HP measured 12 months after implantation, in relation to the therapy applied – the number and percent of patients.
\\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:{caption:"Highly Cited",originalUrl:"/media/original/117"}},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"}}]},chapter:{item:{type:"chapter",id:"77381",title:"Corticosteroids in Otorhinolaryngology",doi:"10.5772/intechopen.98636",slug:"corticosteroids-in-otorhinolaryngology",body:'Corticosteroids play an important role in the pharmacological treatment in different otorhinolaryngological disorders such as Sudden Sensorineural Hearing Loss (SSNHL), Meniere’s Disease (MD), Tinnitus and as a supportive treatment in the different ENT (ear-nose-throat) surgery procedures, including cochlear implantation (CI). The effectiveness of therapy of corticosteroids in otorhinolaryngology depends on many different factors. The main are: the duration of the therapy, occurrence or not of adverse reactions, especially in those patients with additional risk factors as comorbidities. A widely discussed challenge among ENT scientists is the optimal way of administration of corticosteroids – local or systemic – due to the different pharmacokinetic and pharmacodynamic properties of corticosteroids. One of these is the effective delivery way of a drug to its place of action, because of the presence of blood-labyrinth barrier (BLB) and the inaccessibility due to the inner ear.
From a pharmacokinetic point of view, the inner ear can be considered to be made up of multiple fluid compartments in hydrostatic balance (maintained by the blood-labyrinth barrier). The pharmacokinetic process is helpfully described by the acronym LADME (L – liberation; A – absorption; D – distribution; M – metabolism; E – elimination). The first step – liberation – means that the drug (or its carrier) must be water-soluble, so it can easily be carried in the blood [1].
The next pharmacokinetic step is absorption and depends on lipophilicity and the solubility of the drug [1]. Only a few drugs can be used effectively in otorhinolaryngological practice due to the difficulty of achieving sufficient concentrations in the inner ear [2]. Two groups of drugs are commonly used in clinical practice: aminoglycosides (mainly gentamicin) in the pharmacotherapy of Meniere’s disease, and corticosteroids (dexamethasone, triamcinolone) in pharmacotherapy for idiopathic sudden sensorineural hearing loss and other cases of acute hearing loss [3].
The distribution process depends on many different factors as a route of administration, mode of administration, single or repeated administration, dose, ionic composition, pH, and osmolarity. The elimination of a drug from the body (its clearance rate) depends on the same set of chemical and physical properties. A key factor here is the protein binding of the drug: the greater the protein binding of the drug, the longer its therapeutic activity. The finite binding between the protein and the drug molecule allows the drug to gradually liberate.
As far as, the inner ear drug delivery strategies are concerned, three routes of administration are possible: systemic (intravenous, oral), intratympanic, and intracochlear [4]. Systemic administration of glucocorticoids is reasonable due to pharmacological properties such as the lipophilic nature of glucocorticoids and vascularity of the middle ear mucosa [5]. Blood labyrinth barrier (BLB) and round window membrane (RWM) are two main challenges in delivering drugs to the inner ear. Blood labyrinth barrier is the most important barrier that separates the inner ear from systemic blood circulation and, as a result, maintains the microhomeostasis in the inner ear. This barrier protects also the integrity of the inner ear due to the presence of efflux pumps system such as MRP-1 (multidrug resistance-related protein-1) and P-glycoprotein. The tight junctions permit to penetrate only small lipid-soluble molecules. The concentration of corticoids in the perilymph increase when the osmotic agent (e.g. glycerol) is added. RWM is a soft tissue barrier which role is to separate the inner ear from the middle ear and it is permeable to low molecular weight molecules such as corticoids. Generally and despite the adverse effects, systemic delivery (oral, intravenous, intramuscular routes) is still considered as the most convenient method of drug administration and the first-line approach in the treatment of inner ear disorders [4]. Additionally, both oral and intravenous route of administration is complied with the characteristic of medical products used in this study.
The intratympanic route of administration may be performed via injection or perfusion to the middle ear. The drawbacks of intratympanic delivery of drug include such barriers as: anatomic barriers (RWM), loss of drug in the middle ear cavity through the Eustachian tube and the pharmacokinetic profile of administrated drugs is unknown or variable [6, 7]. As a result, the number and percentage of drugs that may enter the inner ear are relatively low.
The intracochlear route of drug delivery can bypass the middle ear and allows drug to get the direct place of action. Although this strategy seems to be more risky in terms of deafness, according to the observations of surgical procedures which include perforation and significant manipulations [8]. Currently, there is no available safe and effective technique for intracochlear drug administration not only in terms of medical device but also in terms of appropriate drug formulation [4].
In the summary, the inner ear is a very subtle and complicated organ from anatomical and physiological point of view. Hearing loss may be one of the most dangerous and severe adverse effects in the inner ear caused by novel drug delivery systems. All routes of drug administration should be carefully examined and considered.
In a study published in 2018, Plontke, Götze, Rahne & Liebau compared the effects of dexamethasone with saline (in a guinea pig model). Both substances were administrated intravenously 60 minutes before implantation. The conclusion was that dexamethasone could reduce scarring in the hook region or near the electrode tip, but they did not see any relation between dexamethasone and reduction of fibrosis relating to cochleostomy. At the same time, in vitro studies have shown a correlation between reduction (loss) of auditory cells after exposure to tumor necrosis factor-alpha and dexamethasone-releasing polymer (used to coat the CI electrode carrier) [9, 10, 11, 12].
Cochlear implantation is a golden standard for patients who suffer from severe to profound hearing loss. The preservation of hearing in patients who underwent cochlear implantation depends, in the first place, on surgical technique, and in the second place, on the selecting of the appropriate electrode. The pharmacological treatment, such as administration of corticosteroids in different periods of cochlear implantation, is the third important factor [6, 7]. Insertion of the frequency-specific electrode array into the cochlea is a delicate operation and requires a very careful surgical technique. Even with the utmost care, however, it is difficult not to cause some tissue damage, especially in cases of partial deafness where there are still some partially functioning hair cells. In this situation, the use of corticosteroids (local or systemic) is important: these drugs can reduce oxidative stress, inflammatory reaction, and the apoptosis of hair cells due to insertion damage. A major challenge in effectively delivering pharmacological agents to the cochlea is its physical inaccessibility and the presence of a blood-labyrinth barrier. These factors are especially apt for patients suffering partial deafness, where the hair cells at the apex of the cochlea (responsible for receiving low frequencies) are anatomically remote.
Symptoms of Meniere\'s disease are defined as recurring episodes of spontaneous, usually rotational vertigo, sensorineural hearing loss, tinnitus, and a feeling of fullness or pressure in the affected ear for up to decades. The disease can be unilateral or bilateral. The diagnosis of the disease is made based on the symptoms present, however, it is sometimes difficult to make, because the diagnosis should exclude other diseases that exhibit symptoms similar to Meniere\'s disease, such as dizziness of other origins, occurring independently with hearing loss and tinnitus, and may react differently to treatment (e.g. mild positional vertigo, acute labyrinthitis, migraine) and to hearing neuronal. The disease most often affects adults between the ages of 30 and 60. It is estimated to affect 50-200/100,000 cases annually in Europe [13].
Meniere’s disease is associated with anatomical changes in the inner ear: the so-called endolymphatic swellings. The volume of the endolymph, which fills the endolymphatic labyrinth, increases while the volume of the perilymph, which surrounds the endolymphatic labyrinth and fills the bony labyrinth, decreases. However, swelling occurs in many other conditions associated with hearing loss and there is no known cause of this condition. Specific disorders associated with swelling (such as temporal bone fracture, syphilis, end-stage otosclerosis, and auditory nerve neuroma) may produce symptoms similar to those of Meniere\'s disease. Meniere\'s disease initially progresses but changes unpredictably. It is difficult to distinguish natural resolution from treatment effects, as dizziness resolves in 57% of patients after 2 years and 71% after 8 years with the disease [13, 14].
The primary goal of pharmacotherapy is to reduce the frequency, duration, and severity of vertigo attacks. The secondary goals are to stop the progression of hearing loss and to reduce the occurrence of tinnitus. Unfortunately, no medication can currently slow or stop the progression of hearing loss or stop tinnitus.
The use of corticosteroids (CS) in the treatment of MD has been implicated because of the presence of autoimmune disorders in the course of the disease, and the role of the innate immune system and inflammation in the pathophysiology of MD. Studies have revealed the presence of glucocorticoid receptors in the inner ear. The action of corticosteroids in the course of MD is based on their anti-inflammatory and immunosuppressive effects, as well as regulation of inner ear homeostasis [15, 16, 17]. The treatment of MD includes the use of oral dexamethasone or methylprednisolone to reduce vomiting and vestibular symptoms, particularly in cases of marked hearing loss, but there are no RCTs showing any long-term benefit of steroids in MD [16]. When administered by intratympanic injection, CS achieve higher concentrations in the inner ear compared to systemic administration, with fewer systemic side effects [16, 18]. Substances administered intratympanically include dexamethasone and methylprednisolone, one that triamcinolone is also a therapeutic option. Studies have shown that methylprednisolone gives higher concentrations in the endolymph and perilymph than dexamethasone, but the latter drug may be more effective because it is more rapidly absorbed by endocytosis into the vascular striatum and surrounding tissues, where it acts intracellularly [19, 20]. Several retrospective/prospective control placebo or non-control studies have assessed intratympanic administration of CS, with varying remission results [14, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31]. An RCT study by Garduño-Anaya et al. showed that inner ear perfusion with dexamethasone (4 mg/ml) in a group of patients with unilateral Meniere\'s disease, demonstrated 82% complete control of vertigo compared to placebo (57%) [25]. In a subsequent study using an extended-release form of intrathecally administered dexamethasone, the form was shown to reduce the number of definitive days with dizziness, the severity of dizziness, and the mean daily number of dizziness compared with placebo at month 3 after drug administration [32, 33]. The systematic review combined these two RCTs with the Garduño-Anaya study with a total of 220 patients. The authors of this new review conclude that there is still no solid confirmation that ITC has a positive effect in MD [16, 34]. Although the results of some studies support the conclusion that high-dose steroid is effective in treating MD, the optimal treatment protocol has not yet been properly established. In addition, the development of an appropriate protocol to confirm the unequivocal efficacy of CS in MD is difficult because there is considerable variability in patients\' symptoms and over time, as well as a group of patients in the population who do not respond to CS treatment [14, 35, 36].
Sudden sensorineural hearing loss (SSNHL) is a syndrome that develops rapidly, with hearing loss progressing over 72 hours, hearing loss observed by at least 30 dB at 3 consecutive frequencies on tonal audiometry. It is considered an otologic emergency requiring immediate diagnosis and treatment. The disease can occur at any age; however, it most commonly affects patients 65 years of age or older. The annual incidence of SSNHL is 5-27 per 100,000. According to clinical guidelines for the treatment of SSNHL, systemic CS is recommended as initial therapy and intratympanic CS is recommended as salvage therapy, but the latter is increasingly used as first-line therapy. In addition, pharmacotherapeutic models combining both routes of administration are appropriate [37]. Because of the risk of catastrophic consequences of permanent severe hearing loss, administration of CS should be done as soon as possible, allowing the greatest improvement to be seen within the first two weeks, but continuing therapy for an additional 6 weeks. The mechanism of action of CS is still uncertain, but its effect is possible due to its ability to reduce inflammation and swelling [38]. Treatment uses a 7-14 day series of oral high doses of prednisone — (1 mg/kg/d max. 60 mg/d), methylprednisolone — 48 mg/d or dexamethasone at 10 mg/d, despite possible side effects [39]. Treatment by intratympanic injection has efficacy equivalent to systemic administration with the benefit of reducing the proportion of adverse reactions occurring after systemic administration as well as when oral administration is not possible or contraindicated [40, 41, 42, 43, 44, 45, 46]. In addition, Crane et al. also looked at the efficacy of intratympanically administered steroids against intratympanically administered steroids as initial therapy and showed no overall superiority of intratympanically administered steroids over systemic steroids, with the single exception of the Battaglia et al. study, which showed an advantage of using intratympanically administered CS without or in combination with systemic versus using systemic CS alone [39, 47, 48]. The frequency of IT steroid administration also varies widely in different studies, and may be self-administered by the patient through a pressure equalization tube several times a day to physician administration from once a day to once a week or less frequently. Intratympanic treatments include: Dexamethasone (DEX) at a dose of 1.5-2 mg, Methylprednisolone at a dose of 25-40 mg or Triamcinolone Acetonide at a dose of 40 mg [39, 49]. Alexander et al. in their retrospective study comparing the response to two different doses of DEX demonstrated that in patients receiving DEX the preferred unit dose of 24 mg/mL dexamethasone in a series of three doses over a 1-3 week period in a variable dose from 0.5-1 mL dependent on anatomical [50]. Given the available literature, corticosteroids may not be used to treat SSNHL in every case. However, for a patient with severe to profound SSNHL, corticosteroid treatment is one of the few treatment options for which there are any data indicating efficacy, although even these data are somewhat inconclusive.
