Average physicochemical composition of the different types of olive mill effluents [23, 24, 25, 26, 27, 28].
\\n\\n
\\n"}]',published:!0,mainMedia:{caption:"Milestone",originalUrl:"/media/original/124"}},components:[{type:"htmlEditorComponent",content:'
Barely three months into the new year and we are happy to announce a monumental milestone reached - 150 million downloads.
\n\nThis achievement solidifies IntechOpen’s place as a pioneer in Open Access publishing and the home to some of the most relevant scientific research available through Open Access.
\n\nWe are so proud to have worked with so many bright minds throughout the years who have helped us spread knowledge through the power of Open Access and we look forward to continuing to support some of the greatest thinkers of our day.
\n\nThank you for making IntechOpen your place of learning, sharing, and discovery, and here’s to 150 million more!
\n\n\n\n\n'}],latestNews:[{slug:"intechopen-supports-asapbio-s-new-initiative-publish-your-reviews-20220729",title:"IntechOpen Supports ASAPbio’s New Initiative Publish Your Reviews"},{slug:"webinar-introduction-to-open-science-wednesday-18-may-1-pm-cest-20220518",title:"Webinar: Introduction to Open Science | Wednesday 18 May, 1 PM CEST"},{slug:"step-in-the-right-direction-intechopen-launches-a-portfolio-of-open-science-journals-20220414",title:"Step in the Right Direction: IntechOpen Launches a Portfolio of Open Science Journals"},{slug:"let-s-meet-at-london-book-fair-5-7-april-2022-olympia-london-20220321",title:"Let’s meet at London Book Fair, 5-7 April 2022, Olympia London"},{slug:"50-books-published-as-part-of-intechopen-and-knowledge-unlatched-ku-collaboration-20220316",title:"50 Books published as part of IntechOpen and Knowledge Unlatched (KU) Collaboration"},{slug:"intechopen-joins-the-united-nations-sustainable-development-goals-publishers-compact-20221702",title:"IntechOpen joins the United Nations Sustainable Development Goals Publishers Compact"},{slug:"intechopen-signs-exclusive-representation-agreement-with-lsr-libros-servicios-y-representaciones-s-a-de-c-v-20211123",title:"IntechOpen Signs Exclusive Representation Agreement with LSR Libros Servicios y Representaciones S.A. de C.V"},{slug:"intechopen-expands-partnership-with-research4life-20211110",title:"IntechOpen Expands Partnership with Research4Life"}]},book:{item:{type:"book",id:"5916",leadTitle:null,fullTitle:"Dermatologic Surgery and Procedures",title:"Dermatologic Surgery and Procedures",subtitle:null,reviewType:"peer-reviewed",abstract:"This book is intended for dermatologists, skin surgeons, and general practitioners who are interested in skin surgery and cosmetic procedures. The topics of broad and current interest in shaping the practice nowadays have been selected by the editor, Dr. Pierre Vereecken, MD, PhD, allowing the reader to expand his/her skills and surgical techniques. This book aims to meet the need for a practical guide to help the clinicians to extend their offer in daily practice in dermatology and corrective and skin cancer surgery.",isbn:"978-953-51-3852-5",printIsbn:"978-953-51-3851-8",pdfIsbn:"978-953-51-3995-9",doi:"10.5772/66008",price:119,priceEur:129,priceUsd:155,slug:"dermatologic-surgery-and-procedures",numberOfPages:234,isOpenForSubmission:!1,isInWos:null,isInBkci:!1,hash:"4db72fff153d0878ec21a7e7b71515d8",bookSignature:"Pierre Vereecken",publishedDate:"February 28th 2018",coverURL:"https://cdn.intechopen.com/books/images_new/5916.jpg",numberOfDownloads:16298,numberOfWosCitations:4,numberOfCrossrefCitations:6,numberOfCrossrefCitationsByBook:0,numberOfDimensionsCitations:10,numberOfDimensionsCitationsByBook:0,hasAltmetrics:0,numberOfTotalCitations:20,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"December 7th 2016",dateEndSecondStepPublish:"December 21st 2016",dateEndThirdStepPublish:"September 16th 2017",dateEndFourthStepPublish:"October 16th 2017",dateEndFifthStepPublish:"December 16th 2017",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6",editedByType:"Edited by",kuFlag:!1,featuredMarkup:null,editors:[{id:"157965",title:"Dr.",name:"Pierre",middleName:null,surname:"Vereecken",slug:"pierre-vereecken",fullName:"Pierre Vereecken",profilePictureURL:"https://mts.intechopen.com/storage/users/157965/images/system/157965.jpg",biography:"Dr. Pierre Vereecken, MD, PhD, is a Doctor of Medicine graduate and is certified and specialized in dermatology (general, aesthetic, and corrective) and skin oncology. He studied medicine in Brussels, Belgium (1991, ULB), and obtained his PhD degree from the same university in 2008, with a research work on the topic of cutaneous malignant melanoma biology and progression. After working for the Belgian Army (Belgium, Germany) and the United Nations Protection Force (Central Bosnia), he was the head of the Department of Dermatology in academic hospitals (Brugmann University Public Hospital, Belgium, and Saint-Luc University U.C.L. Hospital, Belgium). He is convinced that knowledge has to be shared with not only colleagues, specialists, or GPs but also nurses for the best care of our patients. He also emphasizes the need for a better communication of medical information with patients. In 2010, he decided to dedicate his own practice to patients and research and to build an international dermatologic network, Cliderm. He also founded the European Institute for Dermatological Practice and Research, a multifaceted organization that aims to promote clinical dermatology and dermatological research in the European Union. He has published more than 100 scientific papers in international medical literature and also edited and authored chapters for more than 20 books.",institutionString:"CLIDERM (Clinics in Dermatology)",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"2",institution:null}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"1398",title:"Dermatopathology",slug:"dermatopathology"}],chapters:[{id:"58693",title:"Local Anesthesia",doi:"10.5772/intechopen.72930",slug:"local-anesthesia",totalDownloads:1266,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Local anesthesia is a routine procedure in dermatological practice. This chapter deals with the basic principles of pharmacology and pharmacodynamics related to the most commonly used anesthetics in dermatology as well as its side effects, the most common anesthetic solutions, anesthesia techniques, and topical anesthesia.",signatures:"Caio Lamunier de Abreu Camargo",downloadPdfUrl:"/chapter/pdf-download/58693",previewPdfUrl:"/chapter/pdf-preview/58693",authors:[{id:"219137",title:"M.D.",name:"Caio",surname:"Camargo",slug:"caio-camargo",fullName:"Caio Camargo"}],corrections:null},{id:"56603",title:"Cryotherapy for Common Premalignant and Malignant Skin Disorders",doi:"10.5772/intechopen.70286",slug:"cryotherapy-for-common-premalignant-and-malignant-skin-disorders",totalDownloads:1500,totalCrossrefCites:0,totalDimensionsCites:1,hasAltmetrics:0,abstract:"Cryotherapy, also known as cryosurgery or cryoablation, is a common dermatological treatment that is an expanded area from benign to malignant lesions. The system has been designed as a localized freezing cold that causes the destruction of cell integrity. The treatment has been also used for all ages, which is not required to have a condition of wellness. It is convenient, fast, and easy to apply in clinics, and there is no need for anesthesia. Additionally, multiple lesions are also cured in the same sessions. After the treatment, recovery period has not taken much longer and also has simple adverse effects, which are tolerable. Lastly, cryotherapy has gained excellent cosmetic results. It is highly effective for actinic keratosis and is the treatment of choice for most old patients who show poor cooperation and recurrent multiple lesions. Additionally, due to increasing premalignant lesions all over the world associated with increasing age, it is a considerable choice for lentigo maligna and Bowen’s disease. In non-melanoma skin cancers, it is also the most important option in patients who do not undergo surgery and when other options are not appropriate. In this chapter, the use of cryotherapy for premalignant and malignant cutaneous disorders has been mainly focused.",signatures:"Sevgi Akarsu and Isil Kamberoglu",downloadPdfUrl:"/chapter/pdf-download/56603",previewPdfUrl:"/chapter/pdf-preview/56603",authors:[{id:"182444",title:"Prof.",name:"Sevgi",surname:"Akarsu",slug:"sevgi-akarsu",fullName:"Sevgi Akarsu"},{id:"194631",title:"Dr.",name:"Işıl",surname:"Kamberoğlu Turan",slug:"isil-kamberoglu-turan",fullName:"Işıl Kamberoğlu Turan"}],corrections:null},{id:"57105",title:"Application of Cryogenic Methods in Skin Diseases of Different Etiology",doi:"10.5772/intechopen.70509",slug:"application-of-cryogenic-methods-in-skin-diseases-of-different-etiology",totalDownloads:1599,totalCrossrefCites:2,totalDimensionsCites:2,hasAltmetrics:0,abstract:"The modern demand for effective treatment options in dermatology was successfully addressed by the invention of cryogenic method. By 2009, Dr. V.I. Kochenov had developed and patented cryogenic set of instruments based on 30 years of his personal clinical experience. The set includes a number of instruments, which could be used independently. It allows implementing a wide range of therapeutic and surgical procedures and has no commercially available alternatives. The main applications of the set include cryogenic revitalization, and treatment for such common dermatological ailments as psoriasis, warts, acne, hypertrophic scars, purulent diseases of the skin and subcutaneous fat, epithelial cysts, skin hemangiomas, precancerous skin lesions, and even malignant melanoma of the skin. A brief overview of etiology, classification and pathogenesis of these maladies is presented alongside with the step-by-step guidelines to cryo-exposure procedures. Not only guidelines but also comprehensive theoretical and practical training is provided to physicians at the center which was established at Nizhny Novgorod State Medical Academy. Physicians at Scientific Clinical Center of Medical Cryology “OnKolor” have been using the set, which proved to be effective even in the most difficult and otherwise costly cases. The procedures that have pronounced cosmetic effect, leaves no scars and dark spots.",signatures:"Tatyana Gennadyevna Kotova, Sergei Nikolaevich Tsybusov,\nVladimir Ivanovich Kochenov and Maksim Igorevich Tcyganov",downloadPdfUrl:"/chapter/pdf-download/57105",previewPdfUrl:"/chapter/pdf-preview/57105",authors:[{id:"203916",title:"Ph.D.",name:"Tatyana",surname:"Kotova",slug:"tatyana-kotova",fullName:"Tatyana Kotova"},{id:"219207",title:"Dr.",name:"Sergei Nikolaevich",surname:"Tsybusov",slug:"sergei-nikolaevich-tsybusov",fullName:"Sergei Nikolaevich Tsybusov"},{id:"219208",title:"Dr.",name:"Vladimir Ivanovich",surname:"Kochenov",slug:"vladimir-ivanovich-kochenov",fullName:"Vladimir Ivanovich Kochenov"}],corrections:null},{id:"58133",title:"Simultaneous Excisions and Extemporary Skin Plastics: New Reconstructive Techniques after Tumor Surgery",doi:"10.5772/intechopen.71691",slug:"simultaneous-excisions-and-extemporary-skin-plastics-new-reconstructive-techniques-after-tumor-surge",totalDownloads:1063,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Occurrence of two or more skin tumors closely situated to each other is not so rare in clinical dermasurgical practice. Excision of multiple contiguous skin lesions can represent a major dermasurgical problem that can be solved in different surgical times. However, in our opinion, the best therapeutic solution is to carry out the removal in a single surgical session; this choice allows saving time, an easier plastic reconstruction, and better esthetic results. Many different reconstructive procedures can be designed and applied, to achieve the best result. The simplest Burow’s triangle flap permits excision of two contiguous lesions with less tension compared to two fusiform cuts, but many other plastic solutions can be chosen to satisfy the needs of different anatomical sites and according to skin features. In the author’s personal experience, of about 8000 patients who have undergone dermatologic surgery over the past 20 years, the presence of multiple contiguous lesions occurred in about 200 cases. In all of these, triangle, rotation, advancement, or transposition flaps allowed simultaneous removals, saving time and money and giving better esthetic results compared to multiple direct excision carried out at successive times. In this chapter, the different techniques are described and illustrated in detail.",signatures:"Paolo Boggio, Benedetta Miglino, Federica Veronese, Rossana\nTiberio and Paola Savoia",downloadPdfUrl:"/chapter/pdf-download/58133",previewPdfUrl:"/chapter/pdf-preview/58133",authors:[{id:"34125",title:"Dr.",name:"Paola",surname:"Savoia",slug:"paola-savoia",fullName:"Paola Savoia"},{id:"219854",title:"Dr.",name:"Paolo",surname:"Boggio",slug:"paolo-boggio",fullName:"Paolo Boggio"},{id:"219855",title:"Dr.",name:"Benedetta",surname:"Miglino",slug:"benedetta-miglino",fullName:"Benedetta Miglino"},{id:"223433",title:"Dr.",name:"Rossana",surname:"Tiberio",slug:"rossana-tiberio",fullName:"Rossana Tiberio"},{id:"223434",title:"Dr.",name:"Federica",surname:"Veronese",slug:"federica-veronese",fullName:"Federica Veronese"}],corrections:null},{id:"56876",title:"Mohs Micrographic Surgery",doi:"10.5772/intechopen.70285",slug:"mohs-micrographic-surgery",totalDownloads:1370,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Mohs micrographic surgery (MMS) is used to obtain clear margins in skin cancer treatment. MMS involves staged excisions and complete margin assessment of the specimen from fresh tissue frozen sectioning. It has been shown to achieve higher cure rates with malignancies, including basal cell carcinoma (BCC), squamous cell carcinoma (SCC), lentigo maligna, melanoma in situ and dermatofibrosarcoma protuberans. This technique is especially useful in face, feet and hand regions to avoid cosmetic deformities.",signatures:"Merdan Serin",downloadPdfUrl:"/chapter/pdf-download/56876",previewPdfUrl:"/chapter/pdf-preview/56876",authors:[{id:"199977",title:"Dr.",name:"Merdan",surname:"Serin",slug:"merdan-serin",fullName:"Merdan Serin"}],corrections:null},{id:"58016",title:"CO2 Laser-Assisted Otoplasty: A New Dermatosurgical Procedure",doi:"10.5772/intechopen.71992",slug:"co2-laser-assisted-otoplasty-a-new-dermatosurgical-procedure",totalDownloads:1391,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Otoplasty is the surgical procedure characteristically performed to improve the appearance of unpleasant, protruding auricles. An incision in the back of the ear with or without excision of cartilage is the usual approach. A novel technique performed with CO2 laser is presented. The objective of CO2 laser-assisted otoplasty is to decrease the mastoid-scapha angle up to approximately 30°; also, the conchal-scapha angle should be reduced to its usual of approximately 90°. The aims of this procedure are to restructure the scapha and the antihelix fold, to diminish the size of the concha (hinge effect), and to relocate the reshaped ear closer to the head in esthetically desired angles, not only horizontally (lateral angle), but also (and of extreme importance for most patients) vertically (superior angle).",signatures:"Hector Leal Silva",downloadPdfUrl:"/chapter/pdf-download/58016",previewPdfUrl:"/chapter/pdf-preview/58016",authors:[{id:"204525",title:"Dr.",name:"Hector",surname:"Leal Silva",slug:"hector-leal-silva",fullName:"Hector Leal Silva"}],corrections:null},{id:"57073",title:"Photodynamic Therapy and Skin Cancer",doi:"10.5772/intechopen.70309",slug:"photodynamic-therapy-and-skin-cancer",totalDownloads:1511,totalCrossrefCites:3,totalDimensionsCites:4,hasAltmetrics:0,abstract:"Non-melanoma skin cancer (NMSC) is the most common type of cancer among white skin individuals worldwide with an increasing incidence over the last years. NMSC is mostly treated with surgical or non-invasive methods such as cryotherapy or topical chemotherapeutics. Over the last years, there has been a rapidly growing interest in the use of photodynamic therapy (PDT) which is a well-tolerated, safe and effective alternative treatment option. PDT involves a photosensitizer, a light source and tissue oxygen and is based on a photo-oxidation reaction in the target tissue which results to a selective destruction of the cancer cells. PDT has been approved for treatment of actinic keratosis, Bowen’s disease and basal cell carcinoma in Europe. Off-label uses include treatment of invasive squamous cell carcinoma, cutaneous T-cell lymphoma, Kaposi’s sarcoma, Paget’s disease and prevention of recurrence of squamous cell carcinoma in organ-transplant recipients. Also combination of PDT with other treatment options such as cryotherapy, surgery and topical therapies has been reported with improved efficacy, tolerability and long-term results. Development of novel photosensitizers and light sources together with targeted delivery systems will increase specificity, efficiency and treatment field of PDT in the future. This chapter aims to give the reader an overview of the important applications of PDT, including indications, approved treatments, advantages and disadvantages of this method such as future trends.",signatures:"Eleni Papakonstantinou, Florian Löhr and Ulrike Raap",downloadPdfUrl:"/chapter/pdf-download/57073",previewPdfUrl:"/chapter/pdf-preview/57073",authors:[{id:"203520",title:"Dr.",name:"Eleni",surname:"Papakonstantinou",slug:"eleni-papakonstantinou",fullName:"Eleni Papakonstantinou"},{id:"203630",title:"Dr.",name:"Ulrike",surname:"Raap",slug:"ulrike-raap",fullName:"Ulrike Raap"},{id:"205792",title:"M.D.",name:"Florian",surname:"Löhr",slug:"florian-lohr",fullName:"Florian Löhr"}],corrections:null},{id:"57377",title:"Advanced Technologies in