Unilateral Fourth Nerve Palsy due to Presumed Metastatic Melanoma.

ABSTRACT: An 81-year-old man with a history of metastatic melanoma presented with sudden onset of painless, binocular vertical diplopia. The clinical examination was consistent with a right fourth nerve palsy. An MRI of the head revealed a mass dorsal to the right tectum at the level of the inferior colliculus. An MRI just 4 months prior did not show a lesion in that location. An MRA of the head did not show an aneurysm. This is a rare case of an isolated fourth nerve palsy believed to be due to metastatic melanoma compressing the nerve along the dorsal midbrain.

Targeted radiotherapy of pigmented melanoma with 131I-5-IPN.

PURPOSE: There has been no satisfactory treatment for advanced melanoma until now. Targeted radionuclide therapy (TRNT) may be a promising option for this heretofore lethal disease. Our goal in this study was to synthesize 131I-N-(2-(diethylamino)ethyl)-5-(iodo-131I)picolinamide (131I-5-IPN) and evaluate its therapeutic ability and toxicity as a radioiodinated melanin-targeting therapeutic agent. METHODS: The trimethylstannyl precursor was synthesized and labeled with 131I to obtain 131I-5-IPN. The pharmacokinetics of 131I-5-IPN was evaluated through SPECT imaging, and its biodistribution was assessed in B16F10 tumor models and in A375 human-to-mouse xenografts. For TRNT, B16F10 melanoma-bearing mice were randomly allocated to receive one of five treatments (n = 10 per group): group A (the control group) received 0.1 mL saline; group B was treated with an equimolar dose of unlabeled precursor; group C received 18.5 MBq of [131I]NaI; group D and E received one or two dose of 18.5 MBq 131I-5-IPN, respectively. TRNT efficacy was evaluated through tumor volume measurement and biology study. The toxic effects of 131I-5-IPN on vital organs were assessed with laboratory tests and histopathological examination. The radiation absorbed dose to vital organs was estimated based on biodistribution data. RESULTS: 131I-5-IPN was successfully prepared with a good radiochemistry yield (55% ± 5%, n = 5), and it exhibited a high uptake ratio in melanin-positive B16F10 cells which indicating high specificity. SPECT imaging and biodistribution of 131I-5-IPN showed lasting high tumor uptake in pigmented B16F10 models for 72 h. TRNT with 131I-5-IPN led to a significant anti-tumor effect and Groups D and E displayed an extended median survival compared to groups A, B, and C. The highest absorbed dose to a vital organ was 0.25 mSv/MBq to the liver; no obvious injury to the liver or kidneys was observed during treatment. 131I-5-IPN treatment was associated with reduction of expression of proliferating cell nuclear antigen (PCNA) and Ki67 and cell cycle blockage in G2/M phase in tumor tissues. Decreased vascular endothelial growth factor and CD31 expression, implying reduced tumor growth, was noted after TRNT. CONCLUSION: We successfully synthesized 131I-5-IPN, which presents long-time retention in melanotic melanoma. TRNT with 131I-5-IPN has the potential to be a safe and effective strategy for management of pigmented melanoma.

Orbital melanoma masquerading as a "Galloping haemangioma".

We describe a 32-year-old pregnant woman who was referred to our clinic after 6 weeks of observation elsewhere with a rapidly expanding orbital mass, proptosed globe and slowly decreasing of vision in her left eye. To our examination the patient presented with congested optic disc fine macular striae and some slight choroidal elevation without any retinal pigmentation. An MRI scan without contrast was performed, suggesting the signal charactheristics of an orbital mass consistent with a cellular lesion such as a cavernous hemangioma or a solitary fibrous tumour. Despite the benign-looking imaging, the fast-growing pattern of the lesion suggested a more sinister picture. A fine needle aspiration of the orbital mass was carried out, revealing the presence of an amelanotic melanoma. This case highlights the importance of considering the presence of a melanoma when there is a clear history of a rapid lesion progression.

