Publications by authors named "Andrew W Stacey"

46 Publications

Sex, gender, and retinoblastoma: analysis of 4351 patients from 153 countries.

Eye (Lond) 2021 Jul 16. Epub 2021 Jul 16.

International Centre for Eye Helath, London School of Hygiene & Tropical Medicine, London, UK.

Objective: To investigate in a large global sample of patients with retinoblastoma whether sex predilection exists for this childhood eye cancer.

Methods: A cross-sectional analysis including 4351 treatment-naive retinoblastoma patients from 153 countries who presented to 278 treatment centers across the world in 2017. The sex ratio (male/female) in the sample was compared to the sex ratio at birth by means of a two-sided proportions test at global level, country economic grouping, continent, and for selected countries.

Results: For the entire sample, the mean retinoblastoma sex ratio, 1.20, was higher than the weighted global sex ratio at birth, 1.07 (p < 0.001). Analysis at economic grouping, continent, and country-level demonstrated differences in the sex ratio in the sample compared to the ratio at birth in lower-middle-income countries (n = 1940), 1.23 vs. 1.07 (p = 0.019); Asia (n = 2276), 1.28 vs. 1.06 (p < 0.001); and India (n = 558), 1.52 vs. 1.11 (p = 0.008). Sensitivity analysis, excluding data from India, showed that differences remained significant for the remaining sample (χ = 6.925, corrected p = 0.025) and for Asia (χ = 5.084, corrected p = 0.036). Excluding data from Asia, differences for the remaining sample were nonsignificant (χ = 2.205, p = 0.14).

Conclusions: No proof of sex predilection in retinoblastoma was found in the present study, which is estimated to include over half of new retinoblastoma patients worldwide in 2017. A high male to female ratio in Asian countries, India in specific, which may have had an impact on global-level analysis, is likely due to gender discrimination in access to care in these countries, rather than a biological difference between sexes.
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http://dx.doi.org/10.1038/s41433-021-01675-yDOI Listing
July 2021

Lag Time between Onset of First Symptom and Treatment of Retinoblastoma: An International Collaborative Study of 692 Patients from 10 Countries.

Cancers (Basel) 2021 Apr 19;13(8). Epub 2021 Apr 19.

Department of Ophthalmology, University of Washington, Seattle, WA 98195, USA.

Background: The relationship between lag time and outcomes in retinoblastoma (RB) is unclear. In this study, we aimed to study the effect of lag time between onset of symptoms and diagnosis of retinoblastoma (RB) in countries based on their national-income and analyse its effect on the outcomes.

Methods: We performed a prospective study of 692 patients from 11 RB centres in 10 countries from 1 January 2019 to 31 December 2019.

Results: The following factors were significantly different among different countries based on national-income level: age at diagnosis of RB ( = 0.001), distance from home to nearest primary healthcare centre ( = 0.03) and mean lag time between detection of first symptom to visit to RB treatment centre ( = 0.0007). After adjusting for country income, increased lag time between onset of symptoms and diagnosis of RB was associated with higher chances of an advanced tumour at presentation ( < 0.001), higher chances of high-risk histopathology features ( = 0.003), regional lymph node metastasis ( < 0.001), systemic metastasis ( < 0.001) and death ( < 0.001).

Conclusions: There is a significant difference in the lag time between onset of signs and symptoms and referral to an RB treatment centre among countries based on national income resulting in significant differences in the presenting features and clinical outcomes.
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http://dx.doi.org/10.3390/cancers13081956DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8073369PMC
April 2021

Progressive Preretinal Fibrosis with Late, Ossifying, Proliferative Retinopathy following Treatment for Retinoblastoma.

Ocul Oncol Pathol 2021 Mar 25;7(1):44-47. Epub 2020 Sep 25.

Department of Ophthalmology, University of Washington, Seattle, Washington, USA.

We report a case of retinal atrophy and progressive preretinal fibrosis in an eye previously treated with intravenous and intra-arterial chemotherapy (IAC), which evolved immediately after treatment with intravitreal injection of melphalan. The atrophy and fibrosis progressed later to proliferative retinopathy with dystrophic ossification. The patient was originally diagnosed with bilateral retinoblastoma at 4 months of age and was treated with systemic chemotherapy followed by IAC. New vitreous seeds developed and required treatment with intravitreal chemotherapy. There was resolution of vitreous seeding after 2 doses of intravitreal melphalan, but clinically the eye developed new, widespread retinal atrophy and fibrosis within 1 month of the second injection. This was followed by phthisis and late proliferative retinopathy nearly 1 year later. Retinoblastoma specialists should be aware of this potential complication of combined chemotherapy treatments.
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http://dx.doi.org/10.1159/000509809DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7989767PMC
March 2021

Incidence of Retinoblastoma Has Increased: Results from 40 European Countries.

Ophthalmology 2021 Jan 26. Epub 2021 Jan 26.

International Centre for Eye Health, London School of Hygiene & Tropical Medicine, London, United Kingdom; Goldschleger Eye Institute, Sheba Medical Center, Tel Hashomer, Tel-Aviv University, Tel-Aviv, Israel.

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http://dx.doi.org/10.1016/j.ophtha.2021.01.024DOI Listing
January 2021

Radiation dose reduction during intra-arterial chemotherapy for retinoblastoma: a retrospective analysis of 96 consecutive pediatric interventions using five distinct protocols.

Pediatr Radiol 2021 Apr 24;51(4):649-657. Epub 2020 Nov 24.

Section of Neurointerventional Radiology, Department of Radiology, Seattle Children's Hospital, University of Washington, Seattle, WA, USA.

Background: Intra-arterial chemotherapy (IAC) represents a mainstay of retinoblastoma treatment in children. Patients with retinoblastoma are uniquely at risk for secondary malignancies and are sensitive to the ionizing effects of radiation.

Objective: To retrospectively review a single institution's experience with IAC for retinoblastoma and the effect of variable intra-procedural imaging techniques on radiation exposure.