Tinnitus is the perception of sound without an external stimulus. This symptom can occur alone or with other disorders such as hearing loss. Subjective tinnitus is the most common form of tinnitus, and globally, it can be detected in almost 10% of the general population, and approximately 20% of adults with tinnitus require clinical intervention. The most common site of subjective tinnitus is the cochlea, but other auditory pathways may also be responsible. Tinnitus can occur on one or both sides of the head and can be perceived as coming from inside the head or from outside the head, and is most common with coexisting sensorineural hearing loss. The presence of tinnitus has been shown to affect a patient\'s quality of life (QOL) in a variety of ways, ranging from a mild deterioration in QOL to severe anxiety, depression, and extreme life-altering events, including the presence of active suicidal thoughts. Many different treatments for tinnitus have been described, including: tinnitus correction, tinnitus masking, biofeedback therapy, and various pharmacological treatments; however, these treatments have limited effectiveness. The most common pharmacological treatments include intratympanic administration of aminoglycoside antibiotics and steroids. CS are used in the treatment of tinnitus due to their anti-inflammatory and electrolyte-modifying effects. According to the available literature, the therapeutic effect of drugs administered intratympanically occurs by diffusion through the round window, the annular ligament of the oval window, the capillaries, or through the lymphatic system of the inner ear. However, the effectiveness of intratympanic therapy in the treatment of tinnitus remains limited [51, 52]. The American Academy of Otolaryngology guidelines provide detailed patient management criteria and outline pharmacologic treatment options for patients with varying levels of confidence and recommendations. These recommendations address the treatment of tinnitus with intratympanic steroid injection and present models of pharmacotherapy using dexamethasone or methylprednisolone with or without concomitant therapy. Based on the RCTs cited in the guideline, steroids are not recommended for the treatment of vertigo because no treatment has shown a better response compared to placebo [51, 53, 54, 55, 56]. However, the scientific literature reports positive effects of steroid treatment of tinnitus, indicating that there is still a need for a broad investigation of the contribution of steroids to the treatment of tinnitus. In a study by Yaner et al. a statistically significant parameter score was obtained indicating positive treatment effects with intratympanic dexamethasone versus placebo [52]. Subsequently, a study by Shim et al. indicates the positivity of intratympanic injection of dexamethasone as an adjunctive treatment for tinnitus in patients treated with alprazolam [57]. The positive aspects of adding a steroid to therapy were confirmed by Albu and Chirtes, in their RCT. The addition of dexamethasone to melatonin therapy had a statistically significant effect on reducing tinnitus compared to melatonin alone [58]. Most articles on the subject conclude that intratympanic steroid injections are effective mostly in patients with acute tinnitus and mostly show no effect in those with chronic tinnitus [52, 59]. The studies presented here primarily utilize dexamethasone as the drug administered to the patient; however, it is not the only substance used. The literature reports that intratympanic administration of methylprednisolone has also been studied; however, data detailing the effectiveness of each substance in the treatment of tinnitus remains scarce. Only She et al. in their study compared the efficacy of two types of steroids together with oral carbamazepine, where they found no statistically significant differences indicating the benefit of using individual substances [55]. In opposition to these results indicating an effect of methylprednisolone, is a study by Topak et al. who in their placebo-controlled RCT showed that the steroid had no benefit in the treatment of subjective tinnitus of cochlear origin refractory to treatment [56]. For the treatment of tinnitus, the effect of subcutaneously administered triamcinolone acetonide was analyzed in an RCT by Diao et al. However, it has no obvious benefit over placebo for subjective tinnitus [60]. The use of steroids in the treatment of tinnitus is widespread, as illustrated by the multitude of studies that have been conducted, but there is still a need for strong evidence to support or exclude their use in the treatment of subjective tinnitus.
The main aim of the present study was to compare the hearing preservation levels of partial deafness patients following cochlear implant surgery when two different procedures for administrating dexamethasone (or dexamethasone and prednisone) were used with different cochlear implants. Patients enrolled in the study suffered severe to profound hearing loss and were classified according to the Skarżyński Partial Deafness Treatment (PDT) classification scheme [61] into two groups: PDT-EC (Partial Deafness Treatment – Electrical Stimulation)or PDT-EAS (Partial Deafness Treatment – Electro-Acoustic Stimulation) (Figure 1).
Partial deafness treatment groups for cochlear implantation. ENS – Electro-natural stimulation; EC – Electrical complement; EAS – Electrical-acoustic stimulation; ES – Electrical stimulation.
The inclusion and exclusion criteria were in accordance with the consensus of the international HEARRING group on hearing preservation in cochlear implantation. Study eligibility criteria were participants ≥18 years of age with a cochlear duct ≥27.1 mm (measured by computerized tomography), with:
hearing levels in the range of 10-120 dB HL at frequencies of 125–250 Hz;
hearing levels of 35–120 dB HL at frequencies of 500–1,000 Hz;
hearing levels of 75–120 dB HL at frequencies of 2,000–8,000 Hz.
Exclusion criteria included suffering from a severe disease for which steroid treatment could worsen the patient’s condition or where might be possible interactions between the patient’s medications and steroids. Non-parametric tests were used due to differences in the number of participants between subgroups, the small number of participants in the study, and the violation of normal distribution of pure tone audiometry results [62].
Patients who were enrolled in this prospective study were divided into 3 subgroups. Patients from the first subgroup underwent intravenous (IV) steroid therapy (Figure 2). For patients in the first subgroup, dexamethasone was administrated intravenously (0.1 mg per kg of body mass) 30 minutes before the cochlear implant surgery. The same dose was administered every 12 hours for 3 consecutive days (6 doses). The dexamethasone used in this study was supplied in ampoules of a 2 mL solution (4 mg/mL). Before injection, the sterile contents of the ampoule were diluted with isotonic sodium chloride solution. To standardize corticosteroid delivery, the IV route of administration was chosen.
Scheme of steroid administration in the first subgroup of patients.
Patients from the second subgroup underwent combined oral and IV corticosteroid therapy (prolonged steroid therapy) following cochlear implantation (Figure 3). Prednisone was administrated orally at a dose of 1 mg per kg of body mass 3 days before surgery. Then 30 minutes before the implantation surgery, dexamethasone at a dose of 0.1 mg per kg of body mass was administered IV (as with the first group). During the next 3 days, prednisone was administrated orally (1 mg of prednisone per kg body mass). After this time, the dose was reduced by about 10 mg per day until it reached zero. To investigate the effects of prolonged steroid administration, we chose to compare the IV and oral administration routes.
Scheme of administration of steroids in the second subgroup of patients.
The third subgroup was a control group. Patients enrolled in this group underwent a standard cochlear implantation procedure without steroid treatment.
The primary outcome variables were mean hearing thresholds averaged across all 11 measured frequencies (0.125–8 kHz). A secondary outcome variable was hearing preservation (HP). HP was calculated by comparing hearing thresholds in the 1-year postoperative period with preoperative hearing thresholds according to the HP formula in section 3.3 and classified into one of three levels: minimal, partial, or complete hearing preservation.
The clinical effect of administered substances was evaluated by pure tone audiometry over six different periods: before cochlear implant surgery (first point), at the activation of the audio processor (second point), and 1 (third point), 6 (fourth point), 9 (fifth point), and 12 months (sixth point) after activation of the audio processor. There were three different periods in Medel and Oticon implants: the preoperatively period (the first point), at the activation of the audio processor (the second point), and 12 months after activation of the audio processor (the third point). Non-parametric tests were used due to the differences in size between each of the groups. Statistical analysis was performed using IBM SPSS software v.24.0.
The mean hearing preservation rate (HP) was 52.1% (SD = 36.7) in patients with standard steroid therapy, 71.4% (SD = 22.7) in patients with prolonged steroid therapy, and 22.1% (SD = 33.9) in the control group. The smallest variation in hearing preservation rate was observed in patients with prolonged steroid therapy.
Data concerning hearing preservation converted to three categories (minimal, partial, complete). HP is defined as follows (Figure 4).
Hearing preservation formula.
In this equation, PTApre is the pure tone average measured preoperatively, PTApostis the pure tone average measured postoperatively, and PTAmax is the maximum sound intensity generated by a standard audiometer (usually 120 dB HL) and HP is the degree of hearing preservation as a percentage [63].
Preoperatively, there were no statistically significant differences in hearing thresholds between patients in each of the three subgroups, including the control group, which means that all study participants had similar hearing levels in the preoperative period.
Deterioration of mean hearing thresholds in pure-tone audiometry (PTA) was observed from the first follow-up interval, which is at the time of sound processor activation. Statistically significant differences were observed between the second sub-group (combined steroid treatment: prednisone + dexamethasone) and the control group: patients in the second study subgroup have obtained better PTA results in low frequencies than the control group. A similar observation was made in the measurements performed at 1, 6, 9, and 12 months after activation of the sound processor – patients who underwent the combined (prolonged) glucocorticoid treatment had more stable hearing thresholds in all follow-up periods (Figures 5–8).
Average hearing thresholds in patients from the first subgroup with standard steroid treatment in the preoperative period, upon activation, at 1, 6, 9, and 12 months after CI.
Average hearing thresholds in patients from the second subgroup with combined steroid treatment in the preoperative period, upon activation, at 1, 6, 9, and 12 months after CI.
Average hearing thresholds in patients from the third subgroup (control) with standard steroid treatment in the preoperative period, upon activation, at 1, 6, 9, and 12 months after CI.
Average hearing thresholds in patients with standard steroid treatment (group 1), patients with prolonged steroid treatment (group 2), and control (group 3) in the preoperative period, upon activation, at 1, 6, 9, and 12 months after CI.
The rate of hearing preservation was calculated following the formula based on the PTA measurements performed 12 months after implant activation and preoperatively. The results were then divided into three groups according to the HP classification: minimal HP, partial HP, and complete HP. The smallest variability of results and the highest overall hearing preservation rate (38%) was observed in the second subgroup. All patients from the second subgroup (prolonged steroid treatment) and almost 69% of patients from the first subgroup had partially or fully preserved hearing. The majority of patients from the control group had minimal HP at 70.6% (see Table 1 and Figure 9).
Minimal HP (0–25%) | Partial HP (26%–75%) | Complete HP (75%-100%) | |
---|---|---|---|
Subgroup 1 | 5 (31.2%) | 7 (43.8%) | 4 (25.0%) |
Subgroup 2 | 0 (0.0%) | 8 (61.5%) | 5 (38.5%) |
Control Group | 12 (70.6%) | 3 (17.6%) | 2 (11.8%) |
HP measured 12 months after implantation, in relation to the therapy applied – the number and percent of patients.
Hearing preservation rate (HP) in three subgroups.
The role of glicocorticosteroids in the treatment of ENT diseases is very important. According to the results of this study have clearly shown the effect of steroids (dexamethasone and dexamethasone/prednisone) in stabilizing mean hearing thresholds in both experimental subgroups in comparison with the control subgroup during CI. In the preoperative period, the hearing thresholds of participants in all three subgroups were statistically indistinguishable. During the cochlear implantation, the appropriate scheme of pharmacology (corticosteroids) next to the surgical technique and the technology of cochlear implants are key in the cochlear implantation. The corticosteroids play an important role in the pharmacological treatment in different otorhinolaryngological disorders such as Sudden Sensorineural Hearing Loss (SSNHL), Meniere’s Disease (MD), Tinnitus and as a supportive treatment in the different ENT (ear-nose-throat) surgery procedures, including cochlear implantation (CI). The effectiveness of therapy of corticosteroids in otorhinolaryngology depends on many different factors. The main are: the duration of the therapy, occurrence or not of adverse reactions, especially in those patients with additional risk factors as comorbidities.
