Combined plaque radiotherapy and transpupillary thermotherapy in choroidal melanoma: 5 years' experience.

AIM: To evaluate the results of combined plaque radiotherapy and transpupillary thermotherapy (TTT) in 50 consecutive patients 5 years after treatment. METHODS: 50 adult patients with choroidal melanoma were treated with ruthenium-106 ((106)Ru) plaque radiotherapy combined with TTT. A flat scar was the preferred end point of treatment. The mean tumour thickness was 3.9 mm (range 1.5-8.0 mm), the mean tumour diameter was 11.3 mm (range 5.8-15.0 mm). TTT was performed with an infrared diode laser at 810 nm, a beam diameter of 2-3 mm, and 1 minute exposures. Tumours >5 mm thick received an episcleral contact dose of 800 Gy (106)Ru; tumours 3 mm thick (log rank test p = 0.01). Eight melanomas were amelanotic, seven of which required multiple TTT sessions. In one patient the tumour recurred at the central margin of the treated area; this eye was enucleated. In one patient the tumour failed to regress 6 months after treatment and enucleation was performed at the patient's request. Three eyes developed severe proliferative retinopathy. Radiation maculopathy caused a loss of the best corrected visual acuity: before treatment 31 patients had a best corrected visual acuity of 20/60 or better but in only 12 patients did it remain in this range 5 years after treatment. Three patients developed distant metastasis to the liver. CONCLUSION: The 5 year results for combined plaque radiotherapy and TTT as treatment for choroidal melanoma are favourable in terms of complete tumour regression and low rate of recurrences; however, there was considerable loss of visual acuity as a result of radiation maculopathy.

Transscleral laser thermotherapy of hamster Greene melanoma: inducing tumour necrosis without scleral damage.

The feasibility of using transscleral thermotherapy (TSTT) to induce necrosis of choroidal melanoma without causing damage to the sclera was investigated. Fifty-two subcutaneously implanted hamster melanomas covered by human donor sclera were irradiated for 1 min with an 810 nm laser using a 3 mm spot diameter, with and without cooling of the scleral surface. Immediately after irradiation the temperature of the scleral surface was measured with an infrared camera. Irradiation at 2000 mW, without cooling of the sclera, resulted in tumour necrosis to a mean depth of 4.4 mm and a mean diameter of 5.5 mm, without causing damage to the scleral collagen; the surface temperature of the sclera was 44.5 degrees C, and the estimated temperature at the sclera-tumour interface was 60.1 degrees C. There was a sharp demarcation between the viable and the necrotic part of the tumour. TSTT at 2500 mW, without cooling of the sclera, caused maximal tumour necrosis to a mean depth of 5.2 mm and a mean diameter of 5.9 mm; the scleral layers adjacent to the tumour had an estimated temperature of 67.6 degrees C and showed signs of damage in 14% of the experiments. Cooling of the sclera resulted in less thermal damage to the sclera but also less tumour necrosis. Results indicate that TSTT has potential in the treatment of choroidal melanoma.

Familial chronic central serous chorioretinopathy.

Twenty-seven patients with characteristic, mostly bilateral, fundus lesions of chronic central serous chorioretinopathy (CSC) and a progressive course, and 80 of their relatives, mainly siblings, were examined. Ophthalmologic examination included assessment of visual acuity, Amsler grid testing, ophthalmoscopy and fluorescein angiography. The fundus findings were classified as normal fundus, multiple areas of retinal pigment epithelium (RPE) atrophy or chronic CSC: RPE atrophy with leakage of fluorescein. In 14 (52%) of the 27 families, 1 or more relatives were affected. Thirty-five (44%) of the 80 investigated relatives had fundus lesions: 22 had chronic CSC in one eye, 20 of these had chronic CSC or RPE atrophy in the fellow eye. Thirteen relatives had RPE atrophy in one or both eyes. The mode of inheritance could not be established.

Yellow dye laser thermotherapy of choroidal neovascularisation in age related macular degeneration.

