Sustained regression of a primary choroidal melanoma under the influence of a therapeutic melanoma vaccine.

PURPOSE: To determine whether active specific immunotherapy with lysates of cutaneous melanoma cells, administered with immunologic adjuvant DETOX (Ribi ImmunoChem Research, Inc, Hamilton, MT), is effective in shrinking a primary choroidal melanoma, in an elderly patient already blind in the nontumorous eye. An 81-year-old man was referred with a primary choroidal melanoma of the left eye, with virtual blindness of the right eye due to macular degeneration. He was begun on active specific immunotherapy with an experimental melanoma vaccine (melanoma theraccine) and DETOX on weeks 1, 2, 3, 4, and 6, respected after a hiatus of 2 weeks. After a response was noted, monthly injections were given. RESULTS: The patient had a significant shrinkage of his choroidal melanoma from a height of 4.2 mm to 2.4 mm within 2 months. This was sustained by continual treatment for 21 months until September 1991. After the patient failed to return for 9 months while recuperating from a stroke, the lesion regrew to a height of 3.7 mm and developed an additional lobe. On resumption of monthly treatments, the lesion shrank to 3.4 mm within 3 months, lost the additional lobe, and has since remained stable. No metastases have been found over a period of nearly 4 years on quarterly computed tomographic (CT) scanning of the chest and abdomen, and magnetic resonance imaging of the head. CONCLUSION: Active specific immunotherapy with cutaneous melanoma lysates has caused a clinically useful protracted regression of a primary choroidal melanoma in an elderly patient in whom surgery and radiation therapy were contraindicated. This may represent the first case of a primary choroidal melanoma, and perhaps the only primary tumor, successfully treated with systemic immunotherapy alone. A formal trial of active specific immunotherapy for primary choroidal melanoma in selected patients may be warranted.

Dosimetric calculations and measurements of gold plaque ophthalmic irradiators using iridium-192 and iodine-125 seeds.

The dosimetry of ophthalmic plaques designed to hold iridium-192 or iodine-125 seeds is investigated experimentally and by means of a computer model. A phantom for thermoluminescent dosimetry (TLD) which permits measurements to within 2 mm of the plaque surface is described. TLD data are compared with model calculations that take into account the active length of the seeds, anisotropy of dose distribution from single seeds, and scatter within the phantom. An isotropic point source calculational model is accurate for clinical calculations, particularly at depths greater than 5 mm. Relative central axis dose measurements for 125I in a gold plaque are also in agreement with the model. Comparisons of 192Ir, 125I and 60Co plaques are presented. The relative advantages of using these isotopes in eye plaques are discussed.

Episcleral plaque radiotherapy in the treatment of uveal melanomas.

During an 8-year period, 85 patients with uveal melanomas were treated with episcleral plaque radiotherapy (EPRT). The T-stage was: T1-3 (4%), T2-29 (34%) and T3-53 (62%). The mean tumor elevation was 6.1 mm. Radiation dose was prescribed at the tumor apex and at D5mm. The mean D5mm dose was 150.1 Gy (range 70.5-430 Gy) and the mean dose at the apex was 102.6 Gy (range 29.8-200 Gy). Useful vision (greater than 5/200) was maintained in 73% of patients. The 5-year actuarial survival was 88%. Metastatic disease developed in 9 (11%) patients, 6 of whom died of their disease. Basal tumor dimensions were important factors predicting metastatic disease, p = 0.002. A decrease in tumor evaluation was seen in 82%. There was a much lower incidence of decrease in tumor radial and circumferential dimensions, 47.5 and 46%, respectively, p less than 0.001. Treatment complications were common (56%), particularly in patients with large tumors (72%), p = 0.04. The incidence of complications was higher in patients treated prior to 1988 as compared to those who were treated more recently (67 vs 35%, p = 0.010). There were 13 (15%) patients who had enucleation. This included 12 treated before 1986 and 1 patient treated subsequently (46 vs 2%, p less than 0.001). In a univariate analysis, tumor height and radiation dose at D5mm were important factors predicting enucleation, p = 0.004. In a multivariate analysis, however, the most important factor predicting enucleation was treatment administration prior to 1986, p less than 0.001). A sharp decrease in the incidence of severe complications, including enucleation, as seen after 1985, is likely due to a major effort in treatment optimization.