Multiple simultaneous choroidal melanomas arising in the same eye: globe salvage by radiotherapy.

PURPOSE: Multiple choroidal melanomas arising in the same eye is a very rare entity, usually leading ophthalmologists to entertain other diagnoses. Historically, the only available treatment reported for this rare entity was enucleation. In this study we demonstrate in a series of patients with multiple simultaneous choroidal melanomas that eye salvage is possible using a variety of radiotherapy techniques. OBSERVATIONS: Both patients presented with two simultaneous choroidal melanomas in one eye. The first patient was only 30 years old and presented with two largely amelanotic tumours with large exudative retinal detachment. Cytology from fine needle aspiration biopsies from both tumours with immunohistochemistry confirmed two separate melanomas. Sequential radioactive iodine plaque brachytherapy led to regression of both tumours. The second, older patient's two tumours both had the typical appearance of choroidal melanoma and he underwent proton beam irradiation to the entire field leading to tumour regression. CONCLUSIONS: Multiple choroidal melanomas can rarely arise simultaneously in the same eye, and despite their variable appearance, a definitive diagnosis can be aided by cytology and immunohistochemistry in atypical-appearing cases. While all other previously reported cases have necessitated enucleation, we demonstrate that globe salvage is possible using either proton beam irradiation to the entire tumour field, or with sequential radioactive plaque brachytherapy.

BRACHYTHERAPY ALONE OR WITH NEOADJUVANT PHOTODYNAMIC THERAPY FOR AMELANOTIC CHOROIDAL MELANOMA: Functional Outcomes and Local Tumor Control.

PURPOSE: To compare visual outcomes and local tumor control between two groups of patients with amelanotic choroidal melanoma treated with brachytherapy alone, or neoadjuvant photodynamic therapy before brachytherapy. METHODS: Patients diagnosed with amelanotic choroidal melanoma were recruited for the study and divided into two groups: brachytherapy alone (Group A) and photodynamic therapy preceding brachytherapy (Group B). Patients of both groups were selected to be comparable. RESULTS: Twenty-six patients with amelanotic choroidal melanoma were enrolled in the study. Within Group B, 1 month after photodynamic therapy, ultrasonography showed reduction of tumor height in 11 patients (73.4%). The mean doses of irradiation to macula and optic nerve, at baseline were 74.37 and 52.07 Gy, whereas after photodynamic therapy there was a decrease of 17.26% (P = 0.008) and 21.22% (P = 0.025), respectively. In terms of visual acuity, a mean decrease of 14 ETDRS letters and 5 ETDRS letters was observed at 24 months follow-up, in Groups A and B, respectively (P = 0.001). CONCLUSION: Photodynamic therapy as neoadjuvant therapy before brachytherapy reduces tumor thickness in 73.4% of cases. As a result, a decrease of radiation toxic effects on visual function could be obtained, without compromising disease control.

Dramatic regression of amelanotic choroidal melanoma with PDT following poor response to brachytherapy.

Photodynamic therapy (PDT) has been used for treatment of choroidal neovascular membrane from exudative macular degeneration. Other applications include treatment of some intraocular tumors, such as choroidal hemangioma, vasoproliferative tumor, and choroidal osteoma. The authors report the effect of PDT for amelanotic choroidal melanoma. A 40-year-old woman with an amelanotic choroidal melanoma of 6.5 mm thickness showed poor response to iodine brachytherapy (80 Gy apical dose) with no reduction in thickness at 16 months of follow-up. There was prominent residual tumor. The amelanotic tumor was treated with verteporfin PDT using three overlapping spots (8,600 microns), with avoidance of the optic disc using standard treatment parameters. Dramatic tumor regression over 2 months to a completely flat scar (1.3 mm thickness) was documented and remained stable at 50 months of follow-up. Amelanotic choroidal melanoma with incomplete response following conventional plaque radiotherapy can be treated with verteporfin PDT for consolidation.

Treatment of an amelanotic melanoma using radiation therapy in a lesser Madagascar hedgehog tenrec (Echinops telfairi).