Dermatology",doi:"10.5772/intechopen.70288",slug:"advanced-technologies-in-dermatology",totalDownloads:1535,totalCrossrefCites:1,totalDimensionsCites:1,hasAltmetrics:0,abstract:"Cellular therapies are an attractive area of regenerative medicine. For large partial thickness wound, keratinocytes transplant is suggested. The transplantation of cell graft is achieved by obtaining large amounts of cultured cells from a skin biopsy in 3 weeks. Stem cells can be applied before that, but are also efficient in chronic wound closure. Alternative treatment methods are transplants of allogeneic, biostatic skin and amnion. Amnion can be applied as a skin substitute on shallow facialburn wounds, hand burn wounds, on donor areas and granulating wounds. For medium depth or even deep burns, allogeneic skin is recommended. Thanks to the removing of cells from human allogeneic dermis, collagen scaffolding is obtained. It can be populated de novo by autologous skin cells. Artificial skin substitutes are especially good for hand burns and shallow burns. Even though scarring is a part of normal wound healing, it often leads to a pathological process. When scar treatment methods prove insufficient, surgical intervention becomes necessary. Surgical scar intervention involves removal of the pathological skin tissue fragment and replacing it with healthy skin or application of expanders. Improvement of the visual features can be also achieved by laser therapy.",signatures:"Diana Kitala, Agnieszka Klama-Baryła, Wojciech Łabuś, Marcelina\nMisiuga, Mariusz Nowak and Marek Kawecki",downloadPdfUrl:"/chapter/pdf-download/57377",previewPdfUrl:"/chapter/pdf-preview/57377",authors:[{id:"203598",title:"Ph.D.",name:"Diana",surname:"Kitala",slug:"diana-kitala",fullName:"Diana Kitala"},{id:"204300",title:"Dr.",name:"Agnieszka",surname:"Klama-Baryła",slug:"agnieszka-klama-baryla",fullName:"Agnieszka Klama-Baryła"},{id:"204301",title:"Dr.",name:"Wojciech",surname:"Łabuś",slug:"wojciech-labus",fullName:"Wojciech Łabuś"},{id:"204302",title:"MSc.",name:"Marcelina",surname:"Misiuga",slug:"marcelina-misiuga",fullName:"Marcelina Misiuga"},{id:"204303",title:"Dr.",name:"Mariusz",surname:"Nowak",slug:"mariusz-nowak",fullName:"Mariusz Nowak"},{id:"204304",title:"Prof.",name:"Marek",surname:"Kawecki",slug:"marek-kawecki",fullName:"Marek Kawecki"}],corrections:null},{id:"57503",title:"Treatment of Skin Laxity Using Multisource, Phase-Controlled Radiofrequency",doi:"10.5772/intechopen.71749",slug:"treatment-of-skin-laxity-using-multisource-phase-controlled-radiofrequency",totalDownloads:1498,totalCrossrefCites:0,totalDimensionsCites:2,hasAltmetrics:1,abstract:"Regardless of age, sex and skin type, skin tightening is a common procedure requested by patients seeking cosmetic treatments to improve facial contours and skin laxity. Radiofrequency has been proven to penetrate deeper than optical light sources independent of skin color and to be beneficial for skin tightening. I previously reported on the efficacy of multisource phase-controlled radiofrequency treatment and noninsulated microneedle radiofrequency applicator with fractionated pulse mode. The evaluation process was both subjective and objective; I evaluated objectively using three-dimensional color schematic representation with quantitative volume measurements. These three-dimensional results showed significant improvement after the treatments. The post-treatment volume was drastically reduced as compared to the pretreatment volume. Most of the patients reported satisfaction with the improvement of skin laxity. The advantages of these multisource phase-controlled radiofrequency treatments are their long-lasting high efficacy of tightening effects, and the reduction of discomfort and side effects. These characteristics facilitate repeated treatments as well as provide safe and effective treatment of skin tightening.",signatures:"Yohei Tanaka",downloadPdfUrl:"/chapter/pdf-download/57503",previewPdfUrl:"/chapter/pdf-preview/57503",authors:[{id:"36633",title:"Dr.",name:"Yohei",surname:"Tanaka",slug:"yohei-tanaka",fullName:"Yohei Tanaka"}],corrections:null},{id:"56688",title:"The Wonder Tool Platelet Rich Plasma in Cosmetic Dermatology, Trichology and Hair Transplant",doi:"10.5772/intechopen.70287",slug:"the-wonder-tool-platelet-rich-plasma-in-cosmetic-dermatology-trichology-and-hair-transplant",totalDownloads:2350,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Platelet-rich plasma or PRP therapy is a form of regenerative medicine where body’s own cells, tissues or organs can be utilized by replacing, regenerating or engineering to restore or establish normal function. Various published articles demonstrating the role of PRP therapy in cosmetic procedures like scar revision, facial rejuvenation, stretch mark removal, androgenetic alopecia, alopecia areata and hair transplant were analyzed in depth to understand its efficacy based on facts and figures along with inputs from personal experience. PRP therapy is one of the most upcoming forms of regenerative medicine with the potential to improve the homeostasis of the treated cells and tissues, provided that harvesting standards are maintained.",signatures:"Garg Suruchi, Manchanda Shweta and Garg Chandi",downloadPdfUrl:"/chapter/pdf-download/56688",previewPdfUrl:"/chapter/pdf-preview/56688",authors:[{id:"203666",title:"Dr.",name:"Suruchi",surname:"Garg",slug:"suruchi-garg",fullName:"Suruchi Garg"},{id:"207637",title:"Dr.",name:"Shweta",surname:"Manchanda",slug:"shweta-manchanda",fullName:"Shweta Manchanda"},{id:"207639",title:"Dr.",name:"Chandi",surname:"Garg",slug:"chandi-garg",fullName:"Chandi Garg"}],corrections:null},{id:"57681",title:"Oral Naturally Derived Agents as an Adjuvant Photoprotection after Dermatologic Surgery",doi:"10.5772/intechopen.71750",slug:"oral-naturally-derived-agents-as-an-adjuvant-photoprotection-after-dermatologic-surgery",totalDownloads:1216,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"To be effective in protecting against the harmful effects of ultraviolet radiation (UVR), many photoprotective strategies have been used. Inadequate physical protection, amount of topical application, and allergic reactions to topical agents are limitations associated with current photoprotective strategies. Systemic agents are an emerging alternative, providing promising protection against UVR. This chapter will thoroughly review photoprotective outcomes of oral naturally derived agents from randomized controlled trials using evidence-based method. From total 24 clinical trials with 850 participants, two categories of naturally derived agents were identified. Plant-derived agents include beta-carotene, green tea, golden serpent fern, tomato, cocoa bean, and vitamin E, whereas animal-derived products consist of nicotinamide and omega-3 polyunsaturated fatty acids. 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In the last decades, new advanced separation technologies, less intensive in terms of specific energy consumption than conventional separation ones and “greener” regarding the minor use of chemicals and reagents to achieve the desired separation, have been developed. Concretely, membrane technology can take the lead for these purposes.
In the current scenario, scarcity of water particularly concerns agricultural irrigation, which demands more than 70% of worldwide water consumption [1]. Nevertheless, wastewater regeneration for several purposes such as irrigation stands as a solution to reduce environmental and economic impacts.
Besides, due to population increase, food production has become a major concern worldwide. Food industries are quickly multiplying all over the world because of globalization of markets and the lifting of trade barriers, thus contributing to the large-scale manufacture of a vast range of food and beverage products. Consequently, the high volumes produced, environmental impact, and nutritional value of its by-products/wastes are an enormous challenge that the food industry is facing, with the goal of valorization.
Membrane technology is modular and scalable, is environmentally friendly, requires low maintenance, and can provide high purifying standards [2, 3, 4]. In the last years, there has been a significant trend in the use of membranes for a wide range of applications, and particularly in the field of water and wastewater treatments to replace classic separation unit operations, as well as for the reclamation of effluents of different origins, especially those by-produced in agro-industries.This impulse has been a result of the new membrane materials, module designs, and the optimization of the operating conditions, in specific those for minimization of fouling [2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12].
Concretely, nanofiltration (NF) provides a series of advantages over classic separation processes. For example, for clean water production, NF technology has been replacing or working alongside reverse osmosis in water treatment processes for clean water production (e.g., desalination of brackish water and seawater) and for wastewater treatment (e.g., textile, pulp and paper, pharmaceutical, and agro-industrial) due to the cost-benefit analysis of lower-pressure operations. The specific selectivity toward small solutes and the lower energy consumption of NF membranes have enhanced their use. By contrast, in the food industry, the use of nanofiltration is too low, despite this sector has been the first one to introduce membrane technology in dairies, especially to recover cheese whey. Membrane processes that have been predominantly used are microfiltration and ultrafiltration, e.g., for removal of bacteria or to produce whey protein concentrates from ultrafiltration [13]. So, while research about using nanofiltration for by-products recovery from agro-food industry is increasing, real applications are still very low [14]. Some drawbacks must be inevitably faced when NF is applied on an industrial scale. The main drawback is fouling that reduces the production capacity of the plant and shortens the membrane service lifetime if of irreversible nature, thus increasing the operating and capital costs. Moreover, fouling alters the selectivity of the membrane and thus the rejection efficiency.
This chapter focuses the use of NF for the treatment/valorization of different agro-industrial effluents or by-products, mainly dairy, tomato, artichoke, and olive oil, and addresses membrane fouling as the main drawback against NF competitiveness.
Among agro-industrial effluents, olive mill wastewater (OMW), generated during the production of olive oil in factories commonly known as “mills,” is one of the most heavily polluted wastewater, depending on the procedure used, reaching chemical oxygen demand (COD) values up to 100,000 mg O2 L−1. The volumes of these effluents have increased in the last decades due to the marked increment of olive oil consumption worldwide given its well-proven health-promoting properties (nutritional, antioxidant, anti-inflammatory, cosmetic). This fact led to the change in the extraction technology from batch to continuous production procedures as a response to cope with this higher demand. Currently, average-sized modern olive oil mills generate several tens of cubic meters of OMW daily, which sums up several millions of cubic meters a year.
The same applies to other agro-industrial effluents like tomato and artichoke ones. Moreover, one critical aspect in the treatment management of these types of agro-industrial effluents relies on the high variability in volume and organic load, as well as on the seasonality of by-production. This poses an additional handicap to find efficient treatments focused on this type of effluents.
Otherwise, in dairies, NF has been mostly used for the demineralization of salted and acid whey, substituting reverse osmosis, or to produce desalted lactose-containing whey in a single process. The performance of NF is mainly affected by concentration polarization due to an accumulation of solutes at the membrane surface and, simultaneously, to the increase of osmotic pressure, which reduces the effective transmembrane pressure. The resulting boundary layer is usually the reversible part of NF fouling, in which its characteristics are related to the wall shear stress and the driving force (average transmembrane pressure). Besides, that boundary layer can give rise to irreversible adsorption or precipitation of foulants, namely, calcium phosphates, at the membrane surface [15]. The mineral fouling depends on environmental conditions, such as pH and temperature, and should be controlled during NF process. The prevention and control of fouling in NF of dairy or other products can be done through selection of an adequate feed pretreatment, choice of membrane and module design, and optimizing operating conditions.
Wastewater by-produced during tomato manufacturing is characterized by a dark color and bad odor and presents a considerable concentration in organic compounds, suspended solids, and ground particles [16, 17]. This process water, generated during cleaning, sorting, and moving of tomatoes, constitutes the main tomato industry wastewater and deteriorates very quickly. An additional difficulty for the treatment of these effluents, as previously said, relies on the variability in time and space of composition and pollutant concentration, as it is very seasonal, and depends on the geographical zone, type of fruit, composition, as well as changes in the production, among others. The typical composition of this wastewater, reported by Iaquinta and co-workers [18], is pH around 6.6, high electrical conductivity (2.56 mS cm−1), relatively high COD (1200–1700 mg O2 L−1), and total organic carbon (TOC; 340 mg L−1).
Because of this, tomato manufacturing wastewater cannot be discharged straight in municipal sewage systems, as the high organic content exceeds legal limit standards. Thereby, the treatment of these effluents is needed beforehand. In this framework, Iaquinta and co-workers proposed a combined treatment process comprising a biological treatment followed by NF, at a pilot scale [16, 17]. The used NF membrane was a commercial spiral-wound module (Desal-5 membrane, model DK2540, produced and supplied by Osmonics). NF process optimization was carried out relying on critical flux methods, in order to avoid operating at fouling conditions. Within critical flux conditions, short-term fouling phenomena are drastically reduced, and, consequently, the productivity and the longevity of the membranes are significantly increased. Critical fluxes were measured at different recovery levels. The authors reported purification of the wastewater up to a water compatible with municipal sewer system requirements, with a recovery rate of 90%. A permeate stream with EC of 1778 μS cm−1, COD of 465 mg O2 L−1, and TOC of 168 mg L−1 was attained, and short-term fouling issues could be avoided by operating the system at permeate fluxes about or below 8.2 L hm−2. Moreover, the process was modeled, which permitted the prediction of a final critical flux value equal to 10.1 L hm−2. On the other hand, the authors also prepared a synthetic effluent, by adding mature tomatoes to tap water in a ratio equal to 1:20 and 1:1000, respectively. An analysis performed on the synthetic wastewater confirmed similar chemical characteristics, in line with the real ones. Furthermore, a similar fouling behavior was found for the NF membrane.
Artichoke is cultivated for its immature inflorescence, in which the head flower composes the edible portion. The main producers are Egypt, Italy, and Spain. It is widely consumed as fresh, frozen, or conserved vegetable [18]. Given that just a small part of this vegetable (around 30%) is used in the food industry, artichoke processing generates a huge amount of solid waste (mainly leaves, stems, bracts of the artichoke plant) that is used as animal feedstuff or manure [19] and wastewaters, such as blanching waters, that need to be managed. Nowadays, attempts have been made to reuse waste solid material as a source of health-promoting compounds, leading to improved management of industrial residues and economic benefits for the agricultural and food sector [20, 21].
Artichoke wastewater is the extract from artichoke solid waste. This material contains suspended solids, macromolecules, and prebiotic sugars [18], and it is considered a cheap source of fructo-oligosaccharides. Machado et al. [18] examined the clarification, purification, and concentration of artichoke extract by sequential microfiltration (MF)—aimed to clarify the artichoke extract—followed by NF, to purify and concentrate the prebiotic sugars. The study was performed on a laboratory scale and tested different MF and NF membranes as well as different operation pressures. MF pretreatment achieved total clarification of the extract; that is, 100% prebiotic sugars were reported to be recovered in permeate stream. However, MF membranes presented a certain flux decline (20–40% with respect to the initial values) that the authors attributed to cake layer formation as observed by surface analysis.
Subsequent NF was performed with the permeate of the less fouled MF membrane (polyethersulfone (PES), 50 μm pore size). Three NF membranes were tested for this purpose, that is, NP010 (Microdyn-Nadir, PES, 1 kDa molecular weight cutoff (MWCO)), NP030 (Microdyn-Nadir, PES, 400 Da MWCO), and NF270 (Dow, polyamide, 150–300 Da MWCO). Total retention of prebiotic sugar was achieved with the latter membrane, allowing the obtention of a concentrate pool rich in these compounds, with functional prebiotic properties, which according to the authors could be used as ingredient on foodstuff applications. Nevertheless, the authors pointed that for obtaining a high degree of purification other techniques should be further or alternatively employed.
