EFFECTIVENESS ANALYSIS INJECTION OF BEVACIZUMAB OF INTRA PTERYGIUM TOWARD ANGIOGENESIS AND RECURRENCE PTERYGIUM

NOOR SYAMSU

ABSTRACT

Effectiveness Analysis of Bevacizumab Injections Intra Pterygium toward Angiogenesis And Recurrence Pterygium (guided by Rukiah Syawal and Budu)

Abstract. This study aims to evaluated the effectiveness of intra Pterygium Bevacizumab injection at 1.25 mg and 2.5 mg dose toward the Angiogenesis and recurrence of Pterygium.

This research was a randomized controlled clinical trial with parallel design, to evaluated the level of VEGF expression and the degree of recurrence after intra Pterygium Bevacizumab injection of 1.25 mg and 2.5 mg dose in patients who seek Pterygium treatment on Wahidin Sudirohusodo Hospital Makassar, Balai Kesehatan Mata Masyarakat (BKMM) Makassar, South Sulawesi, Celebes Eye Center (CEC) Makassar, using the "single-blind" method and has been started from June 2012 - January 2013. The method of analysis used in this study is the Chi Square using SPSS 16.0 software.

The results showed: 1.) There was a very significant improvement with p = 0.000 (p <0.01) on Angiogenesis with Bevacizumab injection. It can be concluded that by 2.5 mg Bevacizumab injection, will reduce the occurrence of angiogenesis in Pterygium patients. 2). There is a significant difference with p = 0.009 (p <0.01) on the degree of pterygum recurrence between the group without Bevacizumab injection, group with 1,25 mg injection of Bevacizumab, and group with 2,5 mg injection of Bevacizumab. It can be concluded that by giving Bevacizumab injection at a dose of 2, 5 mg, it would reduce the degree of recurrence in pterygium patients (value of recurrence reaches 0%). 3). The results from statistical calculations showed a significant correlation between VEGF levels with the degree of recurrence, It is shown from the value of p = 0.002 (p <0.01). It can be interpreted that the lower the VEGF level, the chances of recurrence will be smaller.

Keywords: Pterygium, Bevacizumab, Angiogenesis, recurrence.

1. Background

Pterygium is a degenerative process and hyperplastic tissue of conjunctiva in the form of triangular-shaped fibrovascular, which grows in the conjunctiva to the corneal surface and infiltrating (Burrato, 2000; and Barraquer, 2005).

Pterygium commonly seen in the tropics between latitudes 30 ° North and 30 ° South latitude, the region known as the "pterygium belt" (Buratto, 2000; Gazzard, et.al., 2002; Saw, et.al., 2000; Barraquer, 2005; and Detorakis, et.al., 2009). This indicates that sunlight or ultraviolet radiation is a possible causative factor. Not surprisingly, in Indonesia found a high prevalence of pterygium (Gazzard, et.al, 2002). Health survey results Vision and Hearing Department of Health (1996), obtained pterygium among four major eye diseases with a prevalence of 13.9% (Department of Health of Indonesia, 1998). While the results of the survey Blindness and Eye Health in West Java in 2005, with a prevalence rate of pterygium 19, 3% morbidity dominating eyes with refractive errors (58%) and cataract (22.8%) in the population of the age group 40 years and over (Sirlan, et.al., 2005).

There are many options for the treatment of pterygium. Non-surgical treatment consists of the use of lubricant eye drops, or anti-inflammatory vasoconstrictor, and protection from ultraviolet light by wearing sunglasses (Bahar, et.al,. 2008). Surgery to

remove the pterygium tissue is selected therapy. However, until nowdays none of the surgical methods that gives perfect results, with high recurrence rates are still being felt. In addition, the frequent recurrence of the pterygium severity heavier than the primary pterygium (Barraquer, 2005; and Burrato, 2000).

Although many surgical techniques that have been performed since the early 1960s, new ways to deal with pterygium to date continues to be to provide a more effective therapeutic outcomes. The diversity of surgery presented in the literatures also prove that the problem is still unresolved pterygium treatment (Burrato, et.al,. 2000).The ideal pterygium surgery should be able to achieve three main objectives, a low recurrence rate, complications and the absence of a satisfactory cosmetic result. Pterygium surgery were previously considered to be a simple procedure, has become more challenging, although the results obtained are varied (Burrato, 2000; Rocha, 2003; Fernandes, 2005; and Skolnick, 2005).

Etiologic cause of pterygium is still unclear, there is linking with ultraviolet exposure, due to the process of degeneration, and some are expected due to a chronic inflammatory process. Broadly speaking there are three main factors that initiate until finally formed pterygium, such as mitogenic, construction of new vascular tissue, and extracellular matrix remodeling. These three factors together resulted in fibrotic tissue and vascular new, aggressive as a way to grow into and beyond the cornea (Barraquer, 2005). Current knowledge on the biochemical processes that play a role in pterygium growth likely to initiate the development of new therapies that can prevent or stop the growth of pterygium in the early stages.