A 15-yr-old, male lesser Madagascar hedgehog tenrec (Echinops telfairi) presented with a mass caudal to the right ear. Cytology suggested a sarcoma. Surgical removal was attempted. Histology was consistent with a soft tissue sarcoma. The mass recurred within 331 days post operation. Radiation therapy was initiated. Computed tomography was used for staging in conjunction with three-dimensional computerized treatment planning software to permit accurate lesion localization and to optimize normal tissue sparing. A total dose of 6,480 cGy was administered in 24 fractions over 46 days. Transient hind limb paresis developed during the course of the radiation therapy, but resolved after 7 days with prednisone treatment. Minimal acute radiation toxicity was observed. The mass responded with at least a 90% reduction in volume following radiation treatment. The animal survived 266 days from the initiation of treatment. On necropsy, a small mass and granulation tissue were found at the site of the initial neoplasm, indicating good regional control of the tumor; however, extensive metastases to the spleen and liver were present. Immunohistochemically, the original, recurrent, and metastatic populations were strongly positive for HMB 45 and weakly positive for S-100, and the final diagnosis was metastatic amelanotic melanoma.

Metallo-naphthalocyanines as photothermal sensitisers for experimental tumours: in vitro and in vivo studies.

BACKGROUND AND OBJECTIVES: Photothermal sensitisation has been recently proposed as a novel approach for the treatment of solid tumours through the development of a therapeutic modality named photothermal therapy (PTT). The technique involves the use of high power pulsed laser irradiation and photosensitising agents with especially short lifetime (in the subnanosecond range) in the electronically excited states. This study aims to investigate the molecular features of the photosensitiser which optimise the photothermal activity. STUDY DESIGN/MATERIALS AND METHODS: Two octabutoxy-naphthalocyanines centrally coordinated with Pd(II) or Pt(II) ions were prepared by chemical synthesis and tested for their affinity and photothermal sensitisation activity toward a selected tumour cell line, namely B78H1 amelanotic melanoma. Irradiations were performed by using a Ti:sapphire laser operated in a pulsed regime (10 Hz, 30 nanosecond pulses, 120 mJ) at 809 nm (Pt) or 826 nm (Pd). The subcellular distribution pattern of the photosensitiser was also assessed by optical microscopy, while the nature of the photoinduced cell damage was determined by scanning electron microscopy. The results thus obtained provided a basis for subsequent in vivo studies, aimed at defining the phototherapeutic efficiency of the two metallo-naphthalocyanines: the photosensitisers were i.v. injected into C57BL/6 mice bearing a subcutaneously transplanted amelanotic melanoma and at 24 hours post-injection the tumour area was irradiated by the Ti:sapphire laser using the same protocol as above detailed. RESULTS: Both naphthalocyanines exhibited a high affinity for the amelanotic melanoma cells. The subcellular distribution pattern was modulated by the incubation time: after 48 hours incubation with 7.7 microM Pd- and Pt derivatives, the naphthalocyanine appeared to localise in specific sites with a gradual formation of aggregated clusters. Subsequent irradiation of the naphthalocyanine-loaded cells caused an extensive cell death; the photoinduced damage, as observed at the scanning electron microscope, mainly consisted in the formation of large endocellular holes consequent to the loss of cytoplasmic material. This scenario is typical of photothermal sensitisation processes. Lastly, both metallo-naphthalocyanines, and in particular the Pd(II) derivative, promoted an important response by the amelanotic melanoma, when the neoplastic tissue was irradiated by the pulsed Ti:sapphire laser. In certain cases, the photothermal treatment appeared to be curative. In all cases, the in vivo photodamage was confined within the tumour area with no detectable involvement of the perilesional tissues. CONCLUSION: PTT appears to act very efficiently at least on subcutaneous tumours. The technique can be used either in combination with photodynamic therapy (PDT) or as an alternative to PDT in those cases where the latter modality displays a limited efficacy, such as in the treatment of pigmented or poorly vascularised tumours.

