Median (range) anorectal symptoms at baseline and 1 month, annually to 5 years after radiation therapy for prostate carcinoma.
\\n\\n
IntechOpen Book Series will also publish a program of research-driven Thematic Edited Volumes that focus on specific areas and allow for a more in-depth overview of a particular subject.
\\n\\nIntechOpen Book Series will be launching regularly to offer our authors and editors exciting opportunities to publish their research Open Access. We will begin by relaunching some of our existing Book Series in this innovative book format, and will expand in 2022 into rapidly growing research fields that are driving and advancing society.
\\n\\nLaunching 2021
\\n\\nArtificial Intelligence, ISSN 2633-1403
\\n\\nVeterinary Medicine and Science, ISSN 2632-0517
\\n\\nBiochemistry, ISSN 2632-0983
\\n\\nBiomedical Engineering, ISSN 2631-5343
\\n\\nInfectious Diseases, ISSN 2631-6188
\\n\\nPhysiology (Coming Soon)
\\n\\nDentistry (Coming Soon)
\\n\\nWe invite you to explore our IntechOpen Book Series, find the right publishing program for you and reach your desired audience in record time.
\\n\\nNote: Edited in October 2021
\\n"}]',published:!0,mainMedia:{caption:"",originalUrl:"/media/original/132"}},components:[{type:"htmlEditorComponent",content:'With the desire to make book publishing more relevant for the digital age and offer innovative Open Access publishing options, we are thrilled to announce the launch of our new publishing format: IntechOpen Book Series.
\n\nDesigned to cover fast-moving research fields in rapidly expanding areas, our Book Series feature a Topic structure allowing us to present the most relevant sub-disciplines. Book Series are headed by Series Editors, and a team of Topic Editors supported by international Editorial Board members. Topics are always open for submissions, with an Annual Volume published each calendar year.
\n\nAfter a robust peer-review process, accepted works are published quickly, thanks to Online First, ensuring research is made available to the scientific community without delay.
\n\nOur innovative Book Series format brings you:
\n\nIntechOpen Book Series will also publish a program of research-driven Thematic Edited Volumes that focus on specific areas and allow for a more in-depth overview of a particular subject.
\n\nIntechOpen Book Series will be launching regularly to offer our authors and editors exciting opportunities to publish their research Open Access. We will begin by relaunching some of our existing Book Series in this innovative book format, and will expand in 2022 into rapidly growing research fields that are driving and advancing society.
\n\nLaunching 2021
\n\nArtificial Intelligence, ISSN 2633-1403
\n\nVeterinary Medicine and Science, ISSN 2632-0517
\n\nBiochemistry, ISSN 2632-0983
\n\nBiomedical Engineering, ISSN 2631-5343
\n\nInfectious Diseases, ISSN 2631-6188
\n\nPhysiology (Coming Soon)
\n\nDentistry (Coming Soon)
\n\nWe invite you to explore our IntechOpen Book Series, find the right publishing program for you and reach your desired audience in record time.
\n\nNote: Edited in October 2021
\n'}],latestNews:[{slug:"webinar-introduction-to-open-science-wednesday-18-may-1-pm-cest-20220518",title:"Webinar: Introduction to Open Science | Wednesday 18 May, 1 PM CEST"},{slug:"step-in-the-right-direction-intechopen-launches-a-portfolio-of-open-science-journals-20220414",title:"Step in the Right Direction: IntechOpen Launches a Portfolio of Open Science Journals"},{slug:"let-s-meet-at-london-book-fair-5-7-april-2022-olympia-london-20220321",title:"Let’s meet at London Book Fair, 5-7 April 2022, Olympia London"},{slug:"50-books-published-as-part-of-intechopen-and-knowledge-unlatched-ku-collaboration-20220316",title:"50 Books published as part of IntechOpen and Knowledge Unlatched (KU) Collaboration"},{slug:"intechopen-joins-the-united-nations-sustainable-development-goals-publishers-compact-20221702",title:"IntechOpen joins the United Nations Sustainable Development Goals Publishers Compact"},{slug:"intechopen-signs-exclusive-representation-agreement-with-lsr-libros-servicios-y-representaciones-s-a-de-c-v-20211123",title:"IntechOpen Signs Exclusive Representation Agreement with LSR Libros Servicios y Representaciones S.A. de C.V"},{slug:"intechopen-expands-partnership-with-research4life-20211110",title:"IntechOpen Expands Partnership with Research4Life"},{slug:"introducing-intechopen-book-series-a-new-publishing-format-for-oa-books-20210915",title:"Introducing IntechOpen Book Series - A New Publishing Format for OA Books"}]},book:{item:{type:"book",id:"5387",leadTitle:null,fullTitle:"Worldwide Wound Healing - Innovation in Natural and Conventional Methods",title:"Worldwide Wound Healing",subtitle:"Innovation in Natural and Conventional Methods",reviewType:"peer-reviewed",abstract:"The book Worldwide Wound Healing - Innovation in Natural and Conventional Methods develops a set of themes on the healing and treatment of complex wounds through evidence-based practice with innovations in the use of natural and conventional methods. It is an innovative way that promotes the integration of conventional and natural perspectives in wound healing, with a unique focus on the quality of life of the patient.",isbn:"978-953-51-2806-9",printIsbn:"978-953-51-2805-2",pdfIsbn:"978-953-51-7327-4",doi:"10.5772/62668",price:119,priceEur:129,priceUsd:155,slug:"worldwide-wound-healing-innovation-in-natural-and-conventional-methods",numberOfPages:162,isOpenForSubmission:!1,isInWos:null,isInBkci:!1,hash:"7fce44f4147d70a5f22ce850dedc729a",bookSignature:"Cesar Joao Vicente da Fonseca",publishedDate:"December 7th 2016",coverURL:"https://cdn.intechopen.com/books/images_new/5387.jpg",numberOfDownloads:14876,numberOfWosCitations:11,numberOfCrossrefCitations:9,numberOfCrossrefCitationsByBook:0,numberOfDimensionsCitations:19,numberOfDimensionsCitationsByBook:0,hasAltmetrics:1,numberOfTotalCitations:39,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"November 12th 2015",dateEndSecondStepPublish:"December 3rd 2015",dateEndThirdStepPublish:"April 22nd 2016",dateEndFourthStepPublish:"June 6th 2016",dateEndFifthStepPublish:"July 20th 2016",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6",editedByType:"Edited by",kuFlag:!1,featuredMarkup:null,editors:[{id:"182006",title:"Prof.",name:"César",middleName:null,surname:"Fonseca",slug:"cesar-fonseca",fullName:"César Fonseca",profilePictureURL:"https://mts.intechopen.com/storage/users/182006/images/5053_n.jpg",biography:"César João Vicente da Fonseca has received his master’s degree in Health Communication at the Universidade Aberta and PhD degree in Nursing at the University of Lisbon. He is currently a professor in the Universidade de Évora. He develops the following thematic areas: evidence-based practice; clinical decision-making; clinical guidelines; care needs assessment, control, and eradication of pain; reflection of clinical practices; organizational management of social equipment intended for older people; and health indicators of long-term care organizations. He has played roles in coordination and control team of the research and development unit of nursing schools of Lisbon, being responsible for several epidemiological research programs in the field of public health. He is responsible for international publication of several papers and the achievement of several scientific meetings in the areas described above, with international impact. He is part of the Portuguese Health Systems Observatory. Some of the papers that have been published feature great international impact factor and international relevance. There are 150 citations of the article published in international terms.",institutionString:null,position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"1",institution:{name:"University of Évora",institutionURL:null,country:{name:"Portugal"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"1131",title:"Global Health",slug:"global-health"}],chapters:[{id:"53204",title:"Wound Care: Traditional African Medicine Approach",doi:"10.5772/65521",slug:"wound-care-traditional-african-medicine-approach",totalDownloads:2301,totalCrossrefCites:1,totalDimensionsCites:4,hasAltmetrics:0,abstract:"Wound care represents a major health burden in Africa. The types and causes of wounds in Africa are numerous; however, the interventions to these injuries are easily accessed in hospitals in the urban cities, while in most rural communities, the primary source of interventions is traditional medicine (TM). In recent times, there are incidences of preferences to the use of TM in the management of especially challenging wounds even when conventional interventions are available. In some African communities, there are incidences of quasi integration of conventional and traditional African medicine (TAM) in wound care. In the typical traditional African approach to wound care, diverse practices such as the use of herbal medicine, divination, and other physical interventions are common. There appears to be a favorable future for wound management using TAM with the increasing popularity due to various affirmative reasons other than poverty. The recognition, patronage, and uses of TAM for wound care as an alternative or complimentary to the conventional approach is expected to continue, hence, the need for the different regional governments in consonance with the WHO to promote the standardization, regulation, and other factors that will assure the safety and efficacy of the various practices and products of TAM.",signatures:"Philip F. Builders and Modupe I. Builders",downloadPdfUrl:"/chapter/pdf-download/53204",previewPdfUrl:"/chapter/pdf-preview/53204",authors:[{id:"182744",title:"Dr.",name:"Philip",surname:"Builders",slug:"philip-builders",fullName:"Philip Builders"},{id:"193220",title:"Dr.",name:"Modupe",surname:"Builders",slug:"modupe-builders",fullName:"Modupe Builders"}],corrections:null},{id:"53129",title:"Research in Phyto‐Constituents for Treatment of Wounds",doi:"10.5772/65485",slug:"research-in-phyto-constituents-for-treatment-of-wounds",totalDownloads:1819,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Disruption of normal architecture of skin is referred to as wound. There are different types of wounds like contusion, excision, incision, burn, diabetic, etc. The body has its own mechanism to heal wounds in three major overlapping phases, namely inflammatory, proliferative and remodelling. Any agent that promotes the healing process can be utilized as a wound healing agent. Plants have been a great source of medicines to treat wounds. Elucidation of the mechanism of wound healing helped researchers to investigate plants in detail and find out their active constituents. Various biochemical changes take place during the wound healing process, and these changes served as targets for in vitro and in vivo models. In vitro and in vivo models are extensively utilized to evaluate wound healing activity. The present chapter gives an overview of some classes of phyto‐constituents having wound healing activity.",signatures:"Chhaya H. Gadgoli",downloadPdfUrl:"/chapter/pdf-download/53129",previewPdfUrl:"/chapter/pdf-preview/53129",authors:[{id:"182683",title:"Dr.",name:"Chhaya",surname:"Gadgoli",slug:"chhaya-gadgoli",fullName:"Chhaya Gadgoli"}],corrections:null},{id:"52445",title:"In Search of Wound Healing Drugs: A Journey Through Ayurveda",doi:"10.5772/65520",slug:"in-search-of-wound-healing-drugs-a-journey-through-ayurveda",totalDownloads:1693,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Description of wound healing is a recent concern of modern surgery and medical therapeutics, but first evidences are available in ancient Indian system of medicine, namely Ayurveda in the name of Vrana (wounds) and Vranaropaka (wound healing drugs). It has been reported that in different classical Ayurvedic texts, about 164 medicinal plants, 24 metals and minerals and 18 animal products are described for their wound healing activity. The mechanism of the healing process and the selection of drugs from natural resources are very specific in Ayurveda, and