Moreover, this NF membrane (NF270) was reported to yield a high flux (up to 120 L h−1 m−2), as well as the highest retention toward the target species. As reported by the authors, even though NP010 and NP030 membranes present higher MWCO, their filtration fluxes under the given operational conditions were below those yielded by NF270. The former membranes are made of polyethersulfone, which has lower affinity with water than polyamide, the material of which NF270 membrane is made of, and thus lower permeate fluxes were observed.
Another proposal for artichoke wastewater treatment and fractionation was examined recently by Conidi and co-workers [22]. They reported the results of an integrated ultrafiltration (UF) and NF membrane process, at a lab scale. An evaluation of the used membranes was made based on the permeate flux, fouling index and water permeability recovery. Typical chemical composition of artichoke wastewaters reported by these authors is here presented: suspended solids 2.5 ± 0.10 (%), glucose 960 ± 1(mg L−1), fructose 837 ± 1.07 (mg L−1), sucrose 1050 ± 0.41 (mg L−1),total antioxidant activity 8 ± 0.042 (TAA, mM Trolox), chlorogenic acid 251 ± 2.64 (mg L−1), cynarine 164.7 ± 1.41 (mg L−1), and apigenin-7-O-glucoside 101 ± 2 (mg L−1). On the one hand, the used UF membranes were hollow fiber ones and aimed to remove suspended solids from the artichoke extract, to submit the clarified liquor to the NF step. This preliminary UF clarification step permitted the rejection of most suspended solids in the raw water stream. The initial permeate flux was reported to decrease during the UF process by increasing the volume recovery factor (VRF) due to concentration polarization, fouling phenomena, and increased concentration of solutes in the retentate, such that a steady-state permeate flux of 10 kg hm−2 was obtained at VRF of 3. Moreover, it is important to highlight that the initial water permeability of the UF membrane could not be completely recovered after the applied cleaning protocol, which comprised two cleaning steps with alkaline (NaOH) and enzymatic solutions: the NaOH solution cleaning recovered just 65% of the initial water permeability, whereas the subsequent enzymatic cleaning step permitted the recovery of up to 88% of the initial water permeability of the UF membrane.
Regarding the NF step, two different spiral-wound membranes (Microdyn-Nadir Desal DL and GE Water & Process Technologies NP030) with different properties were examined. These membranes were noted to present different selectivity toward phenolic compounds and sugars. Both membranes were observed to provide high rejection toward phenolic compounds (chlorogenic acid, cynarine, and apigenin-7-O-glucoside) and, consequently, toward the total antioxidant activity (TAA). On the other hand, the Desal DL NF membrane was capable to provide high rejection (100%) toward sugar compounds (glucose, fructose, and sucrose) in contrast with NP030 membrane (4%).
Furthermore, the Desal DL membrane yielded higher permeate fluxes than NP030 membrane, despite its minor nominal MWCO: the initial permeate flux was around 21 kg h−1 m−2, which decreased to 18 kg h−1 m−2 at a steady state upon VRF of 3, whereas for NP030, a lower steady-state permeate flux was measured (5 kg h−1 m−2). The fouling index values measured for both selected membranes on the base of their water permeability before and after the treatment of clarified artichoke wastewaters also supported this: the NP030 membrane showed a higher fouling index (41%) in comparison with the Desal DL (1.7%).
As stated by the authors, the proposed process enabled significant advantages in terms of reduction of environmental impact, recovery of high-added-value compounds, saving of water, and energy requirements. It permitted obtaining different valuable products: a retentate fraction (from NP030 membrane) enriched in phenolic compounds suitable for nutraceutical, cosmeceutical, or food application; a retentate fraction (from Desal DL membrane), enriched in sugar compounds, of interest for food applications; and a clear permeate (from Desal DL membrane) which can be reused as process water or for membrane cleaning.
Fouling mechanisms are very important to fully understand what is taking place between the membrane and the effluent, in view of the adoption and implementation of adequate decisions for the successful design of the membrane plant. This comprises the setup of specifically tailored pretreatment process and optimized operating conditions. Irreversible fouling arises quickly on the membranes due to the high concentration of pollutants when wastewater is purified without any pretreatment [2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12]. Therefore, adequate and optimally designed pretreatment processes on each particular feedstock, in other words, pretreatment tailoring of membrane processes, must be developed in order to maximize productivity and minimize fouling.
OMW is characterized by strong odor, violet-dark color, acid pH, high organic matter content, and high saline toxicity, as confirmed by its high EC values [23]. Uncontrolled disposal of these effluents constitutes an environmental hazard, causing contamination of soil and aquifers, underground leaks, water body pollution, strong odor nuisance, plants growth inhibition, hindrance of self-purification processes, as well as negative effects on the aquatic fauna and the ecological status. Due to the presence of high COD load including recalcitrant compounds, as well as fats and lipids, direct discharge of these wastewaters to the municipal sewage treatment plants is not allowed. In fact, as the majority of municipal wastewater treatment plants include biological treatment processes, legal limits for wastewater discharge into sewer system are set to prevent the inhibition of the microbiological activity. Moreover, discharge of OMW to the ground fields and superficial water bodies is currently prohibited in Spain, whereas in Italy as well as in other European countries, only partial discharge on suitable terrains is allowed; otherwise, in Portugal OMW can be stored and used for irrigation of arbustive cultures under controlled manner (Despacho Conjunto 626/2000) [23, 24, 25, 26, 27, 28].
Several wastewater streams can be produced in an olive oil mill, wastewater from the washing of the olives (OWW), olive mill wastewater (OMW-3, only for three-phase mills), wastewater from olive oil washing (OMW-2), and wastewater from cleaning processes. OWW has a high concentration of suspended solids (mainly peel, pulp, ground, branches, and leaf debris) dragged during the olive fruit washing process, but low concentration of dissolved organic matter—which varies in function of the water flow exchange rate in the washing machines and ripeness state—usually below standard limits for discharge on suitable superficial land.
Currently, not only the Mediterranean countries, where this industry is ancestral and represents an important sector of the industrial economy (Spain, Italy, Portugal, Greece, and Northern African countries—Syria, Algeria, Turkey, Morocco, Tunisia, Libya, Lebanon, and Egypt), are affected by this problem but also France, Serbia and Montenegro, Macedonia, Cyprus, Turkey, Israel, and Jordan, as well as the USA, the Middle East, and China, where this industry is growing each year.
The two-phase extraction process appeared in the 1990s as a more ecological system, has been strongly promoted in Spain, and is now being implemented in Portugal and Greece. Nevertheless, the three-phase system is still surviving in other countries where scarcity of financial support has not favored the change of technology. In the two-phase extraction, water injection is only performed in the final vertical centrifugation step (olive oil washing). The effluent volume derived from the decanting process (OMW-2) is thus reduced on average more than 30%, if compared to the three-phase system (OMW-3). On the other hand, OMW-2 contains lower organic load because part of the organic matter remains in the solid waste, which presents higher moisture than the pomace from the three-phase system (60–70 vs. 30–45%). The measured COD in OWW is commonly in the range 4–16 g O2 L−1 in contrast with up to 30–200 g O2 L−1 for OMW-3. Inorganic compounds including chloride, sulfate, and phosphoric salts of potassium, calcium, iron, magnesium, sodium, copper, and traces of other elements are also common traits of OMW and OWW [28]. The average physicochemical composition of the different types of olive mill effluents is briefly reported in Table 1.
Parameter | OMW-3 | OMET-2 | OMW-2 | OWW |
---|---|---|---|---|
pH | 5.4 | 7.2 | 4.9 | 6.3 |
Moisture (%) | 93.4 | 99.4 | 99.3 | 99.7 |
Total solids (%) | 6.6 | 0.59 | 0.6 | 0.27 |
Organic matter (%) | 5.8 | 0.39 | 0.49 | 0.10 |
Ashes (%) | 0.9 | 0.21 | 0.11 | 0.17 |
BOD5 (g O2 L−1) | 42.0 | 0.29 | 0.79 | 0.50 |
COD (g O2 L−1) | 151.4 | 7.1 | 7.8 | 0.8 |
Total phenols (mg L−1) | 921.0 | 86.0 | 157.0 | 4.0 |
EC (mS cm−1) | 7.9 | 1.9 | 1.3 | 0.9 |
Average physicochemical composition of the different types of olive mill effluents [23, 24, 25, 26, 27, 28].
OWW: olive washing wastewater; OMW-3 and OMW-2: olive mill wastewater from three-phase and two-phase continuous extraction procedures; OMET-2: mixture of all effluents produced in the olive mill, including OWW, OMW, and from other activities in the facility (e.g., cleaning and sanitation); COD: chemical oxygen demand; BOD5: biological oxygen demand; EC, electrical conductivity.
The major problem in the treatment of OMW relies on the large volumes produced with high concentration of organic matter (polysaccharides, sugars, polyalcohols, proteins, organic acids, tannins, fatty acids, oil, and organohalogenated pollutants) including a wide variety of phenolic compounds [23, 24, 25, 26, 27, 28]. Among them, phenolic compounds represent one of the major factors related to the environmental problems caused by this effluent and its low biodegradability. They are highly concentrated and carry different negative effects such as phytotoxicity, toxicity against aquatic organisms, suppression of soil microorganisms, and difficulty to decompose. Despite that fact, phenolic compounds possess high antioxidant activity that makes them interesting for the food, pharmaceutical, and cosmetic industry. Because of that, the recovery of these compounds by different physicochemical methodologies should represent an important objective for the olive oil industry, obtaining added-value extracts of one of the main olive oil industry by-products.
Furthermore, geographical dispersion and the small size of olive oil mills, as well as the previously mentioned seasonality of production, are drawbacks for establishing a cost-efficient treatment/management for the produced effluents. Additionally, the physicochemical composition of these effluents is very variable as it depends on the edaphoclimatic conditions of the region and cultivation practices, the processed olives (type, quality, and maturity), as well as the oil extraction process.
Regarding the use of membranes for agro-industrial wastewater stream treatment, characterized by high concentration in colloids and suspended solids, the major technical drawback for implementation is the high fouling potential (Figure 1). Membrane fouling is mainly caused by colloids, soluble organic compounds, and microorganisms and, thus, can be of biological, organic, or scaling source. In any case, fouling increases the feed pressure and obliges to frequent plant shutdown for membrane cleaning procedures. In this regard, as this kind of effluents contain not only high concentrations of organic pollutants but also inorganic matter deleterious scaling problems may happen.
Concentration polarization and membrane fouling mechanisms during membrane filtration: from left to right, (i) pore sealing or complete pore blocking, (ii) intermediate pore blocking, (iii) standard blocking or pore filling/constriction, and (iv) cake or gel layer (adapted from Ochando-Pulido and Martínez-Férez [
Specifically tailored pretreatment processes can be set upstream the membrane module to avoid high fouling rates, especially in cases in which the feed stream would rapidly lead to zero flux conditions if no pretreatment is conducted. Among recent literature on the topic, Stoller and Chianese [11] reported the purification of OWW by batch-sequenced spiral-wound UF and NF polymeric membranes preceded by solid/liquid (S/L) separation by coagulation-flocculation. OWW contains moderate organic pollutant load but is rich in suspended solids. To this end, the authors tested two different polyelectrolytes: aluminum sulfate (AS) or aluminum hydroxide (AH). Despite similar COD and BOD5 removal efficiencies, the former provided enhanced flux (7.7 L h−1 m−2 at 10 bar) of the NF membrane, which yielded a treated permeate dischargeable in municipal sewers. Similar results were obtained by using the same coagulants-flocculants on OMW-3 [12], much more polluted than the former OWW, up to 55,000 mg O2 L−1 COD, in an integrated process comprising MF, UF, NF, and RO in batch sequence, from which a final stream complying with irrigation standards was attained. Moreover, UV photocatalysis (PC) with titanium dioxide anatase nano-powders and aerobic digestion (AD) was compared with the former pretreatment, also yielding an equivalent outlet stream. PC was more efficient upon the lowest residence time (24 for AS vs. 72 h for PC vs. 7 days for AD) and enabled the highest membrane productivity (13.5 L h−1 m−2 at 13 bar).
Results obtained by Stoller and co-workers highlight the importance of adequate pretreatment processes, underlining the fact that higher pollutant abatement is not sufficient to ensure the suitability of the pretreatment. It is necessary to confirm that the shift carried by the pretreatment process on the particle size (dp) distribution of the effluent does not lead to a stream with particles of similar size of the membrane’s pores (Dp) that would cause deleterious fouling problems by pore plugging and clogging [30, 31, 32, 33, 34, 35, 36, 37, 38].
Centrifugation integrated with NF was also tested for OMW-3 [39], permitting to achieve fluxes of up to 21.2–28.3 L h−1 m−2 and COD removal efficiencies of 59.4–79.2% (at 10 bar). For OMW-3, Zirehpour and co-workers applied MF (50, 5, and 0.2 μm) and UF prior to NF [40]. However, MF membrane showed significant fouling problems, common in MF membranes. On the other hand, the commercial UF membrane examined provided higher permeate flux than the lab-made polyethersulfone (PES) one, but the antifouling properties and rejection efficiency of the latter were reported to be superior. Regarding the use of NF membranes, commercial NF-90 and NF-270, as well as NF-(self-made) one, NF-270 yielded higher permeate flux than NF-90 and NF-(self-made), but major rejection efficiency was found for NF-90. NF-90 and NF-(self-made) membranes are fully aromatic polyamide membranes prepared from interfacial polymerization of m-PDA and TMC. These membranes have relatively rough membrane surfaces. Otherwise, NF-270 is a semi-aromatic piperazine-based membrane with considerably smoother surface, significantly higher water permeability, and lower salt rejection than the former ones, as well as higher hydrophilic and negative charge. COD removals from NF-90 at VRF = 1 and VRF = 2.5 were about 93.4% (COD = 690 ± 10 mg O2 L−1) and 79% (COD = 2200 ± 10 mg O2 L−1), respectively. When NF-270 permeation was used as feed to NF-90, the permeate flux of NF-90 was 22.4 L h−1 m−2 at the beginning of VRF filtration, while permeate flux of NF-90 without NF-270 was 15.1 L h−1 m−2, which means that this arrangement with NF-270 followed by NF-90 enhanced the permeate flux (5 L h−1 m−2 at 5 bar) up to 48%.
Another study by Ochando-Pulido and co-workers [41, 42, 43] presented a batch membrane-in-series processes, UF followed by NF, both polymeric in spiral-wound configuration, for the reclamation of OMW-2. Previously, flocculation (pH-T) and UV photocatalysis with ferromagnetic titanium dioxide nanoparticles were performed. The whole pretreatment sequence led to minor membrane area requirements (104.6 and 81.4 m2, respectively) and enhanced productivity supported by minimized fouling rates. A final treated permeate compatible with irrigation use was obtained. On the other hand, the mix (1:1 v/v) of OMW-2 with OWW enhanced significantly the fluxes observed on both UF and NF membranes, 15.5 and 22.2 L h−1 m−2,respectively, which were stable in time [43].
Some authors have also tried to extract added-value compounds contained in these effluents (polyphenols, sugars, pectin) by concentration with membranes. For example, Paraskeva and co-workers fractionated and recovered the phenolic fraction from OMW-3 (Greece) with UF + NF + RO membranes, including 80 μm polypropylene filtration pretreatment [28]. NF spiral-wound polymeric membranes (with 200 Da MWCO) were tested to further purify the UF permeate. In NF tests, a pressure value (TMP) of 20 bar led to satisfactory permeate flow (100–120 L h−1) and 95% rejection of the phenolic concentration. Otherwise, 78% phenolic fraction recovery from OMW-3 (Italy) was achieved by Garcia-Castello et al. [44] with a process comprising ceramic tubular MF (Al2O3, 200 nm average pore size) followed by a hydrophobic polyethersulfone spiral-wound NF (Nadir N30F cutoff 578 Da). The NF polyphenol-enriched permeate, with valuable antioxidant properties, could be used in formulations in food, cosmetic, and pharmaceutical industries after the final vacuum membrane distillation (VMD) or osmotic distillation (OD). However, fouling on the membranes was evidenced throughout the whole proposed treatment process: the initial permeability could not be restored after the cleaning procedure and decayed progressively after each working cycle noticing irreversible fouling phenomena on the membrane.
