Comparative measure of mean pain before, during and after each procedure in 3 representative groups. Pain scale used 0-10. (0 means no pain and 10 high pain).
\\n\\n
Released this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\\n\\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
Note: Edited in March 2021
\\n"}]',published:!0,mainMedia:{caption:"Highly Cited",originalUrl:"/media/original/117"}},components:[{type:"htmlEditorComponent",content:'IntechOpen is proud to announce that 191 of our authors have made the Clarivate™ Highly Cited Researchers List for 2020, ranking them among the top 1% most-cited.
\n\nThroughout the years, the list has named a total of 261 IntechOpen authors as Highly Cited. Of those researchers, 69 have been featured on the list multiple times.
\n\n\n\nReleased this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\n\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
Note: Edited in March 2021
\n'}],latestNews:[{slug:"webinar-introduction-to-open-science-wednesday-18-may-1-pm-cest-20220518",title:"Webinar: Introduction to Open Science | Wednesday 18 May, 1 PM CEST"},{slug:"step-in-the-right-direction-intechopen-launches-a-portfolio-of-open-science-journals-20220414",title:"Step in the Right Direction: IntechOpen Launches a Portfolio of Open Science Journals"},{slug:"let-s-meet-at-london-book-fair-5-7-april-2022-olympia-london-20220321",title:"Let’s meet at London Book Fair, 5-7 April 2022, Olympia London"},{slug:"50-books-published-as-part-of-intechopen-and-knowledge-unlatched-ku-collaboration-20220316",title:"50 Books published as part of IntechOpen and Knowledge Unlatched (KU) Collaboration"},{slug:"intechopen-joins-the-united-nations-sustainable-development-goals-publishers-compact-20221702",title:"IntechOpen joins the United Nations Sustainable Development Goals Publishers Compact"},{slug:"intechopen-signs-exclusive-representation-agreement-with-lsr-libros-servicios-y-representaciones-s-a-de-c-v-20211123",title:"IntechOpen Signs Exclusive Representation Agreement with LSR Libros Servicios y Representaciones S.A. de C.V"},{slug:"intechopen-expands-partnership-with-research4life-20211110",title:"IntechOpen Expands Partnership with Research4Life"},{slug:"introducing-intechopen-book-series-a-new-publishing-format-for-oa-books-20210915",title:"Introducing IntechOpen Book Series - A New Publishing Format for OA Books"}]},book:{item:{type:"book",id:"7049",leadTitle:null,fullTitle:"Cardiac Pacing and Monitoring - New Methods, Modern Devices",title:"Cardiac Pacing and Monitoring",subtitle:"New Methods, Modern Devices",reviewType:"peer-reviewed",abstract:"Different artificial tools, such as heart-pacing devices, wearable and implantable monitors, engineered heart valves and stents, and many other cardiac devices, are in use in medical practice. Recent developments in the methods of cardiac pacing along with appropriate selection of equipment are the purpose of this book. Implantable heart rate management devices and wearable cardiac monitors are discussed. Indications for using specific types of cardiac pacemakers, cardiac resynchronization therapy devices, and implantable cardioverter defibrillators (ICDs) are of interest and their contraindications are considered. Special attention is paid to using leadless devices. The subcutaneous ICD obviates the need for transvenous leads and leadless pacemakers are entirely implantable into the right ventricle. Finally, applications of user-friendly wearable devices for the detection of atrial arrhythmia are debated.",isbn:"978-1-83880-180-9",printIsbn:"978-1-83880-179-3",pdfIsbn:"978-1-83962-147-5",doi:"10.5772/intechopen.73811",price:119,priceEur:129,priceUsd:155,slug:"cardiac-pacing-and-monitoring-new-methods-modern-devices",numberOfPages:104,isOpenForSubmission:!1,isInWos:null,isInBkci:!1,hash:"52722bbabb55cb46dc08d238880f4366",bookSignature:"Mart Min",publishedDate:"April 24th 2019",coverURL:"https://cdn.intechopen.com/books/images_new/7049.jpg",numberOfDownloads:5243,numberOfWosCitations:0,numberOfCrossrefCitations:6,numberOfCrossrefCitationsByBook:0,numberOfDimensionsCitations:6,numberOfDimensionsCitationsByBook:0,hasAltmetrics:0,numberOfTotalCitations:12,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"May 3rd 2018",dateEndSecondStepPublish:"August 15th 2018",dateEndThirdStepPublish:"October 14th 2018",dateEndFourthStepPublish:"January 2nd 2019",dateEndFifthStepPublish:"March 3rd 2019",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6",editedByType:"Edited by",kuFlag:!1,featuredMarkup:null,editors:[{id:"62780",title:"Prof.",name:"Mart",middleName:null,surname:"Min",slug:"mart-min",fullName:"Mart Min",profilePictureURL:"https://mts.intechopen.com/storage/users/62780/images/system/62780.jpg",biography:"Mart Min is a full professor and leading scientist at the Thomas Johann Seebeck Department of Electronics, Tallinn University of Technology, Estonia. He received a Diploma Engineer’s qualification in Electronics from the same university in 1969, and a Ph.D. in Measurement Science from Kyiv Polytechnic, Ukraine in 1984. From 1992 to 1993 he was a guest scientist and professor at the Technical University of Munich and Bundeswehr University, Germany. From 2007 to 2010 he was a leading scientist at the international research group of the Institute of Bioprocessing and Analytical Measurement Technique, Germany. Dr. Min is interested in electronic measurements and signal processing methods with implementations in medicine, including the development of rate-responsive cardiac pacemakers for US companies. He is an author and co-author of more than 250 papers and 40 patents as well as an editor of several scientific books in biomedical engineering. He is a senior life member of the Institute of Electrical and Electronics Engineers (IEEE) Instrumentation and Measurement Society and Engineering in Medicine and Biology Society. He is a member of the International Committee for Promotion of Research in Bio-Impedance (ICPRBI). Professor Emeritus since 2017, Dr. Min continues activities as a research scientist in biomedical electronics.",institutionString:"Tallinn University of Technology",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"3",totalChapterViews:"0",totalEditedBooks:"2",institution:{name:"Tallinn University of Technology",institutionURL:null,country:{name:"Estonia"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"983",title:"Cardiac Electrophysiology",slug:"cardiac-electrophysiology"}],chapters:[{id:"66387",title:"Introductory Chapter: From Basic Foundations to Future Developments",doi:"10.5772/intechopen.85674",slug:"introductory-chapter-from-basic-foundations-to-future-developments",totalDownloads:814,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:null,signatures:"Mart Min",downloadPdfUrl:"/chapter/pdf-download/66387",previewPdfUrl:"/chapter/pdf-preview/66387",authors:[{id:"62780",title:"Prof.",name:"Mart",surname:"Min",slug:"mart-min",fullName:"Mart Min"}],corrections:null},{id:"64733",title:"Clinical Indications for Therapeutic Cardiac Devices",doi:"10.5772/intechopen.82463",slug:"clinical-indications-for-therapeutic-cardiac-devices",totalDownloads:1210,totalCrossrefCites:1,totalDimensionsCites:1,hasAltmetrics:0,abstract:"Both technology and clinical indications have changed since the first cardiac devices. Choosing the right therapy, or abstaining from it, is the key to good clinical management. Pacemakers effectively reduce symptoms of bradycardia, prevent syncope in patients with sick sinus syndrome, and reduce mortality in high-degree atrioventricular block. Cardiac resynchronization therapy improves symptoms and survival in heart failure patients with reduced ejection fraction and ventricular dyssynchrony. Implantable cardioverter defibrillators terminate life-threatening ventricular arrhythmias and are indicated for the prevention of sudden cardiac death, either as secondary prevention in survivors of ventricular fibrillation or ventricular tachycardia with hemodynamic compromise or as primary prevention due to heart failure with reduced ejection fraction or other miscellaneous diseases. More recently, leadless pacemakers and subcutaneous implantable cardioverter defibrillators have been developed as alternatives in specific conditions.",signatures:"Ida Åberg, Gustav Mattsson and Peter Magnusson",downloadPdfUrl:"/chapter/pdf-download/64733",previewPdfUrl:"/chapter/pdf-preview/64733",authors:[null],corrections:null},{id:"63460",title:"The Subcutaneous Implantable Cardioverter-Defibrillator",doi:"10.5772/intechopen.80859",slug:"the-subcutaneous-implantable-cardioverter-defibrillator",totalDownloads:1034,totalCrossrefCites:1,totalDimensionsCites:1,hasAltmetrics:0,abstract:"The subcutaneous ICD (S-ICD) represents an important advancement in defibrillation therapy that obviates the need for a transvenous lead, the most frequent complication with transvenous devices. The S-ICD has been shown similarly safe and effective as transvenous ICD therapy, but the two devices are not interchangeable. The S-ICD is only suitable for patients who do not require bradycardia or antitachycardia pacing functionality. In patients with underlying diseases associated with polymorphic ventricular tachycardia and a long life expectancy, an S-ICD may be the preferred choice. Moreover, it is advantageous in the situation of increased risk of endocarditis, i.e., previous device system infection and immunosuppression, including hemodialysis. In patients with abnormal vascular access and/or right-sided heart structural abnormalities, it may be the only option. The S-ICD is bulkier, the battery longevity is shorter, and the device cost is higher, even though remote follow-up is possible. A two- or three-incision implant procedure has been described with a lateral placement of the device and a single subcutaneous lead. The rate of inappropriate therapy for both S-ICD and transvenous systems is similar, but S-ICD inappropriate shocks are more frequently attributable to oversensing, which can often be resolved with sensing adjustments.",signatures:"Peter Magnusson, Joseph V. Pergolizzi and Jo Ann LeQuang",downloadPdfUrl:"/chapter/pdf-download/63460",previewPdfUrl:"/chapter/pdf-preview/63460",authors:[null],corrections:null},{id:"65740",title:"Leadless Pacemakers",doi:"10.5772/intechopen.83546",slug:"leadless-pacemakers",totalDownloads:1207,totalCrossrefCites:2,totalDimensionsCites:2,hasAltmetrics:0,abstract:"Leadless or transcatheter pacemakers have recently been introduced to market with important benefits and some limitations. Implanted entirely within the right ventricle, these devices eliminate the need for transvenous pacing leads and pacemaker pockets and thus reduce the risk of infections and lead-related problems. Currently, they offer only VVI/R pacing and they cannot provide atrial sensing, antitachycardia pacing, or AV synchrony. They offer a number of features (such as rate response) and electrogram storage, albeit more limited than in a transvenous system. Real-world clinical data are needed to better comment on projected battery life, which manufacturers suggest will be at least equivalent to transvenous devices. Extracting an implanted leadless pacemaker remains a challenge, although proprietary snare and removal systems are available. However, a leadless pacemaker at end of service may be programmed to OOO and left in place; a revised device may be implanted adjacent. These innovative new devices may have important uses in special populations. Initial data on implant success and adverse events are favorable. Currently, there are two leadless pacemakers available: the Micra™ device by Medtronic and the Nanostim™ device by Abbott (formerly St. Jude Medical).",signatures:"Peter Magnusson, Joseph V. Pergolizzi Jr and Jo Ann LeQuang",downloadPdfUrl:"/chapter/pdf-download/65740",previewPdfUrl:"/chapter/pdf-preview/65740",authors:[null],corrections:null},{id:"65376",title:"Atrial Fibrillation and the Role of Thumb ECGs",doi:"10.5772/intechopen.83660",slug:"atrial-fibrillation-and-the-role-of-thumb-ecgs",totalDownloads:978,totalCrossrefCites:2,totalDimensionsCites:2,hasAltmetrics:0,abstract:"Atrial fibrillation (AF) may be underdiagnosed, and there is much that remains unknown about this prevalent and potentially life-threatening arrhythmia. AF epidemiology has been thwarted in part by the fact that about a third of patients with AF have no symptoms, those with symptoms may experience them intermittently or have vague symptoms, and it can be challenging to capture an episode on a 12-lead ECG, which is required for diagnosis. There are many significant knowledge gaps in our understanding of AF etiology and progression. A new user-friendly device that allows for frequent self-monitoring of the heart rhythm has been introduced. With the thumb ECG, patients can record a tracing multiple times a day. A smartphone app will soon allow them to interact with their healthcare providers about these ECG recordings. An ECG parser will allow for an algorithm-directed, rapid, automatic interpretation of these recordings with high specificity and sensitivity. This may help researchers learn more about the so-called silent AF, AF progression (and possible remission), and risk factors for AF. 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Transactivating crRNA (tracrRNA) is partially complementary to and pairs with a pre-crRNA to form an RNA duplex cleaved by RNase III and a crRNA/tracrRNA hybrid acts as a guide for the endonuclease Cas, which cleaves the invading DNA. Currently, it has been successfully used in genome editing such as silencing, enhancing, or modification of specific genes. Plasmids are constructed to express crRNA and tracrRNA together as single-guide RNAs (sgRNA). By the Cas proteins and a specifically designed sgRNA, the organism’s genome can be cleaved at most locations with the only limitation being the availability of an NGG protospacer adjacent motif (PAM) sequence in the targeting site. Efficient genome engineering has been performed in human cells, bacteria, yeasts, zebrafish, nematodes, plants, animals, etc. These findings and their implications may be discussed in the broadest context possible. Future research directions may also be highlighted. In this book, we will explore the development of CRISPR-Cas encoding and its application in basic research.
