Medical Hypotheses 82 (2014) 421–423
Contents lists available at ScienceDirect
Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy
Intraocular beta-radiation for proliferative vitreo-retinopathy Paritosh Shah ⇑, Chee Kon, Sal Rassam Western Sussex Hospitals NHS Trust, Worthing Hospital, Lyndhurst Road, Worthing BN11 2DH, UK
a r t i c l e
i n f o
Article history: Received 21 October 2013 Accepted 10 January 2014
a b s t r a c t Proliferative vitreoretinopathy (PVR) is the most common cause of failure in retinal detachment surgery. PVR is a result of an enhanced healing process. Various surgical and pharmacological methods have failed to provide a definite solution to the problem. Radiation has since long been shown to be effective in similar situations like keloids, pterygia, and post trabeculectomy. Externally delivered radiation has also been tried in PVR, but with limited success. We propose that treatment with intraocularly delivered beta-radiation is a viable method to try and reduce the incidence of PVR after retinal detachment. This can improve the safety of the treatment, reduce potential side effects to surrounding tissues and help achieve a targeted treatment. However, the treatment was limited by the absence of a practical method for intraocular delivery of radiation. This is now possible, as we now have a method which has been shown to be safe in the CABERNET trial. If this can be proved, then it will be an important step towards treating PVR and hence reducing blindness after retinal detachment. Ó 2014 Elsevier Ltd. All rights reserved.
Hypothesis We hypothesize that a one time intraocular exposure to controlled beta-radiation at the time of retinal detachment surgery may result in fewer repeat surgeries for retinal detachment secondary to proliferative vitreo-retinopathy (PVR) when compared to conventional surgery. If it can be proved that beta radiation significantly reduces the failure rate of retinal detachment surgeries due to PVR, then this will be an important step towards treating PVR. Background Proliferative vitreoretinopathy (PVR) is the most common cause of failure in retinal detachment surgery. It can present after pneumatic retinopexy, cryotherapy, laser retinopexy, scleral buckling, vitrectomy or any form of trauma [1,2]. PVR results in 5–10% of all retinal detachment surgery cases. Thus it is a cause of morbidity due to poor vision or blindness. PVR is a reparative process initiated by full- or partial-thickness retinal breaks, retinopexy, and other types of retinal damage. Loss of contact inhibition causes the surrounding glial or retinal pigment epithelial (RPE) cells to migrate to both surfaces of the retina. Glial or RPE cells migrate further and cover the posterior surface of ⇑ Corresponding author. Address: Eye Clinic, Worthing Hospital, Lyndhurst Road, Worthing BN11 2DH, UK. E-mail address: [email protected] (P. Shah). http://dx.doi.org/10.1016/j.mehy.2014.01.008 0306-9877/Ó 2014 Elsevier Ltd. All rights reserved.
the detached posterior hyaloid face and attach to collagen fibers and other components of the extracellular matrix. The migration/ contraction mechanism causes tangential force on the retina to form multiple star folds and fixed folds. The collagen of anterior and posterior vitreous cortex contracts, resulting in tractional and rhegmatogenous retinal detachment.
Classification of PVR PVR has been classified as [3] Grade A: Characterised by vitreous haze, pigmented cells and clumps in the vitreous and pigmented cells on the retina, especially inferior retina. Grade B: Retinal stiffness with wrinkling of the inner retinal surface, vessel tortuosity, rolled edge of retinal tear, and decreased vitreous mobility. Grade C: Full thickness retinal folds measured in clock hours and whether anterior (CA 1–12) or posterior (CP 1–12). Current PVR treatment Treatment for PVR is mainly surgical when it is critical to remove all contractile membranes. However, this is by no means curative, and recurrences are common (6%, Wickham (2011); 19.5%, Bonnet (1984); 28% Chignell et al. (1973)) [4–6].
