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Malignant melanoma of the uvea is the most common primary malignant tumor in the eye. We aimed to analyze GNAQ and GNA11 mutations in uveal melanomas using formalin-fixed, paraffin-embedded material and correlate the results with clinicopathological parameters. Tumor tissue was microdissected followed by amplification of GNAQ exon 4 and 5, GNA11 exon 4 and 5, and finally analyzed by Sanger sequencing. A total of 64.4 GNA11/GNAQ mutations, including ten yet unreported, were found. Two cases showed multiple mutations. Overall survival was significantly shorter in the uveal melanoma cohort with GNAQ exon 5 mutation. In concordance with previous studies, high frequencies of mutations in GNAQ or GNA11 were detected. Interestingly, in about 20% of UM, not yet reported mutations in GNAQ or GNA11 were seen. Rarely, uveal melanoma may harbor double mutations in GNAQ and/or GNA11. Recent data imply, that implementation of GNAQ/GNA11 mutation analysis in routine diagnostic procedures might be helpful for future therapeutic decisions.

To evaluate uveal melanoma cell activity and pathologic features after stereotactic CyberKnife radiosurgery in specimens from five patients. Specimens from five patients treated by CyberKnife radiosurgery in three fractions were included in this study. Because of persistent retinal detachment in 3 patients, tumour endoresection was performed at four, seven and ten month after CyberKnife radiosurgery. At nine and twelve months after treatment, enucleation of the eye globe was performed in 2 patients because of secondary tumour bleeding and missing regression. After histomorphological analysis and determination of Ki67-proliferation index, DNA cytophotometry, fluorescence in-situ hybridization evaluation for chromosome 3 loss, GNA11and GNAQ mutation analysis were performed. Four of the five tumours included in this study showed variable radiation-induced morphologic changes in the form of enlargement of cells and nuclei, cytoplasmic vacuolisation and nuclear fragmentation. The DNA content of a large fraction of tumour cells was hypoploid. On the other hand, single strikingly hyperchromatic melanoma cells showed marked aneuploidy. The proliferation fraction in the three endoresected tumours was very low (<1%), but it was elevated in the enucleation cases. Monosomy 3 was detected in two of the endoresection cases, but none of the enucleation cases. None of the patients experienced a local tumour recurrence, but two of the patients developed liver metastasis. Many melanoma cells seemed to be vital within the first 6 months after CyberKnife radiosurgery, but obvious radiation-induced morphologic changes, including tumour necrosis, hypoploid DNA content plus low Ki-67 index could indicate sublethal cell damage.

Objective: The results of register studies suggest an association between Parkinson's disease (PD) and melanoma. We studied the frequency and profile of early markers of PD in patients with malignant melanoma., Methods: 100 participants were enrolled in a prospective observational study, of whom 65 had a history of high-risk cutaneous (n=53) or uveal (n=12) melanoma (31 women; age, 61.2±14.9 years) and another 35 served as control participants (19 women; 54.6±20.5 years). Participants underwent assessments of motor function (Unified PD Rating Scale; keyboard tapping test), olfactory function, colour vision, depressive symptoms, the Non-Motor Symptoms Questionnaire, and transcranial brain sonography. Raters were blinded to the diagnosis and clinical data of study participants., Results: Patients with melanoma showed increased frequency of substantia nigra hyperechogenicity and prodromal motor and non-motor features of PD, especially asymmetric motor slowing and apathy. Hyposmia and colour vision disturbance were, however, infrequent. Larger echogenicity of substantia nigra correlated with lower serum iron in patients with melanoma, similar to previously reported findings in PD, and independently from the earlier findings, with lighter skin pigmentation. Substantia nigra hyperechogenicity, combined with motor asymmetry or hyposmia, was present at baseline in all participants with mild or definite parkinsonism diagnosed after 1 year. Parkinsonism was specifically related to melanoma location at the sun-exposed skin of the head or neck., Conclusions: History of melanoma was associated with increased prevalence of prodromal markers of PD. Their predictive value needs to be established in long-term investigations. The similarity of serum iron characteristics found in patients with melanoma and PD deserves further research., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Immunoscintigraphy (IS) was performed on 101 patients with space occupying intraocular lesions including choroidal melanomas (85), choroidal naevi (11), non-melanoma metastases (three), and other melanoma simulating lesions (two). Scintigraphic images with conventional and emission computer tomography techniques were obtained after the intravenous injection of 99mTc-labelled F(ab')2 fragments of monoclonal antibody (MoAb) 225.28S directed against the high molecular weight-melanoma associated antigen (HMW-MAA). Immunohistochemistry was performed on sections of four out of 10 melanoma-containing eyes to confirm MoAb binding. IS demonstrated positive scans in 66 out of 85 choroidal melanomas, offering a sensitivity of 78%. Sensitivity was dependent on the lesion size. True negative results were obtained in 15 out of 16 non-melanoma lesions (specificity 94%). False positive antibody accumulation was found in one patient with a post-traumatic subretinal haemorrhage. Immunohistochemistry demonstrated positive MoAb 225.28S binding in all melanoma sections. In summary IS offered substantial sensitivity and specificity in the differentiation of intraocular lesions, particularly choroidal melanomas, naevi, and metastases. In combination with other diagnostic procedures such as ultrasound echography and fluorescein angiography IS proved to be a valuable method in the diagnosis of choroidal melanoma.