some of these have been scientifically screened. Besides a single component of drug, many classical formulations either in the form of polyherbal or herbo-minerals have been cited in Ayurveda from time to time since pre-vedic era to recent modern time. Many traditional folkloric preparations of India were also later on incorporated in Ayurveda utilizing sources of some pockets of Ayurveda in different parts of the country. Chronological development of these drugs on the basis of physical, molecular and clinical parameters is elaborated vividly with some examples of experimentation like Curcuma longa, Pterocarpus santalinus, Cynodon dactylon and a composed formulation named Kshantak Malam.",signatures:"Tuhin K. Biswas, Saheli Banerjee, Nandini Poyra, Srikanta Pandit,\nUtpalendu Jana, Shrabana Chakrabarti and Tapan Seal",downloadPdfUrl:"/chapter/pdf-download/52445",previewPdfUrl:"/chapter/pdf-preview/52445",authors:[{id:"182228",title:"Dr.",name:"Tuhin Kanti",surname:"Biswas",slug:"tuhin-kanti-biswas",fullName:"Tuhin Kanti Biswas"}],corrections:null},{id:"52939",title:"Natural Compounds for Wound Healing",doi:"10.5772/65652",slug:"natural-compounds-for-wound-healing",totalDownloads:3094,totalCrossrefCites:2,totalDimensionsCites:4,hasAltmetrics:0,abstract:"Many plants or plant-derived compounds with high levels of antioxidants and anti-inflammatory, immunomodulatory, and antimicrobial properties could be of great benefit for wound healing. Several studies have documented the use of plant extracts for the development of bioactive wound dressings. The purpose of this chapter is to give an update about the vegetal and bee products, which can be used as bioactive substances in wound dressings or in other formulations for wound healing. The adverse effects of plant and bee extracts, such as contact allergies, are also presented. In order to better exploit the huge reservoir of pharmacologically active plant-derived compounds and extracts, standardized methodology and clinical trials are necessary to give more concrete evidence supporting the use of traditional medicine in wound management.",signatures:"Mihaela Georgescu, Oana Marinas, Marcela Popa, Teodora Stan,\nVeronica Lazar, Serban Vifor Bertesteanu and Mariana Carmen\nChifiriuc",downloadPdfUrl:"/chapter/pdf-download/52939",previewPdfUrl:"/chapter/pdf-preview/52939",authors:[{id:"176120",title:"Dr.",name:"Veronica",surname:"Lazar",slug:"veronica-lazar",fullName:"Veronica Lazar"},{id:"183662",title:"Prof.",name:"Mariana Carmen",surname:"Chifiriuc",slug:"mariana-carmen-chifiriuc",fullName:"Mariana Carmen Chifiriuc"},{id:"186345",title:"BSc.",name:"Mihaela",surname:"Georgescu",slug:"mihaela-georgescu",fullName:"Mihaela Georgescu"},{id:"186346",title:"Dr.",name:"Oana",surname:"Marinas",slug:"oana-marinas",fullName:"Oana Marinas"},{id:"186347",title:"Dr.",name:"Marcela",surname:"Popa",slug:"marcela-popa",fullName:"Marcela Popa"},{id:"186348",title:"Dr.",name:"Teodora",surname:"Stan",slug:"teodora-stan",fullName:"Teodora Stan"},{id:"186349",title:"Dr.",name:"Serban Vifor",surname:"Bertesteanu",slug:"serban-vifor-bertesteanu",fullName:"Serban Vifor Bertesteanu"}],corrections:null},{id:"52856",title:"Nursing Interventions in Prevention and Healing of Leg Ulcers: Systematic Review of the Literature",doi:"10.5772/65719",slug:"nursing-interventions-in-prevention-and-healing-of-leg-ulcers-systematic-review-of-the-literature",totalDownloads:1908,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:1,abstract:"Aim: The purpose of this study was to define nursing interventions for patients with venous, arterial or mixed leg ulcers.",signatures:"César Fonseca, Manuel Lopes, Ana Ramos, Vitor Santos, Antonio\nEsquinas and Pedro Parreira",downloadPdfUrl:"/chapter/pdf-download/52856",previewPdfUrl:"/chapter/pdf-preview/52856",authors:[{id:"182006",title:"Prof.",name:"César",surname:"Fonseca",slug:"cesar-fonseca",fullName:"César Fonseca"}],corrections:null},{id:"52061",title:"Aspects Related to Venous Ulcer Healing and its Influence on Quality of Life",doi:"10.5772/64913",slug:"aspects-related-to-venous-ulcer-healing-and-its-influence-on-quality-of-life",totalDownloads:1738,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Nowadays, the varicose ulcers (VUs) are one of the most worrying leg ulcers and are an important global health problem, with high costs related to the treatment and its complications. Moreover, the quality of life (QOL) of the patient could be affected by pain, sleep disorders, functional impairment, depression, and isolation. The VU patient care is complex, and it is necessary to know the aspects that contribute to the healing process for developing effective strategies. The members of the multidisciplinary health team should identify sociodemographic, clinical, and care aspects that interfere in tissue repair and therefore impacting the QOL. Self-efficacy, adherence to treatment, and self-esteem are other important aspects also related to healing and QOL, with implications for health care and the multidisciplinary team. To sum up, the use of multidisciplinary protocols allows the systematization of care for people with VUs in order to standardize therapeutic interventions with the aim to decrease the healing process time and, as a consequence, to improve the QOL.",signatures:"Gilson V. Torres, Aline M. Pergola-Marconato, Thalyta C. Mansano-\nSchlosser, Rhayssa O. Araújo, Dalva C. Silva, Abigail Gómez-Morales,\nSandra M.S.G.S.O. Torres, Felismina R.P. Mendes and Eulália M.C.\nMaia",downloadPdfUrl:"/chapter/pdf-download/52061",previewPdfUrl:"/chapter/pdf-preview/52061",authors:[{id:"183298",title:"Dr.",name:"Gilson",surname:"Torres",slug:"gilson-torres",fullName:"Gilson Torres"},{id:"183896",title:"Dr.",name:"Thalyta Cristina",surname:"Mansano-Schlosser",slug:"thalyta-cristina-mansano-schlosser",fullName:"Thalyta Cristina Mansano-Schlosser"},{id:"183897",title:"Dr.",name:"Aline Maino",surname:"Pergola-Marconato",slug:"aline-maino-pergola-marconato",fullName:"Aline Maino Pergola-Marconato"},{id:"183898",title:"Dr.",name:"Felismina Rosa",surname:"Perreira Mendes",slug:"felismina-rosa-perreira-mendes",fullName:"Felismina Rosa Perreira Mendes"},{id:"183899",title:"Dr.",name:"Eulalia Maria",surname:"Chaves Maia",slug:"eulalia-maria-chaves-maia",fullName:"Eulalia Maria Chaves Maia"},{id:"183900",title:"MSc.",name:"Sandra Maria Da Solidade Gomes",surname:"Simões De Oliveira Torres",slug:"sandra-maria-da-solidade-gomes-simoes-de-oliveira-torres",fullName:"Sandra Maria Da Solidade Gomes Simões De Oliveira Torres"},{id:"183901",title:"MSc.",name:"Dalva Cezar",surname:"Da Silva",slug:"dalva-cezar-da-silva",fullName:"Dalva Cezar Da Silva"},{id:"183902",title:"MSc.",name:"Rhayssa",surname:"De Oliveira E Araújo",slug:"rhayssa-de-oliveira-e-araujo",fullName:"Rhayssa De Oliveira E Araújo"},{id:"183903",title:"MSc.",name:"Abigail",surname:"Gómez-Morales",slug:"abigail-gomez-morales",fullName:"Abigail Gómez-Morales"}],corrections:null},{id:"53065",title:"Placental Cells and Tissues: The Transformative Rise in Advanced Wound Care",doi:"10.5772/65321",slug:"placental-cells-and-tissues-the-transformative-rise-in-advanced-wound-care",totalDownloads:2328,totalCrossrefCites:6,totalDimensionsCites:11,hasAltmetrics:1,abstract:"The fetal environment has a remarkable capacity for facilitating and guiding tissue development. Placental tissues including the placental disc, umbilical cord, amniotic fluid and amniotic sac are highly specialized tissues responsible for transporting nutrients and coordinating developmental cues during pregnancy and fetal development. Placental tissues are nutrient-rich, structurally complex and immunologically privileged, making them promising allograft therapies for advanced wound care. Amniotic membrane allografts in particular have been shown to be effective therapies for treatment of chronic wounds, including diabetic and venous ulcers, by modulating inflammation, reducing scar tissue formation and enhancing healing. Amniotic membrane has also demonstrated the ability to promote cell proliferation, cell migration and modulate cytokine secretion by a variety of cell types involved in wound healing, including human dermal fibroblasts, microvascular endothelial cells and stem cells. In addition, amniotic membrane allografts have been shown to stimulate stem cell activity, promote angiogenesis and modulate inflammation in vitro and in vivo. Placental tissues are complex tissues composed of extracellular matrix (ECM), cells and a broad array of cytokines that may collectively enhance wound healing by modulating wound environments and stimulating endogenous cells to progress through the normal healing stages of inflammation, proliferation and remodeling.",signatures:"Jeremy J. Lim and Thomas J. Koob",downloadPdfUrl:"/chapter/pdf-download/53065",previewPdfUrl:"/chapter/pdf-preview/53065",authors:[{id:"183322",title:"Ph.D.",name:"Thomas",surname:"Koob",slug:"thomas-koob",fullName:"Thomas Koob"},{id:"194346",title:"Ph.D.",name:"Jeremy",surname:"Lim",slug:"jeremy-lim",fullName:"Jeremy Lim"}],corrections:null}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},subseries:null,tags:null},relatedBooks:[{type:"book",id:"6339",title:"Towards Malaria Elimination",subtitle:"A Leap Forward",isOpenForSubmission:!1,hash:"2ab88726cd9291b2b1c29889c948c902",slug:"towards-malaria-elimination-a-leap-forward",bookSignature:"Sylvie Manguin and Vas Dev",coverURL:"https://cdn.intechopen.com/books/images_new/6339.jpg",editedByType:"Edited by",editors:[{id:"50017",title:"Prof.",name:"Sylvie",surname:"Manguin",slug:"sylvie-manguin",fullName:"Sylvie Manguin"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3432",title:"Current Topics in Public Health",subtitle:null,isOpenForSubmission:!1,hash:"bbfaa5b624db308171170cb70e9de196",slug:"current-topics-in-public-health",bookSignature:"Alfonso J. 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Katsikis",coverURL:"https://cdn.intechopen.com/books/images_new/3037.jpg",editedByType:"Edited by",editors:[{id:"12289",title:"Prof.",name:"Vasilios",surname:"Katsikis",slug:"vasilios-katsikis",fullName:"Vasilios Katsikis"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1485",title:"Applications of Monte Carlo Method in Science and Engineering",subtitle:null,isOpenForSubmission:!1,hash:"08abe20f1549c83cfb208c83e12ee7df",slug:"applications-of-monte-carlo-method-in-science-and-engineering",bookSignature:"Shaul Mordechai",coverURL:"https://cdn.intechopen.com/books/images_new/1485.jpg",editedByType:"Edited by",editors:[{id:"21994",title:"Prof.",name:"Shaul",surname:"Mordechai",slug:"shaul-mordechai",fullName:"Shaul Mordechai"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1025",title:"Engineering Education and Research Using MATLAB",subtitle:null,isOpenForSubmission:!1,hash:"6e4cf9f0e6d7dccba13bc8edc4bf8e70",slug:"engineering-education-and-research-using-matlab",bookSignature:"Ali H. Assi",coverURL:"https://cdn.intechopen.com/books/images_new/1025.jpg",editedByType:"Edited by",editors:[{id:"12279",title:"Dr.",name:"Ali",surname:"Assi",slug:"ali-assi",fullName:"Ali Assi"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"50099",title:"Extracellular Matrix Enhances Therapeutic Effects of Stem Cells in Regenerative Medicine",doi:"10.5772/62229",slug:"extracellular-matrix-enhances-therapeutic-effects-of-stem-cells-in-regenerative-medicine",body:'\nStem cells reside within a specific extracellular microenvironment, which consists of a complex mixture of soluble and insoluble, short- and long-range signals [1]. Extracellular matrix (ECM) to which stem cells adheres is one of the microenvironmental parameters regulated stem-cell fates [2–4]. Once moving outside of their niche, stem cells will quickly lose their developmental potential, which limits the application of stem cell therapy [5]. Besides, mounting evidence on stem cells and their niche indicates that transplanted stem cells are unable to survive and adapt at the site of administration where there is lack of functional vascular network to transport blood, supply oxygen and nutrients, and remove metabolites [6].