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P. Shah et al. / Medical Hypotheses 82 (2014) 421–423
Pharmacologic treatment of PVR
Hypothesis
Pharmacologic treatment is aimed at inhibition of cell migration, proliferation and/or contraction. Various agents like tacrolimus [7], TGF-b inhibitor, decorin [8], 5-fluorouracil and mitomicin-C [9] and steroids have been tried. A ‘cocktail’ of drugs has also been used such as the British cocktail of 5-FU and Low Molecular Weight Heparin [10]. However, none of these have shown to have significant effect in human clinical trials.
We hypothesise that better results may be achieved in controlling and/or reducing the rates of proliferative vitreoretinopathy by trying to deliver the radiation intraocularly, in a more controlled and precise manner. We believe that this is now possible by using the same device used in the CABERNET trial [16]. This intraocular b-radiation delivery system (NeoVista, Inc., Newark, CA) is already certified for intraocular use and is a source of beta irradiation and is designed to deliver a dose 24 Gy over 4 min to the epimacular area for treatment of exudative macular degeneration. After pars plana vitrectomy, the radiation delivery probe is held over the area to be treated. We believe that the same probe can be used to irradiate the retina in an effort to reduce PVR. As PVR commonly occurs on the inferior retina due to the effect of gravity on the released RPE/Gliotic cells, it is possible that it is only the inferior retina that may need to be irradiated [20,21]. This approach can have several advantages over teletherapy which uses a beam of energy that, has to pass through normal tissue to reach its target, thus, unnecessarily irradiating off-target structures. Also, external beam proton delivery systems can have errors of 10–15% or more of the prescribed dose delivered [22]. Even more advanced technology, delivering radiation stereotactically, with robotic tracking software, can have more than a 2 mm of error in the location of the field. There also may be a welldocumented bystander effect in which neighboring cells beyond the target zone die [23]. So, we believe that an intraocular approach of delivering radiation can have significant advantages, and hence a greater potential to be successful. Any study designed to test this hypothesis, should be able to help in establishing the optimum dose of irradiation, determine the efficacy of a single application of beta irradiation on retinal detachment recurrence rates, and determine the safety profile of beta irradiation in PVR. A prospective randomised controlled study should be designed to test the efficacy of intraocular b-radiation in patients undergoing vitrectomy for retinal detachment. The patients can be divided into groups based on the degree of PVR. The control groups receive the conventional treatment only, while the treatment group receives intraocular b-radiation in the area of PVR. In cases without PVR, the inferior retina only is irradiated, peripheral to the vascular arcades. Our hypothesis will be proved if there is a marked reduction in the rates of retinal redetachments, retinectomies, use of silicon oil, and the number of repeat surgeries in the groups receiving radiation.
Radiation Beta rays are fast electrons that lose energy as they pass through cells and interact with molecules. The transferred energy is high enough to disrupt chemical bonds, which results in radical formation (or ionization). These radicals react with the deoxyribonucleic acid in the cells inducing damage and cell death. Kirwan et al. in their review on the uses of beta radiation state that ‘‘Desjardins (1932) noted that a proportion of irradiated cells exhibited either a temporary inhibition of metabolic activity, or a complete and permanent disintegration. Puck et al. demonstrated that the growth of normal fibroblasts in vitro could be inhibited by radiation’’ [11]. Fibroblasts are known to be sensitive to Beta irradiation and this has long been used in the management of excessive Keloid formation in the skin [12]. In the eye, radiation has been shown to inhibit corneal wound healing, with prominent effects on fibroblast proliferation [13]. Pajonk et al. showed the beneficial effect of beta radiation on the recurrence rates of pterygium [14]. Constable et al. described the effects of radiation on tenon’s capsule fibroblasts. They showed that there was no significant effect on cellular migration or contraction, but extracellular matrix production was altered. Fibronectin production was inhibited following higher radiation doses, and collagen I and III production increased after 1000 cGy [15]. While the CABERNET trial evaluating beta-radiation treatment for wet AMD did not reach the primary end-point (which was the percentage of patients loosing less than 15 letters on the ETDRS chart), it did establish an acceptable safety profile of the treatment. It also identified a sub-group of patients who responded well to the treatment and did not need any rescue injections [16].