Materials And Methods: Twenty-four consecutive patients, with a mean age of 30.8±16.3 months (range: 3.2-83.4 months), undergoing IAC for retinoblastoma between May 2014 and May 2020 (72 months) were included. No patients were excluded. The primary outcome was radiation exposure and secondary outcomes included technical success and procedural adverse events. Technical success was defined as catheterization of the ophthalmic or meningolacrimal artery and complete delivery of chemotherapy. Each procedure was retrospectively reviewed and categorized as one of five imaging protocol types. Protocol types were characterized by uniplanar versus multiplanar imaging and digital subtraction angiographic versus roadmap angiographic techniques. Radiation exposure, protocol utilization, the association of protocol and radiation exposure were assessed.

Results: During 96 consecutive interventions, 109 ocular treatments were performed. Thirteen of the 96 (15.5%) treatments were bilateral. Ocular technical success was 106 of 109 (97.2%). All three treatment failures were successfully repeated within a week. Mean fluoroscopy time was 6.4±6.2 min (range: 0.7-31.1 min). Mean air kerma was 36.2±52.2 mGy (range: 1.4-215.0 mGy). There were two major (1.8%) complications and four (3.7%) minor complications. Of the 96 procedures, 10 (10.4%), 9 (9.4%), 13 (13.5%), 28 (29.2%) and 36 (37.5%) were performed using protocol types A, B, C, D and E, respectively. For protocol type A, mean fluoroscopy time was 10.3±6.8 min (range: 3.0-25.4 min) and mean air kerma was 118.2±61.2 mGy (range: 24.5-167.3 mGy). For protocol type E, mean fluoroscopy time was 3.1±3.2 min (range: 0.7-15.1 min) and mean air kerma was 5.4±4.2 mGy (range: 1.4-19.5 mGy). Fluoroscopy time and air kerma decreased over time, corresponding to the reduced use of multiplanar imaging and digital subtraction angiography. In the first quartile (procedures 1-24), 8 (33.3%), 7 (29.2%), 2 (8.3%), 6 (25.0%) and 1 (4.2%) were performed using protocol types A, B, C, D and E, respectively. Mean fluoroscopy time was 10.5±8.2 min (range: 2.4-28.1 min) and mean air kerma was 84.2±71.6 mGy (range: 12.8-215.0 mGy). In the final quartile (procedures 73-96), 24 (100%) procedures were performed using protocol type E. Mean fluoroscopy time was 3.5±4.0 min (range: 0.7-15.1 min) and mean air kerma was 5.0±4.3 mGy (range: 1.4-18.0 mGy), representing 66.7% and 94.1% reductions from the first quartile, respectively. Technical success in the second half of the experience was 100%.

Conclusion: Sequence elimination, consolidation from biplane imaging to lateral-only imaging, and replacing digital subtraction with roadmap angiography dramatically reduced radiation exposure during IAC for retinoblastoma without adversely affecting technical success or safety.
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http://dx.doi.org/10.1007/s00247-020-04892-xDOI Listing
April 2021

The Addition of Topotecan to Melphalan in the Treatment of Retinoblastoma with Intra-arterial Chemotherapy.

Ophthalmol Retina 2020 Nov 19. Epub 2020 Nov 19.

Unit of Ophthalmology, University of Siena, Policlinico "Santa Maria alle Scotte," Siena, Italy.

Purpose: To evaluate the effect of adding topotecan to melphalan for the treatment of retinoblastoma using intra-arterial chemotherapy (IAC).

Design: Single-center, consecutive case series.

Participants: All eyes treated with IAC at the University of Siena, Siena, Italy, from 2008 to 2019.

Methods: Eyes were treated via IAC with either melphalan monotherapy or melphalan plus topotecan. The characteristics and outcomes of these 2 groups were compared.

Main Outcome Measures: The main outcome measure was globe salvage rate. Additionally, a complete summary of all adverse events for all eyes was compared between groups and included local, regional, and systemic events causing both transient and permanent effects.

Results: A total of 193 patients and 208 eyes were treated with IAC between April 2008 and October 2019. Melphalan alone (MA) was used to treat 44 patients and 50 eyes for a total of 191 procedures. The combination of melphalan plus topotecan (MPT) was used to treat 149 patients and 158 eyes for a total of 780 procedures. Groups were similar in terms of age at presentation. The MPT group included more advanced eyes (P < 0.001) and had shorter follow-up time (mean 47 vs. 120 months in the MA group, P < 0.001). The MPT group required less laser and cryotherapy after treatment (32% of eyes vs. 50% of eyes in the MA group, P < 0.001); there was no other difference in the number of adjuvant treatments required between groups. There was no difference in the number of acute adverse events, both systemic and local, between groups. There was no difference in the number of transient or permanent intraocular side effects between groups. Kaplan-Meier survival analysis estimated a better globe salvage rate in the MPT group (66%) compared with the MA group (58%, P = 0.05).

Conclusions: In this case series, the addition of topotecan to melphalan did not alter the IAC side effect profile and may contribute to improved globe salvage.
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http://dx.doi.org/10.1016/j.oret.2020.11.007DOI Listing
November 2020

Adjuvant use of laser in eyes with macular retinoblastoma treated with primary intravenous chemotherapy.

Br J Ophthalmol 2020 Sep 15. Epub 2020 Sep 15.

Royal London Hospital, London, London, UK.

Background: Adjuvant use of laser with systemic chemotherapy for treatment of retinoblastoma may reduce recurrence rates while also causing local side effects. Information is lacking on the effect of laser on visual outcomes.

Methods: A retrospective review of two retinoblastoma centres in the United Kingdom was conducted. Patients were included if there was a macular tumour in at least one eye. Eyes that received chemotherapy alone were compared with eyes that received chemotherapy plus adjuvant laser.

Results: A total of 76 patients and 91 eyes were included in the study. Systemic chemotherapy alone was used in 71 eyes while chemotherapy plus laser was used in 20 eyes. Demographic characteristics of both groups were similar. Macular relapse rates were similar between groups: 22/71 (31%) eyes in chemotherapy group and 9/20 (45%) eyes in laser group (p=0.29). There was no increase in vitreous relapses in the laser group (2/20 eyes), compared with the chemotherapy group 10/71 eyes (p=0.99). Survival analysis demonstrated similar time to first relapse between groups. Final visual acuity was equal between groups with 6/15 or better present in 31.1% of eyes in the chemotherapy group and 37.5% of eyes in the laser group (p=0.76). Presence of tumour at the fovea was predictive of final visual acuity, regardless of treatment group.

