Distribution and prevalence of refractive error in Iranian adult population results of the PERSIAN eye cohort study PECS.

The Persian Eye Cohort Study, a population-based cross-sectional study from 2015 to 2020, examined refractive error prevalence among 48,618 Iranian adults aged 31 to 70. The study encompassed six centers in Iran, employing random cluster sampling for demographic, medical, and socioeconomic data collection through interviews. Ophthalmic exams included visual acuity, automated and manual objective refraction, subjective refraction, slit lamp, and fundus examinations. Using the spherical equivalent definition, the sample population was categorized into groups. Results indicated a mean age of 49.52 ± 9.31 and a mean refractive error of 0.26 diopters (D) ± 1.6 SD (95% CI - 0.27 to -0.24), ranging from -26.1 to + 18.5 SD. Prevalence of myopia (< -0.5D) and hyperopia (> + 0.5D) was 22.6% (95% CI 22.2-23%) and 12.5% (95% CI 12.1-12.8%), respectively. Regarding different age groups, the prevalence of hyperopia and astigmatism exhibited a steady and significant rise with increasing age (p-value < 0.001 for both). The prevalence of Myopia, however, showed a distinctive pattern, initially increasing in adults under 45, declining in those aged 55-64, and rising again among individuals aged 60 and older. Female gender, older age, urban residency, higher education, higher income, and Fars ethnicity were significantly related to a higher prevalence of myopia (p-value < 0.001 for all). Female gender (p-value < 0.001), aging (p-value < 0.001), urban residency (p-value = 0.029), and lower-income (p-value = 0.005) were significantly related to higher prevalence of hyperopia. Astigmatism (> 1D) was prevalent in 25.5% of participants (95% CI 25.1-25.9%) and correlated with male gender, aging, urban residency, illiteracy, and higher income (p-value < 0.001, < 0.001, < 0.001, < 0.001, 0.014, respectively). The study's comparison with regional and international surveys highlighted the increase in myopia among those over 65 due to higher nuclear cataract rates in older adults. Myopia positively related to education, income, and urban residency, while hyperopia did not exhibit such associations.

The Antitumor Effect of Topotecan Loaded Thiolated Chitosan-Dextran Nanoparticles for Intravitreal Chemotherapy: A Xenograft Retinoblastoma Model.

Purpose: This research intended to fabricate the thiolated chitosan-dextran nanoparticles (NPs) containing topotecan (TPH-CMD-TCS-NPs) to assess the ability of NPs in improving the efficacy of intravitreal chemotherapy of retinoblastoma in a rabbit xenograft model. Methods: The coacervation process was used to produce the NPs. The cellular uptake of Cyanine-3 (CY3)-labeled NPs were investigated in human retinoblastoma Y79 cells using confocal microscopy. Also, the prepared TPH-CMD-TCS-NPs were tested in vitro by the tetrazolium dyes II (XTT) and flow cytometry in order to assess their cytotoxicity. In addition, a rabbit xenograft model of retinoblastoma was developed to test the antitumor effectiveness of TPH-CMD-TCS-NPs through intravitreal administration. Results: NPs had a mean diameter, polydispersity index, and zeta potential of 30 ± 4 nm, 0.24 ± 0.03 and +10 ± 3 mV, respectively. NPs (IC50s 40.40 compared to 126.20 nM, P = 0.022) were more effective than free topotecan as a dose-based feature. The tumor reaction to intravitreal chemotherapy with NPs was measured by evaluating the percentage of necrosis in the tumor tissue (91 ± 2%) and vitreous seeds (89 ± 9%) through hematoxylin and eosin (H&E) staining. In comparison with the control group, the TPH-CMD-TCs-NPs treated group showed a significant decrease in tumor volume seven days after the intravitreal injection (P = 0.039). No significant changes were found in the ERG parameters after the intravitreal injection of TPH-CMD-TCs-NPs or TPH (P > 0.05). Conclusion: This investigation revealed definitive antitumor efficacy of TPH-CMD-TCS-NPs by intravitreal administration in the rabbit xenograft retinoblastoma model.

Achieving a one-year-tumor-free survival in a female with primary large cell neuroendocrine carcinoma of the urinary bladder and liver metastasis; a case report.

