Gerasimos Anastassiou

The possible role of radiofrequency radiation in the development of uveal melanoma.

There are few epidemiologic studies dealing with electromagnetic radiation and uveal melanoma. The majority of these studies are exploratory and are based on job and industry titles only. We conducted a hospital-based and population-based case-control study of uveal melanoma and occupational exposures to different sources of electromagnetic radiation, including radiofrequency radiation. We then pooled these results. We interviewed a total of 118 female and male cases with uveal melanoma and 475 controls matching on sex, age, and study regions. Exposure to radiofrequency-transmitting devices was rated as (a) no radiofrequency radiation exposure, (b) possible exposure to mobile phones, or (c) probable/certain exposure to mobile phones. Exposures were rated independently by two of the authors who did not know case or control status. We used conditional logistic regression to calculate odds ratios (ORs) and 95% confidence intervals (95% CIs). We found an elevated risk for exposure to radiofrequency-transmitting devices (exposure to radio sets, OR = 3.0, 95% CI = 1.4–6.3; probable/certain exposure to mobile phones, OR = 4.2, 95% CI = 1.2–14.5). Other sources of electromagnetic radiation such as high-voltage lines, electrical machines, complex electrical environments, visual display terminals, or radar units were not associated with uveal melanoma. This is the first study describing an association between radiofrequency radiation exposure and uveal melanoma. Several methodologic limitations prevent our results from providing clear evidence on the hypothesized association.

Prognostic value of clinical and histopathological parameters in conjunctival melanomas: a retrospective study

Aim: To determine prognostic factors for recurrence of disease and tumour related mortality in patients with conjunctival melanoma. Methods: A retrospective analysis of clinical and histopathological data of 69 patients with histologically verified conjunctival melanoma. Results: As univariate analysis showed, significant risk factors for the development of recurrence were: irregular pigmentation (RR = 2.0, p = 0.0007), incomplete surgical excision (RR = 3.5, p = 0.008), tumour invasion deeper than in substantia propria (RR = 3.9, p = 0.008), and presence of epithelioid tumour cells (RR = 2.9, p = 0.05). For tumour related mortality a significantly increased risk was found for tumour location in palpebral conjunctiva, caruncle, plica, or fornices (RR = 5.9, p = 0.001), for tumour infiltration deeper than the substantia propria (RR = 5.5, p = 0.001), for incomplete surgical excision (RR = 4.4, p = 0.05), and for nodular or mixed (nodular and superficial) growth pattern of the tumours (RR = 1.2, p = 0.002). The use of an adjuvant therapy for the surgical excision of the melanomas had no statistically significant influence upon the development of recurrent disease nor upon the tumour related mortality. Conclusion: These data present similar clinical and histopathological risk factors for patients with conjunctival melanoma as reported previously. The present study also addresses the failure of retrospective studies on conjunctival melanoma to prove the efficacy of a supplementary therapy to surgical excision.

The prognostic value of cyclin D1, p53, and MDM2 protein expression in uveal melanoma.

Malignant uveal melanoma is the commonest primary intraocular tumour in adults. It metastasizes frequently and 50% of patients die within 10 years of diagnosis. The expression of cyclin D1, p53, and MDM2 in uveal melanoma and their relationship to metastasis‐free 5‐year survival was determined, in order to investigate whether these proteins help to distinguish those patients with a favourable prognosis from those with a poorer one. Ninety‐six eyes enucleated for uveal melanomas were immunohistochemically analysed for the protein expression of cyclin D1 and related cell‐cycle markers, p53 and MDM2. The evaluation of the specimens was undertaken by two independent pathologists without knowledge of the outcome. Statistical analysis of clinical, morphological, and immunohistological features was performed. A ‘favourable outcome’ was defined as survival of at least 5 years after diagnosis, without metastases (n=57). An ‘unfavourable outcome’ was defined as death from metastases within the first 5 years after diagnosis of uveal melanoma (n=39). Cyclin D1 positivity (>15% positive tumour cells) as well as p53 positivity (>15% positive tumour cells) was associated with an unfavourable outcome (for cyclin D1: odds ratio=4.2, 95% confidence interval 1.5–11.8, p=0.006; for p53: odds ratio=3.2, 95% confidence interval 1.1–9.3, p=0.03). In addition, cyclin D1 positivity was associated with the presence of extraocular extension of the tumour (p=0.01), with the mixed or epithelioid cell type (p=0.02), and with the tumour cell MIB‐1 positivity (p=0.0001). MDM2 immunoreactivity of the tumour cells showed a potential correlation with clinical outcome (odds ratio=2.1, 95% confidence interval 0.8–5.8, p=0.13). Multiple logistic regression models showed that cyclin D1 positivity is an independent prognostic factor after control for other prognostic markers. The expression of cyclin D1 in uveal melanoma is associated with a more aggressive course and histologically unfavourable disease. This could serve as a further independent prognostic factor in uveal melanoma. Copyright

