Karl R. Olsen

The COMS randomized trial of iodine 125 brachytherapy for choroidal melanoma: IV. Local treatment failure and enucleation in the first 5 years after brachytherapy. COMS report no. 19.

OBJECTIVE To describe the frequency and predictors of local treatment failure and enucleation after iodine 125 (I(125)) brachytherapy in patients with choroidal melanoma treated and followed up in a large randomized clinical trial. DESIGN Prospective, noncomparative, interventional case series within a randomized, multicenter clinical trial. PARTICIPANTS Patients enrolled in the Collaborative Ocular Melanoma Study (COMS) trial of enucleation versus brachytherapy between February 1987 and July 1998; tumors measured 2.5 to 10.0 mm in apical height and no more than 16.0 mm in longest basal dimension. METHODS I(125) brachytherapy was administered via episcleral plaque according to a standard protocol. Follow-up ophthalmic evaluations, including ophthalmic ultrasound and fundus photography, were performed according to a standard protocol at baseline, every 6 months thereafter for 5 years, and subsequently at annual intervals. Survival analysis methods were used to estimate the cumulative risk of postirradiation treatment failure and enucleation. Factors associated with treatment failure and enucleation of plaqued eyes were evaluated using Cox proportional hazards analysis. MAIN OUTCOME MEASURES Reports of enucleation and of local treatment failure, defined as tumor growth, recurrence, or extrascleral extension, derived from clinical reports based on echographic and photographic documentation. RESULTS As of September 30, 2000, 638 of the 650 patients randomized to brachytherapy and so treated had been followed up for 1 year or longer, and 411 had been followed up for at least 5 years. Sixty-nine eyes were enucleated during the first 5 years after brachytherapy, and treatment failure was reported for 57 eyes. The Kaplan-Meier estimate of proportion of patients undergoing enucleation by 5 years was 12.5% (95% confidence interval [CI], 10.0%-15.6%); the risk of treatment failure was 10.3% (95% CI, 8.0%-13.2%). Treatment failure was the most common reason for enucleation within 3 years of treatment; beyond 3 years, ocular pain was most common. Risk factors for enucleation were greater tumor thickness, closer proximity of the posterior tumor border to the foveal avascular zone, and poorer baseline visual acuity in the affected eye. Risk factors for treatment failure were older age, greater tumor thickness, and proximity of the tumor to the foveal avascular zone. Local treatment failure was associated weakly with reduced survival after controlling for baseline tumor and personal characteristics (adjusted risk ratio, 1.5; P = 0.08). CONCLUSIONS Local treatment failure and enucleation were relatively infrequent events after I(125) brachytherapy within the COMS. Treatment failure typically occurred early and was associated weakly with poorer survival. The COMS randomized trial documented the absence of a clinically or statistically significant difference in survival for patients randomly assigned to enucleation versus brachytherapy. This analysis documents the efficacy of brachytherapy to achieve sustained local tumor control and to conserve the globe.

Tissue plasminogen activator treatment of experimental subretinal hemorrhage.

Previous investigators have suggested that subretinal blood damages the retina in part because of its solid fibrin meshwork. The role of fibrinolysis in facilitating the clearance of subretinal hemorrhage and preventing degeneration of the overlying retina was studied. Autologous whole blood (0.1 ml) was injected into the subretinal space of 20 rabbits. Twenty-four hours later, the animals were randomized to subretinal treatment with 2.5 µg of tissue plasminogen activator or a similar volume of physiologic saline. Mean subretinal hemorrhage thickness 3 days after treatment had decreased to 42% of pretreatment thickness in treated eyes and remained unchanged in control eyes (P < 0.0005). By 7 days mean clot thickness was 9% in treated eyes and 60% in controls (P = 0.005). Light microscopy revealed severe progressive retinal degeneration in both groups. No histologic evidence of retinal toxicity was found in cat retina after subretinal injection of tissue plasminogen activator (50 (µg/ml). Although treatment with tissue plasminogen activator accelerated the clearance of subretinal hemorrhage, it failed to prevent secondary retinal degeneration in this rabbit model.

Tissue Plasminogen Activator Thrombolysis during Surgical Evacuation of Experimental Subretinal Hemorrhage

To assess the role for intraoperative thrombolysis during surgical evacuation of massive subretinal hemorrhage, the authors studied the ability of tissue plasminogen activator (tPA) to facilitate removal of an experimental subretinal blood clot through a small drainage retinotomy. In rabbit eyes, a single subretinal injection of tissue plasminogen activator in concentrations of up to 250 micrograms/ml failed to produce significant (greater than 50%) clot dissolution during a 3-hour period. However, repetitive subretinal lavage and aspiration with tPA (50 micrograms/ml) resulted in progressive intraoperative clot dissolution in rabbits and allowed complete evacuation of blood through a small drainage retinotomy in 6 (100%) of 6 cat eyes. Repetitive vigorous subretinal irrigation with saline solution had no discernible effect on clot size in rabbit eyes. Histopathologic examination of cat eyes following tPA-assisted surgical evacuation of subretinal blood showed preservation of the outer retina in 2 eyes and severe atrophy of the outer retina in 4 eyes.

Tissue Plasminogen Activator Treatment of Postoperative Intraocular Fibrin

Intraocular recombinant tissue-type plasminogen activator was used for treatment of postoperative intraocular fibrin clots. Using a rabbit vitrectomy and cyclocryotherapy model of postoperative fibrin, rabbits were randomized on the first postoperative day to receive either an anterior chamber injection of lactated Ringers solution or 25,000, 50,000, or 100,000 IU tissue plasminogen activator (tPA). An intraocular dose of 25,000 IU of tPA produced marked resolution of the fibrin clot 24 hours later. A 50,000 and 100,000 IU dose produced slightly more resolution of the fibrin. No ophthalmoscopic or histologic evidence of intraocular toxicity was seen.