Primary neuroendocrine tumor (NET) of bladder is rare. It has four subtypes, and large cell neuroendocrine carcinoma (LCNEC) is the rarest. LCNEC affects mostly men over 60. Most common symptom is gross hematuria. It has no specific treatment. Metastasis is common and once occurred, average survival would be less than three months. Herein we present diagnostic and therapeutic management of a 65-year-old female with LCNEC of bladder and concurrent high-grade urothelial carcinoma. Despite developing early liver metastasis, she achieved a one-year tumor-free survival.

Retinal Tissue Engineering: Regenerative and Drug Delivery Approaches.

In recent decades, the improvement of photoreceptor-cell transplantation has been used as an effective therapeutic approach to treat retinal degenerative diseases. In this review, the effect of different factors on the differentiation process and stem cells toward photoreceptors along with cell viability, morphology, migration, adhesion, proliferation, and differentiation efficiency is discussed. Scientists are researching to better recognize the reasons for retinal degeneration, as well as discovering novel therapeutic methods to restore lost vision. In this field, several procedures and treatments in the implantation of stem cells-derived retinal cells have been explored for clinical trials. However, the number of these clinical trials is too small to draw sound decisions about whether stem-cell therapies can offer a cure for retinal diseases. Nevertheless, future research directions have started for patients affected by retinal degeneration and promising findings have been obtained.

PERSIAN Eye Cohort Study (PECS): Design, Methodology.

BACKGROUND: To report the study protocol, methodology and latest enrollment data of a large epidemiological multi-central eye cohort named PERSIAN Eye Cohort Study (PECS), originating from the ongoing PERSIAN Cohort Study, to investigate the distribution of ophthalmic disorders in different regions and ethnicities of Iran, and determine their associations with various exposures of ophthalmic and non-ophthalmic nature. METHODS: A central committee designed the study and equipped six chosen centers (Khameneh, Some'e Sara, Hoveizeh, Yazd, Rafsanjan and Zahedan). A focal point in each center conducted the study under close supervision of the central committee. RESULTS: This ongoing study was launched in 2014. Out of 65,580 eligible participants of the PERSIAN Cohort, 48,618 individuals aged 35-70 have been enrolled in the PECS (response rate: 74.13%) until June 2021. Slit lamp and fundus photography were performed for 28,702 (59.03%) and 27,437 (56.43%) individuals, respectively. CONCLUSION: This large epidemiological multi-central eye cohort can improve our epidemiological knowledge of the prevalent ophthalmic disorders in different regions and ethnicities of Iran, and determine their associations with various exposures of ophthalmic and non-ophthalmic nature. This will be very useful for future planned nationwide and global interventions.

Flat irregular pigment epithelial detachment over time and outcome of different treatment regimens.

To present long-term visual and structural outcome of treatment in two forms of flat irregular pigment epithelial detachment (FIPED): avascular (aFIPED) and vascularized (vFIPED) in eyes within pachychoroid spectrum. Prospective interventional case series. FIPED were classified into two subgroups; aFIPED and vFIPED based on OCTA. aFIPED underwent PDT, and vFIPED underwent either PDT, IVB, or combination of PDT&IVB. Vision, subretinal or intraretinal fluid, and choroidal biomarkers such as choroidal thickness, area, choroidal vascular index (CVI), and PED area were measured at baseline and last follow-up. Fifteen eyes with aFIPED were followed for a mean of 14.7 ± 10.8 months. Their vision improved, (0.44 ± 0.37-0.33 ± 0.40 LogMAR, p = 0.009) with significant reduction of fluid, choroidal area, thickness, PED area and increase in CVI. Twenty eyes with vFIPED were followed for a mean of 16.5 ± 8.2 months. The same pattern of choroidal alterations without visual improvement was observed in eyes underwent PDT alone. Combination therapy resulted in improvement of vision (0.38 ± 0.10-0.23 ± 0.17 LogMAR, p = 0.006) with reduction of choroidal area and thickness, with an increase in CVI. IVB alone could not change vision or choroidal structure. Single session PDT may lead to sustained visual improvement and structural change in eyes with aFIPED. Combination of PDT and IVB may be a better choice in eyes with vFIPED.

Erratum: Biodistribution of Cy5-labeled Thiolated and Methylated Chitosan-Carboxymethyl Dextran Nanoparticles in an Animal Model of Retinoblastoma.

[This corrects the article DOI: 10.18502/jovr.v17i1.10171.].