\nThrough enhancing cell retention and engraftment after transplantation, modulating stem cell fate, and promoting functional vasculature formation, co-transplantation stem cells with natural or synthetic ECM that mimic natural extracellular milieu could be a potentially powerful tool to break the current bottleneck and maximize the effectiveness of stem cell therapy [7–9]. These strategies provide considerable hope for the development of stem cell therapy in degenerative diseases. This chapter will provide the insights into the interaction between stem cells and ECM, as well as current knowledge and involvement of stem cell therapy. Moreover, we will discuss the strategy of co-transplantation stem cells and ECM for tissue regeneration with enhanced therapeutic efficacy.
\nWith the capacity of self-renewal and differentiation, stem cells have shown promising potential in regenerative medicine and tissue engineering. So far, stem cell transplantation have been proposed as future therapies for degenerative diseases or injury, including Alzheimer\'s disease [10], type 1 diabetes [11], Parkinson\'s disease [12], cardiac disease [13], muscle damage [14] and many others [15–17]. However, some studies showed that stem cell therapy only had modest improvement, which could be attributed to the fact that transplanted cells were unable to survive and adapt in the diseased area. For instance, low cell retention and engraftment and remarkably cell death after transplantation have been observed by using bioluminescence imaging (BLI) [18].
\nThough it is not clear what signals and underlying pathways cause the acute donor cell death following transplantation, increasing evidence suggests that that a supportive microenvironment is of crucial importance for stem cell survival, proliferation and differentiation [5,19]. For this reason, the strategy to seed stem cells on biomaterials that mimic the biochemical and biophysical properties of native niche could be a viable solution to the above mentioned problems [20] and optimize functional recovery of injured tissue (Figure 1). For instance, Matrigel, a product derived from the Engelbroth-Holm-Swarm (EHS) mouse sarcoma, is one of the most commonly used plate-coating materials for stem cell culture in vitro and effectively applied vehicles for transplanted stem cells [21]. Mounting evidence has demonstrated that Matrigel could affect cell fate in a variety of dimensions [21,22]. However, Matrigel is a complex with unknown variable matrices and numerous mixed growth factors, which makes it impossible for us to get further insights into the interplay of stem cells and ECM. Besides, another reason for safety concern is that Matrigel has been reported contaminated with Lactate Dehydrogenase Elevating Virus [23]. To avoid these problems, artificially synthetic ECM with both high purity and defined components in qualitative and quantitative measures for safe application is strongly demanded [24,25]. Recently, developments in engineered ECM-based microenvironments have gradually exhibited their ability for directing stem cell behaviours, such as adhesion, proliferation, and differentiation [26].
\n\n
Extracellular matrix (ECM), acting in conjunction with the biophysical properties and biochemical extracellular stimuli, is critical to regulate stem cell maintenance and differentiation [27,28]. It has been reported that a form of apoptosis, called “anoikis”, would be initiated when interactions between stem cells and ECM were cut off [19]. Great effort has been made in an attempt to detail the mechanisms, which provides some key information for cell–ECM interplay. For example, recent study investigated changes of genes’ expression after cell detachment by using PCR Array [2]. In that study, researchers found that adhesion molecules expression had no significant difference between cultured human embryonic stem cell-derived endothelial cells (hESC-ECs) and enzymatically dispersed hESC-ECs suspended in Matrigel. However, a series of ECM and adhesion molecules-specific genes was considerably down-regulated in hESC-EC suspended in PBS (Figure 2). These gene-expression data indicated that adding ECM to detached cells could reverse genes down-regulation of ECM pathway, cell adhesion molecules pathway, ECM and adhesion signalling.
\n\n
The assignment of cell fate results from a response to sophisticated extracellular signals [29,30]. There is mounting evidence suggesting that ECM could deliver numerous soluble and immobilized factors that play vital roles in making the fate choice between self-renewal and lineage commitment [31]. Further insights and exquisite control of signals transported by ECM could provide opportunities for enhancing the regenerative efficacy in both in vitro and in vivo and further accelerating the translation of basic science to the clinical setting.
\nThe propagation of soluble signalling molecules controls a great variety of cellular responses, including proliferation [32], polarity [33], migration [34], and differentiation [35]. It has been demonstrated that a specific interaction between cells and ECM is required for the ultimate biological response of soluble molecules [29,36,37]. Interactions with ECM can affect the responses of cell toward signalling messengers. For instance, insulin-triggered activation of insulin receptor substrate (IRS) was intensely enhanced in cells cultured on basement membrane than on collagen I, whereas higher levels of tyrosine phosphorylation of the EGF receptor and Erk was triggered by EGF in cell adhesion to collagen I [36].
\n\n
In living systems, the coordinated effort among cells, growth factors and ECM is required for the successful tissue regeneration. The ability of manipulating biological signals transduced by ECM in a controlled and spatiotemporal manner that mimic the natural regenerative process could provide specific control over the stem cell-based regenerative therapy [38]. The potential therapeutic effect of a peptide-based ECM with the capacity of controlled release nitric oxide (NO), NapFF-NO, was tested in a mouse model of myocardial infarction [9]. The therapeutic effect of adipose-derived-mesenchymal stem cells (ADSCs) was elevated through co-transplantation with NapFF-NO and on-demand NO release (Figure 3). Additionally, the administration of growth factors within the context of the ECM niche could accentuate their therapeutic effects for tissue repair [39]. It was reported that a recombinant fragment of fibronectin (FN) could significantly enhance the regenerative effects of growth factors in models of chronic wounds and bone defects [40].
\nSustained release and improved local retention of regenerative factors, such as growth factors and extracellular substances, are required during tissue regeneration [41]. However, these molecules are suffering from rapid degradation, and therefore they will quickly lose their functionality and clinical efficacy [42]. Additionally, there is evidence that cellular processes are also affected by the interactions between cells and non-soluble constituents of the ECM [43]. For these reasons, immobilization of signalling molecules or functional components to ECM could be suitable for stabilizing these highly reactive molecules, increasing local concentration of biochemical stimuli, and increasing the bioactivity of engineered ECM.
\nA growing number of studies have utilized short synthetic peptides to mimic the biological properties of full-length growth factors and to substitute parent proteins [44,45]. For example, insulin-like growth factor 1 (IGF-1) is considered as an essential biochemical stimulus in tissue regeneration. The C domain of IGF-1 (IGF-1C), a 12 amino acids sequence, had already been proved as the active region of IGF-1 [46]. IGF-1C has been used as substitute for IGF-1 and applied into hydrogel biomaterials as biomimetic material for tissue engineering and regenerative medicine. The proliferation, apoptosis resistance, and paracrine effects of ADSCs were significantly enhanced after they were seeded on chitosan (CS) hydrogel with immobilization of IGF-1C [47]. When co-transplanted ADSCs with CS-IGF-1C hydrogel into ischemic organ, this biomimetic matrix could create a favourable microenvironment for the survival and adaptation of transplanted cells and further promote functional and structural recovery of injured organ (Figure 4).
\n\n
Although it has commonly acknowledged that signals transduced by ECM could direct stem cell fate, there is increasing evidence that physical properties of ECM could also make a great impact on cell behaviours [48–50]. Some of these factors are proven to be of great influence, but we still have a long way to go and a lot of work to do to establish a complete theory. For example, in response to injury, the accumulation of ECM is excess and abnormal, which would cause significant changes to the stiffness of ECM and ultimately lead to tissue fibrosis [51,52].
\nTo test the effect of different stiffness (EY) on cell behaviors, substrates with EY ranging from <1 kPa to 30 kPa were synthesized [53]. The results showed that ECM stiffness has influence on cell proliferation as well as cell differentiation. For instance, neural stem/progenitor cells (NSPCs) could proliferated on substrates with EY <10 kPa. On soft substrates (<1 kPa), neuronal differentiation was promoted; whereas, on relatively stiff substrates (>7 kPa), oligodendrocyte differentiation was favoured. This consequence indicated that matrix stiffness had effect on lineage choice and differentiation. In light of previous data that stiffness was a regulator of differentiation, Shih et al. further explore how matrix affects the osteogenic phenotype of MSCs [54]. They found that the matrix rigidity promoted osteogenic commitment through a α2-integrin-ROCK-FAK-ERK1/2 axis.
\nFascinatingly, it was observed that mesenchymal stem cells all underwent osteogenic differentiation on both stiff and soft polydimethylsiloxane (PDMS) substrates; whereas, the osteoblast differentiation of the same cells was promoted on stiff polyacrylamide (PAAm) hydrogels, and more cell differentiated into adipocytes on soft PAAm hydrogels [55]. The different cellular responses to different substrates indicated that stiffness was not an independent stimulus for differentiation. Further data provided in this study suggested that the differentiation of human mesenchymal stem cells on PAAm was also regulated by the elastic modulus. Consistent with the previous study, Xue et al. reported that matrix elasticity was the main physical parameter directing stem cell differentiation at low cell density; with increased cell density, the cell–cell contact force and interactions took priority over the matrix elasticity [56]. Most notably, although cell differentiation was influenced by elastic modulus, recent discovery found that matrix-promoted adipogenic or osteogenic differentiation could not maintain when the cells were re-seeded into tissue culture plastic (TCP) [57]. Furthermore, global gene expression profiles and DNA-methylation profiles revealed no significant impact caused by matrix with different elasticity. These results indicated that matrix elasticity only exerted a transient influence on stem cell lineage commitment.
\nWhen cells were seeded on ECM with different ligand densities, changes in stem cell viability, size, and shape provided the direct evidence that ligand immobilized to ECM could not be easily separated from the biophysical effects of matrix [58,59]. The spatial arrangement of ligands had a significant influence on MSC behavior [44]. Through manipulating of the ratio of polystyrene-block-poly (ethylene oxide) copolymers (PS-PEO-Ma) in mixtures of block copolymer and polystyrene homopolymer, the lateral spacing of RGD (arginine-glycine-aspartic acid) peptides was under control. With increased lateral spacing, osteogenesis of MSC was reduced while adipogenic differentiation was increased, which was consistent with the results of gene expression levels and alkaline phosphatase activities.
\nMoreover, the type of ligands covalently linked to ECM could also influence stem cell fate determination. The differentiation of MSCs on different composition of adhesion ligands with the same concentration was various. MSCs cultured on fibronectin or laminin matrices tended to undergo adipogenic differentiation; whereas, MSCs cultured on ECM containing collagen preferred to adopt a neurogenic outcome [60].
\nRecent development also demonstrated that macro/nano-scale of ECM was another important physical parameter that could not only change the shape of stem cells but also influence the behaviour of stem cells. A preliminary study demonstrated Zyxin played an important role in nanotopographical feature-facilitated changes in stem cells [48]. On 350 nm grating, expression of Zyxin was down-regulated, which was associated with the accelerated speed of migration and the decreased intracellular tension. Likewise, McMurray et al. revealed that modification in surface nanotopography of thermoplastic polycaprolactone (PCL) would influence intracellular tension, which could maintain the multipotency of stem cells and diminish spontaneous differentiation of MSC [61]. Moreover, his current study further illustrated that nanoscale spatial organization of cell-adhesive ligands bound to ECM could affect lineage commitment of MSCs [62]. By using nanopatterning techniques, arginine-glycine-aspartate (RGD) was covalently linked to the surface of poly (ethyleneglycol) (PEG) hydrogels with different nanospacing. It was interesting to identify that large RGD nanospacing was beneficial for osteogenesis; small RGD nanospacing was conducive to adipogenesis.
