Frederick H. Davidorf

Germline BAP1 mutation predisposes to uveal melanoma, lung adenocarcinoma, meningioma, and other cancers.

Objective To investigate the potential contribution of germline sequence alterations in the BAP1 gene in uveal melanoma (UM) patients with possible predisposition to hereditary cancer. Design A total of 53 unrelated UM patients with high risk for hereditary cancer and five additional family members of one proband were studied. Mutational screening was carried out by direct sequencing. Results Of the 53 UM patients studied, a single patient was identified with a germline BAP1 truncating mutation, c. 799 C→T (p.Q267X), which segregated in several family members and was associated with UM and other cancers. Biallelic inactivation of BAP1 and decreased BAP1 expression were identified in the UM, lung adenocarcinoma and meningioma tumours from three family members with this germline BAP1 mutation. Germline BAP1 variants of uncertain significance, likely non-pathogenic, were also identified in two additional UM patients. Conclusion This study reports a novel hereditary cancer syndrome caused by a germline BAP1 mutation that predisposes patients to UM, lung carcinoma, meningioma, and possibly other cancers. The results indicate that BAP1 is the candidate gene in only a small subset of hereditary UM, suggesting the contribution of other candidate genes.

Ocular Complications Associated with Retrobulbar Injections

The authors describe six complications, of retrobulbar injections documented by fundus photography and fluorescein angiography. These include (1) injection of corticosteroid into the posterior ciliary arterial circulation resulting in emboli in the vasculature of the choroid and the optic nerve head; (2) injection of corticosteroid into the ophthalmic artery resulting in emboli in both the choroidal and retinal circulations; (3) presumed injection of lidocaine and air into the optic nerve sheath adjacent to the globe with extension anteriorly into the subretinal space and the space between the posterior vitreous and the internal limiting membrane; (4) occlusion of the central retinal artery without an associated retrobulbar hemorrhage; (5) trauma to and partial injection of lidocaine in the central retinal artery with embolization into the retinal circulation; and (6) presumed injection of lidocaine into the optic nerve sheath producing a combined central retinal vein and artery occlusion. Alternative techniques that might decrease the incidence of complications associated with retrobulbar injections are discussed.

High Frequency of Submicroscopic Hemizygous Deletion Is a Major Mechanism of Loss of Expression of PTEN in Uveal Melanoma

PURPOSE Although cytogenetic aberrations at 10q have been reported in up to 27% of uveal melanomas, the role of PTEN in the pathogenesis of uveal melanoma is largely unknown. Our aim was to determine the frequency and clinical significance of PTEN alterations in uveal melanomas. PATIENTS AND METHODS We examined PTEN expression using immunohistochemistry in 75 sporadic uveal melanomas, with an average follow-up of 89 months. Molecular cytogenetic alterations were studied using comparative genomic hybridization (CGH). Genotyping was carried out using an intragenic PTEN marker and two flanking markers. Mutational analysis of PTEN was also carried out. RESULTS Of the 75 tumors, 12 (16%) showed no PTEN immunostaining, 32 (42.7%) showed weak to moderate staining and the remaining 31 (38.2%) showed staining similar to the normal internal controls. Using CGH, only two (15.4%) of 13 samples showed any loss of 10q. However, in the 38 tumors with informative genotyping, we found that 29 (76.3%) had loss of heterozygosity (LOH) of at least one PTEN marker, and 15 (39.5%) showed LOH of at least two markers. Mutations in the coding region of PTEN were identified in four (11.4%) of 35 tumors. Further, loss of cytoplasmic PTEN expression by immunohistochemistry was associated with shortened disease-free survival (P = .029). CONCLUSION This is the first demonstration that PTEN is a tumor suppressor involved in uveal melanoma pathogenesis and may be associated with clinical outcome. Our data also suggest that submicroscopic deletion, but not large deletions, is the major mechanism of loss of PTEN expression in uveal melanomas.

Chemotherapy for Treatment of Choroidal Metastases from Breast Carcinoma

Of 15 patients with choroidal metastases from breast carcinoma, eight were treated with radiation therapy and six with chemotherapy. One patient received both. Although five of the six patients receiving chemotherapy died after an average follow-up period of 12 months, these patients generally had more widespread disease and a worse prognosis originally. Chemotherapy proved to be as effective as radiation therapy for this tumor.

Expanding the clinical phenotype of hereditary BAP1 cancer predisposition syndrome, reporting three new cases

The clinical phenotype of BAP1 hereditary cancer predisposition syndrome (MIM 614327) includes uveal melanoma (UM), cutaneous melanoma (CM), renal cell carcinoma (RCC), and mesothelioma. However, the frequency of the syndrome in patients with UM and the association with other cancers are still not clear. In this study, we screened 46 previously untested, unrelated UM patients with high risk for hereditary cancer for germline mutation in BAP1. We also studied four additional patients with a personal or family history suggestive of BAP1 hereditary cancer syndrome. We identified three patients with germline pathogenic mutations (c.2050 C>T, pGln684*; c.1182C>G, p.Tyr394*, and c.1882_1885delTCAC, p. Ser628Profs*8) in BAP1. Two of these three patients presented with UM and the third with a metastatic adenocarcinoma likely from a hepatic cholangiocarcinoma. Reported family histories included UM, mesothelioma, RCC, CM, and several other internal malignancies. The results of this study confirm the association between germline BAP1 mutation and predisposition to UM, mesothelioma, CM and RCC. However, other cancers, such as cholangiocarcinoma and breast carcinoma may be part of the phenotype of this hereditary cancer predisposition syndrome. In addition, the results support the existence of other candidate genes in addition to BAP1 contributing to hereditary predisposition to UM.