AIM: A pilot study of the feasibility of using dye laser thermotherapy (LTT) at a subcoagulation temperature to occlude newly formed vessels in patients with age related macular degeneration (AMD). METHODS: Choroidal neovascularisation (CNV) in 24 eyes with exudative AMD was treated with a continuous wave yellow laser at 578 nm. Parameters were an exposure time of 2 or 5 seconds, a spot size of 750 or 1000 microm, and a laser power of 100-200 mW. The clinical end point was a greyish discoloration at the treatment site. The effect of thermotherapy was documented by ophthalmoscopic and fluorescein angiographic examination. The follow up after LTT was 4-16 months, mean 5 months. RESULTS: LTT resulted in total occlusion of newly formed vessels in 15 eyes (62.5%). Neovascular outgrowth within 6 weeks and recurrences 2-4 months after LTT were observed, each in three eyes. In six of the nine eyes with occlusion of CNV without recurrence the choriocapillaris remained perfused; in two eyes only the large choroidal vessels remained perfused. In six eyes pigmentary changes were the only ophthalmoscopic and fluorescein angiographic signs of treatment. The effect of LTT is rather unpredictable. CONCLUSION: CNV in AMD can effectively be treated by yellow dye laser thermotherapy with preservation of choroidal perfusion. The technique requires dosimetric adaptation.

Temperature dependence of thermal damage to the sclera: exploring the heat tolerance of the sclera for transscleral thermotherapy.

Thermal damage to the human sclera in relation to temperature and duration of exposure was studied in order to determine the heat tolerance of the sclera with respect to transscleral thermotherapy of choroidal melanoma. Samples of human sclera were submerged in saline for 10 sec to 10 min at temperatures of 37-100 degrees C. The effects of heat on the shape, weight and size of the samples were studied. Thermal damage of scleral collagen was examined by polarized light microscopy (LM) and electron microscopy (EM). The sclera was embedded in epoxy resin and stained with toluidine blue for LM and with uranyl acetate and lead citrate for EM. Thermal damage of scleral collagen on polarized LM was graded on a five point scale. Scleral damage was visible on macroscopic examination and on LM and EM in sclera heated at 65 degrees C for 20 sec or longer, at 70 degrees C for 10 sec or longer, and at higher temperatures. A sigmoidal function was used to define the relation between temperature and changes in diameter, thickness, and weight of scleral samples. Using fitted functions, the threshold temperature for thermal damage was estimated to be 59-61 degrees C when samples were heated for 10 min, 62-63 degrees C when heated for 1 min, and 66-67 degrees C when heated for 10 sec; the threshold exposure time at 60 degrees C was estimated to be 7-12 min. These results indicate a temperature of 60 degrees C for 1 min is well tolerated by human donor sclera; information of in vivo studies is required to validate whether this setting can be used in transscleral thermotherapy (TSTT) for choroidal melanoma.

Results of ruthenium irradiation of uveal melanomas: the Dutch experience.

BACKGROUND AND PURPOSE: To update our results of the treatment of uveal melanomas using ruthenium applicators in 49 patients treated with graded doses and subsequently in 52 patients with maximal scleral doses of 800 Gy and an effective top dose of at least 160 Gy. MATERIAL AND METHODS: One hundred and one patients were treated with brachytherapy only, in 25 patients it was combined with transpupillary thermotherapy (TTT). RESULTS: A complete remission was found in 62.6% of the patients and in 31.3% a stable disease with an average follow-up of 74.6 months. Above a top dose of 120 Gy only in one of 95 patients continuous tumour growth after treatment was observed. Useful vision could be preserved in 51.5% of the patients. The initial tumour prominence and top dose strongly correlated with treatment outcome. CONCLUSIONS: Ruthenium application for uveal melanomas with the doses we have used is successful, with a substantial number of patients having their eyes preserved, their tumour controlled and their vision retained. Further improvements can be obtained with ruthenium irradiation with lower maximal scleral doses combined with TTT.

Serotoninergic status in patients with hereditary vascular retinopathy syndrome.

AIM/BACKGROUND: In a new autosomal dominant syndrome (which the authors called hereditary vascular retinopathy (HVR)) cerebral ischaemia, Raynaud's phenomenon, and migraine are the most striking features. As serotonin (5-HT) is known to play a role in vasospastic processes, Raynaud's phenomenon, and migraine they wondered whether the serotoninergic status in patients with HVR is different. Therefore, it was decided to investigate some serotoninergic variables in these patients. METHODS: The study was conducted in 12 patients with HVR, 10 relatives, and 19 healthy controls. The levels of intraplatelet and plasma 5-HT were measured, as well as the plasma levels of its precursor amino acid tryptophan and the ratio of tryptophan to the large neutral amino acids, which compete with the transport of tryptophan through the blood-brain barrier. RESULTS: In both the patients with HVR and in nine relative the concentrations of 5-HT in plasma and platelets were significantly lower than in controls. The plasma levels of tryptophan and the tryptophan ratio were also found to be lower in the patient group compared with the control group, but not in the relatives. CONCLUSION: The observed alterations in 5-HT and its precursor tryptophan strongly suggest the existence of a malfunctioning of the serotoninergic system in the HVR syndrome.

