Major developments in hernia repair without use of artificial materials (tension techniques)
\\n\\n
Released this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\\n\\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
Note: Edited in March 2021
\\n"}]',published:!0,mainMedia:null},components:[{type:"htmlEditorComponent",content:'IntechOpen is proud to announce that 191 of our authors have made the Clarivate™ Highly Cited Researchers List for 2020, ranking them among the top 1% most-cited.
\n\nThroughout the years, the list has named a total of 261 IntechOpen authors as Highly Cited. Of those researchers, 69 have been featured on the list multiple times.
\n\n\n\nReleased this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\n\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
Note: Edited in March 2021
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Venkateswarlu",coverURL:"https://cdn.intechopen.com/books/images_new/371.jpg",editedByType:"Edited by",editors:[{id:"58592",title:"Dr.",name:"Arun",surname:"Shanker",slug:"arun-shanker",fullName:"Arun Shanker"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"72",title:"Ionic Liquids",subtitle:"Theory, Properties, New Approaches",isOpenForSubmission:!1,hash:"d94ffa3cfa10505e3b1d676d46fcd3f5",slug:"ionic-liquids-theory-properties-new-approaches",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/72.jpg",editedByType:"Edited by",editors:[{id:"19816",title:"Prof.",name:"Alexander",surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"46621",title:"History of the Inguinal Hernia Repair",doi:"10.5772/58533",slug:"history-of-the-inguinal-hernia-repair",body:'The inguinal hernia is one of the diseases that haunted the humanity from its very beginning to the modern times. The currently used term „hernia” comes directly from ancient Greece: (kele/hernios in Greek means bud or offshoot). Although the natural course of the disease is relatively slow it eventually reaches the size that severely impairs the patient ability to perform daily activities (Figure 1). That is why already in antique times the surgeons and physicians alike were trying to find the solution for this highly disturbing condition. The mainstay of treatment remained the use of different types of inguinal belts that were supposed to maintain the hernia sac inside the body cavity. To successfully apply the herniary belt the hernia was first manually reduced (Figure 2) and then, the herniary belt, often custom made for a particular patient, was applied. The use of hernia belts was widespread and even today it can be found in some regions of the world.
A man with a 69 years history of inguinal hernia. The patient, Frank Lamb, was a slave in North Carolina and since he was 9 years old suffered from left inguinal hernia. Nevertheless he was forced to hard, daily labor. As a result an important inguino-scrotal herniary sac developed. From: Otis Historical Archives of “National Museum of Health and Medicine”.
Manual reduction of the inguinal hernia and the use of herniary belts. Image courtesy: BIU Santé (Paris) http://www.biusante.parisdescartes.fr/histmed/image?med02083x07ax0493
The wide popularity of the belts was maintained because the surgical option for the cure of inguinal hernia was extremely dangerous and unfortunately not very convincing. One of the first attempts to solve inguinal hernia by the means of surgical knife came from the famous XVIth century Italian anatomist, Gabriele Fallopio. Fallopio proposed wide excision of the sac with surrounding skin and all its contents, securing the neck with an impressive suture (so called the golden stiich). The technique did not become very popular among patients because it resulted in castration and sometimes in the permanent stoma from the cut intestinal loop. The risk of death from bleeding and peritonitis was also important limiting factor of this technique [1]. This is why many barber-surgeons of that time suggested that the operation should be considered „only for marked hernias, which could not be held even with the strongest and surdiest bands at their right place” [2].
Another worth noticing attempt at giving surgical solution to the inguinal hernia was done by Claudius Amyand from London who in 1735 operated on an 11-year-old boy. The patient suffered from a right inguinal hernia complicated by a faecal fistula. The operation performed by Claudius Amyand is important for two reasons. Firstly, it is the earliest description of a hernia containing a vermiform appendix (known today as Amyand’s hernia). And secondly, it is the earliest documented appendicectomy in the history of surgery. On the other hand it shows us that the decision to operate on a hernia patient was made when surgeon was facing a complex problem that required a daredevil solution [3].
The anatomical knowledge of human body was still evolving in XVIIth century. Some advances of the treatment of inguinal hernias, especially incarcerated hernias that posed direct danger of death to the patient if not reduced or operated on has been made in this era. The Spanish anatomist and surgeon Antonio Gimbernat y Arbos after studying anatomy of inguinal canal witnessed an anatomical presentation in London in 1777, performed by famous John Hunter. Gimbernat noticed that Hunter experienced problems in reducing a femoral hernia so he stopped the presentation and told Hunter to cut ligamentum lacunare and this way open femoral canal. After a moment of reflexion Hunter replied: „You’re right Sir. I will operate on femoral hernia only in this way from now on.” Once again, we have to bear in mind that hernia operations in this era were rare and limited to very desperate, live-or-death situations [4].
The fast evolution of medicine and surgery in the XIXth century gave way to some new ideas in the treatment of inguinal hernia. The introduction of antisepsis, asepsis and anesthesia allowed for safer procedures. The advances in anatomical knowledge of hernia lead to the introduction of two important rules for hernia surgery: high ligation of hernia sac and narrowing of the internal inguinal ring. Among techniques that received some fame among XIXth century surgeons we should mention the techniques of William Wood, Vinzenz Czerny and James Heaton. Heaton was performing injection of the mixture of white oak and morphine into the hernia sac to obtain its fibrosis [5]. Czerny was performing the high ligation of the hernia sac and complete closure of the internal inguinal ring with sutures [6]. In the Wood’s method the surgeon was supposed to double ligate herniary sac to perform a natural „plug” and use it to close internal inguinal ring [7]. Unfortunately although these techniques looked appealing at first, in the long term virtually all patients experienced hernia recurrence [5]. Let us also remind the reader that the mortality after these operations was reported to be as high as 7% [8].
„In order to achieve a radical cure of hernia it is absolutely essential to restore those conditions in the area of the hernial orifice, which exist under normal conditions”-Edoardo Bassini.