\nMany attempts at cell therapy have employed ECM to improve efficacy for the following reasons. First, the major obstacle to the application of stem cells, which is known as the extremely poor survival and engraftment of transplanted stem cells, could be minimized by co-transplantation stem cells with ECM [51,63,64]. Second, engineered ECM mimicking the natural stem-cell microenvironments could provide plenty of subtle and instructive cues to control the fate of both transplanted and endogenous cells, including stem cell self-renewal, differentiation, and migration [7,65,66]. Taken together, the development of engineered matrices is promising for the application of stem cells in regenerative medicine.
\nFor both experimental studies and clinical applications, transplanted stem cells are commonly prepared for transplantation as single cells. During this process, interactions between cells and ECM are lost and adhesion-related survival signals are down-regulated, which could cause a decrease in cell viability and initiated apoptosis [67]. Fortunately, recent research discovered that the down-regulated molecules of detached cells could be regained in the presence of Matrigel [4], which provided a theoretical rationale for using ECM as a protective scaffold to enhance viability and to stimulate self-renewal of the transplanted cells.
\nIn support of this finding, recent study demonstrated that biomimetic scaffold could protect the transplanted stem cells, and further promote functional and structural recovery from acute kidney injury (AKI). Through immobilization of the C-domain of insulin-like growth factor 1 (IGF-1C) to chitosan (CS) hydrogel (CS-IGF-1C), an artificial microenvironment for supporting growth of stem cells was synthesized. The pro-proliferative, anti-apoptotic, and pro-angiogenic effects of CS-IGF-1C were demonstrably beneficial for enhancing survival of transplanted stem cells, which could ameliorate renal function [47] (Figure 5).
\n\n
Besides, we could attribute the efficacy of stem cell therapy partly to the pluripotency of stem cells [68,69]. A morphological study of MSCs in collagen type I (Col I) hydrogel and in interfacial polyelectrolyte complexation (IPC) based hydrogels containing Col I discovered that cells were neatly arranged and closely packed in IPC- Col I hydrogel [70]. This uniform arrangement results in notably enhanced commitment to the chondrogenic lineage of MSC, which could be an attractive source of cartilage equivalents for tissue engineering.
\nRecently, a variety of studies have demonstrated that decellularized matrix could provide tissue specific cues for cell growth and lineage commitment [71–73]. Decellularized myocardial matrix hydrogel, which keeps the original structure and natural heart ECM, is the most compelling example among these biomaterials. One of the most inspiring finding is that a mouse heart could contract and beat again after removing its own cells and repopulating the decellularized whole-heart ECMs (DC-ECMs) with multipotential cells that could differentiate in response to the signals from the DC-ECMs. Through repopulating decellularized mouse hearts with induced pluripotent stem cell (iPSC)-derived earliest heart progenitors, the recellularized DC-ECMs exhibited myocardium, vessel-like structures, intracellular Ca2+ transients (CaiT), spontaneous heart contractions and significant response to numerous drug interventions [74].
\nMSCs could mobilize into circulating blood and be recruited to the injury site, which was consistent with the evidence that numbers of MSCs were increased considerably in peripheral blood [75]. Several approaches were used in an attempt to investigate this cell recruitment event. It was unexpected to find that ECM was indispensable for the homing of MSCs toward sites of injury [76]. The homing effect could be inhibited through adding inhibitor of serine proteases and leupeptin to ECM, which illustrated the key role of matrix remodelling in MSC migration. In addition, evidence also indicated that exposing MSCs to injury-associated ECM prior to transplantation could augment the efficiency of MSCs’ intrinsic tropism for injury [77].
\nAs resident stem cells and progenitor cells could be activated to participate tissue regeneration after injury [78,79], ECM designed for cell seeding should also benefit the growth of host cells and support the function of endogenous cells. Encouragingly, evidence suggested that host cells could respond to ECM in the site of injury in vivo. Firstly, immune responses were elicited in hosts, which was identified by the quickly infiltrated CD68+ cells throughout the entire ECM within 3 days after implantation. Then there were indications of myogenesis in the muscle injury area, which was confirmed by morphology and myosin heavy chain positive staining [80].
\nFurthermore, accumulating data suggested that human mesenchymal stem cells (hMSCs) could modulate immune system response through their paracrine effect and then create a pro-regenerative environment in situ. Their paracrine effects could be optimized through encapsulating hMSCs into protective ECM [81]. The recruitment of endogenous macrophages and the M1/M2 polarization were modulated by the trophic factors secreted by hMSCs, which was possibly capable of counteracting the hostile environment and sustaining tissue regeneration. This cell-friendly microenvironment could also be established by administration of ECM alone. Increased stem cell tropism, revascularization, and improved cardiac function induced by chitosan-based ECM were observed in ischemic myocardium [82], which may be attributing to the mechanical support provided by ECM and the therapeutic biomolecules enriched by ECM [83–85].
\nThe ECM is not only a simple scaffold that provides physical supports for stem cells but also a dynamic and complex environment that is capable of regulating cell behaviours. Although the application of natural or synthetic ECM with the aim to enhance therapeutic effects of stem cells is highly appealing for promoting regenerative processes, issues related to efficiency and safety limit their translational use as regenerative medicine. Further identifying specific biochemical and biophysical properties of ECM and understanding the interplay between stem cells and ECM will provide knowledge of stem cell biology and fuel the development of regenerative therapies based on stem cells.
\nThis work was partially supported by grants from the National Natural Science Foundation of China (81371620, 81320108014), Tianjin Natural Science Foundation (14JCZDJC35200) and the Program for Changjiang Scholars and Innovative Research Team in University (IRT13023).
\nAmong the estimated 300,000 patients per year worldwide undergoing radiotherapy for pelvic malignant diseases such as carcinoma of the uterine cervix and corpus, bladder and prostate, nine out of 10 will develop a permanent change in their bowel habit [1]. Furthermore, this UK group and an Australian group of clinician scientists have independently reported that 50% of all patients report an adverse impact on activities of daily living (ADL) after pelvic radiotherapy [1, 2].
The radiation induced bowel symptoms which have the greatest adverse effect on ADL are anorectal symptoms such as increased frequency and urgency of defecation, fecal incontinence and rectal bleeding collectively referred to as Chronic Radiation Proctitis (CRP) [1, 2, 3].
The prevalence of CRP is uncertain. Studies using physician based questionnaires such as the Radiation Therapy Oncology Group (RTOG) scales report a prevalence of only 5–10% [4]. However, because these scales do not evaluate common anorectal symptoms such as urgency of defecation and fecal incontinence, physician based scales probably under-estimate the prevalence of CRP. In support of this, studies that have included patient-based questionnaires such as the Late Effect Normal Tissue – Subjective Objective Management Analytic (LENT – SOMA) scales have reported that up to 78% of patients have persistent anorectal symptoms after radiotherapy for prostate carcinoma [5, 6, 7, 8, 9]. Although persistent anorectal symptoms impair the daily activities of 50% of all patients 5 years after pelvic radiotherapy, the pathophysiology of anorectal dysfunction has not been fully characterized and its treatment is unsatisfactory. Previous physiological studies in patients with anorectal dysfunction after radiotherapy have been limited either by methodological inadequacies [10] or lack of follow-up studies beyond 2 years [11, 12].
The rationale for the selection of each of the 4 listed studies for discussion in this chapter are provided under the sub-headings below:
Pathophysiology and natural history of anorectal sequelae following radiation therapy for carcinoma of the prostate [2]
In view of the limitations of previous physiological studies of anorectal function after radiotherapy for prostate carcinoma, 5 year data from an Australian prospective, longitudinal study of a subset of patients who participated in a Phase III randomized trial comparing a 4 week course of (hypofractionated) radiotherapy with the then conventional 6.5 week schedule of radiotherapy for carcinoma of the prostate [13] will first be presented.
A retrospective study of the effects of pelvic irradiation for gynecological cancer on anorectal function [14])
As at least a third of patients, who have had pelvic radiotherapy for gynecological cancer are reported to suffer significant radiation bowel sequelae [1], anorectal function data from the above retrospective study will be presented next.
Argon Plasma Coagulation Therapy versus Topical Formalin for intractable rectal bleeding and anorectal dysfunction after radiation therapy for prostate carcinoma [15]
As rectal bleeding is the second most common reason for referral to a gastroenterologist after pelvic radiotherapy even though it impairs the ADL’s of only 6% of patients [1], data from the only randomized trial of two current approaches used in the treatment of haemorrhagic radiation proctitis above will follow.
Pudendal nerve injury impairs anorectal function and health related quality of life measures ≥2 years after 3D conformal radiotherapy for prostate cancer [16]
Previous studies of the pathophysiology of anorectal dysfunction after radiotherapy for carcinoma of the prostate including our own have implicated weakness of the external anal sphincter (EAS) and internal anal sphincter (IAS), decreased rectal compliance, increased rectal sensitivity and faster distal colonic transit [2, 17, 18]. The underlying pathogenesis proposed for the observed changes in anorectal dysmotility is either myogenic or neurogenic. However, as muscle tissue particularly striated muscle constituting the EAS is more resistant to radiation damage than neural tissue [2], evidence of pudendal nerve injury after radiotherapy for prostate cancer is presented in the above study [16]. In addition, the editorial accompanying the publication states that the findings show the way forward for the restoration of bowel health of patients who have been adversely affected following pelvic radiotherapy for urological and gynecological malignant diseases [19].
The 34 patients, median age = 68 (range 54–79) years, selected for the above study met the following eligibility criteria:
Were part of the 217 total patient population participating in a previous Phase III randomized trial of two radiation dose schedules [13]
Have completed (7) serial evaluations (before radiotherapy, at 1 month and at 1 yearly intervals to 5 years after completion of radiotherapy) of anorectal function using the same manometric assembly
Have not needed treatment intervention likely to influence anorectal function such as a constant requirement for antidiarrhoeal medication and argon plasma coagulation therapy (APC) for rectal bleeding
Have provided signed informed consent
Of the total patient population of 217 patients, 86 patients (57 completed two serial evaluations of anorectal function using an earlier manometric assembly which meant that later serial measurements were no longer comparable, 5 started radiotherapy before baseline evaluation and 24 patients died before 5 years), failed to meet eligibility criterion (ii), 12 patients, who required APC for rectal bleeding after radiotherapy, failed eligibility criterion (iii) and 85 patients, who withdrew consent for anorectal manometry after radiotherapy because of distant domicile from the laboratory, failed eligibility criterion (iv).
Each of the 34 patients meeting all eligibility criteria for the study underwent evaluations of (i) gastrointestinal symptoms (modified LENT-SOMA scales including effect on activities of daily living (ADL), (ii) anorectal motor and sensory function (manometry with a perfused sleeve and multiport assembly incorporating a highly compliant polyethylene bag in the rectum) and (iii) anal sphincteric morphology (endoanal ultrasound) before radiotherapy and at 1 month, then yearly for 5 years after completion of radiotherapy.
Total GI symptom scores increased after radiotherapy and remained above baseline levels at 5 years (Table 1). At this time, 48% of patients reported impairment of ADL [2].
Baseline | 1 mo | 1 y | 2 y | 3 y | 4 y | 5 y | ANOVA P value | |
---|---|---|---|---|---|---|---|---|
Stool frequency | 0(0–2) | 1(0–2) | 1(0–2) | 1(0–2) | 1(0–1) | 1(0–2) | 1(0–1) | 0.05 |
Stool Consistency | 0(0–1) | 0(0–2) | 0(0–2) | 0(0–2) | 0(0–2) | 0(0–1) | 0(0–2) | ns |
Rectal Pain | 0(0–1) | 0(0–3) | 0(0–1) | 0(0–1) | 0(0–1) | 0(0–1) | 0(0–2) | <.01 |
Rectal mucous discharge | 0(0–2) | 0(0–4) | 0(0–3) | 0(0–3) | 0(0–3) | 0(0–3) | 0(0–3) | <.01 |
Urgency of defecation | 0(0–3) | 0(0–4) | 1(0–3) | 1(0–3) | 1(0–4) | 1(0–3) | 1(0–3) | ns |
Rectal bleeding | 0(0–2) | 0(0–2) | 0(0–2) | 0(0–3) | 0(0–3) | 0(0–2) | 0(0–4) | ns |
Total GI symptom | 2(0–4) | 3(0–10) | 3(0–9)* | 3(0-9)* | 3(0-7)† | 3(0–9)* | 3(0-9)* | <.01 |
Median (range) anorectal symptoms at baseline and 1 month, annually to 5 years after radiation therapy for prostate carcinoma.