An interactive treatment planning system for ophthalmic plaque radiotherapy.

Brachytherapy using removable episcleral plaques containing sealed radioisotope sources is being studied as an alternative to enucleation in the treatment of choroidal melanoma and other tumors of the eye. Encouraging early results have been reported, but late complications which lead to loss of vision continue to be a problem. A randomized national study, the Collaborative Ocular Melanoma Study (COMS) is currently in progress to evaluate the procedure. The COMS specified isotope is 125I. Precise dosimetric calculations near the plaque may correlate strongly with complications and could also be used to optimize isotope loading patterns in the plaques. A microcomputer based treatment planning system has been developed for ophthalmic plaque brachytherapy. The program incorporates an interactive, 3-dimensional, solid-surface, color-graphic interface. The program currently supports 125I and 192Ir seeds which are treated as anisotropic line sources. Collimation effects related to plaque structure are accounted for, permitting detailed study of shielding effectiveness near the lip of a plaque. A dose distribution matrix may be calculated in any subregion of a transverse, sagittal, or coronal planar cross section of the eye, in any plane transecting the plaque and crossing the eye diametrically, or on a spherical surface within or surrounding the eye. Spherical surfaces may be displayed as 3-dimensional perspective projections or as funduscopic diagrams. Isodose contours are interpolated from the dose matrix. A pointer is also available to explicitly calculate and display dose at any location on the dosimetry surface. An interactive editing capability allows new plaque designs to be rapidly added to the system.

Characterization of uveal melanoma cell lines that grow as xenografts in rabbit eyes.

Two cell lines, OCM-1 and OCM-2, were established from biopsied specimens of choroidal melanomas of spindle B and mixed cell type morphologies. Both cell lines were phenotypically malignant. Karyotypic analyses revealed human chromosomes with a modal number of 95 and 85, respectively. These cell lines have been passaged for over 2 years and are essentially immortal. The cells grew without contact inhibition as monolayers in liquid culture or as clones in soft agar. Electron microscopy revealed melanoma cells containing premelanosomes and cultures free from contamination by fibroblasts. To categorize the morphologies of these cultured cells better by the Callender classification, they were grown as xenografts in the anterior chambers of rabbits immunosuppressed with daily i.m. doses of Cyclosporin A (10 mg/kg). Tumor plaques were detected after 10 days. The eyes were enucleated and fixed in formalin and stained with hematoxylin and eosin for histopathological evaluation. The xenograft from OCM-1 was found to consist predominantly of spindle B-type melanoma cells. In contrast, the xenograft from OCM-2 contained epithelioid, spindle B and clear cell ("balloon") melanoma cells. The ability of these cell lines to grow as xenografts confirmed their neoplastic origin. In fact, the types of the uveal melanoma cells in the xenografts resembled those in the original biopsied tumors. This suggests that the morphology of human uveal melanoma cells is an inherited trait and may be genetically fairly stable.

Differential S100 beta expression in choroidal and skin melanomas: quantitation by the polymerase chain reaction.

PURPOSE: S100 beta, a member of a calcium-binding protein family (S100s), is an important clinical marker for skin melanoma. In contrast, uveal melanomas appeared to express S100 beta protein less frequently and to a lesser degree. This study was performed to verify and extend this finding to the mRNA level. METHODS: A quantitative polymerase chain reaction (PCR)-based method was used. A ratio, comparing the S100 beta PCR fragment to that of beta-actin (an internal reference gene), was generated to compare S100 beta mRNA expression among samples. RESULTS: The ratios for skin melanomas (1.2 to 3.9; three tissues and two cell lines) were significantly higher than that for choroidal melanomas (0.1 to 0.63; seven of eight primary tumors and four of four cell lines). Only one choroidal melanoma biopsy had a ratio greater than 1. The PCR products from choroidal melanoma were identical in size and sequence to the S100 beta, as determined by gel electrophoresis and RNA conformational polymorphism. Because the ratios were also low in choroidal melanoma cell lines, the S100 beta phenotype appears to be genetically stable. CONCLUSION: S100 beta is differentially expressed at the RNA and protein levels by skin and choroidal melanomas, which are derived from distinct populations of melanocytes. However, choroidal melanomas expressing little or no S100 beta were significantly stained by antiserum specific for the S100 protein family. Taken together, these data suggest that choroidal melanocytes express another, perhaps even novel, S100 protein(s).

