- Miami, Florida, United States
J. William Harbour
University of Miami, Ophthalmology, Faculty Member
Uveal melanoma (UM) is the most common primary cancer of the eye and is associated with a high rate of metastatic death. UM can be stratified into two main classes based on metastatic risk, with class 1 UM having a low metastatic risk and... more
Uveal melanoma (UM) is the most common primary cancer of the eye and is associated with a high rate of metastatic death. UM can be stratified into two main classes based on metastatic risk, with class 1 UM having a low metastatic risk and class 2 UM having a high metastatic risk. Class 2 UM have a distinctive genomic, transcriptomic, histopathologic, and clinical phenotype characterized by biallelic inactivation of the BAP1 tumor suppressor gene, an immune suppressive microenvironment enriched for M2-polarized macrophages, and poor response to checkpoint inhibitor immunotherapy. To identify potential mechanistic links between BAP1 loss and immune suppression in class 2 UM, we performed an integrated analysis of UM samples, as well as genetically engineered UM cell lines and uveal melanocytes (UMC). Using RNA sequencing (RNA-seq), we found that the most highly up-regulated gene associated with BAP1 loss across these datasets was PROS1, which encodes a ligand that triggers phosphoryla...
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Frequent mutations have been described in the following 5 genes in uveal melanoma (UM): BAP1, EIF1AX, GNA11, GNAQ, and SF3B1. Understanding the prognostic significance of these mutations could facilitate their use in precision medicine.... more
Frequent mutations have been described in the following 5 genes in uveal melanoma (UM): BAP1, EIF1AX, GNA11, GNAQ, and SF3B1. Understanding the prognostic significance of these mutations could facilitate their use in precision medicine. To determine the associations between driver mutations, gene expression profile (GEP) classification, clinicopathologic features, and patient outcomes in UM. Retrospective study of patients with UM treated by enucleation by a single ocular oncologist between November 1, 1998, and July 31, 2014. Clinicopathologic features, patient outcomes, GEP classification (class 1 or class 2), and mutation status were recorded. The study cohort comprised 81 participants. Their mean age was 61.5 years, and 37% (30 of 81) were female. The GEP classification was class 1 in 35 of 81 (43%), class 2 in 42 of 81 (52%), and unknown in 4 of 81 (5%). BAP1 mutations were identified in 29 of 64 (45%), GNAQ mutations in 36 of 81 (44%), GNA11 mutations in 36 of 81 (44%), SF3B1 ...
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Uveal melanoma (UM) can be classified by gene expression profiling (GEP) into Class 1 (low metastatic risk) and Class 2 (high metastatic risk), the latter being strongly associated with mutational inactivation of the tumor suppressor... more
Uveal melanoma (UM) can be classified by gene expression profiling (GEP) into Class 1 (low metastatic risk) and Class 2 (high metastatic risk), the latter being strongly associated with mutational inactivation of the tumor suppressor BAP1. Nevertheless, a small percentage of Class 1 tumors give rise to metastatic disease. The purpose of this study was to identify biomarkers of metastasis in Class 1 tumors. A total of 389 consecutive patients with UM were assigned to Class 1 or Class 2 using a prospectively validated 12-gene prognostic classifier. Selected tumors were further analyzed using global GEP and single nucleotide polymorphism microarrays. PRAME (preferentially expressed antigen in melanoma) mRNA expression was analyzed in 64 Class 1 tumors by qPCR. Among Class 1 UMs, the most significant predictor of metastasis was PRAME mRNA expression (P = 0.0006). The 5-year actuarial rate of metastasis was 0% for Class1(PRAME-), 38% for Class1(PRAME+), and 71% for Class 2 tumors. Median...