The coms randomized trial of iodine 125 brachytherapy for choroidal melanoma

arms, 5- and 10-year all-cause mortality rates were 19% and 35%, respectively; by 12 years, cumulative all-cause mortality was 43% among patients in the 125 I brachytherapyarmand41%amongthoseintheenucleationarm. Five-, 10-, and 12-year rates of death with histopathologicallyconfirmedmelanomametastasiswere10%,18%, and 21%, respectively, in the 125 I brachytherapy arm and 11%,17%,and17%,respectively,intheenucleationarm. Olderageandlargermaximumbasaltumordiameterwere the primary predictors of time to death from all causes and death with melanoma metastasis. Conclusion:Longer follow-up of patients confirmed the earlier report of no survival differences between patients whose tumors were treated with 125 I brachytherapy and those treated with enucleation.

Predictors of Scleral Rupture and the Role of Vitrectomy in Severe Blunt Ocular Trauma

We reviewed retrospectively 40 eyes that had received blunt trauma and had been explored for scleral rupture. Twenty-nine eyes had scleral rupture. Of these 29, ten had ruptures seen preoperatively. Nineteen had occult ruptures. The preoperative findings predictive of scleral rupture were a visual acuity of light perception or no light perception, an intraocular pressure of less than 10 mm Hg, hyphema, and chemosis. Of the 29 ruptures, 27 involved the superior hemisphere and 25 involved the anterior hemisphere of the globe. Ten of 29 eyes (34%) with scleral rupture and eight of 11 eyes (73%) without rupture achieved a final visual acuity of 5/200 or better over an average follow-up period of 6.7 months. Factors prognostic of ambulatory vision for eyes with ruptured and intact globes included an initial visual acuity of 5/200 or better, absence of scleral rupture, and a rupture length of less than 11 mm in eyes with ruptures. The vitrectomized eyes also had a better result, suggesting that early pars plana vitrectomy is of benefit in selected rupture cases.

The Site of Operating Microscope Light-Induced Injury on the Human Retina

We determined the site of the focal illumination from the Zeiss OPMI-6 operating microscope on the retina of the phakic and aphakic human cadaver eye by directly observing the illuminating element image on the posterior scleral surface of the globe. With the eye straight ahead and the operating microscope level, the focal oval area of retinal illumination was located superior to the foveola in both the phakic and aphakic eye. Tilting the operating microscope 10 degrees toward the surgeon displaced the entire illuminating element image 0.50 mm below the foveola in the phakic eye and 0.25 mm below the foveola in the aphakic eye. Rotating the eye inferiorly 10 degrees displaced the entire illuminating element image 1.0 mm below the foveola in the phakic eye and 1.25 mm below the foveola in the aphakic eye. Centering the field of view superiorly (viewing the superior limbus) paradoxically displaced the illuminating element image inferiorly, resulting in central foveal illumination. Foveal light exposure was avoided in most eye positions by tilting the microscope at least 10 degrees toward the surgeon.

MR technique for localization and verification procedures in episcleral brachytherapy

Spatial definition of an intraocular tumor and subsequent determination of the actual position of an implanted eye plaque are essential for adequate ocular brachytherapy treatment planning. However, a method for verification of the plaque placement which would provide required 3-dimensional information is not available at present. In addition, tumor localization procedures, including ultrasonography and CT techniques, cannot always offer the precision needed for 3-dimensional definition of an intraocular target. This communication describes a magnetic resonance imaging technique specifically developed for both localization and verification procedures. A 1.5 Tesla magnetic resonance scanner, spin-echo pulse sequence (echo time 30 msec, repetition time 700 msec), and commercially available surface coil were used to obtain a series of transverse, coronal, and sagittal images of a slice thickness of 3 mm. Usually, eight scans in each of the three planes were needed for adequate coverage of the orbit. The required patient set-up and data acquisition time did not exceed 40 minutes. With a data matrix size of 256 X 256 pixels and 13 cm field of view, localization and verification were accomplished with a precision of 0.5 mm. Our results suggest that the magnetic resonance imaging technique permits precise integration of diagnostic and therapeutic procedures, and in addition provides adequate data for accurate treatment planning. We conclude that magnetic resonance imaging is the preferred diagnostic technique for episcleral brachytherapy.

Measurement of cellular proliferation within the vitreous during experimental proliferative vitreoretinopathy

Cellular proliferation is an important component in the pathogenesis of complex retinal detachments caused by proliferative vitreoretinopathy (PVR). We used flow cytometry to measure the proliferation of cells recovered from the vitreous cavity in an experimental model of tractional retinal detachment induced by homologous fibroblast injection. Two distinct populations of cells were detected. One population comprised smaller, dense cells representing mostly leukocytes. A second population of larger cells contained not only the injected fibroblasts but also high concentrations of host-derived cells with significant proliferative activity, whose number increased for 3 days following injection. Flow cytometry was useful for analysis of the recovered cells for concentration, morphologic features and proliferation. This technique may be applicable in the identification of patients at high risk for the development of PVR.

Leber congenital amaurosis in siblings with diffuse dysmyelination

Two brothers are described with the previously unrecognized combination of Leber amaurosis and abnormal myelin detected by magnetic resonance imaging. Both have evidence of delayed psychomotor development and one has autistic features. A possible relationship with infantile autism or a peroxisomal dysfunction syndrome is explored. No peroxisomal defect was found in these patients.