Biodistribution of Cy5-labeled Thiolated and Methylated Chitosan-Carboxymethyl Dextran Nanoparticles in an Animal Model of Retinoblastoma.

PURPOSE: The use of more potent medicine for local chemotherapy of retinoblastoma in order to minimize local and systemic adverse effects is essential. The main goal of this investigation was to assess the biodistribution of thiolated and methylated chitosan-carboxymethyl dextran nanoparticles (CMD-TCs-NPs and CMD-TMC-NPs) following intravitreal (IVT) injection into rat eyes with retinoblastoma. METHODS: An ionic gelation method was used to fabricate Cy5-labelled CMD-TCs-NPs and CMD-TMC-NPs. The NPs were characterized. Cellular internalization of Cy5-labelled NPs was investigated using confocal microscopy and the absorption of labeled NPs was quantified by flow cytometry in human retinoblastoma (Y79) cells. In addition, the Cy5-labeled distribution of nanoparticles in the posterior segment of the eye was histologically imaged by confocal microscopy after IVT injection of NPs into the eyes of rats with retinoblastoma. RESULTS: CMD-TCs-NPs and CMD-TMC-NPs showed a mean diameter of 34 ± 3.78 nm and 42 ± 4.23 nm and zeta potential of +11 ± 2.27 mV and +29 ± 4.31mV, respectively. The in vivo study of intraocular biodistribution of Cy5-labeled CMD-TCs-NPs and CMD-TMC-NPs revealed that there is more affinity of CMD-TCs-NPs to the retina and retinoblastoma tumor after IVT administration while methylated chitosan nanoparticles are immobilized in the vitreous and are not able to reach the retina even after 24 hr. CONCLUSION: The ionic gelation technique was efficient in synthesizing a biocompatible polymeric nanosystem for drug delivery into the posterior segment of the eye. The current study demonstrated increased ocular bioavailability of CMD-TCs-NPs relative to CMD-TMC-NPs in retinoblastoma induced rat eyes.

Prevalence and Burden of Refractive Errors at National and Sub-national Levels in Iran.

PURPOSE: To estimate the prevalence, burden of refractive errors and their associated trend from 1990 to 2018 and geographic inequalities in Iran. METHODS: Data regarding the epidemiology of refractive errors was extracted from three different sources: systematic review of published literature, data from visual school screening programs, and data from Iran's national health survey (NHS). The pool of all available data on refractive errors as well as demographic, location, and socioeconomic status covariates were fitted in spatio-temporal and Gaussian process regression models to predict the prevalence of refractive errors from the years 1990 to 2018 in 31 provinces grouped by age and sex in order to calculate years lived with disability (YLDs). RESULTS: In 2018, the age-adjusted prevalence of refractive errors was 16.32% (95% uncertainty interval [UI]: 12.44-21.48%) in both sexes, 17.98% (95% UI: 13.74-23.61%) in women, and 14.66% (95% UI: 11.14-19.36%) in men. The prevalence of refractive errors reveals that it increases with age. Refractive errors contributed to 441.41 and 348.38 YLDs in men and women, respectively. The age-standardized prevalence growth was 31.30% in females and 24.32% in males from the years 1990 to 2018. Significant geographical heterogeneity was observed. The age-standardized YLDs rates of refractive errors represent an increasing trend of 28.9% increase from 1990 to 2018. CONCLUSION: Over 28 years, the prevalence of refractive errors increased significantly. Women tend to have higher rates of prevalence. The prevalence increased in older ages. Border provinces had the lowest prevalence. Age-standardized YLDs rates of refractive errors increased by about 30%.

Risk Factors for Uncorrected Refractive Error: Persian Cohort Eye Study - Rafsanjan Center.