Research Interests: Medicine, Humans, Female, Melanoma, Male, and 5 moreAged, Middle Aged, Adult, Disease Free Survival, and Neoplasm metastasis
Uveal melanoma (UM) is the most common cancer of the eye and leads to metastatic death in up to half of patients. Genomic prognostic biomarkers play an important role in clinical management in UM. However, research has been conducted... more
Uveal melanoma (UM) is the most common cancer of the eye and leads to metastatic death in up to half of patients. Genomic prognostic biomarkers play an important role in clinical management in UM. However, research has been conducted almost exclusively in patients of European descent, such that the association between genetic admixture and prognostic biomarkers is unknown. In this study, we compiled 1381 control genomes from West African, European, East Asian, and Native American individuals, assembled a bioinformatic pipeline for assessing global and local ancestry, and performed an initial pilot study of 141 UM patients from our international referral center that manages many admixed individuals. Global and local estimates were associated with genomic prognostic determinants. Expression quantitative trait loci (eQTL) analysis was performed on variants found in segments. Globally, after correction for multiple testing, no prognostic variable was significantly enriched in a given an...
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To report an atypical case of a patient with symptomatic retinocytoma associated with diffuse calcified vitreous seeds. Retrospective chart review. A 46-year-old healthy woman presented with a history of floaters in the right eye for... more
To report an atypical case of a patient with symptomatic retinocytoma associated with diffuse calcified vitreous seeds. Retrospective chart review. A 46-year-old healthy woman presented with a history of floaters in the right eye for several months. She had been referred for abnormal findings in the retina and vitreous on routine examination. Visual acuity was 20/20. An incidental retinocytoma associated with extensive calcified vitreous seeding was observed. Enhanced depth optical coherence tomography showed an absence of normal retinal layers with numerous cystoid cavities throughout the lesion. High-resolution 20-MHz posterior B-scan ultrasonography demonstrated that the calcified vitreous seeds emanated from the peaked portion of the retinal tumor. Calcified vitreous seeding is a rare finding associated with retinocytomas. Enhanced depth imaging optical coherence tomography and high-resolution B-scan ultrasonography may be useful tools in the diagnosis of this uncommon retinal t...
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Clinical outcomes for enucleation vary widely, depending on surgical technique, implant choice, and indications for enucleation. The goal of this study was to compare complications of enucleation using hydroxyapatite versus polyethylene... more
Clinical outcomes for enucleation vary widely, depending on surgical technique, implant choice, and indications for enucleation. The goal of this study was to compare complications of enucleation using hydroxyapatite versus polyethylene orbital implants for 1 indication: uveal melanoma in adults. Retrospective chart review Consecutive case series of patients who were enucleated for uveal melanoma by a single surgeon (J.W.H.) from 1999-2009. A retrospective chart review was performed to record clinical and histopathologic features, surgical technique, orbital implant characteristics, and outcomes in a consecutive series of patients with uveal melanoma who were treated by enucleation by a single surgeon (J.W.H.) between 1999 and 2009. This study included 139 patients; 64 received hydroxyapatite implants, and 75 received polyethylene implants wrapped in donor sclera. Complications included blepharoptosis in 4 (2.9%), conjunctival cyst in 2 (1.4%), volume deficit in 2 (1.4%), implant ex...
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Uveal (ocular) melanoma is an aggressive cancer that metastasizes in up to half of patients. Uveal melanoma spreads preferentially to the liver, and the metastatic disease is almost always fatal. There are no effective therapies for... more
Uveal (ocular) melanoma is an aggressive cancer that metastasizes in up to half of patients. Uveal melanoma spreads preferentially to the liver, and the metastatic disease is almost always fatal. There are no effective therapies for advanced metastatic disease, so the most promising strategy for improving survival is to detect metastasis at an earlier stage or to treat high-risk patients in an adjuvant setting. An accurate test for identifying high-risk patients would allow for such personalized management as well as for stratification of high-risk patients into clinical trials of adjuvant therapy.We developed a gene expression profile (GEP) that distinguishes between primary uveal melanomas that have a low metastatic risk (class 1 tumors) and those with a high metastatic risk (class 2 tumors). We migrated the GEP from a high-density microarray platform to a 15-gene, qPCR-based assay that is now performed in a College of American Pathologists (CAP)-accredited Clinical Laboratory Imp...
