\r\n\tEven though video surveillance systems have been part an integral part of the public and security sectors for decades, there is a significant interest in them outside of those industries. This interest is largely due to increased crime rates and security threats all around the globe, which are driving a continuous growth of the video surveillance market. According to a recent report, the video surveillance market was valued at $29.98 billion in 2016 and is expected to reach a value of $72.19 billion by 2022. This market potential is also propelled by recent advances in Artificial Intelligence and Computer Vision research fields—boosting the intelligence, scalability, and accuracy of intelligent video surveillance solutions.
\r\n
\r\n\tThe book's goal is to provide a game-changing and cross-disciplinary forum that brings together experts from academia, industry, and government to advance the frontiers of theories, methods, systems, and applications.
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Since then, he has been working on several research topics regarding artificial intelligence and computer vision. Dr. Mazzeo joined the Italian National Research Council of Italy (CNR) as a researcher\nin 2002. He is currently involved in projects for algorithms for video object tracking, face detection and recognition, facial expression recognition, deep neural networks, and machine learning. He has authored and co-authored 100 publications, including more than fifteen papers published in international journals and book chapters. He has also co-authored five national and international patents. Dr. Mazzeo acts as a reviewer for several international journals and for some book publishers. 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1. Introduction
Formalin-fixed paraffin-embedded (FFPE) tissues are of great importance to retrospective studies. Their main advantage lies on the possibility of correlating genetic and molecular biology analyses with data from patients’ medical records and clinical outcomes [1].
Formalin fixation is the most widely used method for tissue fragment preservation. It is a low-cost and easy-to-handle method, which preserves good morphological cell quality. The method is compatible with the antibodies used in the immunohistochemistry technique [2]. However, although formalin fixation and routine histological processing techniques preserve tissue cellular morphology and protein integrity, they also impair the obtainment of nucleic acids with the same quality, especially RNA, since they degrade and chemically modify such acids [3, 4].
Formalin replacement by other tissue fixatives such as Bouin, Carnoy, alcohol or HOPE (glutamic acid buffer Hepes-mediated organic solvent effect protection) may be an alternative to reverse the problem [4, 5]. However, since formalin is the fixative of choice in most pathology departments, several research groups have sought to reverse the chemical changes caused by this fixative type.
Although several papers describe techniques that allow FFPE tissue nucleic acid extracting process [6–8, 3, 1, 4], so far there is no consensus in the literature about the best protocol to be used in this type of material.
The studies based on such approach not often detail the used methodology. Besides, not all the published techniques were reproduced by our group. It took us approximately 8 months to standardize the DNA and RNA extraction process in our FFPE tissues research.
The current chapter aims to describe the factors affecting the process of nucleic acid extraction from FFPE tissue, compare the available protocols and to describe the modifications developed by our group in some protocols that enable nucleic acids obtainment in satisfactory quantity and quality for molecular biology studies.
2. Factors affecting nucleic acids extraction from FFPE tissues
Difficulties in obtaining quality nucleic acids, especially RNA, cause degradation and chemical modification, despite the fixation in formalin and the routine histological processing techniques used to preserve cellular morphology and tissues’ protein integrity [3–4].
Nucleic acids extraction from FFPE tissue shows some critical issues that may affect the quality of the obtained DNA or RNA as well as these samples’ subsequent amplification process. Such critical matters include tissue fixing and clamping as well as the post-fixing stage (tissue cutting preparations, deparaffinization and hydration processes, in addition to other stages of the extraction process itself, such as digestion and purification), which will be described below [9].
Pre-fixation is defined as the period between tissue collection and the beginning of the setting process. The material starts degrading shortly after its collection, right when the tissue is exposed to hypoxia and to the DNases and RNases found in the environment. The first biochemical modifications emerge after 10 min of anoxia. Thus, it is very important to reduce the pre-clamping time to seconds [4, 9].
The fixing conditions (time, temperature and fixative type) and, in some cases, the descaling processes alter material preservation and directly influence the quantity and quality of the obtained nucleic acid. Fixations kept in formalin solution for more than a week destroy the nucleic acids and lead to the cross-linking of all tissue components. It results in highly fragmented nucleic acids, which are more resistant to the extraction process [2, 3, 9].
Chemical studies have shown that formaldehyde breaks hydrogen bonds in double-stranded DNA adenine- and thymine-rich regions. It creates new chemical interactions in protein folding, thus resulting in bonds between DNA proteins and DNA fragmentation [10].
RNA messenger (mRNA) obtained from FFPE tissues is often not intact. It is usually degraded to less than 300 base pairs [1]. However, Hamatani et al. (2006) [11] found that 80% of the RNA samples presenting 60 base pairs may be sufficiently amplified by polymerase chain reactions (PCR). All post-fixation stages, such as the paraffin blocks attainment sections, are also essential to the obtainment of high-quality nucleic acids.
Contamination is one of the critical issues affecting the quality of the samples. Thus, it is necessary to decontaminate the workstation as well as to use DNases- and RNases-free tools. These DNases and RNases result from paraffin block cuts used to extract the nucleic acid of interest [2].
Although some authors state that deparaffinization is not a required step [2], most protocols suggest that the material must be deparaffinized before the extraction process in order to obtain nucleic acids in a more efficient way. Most protocols use solvent (usually xylene) to remove the paraffin cuts, and this procedure is followed by ethanol-based rehydration.
No matter the used protocol, digestion is the first step in the nucleic acid extraction process, and it aims to lyse membranes in order to release the cellular components. This step may be accomplished by several methods, such as elevated temperatures, enzymatic digestion, mechanical disruption or even by using other detergents or according to cell type solutions. In general, enzymatic digestion with proteinase K is used in most protocols; however, the concentrations and the incubation times are highly variable [9].
Nucleic acids purification is the next stage. Literature reports protocols using organic solvents (such as phenol-chloroform) [12–14], salt (salting out) [15] and other substances (Chelex-100) [16] as well as protocols using commercial kits available in the market [9].
Li et al. (2008) [1] observed that RNA extraction protocols based on proteinase K digestion followed by DNase, column purification and elution treatments led to good results in FFPE samples. These authors have shown that proteinase K is essential to degrade covalently linked proteins in order to release RNA from the cell array and to inactivate RNAses, which tend to be stable.
Ribeiro-Silva and Garcia (2008) [4] have shown that proteinase K is used to degrade proteins bound to nucleic acids and that the incubation between 60°C and 70°C removes the methylol groups added by formalin. RNA isolation by denaturing agents prevents the RNases action. In addition, deoxyribonuclease (DNase) incubation is required to remove the deoxyribonucleic acid (DNA) sample. Finally, purification by precipitation with alcohol porous column removes any residue and contaminants.
All tested protocols will be detailed in the sections below, as well as the changes suggested to determine the protocols that would be viable to the obtainment of nucleic acids presenting adequate quality for molecular biology studies.
3. Preparing FFPE tissue sections for nucleic acids extraction
All samples included in the studies conducted by our team result from biopsies performed in diffuse large B cell lymphoma patients, from lymph node samples or from reaction amygdala samples stored in the Pathology Department of Hospital das Clínicas, Medical School of University of São Paulo. All the herein used samples were formalin-fixed and paraffin-embedded (FFPE) according to the standard methods described in the literature.
Four 20-μm thick cuts were performed in each sample using routine histological techniques. The sections were placed into 1.5 mL RNase- and DNase-free microtubes, and they were subsequently subjected to RNA and DNA extraction processes.
The first protocol used to prepare the cuts in the nucleic acid extraction process (suggested for the majority of commercial kits and protocols) consisted of deparaffinizing the sections with xylene and of rehydrating them with ethanol. In order to do so, 1 mL xylene PA was added to each sample (Synth® Diadema, SP, Brazil), and it was followed by homogenization using Vortex Genie 2T (Scientific Industries, Inc., Bohemia, NY, USA) and by incubation at 50°C, for 5 min, in digital thermomixer (Eppendorf AG, Hamburg, Germany). After incubation, the samples were centrifuged at maximum speed for 5 min in the R-5418 microfuge (Eppendorf AG, Hamburg, Germany). The xylene was discarded and the cell button was washed two times with absolute ethanol (Merck KGaA, Darmstadt, Germany). The supernatant was discarded after each wash. After the cell button was completely dried, the extraction process started, as it is described in the following sections.
Moreover, even after some RNA extraction methods that allowed finding some viable options were compared, it was observed that not all the extracted samples showed successful amplification in PCR reactions [17].
None of the previous studies available in the literature described the possible factors that could influence the amplification success. Therefore, the current study made the option of investigating some of the potential interferences in the nucleic acid obtainment process, namely: tissue fragment size, blocks’ storage time, used fixative type, different cDNA synthesis primers and different primer sequences, among others [18].
After the aforementioned study, the tissue preparation protocol for RNA extraction process was modified by including a washing step. It consisted of using 1 ml phosphate buffer saline (PBS) with 5 min incubation at room temperature, followed by full speed centrifugation for 5 min in the R-5418 microfuge (Eppendorf AG, Hamburg, Germany). This procedure is done to remove possible fixative residues that could work as PCR inhibitors [18]. Next, the same process was used in the DNA extraction performed by our team.
Such protocol change was done under the assumption that the amplification failure in PCR reactions could be caused by the presence of contaminants such as fixative waste working as PCR inhibitors.
The results show that the PBS washing step inclusion in the samples’ extraction preparation process led to some statistically significant advantages such as the obtainment of better RNA concentration results (p = 0.00025), even when the same initial amount of tissue was used. In addition, the washing step allowed obtaining better sample purity levels (p = 0.0000001), increasing the samples amplification success (p = 0.018) both in the standard and in the real-time PCR reactions [18].
Two possible factors may have influenced the improved amplification efficiency of these samples. The first is based on the fact that formalin is water-soluble, thus the PBS washing step may have led to tissue-fixation residues’ solubilization and removal, and it could possibly work as PCR inhibitors. Furthermore, previous studies suggested that pH values between 6.5 and 9.0 are optimal for amplification [11, 9]. Then, the PBS solution may have possibly altered pH levels, thus increasing the quality of the obtained RNA and the amplification success.
Despite the influence of the PBS-based washing step addition on the samples’ successful amplification, we observed the fixative interference in this process too. Formalin-fixed samples showed more successful PCR amplification reactions than those fixed in formaldehyde or in Bouin\'s solution, even after further PBS washing (p = 0.000018) [18].
Another fact observed by our team refers to the paraffin-embedded tissue fragment size. All fragments size equals to or greater than 1.0 cm had the most successful samples’ amplification (p = 0.034) [18]. This may be possibly due to the fact that smaller tissues may increase the fixative absorption and, consequently, cause greater nucleic acids degradation and chemical modification in the full extent of the tissue.
No impact was found on the amplification success when the other variables suggested in our study were tested (tissue type, block age, different primers used in the cDNA synthesis or the endogenous genes used in the PCR reaction), regardless of the use (or not) of the PBS washing step [18].
This protocol change was kept in the preparation of samples subjected to DNA extraction, due to the statistically significant impact caused by the PBS washing step inclusion on either the obtainment of better RNA concentrations or purity relations.
It is possible to conclude that this sample preparation is an essential step to obtain better quality nucleic acids for molecular biology studies.
4. RNA extraction from FFPE tissues
Three different RNA extraction protocols were tested, as described below:
Protocol 1: Commercial kit RECOVERALL Total Nucleic Acid Isolation Optimized for FFPE Samples (Ambion, Inc., Austin, Texas, USA) [17–18]
Two hundred (200μ l) of digestion buffer and 5 μL protease were used for tissue lysis in each sample. It was followed by incubation for 15 min at 50°C and for 15 min at 80°C. Next, RNA isolation was held by the addition of 790 μL buffer containing absolute ethanol and by the subsequent passage through the separation column. After washing the column with two wash buffers, realized treatment with DNAse and further washing with two buffers, according to the manufacturer\'s instructions. The eluted RNA was obtained by using 60 μL of the kit elution buffer at RT. After incubation for 5 min at room temperature, the samples were centrifuged at maximum speed and the obtained RNA was stored at –80°C until its use.
Protocol 2: Paradise®Whole Transcript RT Reagent kit System (Arcturus Bioscience, Inc., Mountain View, California, USA) [17]
Incubation with buffer containing proteinase K was held for 20 h, at 37°C, after the samples’ preparation process, to digest the proteins. The RNA isolation was performed by two successive washes using buffer containing the ethanol kit. Then, the samples were purified by passing them through the column kit according to the manufacturer\'s instructions. Subsequently, samples were incubated with buffer containing DNase at 37°C for 15 min and at 4°C for 1 min. DNase inactivation was performed by incubating the samples at 70°C for 10 min and at 4°C for 1 min. The RNA samples were stored at –80°C until they were used.
The RNA extraction by Trizol method was performed as recommended by Körbler et al. (2003) [8] and Antica et al. (2010) [19]. The tissue was digested by incubating the samples in buffer containing 10 mM NaCl, 500 mM Tris pH 7.6, 20 mM ethylenediaminetetraacetic acid (EDTA), 1% sodium dodecyl sulfate (SDS) and 500 μg/mL proteinase K. First, the sample was incubated at 55°C, for 3 h; then, it was incubated at 45°C overnight with proteinase K inactivation by elevating the temperature to 100°C for 7 min in the next day. Finally, all samples were subjected to RNA extraction process according to the classic Trizol method previously described by Chomczynski and Sacchi (1988) [20]. The obtained RNA was stored at –80°C until it was used.
4.1. Evaluating RNA concentration and quality
NanoDrop equipment (NanoDrop Technologies, Inc. Wilmington, DE) was used to evaluate the concentration and purity of RNA samples extracted according to the three protocols described above. RNA amounts above 50 ng/μl with purity between 1.7 and 1.9 were considered to be suitable.
4.2. Results and comments on the herein described RNA extraction protocols
The purity levels and degrees obtained by the three protocols were satisfactory (over 50 ng/μL and purity concentrations between 1.8 and 1.9). However, only samples obtained according to protocols 1 (Ambion) and 2 (Arcturus Bioscience) showed appropriate amplification in real-time PCR reactions [17].
Despite the RNA produced with appropriate concentrations and purity degrees, the samples obtained by the Trizol method showed no amplification in real-time PCR reactions. It corroborates the results found by Witchell et al. (2008) [5], but it did not confirm the data obtained by Körbler et al. (2003) [8] and Antica et al. (2010) [20].
After these results were published, it was decided to check the impact of the residuals and potential contaminants. Thus, the purification step using alcohol in a porous column of the QIAamp®Viral RNA Mini Kit for commercial extraction (Qiagen) was adopted. In brief, after isopropyl alcohol was added to the samples, DNA was filtered using the purification column, according to the manufacturer\'s recommendations. It was done by transferring the samples to the Kit\'s purification columns, which were centrifuged at 8,000 g for 1 min. Subsequently, the column products were moved to other tubes. Next, 500μ L buffer AW1 was added to column and it was once again centrifuged at 8,000 g for 1 min. After the filtrate was discarded and the column transferred from the column to another tube, 500 μL Buffer AW2 was added to the solution and a new centrifugation was performed at 14,000 g for 3 min. Then, the column was shifted into a sterile 1.5 mL tube and 60μ L elution buffer was added to it. After the reaction was incubated for 5 min at RT, the tubes were centrifuged at 8,000 g for 1 min and the obtained RNA was stored at –80°C.
A significant improvement was found in the quality of the samples as well as in their adequate amplification in real-time PCR reactions. Thus, RNA extraction from FFPE samples of the three tested protocols became feasible. However, protocol 1 (Ambion commercial Kit) was used as the standard method in current research by taking into account the protocol’s practicality and cost.
5. DNA extraction from FFPE tissues
Two different RNA extraction protocols were tested (unpublished data) as described below.
After the sections were prepared and the button cell was completely dried as described in Section 3, tissue digestion was performed by adding 480 μL Tris-EDTA buffer (TE) and 20 μL proteinase K (200 mg/ml) to each sample. Next, these samples were incubated at 37°C for approximately 16 h in the digital thermomixer (Eppendorf AG, Hamburg, Germany). The temperature was then raised up to 90°C for 10 min to inactivate the proteinase K.
One (1) ml of the mixture was added to phenol:chloroform:isoamyl alcohol (Invitrogen Corporation, Carlsbad, CA, USA) at the ratio 25:24:1, respectively. After homogenization using the Vortex Genie 2T (Scientific Industries, Inc., Bohemia, NY, USA), samples were centrifuged at 13,000 g for 15 min at the 5418-R microcentrifuge (Eppendorf AG, Hamburg, Germany). The supernatant was transferred to a fresh 1.5 ml DNase- and RNase-free microfuge tube, and 1 mL of the phenol:chloroform:isoamyl alcohol (25:24:1) mixture was added to it. Then, the centrifugation process was repeated under the same conditions.