It wasn’t until 1887 that the real breakthrough in the treatment of inguinal hernia came. All started with a young student from Pavia University, Edoardo Bassini entering in the ranks of Giuseppe Garibaldi’s army. During the battle against papal guards near Villa Glori in Rome, Bassini received a bayonet wound in his right groin. After remaining unconscious in the battlefield for several hours he finally recovered only to find out that the bayonet has penetrated the intestinal wall and the coecal fistula has formed within the wound. He turned for help to his university professor Luigi Porta and remained a patient in Pavia for almost 6 months. The coecostomy finally closed but during that time Bassini studied extensively the anatomy and physiology of the inguinal region. Afterwards he started to perform inguinal hernia operation with the techniques of Wood and Heaton but all operated hernias recurred. At this point Bassini realized that the problem was more within the diseased anatomy and physiology of the inguinal canal than in the technique itself. Therefore he come up with the idea that only complete reconstruction of the anatomy of the inguinal canal can lead to a full recovery from inguinal hernia [5]. The meticulous anatomical knowledge led to a surgical technique that Bassini applied with important success to his patients in Padua, where he started to practice after graduation. Bassini has presented his first results in Padua in Italian during surgical congress in Genoa [9] and after a few years in German to gain a wider audience [10]. Within few years his original method (Figure 3) become a classic. His achievement is even more impressive if we realize that all subsequent methods of inguinal hernia surgery until introduction of artificial materials were in fact variants of Bassini concept. The popularization of the Bassini technique was so successful because it was a breakthrough concept but also because Bassini’s pupils (among them Atillo Catterina) have done a lot to promote his achievements [11].
The schematic drawing of the Bassini technique from the German version of his original publication: Ueber de bechandlung des Leistenbruches. Archiv fur Klinische Chirurgie 1890;40:429 [
The main difference of Halsted proposition from Bassini method was the localization of the spermatic cord. After reconstructing the inguinal canal Halsted was leaving spermatic cord in the subcutaneous position. It allowed for closure of the posterior wall of the inguinal canal with a very strong, transfixing sutures. Unfortunately among the first five patients operated by Halsted himself, one developed urinary fistula due to too deep transfixing sutures that pierced through urinary bladder wall. The fistula eventually closed but it showed clearly the risk of too deep sutures placed in the transverse fascia and in the preperitoneum [12].
The subcutaneous position of the spermatic cord exactly as in the Halsted’s method was applied also in several other modifications proposed by several surgeons in the years to come. Among them we would like to cite a method described by Paolo Postempski from Rome (Figure 4) [13].
Schematic representation of the Postempski repair. Note subcutaneous position of the spermatic cord as in the Halsted’s method. Drawing by dr Jerzy W.Mituś based on Gangeri G. Risorse in chirurgia generale. Kofler Editore, Bassano del Grappa 2006 [
Among many variants of Bassini method it would be also interested to mention „The Polish technique” developed by Zdzisław Sławiński in Warsaw and popularized during the World War I. It has gained important fame especially after Sławiński operated with success on cardinal Achille Ratii who later become pope Pio XI. The peculiarity of this technique consisted on dissecting only the neck of the hernia sac, ligating and cutting it and leaving the cut sac „in situ” [14].
At the advent of World War II Chester McVay from Ann Arbor popularized his concept of inguinal hernia repair using Cooper’s ligament instead of inguinal ligament as a lower edge of sutures aimed at reconstructing posterior wall of the inguinal canal. In McVay’s opinion the use of inguinal ligament by all his predecessors was a „fundamental error” that has led to high hernia recurrence rate [15].
Probably the last big step in the evolution of the „tension” repairs of inguinal hernias was the method described and mastered over the years by Edward Earl Shouldice from Toronto. His idea started in the fifties and was slowly evolving to reach a very mature technique. Shouldice advocated meticulous dissection, complete incision of the transverse fascia, sutures with monofilament rather than silk, oversewing of the posterior wall of inguinal canal by four layers of fascia and aponeuroses of oblique muscles and finally rapid ambulation of the patient (patient were walking home after 2-3 days when at that time it was customary for other surgeons to retain their hernia patients up to 3 weeks in bed). Interestingly there exist no single description of the technique published by Shouldice. Apparently, Shouldice thought that all those willing to learn his technique should come to Toronto and see him performing the famous „Canadian repair”. Indeed, the 3% hernia recurrence rate in Shouldice Hernia Hospital was impressive at the time when majority of hospitals experienced even 20% of hernia recurrence. The Shouldice repair can be seen as a final, close to perfect state of Bassini method. As Robert Bendavid stated:”The Shouldice repair, which on occasion is referred to as the Canadian operation, is a derivation of the Bassini repair and incorporates succinct changes, which must be appreciated. It will become evident why Earle Shouldice can be considered the heir to Bassini and to have enhanced that envious stature” [16].
At the advent of wide availability of prosthetic materials the tension repairs have seen a major decline in their use. However, several surgeons see the classic techniques as an interesting and viable option for a selected group of hernia patient. The most popular techniques used until recently (and in some cases even today) include the Bassini, Postempski and Shouldice operations [17]. The major developments in the history of tension repairs of inguinal hernia are shown in the Table 1.
\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t
Edoardo Bassini | \n\t\t\t1887 | \n\t\t\treconstructing the anatomy of the inguinal canal | \n\t\t
William Steward Halsted | \n\t\t\t1889 | \n\t\t\tsubcutaneous position of the spermatic cord | \n\t\t
Paolo Postempski | \n\t\t\t1890 | \n\t\t\tsubcutaneous position of the spermatic cord and closure of external inguinal ring | \n\t\t
Zdzisław Sławiński | \n\t\t\t1916 | \n\t\t\therniary sac left „in situ”, the neck of the sac used to close internal ring | \n\t\t
Chester McVay | \n\t\t\t1942 | \n\t\t\tCooper’s ligament instead of inguinal (Poupart’s) ligament for the reconstruction | \n\t\t
Edward Earl Shouldice | \n\t\t\t1953 | \n\t\t\tincision and reconstruction of the transverse fascia | \n\t\t
Major developments in hernia repair without use of artificial materials (tension techniques)
The second single biggest step in the history of inguinal hernia surgery came when Theodore Billroth’s dream came true. In the XIX-th century Billroth stated that: „If we could artificially produce tissues of the density and toughness of fascia and tendon, the secret of radical cure radical cure of hernia would be discovered.” If Bassini idea was to reconstruct completely the inguinal canal, it was the availability of modern prosthetic materials that let perform this reconstruction in a best possible way.