",isbn:"978-1-80356-816-4",printIsbn:"978-1-80356-815-7",pdfIsbn:"978-1-80356-817-1",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!0,isSalesforceBook:!1,isNomenclature:!1,hash:"4051570f538bd3315e051267180abe37",bookSignature:"Dr. Yuan-Chuan Chen",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/11804.jpg",keywords:"crRNA, tracr RNA, sgRNA, PAM sequence, Encoding, Silencing, Enhancing, Modification, Genetic Engineering, Animal Model, Delivery Tool, CRISPR",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"March 30th 2022",dateEndSecondStepPublish:"June 10th 2022",dateEndThirdStepPublish:"August 9th 2022",dateEndFourthStepPublish:"October 28th 2022",dateEndFifthStepPublish:"December 27th 2022",dateConfirmationOfParticipation:null,remainingDaysToSecondStep:"25 days",secondStepPassed:!0,areRegistrationsClosed:!1,currentStepOfPublishingProcess:3,editedByType:null,kuFlag:!1,biosketch:"Yuan-Chuan Chen completed his Ph.D. in Comparative Biochemistry at the University of California, Berkeley (UCB), USA. His studies are focusing on the discovery, production, application of biopharmaceuticals. Additionally, he is interested in basic research and human therapeutics using CRISPR/Cas9.",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"185559",title:"Dr.",name:"Yuan-Chuan",middleName:null,surname:"Chen",slug:"yuan-chuan-chen",fullName:"Yuan-Chuan Chen",profilePictureURL:"https://mts.intechopen.com/storage/users/185559/images/system/185559.jpg",biography:"Yuan-Chuan Chen completed his PhD in Comparative Biochemistry at the University of California, Berkeley (UCB), USA and had postdoctoral studies at the Taiwan Food and Drug Administration (TFDA). His research interests include Pharmacy/Pharmacology, Biochemistry, Microbiology/Virology, Cell/Molecule Biology, Biotechnology/Nanotechnology, Cell/Gene therapy and Policy/Regulation. He has participated in publishing many co-authored articles in peer-reviewed journals and book chapters in the fields of basic science, biomedicine, and related policy/regulation. He is now an assistant professor in Jenteh Junior College of Medicine, Nursing and Management, Taiwan. He is also an adjunct member in the biopharmaceutical division of Chinese Pharmacopoeia (Taiwan) Revising Committee (9th edition) and has reviewed many materials for Pharmacopoeia revising. His research is focusing on the discovery, production, application, perspectives and challenges of biopharmaceuticals. He is interested in basic research, the development of agricultural/industrial products and human therapeutics using the CRISPR/Cas9 system. Additionally, he is specialized in genomic studies including genomic analysis, gene function, and gene expression and control.",institutionString:"Jenteh Junior College of Medicine, Nursing and Management",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"6",totalChapterViews:"0",totalEditedBooks:"2",institution:null}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"6",title:"Biochemistry, Genetics and Molecular Biology",slug:"biochemistry-genetics-and-molecular-biology"}],chapters:null,productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"453623",firstName:"Silvia",lastName:"Sabo",middleName:null,title:"Mrs.",imageUrl:"https://mts.intechopen.com/storage/users/453623/images/20396_n.jpg",email:"silvia@intechopen.com",biography:null}},relatedBooks:[{type:"book",id:"6694",title:"New Trends in Ion Exchange Studies",subtitle:null,isOpenForSubmission:!1,hash:"3de8c8b090fd8faa7c11ec5b387c486a",slug:"new-trends-in-ion-exchange-studies",bookSignature:"Selcan Karakuş",coverURL:"https://cdn.intechopen.com/books/images_new/6694.jpg",editedByType:"Edited by",editors:[{id:"206110",title:"Dr.",name:"Selcan",surname:"Karakuş",slug:"selcan-karakus",fullName:"Selcan Karakuş"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1591",title:"Infrared Spectroscopy",subtitle:"Materials Science, Engineering and Technology",isOpenForSubmission:!1,hash:"99b4b7b71a8caeb693ed762b40b017f4",slug:"infrared-spectroscopy-materials-science-engineering-and-technology",bookSignature:"Theophile Theophanides",coverURL:"https://cdn.intechopen.com/books/images_new/1591.jpg",editedByType:"Edited by",editors:[{id:"37194",title:"Dr.",name:"Theophile",surname:"Theophanides",slug:"theophile-theophanides",fullName:"Theophile Theophanides"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3161",title:"Frontiers in Guided Wave Optics and Optoelectronics",subtitle:null,isOpenForSubmission:!1,hash:"deb44e9c99f82bbce1083abea743146c",slug:"frontiers-in-guided-wave-optics-and-optoelectronics",bookSignature:"Bishnu Pal",coverURL:"https://cdn.intechopen.com/books/images_new/3161.jpg",editedByType:"Edited by",editors:[{id:"4782",title:"Prof.",name:"Bishnu",surname:"Pal",slug:"bishnu-pal",fullName:"Bishnu Pal"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"371",title:"Abiotic Stress in Plants",subtitle:"Mechanisms and Adaptations",isOpenForSubmission:!1,hash:"588466f487e307619849d72389178a74",slug:"abiotic-stress-in-plants-mechanisms-and-adaptations",bookSignature:"Arun Shanker and B. Venkateswarlu",coverURL:"https://cdn.intechopen.com/books/images_new/371.jpg",editedByType:"Edited by",editors:[{id:"58592",title:"Dr.",name:"Arun",surname:"Shanker",slug:"arun-shanker",fullName:"Arun Shanker"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3092",title:"Anopheles mosquitoes",subtitle:"New insights into malaria vectors",isOpenForSubmission:!1,hash:"c9e622485316d5e296288bf24d2b0d64",slug:"anopheles-mosquitoes-new-insights-into-malaria-vectors",bookSignature:"Sylvie Manguin",coverURL:"https://cdn.intechopen.com/books/images_new/3092.jpg",editedByType:"Edited by",editors:[{id:"50017",title:"Prof.",name:"Sylvie",surname:"Manguin",slug:"sylvie-manguin",fullName:"Sylvie Manguin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"72",title:"Ionic Liquids",subtitle:"Theory, Properties, New Approaches",isOpenForSubmission:!1,hash:"d94ffa3cfa10505e3b1d676d46fcd3f5",slug:"ionic-liquids-theory-properties-new-approaches",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/72.jpg",editedByType:"Edited by",editors:[{id:"19816",title:"Prof.",name:"Alexander",surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"2270",title:"Fourier Transform",subtitle:"Materials Analysis",isOpenForSubmission:!1,hash:"5e094b066da527193e878e160b4772af",slug:"fourier-transform-materials-analysis",bookSignature:"Salih Mohammed Salih",coverURL:"https://cdn.intechopen.com/books/images_new/2270.jpg",editedByType:"Edited by",editors:[{id:"111691",title:"Dr.Ing.",name:"Salih",surname:"Salih",slug:"salih-salih",fullName:"Salih Salih"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"117",title:"Artificial Neural Networks",subtitle:"Methodological Advances and Biomedical Applications",isOpenForSubmission:!1,hash:null,slug:"artificial-neural-networks-methodological-advances-and-biomedical-applications",bookSignature:"Kenji Suzuki",coverURL:"https://cdn.intechopen.com/books/images_new/117.jpg",editedByType:"Edited by",editors:[{id:"3095",title:"Prof.",name:"Kenji",surname:"Suzuki",slug:"kenji-suzuki",fullName:"Kenji Suzuki"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3828",title:"Application of Nanotechnology in Drug Delivery",subtitle:null,isOpenForSubmission:!1,hash:"51a27e7adbfafcfedb6e9683f209cba4",slug:"application-of-nanotechnology-in-drug-delivery",bookSignature:"Ali Demir Sezer",coverURL:"https://cdn.intechopen.com/books/images_new/3828.jpg",editedByType:"Edited by",editors:[{id:"62389",title:"PhD.",name:"Ali Demir",surname:"Sezer",slug:"ali-demir-sezer",fullName:"Ali Demir Sezer"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"872",title:"Organic Pollutants Ten Years After the Stockholm Convention",subtitle:"Environmental and Analytical Update",isOpenForSubmission:!1,hash:"f01dc7077e1d23f3d8f5454985cafa0a",slug:"organic-pollutants-ten-years-after-the-stockholm-convention-environmental-and-analytical-update",bookSignature:"Tomasz Puzyn and Aleksandra Mostrag-Szlichtyng",coverURL:"https://cdn.intechopen.com/books/images_new/872.jpg",editedByType:"Edited by",editors:[{id:"84887",title:"Dr.",name:"Tomasz",surname:"Puzyn",slug:"tomasz-puzyn",fullName:"Tomasz Puzyn"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"39054",title:"Cybertherapy in Medicine – Experience at the Universidad Panamericana, IMSS and ISSSTE Mexico",doi:"10.5772/52349",slug:"cybertherapy-in-medicine-experience-at-the-universidad-panamericana-imss-and-issste-mexico",body:'There are many reports of Virtual Reality analysis and clinical applications in Medicine since the end of the last century for many authors. In trauma head injuries [1], during chemotherapy in children [2], in burn wound care [3,4,5], lumbar puncture [6,], breast cancer [7], vein puncture [8], pain distraction [9,10,11,12], dental pain control [13], leg ulcer relief [14], night vision technology with robot control to treat bourn injuries using robot-like arm mounted VR goggles [15]. The first case reports related with VR and medical invasive procedures and surgery in hospitals was in 2004 with our group, beginning with upper gastrointestinal endoscopies and so on, until introduce VR in postoperative care unit of cardiac surgery [16,17].
Pain and anxiety in outpatients and inpatients is a regular symptom in hospitals. For pain are available medications and for anxiety also. Patients in; in-rooms, operating rooms and another different places, get treatments with medical and surgical procedures, and pain and anxiety are the meanly symptom. In this project we try to demonstrate that virtual reality is a complementary tool to reduce pain and anxiety in hospitals during medical procedures including surgical procedures. There are a lot reason and justifications to use VR in hospitals, as follows.
The conditions to perform the following project are. Consent informed, full consciousness; agree to participate in the project; completeness vision, controlled cardiovascular and respiratory disease. Patients were afíliate at Instituto Mexicano del Seguro Social (IMSS) and Instituto de Seguridad y Servicios Sociales para los Trabajadores del Estado, (ISSSTE). In case of newborns, parents signed consent informed.
Technique. Before each procedure, nurse measured blood pressure, heart rate, breath rate (In the case of patients in unit cares, we considered arterial blood gases). Physician asks patients about his-her feelings (Anxiety) in a scale of 0 to 10 (where 0 is no pain and 10 is high pain). Physician installed the following equipment also: Laptop with 3 virtual scenarios (Enchanted forest, cliff final, icy city see figure 2) and connected to a vision goggles eMagin. When we used smart phones (Nokia N95 and iPhone G3) and PSP2 we used a mp3 video with a green valley scenario connected to goggles. Once set up the equipment, it was installed in the patient´s head. Physician begins the procedure and in the middle of the procedure, nurse measured vital signs again and physician repeats the same question about the feelings (Anxiety and pain). Head Mounted display is removed of the head´s patient at the end of each procedure and 15 minutes after, nurse made the third measure of vital signs and physician asks the feelings of the patient again. In the case of Night Vision Goggles (NV) for ambulatory surgery for total darkness was necessary to perform open surgery on rabbits at the school of Medicine at the Universidad Panamericana in 9 rabbits under general anesthesia before to make ambulatory surgeries on humans. NV equipment needs a scrub nurse to hold all equipment on the head of surgeon and first assistant after dressing with sterile clothing. Cables were connected beside the surgical table. Diagnosis of surgery group: big lipomas on head, arms, legs or abdomen, non complicated inguinal and umbilical hernias. Complicated and non complicated postoperative hernias in the abdominal wall. For Laparoscopic group: non acute cholecystitis, and inguinal hernias. With night vision technology group: big lipomas on arms, legs and non complicated inguinal hernia. Diagnosis for postoperative care unit of cardiac surgery: aortic and mitral valves rechange and coronary revascularization. Colposcopy group: cervicitis and premalignant lesions in cervix. Neonatology group: premature newborns in recovery with more than 5 days to 2 months of hospitalizations with multiple diagnosis such as necrotizing enterocolitis, sepsis, respiratory disorders. In the kidney transplantation only one patient in the recovery used VR. In obstetrics, patients with 48 weeks of pregnant with 5 to 10 of cervical dilation participate with normal fetus in labor room where epidural or spinal block were installed and we follow the same patients to the delivery room and to the operating rooms. In the group of endoscopy, diagnosis was hiatal hernia, peptic disease and colon disorder.
The comparative measure of pain were made before, during and after each procedure in all groups using Virtual Reality and the control group, except in patients without any medical procedure such as the group of care unit of cardiac surgery and neonatology. The statistical method to measure pain used was the mean into the scale of 0 to 10 (Cero is no pain and 10 is high level of pain). We present statistical results in the 3 representative groups where pain and anxiety are high such as colposcopy (see table 3), ambulatory surgery (see table 4) and postoperative care unit of cardiac surgery (See table 5). With the results of these groups we can appreciate the possibilities to use this technique in another groups into the hospitals because we have been tested VR in a group seriously ills in critical care units in cardiac surgery and manipulations of tissues including abdominal cavity in ambulatory surgery group. In table 1 we measured mean pain (see figure 1) between before to during the procedure and between before to after (see table 1). In the colposcopy group that used VR the mean pain before the procedure was 7.5 and during was 5.35 with a difference of 2.15 that correspond of 28.66 % of reduction of pain. In the group of colposcopy that didn’t use VR the mean pain before was 6.43 and during 6.78 with an increase and difference of 0.35 that correspond of 5.44 % of increasing of pain, in the same group considering mean pain before of 6.43 and 4.83 after, the difference was 1.6 that correspond of 24.88 % of reduction of pain. In all groups we demonstrated an important reduction of pain using VR during medical or surgical procedures (see table 2). In care unit of cardiac surgery group the mean pain before were 8 and after 30 was 3.64 with a difference of 4.36 that correspond to 54.5% of reduction of pain-anxiety (See table 2). In the group of surgery there were a mean of pain before of 5.7 and during the procedure 3.93 with a difference of 1.8 that correspond of 31.41 % of reduction on pain. Considering the mean pain before of 5.73 and 2.09 after, there is a difference of 3.64 that correspond to 63 % of reduction of pain. In the group of surgery that didn’t use VR the pain mean were 5.57 before and during 5.19 with a difference of 0.48 that correspond to 6.8% of reduction, and considering the mean pain before of 5.57 and 3.52 after there is a difference of 2.05 that correspond to 36.80 % of reduction of pain. With these results we can appreciate the impact of distraction of VR to reduce anxiety and subsequently visceral and somatic pain in the case of surgery with regional anesthesia well placed.
Mean equation to obtain results
MEAN of pain and anxiety | Colposcopy with HMD | Colposcopy no HMD | Critical care unit of cardiac surgery | Ambulatory surgery. with HMD | Ambulatory surgery. No HMD |
Before | 7.5 | 6.43 | 8 | 5.73 | 5.57 |
During | 5.35 | 6.78 | 3.93 | 5.19 | |
After | 2.7 | 4.83 | 3.64 | 2.09 | 3.52 |
Comparative measure of mean pain before, during and after each procedure in 3 representative groups. Pain scale used 0-10. (0 means no pain and 10 high pain).
% of pain and anxiety Reduction | Colposcopy with HMD | Colposcopy no HMD | Critical care unit of cardiac surgery | Ambulatory surgery. with HMD | Ambulatory surgery. No HMD |
Before - during | 28.66 % | 5.44 % | 54.5 % | 31.41 % | 6.8 % |
Before - after | 64 % | 24.88 % | 63 % | 36.80 % |
Pain and anxiety percentage reduction, between before and during procedures. Pain scale used 0-10. (0 means no pain and 10 higher pain).
As a result of patient selection, we suggest the following general criteria to use VR in Medicine: 1.- Patients with voluntary participation, and signed authorization with written consent informed, (Patients under 18 years of age need written informed consent from parents), 2.- Medical control of cardiovascular, respiratory and neurological diseases, and 3.- full consciousness. (See figures 2 to 12)
Colposcopy. Group with VR (left) and control group (right)
Ambulatory surgery. Group with VR (left) and control group (right)
Postoperative Care Unit of cardiac surgery
Medical complications. 2 patients of 22 in care unit of cardiac surgery group presented cardiac arrhythmias during the virtual navigation due to the slow effort on the bed, the treatment was the immediately disruption of VR exposure with total recovery. In ambulatory surgery group with local anesthesia, 2 patients presented nausea and vertigoes using VR and after 30 minutes patients become tired to carry goggles on their heads in the same position, for this reason we used a projector to display a screen in the roof of the operating room. In the subgroup of endoscopic surgery under regional anesthesia, 3 patients of 5, presented chest pain secondary of neumoperitoneum and it was necessary convert regional anesthesia to general (For this reason we don´t suggest VR for endoscopic surgery under regional anesthesia). (See table 6).
Care unit of cardiac surgery | Care Unit | 2 patients presented arrhythmias. |
Surgery | General Surgery Endoscopic surgery Urology Angiology Dermatology Orthopedic Angiology Pediatric Obstetric | 2 patients presented nausea and vertigoes, another one presented pain in peritoneum manipulation. 3 patients presented chest pain and difficulty breathing None None None None None None None None |
Anesthesia | Epidural/spinal block | None |
Obstetric | Labour room Childbirth room | None None |
Endoscopy | Upper Endoscopy Colonoscopy | None None |
Complications
Technical limitations. In ambulatory surgery, patients need to move their hands to get more distraction; but they hands tied to the table to avoid contamination and in the other hand they become tired with the goggles on their heads and after 45 minutes they prefer change the projection of the scenario to the roof of the operating room. With NV we found limitation for surgeon’s motions for the cables connected to the wall beside the table one meter away. We had distorted vision for the glasses used, and the vision was in black and white color. The surgical time was small longer than conventional surgical time. In neonatology group, newborns present 5 to 8 seconds of attention for VR. It was difficult to evaluate the benefits of this technology, this is the reason we don´t present statistical results. We suggest using another kind of device of VR to interact with these patients who have limited vision.
We found differences results according with age, gender, procedures, culture, origin of regions, diagnosis, prognosis, but in all groups we found reduction of pain and anxiety, one more than others, except the subgroup of endoscopic surgery, the only one we don´t suggest use VR.. The group that enjoyed better the virtual scenarios was patients between 5 to 14 years of age in pediatric group. The older patients demonstrated curiosity of new technology that had in their hands.
There where patients exposed with Virtual Reality in different conditions like age, sex, medical procedures and different physicians but all results show us reduction of anxiety and pain. The answers were different in each group because pathways of pain involved are two, somatic and visceral. Tissues and organs manipulated were different, for instance: Skin, fat, muscles, fascias, peritoneum, cervix, uterus, peritoneum, spine´s dura, ligaments, small and medium vessels, gallbladder, omentum, visceral peritoneum, parietal peritoneum, esophagus, stomach and colon´s mucous. On the other hand, Patient´s psyche played an important role for anxiety and pain. All patients required medications for local and regional anesthesia such as analgesics, sedatives, in different dosages. The high level of pain we saw in all groups of patients was those who underwent endoscopic surgery.
In the beginning of our experience, we used a Spider HMD game to distract patients under upper GI endoscopy in 2004. Thanks of these results we improved the devices introducing Virtual reality scenarios and a HMD developed by Brenda and Mark Wiederhold from the Virtual Reality Medical center from San Diego CA. Clinical applications were done at the Instituto de Seguridad y Servicios Sociales para los Trabajadores del Estado I.S.S.S.T.E. and at the Instituto Mexicano del Seguro Social IMSS, Public Health Centers in Mexico City. There were big and small groups because the results from critical care unit of cardiac surgery and ambulatory surgery allow us to conclude the usefulness of virtual reality to reduce pain and anxiety in inpatients without minimal complications and permit us to limit virtual applications in all areas of Medicine. If patients in critical care unit presented no more than 2 complications and in surgery we consider absolutely contraindicated in endoscopic surgery is obvious to use virtual reality without major risk in the rest of areas of medicine if we follow the absolute indications.
Virtual reality is a not invasive method, easy to use, easy to install and easy to carry and each day new generations of technology are lighter, smaller such as smartphones, PSP 2, iPADs that permit more interaction with users using friendly feedbacks such as tracking (Kinect), 3D images permit more immersion with Interactive screens that could be considered in future works because U screens, virtual cubes and cave could be an option for patients because these screens have demonstrated the utility in rehabilitation for the big space for body motions and for the stereoscopic immersion.
