\r\n\tgastrointestinal motility specialists, otolaryngologists, surgeons, speech therapists, medical oncologists and radiation oncologists) are involved in the management of dysphonia and dysphagia. In the recent years, there have been many updates in the management of these disorders. This book will discuss systematically the different etiologies and management of dysphonia, maxillofacial, oropharyngeal and esophageal dysphagia. This book will be a good
\r\n\tguide to the practicing physicians for the management of voice and swallowing disorders.
Periodontal disease is represented by inflammatory processes that affect the tooth’s support / anchoring system and lead to tooth loss and negative effects on the oral health. Tooth loss and decreasing number of contacts between antagonist teeth was placed in relation to the educational level, marital status and incomes. Changes in periodontal status have been associated with oral factors and different systemic diseases.
Maxillary represents a morphofunctional very complex entity, consisting of various components whose smooth work ensures performance of specific key like mastication, phonation, physiognomy and self-preservation, contributing in the same time, cooperation with other organs and tissues, to swallowing and respiration.
All physiological interrelationships of the components of the ensemble: the jaws including teeth with periodontal tissues, buccal mucosa, tongue, salivary glands, temporomandibular joint, neuromuscular complex and the veins that irrigate the functional territory providing nutrition, are directed by the central nervous system [1,2]. This dependence is due to the permanently received information by cortex from the entire reception network of maxillary. It satisfies the balance and health of each organ this way, in which the occlusion coordinates integrates.
It is acknowledged that any pain occurred in the maxillary area generated by a traumatogenic occlusion occurs not only locally, but also away from the mouth. Any alteration occurred in one of the components of the maxillary (under the action of certain triggers cumulated with the favoring ones), happens on a common ground: occlusion. On the other hand, disorganisation at the dental arches level, with a disruption of movement, can affect one of the elements of the same assembly, occurring dysfunctional disorders.
As teeth are dependent on their supporting tissues which keep them in the pockets of the maxillary bones, the periodontal complex depends on the activity of dental arches, normal occlusal function leading to a morphofunctional mechanical stimulation that manages the responsible biological mechanisms for the proper integrity of the periodontium .
The analysis of functional occlusion should be used as the basis for all conservative dental treatment, periodontal, prosthetic and orthodontic surgery.
Due to the functional differentiation structure of periodontal tissues and topographical situation of the two components (shell and supportive) defenses and resistance against aggressive risk factors direct or indirect is special, being conditioned by their character. On periodontal coating will act primarily micro-irritation local agents and at the periodontal support component factors of functional order, resulting dysfunction appearance. Risk factors that contribute to the disturbance or alteration action of periodontal can be classified into three big categories:
General favorable factors with dysmetabolic character that alters nutrition of the body, including the marginal periodontium.
Local disturbing or precipitating factors that can be very divers, responsible for local trophicity change of periodontium.
Aggravating regional factors that alter regional trophicity due to the presence of mandibular dysfunction caused by premature occlusal contacts and interference.
Studies performed on occlusal function and dysfunction shows that traumatic dental pain can be caused by traumatic injury to periodontal, cracks or fractures of teeth vital and a change of direction forces acting on periodontal dental units .
The occlusion was defined as the ratio of static contact between the two arches, regardless of the position occupied by the jaw to the cranium, unlike the interdental articulation, which requires dynamic contact of the dental arch.
Dynamic occlusal reports are made by the two arches during the performance of the stomatognathic system and during parafunctions. Occlusion is considered one of the three determinants of mandibular dynamics. In the same time, occlusion shows a anterior determinant (the front arches) and a posterior determinant (the arch side), between which there is a balance and interaction summarized in the context of mutual protection. Under this concept between the two determinants of occlusion there is a mutual protection, acting on static and dynamic phases of occlusion .
Dental occlusion is meant to stabilize the mandible position to the skull, participating in the development of systemic functions. Occlusal disorders occur as a result of dental anomalies of number, volume, position, dental crown injuries, dental migrations, edentulous, change of occlusion parameters, and secondary musculoskeletal joint dysfunction. Clinically it manifests as premature contacts (characterized by occlusion static phases), occlusal interference (in mandibular dynamic with dental contact), localized abrasion (at a tooth or dental group that takes over occlusal) or generalized to the whole arch.
Occlusal contacts can occur in the static and dynamic positions the jaw. Any occlusal contact that prevents uniform coaptation of support areas and occlusal contact points is called premature occlusal contact. Occlusal contact occurs early in the static occlusion (at the end of the terminal occlusion trajectory), or in the dynamic occlusion when the path of the jaw movement interferes with the dental contact.
Premature contact is always traumatizing for stomatognathic system elements. Traumatogenic capacity of a contact point depends on several factors such as the point of contact location, the size of the contact point, the state of the contact surfaces .
This way, if the point of contact is on a bigger surface, the friction force increases with it, and its pathogen potential. A reduced in size contact point, but between two rough surfaces can be as traumatic or even more than one big point on a polished surface, due to the high friction coefficient. Contacts may be multiple and symmetrical, while maintaining the mandible in a position close to or almost identical to the centric relation or intercuspation position without deviations above it, the rear or side. This rarely happens because the presence of small occlusal contacts creates what is called an occlusal instability. Clinical evaluation of static and dynamic occlusion cannot be made without registration cranio-mandibular relations. Within the tendency to establish maximum intercuspation contact (in patients with long-centric) and centric occlusion (in patients with point-centric), jaw moves from rest position, rising to the jaw with the action of high muscles .
Dynamic occlusion analysis is performed through a test movement printed to the jaw, and also during mastication, phonation and deglutition movements. The analysis of the test movements (retrusion, protrusion, left and right laterality) often reveals the presence of occlusion blockages or of some traumatic sliding slopes. The retrusion movement performed between maximum intercuspation and centric relation can be blocked by some premature contacts, thus preventing the mandible excursion to centric relation during deglutition. The protrusion can register early contacts in the lateral area which would prevent the previous guidance of the occlusion on the retro incisive slope. The deeper is the occlusion, the larger is the trajectory of the protrusion. The premature contact points of the previous area in the protrusion movement prevent balanced contact of the whole frontal group in the guide movement, creating an overload of the teeth which keep the contact .
The test movements with left and right side orientation can reveal an inequality of the trajectories due to movement blocking through occlusal obstacles or due to their different orientation depending on the inclined planes which produce them. In the laterality movement there is recorded the most intense traumatogenic activity at the level of the interferences that may occur on the inactive or swing area, by turning the mandibular into lower grade leverage, therefore, more traumatic. In many cases, laterality or protrusion movement also causes a slight mobilization of the teeth which are in premature contact .
Occlusal force action on periodontal unit depends on the intensity, duration, direction of force, and the effects are also influenced by the state of tissue over which the force acts. The periodontal occlusal trauma is the degenerative injury that occurs when the occlusal forces exceed the adaptive capacity of the supporting tissue. Given that the dento-dental gearing is a cusp – fossa kind, the efforts leading is made in the long axis of the teeth. In normal circumstances, this condition is achieved by the way in which the teeth are implanted in the dental alveoli since their arcade eruption and through the manner in which are realized the dento-dental contacts in centric relation and maximum intercuspation, moments in which the masticatory pressures are maximum. In the teeth and periodontal tissue normal function, a particular importance has the correct position of dental organs, this being possible due to the presence of the balance between the multiple factors that are interrelated (presence of dental arcade integrity, the nature of the existing relations between adjacent teeth through contact areas and their character, dental morphology and cusps inclination, physiological mesial migration of teeth, physiological abrasion of teeth and their axial tilt, biological resistance of the healthy periodontium, lips, cheeks and tongue tone.
In the moment of integrity loss of dental arches, there occur multiple changes not only in the expense of odonto-periodontal units, but also for other components of the stomatognathic system, which demonstrates once again the present physiological interrelations between constituents of the complex.
Closely related to biomechanical homeostasis specific of the periodontium, the whole structural complex of the dento-maxillary system is conditioned by a series of morphological and functional elements that fit in the principle of inclined planes, among which the most important ones would be:
Maximum and proximal vestibule-oral convexities of teeth ensure self-defense and self-stimulation of marginal periodontium through its protection against micro traumas that occur during mastication.
The specific morphology of the frontal inferior teeth, vestibule-oral flattened in the third incisal and mesial-distal cervical narrowed to align them in a circle, defends the periodontium from pressures coming from the vestibule to the oral.
Teeth roots’ number and conical shape avoid the uneven application of the cementum-alveolar walls.
Oral tilt of lower molars and vestibular tilt of the upper ones direct the masticatory pressures in the axial direction of these teeth while concentrating inwards massive facial.
When masticatory pressures are routed and transmitted in the long axis of the teeth, the ligaments that form the periodontal membrane are not crushed, but they act almost entirely, and are subject to forces with functional direction that determine their uniform extent, in functional limits with trophic effect on alveolar bone. After force’s cessation, ligaments return to their spiral resting shape . Taking into account that masticatory pressures are not permanent, periodontal ligaments are submitted to a real functional gymnastics, functional tasks interspersed with periods of rest, which stimulates periodontium, periodontal membrane and alveolar bone, and keeps it in normal parameters.
Local causes of traumatic occlusion with its negative consequences on the dento-maxillary are varied:
Untreated caries, besides pulpal and periapical complications, they may also lead to occlusal disharmony and dysfunction by horizontal migration of proximal caries teeth or of their neighbors disturbing occlusal curves, vertical migration of antagonist teeth, of one tooth with occlusal caries or which considerably reduced the height of its crown, tipping of neighboring or antagonist caries teeth.