The supernatant was transferred to a new 1.5 mL DNase- and RNase-free microtube and 20 μL of 3M sodium acetate and 900 μL of absolute ethanol (Merck KGaA, Darmstadt, Germany) were added to it. The samples were homogenized by inversion and incubated at 20°C for at least 30 min. The samples were centrifuged at 13,000 g for 15 min. The supernatant was discarded and the pellet was completely dried. Samples were resuspended in 50 mL TE buffer and stored at –20°C, until they were used.
Protocol 2: Phenol-chloroform method (modified by our team)
By following the same reasoning used to modify the RNA extraction protocol by Trizol method, the current study made the option to add a DNA purification step using the QIAamp DNA Blood Mini Kit commercial columns (Qiagen, Hilden, Germany) to check the impact from residual and potential contaminants.
As it was described in the previous protocol, the samples were transferred to the column commercial kit – QIAamp DNA Blood Mini Kit (Qiagen, Hilden, Germany), after being incubated with 3M sodium acetate and absolute ethanol. Subsequently, they were centrifuged at 8,000 rpm for 1 min in the 5418- R microfuge (Eppendorf AG, Hamburg, Germany). The filtrate was discarded, and the column was transferred to a new tube and 500 μL of buffer AW1 were added to it. Then, the samples were centrifuged at 8,000 rpm for 1 min in the 5418-R microcentrifuge (Eppendorf AG, Hamburg, Germany).
After the filtrate was discarded and the column transferred to a new tube, a second wash was performed using 500 μL buffer AW2. The samples were centrifuged at 14,000 rpm for 3 min in the 5418-R microcentrifuge (Eppendorf AG, Hamburg, Germany).
Columns were transferred to a 1.5 mL DNases- and RNases-free microtube and 200 μL of buffer AE were added to the center of the column. The samples were then incubated at room temperature for 5 min, and it was followed by centrifugation at 8,000 rpm for 1 min in the 5418-R microfuge (Eppendorf AG, Hamburg, Germany). The samples were stored at –20°C until they were used.
5.1. DNA quality quantification and analysis
The DNA samples\' concentration and purity were set by spectrophotometry in NanoDrop®ND-2000 machine (Thermo Fisher Scientific, Wilmington, DE). Samples with absorbance ratios (A280 / A260nm) between 1.7 and 1.9 were considered to be appropriate.
5.2. Results and comments on the herein described DNA extraction protocols
Despite the DNA produced with suitable concentrations and purity degrees, not all the samples obtained by the phenol-chloroform method showed amplification in real-time PCR reactions. It corroborated the results by Witchell et al. (2008) [5], but it did not confirm the data obtained by Körbler et al. (2003) [8] and Antica et al. (2010) [19].
A significant improvement was observed in the quality of the samples and adequate amplification in real-time PCR reactions performed according to method 2. Thus, DNA extraction from FFPE samples of the three tested protocols has become more viable. However, taking into account both the protocol practicality and the cost, the protocol 1 (Ambion commercial Kit) was used as the standard method for the current research.
Acknowledgments
The authors thank Fundação de Amparo à Pesquisa do Estado de São Paulo (State of São Paulo Research Support Foundation) for the granted funding.
\n',keywords:"DNA, RNA, FFPE, extraction",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/49457.pdf",chapterXML:"https://mts.intechopen.com/source/xml/49457.xml",downloadPdfUrl:"/chapter/pdf-download/49457",previewPdfUrl:"/chapter/pdf-preview/49457",totalDownloads:2649,totalViews:525,totalCrossrefCites:2,totalDimensionsCites:5,totalAltmetricsMentions:0,impactScore:2,impactScorePercentile:81,impactScoreQuartile:4,hasAltmetrics:0,dateSubmitted:"May 5th 2015",dateReviewed:"September 22nd 2015",datePrePublished:null,datePublished:"March 16th 2016",dateFinished:"November 2nd 2015",readingETA:"0",abstract:"Formalin-fixed paraffin-embedded (FFPE) tissues are an important sample source for retrospective studies. Despite its ability to preserve proteins and cell morphology, formalin hinders molecular biology tests since it fragments and chemically modifies nucleic acids, especially RNA. Although several studies describe techniques that allow extracting nucleic acids from FFPE tissues, so far there is no consensus in the literature about the best protocol to be used in this type of material. Thus, the current chapter aims to describe the factors affecting the FFPE tissue nucleic acid extracting process, compare the available protocols and to describe the modifications developed by our group in some protocols. Such modifications enable nucleic acids obtainment in satisfactory quantity and quality for molecular biology studies.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/49457",risUrl:"/chapter/ris/49457",book:{id:"5092",slug:"nucleic-acids-from-basic-aspects-to-laboratory-tools"},signatures:"Gisele R. Gouveia, Suzete C. Ferreira, Sheila A. C. Siqueira and Juliana Pereira",authors:[{id:"176651",title:"Dr.",name:"Gisele",middleName:null,surname:"Gouveia",fullName:"Gisele Gouveia",slug:"gisele-gouveia",email:"gisele.rgouveia@gmail.com",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:{name:"University of Sao Paulo",institutionURL:null,country:{name:"Brazil"}}},{id:"177720",title:"MSc.",name:"Suzete",middleName:null,surname:"Ferreira",fullName:"Suzete Ferreira",slug:"suzete-ferreira",email:"lom.suzy@gmail.com",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null},{id:"177721",title:"Dr.",name:"Sheila",middleName:null,surname:"Siqueira",fullName:"Sheila Siqueira",slug:"sheila-siqueira",email:"sheila.siqueira@hc.fm.usp.br",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null},{id:"177722",title:"Dr.",name:"Juliana",middleName:null,surname:"Pereira",fullName:"Juliana Pereira",slug:"juliana-pereira",email:"julianapereira29@hotmail.com",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Factors affecting nucleic acids extraction from FFPE tissues",level:"1"},{id:"sec_3",title:"3. Preparing FFPE tissue sections for nucleic acids extraction",level:"1"},{id:"sec_4",title:"4. RNA extraction from FFPE tissues",level:"1"},{id:"sec_4_2",title:"4.1. Evaluating RNA concentration and quality",level:"2"},{id:"sec_5_2",title:"4.2. Results and comments on the herein described RNA extraction protocols",level:"2"},{id:"sec_7",title:"5. DNA extraction from FFPE tissues",level:"1"},{id:"sec_7_2",title:"5.1. DNA quality quantification and analysis",level:"2"},{id:"sec_8_2",title:"5.2. Results and comments on the herein described DNA extraction protocols",level:"2"},{id:"sec_10",title:"Acknowledgments",level:"1"}],chapterReferences:[{id:"B1",body:'Li J, et al. Improved RNA quality and TaqMan®Preamplification method (PreAmp) to enhance expression analysis from formalin fixed paraffin embedded (FFPE) materials. BMC Biotechnol 2008;8:1–11.'},{id:"B2",body:'Lehmann U, Kreipe H. Real-time PCR analysis of DNA and RNA extracted from formalin-fixed and paraffin embedded biopsies. Methods 2001;25:409–18.'},{id:"B3",body:'Doleshal M, et al. Evaluation and validation of RNA extraction methods for MicroRNA expression analyses in formalin-fixed, paraffin-embedded tissues. J Molecul Diag 2008;10(3):203–11.'},{id:"B4",body:'Ribeiro-Silva A, Garcia SB. Estudo comparativo de três diferentes procedimentos para extração de RNA a partir de amostras fixadas em parafina e embebidas em parafina. J Brasil Patol Med Lab 2008;44(2):123–30.'},{id:"B5",body:'Witchell J, et al. RNA isolation and quantitative PCR from HOPE- and formalin-fixed bovine lymph node tissues. Pathol Res Practice 2008;204:105–11.'},{id:"B6",body:'Impraim CC, Saiki RK, Erlich HA, Treplitz RL. Analysis of DNA extraction from formalin-fixed, paraffin-embedded tissues by enzymatic and hybridization with sequence-specific oligonucleotides. Biochem Biophys Res Com 1987;142:710–6.'},{id:"B7",body:'Shibata DK, Amheim N, Martin WJ. Detection of human papiloma virus in paraffin-embedded tissue using the polymerase chain reaction. J Exp Med 1988;167(1):225–30.'},{id:"B8",body:'Körbler T, et al. A simple method for RNA isolation from formalin-fixed and paraffin-embedded lymphatic tissues. Experiment Molecul Pathol 2003;74:336–40.'},{id:"B9",body:'Scorsato AP, Telles JEQ. Fatores que interferem na qualidade do DNA extraído de amostras biológicas armazenadas em blocos de parafina. J Brasil Patol Med Lab 2011;47(5):541–8.'},{id:"B10",body:'Srinivasan M, Sedmak D, Jweell S. Effect of fixatives and tissue processing on the content and integrity of nucleic acids. AJP 2002;161(6):1961–71.'},{id:"B11",body:'Hamatani K, et al. Improved RT-PCR amplification for molecular analyses with long-term preserved formalin-fixed, paraffin-embedded tissues specimens. J Histochem Cytochem 2006;54(7):773–80.'},{id:"B12",body:'Coombs NJ, Gough AC, Primrose JN. Optimisation of DNA and RNA extraction from archival formalin-fixed tissue. Nucleic Acids Res 1999;27(16):e12.'},{id:"B13",body:'Mesquita RA, et al. Avaliação de três métodos de extração de DNA de material parafinado para amplificação de DNA genômico pela técnica da PCR. Pesq Odontol Bras. 2001;15(4):314–9.'},{id:"B14",body:'Cao W, et al. Comparison of methods for DNA extraction from paraffin-embedded tissues and buccal cells. Cancer Detect Prevent. 2003;27:397–404.'},{id:"B15",body:'Rivero ERC, et al. Simple salting-out method for DNA extraction from formalin-fixed paraffin-embedded tissues. Pathol Res Practice 2006;202:523–9.'},{id:"B16",body:'Simonato LE, et al. Avaliação de dois métodos de extração de DNA de material parafinado para amplificação em PCR. J Bras Patol Med Lab 2007;43(2):121–7.'},{id:"B17",body:'Gouveia GR, Ferreira SC, Sabino EC, Siqueira SAC, Pereira J. Comparação de três protocolos distintos para extração de RNA de amostras fixadas em formalina e emblocadas em parafina. J Brasil Patol Med Lab 2011;47(6):649–54.'},{id:"B18",body:'Gouveia GR, Ferreira SC, Ferreira JE, Siqueira SAC, Pereira J. Comparison of two methods of RNA extraction from formalin-fixed paraffin-embedded tissue specimens. BioMed Res Int 2014;2014:1–5.'},{id:"B19",body:'Antica M, Paradzik M, Novak S, Dzebro S, Dominis M. Gene expression in formalin-fixed paraffin-embedded lymph nodes. J Immunol Methods 2010;359(1–2):42–6.'},{id:"B20",body:'Chomczynski P, Sacchi N. Single step method of RNA isolation by acidic guanidium thiocyanatephenol-chlorophorm extraction. Anal Biochem 1988;162:156–9.'},{id:"B21",body:'Carvalho VC, Ricci G, Affonso R. Guia de Práticas em Biologia Molecular. São Paulo: Yendis, 2010.'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Gisele R. Gouveia",address:"gisele.rgouveia@gmail.com; gisele.gouveia@usp.br",affiliation:'
Medical School of University of São Paulo (FMUSP), São Paulo, SP, Brazil
'},{corresp:null,contributorFullName:"Suzete C. Ferreira",address:null,affiliation:'
Molecular Biology Department of São Paulo Blood Center/Fundação Pró-Sangue, São Paulo, SP, Brazil
'},{corresp:null,contributorFullName:"Sheila A. C. Siqueira",address:null,affiliation:'
Pathology Service at Hospital das Clínicas (HC-FMUSP), São Paulo, SP, Brazil
Medical School of University of São Paulo (FMUSP), São Paulo, SP, Brazil
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1. Introduction
Mucosal melanomas of the head and neck are very rare malignancies that present with aggressive behavior, including frequent local recurrence, and poor prognosis. First described by Weber in 1859 [1] and classified as its own distinct disease by Lucke et al. in 1869 [2], they represent a small fraction of all head and neck melanomas.
Unlike cutaneous melanomas, which incidence is believed to be rising over the years, the incidence of mucosal melanomas seems to remain stable [2]. Its annual incidence rate in Europe was estimated in 1.5 per million, with slight female predominance (1.2 vs. 1.0 per million) and in people aged over of 65 years [3], with median age at diagnosis ranging around 70 years old – developing at more advanced ages when compared to cutaneous melanomas. Significant variation between races is observed, with the Japanese more likely to be affected (8%) when compared to Caucasians [4], especially regarding oral cavity mucosal melanoma, suggesting association of this particular subtype with common hereditary or environmental factors, still not identified [5]. Mucosal melanomas represent 0.8 to 3.7% of all melanomas, 0.03% of all neoplasms [6] and occur most commonly in the head and neck (55%) [7], mainly in the nasal cavity (lateral wall and septum) and paranasal sinuses (ethmoid and maxillary sinuses) [6], followed by the oral cavity – approximately 80% in the mucosa of the upper jaws (maxillary anterior gingiva), in the keratinizing mucosa of the palate and alveolar gingivae [8] -, pharynx, larynx, and upper esophagus [3, 9].
To date there are no clearly established risk factors for the mucosal melanoma development [5]. Cigarette smoking seems to be a risk factor for the oral tumor, while exposure to formaldehyde has been suggested as risk factor for the sinonasal malignancy. Association with viruses, such as human papilloma viruses, human herpes viruses or polymavirus is unlikely. Although sun radiation is a well-established risk factor for cutaneous melanoma, there is no evidence of its implication in mucosal melanoma pathogenesis, since its common locations preclude exposure to UV light [3].
Another particularity of mucosal melanomas, divergent from the cutaneous ones, is the more hostile behavior and frequent neoplastic dissemination, which results in greater death rate [10]. The mucosal melanoma aggressive clinical course results in very poor prognosis, especially among old male patients, likely due to little understanding of this rare malignancy and delayed detection, given the lack of specific clinical features for diagnosis, a challenging scenario for clinicians and pathologists [4]. Studies made on European cases diagnosed between 2000 and 2007 showed survival rates in 1, 3 and 5 years of 63%, 30% and 20%, respectively, as well as high rates of locoregional recurrence and distant metastasis [3, 11].
Tumor arising from the respiratory mucosa (such as the nasal cavity) have different clinical and pathological features when compared to those involving oral mucosa, as melanomas originating from non-squamous mucosa behave differently than those originating from multilayered squamous mucosa [11], but still they share similar adverse outcomes and prognosis and, therefore, will be discussed further in this chapter [1].
2. Pathology and biology
Melanomas are malignant tumors arising from pigment cells - melanocytes. Tumors can either develop from stem melanocytes with cytogenetic variations or mature melanocytes with secondary cytogenetic alterations due to external stimuli [6]. Precursors of melanocytes migrate from the neural crest to their final destination through embryonic mesenchyme, along specific pathways, most of them ending up in the epidermis and dermis of the skin, while some of them can be found in other locations, such as the mucosal membranes of the respiratory, gastrointestinal, and genitourinary tract [2, 3]. Melanin, the main product of melanocytes, may be missing in rare cases (2 to 8%), resulting in a non-pigmented lesion, referred as amelanotic malignant melanoma [9]. The presence and the function of melanocytes in the mucosa remain unclear. A few studies have supported the hypothesis of anti-oxidative, antimicrobial and immunological functions [3, 6]. In the sinonasal region, melanocytes take part in the metabolization of polycyclic aromatic hydrocarbons, suggesting association between inhaled environmental and immune factors and the development of mucosal melanoma in this particular site [5].
The etiology and pathogenesis of mucosal melanoma of the head and neck is still not fully understood. Whether it is due to preexisting mucosal nevi or racial pigmentation affecting its site, no risk factors have been unequivocally linked to those features. Despite the common association between cutaneous melanomas and sun exposure, mucosal melanomas are associated with embryology alterations (justifying the close proximity of commonly affected areas), inhaled and ingested carcinogens (e.g. smoking and formaldehyde exposure) and family history. Reports suggest that smoking patients have greater prevalence of pigmented oral lesions due to a hyper-production of melanocytes in the oral mucosa. Furthermore, 33% of oral cavity mucosal melanomas are preceded by pathological oral melanosis - increased number of normal or atypical melanocytes in the basal cell layer of the oral epithelium. Even though, conflicting data suggest oral melanosis should not be considered a pre-cancerous lesion [6]. Molecular studies of mucosal melanoma show several genetic changes in intracellular signaling cascades, which may constitute the distinct pathogenic mechanisms among these malignancies. Genomic hybridization studies have shown varied chromosomal aberrations - gains of 1q, 6p and 8q; gain of function mutations, such as K642E, L576P, D816H and V559A; amplifications of the 4q12 locus [11].