On the other hand, Di Lecce et al. [45] proposed the fractionation of OMW-3 by a two-step MF and NF membrane process, at a pilot scale. The MF membranes were tubular made of polypropylene, whereas the NF membrane was in spiral-wound configuration and consisted of a polyamide thin-film composite. Filtration through cotton fabric filters was performed as pretreatment. In these conditions, the NF membrane achieved 98% rejection of COD, dry matter, and phenols. The quality of the obtained purified NF permeate was close to the standards established for its discharge in surface water bodies, but the dynamic performance of the membranes was not reported.
Recently, Ochando-Pulido and co-workers [46] reported the simultaneous phenol recovery and treatment of OMW-2 by NF. In their work, a polymeric TFC NF membrane was studied. Primarily, different pretreatments (sedimentation, centrifugation, and coagulation-flocculation) upstream the membrane unit were examined, adequating the effluent characteristics, that is, reducing the organic and inorganic concentration without compromising the phenolic content for its ulterior recovery. Among them, centrifugation was the most effective pretreatment in terms of TSS abatement, providing 85.7% recovery of supernatant (only 14.3% sludge), no phenolic compounds loss, and subsequently the highest EC and COD NF rejection. The fact that centrifuges are already available in the olive mills, implying minimization of fixed costs and needless of chemicals (flocculants), reinforces the proposed process. Moreover, this pretreatment enhanced the downstream stable membrane flux, up to 64.52 L h−1 m−2, concentrating the feed up to 8.4 times. The obtention of a permeate stream with very good saline quality, 86.8% reduced COD, and practically free of phenolic content, thus minimized in its recalcitrant and phytotoxic potential, and a concentrate pool enriched in high-added-value antioxidant compounds (up to 1315.7 mg L−1) would contribute to the economic feasibility of the reclamation process.
As it can be seen (Table 2), interesting added-value compounds contained in OMW may be recovered, concentrated, and fractionated with the aid of the adequate membranes, to counterbalance the treatment process costs of these agro-industrial effluents. Further investigation is still to be done to comprehend, model, control, and minimize associated fouling problems and the selection of optimal membrane materials.
Author/s | Raw OME source | Tretment process target | Scale | Process flow-scheme | Used membranes characteristics | Dynamic fouling-flux behaviour | Achieved standards | Results |
---|---|---|---|---|---|---|---|---|
Stoller et al. [37] | Continuous 3-phase olive oil extraction | OVW and OVW for sewers discharge or irrigation + fouling inhibition and prediction | Pilot (batch) | (1) Pretreatment among flocculation/UV-TiO2 photocatalysis/aerobic digestion/MF, followed by (2) UF + NF + RO | Composite SW MF (300 nm), UF (2 nm), NF (0.5 nm) and RO (<0.1 nm); operating below critical pressure | Lowest flux drops MF 17.3–18.9%, UF 23.1%, NF 18.5%, RO 22.9–23.7%; reversible fouling removed after cleaning | Overall COD abatement 98.8–99.4% | Italian standards for municipal sewer system discharge (COD values below 500 mg L−1) achieved |
Paraskeva et al. [28] | Continuous 3-phase olive oil extraction | Fractionation of value by-products to and effluent reclamation | Pilot (batch) | (1) 80 μm polypropylene filter, (2) UF, (3) NF and (4) RO | Multichannel UF (zirconia, 100 nm, 1–2.25 bar); polymeric SW NF (200 Da, 20 bar) and SW RO (100 Da, 40 bar) | Fouling data not reported; 100–120 L h−1 within NF, 30–32 L h−1 with RO | 90% lipids and 50% phenols separated by UF; 95% phenols removal | Effluent suitable for irrigation or aquatic receptors |
Coskun et al. [39] | Continuous 3-phase olive oil extraction | OMW reclamation for sewers discharge or reuse in process | Pilot (continuous) | (1) Centrifugation, (2) UF, (3) NF and (4) RO | UF cellulose and polyehtersulfone, NF polyamide and RO polyamide | Permeate fluxes up to 21.2–28.3 L m−2 h for NF membranes and 12.6–15.5 L m−2 h for RO membranes | COD removal 59.4 –79.2% for NF membranes, whereas 96.2–96.3% for RO membranes | Even though these values of conductivities were within acceptable standards for drinking waters, higher effluent COD values were observed, due to fermentation products during storage of the raw effluent |
Garcia-Castello et al. [44] | Continuous 3-phase olive oil extraction | OVW reclamation + selective separation of added-value products | Pilot (batch) | (1) MF, (2) NF and (3) OD or VMD | MF ceramic (Al2O3, 200 nm, 0.72 ± 1 bar); SW NF (hydrophobic PES, 578 Da, 8 bar) | 35% MF initial flux drop and incomplete restore after cleaning (106 L h−1 m−2 bar); 35% NF initial flux (4.68 L h−1 m−2) drop above VRF = 3 | MF achieved 91 and 26% TSS and TOC reduction; NF removed 63% TOC and TC reduction in MF permeate | NF permeate stream containing polyphenolic compounds for food, cosmetic or pharmaceutical sectors; 0.5 g L−1 free LMW polyphenols, with 56% hydroxytyrosol, obtained by treating the NF permeate by OD |
Zirehpour et al. [40] | Continuous 3-phase olive oil extraction | OMW reclamation for irrigation reuse purposes | Pilot (continuous) | MF-UF-NF membrane system | MF (50, 5 and 0.2 μm), UF (100–35 kDa) and NF (450–150 Da) | 34.1 L h−1 m−2 for UF and 9.4 L h−1 m−2 for NF | 51.2% UF COD rejection and 64% NF salt rejection (VRF = 4) | 98.8% COD removal in whole integrated system, with applied pressure for NF lower (5 bar) in comparison with other studies |
Ochando et al. [41, 42, 43] | Continuous 2-phase olive oil extraction | OMW reclamation for sewers discharge or reuse in process | Pilot (semi-continuous) | (1) UF followed by (2) NF and (3) RO | Composite PA/PS SW | 13.2 L h−1 m−2 for UF 10.5 L h−1 m−2 for NF steady-state performances | 90.5% UF and 82.8% NF COD removal | Final treated effluent compliant with standards for reuse in olives washing machines |
Main research works on olive mill wastewaters treatment by nanofiltration membrane technology.
SW: spiral-wound; LMW: low molecular weight; OD: osmotic distillation; VMD: vacuum membrane distillation; CA: cellulose acetate; PES: polyethersulfone; PS: polysulfone; PA: polyamide; PVDF: polyvinylidenefluoride ; ZO: zirconium oxide; VRF: volume recovery factor.
The largest by-product from the milk processing industry is cheese whey [47]. Worldwide, whey production is estimated at 180–190 million tons per year, which is one of the most challenging and demanding environmental aspects of this activity since only 50% is currently processed into products, such as whey protein concentrates and isolates [48]. Cheese whey contains about 55% of the nutrients of milk, namely, soluble proteins (20% of the milk proteins), lactose, minerals, and vitamins, which give it a high nutritional value [49]. On the other hand, this composition is also responsible by its high environmental impact, with values of BOD5 and COD in the range 27–60 and 50–102 g L−1, respectively [50].
Due to the physical-chemical composition of ultrafiltration permeates, where lactose is the major compound of the dry matter and several ions are present (sodium, potassium, calcium, magnesium, chloride, phosphate, citrate), nanofiltration can play an important role in separation/valorization of this fraction.
One of the most important uses of nanofiltration is the production of whey-demineralized lactose concentrates for the food industry, or even, if enough purification is achieved, for pharmaceutical purposes. During nanofiltration of these permeates, some problems can occur. The accumulation of solutes of lower molecular weight on the membrane surface leads to an increased osmotic pressure and polarization concentration phenomena, giving rise to a lower performance, with a decrease of permeate fluxes and altering its selectivity. However, the major drawback of this process is the fouling caused by mineral precipitation of calcium phosphates.
Rice and co-workers [51] carried out nanofiltration of ultrafiltration permeates using polyamide membranes NF270. They observed a severe flux decline during filtration at high temperatures and pH, due to calcium phosphate precipitation, because of its lower solubility in these operating conditions. However, washing with an acid solution allowed to recover water flux. Those authors suggested that by changing the pH of the feed, fouling could be avoided, despite changing the separation properties of the membrane.
Cuartas-Uribe and co-workers [52] also studied the concentration of lactose from whey ultrafiltration permeates, combining concentration by nanofiltration with continuous diafiltration modes, and found that the best operating conditions were a transmembrane pressure of 2.0 MPa and a volume dilution factor of around 2.0, because a good removal of chloride was possible with the lowest lactose loss for the permeate. Authors claimed that no fouling problems were detected during NF tests, but experiments at a larger scale to evaluate the economic feasibility of the process are essential.
Dairy wastewaters, generated during production of dairy products (milk, cheese, butter, yogurt), usually contain remains of milk, casein fines, protein, lipids, lactose, starters, enzymes, detergents, and chemicals from the cleaning and disinfection processes used in the plant. Similar to what happens with the recovery of cheese whey nutrients, where membrane technologies have a very prominent place, also in the treatment of wastewater from dairy products, their use has been growing a lot. The most used membrane processes are mainly ultrafiltration, nanofiltration, and reverse osmosis. When nanofiltration or reverse osmosis are directly used to recover the nutrients (proteins, lactose) contained in dairy wastewaters, also chemicals are retained by the membrane, whereby the use of retentates is a major problem. Besides, during this process, the increase of concentration polarization and osmotic pressure phenomena, due to accumulation of small organic molecules and salts near the membrane surface, leads to a sharp decrease of permeate fluxes and change membrane selectivity.
Luo and co-workers [53], based on the knowledge about recovery of nutrients from cheese whey, proposed a two-stage UF/NF process for the treatment of a model dairy wastewater, being in mind that at the first stage (UF) protein was recovered, and at the second one (NF), a retentate rich in lactose and a permeate free of organics was produced. The authors suggested that both UF and NF retentates of UF could be used for bioenergy production. To control the performance of the membranes used in both stages, the authors calculated the membrane hydraulic permeability before and after the trials, the recovery of solutes, the apparent rejections of solutes, and the irreversible fouling. Based on their experimental results, they concluded that a sequence of UF/NF to treat model dairy wastewaters can be a good proposal to solve the problem of the large volumes of these effluents that are produced worldwide. However, it should be emphasized that experiments with real solutions are needed, due to the complex composition of these types of samples, where other compounds, such as casein fines, lipids, microorganisms, detergents, and other cleaning chemicals, are also present, thus affecting membrane performance.
In order to improve the process proposed by previous researchers, Chen and co-workers [54] proposed an integrated process for reclamation of dairy wastewaters using a model solution. This process includes isoelectric precipitation of caseins—ultrafiltration-nanofiltration of the permeates of UF, producing a lactose concentrate which was used for acid lactic production through fermentation by
Bertoluzzi and co-workers [55] compared the performance of two double-stage membrane processes for treatment of dairy wastewaters: (i) microfiltration (MF) plus NF and (ii) MF plus OI. For MF, a hollow fiber module was used, being membranes made of poly(ether sulfonate)/poly(vinyl pyrrolidone) (PES/ PVP) mixture with a 0.20 μm pore size. In the NF and RO experiments, polymeric flat-type membranes were used, being these membranes made of polyamide composites. For the NF experiments, they used two different membranes (NF90 and NF), which are made of the same material but have different rejection properties, since NF90 is a tighter membrane, while the other one is a looser membrane, as can also be confirmed by their hydraulic permeabilities to pure water. Before the experiments, the dairy wastewater was pre-filtrated across a filter of 0.25 μm to remove solids and to avoid a quick fouling of membranes. After that, microfiltration was also used as a pretreatment for the next operation (NF or OI) with the objective of improving their performance. The authors found that the sequence of MF followed by RO allowed a better removal of total solids and organic matter. Besides, the composition of the final permeate was compatible with the discharge on receiving waters according to the Brazilian environmental regulations or could be used in cleaning-in-place processes in the dairy factory. Although the results of this study are a good basis for other similar dairy wastewaters, since the variety of manufacturing processes involved in dairy products used is too large, for each type of sample/desired goal, a previous study is always necessary.
Dairy by-products and wastewaters contain high nutritive, functional, and bioactive compounds, which can be recovered to produce food or other applications (Table 3). Nanofiltration, due to its specific characteristics, can play a role in the recovery/valorization of those compounds, allowing at the same time the reuse of its main component, the water. Nevertheless, a deep insight about its separation mechanisms and detailed knowledge on feed composition is necessary to control fouling phenomena.
Author/s | Byproducts/dairy wastewaters | Module | Pretreatment | Membrane characterisitics | Achieved standards | Results |
---|---|---|---|---|---|---|
Cuartas-Uribe et al. [52] | Cheese whey | Spiral wounded module with an active surface of 2.51 m2 (batch and continuous) | Pre-concentration by ultrafiltration | Thin film composite (TFC), DS-5DL, with polyamide active surface (cut-off of 150–300 Da) | Both lactose and whey demineralization were achieved with the combined process concentration/continuous diafiltration | NF permeate should be further treated in order to discharge into sewers, due to this COD values |
Luo et al. [53] | Model and real dairy wastewaters | Rotating disk module (RDM) | Real effluents pretreated by two sieves with pore sizes of 0.25 and 0.10 mm | NF 270 made of polyamide and with cut-off 150–200 Da | Dairy wastewaters with pH between 7–8 are most suitable to be treated by NF using RDM due to a good compromise between permeate flux, membrane fouling and permeate quality. Membrane fouling is very sensitive to pH in the range 8–10 | Similarity between model and real dairy wastewaters can be a valuable tool for process control in industrial applications |
Luo et al. [53] | Model dairy wastewater | Dead-end filtration with a stirring cell fitted with a membrane disk | Previous separation of proteins and lipids by ultrafiltration | Several NF membranes were tested: NF270, NF90, Nanomax50, Desal-5 DL and Desal-5 DK, all of them with a surface layer oy polyamide, but with different cut-off´s | A two stage UF/NF for treatment of dairy wastewaters revealed to be a good method to purify dairy wastewaters. The combination of Ultracell for UF followed by NF of permeates with membranes NF270 was the best option, for purification | Retentates of UF were used for production of biofuels; lactose retained in NF was used for biogas production and the final permeate was a reusable water |
Chen et al. [54] | Model dairy wastewater | Dead-end filtration cell for UF/NF (lab scale) and pilot plant for NF | Separation between caseins and whey proteins by isoeletric precipitation and centrfugation, followed by UF of supernatants to concentrate whey proteins | Four UF membranes were used: PES5, PES10, PES30 and Ultracell PLGC, made of different surface materials (polyethersulphone and regenerated cellulose) and cut-off´s. Membrane NF270 was used in the pilot scale tests | Both IP pretreatment and membrane surface material contributed to reduce irreversible fouling of UF and NF membranes. The combination of a previous removal of caseins followed by UF with the most hydrophilic membranes (Ultracell PLGC) allowed to drastically reduced the increasing pressure, thus improving the performance of UF and NF | Production of water of a better quality and simultaneous recovery of whey proteins, lactic acid (through lactose fermentation) and cells. Lactic acid and cells can be used for bioplastics production |
Some research works about the use of nanofiltration for recovery of dairy byproducts and dairy wastewaters purification.
This chapter focused on the use of NF for the treatment of different agro-industrial effluents, dairy, tomato, artichoke, and olive oil. Appropriate pretreatments to avoid membrane fouling have also been addressed as this is the main drawback against NF competitiveness. Among them, other pressure-driven membrane processes, such as microfiltration and ultrafiltration, are used as pretreatment, thus avoiding the use of chemicals. From our review, it was possible to conclude that the implementation of the circular economy vision to the mentioned production chains can be an interesting strategy to balance the investment costs that need to be carried out in order to build treatment plants. In fact, the recovery of added-value molecules (such as lactose and derivatives, polysaccharides, polyphenols, etc.) and of water can be a key aspect for the viability of the treatment processes. As previously said, water scarcity is a growing problem in Mediterranean countries, and therefore alternative sources of water are highly valued. For all of these reasons, it is considered that NF deployment is expected to grow in the forthcoming years.
Chronic myeloproliferative disorders are a group of clonal diseases of the stem cell. It is a group of several diseases with some common features. They derive from a multipotential hematopoietic stem cell. A clone of neoplastic cells in all these neoplams is characterized by a lower proliferative activity than that of acute myeloproliferative diseases. In each of these diseases, leukocytosis, thrombocythemia, and polyglobulia may appear at some stage, depending on the diagnosis [1, 2].