Radiation and PVR Radiation therapy has also been utilised as a means of preventing proliferative vitreoretinopathy. Meredith et al., showed that irradiating fibroblasts with a 6 Gy dose of X-ray radiation resulted in a reduction of formation of tractional retinal detachment [17]. Binder et al., used 3000 cGY of radiation but did not find any advantage [18]. We believe that this treatment can be successful because proliferating cells are more responsive to beta irradiation than established fibrosis – law of Bergonie and Tribondeau [19]. By observing the effects of radiation on rabbit testicles, they also showed that immature or young cells and tissues are more radiosensitive, resistance to radiation increases with increased cell maturity and low metabolic rate decreases radiosensitivity and high metabolic rate increases radiosensitivity. High proliferation (reproductive) rate for cells and fast growth rate increases the radiosensitivity of those cells. However, the radiation delivered in previous reports was either on in vitro cells or by external beam radiation.
Conflict of interest We declare that we have no financial or personal relationships with other people or organizations that can inappropriately influence our work, there is no professional or other personal interest of any nature or kind in any product, service and/or company that could be construed as influencing the position presented in, or the review of, the manuscript entitled ‘‘Intraocular beta radiation for proliferative vitreoretinopathy’’. References [1] Machemer R. Pathogenesis and classification of massive preretinal proliferation. Br J Ophthalmol 1978;62(11):737–47. [2] Ryan SJ. The pathophysiology of proliferative vitreoretinopathy in its management. Am J Ophthalmol 1985;100:188–93.
P. Shah et al. / Medical Hypotheses 82 (2014) 421–423 [3] Machemer R, Aaberg T, Freeman H, Irvine A, Lean J, Michels R. An updated classification of retinal detachment with proliferative vitreoretinopathy. Am J Ophthalmol 1991;112(2):159–65. [4] Wickham L, Ho-Yen G, Bunce C, Wong D, Charteris D. Surgical failure following primary retinal detachment surgery by vitrectomy: risk factors and functional outcomes. Br J Ophthalmol 2011;95(9):1234–8. [5] Bonnet M. Clinical factors predisposing to massive proliferative vitreoretinopathy in rhegmatogenous retinal detachment. Ophthalmologica 1984;188(3):148–52. [6] Chignell A, Fison L, Davies E, Hartley R, Gundry M. Failure in retinal detachment surgery. Br J Ophthalmol 1973;57(8):525. [7] Turgut B, Uyar F, Ustundag B, Celiker U, Akpolat N, Demir T. The impact of tacrolimus on growth factors in experimental proliferative vitreoretinopathy. Retina 2012;32(2):232–41. [8] Nassar K, Lüke J, Lüke M, Kamal M, El-Nabi E, Soliman M, et al. The novel use of decorin in prevention of the development of proliferative vitreoretinopathy (PVR). Graefe’s Arch Clin Exp Ophthalmol 2011;249(11):1649–60. [9] Yu HG, Chung H. Antiproliferative effect of mitomycin C on experimental proliferative vitreoretinopathy in rabbits. Korean J Ophthalmol 1997;11(2):98–105. [10] Asaria R, Kon C, Bunce C, Charteris D, Wong D, Khaw P, et al. Adjuvant 5fluorouracil and heparin prevents proliferative vitreoretinopathy: results from a randomized, double-blind, controlled clinical trial. Ophthalmology 2001;108(7):1179–83. [11] Kirwan JF, Constable PH, Murdoch IE, Khaw PT. Beta irradiation: new uses for an old treatment: a review. Eye 2003;17(2):207–15. [12] Kal HB, Veen RE, Jürgenliemk-Schulz IM. Dose-effect relationships for recurrence of keloid and pterygium after surgery and radiotherapy. Int J Radiat Oncol Biol Phys 2009;74(1):245–51. [13] Morrison DR, Kanai A, Gasset AR. Beta radiation inhibition of corneal healing. I. Tensile strength and ultrastructure change. Invest Ophthalmol 1971;10: 826–39.
