Samuel K Houston

Current Update on Retinoblastoma

Treatment of retinoblastoma has undergone significant advancements over the past few decades, as globe-salvaging therapies with chemoreduction and focal consolidation are favored over external beam radiation and enucleation. With current chemotherapy protocols and focal laser, survival in the United States and other developed countries has now climbed to almost 100% with many children maintaining functional vision. However, in other continents such as Africa, survival rates drop significantly.1, 2 Additionally, children with advanced tumors often require enucleation. Novel therapeutic directions are actively being pursued for these advanced retinoblastoma tumors, as well as development of treatments that decrease associated risks of systemic chemotherapy. Additionally, there are a number of experimental adjuvant therapies that have been shown to be efficacious in animal models, and may be part of the future armamentarium of cancer treatment. Finally, novel imaging modalities are being developed that may aid in the diagnosis and management of retinoblastoma in the future. The following review discusses current updates on retinoblastoma.

Combination therapy with triamcinolone acetonide and bevacizumab for the treatment of severe radiation maculopathy in patients with posterior uveal melanoma

Purpose To evaluate the role of intravitreal triamcinolone acetonide in patients who developed severe, visually compromising radiation maculopathy or progressed despite anti-angiogenic treatments. Methods An Institutional Review Board approved, consecutive, retrospective study from 2006 to 2009 of patients who developed severe, visually compromising radiation retinopathy manifesting as macular edema secondary to iodine-125 plaque brachytherapy for posterior uveal melanoma, were treated with a combination of intravitreal bevacizumab and intravitreal triamcinolone. Patients were evaluated with spectral domain optical coherence tomography (SD-OCT) at 2–4 month intervals following plaque removal. Treatment with intravitreal bevacizumab commenced at the first signs of visually compromising macular edema diagnosed with SD-OCT. Triamcinolone acetonide was administered to patients with severe maculopathy as consolidative therapy, or for patients that were refractory to repeated bevacizumab injections with persistent or worsening cystoid macular edema and lack of improvement or progressive worsening of best corrected visual acuity (BCVA). Results Twenty-five patients were evaluated after receiving a combination of intravitreal bevacizumab and triamcinolone. Initial treatment commenced at a mean of 14.5 (range of 2–42) months after plaque brachytherapy. Patients were given a mean of two injections (range 1–6) of triamcinolone acetonide, and a mean of 8.8 bevacizumab injections (range of 1–26) with a mean follow-up of 31.2 months. Radiation maculopathy upon first detection had a mean SD-OCT grade of 3.6 (median = 4), with an associated mean entry level BCVA of 20/70. Visual acuity at time of first intravitreal triamcinolone was 20/138. At last follow-up (mean of 45.5 months after plaque brachytherapy) mean BCVA was 20/136; however, 9 of 25 (36%) patients who presented with severe radiation maculopathy demonstrated 20/50 or better vision at last follow-up. Conclusion This case series suggests a beneficial role for intravitreal triamcinolone as a consolidation treatment for patients who present with severe radiation maculopathy or as an adjuvant to bevacizumab for refractory or progressive maculopathy.

Early SD-OCT diagnosis followed by prompt treatment of radiation maculopathy using intravitreal bevacizumab maintains functional visual acuity

Purpose: To evaluate the benefits of intravitreal bevacizumab in patients with visually compromising radiation maculopathy following iodine-125 plaque brachytherapy for uveal melanoma. Methods: In this Institutional Review Board-approved, consecutive, retrospective study from 2006–2009 of patients maintaining 20/50 or better vision following treatment for visually compromising radiation maculopathy, patients were evaluated with spectral domain optical coherence tomography at 2–4 month intervals following plaque removal. Treatment with intra-vitreal bevacizumab commenced at the first signs of radiation vasculopathy on spectral domain optical coherence tomography with associated decreased best corrected visual acuity, followed by repeat injections for recurrent or persistent vasculopathic changes. Results: At 3 years following plaque brachytherapy, 81 of 159 (50.9%) patients treated for radiation maculopathy demonstrated 20/50 or better vision at median follow up of 36 months, which demonstrates significant improvement in vision as compared to the Collaborative Ocular Melanoma Study (P < 0.0001). These 81 patients were given a mean of five injections (range 1–17) over a mean of 17.6 months (range 1–54 months), starting at 15.8 months (range 3–50 months) after plaque brachytherapy. For those eyes that maintained 20/50 or better vision at the final follow-up, pretreatment mean best corrected visual acuity of 20/43 improved to 20/31. Conclusion: This study demonstrates that spectral domain optical coherence tomography can detect early vasculopathic changes secondary to radiation maculopathy and that prompt treatment with intravitreal bevacizumab may delay vision loss and maintain or possibly improve visual acuity in half of eyes diagnosed with radiation maculopathy. Radiation maculopathy remains a therapeutically manageable morbidity associated with radiation therapy for posterior uveal melanoma.

