Tumor parameters predict the risk of side effects after ruthenium-106 plaque brachytherapy of uveal melanomas.

BACKGROUND: To report on radiation-related side effects and complications after ruthenium-106 plaque brachytherapy of uveal melanomas. METHODS: Medical records of 143 eyes with uveal melanoma, treated by ruthenium-106 brachytherapy between 1997 and 2012 at a single center, were analyzed. We evaluated the occurrence of radiation-related side effects on the anterior and posterior segment of the eye. The influence of patient, tumor and treatment parameters on outcome was analyzed by multivariate time to event analysis considering competing risks. RESULTS: The median overall follow-up was 37.9 months. After treatment, the estimated risk at 12, 24 and 48 months for developing anterior segment complications was 25.3%, 37.5% and 50.3% for cataract formation and 5.4%, 6.4% and 8.1% for secondary glaucoma, respectively. The estimated risk for the occurrence of posterior segment complications 12, 24 and 48 months after treatment was 3.1%, 6.7% and 18.3% for radiation retinopathy, 18.3%, 27.1% and 42.6% for radiation maculopathy and 16.5%, 21.0% and 32.8% for radiation neuropathy, respectively. The risk of an increase in retinal detachment after treatment was 14.7%, 14.7% and 17.4% at 12, 24 and 48 months, respectively. The risk of vitreous hemorrhage occurring after treatment was 6.2%, 8.1% and 12.7%, and the risk of tumor vasculopathy was 15.4%, 17.4% and 19.0%. Scleral necrosis was observed in one patient. CONCLUSION: Radiation-related side effects and complications are common among patients treated with ruthenium brachytherapy for uveal melanoma. However, the risk for those largely depends on individual tumor parameters. Before treatment, patients should be informed of their specific risks to develop various side effects. Patient information before treatment should cover not only general information about the treatment and possible complications and side effects but should also give details on the specific risks of the patient in her individual situation. This also includes elucidating the patient's individual resources and expectations and her willingness for long-term regular follow-up examinations and secondary adjunct treatments.

Iris Freckles a Potential Biomarker for Chronic Sun Damage.

Purpose: To investigate the role of sunlight exposure in iris freckles formation. Methods: We prospectively examined volunteers attending a skin cancer screening program conducted by ophthalmologists and dermatologists. Frequency and topographical variability of iris freckles were noted and associated with behavioral and dermatologic characteristics indicating high sun exposure. Results: Six hundred thirty-two participants (n = 360; 57% female) were examined. Mean age of all participants was 38.4 ± 18.4 years (range, 4-84 years). Of all individuals, 76.1% (n = 481) exhibited at least one iris freckle. Most freckles were observed in the inferior temporal quadrant. The presence of iris freckles was associated with higher age (participants with iris freckles: 41.8 ± 16.8 years versus participants without iris freckles: 27.6 ± 19.2 years), a high number of sunburns during lifetime (>10: 31% vs. 19%), sunlight-damaged skin (26% vs. 11%), presence of actinic lentigines (72% vs. 45%), and a high total nevus body count (>10; 78% vs. 67%). Conclusions: The association of iris freckles, behavioral factors, and dermatologic findings, as well as the topographical distribution, indicate that sunlight exposure may trigger the formation of iris freckles. The evaluation of iris freckles offers an easily accessible potential biomarker, which might be helpful in indicating sun damage on the skin associated with cutaneous malignancies. Furthermore, the evaluation of iris freckles could also be helpful in understanding the role of sunlight in several ophthalmologic diseases.

A Unifying Concept of Uveal Pigment Cell Distribution and Dissemination Based on an Animal Model: Insights into Ocular Melanogenesis.

Pigmented cells are derived from neural crest cells, which migrate along the peripheral nerve sheets into their specific final region. During their migration, cells progressively acquire pigment-producing capabilities, maturation, and the shape of melanocytes. These insights, along with specific clinical characteristics of melanocytic nevi, have led to new concepts of cutaneous, periocular, and iris nevogenesis. To further elucidate the specific ocular embryogenic melanoblast distribution and dissemination - that could explain the distinct distribution of uveal melanocytic neoplasms - we investigated the ocular pigmentation of dogs affected by a specific mutation called Merle, which results in either pigment- (wild type) or non-pigment- (mutated type) producing cells. Based on our observations, we propose a unifying concept of uveal pigment cell distribution and dissemination, which postulates melanoblast migration and maturation following the trigeminal V1 branch and, later, their entrance into the eye along the ciliary nerves and their finest iris branches. Our concept provides an explanation not only for the specific distribution of ocular melanocytic lesions, including uveal and iris nevi, but also for the different locations depending on the metastatic potential of the ocular melanoma. Though speculative, the higher metastatic potential of posterior uveal melanomas compared to iris melanomas may be related to a less differentiated stage in the maturation of migrating melanocytes in the posterior segment compared to the anterior segment of the eye. However, there is a need of further studies focusing on cell differentiation markers of melanocytes at different locations in the eye.

