The Experts below are selected from a list of 333 Experts worldwide ranked by ideXlab platform
Timothy G. Murray - One of the best experts on this subject based on the ideXlab platform.
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Abstract 4642: Combined glycolytic inhibition and anti-vascular treatment in retinoblastoma: Novel strategy for tumor control avoids chemotherapy
Experimental and Molecular Therapeutics, 2012Co-Authors: Timothy G. Murray, Yolanda Piña, Steve Houston, Christina L. Decatur, Ted LampidisAbstract:Purpose: The purpose of this study was to evaluate the combination treatment of glycolytic inhibitors and anti-angiogenic agents on tumor burden and hypoxia in advanced retinoblastoma using the LHbetaTag murine transgenic retinoblastoma model. Methods: Under IACUC protocol, thirty advanced LHbetaTag mice (16 weeks of age) were divided into 5 groups (n=6 per group) and treated with periocular injections of (a) saline, (b) 2-deoxy-glucose (2-DG), (c) Anecortave acetate (AA) or (d) 2-DG plus AA (one day post AA treatment) or (e) 2-DG plus AA (one week post AA treatment). Eyes were enucleated at 21 weeks and tumor sections were analyzed for tumor burden and intra-tumoral hypoxia. Results: Combined treatment with 2-DG and AA (both 2-DG one day and one week post AA treatment) showed significant reduction in tumor burden compared to saline control (61% and 56% respectively, p Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4642. doi:1538-7445.AM2012-4642
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Abstract 5352: Novel treatment approaches in retinoblastoma: Impact of combination therapy on tumor burden
Tumor Biology, 2011Co-Authors: Samuel K. Houston, Timothy G. Murray, Christina L. Decatur, Nikesh Shah, Ludimila Cavalcante, Yolanda PiñaAbstract:Purpose: The purpose of the current study is to examine vessel targeting, chemotherapy, and mammalian target of rapamycin (mTOR) inhibitor agents in LHBETATAG retinal tumors and their impact on tumor burden. Methods: Group A: Ten-week-old, LHBETATAG mice (n=30) received a single subconjunctival injection of Anecortave acetate (AA; 1200, 600, 300, and 150 µg) delivered to right eyes only. Group B: Ten-week-old, LHBETATAG mice (n=30) received a single subconjunctival injection of AA (600, 300, and 150 µg) delivered to right eyes only, either during a cycle of carboplatin (six subconjunctival deliveries) or after the completed cycle. Carboplatin was delivered at the subtherapeutic concentration of 62.5 µg. All animals were euthanatized at 16 weeks of age, and the eyes were examined histopathologically. Group C: Eighteen-week-old, LHBETATAG mice received (n=30) subconjunctival injections of rapamycin once weekly for two consecutive weeks (0.00333, 0.167, 3.33, and 6.67 mg/kg). Tumor sections were analyzed for tumor burden with immunohistochemistry techniques. Results: A statistically significant reduction in tumor burden was detected after a single periocular injection of AA. The reduction of tumor burden followed a U-shaped dose-response curve. Tumor burden was significantly decreased when AA and carboplatin were combined. However, varying doses and delivery schedule of these agents had significant impact on the effectiveness of the combined treatment. The most effective scheme was delivering a low dose (150-300 µg) of AA after a complete cycle of carboplatin. Reduction in tumor burden were significantly different between rapamycin doses and control (p Conclusions: AA, as monotherapy or as adjuvant therapy, significantly controlled tumor burden in a murine model of retinoblastoma. Moreover, adjuvant therapy enabled the use of typically subtherapeutic carboplatin doses without decreasing efficacy of the therapy. Inhibition of mTOR reduced tumor burden during late disease in the LHBETATAG retinoblastoma tumor model. Rapamycin may have a role in combination with chemotherapy or other adjuvant therapies to enhance retinoblastoma tumor control. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5352. doi:10.1158/1538-7445.AM2011-5352
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Novel retinoblastoma treatment avoids chemotherapy: the effect of optimally timed combination therapy with angiogenic and glycolytic inhibitors on LHBETATAG retinoblastoma tumors
Dove Medical Press, 2011Co-Authors: Samuel K. Houston, Yolanda Pi&, Timothy G. MurrayAbstract:Samuel K Houston1, Yolanda Piña1, Timothy G Murray1, Hinda Boutrid1, Colleen Cebulla2, Amy C Schefler1, Wei Shi1, Magda Celdran1, William Feuer1, Jaime Merchan3, Ted J Lampidis41Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL, USA; 2Department of Ophthalmology, The Ohio State University, Columbus, OH, USA; 3Division of Hematology/Oncology, Department of Medicine, 4Department of Cell Biology and Anatomy, University of Miami Miller School of Medicine and Sylvester Comprehensive Cancer Center, Miami, FL, USAPurpose: The 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.Methods: LHBETATAG 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.Results: Eyes 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.Conclusions: Combination 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.Keywords: retinoblastoma, adjuvant therapies, angiogenic inhibitors, glycolytic inhibitor
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Gelatinase Expression in Retinoblastoma: Modulation of LHBETATAG Retinal Tumor Development by Anecortave Acetate
Investigative ophthalmology & visual science, 2010Co-Authors: M. Livia Bajenaru, Timothy G. Murray, William J. Feuer, M.-e. Jockovich, Yolanda Piña, Colleen M. Cebulla, Maria-encarna Marin CastañoAbstract:Retinoblastoma (RB) is the most common intraocular tumor of childhood.1 Although current treatments are effective, they lead to a number of local and systemic complications.2–4 Recent research efforts have focused on developing adjunctive treatment modalities that concentrate on improving local tumor control and reducing the toxicity of systemic chemotherapy. Chemotherapy failures require either radiotherapy, with an increased risk for second cancers,5,6 or permanent removal of one or both eyes.7 Even in successful cases, current chemotherapeutic regimens produce significant morbidity, including bone marrow suppression, resulting in unplanned hospitalization, transfusion, or both in up to 75% of patients.8 Several treatment strategies are being investigated, including the use of vessel-targeting therapy and glycolytic inhibitors. Vessel-targeting therapy has been shown to be an effective treatment for reducing tumor burden in the LHBETATAG mouse model of RB and is promising as future translational adjuvant therapy.9–12 Our recent studies using this mouse model of RB have shown that advanced tumors contain regions of hypoxia that can be selectively targeted using 2-deoxy-d-glucose, a glycolytic inhibitor.13 The angiogenic capacity of RB tumors has been demonstrated,14–16 and it is correlated with invasive growth and metastasis.17–19 We have shown that a single periocular injection of the antiangiogenic agent Anecortave acetate (AA) significantly reduces tumor burden in the LHBETATAG transgenic mouse model of RB.9 LHBETATAG transgenic mice develop bilateral, heritable retinal tumors with the histologic and clinical features of human RB.20 AA is a cortisene, a steroid derivative that has been shown to inhibit blood vessel growth in a number of preclinical models of angiogenesis without typical glucocorticoid side effects such as intraocular pressure elevation, cataract, and anti-inflammatory activity.21 However, the mechanism of action of AA is not fully understood. In this study, gel and in situ zymography techniques were used to asses whether gelatinase modulation may be a mechanism of tumor reduction in transgenic RB eyes treated with AA.