Conclusion: Adjuvant laser in the treatment of retinoblastoma is safe and does not lead to increased rate of vitreous recurrence. Final visual acuity is determined by the presence of tumour at the fovea and not the use of laser.
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http://dx.doi.org/10.1136/bjophthalmol-2020-316862DOI Listing
September 2020

Travel burden and clinical presentation of retinoblastoma: analysis of 1024 patients from 43 African countries and 518 patients from 40 European countries.

Br J Ophthalmol 2020 Sep 15. Epub 2020 Sep 15.

Pediatric Oncology Unit, Hospital Universitario y Politécnico La Fe, Valencia, Spain.

Background: The travel distance from home to a treatment centre, which may impact the stage at diagnosis, has not been investigated for retinoblastoma, the most common childhood eye cancer. We aimed to investigate the travel burden and its impact on clinical presentation in a large sample of patients with retinoblastoma from Africa and Europe.

Methods: A cross-sectional analysis including 518 treatment-naïve patients with retinoblastoma residing in 40 European countries and 1024 treatment-naïve patients with retinoblastoma residing in 43 African countries.

Results: Capture rate was 42.2% of expected patients from Africa and 108.8% from Europe. African patients were older (95% CI -12.4 to -5.4, p<0.001), had fewer cases of familial retinoblastoma (95% CI 2.0 to 5.3, p<0.001) and presented with more advanced disease (95% CI 6.0 to 9.8, p<0.001); 43.4% and 15.4% of Africans had extraocular retinoblastoma and distant metastasis at the time of diagnosis, respectively, compared to 2.9% and 1.0% of the Europeans. To reach a retinoblastoma centre, European patients travelled 421.8 km compared to Africans who travelled 185.7 km (p<0.001). On regression analysis, lower-national income level, African residence and older age (p<0.001), but not travel distance (p=0.19), were risk factors for advanced disease.

Conclusions: Fewer than half the expected number of patients with retinoblastoma presented to African referral centres in 2017, suggesting poor awareness or other barriers to access. Despite the relatively shorter distance travelled by African patients, they presented with later-stage disease. Health education about retinoblastoma is needed for carers and health workers in Africa in order to increase capture rate and promote early referral.
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http://dx.doi.org/10.1136/bjophthalmol-2020-316613DOI Listing
September 2020

A Review of Hypertensive Retinopathy and Chorioretinopathy.

Clin Optom (Auckl) 2020 5;12:67-73. Epub 2020 May 5.

Department of Ophthalmology, University of Washington, Seattle, WA 98104, USA.

Hypertensive retinopathy and choroidopathy have important short- and long-term implications on patients' overall health and mortality. Eye care professionals should be familiar with the severity staging of these entities and be able to readily recognize and refer patients who are in need of systemic blood pressure control. This paper will review the diagnosis, staging, treatment, and long-term implications for vision and mortality of patients with hypertensive retinopathy and choroidopathy.
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http://dx.doi.org/10.2147/OPTO.S183492DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7211319PMC
May 2020

The Concept of Minimal Residual Disease in the Treatment and Staging of Vitreoretinal Lymphoma.

Retina 2020 Jul;40(7):1213-1214

Department of Ophthalmology and Molecular Medicine, Mayo Clinic, Rochester, Minnesota.

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http://dx.doi.org/10.1097/IAE.0000000000002851DOI Listing
July 2020

Global Retinoblastoma Presentation and Analysis by National Income Level.

JAMA Oncol 2020 05;6(5):685-695

Imam Hussein Cancer Center, Karbala, Iraq.

Importance: Early diagnosis of retinoblastoma, the most common intraocular cancer, can save both a child's life and vision. However, anecdotal evidence suggests that many children across the world are diagnosed late. To our knowledge, the clinical presentation of retinoblastoma has never been assessed on a global scale.

Objectives: To report the retinoblastoma stage at diagnosis in patients across the world during a single year, to investigate associations between clinical variables and national income level, and to investigate risk factors for advanced disease at diagnosis.

Design, Setting, And Participants: A total of 278 retinoblastoma treatment centers were recruited from June 2017 through December 2018 to participate in a cross-sectional analysis of treatment-naive patients with retinoblastoma who were diagnosed in 2017.

Main Outcomes And Measures: Age at presentation, proportion of familial history of retinoblastoma, and tumor stage and metastasis.

Results: The cohort included 4351 new patients from 153 countries; the median age at diagnosis was 30.5 (interquartile range, 18.3-45.9) months, and 1976 patients (45.4%) were female. Most patients (n = 3685 [84.7%]) were from low- and middle-income countries (LMICs). Globally, the most common indication for referral was leukocoria (n = 2638 [62.8%]), followed by strabismus (n = 429 [10.2%]) and proptosis (n = 309 [7.4%]). Patients from high-income countries (HICs) were diagnosed at a median age of 14.1 months, with 656 of 666 (98.5%) patients having intraocular retinoblastoma and 2 (0.3%) having metastasis. Patients from low-income countries were diagnosed at a median age of 30.5 months, with 256 of 521 (49.1%) having extraocular retinoblastoma and 94 of 498 (18.9%) having metastasis. Lower national income level was associated with older presentation age, higher proportion of locally advanced disease and distant metastasis, and smaller proportion of familial history of retinoblastoma. Advanced disease at diagnosis was more common in LMICs even after adjusting for age (odds ratio for low-income countries vs upper-middle-income countries and HICs, 17.92 [95% CI, 12.94-24.80], and for lower-middle-income countries vs upper-middle-income countries and HICs, 5.74 [95% CI, 4.30-7.68]).