The research on interferon has been going on since the 1950s [3]. Then, the attention was paid to its influence on the immune system. It has been noted that it can exert an antiproliferative effect by stimulating cells of the immune system [4]. In 1987, a publication by Ludwig et al. was published, which reported the effectiveness of interferon alpha in the treatment of chronic myeloproliferative disorders [5].
More and more new studies have been showing the effectiveness of interferon alpha in reducing the number of platelets, reducing the need for phlebotomies in patients with polycythemia vera and also in reducing the number of leukocytes. Moreover, interferon reduced the symptoms of myeloproliferative disorders such as redness and itching of the skin. Additionally, it turned out to be effective in reducing the size of the spleen.
Further studies on the assessment of remission using molecular-level response assessments indicate that the interferon action in chronic myeloproliferation diseases targets cells from the mutant clone with no effect on normal bone marrow cells [6].
Over the years, interferon alpha-2a and interferon alpha-2b have been introduced into the treatment of chronic myeloproliferation, followed by their pegylated forms. The introduction of pegylated forms allowed for a reduction in the number of side effects and less frequent administration of the drug to patients. In recent years, monopegylated interferon alpha-2b has been used to further increase the interval between drug administrations while maintaining its antiproliferative efficacy.
The exact mechanism of action of interferon alpha in the treatment of chronic myeloproliferative disease is still not fully understood, but it has an impact on JAK2 (Janus Kinase) signal transducers and activates the STAT signal pathway (Janus Kinase/SignalTransducer and Activator of Transcription).
Interferon alpha binds to IFNAR1 and IFNAR2c, which are type I interferon receptors. Interferon alpha has an impact on JAK2(Janus Kinase) signal transducers and activates the STAT signal pathway. The disturbances in this signaling pathway are observed in chronic myeloproliferative disorders [7].
Interferon inhibits the JAK-STAT signaling pathway by directly inhibiting the action of thrombopoietin in this pathway [8].
So far, three driver mutations have been described in the course of chronic myeloproliferative diseases that affect the functioning of the JAK-STAT pathway.
JAK2 kinase and JAK1, JAK3, and TYK2 kinases belong to the family of non-receptor tyrosine kinases. They are involved in the intracellular signal transduction of the JAK-STAT pathway. It is a system of intracellular proteins used by growth factors and cytokines to express genes that regulate cell activation, proliferation, and differentiation. The mechanism of JAK activation is based on the autophosphorylation of tyrosine residues that occurs after ligand binds to the receptor. JAK2 kinase transmits signals from the hematopoietic cytokine receptors of the myeloid lineage (erythropoietin, granulocyte-colony stimulating factor thrombopoietin, and lymphoid lineage [9].
A somatic G/T point mutation in exon 14 of the JAK2 kinase gene converts valine to phenylalanine at position 617 (V617F) in the JAK2 pseudokinase domain, which allows constitutive, ligand-independent activation of the receptor to trigger a proliferative signal [10].
Mutation of the MPL gene, which encodes the receptor for thrombopoietin, increases the sensitivity of magekaryocytes to the action of thrombopoietin, which stimulates their proliferation [11].
Malfunction of calreticulin as a result of mutation of the CARL gene leads to the activation of the MPL-JAK/STAT signaling pathway, which is independent of the ligand, as calreticulin is responsible, for the proper formation of the MPL receptor. Consequently, there is a clonal proliferation of hematopoietic stem cells [12].
Below, we provide an overview of some clinical studies on the efficacy of interferon in chronic myeloproliferative disorders.
Polycythemia vera (PV) is characterized by an increase in the number of erythrocytes in the peripheral blood.
Polycythemia vera is caused by a clonal mutation in the multipotential hematopoietic stem cell of the bone marrow. The mutation leads to an uncontrolled proliferation of the mutated cell clone, independent of erythropoietin and other regulatory factors. As the mutation takes place at an early stage of hematopoiesis, an increase of the number of erythrocytes as well as of leukocytes and platelets is observed in the peripheral blood. The cause of proliferation in PV independent from external factors is a mutation in the Janus 2 (JAK2) tyrosine kinase gene. The V617F point mutation in the JAK2 gene is responsible for about 96% mutation, and in the remaining cases the mutation arises in exon 12. Both mutations lead to constitutive activation of the JAK-STAT signaling pathway [13].
As a result of the uncontrolled proliferation, blood viscosity increases, which generates symptoms such as headaches and dizziness, visual disturbances, or erythromelalgia. As the number of all hematopoietic cells, including the granulocytes ones, increases, the difficult to control symptoms of their hyperdegranulation may appear, among which gastric ulcer or skin itching is often observed. During the disease progression, the spleen and liver become enlarged.
The most common complication of the disease is episodes of thrombosis, especially arterial one. During the course of the disease, it can also evolve into myelofibrosis or acute myeloid leukemia.
The treatment of PV is aimed at preventing thromboembolic complications, relieving the general symptoms, the appearance of hepatosplenomegaly as well as preventing its progression.
Each patient should receive an antiplatelet drug chronically, and usually acetylsalicylic acid is the choice. Most often, the treatment is started with phlebotomy in order to rapidly lower the hematocrit level. If cytoreductive therapy is necessary, the drugs of first choice are hydroxycarbamide and interferon [2].
However, the research on the mechanism of the action of interferons is still ongoing. In vitro studies with CD34+ cells from peripheral blood of patients diagnosed with polycythemia vera showed that interferon inhibits clonal changed cells selectively. It was found that interferon alpha-2b and pegylated interferon alpha-2a reduce the percentage of cells with JAK2 V617F mutation by about 40%. Pegylated interferon alpha-2a works by activating mitogen-activated protein kinase P38. It affects CD34+ cells of patients with polycythemia vera by increasing the rate of their apoptosis [6].
A case of a patient with PV with a confirmed chromosomal translocation t(6;8) treated with interferon alpha-2b, which resulted in a reduction of the clone with translocation by 50% from the baseline value, was also described [14].
In 2019, the results of a phase II multicenter study were published, which aimed at assessing the effectiveness of recombinant pegylated interferon alpha-2a in cases of refractory to previously hydroxycarbamide therapy. The study included 65 patients with essential thrombocythemia (ET) and 50 patients with polycythemia vera. All patients had previously been treated with hydroxycarbamide and showed resistance to this drug or its intolerance.
The assessment of the response was performed after 12 months of treatment. Overall response rate to interferon was higher in patients diagnosed with ET than in patients with polycythemia vera. In essential thrombocythemia, the percentage of achieved complete remissions was 43 and 26% of partial remissions. The remission rate in ET patients was higher if calreticulin CALR gene mutation was present. Patients with polycythemia vera achieved complete remission in 22% of cases and partial remission in 38% of cases.
Treatment-related side effects that follow to discontinuation of treatment were reported in almost 14% of patients [15].
The duration of response to treatment with pegylated interferon alpha-2a and the assessment of its safety in long-term use in patients with chronic myeloproliferative disorders was the goal of a phase II of the single-center study. Forty-three adult patients with polycythemia vera and 40 patients with essential thrombocythemia were enrolled in the study. The complete hematological response was defined as a decrease in hemoglobin concentration below 15.0 g/l, without phlebotomies, a resolution of splenomegaly, and no thrombotic episodes in the case of PV, and for essential thrombocythemia—a decrease platelet count below 440,000/μl and two other conditions as above. The assessment of the hematological response was performed every 3–6 months. The median follow-up was 83 months.
The hematological response was obtained in 80% of cases for the entire group. In patients with polycythemia vera, 77% of patients achieved a complete response (CR) while 7% a partial response (PR). The duration of response averaged 65 months for CR and 35 months for PR. In the group of patients diagnosed with essential thrombocythemia, CR was achieved in 73% and PR in 3%. The durance of CR was 58 months and PR was 25 months.
The molecular response for the entire group was achieved in 63% of cases.
The overall analysis showed that the duration of hematological remission and its achievement with pegylated interferon alpha-2a treatment is not affected neither by baseline disease characteristics nor JAK2 allele burden and disease molecular status. There was also no effect on age, sex, or the presence of splenomegaly.
During the course of the study, 22% of patients discontinued the treatment, because of toxicity. Toxicity was the greatest at the beginning of treatment. The starting dose was 450 μg per week and was gradually tapered off.
Thus, on the basis of the above observations, the researchers established that pegylated interferon alpha-2a may give long-term hematological and molecular remissions [16].
The assessment of pegylated interferon alpha-2a in group of patients diagnosed with polycythemia vera only was performed. The evaluation was carried out on a group of 27 patients. Interferon decreased the JAK2 V617F allele burden in 89% of cases. In three patients who were JAK2 homozygous at baseline, after the interferon alpha-2a treatment wild-type of JAK2 reappeared. The reduction of the JAK2 allele burden was estimated from 49% to an average 27%, and additional in one patient the mutant JAK2 allele was not detectable after treatment. It can therefore be postulated that the action of pegylated interferon alpha-2a is directed to cells of the polycythemia vera clone [17].
In 2005, the results of treatment by pegylated interferon alpha-2b of 21 patients diagnosed with polycythemia vera and 21 patients diagnosed with essential thrombocythemia were published. In the case of polycythemia vera in 14 patients, PRV-1 gene mutation was initially detected. In 36% of cases, PRV-1 expression normalized after treatment with pegylated interferon alpha-2b. For the entire group of 42 patients, the remission assessment showed that complete remission was achieved in 69% cases after 6 months of treatment. However, only in 19 patients remission was still maintained 2 years after the start of the study. Pegylated interferon alpha-2b was equally effective in patients with PV and ET. The use and the type of prior therapy did not affect the achievement of remission [18].
Another study with enrolled only PV patients included 136 patients. They were divided into two arms. One group received interferon alpha-2b and the other group received hydroxycarbamide. Interferon dosage was administered in 3 million units three times a week for 2 years and then 5 million units two times a week. Hydroxycarbamide was administered at a dose between 15 and 20 mg/kg/day.
In the group of patients treated with interferon, a significantly lower percentage of patients developed erythromelalgia (9.4%) and distal parasthesia (14%) compared with the group treated with hydroxycarbamide, for whom these percentages were respectively: 29 and 37.5%. Interferon alpha-2b was found to be more effective in inducing a molecular response, which was achieved in 54.7% of cases, in comparison with hydroxycarbamide—19.4% of cases, despite the fact that the percentage of achieved general hematological responses did not differ between the groups and amounted about 70%. The 5-year progression free period in the interferon group was achieved in a higher percentage (66%) than in the hydroxycarbamide group (46.7%) [19].
The most recent form of interferon approved by the
Thanks to these changes to the structure of the molecule, it was possible to achieve a significant increase in its half-life. Ropeginterferon can be administered subcutaneously to patients every 14 days. The clinical trials conducted so far have assessed the ropeginterferon dose from 50 micrograms to a maximum dose of 500 microgams administered as standard every 2 weeks. The possible dose change in case of side effects includes not only the reduction of the drug dose itself, but also the extension of the interval between doses. The extension of the dosing interval up to 4 weeks was assessed.
Ropeginterforn was approved in 2019 by the EMA for the use in patients diagnosed with polycythemia vera without splenomegaly, as monotherapy.
Ropeginterferon, like the previous forms of interferons used in treatment, is contraindicated in patients with severe mental disorders, such as severe depression. It is also a contraindication in patients with noncompensatory standard treatment of disorders of the thyroid gland as well as severe forms of autoimmune diseases. The safety profile of ropeginterferon is similar to that of other forms of alpha interferons. The most common side effects are flu-like symptoms [20].
Ropeginterferon has been shown to exhibit in vitro activity against JAK2-mutant cells. The activity of ropeginterferon against JAK2-positive cells is similar to that of other forms of interferons used actually for standard therapy. Ropeginterferon has an inhibitory effect on erythroid progenitor cells with a mutant JAK2 gene. At the same time, it has almost no effect on progenitor cells without the mutated allele (JAK2-wile-type) and normal CD34+ cells. A gradual decrease of JAK2-positive cells was observed in patients with PV during ropeginterferon treatment. The examination was performed after 6 and 12 months of treatment. In comparison, the reduction in the percentage of JAK2 positive cells in patients treated with hydroxycarbamide was significantly lower.
These results may suggest that ropeginterferon may cause elimination of the mutant clone, but further prospective clinical trials are needed to confirm this theory. The evaluation was performed on a group of patients enrolled in the PROUD-PV study who were treated in France [21].
In 2017, a multicenter study was opened in Italy. The study was of the second phase. In total, 127 patients with polycythemia vera were included in the study. All patients enrolled on the study had low-risk PV. The clinical trial consisted of two arms. Patients received phlebotomies and low-dose aspirin in one arm and ropeginterferon in the other arm. The aim of the study was to achieve a hematocrit of 45% or lower without any evidence of disease progression. Ropeginterferon was administered every 2 weeks at a constant dose of 100 μg.
The response to the treatment was assessed after 12 months. The reduction of hematocrit to the assumed level was achieved in significantly higher percentage of patients in the ropeginterferon group than of patients who received only phlebotomies and aspirin. In addition, none of the patients treated with ropeginterferon experienced disease progression during the course of the study, while among those treated with phlebotomies, 8% of patients progressed.
Grade 4 or 5 adverse events were not observed in patients treated with ropeginterferon, and the incidence of remaining adverse event (AE) was small and comparable in both arms. The most common side effects in the ropeginterferon group were flu-like symptoms and neutropenia; however, the third-grade neutropenia was the most common (8% of cases) [22].
One of the most important clinical studies on the use of ropeginterferon was the PROUD-PV study and its continuation: the CONTINUATION-PV study. These were three-phase, multicenter studies. The aim of the study was to compare the effectiveness of ropeginterferon in relation to hydroxycarbamide. The study included adult patients diagnosed with polycythemia vera treated with hydroxycarbamide for less than 3 years and no cytoreductive treatment at all. In total, 257 patients received this treatment. The patients were divided into two groups: those receiving ropeginterferon or the other being given hydroxycarbamide.
During the PROUD-study, drug doses were increased until the hematocrit was achieved below 45% without the use of phlebotomies, and the normalization of the number of leukocytes and platelets was reached.
The PROUD-PV study lasted 12 months. After this time, the patients continued the treatment under the CONTINUATION-PV study for further 36 months. After the final analysis performed in the 12th month at the end of PROUD study, it was found that the hematological response rates did not differ between the ropeginterferon and hydroxycarbamide treatment groups. These were consecutively 43% in the ropeginterferon arm and 46% in the control arm.
However, after analyzing the CONTINUATION- PV study, it turned out that after 36 months of treatment, the rates of hematological responses begin to prevail in the group of patients receiving ropeginterferon, 53% versus 38% in the control group. Thus, from the above data, it can be seen that the response rate to ropeginterferon increases with the duration of treatment [23].
Another analysis of patients participating in the PROUD and CONTINUATION studies was based on the assessment of treatment results after 24 months, dividing patients into two groups according to age (under and over 60 years).
The initial comparison of both groups of patients showed that older patients had a more aggressive course of the disease. Patients over 60 years of age had a higher percentage of cells with a mutant JAK2 allele. They experienced both general symptoms and some complications, such as thrombosis, more frequently. Both patients under 60 years of age and over 60 years of age in the ropeginterferon arm had a higher rate of molecular response, namely 77.1 and 58.7% compared with the HU remission: 33.3 and 36.1%, respectively. Significantly higher reductions in the JAK2 allele were observed in both groups of patients after ropeginterferon treatment: it was 54.8% for younger patients and 35.1% for elderly patients. For comparison, this difference in the group of patients treated with HU was 4.5 and 18.4%, respectively.
What is more, the age did not affect the frequency of ropeginterferon side effects. In addition, the incidence of adverse ropeginterferon disorders was similar to that observed in the hydroxycarbamide group [24].
Essential thrombocythemia is a clonal growth of multipotential stem cells in the bone marrow. The consequence of this is increased proliferation of megakaryocytes in the bone marrow and an increase in the number of platelets in the peripheral blood. The level of platelets above 450,000/μl is considered a diagnostic criterion.
Essential thrombocythemia may progress over time to a more aggressive form of myeloproliferation, i.e., myelofibrosis. The disease can also evolve into acute myeloid leukemia or myelodysplastic syndrome, both with very poor prognosis. Thromboembolic complications are serious, and they concern over 20% of patients. Thrombosis occurs in the artery and venous area. Moreover, in patients with a very high platelet count, above 1,000,000/μl, bleeding may occur as a result of secondary von Willebrand syndrome [1, 2].