Ruthenium-106 plaque brachytherapy for uveal melanoma.

BACKGROUND: To report on local tumour control, eye preservation and visual outcome after ruthenium-106 brachytherapy for uveal melanoma. METHODS: Medical records of 143 eyes with uveal melanoma, treated by ruthenium-106 brachytherapy between 1997 and 2012 at one single centre, were included. Primary outcome measures were local tumour control, eye preservation and visual outcome. The influence of patient, tumour and treatment parameters on outcome was analysed by time to event analysis and competing risk regression. RESULTS: The median overall follow-up was 37.9 months. Tumour control: recurrent tumour growth was observed in 17 patients. The estimated local tumour recurrence rate at 12, 24 and 48 months after irradiation was 3%, 8.4% and 14.7%, respectively. The only significant risk factors for tumour recurrence were age (p=0.046) and reduced initial visual acuity (VA, p=0.045). No significant difference could be shown for tumour size or tumour category (T1-T2 vs T3-T4), and for any other tumour or treatment parameters (including combined transpupillary thermo-therapy (TTT)).Eye preservation: The likelihood of keeping the eye 12, 24 and 48 months after irradiation was 97.7%, 94.7% and 91.8%, respectively. Most significant risk factors for secondary enucleation were initial VA (p<0.001), tumour height (p=0.002) and tumour category (p=0.015). VISION: The chances of keeping VA of 20/200 or better at 1, 2 and 5 years after treatment were 86.4%, 80.8% and 61.7%, respectively. Patients receiving sandwich-TTT showed significantly worse visual outcomes. CONCLUSIONS: Ruthenium-106 brachytherapy appears to be a useful treatment regarding tumour control, eye preservation and visual function. Adjunct sandwich therapy resulted in worse visual outcome.

New insights into oculodermal nevogenesis and proposal for a new iris nevus classification.

BACKGROUND/AIMS: To gain more knowledge about presence and dermatological associations of iris nevi as well as possible pathways involved in the formation of iris nevi. METHODS: We conducted a prospective, interdisciplinary observational study. Presence, morphology, topography of iris and cutaneous nevi as well as factors indicating sun-exposure were noted. RESULTS: A total of 632 participants including 360 (57%) women were examined. Of those, 26 subjects revealed 27 iris nevi. According to the current classification, all iris nevi were judged as solitary with the majority of them (n=20; 74%) located in the lower quadrants. In six (22.2%) cases we noted a peculiar 'incomplete sectoral pattern'; these nevi were located close to the pupil, were larger and had a more elongated, triangular shape compared with those located distant from the pupil, which appeared smaller and more roundish. Notably, five of these six peculiar (incomplete sectoral) iris nevi were located on the upper half of the iris. CONCLUSIONS: Based on our findings we propose classifying iris nevi into sectoral, incomplete sectoral and solitary subtypes. Additionally, we set up a hypothetic concept of oculodermal nevogenesis suggesting a time-dependent embryogenic alteration affecting the normal melanocyte location, migration and maturation along peripheral nerve sheets. Our new concept explains well the morphology and extension of benign melanocytic proliferations in the ocular region as well as their relation to uveal melanoma.

Local tumour control and eye preservation after gamma-knife radiosurgery of choroidal melanomas.