Lens transmission by fluorophotometry after brachytherapy and thermotherapy of choroidal melanoma.

We studied the effect of transpupillary thermotherapy (TTT) by a diode laser at 810 nm combined with episcleral ruthenium-106 plaque treatment (106Ru) on lens transparency in patients with choroidal melanoma. Lens transmission of blue-green light was measured by fluorophotometry in 17 patients treated with 106Ru treatment and TTT (measured 0.36 years after treatment), 12 patients treated with 106Ru alone (measured 19 years after treatment) and 25 age-matched healthy controls. Differences in lens transmission were not significant between treated and untreated fellow eyes (p > 0.15) nor between patient and control eyes (p > 0.25). TTT of choroidal melanoma combined with 106Ru plaque irradiation did not have a significant effect on the lens transparency up to 6 years after treatment.

Transpupillary thermotherapy: results in 50 patients with choroidal melanoma.

OBJECTIVE: To evaluate the efficacy and safety of transpupillary thermotherapy in treating choroidal melanoma. METHODS AND PATIENTS: To perform transpupillary thermotherapy, infrared diode laser energy at 810 nm was used with a beam diameter of about 3 mm and 1-minute exposure time. All 50 patients had choroidal melanoma. We performed transpupillary thermotherapy in 21 tumors that had responded insufficiently to 800 Gy ruthenium 106 brachytherapy; it was combined with 800 Gy106Ru brachytherapy for 10 tumors greater than 5 mm in height and with 600 Gy for 19 tumors 5 mm or less in height. RESULTS: All but 1 tumor exhibited reduction in tumor height within a mean follow-up of 20.5 months (range, 6-49 months). In 41 eyes (82%), the tumor flattened completely. Visual acuity was 20/60 or better in 43 eyes (86%) before treatment and in 14 eyes (28%) at the last examination because of radiation vasculopathy. Neovascular glaucoma developed in 1 eye, and total retinal detachment developed in 2 eyes. Tumor recurrence was observed in 1 patient. CONCLUSIONS: Although long-term results are necessary to properly appraise this new therapy, transpupillary thermotherapy may be useful as a complementary modality to brachytherapy.

Histopathological findings in human choroidal melanomas after transpupillary thermotherapy.

AIMS: The effect of transpupillary thermotherapy (TTT) on human choroidal melanomas was investigated by means of histopathology. METHODS: Before enucleation TTT was performed in 11 eyes with a xenon are photocoagulator with a red filter or a diode laser at 810 nm. The exposure time was 1 minute; the estimated temperature at the top of the tumour was about 65 degrees C. RESULTS: Seven of 11 tumours developed necrosis to a maximum depth of 3.9 mm with a sharp demarcation between the necrotic and the viable part of the tumour. The depth correlated with penetration of heat into the tumour. Scattered small haemorrhages in the transitional zone between the necrotic and the viable part of the tumour were observed in three eyes but large haemorrhages were absent. Ocular media were not affected owing to the low rate of absorption of radiation at 810 nm. TTT did not cause significant scleral damage. Intrascleral tumour cells with a viable appearance were observed in one eye, where the tumour was almost totally necrotic. CONCLUSION: Results show that TTT has potential as a conservative therapeutic treatment for choroidal melanomas.

Function and morphology of the retinal pigment epithelium after light-induced damage.