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[14] Pajonk F, Flick H, Mittelviefhaus H, Slanina J, Snibson GR, Luu CD, et al. A prospective randomised controlled trial of beta radiation, mitomycin C, and conjunctival transplantation in the surgical management of pterygium. Invest Ophthalmol Vis Sci 1996;37:s703. [15] Constable P, Occleston N, Cordeiro M, Kon C, Khaw PT. Long term growth arrest of human tenons fibroblasts following single doses of beta irradiation. Br J Ophthalmol 1998;82:448–52. [16] Dugel PU, Bebchuk JD, Nau J, Reichel E, Singer M, Barak A, et al. Epimacular brachytherapy for neovascular age-related macular degeneration: a randomized, controlled trial (CABERNET). Ophthalmology 2013;120(2): 317–27. [17] Meredith TA, Ficker L, Stevens R, Olkowski Z, Anderson M, Hartmann J, et al. Suppression of experimental tractional retinal detachment by low-dose radiation therapy. Arch Ophthalmol 1988;106:673–5. [18] Binder S, Bonnet M, Velikay M, Gerard JP, Stolba U, Wedrich A, et al. Radiation therapy in proliferative vitreoretinopathy. A prospective randomized study. Graefes Arch Clin Exp Ophthalmol 1994;232:211–4. [19] Bergonié J, Tribondeau L. Interpretation of some results of radiotherapy and an attempt at determining a logical technique of treatment/De Quelques Résultats de la Radiotherapie et Essai de Fixation d’une Technique Rationnelle. Radiat Res 1959;11(4):587–8. [20] Singh AK, Glaser BM, Lenor M, Michels RG. Gravity-dependent distribution of retinal pigment epithelial cells dispersed into the vitreous cavity. Retina 1986;6:77. [21] Duke Elder S, Dobree JH. Detachment and folding of retina. Duke-Elder Syst Ophthalmol 1967;10:809. [22] Paganetti H, Niemierko A, Ancukiewicz M, et al. Relative biological effectiveness (RBE) values for proton beam therapy. Int J Radiat Oncol Biol Phys 2002;53:407–21. [23] Prise KM, Belyakov OV, Folkard M, Michael BD. Studies of bystander effects in human fibroblasts using a charged particle microbeam. Int J Radiat Biol 1998;74:793–8.
Contents lists available at ScienceDirect
Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy
Intraocular beta-radiation for proliferative vitreo-retinopathy Paritosh Shah ⇑, Chee Kon, Sal Rassam Western Sussex Hospitals NHS Trust, Worthing Hospital, Lyndhurst Road, Worthing BN11 2DH, UK
a r t i c l e
i n f o
Article history: Received 21 October 2013 Accepted 10 January 2014
a b s t r a c t Proliferative vitreoretinopathy (PVR) is the most common cause of failure in retinal detachment surgery. PVR is a result of an enhanced healing process. Various surgical and pharmacological methods have failed to provide a definite solution to the problem. Radiation has since long been shown to be effective in similar situations like keloids, pterygia, and post trabeculectomy. Externally delivered radiation has also been tried in PVR, but with limited success. We propose that treatment with intraocularly delivered beta-radiation is a viable method to try and reduce the incidence of PVR after retinal detachment. This can improve the safety of the treatment, reduce potential side effects to surrounding tissues and help achieve a targeted treatment. However, the treatment was limited by the absence of a practical method for intraocular delivery of radiation. This is now possible, as we now have a method which has been shown to be safe in the CABERNET trial. If this can be proved, then it will be an important step towards treating PVR and hence reducing blindness after retinal detachment. Ó 2014 Elsevier Ltd. All rights reserved.