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Increased hypoxia following vessel targeting in a murine model of retinoblastoma.
Investigative ophthalmology & visual science, 2009Co-Authors: H. Boutrid, William J. Feuer, M.-e. Jockovich, Yolanda Piña, Colleen M. Cebulla, Theodore J. Lampidis, Timothy G. MurrayAbstract:PURPOSE The purpose of this study was to evaluate the effects of vessel targeting and chemotherapy agents on inducing hypoxic regions in LH(BETA)T(AG) murine retinal tumors. METHODS. Twelve- and 16-week-old LH(BETA)T(AG) transgenic retinoblastoma mice were treated with periocular injections to the right eye only of saline (n = 42), Anecortave acetate (a single injection; 300 microg/20 microL; n = 42), or carboplatin (two injections per week for 3 weeks; 62.5 microg/20 microL; n = 42). Eyes were enucleated 1 day, 1 week, and 1 month after injection. To assess hypoxia, mice received 60 mg/kg pimonidazole via intraperitoneal injection. Eyes were enucleated, and tumor sections were analyzed. RESULTS Levels of hypoxia significantly increase in 16-week-old animals 1 day and 1 week after treatment with Anecortave acetate, a known angiostatic agent. Eyes treated with Anecortave acetate showed a 28% (P < 0.001) increase in hypoxic regions in comparison with the saline-treated control group 1 day after injection and a 17% (P < 0.001) increase 1 week after injection. In early tumors of 12-week-old animals, levels of hypoxia increased by 2.0% (P = 0.011) 1 day after Anecortave acetate injection compared to controls. Levels of hypoxia significantly decrease in 16-week-old animals 1 week and 1 month after treatment with carboplatin, a chemotherapeutic agent. Eyes treated with carboplatin showed a 21.7% (P = 0.017) decrease in hypoxic regions in comparison with the saline-treated control group 1 week after injection and a 4.51% (P < 0.001) decrease 1 month after injection. In early tumors of 12-week-old animals, levels of hypoxia decreased by 0.0429% (P < 0.001) 1 month after carboplatin injection compared with controls. CONCLUSIONS Treatment with a vessel-targeting agent results in changes in the tumor microenvironment as early as 1 day after treatment. By increasing hypoxia in tumors, vessel-targeting agents can be combined with glycolytic inhibitors which have been shown previously to target hypoxic regions in this transgenic model. This approach may have benefits for children with this disease and should be further investigated.
Jason S. Slakter - One of the best experts on this subject based on the ideXlab platform.
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The Digital Angiography Reading Center (DARC) role in the Anecortave acetate clinical trials.
Survey of Ophthalmology, 2007Co-Authors: Jason S. Slakter, Cynthia Carvalho, Hannah ColemanAbstract:Advances in digital camera and computer technology have resulted in imaging systems providing clinically relevant information equivalent to traditional film-based techniques. The Digital Angiography Reading Center (DARC) was created to provide the next generation in reading center assessment for clinical trials of retinal disease. A fully digital angiographic imaging protocol was implemented with the Anecortave acetate clinical studies. For image evaluation readers followed a standard manual of definitions and guidelines. Eligibility was determined based on protocol specific criteria. Rapid communication of images between the study sites and DARC permitted screening for eligibility and pre-treatment stratification of all patients prior to enrollment. This screening process was designed to eliminate angiographically ineligible patients from the clinical trials. The result was a reduction in the total number of patients needed to obtain sufficient evaluable patients for statistical assessment of treatment outcome. Digital angiography can be successfully used in clinical trials for retinal disease.
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Anecortave acetate: a treatment for age-related macular degeneration
Aging Health, 2006Co-Authors: Jason S. SlakterAbstract:Anecortave acetate inhibits the growth of blood vessels present in choroidal neovascularization that are associated with exudative age-related macular degeneration independent of the inciting cause of angiogenesis. When Anecortave acetate is administered as a posterior juxtascleral depot outside the eye, effective levels of the drug are delivered to the macula for 6 months. Anecortave acetate 15 mg has been shown to be efficacious at inhibiting vision loss and choroidal neovascularization lesion growth in a placebo-controlled, double-masked clinical trial in patients with exudative age-related macular degeneration. Depot administration is well suited for controlling active choroidal neovascularization, as well as suppressing choroidal neovascularization development. Finally, clinical studies have demonstrated that Anecortave acetate has excellent ocular and systemic safety profiles.
