Again, using briefs supplied by Ophthalmology Times and Ocular Surgery News, here are the highlights from the second day of the Retina 2007 Subspecialty Day presentations.
First, here are the reports from the special session held at the end of the day, wherein Dr. Susan Desmond-Hellmann, president of product development for Genentech, spoke to the assembled retinal specialists and then answered some of their questions.
Genentech official urges cooperation in address to AAO attendees (OSN, OT)
In a special session held immediately after the close of Day 2 of the American Academy of Ophthalmology (AAO) Retina Subspecialty Day program, Susan Desmond-Hellmann, MD, MPH, president, product development, Genentech, implored the ophthalmology community to work in collaboration with the company in the interest of achieving the common goal of better patient care.
Speaking on behalf of the manufacturer regarding its decision to stop distribution of bevacizumab (Avastin) to compounding pharmacies, Dr. Desmond-Hellmann told attendees that in the short time she had to speak, she would not be making a corporate presentation defending the development of ranibizumab (Lucentis) or the recent actions relating to bevacizumab. She also expressed hope that ophthalmologists recognized recent efforts the company had made toward achieving a resolution as well as the challenges it faces operating in a highly regulated industry.
Dr. Desmond-Hellmann emphasized that the manufacturer will not interfere with the ophthalmologist's prescribing choice. "When we made our decision about the compounding pharmacies our belief then — and our belief now — is that physicians will still be able to obtain Avastin," she said.
Genentech has cited the U.S. Food and Drug Administration's concerns over the sterility and packaging of Avastin (bevacizumab) as its primary motivation behind the decision. "We cannot jeopardize our commitment to tens of thousands of other patients by risking FDA action against us," Dr. Desmond-Hellmann said. To that end, the company is actively working to address existing concerns and aims to implement changes that will expedite patient access to treatment.
"We're willing to do everything possible to make sure patients have access to Lucentis (ranibizumab, Genentech)," she said. Like bevacizumab, Lucentis inhibits VEGF. However, as physicians at the session pointed out, Lucentis is much more expensive.
Dr. Desmond-Hellmann pointed out that the manufacturer is committed to addressing unmet therapeutic needs in ophthalmology, and she acknowledged the important role of ophthalmologists in the development of ranibizumab as a treatment for age-related macular degeneration (AMD) and its investigation in other indications. The pre-marketing program of ranibizumab for AMD together with its current active clinical development program, which includes ongoing phase III trials in diabetic macular edema and retinal vein occlusion as well as nearly 50 investigator-sponsored trials under review, underscore the progress and promise that are possible through cooperation, she said.
"There are thousands of patients who come to you desperate for their sight and you have nothing to help them. That will continue to be the case if we don't put our collective efforts together towards solutions," Dr. Desmond-Hellmann said.
She relayed that in 1995, the manufacturer was embroiled in a somewhat similar situation with oncologists regarding the development of trastuzumab (Herceptin) as an adjuvant treatment for a serious and deadly form of breast cancer. However, through the help and collaboration of leading oncologists and patient advocates, a resolution was achieved that led to that drug's approval and changed the prognosis of affected women in the future.
Reflecting on that history, Dr. Desmond-Hellmann ended by saying she hoped she might be invited back to the 2017 annual meeting of the AAO and be able to relate to the audience how the manufacturer and ophthalmologists made together the conscious decision to stop resisting one another and work together to achieve more than either could do alone.
"On behalf of Genentech, you have my commitment we will do everything possible to make this a reality," Dr. Desmond-Hellmann said.
During the subsequent Q&A session, Daniel F. Martin, MD, a member of the session's panel, questioned Genentech's refusal to support the upcoming Comparison of Age-Related Macular Degeneration Treatment Trials (CATT) trial, which is expected to evaluate both bevacizumab and ranibizumab in the treatment of age-related macular degeneration. The trial is jointly sponsored by the National Institutes of Health and the National Eye Institute. "We are the only trial that is sufficiently powered to show a difference," Dr. Martin said.
Genentech will not support the CATT trial because ranibizumab has already been approved as a safe and effective treatment for AMD, Dr. Desmond-Hellmann said. "We are challenged by the CATT trial because we feel that the need is (already) met," she said.
(To hear an audio version of the full one-hour presentation and Q&A session, use this link.)