Intravitreal bevacizumab combined with plaque brachytherapy reduces melanoma tumor volume and enhances resolution of exudative detachment.

Background The purpose of this study was to evaluate intravitreal bevacizumab as an adjuvant treatment to plaque brachytherapy in the treatment of choroidal melanoma. Methods This was a retrospective, consecutive study of 124 patients treated from 2007 to 2009 for choroidal melanoma with plaque brachytherapy. Patients were treated with I-125 plaque brachytherapy with 2 mm margins and 85 Gy to the tumor apex. Consecutive patients were injected intravitreally with 2.5 mg/0.1 mL bevacizumab at a site away from the primary tumor and immediately following plaque removal. Choroidal melanomas were observed using indirect ophthalmoscopy, wide-angle photography, and ultrasound. The main outcome measures were tumor volume, resolution of exudative retinal detachment, and visual acuity. Results One hundred and twenty-four patients met our inclusion criteria and were included in the analysis. The mean patient age was 65.7 years, and the mean apical tumor height was 4.0 ± 2.7 mm and basal diameter was 12.7 ± 3.0 mm. Mean follow-up was 24 months. Prior to treatment, 100% of tumors had exudative retinal detachment, and pretreatment visual acuity was 20/55 (median 20/40). Tumor control was 100%, metastasis was 0% at last follow-up, and 89.8% had complete resolution of exudative retinal detachment, with a mean time to resolution of 3.36 months. At one month, 43% had complete resolution of exudative retinal detachment, which increased to 73% at 4 months. Visual acuity was 20/62 (median 20/40) at 4 months, with stabilization to 20/57 (median 20/40) at 8 months, 20/56 (median 20/30) at 12 months, and 20/68 (median 20/50) at 24 months. Tumor volume following combined therapy was shown to be reduced by 22.2% at 3 months, 28.9% at 6 months, 39.3% at 12 months, and 52.2% at 24 months (all P < 0.001). All patients tolerated the procedure well without systemic side effects. Conclusion Intravitreal bevacizumab may be used as an adjuvant agent following plaque brachytherapy. Treated choroidal melanomas show reduction in tumor volume as well as resolution of exudative retinal detachments.

Evaluation of the surgical learning curve for I-125 episcleral plaque placement for the treatment of posterior uveal melanoma: a two decade review.

Purpose To evaluate the surgical learning curve in episceral plaque brachytherapy placement in the management of posterior uveal melanoma. Methods A retrospective chart review of two cohorts of 250 consecutive patients undergoing plaque placement for posterior uveal melanoma from 2002 to 2004 and from 2008 to 2009 was conducted. The plaque–tumor apposition rates verified by intraoperative echography were evaluated and correlated with surgical volume over a 19-year period. Results In an initial study of 29 consecutive patients undergoing plaque placement from January 1992 to January 1995, a suboptimal plaque placement rate of 21% (n = 29) was identified. This percentage declined to 12% (n = 100) from January 2002 to January 2004, and further declined to 4% (n = 150) from June 2008 to August 2009. The tumor–plaque apposition rates for these three groups were 79% (1992–1995), 88% (2002–2004), and 96% (2008–2009). An estimated surgical volume of 1275 cases was performed to achieve a >90% precision rate for first application of primary plaque centration. Conclusion There are challenges to mastering the precise placement of radioactive plaques for posterior uveal melanoma. We have demonstrated a significant learning curve for plaque placement techniques, and have emphasized the importance of intraoperative ultrasound in the verification of plaque placement, thus allowing for intraoperative repositioning.