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Anecortave acetate for the treatment of idiopathic perifoveal telangiectasia: a pilot study.
Retina (Philadelphia Pa.), 2006Co-Authors: Chiara M. Eandi, Jason S. Slakter, Michael D. Ober, K. Bailey Freund, Christina M. Klais, John A. Sorenson, Lawrence A. YannuzziAbstract:PURPOSE To investigate the use of Anecortave acetate, a new angiostatic cortisene, for the treatment of the leakage and/or neovascularization associated with idiopathic perifoveal telangiectasia (IPT) in an open label prospective pilot study. METHODS Seven eyes of six patients were treated with posterior juxtascleral administration of Anecortave acetate delivered adjacent to the macula using a specially designed curved cannula. A full clinical examination and fluorescein angiography were performed at baseline and at 3-month intervals. The primary efficacy outcome for this pilot study was the mean change in visual acuity (Early Treatment Diabetic Retinopathy Study) from baseline. RESULTS The visual acuity remained unchanged in two eyes of two patients with nonproliferative disease after 24 months. The five eyes of four patients presenting with subretinal neovascularization, the proliferative stage of IPT, showed stabilization or improvement of lesion size, resolution of leakage, and stabilization of vision at last follow-up. CONCLUSION The results of this study suggest that Anecortave acetate may inhibit retinal and subretinal permeability as well as neovascular proliferation in patients with IPT. A larger study accordingly should be designed in the future to evaluate the effectiveness and treatment of IPT with this drug.
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Anecortave acetate treatment for retinal angiomatous proliferation: a pilot study.
Retina (Philadelphia Pa.), 2006Co-Authors: Christina M. Klais, Jason S. Slakter, Chiara M. Eandi, Michael D. Ober, K. Bailey Freund, John A. Sorenson, Sara N Sadeghi, Richard F. Spaide, Lawrence A. YannuzziAbstract:Purpose:The purpose of this study was to evaluate Anecortave acetate treatment of retinal angiomatous proliferation (RAP), a neovascular form of age-related macular degeneration, with specific regard to inhibition of neovascularization and maintenance of vision.Methods:Thirty-four patients with RAP
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Anecortave acetate for treating or preventing choroidal neovascularization.
Ophthalmology clinics of North America, 2006Co-Authors: Jason S. SlakterAbstract:Although there have been treatments and pharmacologic agents approved in the last several years to treat advanced stages of AMD, these treatments do not halt disease progression. Furthermore, it is clear that when dry AMD progresses to CNV in one eye, there is a substantial risk that it will progress in the other eye. Sight-preservation at early stages of the disease should be a key goal of research, yet there are no approved therapies for halting the progression of early stages of AMD. Patients may be encouraged to use vitamin supplements, cease smoking, and eat a healthy diet; however, these recommendations are not appropriate for all patients, nor are they embraced by everyone. A pharmacologic agent capable of targeting the early stages of AMD would be a welcome addition to the armamentarium of options for managing AMD. Trials are ongoing to evaluate the role of Anecortave acetate as a prophylactic treatment to slow the progression of the early stages of AMD. Completed clinical studies have demonstrated that Anecortave acetate possesses a mechanism of action that decreases CNV growth irrespective of the inciting angiogenic stimulus, has a dosing-interval that allows its use as prophylactic therapy, and is safe. The economic benefits associated with prevention and progression to advanced AMD, in even a small proportion of cases, is significant and could result in substantial cost savings to society as a whole while providing countless benefits to individual patients in terms of continued independent function, self-sufficiency, and improved quality of life.
Yolanda Piña - One of the best experts on this subject based on the ideXlab platform.
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Abstract 4642: Combined glycolytic inhibition and anti-vascular treatment in retinoblastoma: Novel strategy for tumor control avoids chemotherapy
Experimental and Molecular Therapeutics, 2012Co-Authors: Timothy G. Murray, Yolanda Piña, Steve Houston, Christina L. Decatur, Ted LampidisAbstract:Purpose: The purpose of this study was to evaluate the combination treatment of glycolytic inhibitors and anti-angiogenic agents on tumor burden and hypoxia in advanced retinoblastoma using the LHbetaTag murine transgenic retinoblastoma model. Methods: Under IACUC protocol, thirty advanced LHbetaTag mice (16 weeks of age) were divided into 5 groups (n=6 per group) and treated with periocular injections of (a) saline, (b) 2-deoxy-glucose (2-DG), (c) Anecortave acetate (AA) or (d) 2-DG plus AA (one day post AA treatment) or (e) 2-DG plus AA (one week post AA treatment). Eyes were enucleated at 21 weeks and tumor sections were analyzed for tumor burden and intra-tumoral hypoxia. Results: Combined treatment with 2-DG and AA (both 2-DG one day and one week post AA treatment) showed significant reduction in tumor burden compared to saline control (61% and 56% respectively, p Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4642. doi:1538-7445.AM2012-4642
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Abstract 5352: Novel treatment approaches in retinoblastoma: Impact of combination therapy on tumor burden