The authors declare no conflict of interest.
MD | Meniere’s Disease |
SSNHL | Sudden Sensorineural Hearing Loss |
ENT | Ear-Nose-Throat |
BLB | Blood-Labyrinth-Barrier |
CI | Cochlear Implantation |
CS | Corticosteroids |
LADME | L – liberation; A – absorption; D – distribution; M – metabolism; E – elimination |
RWM | Round Window Membrane |
DEX | Dexamethasone |
QOL | Quality of Life |
RCT | Randomized Clinical Trial(s) |
PDT | Partial Deafness Treatment |
PDT–EC | Partial Deafness Treatment – Electrical Stimulation |
PDT–EAS | Partial Deafness Treatment – Electro-Acoustic Stimulation |
Liver was always considered to be ‘highly sensitive’ to radiation therapy and was not considered ‘safe’ for radiation therapy treatment. For many years, maximal tolerable dose (mean liver dose) for liver was considered to be low and radiation dose required for therapeutic effect for liver tumors (Hepatocellular carcinoma, Cholangiocarcinoma) was considered high. Hence, radiation therapy was mostly not considered for liver tumors. Liver is a moving organ and movement of liver is dependent on many factors such as breathing pattern, stomach filling, peristaltic movements, and hence liver movement is not predictable. There were no appropriate tracking technology or high dose radiation delivery technology in ‘moving’ targets like liver. Hence, in early years of radiation therapy there are only a few anecdotal reports of radiation therapy delivery in liver tumors. In recent years, with advent of motion management system and technology to deliver high dose of radiation therapy that has increased the usage and literature about radiation therapy in liver tumors regarding both response to treatment and toxicities. In liver tumors, radiation therapy is mostly recommended in hepatocellular carcinoma (HCC), intra-hepatic cholangiocarcinoma and liver metastasis.
The most significant radiation induced liver toxicity was described by Ingold et al. as “Radiation hepatitis” [1]. Historically, radiation to liver lesions with curative intent or incidental exposure during adjacent organ treatment or total body irradiation implied whole organ irradiation due to lack of high precision technology. This kind of whole organ irradiation led to a classic clinical picture which was then termed as “RILD.” In 1966, Reed et al. have worked on pathology of radiation injury to liver and have established that the early changes are obliteration of small vasculature followed by secondary effects such as hyperemia and cell loss. They have also concluded that there is effective re-establishment of hepatic vasculature and return of normal hepatic structure with time [2]. Liver consists of hepatocytes connected as parallel structures and hence liver is considered a ‘parallel’ structure. This means, even if a small portion of liver is damaged, other part of the liver will work as ‘parallel’ structure and there will be no functional damage. If a large portion of liver is damaged and hence the ‘parallel’ architecture is affected then there will be disruption of function. This means, mean dose to liver is critical, whereas maximum dose or small high dose to liver may not have clinical relevance. In conventional fractionation, the whole liver could be treated only to the doses of 30–35Gy safely which serves only the purpose of palliation rather than cure. This aspect had set radiation aside of the curative liver therapy for many decades. With the advent of technological advancements like IMRT, especially SBRT, the notion of highly precise and accurate treatment has been made practically possible. This enabled focusing high doses of radiation to the tumor, sparing the normal liver thus bringing back the option of radiation for liver lesions into light once again. With the use of these, a significant portion of liver could be saved from high doses of radiation. The toxicity profile for this kind of focused radiation was certainly different from that of whole organ irradiation. There have been attempts made to characterize the effects caused by the high precision radiation. Thus the QUANTEC liver paper distinguished RILD to ‘classic’ and ‘non-classic’ types [3].
Defined as ‘anicteric hepatomegaly and ascites’, also can also have elevated alkaline phosphatase (more than twice the upper limit of normal or baseline value).
This is the type of clinical picture encountered following irradiation of whole or greater part of the organ. As explained by Reed and Cox [2], this is related to the hepatic vascular changes leading to hepatic parenchymal necrosis. Although it takes time, this phenomenon is seen to be reversible in most of the cases. But the repair of hepatic structure is dependent on the baseline liver status. The incidence described in the 2000s was 5–10% if mean liver dose constraint of 30–35 Gy was met.
Defined by elevated liver transaminases more than five times the upper limit of normal or a decline in liver function (measured by a worsening of Child-Pugh score by 2 or more), in the absence of classic RILD. In patients with baseline values more than five times the upper limit of normal, CTCAE Grade 4 levels within 3 months after completion of RT.
This is the type of RILD that is encountered typically after high dose radiation to a smaller part of liver. It is commonly associated with infective etiology. Although the exact pathogenesis is un-clear, it involves loss of regenerating hepatocytes. This is usually not irreversible.
The characteristics of them are summarized in Table 1.
Classic RILD | Non-classic RILD | |
---|---|---|
Time to presentation post Rx | 2 weeks to 3 months | 1 week to 3 months |
Prone candidates | Otherwise fairly well-functioning pre-treatment liver | Common in those with poor liver function (hepatitis B infection, Child-Pugh Classes B and C) |
Patho-physiology | There is occlusion and obliteration of the central veins of the hepatic lobules, retrograde congestion, and secondary hepatocyte necrosis | Un-clear but involves loss of regenerating hepatocytes and reactivation of hepatitis |
Jaundice | − | ++ |
Ascites | +++ | + |
Laboratory findings | ||
Increased Bilirubin | + | +++ |
Increased AST | 2 times ULN | 5 times ULN |
Increased ALP | +++ | + |
Differences between classic and non-classic RILD.
Common Terminology Criteria for Adverse Events (CTCAE) version 5 has graded various symptoms like hepatic pain, hepatic necrosis, hepatic hemorrhage distinctly. Hepatic failure is defined as a disorder characterized by the inability of the liver to metabolize chemicals in the body. Asterixis, mild encephalopathy is grade 3 whereas moderate to severe encephalopathy and coma is grade 4 and death is grade 5 (Table 2).
CTCAE term | Grade 1 | Grade 2 | Grade 3 | Grade 4 |
---|---|---|---|---|
Hepatic pain (Sensation of marked discomfort in the liver region) | Mild pain | Moderate pain; limiting instrumental ADL | Severe pain; limiting self-care ADL | — |
Hepatic hemorrhage (Bleeding from liver) | Mild symptoms; intervention not indicated | Moderate symptoms; intervention indicated | Transfusion indicated; invasive intervention indicated; hospitalization | Life-threatening consequences; urgent intervention indicated |
Hepatic necrosis (A disorder characterized by a necrotic process occurring in the hepatic parenchyma) | — | — | — | Life-threatening consequences; urgent invasive intervention indicated |
Hepatic failure (A disorder characterized by the inability of the liver to metabolize chemicals in the body) | — | — | Asterixis, mild encephalopathy; drug induced liver injury; limiting ADL | Life-threatening consequences; moderate to severe encephalopathy; coma |
Sinusoidal obstruction syndrome (A disorder characterized by severe hepatic injury as a result of the blood vessels of the liver becoming inflamed and/or blocked) | — | Blood bilirubin 2–5 mg/dL; minor interventions required (i.e., blood product, diuretic, oxygen) | Blood bilirubin >5 mg/dL; coagulation modifier indicated (e.g., defibrotide); reversal of flow on ultrasound | Life-threatening consequences (e.g., ventilatory support, dialysis, plasmapheresis, peritoneal drainage) |
CTCAE Grading of liver toxicity.
Taking into account the wider applicability in cancer treatment, the CTCAE toxicity grading is non-specific to radiation induced toxicity. It does not take into consideration the performance status of the patient, baseline liver function and the relative changes in liver function caused by radiation, which is more clinically relevant and a predictor of reversibility of the RILD.
The Radiation Therapy Oncology Group (RTOG) liver toxicity grading includes nausea, dyspepsia as grade 1, abnormal liver function tests with normal serum albumin as grade 2, disabling hepatic insufficiency with low albumin, edema, ascites as grade 3 and necrosis, encephalopathy, hepatic coma as grade 4, death as grade 5 (Table 3) [4].
Grade 0 | Grade 1 | Grade 2 | Grade 3 | Grade 4 | Grade 5 | |
---|---|---|---|---|---|---|
Liver toxicity | None | Mild lassitude; nausea, dyspepsia; slightly abnormal liver function | Moderate symptoms; some abnormal liver function tests; serum albumin normal | Disabling hepatitic insufficiency; liver function tests grossly abnormal; low albumin; edema or ascites | Necrosis/Hepatic coma or encephalopathy | Death directly related to radiation induced late effects |
RTOG/EORTC late morbidity grading.
The drawback of this grading system is again the lack of specificity in scoring of liver function tests.
RILD can be an acute or sub-acute phenomenon. It typically occurs 4–8 weeks, but can occur 7–90 days post radiation [5]. Rarely, it is seen to occur as late as 7 months. Though there has not been much variation in time to presentation between classic and non-classic RILD, classic tends to occur earlier. The clinical manifestations of RILD are non-specific but patients typically present with symptoms like fatigue, weight gain, increased abdominal girth, rarely abdominal pain. There can be signs of hepatomegaly, ascites, altered liver function, elevated alkaline phosphatase disproportionate to other liver enzymes. In case of non-classic RILD, there can be jaundice and marked elevation of liver enzymes. RILD is essentially a diagnosis of exclusion. Radiologic sequel is seen as sharply demarcated low attenuation areas on CT. In case of steatotactic liver background, there can be areas of elevated attenuation. MRI can show areas of increased T2 signal keeping in with acute inflammation [6].
Various empiric end points have been used to describe RILD, which include deterioration in Child Pugh score and RTOG/CTCAE grade 2–4 abnormal laboratory values. One such end point evaluated is Child Pugh (CP) score declining by 2 or more scores. Chapman et al. tried to define clinically relevant endpoints in cirrhotic patients post SBRT or proton beam therapy. In the retrospective review of 48 patients, multivariate analysis showed that Child Pugh Score increase of ≥1 or ≥ 2, CTCAE AST toxicity grade change were the strongest predictors of OS and RILD specific survival also [7]. This has been confirmed by other studies also. In a prospective study evaluating Child Pugh score as a tool for assessment of acute toxicity of liver SBRT, 94 patients were analyzed and 15% had RILD. In CP score assessment at 2 month follow up, 46 (38%) had no change in CP score. Decline of 1-, 2- & 3-point CP score from baseline was in 17%, 10%, 14%. Improvement in CP score of 1- & 2- point from baseline was in 9% and 1% respectively. CP score change after SBRT correlated with the post RT acute toxicities in the study and hence CP score change was considered as an objective scoring system to evaluate the radiation induced liver injury after SBRT treatment [8].
Other parameters include Model for End-stage Liver Disease (MELD) score, CLIP score, GRETCH score, albumin-bilirubin (ALBI) score, PIVKA, AFP grade (Figure 1).
Time frame of different scoring system.
The MELD score is a chronic liver disease severity scoring system that is calculated from serum bilirubin, creatinine and INR, but modified to include serum sodium concentration (MELD-Na) [9]. It was originally developed to predict three-month mortality following transjugular intrahepatic portosystemic shunt (TIPS) placement. It is frequently used for patients being evaluated for transplant.
The CLIP score includes Child-Pugh stage, tumor morphology and extension, serum alfa-fetoprotein (AFP) levels, and portal vein thrombosis [10]. It takes into account both liver function and tumor characteristics and has been validated for HCC staging in relation to Okuda staging of HCC. But as a parameter for radiation induced liver toxicity, it is yet to be validated (Table 4).
0 | 1 | 2 | |
---|---|---|---|
Child Pugh stage | A | B | C |
Tumor morphology | Unimodular & extension <50% | Multinodular & extension <50% | Massive or extension >50% |
AFP | <400 | >400 | |
Portal vein thrombosis | − | + |
CLIP scoring system.
ALBI score is a discriminatory method of assessing liver function in HCC with values of only albumin and bilirubin [11]. Validation of ALBI score as a tool in radiation toxicity assessment is undecided, but retrospective evidence indicates similar performance as with the CP score [12].
The Groupe d’Etude et de Traitement du Carcinome Hépatocellulaire (GRETCH) score uses objective measures including bilirubin, alkaline phosphatase, AFP along with performance status and portal obstruction to predict survival outcomes. This prognostic system did not prove superior to other currently utilized scoring system and is not widely used world over [13] (Table 5).