P < .05 Compared with baseline.
P < .01 Compared with baseline.
From Yeoh et al. [2], with permission.
The prevalence of persistent urgency of defaecation (44%) was doubled that of rectal bleeding (21%) at 5 years. The % of patients free from the risk of urgency of defecation was significantly less than that of rectal bleeding (Figure 1).
Percent of patients free from urgency of defaecation vs. rectal bleeding 5 years after radiation therapy. GI = gastrointestinal. (From Yeoh et al. [
All measures of anorectal motor function remained below baseline levels at 5 years (Table 2). Furthermore, anal pressures in response to voluntary squeeze and increased intra-abdominal pressure progressively decreased after radiotherapy.
Baseline | 1 mo | 1 y | 2y | 3y | 4y | 5y | ANOVA | |
---|---|---|---|---|---|---|---|---|
Basal pressure (mm Hg) | 65 ± 3 | 63 ± 3 | 59 ± 3 | 60 ± 3 | 54 ± 3† | 57 ± 3 | 56 ± 3* | <.001 |
Squeeze Pressure (mm Hg) | 128 ± 10 | 126 ± 9 | 106 ± 6* | 105 ± 6† | 104 ± 5† | 103 ± 6† | 99 ± 6‡ | <.0001 |
Increased intra-abdominal Pressure (mm Hg) | 104 ± 5 | 99 ± 4 | 96 ± 5 | 99 ± 5 | 94 ± 4 | 92 ± 5 | 90 ± 5* | <.05 |
First Perception (mL) | 24 ± 2 | 17 ± 1† | 17 ± 1† | 15 ± 1‡ | 14 ± 1‡ | 14 ± 1‡ | 15 ± 1‡ | <.0001 |
Desire to defecate (mL) | 63 ± 7 | 44 ± 5 | 58 ± 6 | 40 ± 4* | 42 ± 3 | 51 ± 6 | 60 ± 8 | <.0001 |
Rectal compliance(mL) | 8.2 ± 0.6 | 7.4 ± 0.5 | 6.8 ± 0.7 | 6.2 ± 0.8* | 6.4 ± 0.7 | 5.7 ± 0.5† | 5.5 ± 0.6† | <0.001 |
IAS thickness(mm) | 2.4 ± 0.1 | 2.2 ± 0.1 | 2.2 ± 0.2 | 2.1 ± 0.1 | 2.1 ± 0.1 | 2.2 ± 01 | 2.3 ± 0.1 | ns |
EAS thickness (mm) | 10.7 ± 0.5 | 11.2 ± 0.5 | 11.2 ± 0.5 | 10.5 ± 0.5 | 10.3 ± 0.7 | 9.6 ± 0.4 | 9.7 ± 0.7 | Ns |
Mean (± SE) anal pressurres (sleeve), rectal sensory volumes, rectal compliance, and anal sphincter thickness at baseline and I month, annually to 5 years after radiation therapy for prostate carcinoma.
P < .05 compared with baseline.
P < .01 compared with baseline.
P < .0001 compared with baseline.
From Yeoh et al. [2], with permission.
The volume for first perception of rectal distension and that associated with the desire to defaecate both decreased after radiotherapy although only threshold volumes for sensory perception at 5 years remained below those recorded at baseline (Table 2). Rectal compliance progressively reduced with time after radiotherapy and remained persistently lower at 5 years compared with that recorded at baseline Table 2).
Radiotherapy had no effect on the thicknesses of the IAS and EAS (Table 2).
There were no differences in any of the GI symptoms nor in any anorectal functional and anal sphincteric morphological measurements between patients randomized to the 2 radiation dose schedules.
5 years after radiotherapy for carcinoma of the prostate, persistent GI symptoms continue to have a significant impact on ADL of almost 50% of all patients. At this time, the prevalence of urgency of defecation (44%) was doubled that of rectal bleeding (21%). Increased GI symptoms after radiotherapy were associated with progressive or persistent reductions of basal anal pressures and pressures in response to voluntary squeeze and increased intra-abdominal pressures, rectal compliance and volumes of sensory perception and desire to defaecate. These physiological changes, which suggest weakness of the IAS and EAS as well as stiffness of the rectal wall and consequent increased rectal sensitivity, are the pathogenetic basis for anorectal dysfunction after radiotherapy for carcinoma of the prostate. The etiology of the motility changes is likely to be neurogenic in the intrinsic neural network in the bowel wall and/or extrinsic nerve supply such as the pudendal nerves since muscle tissue, particularly striated muscle is more resistant to radiation damage.
The 15 patients, median age = 67 (range 47–84) years, selected for the study met the following eligibility criteria:
Were part of the 33 total patient population who completed pelvic and abdominal irradiation 5–10 years earlier for carcinoma of the cervix (n = 30) and endometrium (n = 3) who participated in a previous prospective longitudinal study of changes in gastrointestinal function after pelvic radiotherapy [20]
Had not needed treatment intervention likely to influence anorectal function such as a constant requirement for antidiarrhoeal medication
Had provided signed informed consent
Of the original total patient population of 33 patients, 6 had died and 2 had been lost to follow-up since completing the previous study [20]. The 25 remaining patients were invited to participate in this study, 10 refused including two patients who had intermittent episodes of rectal bleeding.
9 healthy females, median age = 63 (range 41–70) years served as control subjects.
The following parameters were assessed in each subject: (i) anorectal symptoms (questionnaire), (ii) anorectal motor and sensory function (manometry with a perfused sleeve and multiport assembly incorporating a highly compliant latex balloon in the rectum and concurrent electromyography of the anal sphincters) and (iii) anal sphincteric morphology (endoanal ultrasound).
Total anorectal symptom scores was significantly greater in the patients compared with the control subjects (Table 3). Urgency of defaecation was the most frequent symptom, occurring in 10 of the 15 patients (67%). Four of these patients also had fecal incontinence [14]. Urgency of defecation in eight of the 10 patients resulted in changes in lifestyle such that the patients were either housebound or could only go out if there was a toilet nearby [14].
Parameters/subjects | Fecal incontinence | Urgency of defecation | Symptom score* | No. of bowel actions/week* | No. of babies* | No. with large babies | No. who had forceps | ||
---|---|---|---|---|---|---|---|---|---|
Diurnal | Nocturnal | Both | |||||||
Patients | 3/15 | 1/15 | 10/15 | 10/15† | 3‡(0-8) | 13(13-28) | 3(0–12) | 4/15 | 3/15 |
Normal | 0/9 | 0/9 | 1/9 | 1/9 | 0(0) | 7(7–14) | 3(0–4) | 2/9 | 2/9 |
Anorectal symptoms including bowel habits and obstetric parameters in patients and normal subjects.
Median (range).
From Yeoh et al. [14], with permission.
Basal minimum pressures just proximal to the anal canal (4 cm from the anal verge) were lower in the patients than the control subjects (p = 0.05) and there was a trend for lower basal maximum pressures at the same site (p = 0.07, Table 4).
Normal | Patients | ||
---|---|---|---|
EAS (mm) | 8.8 ± 0.5 | 9 ± 0.4 | 0.78 |
IAS (mm) | 2.8 ± 0.2 | 2.3 ± 0.2 | 0.65 |
Anal 0.5 cm† | 64 ± 12.5 | 45.1 ± 5.5 | 0.13 |
Sleeve | 58.7 ± 6.3 | 53.3 ± 6.2 | 0.58 |
Anorectal 4 cm† | 22 ± 5.8 | 12.1 ± 1.9 | 0.07 |
Anal 0.5 cm† | 32.2 ± 8.2 | 33.1 ± 5.0 | 0.93 |
Sleeve | 44.3 ± 5.6 | 41.5 ± 5.9 | 0.75 |
Anorectal 4 cm† | 14.1 ± 3.3 | 8.1 ± 1.0 | 0.05 |
Anal 0.5 cm† | 108.2 ± 21.6 | 70 ± 10.0 | 0.08 |
Sleeve | 103 ± 10.2 | 68.1 ± 7.2 | 0.01 |
Anorectal 4 cm† | 26.4 ± 4.6 | 16.3 ± 1.8 | 0.03 |
Change EMG activity (mm) | 6.7 ± 1.8 | 6.2 ± 0.8 | 0.75 |
Anal 0.5 cm† | 61.8 ± 11.6 | 49.4 ± 0.8 | 0.35 |
Sleeve | 70.1 ± 7.5 | 65.6 ± 7.8 | 0.7 |
Anorectal 4 cm† | 35.8 ± 3.7 | 30.5 ± 2.2 | 0.21 |
Change EMG activity (mm) | 3.8 ± 1.0 | 3.4 ± 0.5 | 0.75 |
Maximum thickness of IAS and EAS and anorectal pressures (basal, in response to voluntary squeeze and blowing up a party balloon).
Data are mean values ±SEM.
Manometric port distances from anal verge.
From Yeoh et al. [14], with permission.
Squeeze pressures measured at the sleeve sensor and at 4 cm from the anal verge were lower in the patients (p < 0.05, Table 4) and were below the control range in five patients [14].
In the patients, residual anorectal pressures measured at 0.5 cm from the anal verge in response to rectal distension were less (p ≤ 0.05) at volumes of 10 ml, 20 ml and 40 ml (Table 5). There was also a trend for lower pressures in the patients at the highest (100 ml) volume (p = 0.09).
Normal | Patients | ||
---|---|---|---|
Anal 0.5 cm† | 47.3 ± 10.8 | 27.7 ± 4.1 | 0.05 |
Sleeve | 41.6 ± 7.9 | 30.8 ± 4.3 | 0.2 |
Anorectal 4 cm† | 8.6 ± 1.5 | 8.1 ± 0.6 | 0.77 |
Anal 0.5 cm* | 40.2 ± 5.9 | 24.6 ± 3.0 | 0.02 |
Sleeve | 34.2 ± 7.5 | 26.7 ± 3.4 | 0.31 |
Anorectal 4 cm† | 10.4 ± 1.9 | 9.1 ± 0.7 | 0.44 |
Anal 0.5 cm† | 35.6 ± 4.8 | 23.1 ± 3.2 | 0.04 |
Sleeve | 30.2 ± 4.7 | 30.3 ± 3.7 | 0.99 |
Anorectal 4 cm† | 12 ± 1.7 | 10.2 ± 0.8 | 0.3 |
Anal 0.5 cm† | 43.5 ± 12.0 | 29.9 ± 7.6 | 0.33 |
Sleeve | 31.1 ± 6.0 | 30.9 ± 4.0 | 0.98 |
Anorectal 4 cm† | 17 ± 2.5 | 12.8 ± 1.3 | 0.12 |
Anal 0.5 cm† | 43.8 ± 11.8 | 20.1 ± 6.3 | 0.09 |
Sleeve | 30.5 ± 6.9 | 35.5 ± 5.7 | 0.59 |
Anorectal 4 cm† | 13.7 ± 2.5 | 19 ± 6.6 | 0.49 |
A higher proportion of patients perceived the desire to defecate at lower rectal volumes than the controls (p < 0.05, Figure 2). The slope of the pressure/volume relationship associated with rectal distension volumes of 20 ml, 40 ml, 60 ml, 100 ml and overall slope was greater in the patients (p < 0.05, p < 0.01, p < 0.001, p < 0.001 and p < 0.05 respectively than the controls, suggesting that rectal compliance was reduced in the patients (Figure 3).