Tumor Biology, 2011Co-Authors: Samuel K. Houston, Timothy G. Murray, Christina L. Decatur, Nikesh Shah, Ludimila Cavalcante, Yolanda PiñaAbstract:Purpose: The purpose of the current study is to examine vessel targeting, chemotherapy, and mammalian target of rapamycin (mTOR) inhibitor agents in LHBETATAG retinal tumors and their impact on tumor burden. Methods: Group A: Ten-week-old, LHBETATAG mice (n=30) received a single subconjunctival injection of Anecortave acetate (AA; 1200, 600, 300, and 150 µg) delivered to right eyes only. Group B: Ten-week-old, LHBETATAG mice (n=30) received a single subconjunctival injection of AA (600, 300, and 150 µg) delivered to right eyes only, either during a cycle of carboplatin (six subconjunctival deliveries) or after the completed cycle. Carboplatin was delivered at the subtherapeutic concentration of 62.5 µg. All animals were euthanatized at 16 weeks of age, and the eyes were examined histopathologically. Group C: Eighteen-week-old, LHBETATAG mice received (n=30) subconjunctival injections of rapamycin once weekly for two consecutive weeks (0.00333, 0.167, 3.33, and 6.67 mg/kg). Tumor sections were analyzed for tumor burden with immunohistochemistry techniques. Results: A statistically significant reduction in tumor burden was detected after a single periocular injection of AA. The reduction of tumor burden followed a U-shaped dose-response curve. Tumor burden was significantly decreased when AA and carboplatin were combined. However, varying doses and delivery schedule of these agents had significant impact on the effectiveness of the combined treatment. The most effective scheme was delivering a low dose (150-300 µg) of AA after a complete cycle of carboplatin. Reduction in tumor burden were significantly different between rapamycin doses and control (p Conclusions: AA, as monotherapy or as adjuvant therapy, significantly controlled tumor burden in a murine model of retinoblastoma. Moreover, adjuvant therapy enabled the use of typically subtherapeutic carboplatin doses without decreasing efficacy of the therapy. Inhibition of mTOR reduced tumor burden during late disease in the LHBETATAG retinoblastoma tumor model. Rapamycin may have a role in combination with chemotherapy or other adjuvant therapies to enhance retinoblastoma tumor control. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5352. doi:10.1158/1538-7445.AM2011-5352
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Gelatinase Expression in Retinoblastoma: Modulation of LHBETATAG Retinal Tumor Development by Anecortave Acetate
Investigative ophthalmology & visual science, 2010Co-Authors: M. Livia Bajenaru, Timothy G. Murray, William J. Feuer, M.-e. Jockovich, Yolanda Piña, Colleen M. Cebulla, Maria-encarna Marin CastañoAbstract:Retinoblastoma (RB) is the most common intraocular tumor of childhood.1 Although current treatments are effective, they lead to a number of local and systemic complications.2–4 Recent research efforts have focused on developing adjunctive treatment modalities that concentrate on improving local tumor control and reducing the toxicity of systemic chemotherapy. Chemotherapy failures require either radiotherapy, with an increased risk for second cancers,5,6 or permanent removal of one or both eyes.7 Even in successful cases, current chemotherapeutic regimens produce significant morbidity, including bone marrow suppression, resulting in unplanned hospitalization, transfusion, or both in up to 75% of patients.8 Several treatment strategies are being investigated, including the use of vessel-targeting therapy and glycolytic inhibitors. Vessel-targeting therapy has been shown to be an effective treatment for reducing tumor burden in the LHBETATAG mouse model of RB and is promising as future translational adjuvant therapy.9–12 Our recent studies using this mouse model of RB have shown that advanced tumors contain regions of hypoxia that can be selectively targeted using 2-deoxy-d-glucose, a glycolytic inhibitor.13 The angiogenic capacity of RB tumors has been demonstrated,14–16 and it is correlated with invasive growth and metastasis.17–19 We have shown that a single periocular injection of the antiangiogenic agent Anecortave acetate (AA) significantly reduces tumor burden in the LHBETATAG transgenic mouse model of RB.9 LHBETATAG transgenic mice develop bilateral, heritable retinal tumors with the histologic and clinical features of human RB.20 AA is a cortisene, a steroid derivative that has been shown to inhibit blood vessel growth in a number of preclinical models of angiogenesis without typical glucocorticoid side effects such as intraocular pressure elevation, cataract, and anti-inflammatory activity.21 However, the mechanism of action of AA is not fully understood. In this study, gel and in situ zymography techniques were used to asses whether gelatinase modulation may be a mechanism of tumor reduction in transgenic RB eyes treated with AA.
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Increased hypoxia following vessel targeting in a murine model of retinoblastoma.
Investigative ophthalmology & visual science, 2009Co-Authors: H. Boutrid, William J. Feuer, M.-e. Jockovich, Yolanda Piña, Colleen M. Cebulla, Theodore J. Lampidis, Timothy G. MurrayAbstract:PURPOSE The purpose of this study was to evaluate the effects of vessel targeting and chemotherapy agents on inducing hypoxic regions in LH(BETA)T(AG) murine retinal tumors. METHODS. Twelve- and 16-week-old LH(BETA)T(AG) transgenic retinoblastoma mice were treated with periocular injections to the right eye only of saline (n = 42), Anecortave acetate (a single injection; 300 microg/20 microL; n = 42), or carboplatin (two injections per week for 3 weeks; 62.5 microg/20 microL; n = 42). Eyes were enucleated 1 day, 1 week, and 1 month after injection. To assess hypoxia, mice received 60 mg/kg pimonidazole via intraperitoneal injection. Eyes were enucleated, and tumor sections were analyzed. RESULTS Levels of hypoxia significantly increase in 16-week-old animals 1 day and 1 week after treatment with Anecortave acetate, a known angiostatic agent. Eyes treated with Anecortave acetate showed a 28% (P < 0.001) increase in hypoxic regions in comparison with the saline-treated control group 1 day after injection and a 17% (P < 0.001) increase 1 week after injection. In early tumors of 12-week-old animals, levels of hypoxia increased by 2.0% (P = 0.011) 1 day after Anecortave acetate injection compared to controls. Levels of hypoxia significantly decrease in 16-week-old animals 1 week and 1 month after treatment with carboplatin, a chemotherapeutic agent. Eyes treated with carboplatin showed a 21.7% (P = 0.017) decrease in hypoxic regions in comparison with the saline-treated control group 1 week after injection and a 4.51% (P < 0.001) decrease 1 month after injection. In early tumors of 12-week-old animals, levels of hypoxia decreased by 0.0429% (P < 0.001) 1 month after carboplatin injection compared with controls. CONCLUSIONS Treatment with a vessel-targeting agent results in changes in the tumor microenvironment as early as 1 day after treatment. By increasing hypoxia in tumors, vessel-targeting agents can be combined with glycolytic inhibitors which have been shown previously to target hypoxic regions in this transgenic model. This approach may have benefits for children with this disease and should be further investigated.