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Torpedo maculopathy is a congenital solitary, oval-shaped lesion typically located temporal to the center of the macula. Congenital hypertrophy of the retinal pigment epithelium (RPE), RPE lesions of Gardner syndrome, and other lesions... more
Torpedo maculopathy is a congenital solitary, oval-shaped lesion typically located temporal to the center of the macula. Congenital hypertrophy of the retinal pigment epithelium (RPE), RPE lesions of Gardner syndrome, and other lesions can present with similar characteristics. Because of its unique clinical and imaging features, torpedo maculopathy generally can be differentiated from other posterior segment lesions.
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A priority in the management of patients with potentially curable or indolent cancers is to maximize tumor control while minimizing the iatrogenic complications that may occur many years later. A balance between these short-term and... more
A priority in the management of patients with potentially curable or indolent cancers is to maximize tumor control while minimizing the iatrogenic complications that may occur many years later. A balance between these short-term and long-term goals can sometimes be elusive, as seen in the ongoing contro- versy over the role of external beam radiation therapy (EBRT) in the initial treatment of patients with early-stage Hodgkin's dis- ease (1). In the case of hereditary retinoblastoma, where more patients in the United States die of second primary cancers (many induced by EBRT) than from their initial eye tumor (2), the treatment for intraocular disease has recently undergone dramatic changes to minimize the delayed tumorigenic potential of EBRT. These changes focus on the substitution of EBRT with chemotherapy, followed by local consolidative modalities such as laser hyperthermia and cryotherapy. However, some patients are not responsive to chemotherapy and may still require EBR...
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Small cell lung cancer (SCLC) has been associated with loss of heterozygosity at several distinct genetic loci including chromosomes 3p, 13q, and 17p. To determine whether the retinoblastoma gene (Rb) localized at 13q14, might be the... more
Small cell lung cancer (SCLC) has been associated with loss of heterozygosity at several distinct genetic loci including chromosomes 3p, 13q, and 17p. To determine whether the retinoblastoma gene (Rb) localized at 13q14, might be the target of recessive mutations in lung cancer, eight primary SCLC tumors and 50 cell lines representing all major histologic types of lung cancer were examined with the Rb complementary DNA probe. Structural abnormalities within the Rb gene were observed in 1/8 (13%) primary SCLC tumors, 4/22 (18%) SCLC lines, and 1/4 (25%) pulmonary carcinoid lines (comparable to the 20 to 40% observed in retinoblastoma), but were not detected in other major types of lung cancer. Rb messenger RNA expression was absent in 60% of the SCLC lines and 75% of pulmonary carcinoid lines, including all samples with DNA abnormalities. In contrast, Rb transcripts were found in 90% of non-SCLC lung cancer lines and in normal human lung. The finding of abnormalities of the Rb gene in SCLC and pulmonary carcinoids (both neuroendocrine tumors) suggests that this gene may be involved in the pathogenesis of a common adult malignancy.
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Plaque radiotherapy has been reported to have a higher relapse rate than charged-particle radiotherapy for posteriorly located uveal melanomas, which also are more technically difficult to localize accurately. The authors used... more
Plaque radiotherapy has been reported to have a higher relapse rate than charged-particle radiotherapy for posteriorly located uveal melanomas, which also are more technically difficult to localize accurately. The authors used intraoperative echography in patients with posterior uveal melanoma to determine the rate of inaccurate localization of iodine 125(125I) episcleral plaques using standard localization techniques. The authors reviewed the records of 29 consecutive patients with medium-sized posterior uveal melanomas who underwent 125I episcleral plaque radiotherapy with intraoperative echographic verification of plaque placement. After careful plaque placement using standard localization techniques, 4 of 29 plaques (14%) did not cover at least one tumor margin. All four of these plaques were associated with posterior tumors with at least one margin posterior to the temporal arcades. Two (7%) additional juxtapapillary plaques were displaced away from the sclera by the optic nerve. In all six cases, it was possible to immediately reposition the plaque to achieve coverage of all tumor margins. Placement of 125I episcleral radioactive plaques for posteriorly located uveal melanomas using standard localization techniques occasionally results in suboptimal plaque positioning. Intraoperative echography can identify plaques that are localized poorly and allows immediate adjustment to achieve optimal plaque positioning.