Purpose: To determine the prevalence of visually significant uncorrected refractive error (URE) in Rafsanjan and investigate the related factors. URE is the leading cause of visual impairment (VI) which causes the second-highest number of years lived with disability. The URE is a preventable health problem. Methods: In this cross-sectional study participants from Rafsanjan who were 35-70 years were enrolled between 2014 and 2020. Demographic and clinical characteristics data were gathered, and eye examination was performed. Visually significant URE was defined as present if habitual visual acuity was (HVA; visual acuity with present optical correction) >0.3 logMAR in the best eye and the visual acuity of that eye showed >0.2 logMAR improvement after the best correction. Logistic regression was used to determine the association between predicting variables (age, sex, wealth, education, employment, diabetes, cataract, and refractive error characteristics) and outcome (URE). Results: Among the 6991 participants of Rafsanjan subcohort of the Persian Eye Cohort, 311 (4.4%) had a visually significant URE. Diabetes was significantly more prevalent in the participants with visually significant URE, at 18.7% versus 13.1% in patients without significant URE (P = 0.004). In the final model, each year of increase in age was associated with 3% higher URE (95% confidence interval [CI]: 1.01-1.05). In comparison to low hyperopia, participants with low myopia had 5.17 times more odds of visually significant URE (95% CI: 3.38-7.93). However, antimetropia decreased the risk of visually significant URE (95% CI: 0.02-0.37). Conclusion: Policymakers should pay special attention to elderly patients with myopia to effectively reduce the prevalence of visually significant URE.

Applications of Haptic Technology, Virtual Reality, and Artificial Intelligence in Medical Training During the COVID-19 Pandemic.

This paper examines how haptic technology, virtual reality, and artificial intelligence help to reduce the physical contact in medical training during the COVID-19 Pandemic. Notably, any mistake made by the trainees during the education process might lead to undesired complications for the patient. Therefore, training of the medical skills to the trainees have always been a challenging issue for the expert surgeons, and this is even more challenging in pandemics. The current method of surgery training needs the novice surgeons to attend some courses, watch some procedure, and conduct their initial operations under the direct supervision of an expert surgeon. Owing to the requirement of physical contact in this method of medical training, the involved people including the novice and expert surgeons confront a potential risk of infection to the virus. This survey paper reviews recent technological breakthroughs along with new areas in which assistive technologies might provide a viable solution to reduce the physical contact in the medical institutes during the COVID-19 pandemic and similar crises.

Fibrinogen prophylaxis for reducing perioperative bleeding in patients undergoing radical cystectomy: A double-blind placebo-controlled randomized trial.

OBJECTIVE: Excessive bleeding is an important complication of radical cystectomy. We aimed to assess whether preoperative administration of fibrinogen decreases perioperative bleeding and improves the outcome of radical cystectomy. DESIGN: Double-blinded randomized trial with two parallel arms. SETTING: The study was conducted in the department of surgery at a teaching hospital affiliated with a University of Medical Sciences. PATIENTS: In total, 70 men undergoing radical cystectomy were randomized to fibrinogen (n = 35) and placebo-control groups. Mean (SD) age was 64.7 (7.4) years. INTERVENTIONS: The intervention group received 2 g fibrinogen concentrate diluted in 100 ml distilled water, and the control group received 100 ml normal saline; both intravenously 15 ̶ 30 min before the start of the surgery. OUTCOME MEASURES: The primary outcome was the amount of perioperative blood loss. The secondary outcomes were hemodynamic features and vital signs. MAIN RESULTS: Fibrinogen significantly decreased the volume of blood loss (p < 0.001) and the total number of transfused packed-cell units per group (38 vs. 115 units); and compensated the decrease of HCO3 (p = 0.030), the mean arterial pressure (p < 0.001), hemoglobin O2 saturation (p = 0.001), heart rate (p < 0.001), and temperature (p < 0.001) throughout the surgery compared with the placebo. Patients in the fibrinogen group had shorter Intensive Care Unit (p = 0.001) and hospital (p < 0.001) stay. We did not find any adverse reaction in our patients receiving fibrinogen concentrate. CONCLUSION: Fibrinogen concentrate reduces perioperative bleeding and the need for blood transfusion in radical cystectomy. It improves the outcomes of the surgery and decreases patients' length of stay in the healthcare system following radical cystectomy. REGISTRATION: Iranian Registry of Clinical Trials (IRCT) http://www.irct.ir/, reference number: IRCT20191013045091N1. ETHICS CODE: Shahid Beheshti University of Medical Sciences, reference number: IR.SBMU.RETECH.REC.1398.033.

Comparison of Single Monthly Instillations of Intra-Vesical Bacillus Calmette-Guerin Maintenance Therapy with Southwest Oncology Group Regimen in Non-Muscle Invasive Bladder Cancer Patients-A Retrospective Analysis In a Single Institute.