Conclusions And Relevance: This study is estimated to have included more than half of all new retinoblastoma cases worldwide in 2017. Children from LMICs, where the main global retinoblastoma burden lies, presented at an older age with more advanced disease and demonstrated a smaller proportion of familial history of retinoblastoma, likely because many do not reach a childbearing age. Given that retinoblastoma is curable, these data are concerning and mandate intervention at national and international levels. Further studies are needed to investigate factors, other than age at presentation, that may be associated with advanced disease in LMICs.
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http://dx.doi.org/10.1001/jamaoncol.2019.6716DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7047856PMC
May 2020

Whole Exome Sequencing Identifies Candidate Genes Associated with Hereditary Predisposition to Uveal Melanoma.

Ophthalmology 2020 05 18;127(5):668-678. Epub 2019 Nov 18.

Department of Ophthalmology and Visual Science, Havener Eye Institute, The Ohio State University, Columbus, Ohio.

Purpose: To identify susceptibility genes associated with hereditary predisposition to uveal melanoma (UM) in patients with no detectable germline BAP1 alterations.

Design: Retrospective case series from academic referral centers.

Participants: Cohort of 154 UM patients with high risk of hereditary cancer defined as patients with 1 or more of the following: (1) familial UM, (2) young age (<35 years) at diagnosis, (3) personal history of other primary cancers, and (4) family history of 2 or more primary cancers with no detectable mutation or deletion in BAP1 gene.

Methods: Whole exome sequencing, a cancer gene panel, or both were carried out. Probands included 27 patients with familial UM, 1 patient with bilateral UM, 1 patient with congenital UM, and 125 UM patients with strong personal or family histories, or both, of cancer. Functional validation of variants was carried out by immunohistochemistry, reverse-transcriptase polymerase chain reaction, and genotyping.

Main Outcome Measures: Clinical characterization of UM patients with germline alterations in known cancer genes.

Results: We identified actionable pathogenic variants in 8 known hereditary cancer predisposition genes (PALB2, MLH1, MSH6, CHEK2, SMARCE1, ATM, BRCA1, and CTNNA1) in 9 patients, including 3 of 27 patients (11%) with familial UM and 6 of 127 patients (4.7%) with a high risk for cancer. Two patients showed pathogenic variants in CHEK2 and PALB2, whereas variants in the other genes each occurred in 1 patient. Biallelic inactivation of PALB2 and MLH1 was observed in tumors from the respective patients. The frequencies of pathogenic variants in PALB2, MLH1, and SMARCE1 in UM patients were significantly higher than the observed frequencies in noncancer controls (PALB2: P = 0.02; odds ratio, 8.9; 95% confidence interval, 1.5-30.6; MLH1: P = 0.04; odds ratio, 25.4; 95% confidence interval, 1.2-143; SMARCE1: P = 0.001; odds ratio, 2047; 95% confidence interval, 52-4.5e15, respectively).

Conclusions: The study provided moderate evidence of gene and disease association of germline mutations in PALB2 and MLH1 with hereditary predisposition to UM. It also identified several other candidate susceptibility genes. The results suggest locus heterogeneity in predisposition to UM. Genetic testing for hereditary predisposition to cancer is warranted in UM patients with strong personal or family history of cancers, or both.
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http://dx.doi.org/10.1016/j.ophtha.2019.11.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7183432PMC
May 2020

Clinical Features and Multi-Modality Imaging of Isolated Retinal Astrocytic Hamartoma.

Ophthalmic Surg Lasers Imaging Retina 2019 02;50(2):e1-e9

Background And Objective: To identify the clinical and imaging characteristics of isolated retinal astrocytic hamartomas (IRAH).

Patients And Methods: A case series of eight patients diagnosed with IRAH.

Results: The average age at diagnosis was 32 years (range: 9 years to 80 years). After a median follow-up time of 59 months, none of the lesions had demonstrated any change or growth. Fundus fluorescein angiogram identified hyperfluorescence in five of six imaged lesions. Fundus autofluorescence (FAF) changes were seen in all eight cases. Ocular ultrasound was able to identify a lesion in only five of the seven cases. Optical coherence tomography (OCT) was able to document the tumor thickness and level of retinal invasion in all cases.

Conclusions: Multimodal imaging is useful for the diagnosis and monitoring of IRAH. OCT and FAF are sensitivity tools for identifying IRA and can be used to follow the thickness and margins of these lesions. [Ophthalmic Surg Lasers Imaging Retina. 2019;50:e1-e9.].
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http://dx.doi.org/10.3928/23258160-20190129-12DOI Listing
February 2019

The Incidence of Binocular Visual Impairment and Blindness in Children with Bilateral Retinoblastoma.

Ocul Oncol Pathol 2019 Jan 19;5(1):1-7. Epub 2018 Jun 19.

The Royal London Hospital, Barts Health NHS Trust, London, United Kingdom.

Purpose: The study aimed to assess the incidence of and risk factors leading to visual impairment and legal blindness in children with retinoblastoma.

Procedures: This is a single-center, retrospective case series of all patients with bilateral retinoblastoma presenting from 2010 to 2014.

Results: A total of 44 patients were included in the study. Visual impairment was present in 14 (38%) children, legal blindness was present in 7 (19%) children. Bilateral macular tumors (BMT) were associated with visual impairment (12 of 18 patients with BMT, 2 of 19 patients without BMT, = 0.0006) and legal blindness (7 of 18 patients with BMT, 0 of 19 patients without BMT, = 0.003). The International Intraocular Retinoblastoma Classification (IIRC) of the better eye also predicted visual impairment (16% in IIRC Group a, b, c, 75% in IIRC Group D, E, = 0.004) and blindness (3% eye in IIRC Group a, b, c, 50% in Group D, E, = 0.005). Various non-Snellen visual acuity measures were able to predict visual impairment in pre-verbal children, providing them with early assistance.

Conclusions: The rates of visual impairment and blindness reported in this paper can be used to counsel families regarding the risk of binocular visual impairment. Early detection and support for visually impaired infants are essential as development can be affected by severe visual impairment.
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http://dx.doi.org/10.1159/000489313DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6341332PMC
January 2019

Rapidly Progressive, Isolated Subretinal Leukemic Relapse: A Case Report.

Ocul Oncol Pathol 2018 Jun 22;4(4):220-224. Epub 2017 Dec 22.