Massive suprachoroidal hemorrhage with central retinal apposition. A clinical and echographic study.

We reviewed the charts of 18 patients diagnosed with a massive suprachoroidal hemorrhage (MSCH) with central retinal apposition (kissing configuration). Four cases occurred intraoperatively (expulsive), eight after a surgical procedure (delayed), and six associated with blunt or perforating injury (traumatic). In this study, echography was used to monitor the course of MSCH; the mean time for clot lysis was 14 days, and the mean duration of central retinal apposition was 15 days. The expulsive MSCHs were all allowed to resolve spontaneously, with good initial visual outcome in three of the four eyes in which they occurred. In the delayed MSCH group, the majority of patients attained their prehemorrhage visual acuity, with or without early surgical intervention. In the traumatic MSCH group, retinal detachment was a constant complication in all patients. All six patients in the traumatic MSCH group had a poor visual outcome, despite early surgical intervention in five patients. The results of this study suggest that not all MSCHs need to be drained surgically and that, when surgical drainage is indicated, echography may be a useful adjunct in determining the optimal time of drainage.

Photodynamic therapy of experimental subchoroidal melanoma using chloroaluminum sulfonated phthalocyanine.

Although photodynamic therapy has shown great promise for the treatment of a variety of malignant neoplasms, the role of this new therapeutic modality in the clinical management of intraocular tumors remains incompletely understood. This study examines the effects of photodynamic therapy using chloroaluminum sulfonated phthalocyanine on Greene hamster melanoma transplanted into the subchoroidal space in rabbits. Twenty-four hours after intravenous administration of chloroaluminum sulfonated phthalocyanine (5 mg/kg), tumors were irradiated with 675 nm of light at total light doses of 7 to 60 J/cm2. The results show that tumor growth was arrested at total light doses of 22 to 60 J/cm2. At total light doses of 15 to 21 J/cm2, tumor growth was initially arrested. However, regrowth of these tumors was apparent within 7 days. Total light doses of less than 15 J/cm2 showed no response. Complications of photodynamic therapy, such as intraretinal or subretinal hemorrhages and retinal detachment, were seen only in animals who received total light doses in excess of 43 J/cm2.

Pars plana vitrectomy for acute retinal detachment in penetrating ocular injuries.

We studied 41 eyes with acute retinal detachment after penetrating ocular trauma in a retrospective cohort analysis. Pars plana vitrectomy was performed in 28 eyes, while the remaining 13 eyes had only primary repair and closure of the wound. The two groups differed in the type of trauma (more gunshot wounds in the vitrectomy group and more blunt injuries in the nonvitrectomized group). Visual success (visual acuity of 5/200 or better) was observed in 10 (37%) of the eyes treated by vitrectomy compared with one (8%) of the eyes in the nonvitrectomy group. Anatomic success was achieved in 21 (75%) of the eyes in the vitrectomy group but in only one (8%) of those in the nonvitrectomy group. Enucleation or phthisis was observed in seven (54%) of the eyes in the nonvitrectomy group compared with only five (18%) in the vitrectomy group. Significant prognostic factors for anatomic outcome in the vitrectomy group were the location of the laceration and the presence of the lens.

Branch retinal artery occlusion associated with directional coronary atherectomy after percutaneous transluminal coronary angioplasty.