Through the loss of interdental contact point due to proximal caries, the fibrous foods can directly damage the marginal periodontium, which leads to periodontal damage and possible installation of a secondary occlusal trauma.
The edentation without prosthesis acts by cancelling the dental arches continuity, due to loss of contact points, interrupting the continuity of the over alveoli ligaments system that normally form a connecting strap between teeth.
Also, the horizontal migration of teeth which border the edentulous breaches makes possible the spaces appearance between teeth and traumatic food impact of interdental gums papillae.
Dental iatrogenic is often represented by inadequate fillings, inappropriate prosthetic marginal axial or transversal or which does not restore correctly proximal contact surfaces or natural convexities vestibule-oral and /or determine at the level of soft tissue rejection reactions, caused by prosthetic material.
The erroneous occlusal articular balancing compromised by grinding the occlusal stops and slopes guide altering vertical occlusal dimension and interdental space also produce occlusal dysfunction.
Alteration of the morphology of dental crowns by pathological abrasion produces a broadening of the occlusal plane, constituting a cause of overload of odonto-periodontal units by masticatory forces.
Primary malposition of some permanent teeth which erupt vicious in the three spatial planes. In this category, there are included anomalies of position: infra, over, predental, retrodental, vestibular or oral of some teeth, different combinations of malposition: mesiovestibular position and distovestibular position.
Isolated dental anomalies of form and volume can be generating occlusal interference by inconsistencies that appear in reports to other normally developed teeth. It produces a change in the position of teeth, bone implant base change, changing cuspid plans finally affecting occlusion reports.
Occlusal vicious habits and tics are multiple and a source of risk factors for a dysfunctional maxillary. The most common harmful habits are: onychophagy (nail biting), biting objects (pipe, rubber, glasses frames), the practice of keeping and tighten between teeth, needle, nails, pencil, while working.
Dentoalveolar fractures or maxillary bones may lead to dysfunctional occlusal interference. When the traumatic accident caused significant displacement of bone fragments of jaw, they rarely can be reduced in such a manner that there will be no significant occlusal changes after consolidation.
Multiple parafunctions are the most common sources of occlusal dysfunction, bruxism holding priority. It is conditioned by the existence of occlusal disharmonies caused by premature dental contacts and occlusal interferences with an important role for multi-causal dysfunctional factors of the maxillary.
With a change of direction of force, normal pressure of normal muscle contractions become traumatic for periodontal membrane crushed between the tooth and alveolar wall it has no irrigation and normal metabolism anymore, and on the other hand, not all ligaments take functional tasks. Besides periodontal membrane suffering appears a harmful effect on alveolus: pressure causes bone lysis. Bone lysis always occurs in the way the force that causes pressure on the bone acts, which results in a stronger inclination of the tooth, like this appears traumatic periodontal conditions. By tilting the teeth it can escape the occlusal pressures making even dental contact to disappear; periodontal pain does not disappear with the disappearance of dental tooth contact as lack of stimuli periodontium undergoes hyaline degeneration of hypofunction . Following these considerations to set the concept of primary occlusal trauma which means the harmful effect of occlusal forces on initial healthy periodontal when the direction, intensity or duration of occlusal force are beyond functional parameters: direction outside the long axis of the tooth, too long time, too much intensity. In this context, it should be emphasized that most studies are in agreement that the primary occlusal trauma (in the absence of superimposed etiologic factors, inflammatory, degenerative-dystrophic) does not causes periodontal disease but isolated periodontal lesions. Experience has shown that when the periodontium is weakened, initial periodontal suffering having other causes than occlusal, occlusal requests, even with optimal direction, the long axis of the teeth, even if they are intermittent, or even if the intensity normal, all lead to a periodontal trauma [9,10,11]. In this case, it is a secondary occlusal trauma in which the occlusal forces act on a previously weakened tooth periodontium. Obviously for already weaken teeth periodontium faulty forces within that direction, intensity or duration, have bad effects. Great difficulty occurs when, after periodontal is affected by an occlusal trauma, inflammatory component is superimposed, because at the moment it is hard to tell whether it is a primary or secondary occlusal trauma.
We can describe the three stages of occlusal trauma: stage of aggression, stage of repair and periodontal adaptation stage. During the stage of aggression collagen and osteogenic activity is inhibited, so that when the injury is not too strong to stimulate repair possibilities. If the trauma is not excessive, overcoming repair potential has serious periodontal consequences. If trauma is not excessive, it can reach the third stage, the periodontal adaptation. .
Disorders at the level of occlusive parameters characterized by shortening and cutting of occlusal areas, their artificial or mixed incorrectly realization, discontinuities, incorrect reconstructions of retroincisal slope, changes in the integrity and shape of support and guidance cusps, altered occlusion curves, uneven occlusal plane, are important factors of occlusal dysfunction, resulting in changes in jaw dynamic patterns, with muscle and joint response, taking into account the role of the dental determinant in achieving mandibular dynamics.
It is worth noting that the teeth in occlusal trauma, especially those with pathological abrasion, fractures may occur in low varnish areas, which can go up to an aspect of,, shelling " of dental crown .
True cuneiform lesions (mylolysis) are missing carious dentin being located strictly in the varnish. These are considered by many authors as pathognomonic lesions for teeth in occlusal trauma [13,14]. These lesions with lack of dental hard tissues are located on the vestibular side. The section looks like an obtuse angle open to the mouth vestibule. The lesion affects hard coronary tissues but extends to the root cementum, in the same time with marginal periodontal retraction [5,15,16]. The color of the cuneiform lesions walls is slightly modified and they have a hard consistency, heat sensitivity or chemical is inconsistent and injury has a slow progress. If you are creating a five grade cavity lesion evolves rapidly while getting the characteristics of dental cavity. Occlusal obstacles and / or occlusal parafunctions often cause appearance of pathological abrasion . It should be clinically noted how the abrasion is dependent on other factors. It is demonstrates that the patient\'s age, degree of abrasion of tooth of specific subject, the presence of eccentric abrasion (which betrays occlusion function) are factors that cause pathological abrasion .
Studies show that reducing the masticatory field by edentation accelerates abrasion. Local hyperacidity (by diet or acid regurgitation) can lead to erosion (as opposed to abrasion) . Presence of enamel dystrophy and dysplasia, in one word the quality of dental hard tissues is an important factor that causes tooth wear .Another extremely important factor that can cause tooth wear is the abrasive capacity of prosthetic restoration materials.Isolated clinical examination makes it virtually impossible to determine the rate of pathological abrasion. Therefore it is prudent that in such cases to make exploratory therapeutic methods (selective grinding, temporary dentures) before major restaurateurs interventions. In this way, the dentist is able to identify more precisely the primary determinant of pathological abrasion and abrasion evolution speed.General pathological abrasion-is the abrasion inconsistent with biological age. The generalized pathological abrasion is a major sign of dysfunctional occlusal [18,19].
Periodontal pockets do not occur in primary occlusal trauma, but usually in secondary, on a periodontium already affected in the presence of infectious and local irritative factors. As long as the inflammation is limited to the gum, it is not aggravated by traumatic occlusal forces, but when the inflammatory process spreads to desmodontium own tissue, the occlusal trauma becomes a co-destruction factor of support structures, protecting the periodontal pockets of bones. A periodontal pockets is pathological deepening of the gingivodental fosse which is formed gradually, resulting the destruction of tooth support tissue and its mobility, finally leading to its expulsion of .
Destructive alveolar processes represent another consequence of the occlusal trauma phenomenon. Alveolar bone, despite of its appearance rigidity, is less stable than periodontal tissue, as is continuous-changing structure by obvious resorption phenomenon in the pressure area and by apposition ones manifested within traction territory. In the case of occlusal trauma, the destructive effect on alveolar bone is directly proportional to the overload degree, their frequency and duration being inversely proportional to the resistance of the tissue. On such a field, under the action of repeated occlusion constraints, the negative effects of occlusal trauma occur more easily, periodontal disease having a fast and serious evolution. In conjunction of any occlusal trauma caused by bruxism amid a normal gum, first the bone destruction presents the characteristic of an aseptic process, lytic, of some areas that cannot be radiologically detected yet. In later stages, due to parafunction persistence, destructive phenomena complicate, the blood nutrition being even more deficient, due to prolonged action of pressure forces, amid local irritations (tartar and plaque) will contribute to the failure of the epithelial barrier to invasion of microorganisms and toxins. The existing bone bags, along with the gum ones installed will progress simultaneously, adding also the gingival retraction . Another result of the occlusion dysfunction is represented by the opening of the interproximal contacts. The consequence of periodontal changes caused by occlusal trauma is represented by dental mobility, dental migrations, and gingivorragia. Mobility is due to an occlusal trauma exerted on that tooth, the tooth receiving abnormal forces which pressure it during protrusion and laterotrusion movements.