The best advantage for the healthcare institutions we found in the group for ambulatory surgery was to reduce the half of dosage of medication of fentanyl, and midazolam, and in many cases we avoid totally these medications in the intraoperative. This advantage represent an important saving for institutions always considering and appropriate selection of patients with absence of cardiovascular and respiratory disease that could permit physician works without concerns during procedures. With these results we can give the following advantages as: reduction of medication (Analgesic and in several cases, drugs to reduce anxiety as fentanyl and mydazolam), bed days and specially increase the wellbeing of patients. There were small groups of one or two patients that should increase the number of cases to get reliable results, however theirs results are a clear indicator of benefits of virtual reality. We didn’t consider more areas of medicine, but we involve representative as surgical and clinical areas and both sex, males and females and different ages, newborns and adults. Technology developments permit use small device such as mobile phones to connect to head mounted display instead of laptops; they facilitate the handling of the virtual scenarios. 3D scenarios will permit more immersion in patients (see table 7). Display scenario on the wall is an option for navigations instead to use HMD which can be tiring for patients in prolonged time. Virtual reality is useful in hospital and we consider that in the future, virtual rooms could be integrated inside services, operating rooms, and waiting rooms.
Interface used | Virtual scenario | Area | Cases | Control group | Patients participants | |
Ambulatory Surgery | Laptop | Enchanted forest | Surgery | 53 | 31 | 84 |
Ambulatory Surgery | Laptop & Night vision | Enchanted forest | Surgery | 5 | 0 | 5 |
Ambulatory Surgery | Nokia | Green valley video | Surgery | 23 | 0 | 23 |
Ambulatory Surgery | PSP2 | Green valley video | Surgery | 24 | 0 | 24 |
Ambulatory Surgery | X BOX | Video | Surgery | 2 | 0 | 2 |
Ambulatory Surgery | iPhone G3 | Green valley video | Surgery | 2 | 0 | 2 |
Pediatric surgery | PSP2 | Green valley video | Pediatric surgery | 1 | 0 | 1 |
Recovery surgery | Laptop | Enchanted forest | Kidney transplantation | 1 | 0 | 1 |
Surgical cleaning | Laptop | Enchanted forest | Surgery-Infectology | 11 | 10 | 21 |
Epidural blockage | Laptop | Enchanted forest | Anesthesia | 4 | 3 | 7 |
Labor room | Laptop | Enchanted forest | Obstetric | |||
Cesarean | Laptop | Enchanted forest | Obstetric | 1 | 1 | 2 |
Delivery Room | Laptop | Enchanted forest | Obstetric | 1 | 2 | 3 |
Neonatology Unit care | Laptop | Enchanted forest | Neonatology | 5 | 0 | 5 |
Colposcopy | Laptop | Enchanted forest | Ginecology | 20 | 23 | 43 |
Upper GI Endoscopy | Spider HMD Game | Spider game | Endoscopy | 200 | 200 | 400 |
Colonoscopy | Laptop | Enchanted forest | Endoscopy | 3 | 0 | 3 |
Unit care | Laptop | Enchanted forest | Cardiac surgery | 20 | 22 | 42 |
TOTAL PATIENTS | 376 | 292 | 668 |
Interfaces and VR scenarios used in each group as well as the total patients participants in the groups studied and controls.
Enchanted forest scenario used in the majority of procedures.
Upper Gastrointestinal Endoscopy.
Ambulatory surgery with regional anesthesia
Endoscopic surgery with regional anesthesia
Care unit of cardiac surgery
Labor room
Anesthesia. Epidural/ spinal block
Delivery room
Recovery room. Post cesarean surgery
Neonatology care unit
Meningiomas (MN) are a type of central nervous system (CNS) tumors that arise from the leptomeningeal arachnoid covering the encephalon and the spinal cord, more specifically, from the arachnoid cap cells [1]. In adults, MN accounts for approximately 37.6% of all primary brain tumors, and corresponds to the most common intracranial tumor in adults over 35 years [1, 2]. According to Ostrom et al., incidence of MN in the United States (US) is 8.83 per 100,000 per year [3]. Around 90% of all MN cases are diagnosed intracranially, with the rest arising from the spinal arachnoid [4]. The median age at diagnosis for MN is 65 years [4] with the majority of patients being in the range of 55–74 [4]. Cases in the pediatric population are extremely rare, corresponding only to 0.4–4.6% of all pediatric tumors [2]. There is a female predominance in case proportion, with a female:male ratio of 3:1 for all MN, and 9:1 for spinal cord MNs [2, 5]. MNs are characterized for being slow in growth and often not infiltrative, with an insidious development of symptoms. Clinical presentation of MN might vary from patient to patient, with tumor localization being the main determining factor of clinical features. Signs and symptoms might include headaches because of increased intracranial pressure, focal neurological deficits (mainly cranial nerve focalization), and seizures. In the case of MN developing in the frontal lobe, personality changes, altered mental status and mood disturbances might appear [6].
According to the World Health Organization (WHO), MN is classified in three subtypes: common type or WHO grade I, atypical/intermediate type or WHO grade II and the anaplastic/malignant type or WHO grade III. These high-grade tumors might develop
As high-grade MN continue to be a difficult to treat condition, with high recurrence and low response rates, molecular insights into precision medicine have been investigated in the last two decades. With a better understanding of the cellular and molecular pathways underlying MN pathophysiology, recurrence and malignancy, newer therapies have been considered as possible candidates for the treatment of these conditions. Some agents include newer systemic chemotherapeutic agents like trabectedin, inhibitors of the Epidermal Growth Factor Receptor (EGFR) like erlotinib and gefitinib, inhibitors of the Platelet-Derived Growth Factor Receptor (PDGFR), inhibitors of mTOR, especially from the complex 1 (mTORC1) as well as its upstream and downstream elements (AKT/PI3K and MEK). The biological process of angiogenesis is also under research, with ongoing trials with anti-angiogenic agents from the Tyrosine Kinase Inhibitors (TKIs) targeting the Vascular Endothelial Growth Factor (VEGF) pathway, as well as antibody agents like bevacizumab. As it is expected, immunotherapy with checkpoint inhibitors is also under current investigation, with anti-PD1 and anti-PD-L1 monoclonal antibodies being tested in clinical trials. In this chapter we are going to cover the molecular biology of MNs, especially in the cases of grade II and grade III MN. We will also discuss the current knowledge in systemic treatments as well as therapies in clinical trials and possible candidates that are being tested
Advancements in understanding the pathophysiology and molecular biology of MNs are critical for improving risk evaluation and prognosis. Similarly, to design novel treatments aimed at blocking canonical pathways involved in carcinogenesis and disease evolution. As molecular analyzes of meningiomas continue to evolve, several cytogenetic, genomic, epigenetic, and expression alterations associated with tumor aggressiveness and proclivity for recurrence have been identified as potential biomarkers to enhance risk stratification [12]. Recently, several seminal studies evaluating the genomics of intracranial meningiomas have rapidly changed the understanding of the disease. The importance of NF2 (neurofibromin 2), TRAF7 (tumor necrosis factor [TNF] receptor-associated factor 7), KLF4 (Kruppel-like factor-4), AKT1, SMO (smoothened), PIK3CA (phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha), and POLR2 (RNA polymerase II subunit A) demonstrates that there are at least six distinct mutational classes of meningiomas. In addition, six methylation classes of meningioma have been appreciated, enabling improved prognosis prediction compared with traditional WHO grades. Genomic studies have shed light on the nature of recurrent meningioma, distinct intracranial locations and mutational patterns, and a potential embryonic cancer stem cell-like origin [13, 14, 15, 16] (Figure 1).
Main cytogenetic and recurrent genetic alterations in recurrent and high-grade meningiomas according to the WHO classification and anatomical location.
A large number of meningiomas possess a normal karyotype, with an overall low incidence of genomic alterations (including somatic copy number alterations—SCNA, rearrangements, and low mutational burden) [17, 18, 19]. However, these disruptions increase following tumor grade, the number of recurrences, and biological aggressiveness. More than half of all identified genomic alterations involve the NF2, which underlies inherited Neurofibromatosis syndrome. Indeed, the most significant SCNA in meningioma is chromosome 22 monosomy, which is present in ~56% of cases and leads to losing the genomic locus containing NF2 (22q12.2) [20, 21]. Among grade I meningiomas, those carrying NF2 alterations are more likely to progress than those with a normal karyotype. In addition, the frequency of NF2 aberrations increases with tumor grade.
Loss of heterozygosity on chromosome 1p is present in 16% of MNs [22]. Characterization of the smallest region of overlapping deletion on this chromosome spans ~3.7 megabases and identified 59 genes, 17 of which have putative tumor-suppressive functions based on gene ontology. The protein methyltransferase and tumor suppressor RIZ1, is located on chromosome 1p, and studies implicate its loss of expression in meningioma progression [23]. Loss of the CDKN2A/CDNK2B locus on chromosome 9q is common in grade II meningiomas that transition to anaplastic lesions [24]. Additionally, a study showed that the levels of p16 and p15, the proteins encoded by CDKN2A and CDKN2B, may hold prognostic significance and/or represent a promising therapeutic target [25]. Recently, Nassiri et al. described four consensus molecular groups of MN by combining DNA somatic copy-number aberrations, DNA somatic point mutations, DNA methylation, and messenger RNA abundance in a unified analysis [26]. These molecular groups predicted clinical outcomes compared with existing classification schemes. Each molecular group showed distinctive and prototypical biology (immunogenic, benign NF2 wild-type, hypermetabolic and proliferative) that informed therapeutic options. Proteogenomic characterization reinforced the robustness of defined molecular groups and uncovered highly abundant and group-specific protein targets [26].
Globally, meningiomas have a low mutation rate (~3.5 mutations per megabase) compared to other cancers [25]. Various efforts to genotype the disease using NGS have identified NF2 mutations as the predominant alteration in spontaneous and Neurofibromatosis syndrome-associated tumors [24], at a frequency of ~40% in low grade and nearly 80% in high-grade tumors [27]. MNs related to alterations in NF2 were more common in the cerebral convexities and posterior skull base than those found in other anatomic locations, and up to 13% were associated with other co-mutations, including single mutations in CREBBP, PIK3CA (R108H), PIK3R1, BRCA1, and SMARCB1 [27]. Unfortunately, within NF2 mutated meningiomas, none of these identified mutations can predict the chance of recurrence, which can vary widely.
TERT promoter mutations have recently been reported in ~6% of all MNs, with ~80% of these also harboring alterations (mutations or deletions) at the NF2 locus [28]. Similar to overall mutational burden, TERT mutations increase with tumor grade. In grade I MN, TERT C228T and C250T mutations are linked with transformation to higher grades [28], prompting many neuro-oncologists to consider standardized testing for TERT promoter mutations. Further studies demonstrate that the presence of C228T and C250T correlates with increased TERT mRNA and functional increases in telomerase activity [29]. In grade II or III tumors, univariate analysis revealed a significant association with decreased PFS (progression-free survival; median 12.5 vs. 26 months,
Non-NF2 mutated meningiomas, which generally have a benign behavior, are usually chromosomally stable, and often located in the anterior, medial, or skull base regions, possess a distinct mutational landscape [27]. Recent high throughput sequencing studies suggest an average of only 1.56 (SD ± 1.07) genomic alterations (GAs) per non-NF2 mutated tumor [31]. The pro-apoptotic E3 ubiquitin ligase, tumor necrosis factor receptor-associated factor 7 (TRAF7) is mutated ~25% of all meningiomas [31]. Such alterations occur in the C-terminal WD40 protein interaction domain, suggesting they may alter protein-protein interactions with MAPK and NF-kB family members [32]. While TRAF7 mutation is mutually exclusive with NF2 mutations, it is almost always correlated with PI3K and activating E17K mutation in AKT1, with the K409Q alteration of KLF4 [33].
AKT1, also referred to as protein kinase B, is a well-known oncogene. AKT activation relies on the PI3K pathway and is recognized as a critical node in the mTOR pathway. The E17 hotspot is the most characterized of AKT1 mutations and leads to constitutive activation of the protein. Mutations in AKT1 have also been shown to confer resistance to allosteric kinase inhibitors in vitro and are oncogenic in many solid tumors. Specifically, the E17K mutation is found in 7–12% of grade I meningiomas [34], is enriched in the meningothelial subtype [17], and is predictive of decreased PFS in olfactory groove tumors [35]. Altering the same signaling pathway PIK3CA mutations are also found in ~7% of non-NF2 tumors and are mutually exclusive with AKT1 mutation [36]. Targeted sequencing of this gene revealed novel non-synonymous mutations, A3140T and A3140G, which are reported as pathogenic, and C112T, which is also predicted to be pathogenic [31]. Indeed, increased PI3K signaling is related to aggressive behavior, especially within high-grade meningiomas [37], suggesting that therapeutics targeted toward this pathway may be a potential option.
Sequencing of 71 meningiomas genes recently identified two novel missense mutations in FGFR3, T932C, and G1376C, both of which were predicted to be pathogenic [31]. Identifying these mutations in patients with skull base low-grade tumors was associated with a good prognosis, given the absence of recurrence and the requirement of IMRT. KLF4 gene encodes a protein that belongs to the Kruppel family of transcription factors. The encoded zinc finger protein is required to control the G1-to-S transition of the cell cycle following DNA damage by mediating the tumor suppressor gene p53. In addition, KLF4 is involved in the differentiation of epithelial cells and may also function in skin, skeletal, and kidney development [38]. In meningiomas, KLF4 is thought to act as a tumor suppressor gene, expressed in low-grade tumors and downregulated in anaplastic tumors. At the genomic level, KLF4 is mutated in ~12% of grade I meningiomas, virtually all of which are of the secretory sub-type and harbor TRAF7 mutations [39]. All identified KLF4 mutations result in a K409Q substitution within the DNA binding domain, which likely alters several protein functions [40].
SMO (Smoothened, Frizzled Class Receptor) gene encoded a G protein-coupled receptor that interacts with the patched protein, a receptor for hedgehog proteins. Mutations in SMO, which result in L412F or W535L substitutions, lead to functional activation of Hedgehog signaling in meningioma [17, 41]. These mutations are present in ~5.5% of grade I meningiomas and are mutually exclusive with TRAF7, KLF4, and AKT1 mutations [27]. Meningiomas with the L412F mutation are more likely to recur (XX) and are enriched at the midline, perhaps due to the role that Hedgehog signaling plays in hemisphere separation during development [36]. Mutations in the Hedgehog family member SUFU are also found at low frequencies in sporadic meningiomas, and their germinal counterpart is also present in familial meningiomatosis [42]. Additional hedgehog family germline mutations occur in SMARCE1 and SMARCB1, though these carry less risk of recurrence than familial NF2 mutations [43, 44].
POLR2A (RNA Polymerase II Subunit A) catalyzes the transcription of DNA into RNA using the four ribonucleoside triphosphates as substrates. In addition, POLR2A is the largest and catalytic component of RNA polymerase II which synthesizes mRNA precursors and many functional non-coding RNAs. POLR2A encodes RPB1 (DNA-directed RNA polymerase II subunit), a gene found altered in about 6% of meningiomas [42]. From another perspective, inactivating somatic and germline mutations or gene deletions in the BAP1 tumor suppressor gene are explicitly found within high-grade rhabdoid meningioma [45]. Also, the loss of BAP1 is correlated with tumor aggressiveness and decreased time to progression. Alterations in the SWI/SNF pathway, specifically mutations in ARID1A, were recently found in 12% of high-grade meningiomas. Other components of this canonical pathway, including SMARCB1, SMARCA4, and PBRM1, are altered in up to 15% of patients with non-NF2-dependent meningiomas [46].
Through whole-genome analysis, global DNA methylation profiling has demonstrated that higher methylation levels are associated with increased tumor aggressiveness and risk of recurrence. DNA methylation is an epigenetic change hypothesized to contribute to genomic instability by silencing genes involved with DNA repair and control of cell cycling. Evidence suggests that methylation status may predict tumor behavior more accurately than the current WHO classification, thus, DNA methylation status has been proposed as an alternative classification system for MNs [47]. The most important genes involved in the DNA methylation of MNs are tissue inhibitors of metalloproteinase 3 (TIMP3), cyclin-dependent kinase inhibitor 2A (CDKN2A), and tumor protein 73 (TP73), which are hypermethylated in at least 10% of cases [48]. TIMP3 hypermethylation results in transcriptional downregulation and inhibits its tumor suppressor properties [49]. In addition, TIMP3 is frequently hypermethylated in higher-grade MNs (40–60%) and is related to a decrease in relapse-free time and increased biological aggressiveness [50]. Notably, TIMP3 is found on chromosome 22q12, and almost all cases with gene hypermethylation had a concurrent allelic loss of 22q. About 60–80% of high-grade meningiomas carry TP73 promoter methylation, a queue event not common in grade I tumors, suggesting its potential use as a marker for high-grade lesions [51].