Expression of the Cell Adhesion Molecules ICAM-1, VCAM-1 and NCAM in Uveal Melanoma: A Clinicopathological Study

To investigate the relationship between the expression of the cell adhesion molecules intercellular cell adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and neural cell adhesion molecule (NCAM) in uveal melanoma and the metastatic spread in the first 5 years after diagnosis, we performed a hospital-based case-control study with human tissue from 90 patients who underwent enucleation for primary uveal melanoma (iris melanoma excluded). Thirty-five patients developed metastasis within the first 5 years, and 55 patients lived metastasis-free for at least 5 years after enucleation. The paraffin-embedded and formalin-fixed globes were studied by immunohistochemistry with monoclonal antibodies for ICAM-1, VCAM-1 and NCAM. A strong ICAM-1 positivity (more than 75% of the tumor cells stained positive) was detected in 73 tumors (81%). The expression of 75% or less ICAM-1 positive cells in tumors was strongly associated with the development of metastases (odds ratio: 7.5, p = 0.001). Multiple logistic regression models showed that ICAM-1 is an independent risk factor for metastasis even after control for important prognostic markers like extraocular growth, ciliary body involvement, scleral infiltration and cell type. VCAM-1 was expressed in 24 out of 88 tumors (27.3%) and NCAM only in 14 out of 87 tumors (16%). Only spindle cells stained positive with anti-NCAM. NCAM and VCAM-1 expression was not related to metastasis. Our results show that the loss of ICAM-1 expression is associated with an increased risk of metastasis within the first 5 years after diagnosis.

Loss of heterozygosity of 1p in uveal melanomas with monosomy 3

Gains and losses of chromosomes 1, 3, 6 and 8 are nonrandom chromosomal aberrations in uveal melanoma. Monosomy 3 is the most frequent abnormality and is associated with poor prognosis. To identify regions of allelic loss on the short arm of chromosome 1 and to investigate if these alterations contribute to uveal melanoma progression, we performed microsatellite analysis of 10 loci in 70 uveal melanomas. A total of 51 tumors were obtained from patients with clinical follow‐up data, 19 tumors were from recent patients without follow‐up. Loss of heterozygosity (LOH) of at least 1 marker was more frequent in tumors with monosomy 3 (40%) than in tumors with disomy 3 (10%). In particular, loss of the entire short arm of chromosome 1 was only observed in tumors with monosomy 3 (p = 0.0001). By comparing the extent of 1p LOH in all tumors with monosomy 3, we were able to define a smallest region of overlap (SRO) of approximately 55 Mb, which is flanked by markers D1S507 and D1S198. On the basis of our data and published cytogenetic data, we propose that 1p31 harbors genes involved in the progression of uveal melanoma with monosomy 3.

Assessment of genomic instability in breast cancer and uveal melanoma by random amplified polymorphic DNA analysis

Some types of cancer have been associated with abnormal DNA fingerprinting. We used random amplified polymorphic DNA (RAPD) to generate fingerprints that detect genomic alterations in human breast cancer. Primers were designed by choosing sequences involved in the development of DNA mutations. Seventeen primers in 44 different combinations were used to screen a total of 6 breast cancer DNA/normal DNA pairs and 6 uveal melanoma DNA/normal DNA pairs. Forty‐five percent of these combinations reliably detected quantitative differences in the breast cancer pairs, while only 18% of these combinations detected differences in the uveal melanoma pairs. Fourteen (32%) and 12 (27%) primers generated a smear or did not produce any band patterns in the first and second cases, respectively. Taking into account the ability of RAPD to screen the whole genome, our results suggest that the genomic damage in breast cancer is significantly higher than in uveal melanoma. Our study confirms other reports that the molecular karyotypes produced with random priming, called amplotypes, are very useful for assessing genomic damage in cancer.