Inhibition of melanogenesis as a radiation sensitizer for melanoma therapy.

Melanin pigment displays strong photo- and radioprotective properties, suggesting that inhibition melanogenesis could increase sensitivity of melanoma to ionizing radiation. We tested this concept in human melanoma cells cultured in either Ham's F10 medium to maintain amelanotic phenotype or DMEM to induce/stimulate melanin production, respectively; N-phenylthiourea (PTU) and D-penicillamine were used as an inhibitor of melanogenesis. Melanogenic activity was evaluated by visual inspection (color of cell pellets) or by measurement of tyrosinase (dopa oxidase) activity assay. Amelanotic cells or cells with various melanin content were exposed to gamma radiation and tested for viability and colony forming capability. Gamma radiation at doses of 2-15 Gy inhibited cell viability and colony forming efficiency in dose- and time-dependent manner, but pigmented melanoma cells were significantly more resistant to gamma radiation than nonpigmented cells (p < 0.05-0.001). Both PTU and D-penicillamine inhibited strongly tyrosinase activity and melanin production in melanoma cells (p < 0.05-0.001). Furthermore, inhibition of melanogenesis by PTU or D-penicillamine resulted in enhancement of melanoma cells sensitivity to killing by gamma rays. In conclusion, the results of these cell culture experiments give support to a clinical trial of pharmacologically induced decrease in melanin synthesis to enhance the efficacy of radiotherapy in advanced melanomas.

Improvement of the tumor-suppressive effect of boron neutron capture therapy for amelanotic melanoma by intratumoral injection of the tyrosinase gene.

Boron neutron capture therapy (BNCT) is successful when there is a sufficient (10)B concentration in tumor cells. In melanoma, (10)B-para-boronophenylalanine (BPA) accumulation is proportional to melanin-producing activity. This study was done to confirm enhancement of the tumor-suppressive effect of BNCT on amelanotic melanoma by intratumoral injection of the tyrosinase gene. D178 or FF amelanotic melanomas were implanted s.c. in Syrian hamsters. One group of D178- or FF-bearing hamsters (TD178 or TFF group) received intratumoral injections of pcDNA-Tyrs constructed as a tyrosinase expression plasmid. The other hamsters (pD178 and pFF groups) were injected with pUC119, and control hamsters (D178 and FF groups) only with transfection reagents. All the groups underwent immunofluorescence analysis of tyrosinase expression and BPA biodistribution studies. BNCT experiments were done at the Kyoto University Research Reactor. Tyrosinase expression increased in the tumors of the TD178 and TFF groups but remained the same in the pD178 and pFF groups. Tumor boron concentrations in the TD178 and TFF groups increased significantly (TD178: 49.7 +/- 12.6 versus D178: 27.2 +/- 4.9 microg/g, P < 0.0001; TFF: 30.7 +/- 6.6 versus FF: 13.0 +/- 4.7 microg/g, P < 0.0001). The BNCT tumor-suppressive effect was marked in the TD178 and TFF groups. In vivo transfection with the tyrosinase gene increased BPA accumulation in the tumors, the BNCT tumor-suppressive effect on amelanotic melanoma being significantly enhanced. These findings suggest a potential new clinical strategy for the treatment of amelanotic melanoma with BNCT.

A primary amelanotic melanoma of the vagina, diagnosed by immunohistochemical staining with HMB-45, which recurred as a pigmented melanoma.

Usually, malignant melanoma is readily diagnosed by the presence of melanin granules. Although amelanotic melanoma contains a few melanin granules, it is often difficult to differentiate from non-epithelial malignant tumours. This report describes a case of amelanotic melanoma of the vagina, which was originally suspected to be a non-epithelial malignant tumour, but was subsequently correctly diagnosed by immunohistochemical staining with the HMB-45 antibody and for the S-100 protein. A light grey tumour with superficial ulceration was located in the upper third of the vagina. The patient was treated with irradiation followed by chemotherapy. Subsequently, the tumour disappeared and cytology was negative; thus, she achieved complete remission. However, 20 months after complete remission, the tumour recurred locally: the site had a grossly black appearance, which was pathognomonic for a malignant melanoma. Thus, HMB-45 and S-100 protein immunohistochemistry confirmed the diagnosis of amelanotic melanoma.