Vascular proliferation play role in pterygium growth processes. Some writings and recent studies showed that the role of angiogenesis in the onset of pterygium (Marcovici, et.al. 2002) found that vascular endothelial growth factors (VEGF) and von Willebrand factor (vWF) over-expression in pterygium tissue. Aspiotis, et.al., (2005) get the angiogenic factor VEGF has a very high expression in pterygium tissue and in accordance with micro vascular density (microvessel density/MVD) were higher in pterygium compared with conjunctival tissue normal. Research conducted by Yan, et.al., (2007), also get a high expression of cyclooxigenase-2 (Cox-2) and VEGF in pterygium tissue, which shows why the multiplication of abnormal blood vessels happened in pterygium. Based on their research concluded the possibility of using Cox-2 specific inhibitors and VEGF as a novel therapeutic target for pterygium. Dushku, et.al., (2001), found that the active matrilysine (MMP7) play a role in the angiogenesis process which is characteristic of pterygium tissue. In another study by examining pterygium tissue that has been dyed turned out the number of microvascular (Neovascularization) in pterygium tissue was also higher than normal conjunctival tissue (Farrah, et.al., 2006).

Neovascularization can occur due to a process of angiogenesis stimulated by VEGF. In the area there is a pterygium is more prominent that the ocular surface, this area will be rapidly running dry when tears spread, which if prolonged will cause the area experienced hypoxia and will stimulate the Neovascularization. (Lee, et.al., 2001; Felmeden, et.al., 2002), found that the level of nitric oxide (NO) together with the expression of VEGF in pterygium tissue is higher than normal conjunctival tissue. Increased NO levels showed ischemic condition. The most important angiogenesis mediator known is VEGF, and therefore giving antiangiogenesis factor (anti-VEGF) could inhibit neovascularization and could stop the progression of growth or prevent recurrence of pterygium (Fernandes, et.al.,2005).

One antiangiogenic agentsis Bevacizumab. This drug was originally approved by the FDA for the treatment of colorectal cancer and is now being tested for breast cancer (Ferrara, 2001).For eye diseases with impaired vascular permeability of these drugs have been tested in "off-label" in age-related macular degeneration (ARMD), neovascularglaucoma, proliferative diabetic retinopathy (PDR) and central retinal venous obstruction (CRVO). Bevacizumab provision could be systemic but due to the risk of systemic administration of a lot more, so to minimize the risk of systemic administration of intravitreal be an option (Ferrara, 2001; Hosseini, et.al.,2007; dan Collet, et.al.,2007).There have been many studies that provide the intravitreal injection of Bevacizumab with varying

doses of 1.25 mg and 2.5 mg, in patients with PDR and managed to produce regression Retinal Neovascularization, accompanied by a significant improvement in visual acuity (Gazzard, 2002; dan Hosseini, et.al.,2007; and Collet, et.al.,2007).

Avery, et.al., (2005), and Spaide, et.al., (2006), has been conducting research with Bevacizumab intravitreal injection of 1.25 mg / 0.05 cc in patients with diabetic retinopathy is accompanied by vitreous hemorrhage. Similarly, Collet, et.al, (2007), and Gail, et al, (2009), who did the same study, intravitreal injection of Bevacizumab at a dose of 1.25 mg in patients with diabetic retinopathy Neovascularization heavy. Horitoglu, et.al., (2005) Avery (2005), states that the intravitreal Bevacizumab administration at a dose of 2.5 mg showed improvement of visual acuity and retinal thickness decreased, in patients with diabetic macular edema that did not respond to photocoagulation and intravitreal injection of Triamcinolone , and vitrectomy. Bashshur, et.al., (2000); and Avery (2005), intravitreal injection of Bevacizumab at a dose of 2.5 mg in patients with type ARMD neovaskuler and do Bevacizumab injection at a dose of 1.25 mg and 2.5 mg in patients with CRVO, and proved that the dose of 2.5 mg no toxic effect on the retina, although this drug penetrates the entire thickness of the retina. On examination on multifocal ERG, seem macular function improvement after injection of Bevacizumab (Avastin) (Gazzard, 2002;, and Hosseini, et.al., 2007).

Use of Bevacizumab has also been tried on corneal neovascularisation topically and subconjungtival turns neovacularisation reduction effect as has been reported by Kim et al, (2008, Bahar, et.al., 2008, Park, JH, 2012).

Use of Bevacizumab for pterygium has not been widely reported, only a few researchers suggested as one additional alternative therapies other than surgery for pterygium.