Recently, several studies highlighted the importance of global methylation profiles in the molecular subclassification of meningiomas [52], Olar et al. demonstrated that unsupervised clustering of DNA methylation data classified meningiomas into two distinct subgroups associated with recurrence-free survival. A statistically significant association between DNA methylation subclasses and tumor recurrence was maintained after adjusting for clinical factors, such as WHO grade and Simpson grade [41]. Similarly, Sahm et al. identified two major groups and six subgroups of meningiomas based on unsupervised clustering of DNA methylation data, with significantly different genomic makeup and clinical behaviors. Interestingly, most non-NF2 meningiomas clustered together into a single benign subgroup [53]. These initial efforts suggest that epigenetic signatures may have solid clinical associations with tumor recurrence, to a more significant extent than can be correlated with mutational genetic analysis and could be used clinically to stratify patients. An additional manifestation of the importance of epigenetic changes in meningioma clinical behavior was recently shown, describing an increased risk of recurrence in tumors that show a loss of histone H3K27 trimethylation [54].
Classically, the identification of meningiomas using immunohistochemistry has been done using the expression of the progesterone receptor (PR) and the epithelial membrane antigen (EMA). However, over the last few years, it has been found that the specificity of RP for the diagnosis of high-grade meningiomas is low, especially when trying to differentiate between clear cell, fibrous, and microcystic subtypes. Likewise, EMA expression correctly identifies ~90% of grade I meningiomas, but only 75% of grade III, with even lower specificity rates for secretory and microcystic subtypes [55]. Due to these markers’ poor performance, the expression of somatostatin receptor 2A (SSTR2A) in combination with EMA was included, a profile that provides a sensitivity of 100% and specificity of 95%, regardless of tumor grade. Likewise, recent work suggests that the absence of Sox10 and STAT6 [56, 57] are superior approaches to distinguishing meningioma from schwannoma, solitary fibrous tumor, and synovial sarcoma.
In addition, marking for lymphocyte infiltration can contribute to the grading of meningiomas and the prediction of response to some interventions. Most low-grade meningiomas possess a high percentage of CD-3+ T-lymphocytes but relatively few CD20+ B cells; however, across tumor grades, these populations are greatly enriched compared to those seen in peripheral blood mononuclear cells (PBMC) [58]. Flow cytometry analysis reveals evidence of class switching in B cells, an increased percentage of CD8+ cells compared to CD4+ T cells, and a prevalence of CD45RO+/CD45RA− effector cells compared to naive T cells [59]. This information allows predicting that tumor-infiltrating immune cells have had exposure to various tumor antigens despite low BMR. Among high-grade meningiomas and particularly anaplastic tumors, there is a reduction in the count of CD4+, CD8+, and PD-1+ T cells, and an increase in the number of FoxP3+ T-regulatory cells (Tregs) [60]. This immune cell phenotype, also observed in other tumor types, is associated with tumor-mediated evasion of the immune system.
Du et al. report high levels of PD-L1 mRNA, which correlated to protein expression levels, in ~40% of grade I, 60% of grade II, and 77–88% of grade III meningiomas [59]. Nevertheless, Everson et al. only identified PD-L1 expression in 25% of grade III cases, with no expression detected in grade I or II cases [25]. The controversy has been amplified since PD-L1 does not predict outcomes. However, in the future, the expression of TIM-3 and LAG-3 could be helpful to consider the use of agonist monoclonal antibodies [58]. Another potential biomarkers that could predict the response to targeted therapies are EGFR expression, which is present in up to 90% of meningiomas [25]. Furthermore, the expression of TOP2A (35% of the samples) is associated with a higher tumor grade and could be useful to assess the usefulness of anthracyclines or trabectedin. Likewise, TOP1 over-expression is observed in 29% of meningiomas and correlates with sensitivity to irinotecan and topotecan, while elevated levels of PDGFR and c-MET are observed in more than 20% of cases [25] (Figure 2).
Signaling pathways and potential targets implicated in high-grade meningiomas.
The classical first-line treatment for all MNs is surgery. However, high grade meningiomas have a high recurrence rate; up to 60% of tumors may recur after 15 years of complete resection [12, 61]. Unfortunately, at the moment there are no standard effective treatments determined because of lack of existent evidence [12]. The use of systemic treatments as standard care remains experimental and is reserved for cases of recurrent/progressive disease not suitable for surgery or radiotherapy [62]. Hereafter we are going to present some of the systemic strategies currently in used and under study. A summary of the main therapies that have shown some benefit in MN treatment can be seen in Table 1, and a summary of current active clinical trials is shown in Table 2.
Type of agent | Medication | Mechanism of action |
---|---|---|
Chemotherapy | Temozolomide | Alkylating agent |
Irinotecan | Topoisomerase 1 inhibitor | |
Hydroxyurea | Ribonucleotide reductase inhibitor | |
Trabectedin | Mechanism unclear | |
Plant-derived agents | AKBA | Induction of apoptosis and antiinflammatory |
Curcumin | Interaction with multiple cell signaling proteins | |
EGFR antagonists | Gefitinib | EGFR antagonist |
Erlotinib | EGFR antagonist | |
Monoclonal antibodies | Humanized antibodies to EGFR | |
PDGFR antagonists | Imatinib | PDGFR antagonist |
Satinib | PDGFR inhibitors | |
Nilotinib | PDGFR inhibitors | |
mTOR inhibitors | Temsirolimus | mTOR inhibitor |
Vistusertib | mTOR inhibitor | |
Everolimus | mTOR inhibitor | |
VEGFR antagonists | Bevacizumab | Humanized monoclonal antibody to VEGFR |
Cediranib | VEGFR antagonist | |
Combination antagonists | Sorafenib | VEGFR and PDGFR antagonist |
Sunitinib | VEGFR and PDGFR antagonist | |
Vatalanib | VEGFR and PDGFR antagonist | |
Hormonal agents | Megestrol Mifepristone | Progesterone receptor partial agonist Progesterone receptor competitive antagonist |
Tamoxifen | Estrogen receptor antagonist | |
Octreotide Pasireotide | Somatostatin mimetic Somatostatin mimetic | |
Pegvisomant | Growth hormone receptor antagonist | |
Lutathera | Somatostatin receptor afinity and radiation β- emission | |
Fenretinide | Synthetic retinoid induces apoptosis | |
Immunomodulators | IFNα 2B | Antiproliferative and antiangiogenic |
Nivolumab Pembrolizumab Aveoumab Sintilimab | PD-1 receptor and ligand inhibitors | |
Trametinib | Inhibits MEK1 and MEK2 | |
Alpelisib | PI3K inhibitor | |
Ipililumab | CTLA-4 blockade | |
Oncolytic virus | Adenovirus | Antineoplastic effect against the malignant meningioma and significant tumor regression |
Herpes virus | Replication of adenovirus and oncolysis at high dose and at a lower dose meningioma cells killing | |
Farnesyl transferase inhibitors | Tipifarnib | Farnesyl transferase inhibitor |
Possible adjunctive agents | Calcium channel blockers | Reduction of intracellular calcium concentrations |
Statins | MAPK pathway inhibition | |
Antiretrovirals | Protein downregulation | |
RNAi | Antisense abrogation of mRNA strands |
A summary of different agents with promising evidence in the treatment of high-grade meningioma.
ClinicalTrials.gov Identifier | Status | Intervention | Arms | Outcomes |
---|---|---|---|---|
NCT03071874 | Active, not recruiting | AZD2014 a dual mTORC1/mTORC2 inhibitor | Experimental: AZD2014 | PFS OS Radiographic response rate Duration of radiographic response Frequency of adverse events |
NCT02648997 | Recruiting | Nivolumab 240 mg every 2 weeks Nivolumab 480 mg once every 4 weeks | Experimental: Cohort 1 (original cohort): Nivolumab Monotherapy | PFS Median PFS Median OS Objective radiologic response rate Adverse events |
Ipilimumab 1 mg/kg every 3 weeks Nivolumab 480 mg once every 4 weeks Nivolumab 3 mg/kg every 3 weeks External Beam RT | Experimental: Cohort 2: Nivolumab in Combination with Ipilimumab | PFS Median PFS Median OS Objective radiologic response rate Adverse events | ||
NCT03279692 | Active, not recruiting | Pembrolizumab | Experimental: Pembrolizumab | PFS OS Toxicity Intracraneal response |
NCT04997317 | Recruiting | 177Lu-DOTA-JR11 (Phase 0); Cycle 1 and Cycle 2 (cross-over) 177Lu-DOTATOC (Phase 0); Cycle 1 and Cycle 2 (cross-over), Cycle 3 and 4 | Active Comparator: Phase 0: Group A | Change in Tumor-to-dose limiting organ dose ratio T-to-bone marrow Change in Tumor-to-dose limiting organ dose ratio T-to-kidney Assessment of treatment safety (phase I/II) by number of AEs graded according to CTCAE v5.0 |
177Lu-DOTA-JR11 (Phase 0); Cycle 1 and Cycle 2 (cross-over) 177Lu-DOTATOC (Phase 0); Cycle 1 and Cycle 2 (cross-over), Cycle 3 and 4 | Active Comparator: Phase 0: Group B | |||
177Lu-DOTA-JR11 (Phase I/II) | Active Comparator: Phase I/II | |||
NCT03971461 | Recruiting | Lutathera | Experimental: Lutathera | PFS at 6 months Objective response rate OS at 12 months PFS OS |
NCT04082520 | Recruiting | Gallium Ga 68-DOTATATE Lutetium Lu 177 Dotatate Magnetic Resonance Imaging Positron Emission Tomography Quality-of-Life Assessment Questionnaire Administration | Treatment (gallium Ga 68-DOTATATE PET/MRI, Lutathera) | PFS at 6 months OS PFS Adverse events incidence Change in quality of life Local control Duration of local control Objective response to treatment Response rate by volumetric analysis |
NCT03016091 | Recruiting | Pembrolizumab | Experimental: Arm 1 IV Pembrolizumab | PFS at 6 months PFS at 12 months OS |
NCT03604978 | Recruiting | Ipilimumab Nivolumab Stereotactic Radiosurgery | Patients receive nivolumab | Maximum tolerated combination of radiosurgery and nivolumab plus or minus ipilimumab Incidence of adverse event profile Objective response rate Objective radiological response PFS OS Changes of peripheral T-cells |
NCT02333565 | Unknown | Everolimus Octreotide | Experimental: Combinaison everolimus and octreotide | PFS rate |
NCT04501705 | Recruiting | Apatinib mesylate | Experimental: test group | PFS-6% ORR OS |
NCT03267836 | Recruiting | Avelumab Proton surgery | Experimental: Avelumab + proton therapy | Immunogenicity Safety of therapy Pathologic response PFS OS |
NCT04728568 | Recruiting | Sintilimab | Experimental: Sintilimab | PFS at 6 months OS |
NCT03631953 | Recruiting | Trametinib Alpelisib | Experimental: Alpelisib in combination with Trametinib administered | Dose Limiting Toxicity (DLT) rate of combination Alpelisib and Trametinib |
NCT00904735 | Unknown | Hydroxyurea Imatinib mesylate | Experimental: Arm I Patients receive hydroxyurea and imatinib | PFS Survival Response rate according to MacDonald criteria Toxicity as assessed by NCI CTCAE v. 3.0 |
Hydroxyurea | Experimental: Arm II Patients receive hydroxyurea |
A summary of currently ongoing clinical trials that assess the effectiveness and safety of different systemic therapies in high-grade meningiomas.
It is known that chemotherapy is poorly effective as adjuvant treatment after surgery and radiotherapy. Some clinical trials and case series have shown a minimal or no impact in patients’ outcomes. However, some agents are being tested in several clinical trials [63].
Hydroxyurea is a ribonucleotide reductase inhibitor that was initially developed to treat myeloproliferative disorders and chronic myelogenous leukemia [64]. It induces apoptosis in meningioma cells, arresting meningioma cells in the S-phase of the cell cycle [63]. In pre-clinical trials from Schrell et al., they demonstrated that hydroxyurea prevent recurrence for 24 months in patients who had complete resection [65, 66]. However, clinical trials, failed to provide similar results showing that 50% of the patients achieve stable disease, a median PFS of 44–176 weeks and acceptable toxicity [63, 65, 66, 67, 68, 69, 70, 71]. Other retrospective studies with small sample sizes, have shown a median PFS of 10–80 weeks [64]. Weston et al. also found that hydroxyurea may prevent progression, but does not reduce tumor size and causes significant side effects [72]. It is important to emphasize that in these trials many patients did not received radiotherapy or that radiotherapy was administered concurrently, making data interpretation difficult [73]. In addition, a retrospective study of 60 patients from Chamberlain et al. reported a disease progression in 65% of the patients and a median PFS of 4 months in patients treated with hydroxyurea after recurrence (Chamberlain and Johnston, 2011). Finally, some studies suggest hydroxyurea may have outcomes equivalent to those when radiation therapy was used [74].
Additionally, some studies reported reduction of hydroxyurea efficacy when other concomitant therapies are administrated [64]. In a study by Reardon et al., hydroxyurea and imatinib were used to treat patients with recurrent refractory meningiomas, a good tolerance was reported; however, the combination did not affect survival [75]. Other authors suggest that chemotherapy should be based on expression of drug resistance genes, in patients whose mRNA analysis predicted sensitivity to chemotherapy. In these cases, a concomitant treatment with mitoxantrone and hydroxyurea reported long-term efficacy [61]. Currently, some investigators are looking for the role of hydroxyurea as an adjunct to other therapies, such as calcium channel blockers, as calcium channel antagonists have an inhibitory effect on meningioma growth in culture [76]. For this matter, Ragel et al. reported that calcium channel antagonists can block stimulatory effects of growth factors on meningioma cell cultures and increase hydroxyurea effectiveness [77]. Evidence of hydroxyurea treatment in patients with high grade meningioma varies widely across patients. Demonstrating that this treatment is generally well-tolerated but evidence in tumor control is not conclusive to establish a standard treatment in high-grade MNs.
Trabectedin it is an alkylating agent used in soft tissue sarcomas. It inhibits transcription, its mechanism is not completely understood but some studies reported decreased cell proliferation, induction of apoptosis and inhibition of transcription factor binding by binding to the minor groove of the DNA helix [78]. In the randomized phase II clinical trial NCT02234050 by EORTC Brain Tumor Group (EORTC-1320-BTG), treatment with trabectidin in grade II/III meningiomas did not improve PFS or OS and it was associated with significantly higher toxicity as compared to local standard care. A median PFS of 4.17 months was reported in the local standard care arm and of 2.43 months in the trabectedin arm (hazard ratio [HR] for progression, 1.42; 80% CI, 1.00–2.03;
Temozolomide another alkylating agent, used as standard care in management of glioma. It does not prolong PFS in clinical trials of recurrent meningioma [80]. It is believed that the no effect on meningioma could be due to intact activity of the DNA repair enzyme O6-methylguanine DNA methyltransferase (MGMT) [63, 81, 82].
Chamberlain et al. reported a median time tumor progression of 4.6 years and median OS of 5.3 years in patients treated with cyclophosphamide, doxorubicin, and vincristine. They also reported high toxicity and very low response. However, without a control group the results are difficult to interpret [83]. Some small case series also reported results by administrating cyclophosphamide, adriamycin, vincristine, isofosfamide/mesna or adriamycin/dacarbazine, but the evidence is limited [84]. In some in vitro an in vivo animal studies, was reported that irinotecan has an anti-meningioma effect. However, it did not show benefits in phase II clinical trials [81, 82, 85].
Finally, some preclinical studies evaluated the response of Plant-Derived Chemotherapeutic Agents. Curic et al. described an antitumorigenic properties from curcumin (from the spice plant
Unlike other solid tumors, MN presents with a low mutation rate of approximately 3.5 mutations per megabase [25]. However, the case of high-grade MNs has been evaluated recently. Bi et al. analyzed 39 samples of high-grade MN and found an average of 23 (range 1–223) nonsynonymous coding alterations. This number of alterations is similar to that of craniopharyngioma and thyroid cancer, but considerably lower than other aggressive tumors like head and neck carcinoma, colorectal carcinoma and melanoma [34]. Because of its relatively low mutational burden, very few potential molecular targets have been identified. Interestingly, Bi et al. found that non-NF2 driver mutations in high-grade MN was considerably lower than in low grade MN, which reduces the number of possible targets than can be addressed. In the other hand, NF2 is usually altered in high-grade MN (80% of cases) more frequently than in low grade MN (40%). Most of genetic and regulatory alterations that have been described in high grade MN occur downstream to a disrupted NF2 protein. Some of the pathways altered might involve Rac1/Cdc42, Ras/JNK and the master regulator AP-1 [89]. Furthermore, one of the main pathways associated with NF2 is the mTOR signaling cascade. NF2 naturally acts as a repressor of the mTORC1 and mTORC2, and when it is mutated, unregulated activation of this pathway occurs. Based on this, mTOR and some of its upstream/downstream effectors (Akt/PI3K) have been identified as potential targets. Other pathways regulated by receptor tyrosine kinases (RTKs) like EGFR, PDGFR and VEGFR (angiogenesis) are also being studied.