The purpose of this study was to determine the threshold energy for light-induced functional damage of the retinal pigment epithelium at various wavelengths. Retinas of 58 pigmented and 21 albino rabbits were exposed to low intensity broadband blue light (400-520 nm), yellow light (510-740 nm), and narrowband blue light (408, 417, 439, 455, 485, 501 nm, respectively; deltalambda = 10-13 nm). The intensity values were 50, 280, and 5 mW x cm (-2), respectively, and the illumination time was 0.5 up to 5 h. The cumulative dose of light energy was calculated from these data (J x cm(-2)). The blood-retinal barrier dysfunction was evaluated in vivo using fluorophotometry to measure the leakage of fluorescein into the vitreous after intravenous injection and in vitro using light and electron microscopy after an in vivo intraarterial injection of horseradish peroxidase (HRP). The threshold energy for fluorescein leakage was 50 J x cm (-2) for blue light and 1,600 J x cm(-2) for yellow light. After broadband blue light exposure, the HRP reaction product was seen in the cytoplasm of the retinal pigment epithelium (RPE) cells and in the subretinal space but only if fluorescein leakage had been observed. Threshold energy and fluorescein leakage as a function of light energy were similar for albino and pigmented rabbits (P > 0.5). Only after yellow light exposure in excess of 3,700 J x cm(-2) was fluorescein leakage found. In that case complete disruption of the RPE was seen, but no HRP was observed in the RPE cytoplasm. Of the narrow-band blue light exposures, only that at lambda = 418 nm caused a significant increase in fluorescein leakage; the threshold energy was 18 J x cm(- 2). Blue light was found to be at least 30 times more efficient than yellow light in causing dysfunction of the blood-retinal barrier. The most efficient wavelength was 418 nm, corresponding with the absorption spectrum of cytochrome c oxidase. Melanin seemed to play no role. The presence or absence of melanin in the RPE appeared to have no influence on the threshold energy.

Familial central serous retinopathy.

PURPOSE: To study the familial occurrence of central serous retinopathy (CSR). METHODS: We pooled data from eight eye clinics in Western Europe. RESULTS: We collected 11 families that each had two to four members with CSR. In 10 families siblings and in one family a mother and son were affected. Sixty percent of the patients were male and 40% female. CSR was found in 55 (92%) of 60 eyes, 44 (80%) showing a chronic course. In 25 patients (83%) both eyes were affected. Most recent visual acuity was 0.5 or less in 17 (39%) and 0.2 or less in 8 (18%) of the eyes with chronic CSR. CONCLUSION: Our findings of familial occurrence and a chronic disorder that is progressive, diffuse, and bilateral suggest an inborn disposition to develop a clinically manifest disintegration of the retinal pigment epithelium in adulthood.

Light and electron microscopic findings on experimental melanomas after hyperthermia at 50 degrees C.

The effect of hyperthermia, 50 degrees C applied for 5 min, on the development of lesions in hamster Greene melanomas was investigated. Hyperthermia was induced by a laser that produced radiation at 780-880 nm. Hamster melanomas were also examined after arrest of the blood circulation to differentiate between heat-induced lesions and those caused by ischaemia due to vascular occlusion. Tumours were removed 5 and 30 min and 1, 3, 6 and 24 h after thermotherapy. The cytotoxic effects of heat and ischaemia were examined by light and electron microscopy. Hyperchromatic nuclear staining, the first hyperthermia-induced lesion, was detected in the superficial layers of the tumour 5 min after heat treatment. The lesions had progressed to severe pyknosis and extended into deeper layers of the tumour 1 h after hyperthermia. At 24 h necrosis was observed at a depth of 6 mm. The hyperthermia-induced lesions differed markedly from the ischaemia-induced lesions, in that the latter showed early mitochondrial damage but nuclear pyknosis did not become manifest until 3 h after arrest of the blood circulation.

Transpupillary thermotherapy in choroidal melanomas.

OBJECTIVE: To determine safety and efficacy of transpupillary thermotherapy (TTT) as a new treatment for choroidal melanoma. METHODS AND PATIENTS: To perform TTT, diode laser energy at 810 nm was used with a beam diameter of 1.5 to 4.5 mm for a 1-minute exposure. All 12 patients had choroidal melanoma. Six had had insufficient response to ruthenium 106 (106Ru) brachytherapy. Three patients with tumors more than 5 mm in height were treated simultaneously with 106Ru and TTT. Three patients with juxtapapillary or macular tumors were treated by TTT only. RESULTS: All but one tumor exhibited a reduction of tumor height in a follow-up period of 3 to 14 months. Side effects were minimal. Severe visual loss occurred in two patients due to radiation retinopathy, in two patients whose foveas were included in the TTT area, and in one patient resulting from a serous retinal detachment that extended over the posterior pole. CONCLUSIONS: Treatment with TTT may be useful as a complementary modality to brachytherapy. A longer follow-up period is required for final evaluation.

Analysis of tear fluid proteins in insulin-dependent diabetes mellitus.

