J. A. Oosterhuis

Transpupillary thermotherapy (TTT) by infrared irradiation of choroidal melanoma.

We studied the destructive effect of hyperthermia at sub-photocoagulation level of 45–60 °C on melanomas. Optimal conditions for spreading of heat into tissue are a wavelength of 700–900 nm, a temperature of 45–60 °C, an exposure time of 1 minute or more, and a beam diameter of several millimeters. In hamsters with subcutaneous melanomas we obtained a tumour necrosis of 6 mm depth at 60 °C and one minute exposure time. We performed transpupillary thermotherapy (TTT) with a diode laser at 810 nm in patients with choroidal melanomas prior to enucleation. Treatment is based on the fortunate situation that irradiation at this wavelength combines optimal tissue penetration with a low absorption by clear ocular media of 5% or less. In 3 TTT-treated eyes histopathology showed a depth of necrosis of 0.9, 3.4, and 3.9 mm. TTT may become a new useful treatment modality for choroidal melanoma but its ultimate value has yet to be assessed.

Corneal epithelial permeability after instillation of ophthalmic solutions containing local anaesthetics and preservatives

The effect of the local anaesthetics oxybuprocaine (OBu) and tetracaine (Tetra) and the preservatives chlorhexidine (CH) and benzalkonium chloride (BAK) on corneal epithelial permeability was studied by fluorophotometry in normal human eyes. Five instillations of one drop ophthalmic solution of the compounds were administered to one eye at 2-minute intervals; a control solution was instilled into the fellow eye. The increase in corneal epithelial permeability, expressed as the permeability ratio between the treated and control eye, was not significant after instillation of the anaesthetics. The preservatives and the combination OBu + CH increased corneal epithelial permeability significantly (P less than 0.05). OBu + BAK and Tetra + BAK increased permeability to a far greater extent (P less than 0.005).

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 (106Ru) 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 106Ru; tumours ⩽5 mm thick received a contact dose of 600 Gy 106Ru. TTT was repeated in case of incomplete tumour regression after combined therapy. Results: Complete tumour regression was obtained in 45 patients. It required one, two, or three TTT sessions in 32, 11, and two patients, respectively. In tumours ⩽3 mm thick complete flattening was achieved significantly faster than in 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.

Primary choroidal and cutaneous melanomas, bilateral choroidal melanomas, and familial occurrence of melanomas.

The medical history of a patient with a familial atypical multiple more melanoma syndrome revealed a combination of rare findings: occurrence of a melanoma in both eyes, development of 3 separate skin melanomas, and occurrence of other malignancies in the family. Another patient developed a choroidal and a skin melanoma, but there were no known malignancies in the family. A third patient with a choroidal melanoma had a mother with an ethmoidal melanoma.

A Simple Method for Determination of Corneal Epithelial Permeability in Humans

A simple method for the determination of human corneal epithelial permeability to fluorescein is presented. The method consists of applying a 1% sodium fluorescein solution to the cornea for 8 minutes by means of an eye bath, rinsing the eye, and measuring corneal fluorescence by fluorophotometry. The permeability value is calculated from the corneal fluorescein concentration immediately after the bathing period. Mean permeability value determined in 86 eyes of 46 volunteers aged 15 to 67 years (mean 30.9 years) was 0.038 nm/s +/- 0.017 SD. No significant correlation with age was found (corr. coeff. = 0.17, P = 0.28). The reproducibility was within 10%.

In vivo Assessment of Lens Transmission for Blue-Green Light by Autofluorescence Measurement

A simple quantitative and reproducible method for evaluating lens transmission (lambda = 490 and 530 nm) is described. It is based on the measurement of autofluorescence in the anterior and the posterior part of the lens by means of a fluorophotometer, assuming an about equal fluorescence quantum efficiency in both parts. Consequently any difference in fluorescence between both parts can be attributed to a loss of exciting and fluorescent light in the lens. For both wavelengths, the average lens transmission is determined by this method in a normal population as a function of age.

