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Carolyn P Graeber,
Y Pierre Gobin,
Brian P Marr,
Ira J Dunkel,
Scott E Brodie,
Norbert Bornfeld,
Devron H Char,
Robert Folberg,
Saskia M Imhof, Amy Y Lin,
Jesse L Berry,
Saleh Al Mesfer,
Annette C Moll,
David H Abramson
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ABSTRACT: Intra-arterial chemotherapy (chemosurgery) for the treatment of retinoblastoma has been performed more than 1600 times (more than 1400 times in Japan and 200 times in New York) over the past 20 years.Despite this treatment's success some eyes cannot be saved and require enucleation. Here we report the histopathologic findings of the remaining intraocular tumor of eyes that were enucleated following treatment that included chemosurgery in New York City.
Independent histopathologic review of the enucleated eyes was correlated with the clinical findings that prompted enucleation.
Between May 1, 2006 and April 30, 2009, 56 eyes received chemosurgery at our institution, and 10 of these were enucleated subsequently. All were Reese Ellsworth Group 5 at enucleation. Of the 21 eyes that were treated with chemosurgery as the primary treatment, 1 (5%) was enucleated subsequently; its histopathology revealed residual non-necrotic, non-calcified tumor. Of the 34 eyes treated with chemosurgery after other treatments, 9 (24%) were enucleated, and 5 of these eyes contained non-calcified, non-necrotic tumor. None was enucleated for complications of chemosurgery. All patients were alive and free of metastatic disease as of September 2009.
A significant number of eyes with advanced intraocular retinoblastoma avoided enucleation as a result of chemosurgery. The rate of eyes that were enucleated was higher when chemosurgery was the secondary rather than the primary treatment. Of the eight eyes enucleated for progressive disease six had non-necrotic, non-calcified tumor cells.
The Open Ophthalmology Journal 01/2011; 5:1-5.
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ABSTRACT: The aim of this study is to report the clinicopathologic characteristics of 3 cases of alveolar rhabdomyosarcoma with neuroendocrine/neuronal differentiation. Specimens of 3 cases of alveolar rhabdomyosarcoma were studied using histologic, immunohistochemical, ultrastructural, and molecular genetic techniques. The patients were a 19-year-old man with metastatic alveolar rhabdomyosarcoma in a groin lymph node, a 16-year-old girl with alveolar rhabdomyosarcoma of the perineum, and a 20-year-old man with recurrent orbital alveolar rhabdomyosarcoma. Microscopically, case 1 was composed of compact sheets of medium to large tumor cells. Cases 2 and 3 were small blue round cell tumors. Cases 1 and 3 were solid throughout, whereas case 2 demonstrated alveolar and solid architecture. By immunohistochemistry, the following markers were positive: desmin (3/3), myogenin (3/3), synaptophysin (3/3), and chromogranin (2/3). Ultrastructurally, sarcomeric filaments were seen in all cases, while neuroendocrine granules were detected only in case 1. PAX:FKHR fusion transcript was identified in case 2, case 3 had a variant PAX3 transcript, and case 1 was negative. The data presented expands the known differentiation of alveolar rhabdomyosarcoma.
International Journal of Surgical Pathology 08/2008; 17(2):135-41. · 1.00 Impact Factor
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ABSTRACT: The "de novo" formation of fluid-conducting patterns by tumor cells, termed vasculogenic mimicry (VM), is associated with increased mortality in many different solid tumors.
To identify VM patterns in hepatocellular carcinoma (HCC) and to determine whether these patterns were associated with more rapid tumor recurrence after orthotopic liver transplantation.
Subjects included 20 patients who underwent orthotopic liver transplantation and were found to have HCC in the liver explant. Samples from 5 normal postmortem livers and 5 explanted livers with hepatitis C virus cirrhosis without HCC served as control tissues. Patterned matrix VM expression in HCC was identified by the presence of laminin-positive loops surrounding packets of tumor cells. Time to HCC recurrence after orthotopic liver transplantation was compared between patients with and without patterned VM expression. The relationships among VM in HCC, cause of chronic liver disease, serum alpha-fetoprotein level at the time of diagnosis, tissue expression by epidermal growth factor receptor, and endothelial markers including vascular endothelial growth factor and CD31 were assessed.