BACKGROUND/AIMS: To report on local tumour control and eye preservation after gamma knife radiosurgery (GK-RS) to treat choroidal melanomas. METHODS: A total of 189 patients with choroidal melanoma were treated with GK-RS, with treatment doses between 25 and 80 Grays. The main outcome measures of our retrospective analysis were local tumour control, time to recurrence, eye retention rate and the reason for and time to secondary enucleation. Patient-associated, tumour-associated and treatment-associated parameters were evaluated as potential risk factors. RESULTS: Local tumour control was achieved in 94.4% of patients. The estimated tumour control rates were 97.6% at 1 year, 94.2% at 5 years and 92.4% at 10 years after treatment. Recurrence was observed between 3.1 months and 60.7 months post-treatment (median: 13.5 months). Advanced tumour stage (Tumour, Node, Metastasis (TNM) 3-4) was the most important risk factor for recurrence (Fine-Gray model; subhazard ratio, SHR: 3.3; p=0.079). The treatment dose was not related to tumour recurrence. The eye preservation rate was 81.6% at 5 years after treatment, remaining stable thereafter. Twenty-five eyes (14.1%) had to be enucleated at between 17 days and 68.0 months (median: 13.9 months) after GK-RS, and advanced tumour stage (Cox model; p=0.005), treatment dose (p=0.048), pretreatment visual acuity (p=0.016), and retinal detachment (p=0.027) were risk factors for requiring enucleation. CONCLUSIONS: GK-RS achieved a high tumour control rate, comparable to linear accelerator-based radiotherapy. Advanced TNM stage was a predictive risk factor for tumour recurrence and for secondary enucleation after GK-RS. Lower treatment doses were unrelated to tumour recurrence, although they were associated with an improved eye retention rate.

Influence of single-fraction Gamma-Knife radiosurgery on ocular surface and tear function in choroidal melanoma patients.

AIM: To evaluate ocular surface and tear function in patients with choroidal melanoma treated with single-fraction radiosurgery. METHODS: 36 patients (median age 62 years; range 26-84 years) were enrolled between 2001 and 2006 at a single institution. They were treated with the Leksell Gamma Knife in one fraction with a median dose of 30 Gy (range 25-35 Gy). In both eyes of all patients treated subjective symptom score (visual analogue scale) was evaluated, central corneal sensitivity testing, Schirmer test without local anaesthesia, and corneal and conjunctival staining were performed before therapy and 3, 6, 12, 24 and 36 months thereafter. The respective untreated fellow eye served as control. RESULTS: Three months after radiosurgery, the subjective dry eye symptom score and lissamine green staining score of the ocular surface were significantly higher in the treated eyes compared with the fellow eyes (p<0.001, p=0.028, respectively). After 12 months, a significant difference between the treated and the fellow eyes in corneal sensitivity (p=0.041) and corneal fluorescein staining (p=0.002) was found when compared with pretreatment values. After 24 months Schirmer test values without local anaesthesia were significantly reduced in the treated eyes vis-à-vis untreated fellow eyes and pretreatment values (p=0.004). The dose applied to the lacrimal gland was significantly correlated to ocular surface staining scores (p=0.001) and Schirmer test values (p=0.026) at 24 months after irradiation. CONCLUSIONS: Stereotactic single-fraction Gamma-Knife radiotherapy of choroidal melanoma with a median dose of 30 Gy significantly affected ocular surface and tear function and increased dry eye symptoms and signs.

Visual acuity after Gamma-Knife radiosurgery of choroidal melanomas.

BACKGROUND/AIMS: To report on conservation of visual acuity after Gamma-Knife radiosurgery of choroidal melanoma. METHODS: A total of 189 patients with choroidal melanoma were treated with Gamma-Knife stereotactic single-fraction radiosurgery at a single institution between June 1992 and May 2010. The main outcome measure of our retrospective analysis was conservation of pretreatment visual acuity of 20/40 or better, 20/200 or better and counting fingers (CF) or better, over time of follow-up. Patient, tumour and treatment parameters were evaluated as potential risk factors for visual loss. RESULTS: Five years after treatment, the actuarial probability of keeping visual acuity better than 20/40, 20/200 and CF was 13%, 14% and 36%, respectively. The majority of patients (84.7%) encountered a deterioration of vision after treatment. The most important risk factors for visual loss were tumour height, longest basal diameter, distance to the optic disk and/or foveola, and retinal detachment before treatment. Treatment dose, and patient characteristics (age, sex, concurrent systemic diseases) were less important. Local tumour control rate was 94.4% after a median follow-up of 39.5 months. CONCLUSIONS: Visual outcome after single-fraction Gamma-Knife radiotherapy is comparable with linear accelerator (LINAC) based fractionated stereotactic radiotherapy, inferior to proton beam radiotherapy, and depends primarily on tumour size, location and pre-existing retinal detachment.

Intraoperative medialization of medial rectus muscle as a new endoscopic technique for approaching intraconal lesions.