Transpupillary thermotherapy of choroidal melanoma with or without brachytherapy: a dilemma.

Transpupillary thermotherapy (TTT) is a new approach to the treatment of choroidal melanoma with heat. The early treatment results seem favourable with regard to local tumour control and retained visual acuity; no early metastasis was found. The reported rate of complications is low. 3 The heat treatment is performed with a temperature calculated at 45–65°C, induced by an infrared diode laser (810 nm) with a large beam diameter (3 mm) and a long exposure time of 1 minute per application. These factors promote a deep penetration of heat into the choroidal melanoma. The result is tumour necrosis up to 3.9 mm deep and occlusion of blood vessels in the treated area as shown on histopathology. Depending on the pigmentation of the tumour, the energy is raised or lowered stepwise until the desired eVect occurs. The tumour is treated by overlapping applications extending beyond the margin of the tumour. The exposure time should not be shortened to less than 1 minute, as it takes 40 seconds to reach a temperature at subcoagulation level. TTT is performed as an outpatient procedure and can be easily repeated. Treatment results can be evaluated in several ways. The outcome is favourable when the choroidal melanoma develops into a scar on ophthalmoscopic examination, substantial regression of the tumour thickness is seen on ultrasonography together with an increased reflectivity on the diagnostic A-scan, and hypofluorescence is visible in the treated area on the early and late phases of the fluorescein angiogram. TTT is not indicated in melanoma patients with severe media opacities, in patients with insufficient dilatation of the pupil, or in elevated, peripherally located melanomas. Simultaneous use of TTT with brachytherapy in the management of melanomas is called “sandwich therapy”, where the eVect of TTT is maximal at the top of the tumour and brachytherapy eYciently treats the base of the tumour. 2 4 Combining both treatments has several advantages. It enabled us to treat patients with tumours thicker than 5 mm, generally the maximum height for ruthenium106 brachytherapy. 2 InsuYcient melanoma regression and/or recurrences after a combined treatment might be retreated with TTT alone. The combination might also lead to a decreased radiation dose of the isotope used in brachytherapy. In principle, TTT can also be applied as the sole therapy. A satisfactory local tumour control is reported in the early years after TTT as sole therapy for small choroidal melanomas. TTT as sole therapy seems especially attractive in treating small choroidal melanomas in and around the posterior pole. Visual outcome may be better after TTT than after brachytherapy because the laser beam, but not the radiation beam delivered by the radioactive plaque, can be focused. As the macular capillaries are very radiosensitive to brachytherapy, this may finally result in radiation maculopathy with a considerable loss of central vision. However, after extramacular applications of sole TTT, macular complications such as transient cystoid macular oedema may be also seen. A dense scotoma is generally produced by TTT at the time of application, whereas a scotoma after brachytherapy usually does not develop for up to a year or several years. If heat treatment is performed as sole therapy, eVective treatment of the sclera over the tumour is as important as treatment of the tumour itself because intraand episcleral tumour invasion is present in, respectively, 55.7% and 8.2% of patients with medium and large tumours. In a group of 21 patients with enucleated small melanomas, 17 showed scleral ingrowth on histopathological examination. Intrascleral melanoma cells surviving treatment might be a focus for tumour recurrence, which is associated with a two to threefold higher risk of metastasis. This is evident from the results after photocoagulation treatment of choroidal melanomas showing a high rate of tumour regrowth. This might be attributed to the low depth of photocoagulation penetration, insuYcient to destroy the intrascleral melanoma cells. In TTT as sole therapy, the question arises as to whether the eVect of the heat induced by TTT to the choroidal melanoma is identical to the eVect of the heat to the possible melanoma cells in the sclera. In one eye, intentionally enucleated after experimental TTT, total tumour necrosis up to the sclera was visible on histopathological examination. Despite heat damage to the inner layers of the sclera which was evident from scleral oedema and necrosis of sclerocytes, a cluster of tumour cells with a viable aspect was located near the inner border of the sclera. A recent clinicopathological report on two cases of recurrent juxtapapillary choroidal melanoma after TTT revealed tumour cells appearing histopathologically intact and presumably viable. One patient was insuYciently treated with TTT because of cataract, another patient was treated with TTT and brachytherapy. Interpreting these data, we have to keep in mind that a pathologist is often unable to guess viability of melanoma cells in an enucleated eye after any treatment, especially in an undertreated eye. Unfortunately, no sensitive clinical techniques evaluate the eVect of TTT on intrascleral and episcleral tumour cells, their destruction, and the early development of extrascleral recurrences. To reduce the risk of insuYcient treatment of the sclera and because episcleral tumour recurrences rarely develop as a late complication of brachytherapy, one may consider combining TTT with brachytherapy (the sandwich therapy). TTT remains an investigative procedure until long term results are available. In the meantime we have to choose between TTT as sole or combined treatment for patients with choroidal melanoma.