Patterned matrix VM was identified in 11 of 20 primary HCC tissue samples. Vasculogenic mimicry was absent in all 10 control cases and was not identified in any area of dysplasia. The expression of VM in HCC lesions in liver explants was associated with more rapid posttransplant recurrence (P = .01). Vasculogenic mimicry was not associated with the cause of liver disease, serum alpha-fetoprotein level at time of diagnosis, or expression of epidermal growth factor receptor, vascular endothelial growth factor, or CD31.
Vasculogenic mimicry of the patterned matrix type is present in hepatocellular carcinoma and is associated with tumor recurrence after orthotopic liver transplantation. Vasculogenic mimicry lesions are not associated with endothelial markers in HCC.
Archives of pathology & laboratory medicine 01/2008; 131(12):1776-81. · 2.58 Impact Factor
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Vivian Barak,
Shahar Frenkel,
Klara Valyi-Nagy,
Lu Leach,
Marsha A Apushkin, Amy Y Lin,
Inna Kalickman,
Nikola A Baumann,
Jacob Pe'er,
Andrew J Maniotis,
Robert Folberg
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ABSTRACT: To develop a method to screen for serum biomarkers of early hepatic metastasis from uveal melanoma.
Cytokeratin 18 (TPS) was identified from gene expression profiles as protein generated by highly invasive uveal melanoma cells. Sera were collected from two groups of 15 SCID mice 2 weeks after injection of either tissue culture medium or MUM2B human metastatic uveal melanoma cells into the mouse liver. Serum TPS levels were assayed in 53 healthy human controls, 64 uveal melanoma patients who were disease free for at least 10 years, and 37 patients with metastatic uveal melanoma.
After 2 weeks, small hepatic nodules (0.1-2.8 mm; mean, 0.80 mm) developed in 11 of 15 mice injected with MUM2B cells. Serum TPS levels in media-injected mice (84.7 U/L) were substantially lower than levels in MUM2B-injected mice (601 mug/L). TPS levels were significantly higher (P < 0.0001) in patients with metastatic uveal melanoma (139.63 +/- 22.20) than in healthy controls (54.23 +/- 0.01) or in patients free of disease (69.29 +/- 9.76). Significant differences were found between TPS levels before and after the development of hepatic metastases (P < 0.01), and serum TPS levels became elevated in four patients at least 6 months before the detection of hepatic metastases by abdominal ultrasonography.
The direct-injection model of uveal melanoma in the mouse liver may be used to screen for potential serum biomarkers of metastatic uveal melanoma.
Investigative Ophthalmology & Visual Science 11/2007; 48(10):4399-402. · 3.60 Impact Factor
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ABSTRACT: To model the behavior of uveal melanoma in the liver.
A 15-muL suspension of metastatic MUM2B or either primary OCM1 or M619 uveal melanoma cells was injected into the liver parenchyma of 105 CB17 SCID mice through a 1-cm abdominal incision. Animals were killed at 2, 4, 6, or 8 weeks after injection. Before euthanatization, 3% FITC-BSA buffer was injected into the retro-orbital plexus of one eye of three mice. Liver tissues were examined by light and fluorescence microscopy, and were stained with human anti-laminin. Vasculogenic mimicry patterns were reconstructed from serial laser scanning confocal microscopic stacks.
OCM1a cells formed microscopic nodules in the mouse liver within 2 weeks after injection and metastasized to the lung 6 weeks later. By contrast, M619 and MUM2B cells formed expansile nodules in the liver within 2 weeks and gave rise to pulmonary metastases within 4 weeks after injection. Vasculogenic mimicry patterns, composed of human laminin and identical with those in human primary and metastatic uveal melanomas, were detected in the animal model. The detection of human rather than mouse laminin in the vasculogenic mimicry patterns in this model demonstrates that these patterns were of tumor cell origin and were not co-opted from the mouse liver microenvironment.
There are currently no effective treatments for metastatic uveal melanoma. This direct-injection model focuses on critical interactions between the tumor cell and the liver. It provides for translationally relevant approaches to the development of new modalities to detect small tumor burdens in patients, to study the biology of clinical dormancy of metastatic disease in uveal melanoma, to design and test novel treatments to prevent the emergence of clinically manifest liver metastases after dormancy, and to treat established uveal melanoma metastases.