Hypothesis We hypothesize that a one time intraocular exposure to controlled beta-radiation at the time of retinal detachment surgery may result in fewer repeat surgeries for retinal detachment secondary to proliferative vitreo-retinopathy (PVR) when compared to conventional surgery. If it can be proved that beta radiation significantly reduces the failure rate of retinal detachment surgeries due to PVR, then this will be an important step towards treating PVR. Background Proliferative vitreoretinopathy (PVR) is the most common cause of failure in retinal detachment surgery. It can present after pneumatic retinopexy, cryotherapy, laser retinopexy, scleral buckling, vitrectomy or any form of trauma [1,2]. PVR results in 5–10% of all retinal detachment surgery cases. Thus it is a cause of morbidity due to poor vision or blindness. PVR is a reparative process initiated by full- or partial-thickness retinal breaks, retinopexy, and other types of retinal damage. Loss of contact inhibition causes the surrounding glial or retinal pigment epithelial (RPE) cells to migrate to both surfaces of the retina. Glial or RPE cells migrate further and cover the posterior surface of ⇑ Corresponding author. Address: Eye Clinic, Worthing Hospital, Lyndhurst Road, Worthing BN11 2DH, UK. E-mail address: [email protected] (P. Shah). http://dx.doi.org/10.1016/j.mehy.2014.01.008 0306-9877/Ó 2014 Elsevier Ltd. All rights reserved.
the detached posterior hyaloid face and attach to collagen fibers and other components of the extracellular matrix. The migration/ contraction mechanism causes tangential force on the retina to form multiple star folds and fixed folds. The collagen of anterior and posterior vitreous cortex contracts, resulting in tractional and rhegmatogenous retinal detachment.
Classification of PVR PVR has been classified as [3] Grade A: Characterised by vitreous haze, pigmented cells and clumps in the vitreous and pigmented cells on the retina, especially inferior retina. Grade B: Retinal stiffness with wrinkling of the inner retinal surface, vessel tortuosity, rolled edge of retinal tear, and decreased vitreous mobility. Grade C: Full thickness retinal folds measured in clock hours and whether anterior (CA 1–12) or posterior (CP 1–12). Current PVR treatment Treatment for PVR is mainly surgical when it is critical to remove all contractile membranes. However, this is by no means curative, and recurrences are common (6%, Wickham (2011); 19.5%, Bonnet (1984); 28% Chignell et al. (1973)) [4–6].
422
P. Shah et al. / Medical Hypotheses 82 (2014) 421–423
Pharmacologic treatment of PVR
Hypothesis
Pharmacologic treatment is aimed at inhibition of cell migration, proliferation and/or contraction. Various agents like tacrolimus [7], TGF-b inhibitor, decorin [8], 5-fluorouracil and mitomicin-C [9] and steroids have been tried. A ‘cocktail’ of drugs has also been used such as the British cocktail of 5-FU and Low Molecular Weight Heparin [10]. However, none of these have shown to have significant effect in human clinical trials.
We hypothesise that better results may be achieved in controlling and/or reducing the rates of proliferative vitreoretinopathy by trying to deliver the radiation intraocularly, in a more controlled and precise manner. We believe that this is now possible by using the same device used in the CABERNET trial [16]. This intraocular b-radiation delivery system (NeoVista, Inc., Newark, CA) is already certified for intraocular use and is a source of beta irradiation and is designed to deliver a dose 24 Gy over 4 min to the epimacular area for treatment of exudative macular degeneration. After pars plana vitrectomy, the radiation delivery probe is held over the area to be treated. We believe that the same probe can be used to irradiate the retina in an effort to reduce PVR. As PVR commonly occurs on the inferior retina due to the effect of gravity on the released RPE/Gliotic cells, it is possible that it is only the inferior retina that may need to be irradiated [20,21]. This approach can have several advantages over teletherapy which uses a beam of energy that, has to pass through normal tissue to reach its target, thus, unnecessarily irradiating off-target structures. Also, external beam proton delivery systems can have errors of 10–15% or more of the prescribed dose delivered [22]. Even more advanced technology, delivering radiation stereotactically, with robotic tracking software, can have more than a 2 mm of error in the location of the field. There also may be a welldocumented bystander effect in which neighboring cells beyond the target zone die [23]. So, we believe that an intraocular approach of delivering radiation can have significant advantages, and hence a greater potential to be successful. Any study designed to test this hypothesis, should be able to help in establishing the optimum dose of irradiation, determine the efficacy of a single application of beta irradiation on retinal detachment recurrence rates, and determine the safety profile of beta irradiation in PVR. A prospective randomised controlled study should be designed to test the efficacy of intraocular b-radiation in patients undergoing vitrectomy for retinal detachment. The patients can be divided into groups based on the degree of PVR. The control groups receive the conventional treatment only, while the treatment group receives intraocular b-radiation in the area of PVR. In cases without PVR, the inferior retina only is irradiated, peripheral to the vascular arcades. Our hypothesis will be proved if there is a marked reduction in the rates of retinal redetachments, retinectomies, use of silicon oil, and the number of repeat surgeries in the groups receiving radiation.