PURPOSE: To report a case of branch retinal artery occlusion after atherectomy. METHODS: A 51-year-old man complained of visual loss in the right eye after directional coronary atherectomy, performed secondary to a complicated percutaneous transluminal coronary angioplasty. He underwent a full ophthalmologic examination, including fluorescein angiography and Doppler ultrasound. RESULTS: Visual Acuity was 20/30 with an inferior scotoma present in the right eye. There were three Hollenhorst plaques present inside the superotemporal vascular arcade. CONCLUSIONS: There is a small but definite risk of retinal microinfarctions after atherectomy.

Intraoperative argon endophotocoagulation for recurrent vitreous hemorrhage after vitrectomy for diabetic retinopathy.

We reviewed the medical records of 103 consecutive cases of vitrectomy performed for complications of diabetic retinopathy to determine if the introduction of argon laser endophotocoagulation had reduced the incidence of recurrent vitreous hemorrhage. Twenty-six eyes (48%) treated with endophotocoagulation and 35 (71%) eyes not receiving laser treatment had a recurrent hemorrhage. Follow-up was shorter for the eyes treated with endophotocoagulation, but a log-rank analysis to allow for this variable confirmed the benefit of laser photocoagulation (P less than .05). The proportion of eyes requiring surgical removal of the hemorrhage was also significantly lower in the group receiving endophotocoagulation (P less than .05). The beneficial effect of intraoperative laser treatment was independent of the amount of preoperative laser treatment, aphakia, and indications for the original vitrectomy surgery.

Rapidly progressive outer retinal necrosis in the acquired immunodeficiency syndrome.

Two patients, both seropositive for the human immunodeficiency virus, developed rapidly progressive retinal necrosis associated with a systemic herpes zoster infection. The retinitis in these patients was characterized by primary involvement of the outer retina, with sparing of the inner retina and retinal vasculature until late in the disease process; a rapidly progressive course; poor response to intravenous acyclovir; and development of rhegmatogenous retinal detachment. In one of the patients, the retinitis was initially multifocal. Electron microscopy of a retinal biopsy specimen from one of the patients demonstrated virus particles consistent with a herpesvirus, and polymerase chain reaction disclosed herpesvirus in a retinal biopsy specimen of the other patient. This entity may represent a distinct form of acute retinal necrosis that is seen in immunocompromised individuals.

Vitrectomy for perforating eye injuries from shotgun pellets.

Pars plana vitrectomy and scleral buckling were performed on 22 eyes of 19 patients for treatment of perforating eye injuries from shotgun pellets. We reviewed the intraoperative findings at the time of vitrectomy to determine what factors might influence final visual acuity. The presence of a total retinal detachment at vitrectomy portended a poor prognosis when compared with eyes without total retinal detachment, as only one of ten eyes with total retinal detachment obtained useful vision (P = .002). Preoperative separation of the posterior vitreous was associated with a favorable outcome when compared with the absence of posterior vitreous detachment (P = .035), as ten of 16 eyes with posterior vitreous detachment at the time of vitrectomy ultimately achieved functional vision. The locations of the exit wounds did not affect visual success in the overall series of patients. However, in the patients who achieved visual success, exit wounds outside the vascular arcades were more likely to be associated with final visual acuities of, or better than, 20/70 than were those within the arcades (P = .022). Other prognostic factors, such as the number of perforations and the use of cryotherapy, were also examined for their effects on final visual outcome. However, these factors did not appear to affect visual outcome statistically.

Repair of retinal detachment caused by cytomegalovirus retinitis in patients with the acquired immunodeficiency syndrome.

Twenty-two eyes of 19 patients with the acquired immunodeficiency syndrome who had pars plana vitrectomy and silicone-oil injection after retinal detachment caused by cytomegalovirus retinitis were studied. All patients but one were monitored until time of death. The postoperative survival time and the factors that predicted anatomic success (retinal attachment) and functional success (visual acuity) were analyzed. No intraoperative complications were encountered. The mean survival time after surgery was four months. Of all of the preoperative and intraoperative factors studied, only the duration of cytomegalovirus retinitis was predictive of survival (P less than .03). The anatomic success rate was 89.5% (17 of 19 patients). None of the factors showed a trend or statistical significance in relation to anatomic success. Fifteen of 19 patients (79%) had lost at least two lines of Snellen visual acuity at time of death. Vision declined in a bimodal pattern (within the first postoperative month and after four months postoperatively). The optic nerve was pink and well perfused preoperatively in 16 of 19 patients (81.8%), but optic-nerve atrophy was observed postoperatively in 18 of 19 patients (95.5%). There was a trend for functional success to be influenced by increased intraocular pressure and optic-nerve atrophy, although our sample size was too small for statistical significance.