A Randomized Study of Methanol-Extraction Residue of Bacille Calmette-Guerin as Postsurgical Adjuvant Therapy of Uveal Melanoma

A randomized controlled clinical trial of methanol-extracted residue of bacille Calmette-Guerin adjuvant treatment of posterior uveal melanoma was undertaken. Of 113 patients, 34 patients received adjuvant immunotherapy and 79 patients received no treatment. No difference in survival was observed between the adjuvant-treated group and the control group of patients. This study found that the size of the tumor was a highly significant risk factor for death caused by metastasis of uveal melanomas. The standard deviation of the nucleolar area of the neoplastic cells was a significant risk factor, even though patients with tumors composed of Callenders spindle-type cells were not included in the study.

Ocular Toxicity Of Vitreal Pluronic Polyol F-127

To evaluate pluronic polyol F-127 (PF-127) as a vitreous substitute and an intraocular drug delivery system, a total vitrectomy was performed on 18 New Zealand rabbits (18 eyes). The vitreous was replaced with either PF-127 (9 eyes) or balanced salt solution (9 eyes). There was little difference clinically between the eyes containing PF-127 and the control eyes. Both groups showed mild postoperative inflammation, with no differences in intraocular pressures. Histopathologic findings for the control group showed no significant retinal alteration, and serial ERG findings were within normal limits. In contrast, the eyes containing PF-127 showed marked destruction of the retina by 2 weeks after surgery. The ERG amplitudes decreased dramatically to a flat tracing by 24 hours after surgery. Although it is attractive as a potential vitreous substitute, PF-127 is not safe for human use, at least at the concentration used.

The melanoma controversy. A comparion of choroidal, cutaneous, and iris melanomas

Controversy exists regarding the management of patients with choroidal melanomas. Some experts argue that these neoplasms behave differently than other types of melanomas, and that enucleation rather than tumor burden is responsible for metastases. A review of the literature involving death rates of patients diagnosed with melanomas of the choroid, skin and iris demonstrates the importance of tumor volume as a prognostic indicator. In each instance, the smaller the tumor burden, the better the prognosis. Death rates from metastases involving small choroidal tumors (less than 300 mm) were surprisingly similar to to those from cutaneous melanomas of the same size. Large tumors of the choroid carried a much higher death rate, as did large tumors of the skin. While studies involving iris melanomas reported only a 2.6% death rate, the average volume of an iris melanoma is only 55 mm. We believe that biologically all melanomas have the same potential for metastatic growth and that the size of the tumor may be the most important variable with regard to prognosis.

The prognostic significance of lymphocytic infiltration in malignant melanoma of the choroid.

Lymphocytic and plasmocytic infiltration surrounding a malignant tumor probably represents an immunologic response of the host directed against the neoplasm. It has been documented that lymphocytic infiltration has a favorable effect on prognosis in a number of human tumor systems, including cutaneous melanoma. In the present study, 309 consecutive cases of choroidal melanoma were examined for cellular infiltration, and these data were correlated with other histologic parameters and with prognosis. An intense cellular infiltration was found in 15 tumors (4.9%) and a moderate infiltration in 37 (12.0%). Tumors with cellular infiltration were significantly larger and more vascularized than the remaining tumors, which may be related to the accessibility of the immune system to the tumor. There was a higher percentage of poorly differentiated tumors among the tumors with cellular infiltration. However, it does not appear that cellular infiltration favorably influences the prognosis of choroidal melanoma. The 5‐year survival rates of patients with like cell types did not depend upon the degree of cellular infiltration demonstrated by the primary tumor. Although choroidal melanomas are capable of inciting an immune response, this response is apparently ineffective in preventing metastatic spread.

Monosomy 3 status of uveal melanoma metastases is associated with rapidly progressive tumors and short survival.

The aim of the study was to investigate the molecular genetics of uveal melanoma (UM) metastases and correlate it with disease progression. Twelve pathologically confirmed UM metastases from 11 patients were included. Molecular genetic alterations in chromosomes 3 (including the BAP1 region), 8q, 6p, and 1p were investigated by microsatellite genotyping. Mutations in codon 209 of GNAQ and GNA11 genes were studied by restriction-fragment length polymorphism (RFLP). We identified monosomy of chromosome 3 in tumors from four patients with an average survival of 5 months (range 1-8 months) from time of diagnosis of metastatic disease. In contrast, tumors with either disomy or partial chromosome 3 alterations showed significantly slower metastatic disease progression with an average survival of 69 months (range 40-123 months, p = 0.003). Alterations in chromosomal arms 1p, 6p, and 8q and mutations in either GNAQ or GNA11 showed no association with disease progression. Prominent mononuclear inflammatory infiltrate was observed in tumors from patients with slowly progressive disease. In conclusion, in UM metastases, monosomy 3 is associated with highly aggressive, rapidly progressive disease while disomy or partial change of 3 and prominent mononuclear inflammatory infiltrate in the tumor is associated with better prognosis. These findings should be considered when designing clinical trials testing effectiveness of various therapies of metastatic UM.