The EGFR pathway has been demonstrated to play a role in the tumorigenesis of a great proportion of meningioma cases. Torp et al. demonstrated that EGFR expression is not detectable in healthy and injured adult human meninges, but is expressed in cases of meningioma [90]. Arnli et al. also showed that EGFR was absent in healthy meninges but present in MN [91]. Narla et al. analyzed 79 samples of MN using immunohistochemistry, to detect EGFR expression. They found that EGFR was expressed in all different grades of MN, but its expression was considerably higher in grade I MN (82.93%), than grade II MN (35.71%) and grade III MN (20%) (
Similar results were published by Wernicke et al. who found in a cohort of 89 MN samples that EGFR expression was more common in grade I MN than in other grades. They also showed that the staining percentage (SP) of immunoreactive cells was associated with histopathologic subtypes (
In 2010, results from a phase II trial of erlotinib and gefitinib for the treatment of MN were published. Erlotinib is an orally available, reversible TKI directed against EGFR. Its use has been approved in different neoplastic disorders including non-small cell lung cancer (NSCLC) and pancreatic cancer [98]. Gefitinib is a first-generation EGFR-TKI also approved for the treatment of locally advanced and advanced NSCLC [99]. In 2010, a clinical trial enrolled patients with recurrent histologically confirmed MN that were treated with no more than 2 chemotherapy regimens.
The study evaluated 25 patients with a median age of 57 years. From this cohort, 16 patients received gefitinib and 9 received erlotinib. Nine patients had atypical MN and 8 had anaplastic MN. PFS and OS were assessed at 6 and 12 months. For patients with low-grade histology, PFS-6 was 25%, PFS12 was 13%, OS-6 was 63% and OS12 50%. In the other hand, high-grade meningiomas seemed to respond a little better with a PFS6 of 29%, PFS-12 18%, OS6 71% and OS-12 65%. When statistical analysis was done no significant difference between low-grade and high-grade MN was seen [100]. Survival outcomes were not significantly better than that of standard treatment.
In 2020 Ferluga et al. found that STAT1 is overexpressed and present a constitutive phosphorylation in MN. They also found that this overactivation was not associated with the JAK-STAT pathway but instead it was induced by the constitutive phosphorylation of EGFR. They even demonstrated that STAT1 knockdown models presented a significant reduction of cellular proliferation as well as a deactivation of AKT and ERK1/2. The most interesting finding of this study was that the researchers used BM-1 cells and exposed them to three different EGFR inhibitors, two from second generation (canertinib and afatinib) and one first generation (erlotinib). After exposure to canertinib and afatinib, a decrease in about 60% of STAT1 expression was seen as well as an almost complete elimination of phosphorylated forms of STAT1, this effect was not seen after exposure to erlotinib.
Lapatinib is a dual EGFR/ErbB2 inhibitor currently approved for the treatment of advanced breast cancer with ErbB2 (HER2) expression [101]. There is preclinical evidence of lapatinib efficacy in decreasing tumoral growth in NF2-related Schwannomas. Ammoun et al. demonstrated that when NF2 is mutated or lost, there is an upregulation of different RTKs in Schwannoma, with EGFR and HER2 being two of the highest expressed [102]. Similar results have been seen in NF2-related MN. When the researchers added lapatinib at 5 and 10 μM concentrations to cultures of Schwannoma cells derived from patients’ samples, they found that lapatinib successfully induced inhibition of the intracellular pathways downstream HER2, including ERK 1/2 and Akt. They also showed that after 24 h of exposure to lapatinib, cell viability decreased in a dose-dependent manner, with statistically significant differences between both concentrations of lapatinib to baseline, and from lapatinib 5 μM to lapatinib 10 μM [102].
The same group of researchers also tested lapatinib during a phase II clinical trial, with good results in terms of volumetric response, progression-free survival and safety profile [103]. Six years after this trial, the authors did a retrospective analysis of patients presenting with NF2-related meningiomas from the same cohort of patients with Schwannoma. Eight patients fulfilled criteria for analysis. After two months under treatment with lapatinib, the best volumetric response achieved was 26.1%. It is important to mention that in the group that was receiving lapatinib, two tumors increased in volume by more than 20%. Results from this analysis were confusing, with no clear benefit of lapatinib, however, the sample was extremely small, and the analysis was retrospective. This study might influence the development of future, prospective, larger clinical trials specifically for patients with MN [104].
In 2001, Crombet et al. published their results on the efficacy of a mouse anti-human neutralizing monoclonal antibody against EGFR (ior egf/r3). They performed a phase I clinical trial using this antibody in 9 patients with high-grade brain tumors that persisted or relapased after surgery. Only one of the patients had MN (hemangiopericytic). The patient had 48 years old and a Karnofsky Performance Score of 90. She received four doses of 160 mg of antibody. At the end of the study, no objective response was seen in any of the patients, however the remained with stable disease until 6 months after the last antibody dose [105]. Even though EGFR inhibition has revolutionized cancer care in neoplasms with high incidence like NSCLC and colorectal cancer, these effects have not been seen in brain tumors, even when EGFR upregulation has been proved. Further studies must be performed with newer and more effective EGFR inhibitors, including monoclonal antibodies.
PDGFR is another RTK whose expression is critical during development, as well as in the growth and differentiation of certain cell lineages. Its role in multiple chronic diseases have been studied, and it is considered a possible target in conditions like cancer, fibrosis, neurological disorders and atherosclerosis. The PDGF/PDGFR axis promotes cell proliferation, survival and migration primarily in cells of mesenchymal origin [106]. The ligands for PDGFR are four different polypeptide chains (PDGF-A, PDGF-B, PDGF-C and PDGF-D) which can be organized in an array of dimers that behave as functional growth factors (PDGF-AA, PDGF-BB, PDGF-AB, PDGF-CC and PDGF-DD [107]. These ligands have two different receptors, PDGFRα and PDGFRβ. The different ligands bind to the receptors with a differential specificity. PDGF-A, -B and -C will bind strongly to PDGFRα while the others will bind to PDGFRβ [106].
It has been demonstrated that MN expresses different forms of PDGF ligands, namely PDGF-AA and PDGF-BB, and expresses considerable levels of PDGFRβ. It has been shown that the PDGF/PDGFR axis might play a key role in the tumorigenesis of MN. Black et al. proved that PDGFRβ in MN cells derived from patients are susceptible to the stimulation with PDGF-BB ligands, with a shown increased in the activation of MAPK [21] and c-fos, a critical part of the master regulator AP-1, and a recognized proto-oncogene [108, 109]. Unlike EGFR expression, PDGFR levels appear to be higher in atypical and anaplastic MN than in grade I MN. In those MN that express PDGFR and the aforementioned PDGF ligands, there is an autocrine loop that supports maintenance and cell growth [109]. Todo et al. demonstrated that there is a considerable decrease in meningioma cells proliferation when these cells are given a neutralizing antibody against PDGF-BB. They saw a similar but less potent behavior when an anti-PDGF-AA antibody, also suggesting that the PDGF-BB pathway is the most important for meningioma maintenance [110].
Imatinib, a potent PDGF inhibitor currently used in different conditions (mainly chronic myeloid leukemia), has also been proven in MN patients. Imatinib possess a very low IC50 of 0.1 μM, this is especially important in MN as the blood-brain-barrier might decrease the flux of imatinib and other drug particles into the brain. In the NABTC 01–08 study, 23 patients with MN were enrolled, with 13 patients bearing low grade tumors, five with atypical MN and five with anaplastic MN. Response was only evaluated in 19 patients from whom 10 patients experienced disease progression. The rest of the patients remained disease stable. Median PFS was only 2 months, with a PFS6 of 29.4%. When analyzed separately, PFS for grade I MN was 3 months and PFS6 was as high as 45%. In the case of high-grade MN, PFS was 2 months but PFS6 was 0%.
The current landscape of PDGF inhibition is somewhat promising. Other agents like sunitnib, MLN518, dasatinib, AMN 107, pazopanib, sorafenib, CP673451 and CHIR 265 have been studied [111]. Furthermore, combination therapies using imatinib and other different agents like hydroxyurea [112], which has showed some benefit in the treatment of glioblastoma in a Phase I/II trial [113].
The mTORC1 (mammalian target of rapamycin complex 1) pathway has been reported to interact with merlin as a negative regulator of cell growth control [114]. mTOR is a serine/threonine kinase involved in cell signaling controlling transcription, actin cytoskeleton organization, translational activation, and metabolism in response to environmental cues [9]. The protein exists in two distinct multiprotein complexes. The rapamycin-sensitive complex mTORC1 regulates cell growth and proliferation in response to growth factors and metabolic conditions, whereas the rapamycin-insensitive mTORC2 regulates locally restricted growth processes within a cell and is involved in cell migration. Merlin was shown to enhance the kinase activity of mTORC2 [115].
Previously, Pachou et al. [116] found that mTORC1 is activated in the majority of MNs (7–10%) and that systemic mTORC1 inhibition can impair meningioma tumor formation in vivo. In addition, Akt is well known to be an upstream element of mTORC1 and to be activated in meningioma cells by platelet-derived growth factor [117]. PDGF also induces phosphorylation of p70S6K, the expression of which was reported to be increased in malignant MNs [118].
Several groups analyzed the biological effects of everolimus and temsirolimus on meningioma cell viability. They could clearly show that both inhibitors were effective in reducing meningioma cell viability and proliferation [114]. Moreover, evidence was found that the NF2 gene status may affect the response to both inhibitors but differentially activated mTOR pathways could not explain this result in isogenic meningioma cell lines with and without merlin expression [119]. Further, octreotide was shown to augment the inhibitory effect on the mTOR pathway in meningioma cell lines because mTOR inhibition increases the hyperphosphorylation of AKT which thereby increases cell proliferation [120].
In 2020, Graillon et al. reported the results of the CEVOREM trial, a phase II open label study that evaluated the combination of everolimus and octreotide in 20 high-grade MNs patients. Furthermore, four patients harbored NF2 germline mutation [121]. The overall PFS6 was 55% (95% CI 31.3–73.5%), and 6- and 12-month OS rates were 90% (95% CI 65.6–97.4%) and 75% (95% CI 50.0–88.7%), respectively. A decrease >50% was observed in the growth rate at 3 months in 78% of tumors. In addition, the median tumor growth rate decreased from 16.6%/3 months before inclusion to 0.02%/3 months at 3 months (
In a small trial, everolimus has also been studied in conjunction with bevacizumab without finding any objective tumor response but showing a slight increase in PFS for those with high-grade MNs (NCT00972335) [122]. In this study, 88% of the 18 patients showed SD for a median duration of 10 months (2–29 months). Nevertheless, overall median PFS was 22 months (95% CI 4.5–26.8), higher for patients with WHO grade II and III than grade I tumors (22.0 months vs. 17.5 months). Four patients discontinued treatment due to toxicity (proteinuria, 2; colitis, 1, thrombocytopenia, 1), but another grade 3 toxicity was uncommon, and no patient had grade 4 toxicity. The interesting improvement in higher histological grade MNs could be due to their increased vasculature and the increased dependence on the mTOR pathway of these lesions [122].
There is currently a phase 0, single group assignment, trial for everolimus in NF2 mutant MNs and vestibular schwannomas (NCT01880749). There are two single group assignment phase II trials of another mTOR inhibitor, AZD2014; NCT03071874 for recurrent grade II/III MNs and NCT02831257 for NF2 patients with MNs. These trials will help determine the efficacy of mTOR inhibition in patients with these challenging lesions. Besides, a case report of a female patient with metastatic meningotheliomatous meningioma involving the brain and the lung was treated with the pan-AKT inhibitor, AZD5363 for AKT1E17K mutation, showed a favorable and durable response [123]. Ex vivo cultured meningioma cells revealed sensitivity to the drug as shown by pan-AKT accumulation on immunoblots. The patient has been treated for more than a year with a response which warrants further research [123].
Angiogenesis depends on the balance between angiogenic and anti-angiogenic regulators [124]. Among the former, VEGF has been demonstrated to play an essential role in stimulating angiogenesis by promoting the migration, proliferation, and tube formation of endothelial cells. VEGF upregulation has been shown in MNs, suggesting its role as a pro-angiogenic factor responsible for edema formation in these tumors [125, 126, 127].
Neoangiogenesis in MNs is regulated by the balance between concentrations of both VEGF and semaphorin 3A (SEMA3A) in the tumor’s microenvironment rather than by VEGF alone [125]. Accordingly, neo-angiogenesis would be blocked or stimulated depending on the prevalence of VEGF or SEMA3A with a high ratio between VEGF and SEMA3A as a negative predictor of recurrences [125]. Additionally, VEGF expression in MNs seems to be enhanced by hypoxia-inducible factor 1-alpha [128] and EGF [129], and reduced by dexamethasone.
Caveolin-1 (cav-1), which is a 20-KDa protein mainly expressed by fibroblasts, endothelial cells, myocytes, and adipocytes, seems to be involved in the oncogenesis and progression of several neoplasms, including MNs [130]. Similar to what has been reported in several solid tumors, a significant correlation has been shown between tumor-cell-derived cav-1 and microvascular density (MVD) in MNs [131], suggesting that this protein behaves as a pro-angiogenic factor. Consistent with this hypothesis, cav-1 has been shown to regulate endothelial cell growth and differentiation and to stimulate capillary tubule formation in vitro [132]. Moreover, VEGF-mediated pathological angiogenesis is strikingly reduced in cav-1 knock-out mice [133]. On the other hand, the association between cav-1 expression and MVD may also be related to factors regulating both the MNs neo-angiogenesis and cav-1 expression. Indeed, cav-1 may function as a pro-tumorigenic factor that can stimulate cell proliferation, following its tyrosine-14 phosphorylation by Src kinase [134].
Endothelin-1 (ET-1) has been demonstrated to play a role in the mechanism of meningioma tumorigenesis via the ETA receptor [135]. ET-1 expression/upregulation may contribute to meningioma growth by inducing the formation of new blood vessels. Indeed, a significant correlation has been shown between the expression of ET-1 and that of VEGF or MVD in MNs, in agreement with its proangiogenic action in these tumors.
Following these biological considerations, several angiogenesis inhibitors, such as bevacizumab, sunitinib, and vatalanib, have been evaluated in phase II trials with promising results [136]. The efficacy and safety of bevacizumab were evaluated in grades II and III MNs, finding a PFS6 of 43.8%. In addition, a review of 22 additional case reports for a total of 92 patients revealed a PFS of 16.8 months with 6 months PFS of 73% in those exposed to bevacizumab [137]. A phase II trial designed for all grades recurrent MNs that included 15 patients (15, 22, and 13 grade I, II, and III, respectively) showed stability of the disease in 100% of benign tumors and 82–85% among those with high-grade injuries. In addition, the PFS6, the median PFS, and OS, were 87%, 22.5 months, and 35.6 months for patients with grade I tumors, while this distribution was 77%, 15.3 months, and not reached for grade II, and 46%, 3.7 months, and 12.4 months for grade III, respectively [138]. There is an ongoing phase II trial evaluating bevacizumab in recurrent and progressive MNs (NCT01125046).
Kaley et al. reported a prospective, multicenter single-arm phase 2 trial that investigated the efficacy of sunitinib, a tyrosine kinase inhibitor that inhibits VEGF and PDGF receptors, which are over-expressed in MNs [139]. Thirty-six patients with grade II and III recurrent or progressive MNs were enrolled. They were heavily pre-treated (median five recurrences) and received sunitinib at 50 mg per day for days 1–28 of a 42-day cycle. The PFS6 was 42%, the median PFS was 5.2 months (95% CI 2.8–8.3), and the median overall survival was 24.6 months (16.5–38.4). Adverse events included four (8%) intratumoral hemorrhages, of which one was fatal, one (2%) grade 4 thrombotic microangiopathy, and one (2%) grade 3 gastrointestinal perforation. MRI perfusion in the exploratory group indicated that sunitinib is an active agent, and expression of VEGFR2 predicted PFS with a median of 1.4 months in VEGFR2-negative patients versus 6.4 months in VEGFR2- positive patients (
Evidence suggests that meningioma growth could be hormone dependent because of the female predominance specially after puberty and reproductive years. Additionally, that 30% of the meningiomas are estrogen receptor positive and 70% are progesterone receptor positive [76]. It is also known, that high grade meningiomas express more estrogen receptors whereas benign meningiomas express more progesterone receptors [141]. It is also important to add, that approximately 90% of meningiomas express somatostatin receptors [142]. Therefore, hormonal therapies have been utilized in high grade meningioma treatment.
Due to estrogen receptors low expression, treatment with tamoxifen (estrogen receptor antagonist) has not shown effective results. Additionally, there is not any reports of androgen receptor antagonists in meningiomas [143]. In 1993 Goodwin et al. in a retrospective case series of 21 patients with meningioma treated with tamoxifen, they reported response in only 1 patient and disease progression in 10 patients [144]. Additionally, in a case study from Markwalder et al. a small group of patients with inoperable meningiomas that received tamoxifen were studied and only two patients show radiographical partial response [145].