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Mechanism of retinoblastoma tumor cell death after focal chemotherapy, radiation, and vascular targeting therapy in a mouse model.
Investigative ophthalmology & visual science, 2007Co-Authors: M.-e. Jockovich, William J. Feuer, Yolanda Piña, Colleen M. Cebulla, Fernando Suarez, Armando Alegret, Bc Hayden, Timothy G. MurrayAbstract:PURPOSE To evaluate the mechanism and timing of retinal tumor cell death in the LH(BETA)T(AG) mouse model of retinoblastoma after treatment with vascular targeting therapies and conventional therapies (focal chemotherapy and radiation). METHODS For vascular targeting therapy, 12- or 16-week-old mice were treated with a single subconjunctival injection of either Anecortave acetate (300 microg) or combretastatin A4 (1.5 mg). Eyes were analyzed at 1 day and 1 week after treatment. Tumor cell death was evaluated using TUNEL assays or immunofluorescence analysis of activated caspase 3 to detect apoptosis. Histopathologic analysis was performed to identify areas of necrosis. For conventional therapy, LH(BETA)T(AG) mice were treated with six serial subconjunctival injections of focally delivered carboplatin chemotherapy (100 microg/delivery) or hyperfractionated external beam radiotherapy (EBRT; 15 Gy total dose). Cell death was analyzed by TUNEL assay. RESULTS The highest levels of apoptotic cell death were seen 1 day after treatment in all treatment groups compared with vehicle controls. At 1 week after treatment, apoptotic cell death remained significantly elevated in the EBRT and carboplatin groups, but not after vessel targeting therapy. No significant necrosis was detected by histology in tumors of treated or of control eyes. CONCLUSIONS Conventional therapies (focal carboplatin chemotherapy and EBRT) and vascular targeting agents significantly increase cell death through apoptosis, while not having a significant effect on necrosis in this murine model of retinoblastoma. These studies will aid in the optimization of delivery schemes of combined treatment modalities.
William J. Feuer - One of the best experts on this subject based on the ideXlab platform.
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Gelatinase Expression in Retinoblastoma: Modulation of LHBETATAG Retinal Tumor Development by Anecortave Acetate
Investigative ophthalmology & visual science, 2010Co-Authors: M. Livia Bajenaru, Timothy G. Murray, William J. Feuer, M.-e. Jockovich, Yolanda Piña, Colleen M. Cebulla, Maria-encarna Marin CastañoAbstract:Retinoblastoma (RB) is the most common intraocular tumor of childhood.1 Although current treatments are effective, they lead to a number of local and systemic complications.2–4 Recent research efforts have focused on developing adjunctive treatment modalities that concentrate on improving local tumor control and reducing the toxicity of systemic chemotherapy. Chemotherapy failures require either radiotherapy, with an increased risk for second cancers,5,6 or permanent removal of one or both eyes.7 Even in successful cases, current chemotherapeutic regimens produce significant morbidity, including bone marrow suppression, resulting in unplanned hospitalization, transfusion, or both in up to 75% of patients.8 Several treatment strategies are being investigated, including the use of vessel-targeting therapy and glycolytic inhibitors. Vessel-targeting therapy has been shown to be an effective treatment for reducing tumor burden in the LHBETATAG mouse model of RB and is promising as future translational adjuvant therapy.9–12 Our recent studies using this mouse model of RB have shown that advanced tumors contain regions of hypoxia that can be selectively targeted using 2-deoxy-d-glucose, a glycolytic inhibitor.13 The angiogenic capacity of RB tumors has been demonstrated,14–16 and it is correlated with invasive growth and metastasis.17–19 We have shown that a single periocular injection of the antiangiogenic agent Anecortave acetate (AA) significantly reduces tumor burden in the LHBETATAG transgenic mouse model of RB.9 LHBETATAG transgenic mice develop bilateral, heritable retinal tumors with the histologic and clinical features of human RB.20 AA is a cortisene, a steroid derivative that has been shown to inhibit blood vessel growth in a number of preclinical models of angiogenesis without typical glucocorticoid side effects such as intraocular pressure elevation, cataract, and anti-inflammatory activity.21 However, the mechanism of action of AA is not fully understood. In this study, gel and in situ zymography techniques were used to asses whether gelatinase modulation may be a mechanism of tumor reduction in transgenic RB eyes treated with AA.
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Increased hypoxia following vessel targeting in a murine model of retinoblastoma.