The more frequently there are affected the monoradiculars that are subjected to occlusal trauma producing bone lysis in the support periodontium level. Because of dental mobility is difficult to detect when occlusal trauma occurs, requiring consideration of occlusion, both in centric relation and maximum intercuspation and also in protrusion and laterotrusion movements. Pathological tooth migration is a phenomenon that occurs due to poor periodontal structure, exacerbating existing traumatic occlusion with more pronounced effect of paraxial transmission of masticatory forces so harmful to the entire dento-maxillary system. Changing the position of one or more teeth causes ‘contact rupture’ between them, creating spaces (trema, diastema) favoring mechanical injury of epithelial insertion with papilla inflammation often accompanied by bleeding. Implantation of the pluriradiculars is more favorable for the capacity of trauma resistance when the roots are divergent. In fact, all aspects mentioned above influence the capacity of occlusal trauma resistance, making a normal request to appear as supraliminal, emphasizing the traumatogenic character of occlusal forces [3, 21].
Coating or superficial periodontium injuries take various clinical forms depending on the intensity, duration and direction on which occlusal trauma manifests. Occlusal trauma can cause a progressive denudation of teeth roots, characterized by moving the gum to the tooth apex. There are two sets of gum retractions: one which is detected on physical examination, another one hidden, and a part of the root being covered by the inflamed wall of a periodontal pocket. It should be noted that gingival retraction may involve all insertion area from the level of dental package, or only partially. The most common areas are the vestibular and oral of one tooth, of a group of teeth or even of a complete dental arch.
Traumatic dental hygiene habits can worsen the gingival recessions at the level of vestibular teeth face, this being associated with the occurrence and emphasis of cuneiform injuries, which is a pathognomonic sign that the tooth / teeth in question are in occlusal trauma .
Occlusal trauma causes and aggravates the gingival retraction, thus accelerating the initial epithelial proliferation by a local irritation, clinical form known as Mc Call’s garlands or festoons. It also can reveal injuries as cracks (Stillman’s fissures). These identities are pathological bag bottoms in which the ulcerative process developed, they could spontaneously cicatrize or persist in the form of deep fissures with rolled edges [23, 24, 25]. Papilla and gingivitis occurring as a result of opening the cervical interproximal space arise as a consequence of the loss of dental contact points in the presence of partial edentation which are accompanied by migrations, tipping or translations of the limiting dental units to edentulous breaches. The opening of interproximal space allows food particles penetration, thus injuring the gingival papillae.
Local examination reveals the presence of gingival inflammation that may be associated with bleeding. In advanced stages there is a junction of the vestibular and oral gums, accompanied by a slight extrusion of the affected tooth. Interradicular space dissection is characterized by roots denudation, gingival epithelium covering the limbus bone top retreating. Reaching bifurcation or trifurcation root is generally due to deepening of vestibular gingivodental or oral channel [26, 27].
Any indiscriminate therapeutic act in terms of ignorance or underestimation the capacity features and adaptive limit capacity, respectively of teeth defense, periodontium, temporomandibular joint, jaw bones, neuromuscular and vascular complexes, is likely to confuse the morphofunctional balance of dento-maxillary system, thus prejudicing the treated subject through iatrogenesis.
The interrelation between the periodontal health status, the presence of dento-maxillary anomalies and the orthodontic treatment remains a controversial issue in the literature , reflected in the great diversity of the findings of studies that address this issue. Some researchers promote the idea that the presence of dento-maxillary anomalies is a risk factor in the development of periodontal pathology: [29-34];
The dento-maxillary anomalies may represent a risk factor in producing chronic marginal periodontitis as they maintain the periodontal inflammation, while changing the intensity and direction of occlusal forces. Other periodontal changes as insufficient attached gingiva width and low height of the alveolar bone were also observed and associated with the presence of dento-maxillary anomalies in general, or a single misaligned teeth [35, 36], as well as people with evident dento-maxillary anomalies were discovered to whom periodontal changes were minimal or nonexistent .
They are a risk factor for the presence of septic inflammation, because due to the disparity between mesial-distal sizes of permanent teeth and corresponding alveolar arches’ perimeter, various dental malposition occur, localized mainly in incisor-canine region (Figure 1), which causes retention of food debris and plaque, and difficulty in removing them by self-cleaning or artificial cleaning . This correlation is weaker in the maxilla compared to the mandible .
The fact that malocclusion with crowding is a risk factor in the development of periodontal pathology is supported by studies that have reported the existence of a strong correlation between the presence of this anomaly and the occurrence of periodontal pockets, ; ; or the reduction of alveolar bone.
Anatomical conditions specific to this anomaly are unfavorable because interdental septa are thin, interdental papillae are laminated, with low volume and with poor blood circulation, unfavorable for a good gingival-periodontal nutrition .
DAD cause periodontal adaptive phenomena such as: hiperkeratinized epithelium, gingival chorion fibrosis, flattening dental papilla (which become a plateau or even concave aspect) (Figure 2). The presence of this anomaly may favor direct trauma on interdental papillae by food fragments.
Many specialized studies could not establish any positive correlation between incongruence with spacing and periodontal parameters in conditions of a rigorous hygiene, so that there are authors who consider that the indication for closure of interdental spaces is aesthetic rather than for periodontal dental health maintaining. 
In the anterior open bite teeth are not functionaly requested during mastication (missing the food cut), and the self-cleaning phenomenon is absent favoring installation of gingival inflammation and hyperplastic changes. In contrast, lateral teeth are in occlusal contact and they are overworked during masticatory effort, they being almost in a state of permanent occlusal trauma due to the transfer of mandibular movements’ previous guide of the lateral teeth .
We thus witness the periodontal space widening, gingival retraction emergence and horizontal bone atrophy of these teeth.
According to Macht and Zubery , in this syndrome we are witnessing a significant increase in the gingival inflammation, consequence of the enhancing virulence of the dehydrated plaque (due to lack of labial competence), and an increase in the length of the clinical crowns of incisors, which may suggest that open bite predisposes patients to the development of gingival retractions localized in the incisor segment (Figure 3).
In the deep bite syndrome, anterior teeth don\'t have stable occlusal stops, and their implantation remains normal just as long as inflammation isn\'t installed due to the presence of plaque. When gingival-periodontal injuries of microbial cause occur, the anterior teeth implantation degrades, it begins a process of accelerated active eruption of the anterior inferior teeth, with the possibility of their direct trauma to the incisive upper periodontium , and the progression of periodontal lesions. Deep bite syndrome will lead in these conditions to increased periodontal pocket depth and marginal gingival retractions appearance 
Due to inocclusion lips and upper lip hypotrophy, bacterial accumulation occurs in the anterior dental area, the immunological role of saliva is reduced, and on long-term increases the frequency of periodontal lesions . Similar to open bite, in the anterior dental regions, a fragile periodontal can be structured (Figure 4), prone to periodontal lesions because of unstable interdental contacts. The same fragile periodontium can be observed in the side areas, due to unilateral or bilateral crossbite (consequences of a different degree of compression of the two jaws).
There is no concordance of views regarding correlations between sagittal inocclusion (overjet) and periodontal parameters. Authors such as Davies et al. 1991,  or Geiger et al., 1976,  support the existence of a significant correlation between plaque index, periodontal diseases and severe anterior overjet (> 6 mm), while Buckley, 1981  considers that there is no significant correlation between the presence of overjet and plaque index, or gingival inflammation index.
According to Torres et al., 2006,  an increase in the plaque index occurs only in subjects with sagittal inocclusion > 6, and after Bjornaas et al. 1994 , to adulthood, in the presence of a severe sagittal inocclusion (overjet ≥8mm), there is a reduction of alveolar bone level with ≈0,96mm in the upper anterior area, and with ≈0,35 mm in the lower area.
In mandibular prognathism, the lingual pressure (of the protrude tongue and low positioned) continuously exercised on the lower incisors\' lingual face and the occlusal trauma due to anterior crossbite can lead to important vestibulo-version of the mandibular incisors with fine periodontal biotypes inducing and the presence of a very thin vestibular cortical bone, located away from the cemento-enamel junction.
Transferring anterior guide on the lateral teeth, found in this group of anomalies, leads to the lateral dental area overloading concurrent to a less loading of the front area (no food incision) . Therefore we can expect the emergence of periodontal changes like horizontal bone atrophy and epithelial insertion\'s descent .
Periodontal changes occur early in reverse gear and consist of the occurrence of significant gingival retraction of the lower incisors\' vestibular face ("disposal trench"), possibly a tooth mobility, following a permanent occlusal trauma.
These periodontal changes can regress spontaneously if orthodontic treatment is instituted early .
There is no uniformity of opinion or about the association between anterior crossbite with different periodontal parameters. Ngom et al. researches 2005,  have reported the presence of a significant correlation between anterior crossbite and the percentage of gingival retraction, but not with the plaque index and the gingival pockets depth, while Hashim and Al-Jasser\'s researches, 1996,  have found a significant correlation between crossbite, the plaque index and the periodontal pocket depth. The difference between the two studies may be due to differences in age and dental hygiene of the subjects investigated. Silness and Roynstrand, 1984,  opines that the crossbite teeth show more frequently signs of periodontal disease compared to those dealing a normal occlusion.
Next to specific anatomical defects, the delays in the formation and timing of tooth eruption, the need for long orthodontic treatment [56, 57] and the presence of prosthetic restorations are factors contributing to the reduction of the alveolar bone level in areas adjacent to dehiscence .
Multiple dental malposition, segmental alveolar gaps, soft tissue folds made before palatoplasty, the presence of scar tissue or oro-nasal communications persisting after surgical closure of the defect, make oral hygiene maintenance a difficult task, increasing risk and progression of periodontal disease [59, 60, 61].