Radiation Beta rays are fast electrons that lose energy as they pass through cells and interact with molecules. The transferred energy is high enough to disrupt chemical bonds, which results in radical formation (or ionization). These radicals react with the deoxyribonucleic acid in the cells inducing damage and cell death. Kirwan et al. in their review on the uses of beta radiation state that ‘‘Desjardins (1932) noted that a proportion of irradiated cells exhibited either a temporary inhibition of metabolic activity, or a complete and permanent disintegration. Puck et al. demonstrated that the growth of normal fibroblasts in vitro could be inhibited by radiation’’ [11]. Fibroblasts are known to be sensitive to Beta irradiation and this has long been used in the management of excessive Keloid formation in the skin [12]. In the eye, radiation has been shown to inhibit corneal wound healing, with prominent effects on fibroblast proliferation [13]. Pajonk et al. showed the beneficial effect of beta radiation on the recurrence rates of pterygium [14]. Constable et al. described the effects of radiation on tenon’s capsule fibroblasts. They showed that there was no significant effect on cellular migration or contraction, but extracellular matrix production was altered. Fibronectin production was inhibited following higher radiation doses, and collagen I and III production increased after 1000 cGy [15]. While the CABERNET trial evaluating beta-radiation treatment for wet AMD did not reach the primary end-point (which was the percentage of patients loosing less than 15 letters on the ETDRS chart), it did establish an acceptable safety profile of the treatment. It also identified a sub-group of patients who responded well to the treatment and did not need any rescue injections [16].
Radiation and PVR Radiation therapy has also been utilised as a means of preventing proliferative vitreoretinopathy. Meredith et al., showed that irradiating fibroblasts with a 6 Gy dose of X-ray radiation resulted in a reduction of formation of tractional retinal detachment [17]. Binder et al., used 3000 cGY of radiation but did not find any advantage [18]. We believe that this treatment can be successful because proliferating cells are more responsive to beta irradiation than established fibrosis – law of Bergonie and Tribondeau [19]. By observing the effects of radiation on rabbit testicles, they also showed that immature or young cells and tissues are more radiosensitive, resistance to radiation increases with increased cell maturity and low metabolic rate decreases radiosensitivity and high metabolic rate increases radiosensitivity. High proliferation (reproductive) rate for cells and fast growth rate increases the radiosensitivity of those cells. However, the radiation delivered in previous reports was either on in vitro cells or by external beam radiation.
Conflict of interest We declare that we have no financial or personal relationships with other people or organizations that can inappropriately influence our work, there is no professional or other personal interest of any nature or kind in any product, service and/or company that could be construed as influencing the position presented in, or the review of, the manuscript entitled ‘‘Intraocular beta radiation for proliferative vitreoretinopathy’’. References [1] Machemer R. Pathogenesis and classification of massive preretinal proliferation. Br J Ophthalmol 1978;62(11):737–47. [2] Ryan SJ. The pathophysiology of proliferative vitreoretinopathy in its management. Am J Ophthalmol 1985;100:188–93.