Rectal volumes at which patients and normal subjects felt desire to defaecate. (From Yeoh et al. [
Pressure/volume relationship in patients and controls associated with rectal distension (from Yeoh et al. [
There were no differences in external anal sphincteric electrical activity between the patients and control subjects in response to voluntary squeeze and blowing up a party balloon (Table 4). Either basal pressures, pressures generated in response to rectal distension, voluntary squeeze and blowing up a party balloon were below the control range in 14 of the 15 patients, including all 10 patients with anorectal symptoms [14].
There was no difference in mean EAS and IAS thickness between the two groups (Table 4) nor difference in thicknesses of the EAS and IAS in patients with and without urgency of defaecation [14].
The data indicate that (i) urgency of defaecation, occurring in 10 out 15 (67%) of patients 10–15 years after pelvic irradiation for gynecological cancer resulted in eight of the 10 patients being either housebound or only able to go out if there was a toilet nearby, (ii) anorectal symptoms were associated with multiple parameters of anorectal dysfunction including weakness of the external anal sphincter, stiffness of the rectal wall and consequent increase in rectal sensitivity.
The 30 patients, median age = 72 (range 49–87) years selected for the study met the following eligibility criteria:
Had completed radiotherapy for prostate carcinoma ≥6 months previously
had intractable rectal bleeding (defined as ≥1x per week and/or requiring blood transfusions) attributed to CRP at colonoscopy
had no constant requirement for medications likely to influence anorectal motility such as opioid analgesics and anti-diarrhoeal agents
Had provided signed informed consent
The 30 eligible patients were randomized to treatment with APC (n = 17) or topical formalin (n = 13).
Each patient underwent evaluations of (i) anorectal symptoms (validated questionnaires including modified LENT-SOMA scales for GI symptoms and visual analogue scales for rectal bleeding), (ii) anorectal motor and sensory function (manometry with a perfused sleeve and multiport assembly incorporating a highly compliant polyethylene bag in the rectum) and (iii) anal sphincteric morphology (endoanal ultrasound) before and after the treatment endpoint (defined as reduction of rectal bleeding to 1x per month or better, reduction of visual analogue scales to ≤25 mm, no longer needing blood transfusions). Cross-over to the other therapy was allowed if the treatment endpoint was not reached after 4 treatment sessions.
Rectal bleeding was controlled in twenty nine of the 30 patients after a median of 2 treatment sessions of APC or topical formalin. One patient, initially treated with APC, failed after 4 treatment sessions but achieved control after 3 sessions of cross-over topical formalin, Control of rectal bleeding was evidenced by reductions of its frequency to ≤1x per month, VAS ≤ 25 mm (Figures 4 and 5, Table 6) and no further requirement for blood transfusion in the 2 patients (1 each in APC and topical formalin groups) needing this before randomization to therapy.
Visual analogue scale (VAS) before (pre) and after (post) APC treatment. (From Yeoh et al. [
Visual analogue scale (VAS) before (pre) and after (post) topical formalin treatment. (From Yeoh et al. [
Wilcoxon rank sum test for listed parameters | Before APC | After APC | Before formalin | After formalin | ||
---|---|---|---|---|---|---|
No. of bowel actions per week | 14(4–39) | 16(7–46) | NS | 16(3–32) | 14(4–42) | NS |
Fecal incontinence scores | 0(0–10) | 0(0–4) | NS | 0(0–3) | 0(0–2) | NS |
Urgency of defecation scores | 3(0–6) | 4(0–6) | NS | 4(0–6) | 4(0–6) | NS |
Rectal bleeding scores | 3(1–4) | 1(0–2) | .0001 | 3(2–4) | 1(0–2) | .001 |
VAS for rectal bleeding (mm) | 52(22–75) | 14(0–34) | .05 | 50(32–100) | 13(0–25) | .01 |
Effect on anorectal symptom parameters of argon plasma coagulation therapy (APC) and topical formalin treatment.
Abbreviations: NS, not significant; VAS, visual analogue scale; Values are median (range).
From Yeoh et al. [15], with permission.
The durability of control of rectal bleeding by APC and topical formalin was evidenced by only 1 patient in each group needing further therapy after a median (range) follow-up of 111 (29–170) months [15].
No effect on other anorectal symptoms, such as increased frequency and urgency of defecation and fecal incontinence, was observed (Table 6).
Other than a reduction in rectal compliance and volumes of sensory perception after APC, no effects on parameters of anorectal function and anal sphincteric morphology were observed (Table 7).
Student’s | Before APC | After APC | Before formalian | After formalin | ||
---|---|---|---|---|---|---|
Basal pressure (mm Hg) | 52 ± 4 | 58 ± 2 | NS | 58 ± 5 | 51 ± 3 | NS |
Squeeze pressure (mm Hg) | 95 ± 8 | 100 ± 9 | NS | 97 ± 6 | 89 ± 6 | NS |
Increased intra-abdominal pressure (mm Hg) | 85 ± 4 | 88 ± 6 | NS | 87 ± 6 | 92 ± 6 | NS |
Threshold of perception pressure (mm Hg) | 16 ± 1 | 17 ± 1 | NS | 18 ± 2 | 19 ± 2 | NS |
Threshold of perception volume (mL) | 19 ± 2 | 14 ± 1 | .05 | 17 ± 3 | 14 ± 1 | NS |
Desire to defecate (mL) | 61 ± 10 | 48 ± 5 | NS | 45 ± 11 | 47 ± 9 | NS |
Rectal compliance (mm Hg/mL) | 4.2 ± 0.4 | 3.3 ± 0.4 | .01 | 8.1 ± 2.6 | 4.3 ± 0.7 | NS |
IAS thickness (mm) | 2.4 ± 0.1 | 2.2 ± 0.1 | NS | 2.4 ± 0.1 | 2.4 ± 0.2 | NS |
EAS thickness (mm) | 10.0 ± 0.5 | 10.5 ± 0.5 | NS | 11.5 ± 0.6 | 11.2 ± 0.6 | NS |
Effect on anorectal function and anal sphincteric morphology parameters of argon plasma coagulation therapy (APC) and topical formalin treatment.
From Yeoh et al. [15], with permission.
APC and topical formalin had comparable efficacy in the durable control of rectal bleeding associated with chronic radiation proctitis but no beneficial effect on anorectal dysfunction.
The 25 patients, median age = 76 (range 64–83) years, selected for the above study met the following eligibility criteria:
Were part of 80 patients still attending follow up ≥2 years after 3D conformal radiotherapy ± high dose rate brachytherapy (HDR) for localized prostate carcinoma under the supervision of the same tertiary institution based Radiation Oncologist
Had no clinical or radiological signs of relapse
Had not needed treatment intervention likely to influence anorectal function such as a constant requirement for antidiarrhoeal medication nor argon plasma coagulation therapy (APC) for rectal bleeding
Had provided signed informed consent
Of the 80 patients invited to participate in the study, 48 refused, 7 were ineligible (6 had APC for rectal bleeding, 1 patient had received 2D radiotherapy).
25 age matched patients with localized prostate carcinoma in a recent randomized radiotherapy study served as control subjects [21].
Each subject underwent the following evaluations: (i) GI symptoms (modified LENT-SOMA scales), (ii) generic and disease specific HRQoL measures (EORTC QLQ-C30 and EORTC QLQ-PR25 questionnaires), (iii) anorectal motor and sensory function (manometry with a perfused sleeve and multiport assembly incorporating a highly compliant polyethylene bag in the rectum), (iv) pudendal nerve function (terminal motor nerve latency) and (v) anal sphincteric morphology (endoanal ultrasound).
The data of the 25 patients ≥2 years after 3D conformal radiotherapy for prostate cancer were compared with the before radiotherapy (baseline) data of the 25 control subjects.
The data of symptomatic (defined as patients with Total LENT-SOMA GI symptom scores ≥5, n = 13) and asymptomatic (defined as patients with Total LENT-SOMA GI symptom scores ≤4, n = 12) patients among the 25 patients ≥2 years after 3D conformal radiotherapy were also compared.
Patients in this study had significantly higher modified LENT – SOMA frequency and urgency of defaecation, rectal bleeding and mucous discharge scores ≥2 years after 3D conformal radiotherapy compared to the age matched control subjects before radiotherapy (Table 8). The patients also had worse (lower) EORTC QLQ-C30 cognitive functioning scores and worse (higher) EORTC QLQ-PR25 bowel symptom scores compared to the controls before radiotherapy (Table 8).
LENTSOMA | Whole Patient Group | Age Matched Patient Group | p value |
---|---|---|---|
1 (0–3) | 0 (0–1) | <0.01 | |
0 (0–2) | 0 (0–1) | ns | |
0 (0–2) | 0 (0–2) | ns | |
0 (0–3) | 0 (0–1) | <0.05 | |
2 (0–4) | 1 (0–2) | <0.001 | |
0 (0–3) | 0 (0–0) | <0.0001 | |
100 (60–100) | 93 (47–100) | ns | |
100 (50–100) | 100 (17–100) | ns | |
83 (58–100) | 83 (67–100) | ns | |
83 (50–100) | 83 (67–100) | <0.05 | |
100 (50–100) | 100 (33–100) | ns | |
83 (17–100) | 83 (33–100) | ns | |
0 (0–33) | 0 (0–100) | ns | |
33 (0–100) | 33 (0–100) | ns | |
0 (0–33) | 0 (0–33) | ns | |
0 (0–17) | 0 (0–33) | ns | |
0 (0–67) | 0 (0–67) | ns | |
0 (0–100) | 0 (0–33) | ns | |
22 (0–44) | 22 (0–78) | ns | |
0 (0–100) | 0 (0–100) | ns | |
0 (0–33) | 0 (0–67) | ns | |
17 (0–58) | 13 (0–67) | ns | |
8 (0–42) | 0 (0–17) | <0.01 | |
6 (0–50) | 6 (0–50) | ns |
Comparison of modified LENT-SOMA GI symptoms and EORTC generic (QOL-C30) and disease specific (QLQ-PR25) HRQoL data between whole patient group and age matched patients before radiotherapy.
From Yeoh et al. [16], with permission.
Symptomatic patients had significantly higher (i) modified LENT SOMA urgency of defaecation and rectal bleeding scores and (ii) EORTC QLQ-PR25 bowel and urinary symptom scores compared with asymptomatic patients (Table 9). Symptomatic patients also had worse (lower) EORTC QLQ-C30 social and emotional functional as well as global health scores compared to asymptomatic patients (Table 9).
LENT-SOMA | Symptomatic patients | Asymptomatic patients | |
---|---|---|---|
Frequency | 1(0–3) | 1(0–1) | ns |
Diarrhea | 1(0–2) | 0(0–2) | ns |
Pain | 0(0–2) | 0(0–2) | ns |
Mucous | 1(0–3) | 0(0–1) | ns |
Urgency | 3(1–4) | 1(0–4) | <.01 |
Bleeding | 1(0–3) | 0(0–1) | <.001 |
Physical functioning | 87(60–100) | 100(73–100) | ns |
Role functioning | 100(50–100) | 100(67–100) | ns |
Emotional functioning | 75(58–100) | 96(67–100) | =.05 |
Cognitive functioning | 83(50–100) | 83(67–100) | ns |
Social functioning | 83(50–100) | 100(67–100) | <.001 |
Global health status | 67(50–83) | 83(17–100) | <.05 |
Dyspnea | 0(0–33) | 0(0–33) | ns |
Insomnia | 33(0–100) | 33(0–33) | ns |
Appetite loss | 0(0–33) | 0(0–0) | ns |
Nausea of vomiting | 0(0–17) | 0(0–17) | ns |
Constipation | 33(0–67) | 33(0–33) | ns |
Diarrhea | 0(0–100) | 0(0–33) | =.05 |
Fatigue | 33(0–44) | 11(0–33) | <.05 |
Pain | 0(0–33) | 0(0–100) | ns |
Financial difficulty | 0(0–33) | 0(0–0) | ns |
Urinary symptoms | 25(0–58) | 10(0–25) | <.05 |
Bowel symptoms | 25(8–42) | 0(0–25) | <.001 |
Hormonal treatment-related symptoms | 11(0–50) | 6(0–33) | ns |
Comparison of modified LENT-SOMA GI symptoms and EORTC generic (QOL-C30) and disease specific (QLQ-PR25) HRQoL data between symptomatic and asymptomatic patients.