Comparing the periodontium from patients with cleft lip and cleft palate, to the one from patients with cleft palate only, Gaggl et al., 1999, [62 found that the first have a predisposition to deep periodontal destructions in the teeth adjacent to the splicing area, while in patients that only have cleft palate, clinical peridental appearance may be similar to that of subjects without malformations. However, Dewinter and Quirynen state that the periodontium of the teeth from the splicing zone or near it, in patients with unilateral cleft, can cope relatively well to a long orthodontic treatment or to a combined periodontal-orthodontic treatment .
The three main reasons justifying the need for orthodontic treatment are: to improve facial and dental aesthetics, oro-dental health and the normal oral functions .
In the absence of periodontal diseases and in the presence of a proper oral hygiene, a well led orthodontic treatment should not have, on long-term, significant effects on periodontal supportive structures. According to Graber et al., 2005,  it is possible to occur a decrease in the alveolar bone\'s volume and height, as an adaptive process to the trauma.
The main clinical periodontal effects that can be seen in the oral cavity after insertion of orthodontic appliances are: gingival hyperplasia, marginal gingival retraction, irreversible loss of bone support and excessive fibrous tissue that prevents complete closure of the post extraction spaces .
A periodontal change frequently observed during orthodontic treatment, especially with fixed appliances, is the emergence of gingival overgrowth .
Scope, they can be localized or generalized, but seem to be more common in mandibular incisors region (67, 68) (Figure 5).
Other authors (69) believe that overgrowths may be marginal, diffuse, papillary, or discrete and have four degrees of severity:
0-no gingival overgrowth;
I – gingival overgrowth extended only to the dental papilla;
II-gingival overgrowth covering the papilla and marginal gingiva;
III-gingival overgrowth covers three quarters or more of the dental crown.
Since gingival overgrowth is a factor limiting or preventing orthodontic tooth movement, it often requires its removal by gingivectomy, which removes all fibrous tissues around the tooth and at the same time allows gum\'s reshaping or remodeling . After gingivectomy, periodontal condition is improving, so the orthodontic mechanic’s normal course is possible. If it does not prevent the effectiveness of orthodontic treatment and causes no discomfort to the patient, gum volume enlargement can be removed after the completion of orthodontic treatment, if it does not regress spontaneously.
Sometimes, the incidence of gingival recessions in patients with a fixed orthodontic appliance can be up to 10% . In addition, repeated trauma on marginal gingiva by teeth movements and plaque accumulation, inherent with the application of orthodontic appliances, can lead to the formation of marginal gingival retractions. Moreover, mucogingival problems prior to the initiation of orthodontic treatment could be exacerbated by the application of orthodontic force . It seems that the lower incisors are the teeth most likely to develop marginal gingival retractions, the mechanism of their occurrence being the excessive force applying, which does not allow bone\'s repairing or remodeling during teeth movement with the existence of a thin or non-existent vestibular cortical and an inadequate or absent keratinized gum .
During the initial phase of orthodontic treatment, orthodontic forces induce a response to the mechanical stress from periodontium and a net of events it is produced: angiogenesis, aseptic inflammation and periodontal remodeling .
Gingival crevicular fluid (GCF) is used to determine the presence and levels of biomarkers expressed during the first phase of orthodontic treatment, this cascade of substances comprising cytokines, metalloproteinases and other mediators of complex transformations in the periodontium [72, 73].
In studies funded by the grant ID573/2008 of the Ministry of Education and Research of Romania, we measured the levels of Pentraxin-3 (PTX3), Thrombospondin1 (TSP1), Lipocalin2/Matrix metalloproteinase 9 (MMP9/NGAL) complex and Matrix metalloproteinase 9 (MMP9) in GCF at different time points of the first 2 weeks of orthodontic treatment, to determine the relationship between these values and theirs implication in inflammation and angiogenesis balance, in the situation of a good control of the bacterial plaque [74, 75].
GCF samples were collected from orthodontic patients requiring upper canine distalization with first premolar extraction. For the orthodontic appliance, there are placed brackets Roth 0.018 inch (GAC Intl, Bohemia, USA) with 0.012 inch NiTi archwire (GAC Intl, Bohemia, USA) and a laceback made from 0.010 inch stainless wire, placed and activated 21 days after the premolar extraction.
Using the statistical analysis, our results show a change in time of PTX3, TSP1, MMP9/NGAL and MMP9 levels in GCF of patients with this method of orthodontic treatment and suggest their stronger involvement in inflammation and angiogenesis processes in PDL during orthodontic periodontal remodeling, in the situation of a healthy periodontium and a good control of the bacterial plaque.
The gingival overgrowth as a reaction of the orthodontic treatment was longtime considered by the clinicians as an inflammatory result of the retention of the bacterial plaque by the orthodontic devices. Clinical observations showed that the gingival overgrowth appear also in patients with good oral hygiene, without any clinical signs of gingival inflammation.
Our studies [76,77] in the grant ID573/2008 funded by the Ministry of Education and Research in Romania showed that the gingival overgrowth during the fixed orthodontic treatment appears at the beginning, without any inflammatory signs, as a result of the mechanical stress and periodontal remodeling during the orthodontic movement, the MMP8 and MMP9 acting as indicators of this situation.The inflammation of gingiva occurs as a consequence of the accumulation of the bacterial plaque favorized by the orthodontic devices.
Gingivectomy was performed in patient with gingival overgrowth in the first eight weeks of the orthodontic treatment and the material obtained was used for histologic and immunohistochemical study.
Diabetes mellitus (DM) and periodontitis are both chronic inflammatory disorders and which enhances their severity, worsen each other prognosis and share a number of pathogenic mechanisms with common inflammatory mediators which have been investigated as possible biomarkers of disease status.These improved diagnostic efforts resulting from utilization of biomarkers should enable optimal treatment planning, also assist in monitoring clinical response to treatment and more focused prevention of common human conditions. The most important inflammatory mediators linked to initiation and progression of periodontal disease is a complex network of pro-inflammatory cytokines, matrix metalloproteinases (MMPs) and prostaglandins . The vast majority of studies of cytokines, adipokines and other mediators in periodontitis and diabetes have been small-scale clinical studies using GCF(gingival crevicular fluid), saliva or gingival tissues samples which have focused on limited number of mediators and many inconclusive because of limitation in study design. Nevertheless there are promising data on certain mediators such IL-1β, IL-6, TNF-α and emerging data on RANKL and OPG; these are likely to have a central role in the pathogenesis of periodontitis in diabetic patients [79, 80]. Complex interactions between individual mediators and emergent pathways, for example, synergy in cytokine signaling, will not be apparent from simple disease association studies of a limited number of molecules [79, 80].
There are studies suggesting that pro-inflammatory cytokines which induce chronic inflammatory diseases including periodontitis, could increase insulin resistance [81, 82]. Both TNF-α and IL-6 are produced in adipose tissue, and a large quantity of circulating IL-6 is derived . There are also studies which correlate periodontitis to obesity [84, 85]. These directions of research suggest that obesity, diabetes and periodontitis may be related to each other.
Effective periodontal treatment in patients with DM significantly reduced GCF [86, 87] and serum levels of several mediators, such as IL6, TNF, adiponectin [88, 89, 90], MMP2, MMP9 , thus leading to reduced systemic inflammation.
In the effort to establish a pathway for the periodontitis-DM-obesity co-morbidity, some studies have determined genetic polymorphisms for IL6 and IL1 [92, 93]. These cytokines have been previously measured in blood and GFC from patients with these diseases.
Because fatty tissue serves as a reservoir for inflammatory cytokines, an increase in body fat may determine an increase of the inflammatory response of the host in periodontal disease .
In 2014, a study concerning the low fibers rich and fat poor diet for 8 weeks, demonstrated an improvement of the periodontal disease’s markers, their levels returning to the initial value after follow-up period . A study proposed the hyperinflammatory state observed in obesity, determined by the increase in cytokine levels, as mechanism to explain this relation .Aknowledgment
Immunological and immunohistochemical studies of MMP9/NGAL, TSP1, PTX3, MMP8 and MMP9 in GCF and gingival tissue of orthodontic patients were funded by the grant ID573/2008 of the Ministry of Education and Research of Romania, IDEAS competition of CNCSIS.