Weight | 0 | 1 | 2 | 3 |
---|---|---|---|---|
Karnofsky index | >80 | <80 | ||
Serum Bilirubin (umol/L) | <50 | >50 | ||
Serum ALP | <2x ULN | >2x ULN | ||
Serum AFP (ug/L) | <35 | >35 | ||
Portal obstruction | − | + |
GRETCH Scoring system.
AFP is a well-established tumor marker for diagnosis of HCC that is detected in approximately 39–65% of HCC patients. AFP level normalization in a previously elevated patient within 3 months after SBRT is a prognostic surrogate for OS and PFS in patients with small HCC [14]. It is also useful in follow up of patients to detect early recurrence because the AFP level is related to the tumor activity. AFP stage for each prognostic group show clear survival differences (P < 0.0001), similar to the BCLC classification. However, survival differences among patient populations assigned to AFP stage B and C are not significant. In non-cirrhotic patients, the AFP staging system has a lower p-value than the BCLC classification.
Protein induced by vitamin K absence-II (PIVKA-II) is a potential screening marker for HCC and is an upcoming diagnostic tool that complements AFP [15]. Its role as a prognostic or predictive marker is yet to be determined.
Hepatocytes are involved in the synthesis of most coagulation factors, such as fibrinogen, prothrombin, factor V, VII, IX, X, XI, XII, as well as protein C, S, and antithrombin, whereas liver sinusoidal endothelial cells produce factor VIII and von Willebrand factor. Acute liver injury primarily decreases the vitamin K-dependent factors - prothrombin; factors VII, IX, and X.
All these staging and scoring system have their own merits and demerits. Unfortunately, none of these scoring systems are validated in multiple prospective series. Hence, these systems are followed as per institutional preferences (Figure 2 and Table 6).
Overlapping between different scoring systems.
Okuda | CLIP | GRETCH | |
---|---|---|---|
Child Pugh score | X | ||
Ascitis | X | ||
Albumin | X | ||
Total bilirubin | X | X | |
Alkaline phosphatase | X | ||
Alpha fetoprotein | X | X | |
Tumor size | X | X | |
Numbers of nodules | X | ||
Portal vein thrombosis | X | X | |
Presence symptoms | X |
Comparison between different scoring systems.
Liver is a fairly radio-sensitive organ. This has been evident from the pain control rates of 73–83% have been reported after RT for HCC [16, 17]. In the 1991 Emami report, the liver tolerance doses or TD 5/5 (dose expected to result in 5% complication rate in 5 years) were set as 50 Gy for one-third of the liver, 35 Gy for two-thirds of the liver, and 30 Gy for the whole liver [18]. Nevertheless, the primary liver tumors have not been irradiated with curative intent for a long period of time attributed to the conventional radiation portals practically including the whole organ.
With the advent of SBRT, very high doses can be delivered focally to the tumor, which are known to result in vascular injury and also an ablative effect on the tumor, in addition to the conventional DNA damage through dsDNA breaks. On the other hand, when these high doses of RT are being planned, one has to be extremely cautious regarding the precision and accuracy of the treatment. To account for inter and intra-fraction errors, various modalities like 4D CT, abdominal compression, voluntary breath hold, active breathing control and image-guidance during RT delivery can be used. The potential for tumoricidal doses to be delivered to focal HCC was first described by Dawson et al. at the University of Michigan by using an individualized dose allocation approach based on a normal tissue control probability (NTCP) calculation in 203 patients [19].
The Lyman–Kutcher–Burman (LKB)-NTCP model was used to assess dose-volume risk of RILD. The Lyman model assumes a sigmoid relationship between a dose of uniform radiation given to a volume of an organ and the chance of a complication occurring.
Various parameters have been looked into:
Effective volume (Veff): to allow volume-dose distribution comparisons between plans
TD50: tolerance dose associated with 50% chance of complication for uniform liver irradiation
m: steepness of dose response at TD50
n: defines the effect of the volume on a scale from zero to one [19].
Lausch et al. at the London Regional Cancer Program (LRCP), developed the logistic TCP model. They retrospectively reviewed 36 patients with HCC treated with median 4 Gy per fraction (range: 2–10 Gy) to a median cumulative dose of 52 Gy (range: 29–83 Gy) on a radiobiologically guided dose escalation protocol. The protocol called for prescribing the highest possible dose that met the constraint of keeping the estimated risk of RILD to <5%. They demonstrated that the D50 (dose that would result in a 50% LC) at 6 months was 53 Gy equivalent dose if given in 2 Gy fractions (EQD2). In contrast, the D50 for metastatic disease to the liver was 70 Gy EQD2 demonstrating that HCC is relatively radiosensitive compared to other tumor types, including colorectal carcinoma metastatic to the liver. The D90 was found to be 84 Gy EQD2 suggesting that increasing dose results in increased LC [20]. Jang et al. developed another logistic TCP model based on tumor size. They demonstrated that higher doses (cumulative and per fraction) are required to achieve the same TCP for larger lesions. For lesions <5 cm vs. lesions >5 cm, doses had to be escalated from 51 to 61 Gy in three fractions to achieve a 2-year LC of 90%. They have also reported that D50 was 62.9 Gy EQD2 (range: 58–69 Gy EQD2) [21].
Ohri et al. published another TCP model from data of 431 primary liver tumors and 290 liver metastases. The 1-, 2-, and 3-year actuarial local control rates after SBRT for primary liver tumors were 93%, 89%, and 86%, respectively. Lower 1- (90%), 2- (79%), and 3-year (76%) actuarial local control rates were observed for liver metastases (p = .011). Among patients treated with SBRT for primary liver tumors, there was no evidence that local control is influenced by BED within the range of schedules used. For liver metastases, on the other hand, outcomes were significantly better for lesions treated with BEDs exceeding 100 Gy10 (3-year local control 93%) than for those treated with BEDs of ≤100 Gy10 (3-year local control 65%, P < .001) [22].
In 2010, Quantitative Analysis of Normal Tissue Effects in the Clinic (QUANTEC) reported recommendations that mean normal liver dose should be <18 Gy for baseline CP-A patients and < 6 Gy for those with CP-B, for a 6-fraction SBRT regimen (Table 7) [3, 28].
Author | n | Selection | Dose | Radiation technique | Liver dose parameters | CP status (%) | Toxicity |
---|---|---|---|---|---|---|---|
Dawson et al. 2002 [19] | 203 | Unresectable intrahepatic cancer (HCC, cholangiocarcinoma, liver mets) | 52.8 (range: 24–90) | 3D-CRT | Median: 32.0 Gy (Range 14.9–44.0) LKB NTCP Median: 0.05 (Range 0.00–0.46) | — | RILD (n = 19, 9%) without RILD (n = 184, 91%) |
Xi et al. 2013 [23] | 41 | HCC with marcovascular invasion | 36 Gy (range, 30–48 Gy) in six fractions | SBRT using VMAT | Mean dose ≤18 Gy | Only CP class A | No Grade 4/5 toxicity |
Andolino et al. 2011 [24] | 60 | HCC | CP A: 30–48/3 CP B: 24–48/5 | SBRT | CP A: 1/3rd of the uninvolved liver was restricted to ≤10 Gy, and ≥ 500 cc of uninvolved liver received <7Gy. CP B: 1/3rd of the uninvolved liver was restricted to ≤18 Gy, and ≥ 500 cc of uninvolved liver received <12 Gy. | CP A: 36 CP B: 24 | 36.7%; 20% CP Progression 17 patients had grade 2 at baseline (out of 21 with grade ≥ 2 toxicity) |
Tse et al. 2008 [25] | 31 | HCC and intrahepatic cholangiocarcinoma | 36.0 Gy (24.0 to 54.0 Gy) in 6 fractions | SBRT | LKB – NTCP model | Only CP class A | Grade 3 liver enzymes were seen in five patients (12%). |
Son et al. 2010 [26] | 47 | HCC | 30–39 Gy (median: 36 Gy) | SBRT | V20 ≤ 50%; Total liver volume receiving <18 Gray (Gy) of radiation should be >800 cm3 | CP A: 89% CP B: 8% CP C: 3% | 33% had ≥ Grade 2 hepatic toxicity 11% had progression of CP class |
Mizumoto et al. 2012 [27] | 259 | HCC | 66 GyE in 10 fractions to 77.0 GyE in 35 fractions | Proton Beam Therapy | Mean dose and V0–30 were identified as significant factors; preferred V0: 30% | CP A: 198 CP B: 58 CP C: 3 | Change in CP score ≥ 2 in 11% at 12 months and 22% at 24 months |
Summarizing various trials involving liver RT.
The dose recommendations for SBRT as per QUANTEC [3] for 5% or less risk of RILD are:
Mean normal liver dose (liver minus gross tumor volume).
<13 Gy for primary liver cancer, in three fractions.
<18 Gy for primary liver cancer, in six fractions.
<15 Gy for liver metastases, in three fractions.
<20 Gy for liver metastases, in six fractions.
<6 Gy for primary liver cancer, Child-Pugh B, in 4–6 Gy per fraction (for classic or non-classic RILD).
Critical volume model-based ≥700 mL of normal liver receives ≤15 Gy in three to five fractions.
Liver being comprised of hepatic lobules as functional subunits is a parallel organ. As a result, the mean dose and a critical volume being spared of high dose is of significance rather than the Dmax. The University of Colorado phase 1 clinical trial of SBRT for liver metastases described the importance of the liver volume spared, that is, the ‘critical volume model,’ a concept akin to surgical sparing of the future liver remnant. They have estimated that a typical normal liver volume is approximately 2000 mL and specified that a minimum volume of 700 mL or 35% of normal liver should remain uninjured by SBRT i.e. at least 700 mL of normal liver (entire liver minus cumulative GTV) had to receive at total dose less than 15 Gy [29]. This critical volume concept has also been applied to patients with HCC. Dyk et al. retrospectively analyzed 46 patients, of which 91% are CP-A status, treated with liver SBRT for either metastatic or primary liver malignancies and found the liver volume at 25 Gy (V25) > 32% was associated with CP-class progression on Univariate analysis [30]. Son et al. retrospective review of 47 patients with HCC, of which 68% are CP-A status and showed the volume of normal liver receiving <18 Gy should be >800 cc to avoid CP class progression on Multivariate analysis [26]. Since all these studies constitute predominantly Child A patients, if these dosimetric parameters can be applied to Child B or C still uncertain. Indiana University group have further performed a phase II trial and reported their toxicity data in CP-A (n = 38) and -B (n = 21) patients [31]. For a treatment regimen of 48 Gy in 3 fractions, CP-A patients were required to either limit the dose to 33% of the uninvolved liver (D33%) < 10 Gy and/or maintain the liver volume receiving <7 Gy to <500 cc. For a more conservative treatment regimen of 40 Gy in 5 fractions, CP-B7 patients had to meet constraints of D33% < 18 Gy and/or > 500 cc receiving <12 Gy. Dosimetric correlates were identified for grade 3 to 4 hepatic enzyme toxicity observed in 10.5% and 38.8% of CP-A and CP-B patients, respectively. However, the lower limit of the normal liver volume seems to vary between different races and ethnicities. Because heights and body weights vary so is the body surface area and so is the normal liver volume. Hence an absolute normal liver volume or its percentage to be spared may not be the optimal parameter to evaluate the liver function required for patients. The concept of body surface area (BSA) and Basal Metabolic Index (BMI) guided estimation of optimal liver volume need to be spared during SBRT treatment may be the future of liver SBRT program.
The conventional techniques like 2D and 3D CRT led to more of classic RILD owing to the wide radiation portals. With the technological advancements like IMRT, robotic SBRT with tumor tracking high accuracy in radiation treatment became possible and the necessity for additional ITV margin has been eliminated. Sharp dose gradient helps to deliver higher dose to the target and spare normal liver. With real time image guidance high precision therapy, PTV margin can be cut down. Thus, high doses can be focused to the tumor with minimal margin. Although the incidence of RILD decreased, this may led to higher probability of non-classic RILD.