The treatment of ET is primarily aimed to prevent thrombotic complications.
In low-risk patients, only acetylsalicylic acid is used. In cases of high-risk patients, hydroxycarbamide is the first-line drug for most patients. Anagrelide and interferon are commonly used as second-line drugs.
Due to the possible effects of hydroxycarbamide of cytogenetic changes in the bone marrow cells after long-lasting usage, some experts recommend the use of interferon in younger patients in the first line. Interferon is also used as the drug of choice in patients planning a pregnancy [25].
The efficacy of pegylated interferon alpha-2a was assessed on the basis of the group of 39 patients with essential thrombocythemia and 40 patients with polycythemia vera.
Of the overall group, 81% of patients were previously treated prior to the study entry. The patients received pegylated interferon alpha-2a in a dose of 90 μg once a week. The dose of 450 μg was associated with a high percentage of intolerance.
In patients with essential thrombocythemia, the complete remission was achieved in 76%, while the overall hematological response rate brought 81%. Moreover, the molecular remission was achieved in 38%, in 14% of cases, JAK2 transcript became not detectable.
Patients diagnosed with polycythemia vera achieved 70% complete hematological remission and 80% general hematological response to treatment. JAK2 transcript was undetectable in 6% of patients. Molecular remission was achieved in 54% of cases.
Pegylated interferon alpha-2a at the dose of 90 μg per week was very well tolerated. In total, 20% of patients experienced a grade of 3 or 4 of adverse reaction, which was neutropenia. In addition, an increase in liver function tests was observed. Grade 4 of AE was not observed among patients who started the treatment with 90 μg/week while grade 3 neutropenia was an adverse event in only 7% of cases [26].
The effect of interferon alpha-2b treatment in patients with ET and PV was investigated. The study was prospective. Some of the results concerning the group of patients with polycythemia vera are presented in the subsection on polycythemia vera. In total, 123 patients with diagnosed essential thrombocythemia participated in the study. All of them received interferon alpha-2b. The patients were divided into two groups depending on the presence of the JAK2 V617F mutation. The enrolled patients were between 18 and 65 years of age. The treatment they received was, sequentially, interferon alpha-2b in the dose of 3 million units three times a week for the first 2 years, after which time the dose was changed into a maintenance dose, which amounted to 5 million units two times a week.
The analysis showed that the patients with the JAK2 V617F mutation present in a higher percentage achieved an overall hematological response as well as a complete hematological response. The overall hematological response was achieved in 83% of patients with JAK2 mutation, and the complete hematological remission was achieved in 23 cases. In the group of ET patients without the JAK2 V617F mutation, overall hematological response was achieved in 61.4%, while the complete hematological remission was achieved in 12 patients. The 5-year progression-free survival was obtained in 75.9% in the JAKV617F group and only in 47.6% without the mutation.
A significant proportion of patients experienced mild side effects. Grade 3 and 4 of adverse events were severe, most of them being a fever. The isolated cases of elevated liver tests and nausea have also been reported [19].
Pegylated interferon alpha-2b in patients with essential thrombocythemia who were previously treated with hydroxycarbamide, anagrelide, and other forms of interferon alpha, however, due to the lack of efficacy or toxicity, the patients required a change of treatment, was assessed. Pegylated interferon alpha-2b turned out to be effective in these cases. It led to the complete hematological remission in 91% of patients after 2 months of therapy, and in 100% of patients after 4 months. However, merely 11 patients participated in the study. Also only two patients required treatment discontinuation due to the side effects such as depression and general fatigue grade 3 [27].
In case of pregnant patients, interferon is currently considered the only safe cytoreductive drug. Over the years, several analyses of the results of interferon treatment during pregnancy have been carried out.
The assessment of 34 pregnancies in 23 women diagnosed with ET was performed retrospectively. All the pregnancies included in the analysis were of high risk. This high risk was associated with a high platelet count above 1,500,000/μl, a history of thrombotic episode, severe microcirculation disorders, or a history of major hemorrhage.
It turned out that the use of interferon allowed the birth of an alive child in 73.5% of cases. There was no difference in efficacy between the basic and pegylated forms of interferon alpha. In pregnancies without interferon treatment, the percentage of live births was only 60%. Moreover, it was not found if the presence of the JAK2 V617F mutation had any influence on the course of pregnancy [28].
An analysis of the course of pregnancy in patients with ET was assessed in Italy. Data from 17 centers were taken into account. Data from 122 pregnancies were collected from 92 women. In patients diagnosed with essential thrombocythemia, the risk of the spontaneous loss of pregnancy is about 2.5 times higher than among the general population. In the contrary to the study quoted above, it was found that the presence of the JAK2 mutation increases the risk of pregnancy loss. The proportion of live births in patients exposed to interferon during pregnancy was 95%, compared with 71.6% in the group of patients not treated with interferon.
The multivariate analysis also showed that the use of acetylsalicylic acid during pregnancy had no effect on the live birth rate of patients with ET [29].
Whatever its form, interferon is the drug of first choice in pregnancy. Hydroxycarbamide and anagrelide should be withdrawn for about 6 months, and at least for 3 months, before the planned conception. Experts recommend the use of interferon in high-risk pregnancies [30]. A Japanese analysis of 10 consecutive pregnancies in ET patients showed 100% live births in patients who received interferon [31].
In myelofibrosis (MF), monoclonal megakaryocytes produce cytokines that stimulate the proliferation of normal, non-neoplastic fibroblasts and stimulate angiogenesis. The consequence of this is the gradual fibrosis of the bone marrow, impaired hematopoiesis in the bone marrow, and the formation of extramedullary location mainly in the sites of fetal hematopoiesis, i.e., in the spleen and the liver.
The production of various cytokines by neoplastic megakaryocytes leads to the proliferation of normal, noncancerous fibroblasts as well as to increased angiogenesis.
Progressive bone marrow fibrosis leads to worsening anemia and thrombocytopenia. On the other hand, the production of proinflammatory cytokines by megakaryoblasts leads to the general symptoms such as weight loss, fever, joint pain, night sweats, and consequently, progressive worsening of general condition.
The prognosis for myelofibrosis is poor. In about 20% of patients, myelofibrosis evolves into acute myeloid leukemia with poor prognosis.
Currently, the only effective method of treatment that gives a chance to prolong the life is allogeneic bone marrow transplantation. However, this method is only available to younger patients.
The goal of treatment of patients who have not been qualified for allotranspalntation is to reduce the symptoms and to improve the patient’s quality of life. In case of leukocytosis cytoreducing drugs, such as hydroxycarbamide, melphalan, or cladribine can be used. They cause a reduction in the number of leukocytes and may, to some extent, inhibit splenomegaly. Interferon alpha has been used successfully for the treatment of myelofibrosis for many years. The results of its effectiveness will be presented below [2].
Currently, the JAK2 inhibitor ruxolitinib is approved for the treatment of myelofibrosis with enlarged spleen in intermediate and high-risk patients. Ruxolitinib reduces the size of the spleen, reduces general symptoms, and improves the quality of life; however, it does not prolong the overall survival of patients [32].
In 2015, the results of a retrospective study were published to compare the histological parameters of the bone marrow before and after interferon treatment. Twelve patients diagnosed with primary myelofibrosis as well as post-PV MF and post-ET MF were enrolled in the study. Patients were treated with pegylated recombinant interferon alpha-2a or recombinant interferon alpha-2b in standard doses. The time of treatment was from 1 to 10 years. Some patients had previously been treated with hydroxycarbamide or anagrelide. In all cases, karyotype was normal. The prognostic factor of Dynamic International Prognostic Scoring System (DIPSS) was assessed at the beginning as well as during the treatment.
Bone marrow cellularity decreased in cases with increased bone marrow cellularity before the treatment. After the interferon treatment, a reduction in the degree of bone marrow fibrosis was found. The parameters, such as the density of naked nuclei and the density of megakaryocytes in the bone marrow, also improved.
It proves that if the JAK2 V617F mutation had been present, DIPSS was decreased after interferon treatment. This relationship was not observed in patients without the JAK2 V617F mutation. The improvement in peripheral blood morphological parameters and the overall clinical improvement correlated with the improvement in the assessed histological parameters of the bone marrow.
Before the initiation of interferon, seven patients had splenomegaly. During the treatment with interferon, the complete resolution of splenomegaly was achieved in 17% of patients (two cases), and its size decreased in 25% (three cases). A good clinical response was achieved in 83% during interferon therapy. There was no significant difference in response between the two types of interferon used [33].
A prospective study was also conducted in patients with low and intermediate-1 risk group myelofibrosis. Seventeen patients were enrolled. Patients received interferon alpha-2b (0.5–3 milion units/three times a week) or pegylated interferon alpha-2a (45–90 μg/week). The duration of therapy was on average 3.3 years.
Most of the patients responded to the treatment. Partial remission was found in seven patients and complete remission in two patients. Moreover, in four cases, the disease was stabilized and in one case the clinical improvement was achieved. Three patients did not respond to treatment at all and progressed to myelofibrosis. Additionally, the assessment in reducing spleen size was performed. At baseline, 15 patients have splenomegaly, nine of them achieved the compete regression of spleen size [34].
However, the efficacy of interferon in the treatment of myelofibrosis appears to be limited only to a less advanced form, when the bone marrow still has an adequate percentage of normal hemopoiesis and the marrow stroma is not significantly fibrotic. In more advanced stages, interferon was not shown to have any significant effect on the regression of the fibrosis process [35].
In 2020, the results of the COMBI study were published. That was a two-phase, multicenter, single-arm study that investigated the efficacy and safety of the combination of ruxolitinib and pegylated interferon alpha. Thirty-two patients with PV and 18 patients with primary and secondary myelofibrosis participated in the study. The patients were at age 18 and older. Remission was achieved in 44% of myelofibrosis cases, including 28% (5 patients) of complete remission. In patients with PV, the results were slightly worse: 31% of remissions, including 9% of complete remissions. Patients received pegylated interferon alpha-2a (45 μg/week) or pegylated interferon alpha-2b (35 μg/week) in low doses and ruxolitinib in doses of 5–20 mg twice a day.
For the entire group of patients (with PV and MF), the initial JAK2 allele burden was 47% at baseline, and after 2 years of treatment with interferon and ruxolitinib, it decreased to 12%.
The treatment toxicity was low. The highest incidence of side effects occurred at initiation of therapy. It was mostly anemia and thrombocytopenia.
The observations from the COMBI study show that, for the combination of interferon in lower doses with ruxolitinib, it may be effective and well tolerated even in the group of patients who had intolerance to interferon used as the only drug in higher doses. The combined treatment improved the bone marrow in terms of fibrosis and its cellularity. It also allowed to improve the value of peripheral blood counts [36].
It is currently known that some of the additional mutations are associated with a worse prognosis in patients with myelorpoliferation, including patients with myelofibrosis. Some of these mutations have been identified as high-risk molecular mutations. These are ASXL1, EZH2, IDH1/2, or SRSF2. Earlier studies have shown their association with a more aggressive course of the disease, worse prognosis, and shorter survival of patients, as well as a poorer response to treatment. Due to their importance, they have been included in the diagnostic criteria of myelofibrosis [37].
It is also known that the presence of driver mutations, i.e., JAK2, CALR, and MPL or triple negativity, may affect the course of myeloproliferation, including the incidence of thromboembolic complications.
The assessment of the influence of driver mutations and a panel of selected additional mutations on the effectiveness of interferon treatment in patients with myelofibrosis was performed on a group of 30 patients. Only the patients with low- and intermediate-1-risk were enrolled in the study. The treatment with pegylated interferon alpha-2a or interferon alpha-2b resulted in a complete remission in two patients and partial remission in nine patients. The disease progressed in three cases. One patient relapsed and four died. The remaining patients achieved a clinical improvement or disease stabilization. In the studied group, it was not found if the effectiveness of interferon treatment was influenced by the lack of driver mutations. Among the group of four patients with additional mutations, two died and one had disease progression. It was a mutation of ASXL1 and SRSF2. The treatment with interferon in patients without additional molecular mutations in the early stages of the disease may prevent further progression of the disease [38].
The side effects of interferon in the group of patients with myelofibrosis are similar to those occurring after the treatment of other chronic myeloproliferative diseases. The most frequently described are hematological toxicity- anemia and thrombocytopenia, less often is the appearance of leukopenia. Hematological toxicity usually resolves with dose reduction or extension of the dose interval. The most frequently nonhematological toxicity was fatigue, muscle pain, weakness, and depression symptoms. All symptoms are usually mild and do not exceed grade 2 [38].
However, the use of interferon in the treatment of myelofibrosis has not been recommended as a standard therapy. Interferon is still being evaluated in clinical trials, or it is used in selected patients as a nonstandard therapy in this diagnosis.
Mastocytosis is characterized by an excessive proliferation of abnormal mast cells and their accumulation in various organs.
The basis for the development of mastocytosis is ligand-independent activation of the KIT receptor, resulting from mutations in the KIT proto-oncogene. The KIT receptor is a trans membrane receptor with tyrosine kinase’s activity. Its activation stimulates the proliferation of mast cells. That excessive numbers of mast cells infiltrate tissues and organs and release mediators such as histamine, interleukine-6, tryptase, heparin, and others, which are responsible for the appearance of symptoms typical of mastocytosis. In addition, the infiltration of tissues for mast cells itself causes damage to the affected organs.
The prognosis of mastocytosis depends on the type of the disease. In the case of cutaneous mastocytosis (CM), in the majority of cases prognosis is good and the disease does not shorten the patient’s life, but in aggressive systemic mastocytosis (ASM), the average follow-up is about 40 months. Mast cell leukemia has a poor prognosis with a median follow-up of approximately 1 year.
Systemic mastocytosis usually requires the implementation of cytoreductive therapy. The first line of therapy is interferon alone or its combination with corticosteroids. In aggressive systemic mastocytosis, the first line in addition to interferon 2-CdA can be used. An effective drug turned out to be midostaurin in the case of the present KIT mutation. In patients without the KIT D816V mutation, treatment with imatinib may be effective. In the case of mast cell leukemia, multidrug chemotherapy is most often required, as in acute leukemias, followed by bone marrow transplantation [39].
Systemic mastocytosis requiring treatment is a rare disease, this is why the studies available in the literature evaluating various therapies concern mostly small groups of patients.
In 2002, the French authors presented their experiences on the use of interferon in patients with systemic mastocytosis. They included 20 patients. The patients received interferon alpha-2b in gradually increased doses.
The patients were assessed after 6 months. In cases in which bone marrow was infiltrated for mast cells at baseline, it still remained infiltrated after 6 months of treatment.
However, the responses were obtained in terms of symptoms related to mast cell degranulation. Partial remission was achieved in 35% of patients and minor remission in 30%. It concerns mainly skin lesions and vascular congestion. Moreover, the assessment of the histamine level in the plasma revealed a decrease of it in patients who previously presented symptoms related to the degranulation of mast cells, such as gastrointestinal disorders and flushing.
A high percentage of side effects were found during treatment. They concerned 35% of patients. Depression and cytopenia were most frequent ones [40].
Another analysis was a report of five patients with systemic mastocytosis treated with interferon and prednisolone. All patients received interferon alpha-2b in a dose of 3 million units three times a week and four patients additionally received prednisolone. Four patients responded to interferon treatment at varying degrees. One patient, who at baseline had bone marrow involvement by mast cells in above 10%, progressed to mast cell leukemia. In two patients, the symptoms C resolved completely and in one of them they partially disappeared. In one case, stabilizing disease was achieved [41].
In 2009, a retrospective analysis of patients treated with cytoreductive therapy due to mastocytosis was published. The authors collected data from 108 patients treated at the Mayo Clinic. This analysis allowed for the comparison of the efficacy of four drugs used in systemic mastocytosis. There were interferon alpha alone or in the combination with prednisone—among 40 patients, hydroxycarbamide—among 26 ones, imatinib—among 22 persons, and 2-chlorodeoxyadenosine (2-CdA)—among 22 patients.
After dividing the patients into three additional groups on the basis of the type of mastocytosis—indolent systemic mastocytosis, aggressive systemic mastocytosis, and systemic mastocytosis associated with another clonal hematological nonmast cell lineage disease (SM-AHNMD)—the effectiveness of each of type of therapy was assessed.