Ovarian cancer (OC) is the leading cause of death from gynecologic malignancies in the United States . It is estimated that 22,240 women will be diagnosed with OC, and 14,080 women will die of the disease in 2017 . Ovarian malignancies can be primary (arising from normal structures within the ovary) or secondary (arising from non-ovarian tissue). Approximately 90% of all primary OC are epithelial carcinomas . Epithelial ovarian cancer (EOC) is sensitive to many chemotherapeutic agents, and the current standard treatment consists of cytoreductive surgery followed by chemotherapy with platinum compounds such as cisplatin or carboplatin and a taxane agent such as paclitaxel . A high percentage of patients with advanced EOC however, eventually develop recurrent disease within 3 years and only 10–30% of patients presenting with stage III or IV disease survive 5 years following initial diagnosis [3, 4]. This poor survival rate is mainly due to the development of chemotherapy resistance following several rounds of treatment. In many cases, initial recurrences are platinum-sensitive but the disease eventually becomes platinum-resistant; which is defined as disease progressing within 6 months of platinum-based therapy [4, 5]. Platinum-resistant patients are subsequently limited to non-platinum and non-taxane chemotherapy treatment options such as topotecan, gemcitabine, and pegylated liposomal doxorubicin which have shown moderate therapeutic success . Alternative treatment options for platinum-resistant disease are, therefore, constantly being explored and immunotherapy and targeted agents are increasingly undergoing clinical trials which are showing positive results.\n
The serendipitous discovery that platinum coordination complexes blocked bacterial replication led to the hypothesis that these complexes could be of great clinical value as anti-tumor agents . Cis-diamminedichloroplatinum II (cisplatin) was the first drug in its class successfully marketed followed by carboplatin and oxaliplatin. All three drugs have similar mechanisms of action. Cisplatin and carboplatin are approved for the treatment of OC; while tumor cell resistance mechanisms to both drugs are similar they differ in their pharmacokinetic and toxicity profiles . Oxaliplatin is highly effective in colorectal cancers because it’s mechanism of action (MOA) is not limited to that of the other platinum compounds .\n
Cisplatin, the prototype platinum compound, is taken up into cells by passive diffusion or via the active copper transporter 1 (CTR1) . The subsequent activation of cisplatin is mediated by the displacement of chloride atoms by water to form a highly reactive electrophile that targets nucleophilic sites on DNA and DNA-associated proteins. The N-7 guanine base is most susceptible, although the O-6 guanine, N1, N3 adenine, and N3 cytosine are also targeted. Cisplatin DNA interactions result in the formation of both mono- and bifunctional adducts with the latter forming cis-Pt (NH3)2-d(GpG) at twice the rate of cis-Pt (NH3)2-d(ApG). Interstrand crosslinks are not as common. The bulky adducts between DNA and cisplatin can bend the helix and unwind DNA. The critical importance is the recognition of DNA-cisplatin adducts by proteins that either initiate DNA repair by nucleotide excision repair (NER) or inhibit repair through high mobility group (HMG) proteins. Platinum compounds are cell cycle non-specific (CCNS) causing arrest in S/G2 .\n
Multiple mechanisms are thought to play a role in tumor cell resistance to cisplatin due to the heterogeneity of the disease. Resistance to cisplatin typically confers resistance to carboplatin, but not to oxaliplatin. Some common mechanisms of tumor cell resistance to cisplatin in OC includes increased repair to damaged DNA , drug efflux by copper efflux transporters ATP7A  and ATP7B , reduced uptake by CTR1 , and increased expression of glutathione and GSH-S-transferase, which are electron donors forming conjugates with cisplatin and rendering it inactive . Both increased efflux and reduced uptake result in reduced drug accumulation. Overexpression of epidermal growth factor (EGF) and its receptor (EGFR) in cancer cells are critical for growth and survival and EGFR overactivity using autocrine and/or paracrine signals is associated with platinum resistance . The overexpression of the tyrosine kinase; focal adhesion kinase, has also been linked to platinum resistance in OC through several mechanisms including increased expression of the transcription factor OCT4 and the cell surface protein N-cadherin, as well as increased aldehyde dehydrogenase (ALDH) activity [15, 16].\n
Although there are many chemotherapeutic agents available, the level of response of platinum-resistant ovarian cancer (OC-Pt) to these drugs is increasingly diminished as the disease progresses . In the past decade, this has fueled a consistent increase in the development of targeted therapies aimed at either supplementing chemotherapeutic regimens or providing novel monotherapy in OC-Pt . Categories of targeted drugs that are undergoing clinical trials or have received FDA approval for OC-Pt include focal adhesion kinase (FAK) inhibitors, poly(adenosine diphosphate [ADP] ribose) polymerase (PARP) inhibitors, anti-angiogenic agents, epidermal growth factor receptor targeting agents, folate receptor antagonists, and insulin growth factor receptor inhibitors.\n
PARP inhibitors are a group of targeted drugs that have been at the forefront of emerging OC-Pt therapeutics over the past decade [18, 19]. Human PARPs comprise a total of 17 enzymes . The PARP-1 isoform was the first member of the family to be described and it is the major active PARP enzyme in human cells with the remainder of activity mainly attributed to the PARP-2 isoform . Both PARP-1 and PARP-2 are DNA damage repair enzymes . Human PARP-1 (113 kDa) is a nuclear protein/enzyme which binds with DNA and promotes DNA repair by releasing PARP-1 from DNA and allows recruitment of proteins involved in both base excisional repair (BER) and homologous recombination . Human PARP-2 (62 kDa) is a nuclear protein that binds less efficiently to DNA single-strand breaks but instead recognizes gaps and flap structures . These DNA repair properties of PARPs have made them important anticancer targets in a variety of cancers including OC.\n
The inhibition of PARP enzymes, especially PARP-1, results in an excess of single-strand breaks, which subsequently causes double-strand breaks to occur as DNA replicates . Under normal circumstances, defects such as double-strand breaks are usually repaired by the homologous recombination process that involves breast cancer type susceptibility (BRCA) proteins. Tumors with defective homologous recombination, including BRCA1/2-mutated OCs, are therefore very sensitive to PARP inhibition .\n
PARP inhibitor drugs are able to cause cancer cell death by inhibiting repair of single-strand breaks and subsequently trapping PARP on DNA, forming cytotoxic PARP-DNA complexes . Several small molecular PARP inhibitor drugs are now undergoing clinical trials and two of them (olaparib and rucaparib) have already been approved by the FDA for use in OC-Pt.\n
Olaparib (Lynparza), a product of AstraZeneca, received approval from the U.S. Food and Drug Administration (FDA) in December 2014. Olaparib is an inhibitor of several PARP enzymes, including PARP1, PARP2, and PARP3 . The orally administered drug is used for monotherapy in patients with germline BRCA-mutated advanced recurrent OC-Pt . Phase II clinical trials have shown that olaparib significantly improves progression-free survival (PFS) in OC-Pt with similar rates of response reported in patients with BRCA1- and BRCA2-mutated disease . The most common side effects observed with olaparib were mild gastrointestinal irritation, anemia, and severe fatigue.\n
Rucaparib (Rubraca), a product of Clovis Oncology, was granted accelerated approval from the FDA on December 19, 2016 for the treatment of patients with deleterious BRCA mutation (germline and/or somatic) associated with advanced OC, which had been treated with two or more chemotherapies that included those with OC-Pt. Rucaparib is also a non-specific inhibitor of several PARP enzymes, including PARP1, PARP2, and PARP3 . The ARIEL2 and Study 10 clinical trials produced critical integrated efficacy and safety data in OC-Pt patients which showed that the average response rate was approximately 25% with minimal differences between patients who harbored a BRCA1 mutation, and those who harbored a BRCA2 mutation . Adverse reactions to the drug included fatigue, anemia, dysgeusia, and decreased appetite .\n
A third PARP inhibitor niraparib (Zejula), a product of Tesaro, was approved on March 27, 2017 to maintain treatment of adult patients with recurrent epithelial ovarian and fallopian tube cancer that is completely or partially responsive to platinum-based chemotherapy. Niraparib inhibits both PARP1 and PARP2 and currently has no specific indications in OC-Pt .\n
It is generally accepted that the major categories of cancers that are sensitive to PARP inhibitors are BRCA-mutated cancers. Interestingly, drug resistance to PARP inhibitors have been linked to the development of secondary mutations in the BRCA gene themselves . These secondary mutations can restore functional BRCA1 or BRCA2 genes leading to deleterious consequences in patients with cancer . Other mechanisms of resistance to PARP inhibitors include increased multi drug resistance protein-1 (MDR-1) activity, which leads to increased drug efflux from cancer cells as well as reduced expression of tumor suppressor p53-binding protein 1 (TP53BP1), which is required for non-homologous end-joining DNA repair . Many of these resistance mechanisms are active in OC-Pt [10, 11, 12, 13, 14, 15, 16] and therefore can potentially circumvent the therapeutic effects of PARP inhibitors. Nonetheless, PARP inhibitors show much promise in OC-Pt therapeutics.\n