Re-radiation in liver tumors are not common in clinical practice. There are only few published literature in this aspect and no standard consensus regarding dosage schedule. In most of the subsites, such as in head & neck cancer or cervical cancer, in re-irradiation setting there is usually reduction of total dose (BED). Treatment volume is limited and fractionation schedule modified depending upon ‘time to re-treat’. Irradiated volume also important in selection of fractionation schedule. Usually, in head & neck cancer 7 year time is considered ‘safe’ to re-challenge with full dose of radiation therapy. In case of re-radiation before that period, there is a reduction of dose depending upon the ‘time to re-treat’. Usually 15% dose ‘decay’ considered in 1st year after radiation therapy and then every year 10% ‘decay’ in dose. As the time gap between primary radiation therapy and re-irradiation increase, safer to deliver higher (adequate) dose of radiation therapy to the target. In re-radiation of liver tumors this standard practice is not followed. In fact, in few studies there are better results (OS) in patients treated with higher dose in re-radiation setting. Child Pugh Score and ‘time to re-treat’ are considered significant prognostic factors. There is no compromise in irradiated volume as well. Tolerance of liver is low, but fortunately in re-radiation setting, liver tolerates radiation comparatively better than other subsites. High dose radiation therapy work like thrombo-embolism, embolizing blood supply to a portion of liver and stimulating proliferating of hepatocytes from adjacent normal liver. Proliferating hepatocytes causes hypertrophy of the liver portion which is naive to radiation therapy. This proliferating hepatocytes replace the post-CK necrotic liver. Hence, the ‘new’ regenerated portion of liver tolerate better than previously treated liver. Different cytokines liberated from the necrosed liver tissue may also stimulate hypertrophy of liver. After RT, there is fibrosis as well, and this fibrosis may lead to shrinkage of liver volume. Post-CK, there is 50% regression of the involved liver due to radiation injury, on the other hand there is 320% compensatory hypertrophy of the contralateral liver lobe [2]. This phenomenon negates the implications of firbosis, and hypertrophy has more predominant impact. Shrinkage of liver volume is expected to be more with higher integral dose of radiation therapy. In few studies, there is transient reduction of liver volume of about 20% at 3 months post-CK. However, at one year follow up there is only 10% shrinkage compared to pre-treatment volume. Even after repeat CK, liver volume is mostly maintained due to compensatory hypertrophy. Most severe complication after re-radiation is radiation induced liver disease (RILD). It is a syndrome of ascites, elevated transaminase level, and anicteric hepatomegaly. Usually occurs in a proportion of patient after receiving whole liver doses of >30–35 Gy. However, retrospective series of partial liver radiation have demonstrated that liver tolerance not only depends upon the total dose of radiation therapy, but also on pre-treatment Child-Pugh score, viral load and volume of tumor as well. Partial liver may be safely treated with radiation if adequate liver volume is preserved. In re-radiation, as the hypertrophied liver is mostly radiation naive, re-radiation is possible with adequate dose in small volume recurrences [33, 38].
As stereotactic radiosurgery (SRS) applications moved to extra-cranial sites, the primary challenge was that SRS technologies were initially designed to deliver very precise treatments for non-moving targets. Therefore, methods to compensate for respiratory motion like fluoroscopy, surrogate markers [34] (spirometry, fiducials), 4D-CT and dynamic MRI were developed. Owing to the differential degree of movement of liver antero-posteriorly and cranio-caudally, and also between the lobes of liver, internal fiducial markers are ideal for tumor tracking. For fiducial tracking and CT slice thickness of 0.625 mm–1.25 mm, the system accuracy has been shown to be 0.7 +/− 0.3 mm. Per cutaneous fiducial insertion can be done ultrasonography guided or CT- guided under sterile conditions by interventional radiologist. Being an invasive procedure, complications like pain, bleeding, pneumothorax can be seen. Some of them might require chest tube placement, paracentesis, embolization. The technique of using “sterile blood patch” post fiducial insertion to prevent pneumothorax is in use. The main factor to prevent these remain the technical expertise. Apart from the acute complications, there can be migration of fiducials within the liver, rarely extra-hepatic sites also. Hence radiation planning and delivery is recommended to be scheduled after an interval of 48–72 hours post fiducial insertion [37, 39]. Park SH et al. retrospectively reviewed 101 patients with USG guided intrahepatic fiducial placement. There were no major complications, although 12 patients (12%) developed minor complications. Technical success was achieved in 291 (97%) fiducial placement. Of 101 patients, in 72/101 patients (71%) fiducials placement was ideal. Marsico M et al. (n = 15) assessed how different types of markers affects the tracking accuracy of Cyberknife. Ohta K et al. reported (n = 18) success rate of 100% (18/18) for fiducial placement in liver tumors. Only one patient (6%) had mild pneumothorax. There was no gross migration after placement. Choi J-H et al. (n = 32) evaluated the safety and technical feasibility of endoscopic ultrasonography (EUS)-guided fiducial placement. 23/32 patients (91%) had successful placement and only One patient (3%) developed mild pancreatitis which subsided with supportive care. Kim JH et al. (n = 77) evaluated the safety and technical success rate of an USG guided fiducial marker implantation. 21% had minor complications. Abdominal pain was the most common complication(14%). Fiducial migration occurred in 5 patients (6.5%). Dutta et al. analyzed 108 fiducials placed in 36 patients. Post-fiducial pain score 0–1 in 26 (72%) and score 3–4 was in 2 (6%). Five (14%) admitted in ‘day-care’ (2 mild pneumothorax, 3 pain). One patient (3%) admitted for hemothorax and died. Fiducial placement complications are usually rare, less than 3% patient need admission or have decompensation (change of Child Pugh Score > 2) [37, 39, 40].
The primary factor to prevent RILD is the better technique of radiation. SBRT with motion management techniques and real time tumor tracking is the best technique that can be used. Respecting the liver special constraints like mean liver dose and sparing a critical volume of liver from dose spill are the subsequent critical factors. Patient related factors like co-morbidities, nutritional status has to assessed prior to starting the treatment and the required dietary corrections have to be made. Feng et al. evaluated the role of amifostine as a radio protector in dose-escalated whole liver radiation therapy [41]. The study included 23 patients and a maximum dose of 40 Gy was used. This was compared with previously treated patients by logistical regression model. It was observed that the use of amifostine increased the liver tolerance by 3.3 +/−1.1 Gy. Selenium and Vitamin E are also shown to reduce the incidence of RILD in animal models by reducing liver lipid peroxidation and maintaining the endogenous liver antioxidant defense [34].
No established therapies for classic RILD exist. There are no specific guidelines for the management of RILD. Suggestions for use of anticoagulants and steroids have been made, but it is primarily supportive care and diuretics are often used for the ascites. Although a few patients may recover, ample fraction will eventually die of liver failure. Thus proper patient selection to prevent RILD is crucial.
Radiation induced liver injury is potentially hazardous complication. There is no definitive treatment and a proportion of patient may land up in gross decompensation. Usually supportive care, diuretics, albumin supplement, vitamin K replacement may be useful. Better case selection will avert incidence of RILD. Precise imaging, contouring, planning and respecting normal tissue constraints are critical. Radiation delivery with motion management and image guidance will allow delivery of higher dose and spare normal liver and hence will improve response to treatment and reduce RILD.
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",metaTitle:"Waiver Policy",metaDescription:"We feel that financial barriers should never prevent researchers from publishing their research. With the need to make scientific research more publically available and support the benefits of Open Access, more institutions and funders have dedicated funds to assist their faculty members and researchers cover the APCs associated with publishing in Open Access. Below we have outlined several options available to secure financing for your Open Access publication.",metaKeywords:null,canonicalURL:"/page/waiver-policy",contentRaw:'[{"type":"htmlEditorComponent","content":"At IntechOpen, the majority of OAPFs are paid by an Author’s institution or funding agency - Institutions (73%) vs. Authors (23%).
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\\n"}]'},components:[{type:"htmlEditorComponent",content:'At IntechOpen, the majority of OAPFs are paid by an Author’s institution or funding agency - Institutions (73%) vs. Authors (23%).
\n\nThe first step in obtaining funds for your Open Access publication begins with your institution or library. IntechOpen’s publishing standards align with most institutional funding programs. Our advice is to petition your institution for help in financing your Open Access publication.
\n\nHowever, as Open Access becomes a more commonly used publishing option for the dissemination of scientific and scholarly content, in addition to institutions, there are a growing number of funders who allow the use of grants for covering OA publication costs, or have established separate funds for the same purpose.
\n\nPlease consult our Open Access Funding page to explore some of these funding opportunities and learn more about how you could finance your IntechOpen publication. Keep in mind that this list is not definitive, and while we are constantly updating and informing our Authors of new funding opportunities, we recommend that you always check with your institution first.
\n\nFor Authors who are unable to obtain funding from their institution or research funding bodies and still need help in covering publication costs, IntechOpen offers the possibility of applying for a Waiver.
\n\nOur mission is to support Authors in publishing their research and making an impact within the scientific community. Currently, 14% of Authors receive full waivers and 6% receive partial waivers.
\n\nWhile providing support and advice to all our international Authors, waiver priority will be given to those Authors who reside in countries that are classified by the World Bank as low-income economies. In this way, we can help ensure that the scientific work being carried out can make an impact within the worldwide scientific community, no matter where an Author might live.
\n\nThe application process is open after your submitted manuscript has been accepted for publication. To apply, please fill out a Waiver Request Form and send it to your Author Service Manager. If you have an official letter from your university or institution showing that funds for your OA publication are unavailable, please attach that as well. The Waiver Request will normally be addressed within one week from the application date. All chapters that receive waivers or partial waivers will be designated as such online.