The introduction of first artificial materials that could be used to reinforce herniary defect date back to 1944 when nylon has been introduced. Although the first experiences were not very promising in the years to come several new materials have been patented and become commercially available: in 1958 polietylene, in 1959 politetrafluoroetilene (PTFE) and in 1963 goretex.
Apart from many small details that differentiate various tension-free (i.e.: with some kind of mesh implant) techniques the fundamental is the position of the mesh. In general the terms „onlay” and „sublay” were in reference to the position of mesh in relation to posterior wall of the inguinal canal. The „onlay” technique (Figure 5) consist on placing the mesh superficially to posterior inguinal canal wall and „sublay” position requires formation of space for mesh in the preperitoneal space (Figure 6 and Figure 7). The more popular „onlay” techniques include the modifications by: Lichtenstein, Gilbert, Rutkow-Robbins, Trabucco, Valenti as well as PHS-Prolene Hernia System method.
The “onlay” position of the mesh (in red); here in the Lichtenstein repair. Drawing by dr Jerzy W.Mituś based on Gangeri G. Risorse in chirurgia generale. Kofler Editore, Bassano del Grappa 2006 [
The “sublay” position of the mesh (in red). Drawing by dr Jerzy W.Mituś based on Gangeri G. Risorse in chirurgia generale. Kofler Editore, Bassano del Grappa 2006 [
The “sublay” position of the mesh as seen upfront. Drawing by dr Jerzy W.Mituś based on Gangeri G. Risorse in chirurgia generale. Kofler Editore, Bassano del Grappa 2006 [
Initially the idea was to use the mesh to reinforce the posterior wall of the inguinal canal after performing a standard repair as in „tense” repairs. For example in the technique described in 1959 by Francis Usher the defect was reconstruct as in the Bassini operation and the Marlex (polietilene) mesh was placed on the reconstructed posterior wall to reinforce the approximated tissues [18].
It wasn’t until 1984 when Irvin Lichtenstein from Los Angeles proposed repairing the posterior wall of inguinal canal with mesh without previous incision and reconstruction. In his own words: „There is evidence that to incise a strong posterior layer and, then, to reconstruct it as in the Bassini, Shouldice or McVay repair is inappropriate, disruptive and even meddlesome. The application of a wide sheet of harmless prosthetic mesh, one which serves only to strengthen such a floor, is harmless and should reduce the incidence of recurrences” [19]. And indeed the results of Lichtenstein repair were excellent: in a first 1000 patients operated by Lichtenstein and followed 5 years after surgery there weren’t a single case of recurrence. It was truly a remarkable result and this is clearly one of the reasons the Lichtenstein repair is popular until today.
It was also Lichtenstein who introduce the concept of „cigarette” plug made from marlex mesh to repair fenmoral defect. This concept has been further developed by Arthur Gilbert from Miami who proposed preparing a cone from mesh and introduce it through the herniary defect without the use of sutures. This technique finally developed further when Ira Rutkow and Alan Robins from New Jersey described repair with both mesh (as in Lichtenstein repair) and plug (as in Gilbert technique). At first the technique coined „plugstein” was performed without sutures to finally reach a phase with the use of fixating sutures [20].
More recently in 1999 Arthur Gilbert described a technique that allows to place a mesh both in „onlay” and „sublay” position. His Prolene Hernia System (PHS) consisted on introducing a sophisticated mesh build from two meshes of different shape connected with a small tube. This allowed to reinforce the posterior wall of the inguinal canal both from preperitoneal site and from the „onlay” position [21]. In Table 2 the most important steps in tension-free repair can be observed.
\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t
Francis Usher | \n\t\t\t1959 | \n\t\t\treinforcing Bassini technique with mesh | \n\t\t
Irvin Lichtenstein | \n\t\t\t1984 | \n\t\t\tplacing the mesh to reinforce the posterior wall of the inguinal canal | \n\t\t
Arthur Gilbert | \n\t\t\t1987 | \n\t\t\tcone-plug to cover defect | \n\t\t
Ira Rutkow and Alan Robins | \n\t\t\t1998 | \n\t\t\tmesh and plug repair | \n\t\t
Arthur Gilbert | \n\t\t\t1999 | \n\t\t\tProlene Hernia System | \n\t\t
Techniques in tension-free repairs
In 1969 Rene Stoppa from Amiens developed a technique of GPRVS (giant prosthetic reinforcement of the visceral sac). This technique was supposed to be applied to large, complicated and bilateral inguinal hernias and consisted on implanting a large polyester mesh in preperitoneal connective tissue between the peritoneum and
The advent of minimally invasive techniques have seen an important number of laparoscopic and endoscopic approaches to inguinal hernia. A TAPP (transabdominal pre-peritoneal) technique described in 1993 is based on the same principle as the technique published by Lawson Tait in 1891. Tait described a transabdominal approach to inguinal hernia performed simultaneously with other interventions requiring a laparotomy [24]. In TAPP the same rationale is used in laparoscopy and an artificial mesh is placed in preperitoneal position after incising the peritoneum [25]. Another endoscopic procedure is TEP (totally extraperitoneal) in which an endoscope is introduced into Retzius and Bogros space after creating a space for gas insuflation with a specially designed balloon [26]. Afterwards, a mesh is placed in preperitoneal space and the operation is concluded. And finally an IPOM (intraperitoneal onlay mesh) is a laparoscopic technique developped in 1991 and consisting on placing a politetrafluoretilene mesh directly on the defect from pertitoneal side and securing it with a double crown of staplers [27].
After initial enthusiasm for the endoscopic hernia repairs it became clear that although these techniques have some important advantages for patients in no way can they be considered the ideal operation for every patient. Today, endoscopic techniques, while still popular in some centers, coexist peacefully with traditional open techniques of hernia repair. In a review of inguinal hernia repairs performed in USA until 2003 the most commonly used techniques were: Lichtenstein repair (350.000/year), Rutkow-Robins repair (200.000/year), endoscopic repairs (75.000/year), Bassini repair (50.000/year), McVay (less than 50.000/year) and Shouldice repair (less than 50.000/year) [28]. The use of endoscopic techniques is commonly accepted for the treatment of recurrent and bilateral hernias. As seen in the numbers cited above, when facing a non-complicated primary inguinal hernia the vast majority of today’s surgeons choose tension-free repairs as described by Lichtenstein and Rutkow [29].