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Uveal melanoma (UM) is the most common primary cancer of the eye and has a strong propensity for metastasis. Although there have been many recent improvements in the diagnosis and treatment of UM, and only 2-4% of patients present with... more
Uveal melanoma (UM) is the most common primary cancer of the eye and has a strong propensity for metastasis. Although there have been many recent improvements in the diagnosis and treatment of UM, and only 2-4% of patients present with detectable metastasis, up to half of patients are at risk for dying of metastatic disease. Clinicopathologic factors are not accurate enough for individualized patient care. Chromosomal alterations have been used for prognostic purposes, but the routine clinical use of these methods is limited by their susceptibility to sampling error resulting from tumor heterogeneity, limited clinical validation, lack of standardized testing platforms, and high technical failure rates. In contrast, the DecisionDx-UM gene expression profile test is a stand-alone platform which requires no other information for maximal prognostic accuracy and which circumvents many of the drawbacks of chromosomal methods through the use of a highly sensitive microfluidics, PCR-based platform that simultaneously measures the expression of 15 carefully selected genes from primary uveal melanoma samples obtained by fine needle biopsy. Low metastatic risk is reported as Class 1, and high metastatic risk as Class 2. The test allows patients to be stratified into risk categories such that high-risk patients can be offered intensive metastatic surveillance and adjuvant therapy while low-risk patients can be spared these interventions. This test is now used as part of the standard of care in many ocular oncology centers.
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Metastasis of tumor cells to distant organs is the leading cause of death in melanoma. Yet, the mechanisms of metastasis remain poorly understood. One key question is whether all cells in a primary tumor are equally likely to metastasize... more
Metastasis of tumor cells to distant organs is the leading cause of death in melanoma. Yet, the mechanisms of metastasis remain poorly understood. One key question is whether all cells in a primary tumor are equally likely to metastasize or whether subpopulations of cells preferentially give rise to metastases. Here, we identified a subpopulation of uveal melanoma cells expressing the multidrug resistance transporter ABCB1 that are highly metastatic compared to ABCB1(-) bulk tumor cells. ABCB1(+) cells also exhibited enhanced clonogenicity, anchorage-independent growth, tumorigenicity and mitochondrial activity compared to ABCB1(-) cells. A375 cutaneous melanoma cells contained a similar subpopulation of highly metastatic ABCB1(+) cells. These findings suggest that some uveal melanoma cells have greater potential for metastasis than others and that a better understanding of such cells may be necessary for more successful therapies for metastatic melanoma.
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This study aimed to determine the distribution of germline mutations in the retinoblastoma (RB) gene in patients with retinoblastoma to design more effective genetic testing. A meta-analysis. 192 cases identified from literature. All... more
This study aimed to determine the distribution of germline mutations in the retinoblastoma (RB) gene in patients with retinoblastoma to design more effective genetic testing. A meta-analysis. 192 cases identified from literature. All identifiable reported cases of bilateral retinoblastoma, which included DNA sequence analysis of the RB gene, were reviewed. Type of genetic mutation. Among 192 patients with retinoblastoma with identifiable germline mutations in the RB gene, the DNA alteration was a nonsense mutation in 83 (43%), frameshift in 67 (35%), intron mutation in 23 (12%), missense mutation in 11 (6%), in-frame deletion in 5 (3%), and promoter mutation in 3 (2%). Mutations were distributed throughout 24 of the 27 exons of the RB gene with no single mutational "hotspot." Exons 8, 17, 18, and 23 were involved most often, and 189 (98%) of the mutations were predicted to affect the RB large pocket domain. A single genetic test is unlikely to detect all germline RB gene mutations in patients with retinoblastoma because of the variety of types and locations of mutations that occur. However, a series of complementary tests may be able to rapidly detect mutations based on the observation that most mutations alter the protein size and disrupt the large pocket domain.