The highest response rates in indolent and aggressive mastocytosis were achieved with interferon treatment. They were 60% of the responses in both groups, and in the SM-AHNMD group of patients, the percentage was also one of the highest and amounted to 45%. The second most effective drug was 2-CdA. The response rates were 56% for indolent MS, 50% for aggressive MS, and 55% for SM-AHNMD. The patients treated with imatinib achieved response in 14, 50, and 9% by following groups, respectively. In contrast, patients with indolent and aggressive systemic mastocytosis did not respond to hydroxycarbamide treatment at all. The response rate in both groups was 0%. However, patients with MS associated with another clonal hematological nonmast cell lineage disease achieved 21% response to hydroxycarbamide. Additionally, it was found that only interferon relieved symptoms caused by the release of inflammatory mediators by mast cells.
The additional analysis showed no influence of the TET 2 mutation on the response to treatment [42].
In the literature, there are also single cases of mastocytosis presenting trials of nonstandard treatment. That is description of a patient with systemic mastocytosis with mast cell bone marrow involvement. Mutation of c-kit Asp816Val was present. Patient progressed despite treatment with dasatinib and 2-chlorodeoxyadenosine. The patient developed symptoms related to the degranulation of mast cells and increased ascites.
The patient was treated with pranlukast, which is an anti-leukotriene receptor antagonist due to an asthma episode. The rate of ascites growth decreased significantly after one administration. The patient required paracentesis every 10 days and not every 3 days, as before starting to take the drug. After 15 days of treatment with pranlukast, the patient received interferon alpha, which resulted in complete regression of ascites, resolution of pancytopenia, and complete disappearance of the c-kit mutation clone. The infiltration of mast cells in the bone marrow significantly decreased [43].
Interferon alpha was also effective in a patient with systemic mastocytosis associated with myelodysplastic syndrome with the c-kit D816V mutation, which was refractory to imatinib treatment [44].
Interferon alpha also proved to be effective in the treatment of osteoporotic lesions appearing in the course of mastocytosis.
The series of 10 cases with resolved mastocytosis and osteoporosis-related fractures was presented in 2011. The patients received interferon alpha in a dose of 1.5 million units three times a week as well as pamindronic acid. The patients were treated for an average of 60 months. For the first 2 years, pamindronate was given at a dose of 1 mg/kg every month, and then every 3 months.
During the course of the study, no patient had a new-bone fracture. The level of alkaline phosphatase decreased by 25% in relation to the value before treatment and tryptase by 34%. Bone density increased during treated with interferon and pamindronate. The increase was on average 12% in the spine bones and 1.9% in the hip bones. At the same time, there was no increase in the density of the hip bone and a minimal increase in the density of the spine in patients treated with pamindronate alone.
The results of this observation suggest that it is beneficial to add low doses of interferon alpha to pamindronate treatment in terms of bone density increase [45].
That experiences show that interferon used in systemic mastocytosis significantly improves the quality of life of patients by inhibiting the symptoms caused by degranulation of mast cells. They prevent bone fractures and, in some patients, they cause remission of bone marrow infiltration by mast cells.
Chronic neutrophilic leukemia (CNL) is a very rare disease. It is characterized by the clonal proliferation of mature neutrophils.
The diagnostic criteria proposed by the World Health Organization (WHO) comprise leukocyte counts above 25,000/μl (including more than 80% of rod and segmented
Physical examination often shows enlargement of the liver and spleen, moreover, patients complain on weight loss and weakness [1].
The prognosis varies. The average survival time for patients with CNL is less than 2 years.
Only few descriptions of chronic neutrophilic leukemia are available in the literature, and these are mostly single case reports.
Because it is an extremely rare disease, there are no established and generally accepted treatment standards. In most cases, patients are given hydroxycarbamide or interferon. Patients who are eligible for a bone marrow transplant may benefit from this treatment. Bone marrow allotransplantation remains the only method that gives a chance for a significant extension of life.
The German authors presented a series of 14 cases of chronic neutrophilic leukemia. The group of patients consisted of eight women and six men. The average age was 64.7 years. From the entire group of patients, longer survival was achieved only in three cases. One of these patients was treated with interferon alpha and achieved hematological remission, the other underwent bone marrow allotransplantation from a family donor, and the third one was treated with hydroxycarbamide and transfusions as needed. The follow-up period of the patient after allogeneic matched related donor transplantation (allo-MRD) was 73 months, and for the patient after interferon treatment it was 41 months.
The remaining patients died within 2 years of diagnosis. Six patients, the largest group, died due to intracranial bleeding, three patients died because of leukemia cell tissue infiltration, one patient because of the disease transformation into leukemia, and one patient because of pneumonia [46].
It can be seen from these experiences that treatment with interferon alpha can significantly extend the survival time of patients.
The case of a 40-year-old woman diagnosed with chronic neutrophilic leukemia is presented by Yassin and coauthors. Initially, the patient had almost 41,000 leukocytes in the peripheral blood. In a physical examination, splenomegaly and hepatomegaly were not present. Patient received pegylated interferon alpha-2a. The initially dose was 50 μg once a week for the first 2 weeks, then the dose was increased to 135 μg weekly for 6 weeks, and then the dose interval was extended to another 2 weeks. As a result of the treatment, the general condition of the patient improved and the parameters of peripheral blood counts were normalized [47].
Another case report presented in the literature describes a 41-year-old woman diagnosed with CNL accompanied by focal segmental glomerulosclerosis (FSGS). The patient had increasing leukocytosis for several months. On the admission to the hospital, leukocytosis was 94,000/μl. Moreover, the number of platelets in the morphology exceeded 1,000,000/μl. More than a year earlier, the patient had splenectomy due to splenomegaly and spleen infraction.
Additionally, JAK2 V617F mutation was found. Some authors suggest that the presence of JAK2 mutation may be associated with longer survival in CNL.
The patient received hydroxycarbamide for 3 months and reduction in the number of leukocytes was achieved. After this time, interferon alpha-2b was added to hydroxycarbamide. As a result, focal segmental glomerulosclerosis disappeared and the renal tests improved [48].
Another case of chronic neutrophilic leukemia with a JAK2 gene mutation concerns a 53-year-old man. The patient’s baseline leukocytosis was 33,500/μl, including the neutrophil count of 29,700/μl. The patient also had splenomegaly.
The treatment with interferon alpha-2b at a dose of 3 million units every other day was started. After a month of treatment, the number of leukocytes was reduced to less than 10,000/μl. Then the patient was treated chronically with interferon alpha-2b in doses of 3 million units every 2 weeks. As a result of the therapy, the number of leukocytes remains between 8 and 10,000/μl. The patient remains in general good condition [49].
A series of two CNL cases are also shown. The first patient was a 70-year-old woman with stable leukocytosis of about 35,000/μl and the remaining morphology parameters in normal range. The patient was only observed for 5 years until hepasplenomegaly progressed rapidly. Then, interferon alpha-2b was included. Due to the treatment, the rapid regression of hepatosplenomegaly was achieved.
The second case is a 68-year-old woman with baseline leukocytosis of almost 14,000/μl. In this case, the treatment with hydroxycarbamide was started immediately. However, no improvement was achieved. After 6 weeks of HU treatment, interferon alpha-2b 3 million units 3 times a week was implemented and leukocytosis decreased. Due to the interferon treatment, the disease stabilized for a long time. Because the patient experienced an adverse reaction, a severe flu-like syndrome, interferon was discontinued. After interferon withdrawal, the disease progressed gradually and the treatment attempts by busulfan and 6-mercaptopurine were unsuccessful. Therefore, interferon was readministered and the disease went into remission. Interferon treatment was continued at a reduced dose. The disease regression was achieved again.
Additionally, the patient showed an improvement in the function of granulocytes in terms of phagocytosis and an improvement in neutral killer (NK) cell function after treatment with interferon [50].
The above examples show that interferon alpha is effective in the treatment of chronic neutrophilic leukemia. The side effects are rare and can be managed with dose reductions. Moreover, in these cases, interferon is also effective in a reduced dose. Disease remission or regression can be achieved without typical of CNL complications, such as intracranial bleeding.
Interferon has been used in the past to treat chronic myeloid leukemia. The treatment with tyrosine kinase inhibitors is now a standard practice. However, in a small number of patients, they are ineffective or exhibit unmanageable toxicity. Therefore, the attempts are underway to use interferon in combination with TKI in lower doses, which is to ensure the enhancement of the antiproliferative effect while reducing the toxicity.
There are ongoing attempts to use ropeginterferon in patients diagnosed with chronic myeloid leukemia, in whom treatment with imatinib alone has not led to deep molecular response (DMR). The first phase study was conducted in a small group of patients with chronic myeloid leukemia. The patients in first chronic phase treated with imatinib who did not achieve DMR, but in complete hematologic remission and complete cytogenetic remission, were included in the study. Patients have been treated with imatinib for at least 18 months. Twelve patients were enrolled in the study, and they completed the study according to the protocol. These patients received additional ropeginterferon to imatinib and four achieved DMR. Low toxicity was observed during the treatment. Among the hematological toxicities, neutropenia was the most common. There was no nonhematological toxicity with a degree higher than 1/2 during the treatment. Moreover, it has been found that better effects and fewer side effects are obtained when ropeginterferon is administered for a longer time, but in lower doses. The comparison of the effectiveness of interferon in chronic myeloproliferative disorders based on selected articles is presented in Table 1 [51].
Source | Type of trial | Interferon | Diagnosis | No. | Prior treatment status | Response rate |
---|---|---|---|---|---|---|
Yacoubet al. [15] | Phase II, multicenter | Pegylated IFN alfa-2a | PV | 50 | Resistance to HU or HU intolerance | CR:22% PR:38% |
ET | 65 | CR:43% PR:26% | ||||
Masarova et al. [16] | Phase II, single-center | Pegylated IFN alfa-2a | PV | 43 | Untreated or previously treated with cytoreductive therapy | CR:77% PR:7% |
ET | 40 | CR:73% PR:3% | ||||
Samuelsson et al. [18] | Phase II | Pegylated IFN alfa-2b | PV | 21 | Untreated or previously treated with cytoreductive therapy | CR: 69% for the entire group |
ET | 21 | |||||
Huang BT et al. [19] | Open label, multicenter | IFN alfa-2b | PV | 136 | Untreated or previously treated with cytoreductive therapy | OHR:70% Molecular response:54.7% |
ET | 123 | OHR (JAK2+ patients):83% CHR:23 cases OHR (JAK2-patients): 61.4% CHR:12 cases | ||||
Gisslinger et al. [23] | phase III, multicenter | Ropeginterferon | PV | 257 | Previously treated | OHR:53% |
Quintás-Cardama et al. [26] | phase II | Pegylated IFN alfa-2a | PV | 40 | Untreated or previously treated with cytoreductive therapy | OHR:80% CR:70% Molecular remission:54% |
ET | 39 | OHR:81% CR:76% Molecular remission:38% | ||||
Sørensen et al. [36] | Phase III, multicenter, COMBI | Pegylated IFN alfa-2a with ruxolitinib or Pegylated IFN alfa-2b with ruxolitinib | PV | 32 | Untreated or previously treated with cytoreductive therapy | OHR:44% CR:28% |
MF | 18 | OHR:31% CR:9% | ||||
Casassus et al. [40] | Open label, multicenter | IFN alpha-2b | Mastocytosis | 20 | Untreated and previously treated | PR:35% Minor remission: 30% |
Comparison of the effectiveness of interferon in chronic myeloproliferative disorders.
PV: polycythemia vera; ET: essential thrombocythemia; MF: myelofibrosis; HU: hydroxycarbamide/hydroxyurea; CR: complete remission; PR: partial remission; and OHR: overall hematological response.
Interferon alpha appears to be an effective and safe drug in the most type of chronic myeloproliferative disorders. Nowadays, all forms of its using have similar effectiveness. Interferon alpha can be effective even in cases of resistance for first-line treatment. Trial research is currently underway to combine it with some new drugs, such as ruxolitinib, and to add it to the already well-established therapy, it is a promising option for patients with refractory disease.
From time to time, new forms of interferon, such as ropeginterferon, are introduced, which gives hope for better effectiveness, better safety profile, and greater comfort in its use for patients who have to be treated for many years. In the case of the use of interferons alpha in the treatment of chronic myeloproliferative diseases, there are still opportunities to extend its use and to study its combination with newly introduced drugs.