Histological data indicate the importance of tumor vascularization as a determinant of the biological behavior and the response to radiotherapy in choroidal melanoma. Duplex ultrasound and color Doppler imaging, the combination of B-mode ultrasound and pulse-waved Doppler analysis, were used to measure quantitatively neovascular blood flow in 31 patients with choroidal melanoma. Follow-up studies (20 patients) were performed to investigate the change of tumor blood flow in choroidal melanomas after radiotherapy. Blood flow was detected in 30 out of 31 melanomas (size 3.1-17.8 mm) within the tumor and at the tumor base with a mean peak systolic frequency of 1.0 kHz (range 0.3-2.7 kHz), a mean end diastolic frequency of 0.3 kHz (range 0.1-1.0 kHz), and a mean frequency of 0.7 kHz (range 0.2-1.3 kHz). Two and six months after 106Ru/106Rh beta-ray application, 19 patients showed a significant decrease in peak systolic frequency. This occurred with and in advance of the decrease in the tumor size. In one patient, a rising maximum systolic frequency after radiotherapy marked a recurrent tumor growth. Results indicate that the quantitative measurement of tumor blood flow by duplex ultrasound and color Doppler imaging may be a new diagnostic modality for monitoring the effectiveness of radiotherapy in choroidal melanoma.

The tumor response to radiotherapy depends highly on the local oxygen concentration, which is governed by the tumor's microcirculatory network. The aim of this prospective study was to quantitate the neovascular blood flow in human choroidal melanomas prior to 106Ru/106Rh irradiation and during a 1-year follow-up period. Pulsatile blood flow was elicited by means of duplex and color Doppler ultrasound in 54 of a total of 55 untreated melanomas with a mean peak systolic frequency of 1.0 kHz (range 0.3-2.7 kHz). The neovascular blood flow decreased significantly 4 and 6 months after beta-irradiation. No intrinsic tumor vascularity was detected 8 and 12 months after treatment. In 3 patients, a rising peak systolic frequency occurred following radiotherapy in advance of recurrent tumor growth. Results indicate that the noninvasive quantitation of neovascular blood flow in irradiated choroidal melanomas by pulsed Doppler ultrasound offers a new diagnostic modality for assessing tumor recurrence.

Duplex ultrasound imaging combines the investigation of morphological structures and hemodynamic data analysis. In ophthalmology the technique permits a non-invasive evaluation of retinal and orbital vascular disorders for diagnostic purposes as well as the quantitative measurement of vascularity in intraocular and orbital tumors. We present current approaches to quantitate velocity patterns in the ophthalmic and retinal artery by Duplex ultrasound imaging. Results and clinical applications of Duplex ultrasonography studies designed to characterize the vascular network in intraocular and orbital tumors are reviewed.