BACKGROUND: Intraconal tumors of the orbit are rare entities and surgical treatment is challenging. Endoscopic transnasal approaches to the orbit offer a new perspective for surgery, although only few reports exist in literature. This study displays the Graz experience with endoscopic approaches to intraorbital tumors between 2006 and 2010 introducing a novel endoscopic technique for temporary medialization of the medial rectus muscle facilitating access to the orbital cone. METHODS: A retrospective analysis of patients' charts was performed. RESULTS: For approaches to intraconal lesions a special endoscopic temporary medialization technique of the medial rectus muscle through applying transseptal sutures was developed. Six patients (four male and two female patients) have been included in this study presenting with intraconal/intraorbital tumors. Three patients underwent endoscopic surgery for two hemangiomas and one Schwannoma, respectively, and three patients were successfully biopsied endoscopically revealing one malignant melanoma, one malignant lymphoma, and one optic glioma each. Both hemangiomas were completely resected without any deterioration of vision. The Schwannoma was partially resected with postoperative imaging showing no tumor progression within 3 months. No intraoperative complications occurred. Five cases were performed with computer assisted surgery using CT/MR fusion navigation. CONCLUSION: Although technically challenging, the endoscopic approach to the orbit, even for intraconal lesions with medialization of the medial rectus muscle, can be safe and promising for well-selected cases. Good postoperative results and sufficient material acquisition for proper histological examination can be obtained. Advantages are good visualization of the surgical field and avoidance of external scars. Limitations to endoscopic techniques are tumors in the lateral superior and lateral inferior quadrant of the orbit.

Surgical smoke management for minimally invasive (micro)endoscopy: an experimental study.

BACKGROUND: The aim of this study was to investigate the use of surgical smoke-producing procedures such as laser ablation or electrosurgery in minimally invasive microendoscopic procedures. This study proposes a technical solution to efficiently remove surgical smoke from very small endoscopic cavities using microports as small as 20 G (0.9 mm) in diameter. METHODS: The experimental laboratory study used small, rigid, transparent plastic cavity models connected with tubes and pressure sensors to establish an endoscopic in vitro laboratory model. A Kalium-Titanyl-Phosphate (KTP) laser with a 0.5-mm fiber optic probe was used to produce smoke from bovine scleral tissue in the cavity. Endoscopic gas insufflation into the model was generated by pressurized air and a microvalve. A laboratory vacuum pump provided smoke and gas suction via a microvalve. A self-built control and steering system was utilized to control intracavital pressure during experimental insufflation and suction. RESULTS: Problems related to smoke-generating processes, such as laser vaporization or electrocautery, in small closed cavities were first analyzed. A theoretical and mechatronic laboratory model was established and tested. Intracavital pressure and gas flow were measured first without and then with smoke generation. A new construction design for the suction tube was proposed due to rapid obstruction by smoke particles. CONCLUSIONS: Surgical smoke evacuation from endoscopic cavities that are as small as 2 cm in diameter via minimally invasive ports as small as 20 G (0.9 mm) in diameter may be safe and efficient if sufficient gas exchange is provided during smoke generation by laser or electrosurgical instruments. However, maintaining a low and constant pressure in the cavity during gas exchange and adopting a special construction design for the suction tube are essential to provide an excellent view during the surgical maneuver and to minimize potential toxic side effects of the smoke.

Impact of dose rate on clinical course in uveal melanoma after brachytherapy with ruthenium-106.

BACKGROUND AND PURPOSE: It has been suggested that the actual dose rate of an irradiating source may be a distinct influencing factor for the biological effect after brachytherapy with ruthenium-106 for uveal melanoma. The purpose of this study was to investigate a hypothesized impact of the dose rate on the clinical and echographic course after brachytherapy. PATIENTS AND METHODS: In total, 45 patients were included in this retrospective study. According to the actual dose rate, two groups were defined: group 1 with a dose rate <4 Gy/h and group 2 with a dose rate >or=4 Gy/h. Regarding age, tumor height, basal diameter, scleral and apical dose, differences between the groups were not significant. Clinical parameters, including early and late side effects, and echographic courses were compared. RESULTS: A significantly lower metastatic rate was found in group 2. Using univariate Cox proportional hazards regression, only dose rate predicted metastatic spread significantly (p<0.05), while in a multivariate analysis, using age at the time of treatment, greatest tumor height and greatest basal diameter as covariates, the variable dose rate was of borderline significance (p=0.077). Patients in group 2 had more early side effects and more pronounced visual decline, but these differences were of borderline significance with p-values of 0.072 and 0.064, respectively. CONCLUSION: These data suggest that a higher dose rate may confer a lower risk for metastatic spread, but may be associated with more side effects and more pronounced visual decline.

Retinoblastoma: a proposal for a multimodal treatment concept for intraocular retinoblastoma in Austria.