Department of Ophthalmology, University of Washington, WA, USA.

Purpose: The aim of this paper is to describe a case of relapsed pediatric acute lymphoblastic leukemia (ALL) presenting as a rapidly progressive subretinal infiltrate, as diagnosed by ultrasound-guided fine needle aspiration (FNA).

Methods: We conducted a clinical pathological retrospective chart review.

Results: Eleven months after documented remission of T-cell ALL while on maintenance therapy, this 17-year-old patient presented with acute open angle glaucoma in the right eye. B-scan ultrasonography suggested total retinal detachment. Eight weeks later, based on routine cerebrospinal fluid analysis, the patient was diagnosed with central nervous system relapse of T-cell ALL. Repeat B-scan 1 week later showed a new hyperechoic subretinal mass. FNA of the mass confirmed leukemic infiltrate. The involved eye was enucleated, demonstrating leukemic cells throughout the subretinal space, choroid, and the optic nerve. Following hematopoietic stem cell transplant, the patient continues to maintain bone marrow remission 5 months after enucleation without involvement in the opposite eye.

Conclusion: Retinal detachment in any patient with a history of leukemia should raise the possibility of relapse and may warrant aspiration/biopsy if other means of diagnosing relapse are inconclusive. Subretinal infiltrate may progress rapidly and prompt diagnosis is paramount to tailoring therapy and preserving vision.
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http://dx.doi.org/10.1159/000484054DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6322080PMC
June 2018

Strabismus in retinoblastoma survivors with long-term follow-up.

J AAPOS 2018 08 1;22(4):276.e1-276.e7. Epub 2018 Aug 1.

Retinoblastoma Service, Royal London Hospital, London, United Kingdom.

Purpose: To report the long-term strabismus rate in salvaged retinoblastoma (Rb) patients and investigate possible risk factors leading to strabismus.

Methods: The medical records of patients with Rb presenting at a single institution over a 9-year period were reviewed retrospectively with regard to ocular alignment outcomes after long-term follow-up.

Results: A total of 64 eyes of 42 patients (22 bilateral cases [52%]) were included, presenting with International Intraocular Retinoblastoma Classification (IIRC) in the worse eye as follows: group A (n = 1), B (n = 16), C (n = 12), D (n = 11), no Rb (n = 2). Fifteen patients (36%) were initially referred because of family history of Rb. Mean age at presentation was 8.2 months (range, 0.3-58.3 months). Overall treatments included intravenous chemotherapy (62 eyes), intraophthalmic artery chemotherapy (10 eyes), brachytherapy (11 eyes), transpupillary thermotherapy (22 eyes), cryotherapy (47 eyes), and external beam radiotherapy (4 eyes). At final follow-up (mean, 93.7 months), 69% of patients had strabismus, with exotropia being the most common type (n = 18), followed by esotropia (n = 8), and alternate exotropia/esotropia (n = 3). On univariate analysis, the worse eye group IIRC and cTNMH, sporadic cases, strabismus, and foveal tumor at presentation were found to be significantly associated with strabismus at final follow-up (P ≤ 0.043). On multivariate analysis, only foveal involvement was found to be significant (P < 0.001).

Conclusions: Strabismus, exotropia in particular, is a common adverse sequela following successful conservative treatment for Rb, with 69% of the present cohort having some type of deviation after long-term follow-up, for which foveal tumor at presentation was found to be a significant risk factor.
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http://dx.doi.org/10.1016/j.jaapos.2018.03.007DOI Listing
August 2018

Primary photodynamic therapy with verteporfin for pigmented posterior pole cT1a choroidal melanoma: a 3-year retrospective analysis.

Br J Ophthalmol 2018 12 13;102(12):1705-1710. Epub 2018 Feb 13.

Ocular Oncology Service, Moorfields Eye Hospital NHS Foundation Trust, London, UK.

Aims: To investigate the outcomes of primary photodynamic therapy (PDT) for pigmented posterior pole cT1a choroidal melanoma.

Methods: Retrospective interventional consecutive case series of 26 patients (26 eyes) with pigmented posterior pole cT1a choroidal melanoma, who were treated with 3 sessions of PDT and followed-up thereafter.

Results: Included were 11 males and 15 females that presented at a median age of 66 years (mean: 64) with transformed naevi (n=11) or suspicious lesions (n=15) with ≥3 risk factors for growth, with lipofuscin in all. In all cases, diagnosis was clinically based (no tissue biopsy). Tumour control was achieved in 16 (62%) patients in a median follow-up time of 29 months (mean: 27). Ten patients failed treatment by form of radial expansion, diagnosed in a median time of 13 months (mean: 12) from last treatment. By Kaplan-Meier analysis, success rate after 1, 2 and 3 years was 85%, 59% and 51%, respectively. On statistical analysis, number of suspicious features was found to be the only risk factor predicting failure (P=0.046). One patient developed macula-sparing branch retinal artery occlusion after treatment. Following PDT, subretinal fluid resolved in all cases and visual acuity significantly improved in all treatment-success cases (P=0.043). There were no cases of metastatic spread.

Conclusion: Primary PDT resulted in tumour regression of small, pigmented choroidal melanoma in 62% after a mean of 27 months. Treatment was more effective in tumours with three or less risk factors for growth, and resulted with fluid elimination and significant improvement in vision in treatment-success cases.
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http://dx.doi.org/10.1136/bjophthalmol-2017-311747DOI Listing
December 2018

Late Solitary Extraocular Recurrence From Previously Resected Iris Melanoma.

Am J Ophthalmol 2017 Sep 1;181:97-105. Epub 2017 Jul 1.

Ocular Oncology Service, Moorfields Eye Hospital, London, United Kingdom; UCL Institute of Ophthalmology, London, United Kingdom.

Purpose: To report on cases of late extraocular relapse of previously resected iris melanoma, without concurrent intraocular recurrence.

Design: Retrospective case series.

Methods: A retrospective chart review of 4 patients diagnosed with late subconjunctival relapse of previously resected iris melanoma.