Currently, due to the lack of evidence of anti-estrogenic agents’ effect on meningioma no recommendation is available. Mifepristone is a progesterone receptor inhibitor. In a study published in 1991 by Wolfsberger et al., they used mifepristone as treatment of unresectable meningioma patients, they reported that five patients showed reduction of tumor size on neuroimaging and visual field improvement; in addition, three patients experienced headache relief and improvement in extraocular muscle function. No toxicities were reported [141]. Other study by Lamberts et al. reported stable disease in three patients, tumor size reduction in other three patients and no toxicities were reported [146]. These studies were limited because of the small sample size and tumor stage wasn’t described in any of them. Therefore, more studies are needed to conclude the effect of mifeprisotne in high grade meningiomas. Other trial by Ji et al. reported a median PFS of 10 months and a median OS of 31 months in the mifepristone arm of patients with recurrent meningioma [147]. Additionally, in 2006 Grunberg et al. reported a reduction of less than 10% of the tumor area without clinical improvement in eight patients with unresectable meningioma who received mifepristone [148].
Megestrol acetate is an oral progesterone agonist that was used in a small trial. However no response was observed in high grade meningiomas [76]. So far there is no evidence that supports the use of progesterone receptor inhibitors in high grade meningiomas.
Somatostatin is important in regulation and proliferation of normal cells and tumor cells. It is known that meningiomas report the highest frequency of somatostatin receptor expression in brain tumors, especially the sst2A subtype. It is also reported that somatostatin inhibits meningioma growth in vitro in most studies, but increases meningioma proliferation in some [76].
Chamberlan et al. reported that 31% of patients demonstrated a partial radiographic response and 44% achieved PFS at 6 months with minimal toxicity in patients treated with octreotide (a somatostatin agonist). Furthermore, one-third of patients showed stable disease after treatment [149]. Therefore, somatostatin analogs are recommended for systemic treatment of unresectable or radiorefractory relapsed meningiomas [150]. The phase II CEVOREM trial explored the efficacy of the combination of everolimus (an mTOR inhibitor) and octreotide in high grade meningiomas treatment. The trial reported that the 6-month progression-free survival rate was 55% and the 6-month overall survival was 90% and 12-month survival rate was 90%. Additionally, a decrease of more than 50% was observed in the growth rate at 3 months in 78% of the tumors. That happens because, octreotide suppressed AKT activation during everolimus treatment and synergistically reduced expression of downstream proteins [121]. The previous results suggest that the combination of everolimus and octreotide could be a very good option to treat high grade meningiomas, however more studies are needed. In other phase II trial by Johnson et al. only 2 of 12 high grade cases experience long progression-free intervals, but at the end all patients experienced disease progression with median time of 17 weeks; a median survival 2.7 years was reported and octreotide was well-tolerated [151]. Additionally, an in- vitro study by Graillon et al. reported a significant anti-proliferative effects octreotide, but no apoptotic response [152].
Parasoreotide (SOM230C) is an intramuscularly long-acting somatostatin analogue. In the phase II trial by Norden et al., they reported that pasireotide has limited activity in recurrent meningiomas, a PFS-6 of 17% and median PFS of 15 weeks were reported. Furthermore, expression of somatostatin receptor was predictive of favorable response. However the findings in this trial require further investigation [153]. These findings are promising, nevertheless, larger randomized studies should be conducted to make a solid conclusion.
Growth hormone is secreted by the pituitary gland, and it induces production of insulin-like growth factor-I (IGF-I-), these hormones influence normal growth and metabolism [73]. There is existent evidence that reports abuntant growth hormone receptors expression in meningioma cells. There is also reported that inhibition of these receptors represents a decreased meningioma cell proliferation [154]. McCutcheon et al. reported that administration of pegvisomant reduces meningioma growth and in some cases causes tumor regression. Pegvisomant blocks growth hormone receptors and induces downregulation of the GH/IGF-I axis [155]. In other study, Puduvalli et al. reported that fenretinide, a synthetic retinoid, induced apoptosis in meningioma primary cells tested, it also increases levels of the death receptor DR5 and causes mitochondrial membrane depolarization. They also reported eradication of IGF-I proliferation in the meningioma cells [156].
Finally, insulin-like growth factor-II acts like IGF-I. In multiple studies have reported that the invasiveness of meningiomas is correlated to levels of IGF-II expression [157]. However, several studies are needed to establish IGF-II blockade could be an option to treat patients with meningiomas. These results provide preliminary evidence, but further studies are needed to explore these options as treatment against meningioma.
Existent evidence, shows that recombinant interferon-α (INF-α) is a biologic agent able to inhibit DNA synthesis, it binds to the interferon-a/b receptor and is involved in cell resistance to viral infection [64]. In 1991 in vitro studies also reported that interferon-alpha inhibits tumor cells growth [158].
In 1997 Kaba et al., reported a minor reduction of tumor size in one patient and a stable disease that lasted up to 14 months in four of six patients with recurrent unresectable meningioma who received INF-α 2b [159]. Other study in 2001, reported a stable disease that lasted up to eight years in nine of twelve patients treated with INF-α [160]. In 2008 Chamberlain and Glantz, reported in a phase II study that 26 of 35 patients that received treatment with INF-α demonstrated stable disease after the first 3 cycles and that 9 patients developed progressive disease. Additionally, a PFS rate was 54% at 6 months and 31% at 12 months were reported, median time to tumor progression was 7 months and median survival was 8 months. Furthermore, no patient demonstrated neuroradiographic complete or partial response, fatigue, anemia and leukopenia were the most common toxicities but overall, the drug was safe. A limitation form this study is that it was conducted only in patients with refractory grade I meningiomas [161]. Currently, these options are used as therapy for recurrent meningiomas or progression following surgery and radiation. It is also used for meningiomas that no respond to standard treatment options. Nevertheless, evidence that supports the use of interferons for meningiomas is poor.
Oncolytic viruses are biologic anti-tumor agents that selectively kill tumor cells leaving non tumoral cells intact [63]. A lot of oncolytic viruses have been investigated in different clinical trials, however no clinical trials have been conducted in meningiomas [162].
There are a few preclinical trials conducted in meningioma models. In 2005 Grill et al. evaluated the efficacy of conditionally replicating adenovirus (Ad) for oncolysis of meningiomas of 12 patients. Four different Ads were constructed and tested on meningioma cells and spheroids: Ad with an E1ACR2 deletion (Ad.d24), Ad with complete E1 region (Ad.E1+), Ad encoding the luciferase marker gene (Ad.Luc) and Ad encoding the luciferase gene in the E3 region (Ad.E1Luc). They demonstrated replication of adenovirus and oncolysis in primary cell cultures of meningioma cells at high dose (greater than 50 plaque-forming units per cell). Additionally, they also reported that at a lower dose (5 plaque-forming units per cell), Ad.d24 kills meningioma cells more efficiently than Ad.E1+ in benign, atypical, and malignant meningiomas [163].
Herpes virus it has a large dsDNA with more than 30 kb making the virus encoding for nonessential genes, this feature allows for genetic manipulation. Additionally, herpesviruses have a good safety profile, because they replicate in the nucleus without causing insertional mutagenesis [164].
In 1992, Market et al. added thymidine kinase-negative herpes simplex-I mutant virus, d/sptk, to meningioma cell cultures. They reported an antineoplastic effect against the malignant meningioma and significant tumor regressions [165]. In the study from Yazaki et al., reported that mutant herpes simplex virus (termed G207) can replicate and kill cells from human malignant meningiomas in cell culture. They also reported tumor growth reduction in nude mice harboring human malignant meningioma [166]. Additionally, it is reported that efficacy of oncolytic herpes simplex viruses (HSV) as single agent is unsatisfactory; so in 2006 Liu et al. demonstrated that oncolytic HSV encoding dnFGFR enhances antitumor efficacy [167]. In 2016 Nigim et al., reported that G47∆, an oncolytic HSV derived from G207, was able to replicate and kill several human primary meningioma cultures in vitro. They also reported that this treatment prolonged survival, with 20% of mice surviving more than160 days. Furthermore, a lack of signs of encephalitic associated with G47∆ treatment was reported [168]. In 2018, they also reported that the mechanism of action of oHSV enables killing NF2 intact and mutant meningiomas and meningiomas that harbor other mutations [63].
Several studies have demonstrated the ability of oncolytic viruses to recruit T cells and induce immune responses against virus and tumor. Furthermore, some studies have demonstrated that oncolytic viruses combined with other cancer therapies, create synergistic effects in brain cancer treatment. Although many questions remain to be answered to fully exploit the therapeutic potential of oncolytic viruses against meningiomas [169].
Several studies have aimed to characterize the interactions between MNs and the immune system. Specifically, studies of the immune microenvironment in MNs have revealed that NY-ESO-1, PD-L1, PD-L2, B7-H3, and CTLA-4 are expressed in MNs and may be at least partly responsible for the suppression of the anti-tumor immune response [170, 171]. PD-L1 is expressed in MNs, and expression levels are higher for higher-grade tumors [172]. The expression of these proteins has been associated with tumor progression, recurrence, and poor survival outcomes. Fang et al. extensively characterized the immune infiltrate in MNs and found that the immune cells infiltrating MNs are mainly antigen-experienced T cells and B cells [58]. In their study, B cells were activated and underwent immunoglobulin class switching, somatic hypermutation, and clonal expansion. T-cells demonstrated evidence of antigen exposure and increased expression of PD-1 and TIM-3, which can be a sign of an exhausted phenotype. Tumor-infiltrating lymphocytes in MNs are mainly T-cells. Interestingly in anaplastic MNs, the number of CD4 and CD8 T-cells is low. At the same time, the proportion of Tregs is increased [59]. These data support the notion that an immunosuppressive microenvironment in MNs may contribute to tumor progression.
In a mouse model of meningioma, infusion of anti-PD1 antibody avelumab plus highly-active NK cells (HaNK) led to increased survival, showing the importance of innate NK cell activity [173]. Currently there are two case reports on PD-L1 checkpoint inhibition for recurrent MNs [174, 175]. The cases report disease-free recurrence for >2 years in one patient and > 6 months in another patient, with both having reductions in tumor volume, cerebral edema, and patient-reported symptoms following nivolumab treatment. Based on the existing evidence on PD-L1 expression in recurrent MNs, five clinical trials are enrolling patients with to receive anti-PD1 antibodies nivolumab, avelumab, or pembrolizumab. An ongoing phase II trial is designed to compare nivolumab alone to combination therapy with the anti-CTLA-4 antibody ipilimumab (NCT02648997). A phase Ib trial will investigate the preoperative use of avelumab in combination with hypo-fractionated proton radiotherapy for 3 months to evaluate its effect on the size of unresected MNs (NCT03267836). The other trials are recruiting patients with recurrent MNs to receive adjuvant immunotherapy as PD1 blockade.
Chimeric Antigen Receptor (CAR) T cell therapies are a novel therapeutic approach to cancer. The standard treatment consists in the leukapheresis of autologous peripheral blood mononuclear cells from the patient bearing the tumor. After successful leukapheresis, T cell isolation is performed. T cells are then grown in culture and are further transduced with a lentiviral vector carrying an integrative plasmid that encodes the CAR, which is essentially a fusion protein containing a single-chain variable fragment derived from a full antibody, plus a transmembrane domain and different array of intracellular co-receptor and co-stimulatory domains that will trigger the intracellular signaling necessary for T cell activation [176].
CAR-T cell therapies were initially approved in 2017 (axi-cel and tisa-cel) for the treatment of relapsed/refractory diffuse large B cell lymphoma and relapsed/refractory B-cell acute lymphoblastic leukemia [177]. Unfortunately, the landscape of CAR-T cell therapies in solid tumors has not been promising, mainly due to different resistance from typical features of the tumor microenvironment like high acidity, immune effector exhaustion induction and the extracellular matrix. Different workaround strategies have been explored to address these problems and currently, highly engineered cells and very complex therapies (CAR-Ts in combination with checkpoint inhibition, or small molecules, or chemotherapy, or immunomodulators) are under study in different clinical trials [178].
Brain tumors have not been an exception in CAR-T development, with glioblastoma being the most attacked condition. Tang et al. reported a case of a patient with an anaplastic MN that underwent three surgical resections and had an Ommaya device implanted. IHC from her tumor sample showed a high expression of B7-H3, also known as CD276 ([179], p. 3). The researchers prepared CAR-Ts from autologous PBMCs, and during CAR-T development patient recur and CAR-Ts were administered in three doses via the Ommaya device. A fourth surgical treatment was performed as patient was progressing quickly, and unfortunately the patient died one day after surgery. Post-mortem analysis of the tumor sample showed that CAR-T indeed penetrated the tumor and successfully targeted some cells expressing B7-H3, however, as not all the tumor was expressing this molecule, antigen loss and selection of other cells with a different transcriptome occurred [180]. Even though results were not as expected, this case marks an important step toward the development of cell therapies of different natures, to treat brain tumors, especially those of high recurrency and aggressiveness.
Treatment in MN has remained similar since some decades ago. Major improvements in survival are achieved mainly by surgery and radiation therapy. Most cases of MN will respond to these conventional therapies, however, transformation of low-grade MN to high-grade MN, or de novo high-grade MN are highly recurrent and impose a very low survivability. For these tumors, surgery and radiation therapy are less than enough. With the era of genomic analysis and a better understanding of the genetic basis of cancer, different molecular targets and new therapeutic approaches have been studied for high-grade MN treatment. In this review we went through the main critical advancements in evidence that suggests that molecular targeting might be the future of high-grade MN treatment. To the date, all these molecular approaches are still under study, a conventional management is still the mainstay, but we hope in the following years, new evidence of the clinical relevance of these therapies is available and introduction of them into the therapeutic arsenal could be a true.
This is a brief overview of the main steps involved in publishing with IntechOpen Compacts, Monographs and Edited Books. Once you submit your proposal you will be appointed a Author Service Manager who will be your single point of contact and lead you through all the described steps below.
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\n\nAfter we receive your proof corrections and a final typeset of the manuscript is approved, your manuscript is sent to our in house DTP department for technical formatting and online publication preparation.
\n\nAdditionally, you will be asked to provide a profile picture (face or chest-up portrait photograph) and a short summary of the book which is required for the book cover design.