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Uveal melanoma (UM) is the most common primary intraocular malignancy and the second most common form of melanoma. UM has a strong tendency for metastatic disease, and no effective treatments have yet been identified. Activating oncogenic... more
Uveal melanoma (UM) is the most common primary intraocular malignancy and the second most common form of melanoma. UM has a strong tendency for metastatic disease, and no effective treatments have yet been identified. Activating oncogenic mutations are commonly found in GNAQ and GNA11 in UM, and inhibiting key downstream effectors of the GNAQ/11 signaling pathway represents a rational therapeutic approach for treating metastatic UM. Chen et al., doi:10.1038/onc.2013.418, now confirm activation of the MAPK and PKC pathways as a result of GNAQ and GNA11 activating mutations in melanocytes, and they demonstrate that MAPK activation occurs downstream of PKC activation. PKC inhibitors disrupt MAPK signaling and block proliferation of GNAQ/11 mutant UM cell lines and slow the in vivo growth of xenografted UM tumors without inducing their shrinkage. However, a combination of PKC and MEK inhibition led to sustained MAPK pathway inhibition and tumor regression in vivo. Hence, the authors concluded that MEK and PKC inhibition is synergistic, with superior efficacy to treatment of GNAQ/GNA11 mutant UMs with either drug alone.
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Uveal (ocular) melanoma is a highly aggressive cancer that leads to metastatic death in up to half of patients despite successful local therapy. Biomarkers of metastatic risk are critically needed to institute new adjuvant treatment... more
Uveal (ocular) melanoma is a highly aggressive cancer that leads to metastatic death in up to half of patients despite successful local therapy. Biomarkers of metastatic risk are critically needed to institute new adjuvant treatment strategies in high-risk patients. Previously, we showed that two prognostically significant molecular subtypes of uveal melanoma could be identified based on gene expression profiling of the primary tumor. In this study, we investigated the value of micro-RNA (miRNA) expression patterns in predicting metastatic risk. A genome-wide, microarray-based approach was used to screen for differentially expressed miRNAs using the Agilent miRNA microarray (Agilent Technologies, Foster City, California, USA) platform containing probes for 470 human miRNAs. Unsupervised analysis was performed using principal component analysis, and supervised analysis was performed using significance analysis of microarrays. Tumors readily clustered based on miRNA expression into two groups that corresponded to the gene expression-based subtypes: class 1 (low metastatic risk) and class 2 (high metastatic risk). The most significant discriminators were let-7b and miR-199a, and the expression of these miRNAs was validated by quantitative PCR. A classifier that included the top six miRNA discriminators accurately distinguished class 1 from class 2 tumors with 100% sensitivity and specificity. miRNA expression may represent a highly accurate biomarker for metastatic risk in uveal melanoma. In addition, these results may provide new insights into the role of miRNAs in tumor progression and the metastatic phenotype.
Research Interests: Principal Component Analysis, Gene expression, Quantitative PCR, Humans, Female, and 15 moreMelanoma, Male, Gene Dosage, Clinical Sciences, Aged, Middle Aged, microRNAs, Adult, Disease Progression, Gene expression profiling, Differential expression, Neoplasm staging, High risk, Neoplasm metastasis, and Expression pattern
A priority in the management of patients with potentially curable or indolent cancers is to maximize tumor control while minimizing the iatrogenic complications that may occur many years later. A balance between these short-term and... more
A priority in the management of patients with potentially curable or indolent cancers is to maximize tumor control while minimizing the iatrogenic complications that may occur many years later. A balance between these short-term and long-term goals can sometimes be ...
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Despite a century of advances in the clinical management of uveal melanoma, there has been no demonstrable improvement in patient survival. This remarkable fact underscores the deceptively complex uveal melanoma molecular pathophysiology... more
Despite a century of advances in the clinical management of uveal melanoma, there has been no demonstrable improvement in patient survival. This remarkable fact underscores the deceptively complex uveal melanoma molecular pathophysiology and implies that ...
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In the past decade, there have been impressive advances in our understanding of chromosomal, genetic and molecular alterations that occur in uveal melanoma. Nevertheless, a coherent picture of the molecular pathogenesis of this eye cancer... more
In the past decade, there have been impressive advances in our understanding of chromosomal, genetic and molecular alterations that occur in uveal melanoma. Nevertheless, a coherent picture of the molecular pathogenesis of this eye cancer is yet to emerge. Herein, we review the findings to date, discuss the insights they provide, and suggest future directions for molecular research in uveal melanoma.