Focal, Periocular Delivery of 2-Deoxy-d-Glucose as Adjuvant to Chemotherapy for Treatment of Advanced Retinoblastoma

PURPOSEnThe aim of this study was to evaluate the changes in tumor burden and hypoxia in the LH(BETA)T(AG) retinal tumors after treatment with a focal, single-modality, and combination therapy using periocular carboplatin and 2-deoxy-d-glucose (2-DG).nnnMETHODSnSeventeen-week-old LH(BETA)T(AG) transgenic mice (n = 25) were treated with periocular injections of varying doses of 2-DG (62.5, 125, 250, 500 mg/kg) to obtain a dose response. Same-aged mice (n = 30) received periocular injections of saline, carboplatin, and 2-DG. Mice were divided into six groups: saline; carboplatin (31.25 μg/20 μL, subtherapeutic dose); 2-DG (250 mg/kg); 2-DG (500 mg/kg); carboplatin (31.25 μg/20 μL) and 2-DG (250 mg/kg); and carboplatin (31.25 μg/20 μL) and 2-DG (500 mg/kg). Injections were administered twice weekly for three consecutive weeks. Eyes were enucleated at 20 weeks of age, snap frozen, and analyzed for hypoxic regions and tumor volume.nnnRESULTSnThe difference in percentage of hypoxia after treatment with 500 mg/kg 2-DG was statistically significant from the other dose groups (P < 0.015). The difference in tumor burden was statistically significant from the 250 mg/kg dose (P < 0.015) and 500 mg/kg dose (P < 0.001). Highly significant differences were found between the treatment types for tumor burden, percentage of hypoxia, and pimonidazole intensity (P < 0.001). Tumor burden decreased significantly after all forms of treatment (P < 0.001); however, tumor burden became significantly more reduced after treatment with combination therapy of carboplatin and 2-DG than with either treatment alone (P < 0.001). The percentage of hypoxia and pimonidazole intensity decreased after treatment with 2-DG alone and in combination with carboplatin (P < 0.001) in all treatment groups using 2-DG regardless of the 2-DG dose used. There was no percentage reduction of hypoxia after treatment with carboplatin alone (P = 0.25).nnnCONCLUSIONSnThis study demonstrates the efficacy of focal, periocular 2-DG as an adjunct to carboplatin chemotherapy to decrease both intratumoral hypoxia and tumor burden. Hypoxia is increasingly present in advanced disease of LH(BETA)T(AG) retinal tumors. The use of glycolytic inhibitors as a therapeutic strategy has the potential to enhance current retinoblastoma treatments.

Advanced retinoblastoma treatment: targeting hypoxia by inhibition of the mammalian target of rapamycin (mTOR) in LHBETATAG retinal tumors

Purpose: The purpose of this study is to analyze the dose response of the mammalian target of rapamycin (mTOR) inhibitor, rapamycin, on tumor burden and hypoxia, and study the treatment effect on vasculature in LHBETATAG retinal tumors. Methods: This study was approved by the Institutional Animal Care and Use Committee and follows Association for Research in Vision and Ophthalmology guidelines. Eighteen-week-old LHBETATAG retinal tumor eyes (n = 30) were evaluated. Mice were divided into five groups and received periocular injections once weekly for two consecutive weeks of: a) 80% DMSO (dimethyl sulfoxide, vehicle control), b) 0.00333 mg/kg, c) 0.167 mg/kg, d) 3.33 mg/kg, and e) 6.67 mg/kg of rapamycin. Tumor sections were analyzed for hypoxia, tumor burden, and vasculature with immunohistochemistry techniques. Results: Reduction in tumor burden and hypoxia was significantly different between rapamycin doses and control (P < 0.002). Eyes treated with rapamycin at 0.167, 3.33, and 6.67 mg/kg showed a significant decrease in tumor burden in comparison with the vehicle control group (P = 0.019, P = 0.001, P = 0.009, respectively) and the 0.00333 mg/kg dose response (P = 0.023, P = 0.001, P = 0.010, respectively). Eyes treated with rapamycin at 3.33 mg/kg showed a significant reduction in the amount of hypoxia in comparison with the lower concentration groups (0.00333 and 0.167 mg/kg) of rapamycin (P = 0.024 and P = 0.052, respectively). The number of mature vessels was significantly lower in the 3.33 mg/kg treated versus vehicle control (P = 0.015; equal variances assumed, t-test for equality of means). The number of neovessels was not significantly different between both groups (P = 0.092). Conclusion: Inhibition of mTOR was shown to reduce tumor burden, hypoxia, and vasculature in the LHBETATAG retinoblastoma tumor model. Rapamycin may have a role in combination with chemotherapy or other adjuvant therapies to enhance retinoblastoma tumor control.

Regional and temporal differences in gene expression of LH(BETA)T(AG) retinoblastoma tumors.