Role of Angiogenesis in the process Pterygium evidenced by many of the most important angiogenic factor involvement in Pterygium pathogenetic is VEGF (Detorakis, 2009, Bradley, 2010). Current antiangiogenic studied for many eye diseases are Bevacizumab. For that see the role as an anti-VEGF Bevacizumab in the treatment of pterygium, it is necessary and important to do research to look at the effect of pterygium on the intra Bevacizumab Angiogenesis in pterygium, which is more effective dose and optimal, and how the outcome of this Bevacizumab may inhibit or reduce recurrence Pterygium.Relationship between the level of VEGF expression to this recurrence. From our literature search there is no researches mention bevacizumab injection intra pterygium in Indonesia and we have not come across literature who wrote the VEGF expression level in relation to the onset of pterygium recurrence.

2. Methods2.1. Research Design

This study is a Randomized Controlled Clinical Trial (RCTs) with parallel design, to assess the level of VEGF expression after injection of intra pterygium Bevacizumab 1.25 mg and 2.5 mg in patients with pterygium. The research was conducted by using the "single-blind" methods.2.2. Location and Time Research

This research has been conducted on patients with pterygium that were treated in hospital. Wahidin Sudirohusodo (RSWS) Makassar, Balai Kesehatan Mata Masyarakat (BKMM) South Sulawesi, Celebes Eye Center (CEC) Makassar, and has been started from June 2012-January 2013, for about 8 months.2.3. Population and Samplea) The population is all patients that were diagnosed with pterygium who were treated in hospital. Wahidin Sudirohusodo Makassar, BKMM, and CEC Makassar.b) The sample is pterygium patients.Samples were taken for all patients who met the study criteria and were performed ophthalmology examination.

c) The samples were divided randomly into two groups.Group of patients with pterygium that were given injections of 1.25 mg subcongjuntival Bevacizumab and group that were given injections of 2.5 mg subcongjuntival Bevacizumab.d) Inclusion Criteria:1. Pterygium patients treated in RSWS Makassar, BKMM and CEC.2. Aged under 50 years3. Possible to perform the examination.4. Willing to be included in the study.e) Exclusion Criteria:1. Patient refused to follow the research.2. Pseudo pterygium.3. History of pterygium surgery before.4. Suffer from hypertension or diabetes mellitus.f) Sample size:To estimate the sample size using the Isaac & Michael table. Population of pterygium patients in Wahidin Sudirohusodo Hospital in 2007 was 114 patients, so that the number of eligible sample inclusion within 6 months was 60 patients (statistical consultation).2.4. Research Feasibility of Ethics permits

In this study, all the actions carried out with the approval of the subject through the informed consent sheet, after the subjects received an explanation for the action to be performed, as well as conduct research meet the requirements for implementation of the Biomedical Research Ethics Committee of the Medical Faculty at the University of Hasanuddin.2.5. Classification of Variables

In this study several variables can be identified based on the role and scale.Based on the role or function:1.The independent variable was Angiogenesis pterygium.2. Dependent variable is the level of expression of VEGF in pterygium tissue, and recurrence

of pterygium.3. Variable moderator is an Bevacizumab injection intra pterygium4. Variable control are operating techniques, age, additional therapy, and jobs.2.6. Operational definitions and objective criteria1. Operational definitions

a. Pterygium is a triangular-shaped tissue growth fibrovaskuler growing from nasal or temporal conjunctiva to the cornea.

b. Angiogenesis in pterygium is the level of expression of VEGF in pterygium tissue that with injection and without injection of Bevacizumab intra pterygium, performed by immunohistochemistry.

c. Injection of Bevacizumab is Bevacizumab drug injected intra pterygium in pterygium tissue.

d. Bevacizumab is an anti-VEGF drugs containing Bevacizumab, a humanized monoclonal antibody recombinat.

e. Pterygium recurrence is whether or not the pterygium back arises in the same area after removal of the pterygium tissue.

2. Objective criteria variablea. Pterygium

Pterygium is a growth of tissue that form a triangle fibrovaskular, the centripetal growth of the nasal or temporal to the cornea and has the classification:1. Pterygium membrane type, if the pterygium thin, translucent and containing 1-2 veins.2. Pterygium vascular type, if it contains many blood vessels (5 or more).3. Pterygium sarkomatosum type, if there is a conjunctival epithelial tissue hypertrophy.