Special attention is addressed to the high incidence of activating mutations in the c-KIT (CD117) oncogene, present in 80% of all primary mucosal melanomas, whereas it seems not to have pathogenic importance in cutaneous melanomas [2, 5, 11]. KIT is a transmembrane tyrosine kinase receptor, expressed on melanocytes, but also on hematopoietic progenitor cells, mast cells, primordial germ cells, and interstitial cells of Cajal. Activating mutations and amplifications generate activation of growth and proliferation pathways, which seem to be important and common in acral and mucosal melanoma, both tumors unrelated to sun exposure [8]. Screening for KIT aberrations may have diagnostic value, given the evidence of a possible pathogenic role of this gene in mucosal melanomas, as well as a possible a therapeutic target in these patients [12]. Therapeutic c-KIT blockade could be useful in the treatment of patients with activating KIT mutation [6]. New drugs, such as imatinib, work on this pathway [8].
Along its signaling pathway, Microphthalmia-associated transcription factor (MITF) is referred to be involved in melanocyte development. The amplification of this gene is found in approximately 15-20% of primary mucosal melanomas. RAS-mitogen activated protein kinase related genes overexpression were found in up to 90% of primary mucosal melanomas [11]. Mutations in B-type Raf gene (proto-oncogene BRaf), present in up to 70% of cutaneous melanomas, have been detected in less than 10% of primary mucosal melanomas [2, 11]. Differently from the Human Papillomavirus (HPV) infection, which leads to p16/INK4a overexpression, loss of p16 expression, CDKN2A mutations, and loss of heterozygosity are observed in up to 50% of primary mucosal melanomas. GNAQ/11 mutations were observed in only 9.5% of the patients, who also presented shorter mean survival when compared to patients with wild type GNAQ/11. Programmed death-ligand 1 (PD-L1) expression seems to occur less frequently in patients with mucosal melanoma, which may lead to believe that mucosal melanomas are less immunogenic due to a lower mutational burden [2]. Primary sinonasal melanomas develop due to distinct genetic abnormalities, that lead to diffuse activation of the PI3K/Akt and RAS-MAPK pathways. These specific genetic pathway alterations, however, are not associated with different prognosis [6].
The key molecular events that trigger the malignancy development and progression is still unknown, which makes it difficult to work on new specific or multimodal treatment for this disease [12]. We can observe that mucosal melanoma is one unique subgroup in a vast emerging molecular classification system of melanoma. The complete understanding of these mechanisms may hopefully lead to a future of more optimized target therapy [11].
3. Diagnosis
Melanomas are malignant tumors arising from pigment cells—melanocytes. Melanocytes in mucosal membranes are distributed to the oral cavity, nasal cavity, paranasal sinuses, esophagus, larynx, vagina, cervix, rectum, and anus [13].
Mucosal melanoma of the head and neck (HNMM) region constitutes 55% of all mucosal melanomas, but <10% of all melanomas of the head and neck region. A majority of these tumors are found in the sinonasal regions (55%), while the rest are located in the oral cavity (25–40%) [13, 14, 15, 16]. Mucosal melanomas generally present at a later stage, are more aggressive and carry a worse prognosis regardless of the stage at diagnosis [17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31].
Of all mucosal melanomas, paranasal sinus has the worst prognosis. The best prognosis locations are the nasal and oral cavity [15]. In contrast to cutaneous melanomas, mucosal melanomas more frequently are amelanotic and present in a multifocal fashion [17]. Early detection provides the best chance at survival but is often difficult due to anatomic location [17, 22, 27, 29]. Mucosal melanoma remains a challenge for several reasons: firstly, the clinical diagnosis often occurs relatively late, because it is not usually confirmed before the disease is symptomatic; secondly, traditional aspects of cutaneous melanoma clinical staging may not apply; and thirdly histological diagnosis can be difficult due to its rarity and variable appearance.
3.1 Clinical signs and symptoms
Presenting symptoms of mucosal melanomas differ in relation to the site of origin.
3.1.1 Primary mucosal melanomas of the nose and paranasal sinuses
Sinonasal primary mucosal melanomas (PMM) account for <1% of all melanomas and <5% of all sinonasal tract neoplasms [32].
In the sinonasal tract, early signs and symptoms are similar to those encountered in inflammatory benign conditions and therefore may be overlooked for some time [33].
The tumors can present with non-specific symptoms including nasal obstruction, facial pain, rhinorrhea and epistaxis [34]. In advanced stage primary tumors, symptoms such as diplopia, exophthalmos, ophthalmoplegia, headache, skin infiltration and ulceration, can occur [11].
At endoscopy, MM may present as a polypoid, with strict unilateral involvement in most cases. Lesions may have different degrees of pigmentation, with the possibility of diversely pigmented areas within the same mass. It can assume dark, brown, red, or pale white colors.
Compared with oral melanoma, completely amelanotic tumors are rare but when they do occur are associated with an even worse prognosis because of a more aggressive biology and greater difficulty in diagnosis [33]. Furthermore, multiple lesions (satellite lesions) can be frequently observed, even centimeters away from the main tumor, with spreading occurring along the mucosal/submucosal planes.
Among sinonasal cases, approximately 80% are located in the nasal cavity itself, most commonly the middle and inferior turbinates, lateral nasal wall and nasal septum, while 20% occur in the paranasal sinuses [13, 15, 16].
Concurrent nasal and paranasal lesions are infrequent.
The most frequently involved paranasal sinus is the maxillary sinus followed by the ethmoid, frontal and sphenoid sinuses respectively [11]. Primary lesions of the sphenoid and frontal sinus are exceedingly rare [11, 35].
Most of the patients with melanomas of the nasal cavity (75%) are diagnosed with clinically localized disease. That is the reason why patients with nasal melanoma have a more favorable prognosis when compared with melanoma arising from other head and neck sites. However, melanomas of the paranasal sinuses are usually advanced at presentation. PMMs of the ethmoid and maxillary sinuses have a worse prognosis than those arising from other sites. This is related to the higher T classification and late symptomatology. When occurs infiltration into the orbit, skull base, infratemporal fossa or facial soft tissue, the outcome is very poor [36, 37, 38, 39]. At initial diagnosis, lymphatic metastases are present in 10% to 20% of patients with sinonasal PMMs, and <10% of patients have evidence of distant metastases [40]. 40% of cases will develop distant metastases in lungs, brain, bone, and liver, during the course of the disease [41]. Vascular and neural invasion is observed in approximately 40% of patients [42]. Early and repeated recurrences is frequently noticed in malignant melanomas of the nasal cavity and paranal sinuses.
3.1.2 Primary mucosal melanomas of the oral cavity
Primary mucosal melanomas of the oral cavity account for <1% of all melanomas, 0.5% of all oral malignancies, and 40% of all PMMs of the head and neck. The incidence of oral PMMs is higher in Asians, Africans, Hispanics, and Asian Indians [43, 44, 45].
Oral primary mucosal melanomas tend to present late as they are usually asymptomatic in the early stages and are often unnoticed by patients [11].
Compared to sinonasal disease, it may be diagnosed earlier due to the greater accessibility for inspection and oral examination.
Oral MM generally presents as a hyperpigmented lesion (Figures 1 and 2), with a wide range of colors varying from black, brown, gray to reddish or white. Interestingly, oral lesions may be amelanotic in up to 10–30% of cases; in these patients, diagnosis may be challenging. Amelanotic melanomas may simulate pyogenic granulomas [46, 47].
Figure 1.
Aveolar ridge mucosal melanoma.
Figure 2.
Hard palate mucosal melanoma.
The tumors can be macular, nodular or plaque-like. Just like cutaneous melanomas, melanoma in the mouth may be asymmetric with irregular borders.
There can also be non-specific symptoms including bleeding, ulceration and pain, which is associated with the vertical growth of the lesion [48].
Macular lesions are flat, and up to one-third of patients have a long history of mucosal pigmentation (melanosis) [49, 50], which is considered the radial growth phase before invasion of underlying tissues (vertical growth phase). Nodular tumors, conversely, have an irregular surface and present as ulcerated, exophytic lesions.
As with the sinonasal tract, it is also possible to observe satellite lesions in the oral cavity surrounding the primary lesion [49, 51].
The majority of oral melanomas occur in the maxillary alveolar ridge or the hard palate. Such locations favor early invasion of underlying bone, which may account for their poor prognosis. The buccal mucosa, lips, tongue, floor of the mouth, and uvula can also be affected as well [52].
The involvement of other subsites (floor of the mouth and tongue) is not commonly observed.
Tanaka et al. [52] featured oral MM into 5 types: pigmented, nodular type; non-pigmented, nodular type; pigmented, macular type; pigmented, mixed type; non-pigmented, mixed type. This classification was based in patterns of growth and presence of pigmentation.
25% of the patients with oral cavity melanomas present with lymph node metastases. The likelihood of cervical lymph node metastases increases when the tumor thickness is more than 5 mm [53, 54]. Wu et al. [52], on the other hand, found that MMs with a nodular pattern of growth have a higher risk of nodal involvement compared to macular melanomas.
3.1.3 Primary mucosal melanomas of other head and neck sites
Rare cases of laryngeal [55], oropharyngeal [56] and nasopharyngeal [50, 57] MM have been reported; these lesions are extremely rare, with only sixty cases reported in the literature. The tumors are most commonly located in the supraglottic region (62.2%) followed by the vocal cords (37.8%).
Clinical presentation does not generally differ from that typical of other primary tumors, mainly squamous cell carcinomas, arising in the same sites.
The symptoms of laryngeal MM are dysphagia, hoarseness, and painful sore throat [18, 19, 58].
Pharyngeal lesions may cause hemorrhage, dysphagia and/or dyspnea [19].
Symptoms of nasopharyngeal PMMs are similar to sinonasal PMMs; the tumors usually present with epistaxis, nasal obstruction, and obstruction of the Eustachian tube with serous otitis [19].
Notably, the risk of nodal (65.5%) and distant (59.3%) metastases in pharyngo-laryngeal lesions is definitely higher than in other head and neck subsites [4].
As a general rule, the risk of nodal involvement in HNMM at presentation is higher in oral (25-43%) [47] than in sinonasal lesions (<10%) [35, 53].
The high rates of cervical node involvement at presentation is probably related to the size of primary lesions. 61% of nodal involvement occurs in lesions larger than 4 cm. Levels I (68%), II (68%) and III (23%) are the most commonly involved, whereas the frequency of metastases at levels IV (12%) and V (2%) is much lower [44]. The occurrence of distant metastases at presentation is low (5-10%), with no significant difference between oral and sinonasal lesions [53, 59]. The brain and lungs are the preferential sites of distant localization, whereas multiple organ involvement may be detected in up to one-third of cases [53].
3.2 Histological diagnosis
Head and neck PMMs are usually diagnosed at advanced stages, thus presenting macroscopically as aggressive nodular neoplasms arising from the mucosa; few cases are detected in situ [60]. Histopathological diagnosis is straightforward when the tumor cells are melanin rich. About two thirds of mucosal melanomas contain some intracytoplasmic brown pigment, which has to be confirmed as melanin and can be found in tumor cells or macrophages [61].
The histological features of HNMM can be as diverse as cutaneous melanomas [62], with variable mitotic activity and cell morphology [11]. Approximately 15 to 50% of cases presents with amelanotic lesions [63, 64]; as they can mimic another malignant neoplasms, including squamous cell carcinoma, this diagnosis has been challenging. These tumors frequently have a worse outcome [65, 66].
Histologically, mucosal melanoma is characterized by the proliferation of neoplastic melanocytes with variable phenotypes (epithelioid, spindle, and plasmacytoid cells without maturation and with nuclear changes, appearing as large and hyperchromatic nuclei with prominent nucleoli) that are arranged in a sheet-like, organoid, alveolar, solid, or desmoplastic architecture. They display high mitotic activity and show a pattern of invasion of the submucosa destroying the underlying tissues [67, 68, 69].
Tumors with mixed cell phenotypes are more related with vascular invasion and the development of metastasis. The neoplastic proliferation is commonly found along the junction between the epithelial and lamina propria, but this may be difficult to detect in advanced and ulcerated lesions [70].
Molecular studies have tried to find clinical predictors and immunohistochemical biomarkers to improve outcomes and survival rates.
Immunohistochemical stains may help distinguish mucosal melanoma from other malignancies and from cutaneous melanoma.
PMMs variously express S-100 protein and melanocytic markers, including MART-1/Melan-A, tyrosinase, HMB- 45, and MITF. 62 S-100 protein has greater sensitivity, but HMB-45 is probably more specific [42]. The absence or scarcity of melanin makes the diagnosis difficult and immunohistochemical techniques are required. The cells of amelanotic melanomas are positive for S-100 protein Melan-A, HMB-45, MITF and vimentin; and negative for cytokeratin [71].
One study assessed the expression of DNA mismatch repair and looked for the presence of microsatellite instability in HNMM. They showed that the cells had increased expression of mismatch repair proteins and increased microsatellite stability [72]. Besides these classical markers, the diagnostic potential of other molecules has been evaluated in Primary Oral Mucosal Melanoma (POMM), in particular several adhesion molecules. Integrin beta-3 and CD166 expression is correlated with extensive vascular invasion, while lower expression of CD54 is correlated with cell necrosis [73].
The expression of BCL2 in POMM has an important correlation with a longer overall survival [74].
The expression of podoplanin and CD13 in combination with S100 has been useful in the evaluation of lymph vessel and blood vessel invasion. Both markers are related to a poorer prognosis [75].
Programmed cell death ligand 1 (PDL-1) is known as a potent prognostic biomarker in several human tumors. Although this experimental evidence strongly supports the use of monoclonal antibodies targeting immune checkpoint proteins in MM, PDL-1 expression does not seem to be predictive of patient outcome, at least in melanoma [76]. Indeed, although PDL-1 positive tumors achieve a better responses to immunotherapies, PDL-1 negative patients can also have good outcomes.
3.3 Imaging of melanomas of the head and neck
When malignancy is suspected, computed tomography (CT) and magnetic resonance imaging (MRI) are valuable in defining the locoregional extent of the tumor, which is critical in determining resectability. For more accurate evaluation of MM, magnetic resonance imaging (MRI) is the modality of choice. This modality provide more information about the tumor, the localization, its relation to adjacent structures, and expansive or infiltrative characteristics. The analysis of signals in the different sequences is more.
sophisticated than the analysis of CT densities. The MRI signal of mucosal melanoma is influenced by the amount of melanotic pigment and hemorrhage within the lesion.
CT and MRI, when used together, can be complementary and define even better the invasion and destruction of structures of the skull base by soft-tissue masses.
The paramagnetic properties of melanin and of the free radicals produced by the metals ligated to the pigment itself account for a MRI pattern composed of T1 hyperintensity and T2 hypointensity [77].
MM usually manifests radiologically as an aggressive solid tumor with destructive characteristics related to compression or infiltration. The tumor causes bone destruction and invades adjacent soft tissues [13]. Thus, pre-treatment tumor mapping requires definition of tumor relationships with all surrounding anatomic sites and subsites. It is mandatory the accurate evaluation of involvement of intracranial structures and the surrounding vital structures such as cranial nerves or vessels, the anterior cranial fossa, the orbits, the pterygopalatine fossa and the infratemporal fossa.
Tumors arising along the Eustachian tube or in the nasopharynx can spread to the skull base at the foramen lacerum or along the tube to potentially reach the middle ear.
From a surgical point of view, key elements in the preoperative staging of mucosal melanoma of the oral cavity and oropharynx include depth of submucosal invasion, extension across the midline bone invasion and infiltration of deep space of the suprahyoid neck [77]. When the neoplasm reaches important anatomic crossroads, such as the posterior third of the hard palate, the pterygopalatine fossa, and the foramen ovale, perineural growth should be accurately evaluated.
MRI is the standard imaging modality for postoperative surveillance. Micrometastases may be radiologically occult. Because of the high fluorodeoxyglucose avidity of PMMs, FDG-positron emission tomography (PET)/CT may play an important role in the staging of PMM and in selecting the goals of therapy for patients with suspected metastasis or recurrence [78, 79].