Optimization of 125I ophthalmic plaque brachytherapy.

Episcleral plaques containing 125I sources are often used in the treatment of ocular melanoma. Within four years post-treatment, however, the majority of patients experience some visual loss due to radiation retinopathy. The high incidence of late complications suggests that careful treatment optimization may lead to improved outcome. The goal of optimization would be to reduce the magnitude of vision-limiting complications without compromising tumor control. We have developed a three-dimensional computer model for ophthalmic plaque therapy which permits us to explore the potential of various optimization strategies. One simple strategy which shows promise is to maximize the ratio of dose to the tumor apex (T) compared to dose to the macula (M). By modifying the parameters of source location, activity distribution, source orientation, and shielding we find that the calculated T:M ratio can be varied by a factor of 2 for a common plaque design and posterior tumor location. Margins and dose to the tumor volume remain essentially unchanged.

Paediatric post-traumatic endophthalmitis.

AIMS: A retrospective analysis of children with post-traumatic endophthalmitis was performed to determine if microbiological differences exist between this disease in the paediatric population compared with this disease in adults. METHOD: Twelve cases of post-traumatic endophthalmitis in children were analysed to determine characteristics of this disease in youth. Patient ages varied from 18 months to 13 years; the mean age was 8 years. Gram positive organisms were isolated in eight eyes, Gram negative organisms from four eyes, fungus from one eye, and negative cultures in three eyes. The most common isolates were streptococcal species (56.6%) and staphylococcal species (22.2%). Vitrectomy was performed on eight (66.7%) eyes. RESULTS: Visual acuity of 20/200 or better was obtained in eight eyes (66.7%). Three eyes had vision less than 5/200. One eye developed phthisis bulbi. Nine (75%) patients were younger than 10 years of age, and six (66.7%) of these nine obtained a final visual acuity of 20/200 or better. CONCLUSION: Useful vision can be obtained in children with post-traumatic endophthalmitis with early, aggressive treatment. The microbiology of paediatric post-traumatic endophthalmitis differs from adult disease with streptococcal species as the most common infecting organisms.

Experimental Bacillus cereus post-traumatic endophthalmitis and treatment with ciprofloxacin.

BACKGROUND: Bacillus species remain an important cause of post-traumatic endophthalmitis, often causing permanent visual loss. METHODS: Twenty two rabbits were used to evaluate the clinical and histological findings of Bacillus cereus experimental post-traumatic endophthalmitis. Eyes that had received a scleral laceration and surgical repair were inoculated with Bacillus cereus. Thirty four other rabbits were used to evaluate the efficacy of intravitreal ciprofloxacin in treating experimental disease. RESULTS: Animals developed a post-traumatic endophthalmitis that closely mimicked human disease, characterised by a rapidly progressive and destructive endophthalmitis. Histological evaluation revealed retinal detachment, retinal necrosis, and the infiltration of inflammatory cells into the subretinal space. Intravitreal ciprofloxacin (100 micrograms) prevented the development of disease when given 1 hour and 6 hours after trauma and inoculation. CONCLUSIONS: Clinical and histological examination of experimental Bacillus cereus post-traumatic endophthalmitis suggests that retinal detachment and retinal necrosis play important roles in visual loss. Ciprofloxacin may be of benefit in the management of certain intraocular infections following penetrating injury.

Corneal toxicity study of two perfluorocarbon liquids in rabbit eyes.