The surgical treatment of inguinal hernia has made important steps forward during the last 125 years. However, the fact that we still employ a wide variety of techniques to operate on inguinal hernia clearly shows that the road to a perfect operation is still ahead of us.
The author wish to thank dr Jerzy W.Mituś from Kraków, Poland for the preparation of the Figures 4, 5, 6 and 7.
The recent data regarding the global cancer statistic [1] indicate an increase number of new diagnosed HNSCC cases each year. Despite the efforts, the 5 years OS rate of HNSCC has not improve significantly over the last years. There are several reasons that can be mentioned: the classic causative factors such as alcohol consumption and tobacco usage, the presence of the lymph nodes metastases at the time of the diagnosis, important increase in the HPV infections in the Western world. [2]. Between 40 to 60% of HNSCC treated patients have recurrence and not respond to subsequent therapeutic interventions [3]. Another important reason may be the accentuated heterogeneity of HNSCC at the molecular level, the inability of a clear stratification of the cases and the absence of a certain link between the molecular subtypes and the clinical outcome. A number between four and six molecular types of HNSCC were described in the literature. Chung [4] described four distinct subtypes: first (displays EGFR pathway and hypoxia related molecular signatures), the second is mesenchymal marker enriched, the third has features of normal epithelia and the fourth expresses high levels of transcripts coding for antioxidant and detoxification enzymes. The four groups of HNSCC proposed by Walter [5] are: basal, mesenchymal, atypical, and classical. Five subgroups of HNSCC were described also by another research team: three HPV negative (basal, classical non- HPV and mesenchymal non -HPV) and two HPV positive (classical HPV and mesenchymal HPV) [6]. Other author described six subtypes (immunoreactive, inflammatory, HPV-like, classical, hypoxia associated and mesenchymal) [7]. The heterogeneity of the tumor microenvironment and the clear histological margin used today may be other reasons for tumor recurrences.
\nWe try in the following to identify some major criteria for a better stratification of the cases, and for a better surveillance of the postoperative margins, targeting the personalized therapy.
\nThe head and neck squamous cell carcinomas are epithelial tumors originating in the covering mucosa of oral cavity, larynx, oropharynx, and hypopharynx [8]. In an attempt to cover the heterogeneous spectrum of these tumors, the most used clinical management is based on anatomic location, phenotype, evaluation of the existence of tumor -node-metastasis by the TNM classification and the depth of tumor invasions [9]. The WHO classification of head and neck tumors includes tumors of the nasal cavity, paranasal sinuses and skull base (with the keratinizing, non-keratinizing and spindle cell squamous cell carcinoma types), tumors of the nasopharynx, of the hypopharynx, larynx, trachea, parapharyngeal space (with the conventional, verrucous, basaloid, papillary, spindle cell types of squamous cell carcinomas), tumors of the oral cavity and mobile tongue, of the oropharynx (base of the tongue, tonsils, adenoids) with HPV positive and HPV negative types of squamous cell carcinoma, tumors and tumors-like lesions of the neck and lymph nodes, tumors of salivary glands, odontogenic and maxillofacial bone tumors, tumors of the ear and paraganglion tumors [10].
\nIn the conventional histopathological diagnosis, the squamous cell carcinoma may be graded as well, moderate, and poorly differentiated type. The well differentiated type of keratinized squamous cell carcinoma is characterized by the presence of the keratinizing and para-keratinizing pearls. Morphological features in the moderately differentiated squamous cell carcinoma are nuclear pleomorphism, mitoses, including atypical type and less keratinization. The poorly differentiated type is characterized by the predominance of the immature cells, a high number of typical and atypical mitoses, reduced keratinization and necrosis either over large areas of the section or in the center of the tumor areas, variable in extent. Most HNSCC are moderately- differentiated [11, 12] aspect sustained by our data where a percentage of 73.8% and 71% from HNSCC evaluated cases were diagnosed as G2 [13, 14]. The non-keratinized squamous cell carcinomas have the following morphological features: the existence of a large, interconnected band of tumor epithelial cells without keratinization and minimal or absent necrosis, pleomorphic cells, hyperchromasia and an intense mitotic activity.
\nThe histologic grade prognostic impact remains controversial in HNSCC. It was accepted by the current edition of the Classification of Head and Neck Tumors but with the mention that grading alone does not correlate well with prognosis [15]. It is not a part of the UICC staging system, but some data consider high grade as an indication for the adjuvant treatment in OSCC [16, 17].
\nStarting from these premises it may be launched the question why the patients with the same histological grade have such a heterogeneous therapeutic response and prognosis.
\nThe present molecular classification described four types of HNSCC as following: classical, basal, mesenchymal, and atypical subgroups. Excepted from this are the hypopharyngeal cancers characterized by the absence of the BA subgroup.
\nKeratins are a family of the intermediate filament proteins which are present in epithelial cells. Some of the main functions of keratins are structural in forming the cytoskeleton, protein synthesis, cell growth, signaling, organelle transport, mobility, and cell proliferation [18]. The keratin pattern distribution in a stratified epithelium is as follows: K1, 2, 10 and 11 are positive in cornified cells, K4 and 13 in stratified cells and K5 and 14 in basal cells [19].
\nThe aberrant expression of keratins was found to be associated with HNSCC development and progression. High values of K 8, 17 and 19 immunoexpression were noticed in the biopsies of head and neck squamous cell carcinoma patients [20].
\nKeratin 5 was showed to be expressed with value of score between 1 and 3 (more than 30% positive cells), in squamous cell carcinoma with different histological grade and anatomical localization [21]. K5 together with EGFR, p63, CD 117 may be a helpful marker for define a distinct class of HNSCC (basal -like type, characterized by K5+/EGFR +/p63+/CD117+ profile). On the other hand, keratin 5 expression has been shown to correlate with the intermediate phenotype of cells involved in the epithelial-mesenchymal transition phenomenon [13, 22]. Some data demonstrated the by the immunohistochemical evaluation a loss of epithelial markers such as keratin 76 and epithelial cell adhesion molecule in the HNSCC [23, 24]. E- cadherin, involved in the cancer progression and metastasis by decrease of cellular adhesion and increase in cellular motility is co-expressed with Ep CAM. A decrease of E-cadherin expression associated with HPV 18 positivity were found in well and moderately differentiated type of HNSCC with larynx, oropharynx, pharyngo- laryngeal, and nasal-sinus localization. The rhino-pharynx, hypo-pharyngeal and laryngeal HPV18 negative cases were associated with a decrease of E-cadherin values in the moderately, poorly, and undifferentiated types.