PURPOSE: To compare the efficacy and complication rate of monthly instillations of Bacillus Calmette-Guerin (BCG) as maintenance therapy in intermediate and high risk Non-Muscle Invasive Bladder Cancer (NMIBC) patients with the current standard Southwest Oncology Group (SWOG) protocol. MATERIALS AND METHODS: In this observational retrospective study, 40 intermediate and high risk NMIBC patients, receiving standard BCG maintenance regimen, were compared with another 40 NMIBC patients, undergoing monthly intra-vesical instillations of BCG with regard to recurrence, progression and major and minor adverse effects. RESULTS: The two groups were similar in their basic characteristics except for the older age in the monthly instillation group ( 70.95 ± 9.66 years vs. 64 ± 8.8, p = 0.001). Study objectives between the monthly instillation group and the standard group, including recurrence ( 17.5 % vs. 25%, p = 0.34) and progression rate ( 7.5% vs. 10%, p = 0.54) did not show statistically significant difference. Major and minor complication rate also did not show any difference between the two groups. CONCLUSION: In addition to the currently recommended standard protocol of BCG maintenance therapy, our study shows that the monthly regimen can be recommended in intermediate and high risk NMIBC patients without compromising the efficacy of the treatment.

Cost-effectiveness analysis of tele-retinopathy of prematurity screening in Iran.

AIM: To conduct a cost-utility analysis of the tele-retinopathy of prematurity (ROP) screening program against no screening. METHODS: A decision tree model was developed to identify and treat the infants with threshold ROP through the tele-screening system compared with no screening program from the societal perspective. We used the quality adjusted life years (QALY) index to measure the scenarios' effectiveness, which was discounted for the future years by 0.058. One hundred twenty-six randomly selected newborns with ROP required treatment were investigated to extract the treatment information. We considered the direct medical and non-medical costs in cost calculations analysed by the bottom-up approach. The figures of the model's inputs were calculated using the Monte Carlo simulation that generated 1000 random iteration of the data, and a one-way sensitivity analysis was performed on the model to cope with the potential uncertainties. RESULTS: The total and per capita needed the budget to establish a tele-ROP screening system were estimated at over 1.5 million and 35.13 USD, respectively. The total cost of identifying and treating an ROP case in tele-screening and no screening strategies were obtained as 108.72 and 63.52 USD, respectively, and their lifetime discounted QALY gained were calculated as 15.39 and 15.11, respectively. Therefore, incremental cost-effectiveness ratio (ICER) of tele-screening strategy against the competitive strategy was achieved as 161.43 USD. CONCLUSION: Tele-ROP screening program is one of the most cost-effective interventions in the Iranian health system and has a high priority to receive a budget for implementation.

Intraocular Injection of StivantⓇ (A Biosimilar to Bevacizumab): A Case Series.

PURPOSE: To report the results of intravitreal injection of a bevacizumab biosimilar called StivantⓇ. METHODS: This prospective interventional case series was conducted on eyes with neovascular age-related macular degeneration (nAMD), retinal vein occlusion (RVO), and diabetic macular edema (DME). StivantⓇ was injected in three consecutive months and changes in best-corrected visual acuity (BCVA) and central macular thickness (CMT) were measured at baseline and monthly up to one month after the third injection. RESULTS: Three hundred and eighty-five eyes with DME (234 eyes, 61%), nAMD (87 eyes, 22%), and macular edema secondary to RVO (64 eyes, 17%) were enrolled. The mean ± standard deviation age of the patients was 61.7 ± 7.20 years. The mean BCVA and CMT changed from 0.63 ± 0.3 to 0.51 ± 0.3 LogMAR (P = 0.12 ) and from 420.4 ± 47.3µm at baseline to 316.7 ± 50.6 µm (P < 0.001) in the DME group; from 0.79 ± 0.3 to 0.68 ± 0.3 LogMAR (P = 0.19) and from 376.1 ± 31.7 µm to 303 ± 31.3 µm (P = 0.019) in the nAMD group; and from 0.81 ± 0.4 to 0.63 ± 0.4 LogMAR (P = 0.05) and from 424.21 ± 18 µm to 303.4 ± 18.8 µm (P < 0.001) in the RVO group, respectively. CONCLUSION: Our limited experience showed that the intravitreal injection of StivantⓇ was well tolerated. Although the results of this case series showed relative improvement in CMT one month after the last injection of StivantⓇ, BCVA improvement was statistically significant only in the RVO group. This would be essential to design a randomized clinical trial to evaluate the non-inferiority of StivantⓇ in comparison to bevacizumab.