Perfluorocarbon liquids are fully fluorinated, synthetic, transparent compounds with a high specific gravity. These compounds are being increasingly used as an intraoperative tool for repair of complicated retinal detachments. A potential complication of their use, however, is liquid entering the anterior chamber in aphakic patients. In the study described herein we evaluated the effects of two of these liquids when placed in the anterior chamber of the rabbit eye. Sixteen rabbit eyes underwent anterior chamber injection of 0.05 ml of either perfluoroctane, perfluoropolyether, or balanced salt solution (control eyes). Animals were monitored clinically by biomicroscopy and external photography for up to 14 days, after which they were sacrificed and the corneas processed for light and for scanning electron microscopy. The animals injected with perfluoropolyether showed more intense stromal inflammation and corneal vascularization (p less than 0.02) than did those that received perfluoroctane. However, the perfluoroctane group showed more of the "fish-egging" phenomenon (p less than 0.03). Loss of endothelial cells was similar in the two groups, as determined by light and scanning electron microscopy. These results suggest that the corneal toxicity of these two perfluorocarbon liquids is such that their use as vitreous substitutes should be limited to short-term replacement.

Histopathologic changes following irradiation for uveal tract melanoma.

Histopathologic studies were performed on 38 eyes in patients with uveal melanoma who had enucleation. Of the 38 eyes examined, enucleation was required in 11 (29%) following episcleral radioactive plaque therapy (RPT), which was performed in 83 patients. The reasons for enucleation in the 11 patients who had RPT were progressive tumor in 5 and treatment complications in 6 eyes. The histologic findings in these 11 patients were compared to those seen in 7 patients (18%) who received a planned course of preoperative external beam radiotherapy (RT) prior to enucleation and with 20 uveal melanoma patients (53%) who were treated with enucleation alone. Tumor necrosis was found in the eyes of patients from all three groups examined. It was, however, seen more frequently and to a greater extent in the 11 RPT patients as compared to the 7 preoperative RT and 20 enucleation alone patients, p = .01. There was no difference in the incidence or extent of tumor necrosis in the 7 preoperative RT patients as compared to the 20 primary enucleation patients, p = .18. In all 3 study groups, no correlation was found between tumor size and necrosis. In the 11 RPT patients, necrosis was independent of cell type and the radiation dose. As expected, the RPT patients had a greater incidence of neovascularization on the iris and scleral necrosis than those of the other two study groups (70 vs. 12.5% and 33 vs 0%, respectively), p = .004. A major effort needs to be made to optimize episcleral RPT in order to reduce treatment complications and increase the incidence of primary tumor control.

Episcleral plaque thermoradiotherapy of posterior uveal melanomas.

Episcleral plaque radiotherapy is a widely applied treatment for selected patients with uveal melanomas. This treatment is well tolerated but may produce severe late radiation complications resulting in decreased visual acuity that reduces the attractiveness of conservative therapy. The purpose of this study was to access if the addition of episcleral hyperthermia decreases late radiation complications through radiation dose reduction while maintaining high incidence of local tumor control. In a 3-year period, episcleral plaque thermoradiotherapy was given to 25 patients with uveal melanoma in a Phase I study. The mean tumor height was 6.2 mm and the mean tumor basal area was 173 mm(2). The mean radiation dose given to the tumor apex was 72.2 Gy and the mean hyperthermia temperature, given once for 45 min, was 43.5 degrees C. Of the 25 patients treated, 22 (88%) showed tumor height reduction, 2 (8%) showed no change, and 1 (4%) had an increase in tumor height. At the last follow-up (range, 20-68 months; mean, 31.2 months), a 43% mean tumor height reduction was recorded (p = 0.0002). Of the 22 patients initially showing tumor regression, 2 (9%) had subsequent tumor progression. At least ambulatory vision (>5/200) was maintained by 20 (80%) patients. Severe complications, including hemorrhagic retinal detachment and a large vitreous hemorrhage, were seen in 2 (8%) patients early in this Phase I study. The treatment program was well tolerated by the study patients. Severe late treatment toxicity was sharply reduced by limiting the mean scleral temperature to < or equal to 44 degrees C. This study employing 30% lower radiation doses, showed tumor regression in the majority of patients. Longer follow-up is needed to assess long-term treatment efficacy and late treatment complications.