P. Shah et al. / Medical Hypotheses 82 (2014) 421–423 [3] Machemer R, Aaberg T, Freeman H, Irvine A, Lean J, Michels R. An updated classification of retinal detachment with proliferative vitreoretinopathy. Am J Ophthalmol 1991;112(2):159–65. [4] Wickham L, Ho-Yen G, Bunce C, Wong D, Charteris D. Surgical failure following primary retinal detachment surgery by vitrectomy: risk factors and functional outcomes. Br J Ophthalmol 2011;95(9):1234–8. [5] Bonnet M. Clinical factors predisposing to massive proliferative vitreoretinopathy in rhegmatogenous retinal detachment. Ophthalmologica 1984;188(3):148–52. [6] Chignell A, Fison L, Davies E, Hartley R, Gundry M. Failure in retinal detachment surgery. Br J Ophthalmol 1973;57(8):525. [7] Turgut B, Uyar F, Ustundag B, Celiker U, Akpolat N, Demir T. The impact of tacrolimus on growth factors in experimental proliferative vitreoretinopathy. Retina 2012;32(2):232–41. [8] Nassar K, Lüke J, Lüke M, Kamal M, El-Nabi E, Soliman M, et al. The novel use of decorin in prevention of the development of proliferative vitreoretinopathy (PVR). Graefe’s Arch Clin Exp Ophthalmol 2011;249(11):1649–60. [9] Yu HG, Chung H. Antiproliferative effect of mitomycin C on experimental proliferative vitreoretinopathy in rabbits. Korean J Ophthalmol 1997;11(2):98–105. [10] Asaria R, Kon C, Bunce C, Charteris D, Wong D, Khaw P, et al. Adjuvant 5fluorouracil and heparin prevents proliferative vitreoretinopathy: results from a randomized, double-blind, controlled clinical trial. Ophthalmology 2001;108(7):1179–83. [11] Kirwan JF, Constable PH, Murdoch IE, Khaw PT. Beta irradiation: new uses for an old treatment: a review. Eye 2003;17(2):207–15. [12] Kal HB, Veen RE, Jürgenliemk-Schulz IM. Dose-effect relationships for recurrence of keloid and pterygium after surgery and radiotherapy. Int J Radiat Oncol Biol Phys 2009;74(1):245–51. [13] Morrison DR, Kanai A, Gasset AR. Beta radiation inhibition of corneal healing. I. Tensile strength and ultrastructure change. Invest Ophthalmol 1971;10: 826–39.
423
[14] Pajonk F, Flick H, Mittelviefhaus H, Slanina J, Snibson GR, Luu CD, et al. A prospective randomised controlled trial of beta radiation, mitomycin C, and conjunctival transplantation in the surgical management of pterygium. Invest Ophthalmol Vis Sci 1996;37:s703. [15] Constable P, Occleston N, Cordeiro M, Kon C, Khaw PT. Long term growth arrest of human tenons fibroblasts following single doses of beta irradiation. Br J Ophthalmol 1998;82:448–52. [16] Dugel PU, Bebchuk JD, Nau J, Reichel E, Singer M, Barak A, et al. Epimacular brachytherapy for neovascular age-related macular degeneration: a randomized, controlled trial (CABERNET). Ophthalmology 2013;120(2): 317–27. [17] Meredith TA, Ficker L, Stevens R, Olkowski Z, Anderson M, Hartmann J, et al. Suppression of experimental tractional retinal detachment by low-dose radiation therapy. Arch Ophthalmol 1988;106:673–5. [18] Binder S, Bonnet M, Velikay M, Gerard JP, Stolba U, Wedrich A, et al. Radiation therapy in proliferative vitreoretinopathy. A prospective randomized study. Graefes Arch Clin Exp Ophthalmol 1994;232:211–4. [19] Bergonié J, Tribondeau L. Interpretation of some results of radiotherapy and an attempt at determining a logical technique of treatment/De Quelques Résultats de la Radiotherapie et Essai de Fixation d’une Technique Rationnelle. Radiat Res 1959;11(4):587–8. [20] Singh AK, Glaser BM, Lenor M, Michels RG. Gravity-dependent distribution of retinal pigment epithelial cells dispersed into the vitreous cavity. Retina 1986;6:77. [21] Duke Elder S, Dobree JH. Detachment and folding of retina. Duke-Elder Syst Ophthalmol 1967;10:809. [22] Paganetti H, Niemierko A, Ancukiewicz M, et al. Relative biological effectiveness (RBE) values for proton beam therapy. Int J Radiat Oncol Biol Phys 2002;53:407–21. [23] Prise KM, Belyakov OV, Folkard M, Michael BD. Studies of bystander effects in human fibroblasts using a charged particle microbeam. Int J Radiat Biol 1998;74:793–8.