PURPOSEnThe purpose of this study was to evaluate by microarray the hypothesis that LH(BETA)T(AG) retinoblastoma tumors exhibit regional and temporal variations in gene expression.nnnMETHODSnLH(BETA)T(AG) mice aged 12, 16, and 20 weeks were euthanatized (n = 9). Specimens were taken from five tumor areas (apex, anterior lateral, center, base, and posterior lateral). Samples were hybridized to gene microarrays. The data were preprocessed and analyzed, and genes with a P < 0.01, according to the ANOVA models, and a log(2)-fold change >2.5 were considered to be differentially expressed. Differentially expressed genes were analyzed for overlap with known networks by using pathway analysis tools.nnnRESULTSnThere were significant temporal (P < 10(-8)) and regional differences in gene expression for LH(BETA)T(AG) retinoblastoma tumors. At P < 0.01 and log(2)-fold change >2.5, there were significant changes in gene expression of 190 genes apically, 84 genes anterolaterally, 126 genes posteriorly, 56 genes centrally, and 134 genes at the base. Differentially expressed genes overlapped with known networks, with significant involvement in regulation of cellular proliferation and growth, response to oxygen levels and hypoxia, regulation of cellular processes, cellular signaling cascades, and angiogenesis.nnnCONCLUSIONSnThere are significant temporal and regional variations in the LH(BETA)T(AG) retinoblastoma model. Differentially expressed genes overlap with key pathways that may play pivotal roles in murine retinoblastoma development. These findings suggest the mechanisms involved in tumor growth and progression in murine retinoblastoma tumors and identify pathways for analysis at a functional level, to determine significance in human retinoblastoma. Microarray analysis of LH(BETA)T(AG) retinal tumors showed significant regional and temporal variations in gene expression, including dysregulation of genes involved in hypoxic responses and angiogenesis.

Novel retinoblastoma treatment avoids chemotherapy: the effect of optimally timed combination therapy with angiogenic and glycolytic inhibitors on LHBETATAG retinoblastoma tumors

PURPOSEnThe purpose of this study was to evaluate the effect of optimally timed combination treatment with angiogenic and glycolytic inhibitors on tumor burden, hypoxia, and angiogenesis in advanced retinoblastoma tumors.nnnMETHODSnLH(BETA)T(AG) mice (n =30) were evaluated. Mice were divided into 5 groups (n =6) and received injections at 16 weeks of age (advanced tumors) with a) saline, b) anecortave acetate (AA), c) 2-deoxyglucose (2-DG), d) AA +2-DG (1 day post-AA treatment), or e) AA +2-DG (1 week post-AA treatment). Eyes were enucleated at 21 weeks and tumor sections were analyzed for hypoxia, angiogenesis, and tumor burden.nnnRESULTSnEyes treated with 2-DG 1 day post-AA injection showed a 23% (P =0.03) reduction in tumor burden compared with 2-DG alone and a 61% (P < 0.001) reduction compared with saline-treated eyes. Eyes treated with 2-DG 1 week post-AA injection showed no significant decrease in tumor burden compared with 2-DG alone (P = 0.21) and a 56% (P < 0.001) decrease in comparison with saline-treated eyes. 2-DG significantly reduced the total density of new blood vessels in tumors by 44% compared to saline controls (P < 0.001), but did not affect the density of mature vasculature.nnnCONCLUSIONSnCombination therapy with angiogenic and glycolytic inhibitors significantly enhanced tumor control. Synergistic effects were shown to be dependent on the temporal course of treatment, emphasizing optimal timing. 2-DG was shown to reduce the density of neovessels, demonstrating an antiangiogenic effect in vivo. As a result, angiogenic and glycolytic inhibitors may have significant potential as alternative therapies for treating children with retinoblastoma.

Lasers for the treatment of intraocular tumors.

Lasers are used extensively in ophthalmology for a variety of conditions, including many choroidal and retinal tumors. With technologic advances, current therapy attempts not only to maximize survival with globe-salvaging treatment, but also to preserve vision. Each neoplasm has different indications for primary and adjuvant therapy, as well as differing laser treatment protocols. Additionally, there are numerous laser applications available for use, including laser photocoagulation, transpupillary thermotherapy (TTT), and photodynamic therapy (PDT). The current review outlines the basic principles of laser treatment for intraocular tumors, focusing on the indications, treatment protocols, efficacy, and safety, while also presenting the latest advances in intraocular tumor treatment.