3.4 Staging
Tumor staging for mucosal melanoma remains a challenge. Several staging systems have been suggested, including tumor-nodal-metastases (TNM) staging systems, but none are frequently used. TNM staging is only used for head and neck mucosal melanoma [11, 18].
The often concealed locations of mucosal melanoma result in frequent presentations of advanced disease.
In addition, unique to these anatomic locations are vast vascular and lymphatic networks in close proximity to the primary tumor, allowing for diffuse spread, with approximately one third of patients having nodal involvement at diagnosis [17, 21, 22, 24, 25, 29].
While different staging systems are in place for mucosal melanomas of different primary sites, Ballantyne described a three level staging system for classifying mucosal melanomas in 1970, which continues to be largely used:
Although its major advantage lies in its simplicity, this classification does not include depth of invasion or local tumor extension. The classification provides limited prognostic information as the majority of patients present with stage I disease [80].
To overcome these limitations, the pattern of tumor invasion has been studied in depth by Prasad et al., who reported that progression of the invasion at the microscopic level is associated with clinical worsening and suggests increased aggression.
They proposed microstaging as a prognostic marker, based on invasion of tissue compartments [81]:
Level I (in situ disease)
Level II (superficially invasive: melanoma invading up to the lamina propria)
Level III (deeply invasive: muscle, bone or cartilage).
The study evidenced a statistically significant difference in disease specific survival rates in levels I (75%), II (52%) and III (23%) respectively. However, this classification system is based on histological findings, the disadvantage is that it can only be used in evaluation of tissues following tumor excision, although invasion noted on pre-treatment imaging can be included.
The American Joint Committee on Cancer (AJCC) staging system for head and neck mucosal melanoma is often utilized, beginning at stage III. This focuses on the extent or size of the primary mucosal tumor using it as a predictor for outcome [82]. Mucosal melanomas are aggressive tumors, therefore T1 and T2 are omitted as are stages I and II.
TNM Clinical Classification:
T – Primary Tumor
TX: Primary tumor cannot be assessed
T0: No evidence of primary tumor
T3: Tumor limited to the epithelium and/or submucosa (mucosal disease)
T4a: Moderately advanced disease involving the deep soft tissue, bone, cartilage, or overlying skin T4b: Tumor invades any of the following: brain, dura, skull base, lower cranial nerves (IX, X, XI, XII), masticator space, carotid artery, prevertebral space, mediastinal structures
N – regional lymph nodes.
NX: regional lymph nodes cannot be assessed
N0: no regional lymph node metastasis
N1: regional lymph node metastasis
M – distant metastasis
M0: no distant metastasis
M1: distant metastasis
Stage Grouping
Stage III: T3 N0 M0
Stage IV A: T4a N0 M0
T3 ou T4a, N1, M0
Stage IV B: T4b, Any N, M0
Stage IV C: Any T, Any N, M1
A staging system should be valid as a prognostic tool to target treatment in terms of overall survival, but this system is not yet identified. At this point, tumor thickness greater than 5 mm, more than 10 mitotic figures per high power fields and/or ulceration has been suggested as independent prognostic factors [11]. To develop a uniform staging system a more thorough understanding of the prognostic factors is required [17]. This could facilitate comparisons of the results of different institutions, and help define the best therapy.
4. Treatment/management
There is no clear consensus on the management of head and neck mucosal melanoma, which reflects the rare nature of the disease and complexity of the anatomic site. The late diagnosis, frequently presenting at an advanced stage, denoting the aggressive nature of the disease. Currently, early detection and surgical excision is considered the primary method of treatment.
4.1 Surgery
Surgical treatment is the “gold standard” [80]. Wide excision with clear margins is the first goal in surgical management, once the complete surgical resection with negative margins significantly improves patient prognosis [83], whereas positive surgical margins have been associated with a higher rate of distant metastases, decreased survival measures, and a significantly higher risk of death compared to patients with negative surgical margins [84, 85, 86].
The incision depends on tumor site and size. Due to low rate of regional spread and the lack of effect on survival, elective neck dissection is not recommended. Neck dissection is mandatory only in cases of clinical or radiological positivity neck. Sentinel lymph node biopsy is not usually performed [80, 87, 88].
Surgical excision as a monotherapy should be reserved for patients with small tumors, localized disease and negative margins [89].
For sino-nasal mucosal melanomas, endoscopic techniques or external incision can be used [80, 90, 91]. In cases of oral mucosal tumors, a radical surgical resection with clear margins is the only curative option, and in cases of large masses, maxillectomy or marginal or segmental mandibulectomy is a possibility [11].
For laryngeal or pharyngeal melanomas, for complete resection is necessary total or partial laryngectomy or pharyngectomy [91]. The HNMM can be an aggressive disease and has high recurrences, demanding extensive resection surgery leading to disfigurement [80].
In most cases, complete resection is technically impossible without a destructive or disabling procedure, due to the proximity of the tumor to critical organs, but also because of the acceptable cosmetic result [36, 92], which frequently makes an adjuvant therapy necessary. Supplementary surgery can be executed for patients with recurrent disease and no evidence of distant disease [35, 90].
The National Comprehensive Cancer Network (NCCN, U.S.A.) guidelines emphasize that primary treatment should be surgical for stage III to IVA in the AJCC staging system but state that surgery is not recommended for stages IVB and IVC. These patients should be allocated in clinical trials or offered primary radiation therapy [93].
4.2 Radiotherapy
Radiotherapy (RT) is indicated to control local disease, positive surgical margins, or in case of palliative therapy. The addition of radiotherapy to surgery (adjuvant RT) may reduce the risk loco-regional recurrence without any impact on overall survival and disease-specific survival neither on the risk of distant metastasis [83, 87, 94, 95, 96, 97, 98].
According to the NCCN, adjuvant RT is indicated for patients with resected melanoma with high-risk nodal disease with four or more positive lymph nodes, lymph nodes of ≥3 cm and macroscopic extranodal soft tissue extension [93].
There is no clear indication of the appropriate evidence and the best radiation scheme.
Particle-beam therapy has also been used to facilitate the delivery of high doses to the residual tumor while minimizing exposure to the surrounding normal tissues, avoiding severe adverse effect in patients with tumors proximal to critical anatomical structures [99, 100, 101].
Primary RT alone has been advocated in patients with non-operable disease or a poor performance status [91].
4.3 Chemotherapy
The role of chemotherapy is minor compared to the biological and immunological systemic therapies [102]. The paucity of association of chemotherapy alone with improve overall survival led to its discontinuation as the election treatment for patients with metastatic mucosal melanoma. Therefore, chemotherapy is nowadays used as an adjuvant therapy in combination with other immunotherapeutic and biological drugs [103, 104].
4.4 Biological treatment
The selective inhibitors of various targeted (targeted therapy) have been approved since 2011 and include the BRAF inhibitors, dabrafenib and vemurafenib, the MEK inhibitors, trametinib and binimetinib and c-KIT inhibitors, which provides an attractive opportunity for developing adjuvant therapies for HNMM, mainly for patients with advanced locoregional or metastatic disease.
Vemurafenib, dabrafenib and trametinib are options for patients with BRAF V600 mutations who have unresectable or metastatic melanoma, mostly in combined therapy [3].
The selective inhibition of c-KIT alteration with, for example, the tyrosine kinase inhibitor, imatinib mesylate, has been revealed significant outcomes in patients with the K642E c-KIT gene mutation [27] whereas dasatinib, showed promising results in clinical trials in patients with L576P c-KIT gene mutation, once the KIT gene is mutated or present in increased numbers in mucosal melanoma [28]. Nilotinib is another selective inhibitor of c-KIT that does not require an active transport mechanism to enter cells [3]. Sadly, target therapy for c-KIT-mutated mucosal melanoma does not attempt the clinical reliability detected with BRAF-targeted treatment in cutaneous melanoma.
In clinical trials vemurafenib, a BRAF kinase inhibitor, has been showed greater efficacy and tolerability when compared to the chemotherapeutic dacarbazine [105, 106], as well as binimetinib, a MEK inhibitor (MEK162), administrated before or after immunotherapy with better overall response, progression-free survival, and disease control [107, 108].
4.5 Immunotherapy
A role for biologic treatment, as well as immunotherapy, has emerged over the last decade. Recent studies suggest that immunotherapy may confer survival benefit to patients with advanced disease.
Multiple prospective and retrospective studies support the use of the monoclonal antibody targeting cytotoxic T-lymphocyte-associated antigen-4 (CTLA4), ipilimumab, a promising immunotherapy [109], and the inhibitor of interactions of ligands PD-L1 and PD-L2 with its receptor, programmed death-1 receptor (PD-1), therefore blocking T-cell activation (anti-PD1 agents), nivolumab and pembrolizumab [110].
Nivolumab has been used as a promisor therapy in clinical trials. In patients with ipilimumab monotherapy-refractory or ipilimumab in combination with BRAF inhibitor-refractory metastatic melanoma, nivolumab showed a higher overall survival rate than standard chemotherapy [110, 111]. Furthermore, nivolumab in combination with ipilimumab has been shown a higher overall response rate then monotherapies [112].
Just like nivolumab, other checkpoint inhibitors, like pembrolizumab, have demonstrated more improvement in progression-free survival, toxicity, and overall survival than ipilimumab [113, 114].
Durvalumab and atezolizumab, other anti-PD-L1 antibody monotherapies, have not been very successful [115], whereas ipilimumab, nivolumab and pembrolizumab are standard options for unresectable or metastatic melanoma and may have potential as adjuvant therapy [3].
5. Prognosis
The prognosis of HNMM is relatively dismal, often due to late diagnosis, with 5-year overall survival rate of 25% [116, 117, 118, 119, 120, 121] and higher rates of local recurrence and distant metastases than cutaneous melanomas [10, 122, 123].
Distant metastasis is the most common cause of treatment failure. The most common sites for distant metastases are the lungs, followed by the liver, bones and brain [124].
Local recurrence is frequent and commonly associated to positive surgical margins. Advanced age is associated with decreased survival [59, 83, 98, 124, 125, 126]. Present of distant metastases, advanced T-category, ulceration, vascular invasion, deep infiltration and male gender are associated with a poorer prognosis too [8, 97].
The multidisciplinary team approach can help reduce morbidity and mortality once optimize treatment, reduce costs and minimize adverse events, while maximizing the chances of recovery. A collaborative interprofessional team includes surgery, medical oncology, radiation oncology, radiology, nuclear medicine and pathology [127]. A multidisciplinary team workup will provide proper appraisal evidence based decision-making, and the most helpful treatment planning and care.
6. Conclusion
Mucosal melanoma is an exceedingly rare variant of cutaneous melanoma, with aggressive behavior and less favorable prognosis. This could be because of late diagnosis, patients’ delay or the obscured anatomic site of origin. Unfortunately, because of its rarity, is poorly described and infrequently studied. Establishing guidelines for the clinical course of mucosal melanoma has been challenging.
The etiology and pathogenesis remain unclear. To date there are no clearly established risk factors for its development.
Primary tumor resection is the best treatment that also provides additional prognostic indicators. The type of surgical approach used is dependent upon the location and extension of the tumor, but the goal is negative margins with minimal cosmetic or functional derangements. Unfortunately, achieving melanoma-free margins is often compromised due to the anatomical complexity of the region and the close proximity of critical anatomic structures. Elective neck dissection is indicated for patients with lymph node metastases, especially in oral mucosal melanomas where there is an increased frequency. Adjuvant external beam radiotherapy is generally advocated with chemotherapy and targeted therapy being used for distant metastatic or unresectable disease.
Systemic treatment with immunotherapy can offer scope for modifying the course of the disease but response rates are lower and clinical research remains a priority. More studies and investigations are necessary to provide enough information and increase the survival rates.