\n\n6. INVOICE PAYMENT
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The routine management of oral cancers is firstly surgical resection with or without postoperative adjuncts and other therapies such as the use of postoperative chemoradiation and radiation. Successful treatment of oral cancer patients is a complex issue that requires a multidisciplinary approach, including oral and maxillofacial surgeons, oral and maxillofacial radiologists, ENT specialists, medical and radiological oncologists, prosthodontists, dentists, speech therapists, supportive care experts, and also pathologists or, if possible, oral and maxillofacial pathologists.",book:{id:"8631",slug:"prevention-detection-and-management-of-oral-cancer",title:"Prevention, Detection and Management of Oral Cancer",fullTitle:"Prevention, Detection and Management of Oral Cancer"},signatures:"Nihat Akbulut and Ahmet Altan",authors:[{id:"262769",title:"Dr.",name:"Nihat",middleName:null,surname:"Akbulut",slug:"nihat-akbulut",fullName:"Nihat Akbulut"},{id:"268500",title:"Dr.",name:"Ahmet",middleName:null,surname:"Altan",slug:"ahmet-altan",fullName:"Ahmet Altan"}]},{id:"63395",title:"The Impact of Sequencing Human Genome on Drug Design to Treat Oral Cancer",slug:"the-impact-of-sequencing-human-genome-on-drug-design-to-treat-oral-cancer",totalDownloads:892,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"Of all the known cancers, oral cancer is the most preventable and it is the second most deadly cancer after the breast cancer. 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The sources related to thyroid surgery show that the success of the neck masses with the surgical intervention was limited until the second half of the nineteenth century. Among the names leading the development of thyroid surgery in contemporary times are Emil Theodor Kocher, Theodor Billroth, William James Mayo, and William Stewart Halsted. 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His research interests involve understanding the molecular mechanisms of host defense during human viral infections and developing new predictive, preventive, and therapeutic strategies for them using Japanese encephalitis virus (JEV), HIV, and emerging viruses as a model via stem cell and cell culture technologies. His research work has been published in various high-impact factor journals (Science, PNAS, Nature Medicine) with a high number of citations. He has received many awards and honors in India and abroad including various Young Scientist Awards, BBSRC India Partnering Award, and Dr. JC Bose National Award of Department of Biotechnology, Min. of Science and Technology, Govt. of India. Dr. Saxena is a fellow of various international societies/academies including the Royal College of Pathologists, United Kingdom; Royal Society of Medicine, London; Royal Society of Biology, United Kingdom; Royal Society of Chemistry, London; and Academy of Translational Medicine Professionals, Austria. He was named a Global Leader in Science by The Scientist. He is also an international opinion leader/expert in vaccination for Japanese encephalitis by IPIC (UK).",institutionString:"King George's Medical University",institution:{name:"King George's Medical University",institutionURL:null,country:{name:"India"}}},editorTwo:null,editorThree:null}]},overviewPageOFChapters:{paginationCount:58,paginationItems:[{id:"81961",title:"Antioxidants as an Adjuncts to Periodontal Therapy",doi:"10.5772/intechopen.105016",signatures:"Sura Dakhil Jassim and Ali Abbas Abdulkareem",slug:"antioxidants-as-an-adjuncts-to-periodontal-therapy",totalDownloads:3,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Dental Trauma",coverURL:"https://cdn.intechopen.com/books/images_new/11567.jpg",subseries:{id:"2",title:"Prosthodontics and Implant Dentistry"}}},{id:"82357",title:"Caries Management Aided by Fluorescence-Based Devices",doi:"10.5772/intechopen.105567",signatures:"Atena Galuscan, Daniela Jumanca and Aurora Doris Fratila",slug:"caries-management-aided-by-fluorescence-based-devices",totalDownloads:4,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Dental Caries - The Selection of Restoration Methods and Restorative Materials",coverURL:"https://cdn.intechopen.com/books/images_new/11565.jpg",subseries:{id:"1",title:"Oral Health"}}},{id:"81894",title:"Diet and Nutrition and Their Relationship with Early Childhood Dental Caries",doi:"10.5772/intechopen.105123",signatures:"Luanna Gonçalves Ferreira, Giuliana de Campos Chaves Lamarque and Francisco Wanderley Garcia Paula-Silva",slug:"diet-and-nutrition-and-their-relationship-with-early-childhood-dental-caries",totalDownloads:11,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Dental Caries - The Selection of Restoration Methods and Restorative Materials",coverURL:"https://cdn.intechopen.com/books/images_new/11565.jpg",subseries:{id:"1",title:"Oral Health"}}},{id:"81595",title:"Prosthetic Concepts in Dental Implantology",doi:"10.5772/intechopen.104725",signatures:"Ivica Pelivan",slug:"prosthetic-concepts-in-dental-implantology",totalDownloads:27,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Current Concepts in Dental Implantology - From Science to Clinical Research",coverURL:"https://cdn.intechopen.com/books/images_new/10808.jpg",subseries:{id:"2",title:"Prosthodontics and Implant Dentistry"}}}]},overviewPagePublishedBooks:{paginationCount:8,paginationItems:[{type:"book",id:"6668",title:"Dental Caries",subtitle:"Diagnosis, Prevention and Management",coverURL:"https://cdn.intechopen.com/books/images_new/6668.jpg",slug:"dental-caries-diagnosis-prevention-and-management",publishedDate:"September 19th 2018",editedByType:"Edited by",bookSignature:"Zühre Akarslan",hash:"b0f7667770a391f772726c3013c1b9ba",volumeInSeries:1,fullTitle:"Dental Caries - Diagnosis, Prevention and Management",editors:[{id:"171887",title:"Prof.",name:"Zühre",middleName:null,surname:"Akarslan",slug:"zuhre-akarslan",fullName:"Zühre Akarslan",profilePictureURL:"https://mts.intechopen.com/storage/users/171887/images/system/171887.jpg",biography:"Zühre Akarslan was born in 1977 in Cyprus. She graduated from Gazi University Faculty of Dentistry, Ankara, Turkey in 2000. \r\nLater she received her Ph.D. degree from the Oral Diagnosis and Radiology Department; which was recently renamed as Oral and Dentomaxillofacial Radiology, from the same university. \r\nShe is working as a full-time Associate Professor and is a lecturer and an academic researcher. \r\nHer expertise areas are dental caries, cancer, dental fear and anxiety, gag reflex in dentistry, oral medicine, and dentomaxillofacial radiology.",institutionString:"Gazi University",institution:{name:"Gazi University",institutionURL:null,country:{name:"Turkey"}}}]},{type:"book",id:"7139",title:"Current Approaches in Orthodontics",subtitle:null,coverURL:"https://cdn.intechopen.com/books/images_new/7139.jpg",slug:"current-approaches-in-orthodontics",publishedDate:"April 10th 2019",editedByType:"Edited by",bookSignature:"Belma Işık Aslan and Fatma Deniz Uzuner",hash:"2c77384eeb748cf05a898d65b9dcb48a",volumeInSeries:2,fullTitle:"Current Approaches in Orthodontics",editors:[{id:"42847",title:"Dr.",name:"Belma",middleName:null,surname:"Işik Aslan",slug:"belma-isik-aslan",fullName:"Belma Işik Aslan",profilePictureURL:"https://mts.intechopen.com/storage/users/42847/images/system/42847.jpg",biography:"Dr. Belma IşIk Aslan was born in 1976 in Ankara-TURKEY. After graduating from TED Ankara College in 1994, she attended to Gazi University, Faculty of Dentistry in Ankara. She completed her PhD in orthodontic education at Gazi University between 1999-2005. Dr. Işık Aslan stayed at the Providence Hospital Craniofacial Institude and Reconstructive Surgery in Michigan, USA for three months as an observer. She worked as a specialist doctor at Gazi University, Dentistry Faculty, Department of Orthodontics between 2005-2014. She was appointed as associate professor in January, 2014 and as professor in 2021. Dr. Işık Aslan still works as an instructor at the same faculty. She has published a total of 35 articles, 10 book chapters, 39 conference proceedings both internationally and nationally. Also she was the academic editor of the international book 'Current Advances in Orthodontics'. She is a member of the Turkish Orthodontic Society and Turkish Cleft Lip and Palate Society. She is married and has 2 children. Her knowledge of English is at an advanced level.",institutionString:"Gazi University Dentistry Faculty Department of Orthodontics",institution:null}]},{type:"book",id:"7572",title:"Trauma in Dentistry",subtitle:null,coverURL:"https://cdn.intechopen.com/books/images_new/7572.jpg",slug:"trauma-in-dentistry",publishedDate:"July 3rd 2019",editedByType:"Edited by",bookSignature:"Serdar Gözler",hash:"7cb94732cfb315f8d1e70ebf500eb8a9",volumeInSeries:3,fullTitle:"Trauma in Dentistry",editors:[{id:"204606",title:"Dr.",name:"Serdar",middleName:null,surname:"Gözler",slug:"serdar-gozler",fullName:"Serdar Gözler",profilePictureURL:"https://mts.intechopen.com/storage/users/204606/images/system/204606.jpeg",biography:"Dr. Serdar Gözler has completed his undergraduate studies at the Marmara University Faculty of Dentistry in 1978, followed by an assistantship in the Prosthesis Department of Dicle University Faculty of Dentistry. Starting his PhD work on non-resilient overdentures with Assoc. Prof. Hüsnü Yavuzyılmaz, he continued his studies with Prof. Dr. Gürbüz Öztürk of Istanbul University Faculty of Dentistry Department of Prosthodontics, this time on Gnatology. He attended training programs on occlusion, neurology, neurophysiology, EMG, radiology and biostatistics. In 1982, he presented his PhD thesis \\Gerber and Lauritzen Occlusion Analysis Techniques: Diagnosis Values,\\ at Istanbul University School of Dentistry, Department of Prosthodontics. As he was also working with Prof. Senih Çalıkkocaoğlu on The Physiology of Chewing at the same time, Gözler has written a chapter in Çalıkkocaoğlu\\'s book \\Complete Prostheses\\ entitled \\The Place of Neuromuscular Mechanism in Prosthetic Dentistry.\\ The book was published five times since by the Istanbul University Publications. Having presented in various conferences about occlusion analysis until 1998, Dr. Gözler has also decided to use the T-Scan II occlusion analysis method. Having been personally trained by Dr. Robert Kerstein on this method, Dr. Gözler has been lecturing on the T-Scan Occlusion Analysis Method in conferences both in Turkey and abroad. Dr. Gözler has various articles and presentations on Digital Occlusion Analysis methods. 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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",institutionURL:null,country:{name:"India"}}}]}]},openForSubmissionBooks:{paginationCount:3,paginationItems:[{id:"11570",title:"Influenza - New Approaches",coverURL:"https://cdn.intechopen.com/books/images_new/11570.jpg",hash:"157b379b9d7a4bf5e2cc7a742f155a44",secondStepPassed:!0,currentStepOfPublishingProcess:3,submissionDeadline:"May 10th 2022",isOpenForSubmission:!0,editors:[{id:"139889",title:"Dr.",name:"Seyyed Shamsadin",surname:"Athari",slug:"seyyed-shamsadin-athari",fullName:"Seyyed Shamsadin Athari"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null},{id:"11569",title:"Bacterial Sexually Transmitted Infections - New Findings, Diagnosis, Treatment, and Prevention",coverURL:"https://cdn.intechopen.com/books/images_new/11569.jpg",hash:"069d6142ecb0d46d14920102d48c0e9d",secondStepPassed:!0,currentStepOfPublishingProcess:3,submissionDeadline:"May 31st 2022",isOpenForSubmission:!0,editors:[{id:"189561",title:"Dr.",name:"Mihaela Laura",surname:"Vica",slug:"mihaela-laura-vica",fullName:"Mihaela Laura Vica"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null},{id:"11568",title:"Staphylococcal Infections - Recent Advances and Perspectives",coverURL:"https://cdn.intechopen.com/books/images_new/11568.jpg",hash:"92c881664d1921c7f2d0fee34b78cd08",secondStepPassed:!1,currentStepOfPublishingProcess:2,submissionDeadline:"July 8th 2022",isOpenForSubmission:!0,editors:[{id:"59719",title:"Dr.",name:"Jaime",surname:"Bustos-Martínez",slug:"jaime-bustos-martinez",fullName:"Jaime Bustos-Martínez"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null}]},onlineFirstChapters:{paginationCount:10,paginationItems:[{id:"82380",title:"Evolution of Parasitism and Pathogenic Adaptations in Certain Medically Important Fungi",doi:"10.5772/intechopen.105206",signatures:"Gokul Shankar Sabesan, Ranjit Singh AJA, Ranjith Mehenderkar and Basanta Kumar Mohanty",slug:"evolution-of-parasitism-and-pathogenic-adaptations-in-certain-medically-important-fungi",totalDownloads:4,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Fungal Infectious Diseases - Annual Volume 2022",coverURL:"https://cdn.intechopen.com/books/images_new/11400.jpg",subseries:{id:"4",title:"Fungal Infectious Diseases"}}},{id:"82367",title:"Spatial Variation and Factors Associated with Unsuppressed HIV Viral Load among Women in an HIV Hyperendemic Area of KwaZulu-Natal, South Africa",doi:"10.5772/intechopen.105547",signatures:"Adenike O. 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He also obtained an MSc in Molecular and Genetic Medicine, and a Ph.D. in Clinical Immunology and Human Genetics from the University of Sheffield, UK. He also completed a short-term fellowship in Pediatric Clinical Immunology and Bone Marrow Transplantation at Newcastle General Hospital, England. Dr. Rezaei is a Full Professor of Immunology and Vice Dean of International Affairs and Research, at the School of Medicine, Tehran University of Medical Sciences, and the co-founder and head of the Research Center for Immunodeficiencies. He is also the founding president of the Universal Scientific Education and Research Network (USERN). Dr. Rezaei has directed more than 100 research projects and has designed and participated in several international collaborative projects. He is an editor, editorial assistant, or editorial board member of more than forty international journals. He has edited more than 50 international books, presented more than 500 lectures/posters in congresses/meetings, and published more than 1,100 scientific papers in international journals.",institutionString:"Tehran University of Medical Sciences",institution:{name:"Tehran University of Medical Sciences",country:{name:"Iran"}}},{id:"180733",title:"Dr.",name:"Jean",middleName:null,surname:"Engohang-Ndong",slug:"jean-engohang-ndong",fullName:"Jean Engohang-Ndong",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/180733/images/system/180733.png",biography:"Dr. Jean Engohang-Ndong was born and raised in Gabon. After obtaining his Associate Degree of Science at the University of Science and Technology of Masuku, Gabon, he continued his education in France where he obtained his BS, MS, and Ph.D. in Medical Microbiology. He worked as a post-doctoral fellow at the Public Health Research Institute (PHRI), Newark, NJ for four years before accepting a three-year faculty position at Brigham Young University-Hawaii. Dr. Engohang-Ndong is a tenured faculty member with the academic rank of Full Professor at Kent State University, Ohio, where he teaches a wide range of biological science courses and pursues his research in medical and environmental microbiology. Recently, he expanded his research interest to epidemiology and biostatistics of chronic diseases in Gabon.",institutionString:"Kent State University",institution:{name:"Kent State University",country:{name:"United States of America"}}},{id:"188773",title:"Prof.",name:"Emmanuel",middleName:null,surname:"Drouet",slug:"emmanuel-drouet",fullName:"Emmanuel Drouet",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/188773/images/system/188773.png",biography:"Emmanuel Drouet, PharmD, is a Professor of Virology at the Faculty of Pharmacy, the University Grenoble-Alpes, France. As a head scientist at the Institute of Structural Biology in Grenoble, Dr. Drouet’s research investigates persisting viruses in humans (RNA and DNA viruses) and the balance with our host immune system. He focuses on these viruses’ effects on humans (both their impact on pathology and their symbiotic relationships in humans). He has an excellent track record in the herpesvirus field, and his group is engaged in clinical research in the field of Epstein-Barr virus diseases. He is the editor of the online Encyclopedia of Environment and he coordinates the Universal Health Coverage education program for the BioHealth Computing Schools of the European Institute of Science.",institutionString:null,institution:{name:"Grenoble Alpes University",country:{name:"France"}}},{id:"131400",title:"Prof.",name:"Alfonso J.",middleName:null,surname:"Rodriguez-Morales",slug:"alfonso-j.-rodriguez-morales",fullName:"Alfonso J. Rodriguez-Morales",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/131400/images/system/131400.png",biography:"Dr. Rodriguez-Morales is an expert in tropical and emerging diseases, particularly zoonotic and vector-borne diseases (especially arboviral diseases). He is the president of the Travel Medicine Committee of the Pan-American Infectious Diseases Association (API), as well as the president of the Colombian Association of Infectious Diseases (ACIN). He is a member of the Committee on Tropical Medicine, Zoonoses, and Travel Medicine of ACIN. He is a vice-president of the Latin American Society for Travel Medicine (SLAMVI) and a Member of the Council of the International Society for Infectious Diseases (ISID). Since 2014, he has been recognized as a Senior Researcher, at the Ministry of Science of Colombia. He is a professor at the Faculty of Medicine of the Fundacion Universitaria Autonoma de las Americas, in Pereira, Risaralda, Colombia. He is an External Professor, Master in Research on Tropical Medicine and International Health, Universitat de Barcelona, Spain. He is also a professor at the Master in Clinical Epidemiology and Biostatistics, Universidad Científica del Sur, Lima, Peru. In 2021 he has been awarded the “Raul Isturiz Award” Medal of the API. Also, in 2021, he was awarded with the “Jose Felix Patiño” Asclepius Staff Medal of the Colombian Medical College, due to his scientific contributions to COVID-19 during the pandemic. He is currently the Editor in Chief of the journal Travel Medicine and Infectious Diseases. His Scopus H index is 47 (Google Scholar H index, 68).",institutionString:"Institución Universitaria Visión de las Américas, Colombia",institution:null},{id:"332819",title:"Dr.",name:"Chukwudi Michael",middleName:"Michael",surname:"Egbuche",slug:"chukwudi-michael-egbuche",fullName:"Chukwudi Michael Egbuche",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/332819/images/14624_n.jpg",biography:"I an Dr. Chukwudi Michael Egbuche. I am a Senior Lecturer in the Department of Parasitology and Entomology, Nnamdi Azikiwe University, Awka.",institutionString:null,institution:{name:"Nnamdi Azikiwe University",country:{name:"Nigeria"}}},{id:"284232",title:"Mr.",name:"Nikunj",middleName:"U",surname:"Tandel",slug:"nikunj-tandel",fullName:"Nikunj Tandel",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/284232/images/8275_n.jpg",biography:'Mr. Nikunj Tandel has completed his Master\'s degree in Biotechnology from VIT University, India in the year of 2012. He is having 8 years of research experience especially in the field of malaria epidemiology, immunology, and nanoparticle-based drug delivery system against the infectious diseases, autoimmune disorders and cancer. He has worked for the NIH funded-International Center of Excellence in Malaria Research project "Center for the study of complex malaria in India (CSCMi)" in collaboration with New York University. The preliminary objectives of the study are to understand and develop the evidence-based tools and interventions for the control and prevention of malaria in different sites of the