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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The literature source was Web of Science and SSCI, SCI-EXPANDED, A&HCI, CPCI-S, CPCI-SSH, and ESCI indexes. Fifty-two articles were reviewed; however, 14 of them were not been included in the study. As a result, 38 articles were examined. Level of education, field of education, and material types of AR used in education and reported educational advantages of AR have been investigated. All articles are categorized according to target groups, which are early childhood education, primary education, secondary education, high school education, graduate education, and others. AR technology has been mostly carried out in primary and graduate education. “Science education” is the most explored field of education. Mobile applications and marker-based materials on paper have been mostly preferred. The major advantages indicated in the articles are “Learning/Academic Achievement,” “Motivation,” and “Attitude”.",book:{id:"6543",slug:"state-of-the-art-virtual-reality-and-augmented-reality-knowhow",title:"State of the Art Virtual Reality and Augmented Reality Knowhow",fullTitle:"State of the Art Virtual Reality and Augmented Reality Knowhow"},signatures:"Rabia M. Yilmaz",authors:[{id:"225838",title:"Dr.",name:"Rabia",middleName:null,surname:"Yilmaz",slug:"rabia-yilmaz",fullName:"Rabia Yilmaz"}]},{id:"63639",doi:"10.5772/intechopen.81086",title:"Cooperative Learning: The Foundation for Active Learning",slug:"cooperative-learning-the-foundation-for-active-learning",totalDownloads:3491,totalCrossrefCites:18,totalDimensionsCites:25,abstract:"The role of instructors is evolving from the presenter of information to the designer of active learning processes, environments, and experiences that maximize student engagement. The more active a lesson, the more students tend to engage intellectually and emotionally in the learning activities. Cooperative learning is the foundation on which many of the active learning procedures are based. Cooperative learning is the instructional use of small groups so that students work together to maximize their own and each other’s learning. Most of the active learning procedures, such as problem-based learning, team-learning, collaborative learning, and PALS, require that students work cooperatively in small groups to achieve joint learning goals. Cooperative learning is based on two theories: Structure-Process-Outcome theory and Social Interdependence theory. Four types of cooperative learning have been derived: formal cooperative learning, informal cooperative learning, cooperative base groups, and constructive controversy. There is considerable research confirming the effectiveness of cooperative learning. To be cooperative, however, five basic elements must be structured into the situation: positive interdependence, individual accountability, promotive interaction, social skills, and group processing.",book:{id:"6929",slug:"active-learning-beyond-the-future",title:"Active Learning",fullTitle:"Active Learning - Beyond the Future"},signatures:"David W. Johnson and Roger T. Johnson",authors:[{id:"259976",title:"Dr.",name:"David",middleName:null,surname:"Johnson",slug:"david-johnson",fullName:"David Johnson"},{id:"263004",title:"Dr.",name:"Roger",middleName:null,surname:"Johnson",slug:"roger-johnson",fullName:"Roger Johnson"}]},{id:"58060",doi:"10.5772/intechopen.72341",title:"Pedagogy of the Twenty-First Century: Innovative Teaching Methods",slug:"pedagogy-of-the-twenty-first-century-innovative-teaching-methods",totalDownloads:8833,totalCrossrefCites:17,totalDimensionsCites:23,abstract:"In the twenty-first century, significant changes are occurring related to new scientific discoveries, informatization, globalization, the development of astronautics, robotics, and artificial intelligence. This century is called the age of digital technologies and knowledge. How is the school changing in the new century? How does learning theory change? Currently, you can hear a lot of criticism that the classroom has not changed significantly compared to the last century or even like two centuries ago. Do the teachers succeed in modern changes? The purpose of the chapter is to summarize the current changes in didactics for the use of innovative teaching methods and study the understanding of changes by teachers. In this chapter, we consider four areas: the expansion of the subject of pedagogy, environmental approach to teaching, the digital generation and the changes taking place, and innovation in teaching. The theory of education, figuratively speaking, has two levels. At the macro-level, in the “education-society” relationship, decentralization and diversification, internationalization of education, and the introduction of digital technologies occur. At the micro-level in the “teacher-learner” relationship, there is an active mix of traditional and innovative methods, combination of an activity approach with an energy-informational environment approach, cognition with constructivism and connectivism.",book:{id:"5980",slug:"new-pedagogical-challenges-in-the-21st-century-contributions-of-research-in-education",title:"New Pedagogical Challenges in the 21st Century",fullTitle:"New Pedagogical Challenges in the 21st Century - Contributions of Research in Education"},signatures:"Aigerim Mynbayeva, Zukhra Sadvakassova and Bakhytkul\nAkshalova",authors:[{id:"201997",title:"Dr.",name:"Aigerim",middleName:null,surname:"Mynbayeva",slug:"aigerim-mynbayeva",fullName:"Aigerim Mynbayeva"},{id:"209208",title:"Dr.",name:"Zukhra",middleName:null,surname:"Sadvakassova",slug:"zukhra-sadvakassova",fullName:"Zukhra Sadvakassova"},{id:"209210",title:"Dr.",name:"Bakhytkul",middleName:null,surname:"Akshalova",slug:"bakhytkul-akshalova",fullName:"Bakhytkul Akshalova"}]},{id:"59468",doi:"10.5772/intechopen.74344",title:"Virtual and Augmented Reality: New Frontiers for Clinical Psychology",slug:"virtual-and-augmented-reality-new-frontiers-for-clinical-psychology",totalDownloads:2364,totalCrossrefCites:13,totalDimensionsCites:21,abstract:"In the last decades, the applied approach for the use of virtual reality (VR) and augmented reality (AR) on clinical and health psychology has grown exponentially. These technologies have been used to treat several mental disorders, for example, phobias, stress-related disorders, depression, eating disorders, and chronic pain. The importance of VR/AR for the mental health field comes from three main concepts: (1) VR/AR as an imaginal technology, people can feel “as if they are” in a reality that does not exist in external world; (2) VR/AR as an embodied technology, the experience to feel user’s body inside the virtual environment; and (3) VR/AR as connectivity technology, the “end of geography’. In this chapter, we explore the opportunities provided by VR/AR as technologies to improve people’s quality of life and to discuss new frontiers for their application in mental health and psychological well-being promotion.",book:{id:"6543",slug:"state-of-the-art-virtual-reality-and-augmented-reality-knowhow",title:"State of the Art Virtual Reality and Augmented Reality Knowhow",fullTitle:"State of the Art Virtual Reality and Augmented Reality Knowhow"},signatures:"Sara Ventura, Rosa M. Baños and Cristina Botella",authors:[{id:"106036",title:"Dr.",name:"Rosa Maria",middleName:null,surname:"Baños",slug:"rosa-maria-banos",fullName:"Rosa Maria Baños"},{id:"227763",title:"Ph.D.",name:"Sara",middleName:null,surname:"Ventura",slug:"sara-ventura",fullName:"Sara Ventura"},{id:"229056",title:"Dr.",name:"Cristina",middleName:null,surname:"Botella",slug:"cristina-botella",fullName:"Cristina Botella"}]},{id:"64583",doi:"10.5772/intechopen.81714",title:"Evaluating a Course for Teaching Advanced Programming Concepts with Scratch to Preservice Kindergarten Teachers: A Case Study in Greece",slug:"evaluating-a-course-for-teaching-advanced-programming-concepts-with-scratch-to-preservice-kindergart",totalDownloads:1422,totalCrossrefCites:13,totalDimensionsCites:18,abstract:"Coding is a new literacy for the twenty-first century, and as a literacy, coding enables new ways of thinking and new ways of communicating and expressing ideas, as well as new ways of civic participation. A growing number of countries, in Europe and beyond, have established clear policies and frameworks for introducing computational thinking (CT) and computer programming to young children. In this chapter, we discuss a game-based approach to coding education for preservice kindergarten teachers using Scratch. The aim of using Scratch was to excite students’ interest and familiarize them with the basics of programming in an open-ended, project-based, and personally meaningful environment for a semester course in the Department of Preschool Education in the University of Crete. For 13 weeks, students were introduced to the main Scratch concepts and, afterward, were asked to prepare their projects. For the projects, they were required to design their own interactive stories to teach certain concepts about mathematics or physical science to preschool-age students. The results we obtained were more satisfactory than expected and, in some regards, encouraging if one considers the fact that the research participants had no prior experiences with computational thinking.",book:{id:"6936",slug:"early-childhood-education",title:"Early Childhood Education",fullTitle:"Early Childhood Education"},signatures:"Stamatios Papadakis and Michail Kalogiannakis",authors:null}],mostDownloadedChaptersLast30Days:[{id:"58060",title:"Pedagogy of the Twenty-First Century: Innovative Teaching Methods",slug:"pedagogy-of-the-twenty-first-century-innovative-teaching-methods",totalDownloads:8832,totalCrossrefCites:17,totalDimensionsCites:23,abstract:"In the twenty-first century, significant changes are occurring related to new scientific discoveries, informatization, globalization, the development of astronautics, robotics, and artificial intelligence. This century is called the age of digital technologies and knowledge. How is the school changing in the new century? How does learning theory change? Currently, you can hear a lot of criticism that the classroom has not changed significantly compared to the last century or even like two centuries ago. Do the teachers succeed in modern changes? The purpose of the chapter is to summarize the current changes in didactics for the use of innovative teaching methods and study the understanding of changes by teachers. In this chapter, we consider four areas: the expansion of the subject of pedagogy, environmental approach to teaching, the digital generation and the changes taking place, and innovation in teaching. The theory of education, figuratively speaking, has two levels. At the macro-level, in the “education-society” relationship, decentralization and diversification, internationalization of education, and the introduction of digital technologies occur. At the micro-level in the “teacher-learner” relationship, there is an active mix of traditional and innovative methods, combination of an activity approach with an energy-informational environment approach, cognition with constructivism and connectivism.",book:{id:"5980",slug:"new-pedagogical-challenges-in-the-21st-century-contributions-of-research-in-education",title:"New Pedagogical Challenges in the 21st Century",fullTitle:"New Pedagogical Challenges in the 21st Century - Contributions of Research in Education"},signatures:"Aigerim Mynbayeva, Zukhra Sadvakassova and Bakhytkul\nAkshalova",authors:[{id:"201997",title:"Dr.",name:"Aigerim",middleName:null,surname:"Mynbayeva",slug:"aigerim-mynbayeva",fullName:"Aigerim Mynbayeva"},{id:"209208",title:"Dr.",name:"Zukhra",middleName:null,surname:"Sadvakassova",slug:"zukhra-sadvakassova",fullName:"Zukhra Sadvakassova"},{id:"209210",title:"Dr.",name:"Bakhytkul",middleName:null,surname:"Akshalova",slug:"bakhytkul-akshalova",fullName:"Bakhytkul Akshalova"}]},{id:"61746",title:"Facilitation of Teachers’ Professional Development through Principals’ Instructional Supervision and Teachers’ Knowledge- Management Behaviors",slug:"facilitation-of-teachers-professional-development-through-principals-instructional-supervision-and-t",totalDownloads:3384,totalCrossrefCites:2,totalDimensionsCites:2,abstract:"With the rise of global competition and the focus on teacher quality, teacher professional development is becoming increasingly crucial, and the stress and challenges for principals are more severe than ever. Teachers can improve their professional abilities through principals’ instructional supervision and their own knowledge-management (KM) behaviors to benefit students. Thus, this chapter analyzes the relationship among principals’ instructional supervision, teachers’ KM, and teachers’ professional development. The author believes that principals’ instructional supervision and effective KM can facilitate the professional development of teachers. The author also believes the readers can know the relationships among them, and teachers’ professional development can be improved through principal’s instructional supervision and teachers’ KM behaviors.",book:{id:"6674",slug:"contemporary-pedagogies-in-teacher-education-and-development",title:"Contemporary Pedagogies in Teacher Education and Development",fullTitle:"Contemporary Pedagogies in Teacher Education and Development"},signatures:"Chien-Chin Chen",authors:[{id:"232569",title:"Ph.D.",name:"Chien Chih",middleName:null,surname:"Chen",slug:"chien-chih-chen",fullName:"Chien Chih Chen"}]},{id:"75908",title:"From the Classroom into Virtual Learning Environments: Essential Knowledge, Competences, Skills and Pedagogical Strategies for the 21st Century Teacher Education in Kenya",slug:"from-the-classroom-into-virtual-learning-environments-essential-knowledge-competences-skills-and-ped",totalDownloads:519,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"As teachers in Kenya begin to migrate from the classroom to virtual learning spaces following COVID 19 pandemic, there is pressing need to realign Teacher Education to requisite Knowledge, competences, skills, and attitudes that will support online teaching. This chapter explores these needs using a combination of lived experiences and literature review that captured a meta-analysis of research trends on e-learning. While trends in Teacher Education indicate progression towards adoption of technology, there are disparities between the theory and practice. Evidence from recent research and reports; and the recollected experiences confirmed knowledge, competence, skills and pedagogical gaps in the implementation of online learning, that have been exacerbated by COVID-19. The researcher recommends that teacher education should sensitize and train teacher trainees on how to access, analyze and use new knowledge emerging with technology; they also should be coached on how learners learn with technology and on fundamentals of the communication process. Particularly the course on educational technology, should focus on how to create and manage online courses. The 5-stage E-Moderator Model and Universal Design for Learning (UDL) are recommended as effective pedagogical scaffold for online teaching.",book:{id:"10229",slug:"teacher-education-in-the-21st-century-emerging-skills-for-a-changing-world",title:"Teacher Education in the 21st Century",fullTitle:"Teacher Education in the 21st Century - Emerging Skills for a Changing World"},signatures:"Catherine Adhiambo Amimo",authors:[{id:"333482",title:"Dr.",name:"Catherine Adhiambo",middleName:null,surname:"Amimo",slug:"catherine-adhiambo-amimo",fullName:"Catherine Adhiambo Amimo"}]},{id:"75224",title:"Decoding the Digital Gap in Teacher Education: Three Perspectives across the Globe",slug:"decoding-the-digital-gap-in-teacher-education-three-perspectives-across-the-globe",totalDownloads:589,totalCrossrefCites:0,totalDimensionsCites:4,abstract:"Educational use of technology is regularly assessed, and results often show a gap between educational policies and what is actually practiced. This chapter will help clarify how teacher educators experience the changing educational contexts due to the digital revolution, how their meaning-making shifts, and how outside forces influence those processes. The results are based on comparative international studies. Central for this study is practitioners’ professional digital competence, their attitudes towards digital technology and the use of digital technology in education. We found that the influence and contribution of digital practice is carried out quite differently across the globe. Our research questions were: How do practitioners experience teaching in a rapidly changing context? How do attitudes change due to top-down governing of education? and What motivates teacher educators to implement digital technology?",book:{id:"10229",slug:"teacher-education-in-the-21st-century-emerging-skills-for-a-changing-world",title:"Teacher Education in the 21st Century",fullTitle:"Teacher Education in the 21st Century - Emerging Skills for a Changing World"},signatures:"Steinar Thorvaldsen and Siri Sollied Madsen",authors:[{id:"332624",title:"Associate Prof.",name:"Siri Sollied",middleName:null,surname:"Madsen",slug:"siri-sollied-madsen",fullName:"Siri Sollied Madsen"},{id:"332626",title:"Prof.",name:"Steinar",middleName:null,surname:"Thorvaldsen",slug:"steinar-thorvaldsen",fullName:"Steinar Thorvaldsen"}]},{id:"75416",title:"Self-Study Research: Challenges and Opportunities in Teacher Education",slug:"self-study-research-challenges-and-opportunities-in-teacher-education",totalDownloads:777,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"This article aims to describe what self-study research is, why self-study can be a good approach to teacher educators’ professional development and improvements in practice and highlight some challenges and opportunities in this research approach. In addition, the article will shed light on some methodological aspects related to self-study. Self-study refers to teacher educators who in an intentionally and systematically way examine their practice to improve it, based on a deeper understanding of practice, as well as the context practice takes place. In the article, I argue that engaging in self-study is a learning and development process and an approach to developing personal professionalism, collective professionalism and improvements in practice.",book:{id:"10229",slug:"teacher-education-in-the-21st-century-emerging-skills-for-a-changing-world",title:"Teacher Education in the 21st Century",fullTitle:"Teacher Education in the 21st Century - Emerging Skills for a Changing World"},signatures:"Kåre Hauge",authors:[{id:"332053",title:"Associate Prof.",name:"Kåre",middleName:null,surname:"Hauge",slug:"kare-hauge",fullName:"Kåre Hauge"}]}],onlineFirstChaptersFilter:{topicId:"265",limit:6,offset:0},onlineFirstChaptersCollection:[],onlineFirstChaptersTotal:0},preDownload:{success:null,errors:{}},subscriptionForm:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[],offset:8,limit:8,total:0},allSeries:{pteSeriesList:[{id:"14",title:"Artificial Intelligence",numberOfPublishedBooks:9,numberOfPublishedChapters:90,numberOfOpenTopics:6,numberOfUpcomingTopics:0,issn:"2633-1403",doi:"10.5772/intechopen.79920",isOpenForSubmission:!0},{id:"7",title:"Biomedical Engineering",numberOfPublishedBooks:12,numberOfPublishedChapters:108,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2631-5343",doi:"10.5772/intechopen.71985",isOpenForSubmission:!0}],lsSeriesList:[{id:"11",title:"Biochemistry",numberOfPublishedBooks:33,numberOfPublishedChapters:330,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2632-0983",doi:"10.5772/intechopen.72877",isOpenForSubmission:!0},{id:"25",title:"Environmental Sciences",numberOfPublishedBooks:1,numberOfPublishedChapters:19,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2754-6713",doi:"10.5772/intechopen.100362",isOpenForSubmission:!0},{id:"10",title:"Physiology",numberOfPublishedBooks:14,numberOfPublishedChapters:145,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-8261",doi:"10.5772/intechopen.72796",isOpenForSubmission:!0}],hsSeriesList:[{id:"3",title:"Dentistry",numberOfPublishedBooks:9,numberOfPublishedChapters:141,numberOfOpenTopics:2,numberOfUpcomingTopics:0,issn:"2631-6218",doi:"10.5772/intechopen.71199",isOpenForSubmission:!0},{id:"6",title:"Infectious Diseases",numberOfPublishedBooks:13,numberOfPublishedChapters:124,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-6188",doi:"10.5772/intechopen.71852",isOpenForSubmission:!0},{id:"13",title:"Veterinary Medicine and Science",numberOfPublishedBooks:11,numberOfPublishedChapters:112,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2632-0517",doi:"10.5772/intechopen.73681",isOpenForSubmission:!0}],sshSeriesList:[{id:"22",title:"Business, Management and Economics",numberOfPublishedBooks:1,numberOfPublishedChapters:22,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2753-894X",doi:"10.5772/intechopen.100359",isOpenForSubmission:!0},{id:"23",title:"Education and Human Development",numberOfPublishedBooks:0,numberOfPublishedChapters:11,numberOfOpenTopics:1,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100360",isOpenForSubmission:!0},{id:"24",title:"Sustainable Development",numberOfPublishedBooks:1,numberOfPublishedChapters:19,numberOfOpenTopics:5,numberOfUpcomingTopics:0,issn:"2753-6580",doi:"10.5772/intechopen.100361",isOpenForSubmission:!0}],testimonialsList:[{id:"13",text:"The collaboration with and support of the technical staff of IntechOpen is fantastic. 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",coverUrl:"https://cdn.intechopen.com/series/covers/23.jpg",latestPublicationDate:"August 12th, 2022",hasOnlineFirst:!0,numberOfPublishedBooks:0,editor:{id:"280770",title:"Dr.",name:"Katherine K.M.",middleName:null,surname:"Stavropoulos",slug:"katherine-k.m.-stavropoulos",fullName:"Katherine K.M. Stavropoulos",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRdFuQAK/Profile_Picture_2022-05-24T09:03:48.jpg",biography:"Katherine Stavropoulos received her BA in Psychology from Trinity College, in Connecticut, USA and her Ph.D. in Experimental Psychology from the University of California, San Diego. She completed her postdoctoral work at the Yale Child Study Center with Dr. James McPartland. Dr. Stavropoulos’ doctoral dissertation explored neural correlates of reward anticipation to social versus nonsocial stimuli in children with and without autism spectrum disorders (ASD). She has been a faculty member at the University of California, Riverside in the School of Education since 2016. Her research focuses on translational studies to explore the reward system in ASD, as well as how anxiety contributes to social challenges in ASD. She also investigates how behavioral interventions affect neural activity, behavior, and school performance in children with ASD. She is also involved in the diagnosis of children with ASD and is a licensed clinical psychologist in California. 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