Investigative ophthalmology & visual science, 2009Co-Authors: H. Boutrid, William J. Feuer, M.-e. Jockovich, Yolanda Piña, Colleen M. Cebulla, Theodore J. Lampidis, Timothy G. MurrayAbstract:PURPOSE The purpose of this study was to evaluate the effects of vessel targeting and chemotherapy agents on inducing hypoxic regions in LH(BETA)T(AG) murine retinal tumors. METHODS. Twelve- and 16-week-old LH(BETA)T(AG) transgenic retinoblastoma mice were treated with periocular injections to the right eye only of saline (n = 42), Anecortave acetate (a single injection; 300 microg/20 microL; n = 42), or carboplatin (two injections per week for 3 weeks; 62.5 microg/20 microL; n = 42). Eyes were enucleated 1 day, 1 week, and 1 month after injection. To assess hypoxia, mice received 60 mg/kg pimonidazole via intraperitoneal injection. Eyes were enucleated, and tumor sections were analyzed. RESULTS Levels of hypoxia significantly increase in 16-week-old animals 1 day and 1 week after treatment with Anecortave acetate, a known angiostatic agent. Eyes treated with Anecortave acetate showed a 28% (P < 0.001) increase in hypoxic regions in comparison with the saline-treated control group 1 day after injection and a 17% (P < 0.001) increase 1 week after injection. In early tumors of 12-week-old animals, levels of hypoxia increased by 2.0% (P = 0.011) 1 day after Anecortave acetate injection compared to controls. Levels of hypoxia significantly decrease in 16-week-old animals 1 week and 1 month after treatment with carboplatin, a chemotherapeutic agent. Eyes treated with carboplatin showed a 21.7% (P = 0.017) decrease in hypoxic regions in comparison with the saline-treated control group 1 week after injection and a 4.51% (P < 0.001) decrease 1 month after injection. In early tumors of 12-week-old animals, levels of hypoxia decreased by 0.0429% (P < 0.001) 1 month after carboplatin injection compared with controls. CONCLUSIONS Treatment with a vessel-targeting agent results in changes in the tumor microenvironment as early as 1 day after treatment. By increasing hypoxia in tumors, vessel-targeting agents can be combined with glycolytic inhibitors which have been shown previously to target hypoxic regions in this transgenic model. This approach may have benefits for children with this disease and should be further investigated.
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Mechanism of retinoblastoma tumor cell death after focal chemotherapy, radiation, and vascular targeting therapy in a mouse model.
Investigative ophthalmology & visual science, 2007Co-Authors: M.-e. Jockovich, William J. Feuer, Yolanda Piña, Colleen M. Cebulla, Fernando Suarez, Armando Alegret, Bc Hayden, Timothy G. MurrayAbstract:PURPOSE To evaluate the mechanism and timing of retinal tumor cell death in the LH(BETA)T(AG) mouse model of retinoblastoma after treatment with vascular targeting therapies and conventional therapies (focal chemotherapy and radiation). METHODS For vascular targeting therapy, 12- or 16-week-old mice were treated with a single subconjunctival injection of either Anecortave acetate (300 microg) or combretastatin A4 (1.5 mg). Eyes were analyzed at 1 day and 1 week after treatment. Tumor cell death was evaluated using TUNEL assays or immunofluorescence analysis of activated caspase 3 to detect apoptosis. Histopathologic analysis was performed to identify areas of necrosis. For conventional therapy, LH(BETA)T(AG) mice were treated with six serial subconjunctival injections of focally delivered carboplatin chemotherapy (100 microg/delivery) or hyperfractionated external beam radiotherapy (EBRT; 15 Gy total dose). Cell death was analyzed by TUNEL assay. RESULTS The highest levels of apoptotic cell death were seen 1 day after treatment in all treatment groups compared with vehicle controls. At 1 week after treatment, apoptotic cell death remained significantly elevated in the EBRT and carboplatin groups, but not after vessel targeting therapy. No significant necrosis was detected by histology in tumors of treated or of control eyes. CONCLUSIONS Conventional therapies (focal carboplatin chemotherapy and EBRT) and vascular targeting agents significantly increase cell death through apoptosis, while not having a significant effect on necrosis in this murine model of retinoblastoma. These studies will aid in the optimization of delivery schemes of combined treatment modalities.
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Retinoblastoma tumor vessel maturation impacts efficacy of vessel targeting in the LH(BETA)T(AG) mouse model.
Investigative ophthalmology & visual science, 2007Co-Authors: M.-e. Jockovich, William J. Feuer, Yolanda Piña, M. Livia Bajenaru, Fernando Suarez, M. Elizabeth Fini, Timothy G. MurrayAbstract:PURPOSE. The aim of this study was to quantify tumor cell proliferation and growth, analyze tumor blood vessel development, and determine the efficacy of antiangiogenic and angio-static therapy in targeting mature vessels in retinal tumors of the LH BETA T AG mouse model for retinoblastoma. METHODS. LH BETA T AG mouse retinas were analyzed at 4, 8, 12, and 16 weeks of age. Tumor burden was analyzed by histology; cell proliferation, vessel density, angiogenesis, and vessel maturation were detected by immunofluorescence. To assess the efficacy of mature vessel targeting, 16-week-old mice were treated with single subconjunctival injections of the selective vascular-targeting drug combretastatin A4 prodrug (CA4P) or Anecortave acetate, and eyes were analyzed 1 day and 1 week after injection to determine microvessel density and the number of angiogenic and mature vessels. RESULTS. Increased cell proliferation and angiogenesis were detected in the retinal inner nuclear layer (INL) before morphologic neoplastic changes were evident. As tumor size increased, angiogenesis diminished concomitantly with the appearance of mature vessels. Treatment with CA4P and Anecortave acetate resulted in significant reductions in total vessel density. However, neither drug reduced the amount of α-smooth muscle actin (SMA)-positive, mature vessels. CONCLUSIONS. Results of this study provide new insight into the relationship between tumor growth and blood vessel development in the LH BETA T AG mouse and establish the framework for defining the selective action of two vessel-targeting drugs against new blood vessels compared with mature blood vessels. These findings suggest a high potential value in targeting the process of angiogenesis in the treatment of children with retinoblastoma.