INDIA. Alongside, with the help of next-generation genomics study, the team has studied the antimalarial drug resistance in India. Further, he has extended his research in the development of Humanized mice for the study of liver-stage malaria and identification of molecular marker(s) for the Artemisinin resistance. At present, his research focuses on understanding the role of B cells in the activation of CD8+ T cells in malaria. Received the CSIR-SRF (Senior Research Fellow) award-2018, FIMSA (Federation of Immunological Societies of Asia-Oceania) Travel Bursary award to attend the IUIS-IIS-FIMSA Immunology course-2019',institutionString:"Nirma University",institution:{name:"Nirma University",country:{name:"India"}}},{id:"334383",title:"Ph.D.",name:"Simone",middleName:"Ulrich",surname:"Ulrich Picoli",slug:"simone-ulrich-picoli",fullName:"Simone Ulrich Picoli",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/334383/images/15919_n.jpg",biography:"Graduated in Pharmacy from Universidade Luterana do Brasil (1999), Master in Agricultural and Environmental Microbiology from Federal University of Rio Grande do Sul (2002), Specialization in Clinical Microbiology from Universidade de São Paulo, USP (2007) and PhD in Sciences in Gastroenterology and Hepatology (2012). She is currently an Adjunct Professor at Feevale University in Medicine and Biomedicine courses and a permanent professor of the Academic Master\\'s Degree in Virology. She has experience in the field of Microbiology, with an emphasis on Bacteriology, working mainly on the following topics: bacteriophages, bacterial resistance, clinical microbiology and food microbiology.",institutionString:null,institution:{name:"Universidade Feevale",country:{name:"Brazil"}}},{id:"229220",title:"Dr.",name:"Amjad",middleName:"Islam",surname:"Aqib",slug:"amjad-aqib",fullName:"Amjad Aqib",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/229220/images/system/229220.png",biography:"Dr. Amjad Islam Aqib obtained a DVM and MSc (Hons) from University of Agriculture Faisalabad (UAF), Pakistan, and a PhD from the University of Veterinary and Animal Sciences Lahore, Pakistan. Dr. Aqib joined the Department of Clinical Medicine and Surgery at UAF for one year as an assistant professor where he developed a research laboratory designated for pathogenic bacteria. Since 2018, he has been Assistant Professor/Officer in-charge, Department of Medicine, Manager Research Operations and Development-ORIC, and President One Health Club at Cholistan University of Veterinary and Animal Sciences, Bahawalpur, Pakistan. He has nearly 100 publications to his credit. His research interests include epidemiological patterns and molecular analysis of antimicrobial resistance and modulation and vaccine development against animal pathogens of public health concern.",institutionString:"Cholistan University of Veterinary and Animal Sciences",institution:null},{id:"62900",title:"Prof.",name:"Fethi",middleName:null,surname:"Derbel",slug:"fethi-derbel",fullName:"Fethi Derbel",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/62900/images/system/62900.jpeg",biography:"Professor Fethi Derbel was born in 1960 in Tunisia. He received his medical degree from the Sousse Faculty of Medicine at Sousse, University of Sousse, Tunisia. He completed his surgical residency in General Surgery at the University Hospital Farhat Hached of Sousse and was a member of the Unit of Liver Transplantation in the University of Rennes, France. He then worked in the Department of Surgery at the Sahloul University Hospital in Sousse. Professor Derbel is presently working at the Clinique les Oliviers, Sousse, Tunisia. His hospital activities are mostly concerned with laparoscopic, colorectal, pancreatic, hepatobiliary, and gastric surgery. He is also very interested in hernia surgery and performs ventral hernia repairs and inguinal hernia repairs. He has been a member of the GREPA and Tunisian Hernia Society (THS). During his residency, he managed patients suffering from diabetic foot, and he was very interested in this pathology. For this reason, he decided to coordinate a book project dealing with the diabetic foot. Professor Derbel has published many articles in journals and collaborates intensively with IntechOpen Access Publisher as an editor.",institutionString:"Clinique les Oliviers",institution:null},{id:"300144",title:"Dr.",name:"Meriem",middleName:null,surname:"Braiki",slug:"meriem-braiki",fullName:"Meriem Braiki",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/300144/images/system/300144.jpg",biography:"Dr. Meriem Braiki is a specialist in pediatric surgeon from Tunisia. She was born in 1985. She received her medical degree from the University of Medicine at Sousse, Tunisia. She achieved her surgical residency training periods in Pediatric Surgery departments at University Hospitals in Monastir, Tunis and France.\r\nShe is currently working at the Pediatric surgery department, Sidi Bouzid Hospital, Tunisia. Her hospital activities are mostly concerned with laparoscopic, parietal, urological and digestive surgery. She has published several articles in diffrent journals.",institutionString:"Sidi Bouzid Regional Hospital",institution:null},{id:"229481",title:"Dr.",name:"Erika M.",middleName:"Martins",surname:"de Carvalho",slug:"erika-m.-de-carvalho",fullName:"Erika M. de Carvalho",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/229481/images/6397_n.jpg",biography:null,institutionString:null,institution:{name:"Oswaldo Cruz Foundation",country:{name:"Brazil"}}},{id:"186537",title:"Prof.",name:"Tonay",middleName:null,surname:"Inceboz",slug:"tonay-inceboz",fullName:"Tonay Inceboz",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/186537/images/system/186537.jfif",biography:"I was graduated from Ege University of Medical Faculty (Turkey) in 1988 and completed his Med. PhD degree in Medical Parasitology at the same university. I became an Associate Professor in 2008 and Professor in 2014. I am currently working as a Professor at the Department of Medical Parasitology at Dokuz Eylul University, Izmir, Turkey.\n\nI have given many lectures, presentations in different academic meetings. I have more than 60 articles in peer-reviewed journals, 18 book chapters, 1 book editorship.\n\nMy research interests are Echinococcus granulosus, Echinococcus multilocularis (diagnosis, life cycle, in vitro and in vivo cultivation), and Trichomonas vaginalis (diagnosis, PCR, and in vitro cultivation).",institutionString:"Dokuz Eylül University",institution:{name:"Dokuz Eylül University",country:{name:"Turkey"}}},{id:"71812",title:"Prof.",name:"Hanem Fathy",middleName:"Fathy",surname:"Khater",slug:"hanem-fathy-khater",fullName:"Hanem Fathy Khater",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/71812/images/1167_n.jpg",biography:"Prof. Khater is a Professor of Parasitology at Benha University, Egypt. She studied for her doctoral degree, at the Department of Entomology, College of Agriculture, Food and Natural Resources, University of Missouri, Columbia, USA. She has completed her Ph.D. degrees in Parasitology in Egypt, from where she got the award for “the best scientific Ph.D. dissertation”. She worked at the School of Biological Sciences, Bristol, England, the UK in controlling insects of medical and veterinary importance as a grant from Newton Mosharafa, the British Council. Her research is focused on searching of pesticides against mosquitoes, house flies, lice, green bottle fly, camel nasal botfly, soft and hard ticks, mites, and the diamondback moth as well as control of several parasites using safe and natural materials to avoid drug resistances and environmental contamination.",institutionString:null,institution:{name:"Banha University",country:{name:"Egypt"}}},{id:"99780",title:"Prof.",name:"Omolade",middleName:"Olayinka",surname:"Okwa",slug:"omolade-okwa",fullName:"Omolade Okwa",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/99780/images/system/99780.jpg",biography:"Omolade Olayinka Okwa is presently a Professor of Parasitology at Lagos State University, Nigeria. She has a PhD in Parasitology (1997), an MSc in Cellular Parasitology (1992), and a BSc (Hons) Zoology (1990) all from the University of Ibadan, Nigeria. She teaches parasitology at the undergraduate and postgraduate levels. She was a recipient of a Commonwealth fellowship supported by British Council tenable at the Centre for Entomology and Parasitology (CAEP), Keele University, United Kingdom between 2004 and 2005. She was awarded an Honorary Visiting Research Fellow at the same university from 2005 to 2007. \nShe has been an external examiner to the Department of Veterinary Microbiology and Parasitology, University of Ibadan, MSc programme between 2010 and 2012. She is a member of the Nigerian Society of Experimental Biology (NISEB), Parasitology and Public Health Society of Nigeria (PPSN), Science Association of Nigeria (SAN), Zoological Society of Nigeria (ZSN), and is Vice Chairperson of the Organisation of Women in Science (OWSG), LASU chapter. She served as Head of Department of Zoology and Environmental Biology, Lagos State University from 2007 to 2010 and 2014 to 2016. She is a reviewer for several local and international journals such as Unilag Journal of Science, Libyan Journal of Medicine, Journal of Medicine and Medical Sciences, and Annual Research and Review in Science. \nShe has authored 45 scientific research publications in local and international journals, 8 scientific reviews, 4 books, and 3 book chapters, which includes the books “Malaria Parasites” and “Malaria” which are IntechOpen access publications.",institutionString:"Lagos State University",institution:{name:"Lagos State University",country:{name:"Nigeria"}}},{id:"273100",title:"Dr.",name:"Vijay",middleName:null,surname:"Gayam",slug:"vijay-gayam",fullName:"Vijay Gayam",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/273100/images/system/273100.jpeg",biography:"Dr. Vijay Bhaskar Reddy Gayam is currently practicing as an internist at Interfaith Medical Center in Brooklyn, New York, USA. He is also a Clinical Assistant Professor at the SUNY Downstate University Hospital and Adjunct Professor of Medicine at the American University of Antigua. He is a holder of an M.B.B.S. degree bestowed to him by Osmania Medical College and received his M.D. at Interfaith Medical Center. His career goals thus far have heavily focused on direct patient care, medical education, and clinical research. He currently serves in two leadership capacities; Assistant Program Director of Medicine at Interfaith Medical Center and as a Councilor for the American\r\nFederation for Medical Research. As a true academician and researcher, he has more than 50 papers indexed in international peer-reviewed journals. He has also presented numerous papers in multiple national and international scientific conferences. His areas of research interest include general internal medicine, gastroenterology and hepatology. He serves as an editor, editorial board member and reviewer for multiple international journals. His research on Hepatitis C has been very successful and has led to multiple research awards, including the 'Equity in Prevention and Treatment Award” from the New York Department of Health Viral Hepatitis Symposium (2018) and the 'Presidential Poster Award” awarded to him by the American College of Gastroenterology (2018). He was also awarded 'Outstanding Clinician in General Medicine” by Venus International Foundation for his extensive research expertise and services, perform over and above the standard expected in the advancement of healthcare, patient safety and quality of care.",institutionString:"Interfaith Medical Center",institution:{name:"Interfaith Medical Center",country:{name:"United States of America"}}},{id:"93517",title:"Dr.",name:"Clement",middleName:"Adebajo",surname:"Meseko",slug:"clement-meseko",fullName:"Clement Meseko",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/93517/images/system/93517.jpg",biography:"Dr. Clement Meseko obtained DVM and PhD degree in Veterinary Medicine and Virology respectively. He has worked for over 20 years in both private and public sectors including the academia, contributing to knowledge and control of infectious disease. Through the application of epidemiological skill, classical and molecular virological skills, he investigates viruses of economic and public health importance for the mitigation of the negative impact on people, animal and the environment in the context of Onehealth. \r\nDr. Meseko’s field experience on animal and zoonotic diseases and pathogen dynamics at the human-animal interface over the years shaped his carrier in research and scientific inquiries. He has been part of the investigation of Highly Pathogenic Avian Influenza incursions in sub Saharan Africa and monitors swine Influenza (Pandemic influenza Virus) agro-ecology and potential for interspecies transmission. He has authored and reviewed a number of journal articles and book chapters.",institutionString:"National Veterinary Research Institute",institution:{name:"National Veterinary Research Institute",country:{name:"Nigeria"}}},{id:"158026",title:"Prof.",name:"Shailendra K.",middleName:null,surname:"Saxena",slug:"shailendra-k.-saxena",fullName:"Shailendra K. Saxena",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRET3QAO/Profile_Picture_2022-05-10T10:10:26.jpeg",biography:"Professor Dr. Shailendra K. Saxena is a vice dean and professor at King George's Medical University, Lucknow, India. His research interests involve understanding the molecular mechanisms of host defense during human viral infections and developing new predictive, preventive, and therapeutic strategies for them using Japanese encephalitis virus (JEV), HIV, and emerging viruses as a model via stem cell and cell culture technologies. His research work has been published in various high-impact factor journals (Science, PNAS, Nature Medicine) with a high number of citations. He has received many awards and honors in India and abroad including various Young Scientist Awards, BBSRC India Partnering Award, and Dr. JC Bose National Award of Department of Biotechnology, Min. of Science and Technology, Govt. of India. Dr. Saxena is a fellow of various international societies/academies including the Royal College of Pathologists, United Kingdom; Royal Society of Medicine, London; Royal Society of Biology, United Kingdom; Royal Society of Chemistry, London; and Academy of Translational Medicine Professionals, Austria. He was named a Global Leader in Science by The Scientist. He is also an international opinion leader/expert in vaccination for Japanese encephalitis by IPIC (UK).",institutionString:"King George's Medical University",institution:{name:"King George's Medical University",country:{name:"India"}}},{id:"94928",title:"Dr.",name:"Takuo",middleName:null,surname:"Mizukami",slug:"takuo-mizukami",fullName:"Takuo Mizukami",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/94928/images/6402_n.jpg",biography:null,institutionString:null,institution:{name:"National Institute of Infectious Diseases",country:{name:"Japan"}}},{id:"233433",title:"Dr.",name:"Yulia",middleName:null,surname:"Desheva",slug:"yulia-desheva",fullName:"Yulia Desheva",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/233433/images/system/233433.png",biography:"Dr. Yulia Desheva is a leading researcher at the Institute of Experimental Medicine, St. Petersburg, Russia. She is a professor in the Stomatology Faculty, St. Petersburg State University. She has expertise in the development and evaluation of a wide range of live mucosal vaccines against influenza and bacterial complications. Her research interests include immunity against influenza and COVID-19 and the development of immunization schemes for high-risk individuals.",institutionString:'Federal State Budgetary Scientific Institution "Institute of Experimental Medicine"',institution:null},{id:"238958",title:"Mr.",name:"Atamjit",middleName:null,surname:"Singh",slug:"atamjit-singh",fullName:"Atamjit Singh",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/238958/images/6575_n.jpg",biography:null,institutionString:null,institution:null},{id:"333753",title:"Dr.",name:"Rais",middleName:null,surname:"Ahmed",slug:"rais-ahmed",fullName:"Rais Ahmed",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/333753/images/20168_n.jpg",biography:null,institutionString:null,institution:null},{id:"252058",title:"M.Sc.",name:"Juan",middleName:null,surname:"Sulca",slug:"juan-sulca",fullName:"Juan Sulca",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/252058/images/12834_n.jpg",biography:null,institutionString:null,institution:null},{id:"191392",title:"Dr.",name:"Marimuthu",middleName:null,surname:"Govindarajan",slug:"marimuthu-govindarajan",fullName:"Marimuthu Govindarajan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/191392/images/5828_n.jpg",biography:"Dr. M. Govindarajan completed his BSc degree in Zoology at Government Arts College (Autonomous), Kumbakonam, and MSc, MPhil, and PhD degrees at Annamalai University, Annamalai Nagar, Tamil Nadu, India. He is serving as an assistant professor at the Department of Zoology, Annamalai University. His research interests include isolation, identification, and characterization of biologically active molecules from plants and microbes. He has identified more than 20 pure compounds with high mosquitocidal activity and also conducted high-quality research on photochemistry and nanosynthesis. He has published more than 150 studies in journals with impact factor and 2 books in Lambert Academic Publishing, Germany. He serves as an editorial board member in various national and international scientific journals.",institutionString:null,institution:null},{id:"274660",title:"Dr.",name:"Damodar",middleName:null,surname:"Paudel",slug:"damodar-paudel",fullName:"Damodar Paudel",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/274660/images/8176_n.jpg",biography:"I am DrDamodar Paudel,currently working as consultant Physician in Nepal police Hospital.",institutionString:null,institution:null},{id:"241562",title:"Dr.",name:"Melvin",middleName:null,surname:"Sanicas",slug:"melvin-sanicas",fullName:"Melvin Sanicas",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/241562/images/6699_n.jpg",biography:null,institutionString:null,institution:null},{id:"337446",title:"Dr.",name:"Maria",middleName:null,surname:"Zavala-Colon",slug:"maria-zavala-colon",fullName:"Maria Zavala-Colon",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Puerto Rico, Medical Sciences Campus",country:{name:"United States of America"}}},{id:"338856",title:"Mrs.",name:"Nur Alvira",middleName:null,surname:"Pascawati",slug:"nur-alvira-pascawati",fullName:"Nur Alvira Pascawati",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Universitas Respati Yogyakarta",country:{name:"Indonesia"}}},{id:"441116",title:"Dr.",name:"Jovanka M.",middleName:null,surname:"Voyich",slug:"jovanka-m.-voyich",fullName:"Jovanka M. Voyich",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Montana State University",country:{name:"United States of America"}}},{id:"330412",title:"Dr.",name:"Muhammad",middleName:null,surname:"Farhab",slug:"muhammad-farhab",fullName:"Muhammad Farhab",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Agriculture Faisalabad",country:{name:"Pakistan"}}},{id:"349495",title:"Dr.",name:"Muhammad",middleName:null,surname:"Ijaz",slug:"muhammad-ijaz",fullName:"Muhammad Ijaz",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Veterinary and Animal Sciences",country:{name:"Pakistan"}}}]}},subseries:{item:{id:"95",type:"subseries",title:"Urban Planning and Environmental Management",keywords:"Circular economy, Contingency planning and response to disasters, Ecosystem services, Integrated urban water management, Nature-based solutions, Sustainable urban development, Urban green spaces",scope:"