Quality of life in patients with malignant choroidal melanoma after radiotherapy

BackgroundPatient-orientated endpoints have attracted little attention in patients with malignant choroidal melanoma. This study was conducted to explore the long-term effects of malignant choroidal melanoma and radiotherapy on QOL by means of a differentiated and modular QOL approach, including global QOL, social support, and mental health, in comparison with sociodemographically matched healthy controls.MethodsA random sample of 100 outpatients treated by radiotherapy were asked by mail to take part in a psychodiagnostic study [instruments: Short-Form 36 Health-Survey (SF-36), Symptom Checklist-90-Revised, German Social Support Questionnaire]. The same instruments were applied to a healthy control group, which was matched to patients with regard to age, gender, and vocational situation.Results93 patients (average age 61.2 years) responded at an average of 5.5 years (±3.7) after diagnosis. Visual acuity in the affected eye decreased considerably from diagnosis (0.49±0.30) to participation in the study (0.09±0.21). Compared with healthy controls, patients reported on average statistically significantly lower global QOL (SF-36), whereas social support and mental distress did not differ. Frequencies of clinically relevant mental distress were significantly higher in patients than in controls (35.5% vs. 16.1%). Mental distress was associated with poorer visual acuity, but not with the extent of loss of visual acuity or number of follow-up treatments.ConclusionPatients with choroidal melanoma suffer from low long-term global QOL, and every third patient suffers from relevant mental distress. Regular screening for mental distress should be implemented along with psychological counseling. Additional follow-up treatment does not seem to induce mental distress.

The design and the dosimetry of bi-nuclide radioactive ophthalmic applicators.

A novel type of applicator for the treatment of intra-ocular tumors has been developed, based on the two radionuclides 106Ru/106Rh and 125I. The dose distribution of this ophthalmic plaque combines advantageous features of both radionuclides and can be optimally adapted to a tumor thickness in the range 6.5-9 mm, a size which is beyond the dosimetric limitations of the 106Ru/106Rh plaque therapy. Compared with 125I plaques a bi-nuclide plaque allows to maintain the tumor dosage while the dose in the irradiated volume outside of the target volume is significantly reduced. Consequently, radiosensitive structures within the eye can be spared more effectively. Dedicated methods have been developed for the dosimetry of this plaque. These methods are based on our own extensive dosimetric investigations with plastic scintillators. The precondition was the availability, developed in recent years, of a more accurate determination of the absolute dose rate to water of beta- and low energy emitters.

Expression of HSP 90, PTEN and Bcl-2 in conjunctival melanoma

Background In conjunctival melanoma, little is known about the tumour biology and protein-expression patterns. In this study, the authors analysed the expression of the antiapoptotic oncoprotein B cell leukaemia/lymphoma-2 protein (Bcl-2), the tumour-suppressor phosphatase and tensin homologue deleted on chromosome ten (PTEN), and the heat-shock-protein HSP-90 in conjunctival melanoma (CoM) and conjunctival nevi (CoN) by immunohistochemistry (IHC). Material and methods IHC was performed on 70 samples of CoM and 12 samples of CoN. Expression patterns between the diagnosis groups were compared. A receiver operating characteristic analysis was performed to determine the diagnostic value of the antigens. Results HSP-90 (p<0.0001) and PTEN (p=0.001) showed the potential to differentiate between CoM and CoN. Bcl-2 expression was higher in CoM than in CoN (p=0.04). The loss of nuclear PTEN expression was more pronounced in the malignant melanomas than in CoN (p=0.02). Tumours located at unfavourable sites (fornix, palpebral conjunctiva, caruncle) that had developed recurrences expressed almost twice as much HSP-90 than recurrence-free tumours. Conclusions Conjunctival melanocytes differentially express Bcl-2, HSP-90 and PTEN, depending on their entity. HSP-90- and PTEN expression may add relevant information for the differentiation between conjunctival melanoma and nevi.

Phenotypical characteristics, lifestyle, social class and uveal melanoma

PURPOSE To investigate potential risk factors of uveal melanoma, including phenotypical characteristics, eye burns, social class, smoking and alcohol consumption. METHODS A hospital-based and population-based case-control study of uveal melanoma was carried out from 1995 through 1998 and the results pooled. A total of 118 patients (59 men and 59 women) with uveal melanoma and 475 controls matching on sex, age and study regions were interviewed. Conditional logistic regression was used to calculate odds ratios (OR) and 95% confidence intervals (95% CI). RESULTS There was an elevated risk for blue or grey iris color (OR = 3.0, 95% CI 1.5–6.0). Red or blond hair color at age 20 was slightly associated with an increased risk for uveal melanoma (OR = 1.5, 95% CI 0.9–2.4). There was no elevated risk for a history of eye burns (OR = 1.1, 95% CI 0.5–2.4). CONCLUSIONS Among the potential risk factors studied, only the phenotypical characteristics showed an association with the risk of uveal melanoma.