Efficacy of topotecan nanoparticles for intravitreal chemotherapy of retinoblastoma.

Retinoblastoma (Rb) is the most common intraocular malignancy in children that accounts for approximately 4% of all pediatric malignancies. Since chemotherapy is a widely practiced treatment for Rb, there is a growing interest in developing new and effective drugs to overcome systemic and local side effects of chemotherapy to improve the quality of life and increase the chances of survival. This study sought to fabricate thiolated chitosan nanoparticles containing topotecan (TPH-TCs-NPs) with a view of enhancing drug loading and release control. This research was also designed to assess the ability of TPH-TCs-NPs to improve cell association, increase treatment efficacy in retinoblastoma cells and xenograft-rat-model of retinoblastoma, and overcome current topotecan hydrochloride (TPH) intravitreal administration challenges, including stability loss and poor cellular uptake. Modified ionic gelation method was optimized to fabricate TPH-TCs-NPs and TPH-TMC-NPs (N-trimethyl chitosan nanoparticles containing TPH). We characterized the NPs and quantified topotecan loading and release against a free TPH standard. The efficacy of TPH-NPs was quantified in human retinoblastoma cells (Y79) by XTT and flow cytometry measurement. In addition, Y79 cells were injected intravitreally in both eyes of immunodeficient wistar albino rats to create a xenograft-rat-model to compare the antitumor effectiveness of TPH-NPs and TPH by intravitreal administration. TPH-NPs complexation was confirmed by EDX, FTIR, and DSC techniques. TPH-TCs-NPs and TPH-TMC-NPs had high encapsulation efficiency (85.23 ± 2 and 73.34 ± 2% respectively). TPH-TCs-NPs showed a mean diameter, polidispersity index, and zeta potential of 25±2 nm, 0.21 ± 0.03 and +12 ± 2 mV, respectively. As a function of dose, TCs and TMC NPs were more efficacious than free topotecan (IC50s 53.17 and 85.88 nM, relative to 138.30 nM respectively, P = 0.012). Kruskal-Wallis test showed a statistically significant difference between the groups. Additionally, a significant difference between the tumor control and TPH-TCs-NPs treated group in xenograft-rat-model ( Range of P-value: 0.026 to 0.035) was shown by Bonferroni post hoc test. The current investigation demonstrated enhanced efficacy and association of TPH-TCs-NPs relative to free TPH in retinoblastoma cells and tumor in vitro and in vivo.

Comparison of Topical Pigment Epithelium-Derived Factor (PEDF) with Topical Bevacizumab for Accelerating the Regression of Corneal Neovascularization in an Experimental Model of Rabbit Corneal Angiogenesis.

Purpose: To evaluate the anti-angiogenic effect of topical administration of Pigment epithelium-derived factor (PEDF) on the reduction of corneal neovascularization (NV) in comparison to topical Bevacizumab.Methods: 18 eyes of 18 New Zealand rabbits were enrolled. Corneal NV was induced by a 7-0 silk suture. After suture removal, rabbits were randomly divided into three groups. In every group, one eye randomly treated with topical bevacizumab or topical PEDF or saline for 14 days. The area and length of neovascularization were measured by Image J. Histological studies were done in three groups.Results: After 14 days, the mean decrease of corneal NV length was 1.84 ± 0.17 mm (P < .001) in PEDF group and 1.6 ± 0.07 mm (P < .001) in bevacizumab group which was significantly more than the saline group (P = .001 and P < .001, respectively). There was no significant difference between PEDF and bevacizumab group in the reduction of corneal NV length (P = .85). The mean decrease of corneal NV area was 4.94 ± 0.55 mm2 (P < .001) in PEDF group and 4.23 ± 0.29 mm2 in the bevacizumab group (P < .001). PEDF and bevacizumab significantly decreased corneal NV area in comparison to the saline group (p = .017, p = .001, respectively). The mean decrease of corneal NV area did not show a significant difference between PEDF and bevacizumab groups (P = .72).Conclusion: Topical PEDF might be an effective and safe treatment option as bevacizumab in a short-term use, indicating that it is as good as the standard. However, long-term effect is required to be investigated.