\n',keywords:"mucosal, melanoma, head and neck",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/73473.pdf",chapterXML:"https://mts.intechopen.com/source/xml/73473.xml",downloadPdfUrl:"/chapter/pdf-download/73473",previewPdfUrl:"/chapter/pdf-preview/73473",totalDownloads:369,totalViews:0,totalCrossrefCites:0,dateSubmitted:"May 26th 2020",dateReviewed:"August 31st 2020",datePrePublished:"October 6th 2020",datePublished:"May 27th 2021",dateFinished:"October 6th 2020",readingETA:"0",abstract:"Mucosal melanomas of the head and neck are very rare malignancies that present with aggressive behavior and poor prognosis. Usually diagnosed at advanced stages, thus presenting macroscopically as aggressive nodular neoplasms arising from the mucosa; few cases are detected in situ. Tumor staging for mucosal melanoma remains a challenge. Several staging systems have been suggested, including tumor-nodal-metastases (TNM) staging systems, but none are frequently used. There is no clear consensus on the management of head and neck mucosal melanoma, which reflects the rare nature of the disease and complexity of the anatomic site. The late diagnosis, frequently presenting at an advanced stage, denotes the aggressive nature of the disease. Currently, early detection and surgical excision is considered the primary method of treatment. The multidisciplinary team approach can help reduce morbidity and mortality once optimize treatment, reduce costs and minimize adverse events, while maximizing the chances of recovery.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/73473",risUrl:"/chapter/ris/73473",signatures:"Ullyanov Bezerra Toscano de Mendonça, Júlia Guimarães Soffientini, Victoria Ficher Barbosa and Keren Cozer",book:{id:"10338",type:"book",title:"Melanoma",subtitle:null,fullTitle:"Melanoma",slug:"melanoma",publishedDate:"May 27th 2021",bookSignature:"Ahmed Lasfar and Karine Cohen-Solal",coverURL:"https://cdn.intechopen.com/books/images_new/10338.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",isbn:"978-1-83880-879-2",printIsbn:"978-1-83880-878-5",pdfIsbn:"978-1-83880-880-8",isAvailableForWebshopOrdering:!0,editors:[{id:"32546",title:"Dr.",name:"Ahmed",middleName:null,surname:"Lasfar",slug:"ahmed-lasfar",fullName:"Ahmed Lasfar"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:[{id:"322090",title:"Ph.D.",name:"Ullyanov",middleName:"Bezerra Toscano",surname:"Mendonca",fullName:"Ullyanov Mendonca",slug:"ullyanov-mendonca",email:"ullyanov@yahoo.com.br",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null},{id:"324263",title:"Dr.",name:"Victoria",middleName:null,surname:"Ficher Barbosa",fullName:"Victoria Ficher Barbosa",slug:"victoria-ficher-barbosa",email:"victoriaficher@gmail.com",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:{name:"Federal University of Rio de Janeiro",institutionURL:null,country:{name:"Brazil"}}},{id:"324627",title:"Dr.",name:"Julia",middleName:null,surname:"Soffientini",fullName:"Julia Soffientini",slug:"julia-soffientini",email:"jusoffientini@hotmail.com",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null},{id:"324628",title:"Dr.",name:"Keren",middleName:null,surname:"Cozer",fullName:"Keren Cozer",slug:"keren-cozer",email:"kerencozer@gmail.com",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Pathology and biology",level:"1"},{id:"sec_3",title:"3. Diagnosis",level:"1"},{id:"sec_3_2",title:"3.1 Clinical signs and symptoms",level:"2"},{id:"sec_3_3",title:"3.1.1 Primary mucosal melanomas of the nose and paranasal sinuses",level:"3"},{id:"sec_4_3",title:"3.1.2 Primary mucosal melanomas of the oral cavity",level:"3"},{id:"sec_5_3",title:"3.1.3 Primary mucosal melanomas of other head and neck sites",level:"3"},{id:"sec_7_2",title:"3.2 Histological diagnosis",level:"2"},{id:"sec_8_2",title:"3.3 Imaging of melanomas of the head and neck",level:"2"},{id:"sec_9_2",title:"3.4 Staging",level:"2"},{id:"sec_11",title:"4. Treatment/management",level:"1"},{id:"sec_11_2",title:"4.1 Surgery",level:"2"},{id:"sec_12_2",title:"4.2 Radiotherapy",level:"2"},{id:"sec_13_2",title:"4.3 Chemotherapy",level:"2"},{id:"sec_14_2",title:"4.4 Biological treatment",level:"2"},{id:"sec_15_2",title:"4.5 Immunotherapy",level:"2"},{id:"sec_17",title:"5. Prognosis",level:"1"},{id:"sec_18",title:"6. Conclusion",level:"1"}],chapterReferences:[{id:"B1",body:'Weber CO. Surgical experience and research, in addition to interesting observations from the Surgical Clinic and the Protestant Hospital Bonn. Berlin, Germany: G. Reimer; 1859. pp 304-305'},{id:"B2",body:'Yde SS, Sjoegren P, Heje M, Stolle LB. Mucosal Melanoma: a Literature Review. Current Oncology Reports. 2018 Mar;20(3):28'},{id:"B3",body:'Ascierto PA, Accorona R, Botti G, et al. Mucosal melanoma of the head and neck. Crit Rev Oncol Hematol. 2017;112:136-152'},{id:"B4",body:'Green B, Elhamshary A, Gomez R, Rahimi S, Brennan PA. An update on the current management of head and neck mucosal melanoma. J Oral Pathol Med. 2017;46(7):475-479'},{id:"B5",body:'Spencer KR, Mehnert JM. Mucosal Melanoma: Epidemiology, Biology and Treatment. Cancer Treat Res. 2016;167:295-320'},{id:"B6",body:'Paolino G, Didona D, Macrì G, et al. Nasopharyngeal Melanoma. In: Scott JF, Gerstenblith MR, editors. 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Otolaryngol Clin North Am.2016; 49: 183-200'},{id:"B91",body:'Lazarev S, Gupta V, Hu K, Harrison LB and Bakst R: Mucosal melanoma of the head and neck: a systematic review of the literature. Int J Radiation Oncol Biol Phys 90(5): 1108-1118, 2014'},{id:"B92",body:'Dauer EH, Lewis JE, Rohlinger AL, Weaver AL and Olsen KD: Sinonasal melanoma: a clinicopathologic review of 61 cases. Otolaryngol Head Neck Surg 138: 347-352, 2008'},{id:"B93",body:'http://www.nccn.org/professionals/physician_gls/f_guidelines.asp#site'},{id:"B94",body:'Wushou A, Zhao YJ. The management and site-specific prognostic factors of primary oral mucosal malignant melanoma. J Craniofac Surg 2015;26: 430-434'},{id:"B95",body:'Wushou A, Hou J, Zhao Y-J, Miao X-C. Postoperative adjuvant radiotherapy improves loco-regional recurrence of head and neck mucosal melanoma. J Craniomaxillofac Surg 2015;43:553-558'},{id:"B96",body:'Li W, Yu Y, Wang H, Yan A, Jiang X. Evaluation of the prognostic impact of postoperative adjuvant radiotherapy on head and neck mucosal melanoma: a meta-analysis. BMC Cancer 2015;15:758'},{id:"B97",body:'Lawaetz M, Birch–Johansen F, Friis S, et al. Primary mucosal melanoma of the head and neck in Denmark, 1982-2012: demographic and clinical aspects. A retrospective DAHANCA study. Acta Oncol 2016;55:1001-1008'},{id:"B98",body:'Samstein RM, Carvajal RD, Postow MA, et al. Localized sinonasal mucosal melanoma: outcomes and associations with stage, radiotherapy, and positron emission tomography response. Head Neck. 2016;38(9):1310-1317'},{id:"B99",body:'Zenda S, Kawashima M, Nishio T, et al. Proton beam therapy as a nonsurgical approach to mucosal melanoma of the head and neck: a pilot study. Int J Radiat Oncol Biol Phys. 2011;81(1):135-139'},{id:"B100",body:'Yanagi T, Mizoe J-E, Hasegawa A, et al. Mucosal malignant melanoma of the head and neck treated by carbon ion radiotherapy. 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Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011;364(26):2507-2516'},{id:"B107",body:'Ascierto PA, Schadendorf D, Berking C, et al. MEK162 for patients with advanced melanoma harbouring NRAS or Val600 BRAF mutations: a non-randomised, open-label Phase 2 study. Lancet Oncol. 2013;14(3):249-256. doi:10.1016/S1470-2045(13)70024-X'},{id:"B108",body:'Flaherty K, Arenberger P, Ascierto PA, et al. NEMO: a Phase 3 trial of binimetinib (MEK162) versus dacarbazine in patients with untreated or progressed after first-line immunotherapy unresectable or metastatic NRAS -mutant cutaneous melanoma. J Clin Oncol. 2014;32(15_suppl): TPS9102–TPS9102'},{id:"B109",body:'Schadendorf D, Hodi FS, Robert C, et al. Pooled analysis of long-term survival data from Phase II and Phase III trials of ipilimumab in unresectable or metastatic melanoma. J Clin Oncol. 2015;33 (17):1889-1894'},{id:"B110",body:'Robert C, Long GV, Brady B, et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med. 2015;372(4):320-330'},{id:"B111",body:'Weber JS, D’Angelo SP, Minor D, et al. Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 2015;16(4):375-384'},{id:"B112",body:'D’Angelo SP, Larkin J, Sosman JA, et al. Efficacy and safety of nivolumab alone or in combination with ipilimumab in patients with mucosal melanoma: a pooled analysis. J Clin Oncol. 2017;35 (2):226-235'},{id:"B113",body:'Robert C, Schachter J, Long GV, et al. Pembrolizumab versus ipilimumab in advanced melanoma. N Engl J Med. 2015;372 (26):2521-2532'},{id:"B114",body:'Ribas A, Puzanov I, Dummer R, et al. Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial. Lancet Oncol. 2015;16(8):908-918'},{id:"B115",body:'Redman JM, Gibney GT, Atkins MB. Advances in immunotherapy for melanoma. BMC Med. 2016;14(1):20'},{id:"B116",body:'Gal TJ, Silver N, Huang B. Demographics and treatment trends in sinonasal mucosal melanoma. Laryngoscope 2011;121:2026-2033'},{id:"B117",body:'Kingdom TT, Kaplan MJ. Mucosal melanoma of the nasal cavity and paranasal sinuses. Head Neck 1995;17:184-189'},{id:"B118",body:'Nakashima JP, Vi_egas CM, Fassizoli AL, et al. Postoperative adjuvant radiation therapy in the treatment of primary head and neck mucosal melanomas. ORL J Otorhinolaryngol Relat Spec 2008;70:344-351'},{id:"B119",body:'Owens JM, Roberts DB, Myers JN. The role of postoperative adjuvant radiation therapy in the treatment of mucosal melanomas of the head and neck region. Arch Otolaryngol Head Neck Surg 2003;129:864-868'},{id:"B120",body:'Temam S, Mamelle G, Marandas P, et al. Postoperative radiotherapy for primary mucosal melanoma of the head and neck. Cancer 2005;103: 313-319'},{id:"B121",body:'Yii NW, Eisen T, Nicolson M, et al. Mucosal malignant melanoma of the head and neck: the Marsden experience over half a century. Clin Oncol (R Coll Radiol) 2003;15:199-204'},{id:"B122",body:'MoriM, Sugiura M, Kono M,Matsumoto T, Sawada M, Yokota K, Yasue S, Shibata S, Sakakibara A, Nakamura S, Tomita Y, Akiyama M (2013) Clinico-pathologic analysis of 66 Japanese thin melanomas with metastasis of sentinel or regional lymph node. J Cutan Pathol 20:1027-34'},{id:"B123",body:'Thompson LD, Wieneke JA, Miettinen M (2003) Sinonasal tract and nasopharyngeal melanomas: a clinicopathologic study of 115 cases with a proposed staging system. Am J Surg Pathol 27(5):594-611'},{id:"B124",body:'Amit M, Tam S, Abdelmeguid AS, et al. Patterns of treatment failure in patients with sinonasal mucosal melanoma. Ann Surg Oncol. 2018;25(6):1723-1729'},{id:"B125",body:'Konuthula N, Khan MN, Parasher A, et al. The presentation and outcomes of mucosal melanoma in 695 patients. Int Forum Allergy Rhinol. 2017;7(1):99-105'},{id:"B126",body:'Low CM, Price DL, Moore EJ, et al. Nodal and distant metastases in sinonasal mucosal melanoma: a population-based analysis. Laryngoscope. 2019'},{id:"B127",body:'Mazzaferro V, Majno P. Principles for the best multidisciplinary meetings. Lancet Oncol. 2011;12(4):323-325'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Ullyanov Bezerra Toscano de Mendonça",address:"ullyanov@yahoo.com.br",affiliation:'
Department of Otolaryngology-Head and Neck Surgery, Federal University of Rio de Janeiro-UFRJ, RJ, Brazil
Department of Otolaryngology-Head and Neck Surgery, Federal University of Rio de Janeiro-UFRJ, RJ, Brazil
'}],corrections:null},book:{id:"10338",type:"book",title:"Melanoma",subtitle:null,fullTitle:"Melanoma",slug:"melanoma",publishedDate:"May 27th 2021",bookSignature:"Ahmed Lasfar and Karine Cohen-Solal",coverURL:"https://cdn.intechopen.com/books/images_new/10338.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",isbn:"978-1-83880-879-2",printIsbn:"978-1-83880-878-5",pdfIsbn:"978-1-83880-880-8",isAvailableForWebshopOrdering:!0,editors:[{id:"32546",title:"Dr.",name:"Ahmed",middleName:null,surname:"Lasfar",slug:"ahmed-lasfar",fullName:"Ahmed Lasfar"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}}},profile:{item:{id:"102095",title:"MSc.",name:"Viviane Gomes Costa",middleName:null,surname:"Abreu",email:"vgcabreu@yahoo.com.br",fullName:"Viviane Gomes Costa Abreu",slug:"viviane-gomes-costa-abreu",position:null,biography:null,institutionString:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",totalCites:0,totalChapterViews:"0",outsideEditionCount:0,totalAuthoredChapters:"2",totalEditedBooks:"0",personalWebsiteURL:null,twitterURL:null,linkedinURL:null,institution:{name:"Universidade Federal de Minas Gerais",institutionURL:null,country:{name:"Brazil"}}},booksEdited:[],chaptersAuthored:[{id:"39251",title:"Relationships Between Chemical Structure and Activity of Triterpenes Against Gram-Positive and Gram-Negative Bacteria",slug:"relationships-between-chemical-structure-and-activity-of-triterpenes-against-gram-positive-and-gram-",abstract:null,signatures:"A. G. Pacheco, A. F. C. Alcântara, V. G. C. Abreu and G. M. Corrêa",authors:[{id:"90992",title:"Dr.",name:"Alison",surname:"Pacheco",fullName:"Alison Pacheco",slug:"alison-pacheco",email:"alisonpacheco@qui.mest.ufmg.br"},{id:"102094",title:"Dr.",name:"Antonio Flavio Carvalho",surname:"Alcantara",fullName:"Antonio Flavio Carvalho Alcantara",slug:"antonio-flavio-carvalho-alcantara",email:"aalcantara@zeus.qui.ufmg.br"},{id:"102095",title:"MSc.",name:"Viviane Gomes Costa",surname:"Abreu",fullName:"Viviane Gomes Costa Abreu",slug:"viviane-gomes-costa-abreu",email:"vgcabreu@yahoo.com.br"},{id:"102096",title:"MSc.",name:"Geone Maia",surname:"Correa",fullName:"Geone Maia Correa",slug:"geone-maia-correa",email:"geone_maia@yahoo.com.br"}],book:{id:"2129",title:"A Search for Antibacterial Agents",slug:"a-search-for-antibacterial-agents",productType:{id:"1",title:"Edited Volume"}}},{id:"55119",title:"Effects of Gamma Radiation on Essential Oils: A Review",slug:"effects-of-gamma-radiation-on-essential-oils-a-review",abstract:"γ-Radiation provides an effective alternative method to reduce or eliminate microbial contamination of medicinal herbs and other plant materials. However, a search in the literature is important to describe the effects of γ-radiation on the content and integrity of secondary metabolites from plants. The present work provides a review of the effects of γ-radiation on extraction yields and chemical composition of essential oils isolated from roots, rhizome and cortex, leaves, fruits, seeds, flowers, and whole plant. In addition, this review describes the effects of γ-radiation on terpenes. The informations in the present work may assist in research about essential oils and dose of γ-radiation that is able to biologically decontaminate without causing chemical changes in secondary metabolites. These reports in the literature can describe the behavior of many of these metabolites when subjected to various doses of radiation.",signatures:"Clináscia Rodrigues Rocha Araújo, Geone Maia Corrêa, Viviane\nGomes da Costa Abreu, Thiago de Melo Silva, Aura María Blandón\nOsorio, Patrícia Machado de Oliveira and Antônio Flávio de\nCarvalho Alcântara",authors:[{id:"102095",title:"MSc.",name:"Viviane Gomes Costa",surname:"Abreu",fullName:"Viviane Gomes Costa Abreu",slug:"viviane-gomes-costa-abreu",email:"vgcabreu@yahoo.com.br"},{id:"102096",title:"MSc.",name:"Geone Maia",surname:"Correa",fullName:"Geone Maia Correa",slug:"geone-maia-correa",email:"geone_maia@yahoo.com.br"},{id:"191024",title:"M.Sc.",name:"Aura María",surname:"Blandón Osorio",fullName:"Aura María Blandón Osorio",slug:"aura-maria-blandon-osorio",email:"aurambo@ufmg.br"},{id:"192303",title:"Dr.",name:"Clináscia",surname:"Rodrigues Rocha Araújo",fullName:"Clináscia Rodrigues Rocha Araújo",slug:"clinascia-rodrigues-rocha-araujo",email:"clinascia2r@yahoo.com.br"},{id:"192304",title:"Dr.",name:"Thiago",surname:"de Melo Silva",fullName:"Thiago de Melo Silva",slug:"thiago-de-melo-silva",email:"silvatm@bol.com.br"},{id:"192305",title:"Dr.",name:"Patrícia",surname:"Machado de Oliveira",fullName:"Patrícia Machado de Oliveira",slug:"patricia-machado-de-oliveira",email:"patricia.oliveira@ufvjm.edu.br"},{id:"192306",title:"Dr.",name:"Antônio Flávio",surname:"de Carvalho Alcântara",fullName:"Antônio Flávio de Carvalho Alcântara",slug:"antonio-flavio-de-carvalho-alcantara",email:"aalcantara@mail.qui.ufmg.br"}],book:{id:"5451",title:"New Insights on Gamma Rays",slug:"new-insights-on-gamma-rays",productType:{id:"1",title:"Edited Volume"}}}],collaborators:[{id:"90992",title:"Dr.",name:"Alison",surname:"Pacheco",slug:"alison-pacheco",fullName:"Alison Pacheco",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Universidade Federal de Minas Gerais",institutionURL:null,country:{name:"Brazil"}}},{id:"91022",title:"Dr.",name:"Bikash Kumar",surname:"Jena",slug:"bikash-kumar-jena",fullName:"Bikash Kumar Jena",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/91022/images/3008_n.jpg",biography:null,institutionString:null,institution:{name:"Institute of Minerals and Materials Technology",institutionURL:null,country:{name:"India"}}},{id:"92290",title:"Dr.",name:"Herve Martial Poumale",surname:"Poumale",slug:"herve-martial-poumale-poumale",fullName:"Herve Martial Poumale Poumale",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/92290/images/1092_n.jpg",biography:"Dr. H.M.P.P.",institutionString:null,institution:{name:"Université de Yaoundé I",institutionURL:null,country:{name:"Cameroon"}}},{id:"92292",title:"Prof.",name:"Marcela",surname:"Rizzotto",slug:"marcela-rizzotto",fullName:"Marcela Rizzotto",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"National University of Rosario",institutionURL:null,country:{name:"Argentina"}}},{id:"95684",title:"Dr.",name:"Moustafa",surname:"Fouda",slug:"moustafa-fouda",fullName:"Moustafa Fouda",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"King Saud University",institutionURL:null,country:{name:"Saudi Arabia"}}},{id:"98515",title:"Dr.",name:"Jolanta",surname:"Krol",slug:"jolanta-krol",fullName:"Jolanta Krol",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Life Sciences",institutionURL:null,country:{name:"Poland"}}},{id:"102094",title:"Dr.",name:"Antonio Flavio Carvalho",surname:"Alcantara",slug:"antonio-flavio-carvalho-alcantara",fullName:"Antonio Flavio Carvalho Alcantara",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Universidade Federal de Minas Gerais",institutionURL:null,country:{name:"Brazil"}}},{id:"102096",title:"MSc.",name:"Geone Maia",surname:"Correa",slug:"geone-maia-correa",fullName:"Geone Maia Correa",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Universidade Federal de Minas Gerais",institutionURL:null,country:{name:"Brazil"}}},{id:"102231",title:"Prof.",name:"Metin",surname:"Tulu",slug:"metin-tulu",fullName:"Metin Tulu",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Yıldız Technical University",institutionURL:null,country:{name:"Turkey"}}},{id:"156046",title:"Dr.",name:"Aneta",surname:"Brodziak",slug:"aneta-brodziak",fullName:"Aneta Brodziak",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null}]},generic:{page:{slug:"OA-publishing-fees",title:"Open Access Publishing Fees",intro:"
The Open Access model is applied to all of our publications and is designed to eliminate subscriptions and pay-per-view fees. This approach ensures free, immediate access to full text versions of your research.