SUB-RETINAL IMPLANTS (OSN, OT)
ASR subretinal implant for retinitis pigmentosa disappointing
The visual acuity improvements from implantation of the Artificial Silicon Retina (ASR device, Optobionics Corp.) for treatment of vision loss associated with retinitis pigmentosa were "underwhelming," with the 2-year data showing that only 8% of implanted eyes gained 10 letters or more, according to John Pollack, MD.
The device, which is 2.0 mm in diameter and 25 microns thick, is proposed to work by solar power. The light incident on the surface creates a negative charge on the chip. The cells in contact with the chip surface are stimulated and release neurotrophic factors, which results in improved functioning of existing retinal cells. The device is implanted during vitrectomy through a retinotomy, Dr. Pollack, assistant professor of ophthalmology, Rush University Medical Center, Chicago, explained. During a feasibility study at three clinical sites, 20 patients were implanted with the device in one randomly selected eye. Adverse events included migration and fracture of the device and chronic anterior segment implantation, cystoid macular edema, visually relevant cataract, and retinoschisis/macular hole.
"The 2-year data indicated that 16% of eyes had an increase of 10 letters compared with 5% of the fellow eyes, and 11% had a decrease of 10 letters compared with 21% of the fellow eyes," Dr. Pollack reported.
When the investigators evaluated the 1-year data and did subgroup analysis they considered confounding factors of cataract progression and dilated pupils during vision testing, which increased glare, reduced contrast sensitivity, and possibly negatively affected the vision measurements. They found that in eyes that had neither or one confounding factor, 40% of eyes gained 10 or more lines compared with 0% in the fellow eyes.
When they evaluated the 18- to 24-month data, Dr. Pollack reported that the gap narrowed with 40% of eyes that received the device having gained 10 lines of vision compared with 20% of the fellow eyes. In a phase II expansion trial that began in summer 2006 in Mexico City, all 12 patients were pseudophakic and vision testing was done in the undilated state to address the issue of the confounding factors.
In those patients, 8% of implanted eyes gained 10 letters or more compared with 16% of fellow eyes that gained 10 letters or more; 16% of the implanted eyes had a decrease of 10 letters or more compared with 0% of the fellow eyes.
"Implantation of the ASR device has not resulted in significant improvements in Early Treatment Diabetic Retinopathy Study vision. It is possible that the device can be used as an auxiliary power drive or a platform for other forms of subretinal neurostimulation. This intellectual property was purchased by Intelligent Medical Implants," Dr. Pollack said.
Future studies of an investigational subretinal implant used to treat retinitis pigmentosa must take into account potential confounding factors that can impact vision testing. Data from studies of the implant are becoming more reliable now that these factors have been eliminated, according to Dr. Pollack.
The phase 2 expansion study, undertaken by Hugo Quiroz-Mercado, MD, of Mexico City, includes 12 patients with retinitis pigmentosa. "Elimination of the confounding factors in the Mexico study led to improved reliability of the study," Dr. Pollack said.
RETINOPATHY OF PREMATURITY (ROP)
Anti-VEGF therapy is on the horizon for aggressive posterior ROP
Anti-angiogenic therapy for aggressive posterior retinopathy of prematurity (ROP) may be a feasible therapy for these children with this form of ROP, which develops in profoundly immature neonates. The BLOCK-ROP study, which is slated to begin soon, will add to the limited knowledge of the safety and efficacy of an anti-vascular endothelial growth factor (VEGF) drug in treating posterior ROP, Anthony Capone Jr., MD, reported during Retina Subspecialty Day at the annual meeting of the American Academy of Ophthalmology.
"With the advent of FDA-approved drugs for anti-VEGF treatment, the possibility of treating eyes off-label with an anti-VEGF drug has become possible," he said. The rationale for this treatment approach is that VEGF promotes retinal vascularization. The current standard of care is laser treatment to the peripheral retina, which is not universally effective in fostering regression of ROP.
The largest experience to date with anti-VEGF therapy for ROP was carried out in Mexico, Portugal, and New York, in which 53 eyes were treated with one injection of bevacizumab (Avastin, Genentech) and followed for a mean of 6 months. The study included patients who received the standard of care for ROP, eyes that were untreated because of poor visualization, and eyes with high-risk pre-threshold ROP in an institution where laser was unavailable, Dr. Capone recounted. He is clinical associate professor of ophthalmology, Oakland University, Royal Oak, MI.