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He is the author or co-author of more than seventy papers in peer-reviewed journals and conferences as well as the co-author of several books. He serves as a reviewer for many scientific journals, international conferences, and research foundations. Since 2010, Dr. Placzek has been a reviewer of grants and projects (including EU projects) in the field of information technologies.",institutionString:"University of Silesia",institution:{name:"University of Silesia",country:{name:"Poland"}}},{id:"35000",title:"Prof.",name:"Ulrich H.P",middleName:"H.P.",surname:"Fischer",slug:"ulrich-h.p-fischer",fullName:"Ulrich H.P Fischer",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/35000/images/3052_n.jpg",biography:"Academic and Professional Background\nUlrich H. P. has Diploma and PhD degrees in Physics from the Free University Berlin, Germany. He has been working on research positions in the Heinrich-Hertz-Institute in Germany. Several international research projects has been performed with European partners from France, Netherlands, Norway and the UK. He is currently Professor of Communications Systems at the Harz University of Applied Sciences, Germany.\n\nPublications and Publishing\nHe has edited one book, a special interest book about ‘Optoelectronic Packaging’ (VDE, Berlin, Germany), and has published over 100 papers and is owner of several international patents for WDM over POF key elements.\n\nKey Research and Consulting Interests\nUlrich’s research activity has always been related to Spectroscopy and Optical Communications Technology. Specific current interests include the validation of complex instruments, and the application of VR technology to the development and testing of measurement systems. He has been reviewer for several publications of the Optical Society of America\\'s including Photonics Technology Letters and Applied Optics.\n\nPersonal Interests\nThese include motor cycling in a very relaxed manner and performing martial arts.",institutionString:null,institution:{name:"Charité",country:{name:"Germany"}}},{id:"341622",title:"Ph.D.",name:"Eduardo",middleName:null,surname:"Rojas Alvarez",slug:"eduardo-rojas-alvarez",fullName:"Eduardo Rojas Alvarez",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/341622/images/15892_n.jpg",biography:null,institutionString:null,institution:{name:"University of Cuenca",country:{name:"Ecuador"}}},{id:"215610",title:"Prof.",name:"Muhammad",middleName:null,surname:"Sarfraz",slug:"muhammad-sarfraz",fullName:"Muhammad Sarfraz",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/215610/images/system/215610.jpeg",biography:"Muhammad Sarfraz is a professor in the Department of Information Science, Kuwait University. His research interests include computer graphics, computer vision, image processing, machine learning, pattern recognition, soft computing, data science, intelligent systems, information technology, and information systems. Prof. Sarfraz has been a keynote/invited speaker on various platforms around the globe. He has advised various students for their MSc and Ph.D. theses. He has published more than 400 publications as books, journal articles, and conference papers. He is a member of various professional societies and a chair and member of the International Advisory Committees and Organizing Committees of various international conferences. Prof. Sarfraz is also an editor-in-chief and editor of various international journals.",institutionString:"Kuwait University",institution:{name:"Kuwait University",country:{name:"Kuwait"}}},{id:"32650",title:"Prof.",name:"Lukas",middleName:"Willem",surname:"Snyman",slug:"lukas-snyman",fullName:"Lukas Snyman",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/32650/images/4136_n.jpg",biography:"Lukas Willem Snyman received his basic education at primary and high schools in South Africa, Eastern Cape. He enrolled at today's Nelson Metropolitan University and graduated from this university with a BSc in Physics and Mathematics, B.Sc Honors in Physics, MSc in Semiconductor Physics, and a Ph.D. in Semiconductor Physics in 1987. After his studies, he chose an academic career and devoted his energy to the teaching of physics to first, second, and third-year students. After positions as a lecturer at the University of Port Elizabeth, he accepted a position as Associate Professor at the University of Pretoria, South Africa.\r\n\r\nIn 1992, he motivates the concept of 'television and computer-based education” as means to reach large student numbers with only the best of teaching expertise and publishes an article on the concept in the SA Journal of Higher Education of 1993 (and later in 2003). The University of Pretoria subsequently approved a series of test projects on the concept with outreach to Mamelodi and Eerste Rust in 1993. In 1994, the University established a 'Unit for Telematic Education ' as a support section for multiple faculties at the University of Pretoria. In subsequent years, the concept of 'telematic education” subsequently becomes well established in academic circles in South Africa, grew in popularity, and is adopted by many universities and colleges throughout South Africa as a medium of enhancing education and training, as a method to reaching out to far out communities, and as a means to enhance study from the home environment.\r\n\r\nProfessor Snyman in subsequent years pursued research in semiconductor physics, semiconductor devices, microelectronics, and optoelectronics.\r\n\r\nIn 2000 he joined the TUT as a full professor. Here served for a period as head of the Department of Electronic Engineering. Here he makes contributions to solar energy development, microwave and optoelectronic device development, silicon photonics, as well as contributions to new mobile telecommunication systems and network planning in SA.\r\n\r\nCurrently, he teaches electronics and telecommunications at the TUT to audiences ranging from first-year students to Ph.D. level.\r\n\r\nFor his research in the field of 'Silicon Photonics” since 1990, he has published (as author and co-author) about thirty internationally reviewed articles in scientific journals, contributed to more than forty international conferences, about 25 South African provisional patents (as inventor and co-inventor), 8 PCT international patent applications until now. Of these, two USA patents applications, two European Patents, two Korean patents, and ten SA patents have been granted. A further 4 USA patents, 5 European patents, 3 Korean patents, 3 Chinese patents, and 3 Japanese patents are currently under consideration.\r\n\r\nRecently he has also published an extensive scholarly chapter in an internet open access book on 'Integrating Microphotonic Systems and MOEMS into standard Silicon CMOS Integrated circuitry”.\r\n\r\nFurthermore, Professor Snyman recently steered a new initiative at the TUT by introducing a 'Laboratory for Innovative Electronic Systems ' at the Department of Electrical Engineering. The model of this laboratory or center is to primarily combine outputs as achieved by high-level research with lower-level system development and entrepreneurship in a technical university environment. Students are allocated to projects at different levels with PhDs and Master students allocated to the generation of new knowledge and new technologies, while students at the diploma and Baccalaureus level are allocated to electronic systems development with a direct and a near application for application in industry or the commercial and public sectors in South Africa.\r\n\r\nProfessor Snyman received the WIRSAM Award of 1983 and the WIRSAM Award in 1985 in South Africa for best research papers by a young scientist at two international conferences on electron microscopy in South Africa. He subsequently received the SA Microelectronics Award for the best dissertation emanating from studies executed at a South African university in the field of Physics and Microelectronics in South Africa in 1987. In October of 2011, Professor Snyman received the prestigious Institutional Award for 'Innovator of the Year” for 2010 at the Tshwane University of Technology, South Africa. This award was based on the number of patents recognized and granted by local and international institutions as well as for his contributions concerning innovation at the TUT.",institutionString:null,institution:{name:"University of South Africa",country:{name:"South Africa"}}},{id:"317279",title:"Mr.",name:"Ali",middleName:"Usama",surname:"Syed",slug:"ali-syed",fullName:"Ali Syed",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/317279/images/16024_n.png",biography:"A creative, talented, and innovative young professional who is dedicated, well organized, and capable research fellow with two years of experience in graduate-level research, published in engineering journals and book, with related expertise in Bio-robotics, equally passionate about the aesthetics of the mechanical and electronic system, obtained expertise in the use of MS Office, MATLAB, SolidWorks, LabVIEW, Proteus, Fusion 360, having a grasp on python, C++ and assembly language, possess proven ability in acquiring research grants, previous appointments with social and educational societies with experience in administration, current affiliations with IEEE and Web of Science, a confident presenter at conferences and teacher in classrooms, able to explain complex information to audiences of all levels.",institutionString:null,institution:{name:"Air University",country:{name:"Pakistan"}}},{id:"75526",title:"Ph.D.",name:"Zihni Onur",middleName:null,surname:"Uygun",slug:"zihni-onur-uygun",fullName:"Zihni Onur Uygun",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/75526/images/12_n.jpg",biography:"My undergraduate education and my Master of Science educations at Ege University and at Çanakkale Onsekiz Mart University have given me a firm foundation in Biochemistry, Analytical Chemistry, Biosensors, Bioelectronics, Physical Chemistry and Medicine. After obtaining my degree as a MSc in analytical chemistry, I started working as a research assistant in Ege University Medical Faculty in 2014. In parallel, I enrolled to the MSc program at the Department of Medical Biochemistry at Ege University to gain deeper knowledge on medical and biochemical sciences as well as clinical chemistry in 2014. In my PhD I deeply researched on biosensors and bioelectronics and finished in 2020. Now I have eleven SCI-Expanded Index published papers, 6 international book chapters, referee assignments for different SCIE journals, one international patent pending, several international awards, projects and bursaries. In parallel to my research assistant position at Ege University Medical Faculty, Department of Medical Biochemistry, in April 2016, I also founded a Start-Up Company (Denosens Biotechnology LTD) by the support of The Scientific and Technological Research Council of Turkey. Currently, I am also working as a CEO in Denosens Biotechnology. The main purposes of the company, which carries out R&D as a research center, are to develop new generation biosensors and sensors for both point-of-care diagnostics; such as glucose, lactate, cholesterol and cancer biomarker detections. My specific experimental and instrumental skills are Biochemistry, Biosensor, Analytical Chemistry, Electrochemistry, Mobile phone based point-of-care diagnostic device, POCTs and Patient interface designs, HPLC, Tandem Mass Spectrometry, Spectrophotometry, ELISA.",institutionString:null,institution:{name:"Ege University",country:{name:"Turkey"}}},{id:"267434",title:"Dr.",name:"Rohit",middleName:null,surname:"Raja",slug:"rohit-raja",fullName:"Rohit Raja",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/267434/images/system/267434.jpg",biography:"Dr. Rohit Raja received Ph.D. in Computer Science and Engineering from Dr. CVRAMAN University in 2016. His main research interest includes Face recognition and Identification, Digital Image Processing, Signal Processing, and Networking. Presently he is working as Associate Professor in IT Department, Guru Ghasidas Vishwavidyalaya (A Central University), Bilaspur (CG), India. He has authored several Journal and Conference Papers. He has good Academics & Research experience in various areas of CSE and IT. He has filed and successfully published 27 Patents. He has received many time invitations to be a Guest at IEEE Conferences. He has published 100 research papers in various International/National Journals (including IEEE, Springer, etc.) and Proceedings of the reputed International/ National Conferences (including Springer and IEEE). He has been nominated to the board of editors/reviewers of many peer-reviewed and refereed Journals (including IEEE, Springer).",institutionString:"Guru Ghasidas Vishwavidyalaya",institution:{name:"Guru Ghasidas Vishwavidyalaya",country:{name:"India"}}},{id:"246502",title:"Dr.",name:"Jaya T.",middleName:"T",surname:"Varkey",slug:"jaya-t.-varkey",fullName:"Jaya T. Varkey",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/246502/images/11160_n.jpg",biography:"Jaya T. Varkey, PhD, graduated with a degree in Chemistry from Cochin University of Science and Technology, Kerala, India. She obtained a PhD in Chemistry from the School of Chemical Sciences, Mahatma Gandhi University, Kerala, India, and completed a post-doctoral fellowship at the University of Minnesota, USA. She is a research guide at Mahatma Gandhi University and Associate Professor in Chemistry, St. Teresa’s College, Kochi, Kerala, India.