Investigative Ophthalmology & Visual Science 08/2007; 48(7):2967-74. · 3.60 Impact Factor
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Archives of Ophthalmology 06/2007; 125(5):703-5. · 3.71 Impact Factor
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ABSTRACT: We previously described techniques to generate 3-dimensional reconstructions of the tumor microcirculation using immunofluorescence histochemistry and laser scanning confocal microscopy on serial sections from archival formalin-fixed, paraffin-embedded tissues. By aligning sequential z-stacks in an immersive visualization environment (ImmersaDesk), the need to insert fiduciary markers into tissue was eliminated. In this study, we developed methods to stitch overlapping confocal z-series together to extend the surface area of interest well beyond that captured by the confocal microscope objective and developed methods to quantify the distribution of markers of interest in 3 dimensions. These techniques were applied to the problem of comparing the surface area of nonendothelial cell-lined, laminin-rich looping vasculogenic mimicry (VM) patterns that are known to transmit fluid, with the surface area of endothelial cell-lined vessels in metastatic uveal melanoma to the liver in 3 dimensions. After labeling sections with antibodies to CD34 and laminin, the surface area of VM patterns to vessels was calculated by segmenting out structures that labeled with laminin but not with CD34 from those structures labeling with CD34, or CD34 and laminin. In metastatic uveal melanoma tissues featuring colocalization of high microvascular density [66.4 microvessels adjusted for 0.313 mm2 area (range 56.7 to 72.7)] and VM patterning, the surface area of VM patterns was 11.6-fold greater (range 10.8 to 14.1) than the surface provided by CD34-positive vessels. These methods may be extended to visualize and quantify molecular markers in 3 dimensions in a variety of pathologic entities from archival paraffin-embedded tissues.
Applied immunohistochemistry & molecular morphology: AIMM / official publication of the Society for Applied Immunohistochemistry 04/2007; 15(1):113-9. · 1.63 Impact Factor
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Robert Folberg,
Zarema Arbieva,
Jonas Moses,
Amin Hayee,
Tone Sandal,
Shrihari Kadkol, Amy Y Lin,
Klara Valyi-Nagy,
Suman Setty,
Lu Leach,
Patricia Chévez-Barrios,
Peter Larsen,
Dibyen Majumdar,
Jacob Pe'er,
Andrew J Maniotis
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ABSTRACT: The histological detection of laminin-rich vasculogenic mimicry patterns in human primary uveal melanomas is associated with death from metastases. We therefore hypothesized that highly invasive uveal melanoma cells forming vasculogenic mimicry patterns after exposure to a laminin-rich three-dimensional microenvironment would differentially express genes associated with invasive and metastatic behavior. However, we discovered that genes associated with differentiation (GDF15 and ATF3) and suppression of proliferation (CDKNa1/p21) were up-regulated in highly invasive uveal melanoma cells forming vasculogenic mimicry patterns, and genes associated with promotion of invasive and metastatic behavior such as CD44, CCNE2 (cyclin E2), THBS1 (thrombospondin 1), and CSPG2 (chondroitin sulfate proteoglycan; versican) were down-regulated. After forming vasculogenic mimicry patterns, uveal melanoma cells invaded only short distances, failed to replicate, and changed morphologically from the invasive epithelioid to the indolent spindle A phenotype. In human tissue samples, uveal melanoma cells within vasculogenic mimicry patterns assumed the spindle A morphology, and the expression of Ki67 was significantly reduced in adjacent melanoma cells. Thus, the generation of vasculogenic mimicry patterns is accompanied by dampening of the invasive and metastatic uveal melanoma genotype and phenotype and underscores the plasticity of these cells in response to cues from the microenvironment.
American Journal Of Pathology 11/2006; 169(4):1376-89. · 4.89 Impact Factor
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ShriHari S Kadkol, Amy Y Lin,
Vivian Barak,
Inna Kalickman,
Lu Leach,
Klara Valyi-Nagy,
Dibyen Majumdar,
Suman Setty,
Andrew J Maniotis,
Robert Folberg,
Jacob Pe'er
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ABSTRACT: This was a pilot study conducted to examine the expression of osteopontin in uveal melanoma and to determine whether serum osteopontin can be used in detecting metastatic uveal melanoma.