Results: Three female patients and 1 male patient underwent iris tumor resection and presented to our service with suspicious conjunctival lesions at a median of 22 years later (mean: 21 years). None showed intraocular relapse. Treatment of the conjunctival tumors included excisional biopsy (n = 4), followed by cryotherapy (n = 3) and/or brachytherapy (n = 3). In all cases, histopathology confirmed malignant melanoma, with no intraepithelial component or associated melanosis. Genetic sequencing (n = 3) showed wild-type BRAF and NRAS in all. GNA11 mutation was found in 1 case. On array-based comparative genomic hybridization (n = 3), gain of 6p was found in 2 cases and gain of 8 in 2. Overall, findings were strongly suggestive of a diagnosis of late extraocular relapse from previously resected iris melanoma. In a median of 2.5 years (mean: 7.7 years) from the subconjunctival relapse, no further episodes of intraocular/extraocular recurrence were recorded, and all patients were free from distant metastasis.

Conclusions: Patients undergoing iris melanoma resection are at risk of developing late solitary extraocular relapse even more than 30 years after surgery. In the absence of an intraocular component, diagnosis may be challenging, as tumors mimic a primary conjunctival lesion. Management by excisional biopsy followed by adjuvant therapy was successful, and histopathology and genetic analysis supported a diagnosis of extraocular uveal tumor spread rather than a primary conjunctival tumor.
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http://dx.doi.org/10.1016/j.ajo.2017.06.025DOI Listing
September 2017

Primary enucleation for group D retinoblastoma in the era of systemic and targeted chemotherapy: the price of retaining an eye.

Br J Ophthalmol 2018 02 28;102(2):265-271. Epub 2017 Jun 28.

Ocular Oncology Service, Moorfields Eye Hospital, London, UK.

Background: Chemotherapy is increasingly used as primary treatment for group D retinoblastoma, whereas primary enucleation is considered to have a diminishing role. This study aimed to compare the management course, including number of examinations under anaesthesia (EUAs), of group D patients treated by enucleation versus chemotherapy.

Methods: A retrospective analysis of 92 group D patients, of which 40 (37 unilateral) underwent primary enucleation and 52 (17 unilateral) were treated with intravenous chemotherapy. Number of EUAs was compared between the treatment groups with respect to the whole cohort, using univariate and multivariate analysis, and to unilateral cases only.

Results: Patients were followed up for a median of 61 months (mean: 66, range: 14-156), in which time primary enucleated patients had on average seven EUAs and chemotherapy-treated patients 21 EUAs (p<0.001). Chemotherapy, young age, bilateral disease, multifocal tumours, familial and germline retinoblastoma were found on univariate analysis to correlate with increased number of EUAs (p≤0.019). On multivariate analysis, however, only treatment type and presentation age were found significant (p≤0.001). On subanalysis of the unilateral cases, patients undergoing primary enucleation had in average seven EUAs, as compared with 16 in the chemotherapy group (p<0.001). Of the 55 unilateral-presenting patients, a new tumour developed in the fellow eye only in a single familial case.

Conclusion: Group D patients' families should be counselled regarding the significant difference in number of EUAs following primary enucleation versus chemotherapy when deciding on a treatment strategy. In this regard, primary enucleation would be most beneficial for older patients with unilateral disease.
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http://dx.doi.org/10.1136/bjophthalmol-2017-310624DOI Listing
February 2018

Solitary Iris Plasmacytoma With Anterior Chamber Crystalline Deposits.

Cornea 2017 Jul;36(7):875-877

*Moorfields Eye Hospital, London, United Kingdom;†St. Bartholomew's Hospital, London, United Kingdom;‡Department of Ophthalmology, University of Washington, Seattle, WA;§University College London Institute of Ophthalmology, London, United Kingdom; and¶Department of Haematology, North Bristol NHS Trust, Bristol, United Kingdom.

Purpose: To report a case of solitary iris plasmacytoma successfully treated with ruthenium plaque radiotherapy.

Methods: A 44-year-old white woman presented with pain in the right eye and raised intraocular pressure. Her medical history included breast cancer treated 11 years earlier with lumpectomy, lymph node clearance, chemotherapy, and radiotherapy. On examination, the right iris had a tan-colored mass with crystalline deposits visible on the mass surface and on the corneal endothelium. The fundus and left eye were normal. An anterior segment ultrasound scan showed a mass with mixed internal echogenicity and internal blood flow.

Results: An iris biopsy showed an infiltrate of plasma cells. Immunohistochemistry for kappa and lambda light chains demonstrated lambda light chain restriction. Systemic hematologic investigations including complete blood count, serum paraproteins, bone marrow biopsy, and full-body magnetic resonance image were normal. The monoclonal plasma cell infiltrate was consistent with a solitary iris plasmacytoma. The mass was treated with ruthenium plaque radiotherapy. After 4 years of follow-up, the mass remained regressed, and no systemic myeloma has developed.

Conclusions: Iris plasmacytoma is rare and should prompt systemic evaluation to rule out multiple myeloma. Solitary iris plasmacytoma can be successfully treated with plaque radiotherapy.
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http://dx.doi.org/10.1097/ICO.0000000000001222DOI Listing
July 2017

Focal laser treatment in addition to chemotherapy for retinoblastoma.

Cochrane Database Syst Rev 2017 06 7;6:CD012366. Epub 2017 Jun 7.

Moorfields Eye Hospital NHS Foundation Trust, 162 City Road, London, UK, EC1V 2PD.

Background: Retinoblastoma is the most common primary intraocular malignancy of childhood. Systemic chemotherapy is a common treatment for intraocular retinoblastoma, and laser treatment is used as adjuvant therapy during or immediately after chemotherapy courses in selected cases.

Objectives: To compare the effectiveness and safety of adding focal laser therapy to systemically-delivered chemotherapy in treating intraocular retinoblastoma.

Search Methods: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Trials Register) (2016, Issue 9), MEDLINE Ovid (1946 to 20 October 2016), Embase Ovid (1980 to 20 October 2016), LILACS (Latin American and Caribbean Health Sciences Literature Database) (1982 to 20 October 2016), the ISRCTN registry (www.isrctn.com/editAdvancedSearch); searched 20 October 2016, ClinicalTrials.gov (www.clinicaltrials.gov); searched 20 October 2016, and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en); searched 20 October 2016. We did not use any date or language restrictions in the electronic searches for trials.