\nDr. Varkey received a National Young Scientist award from the Indian Science Congress (1995), a UGC Research award (2016–2018), an Indian National Science Academy (INSA) Visiting Scientist award (2018–2019), and a Best Innovative Faculty award from the All India Association for Christian Higher Education (AIACHE) (2019). She Hashas received the Sr. Mary Cecil prize for best research paper three times. She was also awarded a start-up to develop a tea bag water filter. \nDr. Varkey has published two international books and twenty-seven international journal publications. She is an editorial board member for five international journals.",institutionString:"St. Teresa’s College",institution:null},{id:"250668",title:"Dr.",name:"Ali",middleName:null,surname:"Nabipour Chakoli",slug:"ali-nabipour-chakoli",fullName:"Ali Nabipour Chakoli",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/250668/images/system/250668.jpg",biography:"Academic Qualification:\r\n•\tPhD in Materials Physics and Chemistry, From: Sep. 2006, to: Sep. 2010, School of Materials Science and Engineering, Harbin Institute of Technology, Thesis: Structure and Shape Memory Effect of Functionalized MWCNTs/poly (L-lactide-co-ε-caprolactone) Nanocomposites. Supervisor: Prof. Wei Cai,\r\n•\tM.Sc in Applied Physics, From: 1996, to: 1998, Faculty of Physics & Nuclear Science, Amirkabir Uni. of Technology, Tehran, Iran, Thesis: Determination of Boron in Micro alloy Steels with solid state nuclear track detectors by neutron induced auto radiography, Supervisors: Dr. M. Hosseini Ashrafi and Dr. A. Hosseini.\r\n•\tB.Sc. in Applied Physics, From: 1991, to: 1996, Faculty of Physics & Nuclear Science, Amirkabir Uni. of Technology, Tehran, Iran, Thesis: Design of shielding for Am-Be neutron sources for In Vivo neutron activation analysis, Supervisor: Dr. M. Hosseini Ashrafi.\r\n\r\nResearch Experiences:\r\n1.\tNanomaterials, Carbon Nanotubes, Graphene: Synthesis, Functionalization and Characterization,\r\n2.\tMWCNTs/Polymer Composites: Fabrication and Characterization, \r\n3.\tShape Memory Polymers, Biodegradable Polymers, ORC, Collagen,\r\n4.\tMaterials Analysis and Characterizations: TEM, SEM, XPS, FT-IR, Raman, DSC, DMA, TGA, XRD, GPC, Fluoroscopy, \r\n5.\tInteraction of Radiation with Mater, Nuclear Safety and Security, NDT(RT),\r\n6.\tRadiation Detectors, Calibration (SSDL),\r\n7.\tCompleted IAEA e-learning Courses:\r\nNuclear Security (15 Modules),\r\nNuclear Safety:\r\nTSA 2: Regulatory Protection in Occupational Exposure,\r\nTips & Tricks: Radiation Protection in Radiography,\r\nSafety and Quality in Radiotherapy,\r\nCourse on Sealed Radioactive Sources,\r\nCourse on Fundamentals of Environmental Remediation,\r\nCourse on Planning for Environmental Remediation,\r\nKnowledge Management Orientation Course,\r\nFood Irradiation - Technology, Applications and Good Practices,\r\nEmployment:\r\nFrom 2010 to now: Academic staff, Nuclear Science and Technology Research Institute, Kargar Shomali, Tehran, Iran, P.O. Box: 14395-836.\r\nFrom 1997 to 2006: Expert of Materials Analysis and Characterization. Research Center of Agriculture and Medicine. Rajaeeshahr, Karaj, Iran, P. O. Box: 31585-498.",institutionString:"Atomic Energy Organization of Iran",institution:{name:"Atomic Energy Organization of Iran",country:{name:"Iran"}}},{id:"248279",title:"Dr.",name:"Monika",middleName:"Elzbieta",surname:"Machoy",slug:"monika-machoy",fullName:"Monika Machoy",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/248279/images/system/248279.jpeg",biography:"Monika Elżbieta Machoy, MD, graduated with distinction from the Faculty of Medicine and Dentistry at the Pomeranian Medical University in 2009, defended her PhD thesis with summa cum laude in 2016 and is currently employed as a researcher at the Department of Orthodontics of the Pomeranian Medical University. She expanded her professional knowledge during a one-year scholarship program at the Ernst Moritz Arndt University in Greifswald, Germany and during a three-year internship at the Technical University in Dresden, Germany. She has been a speaker at numerous orthodontic conferences, among others, American Association of Orthodontics, European Orthodontic Symposium and numerous conferences of the Polish Orthodontic Society. She conducts research focusing on the effect of orthodontic treatment on dental and periodontal tissues and the causes of pain in orthodontic patients.",institutionString:"Pomeranian Medical University",institution:{name:"Pomeranian Medical University",country:{name:"Poland"}}},{id:"252743",title:"Prof.",name:"Aswini",middleName:"Kumar",surname:"Kar",slug:"aswini-kar",fullName:"Aswini Kar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/252743/images/10381_n.jpg",biography:"uploaded in cv",institutionString:null,institution:{name:"KIIT University",country:{name:"India"}}},{id:"204256",title:"Dr.",name:"Anil",middleName:"Kumar",surname:"Kumar Sahu",slug:"anil-kumar-sahu",fullName:"Anil Kumar Sahu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/204256/images/14201_n.jpg",biography:"I have nearly 11 years of research and teaching experience. I have done my master degree from University Institute of Pharmacy, Pt. Ravi Shankar Shukla University, Raipur, Chhattisgarh India. I have published 16 review and research articles in international and national journals and published 4 chapters in IntechOpen, the world’s leading publisher of Open access books. I have presented many papers at national and international conferences. I have received research award from Indian Drug Manufacturers Association in year 2015. My research interest extends from novel lymphatic drug delivery systems, oral delivery system for herbal bioactive to formulation optimization.",institutionString:null,institution:{name:"Chhattisgarh Swami Vivekanand Technical University",country:{name:"India"}}},{id:"253468",title:"Dr.",name:"Mariusz",middleName:null,surname:"Marzec",slug:"mariusz-marzec",fullName:"Mariusz Marzec",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/253468/images/system/253468.png",biography:"An assistant professor at Department of Biomedical Computer Systems, at Institute of Computer Science, Silesian University in Katowice. Scientific interests: computer analysis and processing of images, biomedical images, databases and programming languages. He is an author and co-author of scientific publications covering analysis and processing of biomedical images and development of database systems.",institutionString:"University of Silesia",institution:{name:"University of Silesia",country:{name:"Poland"}}},{id:"212432",title:"Prof.",name:"Hadi",middleName:null,surname:"Mohammadi",slug:"hadi-mohammadi",fullName:"Hadi Mohammadi",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/212432/images/system/212432.jpeg",biography:"Dr. Hadi Mohammadi is a biomedical engineer with hands-on experience in the design and development of many engineering structures and medical devices through various projects that he has been involved in over the past twenty years. Dr. Mohammadi received his BSc. and MSc. degrees in Mechanical Engineering from Sharif University of Technology, Tehran, Iran, and his PhD. degree in Biomedical Engineering (biomaterials) from the University of Western Ontario. He was a postdoctoral trainee for almost four years at University of Calgary and Harvard Medical School. He is an industry innovator having created the technology to produce lifelike synthetic platforms that can be used for the simulation of almost all cardiovascular reconstructive surgeries. He’s been heavily involved in the design and development of cardiovascular devices and technology for the past 10 years. He is currently an Assistant Professor with the University of British Colombia, Canada.",institutionString:"University of British Columbia",institution:{name:"University of British Columbia",country:{name:"Canada"}}},{id:"254463",title:"Prof.",name:"Haisheng",middleName:null,surname:"Yang",slug:"haisheng-yang",fullName:"Haisheng Yang",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/254463/images/system/254463.jpeg",biography:"Haisheng Yang, Ph.D., Professor and Director of the Department of Biomedical Engineering, College of Life Science and Bioengineering, Beijing University of Technology. He received his Ph.D. degree in Mechanics/Biomechanics from Harbin Institute of Technology (jointly with University of California, Berkeley). Afterwards, he worked as a Postdoctoral Research Associate in the Purdue Musculoskeletal Biology and Mechanics Lab at the Department of Basic Medical Sciences, Purdue University, USA. He also conducted research in the Research Centre of Shriners Hospitals for Children-Canada at McGill University, Canada. Dr. Yang has over 10 years research experience in orthopaedic biomechanics and mechanobiology of bone adaptation and regeneration. He earned an award from Beijing Overseas Talents Aggregation program in 2017 and serves as Beijing Distinguished Professor.",institutionString:null,institution:{name:"Beijing University of Technology",country:{name:"China"}}},{id:"89721",title:"Dr.",name:"Mehmet",middleName:"Cuneyt",surname:"Ozmen",slug:"mehmet-ozmen",fullName:"Mehmet Ozmen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/89721/images/7289_n.jpg",biography:null,institutionString:null,institution:{name:"Gazi University",country:{name:"Turkey"}}},{id:"265335",title:"Mr.",name:"Stefan",middleName:"Radnev",surname:"Stefanov",slug:"stefan-stefanov",fullName:"Stefan Stefanov",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/265335/images/7562_n.jpg",biography:null,institutionString:null,institution:{name:"Medical University Plovdiv",country:{name:"Bulgaria"}}},{id:"242893",title:"Ph.D. Student",name:"Joaquim",middleName:null,surname:"De Moura",slug:"joaquim-de-moura",fullName:"Joaquim De Moura",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/242893/images/7133_n.jpg",biography:"Joaquim de Moura received his degree in Computer Engineering in 2014 from the University of A Coruña (Spain). In 2016, he received his M.Sc degree in Computer Engineering from the same university. He is currently pursuing his Ph.D degree in Computer Science in a collaborative project between ophthalmology centers in Galicia and the University of A Coruña. His research interests include computer vision, machine learning algorithms and analysis and medical imaging processing of various kinds.",institutionString:null,institution:{name:"University of A Coruña",country:{name:"Spain"}}},{id:"294334",title:"B.Sc.",name:"Marc",middleName:null,surname:"Bruggeman",slug:"marc-bruggeman",fullName:"Marc Bruggeman",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/294334/images/8242_n.jpg",biography:"Chemical engineer graduate, with a passion for material science and specific interest in polymers - their near infinite applications intrigue me. \n\nI plan to continue my scientific career in the field of polymeric biomaterials as I am fascinated by intelligent, bioactive and biomimetic materials for use in both consumer and medical applications.",institutionString:null,institution:null},{id:"255757",title:"Dr.",name:"Igor",middleName:"Victorovich",surname:"Lakhno",slug:"igor-lakhno",fullName:"Igor Lakhno",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/255757/images/system/255757.jpg",biography:"Igor Victorovich Lakhno was born in 1971 in Kharkiv (Ukraine). \nMD – 1994, Kharkiv National Medical Univesity.\nOb&Gyn; – 1997, master courses in Kharkiv Medical Academy of Postgraduate Education.\nPh.D. – 1999, Kharkiv National Medical Univesity.