Effect of boron neutron capture therapy for melanotic and amelanotic melanoma transplanted into mouse brain.

In order to develop a protocol to treat brain metastatic melanoma using our 10B-p-boronophenylalanine (BPA) boron neutron capture therapy (BNCT), we initiated the following studies (i), Comparative analyses of boron biodistribution between melanoma proliferating in the brain and skin among melanotic and amelanotic types, and (ii) Therapeutic evaluation of BPA-BNCT for brain melanoma models of both types, using survival times. Our present data have revealed that boron concentration in melanoma proliferating in the brain, the major prerequisite for successful BNCT, showed a positive correlation to melanin synthesizing activity in the same way as melanoma proliferating in skin. Further, the boron concentration ratio of melanoma to normal surrounding tissue for brain melanoma models was considerably higher than that for subcutaneous (s.c.) ones because of the existence of the blood-brain barrier (BBB). Additionally, from analyses of median and mean survival times following BNCT using low, middle, and high neutron doses, the therapeutic effect of BNCT for the amelanotic A1059 melanoma appeared at first glance to be higher than that for the highly BPA attracting and highly relative biological effect equivalent dose obtaining B15b melanoma. As the survival time was dependent on both regression and regrowth curves, and because the brain melanoma model in small animals made it difficult to evaluate these curves separately, we further examined the in vivo growth curve of both types of melanomas following implantation in s.c. tissue. The melanotic B15b melanoma was indeed found to possess much higher growth rate as compared with that of the amelanotic A1059 melanoma. The significance of boron biodistribution studies and BNCT survival curve analyses in forming an effective clinical protocol for individual human cases of melanoma brain metastasis is discussed.

Experimental ruthenium plaque therapy of amelanotic and melanotic melanomas in the hamster eye.

The effects of beta-radiation on melanoma implanted into the hamster's eye were investigated. Two Bomirski hamster melanomas (BHMs), differing in their melanin content, were compared with regard to their radiosensitivity to ruthenium-106 (106Ru) radiation. Tumours growing in the iris were irradiated with 3, 6 or 10 Gy of 106Ru given as a single dose or in four fractions at 24 h Intervals. Tumour growth kinetics and distant metastases were studied, and the eyeballs were examined histologically. Dose-dependent delay of tumour growth was observed in both melanomas. After treatment with a dose of 6 Gy, the Ab amelanotic tumours grew 2.6 times slower, and the Ma melanotic tumours 1.4 times slower than untreated ones. The location of metastases differed in the two tested lines--pigmented metastases were found mainly in the lungs, while unpigmented metastases were found mainly in the kidneys. Histopathological analysis showed signs of blood vessel damage such as endothelial cells swelling, erythrocyte extravasation and tumour necrosis. This last finding increased with the rising dose of beta-radiation. Pigmented tumours were found to be two times more resistant to beta-radiation than amelanotic ones. The pattern of metastases of BHMs is determined by the type of melanoma (Ab or Ma). Exposure to beta-radiation from 106Ru did not significantly affect either the number or size of metastases except at a dose of 10 Gy. This dose caused a statistically significant decrease in the number of metastases in the Ma melanotic subline.

Monitoring of tumor reoxygenation following irradiation by 31P magnetic resonance spectroscopy: an experimental study of human melanoma xenografts.