As a gold Open Access publisher, an Open Access Publishing Fee is payable on acceptance following peer review of the manuscript. In return, we provide high quality publishing services and exclusive benefits for all contributors. IntechOpen is the trusted publishing partner of over 140,000 international scientists and researchers.
\\n\\n
The Open Access Publishing Fee (OAPF) is payable only after your book chapter, monograph or journal article is accepted for publication.
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OAPF Publishing Options
\\n\\n
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1,400 GBP Chapter - Edited Volume
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850 GBP Chapter - Book Series Topic (Annual Volume)
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10,000 GBP Monograph - Long Form
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4,000 GBP Compacts Monograph - Short Form
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850 GBP Journal Article (Across Portfolio)
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During the launching phase journals do not charge an APC, rather they will be funded by IntechOpen.
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*These prices do not include Value-Added Tax (VAT). Residents of European Union countries need to add VAT based on the specific rate in their country of residence. Institutions and companies registered as VAT taxable entities in their own EU member state will not pay VAT as long as provision of the VAT registration number is made during the application process. This is made possible by the EU reverse charge method.
\\n\\n
Services included are:
\\n\\n
\\n\\t
An online manuscript tracking system to facilitate your work
\\n\\t
Personal contact and support throughout the publishing process from your dedicated Author Service Manager
\\n\\t
Assurance that your manuscript meets the highest publishing standards
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English language copyediting and proofreading, including the correction of grammatical, spelling, and other common errors
\\n\\t
XML Typesetting and pagination - web (PDF, HTML) and print files preparation
\\n\\t
Discoverability - electronic citation and linking via DOI
\\n\\t
Permanent and unrestricted online access to your work
\\n
\\n\\n
What isn't covered by the Open Access Publishing Fee?
\\n\\n
If your manuscript:
\\n\\n
\\n\\t
Exceeds the number of pages defined by the publishing guidelines, an additional fee per page may be required
\\n\\t
If a manuscript requires Heavy Editing or Language Polishing, this will incur additional fees.
\\n
\\n\\n
Your Author Service Manager will inform you of any items not covered by the OAPF and provide exact information regarding those additional costs before proceeding.
\\n\\n
Open Access Funding
\\n\\n
To explore funding opportunities and learn more about how you can finance your IntechOpen publication, go to our Open Access Funding page. IntechOpen offers expert assistance to all of its Authors. We can support you in approaching funding bodies and institutions in relation to publishing fees by providing information about compliance with the Open Access policies of your funder or institution. We can also assist with communicating the benefits of Open Access in order to support and strengthen your funding request and provide personal guidance through your application process. You can contact us at funders@intechopen.com for further details or assistance.
\\n\\n
For Authors who are still unable to obtain funding from their institutions or research funding bodies for individual projects, IntechOpen does offer the possibility of applying for a Waiver to offset some or all processing feed. Details regarding our Waiver Policy can be found here.
\\n\\n
Added Value of Publishing with IntechOpen
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Choosing to publish with IntechOpen ensures the following benefits:
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\\n\\t
Indexing and listing across major repositories, see details ...
\\n\\t
Long-term archiving
\\n\\t
Visibility on the world's strongest OA platform
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Live Performance Metrics to track readership and the impact of your chapter
\\n\\t
Dissemination and Promotion
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Benefits of Publishing with IntechOpen
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\\n\\t
Proven world leader in Open Access book publishing with over 10 years experience
\\n\\t
+5,700 OA books published
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Most competitive prices in the market
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Fully compliant with OA funding requirements
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Optimized processes that assure your research is made available to the scientific community without delay
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Personal support during every step of the publication process
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+184,650 citations in Web of Science databases
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Currently strongest OA platform with over 175 million downloads
As a gold Open Access publisher, an Open Access Publishing Fee is payable on acceptance following peer review of the manuscript. In return, we provide high quality publishing services and exclusive benefits for all contributors. IntechOpen is the trusted publishing partner of over 140,000 international scientists and researchers.
\n\n
The Open Access Publishing Fee (OAPF) is payable only after your book chapter, monograph or journal article is accepted for publication.
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OAPF Publishing Options
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\n\t
1,400 GBP Chapter - Edited Volume
\n\t
850 GBP Chapter - Book Series Topic (Annual Volume)
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10,000 GBP Monograph - Long Form
\n\t
4,000 GBP Compacts Monograph - Short Form
\n\t
850 GBP Journal Article (Across Portfolio)
\n
\n\n
During the launching phase journals do not charge an APC, rather they will be funded by IntechOpen.
\n\n
*These prices do not include Value-Added Tax (VAT). Residents of European Union countries need to add VAT based on the specific rate in their country of residence. Institutions and companies registered as VAT taxable entities in their own EU member state will not pay VAT as long as provision of the VAT registration number is made during the application process. This is made possible by the EU reverse charge method.
\n\n
Services included are:
\n\n
\n\t
An online manuscript tracking system to facilitate your work
\n\t
Personal contact and support throughout the publishing process from your dedicated Author Service Manager
\n\t
Assurance that your manuscript meets the highest publishing standards
\n\t
English language copyediting and proofreading, including the correction of grammatical, spelling, and other common errors
\n\t
XML Typesetting and pagination - web (PDF, HTML) and print files preparation
\n\t
Discoverability - electronic citation and linking via DOI
\n\t
Permanent and unrestricted online access to your work
\n
\n\n
What isn't covered by the Open Access Publishing Fee?
\n\n
If your manuscript:
\n\n
\n\t
Exceeds the number of pages defined by the publishing guidelines, an additional fee per page may be required
\n\t
If a manuscript requires Heavy Editing or Language Polishing, this will incur additional fees.
\n
\n\n
Your Author Service Manager will inform you of any items not covered by the OAPF and provide exact information regarding those additional costs before proceeding.
\n\n
Open Access Funding
\n\n
To explore funding opportunities and learn more about how you can finance your IntechOpen publication, go to our Open Access Funding page. IntechOpen offers expert assistance to all of its Authors. We can support you in approaching funding bodies and institutions in relation to publishing fees by providing information about compliance with the Open Access policies of your funder or institution. We can also assist with communicating the benefits of Open Access in order to support and strengthen your funding request and provide personal guidance through your application process. You can contact us at funders@intechopen.com for further details or assistance.
\n\n
For Authors who are still unable to obtain funding from their institutions or research funding bodies for individual projects, IntechOpen does offer the possibility of applying for a Waiver to offset some or all processing feed. Details regarding our Waiver Policy can be found here.
\n\n
Added Value of Publishing with IntechOpen
\n\n
Choosing to publish with IntechOpen ensures the following benefits:
\n\n
\n\t
Indexing and listing across major repositories, see details ...
\n\t
Long-term archiving
\n\t
Visibility on the world's strongest OA platform
\n\t
Live Performance Metrics to track readership and the impact of your chapter
\n\t
Dissemination and Promotion
\n
\n\n
Benefits of Publishing with IntechOpen
\n\n
\n\t
Proven world leader in Open Access book publishing with over 10 years experience
\n\t
+5,700 OA books published
\n\t
Most competitive prices in the market
\n\t
Fully compliant with OA funding requirements
\n\t
Optimized processes that assure your research is made available to the scientific community without delay
\n\t
Personal support during every step of the publication process
\n\t
+184,650 citations in Web of Science databases
\n\t
Currently strongest OA platform with over 175 million downloads
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Crotty Alexander",coverURL:"https://cdn.intechopen.com/books/images_new/6045.jpg",editedByType:"Edited by",editors:[{id:"81926",title:"Dr.",name:"Shymaa",middleName:null,surname:"Enany",slug:"shymaa-enany",fullName:"Shymaa Enany"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}],booksByTopicTotal:1,seriesByTopicCollection:[],seriesByTopicTotal:0,mostCitedChapters:[{id:"53240",doi:"10.5772/66380",title:"Staphylococcus aureus Biofilms and their Impact on the Medical Field",slug:"staphylococcus-aureus-biofilms-and-their-impact-on-the-medical-field",totalDownloads:3776,totalCrossrefCites:18,totalDimensionsCites:34,abstract:"Despite the discovery of antibiotics, the battle against bacteria is so far in their favor, specifically because bugs are able to develop a superstructure named biofilm, to resist and to survive in the environment. Nosocomial infections, a major health problem, are due at 80% to biofilm‐associated infection, and Staphylococcus aureus is the leading bacteria species in this domain. Moreover, the antimicrobial resistance of this bacterial community is accentuated when it is formed by superbugs such as methicillin‐resistant S. aureus (MRSA). In this chapter, the mechanism and the physiology of S. aureus biofilm as well as their consequences in the clinical domains are described. To complete the vision on S. aureus biofilms, some “anti‐biofilm” strategies will be highlighted.",book:{id:"6045",slug:"the-rise-of-virulence-and-antibiotic-resistance-in-staphylococcus-aureus",title:"The Rise of Virulence and Antibiotic Resistance in Staphylococcus aureus",fullTitle:"The Rise of Virulence and Antibiotic Resistance in Staphylococcus aureus"},signatures:"Fany Reffuveille, Jérôme Josse, Quentin Vallé, Céline Mongaret and\nSophie C. Gangloff",authors:[{id:"54351",title:"Prof.",name:"Sophie C.",middleName:null,surname:"Gangloff",slug:"sophie-c.-gangloff",fullName:"Sophie C. Gangloff"},{id:"190356",title:"Ph.D.",name:"Fany",middleName:null,surname:"Reffuveille",slug:"fany-reffuveille",fullName:"Fany Reffuveille"},{id:"191408",title:"Dr.",name:"Jérome",middleName:null,surname:"Josse",slug:"jerome-josse",fullName:"Jérome Josse"},{id:"203850",title:"Dr.",name:"Quentin",middleName:null,surname:"Vallé",slug:"quentin-valle",fullName:"Quentin Vallé"},{id:"203852",title:"Dr.",name:"Céline",middleName:null,surname:"Mongaret",slug:"celine-mongaret",fullName:"Céline Mongaret"}]},{id:"52471",doi:"10.5772/65452",title:"MRSA and MSSA: The Mechanism of Methicillin Resistance and the Influence of Methicillin Resistance on Biofilm Phenotype of Staphylococcus aureus",slug:"mrsa-and-mssa-the-mechanism-of-methicillin-resistance-and-the-influence-of-methicillin-resistance-on",totalDownloads:3159,totalCrossrefCites:6,totalDimensionsCites:9,abstract:"Staphylococcus aureus (S. aureus), which is one of the most common causes of indwelling device–associated, nosocomial, and community-acquired infections, can produce biofilm as a virulence factor. Methicillin-resistant S. aureus (MRSA) that is resistant to β-lactam antibiotics causes life-threatening infections. Biofilm producer strains of S. aureus that causes indwelling device–associated infections resist to antimicrobials and immune system. The combination of methicillin resistance and the ability of biofilm formation of S. aureus makes treatment difficult. Methicillin resistance of S. aureus can affect biofilm phenotype of S. aureus; the mecA gene of MRSA increases biofilm production by inactivating accessory gene regulator (agr) quorum sensing regulator system, which is a two-component regulator system of virulence factor production. The aim of this review is to determine virulence factors of S. aureus, resistance mechanisms of methicillin, and the influence of methicillin resistance on biofilm phenotype of S. aureus.",book:{id:"6045",slug:"the-rise-of-virulence-and-antibiotic-resistance-in-staphylococcus-aureus",title:"The Rise of Virulence and Antibiotic Resistance in Staphylococcus aureus",fullTitle:"The Rise of Virulence and Antibiotic Resistance in Staphylococcus aureus"},signatures:"Sahra Kırmusaoğlu",authors:[{id:"179460",title:"Associate Prof.",name:"Sahra",middleName:null,surname:"Kırmusaoğlu",slug:"sahra-kirmusaoglu",fullName:"Sahra Kırmusaoğlu"}]},{id:"53022",doi:"10.5772/65980",title:"Antimicrobial Activity of Chitosan Membranes Against Staphylococcus Aureus of Clinical Origin",slug:"antimicrobial-activity-of-chitosan-membranes-against-staphylococcus-aureus-of-clinical-origin",totalDownloads:2239,totalCrossrefCites:2,totalDimensionsCites:7,abstract:"Healthy human skin has beneficial microflora and many pathogens causing infections. Staphylococcus aureus is the most prevalent and can have multiresistance to antibiotics. Chitosan is a polysaccharide composed of glucosamine and N-acetyl-D-glucosamine, which is biodegradable and has antimicrobial activity. As part of a national scientific research project for the development and application of biomaterials, we decided to study the effect of different membranes based on chitosan against strains of S. aureus isolated from infected ulcers. The study found that seven of nine strains of S. aureus are sensitive to rifampin and the least eight of nine strains were multiresistant to more than ten antibiotics. All chitosan-based membranes confirm its antimicrobial effect on direct contact with an increase in its diameter. The contact area of the membranes is increased according to the concentration of chitosan. The highest average area increase was the chitosan membranes with honey and glycerin, 88.32%. Chitosan membranes have shown their effectiveness against S. aureus strains of clinical origin. Thus, these materials can be applied for the treatment of chronic ulcers without toxic hazards and resistance caused by antibiotics.",book:{id:"6045",slug:"the-rise-of-virulence-and-antibiotic-resistance-in-staphylococcus-aureus",title:"The Rise of Virulence and Antibiotic Resistance in Staphylococcus aureus",fullTitle:"The Rise of Virulence and Antibiotic Resistance in Staphylococcus aureus"},signatures:"Ana A. Escárcega-Galaz, Jaime López-Cervantes, Dalia I. Sánchez-\nMachado, Olga R. Brito-Zurita and Olga N. Campas-Baypoli",authors:[{id:"190199",title:"Dr.",name:"Dalia I.",middleName:null,surname:"Sánchez-Machado",slug:"dalia-i.-sanchez-machado",fullName:"Dalia I. Sánchez-Machado"},{id:"194979",title:"Dr.",name:"Ana A.",middleName:null,surname:"Escárcega-Galaz",slug:"ana-a.