Selection Criteria: We searched for randomised controlled trials (RCTs) of systemic chemotherapy with versus without adjuvant laser therapy for postequatorial retinoblastoma.

Data Collection And Analysis: We planned to use standard methodological procedures expected by Cochrane. We planned to meta-analyse the primary outcome, that is the proportion of eyes with recurrence of tumours within three years from treatment MAIN RESULTS: No studies met the inclusion criteria for this review.

Authors' Conclusions: No evidence from randomised controlled trials was found to support or refute laser therapy in addition to systemic chemotherapy for postequatorial retinoblastoma.
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http://dx.doi.org/10.1002/14651858.CD012366.pub2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6481366PMC
June 2017

Long-term Visual Acuity, Strabismus, and Nystagmus Outcomes Following Multimodality Treatment in Group D Retinoblastoma Eyes.

Am J Ophthalmol 2017 Jul 10;179:137-144. Epub 2017 May 10.

Moorfields Eye Hospital, London, United Kingdom; Retinoblastoma Service, Royal London Hospital, London, United Kingdom; National Institute for Health Research Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, London, United Kingdom.

Purpose: To analyze the long-term visual acuity, strabismus, and nystagmus outcomes in Group D retinoblastoma following multimodality treatments in a national retinoblastoma referral center.

Design: Retrospective interventional case series.

Methods: A 13-year retrospective chart review of Group D eyes treated initially with intravenous chemotherapy (IVC) and followed up for at least 1 year from last treatment. Risk factors for final visual acuity (VA) were analyzed, and rate of strabismus and nystagmus at last follow-up visit were calculated.

Results: One hundred and four Group D eyes (92 patients) presented to our center during the study period, of which 32 (27 patients) met the inclusion criteria. Following IVC (vincristine, etoposide, and carboplatin), adjuvant treatments included intraophthalmic artery chemotherapy in 5 (16%) eyes, plaque brachytherapy in 5 (16%), transpupillary thermotherapy (TTT) in 18 (56%), and cryotherapy in 24 (75%) eyes. On last examination, 64.41 ± 6.76 months from presentation, mean final VA was 20/283 (logMAR equivalent of 1.15 ± 0.15). On univariate analysis, presentation age, foveal retinoblastoma (at initial examination), use of TTT, and tumor-foveola distance (at last visit) were found to be significant risk factors for worse VA (P < .026). On multivariate analysis, however, only TTT was found to be significant (P = .010). At last visit, 6 of 27 (22%) patients had nystagmus and 12 of 20 (60%) bilaterally salvaged patients had strabismus (n = 10 exotropia and n = 2 esotropia).

Conclusions: After multimodality treatments initiated with IVC, 50% of salvaged Group D retinoblastoma eyes had <20/200 vision, with TTT being a risk factor for worse vision; 60% had strabismus; and 22% had nystagmus.
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http://dx.doi.org/10.1016/j.ajo.2017.05.003DOI Listing
July 2017

High-Risk Histopathology Features in Primary and Secondary Enucleated International Intraocular Retinoblastoma Classification Group D Eyes.

Ophthalmology 2017 06 13;124(6):851-858. Epub 2017 Mar 13.

Ocular Oncology Service, Moorfields Eye Hospital, London, United Kingdom; Retinoblastoma Service, Royal London Hospital, London, United Kingdom; National Institute for Health Research Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust and University College London, Institute of Ophthalmology, London, United Kingdom.

Purpose: To evaluate the rate and identify the risk factors for high-risk histopathologic features in group D retinoblastoma eyes enucleated as primary or secondary treatment.

Design: Retrospective analysis.

Participants: A total of 64 enucleated group D eyes (62 patients), of which 40 (40 patients) were primary and 24 (22 patients) were secondary to other treatments.

Methods: Clinicopathologic correlation of consecutive group D eyes enucleated from 2002 to 2014. High-risk histopathologic features were defined as the presence of anterior chamber seeds, iris infiltration, ciliary body/muscle infiltration, massive (≥3 mm) choroidal invasion, retrolaminar optic nerve invasion, or combined non-massive choroidal and prelaminar/laminar optic nerve invasion.

Main Outcome Measures: High-risk histopathologic features, metastasis, and death.

Results: Of the 64 group D eyes, 37 (58%) were classified as cT2bN0M0H0, 24 (38%) were classified as cT2bN0M0H1, and 3 (5%) were classified as cT2aN0M0H1, according to the 8th edition cTNMH Retinoblastoma Staging. High-risk histopathologic features were detected in 10 eyes (16%) in the entire cohort, 5 eyes (13%) of the primary enucleated group (pT3aNxM0, n = 2 and pT3bNxM0, n = 3, 8th edition pTNM), and 5 eyes (21%) of the secondary enucleated group (pT2bNxM0, n = 2, pT3aNxM0, n = 2 and pT3cNxM0, n = 1). Absence of vitreous seeds at presentation was the only predictive factor found for high-risk histopathologic features in the primary enucleation group (P = 0.042), whereas none were found in the secondary group (P ≥ 0.179). Invasion of the anterior structures (anterior chamber, iris, ciliary body/muscle) was detected significantly more after secondary enucleation (P = 0.048). All patients with high-risk histopathologic features were treated with adjuvant chemotherapy, and no metastases were recorded in a median follow-up time of 73.2 months (mean, 71.5; range, 13.7-153.0).

Conclusions: The choice of primary treatment for group D retinoblastoma should be carefully weighed, because according to this study, 13% of eyes harbor high-risk histopathologic features at presentation, with the absence of vitreous seeds being a potential risk factor. It is of special importance in group D eyes being considered for nonsystemic treatment, such as primary intraophthalmic artery chemotherapy. Secondary enucleated group D eyes with high-risk histopathologic features more commonly involved anterior structures, warranting meticulous clinical and histologic examinations for this subset of patients.
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http://dx.doi.org/10.1016/j.ophtha.2017.01.048DOI Listing
June 2017

Primary intravenous chemotherapy for group D retinoblastoma: a 13-year retrospective analysis.