From Yeoh et al. [16], with permission.
All parameters of anorectal motor and sensory function except for threshold volumes for sensory perception were significantly worse ≥2 years after 3D conformal radiotherapy compared to age matched control subjects before radiotherapy (Table 10).
ARM | Whole patient group | Age matched patient group | |
---|---|---|---|
Basal pressure (mmHg) | 46 ± 4 | 63 ± 3 | <.01 |
Squeeze pressure (mmHg) | 105 ± 8 | 154 ± 8 | <.0001 |
↑Intra-abdominal pressure (mmHg) | 82 ± 5 | 106 ± 5 | <.01 |
IAS (mm) | 2.1 ± 0.1 | 2.6 ± 0.1 | <.05 |
EAS (mm) | 8.0 ± 0.3 | 9.3 ± 0.3 | <.01 |
Threshold perception (mL) | 14 ± 1 | 16 ± 2 | ns |
Desire to defecate sensation (mL) | 68 ± 8 | 97 ± 9 | <.05 |
Rectal compliance (mL/mmHg) | 3.3 ± 0.3 | 5.1 ± 0.4 | <.01 |
FI score | 2(0–8) | 0(0–1) | <.001 |
Urgency score | 2(0–6) | 0(0–3) | <.001 |
Number of bowel actions/week | 10.5(7–24.5) | 7(3.5–21) | <.05 |
Comparison of anorectal function and anal sphincter morphology data between whole patient group and age matched patients before radiotherapy.
From Yeoh et al. [16], with permission.
Unilateral and/or bilateral pudendal nerve responses were delayed in 13/24 (54%) of the patients compared to only 2/20 (10%) aged matched controls before radiotherapy (p < 0.0001, data not shown).
The thickness of both IAS and EAS was significantly less in the patients compared to the control subjects before radiotherapy (Table 10).
Fecal incontinence scores were worse in the symptomatic compared to the asymptomatic patients but no differences were detected in thickness of either IAS or EAS in the patient sub-groups (Table 11).
ARM | Symptomatic patients | Asymptomatic patients | |
---|---|---|---|
Basal pressure (mmHg) | 42 ± 5 | 51 ± 6 | ns |
Squeeze pressure (mmHg) | 92 ± 9 | 119 ± 11 | ns |
↑Intra-abdominal pressure (mmHg) | 78 ± 7 | 86 ± 8 | ns |
IAS (mm) | 2.3 ± 0.2 | 2.1 ± 0.2 | ns |
EAS (mm) | 8.4 ± 0.4 | 7.6 ± 0.3 | ns |
Threshold perception (mL) | 15 ± 2 | 13 ± 1 | ns |
Desire to defecate sensation (mL) | 55 ± 8 | 81 ± 14 | ns |
Rectal compliance (mL/mmHg) | 3.4 ± 0.4 | 3.2 ± 0.4 | ns |
FI score | 3(0–8) | 0(0–3) | <.01 |
Urgency score | 3(0–6) | 0(0–5) | ns |
Number of bowel actions/week | 14(7–24.5) | 10.5(7–17.5) | ns |
Comparison of anorectal function and anal sphincter morphology data between symptomatic and asymptomatic patients.
From Yeoh et al. [16], with permission.
Unilateral and/or bilateral pudendal nerve responses were delayed in 9/13 (69%) of symptomatic compared to only 4/11 (36%) of asymptomatic patients (p < 0.0001, data not shown).
Rectal and anal (i) V40Gy > 65%, (ii) Dmax >60 Gy, (iii) pudendal nerve Dmax >60 Gy and (iv) Anal V60 Gy >40% were associated with a greater prevalence of pudendal nerve function [16].
3D radiotherapy ± high dose rate brachytherapy (HDR) for localized prostate carcinoma impairs functional measures including HRQoL, anorectal and pudendal nerve function ≥2 years after treatment. Radiation dose constraints are proposed for reducing the prevalence of pudendal nerve dysfunction.
The data presented in this chapter, based on studies spanning over two decades examining gastrointestinal effects of pelvic radiotherapy for prostate and gynecological cancer, indicate that despite advances in radiotherapy technology, anorectal dysfunction persist or progressively worsen over a period of 5–10 years after treatment. The multiple deteriorations in anorectal function, consisting of weakness of the anal sphincters, stiffness of the rectal wall and consequent increase in rectal sensitivity, result in ∼50% of patients being housebound and only able to go out if there is a toilet nearby. The studies also show that the prevalence of rectal bleeding is half that of urgency of defaecation. In addition, results of the first randomized trial of Argon Plasma Coagulation Therapy versus topical formalin for intractable rectal bleeding after radiotherapy for prostate cancer indicate that durable control is achieved in 94–100% of patients after a median of 2 sessions of either treatment, only 7% of patients requiring re-treatment after a median follow-up of 9 years [15]. In contrast, therapeutic options for anorectal dysfunction are limited to medications such as loperamide and nicardipine based on pathophysiological evaluation of bowel disorders which include chronic radiation proctitis. For example, nicardipine which increases the rectal threshold for desire to defecate in patients with irritable bowel syndrome and reported to be effective in the treatment of urgency of defecation has been proposed for the treatment of urgency of defecation associated with chronic radiation proctitis since threshold volumes for desire to defecate are also reduced in CRP [14]. Similarly, loperamide, by increasing basal anal and squeeze pressures in patients with fecal incontinence of diverse aetiologies including radiation bowel disease, has been proposed for the treatment of fecal incontinence associated with CRP [14]. However, loperamide reduces stool bulk potentially increasing the risk of rectal bleeding and a lower dose than that prescribed for other bowel disorders is recommended [2]. Whilst the most advanced radiation treatment technique of intensity modulated radiation therapy (IMRT) was not used in the studies here, the prevalence of anorectal toxicity after IMRT for prostate cancer has been reported to be 65%, worse or no different from that reported in studies using less advanced treatment techniques including those reported here [1, 2, 6, 14, 16]. A likely explanation for the failure of IMRT to reduce anorectal dysmotility after treatment is that its underlying pathogenesis is damage to neural tissue in the bowel wall and/or the pudendal nerves [2, 16]. As discussed in the editorial accompanying the published findings of the final study of this chapter [19], the pudendal nerves are not considered as normal tissues at risk of radiation damage and therefore could potentially receive the same if not higher doses of radiation as the prostate target of irradiation. Radiation dose constraints for normal tissues at risk including the pudendal nerves have been proposed (Section 2.4 above) and if applied now that IMRT has been adopted almost universally, patients who need pelvic radiotherapy for urological and gynecological cancer can look forward to a future free of distressing bowel morbidity. Furthermore, the daily insertion of endorectal balloons during radiotherapy (Figure 6), which have been shown to be very well tolerated and to further reduce radiation exposure of the rectal and anal wall (and the anatomically closely related pudendal nerves) by IMRT [5] means a bowel complication free cure of pelvic malignant disease can be realistically achieved in the foreseeable future.
Transverse (top) and sagittal dose distributions of IMRT plans for prostate cancer without (left) and with (right) endorectal balloon in place. Contours: Rectal wall (green), anal wall (purple). (From Smeenk et al. [
The work reported in this chapter is based on 4 published studies of the effect of radiotherapy for prostate and gynecological cancer on anorectal function. All studies were performed in the Departments of Radiation Oncology, Gastroenterology and Colorectal Surgery, Royal Adelaide Hospital, Australia, affiliated with the University of Adelaide with substantial technical expertise for the performance of pudendal nerve terminal motor latency provided by the Department of Gastroenterology and Surgery, Flinders Medical Centre, Australia, affiliated with Flinders University.
The names of the contributors to the 4 published studies, listed as co-authors in the references section, are acknowledged although none of these co-authors contributed to the writing of this chapter.
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\\n\\nAcademic Editors should declare if the Author of a submitted manuscript is affiliated with the same department, faculty, institute, or company as they are.
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\\n"}]'},components:[{type:"htmlEditorComponent",content:"In each instance of a possible Conflict of Interest, IntechOpen aims to disclose the situation in as transparent a way as possible in order to allow readers to judge whether a particular potential Conflict of Interest has influenced the Work of any individual Author, Editor, or Reviewer. IntechOpen takes all possible Conflicts of Interest into account during the review process and ensures maximum transparency in implementing its policies.
\n\nA Conflict of Interest is a situation in which a person's professional judgment may be influenced by a range of factors, including financial gain, material interest, or some other personal or professional interest. For IntechOpen as a publisher, it is essential that all possible Conflicts of Interest are avoided. Each contributor, whether an Author, Editor, or Reviewer, who suspects they may have a Conflict of Interest, is obliged to declare that concern in order to make the publisher and the readership aware of any potential influence on the work being undertaken.
\n\nA Conflict of Interest can be identified at different phases of the publishing process.
\n\nIntechOpen requires:
\n\nCONFLICT OF INTEREST - AUTHOR
\n\nAll Authors are obliged to declare every existing or potential Conflict of Interest, including financial or personal factors, as well as any relationship which could influence their scientific work. Authors must declare Conflicts of Interest at the time of manuscript submission, although they may exceptionally do so at any point during manuscript review. For jointly prepared manuscripts, the corresponding Author is obliged to declare potential Conflicts of Interest of any other Authors who have contributed to the manuscript.
\n\nCONFLICT OF INTEREST – ACADEMIC EDITOR
\n\nEditors can also have Conflicts of Interest. Editors are expected to maintain the highest standards of conduct, which are outlined in our Best Practice Guidelines (templates for Best Practice Guidelines). Among other obligations, it is essential that Editors make transparent declarations of any possible Conflicts of Interest that they might have.
\n\nAvoidance Measures for Academic Editors of Conflicts of Interest:
\n\nFor manuscripts submitted by the Academic Editor (or a scientific advisor), an appropriate person will be appointed to handle and evaluate the manuscript. The appointed handling Editor's identity will not be disclosed to the Author in order to maintain impartiality and anonymity of the review.
\n\nIf a manuscript is submitted by an Author who is a member of an Academic Editor's family or is personally or professionally related to the Academic Editor in any way, either as a friend, colleague, student or mentor, the work will be handled by a different Academic Editor who is not in any way connected to the Author.
\n\nCONFLICT OF INTEREST - REVIEWER
\n\nAll Reviewers are required to declare possible Conflicts of Interest at the beginning of the evaluation process. If a Reviewer feels he or she might have any material, financial or any other conflict of interest with regards to the manuscript being reviewed, he or she is required to declare such concern and, if necessary, request exclusion from any further involvement in the evaluation process. A Reviewer's potential Conflicts of Interest are declared in the review report and presented to the Academic Editor, who then assesses whether or not the declared potential or actual Conflicts of Interest had, or could be perceived to have had, any significant impact on the review itself.
\n\nEXAMPLES OF CONFLICTS OF INTEREST:
\n\nFINANCIAL AND MATERIAL
\n\nNON-FINANCIAL
\n\nAuthors are required to declare all potentially relevant non-financial, financial and material Conflicts of Interest that may have had an influence on their scientific work.
\n\nAcademic Editors and Reviewers are required to declare any non-financial, financial and material Conflicts of Interest that could influence their fair and balanced evaluation of manuscripts. If such conflict exists with regards to a submitted manuscript, Academic Editors and Reviewers should exclude themselves from handling it.