Based on the extent of the invasion to the cornea pterygium, pterygium is classified into 4 stages, namely:1. Stage I, when the pterygium not achieve corneal limbal.2. Stage II, the apex of the pterygium has been reached and passed the limbal, but has not reached the pupillary area.3. Stage III, reaching the apex of the pterygium pupillary area.4. Stage IV, the apex of the pterygium has been through the pupil / optic zone (Aspiotis, et.al., 2006).

b. The expression level of VEGF is the expression levels of VEGF that are found in pterygium tissue samples that were excised after injection and without injection of Bevacizumab Bevacizumab, conducted by immunohistochemical examination.The expression levels of VEGF(Fahmi,2006) assessed as follows:Level 0 = No adaekspresi VEGF in pterygium tissueLevel 1 = Expression of VEGF is less than 10%Level 2 = 10-50%Level 3 = More than 50%

c. Recurrent pterygiumThere are fibrovaskular tissue regrowth in the same place after surgical treatment with or without Bevacizumab injection, at least 1 month after surgery.Recurrence Pterygium are classified based Burato, et.al., (2000): 1. Grade 1: The appearance of the surgical site is no different from the normal site.2. Grade 2: Some episkleral vein at the site of pterygium excision extends up to but not past the limbal and without fibrous tissue.3. Grade 3: Incidence of fibrous tissue in the excised area, but did not invade the cornea.4. Grade 4: True recurrence, with fibrovaskuler tissue invading the cornea.In this study the degree of recurrence were classified as follows:1. No Recurrence: if the patient is in Grade 1 and when the eye tissue looks like normal tissue on post-surgery examination.2. Recurrence: if the patient is in grade 2, grade 3 and grade 4 in the post-surgery examination.

2.7. Methods of AnalysisAll data that were obtained, grouped according to the purpose and types of data. For

further tested by using:1. Univariate analysis

To assess the level of expression of VEGF with Bevacizumab dose of 1.25 mg and 2.5 mg, to see the recurence of pterygium in group that got injection and group that doen’t got injection.

2. Bivariate analysisTest differences in the average value was used to compare between pterygium groups that are getting injections with no injections, comparing the differences in the effectiveness of 1.25 mg and of 2.5 mg dose of Bevacizumab injection, compared the recurrence rate of each group. Data processing and statistical tests performed using SPSS software version 16.0.

3. Assessment results of hypothesis testingAssessment results of the hypothesis test is stated as follows:Not significant when P> 0.05 and significant when P <0.052.8. Research Facilities

Research facilities such as:1. Snellen Test2. Schiotz Tonometer3. Opthalmoscopy 4. Biomicroscopy Slit lamp5. C. Pantocain ED 0.5 %

6. C. Mydriatiil ED 0.5 %7. C. Xitrol ED 8. Examination Form

2.9. Research Procedures1. Each subjects included in this study, recorded their identity and made an informent concent.2. Subjects were examined their visual acuity, tonometry, slit lamp, systemic blood pressure, and fundoscopy.3. Noted the pterygium type, degree / stage and patient age (early photographic documentation done at first visit).4. Do intra Pterygium Bevacizumab injection of 1.25 mg or 2.5 mg after randomized on half of the sample and the other without injection.5. Pterygium surgery in a week after injection while the pterygium without direct injection can be excised anytime.6. All patients received postoperative subconjunctiva injections of Dibekacin and Dexametason, and got medication of eye drops Polydex and Floxa during follow up.7. Pterygium tissue is sent to the pathology clinic to see the level of expression of VEGF.8. Follow-up of patients done at Fist week, second week, third week and fourth week post operative.

Intra pterygium Bevacizumab injection technique:1. Instill Topical anesthesia.2. Provision of povidone iodine on the border of the lid, ciliary and conjunctival surface.3. Put speculum.4. Pterygium tissue is held using conjunctival tissue.5. Enter the drug slowly into the pterygium tissue according to the dosage6. Pull the needle slowly.7. Control bleeding that may arise.8. Press the injection area with a cotton stick containing povidone iodine.9. Instill a topical antibiotic.10. Remove the speculum.

3. Result and Discussion3.1. Result

This research is a clinical trial conducted after obtaining approval from the ethics committee of Hasanuddin University Faculty of Medicine with a registration number UH12040107. Study began in June 2012 and ended in January 2013. Of 70 samples were operated and were followed up only 60 samples that met the study criteria. Then the sample is classified into 3 groups : group 1 of samples got Bevacizumab injection at a dose of 2.5 mg, group 2 of samples got Bevacizumab injection at a dose of 1.25 mg and group 3 was a control group with no injection.

Assessment results for angiogenesis based on the expression levels of VEGF immunohistochemical examinations were performed at the Laboratory of Clinical Pathology, University of Hasanuddin, while recurrences were assessed one month post-surgery to see whether there were or were not blood vessels and fibrovaskuler tissue that growed on the former site of the operation which had passed the corneal limbal.