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Anecortave Acetate as Single and Adjuvant Therapy in the Treatment of Retinal Tumors of LHBETATAG Mice
Investigative ophthalmology & visual science, 2006Co-Authors: Maria Elena Jockovich, Timothy G. Murray, Erika Escalona-benz, Eleut Hernandez, William J. FeuerAbstract:PURPOSE To evaluate the tumor control efficacy of the antiangiogenic agent Anecortave acetate as single and combined therapy, in retinal tumor reduction using the LH(BETA)T(AG) mouse model of retinoblastoma. METHODS Group A: Ten-week-old, LH(BETA)T(AG) mice received a single subconjunctival injection of Anecortave acetate (1200, 600, 300, and 150 microg) delivered to right eyes only. Group B: Ten-week-old, LH(BETA)T(AG) mice received a single subconjunctival injection of Anecortave acetate (600, 300, and 150 microg) delivered to right eyes only, either during a cycle of carboplatin (six subconjunctival deliveries) or after the completed cycle. Carboplatin was delivered at the subtherapeutic concentration of 62.5 microg. All animals were euthanatized at 16 weeks of age, and the eyes were examined histopathologically. RESULTS A statistically significant reduction in tumor burden was detected after a single periocular injection of Anecortave acetate. The reduction of tumor burden followed a U-shaped dose-response curve. Tumor burden was significantly decreased when Anecortave acetate and carboplatin were combined. However, varying doses and delivery schedule of these agents had significant impact on the effectiveness of the combined treatment. The most effective scheme was delivering a low dose (150-300 microg) of Anecortave acetate after a complete cycle of carboplatin. Histopathological evaluation showed no signs of retinal toxicity to Anecortave acetate delivery alone or in combination with carboplatin. CONCLUSIONS Anecortave acetate, as monotherapy or as adjuvant therapy, significantly controlled tumor burden in a murine model of retinoblastoma. Moreover, adjuvant therapy enabled the use of typically subtherapeutic carboplatin doses without decreasing efficacy of the therapy.
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Anecortave acetate for the treatment of exudative age-related macular degeneration--a review of clinical outcomes.
Survey of Ophthalmology, 2007Co-Authors: Stephen R. Russell, Henry L. Hudson, Janice A. JerdanAbstract:Abstract Purpose The angiostatic cortisene Anecortave acetate was evaluated in three safety and efficacy studies of patients with subfoveal choroidal neovascularization secondary to exudative age-related macular degeneration. Methods The Anecortave Acetate Monotherapy Trial enrolled 128 patients randomized to Anecortave acetate (3 mg, 15 mg, or 30 mg) or vehicle administered as a sub-Tenon's posterior juxtascleral depot (PJD) at 6-month intervals. The Anecortave Acetate and photodynamic therapy (PDT) with verteporfin Combination Trial enrolled 136 patients randomized to PDT with verteporfin followed by a single depot administration of Anecortave acetate (15 mg or 30 mg) or vehicle. The Anecortave Acetate 15 mg versus PDT Comparison Trial enrolled 530 patients to receive either Anecortave acetate 15 mg every 6 months + sham PDT every 3 months or PDT with verteporfin every 3 months + sham PJD administration every 6 months. Results Anecortave acetate 15 mg was statistically superior to vehicle in the monotherapy trial at both 12 and 24 months for maintenance of vision and inhibition of CNV lesion growth. In the combination trial, a trend favored adding either Anecortave acetate 15 mg or 30 mg to PDT for these two measures of clinical efficacy, but this short-duration study did not achieve statistical significance. Anecortave acetate 15 mg is comparable to PDT for maintaining vision over the 24-month period in the comparison trial. Conclusions Anecortave acetate is safe and effective treatment for exudative age-related macular degeneration.
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Anecortave acetate for the treatment of exudative age-related macular degeneration--a review of clinical outcomes.
Survey of ophthalmology, 2007Co-Authors: Stephen R. Russell, Henry L. Hudson, Janice A. JerdanAbstract:The angiostatic cortisene Anecortave acetate was evaluated in three safety and efficacy studies of patients with subfoveal choroidal neovascularization secondary to exudative age-related macular degeneration. The Anecortave Acetate Monotherapy Trial enrolled 128 patients randomized to Anecortave acetate (3 mg, 15 mg, or 30 mg) or vehicle administered as a sub-Tenon's posterior juxtascleral depot (PJD) at 6-month intervals. The Anecortave Acetate and photodynamic therapy (PDT) with verteporfin Combination Trial enrolled 136 patients randomized to PDT with verteporfin followed by a single depot administration of Anecortave acetate (15 mg or 30 mg) or vehicle. The Anecortave Acetate 15 mg versus PDT Comparison Trial enrolled 530 patients to receive either Anecortave acetate 15 mg every 6 months + sham PDT every 3 months or PDT with verteporfin every 3 months + sham PJD administration every 6 months. Anecortave acetate 15 mg was statistically superior to vehicle in the monotherapy trial at both 12 and 24 months for maintenance of vision and inhibition of CNV lesion growth. In the combination trial, a trend favored adding either Anecortave acetate 15 mg or 30 mg to PDT for these two measures of clinical efficacy, but this short-duration study did not achieve statistical significance. Anecortave acetate 15 mg is comparable to PDT for maintaining vision over the 24-month period in the comparison trial. Anecortave acetate is safe and effective treatment for exudative age-related macular degeneration.