\n\nAll Authors, Academic Editors, and Reviewers are required to declare all possible financial and material Conflicts of Interest in the last five years, although it is advisable to declare less recent Conflicts of Interest as well.
\n\nEXAMPLES:
\n\nAuthors should declare if they were or they still are Academic Editors of the publications in which they wish to publish their work.
\n\nAuthors should declare if they are board members of an organization that could benefit financially or materially from the publication of their work.
\n\nAcademic Editors should declare if they were coauthors or they have worked on the research project with the Author who has submitted a manuscript.
\n\nAcademic Editors should declare if the Author of a submitted manuscript is affiliated with the same department, faculty, institute, or company as they are.
\n\nPolicy last updated: 2016-06-09
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Her research interests include archaea metabolism, enzymes purification and characterization, gene regulation, carotenoids and bioplastics production, antioxidant\ncompounds, waste water treatments, and brines bioremediation.\nRosa María’s other roles include editorial board member for several journals related\nto biochemistry, reviewer for more than 60 journals (biochemistry, molecular biology, biotechnology, chemistry and microbiology) and president of several organizing committees in international meetings related to the N-cycle or respiratory processes.",institutionString:null,institution:{name:"University of Alicante",institutionURL:null,country:{name:"Spain"}}},editorTwo:null,editorThree:null},{id:"15",title:"Chemical Biology",coverUrl:"https://cdn.intechopen.com/series_topics/covers/15.jpg",isOpenForSubmission:!0,editor:{id:"441442",title:"Dr.",name:"Şükrü",middleName:null,surname:"Beydemir",slug:"sukru-beydemir",fullName:"Şükrü Beydemir",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00003GsUoIQAV/Profile_Picture_1634557147521",biography:"Dr. Şükrü Beydemir obtained a BSc in Chemistry in 1995 from Yüzüncü Yıl University, MSc in Biochemistry in 1998, and PhD in Biochemistry in 2002 from Atatürk University, Turkey. 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Since 1983, he has been a faculty member of the RO Perelman Department of Dermatology, NYU School of Medicine, where he is codirector of a training grant in cutaneous biology. Dr. Blumenberg’s research is focused on the epidermis, expression of keratin genes, transcription profiling, keratinocyte differentiation, inflammatory diseases and cancers, and most recently the effects of the microbiome on the skin. 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Dr. Şentürk currently works as an professor of Biochemistry in the Department of Basic Pharmacy Sciences, Faculty of Pharmacy, Ağri Ibrahim Cecen University, Turkey. \nDr. Şentürk published over 120 scientific papers, reviews, and book chapters and presented several conferences to scientists. \nHis research interests span enzyme inhibitor or activator, protein expression, purification and characterization, drug design and synthesis, toxicology, and pharmacology. \nHis research work has focused on neurodegenerative diseases and cancer treatment. 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He then worked as an Assistant Professor at the Faculty of Science of the same University until 1984. In 1985, Prof. Iadarola became Associate Professor at the Department of Biology and Biotechnologies of the University of Pavia and retired in October 2017. Since then, he has been working as an Adjunct Professor in the same Department at the University of Pavia. His research activity during the first years was primarily focused on the purification and structural characterization of enzymes from animal and plant sources. During this period, Prof. Iadarola familiarized himself with the conventional techniques used in column chromatography, spectrophotometry, manual Edman degradation, and electrophoresis). Since 1995, he has been working on: i) the determination in biological fluids (serum, urine, bronchoalveolar lavage, sputum) of proteolytic activities involved in the degradation processes of connective tissue matrix, and ii) on the identification of biological markers of lung diseases. In this context, he has developed and validated new methodologies (e.g., Capillary Electrophoresis coupled to Laser-Induced Fluorescence, CE-LIF) whose application enabled him to determine both the amounts of biochemical markers (Desmosines) in urine/serum of patients affected by Chronic Obstructive Pulmonary Disease (COPD) and the activity of proteolytic enzymes (Human Neutrophil Elastase, Cathepsin G, Pseudomonas aeruginosa elastase) in sputa of these patients. 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She gained considerable experience in developing and validating new methodologies whose applications allowed her to determine both the amount of biomarkers (Desmosine and Isodesmosine) in the urine of patients affected by COPD, and the activity of proteolytic enzymes (HNE, Cathepsin G, Pseudomonas aeruginosa elastase) in the sputa of these patients. Simona Viglio was also involved in research dealing with the supplementation of amino acids in patients with brain injury and chronic heart failure. She is presently engaged in the development of 2-DE and LC-MS techniques for the study of proteomics in biological fluids. The aim of this research is the identification of potential biomarkers of lung diseases. She is an author of about 90 publications (According to Scopus: H-Index: 23; According to WOS: H-Index: 20) on peer-reviewed journals, a member of the “Società Italiana di Biochimica e Biologia Molecolare,“ and a Consultant Reviewer for International Journal of Molecular Science, Journal of Chromatography A, COPD, Plos ONE and Nutritional Neuroscience.",institutionString:null,position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"2",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"University of Pavia",institutionURL:null,country:{name:"Italy"}}},editorThree:null,series:{id:"11",title:"Biochemistry"}}},seriesLanding:{item:{id:"11",title:"Biochemistry",doi:"10.5772/intechopen.72877",issn:"2632-0983",scope:"Biochemistry, the study of chemical transformations occurring within living organisms, impacts all areas of life sciences, from molecular crystallography and genetics to ecology, medicine, and population biology. Biochemistry examines macromolecules - proteins, nucleic acids, carbohydrates, and lipids – and their building blocks, structures, functions, and interactions. Much of biochemistry is devoted to enzymes, proteins that catalyze chemical reactions, enzyme structures, mechanisms of action and their roles within cells. Biochemistry also studies small signaling molecules, coenzymes, inhibitors, vitamins, and hormones, which play roles in life processes. Biochemical experimentation, besides coopting classical chemistry methods, e.g., chromatography, adopted new techniques, e.g., X-ray diffraction, electron microscopy, NMR, radioisotopes, and developed sophisticated microbial genetic tools, e.g., auxotroph mutants and their revertants, fermentation, etc. More recently, biochemistry embraced the ‘big data’ omics systems. Initial biochemical studies have been exclusively analytic: dissecting, purifying, and examining individual components of a biological system; in the apt words of Efraim Racker (1913 –1991), “Don’t waste clean thinking on dirty enzymes.” Today, however, biochemistry is becoming more agglomerative and comprehensive, setting out to integrate and describe entirely particular biological systems. The ‘big data’ metabolomics can define the complement of small molecules, e.g., in a soil or biofilm sample; proteomics can distinguish all the comprising proteins, e.g., serum; metagenomics can identify all the genes in a complex environment, e.g., the bovine rumen. This Biochemistry Series will address the current research on biomolecules and the emerging trends with great promise.",coverUrl:"https://cdn.intechopen.com/series/covers/11.jpg",latestPublicationDate:"June 29th, 2022",hasOnlineFirst:!0,numberOfOpenTopics:4,numberOfPublishedChapters:318,numberOfPublishedBooks:32,editor:{id:"31610",title:"Dr.",name:"Miroslav",middleName:null,surname:"Blumenberg",fullName:"Miroslav Blumenberg",profilePictureURL:"https://mts.intechopen.com/storage/users/31610/images/system/31610.jpg",biography:"Miroslav Blumenberg, Ph.D., was born in Subotica and received his BSc in Belgrade, Yugoslavia. He completed his Ph.D. at MIT in Organic Chemistry; he followed up his Ph.D. with two postdoctoral study periods at Stanford University. Since 1983, he has been a faculty member of the RO Perelman Department of Dermatology, NYU School of Medicine, where he is codirector of a training grant in cutaneous biology. Dr. Blumenberg’s research is focused on the epidermis, expression of keratin genes, transcription profiling, keratinocyte differentiation, inflammatory diseases and cancers, and most recently the effects of the microbiome on the skin. 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Topics include, but are not limited to: Advanced techniques of cellular and molecular biology (Molecular methodologies, imaging techniques, and bioinformatics); Biological activities at the molecular level; Biological processes of cell functions, cell division, senescence, maintenance, and cell death; Biomolecules interactions; Cancer; Cell biology; Chemical biology; Computational biology; Cytochemistry; Developmental biology; Disease mechanisms and therapeutics; DNA, and RNA metabolism; Gene functions, genetics, and genomics; Genetics; Immunology; Medical microbiology; Molecular biology; Molecular genetics; Molecular processes of cell and organelle dynamics; Neuroscience; Protein biosynthesis, degradation, and functions; Regulation of molecular interactions in a cell; Signalling networks and system biology; Structural biology; Virology and microbiology.",annualVolume:11410,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/14.jpg",editor:{id:"165627",title:"Dr.",name:"Rosa María",middleName:null,surname:"Martínez-Espinosa",fullName:"Rosa María Martínez-Espinosa",profilePictureURL:"https://mts.intechopen.com/storage/users/165627/images/system/165627.jpeg",institutionString:null,institution:{name:"University of Alicante",institutionURL:null,country:{name:"Spain"}}},editorTwo:null,editorThree:null,editorialBoard:[{id:"79367",title:"Dr.",name:"Ana Isabel",middleName:null,surname:"Flores",fullName:"Ana Isabel Flores",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRpIOQA0/Profile_Picture_1632418099564",institutionString:null,institution:{name:"Hospital Universitario 12 De Octubre",institutionURL:null,country:{name:"Spain"}}},{id:"328234",title:"Ph.D.",name:"Christian",middleName:null,surname:"Palavecino",fullName:"Christian Palavecino",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000030DhEhQAK/Profile_Picture_1628835318625",institutionString:null,institution:{name:"Central University of Chile",institutionURL:null,country:{name:"Chile"}}},{id:"186585",title:"Dr.",name:"Francisco Javier",middleName:null,surname:"Martin-Romero",fullName:"Francisco Javier Martin-Romero",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bSB3HQAW/Profile_Picture_1631258137641",institutionString:null,institution:{name:"University of Extremadura",institutionURL:null,country:{name:"Spain"}}}]},{id:"15",title:"Chemical Biology",keywords:"Phenolic Compounds, Essential Oils, Modification of Biomolecules, Glycobiology, Combinatorial Chemistry, Therapeutic peptides, Enzyme Inhibitors",scope:"Chemical biology spans the fields of chemistry and biology involving the application of biological and chemical molecules and techniques. In recent years, the application of chemistry to biological molecules has gained significant interest in medicinal and pharmacological studies. This topic will be devoted to understanding the interplay between biomolecules and chemical compounds, their structure and function, and their potential applications in related fields. Being a part of the biochemistry discipline, the ideas and concepts that have emerged from Chemical Biology have affected other related areas. 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Behind these definitions are hidden all the aspects of normal and pathological functioning of all processes that the topic ‘Metabolism’ will cover within the Biochemistry Series. 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Thus proteomics, an area of research that detects all protein forms expressed in an organism, including splice isoforms and post-translational modifications, is more suitable than genomics for a comprehensive understanding of the biochemical processes that govern life. The most common proteomics applications are currently in the clinical field for the identification, in a variety of biological matrices, of biomarkers for diagnosis and therapeutic intervention of disorders. From the comparison of proteomic profiles of control and disease or different physiological states, which may emerge, changes in protein expression can provide new insights into the roles played by some proteins in human pathologies. Understanding how proteins function and interact with each other is another goal of proteomics that makes this approach even more intriguing. Specialized technology and expertise are required to assess the proteome of any biological sample. Currently, proteomics relies mainly on mass spectrometry (MS) combined with electrophoretic (1 or 2-DE-MS) and/or chromatographic techniques (LC-MS/MS). MS is an excellent tool that has gained popularity in proteomics because of its ability to gather a complex body of information such as cataloging protein expression, identifying protein modification sites, and defining protein interactions. 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