\nThe demonstrated role of cytokeratins in the diagnosis and prognosis of squamous cell carcinomas by using surrogate markers and biopsy tissues, oriented the research in the direction of a non-invasive diagnostic biomarker such as salivary keratins for the HNSCC [14, 19, 25].
\nThe other molecule expressed in the basal cells of stratified epithelium is K14 which has an important role in cell differentiation. It was shown that K14 downregulation is associated with an increase in TAp63 and Notch-1 intracellular expression which regulates genes responsible for differentiation [26].
\nVimentin is an intermediate filament intensely expressed in cells with mesenchymal phenotype. Its expression in oral epithelial cells has been linked by the tumor invasion, metastasis and EMT phenomenon [27].
\nIt was shown that miR-876-5p, a tumor suppressor in HNSCC, represent a novel therapeutic target by acting on vimentin and inhibits metastasis [28].
\nThe potential prognostic role of vimentin was described for TSCC and OSCC [29, 30]. In the first situation, vimentin among the EMT related proteins such as Snail, E- cadherin and N-cadherin are involved. In the second situation, an association between vimentin intense immunoexpression and a high risk for cervical lymph node metastatic potential was noticed. It was showed that vimentin-SOX 2 interrelation may represent an unfavorable risk factor for survival of head and neck squamous cell carcinoma. The loss of SOX2 expression induces cell motility by vimentin up-regulation [31].
\nPodoplanin, a 38 KDa type I transmembrane glycoprotein is overexpressed in different human cancers, including HNSCC.
\nAn interrelation between histological grade differentiation and podoplanin immunoexpression was described in HNSCC. The main pattern of immunoexpression was in the cytoplasm and membrane with focal (mainly in the well differentiated OSCC) and diffuse distribution type (mainly in the moderately and poorly differentiated OSCC). The podoplanin was not expressed in the some of the well and poorly differentiated oral SCC cases. In all the moderately differentiated cases of SCC a positive reaction for podoplanin was noticed. The highest values for podoplanin with cytoplasm and membrane pattern expression was associated with poorly differentiated of oral SCC type. High levels of podoplanin expression was associated with high frequency of lymph node metastasis in OSCC [32]. A tendency of increasing podoplanin expression with decreasing of differentiation grade was noticed [33]. In OSCC was demonstrated the podoplanin involvement in the cytoskeleton remodeling, ECM degradation and tumor invasion. These are realized by co-location, co-ordination of podoplanin, Cdc42 and MT1-MMP in the invadopodia [34].
\nSCCs of the larynx and hypopharynx with high values of podoplanin expression were associated with an unfavorable prognosis also [35]. Podoplanin may have a predictive value of aggressiveness in HNSCC evolution, together with other markers such as EGFR and E-cadherin.
\nAnother pathway through which podoplanin induces a decrease in overall survival was shown in the murine experimental models. Podoplanin expression in the OSCC tumors increased platelet activation and promotes intravascular platelet aggregation and intratumor platelet infiltration. The coagulation state is favorized [36].
\nP53 is a transcription factor that regulates the cell cycle, DNA repair and apoptosis. One of its main role is to maintain cellular integrity after DNA damage. Consecutive to this moment, p53 is regulated in a MDM2-dependent manner and activated by cell cycle checkpoint kinases type 1 and 2 [37]. In normal conditions, p53 may be expressed with a nuclear pattern in basal cells of the epithelium. In HNSCC p53 immunoexpression was described in 50% of the evaluated cases or more. Controversial data concerning p53/EGFR co-expression exists. In our data, 44% of larynx and 70.5% of pharynx cases co-expressed p53/ EGFR. All of the p53 positive cases co-expressed EGFR. These features were noticed by using a double immunohistochemical staining p 53/ EGFR. For larynx localization, p53/ EGFR co-expression was noticed mainly at the periphery of the tumor area (in all of the moderately differentiate cases- \nFigure 1\n, in 25% of well differentiate cases with much more reduced number of co-expressing cells, in 50% of poorly differentiated type). In corresponding lymph nodes of laryngeal tumors, the co-expressing cells were present in the immediate vicinity of the lymphoid tissue and to the periphery of tumor areas. In the center of tumor areas EGFR or p53 positive cells only were found, not co-expressing cells. The distribution pattern of the co-expressing cells from the hypopharynx may be noticed in the \nFigure 2\n. The distribution pattern of co-expressing cells to the periphery of tumor areas was found in the oropharynx, pharyngo-laryngeal and sinus nose localization. The co-expressing cells were absent in the naso-pharyngeal localization. A significant correlation was found between p53 intensity of expression and extranodal extension and tumor grade, mainly grades II and III [38, 39]. All of these p53/EGFR co-expression data may be useful for a better stratification of HNSCC, regarding the diagnostic but the therapy also.
\np53/EGFR co- expression (white arrows) in tumor area in a case of moderately differentiated squamous cell carcinoma with larynx localization, double immunostaining p53/EGFR, ob.X40.
EGFR/p53 immunoexpression, non-keratinized squamous cell carcinoma, moderately differentiated of hypopharynx, double immunostaining p53/EGFR, ob.X40.
The major pathways involved in the tumorigenesis of HNSCC include dysregulation of the following processes: cellular survival and proliferation, cell-cycle control, cellular differentiation and adhesion and invasion signaling. The main important factors involved in the cellular survival and proliferation are: TP53, HRAS, EGFR, PIK3CA. The functional inactivation of the p53 pathway was demonstrated in 80% of HNSCC, that why a therapeutic strategy which focus on the restoration of p53 function was developed for the HPV negative and HPV associated HNSCC. Unfortunately, the adenoviral p53 gene therapy has not been shown to be effective in clinical trials [40, 41].