Solid tumors rely on neovascularization for growth and survival in hypoxic environments. The process of angiogenesis is critical for normal ovarian function and for growth, development, and metastasis of OC cells . The hypoxic environment drives angiogenesis in solid tumors which requires continual and persistent growth of new blood vessels . Data strongly suggest a close correlation between increased levels of hypoxia-inducible factor 1-α (HIF 1-α); a transcription factor stabilized during hypoxia and vascular endothelial growth factor (VEGF) in EOC . VEGF is a potent pro-angiogenic growth factor that is upregulated during hypoxia and is elevated in epithelial ovarian neoplasms . VEGF-A is a major pro-angiogenic growth factor that binds to VEGF receptor-1 (VEGFR-1) and VEGF receptor-2 (VEGFR-2), although VEGFR2 is considered the major target. The VEGF-A/VEGFR-2 interaction activates the RAF/MAPK and PI3K/AKT signaling pathways favoring both proliferation and survival of endothelial cells. Intratumoral protein levels of VEGFR-2 were found to be significantly higher in platinum-resistant OC compared to platinum-sensitive OC patient tumors . Many agents targeting angiogenesis have been developed and several have shown some degree of clinical efficacy in OC-Pt. The anti-angiogenic group of drugs include bevacizumab, aflibercept, nintedanib, trebananib, pazopanib, sunitinib, sorafenib, and cediranib.\n
Bevacizumab (Avastin), a monoclonal antibody that binds to the vascular endothelial growth factor (VEGF)-receptor ligand VEGF-A, is the most extensively investigated anti-angiogenic agent in clinical OC research. Currently, it is the only anti-angiogenic drug that is FDA approved for the treatment of OC as monotherapy or in combination regimens with paclitaxel, topotecan, doxorubicin (pegylated), carboplatin, or gemcitabine for recurrent OC-Pt . Bevacizumab potentiates the cytotoxic effect of chemotherapeutic agents by reducing interstitial fluid pressure and vascular permeability to increase delivery of cytotoxic drugs to cancer cells .\n
A phase II trial of bevacizumab as a single agent in OC-Pt reported that 40.3% of these patients survived progression free for at least 6 months while median PFS and overall survival were 4.7 and 17 months, respectively . Common adverse effects related to bevacizumab were hematologic and gastrointestinal .\n
Subsequent randomized phase III clinical trials focused on the use of bevacizumab with standard chemotherapeutic regimens as first-line treatment in both platinum-sensitive and platinum-resistant OC. AURELIA was the first randomized phase III trial (Study ID#: NCT00976911) to evaluate combined bevacizumab with chemotherapy in OC-Pt . All patients received standard chemotherapy with either paclitaxel or topotecan or liposomal doxorubicin. Patients randomized to arm 2 of the study received bevacizumab (10 mg/kgIV every 2 weeks or 15 mg/kg IV every 3 weeks) concomitantly. The study showed improved PFS and overall response rate with no new safety concerns. The percentage of adverse events associated with chemotherapy + bevacizumab was 57.0% versus 40.3% (chemotherapy alone). Proteinuria and hypertension had the highest incidence rate, whereas gastrointestinal perforations were comparable 2% (bevacizumab) versus 0% (bevacizumab + chemotherapy). Treatment arms that consisted of a higher exposure to chemotherapy in the bevacizumab + chemotherapy combined study group, had a higher incidence rate of hand-foot syndrome and peripheral sensory neuropathy.\n
The topoisomerase I inhibitor Irinotecan (Camptosar), in combination with bevacizumab was evaluated in recurrent OC in an open-label randomized phase III trial (Study ID#: NCT01091259) . This cohort included 19 patients with OC-Pt. The objective response rate for all patients entered was 27.6% and the clinical benefit rate was 72.4%. Adverse events with the addition of bevacizumab relative to GI toxicity was limited to <3% and considered acceptable . These studies show that it is clinically proven that bevacizumab + chemotherapy demonstrate efficacy in OC-Pt and that safety can be achieved with the right dose and combination of drugs.\n
Pazopanib (Votrient) is an oral anti-angiogenic multi-targeted tyrosine kinase inhibitor with activity against VEGFR-1, 2, and 3. Pazopanib is currently FDA approved for advanced renal cell carcinoma and soft tissue carcinoma. The PACOVAR study (Study ID#: NCT01238770) evaluated pazopanib in combination with metronomic cyclophosphamide in 16 patients with platinum-resistant EOC . Metronomic chemotherapy is the close, regular administration of chemotherapy drugs at low, minimally toxic doses, with no prolonged break periods. In the PACOVAR study, median PFS and overall survival were 8.35 and 24.95 months, respectively. The most common adverse events were elevation of liver enzymes, leukopenia, diarrhea, and fatigue. Altogether, five serious adverse events developed in four patients. The study concluded that pazopanib + metronomic cyclophosphamide was a feasible regimen for patients with recurrent OC-Pt.\n
Pazopanib has also shown promising results in mice injected with a highly aggressive cisplatin-resistant SKOV-3 clone of OC cells in combination with metronomic oral topotecan (toperisomerase I inhibitor) .\n
Aflibercept (Ziv-aflibercept/VEGF-trap) mimics the VEGF receptor and has similar ligand binding components to VEGFR-1 and VEGFR-2 . Aflibercept binds to circulating VEGFs and acts like a “VEGF trap” . This primarily results in suppression of VEGF-A and VEGF-B activity and subsequently inhibits the growth of new blood vessels in tumors . Aflibercept was administered at two doses in a randomized, double-blind, phase II trial that assessed response evaluation criteria in solid tumor response rates, as a single agent treatment in recurrent OC-Pt (Study ID#: NCT00327171). The study concluded that the treatment was well tolerated by the patients but the required objective response rate endpoint was not achieved . The participants in this study had received 3–4 prior chemotherapy lines and were resistant to liposomal doxorubicin or topotecan. Hypertension was the most common toxicity observed.\n
Focal adhesion kinase (FAK) is a non-receptor cytoplasmic tyrosine kinase that is encoded by the protein tyrosine kinase 2 (PTK2) gene, and is found in most tissues in the human body . PTK2 gene amplification with subsequent increased activation through phosphorylation occurs in many OCs, where it is involved in promoting cancer cell migration, invasion, adhesion, proliferation, and survival [45, 46, 47]. High FAK activity is generally associated with worse overall cancer patient survival [48, 49]. Several studies have shown that FAK expression is significantly increased in OC-Pt, and that this platinum resistance is associated with increased tumor-associated aldehyde dehydrogenase (ALDH) activity, as well as overexpression of X-linked inhibitor of apoptosis (XIAP) [16, 50]. We have also demonstrated in our studies that platinum-resistant OC cells are resensitized to cisplatin when co-treated with a FAK inhibitor .\n
Several FAK inhibitors have been developed to prevent FAK activation by blocking its phosphorylation sites; which halts its downstream signaling pathways with subsequent reduction in ovarian tumorigenesis and cancer progression. A few of these drugs are now in clinical trials. The FAK inhibitor defactinib from Verastem was evaluated in a phase I study (Study ID#: NCT00787033) which found that OC-Pt patients achieved a prolonged PFS . Defactinib produced grade 1–2 adverse events that were easily managed and reversible, even with continued dosing . A phase I/Ib, open-label (Study ID#: NCT01778803) multi-center, dose-escalation trial of paclitaxel in combination with defactinib was subsequently initiated in OC-Pt patients with advanced cancers . The combination was found to be efficacious with no apparent increase in the severity and incidence of paclitaxel-related toxicities.\n
A phase I/Ib, open-label, multi-center, dose-escalation, and dose expansion trial (Study ID#: NCT02943317) to evaluate the safety, efficacy, pharmacokinetics, and pharmacodynamics of defactinib in combination with the human monoclonal PD-L1 antibody avelumab in recurrent or refractory stage III–IV OC is currently ongoing, and is expected to enroll approximately 100 patients at up to 15 sites across the United States. The FAK inhibitor GSK2256098 was also evaluated in a phase I clinical trial (Study ID#: NCT01138033) in patients with advanced solid tumors including OC-Pt . GSK2256098 significantly reduced FAK activity in tumors of patients that received the drug at a dose of 750 mg twice daily.\n
FAK inhibition is still an emerging area in OC-Pt therapeutics and many clinical trials are underway that will provide more insight into their efficacy in different histological types of OC.\n
Folate receptors (FRs) are proteins that bind folate with high affinity. The FR-α and FR-β isoforms are well characterized as membrane-bound receptors that facilitate the binding and subsequent internalization of folate compounds and their chemical derivatives . The FR-α receptor is significantly overexpressed in EOC where it promotes tumor growth by either an aberrant folate uptake mechanism or dysregulated signaling pathways . The FR-α receptor can also induce platinum resistance by regulating the expression of apoptosis-related molecules; Bcl-2 and Bax and a higher expression of FR-α level has been linked to poor prognosis in OC patients . These properties of the FR-α receptor makes it a prime therapeutic target for OC. In recent years, two drugs (vintafolide and farletuzumab) have gained relevance as FR-α receptor antagonist applicable in OC-Pt. Farletuzumab (MORAb-003), a monoclonal antibody to FR-α was evaluated in a phase III trial (Study ID#: NCT00738699) in combination with paclitaxel for advanced OC-Pt patients . The drug was developed by Morphotek and the study was unfortunately discontinued because of minimal changes in PFS and the occurrence of serious adverse events including neutropenia and atrial fibrillation .\n
Vintafolide (originally known as EC145), is a water-soluble derivative of folic acid that is conjugated to the vinca alkaloid ‘desacetylvinblastine hydrazide’ . The combination of vintafolide with pegylated liposomal doxorubicin (PLD) produced a statistically significant increase in PFS for OC-Pt patients . This result was the outcome of the PRECEDENT trial; a randomized phase II study, that compared the combination of vintafolide + PLD with PLD alone . Patients with FR positive cancer showed improved PFS compared to no PFS benefits in FR negative patients. After this successful phase II trial, a phase III trial called the PROCEED study was initiated (Study ID#: NCT01170650) to further evaluate the efficacy and safety of the vintafolide + PLD (Doxil) combination in OC-Pt patients. The main goal of the study is to determine PFS using version 1.1 of the response evaluation criteria in solid tumor (RECIST), and etarfolatide imaging to determine patients FR status . Etarfolatide is a non-invasive, folate receptor-targeting companion imaging agent, which consists of a small molecule targeting the folate receptor and an imaging agent, which is based on technetium-99 m .\n