"All eyes responded favorably to treatment regarding neovascularization; five eyes worsened. There were no serious systemic adverse events. The authors concluded that further studies were needed to determine the safety and long-term efficacy of the treatment," Dr. Capone said.
The BLOCK-ROP study, a phase I trial will be carried out in the United States and Canada beginning in the fourth quarter of 2007, picks up the challenge and will evaluate the safety of one injection of bevacizumab (0.75 mg) into the vitreous cavity in 22 patients.
"The scientific rationale for using anti-VEGF therapy for ROP is compelling. This is an exciting time in ROP therapy. Approval of standard phase I and II data is appropriate considering the vulnerability of the target population. In the interim, caution is warranted with use of anti-VEGF drugs outside of a clinical trial in premature neonates," Dr. Capone concluded.
SPECTRAL DOMAIN OPTICAL COHERENCE TOMOGRAPHY
Advances in spectral domain 3-D high-resolution OCT
Spectral domain optical coherence tomography (SD-OCT), the latest generation of the technology, is a breakthrough because it has dramatically cut the time required to obtain images by eliminating the moving mirror that was a component of standard OCT, according to Cynthia Toth, MD, professor of ophthalmology, Duke University Medical Center, Durham, NC. In addition to being 50 times faster than conventional OCT, SD-OCT has improved resolution because of improved processing. Another benefit is decreased patient movement artifact, especially in pediatric patients.
"In age-related macular degeneration, there is often motion artifact. It is difficult to sort out drusen and differentiate them from patient motion that could be either or a pigment epithelial defect or normal retinal pigment epithelium (RPE) choroid. Using SD OCT it is easier to isolate drusen from the underlying baseline RPE and to define whether pigment epithelial detachments or RPE abnormalities are present," Dr. Toth stated.
The SD-OCT data can be integrated with the information obtained from angiography and fundus examinations, which allows identification of the location of an abnormality found on OCT. "One benefit of SD-OCT is the creation of the summed voxel projection (SVP), which is helpful for orientation of individual OCT scans. One can collapse 3-D OCT volumes along the depth axis to form a 2-D plane, summing pixels to calculate one representative pixel intensity along each line in the projection," she explained. As a result of prominent shadowing from the retinal vasculature, the SVP image is similar to a fundus photograph and this image can be used to orient the SD-OCT image to a fundus image.
Drawbacks of the technology include large datasets, the need to integrate data with conventional imaging, and normative data are required for the new systems, there are a number of systems from which to choose. An advantage is the availability of portable systems.
"Three-dimensional SD-OCT offers the potential to identify biomarkers and measure changes in disease over time. For clinical and research use, improved methods are needed to export, analyze, summarize, and manage data. These are on the way," Dr. Toth concluded.
NEW NON-THERMAL LASER FOR RETINAL TREATMENT
Non-thermal laser shows promising results for DME
A new non-thermal laser has shown promise in treating a small group of diabetic macular edema patients, according to A.M. Peter Hamilton, MD, in his preliminary report on 61 patients treated with the non-thermal laser treatment, the Ellex 2RT (Ellex Medical Lasers). (2RT stands for Retina Regeneration Therapy.)
With this technology, short pulses of laser energy are used to stimulate the retinal pigment epithelium. The 532-nm wavelength used for a duration of 3 nanoseconds creates a 400-μm spot on the pigment epithelium that does not damage the overlying retina, according to Dr. Hamilton.
The researchers looked at 18 patients over the course of 29 treatment sessions, measuring progress with color photography and fluorescein angiography. The results showed that central macular thickness, as measured on optical coherence tomography (OCT), decreased by more than 5% in 16 patients. It was maintained within 5% in seven patients. And it was increased by more than 5% in six patients.
Dr. Hamilton said the advantages of the laser include: very short exposure time, visual acuity improvements, ability to treat close to the macula, no black holes visible at the time of exposure and good microperimetry. "We can get right in close to the macula without any fear of causing an enlarging burn," he said. "Because this laser is so gentle and because it is not compromising the outer part of the retina, we can treat large areas."
Dr. Hamilton said further study is needed to compare the laser with conventional treatments.