\nAnother important role of p 53 is the expression in the surgical margins. Pathology in the margin represent an considerable prognostic factor for relapse free survival (RFS) in the management of HNSCC treated with primary surgery. In the OSCC, a local recurrence value varies between 10 and 30% even if the histological status of margins is clear. The following surgical margins classification is used by surgeons and pathologists: involved margins (margin ≤1 mm), close margins (margin 1–5 mm) and clear margins (margin >5 mm) [42]. Severe dysplasia and invasive carcinoma needing additional resection while moderate and mild dysplasia do not. Evaluation of the p53 overexpression in histological resection margins of oral and oropharyngeal SCC demonstrated a 5.333 times higher chance of local recurrences if at least one margin overexpressed p53. P53 as an independent risk factor has been demonstrated in early OSCC with dysplastic surgical margin. It may be a useful marker for postoperative decision for these patients [43, 44].
\nBcl-2 (B-cell lymphoma 2) encoded in humans by the Bcl2 gene is a member of the family of regulatory proteins that influence apoptosis through both pro and anti-apoptotic or inhibitory effects. Pro-survival Bcl-2 proteins (Bcl-2, Bcl-xL, MCL-1) inhibit Bcl-2 pro-apoptotic effectors (BAX and BAK).
\nThe immunohistochemical evaluation of cases from our studies, revealed a relatively reduce number of bcl2 cases. The value of positive cases was close to 30%. The differences were noticed between anatomic areas. At the larynx, oropharynx, hypopharynx, nasopharynx, bcl 2expression in some of the cases was found. At the pharingo-larynx, nasal sinus, bcl2 expression was absent. Cases of well and poorly differentiated keratinized squamous cell carcinoma of the larynx were characterized by the absence of Bcl2 immunohistochemical expression in tumor cells. A similar appearance was noticed in the tumor cells of the corresponding lymph node. The Bcl2 immunoexpression had a score value 2 (10–30% positive tumor cells) in primary tumor and corresponding lymph node of the squamous keratinized moderately differentiated larynx carcinoma. The same value was found in the oropharynx. In the lymph node of the non-keratinized moderately differentiated type of the larynx squamous cell carcinoma more than 50% of bcl 2 positive tumor cells were noticed (a value 3 of the score).
\nIn the hypopharynx localization isolated Bcl 2 positive tumor cells were found in the tumor areas (score value 1, with less than 10% Bcl2 positive tumor cells- \nFigure 3\n). An intense Bcl2 expression as intensity and value of the score was expressed in the stromal cells in the vicinity of tumor areas.
\nValue 1 of Bcl2 immunoexpression score inside the tumor area (white arrows), in a moderately differentiated squamous cell carcinoma of the hypopharynx, Bcl2 immunostaining, ob.X40.
The highest value score of Bcl2 (value 3: more than 50% Bcl2 positive tumor cells- \nFigure 4\n) was present in the non-keratinized moderately differentiated squamous cell carcinoma with rhino-pharynx localization. In the group of EGFR positive cases, 3 sub groups were described: EGFR+/p53−/bcl2-, EGFR+/p53+/bcl2+ and EGFR+/p53+/bcl2−/with a significant correlation between N parameter and EGFR expression in this last subgroup. In the K5+/EGFR + cases significant correlation between bcl2 and M (p = 0.01) and N (p = 0.04) parameters were found. Other HNSCC immunohistochemistry data indicated a higher Bcl 2 expression, compare with our data, around 88% of evaluated cases. A significant correlation was reported between the Bcl2 expression and histological grade, lymph node involvement but not clinical stage. They noticed a significant association between p53+/Bcl2 + and histological grade, lymph node involvement [13, 45].
\nValue 3 of Bcl-2 expression score in a moderately differentiated, non-keratinized squamous cell carcinoma of the rhinopharynx, Bcl2 immunostaining, ob. X 20.
Other authors considered that immunohistochemical staining of Bcl2 is not significantly correlated with tumoral aggressiveness and prognosis to the patients diagnosed with laryngeal squamous cell carcinoma and treated with primary surgery [46]. The molecular mechanism and genetic basis of the development of larynx carcinoma have not been fully elucidated. Some data revealed the involvement of Bcl2-Hsp90beta in the anti-apoptotic progression of larynx carcinoma. The disruption of Bcl2-Hsp90beta interaction inhibited the anti-apoptotic ability of Bcl2 and reduced the capsize activation in larynx carcinomas [47].
\nIt was demonstrated the role of miR-15a as a suppressor in HPV positive by targeting bcl2 in HSCC [48]. The effect of Navitoclax (a small inhibitor molecule of Bcl-2/Bcl-xL), in high doses was the death of HNSCC cells. But a limited effect was found in combination with radiation or cisplatin. Co-inhibition of MCL-1 was required to improve approaches targeting Bcl-2/Bcl-xL in HNSCC. [49]
\nBy evaluate two groups of metastatic and non-metastatic primary OSCC, Pavithra et al. [50] found no significant difference in the expression of Bcl2 between the two groups. They sustained that evaluation of Bcl2 along with other apoptotic proteins could define the role in prognosis and pathogenesis of OSCC.
\nTaking into account all these data, bcl2 alone or together with p53 expression may still represent some important markers for tumor agressivity and survival rates in the conditions of a better stratification of the patients.
\nSome of the most important growth factors already described to be involved in the prognosis or therapy resistance of HNSCC are: epidermal growth factor (EGF) and it receptor EGFR, vascular endotelial growth factor (VEGF) and VEGFR 1 and 2 mainly, platelet derived growth factor (PDGF AA) and PDGFR alpha, nerve growth factor (NGF) and transforming growth factor beta (TGF-beta).
\nThere are some molecular-targeted therapies used in the treatment of head and neck squamous cell carcinoma. The molecular targeted therapy such as Cetuximab, panitumumab, zalutumumab and nimotuzumab acts on EGFR monoclonal antibodies; Gefitinib, erlotinib, lapatinib, afatinib, dacomitinib inhibit EGFR tirosin kinase receptors; Bevacizumab (VEGF inhibitor); Sorafenib, sunitinib, vandetanib (VEGFR inhibitors); Rapamycin, temsirolimus, everolimus, torin 1, PP242 and PP30 (PI3K/AKT/mTOR pathway); Pembrolizumab and nivolumab (anti-PD-1).