Results regarding patient characteristics in age, sex, types of occupation and pterygium stages described as follows :

1. Patient CharacteristicsTable 2. Characteristic of The Study Samples

Sample Characteristic Total (n) %

Age

≤30 years 5 6,1

31 - 40 years 12 20,0

41 - 50 years 42 73,9

SexMale 27 44,6

Female 33 55,4

JobIndoor 30 50

Outdoor 30 50

Stadium of Pterygium

1 - -

2 40 66,67

3 20 33,33

4 - -

Table 2 shows that the majority of patients suffering from pterygium were over 41 years old, that as many as 42 people (73.9%) and most of them were female that as many as 36 people (55.4%). The remaining 26.1% were under 30 years ond and male as many as 22 people or 44.6%

Based on the types of occupation, known that patients suffering from pterygium working both inside room and outside room were 30 people each or 50%, and based on pterygium stages, the highest was in grade 2 as many as 40 people or 66.67% and the lowest was in grade 3 as many as 20 people or 33.33%.

2. Analysis of The Results of Intra Pterygium Injection of Bevacizumab with Angiogenesis to The Control Group, The Group Injected with 1.25 mg and The Group Injected with 2.5 mg

In Table 3 can be seen the comparison of the results of clinical trials to Angiogenesis, that the group without injection of Bevacizumab, there were 5 samples (8.3%) at the VEGF level 2 and 10 samples (16.7%) were at level 3. While with the injection of Bevacizumab 1.25 mg, there were 6 samples (10%) at the VEGF level 1, 9 samples (15%) the VEGF level 2, and other 10 samples (16.7%) were at level 3. And in the injection of Bevacizumab 2.5 mg group, there were 6 samples (10%) at the VEGF level 2, other 14 samples (23.3%) were at the VEGF level 1 and no samples at the VEGF level 0 and level 4.

The results of Chi-Square analysis of Table 3 showed significant improvements of Angiogenesis by the injection of Bevacizumab 2,5 mg compared to the injection of Bevacizumab 1,25 mg and no injection of Bevacizumab, which is marked with a p-value below 0.000 (p <0,01).

So it can be said that the injection of Bevacizumab 2.5 mg will reduce the occurrence of angiogenesis in patients with pterygium.

Table 3. Correlation between Bevacizumab injection intra Pterygium with Angiogenesis.

Group

VEGF LevelInjection 2,5 Injection 1,25 Control

Level 1 14 (23,3%) 6 (10,0%) 0

Level 2 6 (10,0%) 9 (15,0%) 10 (16.%)

Level 3 0 5 (8,3%) 10 (16,7%)

Total 20 (33,3%) 20 (33,3%) 20 (33,3%)

Figure 8. Comparison of Bevacizumab injection intra Pterygium to Angiogenesis in

control group, 1,25mg injection group and with 2,5mg

injection group.

In the histogram above it is obviously shown that with the injection of Bevacizumab 2,5 mg, the value of VEGF expression is decreased compared to the group II and the control group.

Figure 9. Immunohistochemistry of Pterygium tissue in several VEGF levels. (A. Level VEGF 1; B. Level VEGF 2; C. Level VEGF 3).

3. Analysis of The Results of Intra Pterygium Injection of Bevacizumab with Degree of Recurrences to The Control Group, The Group Injected with 1.25 mg and The Group Injected with 2.5 mg

In Table 4, we can see the comparison of the average results of clinical trials to recurrence rate based on Burato, et.al., (2000) and after the examination, it shows in group with no injection of Bevacizumab that there were 5 (8.3%) of the total population samples who experienced recurrence while 15 (25%) of the total population samples did not experience recurrence. Whereas in the group with the injection of Bevacizumab 1.25 mg, there was 1 sample (1.7%) experienced recurrence and 19 samples (31.7%) did not experience recurrence. And in the group with the injection of Bevacizumab 2.5 mg, all of the samples (33.3%) did not experience recurrence.

Chi-Square results of Table 4 shows a very significant difference in the degree of recurrency among the group with no injection of Bevacizumab, the group with the injection of Bevacizumab 1.25 mg, and the group with the injection of Bevacizumab 2.5 mg characterized by the value of p as 0.009 (p <0.01).

Or it can be said that the injection of Bevacizumab 2.5 mg would reduce the degree of recurrence in patients with pterygium.

A B

C

Table 4. Corelation between Bevacizumab injection intra Pterygium with Recurrency.

Group

Recurrency2,5 injection 1,25 injection Control

No Recurrency 20 (33,3%) 19 (31,7%) 15 (25,0%)

Recurrent 0 (0,0%) 1 (1,7%) 5 (8,3%)

Total 20 (33,3%) 20 (33,3%) 20 (33,3%)

Figure 10. Comparison of Bevacizumab injection intra Pterygium to Recurrency

rate in control group, 1,25mg injection group and with 2,5mg injection group.

4. Relationship between VEGF Levels and Degree of Recurrences after Intra Pterygium Injection of Bevacizumab to The Control Group, The Group Injected with 1.25 mg of Bevacizumab and The Group Injected with 2.5 mg of Bevacizumab

The result will be shown in this section is a comparison of the clinical trials results of the VEGF levels to the degree recurrence after the intra pterygium injection of Bevacizumab.

