiles of control and disease or different physiological states, which may emerge, changes in protein expression can provide new insights into the roles played by some proteins in human pathologies. Understanding how proteins function and interact with each other is another goal of proteomics that makes this approach even more intriguing. Specialized technology and expertise are required to assess the proteome of any biological sample. 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