Secretory immunoglobulin A, lactoferrin, lysozyme and tear specific pre-albumin were analyzed in stimulated tear fluid of 25 diabetic patients without retinopathy and in 29 diabetic patients with (pre) proliferative retinopathy using high performance liquid chromatography. Results were compared to those obtained in 26 healthy controls to determine the effect of diabetes mellitus on the exocrine function of the main lacrimal gland. Sodium dodecyl sulfate polyacrylamide gel electrophoresis onto minigels was performed on 20 tear samples for verification of high performance liquid chromatography fractions recorded. The mean total protein values in tear fluid (Bradford assay) of diabetics without retinopathy, with retinopathy and healthy controls did not differ significantly (mean in mg/ml +/- SD: 6.4 +/- 2.2, 5.9 +/- 2.0 and 5.7 +/- 1.7, respectively; Mann-Whitney; p > 0.02). High performance liquid chromatography showed an increased secretory immunoglobulin A and decreased peak 5 OD280 (+56% and -38%, respectively; p < 0.02) in patients without retinopathy, whereas in patients with retinopathy lysozyme was increased (+27%; p < 0.01) and tear specific pre-albumin and peak 5 OD280 decreased (-24% and -42%, respectively; p < 0.04), when compared to healthy controls. These inconsistent differences do not uniformly suggest an exocrine dysfunction of the main lacrimal gland in diabetic patients.

Possibilities and limitations of radioimmunoscintigraphy and conventional diagnostic modalities in choroidal melanoma.

A prospective clinical study to assess the value of immunoscintigraphy with a monoclonal antibody (MoAb) against high molecular weight melanoma associated antigen (225.28S) was performed in 43 patients with choroidal melanoma; in six patients with a lesion suspected of being choroidal melanoma, and in seven patients with a benign lesion simulating a choroidal melanoma. The results of immunoscintigraphy in choroidal melanoma were compared with results of conventional diagnostic modalities like ultrasonography and fluorescein angiography. Planar scintigraphy showed a detection rate of 49% which is comparable with other studies. The detection with scintigraphy was correlated to the size of the choroidal melanoma. The use of single photon computed tomography did not increase the sensitivity of immunoscintigraphy. Ultrasonography yielded a correct diagnosis in 37 of 42 melanomas (88%). With fluorescein angiography a correct diagnosis was obtained in 11 of 30 melanomas (36.6%). The value of immunoscintigraphy with MoAb 225.28S in small choroidal melanomas is limited; its reliability increases in large tumours. Immunohistochemistry with MoAb 225.28S showed antigen expression in 95% of the stained tissue specimens of choroidal melanoma.

Blue-light-induced dysfunction of the blood-retinal barrier at the pigment epithelium in albino versus pigmented rabbits.

The purpose of this study was to determine the role of epithelial melanin in blue light phototoxicity of the retina. The first manifestation of the phototoxicity has been shown to be a breakdown of the blood-retinal barrier at the retinal pigment epithelium. The blood-retinal barrier function of six New Zealand albino rabbits was compared to that of four pigmented chinchilla rabbits after exposure to broad-band blue light (400-520 nm). Additionally, the spectral sensitivity of blood-retinal barrier dysfunction was determined by exposing 15 New Zealand albino rabbits to narrow-band blue light with peak intensity at lambda = 408 nm, 418 nm, 439 nm, 455 nm and 485 nm (bandwidth: 11.7-13.5 nm). The blood-retinal barrier function was evaluated with vitreous fluorophotometry. Ultrastructural changes and permeability of the retinal pigment epithelium for horseradish peroxidase were evaluated in the albino rabbits with electron microscopy. Exposure to broad-band blue light up to 832 J cm-2 demonstrated the blood-retinal barrier of albino and pigmented rabbits to be equally sensitive. Electron microscopy of albino rabbits exposed to above-threshold energy demonstrated an increase of inclusion bodies in the retinal pigment epithelium and vacuolation of the cytoplasm. Transcellular passage of intra-arterially administered horseradish peroxidase through the pigment epithelium into the subretinal space was seen. The narrow-band exposures demonstrated that light of 439 nm was more effective than the light of other wavelengths in inducing barrier dysfunction in albino rabbits. This implies that chromophores absorbing at 439 +/- 6 nm were responsible for the phototoxicity in albino rabbits. The results indicate that melanin does not have a damaging nor a protective role in phototoxicity since (1) the presence of melanin is not essential for blue-light-induced photochemical damage to the blood-retinal barrier at the retinal pigment epithelium, and (2) protection from this sort of damage is not greater in melanin containing epithelia than in non-melanin containing epithelia.