In Table 5 we can see that on the examination patients with the VEGF level 3, there were 5 patients or 8.3% who experienced recurrence. In patients with the VEGF level 2, there was 1 patient or 1.7% who experienced recurrence. Whereas in patients with the VEGF level 2 and the VEGF levels 0, no patients experienced recurrence.

Tabel 5. Correlation between VEGF level with recurrency level

Recurrency

VEGF levelNo Recurrency Recurrent

Level 1 20 (33,3%) 0 (0,0%)

Level 2 24 (40,0%) 1 (1,7%)

Level 3 10 (16,7%) 5 (8,3%)

Total 54 (90,0%) 6 (10,0%)

Figure 11. Correlation between VEGF level with Recurrency rate after

Bevacizumab injection intra Pterygium.

The results of statistical calculations shows a significant correlation between the VEGF levels and the degrees of recurrence, by the value of p = 0.002 (p <0,01). It can be interpreted that the smaller the VEGF level, the smaller the chance of recurrence happened.

4. Discussion4.1. Analysis of Patient Characteristics.

From the results presented above, it can be seen that the majority of patients suffering from pterygium is aged over 41 years, as many as 42 people (73.9%) and the remaining 26.1% were aged under 30 years. This is consistent with epidemiological data pterygium which increases with age, especially in the 2nd and 3rd decade of life and the highest incidence between the ages of 20-49. And rarely in the age group below 20 years (Detorakis, 2009, Bradley, 2010). At this age, generally they have a great activity to be outside room. Of course the risk of very large exposure to UVB. UVB which is known as the very strong originator onset of pterygium. Besides, at a young age, the process of cell proliferation, cell mitosis as well as other factors such as inflammation-immunologist is very active, so the UVB exposure will stimulate the process of mitosis, as well as the immunological and inflammatory processes, which is also play a role in the onset of pterygium.

Based on the sex, most of them are female, as many as 36 people (55.4%). and male were 22 men (44.6%). According to the theory, the prevalence of pterygium were more common in men because they spend most of their time in outside activities (Aspiotis, et.al., 2006, and Avastin, 2005). But in this study, we found it was greater in women than in men.

This possibility is due to the awareness of patients and cosmetic complaints by women, more than men.

Based on the types of jobs, it is known that patients suffering from pterygium work inside and outside room, each of 30 people (50%). This is in accordance with the risk factors pterygium is exposed to sunlight, the length of time outside the home, chronic irritation of certain materials in the air (Avastin, 2005). Further explain, although the cause of pterygium is unknown, but those who work outside and exposed to the sun and wind are more prone to suffering from pterygium which originated from conjunctival irritation. Pterygium is more common in tropical and subtropical areas with a prevalence of 2% to 7% in the entire world, and is more common in areas with high ultraviolet radiation, especially UVR-A and UVR-B (290-400nm), which are considered the most potent. In this research, number of people working indoor and outdoors is equal, it is likely due to the limited number of samples in each group.4.2. Analysis of Bevacizumab Injection intra pterygium on Angiogenesis in the

control group, the group injected with the injection of 1.25 mg and 2.5 mg.Research on the level of VEGF as one of the factors causing ptergium can be done

with the many kind of ways and methods. Omar, et al, (2012), Hussein, et al, (2009) research based on VEGF levels. Pterygium grading were assessed before and after the injection of Bevacizumab intra pterygium with a dose of 2.5 mg. After 6 weeks post-injection, there are changes in pterygium grade into a lower grade. In this study it is assumed that if the grade changes to lower mean levels of VEGF also decreased. Research conducted Aspiotis, et.al., (2007), get high levels of VEGF expression in pterygium tissue compared to normal conjunctival tissue.

Based on the results obtained above, it can be seen that the injection of Bevacizumab intra pterygium, can prevent the process of angiogenesis. And is statistically proven that the injection of Bevacizumab at a dose of 2.5 mg intra pterygium was highly significant for the lower levels of VEGF (p = 0.000). This is in accordance with the opinion of Ferara (2001), that was working Bevacizumab binds and neutralizes all VEGF isoforms A , eliminating the circulation of free VEGF and prevents VEGF binding to its receptor. Where the goal is:1. Antibodies are created specifically and only binds to VEGF.2. With inhibition of VEGF, VEGF antibody can inhibit the activity of the receptor with all

interactions (VEGFR-1, VEGFR-2 and neuropilin-1 coreseptor). As a result, the effect of VEGF-mediated proangiogenik by all receptors, can be inhibited by targeting VEGF.