-escarcega-galaz",fullName:"Ana A. Escárcega-Galaz"}]},{id:"53644",doi:"10.5772/66528",title:"Exfoliative Toxins of Staphylococcus aureus",slug:"exfoliative-toxins-of-staphylococcus-aureus",totalDownloads:2357,totalCrossrefCites:3,totalDimensionsCites:6,abstract:"Virulent strains of Staphylococcus aureus secrete exfoliative toxins (ETs) that cause the loss of cell‐cell adhesion in the superficial epidermis. S. aureus ETs are serine proteases, which exhibit exquisite substrate specificity, and their mechanisms of action are extremely complex. To date, four different serotypes of ETs have been identified and three of them (ETA, ETB and ETD) are associated with toxin‐mediated staphylococcal syndromes related to human infections leading to diseases of medical and veterinary importance.",book:{id:"6045",slug:"the-rise-of-virulence-and-antibiotic-resistance-in-staphylococcus-aureus",title:"The Rise of Virulence and Antibiotic Resistance in Staphylococcus aureus",fullTitle:"The Rise of Virulence and Antibiotic Resistance in Staphylococcus aureus"},signatures:"Ricardo B. Mariutti, Natayme R. Tartaglia, Núbia Seyffert, Thiago\nLuiz de Paula Castro, Raghuvir K. Arni, Vasco A. Azevedo, Yves Le\nLoir and Koji Nishifuji",authors:[{id:"192121",title:"Ms.",name:"Natayme",middleName:null,surname:"Tartaglia",slug:"natayme-tartaglia",fullName:"Natayme Tartaglia"},{id:"192122",title:"Dr.",name:"Núbia",middleName:null,surname:"Seyffert",slug:"nubia-seyffert",fullName:"Núbia Seyffert"},{id:"192124",title:"Dr.",name:"Thiago",middleName:null,surname:"Castro",slug:"thiago-castro",fullName:"Thiago Castro"},{id:"192125",title:"Dr.",name:"Koji",middleName:null,surname:"Nishifuji",slug:"koji-nishifuji",fullName:"Koji Nishifuji"},{id:"192126",title:"Dr.",name:"Yves",middleName:null,surname:"Le Loir",slug:"yves-le-loir",fullName:"Yves Le Loir"},{id:"192129",title:"Dr.",name:"Ricardo",middleName:null,surname:"Mariutti",slug:"ricardo-mariutti",fullName:"Ricardo Mariutti"},{id:"192131",title:"Dr.",name:"Raghuvir",middleName:null,surname:"Arni",slug:"raghuvir-arni",fullName:"Raghuvir Arni"},{id:"192132",title:"Dr.",name:"Vasco",middleName:null,surname:"Ariston de Carvalho Azevedo",slug:"vasco-ariston-de-carvalho-azevedo",fullName:"Vasco Ariston de Carvalho Azevedo"}]},{id:"52497",doi:"10.5772/65514",title:"The Evolution and Dissemination of Methicillin Resistance Determinant in Staphylococcus aureus",slug:"the-evolution-and-dissemination-of-methicillin-resistance-determinant-in-staphylococcus-aureus",totalDownloads:1922,totalCrossrefCites:4,totalDimensionsCites:6,abstract:"Staphylococcus aureus is an opportunistic pathogen and is frequently associated with the antimicrobial resistance. There has been horizontal gene transfer of Staphylococcus chromosome cassette mec (SCCmec) among the staphylococcal species that colonize a similar colonization niche, which eventually results in emergence of new variant with enhanced survival ability in terms of antimicrobial resistance and virulence level in S. aureus. Evolution and dissemination of SCCmec structure resulted in the emergence of methicillin-resistant S. aureus (MRSA) clones around the world covering hospital, community, and livestock settings. MRSA also has the ability to resist different antibiotic profiles known as multidrug-resistant S. aureus (MDR S. aureus).",book:{id:"6045",slug:"the-rise-of-virulence-and-antibiotic-resistance-in-staphylococcus-aureus",title:"The Rise of Virulence and Antibiotic Resistance in Staphylococcus aureus",fullTitle:"The Rise of Virulence and Antibiotic Resistance in Staphylococcus aureus"},signatures:"Abdul Rahim Abdul Rachman, Zarizal Suhaili and Mohd Nasir Mohd\nDesa",authors:[{id:"189666",title:"Associate Prof.",name:"Mohd Nasir",middleName:null,surname:"Mohd Desa",slug:"mohd-nasir-mohd-desa",fullName:"Mohd Nasir Mohd Desa"},{id:"191317",title:"Ms.",name:"Zarizal",middleName:null,surname:"Suhaili",slug:"zarizal-suhaili",fullName:"Zarizal Suhaili"},{id:"191318",title:"Mr.",name:"Abdul Rahim",middleName:null,surname:"Abdul Rachman",slug:"abdul-rahim-abdul-rachman",fullName:"Abdul Rahim Abdul Rachman"}]}],mostDownloadedChaptersLast30Days:[{id:"53240",title:"Staphylococcus aureus Biofilms and their Impact on the Medical Field",slug:"staphylococcus-aureus-biofilms-and-their-impact-on-the-medical-field",totalDownloads:3776,totalCrossrefCites:18,totalDimensionsCites:34,abstract:"Despite the discovery of antibiotics, the battle against bacteria is so far in their favor, specifically because bugs are able to develop a superstructure named biofilm, to resist and to survive in the environment. Nosocomial infections, a major health problem, are due at 80% to biofilm‐associated infection, and Staphylococcus aureus is the leading bacteria species in this domain. Moreover, the antimicrobial resistance of this bacterial community is accentuated when it is formed by superbugs such as methicillin‐resistant S. aureus (MRSA). In this chapter, the mechanism and the physiology of S. aureus biofilm as well as their consequences in the clinical domains are described. To complete the vision on S. aureus biofilms, some “anti‐biofilm” strategies will be highlighted.",book:{id:"6045",slug:"the-rise-of-virulence-and-antibiotic-resistance-in-staphylococcus-aureus",title:"The Rise of Virulence and Antibiotic Resistance in Staphylococcus aureus",fullTitle:"The Rise of Virulence and Antibiotic Resistance in Staphylococcus aureus"},signatures:"Fany Reffuveille, Jérôme Josse, Quentin Vallé, Céline Mongaret and\nSophie C. Gangloff",authors:[{id:"54351",title:"Prof.",name:"Sophie C.",middleName:null,surname:"Gangloff",slug:"sophie-c.-gangloff",fullName:"Sophie C. Gangloff"},{id:"190356",title:"Ph.D.",name:"Fany",middleName:null,surname:"Reffuveille",slug:"fany-reffuveille",fullName:"Fany Reffuveille"},{id:"191408",title:"Dr.",name:"Jérome",middleName:null,surname:"Josse",slug:"jerome-josse",fullName:"Jérome Josse"},{id:"203850",title:"Dr.",name:"Quentin",middleName:null,surname:"Vallé",slug:"quentin-valle",fullName:"Quentin Vallé"},{id:"203852",title:"Dr.",name:"Céline",middleName:null,surname:"Mongaret",slug:"celine-mongaret",fullName:"Céline Mongaret"}]},{id:"52471",title:"MRSA and MSSA: The Mechanism of Methicillin Resistance and the Influence of Methicillin Resistance on Biofilm Phenotype of Staphylococcus aureus",slug:"mrsa-and-mssa-the-mechanism-of-methicillin-resistance-and-the-influence-of-methicillin-resistance-on",totalDownloads:3159,totalCrossrefCites:6,totalDimensionsCites:9,abstract:"Staphylococcus aureus (S. aureus), which is one of the most common causes of indwelling device–associated, nosocomial, and community-acquired infections, can produce biofilm as a virulence factor. Methicillin-resistant S. aureus (MRSA) that is resistant to β-lactam antibiotics causes life-threatening infections. Biofilm producer strains of S. aureus that causes indwelling device–associated infections resist to antimicrobials and immune system. The combination of methicillin resistance and the ability of biofilm formation of S. aureus makes treatment difficult. Methicillin resistance of S. aureus can affect biofilm phenotype of S. aureus; the mecA gene of MRSA increases biofilm production by inactivating accessory gene regulator (agr) quorum sensing regulator system, which is a two-component regulator system of virulence factor production. The aim of this review is to determine virulence factors of S. aureus, resistance mechanisms of methicillin, and the influence of methicillin resistance on biofilm phenotype of S. aureus.",book:{id:"6045",slug:"the-rise-of-virulence-and-antibiotic-resistance-in-staphylococcus-aureus",title:"The Rise of Virulence and Antibiotic Resistance in Staphylococcus aureus",fullTitle:"The Rise of Virulence and Antibiotic Resistance in Staphylococcus aureus"},signatures:"Sahra Kırmusaoğlu",authors:[{id:"179460",title:"Associate Prof.",name:"Sahra",middleName:null,surname:"Kırmusaoğlu",slug:"sahra-kirmusaoglu",fullName:"Sahra Kırmusaoğlu"}]},{id:"53157",title:"Surface Proteins of Staphylococcus aureus",slug:"surface-proteins-of-staphylococcus-aureus",totalDownloads:2465,totalCrossrefCites:2,totalDimensionsCites:2,abstract:"Staphylococcus aureus is a commensal bacterium that causes infections such as sepsis, endocarditis, and pneumonia. S. aureus can express a variety of virulence factors, including surface proteins. Surface proteins are characterized by presence of a Sec‐dependent signal sequence at the amino terminal, and the sorting signal domain. Surface proteins are covalently attached to peptidoglycan and they are commonly known as cell wall–anchored (CWA) proteins. CWA proteins have many functions and participate in the pathogenesis of S. aureus. Furthermore, these proteins have been proposed as therapeutic targets for the generation of vaccines. In this chapter, different topics related to CWA proteins of S. aureus are addressed. The molecular structure of CWA proteins and their role as virulence factors of S. aureus are described. Furthermore, the involvement of CWA proteins in the processes of adhesion, invasion of host cells and tissues, evasion of the immune response, and the formation of biofilm is discussed. In addition, the role of CWA proteins in skin infection and the proposal to use them as potential vaccine antigens are described. The information contained in this chapter will help the readers to understand the biology of CWA proteins and to recognize the importance of surface molecules of S. aureus.",book:{id:"6045",slug:"the-rise-of-virulence-and-antibiotic-resistance-in-staphylococcus-aureus",title:"The Rise of Virulence and Antibiotic Resistance in Staphylococcus aureus",fullTitle:"The Rise of Virulence and Antibiotic Resistance in Staphylococcus aureus"},signatures:"Janet Jan-Roblero, Elizabeth García-Gómez, Sandra Rodríguez-\nMartínez, Mario E. Cancino-Diaz and Juan C. Cancino-Diaz",authors:[{id:"181148",title:"Dr.",name:"Juan C.",middleName:null,surname:"Cancino-Diaz",slug:"juan-c.-cancino-diaz",fullName:"Juan C. Cancino-Diaz"},{id:"184949",title:"Dr.",name:"Janet",middleName:null,surname:"Jan-Roblero",slug:"janet-jan-roblero",fullName:"Janet Jan-Roblero"},{id:"184950",title:"Dr.",name:"Sandra",middleName:null,surname:"Rodríguez-Martínez",slug:"sandra-rodriguez-martinez",fullName:"Sandra Rodríguez-Martínez"},{id:"184951",title:"Dr.",name:"Mario E.",middleName:null,surname:"Cancino-Diaz",slug:"mario-e.-cancino-diaz",fullName:"Mario E. Cancino-Diaz"},{id:"194929",title:"Dr.",name:"Elizabeth",middleName:null,surname:"García-Gómez",slug:"elizabeth-garcia-gomez",fullName:"Elizabeth García-Gómez"}]},{id:"53644",title:"Exfoliative Toxins of Staphylococcus aureus",slug:"exfoliative-toxins-of-staphylococcus-aureus",totalDownloads:2357,totalCrossrefCites:3,totalDimensionsCites:6,abstract:"Virulent strains of Staphylococcus aureus secrete exfoliative toxins (ETs) that cause the loss of cell‐cell adhesion in the superficial epidermis. S. aureus ETs are serine proteases, which exhibit exquisite substrate specificity, and their mechanisms of action are extremely complex. To date, four different serotypes of ETs have been identified and three of them (ETA, ETB and ETD) are associated with toxin‐mediated staphylococcal syndromes related to human infections leading to diseases of medical and veterinary importance.",book:{id:"6045",slug:"the-rise-of-virulence-and-antibiotic-resistance-in-staphylococcus-aureus",title:"The Rise of Virulence and Antibiotic Resistance in Staphylococcus aureus",fullTitle:"The Rise of Virulence and Antibiotic Resistance in Staphylococcus aureus"},signatures:"Ricardo B. Mariutti, Natayme R. Tartaglia, Núbia Seyffert, Thiago\nLuiz de Paula Castro, Raghuvir K. Arni, Vasco A. Azevedo, Yves Le\nLoir and Koji Nishifuji",authors:[{id:"192121",title:"Ms.",name:"Natayme",middleName:null,surname:"Tartaglia",slug:"natayme-tartaglia",fullName:"Natayme Tartaglia"},{id:"192122",title:"Dr.",name:"Núbia",middleName:null,surname:"Seyffert",slug:"nubia-seyffert",fullName:"Núbia Seyffert"},{id:"192124",title:"Dr.",name:"Thiago",middleName:null,surname:"Castro",slug:"thiago-castro",fullName:"Thiago Castro"},{id:"192125",title:"Dr.",name:"Koji",middleName:null,surname:"Nishifuji",slug:"koji-nishifuji",fullName:"Koji Nishifuji"},{id:"192126",title:"Dr.",name:"Yves",middleName:null,surname:"Le Loir",slug:"yves-le-loir",fullName:"Yves Le Loir"},{id:"192129",title:"Dr.",name:"Ricardo",middleName:null,surname:"Mariutti",slug:"ricardo-mariutti",fullName:"Ricardo Mariutti"},{id:"192131",title:"Dr.",name:"Raghuvir",middleName:null,surname:"Arni",slug:"raghuvir-arni",fullName:"Raghuvir Arni"},{id:"192132",title:"Dr.",name:"Vasco",middleName:null,surname:"Ariston de Carvalho Azevedo",slug:"vasco-ariston-de-carvalho-azevedo",fullName:"Vasco Ariston de Carvalho Azevedo"}]},{id:"53224",title:"Mechanisms of Horizontal Gene Transfer",slug:"mechanisms-of-horizontal-gene-transfer",totalDownloads:2120,totalCrossrefCites:1,totalDimensionsCites:3,abstract:"Horizontal gene transfer plays important roles in the evolution of S. aureus, and indeed, a variety of virulence factors and antibiotic resistance genes are embedded in a series of mobile genetic elements. In this chapter, we review the mechanisms of horizontal gene transfer, including recent findings on the natural genetic competence. Then, we consider the transfer of two important antibiotic resistance genes: the methicillin resistance gene, mecA (in Staphylococcal Cassette Chromosome) and the linezolid resistance gene, cfr (in plasmid). In either case, distinct mechanisms driving the gene dissemination support the prominent evolutionary ability of this important human pathogen.",book:{id:"6045",slug:"the-rise-of-virulence-and-antibiotic-resistance-in-staphylococcus-aureus",title:"The Rise of Virulence and Antibiotic Resistance in Staphylococcus aureus",fullTitle:"The Rise of Virulence and Antibiotic Resistance in Staphylococcus aureus"},signatures:"Fabio Cafini, Veronica Medrano Romero and Kazuya Morikawa",authors:[{id:"190494",title:"Prof.",name:"Kazuya",middleName:null,surname:"Morikawa",slug:"kazuya-morikawa",fullName:"Kazuya Morikawa"},{id:"196517",title:"Dr.",name:"Fabio",middleName:null,surname:"Cafini",slug:"fabio-cafini",fullName:"Fabio Cafini"},{id:"196518",title:"Ms.",name:"Veronica",middleName:null,surname:"Medrano Romero",slug:"veronica-medrano-romero",fullName:"Veronica Medrano Romero"}]}],onlineFirstChaptersFilter:{topicId:"901",limit:6,offset:0},onlineFirstChaptersCollection:[],onlineFirstChaptersTotal:0},preDownload:{success:null,errors:{}},subscriptionForm:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[],offset:0,limit:8,total:null},allSeries:{pteSeriesList:[],lsSeriesList:[],hsSeriesList:[],sshSeriesList:[],testimonialsList:[]},series:{item:{id:"10",title:"Physiology",doi:"10.5772/intechopen.72796",issn:"2631-8261",scope:"Modern physiology requires a comprehensive understanding of the integration of tissues and organs throughout the mammalian body, including the cooperation between structure and function at the cellular and molecular levels governed by gene and protein expression. While a daunting task, learning is facilitated by identifying common and effective signaling pathways mediated by a variety of factors employed by nature to preserve and sustain homeostatic life. \r\nAs a leading example, the cellular interaction between intracellular concentration of Ca+2 increases, and changes in plasma membrane potential is integral for coordinating blood flow, governing the exocytosis of neurotransmitters, and modulating gene expression and cell effector secretory functions. Furthermore, in this manner, understanding the systemic interaction between the cardiovascular and nervous systems has become more important than ever as human populations' life prolongation, aging and mechanisms of cellular oxidative signaling are utilised for sustaining life. \r\nAltogether, physiological research enables our identification of distinct and precise points of transition from health to the development of multimorbidity throughout the inevitable aging disorders (e.g., diabetes, hypertension, chronic kidney disease, heart failure, peptic ulcer, inflammatory bowel disease, age-related macular degeneration, cancer). With consideration of all organ systems (e.g., brain, heart, lung, gut, skeletal and smooth muscle, liver, pancreas, kidney, eye) and the interactions thereof, this Physiology Series will address the goals of resolving (1) Aging physiology and chronic disease progression (2) Examination of key cellular pathways as they relate to calcium, oxidative stress, and electrical signaling, and (3) how changes in plasma membrane produced by lipid peroxidation products can affect aging physiology, covering new research in the area of cell, human, plant and animal physiology.",coverUrl:"https://cdn.intechopen.com/series/covers/10.jpg",latestPublicationDate:"May 14th, 2022",hasOnlineFirst:!0,numberOfPublishedBooks:11,editor:{id:"35854",title:"Prof.",name:"Tomasz",middleName:null,surname:"Brzozowski",slug:"tomasz-brzozowski",fullName:"Tomasz Brzozowski",profilePictureURL:"https://mts.intechopen.com/storage/users/35854/images/system/35854.jpg",biography:"Prof. Dr. Thomas Brzozowski works as a professor of Human Physiology and is currently Chairman at the Department of Physiology and is V-Dean of the Medical Faculty at Jagiellonian University Medical College, Cracow, Poland. His primary area of interest is physiology and pathophysiology of the gastrointestinal (GI) tract, with the major focus