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... Intensity-modulated radiotherapy might help to reduce the rate of treatment-induced complications, and recent data have succeeded in reducing the predicted risk of severe toxicity to less than 5% while treating the planned target... more
... Intensity-modulated radiotherapy might help to reduce the rate of treatment-induced complications, and recent data have succeeded in reducing the predicted risk of severe toxicity to less than 5% while treating the planned target volume in an optimal manner (Miralbell et al. ...
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Hepatic arterial chemoembolization is an accepted therapy for stage 4 melanoma with liver-dominant metastasis. However, the reports of outcomes are limited. We present our outcomes with hepatic arterial chemoembolization for metastasis of... more
Hepatic arterial chemoembolization is an accepted therapy for stage 4 melanoma with liver-dominant metastasis. However, the reports of outcomes are limited. We present our outcomes with hepatic arterial chemoembolization for metastasis of stage 4 melanoma. Twenty patients with liver-dominant metastasis of ocular or cutaneous melanoma were treated with hepatic arterial chemoembolization. Overall survival and progression-free survival rates were calculated from the first treatment. Patients with intrahepatic tumor progression were treated with additional hepatic arterial chemoembolization. Both overall survival and progression-free survival were analyzed with the Kaplan-Meier method. Tumor pattern on angiography was characterized as either nodular or infiltrative on the basis of angiographic appearance. The 20 patients underwent 46 hepatic arterial chemoembolization sessions (mean, 2.4 sessions; range, 1-5). The mean and median overall survival times were 334 +/- 71 and 271 days, respectively. There were no deaths within 30 days of treatment. Thirteen of the 20 patients had progression of disease. The mean and median progression-free survival times for these patients were 231 +/- 42 and 185 days, respectively. Patients with lesions that had a nodular angiographic appearance had longer progression-free survival than patients with lesions that had an infiltrative appearance (mean progression-free survival time, 249 vs 63 days). Patients with lesions that had a nodular angiographic appearance also survived significantly longer than those with lesions that had an infiltrative angiographic pattern (mean overall survival time, 621 vs 114 days; p = 0.0002). Hepatic arterial chemoembolization for liver-dominant metastasis of stage 4 melanoma is a safe treatment that results in longer survival than has occurred among historical controls. Patients with lesions that have a nodular tumor appearance on angiography survive significantly longer than patients with lesions that have an infiltrative appearance on angiography.
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To evaluate the cytologic findings of vitreous fluids with atypical, suspicious for malignancy or malignant lymphoid cells to assess cytologic parameters that may help in reaching the diagnosis of intraoclular lymphoma. Vitreous aspirates... more
To evaluate the cytologic findings of vitreous fluids with atypical, suspicious for malignancy or malignant lymphoid cells to assess cytologic parameters that may help in reaching the diagnosis of intraoclular lymphoma. Vitreous aspirates with a malignant, suspicious for malignancy or atypical lymphoid population were identified from the files of Barnes-Jewish Hospital during the previous 11 years. Cytologic preparations were reviewed. Pertinent clinical information was obtained from medical records. Thirteen vitreous aspirates from 12 patients were included. The chief complaints included floaters, blurred vision and decreased visual aculity. Bilateral ocular involvement was present in 8 (67%) patients. Three patients had a history of an extraocular lymphoid malignancy. All patients underwent pars plana vitrectomy and collection of the vitreous aspirate. Cytologic diagnoses included: malignant lymphoma (9 of 13), suspicious for malignant lymphoma (3 of 13) and atypical lymphoid population (1 of 13). Most samples had high cellularity (11 of 13) and necrosis (9 of 13). Abnormal lymphoid cells were large (2-4 times the size of a lymphocyte) and had a high nuclear/cytoplasmic ratio, prominent nucleoli, irregular nuclear contours and a fine to coarse chromatin pattern. All cases with malignant cytology had abundant abnormal lymphoid cells; inconclusive cases had few. Immunocytochemistry for CD20 and CD45RO was performed on 9 of 13 samples and was conclusive in 6 of 9. Cytologic analysis of vitreous aspirates can be useful in diagnosing intraocular involvement by malignant lymphoma. Sparse cellularity is the main factor leading to inconclusive diagnoses. Immunostaining can be useful in confirming the lymphoid nature of the malignant cells.