\nDSC – 2019, PL Shupik National Academy of Postgraduate Education \nProfessor – 2021, Department of Obstetrics and Gynecology of VN Karazin Kharkiv National University\nHead of Department – 2021, Department of Perinatology, Obstetrics and gynecology of Kharkiv Medical Academy of Postgraduate Education\nIgor Lakhno has been graduated from international training courses on reproductive medicine and family planning held at Debrecen University (Hungary) in 1997. Since 1998 Lakhno Igor has worked as an associate professor in the department of obstetrics and gynecology of VN Karazin National University and an associate professor of the perinatology, obstetrics, and gynecology department of Kharkiv Medical Academy of Postgraduate Education. Since June 2019 he’s been a professor in the department of obstetrics and gynecology of VN Karazin National University and a professor of the perinatology, obstetrics, and gynecology department. He’s affiliated with Kharkiv Medical Academy of Postgraduate Education as a Head of Department from November 2021. Igor Lakhno has participated in several international projects on fetal non-invasive electrocardiography (with Dr. J. A. Behar (Technion), Prof. D. Hoyer (Jena University), and José Alejandro Díaz Méndez (National Institute of Astrophysics, Optics, and Electronics, Mexico). He’s an author of about 200 printed works and there are 31 of them in Scopus or Web of Science databases. Igor Lakhno is a member of the Editorial Board of Reproductive Health of Woman, Emergency Medicine, and Technology Transfer Innovative Solutions in Medicine (Estonia). He is a medical Editor of “Z turbotoyu pro zhinku”. Igor Lakhno is a reviewer of the Journal of Obstetrics and Gynaecology (Taylor and Francis), British Journal of Obstetrics and Gynecology (Wiley), Informatics in Medicine Unlocked (Elsevier), The Journal of Obstetrics and Gynecology Research (Wiley), Endocrine, Metabolic & Immune Disorders-Drug Targets (Bentham Open), The Open Biomedical Engineering Journal (Bentham Open), etc. He’s defended a dissertation for a DSc degree “Pre-eclampsia: prediction, prevention, and treatment”. Three years ago Igor Lakhno has participated in a training course on innovative technologies in medical education at Lublin Medical University (Poland). Lakhno Igor has participated as a speaker in several international conferences and congresses (International Conference on Biological Oscillations April 10th-14th 2016, Lancaster, UK, The 9th conference of the European Study Group on Cardiovascular Oscillations). His main scientific interests: are obstetrics, women’s health, fetal medicine, and cardiovascular medicine. \nIgor Lakhno is a consultant at Kharkiv municipal perinatal center. He’s graduated from training courses on endoscopy in gynecology. He has 28 years of practical experience in the field.",institutionString:null,institution:null},{id:"244950",title:"Dr.",name:"Salvatore",middleName:null,surname:"Di Lauro",slug:"salvatore-di-lauro",fullName:"Salvatore Di Lauro",position:null,profilePictureURL:"https://intech-files.s3.amazonaws.com/0030O00002bSF1HQAW/ProfilePicture%202021-12-20%2014%3A54%3A14.482",biography:"Name:\n\tSALVATORE DI LAURO\nAddress:\n\tHospital Clínico Universitario Valladolid\nAvda Ramón y Cajal 3\n47005, Valladolid\nSpain\nPhone number: \nFax\nE-mail:\n\t+34 983420000 ext 292\n+34 983420084\nsadilauro@live.it\nDate and place of Birth:\nID Number\nMedical Licence \nLanguages\t09-05-1985. Villaricca (Italy)\n\nY1281863H\n474707061\nItalian (native language)\nSpanish (read, written, spoken)\nEnglish (read, written, spoken)\nPortuguese (read, spoken)\nFrench (read)\n\t\t\nCurrent position (title and company)\tDate (Year)\nVitreo-Retinal consultant in ophthalmology. Hospital Clinico Universitario Valladolid. Sacyl. National Health System.\nVitreo-Retinal consultant in ophthalmology. Instituto Oftalmologico Recoletas. Red Hospitalaria Recoletas. Private practise.\t2017-today\n\n2019-today\n\t\n\t\nEducation (High school, university and postgraduate training > 3 months)\tDate (Year)\nDegree in Medicine and Surgery. University of Neaples 'Federico II”\nResident in Opthalmology. Hospital Clinico Universitario Valladolid\nMaster in Vitreo-Retina. IOBA. University of Valladolid\nFellow of the European Board of Ophthalmology. Paris\nMaster in Research in Ophthalmology. University of Valladolid\t2003-2009\n2012-2016\n2016-2017\n2016\n2012-2013\n\t\nEmployments (company and positions)\tDate (Year)\nResident in Ophthalmology. Hospital Clinico Universitario Valladolid. Sacyl.\nFellow in Vitreo-Retina. IOBA. University of Valladolid\nVitreo-Retinal consultant in ophthalmology. Hospital Clinico Universitario Valladolid. Sacyl. National Health System.\nVitreo-Retinal consultant in ophthalmology. Instituto Oftalmologico Recoletas. Red Hospitalaria Recoletas. \n\t2012-2016\n2016-2017\n2017-today\n\n2019-Today\n\n\n\t\nClinical Research Experience (tasks and role)\tDate (Year)\nAssociated investigator\n\n' FIS PI20/00740: DESARROLLO DE UNA CALCULADORA DE RIESGO DE\nAPARICION DE RETINOPATIA DIABETICA BASADA EN TECNICAS DE IMAGEN MULTIMODAL EN PACIENTES DIABETICOS TIPO 1. Grant by: Ministerio de Ciencia e Innovacion \n\n' (BIO/VA23/14) Estudio clínico multicéntrico y prospectivo para validar dos\nbiomarcadores ubicados en los genes p53 y MDM2 en la predicción de los resultados funcionales de la cirugía del desprendimiento de retina regmatógeno. Grant by: Gerencia Regional de Salud de la Junta de Castilla y León.\n' Estudio multicéntrico, aleatorizado, con enmascaramiento doble, en 2 grupos\nparalelos y de 52 semanas de duración para comparar la eficacia, seguridad e inmunogenicidad de SOK583A1 respecto a Eylea® en pacientes con degeneración macular neovascular asociada a la edad' (CSOK583A12301; N.EUDRA: 2019-004838-41; FASE III). Grant by Hexal AG\n\n' Estudio de fase III, aleatorizado, doble ciego, con grupos paralelos, multicéntrico para comparar la eficacia y la seguridad de QL1205 frente a Lucentis® en pacientes con degeneración macular neovascular asociada a la edad. (EUDRACT: 2018-004486-13). Grant by Qilu Pharmaceutical Co\n\n' Estudio NEUTON: Ensayo clinico en fase IV para evaluar la eficacia de aflibercept en pacientes Naive con Edema MacUlar secundario a Oclusion de Vena CenTral de la Retina (OVCR) en regimen de tratamientO iNdividualizado Treat and Extend (TAE)”, (2014-000975-21). Grant by Fundacion Retinaplus\n\n' Evaluación de la seguridad y bioactividad de anillos de tensión capsular en conejo. Proyecto Procusens. Grant by AJL, S.A.\n\n'Estudio epidemiológico, prospectivo, multicéntrico y abierto\\npara valorar la frecuencia de la conjuntivitis adenovírica diagnosticada mediante el test AdenoPlus®\\nTest en pacientes enfermos de conjuntivitis aguda”\\n. National, multicenter study. Grant by: NICOX.\n\nEuropean multicentric trial: 'Evaluation of clinical outcomes following the use of Systane Hydration in patients with dry eye”. Study Phase 4. Grant by: Alcon Labs'\n\nVLPs Injection and Activation in a Rabbit Model of Uveal Melanoma. Grant by Aura Bioscience\n\nUpdating and characterization of a rabbit model of uveal melanoma. Grant by Aura Bioscience\n\nEnsayo clínico en fase IV para evaluar las variantes genéticas de la vía del VEGF como biomarcadores de eficacia del tratamiento con aflibercept en pacientes con degeneración macular asociada a la edad (DMAE) neovascular. Estudio BIOIMAGE. IMO-AFLI-2013-01\n\nEstudio In-Eye:Ensayo clínico en fase IV, abierto, aleatorizado, de 2 brazos,\nmulticçentrico y de 12 meses de duración, para evaluar la eficacia y seguridad de un régimen de PRN flexible individualizado de 'esperar y extender' versus un régimen PRN según criterios de estabilización mediante evaluaciones mensuales de inyecciones intravítreas de ranibizumab 0,5 mg en pacientes naive con neovascularización coriodea secunaria a la degeneración macular relacionada con la edad. CP: CRFB002AES03T\n\nTREND: Estudio Fase IIIb multicéntrico, randomizado, de 12 meses de\nseguimiento con evaluador de la agudeza visual enmascarado, para evaluar la eficacia y la seguridad de ranibizumab 0.5mg en un régimen de tratar y extender comparado con un régimen mensual, en pacientes con degeneración macular neovascular asociada a la edad. CP: CRFB002A2411 Código Eudra CT:\n2013-002626-23\n\n\n\nPublications\t\n\n2021\n\n\n\n\n2015\n\n\n\n\n2021\n\n\n\n\n\n2021\n\n\n\n\n2015\n\n\n\n\n2015\n\n\n2014\n\n\n\n\n2015-16\n\n\n\n2015\n\n\n2014\n\n\n2014\n\n\n\n\n2014\n\n\n\n\n\n\n\n2014\n\nJose Carlos Pastor; Jimena Rojas; Salvador Pastor-Idoate; Salvatore Di Lauro; Lucia Gonzalez-Buendia; Santiago Delgado-Tirado. Proliferative vitreoretinopathy: A new concept of disease pathogenesis and practical\nconsequences. Progress in Retinal and Eye Research. 51, pp. 125 - 155. 03/2016. DOI: 10.1016/j.preteyeres.2015.07.005\n\n\nLabrador-Velandia S; Alonso-Alonso ML; Di Lauro S; García-Gutierrez MT; Srivastava GK; Pastor JC; Fernandez-Bueno I. Mesenchymal stem cells provide paracrine neuroprotective resources that delay degeneration of co-cultured organotypic neuroretinal cultures.Experimental Eye Research. 185, 17/05/2019. DOI: 10.1016/j.exer.2019.05.011\n\nSalvatore Di Lauro; Maria Teresa Garcia Gutierrez; Ivan Fernandez Bueno. Quantification of pigment epithelium-derived factor (PEDF) in an ex vivo coculture of retinal pigment epithelium cells and neuroretina.\nJournal of Allbiosolution. 2019. ISSN 2605-3535\n\nSonia Labrador Velandia; Salvatore Di Lauro; Alonso-Alonso ML; Tabera Bartolomé S; Srivastava GK; Pastor JC; Fernandez-Bueno I. Biocompatibility of intravitreal injection of human mesenchymal stem cells in immunocompetent rabbits. Graefe's archive for clinical and experimental ophthalmology. 256 - 1, pp. 125 - 134. 01/2018. DOI: 10.1007/s00417-017-3842-3\n\n\nSalvatore Di Lauro, David Rodriguez-Crespo, Manuel J Gayoso, Maria T Garcia-Gutierrez, J Carlos Pastor, Girish K Srivastava, Ivan Fernandez-Bueno. A novel coculture model of porcine central neuroretina explants and retinal pigment epithelium cells. Molecular Vision. 2016 - 22, pp. 243 - 253. 01/2016.\n\nSalvatore Di Lauro. Classifications for Proliferative Vitreoretinopathy ({PVR}): An Analysis of Their Use in Publications over the Last 15 Years. Journal of Ophthalmology. 2016, pp. 1 - 6. 01/2016. DOI: 10.1155/2016/7807596\n\nSalvatore Di Lauro; Rosa Maria Coco; Rosa Maria Sanabria; Enrique Rodriguez de la Rua; Jose Carlos Pastor. Loss of Visual Acuity after Successful Surgery for Macula-On Rhegmatogenous Retinal Detachment in a Prospective Multicentre Study. Journal of Ophthalmology. 2015:821864, 2015. DOI: 10.1155/2015/821864\n\nIvan Fernandez-Bueno; Salvatore Di Lauro; Ivan Alvarez; Jose Carlos Lopez; Maria Teresa Garcia-Gutierrez; Itziar Fernandez; Eva Larra; Jose Carlos Pastor. Safety and Biocompatibility of a New High-Density Polyethylene-Based\nSpherical Integrated Porous Orbital Implant: An Experimental Study in Rabbits. Journal of Ophthalmology. 2015:904096, 2015. DOI: 10.1155/2015/904096\n\nPastor JC; Pastor-Idoate S; Rodríguez-Hernandez I; Rojas J; Fernandez I; Gonzalez-Buendia L; Di Lauro S; Gonzalez-Sarmiento R. Genetics of PVR and RD. Ophthalmologica. 232 - Suppl 1, pp. 28 - 29. 2014\n\nRodriguez-Crespo D; Di Lauro S; Singh AK; Garcia-Gutierrez MT; Garrosa M; Pastor JC; Fernandez-Bueno I; Srivastava GK. Triple-layered mixed co-culture model of RPE cells with neuroretina for evaluating the neuroprotective effects of adipose-MSCs. Cell Tissue Res. 358 - 3, pp. 705 - 716. 2014.\nDOI: 10.1007/s00441-014-1987-5\n\nCarlo De Werra; Salvatore Condurro; Salvatore Tramontano; Mario Perone; Ivana Donzelli; Salvatore Di Lauro; Massimo Di Giuseppe; Rosa Di Micco; Annalisa Pascariello; Antonio Pastore; Giorgio Diamantis; Giuseppe Galloro. Hydatid disease of the liver: thirty years of surgical experience.Chirurgia italiana. 59 - 5, pp. 611 - 636.\n(Italia): 2007. ISSN 0009-4773\n\nChapters in books\n\t\n' Salvador Pastor Idoate; Salvatore Di Lauro; Jose Carlos Pastor Jimeno. PVR: Pathogenesis, Histopathology and Classification. Proliferative Vitreoretinopathy with Small Gauge Vitrectomy. Springer, 2018. ISBN 978-3-319-78445-8\nDOI: 10.1007/978-3-319-78446-5_2. \n\n' Salvatore Di Lauro; Maria Isabel Lopez Galvez. Quistes vítreos en una mujer joven. Problemas diagnósticos en patología retinocoroidea. Sociedad Española de Retina-Vitreo. 2018.\n\n' Salvatore Di Lauro; Salvador Pastor Idoate; Jose Carlos Pastor Jimeno. iOCT in PVR management. OCT Applications in Opthalmology. pp. 1 - 8. INTECH, 2018. DOI: 10.5772/intechopen.78774.\n\n' Rosa Coco Martin; Salvatore Di Lauro; Salvador Pastor Idoate; Jose Carlos Pastor. amponadores, manipuladores y tinciones en la cirugía del traumatismo ocular.Trauma Ocular. Ponencia de la SEO 2018..\n\n' LOPEZ GALVEZ; DI LAURO; CRESPO. OCT angiografia y complicaciones retinianas de la diabetes. PONENCIA SEO 2021, CAPITULO 20. (España): 2021.\n\n' Múltiples desprendimientos neurosensoriales bilaterales en paciente joven. Enfermedades Degenerativas De Retina Y Coroides. SERV 04/2016. \n' González-Buendía L; Di Lauro S; Pastor-Idoate S; Pastor Jimeno JC. Vitreorretinopatía proliferante (VRP) e inflamación: LA INFLAMACIÓN in «INMUNOMODULADORES Y ANTIINFLAMATORIOS: MÁS ALLÁ DE LOS CORTICOIDES. RELACION DE PONENCIAS DE LA SOCIEDAD ESPAÑOLA DE OFTALMOLOGIA. 10/2014.",institutionString:null,institution:null},{id:"243698",title:"Dr.",name:"Xiaogang",middleName:null,surname:"Wang",slug:"xiaogang-wang",fullName:"Xiaogang Wang",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/243698/images/system/243698.png",biography:"Dr. Xiaogang Wang, a faculty member of Shanxi Eye Hospital specializing in the treatment of cataract and retinal disease and a tutor for postgraduate students of Shanxi Medical University, worked in the COOL Lab as an international visiting scholar under the supervision of Dr. David Huang and Yali Jia from October 2012 through November 2013. Dr. Wang earned an MD from Shanxi Medical University and a Ph.D. from Shanghai Jiao Tong University. Dr. Wang was awarded two research project grants focused on multimodal optical coherence tomography imaging and deep learning in cataract and retinal disease, from the National Natural Science Foundation of China. He has published around 30 peer-reviewed journal papers and four book chapters and co-edited one book.",institutionString:null,institution:null},{id:"7227",title:"Dr.",name:"Hiroaki",middleName:null,surname:"Matsui",slug:"hiroaki-matsui",fullName:"Hiroaki Matsui",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Tokyo",country:{name:"Japan"}}},{id:"312999",title:"Dr.",name:"Bernard O.",middleName:null,surname:"Asimeng",slug:"bernard-o.-asimeng",fullName:"Bernard O. 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Dr. Saxena is a fellow of various international societies/academies including the Royal College of Pathologists, United Kingdom; Royal Society of Medicine, London; Royal Society of Biology, United Kingdom; Royal Society of Chemistry, London; and Academy of Translational Medicine Professionals, Austria. He was named a Global Leader in Science by The Scientist. 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