BACKGROUND AND PURPOSE: Inadequate tumor reoxygenation during radiation therapy may cause local treatment failure. This study was aimed at investigating the potential usefulness of 31P-MRS in monitoring tumor reoxygenation following radiation treatment. MATERIALS AND METHODS: Tumors of two human melanoma xenograft lines (BEX-t and HUX-t) were exposed to 15.0 Gy, and then the fraction of radiobiologically hypoxic cells, measured by using the paired survival curve method, or tumor bioenergetic status, measured by 31P-MRS as the (PCr + NTPbeta)/Pi resonance ratio, was determined versus time after the radiation exposure. RESULTS: Untreated BEX-t and HUX-t tumors showed similar fractions of radiobiologically hypoxic cells and similar bioenergetic status, whereas both parameters differed substantially between the lines in irradiated tumors. A close association was found between radiation-induced changes in tumor bioenergetic status and radiation-induced changes in the fraction of radiobiologically hypoxic cells. CONCLUSION: 31P-MRS is a potentially useful method for monitoring tumor reoxygenation following radiation treatment.

Choroidal metastasis in men with metastatic breast cancer.

PURPOSE: To report two cases of choroidal metastasis in metastatic breast cancer in men. METHOD: Case reports of a 50-year-old man with an 8-year history of breast cancer who was initially examined with a solitary amelanotic choroidal tumor and a 62-year-old man with an 8-month history of breast cancer who was initially examined with numerous unilateral amelanotic choroidal tumors. RESULTS: Ophthalmoscopic and echographic characteristics of the choroidal tumors were typical for breast cancer metastasis. Systemic screening disclosed advanced metastatic disease in both patients. Choroidal metastasis could be effectively treated by external beam irradiation. CONCLUSIONS: Although breast cancer is a rare condition in men, it should be considered as a possible primary cancer in cases of choroidal metastasis.

[Choroid melanoma associated with 2 other primary malignant lesions. Apropos of a case]. / Mélanome choroïdien associé à deux autres lésions malignes primitives. A propos d'un cas.

A case of choroidal melanoma associated to two other primitive malignancies is reported. The patient, a 65-year-old woman had an amelanotic choroidal tumor of her left eye. In her clinical history was found a previously treated kidney carcinoma eight years ago. A choroidal metastasis was therefore diagnosed. After radiation therapy, an initial regression was observed. Fifteen months later, the tumor grew again. Enucleation was performed, and histopathology concluded on choroidal malignant melanoma. Three years later, a mammal carcinoma was discovered and treated by mammectomy. Her ophthalmologic and general status remained normal until now. Amelanotic choroidal tumors are difficult to diagnose. Regular follow-up can lead to a change in the diagnosis. The occurrence of multiple cancers is still not fully understood.

Enhanced melanogenesis induced by tyrosinase gene-transfer increases boron-uptake and killing effect of boron neutron capture therapy for amelanotic melanoma.

Specific and powerful cancer killing effect for melanoma by boron neutron capture therapy (BNCT) using DOPA analogue, 10B-p-boronophenylalanine (10B-BPA), has been established, but amelanotic melanoma is insufficiently responsive to 10B-BPA BNCT in comparison with actively melanin-producing melanoma. Although the accumulation mechanism of 10B-BPA within melanoma was not established, we have recently obtained findings suggesting that melanin monomers, key intermediates for melanin polymer formation, play a critical role in 10B-BPA accumulation. In addition, there are some kinds of human amelanotic melanomas, such as MEL2A, in which expression of tyrosinase is repressed or lacking though tyrosinase-related protein (TRP)-1 and TRP-2 are well expressed. Thus, by using a similarly tyrosinase-lacking mouse amelanotic melanoma cell line, A1059, we constructed TA1059 cells by transfecting human tyrosinase-cDNA into these cells. TA1059 cells acquired higher DOPA-oxidase and DOPAchrome tautomerase activity as well as eumelanin content at even higher levels than those of B16F10 cells. TA1059 cells showed about 2.5 times higher P-boronophenylalanine (BPA) uptake than A1059 cells in culture. In animal experiments, by using these cell lines, tumor growth of TA1059 was significantly suppressed by 10B-BPA BNCT as compared with A1059. These findings indicate that the induction of active melanin biosynthesis by melanogenic gene-transfer effectively improves the treatment of amelanotic melanoma by BNCT.