Blood aqueous barrier permeability versus age by fluorophotometry

Values of the diffusion coefficient into the anterior chamber and the blood aqueous barrier permeability as a function of age were determined by fluorophotometry in 58 healthy volunteers. The diffusion coefficient was calculated from aqueous fluorescein concentration and the time integral of non-protein bound fluorescein concentration in plasma. Blood-aqueous barrier permeability was calculated using diffusion coefficient values, the area of fluorescein inflow into the anterior chamber and anterior chamber volume. Values for diffusion coefficient as well as permeability were found to be independent of age between 13 y and 72 y (lin. corr. coeff. 0.2, p = 0.11) mean values were 4.7 .10(-4) min-1 +/- 1.5. 10(-4) SD and 15.4 nm/s +/- 4.8 SD, respectively. The difference between permeability values calculated from fluorophotometric scans at 30, 55 and 65 mins. after fluorescein injection was less than 5% and the 7 months reproducibility was within 15%. There was no significant correlation between simultaneously measured values of blood-retinal and blood-aqueous barrier permeability (lin. corr. coeff. 0.13, p = 0.4).

Diffuse retinal pigment epitheliopathy.

19 patients showing the features of diffuse retinal pigment epitheliopathy, as described by Zweng and Little, were studied. Diffuse retinal pigment epitheliopathy resembles both pigment epithelial detachment and central nervous choriopathy, but can be differentiated by the following characteristic features: widespread distribution of small pigment epithelial detachments, little or no leakage visible on the fluorescence angiogram, extensive pigmentary changes, chronic course with exacerbations and remissions, and fair visual prognosis.

Hematoporphyrin derivative photoradiation treatment of experimental malignant melanoma in the anterior chamber of the rabbit

The effects of Hematoporphyrin Derivative Photoradiation Therapy (HpD-PRT) on Greenes amelanotic melanoma implanted into the anterior chamber of rabbits have been examined by biomicroscopy, fluorescein angiography and histopathology. The tumors were irradiated 24 hours after injection of HpD when both the porphyrin concentration and the porphyrin ratio tumor/iris were highest. Blanching and shrinkage of tumors were the first signs of tumor destruction. Fluorescein angiography as soon as 20 minutes after irradiation found non-perfusion of blood vessels at the tumor surface. Histopathological observation of vessel wall destruction is in agreement with this finding. Subtotal tumor necrosis was demonstrated in 12 out of 13 experiments. Necrosis was complete in only one experiment. Clusters of viable tumor cells were found when shielded behind pigment, at the tumor periphery and around some blood vessels. Lens damage was observed after irradiation when the iris pigment epithelium was disorganized by the tumor. The iris contained high concentrations of porphyrin and PRT resulted in depigmentation, non-perfusion of the capillary bed, damage to larger iris vessels and finally atrophy. Light intensity measurements were performed in vivo during PRT. The average effective attenuation coefficient at 630 nm was 0.56 mm-1 at the beginning of irradiation and 0.87 nm-1 at the end. Results indicate that as a treatment HpD-PRT in itself might be insufficient but may prove to be an effective modality in combination with other tumor destructive therapies.