on the mechanism of GI mucosal defense, protection, and ulcer healing. He was a postdoctoral NIH fellow at the University of California and the Gastroenterology VA Medical Center, Irvine, Long Beach, CA, USA, and at the Gastroenterology Clinics Erlangen-Nuremberg and Munster in Germany. He has published 290 original articles in some of the most prestigious scientific journals and seven book chapters on the pathophysiology of the GI tract, gastroprotection, ulcer healing, drug therapy of peptic ulcers, hormonal regulation of the gut, and inflammatory bowel disease.",institutionString:null,institution:{name:"Jagiellonian University",institutionURL:null,country:{name:"Poland"}}},editorTwo:null,editorThree:null},subseries:{paginationCount:4,paginationItems:[{id:"10",title:"Animal Physiology",coverUrl:"https://cdn.intechopen.com/series_topics/covers/10.jpg",isOpenForSubmission:!0,editor:{id:"202192",title:"Dr.",name:"Catrin",middleName:null,surname:"Rutland",slug:"catrin-rutland",fullName:"Catrin Rutland",profilePictureURL:"https://mts.intechopen.com/storage/users/202192/images/system/202192.png",biography:"Catrin Rutland is an Associate Professor of Anatomy and Developmental Genetics at the University of Nottingham, UK. She obtained a BSc from the University of Derby, England, a master’s degree from Technische Universität München, Germany, and a Ph.D. from the University of Nottingham. She undertook a post-doctoral research fellowship in the School of Medicine before accepting tenure in Veterinary Medicine and Science. Dr. Rutland also obtained an MMedSci (Medical Education) and a Postgraduate Certificate in Higher Education (PGCHE). She is the author of more than sixty peer-reviewed journal articles, twelve books/book chapters, and more than 100 research abstracts in cardiovascular biology and oncology. She is a board member of the European Association of Veterinary Anatomists, Fellow of the Anatomical Society, and Senior Fellow of the Higher Education Academy. Dr. Rutland has also written popular science books for the public. https://orcid.org/0000-0002-2009-4898. www.nottingham.ac.uk/vet/people/catrin.rutland",institutionString:null,institution:{name:"University of Nottingham",institutionURL:null,country:{name:"United Kingdom"}}},editorTwo:null,editorThree:null},{id:"11",title:"Cell Physiology",coverUrl:"https://cdn.intechopen.com/series_topics/covers/11.jpg",isOpenForSubmission:!0,editor:{id:"133493",title:"Prof.",name:"Angel",middleName:null,surname:"Catala",slug:"angel-catala",fullName:"Angel Catala",profilePictureURL:"https://mts.intechopen.com/storage/users/133493/images/3091_n.jpg",biography:"Prof. Dr. Angel Catalá \r\nShort Biography Angel Catalá was born in Rodeo (San Juan, Argentina). He studied \r\nchemistry at the Universidad Nacional de La Plata, Argentina, where received aPh.D. degree in chemistry (Biological Branch) in 1965. From\r\n1964 to 1974, he worked as Assistant in Biochemistry at the School of MedicineUniversidad Nacional de La Plata, Argentina. From 1974 to 1976, he was a Fellowof the National Institutes of Health (NIH) at the University of Connecticut, Health Center, USA. From 1985 to 2004, he served as a Full Professor oBiochemistry at the Universidad Nacional de La Plata, Argentina. He is Member ofthe National Research Council (CONICET), Argentina, and Argentine Society foBiochemistry and Molecular Biology (SAIB). His laboratory has been interested for manyears in the lipid peroxidation of biological membranes from various tissues and different species. Professor Catalá has directed twelve doctoral theses, publishedover 100 papers in peer reviewed journals, several chapters in books andtwelve edited books. Angel Catalá received awards at the 40th InternationaConference Biochemistry of Lipids 1999: Dijon (France). W inner of the Bimbo PanAmerican Nutrition, Food Science and Technology Award 2006 and 2012, South AmericaHuman Nutrition, Professional Category. 2006 award in pharmacology, Bernardo\r\nHoussay, in recognition of his meritorious works of research. Angel Catalá belongto the Editorial Board of Journal of lipids, International Review of Biophysical ChemistryFrontiers in Membrane Physiology and Biophysics, World Journal oExperimental Medicine and Biochemistry Research International, W orld Journal oBiological Chemistry, Oxidative Medicine and Cellular Longevity, Diabetes and thePancreas, International Journal of Chronic Diseases & Therapy, International Journal oNutrition, Co-Editor of The Open Biology Journal.",institutionString:null,institution:{name:"National University of La Plata",institutionURL:null,country:{name:"Argentina"}}},editorTwo:null,editorThree:null},{id:"12",title:"Human Physiology",coverUrl:"https://cdn.intechopen.com/series_topics/covers/12.jpg",isOpenForSubmission:!0,editor:{id:"195829",title:"Prof.",name:"Kunihiro",middleName:null,surname:"Sakuma",slug:"kunihiro-sakuma",fullName:"Kunihiro Sakuma",profilePictureURL:"https://mts.intechopen.com/storage/users/195829/images/system/195829.jpg",biography:"Professor Kunihiro Sakuma, Ph.D., currently works in the Institute for Liberal Arts at the Tokyo Institute of Technology. He is a physiologist working in the field of skeletal muscle. He was awarded his sports science diploma in 1995 by the University of Tsukuba and began his scientific work at the Department of Physiology, Aichi Human Service Center, focusing on the molecular mechanism of congenital muscular dystrophy and normal muscle regeneration. His interest later turned to the molecular mechanism and attenuating strategy of sarcopenia (age-related muscle atrophy). His opinion is to attenuate sarcopenia by improving autophagic defects using nutrient- and pharmaceutical-based treatments.",institutionString:null,institution:{name:"Tokyo Institute of Technology",institutionURL:null,country:{name:"Japan"}}},editorTwo:null,editorThree:{id:"331519",title:"Dr.",name:"Kotomi",middleName:null,surname:"Sakai",slug:"kotomi-sakai",fullName:"Kotomi Sakai",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000031QtFXQA0/Profile_Picture_1637053227318",biography:"Senior researcher Kotomi Sakai, Ph.D., MPH, works at the Research Organization of Science and Technology in Ritsumeikan University. She is a researcher in the geriatric rehabilitation and public health field. She received Ph.D. from Nihon University and MPH from St.Luke’s International University. Her main research interest is sarcopenia in older adults, especially its association with nutritional status. Additionally, to understand how to maintain and improve physical function in older adults, to conduct studies about the mechanism of sarcopenia and determine when possible interventions are needed.",institutionString:null,institution:{name:"Ritsumeikan University",institutionURL:null,country:{name:"Japan"}}}},{id:"13",title:"Plant Physiology",coverUrl:"https://cdn.intechopen.com/series_topics/covers/13.jpg",isOpenForSubmission:!0,editor:{id:"332229",title:"Prof.",name:"Jen-Tsung",middleName:null,surname:"Chen",slug:"jen-tsung-chen",fullName:"Jen-Tsung Chen",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000031RJmlQAG/Profile_Picture_1600760167494",biography:"Dr. Jen-Tsung Chen is currently a professor at the National University of Kaohsiung in Taiwan. He teaches cell biology, genomics, proteomics, medicinal plant biotechnology, and plant tissue culture in college. Dr. Chen's research interests are bioactive compounds, chromatography techniques, in vitro culture, medicinal plants, phytochemicals, and plant biotechnology. He has published over 60 research papers, reviewed over 260 manuscripts, and edited at least 150 papers in international peer-review journals.",institutionString:null,institution:{name:"National University of Kaohsiung",institutionURL:null,country:{name:"Taiwan"}}},editorTwo:null,editorThree:null}]},overviewPageOFChapters:{paginationCount:43,paginationItems:[{id:"81796",title:"Apoptosis-Related Diseases and Peroxisomes",doi:"10.5772/intechopen.105052",signatures:"Meimei Wang, Yakun Liu, Ni Chen, Juan Wang and Ye Zhao",slug:"apoptosis-related-diseases-and-peroxisomes",totalDownloads:2,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"The Metabolic Role of Peroxisome in Health and Disease",coverURL:"https://cdn.intechopen.com/books/images_new/10837.jpg",subseries:{id:"11",title:"Cell Physiology"}}},{id:"81723",title:"Peroxisomal Modulation as Therapeutic Alternative for Tackling Multiple Cancers",doi:"10.5772/intechopen.104873",signatures:"Shazia Usmani, Shadma Wahab, Abdul Hafeez, Shabana Khatoon and Syed Misbahul Hasan",slug:"peroxisomal-modulation-as-therapeutic-alternative-for-tackling-multiple-cancers",totalDownloads:3,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"The Metabolic Role of Peroxisome in Health and Disease",coverURL:"https://cdn.intechopen.com/books/images_new/10837.jpg",subseries:{id:"11",title:"Cell Physiology"}}},{id:"81638",title:"Aging and Neuropsychiatric Disease: A General Overview of Prevalence and Trends",doi:"10.5772/intechopen.103102",signatures:"Jelena Milić",slug:"aging-and-neuropsychiatric-disease-a-general-overview-of-prevalence-and-trends",totalDownloads:14,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Senescence",coverURL:"https://cdn.intechopen.com/books/images_new/10935.jpg",subseries:{id:"11",title:"Cell Physiology"}}},{id:"81566",title:"New and Emerging Technologies for Integrative Ambulatory Autonomic Assessment and Intervention as a Catalyst in the Synergy of Remote Geocoded Biosensing, Algorithmic Networked Cloud Computing, Deep Learning, and Regenerative/Biomic Medicine: Further Real",doi:"10.5772/intechopen.104092",signatures:"Robert L. Drury",slug:"new-and-emerging-technologies-for-integrative-ambulatory-autonomic-assessment-and-intervention-as-a-",totalDownloads:9,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Autonomic Nervous System - Special Interest Topics",coverURL:"https://cdn.intechopen.com/books/images_new/10835.jpg",subseries:{id:"12",title:"Human Physiology"}}}]},overviewPagePublishedBooks:{paginationCount:11,paginationItems:[{type:"book",id:"7264",title:"Calcium and Signal Transduction",subtitle:null,coverURL:"https://cdn.intechopen.com/books/images_new/7264.jpg",slug:"calcium-and-signal-transduction",publishedDate:"October 24th 2018",editedByType:"Edited by",bookSignature:"John N. Buchholz and Erik J. Behringer",hash:"e373a3d1123dbd45fddf75d90e3e7c38",volumeInSeries:1,fullTitle:"Calcium and Signal Transduction",editors:[{id:"89438",title:"Dr.",name:"John N.",middleName:null,surname:"Buchholz",slug:"john-n.-buchholz",fullName:"John N. Buchholz",profilePictureURL:"https://mts.intechopen.com/storage/users/89438/images/6463_n.jpg",biography:"Full Professor and Vice Chair, Division of Pharmacology, Loma Linda University, School of Medicine. He received his B.S. Degree in Biology at La Sierra University, Riverside California (1980) and a PhD in Pharmacology from Loma Linda University School of Medicine (1988). Post-Doctoral Fellow at University of California, Irvine, College of Medicine 1989-1992 with a focus on autonomic nerve function in blood vessels and the impact of aging on the function of these nerves and overall blood vessel function. Twenty years of research funding and served on NIH R01 review panels, Editor-In-Chief of Edorium Journal of Aging Research. Serves as a peer reviewer for biomedical journals. Military Reserve Officer serving with the 100 Support Command, 100 Troop Command, 40 Infantry Division, CA National Guard.",institutionString:null,institution:{name:"Loma Linda University",institutionURL:null,country:{name:"United States of America"}}}]},{type:"book",id:"6925",title:"Endoplasmic Reticulum",subtitle:null,coverURL:"https://cdn.intechopen.com/books/images_new/6925.jpg",slug:"endoplasmic-reticulum",publishedDate:"April 17th 2019",editedByType:"Edited by",bookSignature:"Angel Català",hash:"a9e90d2dbdbc46128dfe7dac9f87c6b4",volumeInSeries:2,fullTitle:"Endoplasmic Reticulum",editors:[{id:"196544",title:"Prof.",name:"Angel",middleName:null,surname:"Catala",slug:"angel-catala",fullName:"Angel Catala",profilePictureURL:"https://mts.intechopen.com/storage/users/196544/images/system/196544.jpg",biography:"Angel Catalá studied chemistry at Universidad Nacional de La Plata, Argentina, where he received a Ph.D. in Chemistry (Biological Branch) in 1965. From 1964 to 1974, he worked as an Assistant in Biochemistry at the School of Medicine at the same university. From 1974 to 1976, he was a fellow of the National Institutes of Health (NIH) at the University of Connecticut, Health Center, USA. From 1985 to 2004, he served as a Full Professor of Biochemistry at the Universidad Nacional de La Plata. He is a member of the National Research Council (CONICET), Argentina, and the Argentine Society for Biochemistry and Molecular Biology (SAIB). His laboratory has been interested for many years in the lipid peroxidation of biological membranes from various tissues and different species. Dr. Catalá has directed twelve doctoral theses, published more than 100 papers in peer-reviewed journals, several chapters in books, and edited twelve books. He received awards at the 40th International Conference Biochemistry of Lipids 1999 in Dijon, France. He is the winner of the Bimbo Pan-American Nutrition, Food Science and Technology Award 2006 and 2012, South America, Human Nutrition, Professional Category. In 2006, he won the Bernardo Houssay award in pharmacology, in recognition of his meritorious works of research. Dr. Catalá belongs to the editorial board of several journals including Journal of Lipids; International Review of Biophysical Chemistry; Frontiers in Membrane Physiology and Biophysics; World Journal of Experimental Medicine and Biochemistry Research International; World Journal of Biological Chemistry, Diabetes, and the Pancreas; International Journal of Chronic Diseases & Therapy; and International Journal of Nutrition. He is the co-editor of The Open Biology Journal and associate editor for Oxidative Medicine and Cellular Longevity.",institutionString:"Universidad Nacional de La Plata",institution:{name:"National University of La Plata",institutionURL:null,country:{name:"Argentina"}}}]},{type:"book",id:"6924",title:"Adenosine Triphosphate in Health and Disease",subtitle:null,coverURL:"https://cdn.intechopen.com/books/images_new/6924.jpg",slug:"adenosine-triphosphate-in-health-and-disease",publishedDate:"April 24th 2019",editedByType:"Edited by",bookSignature:"Gyula Mozsik",hash:"04106c232a3c68fec07ba7cf00d2522d",volumeInSeries:3,fullTitle:"Adenosine Triphosphate in Health and Disease",editors:[{id:"58390",title:"Dr.",name:"Gyula",middleName:null,surname:"Mozsik",slug:"gyula-mozsik",fullName:"Gyula Mozsik",profilePictureURL:"https://mts.intechopen.com/storage/users/58390/images/system/58390.png",biography:"Gyula Mózsik MD, Ph.D., ScD (med), is an emeritus professor of Medicine at the First Department of Medicine, Univesity of Pécs, Hungary. He was head of this department from 1993 to 2003. His specializations are medicine, gastroenterology, clinical pharmacology, clinical nutrition, and dietetics. His research fields are biochemical pharmacological examinations in the human gastrointestinal (GI) mucosa, mechanisms of retinoids, drugs, capsaicin-sensitive afferent nerves, and innovative pharmacological, pharmaceutical, and nutritional (dietary) research in humans. He has published about 360 peer-reviewed papers, 197 book chapters, 692 abstracts, 19 monographs, and has edited 37 books. He has given about 1120 regular and review lectures. He has organized thirty-eight national and international congresses and symposia. He is the founder of the International Conference on Ulcer Research (ICUR); International Union of Pharmacology, Gastrointestinal Section (IUPHAR-GI); Brain-Gut Society symposiums, and gastrointestinal cytoprotective symposiums. He received the Andre Robert Award from IUPHAR-GI in 2014. Fifteen of his students have been appointed as full professors in Egypt, Cuba, and Hungary.",institutionString:"University of Pécs",institution:{name:"University of Pecs",institutionURL:null,country:{name:"Hungary"}}}]},{type:"book",id:"8008",title:"Antioxidants",subtitle:null,coverURL:"https://cdn.intechopen.com/books/images_new/8008.jpg",slug:"antioxidants",publishedDate:"November 6th 2019",editedByType:"Edited by",bookSignature:"Emad Shalaby",hash:"76361b4061e830906267933c1c670027",volumeInSeries:5,fullTitle:"Antioxidants",editors:[{id:"63600",title:"Prof.",name:"Emad",middleName:null,surname:"Shalaby",slug:"emad-shalaby",fullName:"Emad Shalaby",profilePictureURL:"https://mts.intechopen.com/storage/users/63600/images/system/63600.png",biography:"Dr. Emad Shalaby is a professor of biochemistry on the Biochemistry Department Faculty of Agriculture, Cairo University. 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