\nThe EGFR ligands such as EGF, transforming growth factor alpha (TGFA), heparin-binding EGF-like growth factor (HBEGF), amphiregulin (AREG), beta-cellulin (BTC), epiregulin (EREG) and epigen (EPGN) are involved in tumor growth, invasion and metastatic process through EGFR activation. In HNSCC, these ligands/receptors are deregulated. It was noticed an important correlation between mRNA levels of four EGFR ligands and the poor prognosis in HNSCC. The inhibiting EGF- induced AREG expression was proposed as a new treatment option in HNSCC [51].
\nThe EGFR targeting monoclonal antibody, Cetuximab was FDA approved for HNSCC treatment in 2006. But, despite the advances in therapy, the overall five years survival rate of patients with advanced HNSCC remains relatively reduced, around 40–50%. Some data described mutations in various oncogenes and tumor suppressor genes in HNSCC profile, as following: PIK3CA (21%), HRAS (4%), TP53 (72%), CDKN (22%), FBXW7 (5%), KMT2D (MLL2) (18%) and PTEN (2%). PI3K/AKT pathway responsible of proliferation, survive and cell differentiation exhibit alterations in around 34% of patients diagnosed with HNSCC. This pathway may be responsible for tumor escape during EGFR targeting in HNSCC. It was demonstrated the role of PIK3CA and RAS mutations in predicted cetuximab resistance in the first line recurrent and/or metastatic setting and the role of PTEN protein expression loss in predicted resistance to cetuximab when combined to radiotherapy [52].
\nVEGF- A and the others family members (VEGF-B, VEGF-C, VEGF-D) are overexpressed in the majority of HNSCC cases. They act by inducing tumor growth by changing the microvascular density, favorizing cell migration and metastasis. The reduced sensitivity to radiation and progression of HNSCC is associated with stimulation of angiogenesis by tumor cells that undergo radiotherapy. The results of phase I and II clinical trials of Bevacizumab and erlotinib combined administration indicated an increase of median survival by seven months. One of the therapeutic agents, which induce autophagy and inhibits tumor growth was Sorafenib, a serine- threonine protein kinase inhibitor b-Raf, C-Raf, VEGF and PDGFR. Sunitinib, a small molecule kinase inhibitor of VEGFR, PDGFR and c-kit tyrosine kinase has a reduced effect if it is use as monotherapy but associated with Cetuximab favorized the decrease of tumor cell proliferation and an increase of cell differentiation. Vandetanib, which targeted on EGFR, VEGFR2, RTK used in combination with cisplatin and radiotherapy reduced the resistance to EGFR inhibitors in preclinical trials [53]. It was demonstrated also the role of the preoperative or postoperative serum levels of VEGF as a predictive factor for recurrence, disease- free and overall survival of patients with HNSCC [54]. The results obtained on culture cells support the application in clinical practice of the levels of the VEGFR promoters. Methylation of VEGFR1 and VEGFR3 promoters correlated with poor prognosis. It was established a link between methylation of the VEGFR2 promoter and lymph node metastasis [55].
\nConcerning PDGF and their receptor it was found a prognostic role of PDGF serum level in patients with OSCC and a worse prognostic of HNSCC patients induced by the presence of PDGFR-alfa expression in the tumor microenvironment [56, 57].
\nBoth normal and malignant epithelial cells expressed NGF receptors and NGF gene. Neurotrophins are involved in perineural growth in HNSCC, a pathway of tumor progression associated with poor prognosis. Neurotrophins link to low affinity nerve growth factor (LNGFR/p75 neurotrophin receptor-p75 NTR) or to the high affinity Trk (tropomyosin related kinase) tyrosine kinase receptors. P75 NTR was described in an undifferentiated cell population of oral leukoplakia and in OSCC where was associate with a poor prognosis. P75NTR contribute to drug resistance, by involvement in multiple signaling pathways. A correlation between neurotrophin receptor tyrosine kinase (NTRK2) overexpression and epithelial to mesenchymal transition in HNSCC tumor cells was found. It seems that p75NTR might related with NGF -independent therapy resistance in HNSCC, while NTRK1 might transduce a survival signal on NGF and improved cell survival after cell cycle arrest [58].
\nAnother important growth factor with increased importance in HNSCC is hepatocyte growth factor (HGF) and its receptor c-MET. The overexpression of HGF was commonly reported in HNSCC cases. C-MET was overexpressed in lymph node metastasis of HNSCC. C-MET encodes mesenchymal epithelial transition factor which favorized invasion and metastatic potential in cancers. Their overexpression may be associated with worse prognostic and reduced overall survival rate. EGFR and c-MET share common downstream pathways: RAS-RAF-MAPK and PI3K-AKT-mTOR. In the patients with resistance to EGFR targeted therapies c-MET/HGF inhibitors may represent an alternative solution. Capmatinib as monotherapy and Ficlatuzumab combined with Cetuximab are some of c-MET/HGF axis therapeutic solutions.
\nTransforming growth factor beta realized homeostasis between the proliferation and apoptosis of normal epithelial cell by Smads or Smad independent downstream pathways. Tumor suppression and tumor promotion is the main role of TGF beta in HNSCC [59].
\nThe stromal component of the tumor microenvironment contains different cells types such as: cancer associated fibroblast, macrophages, regulatory T cells and mast cells.
\nRegulatory T cells recruitment is regulated by chemokines and associated receptors (CCL28-CCR10 and CXCL12-CXCR4). The immunohistochemical specific markers of these cells are CD4 and CD25. It was identified a subgroup of Tregs, TIM3, with high levels of T-cell immunoglobulin and mucin domain-3. It was notice that these cells are linked with resistance to radiotherapy and their number decrease after PD-1 monoclonal antibody administration. In HNSCC, a high number of Tregs induces a negative prognostic [60].
\nDescribed for the first time by Ehrlich in 1878, mast cells differ through their localization and content, depending on their phenotype: connective tissue MCs and mucosal MCs. Mast cells granules contained preformed mediators such as: tryptase, chymase, cathepsin G, histamine, heparin, serotonin, IL-16, and TNF alpha. Mediators synthesized after mast cell activation are interleukines (IL1, IL 3, IL4, IL 5, IL6, IL 8, IL 10, IL 13, IL 16, platelet activating factor, RANTES, MIF 1 alpha) and arachidonic acid metabolites, prostaglandin and leukotriene C4 [61, 62].