(I am in direct contact with the company and expect to learn more about this exciting new laser treatment for potential regeneration of retinal tissue and present a full writeup at a later time.)
First, here are the reports from the special session held at the end of the day, wherein Dr. Susan Desmond-Hellmann, president of product development for Genentech, spoke to the assembled retinal specialists and then answered some of their questions.
Genentech official urges cooperation in address to AAO attendees (OSN, OT)
In a special session held immediately after the close of Day 2 of the American Academy of Ophthalmology (AAO) Retina Subspecialty Day program, Susan Desmond-Hellmann, MD, MPH, president, product development, Genentech, implored the ophthalmology community to work in collaboration with the company in the interest of achieving the common goal of better patient care.
Speaking on behalf of the manufacturer regarding its decision to stop distribution of bevacizumab (Avastin) to compounding pharmacies, Dr. Desmond-Hellmann told attendees that in the short time she had to speak, she would not be making a corporate presentation defending the development of ranibizumab (Lucentis) or the recent actions relating to bevacizumab. She also expressed hope that ophthalmologists recognized recent efforts the company had made toward achieving a resolution as well as the challenges it faces operating in a highly regulated industry.
Dr. Desmond-Hellmann emphasized that the manufacturer will not interfere with the ophthalmologist's prescribing choice. "When we made our decision about the compounding pharmacies our belief then — and our belief now — is that physicians will still be able to obtain Avastin," she said.
Genentech has cited the U.S. Food and Drug Administration's concerns over the sterility and packaging of Avastin (bevacizumab) as its primary motivation behind the decision. "We cannot jeopardize our commitment to tens of thousands of other patients by risking FDA action against us," Dr. Desmond-Hellmann said. To that end, the company is actively working to address existing concerns and aims to implement changes that will expedite patient access to treatment.
"We're willing to do everything possible to make sure patients have access to Lucentis (ranibizumab, Genentech)," she said. Like bevacizumab, Lucentis inhibits VEGF. However, as physicians at the session pointed out, Lucentis is much more expensive.
Dr. Desmond-Hellmann pointed out that the manufacturer is committed to addressing unmet therapeutic needs in ophthalmology, and she acknowledged the important role of ophthalmologists in the development of ranibizumab as a treatment for age-related macular degeneration (AMD) and its investigation in other indications. The pre-marketing program of ranibizumab for AMD together with its current active clinical development program, which includes ongoing phase III trials in diabetic macular edema and retinal vein occlusion as well as nearly 50 investigator-sponsored trials under review, underscore the progress and promise that are possible through cooperation, she said.
"There are thousands of patients who come to you desperate for their sight and you have nothing to help them. That will continue to be the case if we don't put our collective efforts together towards solutions," Dr. Desmond-Hellmann said.
She relayed that in 1995, the manufacturer was embroiled in a somewhat similar situation with oncologists regarding the development of trastuzumab (Herceptin) as an adjuvant treatment for a serious and deadly form of breast cancer. However, through the help and collaboration of leading oncologists and patient advocates, a resolution was achieved that led to that drug's approval and changed the prognosis of affected women in the future.
Reflecting on that history, Dr. Desmond-Hellmann ended by saying she hoped she might be invited back to the 2017 annual meeting of the AAO and be able to relate to the audience how the manufacturer and ophthalmologists made together the conscious decision to stop resisting one another and work together to achieve more than either could do alone.
"On behalf of Genentech, you have my commitment we will do everything possible to make this a reality," Dr. Desmond-Hellmann said.
During the subsequent Q&A session, Daniel F. Martin, MD, a member of the session's panel, questioned Genentech's refusal to support the upcoming Comparison of Age-Related Macular Degeneration Treatment Trials (CATT) trial, which is expected to evaluate both bevacizumab and ranibizumab in the treatment of age-related macular degeneration. The trial is jointly sponsored by the National Institutes of Health and the National Eye Institute. "We are the only trial that is sufficiently powered to show a difference," Dr. Martin said.
Genentech will not support the CATT trial because ranibizumab has already been approved as a safe and effective treatment for AMD, Dr. Desmond-Hellmann said. "We are challenged by the CATT trial because we feel that the need is (already) met," she said.
(To hear an audio version of the full one-hour presentation and Q&A session, use this link.)