Br J Ophthalmol 2017 Jan 13;101(1):82-88. Epub 2016 Dec 13.

Ocular Oncology Service, Moorfields Eye Hospital NHS Foundation Trust, London, UK.

Background: Eye salvage rate for group D retinoblastoma using intravenous chemotherapy (IVC) as a primary modality is <50%. To report on 13 years' experience with the use of primary IVC for group D retinoblastoma.

Methods: A retrospective analysis of 64 group D eyes (52 patients) treated with primary IVC, from 2002 to 2014.

Results: The median age at presentation was 11.0 months (mean: 18.6, range: 0.6-144.0), 35 (67%) patients had bilateral disease, 38 (73%) germline disease and 8 (15%) cases were familial. In addition to IVC, patients received a median number of three treatments (mean: 6, range: 0-24), including thermotherapy/cryotherapy, plaque radiotherapy, intra-ophthalmic artery chemotherapy (IAC) and/or intravitreous chemotherapy. External beam radiotherapy (EBRT) was used in five eyes, all of which were eventually enucleated. In a median follow-up time of 55 months (mean: 64, range: 14-156), 63% of eyes were salvaged. By the Kaplan-Meier survival analysis, globe salvage rate was 83%, 70%, 59% and 45% at 1, 3, 5 and 10 years, respectively. There were no cases of metastatic spread from intraocular retinoblastoma and no deaths. IVC-related adverse events included febrile neutropenia in 21 (40%) patients and anaphylactic reaction to carboplatin in 2 (4%), all conservatively resolved. Of the patients receiving IAC, third and sixth nerve palsies were documented in two (10%) and one (5%) eyes, respectively.

Conclusions: Primary IVC for group D eyes, with adjuvant treatments as required, was found to be a safe and efficient approach, achieving 63% eye salvage rate, no metastatic spread from intraocular retinoblastoma and no deaths. IAC has now replaced EBRT as a successful salvage treatment.
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http://dx.doi.org/10.1136/bjophthalmol-2016-309710DOI Listing
January 2017

Use of Kaolin-impregnated Gauze for Improvement of Intraoperative Hemostasis and Postoperative Wound Healing in Blepharoplasty.

J Clin Aesthet Dermatol 2016 Jun 1;9(6):51-5. Epub 2016 Jun 1.

Division of Ophthalmology, Section Oculofacial Plastic and Reconstructive Surgery, Ohio University/OhioHealth Doctor's Hospital, Columbus, Ohio;; Department of Ophthalmology, Oral and Maxillofacial Surgery, Grant Medical Center, Columbus, Ohio;; Department of Ophthalmology, The Ohio State University, Columbus, Ohio.

Purpose: Kaolin is a mineral shown to be effective in controlling hemorrhage when combined with standard gauze and applied to wounds. This study investigates the application of kaolin to control intraoperative bleeding and promote wound healing in eyelid surgery.

Methods: This prospective, randomized, double-blind study recruited patients who underwent eyelid surgery. Following skin incision, kaolin-impregnated gauzewas placed in one eyelid wound bed and cotton gauze in the other, then removed. Distinct, individual areas of bleeding were recorded. Standardized photographs were obtained postoperatively on Day 1, 4, and 7. Photographs were graded for edema and ecchymosis by four blinded observers. Patients also completed a survey inquiring which side had more bruising, swelling, and pain at each return visit.

Results: A total of 46 patients completed the study. The number of intraoperative bleeding sites for kaolin versus plain gauze was not significantly different (p=0.96). Photographic grading by blinded observers did not identify any statistically significant differences in postoperative edema at any time point between lids. There was a statistically significant difference for ecchymosis at postoperative Day 4 (p=0.009) and Day 7 (p=0.016). Patient surveys did not show any difference in perceived edema, ecchymosis, or pain between lids.

Conclusion: Intraoperative hemostasis was not affected by the use of kaolin-impregnated gauze. The effectiveness of kaolin in wound healing showed improved ecchymosis at Days 4 and 7 when assessed by blinded observers. Patients did not notice any improvement in postoperative edema, ecchymosis, or pain.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4928457PMC
June 2016

Re: "Periorbital Sclerotherapy Caution".

Ophthalmic Plast Reconstr Surg 2016 May-Jun;32(3):238-9

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http://dx.doi.org/10.1097/IOP.0000000000000704DOI Listing
February 2017

Serial Intravitreal Bevacizumab Injections Slow the Progression of Radiation Maculopathy Following Iodine-125 Plaque Radiotherapy.

Open Ophthalmol J 2016 15;10:103-10. Epub 2016 Mar 15.

Department of Ophthalmology, Kellogg Eye Center, University of Michigan, Ann Arbor, Michigan, USA.

Background And Objective: To assess the outcomes of intravitreal bevacizumab injection in the management of radiation maculopathy secondary to plaque radiotherapy, and to identify optimal treatment strategies.

Study Design: A retrospective review of all choroidal melanoma patients at one referral center who were treated with plaque radiotherapy, subsequently developed radiation maculopathy, and received intravitreal bevacizumab.

Results: A total of 31 patients were identified. The mean visual acuity decreased three Snellen lines in the year leading up to the first bevacizumab injection. After initiating injection therapy, the mean visual acuity remained stable for 9 months. The change in visual acuity of patients who received injections within 90 days of previous injections was significantly better than the visual acuity of those who received injections more than 90 days apart (p=0.0003). Patients who demonstrated late-phase macular leakage on fluorescein angiography at the time of the first bevacizumab injection had better long-term visual acuity outcomes than patients who had no evidence of macular leakage (average of one line improvement of vision vs. ten line loss of vision, p=0.03).

Conclusions: Intravitreal bevacizumab injection was effective in stabilizing visual acuity in patients with radiation maculopathy. Patients benefited most from injections administered every 90 days or sooner. Fluorescein angiography can help identify patients who will respond favorably to treatment.
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http://dx.doi.org/10.2174/1874364101610010103DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4797673PMC
April 2016
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