3. Binding all completely free VEGF, inhibits VEGF receptor-mediated stimulation of VEGF.This study has shown that injection of Bevacizumab at a dose of 2.5 mg has a

significant effect on the healing of pterygium. Injecting a dose greater affinity certainly has more power to VEGF, either free or bind to VEGF receptors, the effect is greater than the low dose especially when compared with the control group, so that the course can decrease the level of expression of VEGF in pterygium tissue. Where it also expressed by Hosseini, et al, (2007); Filipe, 2009, Omar, et al, (2012), who has done Bevacizumab injection at a dose of 1.25 mg and 2.5 mg in patients ptergium, and shown to be effective in reducing pterygium grade becomes smaller, the size and vascularity of diminishing ptergium. In this research work, it is said to peak levels Bevacizumab starting at 1 week post-injection.

In this study, there were no serious side effects such as increased intra-ocular pressure, pain in the eyes, burning sensation, but there are mild subkonjuntival bleeding in 4 patients. This result is similar to research conducted by Avery (2005) and Spaida (2005), who has conducted research with Bevacizumab intravitreal injection of 1.25 mg / 0.05 cc in patients with diabetic retinopathy that is accompanied by vitreous hemorrhage. Therefore researchers used intraviteral therapy to reduce the effects. This is in accordance with the opinion of Ferrara, (2001), and Hosseini, et.al., (2007), who said that the use of Bevacizumab systemic side effects are severe and even fatal, so to avoid this effect in the treatment of eye diseases that are vascular permeability disorders such as ARMD, glaucoma neovaskuler, PDR and CRVO, the intravitreal therapy is an option that can be used. Systemic complications may include bowel perforation, hemorrhagic stroke, myocardial

infarction, hypertension and proteinuria. Complications that can occur in the intravitreal administration, among others: endopthalmitis, retinal detachment, increased intra-ocular pressure (IOP) and thromboembolism.4.3. Analysis of Bevacizumab Injection on the degree of intra pterygium Recurence

in control group, the group injected with the injection of 1.25 mg and 2.5 mg.On these studies the overall recurrence rate in the control group and the group with

injection is 10%. However, if examined, the recurrence rates in each respective group showed significant differences recurence. By injecting 2.5 mg of Bevacizumab, there is no recurrence, in the group with injection of 1.25 mg Bevacizumab, only 1 (1.7%) samples had recurrence, whereas in the control group there were 5 (8.3%) samples had recurrences. Based on the above results it can be concluded that the injection of Bevacizumab 2.5 mg very effective in reducing postoperative recurrence ptergium.

Recurrence rate in this study is also much better than the research conducted by Buratto, et.al., (2000), who obtained the results of recurrence by 26.7% with a simple graft method and 17.2% with the combination autograph transplant stem cell, as well as research that has been conducted by Rocha, (2000) and Rabatti, et.al., (2003), by the method of transplantation of amniotic graft obtained recurrence of 3.2%.

Research conducted in Indonesia, get the recurrence rate varies depending on operating methods and techniques. Such as dr. Sutomo, Surabaya, get a recurrence rate of 50% with bare method sklera Taufik (1985), which examines the relationship pterygium in age, gender, location, and recurrence, recurrence obtained approximately 31.88%, while Syamsu (1998), get a 5.9% recurrence with mitomycin C administration, and Arifin (2003) get a 3.2% pterygium recurrence with amnion transplantation techniques graff.

Compared to some of the above studies that require special techniques and experience, coupled with a long operating time, post-surgical care, as well as long term complications because the use of drugs that are often found in the use of mitomycin, the injection of Bevacizumab intra pterygium may be a good alternative to prevent recurrence of pterygium.

Examination of recurrences in this study is presented from 1 month after surgery. This is in accordance with the opinion of Duskhu, et.al., (2001), and Burrato, et.al., (2003), who said that although longer follow-up are needed to ensure post-surgical recurrence of pterygium is true, there is evidence that 50% -94% of recurrences occurred within the first 3 months, and are therefore not found recurrence within the initial results showed considerable.

4.4. Analysis of the relationship between VEGF Level to the Degrees of Recurrence after intra Bevacizumab injection in the control group, the group injected with the injection of 1.25 mg and 2.5 mg of Bevacizumab.

Based on the results of the relationship between the level of VEGF on the degree of pterygium recurrence in patients after injection of Bevacizumab, indicates that there is a significant relationship between the two. This is shown by the results of calculations performed Chi-square of 0.002 (p <0,01).

In this study, it can be seen that the relationship between the level of VEGF on the degree of recurrence, is the decline in the level of VEGF, will have an impact on the decline in the recurrence rate of pterygium that occurred in patients after injection of Bevacizumab with increasing dose. Not been much research on the relationship between the level of VEGF on the degree of recurrence in patients with pterygium, but it can be explained that the VEGF is the main force behind the entire tumor angiogenesis and blood vessel formation. Where the three main activities of endothelial cells in angiogenesis, namely protease secretion, migration and proliferation. VEGF is able to trigger all three processes and work specifically on endothelial cells. VEGF also acts as a survival factor by inhibiting apoptosis of endothelial cells that could lead to an increase in the specific tumor recurrence after therapy (Rosen, 2002, Plank and Sleeman, 2003).