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Anecortave Acetate (15 Milligrams) versus Photodynamic Therapy for Treatment of Subfoveal Neovascularization in Age-Related Macular Degeneration
Ophthalmology, 2005Co-Authors: Jason S. Slakter, Janice A. Jerdan, Thomas W. Bochow, Donald J. D'amico, Bethany Marks, E. Kenneth SullivanAbstract:Purpose To compare 1-year safety and efficacy of Anecortave acetate 15 mg with photodynamic therapy (PDT) with verteporfin in patients eligible for initial PDT treatment. Design Prospective, masked, randomized, multicenter, parallel group, active control, noninferiority clinical trial. Participants Five hundred thirty patients with predominantly classic subfoveal choroidal neovascularization secondary to age-related macular degeneration were randomized to treatment with either Anecortave acetate 15 mg or PDT. Methods In the Anecortave acetate group, the drug was administered under the Tenon's capsule as a periocular posterior juxtascleral depot (PJD) at the beginning of the study and at month 6. Before the first administration of Anecortave acetate, patients in this treatment group received a sham PDT treatment, and sham PDT treatments were repeated every 3 months if there was evidence of leakage on fluorescein angiography (FA). Patients assigned to PDT received up to 4 PDT treatments at 3-month intervals, as needed based upon FA, and a sham PJD procedure at the beginning of the study and at month 6. Best-corrected visual acuity was determined at baseline and all follow-up visits. Safety data were regularly reviewed by an independent safety committee. Main Outcome Measure Percent responders (patients losing Results Percent responders in the Anecortave acetate and PDT groups were 45% and 49%, respectively (not statistically different, P = 0.43). The confidence interval (CI) for the difference ranged from −13.2% favoring PDT to +5.6% favoring Anecortave acetate. The month 12 clinical outcome for Anecortave acetate was improved in patients for whom reflux was controlled and who were treated within the 6-month treatment window (57% vs. 49%; 95% CI, −4.3% favoring PDT to +21.7% favoring Anecortave acetate). No serious adverse events related to the study drug were reported in either treatment group. Conclusions The safety and efficacy outcomes in this study demonstrate that the benefits of Anecortave acetate for the treatment of choroidal neovascularization outweigh the risks associated with either the drug or the PJD administration procedure.
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Anecortave acetate as monotherapy for treatment of subfoveal neovascularization in age related macular degeneration twelve month clinical outcomes
Ophthalmology, 2003Co-Authors: Donald J Damico, Stephen R. Russell, Henry L. Hudson, Janice A. Jerdan, Lawrence J. Singerman, M F Goldberg, D S Krueger, S P Luna, S M Robertson, Jason S. SlakterAbstract:Purpose: To evaluate safety and efficacy of the angiostatic agent Anecortave acetate, compared with a placebo, for treatment of subfoveal choroidal neovascularization (CNV). Design: Ongoing masked, randomized, placebo-controlled, parallel evaluation of Anecortave acetate (30 mg, 15 mg, and 3 mg) versus a placebo. Participants: There were 128 eyes of 128 patients with subfoveal CNV secondary to age-related macular degeneration who were enrolled and treated, with 80% (102/128) of eyes presenting with predominantly classic lesions at baseline. Methods: All eyes received a posterior juxtascleral depot application of masked study medication or a placebo, with retreatment at 6-month intervals if the masked investigator believed the patient could benefit. Patients received periodic detailed ophthalmic examinations with both fluorescein and indocyanine green angiography, general physical examinations with electrocardiograms, and hematology/serum chemistry/urinalysis. All ophthalmic and systemic safety data were periodically reviewed by the Independent Safety Committee overseeing the study. Main Outcome Measures: Best-corrected logarithm of the minimum angle of resolution (logMAR) vision and fluorescein angiographic lesion characteristics were compared over time and among treatment groups. Results: At month 12, Anecortave acetate (15 mg) administered at 6-month intervals was statistically superior to the placebo for 3 measures of clinical efficacy: mean change from baseline vision (P = 0.0131), stabilization of vision (<3 logMAR line change; P = 0.0323), and prevention of severe vision loss (decrease of ≥6 logMAR lines from baseline; P = 0.0224). Subgroup analysis of predominantly classic lesions revealed that Anecortave acetate (15 mg) was also superior to the placebo at 1 year for each of these 3 measures of visual outcome (Ps = 0.0022, 0.0100, and 0.0299, respectively). Anecortave acetate (15 mg) trended toward significance over the placebo at month 12 for inhibition of total lesion growth and for inhibition of both the total CNV component and the classic CNV component in both the overall and subgroup analyses. The Independent Safety Committee identified no clinically relevant treatment-related safety issues. Conclusions: Anecortave acetate (15 mg) is safe and clinically efficacious at 1 year for maintaining vision, preventing severe vision loss, and inhibiting subfoveal CNV lesion growth.
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Anecortave acetate as monotherapy for the treatment of subfoveal lesions in patients with exudative age-related macular degeneration (AMD): interim (month 6) analysis of clinical safety and efficacy.
Retina (Philadelphia Pa.), 2003Co-Authors: Donald J. D'amico, Stephen R. Russell, Henry L. Hudson, Janice A. Jerdan, Krueger S, Lawrence J. Singerman, Jason S. SlakterAbstract:PURPOSE To evaluate clinical safety and efficacy of the angiostatic agent Anecortave acetate for treatment of subfoveal choroidal neovascularization secondary to AMD. METHODS 128 patients were randomized to placebo treatment or one of three Anecortave acetate doses. Study medication was administered as a posterior juxtascleral injection onto the posterior scleral surface. Best-corrected logMAR vision was obtained at baseline and follow-up visits. Fluorescein angiograms were evaluated for eligibility before enrollment and posttreatment. RESULTS Six months after a single treatment, visual acuity (mean change from baseline logMAR values) was significantly better (P = 0.003) after Anecortave acetate 15 mg than placebo. More patients treated with Anecortave acetate 15 mg than placebo maintained vision (88% versus 70%, P = 0.080), especially those with predominantly classic lesions (92% versus 65%, P = 0.021). Anecortave acetate 15 mg inhibited lesion growth significantly better than placebo (P = 0.001). Trends favoring the other doses over placebo were observed for vision preservation and lesion inhibition, but statistical significance was not achieved. The Independent Safety Committee overseeing this study identified no clinically relevant treatment-related changes. CONCLUSION Anecortave acetate 15 mg is safe and effective for preserving or improving vision and for inhibiting lesion growth in patients with subfoveal AMD.