The targeting of the FR receptor appears to be promising strategy for OC-Pt cancer subsets that significantly overexpress these receptors. New folate conjugates are in development and this area of therapeutics is expected to consistently improve.\n
The insulin-like growth factor (IGF) system consists of IGF-I, IGF-II, their target receptors (IGF-IR, IGF-IIR, insulin receptor (IR), and the insulin-related receptor (IRR)) as well as a family of six different IGF-binding proteins (IGFBPs) . Upon binding of IGFs to IGF-1R and IR (but not IRR and IGF-2R), many signaling pathways can be activated. These downstream signaling mechanisms include the Ras-Raf-MAPK and PI3K-Akt transduction pathways. These transduction mechanisms result in stimulation of cell proliferation, motility, and inhibition of apoptosis . All IGF-signaling system components are expressed in OC and likewise stimulate cell proliferation, invasive, and angiogenic activity of OC cells . More importantly, IGF-1R/IR inhibition in platinum-resistant ovarian cancer cells resensitizes them to the cytotoxic effects of cisplatin; indicating a role of the IGF system in OC-Pt . This highlights a therapeutic opportunity for insulin and insulin-like growth factor receptor inhibition.\n
In the past few years, a number of inhibitors targeting the IGFR/IR have been developed, including antibodies against the receptors and small molecule receptor kinase inhibitors . A trial (Study ID#: NCT01708161) with ganitumab (developed by Amgen), a human monoclonal antibody against IGF-IR, has been completed in patients with solid tumors including OC-Pts. This was a multi-center, open-label, phase Ib/II study. The aim of the phase Ib arm, was to estimate the median toxic doses and/or identify the recommended phase II dose(s) for the combination of BYL719 (a PI3K inhibitor) and ganitumab . The phase II arm assessed the clinical efficacy and safety of the combination in OC patient populations including PIK3CA-mutated or -amplified OCs . Data from this study are yet to be released, but will provide insight on the effect of ganitumab in OC-Pt.\n
A phase I/II trial (Study ID#: NCT00889382) with the small molecule, dual IGF-1R/IR tyrosine kinase inhibitor linsitinib (OSI-906) has also been completed . The study evaluated intermittent and continuous linsitinib dosing and weekly paclitaxel in patients with recurrent EOCs including OC-Pts as well as other solid cancer types (endometrial and primary peritoneal) . Of the 58 patients treated in the study, 3 OC patients showed a partial response, and stable disease was achieved in 10 OC patients. Pharmacokinetic studies showed no significant interactions when linsitinib was administered 2 h prior to paclitaxel. The most common drug-related toxicities were fatigue, nausea, hyperglycemia and drug eruption. Other details of the study outcomes related to PFS have not yet been published.\n
Many compounds are constantly being screened for IGF-IR inhibitory activity, but the similarity between the IGF-IR and the IR receptor presents a challenge for developing selective inhibitors for the IGF-IR. The main concern with this lack of selectivity is that dual inhibitors of IR and IGF-IR, has resulted in hyperglycemia in many clinical trials. This is a major hurdle to overcome in this area of OC therapeutics.\n
The epidermal growth factor receptor (EGFR) is a member of the tyrosine kinase family of growth factor receptors. These receptors play a direct role in regulating cell proliferation, apoptosis, survival, cell differentiation, and migration . The ERbB family of receptor tyrosine kinases includes EGFR (also known as HER1/ErbB1), EGFR2 (HER2/neu/ERbB2), HER3/ErbB3, and HER4/ErbB4 . Dysregulation of the EGFR function has been linked to the pathology of OC  but evidence is conflicting; as other studies have not found strong evidence of a direct link between EGFR expression and function and OC progression. Many factors have been suggested for the mixed results; these include variability in experimental methods, detection procedures, and scoring metrics. Despite the variable study outcomes in OC, evidence supports dysregulated EGFR ligand and receptor expression, heterologous regulation by GPCR ligands, and other non-ligand stimuli initiating chronic activation of EGFRs . This chronic stimulation favors tumor development and progression .\n
The current therapeutic strategy is to inhibit EGFR activity using small molecule tyrosine kinase inhibitors or monoclonal antibodies . Clinical trials have been conducted using the following agents alone and in combination: cetuximab, gefitinib, erlotinib, trastuzumab, and pertuzumab. These treatment regimens were evaluated in patients with recurrent or progressive disease, platinum-sensitive disease, and platinum-resistant/refractory disease among others .\n
Of note, the PENELOPE phase III trial investigated the efficacy of pertuzumab in combination with chemotherapy (single-agent topotecan, weekly paclitaxel, or gemcitabine) for treatment of platinum-resistant patients with downregulated human epidermal growth factor 3 (HER3) mRNA expression . The results showed no significant improvement in PFS for the primary analysis (stratified hazard ratio, 0.74; 95% CI, 0.50–1.11; P = 0.14; median PFS, 4.3 months for pertuzumab plus chemotherapy versus 2.6 months for placebo plus chemotherapy). The study concluded that pertuzumab has the potential to be investigated further despite the lack of significance. To date, clinical trials evaluating anti-EGFR and HER therapies have shown minimal improvement in OC-Pt treatment outcome. Further studies evaluating inhibitors of downstream signaling and simultaneous antagonism of the EGFR and HER have been recommended .\n
Current chemotherapeutic regimens for OC-Pt patients whether monotherapy or combinatorial are inadequate. Immunotherapeutic approaches are now being increasingly explored for these patients where a therapeutic ceiling has been reached with standard chemotherapy. Immunotherapy in OC-Pt patients is just emerging and is currently restricted to clinical trials that have shown promising results. The American Cancer Society defines cancer immunotherapy as ‘treatment that uses your body\'s own immune system to help fight cancer’. Within the tumor microenvironment, the pathological interactions between cancer cells and immune cells is complex and most events spiral into an immunosuppression that causes tumor cells to proliferate and evade immune system attack . There are several categories of immunotherapeutic agents that either stimulate the body’s immune system’s ability to eradicate cancer cells (e.g. cancer vaccines and adoptive T cell transfer), target proteins on the surface of T cells that prevent them from attacking cancer cells (e.g. immune checkpoint inhibitors), or identify specific abnormalities on the surface of cancer cells that render them susceptible to targeted agents (e.g. monoclonal antibodies) . Many of these drugs are being evaluated in OC-Pt patients and are discussed below.\n
Checkpoint proteins are molecules found on the surface of T cells that prevent them from attacking cancer cells . Two such proteins are cytotoxic T lymphocyte antigen-4 (CTLA-4) and programmed death-1 (PD-1) . PD-1 is expressed on the surface of activated T cells and its ligands, PD-L1 and PD-L2 are found on the surface of dendritic cells or macrophages . Interaction of PD-1 with either PD-L1 or PD-L2 results in inhibition of T cell signaling, reduction in T cell numbers, and increased susceptibility of T cells to apoptosis . CTLA-4 regulates T cell priming and activation in the initiation phase of the immune response . The high expression of PD-L1 and PD-L2 on OC cells is associated with shorter PFS . Similarly, evidence suggests that OC patients with low CTLA-4-mediated signals have a better prognosis than patients with high CTLA-4 activity .\n
Several antibodies directed against PD-1 (pembrolizumab, nivolumab, and avelumab), PD-L1 (atezolizumab and durvalumab), and CTLA-4 (ipilimumab) have been evaluated in OC. Nivolumab (Opdivo) is a fully humanized IgG4 antibody that blocks the engagement of PD-1-by-PD-1 ligands . Nivolumab was administered every 2 weeks to patients with advanced or relapsed OC-Pt and response rate was assessed by RECIST . The study included 15 OC-Pt patients and the drug showed encouraging clinical efficacy. Some adverse drug reactions including fever, disorientation, and gait disturbance were observed. A dose escalation study (Study ID#: UMIN000005714) is now under way as a second arm of this trial.\n
Avelumab (Bavencio) is a fully human monoclonal antibody of isotype IgG1 that targets PD-L1. It was evaluated in a phase Ib (Study ID#: NCT01772004) expansion study in 75 patients with recurrent/refractory OC which included OC-Pt . Of this cohort, 8 patients showed a partial response and 33 patients displayed stable disease, which was reported as a disease control rate of 54.7%.\n
One other phase Ib study (KEYNOTE-028/Study ID#: NCT02054806) evaluated the anti-tumor activity and safety of pembrolizumab (Keytruda) in patients with PD-L1 positive advanced OC which included patients refractory to platinum therapy . Pembrolizumab is a humanized antibody that binds to and blocks PD-1. PD-1 blockade with pembrolizumab was well tolerated and displayed anti-tumor activity. Of the 26 patients enrolled in the study, 1 achieved complete response, 2 partial response, and 6 had stable disease. The most common adverse events were fatigue (42.3%), anemia (30.8%), and decreased appetite (30.8%).\n
The role of the PD-1/PD-L1 axis is continuously been studied and characterized in OC and with new information on OC-Pt immunogenicity emerging consistently, this disease is expected to remain a focused target of PD-1/PD-L1 based therapeutics.\n
Inhibition of CTLA-4 during the T cell priming/activation step leads to dysregulated expansion of auto-reactive T cells, including tumor-specific T cells . The anti-CTLA 4 monoclonal antibody ipilimumab (Yervoy) has shown anti-tumor effect in stage IV OC. Ipilimumab is a recombinant human monoclonal antibody (IgG1 kappa immunoglobin) that antagonizes the CTLA-4 immune checkpoint. The administration of ipilimumab to 11 stage IV OC patients previously vaccinated with granulocyte-macrophage colony-stimulating factor (GM-CSF)-modified irradiated autologous tumor cells showed promising results . Ipilimumab caused a reduction or stabilization of CA-125 levels in these patients and no serious toxicities directly attributable to the antibody were observed.\n