\nIn HNSCC, some authors noticed a decrease in mast cell number associated with advanced histological grade in OSCC, other found a significant correlation between mast cells density and G1, G2 histological grade in larynx carcinoma [63, 64].
\nBy the content of their granules such as VEGF or other substances with angiogenic properties, mast cells may stimulate angiogenesis. In the larynx carcinoma, the differentiation grade was correlated with mast cell density but not with the microvascular density [64]. Other data indicated a higher MVD in HNSCC compare with MVD values noticed in dysplasia of the upper respiratory tract epithelium. No significant correlation was found between MVD/CD34 values and local invasiveness (the T feature) in HNSCC [65]. Increased values of MVD and mast cell density were present in OSCC compare with leukoplakia with and without dysplasia. [66]
\nLymphangiogenesis is the process of new lymphatic vessel formation. The growth factors such as VEGF-C, VEGF -D, PDGF-BB and HGF may influence the formation of new lymphatic vessels. Both lymphatic and microvascular density in peritumoral area may have a prognostic value. Some data demonstrated that peritumoral MVD was associated with metastasis and LMVD was inversely related to both metastasis and progression in HNSCC [67]. Other authors compared the intra and peritumoral lymphatic microvascular density and found a significantly lower density in the peri-tumoral areas. They found significant correlation between LMVD values (intra and peri-tumoral) and differentiation degree. From clinical parameters, an important correlation between total LMVD and lymph node status, but not tumor stage was reported [68]. These observations were reconfirmed by other study which reported an important correlation between both high intra-tumoral and peritumoral LVD and lymph node metastasis. The morphology of peri-tumoral lymphatic vessels was similar, with a large lumen, like in the previously study, but the number of lymphatic vessels was higher in peritumoral area compared with intra-tumoral area, opposite to previous study [69].
\nThese results support the importance of the lymphangiogenesis and lymphatic vascular density as risk and prognostic factors of the patients with lymph node metastasis.
\nFrom the mentioned data results the necessity of a better stratification of HNSCC. The novel molecular techniques of the surgical margins can offer a more accurate risk assessment. The results of genetic and molecular biology studies may outline the criteria for the targeted therapy as a fundamental method of cancer treatment in the future.
\nThe authors declare no conflict of interest.
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',metaTitle:"Horizon 2020 Compliance",metaDescription:"General requirements for Open Access to Horizon 2020 research project outputs are found within Guidelines on Open Access to Scientific Publication and Research Data in Horizon 2020. The guidelines, in their simplest form, state that if you are a Horizon 2020 recipient, you must ensure open access to your scientific publications by enabling them to be downloaded, printed and read online. Additionally, said publications must be peer reviewed. ",metaKeywords:null,canonicalURL:null,contentRaw:'[{"type":"htmlEditorComponent","content":"Publishing with IntechOpen means that your scientific publications already meet these basic requirements. It also means that through our utilization of open licensing, our publications are also able to be copied, shared, searched, linked, crawled, and mined for text and data, optimizing our authors' compliance as suggested by the European Commission.
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I am also a member of the team in charge for the supervision of Ph.D. students in the fields of development of silicon based planar waveguide sensor devices, study of inelastic electron tunnelling in planar tunnelling nanostructures for sensing applications and development of organotellurium(IV) compounds for semiconductor applications. I am a specialist in data analysis techniques and nanosurface structure. 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After obtaining a Master's degree in Mechanical Engineering, he continued his PhD studies in Robotics at the Vienna University of Technology. Here he worked as a robotic researcher with the university's Intelligent Manufacturing Systems Group as well as a guest researcher at various European universities, including the Swiss Federal Institute of Technology Lausanne (EPFL). During this time he published more than 20 scientific papers, gave presentations, served as a reviewer for major robotic journals and conferences and most importantly he co-founded and built the International Journal of Advanced Robotic Systems- world's first Open Access journal in the field of robotics. Starting this journal was a pivotal point in his career, since it was a pathway to founding IntechOpen - Open Access publisher focused on addressing academic researchers needs. Alex is a personification of IntechOpen key values being trusted, open and entrepreneurial. Today his focus is on defining the growth and development strategy for the company.",institutionString:null,institution:{name:"TU Wien",country:{name:"Austria"}}},{id:"19816",title:"Prof.",name:"Alexander",middleName:null,surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/19816/images/1607_n.jpg",biography:"Alexander I. Kokorin: born: 1947, Moscow; DSc., PhD; Principal Research Fellow (Research Professor) of Department of Kinetics and Catalysis, N. Semenov Institute of Chemical Physics, Russian Academy of Sciences, Moscow.\r\nArea of research interests: physical chemistry of complex-organized molecular and nanosized systems, including polymer-metal complexes; the surface of doped oxide semiconductors. He is an expert in structural, absorptive, catalytic and photocatalytic properties, in structural organization and dynamic features of ionic liquids, in magnetic interactions between paramagnetic centers. The author or co-author of 3 books, over 200 articles and reviews in scientific journals and books. He is an actual member of the International EPR/ESR Society, European Society on Quantum Solar Energy Conversion, Moscow House of Scientists, of the Board of Moscow Physical Society.",institutionString:null,institution:{name:"Semenov Institute of Chemical Physics",country:{name:"Russia"}}},{id:"62389",title:"PhD.",name:"Ali Demir",middleName:null,surname:"Sezer",slug:"ali-demir-sezer",fullName:"Ali Demir Sezer",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/62389/images/3413_n.jpg",biography:"Dr. Ali Demir Sezer has a Ph.D. from Pharmaceutical Biotechnology at the Faculty of Pharmacy, University of Marmara (Turkey). 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I received a B.Eng. degree in Computer Engineering with First Class Honors in 2008 from Prince of Songkla University, Songkhla, Thailand, where I received a Ph.D. degree in Electrical Engineering. My research interests are primarily in the area of biomedical signal processing and classification notably EMG (electromyography signal), EOG (electrooculography signal), and EEG (electroencephalography signal), image analysis notably breast cancer analysis and optical coherence tomography, and rehabilitation engineering. I became a student member of IEEE in 2008. During October 2011-March 2012, I had worked at School of Computer Science and Electronic Engineering, University of Essex, Colchester, Essex, United Kingdom. In addition, during a B.Eng. 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