SUB-RETINAL IMPLANTS (OSN, OT)
ASR subretinal implant for retinitis pigmentosa disappointing
The visual acuity improvements from implantation of the Artificial Silicon Retina (ASR device, Optobionics Corp.) for treatment of vision loss associated with retinitis pigmentosa were "underwhelming," with the 2-year data showing that only 8% of implanted eyes gained 10 letters or more, according to John Pollack, MD.
The device, which is 2.0 mm in diameter and 25 microns thick, is proposed to work by solar power. The light incident on the surface creates a negative charge on the chip. The cells in contact with the chip surface are stimulated and release neurotrophic factors, which results in improved functioning of existing retinal cells. The device is implanted during vitrectomy through a retinotomy, Dr. Pollack, assistant professor of ophthalmology, Rush University Medical Center, Chicago, explained. During a feasibility study at three clinical sites, 20 patients were implanted with the device in one randomly selected eye. Adverse events included migration and fracture of the device and chronic anterior segment implantation, cystoid macular edema, visually relevant cataract, and retinoschisis/macular hole.
"The 2-year data indicated that 16% of eyes had an increase of 10 letters compared with 5% of the fellow eyes, and 11% had a decrease of 10 letters compared with 21% of the fellow eyes," Dr. Pollack reported.
When the investigators evaluated the 1-year data and did subgroup analysis they considered confounding factors of cataract progression and dilated pupils during vision testing, which increased glare, reduced contrast sensitivity, and possibly negatively affected the vision measurements. They found that in eyes that had neither or one confounding factor, 40% of eyes gained 10 or more lines compared with 0% in the fellow eyes.
When they evaluated the 18- to 24-month data, Dr. Pollack reported that the gap narrowed with 40% of eyes that received the device having gained 10 lines of vision compared with 20% of the fellow eyes. In a phase II expansion trial that began in summer 2006 in Mexico City, all 12 patients were pseudophakic and vision testing was done in the undilated state to address the issue of the confounding factors.
In those patients, 8% of implanted eyes gained 10 letters or more compared with 16% of fellow eyes that gained 10 letters or more; 16% of the implanted eyes had a decrease of 10 letters or more compared with 0% of the fellow eyes.
"Implantation of the ASR device has not resulted in significant improvements in Early Treatment Diabetic Retinopathy Study vision. It is possible that the device can be used as an auxiliary power drive or a platform for other forms of subretinal neurostimulation. This intellectual property was purchased by Intelligent Medical Implants," Dr. Pollack said.
Future studies of an investigational subretinal implant used to treat retinitis pigmentosa must take into account potential confounding factors that can impact vision testing. Data from studies of the implant are becoming more reliable now that these factors have been eliminated, according to Dr. Pollack.
The phase 2 expansion study, undertaken by Hugo Quiroz-Mercado, MD, of Mexico City, includes 12 patients with retinitis pigmentosa. "Elimination of the confounding factors in the Mexico study led to improved reliability of the study," Dr. Pollack said.
RETINOPATHY OF PREMATURITY (ROP)
Anti-VEGF therapy is on the horizon for aggressive posterior ROP
Anti-angiogenic therapy for aggressive posterior retinopathy of prematurity (ROP) may be a feasible therapy for these children with this form of ROP, which develops in profoundly immature neonates. The BLOCK-ROP study, which is slated to begin soon, will add to the limited knowledge of the safety and efficacy of an anti-vascular endothelial growth factor (VEGF) drug in treating posterior ROP, Anthony Capone Jr., MD, reported during Retina Subspecialty Day at the annual meeting of the American Academy of Ophthalmology.
"With the advent of FDA-approved drugs for anti-VEGF treatment, the possibility of treating eyes off-label with an anti-VEGF drug has become possible," he said. The rationale for this treatment approach is that VEGF promotes retinal vascularization. The current standard of care is laser treatment to the peripheral retina, which is not universally effective in fostering regression of ROP.
The largest experience to date with anti-VEGF therapy for ROP was carried out in Mexico, Portugal, and New York, in which 53 eyes were treated with one injection of bevacizumab (Avastin, Genentech) and followed for a mean of 6 months. The study included patients who received the standard of care for ROP, eyes that were untreated because of poor visualization, and eyes with high-risk pre-threshold ROP in an institution where laser was unavailable, Dr. Capone recounted. He is clinical associate professor of ophthalmology, Oakland University, Royal Oak, MI.