In another study in India on tumor nasopharyngeal carcinoma (NPC) to evaluate the correlation between the expression of VEGF, EBV status and recurrences in NPC. VEGF

overexpression obtained in 67% of 103 patients with NPC. The results lead to the expression pattern of VEGF as a potential tumor marker for early diagnosis of metastases and the presence of EBV in NPC associated with upregulation of VEGF (Krishna et al, 2006). Where in the study obtained the conclusion that the increased levels of VEGF as a key trigger recurrence rate in NPC.

On pterygiuym, the role of ultraviolet B suspected as the main cause of both primary pterygium and that recurent. UVB then induces all inflammatory role, mediator release, ocular surface damage, stimulate immunological reactions and increase the level of expression of VEGF and other factors angiogenesis. High levels of expression of VEGF is a signal to stimulate the formation neovaskularisation, together with other factors such as fibroblast growth factor, connective tissue growth factor and other mediators that play a role in the formation of neovascular and fibroblasts, also play a role in the formation of pterygium (Aspiotis, et.al, 2007; Setten, et al, 2003; Lee, et al, 2007; and Roskoski, 2007).

Research on the role of VEGF as one of the causes of pterygium has been done by Aspiotis, et.al., (2007), which has obtained the results of the high levels of expression of VEGF and the number of network mikrovessel pterygium tissue, compared to normal conjunctival tissue. Similarly Seifeld, et.al., (1998), in his research, found the high level of expression of VEGF in pterygium tissue.

Several studies that found high levels of VEGF expression indicating the presence of hypoxia in pterygium tissue. This theory advanced by Girolamo, (2006); Detorakis, et.al., (2009); Bradley, (2010), and Balci, et.al., (2011 ).

The relationship between high levels of expression of VEGF against recurrence has not much to examine, but when look at the role of VEGF on the growth of primary pterygium, it is almost the same as the incidence of pterygium recurrence. Pterygium postoperative course will be determined by the high level of expression of VEGF, a growth factor and other inflammatory mediators such as cytokines, interleukins that play a role in wound healing and angiogenesis terbentuknnya will stimulate tissue growth fibrovaskuler plus pterygium causes predisposing factors such as work (out door working), age and sex that of course will facilitate recurrence.

In this study, it can be concluded that the low levels of VEGF express increasingly reduce the likelihood of recurrence, where the pterygium recurrence seen in the control group with high VEGF expression levels, and has a predisposition originator of recurrence include young age, outdoor work that would facilitate incidence of recurrence.

5. Conclussion and Suggestion5.1. Conclussion

From the result and discussion, some conclusions can be drawn as follows :1. There is a difference of the VEGF expression level between pterygium

injected with Bevacizumab and pterygium did not inject with Bevacizumab with the value of the statistical test Chi-Square p = 0.00.

2. There is a difference in the effectiveness of Angiogenesis inhibition process between dose of 1.25 mg with dose of 2.5 mg. In this study, the intra pterygium injection of Bevacizumab at a dose of 2.5 mg is more effective than the dose of 1.25 mg.

3. There is a difference in the recurrence rate of pterygium after the intra pterygium injection of Bevacizumab at a dose of 1.25 mg and dose of 2.5 compared with the control group, which the Chi Square test showing the value of p = 0.00. In this study, it is showed that the most effective dose to prevent recurrence is dose of 2.5 mg.

4. In this study, it is also demonstrated a significant association between the VEGF expression level with recurrence rates with a value of p = 0.02. It means the smaller the VEGF, the smaller the likelihood of recurrence.

5.2. Suggestion

1. In this study, there is a limitation because only one trigger factor is studied. There is a need of another study to see the other factors such as the other growth factors, immunological factors or inflammatory factors, so we can see what the most influential factor in etiopathology of pterygium is.

2. Longer studies are needed to look at the effectiveness of the injection of Bevacizumab in pterygium.

3. The results of this research are suggested to be an additional alternative to the procedure of pterygium surgery. The injection of Bevacizumab looks effective in reducing the VEGF level and recurrence of pterygium. Besides, this procedure is very simple and has minimal complications compared with the other procedures.

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JOURNAL

EFFECTIVENESS ANALYSIS INJECTION OF BEVACIZUMAB OF INTRA PTERYGIUM TOWARD ANGIOGENESIS AND RECURRENCE PTERYGIUM

BY:

NOOR SYAMSU

P0200307040

PROGRAM PASCASARJANA

UIVERSITAS HASANUDDIN

MAKASSAR

2013