Tremelimumab is a fully human IgG2 monoclonal antibody to CTLA-4. The combination of tremelimumab with the immunotherapeutic agent durvalumab is currently undergoing a phase I trial (Study ID#: NCT01975831) which includes OC-Pt patients . The primary endpoints of this study are to evaluate safety and identify the maximum tolerated dose of the combination. The secondary objectives are to determine effects on tumor response and PFS. Preliminary data show that the combination has a manageable safety profile, with evidence of clinical activity. Trials with anti-CTLA-4 inhibitors in other cancer types have been associated with significant immune-related toxicities , and this might be the major limitation in terms of advancing their application in OC-Pt. More clinical trials are needed in this area of OC-Pt therapeutics.\n
The aim of vaccinations in cancer patients is to sensitize the immune system to recognize, target, and eradicate tumor cells in an approach that employs both adaptive and innate immunity . Vaccines aim to provoke a tumor-specific immune response by increasing tumor-associated antigen (TAA) presentation by antigen-presenting cells (APCs) which subsequently generates tumor-antigen specific cytotoxic T lymphocytes .\n
Dendritic cell, peptide, and recombinant viral vaccines are the main types currently undergoing clinical trials for OC. One promising TAA for dendritic cell vaccines is mucin 1 (MUC-1). MUC-1 is a heavily glycosylated, type 1 transmembrane protein that is overexpressed in a large number of cancers including OCs . While multiple MUC-1 vaccines are now in development, CVac (developed by Prima BioMed) is the leading candidate for OC. In the CAN-003 phase II study, 63 confirmed Stage III or IV OC patients received CVac . While the study cohort did not disclose if the patient cohort included OC-Pts, CVac demonstrated positive trends in progression free survival and immune responses and further studies in OC-Pt patients are warranted.\n
A dendritic cell vaccine pulsed with autologous hypochlorous acid-oxidized OC lysate was also evaluated in a pilot study (Study ID#: NCT01132014) of five subjects with recurrent OC . Of the five patients who received the DC vaccine, two had PFS of 24 months or more.\n
Peptide vaccines rely primarily on the immunogenicity of the injected peptides to stimulate an immune response. In the cancer setting, the peptides chosen for the vaccine are TAAs.\n
A phase I trial of the NY-ESO-1 OLP vaccine showed promising results in advanced OC patients that initially received chemotherapy with at least one platinum-based chemotherapy regimen . NY-ESO-1 OLP contains synthetic overlapping long peptides (OLP) from the cancer-testis antigen NY-ESO-1 . The vaccine was found to be safe and rapidly induced consistent integrated immune responses in nearly all vaccinated patients. A phase I/IIb multi-center study was also conducted to evaluate the safety and immunogenicity of the anti-idiotypic antibody vaccine ACA125 in 119 patients with advanced ovarian carcinoma (including OC-Pt patients) . ACA125 functionally imitates the tumor antigen CA125. Preliminary evidence demonstrated safety and immunogenicity of the vaccine. The study data has not reveal conclusions regarding OC-Pt subgroups and this requires further evaluation.\n
Recombinant viral vaccines utilize genetically modified viruses as vectors for introducing TAA-encoding DNA into cells within the body. PANVAC is a vaccine with payload delivered through two viral vectors: recombinant vaccinia and recombinant fowlpox . The vectors contain transgenes for the tumor-associated antigens epithelial mucin 1 (MUC-1) and carcinoembryonic antigen (CEA). Overexpression of MUC-1 and CEA is seen in OC [87, 88]. In a pilot study of PANVAC in 14 OC patients (including OC-Pt), median time to progression was 2 months and median OS was 15.0 months .\n
Adoptive cell therapy (ACT) involves the infusion of tumor antigen cells to stimulate innate anti-tumor immunity and induce cancer regression . A pilot study in which seven patients with recurrent local OC were given multiple cycles of intraperitoneal infusions of autologous MUC1 peptide-stimulated cytotoxic T lymphocytes has been completed . Clinical benefit was seen in only one patient who was disease free >12 years. While it is difficult to interpret this information in the context of OC-Pt, the study is worth mentioning as at least one patient had received prior platinum therapy.\n
A phase I clinical trial of adoptive transfer of folate receptor-alpha-redirected autologous T cells for recurrent OC cancer was initiated to establish the safety and proof of concept of autologous FRα-redirected T cells administered intravenously, in subjects with recurrent stage II to IV FRα-positive epithelial ovarian carcinoma (including OC-Pt subgroups) . It is also possible that ACT can be used in combination strategies but the challenge with solid tumors such as OCs; is that tumor microenvironment immunity can cause immunosuppression and render ACT ineffective.\n
Toll-like receptors (TLRs) comprise a family of 13 receptors found on hematopoietic and nonhematopoietic cells . The TLR8 subtype is mainly found in monocytes and dendritic cells and it plays an important role in the immune response by recognizing single-stranded RNAs as its natural ligand. Motolimod (Motolid/formerly known as VTX2337) is a synthetic, small molecule, selective agonist of TLR8 that stimulates natural killer cell activity and enhances antibody-dependent cellular cytotoxicity . A phase II randomized, double-blind, placebo-controlled study (Study ID#: NCT01294293), evaluated chemo-immunotherapy combination using motolimod with PLD in recurrent or persistent OC . While the addition of motolimod to PLD did not significantly improve overall survival or PFS, the combination was well tolerated, with no synergistic or unexpected serious toxicity. Another phase II study is also now underway (Study ID#: NCT01666444) in patients with recurrent or persistent epithelial ovarian, fallopian tube, or primary peritoneal cancer. The purpose of this study is to compare the overall survival of patients treated with motolimod + PLD versus those treated with PLD alone in women with recurrent or persistent, epithelial ovarian, fallopian tube, or primary peritoneal cancer. This study will provide further insight on the future of motolimod in OC-Pt.\n
Over the past decade we have learned that OC in general responds poorly (11–25% overall) to single-agent immunotherapy; especially checkpoint blocking strategies . There is very limited data regarding response rates of OC-Pt subgroups specifically, but in most cases these cohorts of patients are integrated in general OC study data, suggesting similar patterns of response. When reviewed collectively, the data suggest that efficient anti-tumor immune response is likely to require combinatorial therapeutic strategies that simultaneously target different stages of tumor escape. Combinations involving immune checkpoint inhibitors, anti-angiogenic agents, and PARP inhibitors are gaining momentum in clinical OC-Pt research and are highlighted below.\n
Currently, several trials combining PARP and immune checkpoint inhibitors are ongoing . An open-label dose escalation study (Study ID#: NCT02485990) of tremelimumab alone or combined with olaparib for recurrent or persistent OC is currently recruiting participants. This study is aimed at determining what dose of tremelimumab and olaparib is safe and effective in patients with persistent OC including those with OC-Pt.\n
A phase I/II Study (Study ID#: NCT02484404) of durvalumab in combination with olaparib and/or cediranib for advanced solid tumors including OC-Pt is currently recruiting. The aim of the phase I arm is to determine the safety of the combination of durvalumab with olaparib or cediranib. Phase II studies will determine the efficacy of these combination in treating OC.\n
The TOPACIO trial (Study ID#: NCT02657889) will evaluate niraparib in combination with pembrolizumab in patients with triple-negative breast cancer or OC-Pt. The primary outcome measures are to determine dose-limiting toxicities of combination treatment with niraparib and pembrolizumab and to determine the objective response rate using RECISTv1.1.\n
The OCTOVA study (Study ID#: NCT03117933), is currently recruiting participants for a randomized phase II trial investigating the efficacy of chemotherapy plus olaparib and cediranib combination therapy in patients with BRCA-mutated OC-Pt. Patients will be randomized to one of three treatment groups: olaparib only, olaparib and cediranib, and the control group paclitaxel. The aim is to compare efficacy and tolerability of the three treatments.\n
A phase II study (Study ID#: NCT02659384) to evaluate the combination of atezolizumab plus bevacizumab and acetylsalicylic acid in recurrent OC-Pt is currently recruiting. The primary aim is to determine PFS at 6 months by RECIST.\n
The administration of ipilimumab in 11 patients with metastatic ovarian carcinoma after vaccination with irradiated autologous tumor cells engineered to secrete GM-CSF (GVAX), showed promising results . Three patients achieved stable disease as measured by CA-125 levels, and one patient achieved an objective response by radiographic criteria and maintained disease control over 4 years with regular infusions of anti-CTLA-4 antibody.\n
There are still many hurdles to overcome in the treatment of OC-Pt but some progress has been made in recent years, especially with the development of new immunotherapeutic agents. The good news is that OC cancer is a targetable tumor and although the OC-Pt subgroup of patients have biologically distinct tumors, both targeted therapies and immunotherapy offer an opportunity to uniquely address these differences. As new agents are developed in these categories, the main challenge with existing and future clinical trials will be the risk of adverse events and toxicities, especially with combination immunotherapeutic regimens, where there is an elevated risk for adverse immune events. A second challenge is the optimization of the dose and schedule of immunotherapeutic combinations in order to maximize the overall risk-benefit profile of a given combination. This requires multiple clinical trials with dose escalation studies that can be expensive. This approach is necessary however, especially in the setting of platinum-resistant OC cancer where much research is still needed.\n