The therapeutic effects of heat (43 degrees C) as an adjunct to irradiation have generated increasing interest in oncology. It was shown that hyperthermia in addition to irradiation may allow for a radiation dose reduction which may be followed by a decreased irradiation - induced ocular morbidity rate. Intraocular malignant tumors offer excellent conditions for heat application since tumor volumes are small and heat can be locally generated to the tumor through the overlying sclera. Additionally, the vascular supply of intraocular melanoma is restricted to the choroid, limiting the blood flow related heat loss. At present, both experimental and clinical thermoradiotherapy for intraocular malignancies is performed by several investigators including Astrahan (Los Angeles), Coleman (New York), Mieler (Milwaukee), Finger and Packer (Manhasset), Swift (San Francisco), Lagendijk (Utrecht), Alberti (Essen) as well as our group in Munich. Both the advantages and disadvantages of the different technical modalities including our newly designed microwave hyperthermia system are discussed and it is emphasized that thermoradiotherapy at present is almost exclusively experimental. However, it is anticipated that future technology of electromagnetic heat induction will increase the existing therapeutic potential of thermoradiotherapy in intraocular malignancies.

Antibodies against tumor-associated antigens ("tumor markers") can be used for the diagnosis of malignant tumors. Eight different monoclonal antibodies, that can recognize tumor-associated antigens of dermal melanomas, were tested in cryostat sections of uveal melanomas. The uveal melanomas showed antigenic differences (e.g., gangliosides) and common antigens (e.g. high molecular weight melanoma-associated antigen) in comparison to dermal melanomas. The implications of these results for diagnosing and even treating uveal melanomas are discussed.

Ultrasonically induced hyperthermia (4.75 MHz) and proton irradiation (160 meV) were evaluated alone and combined to treat experimental choroidal melanoma in 58 rabbit eyes. Threshold tumoricidal doses were established for each modality. Therapy was performed combining subthreshold doses of heat and radiation. Focused ultrasonic energy via an external beam was found to deliver well-localized heat to an intraocular tumor. Ectopic temperature elevations due to soft-tissue-bone interfaces were alleviated by modifying beam alignment. The results indicate that hyperthermia (43 degrees C for one hour) potentiated the tumoricidal effects of radiation, while sparing normal ocular structures. Therefore, we believe that experimental hyperthermia is suitable as an adjuvant treatment modality. This shows that ultrasound hyperthermia has the potential to increase the efficacy of proton irradiation by lowering radiation doses and thus decreasing posttreatment ocular morbidity in human intraocular malignancies.

Immunoscintigraphy of malignant tumours has become an encouraging tool in nuclear medicine. Early diagnosis of small lesions is mandatory for successful cancer therapy. The scintigraphic detectability of small lesions (less than 1 cm in diameter) by immunoscintigraphy is shown in 39 patients suffering from ocular tumours (37 malignant choroidal melanoma, two benign choroidal naevi) using 99Tcm-labelled F(ab')2 fragments of the anti-melanoma monoclonal antibody 225.28S; this antibody recognizes the high molecular weight melanoma-associated antigen. No adverse effects were observed. In terms of true-positive results, single photon emission computed tomography (SPECT) proved to be superior to planar scans (73% versus 41% true-positive results).

Since more than a century ago, temperatures above 40 degrees C have been known to be effective in cancer treatment. Since that time numerous studies have documented that hyperthermia alone causes tumor regression and that the therapeutic effect depends on the amount and duration of heat delivered to a malignant tumor. However, after it was shown that heat combined with irradiation or chemotherapy potentiates the effect of hyperthermia, both thermoradiotherapy and thermochemotherapy were applied in experimental and clinical studies in several medical specialties. In ophthalmic oncology both retinoblastoma and uveal melanoma are treated by irradiation combined with local hyperthermia. In the present paper the use of ultrasound and microwave energy as locally applicable heat sources in intraocular malignancies is described and their suitability discussed. As is the case with malignant skin tumors and malignant tumors of the gastrointestinal and urogenital systems, malignant ocular tumors are accessible to externally applied heat and can thus be treated well by ultrasound and microwave hyperthermia. On the basis of experimental and clinical results gained with both ultrasound and microwave energy the advantages and drawbacks of these two technical modalities in intraocular tumor therapy are pointed out.