Retinoblastoma is the most common intraocular malignancy in childhood. If confined to the globe and managed with current treatment strategies, more than 90% of children survive with preservation of vision in at least one eye, even in bilateral retinoblastoma. Enucleation of the involved eye in unilateral retinoblastoma and of the more involved eye in bilateral disease, together with external beam radiotherapy in advanced bilateral retinoblastoma, formed the two cornerstones of treatment for many years and led to an increase in survival to over 90%. In the early 1990s the extent of the risk of second cancers in the field of radiation became known, the risk increasing by 10% per decade of life. As a consequence, chemotherapy-based regimens were developed as alternative treatments. During the past ten years retinoblastoma treatment has fundamentally changed, with a trend away from enucleation and external beam radiotherapy towards conservative treatments aiming at preservation of the affected globe(s) in selected patients. Systemic neoadjuvant chemotherapy induces tumor regression (chemoreduction), and residual regressed tumor is then treated focally with, for example, transpupillary thermotherapy, cryotherapy and plaque radiotherapy (consolidation). Between 1984 and 2004, 27 patients were treated at the department of ophthalmology in collaboration with the department of pediatrics at the Medical University of Graz. Before 2001, the affected eyes of all patients with unilateral retinoblastoma were enucleated (10 of 10), as were 6 of 7 of the more involved eyes of patients with bilateral disease. A globe-sparing strategy was introduced in 2001 and since then eligible patients have been treated with chemoreduction and focal therapy; 2 of 5 eyes with unilateral disease were salvaged, and both eyes of a patient with bilateral disease. We discuss current treatment options and present a proposal for the management of intraocular retinoblastoma in children in Austria, the Austrian retinoblastoma study, RB A-2003.

Five-year results of prognostic value of tyrosinase in peripheral blood of uveal melanoma patients.

Tyrosinase-based reverse transcriptase-polymerase chain reaction (RT-PCR) is a method for the detection of circulating melanoma cells in peripheral blood. To our knowledge, no long-term studies on the prognostic impact of tyrosinase PCR in uveal melanoma have yet been reported. In this prospective, non-randomized, observational cohort study, we included 41 patients with uveal malignant melanoma. RT-PCR for tyrosinase was performed in each patient before and after treatment. A clinical follow-up was performed for each patient for at least 5 years, including chest X-ray, serum liver enzyme determination, ultrasound of the liver and bone scintigraphy. The PCR results, age of the patients, tumour size, tumour location, tumour therapy, internal reflectivity, histology, development of distant metastasis and survival rate during follow-up were analysed. At the time of diagnosis, tyrosinase messenger RNA (mRNA) in peripheral blood, suggesting the presence of circulating melanoma cells, was detected in 16 of the 41 patients. Sixty-nine percent of the PCR samples with a positive result prior to therapy revealed a negative result after therapy. The internal reflectivity of the tumour (P=0.021) and the 5-year survival (P=0.023) showed a statistically significant association with positive PCR. It can be concluded that tyrosinase RT-PCR is a sensitive method for the detection of melanoma cells in peripheral blood. This study indicates that the presence of tumour cells in peripheral blood correlates with 5-year survival. Our results suggest a prognostic value of this method. Nevertheless, prospective analysis of a larger cohort is needed to determine the ultimate value of RT-PCR for tyrosinase in blood testing.

Lymph node metastases arising from uveal melanoma.

Since the eye lacks lymphatic vessels, uveal melanomas primarily metastasize hematogenously. Here we report the case of a patient with ciliary body ring melanoma who developed lymph node metastases after a fistulating glaucoma operation. A 40-year-old female Caucasian patient presented with unilateral pigment dispersion. Pigment dispersion glaucoma was diagnosed and since the intraocular pressure could not be managed with topical medication, transscleral cyclophotocoagulation and two trabeculectomies had to be performed. Due to enlargement of the pigmented iris mass and cell deposits in the chamber angle, a ciliary body ring melanoma was presumed and the eye enucleated. Histology confirmed the diagnosis of "ciliary body ring melanoma". Six months after enucleation the patient presented multiple metastases including ipsilateral preauricular and submandibular lymph node metastases. The patient died two months later. Lymph node metastases arising from ciliary body melanomas are very rare. Tumor seeding through the trabeculectomy site into the bleb and then via conjunctival lymphatic vessels might be the crucial factor for this pathway of metastases. Therefore, in cases of unilateral pigment dispersion, malignancy should be excluded before fistulating operations are performed.