"All eyes responded favorably to treatment regarding neovascularization; five eyes worsened. There were no serious systemic adverse events. The authors concluded that further studies were needed to determine the safety and long-term efficacy of the treatment," Dr. Capone said.
The BLOCK-ROP study, a phase I trial will be carried out in the United States and Canada beginning in the fourth quarter of 2007, picks up the challenge and will evaluate the safety of one injection of bevacizumab (0.75 mg) into the vitreous cavity in 22 patients.
"The scientific rationale for using anti-VEGF therapy for ROP is compelling. This is an exciting time in ROP therapy. Approval of standard phase I and II data is appropriate considering the vulnerability of the target population. In the interim, caution is warranted with use of anti-VEGF drugs outside of a clinical trial in premature neonates," Dr. Capone concluded.
SPECTRAL DOMAIN OPTICAL COHERENCE TOMOGRAPHY
Advances in spectral domain 3-D high-resolution OCT
Spectral domain optical coherence tomography (SD-OCT), the latest generation of the technology, is a breakthrough because it has dramatically cut the time required to obtain images by eliminating the moving mirror that was a component of standard OCT, according to Cynthia Toth, MD, professor of ophthalmology, Duke University Medical Center, Durham, NC. In addition to being 50 times faster than conventional OCT, SD-OCT has improved resolution because of improved processing. Another benefit is decreased patient movement artifact, especially in pediatric patients.
"In age-related macular degeneration, there is often motion artifact. It is difficult to sort out drusen and differentiate them from patient motion that could be either or a pigment epithelial defect or normal retinal pigment epithelium (RPE) choroid. Using SD OCT it is easier to isolate drusen from the underlying baseline RPE and to define whether pigment epithelial detachments or RPE abnormalities are present," Dr. Toth stated.
The SD-OCT data can be integrated with the information obtained from angiography and fundus examinations, which allows identification of the location of an abnormality found on OCT. "One benefit of SD-OCT is the creation of the summed voxel projection (SVP), which is helpful for orientation of individual OCT scans. One can collapse 3-D OCT volumes along the depth axis to form a 2-D plane, summing pixels to calculate one representative pixel intensity along each line in the projection," she explained. As a result of prominent shadowing from the retinal vasculature, the SVP image is similar to a fundus photograph and this image can be used to orient the SD-OCT image to a fundus image.
Drawbacks of the technology include large datasets, the need to integrate data with conventional imaging, and normative data are required for the new systems, there are a number of systems from which to choose. An advantage is the availability of portable systems.
"Three-dimensional SD-OCT offers the potential to identify biomarkers and measure changes in disease over time. For clinical and research use, improved methods are needed to export, analyze, summarize, and manage data. These are on the way," Dr. Toth concluded.
NEW NON-THERMAL LASER FOR RETINAL TREATMENT
Non-thermal laser shows promising results for DME
A new non-thermal laser has shown promise in treating a small group of diabetic macular edema patients, according to A.M. Peter Hamilton, MD, in his preliminary report on 61 patients treated with the non-thermal laser treatment, the Ellex 2RT (Ellex Medical Lasers). (2RT stands for Retina Regeneration Therapy.)
With this technology, short pulses of laser energy are used to stimulate the retinal pigment epithelium. The 532-nm wavelength used for a duration of 3 nanoseconds creates a 400-μm spot on the pigment epithelium that does not damage the overlying retina, according to Dr. Hamilton.
The researchers looked at 18 patients over the course of 29 treatment sessions, measuring progress with color photography and fluorescein angiography. The results showed that central macular thickness, as measured on optical coherence tomography (OCT), decreased by more than 5% in 16 patients. It was maintained within 5% in seven patients. And it was increased by more than 5% in six patients.
Dr. Hamilton said the advantages of the laser include: very short exposure time, visual acuity improvements, ability to treat close to the macula, no black holes visible at the time of exposure and good microperimetry. "We can get right in close to the macula without any fear of causing an enlarging burn," he said. "Because this laser is so gentle and because it is not compromising the outer part of the retina, we can treat large areas."
Dr. Hamilton said further study is needed to compare the laser with conventional treatments.
(I am in direct contact with the company and expect to learn more about this exciting new laser treatment for potential regeneration of retinal tissue and present a full writeup at a later time.)
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