Osteopontin mRNA was measured in three uveal melanoma cell lines of various invasive potential by real-time PCR. Tissue sections of primary and metastatic uveal melanomas were stained for osteopontin. Serum osteopontin levels were measured by ELISA assays in 15 patients with metastatic uveal melanoma and in 37 patients who were disease-free for at least 10 years after treatment of the primary tumor. Paired serum samples drawn from eight patients before and after development of metastasis were analyzed.
By real-time PCR, highly invasive primary and metastatic uveal melanoma cells expressed 6- and 250-fold excess osteopontin mRNA, respectively, compared with poorly invasive primary uveal melanoma cells. Tissue sections of primary uveal melanomas lacking looping vasculogenic mimicry patterns either did not stain for osteopontin or exhibited weak, diffuse staining. In primary melanomas containing looping vasculogenic mimicry patterns, strong osteopontin staining was detected in the tumor periphery where patterns were located. Diffuse strong expression of osteopontin was detected in eight samples of uveal melanomas metastatic to the liver. Serum osteopontin levels were significantly higher in patients with metastatic uveal melanoma than in patients who had been disease free for at least 10 years after treatment (P = 0.0001) or in age-matched control subjects. Serum osteopontin levels were significantly higher (P = 0.008) after metastasis than before the detection of metastasis in eight patients. When a cutoff of 10 ng/mL was used, the sensitivity and specificity of serum osteopontin in detecting metastatic melanoma was 87.5%, and the area under the receiver operator characteristic curve was 96%.
Osteopontin is expressed diffusely in tissue sections of hepatic metastases from uveal melanoma, and increased serum osteopontin levels correlate with melanoma metastasis to the liver with high specificity and sensitivity.
Investigative Ophthalmology & Visual Science 04/2006; 47(3):802-6. · 3.60 Impact Factor
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ABSTRACT: To determine whether there is an association between gene expression profile and looping extravascular matrix patterns in primary uveal melanomas.
Laboratory investigation.
Formalin-fixed, paraffin-embedded sections from 22 primary uveal melanomas that previously were analyzed by microarray gene expression profiling were stained for periodic acid-Schiff and scored in a masked fashion for the presence of looping extravascular matrix patterns.
A strong association was observed between looping patterns and the unfavorable class 2 molecular prognostic signature (P < .001).
Looping extravascular matrix patterns occur almost exclusively in class 2 uveal melanomas. This finding may provide new insights into the pathogenesis and management of uveal melanoma.
American Journal of Ophthalmology 11/2005; 140(4):748-9. · 4.22 Impact Factor
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ABSTRACT: Molecular analyses indicate that periodic acid-Schiff (PAS)-positive (laminin-rich) patterns in melanomas are generated by invasive tumor cells by vasculogenic mimicry. Some observers, however, consider these patterns to be fibrovascular septa, generated by a stromal host response.
To delineate differences between vasculogenic mimicry patterns and fibrovascular septa in primary uveal melanomas.
Frequency distributions, associations with outcome, and thicknesses of trichrome-positive and PAS-positive looping patterns were determined in 234 primary uveal melanomas. Sequential sections of 13 additional primary uveal melanomas that contained PAS-positive/trichrome-negative looping patterns were stained for type I and type IV collagens, laminin, and fibronectin. Real-time quantitative polymerase chain reaction was performed on RNA from cultured uveal melanoma cells for the expression of COL1A1, COL4A2, and fibronectin.
Trichrome-positive loops were encountered less frequently than PAS-positive loops (10% vs 56%, respectively). Death from metastatic melanoma was strongly associated with PAS-positive (P < .001) but not with trichrome-positive (P = .57) loops. Trichrome-positive loops were significantly thicker than PAS-positive loops (P < .001). The PAS-positive patterns stained positive for laminin, type I and type IV collagens, and fibronectin. Type I collagen was detected within melanoma cells and focally within some PAS-positive patterns. Real-time quantitative polymerase chain reaction revealed 3-fold, 25-fold, and 97-fold increases, respectively, in expression of COL4A2, fibronectin, and COL1A1 by invasive pattern-forming primary melanoma cells compared with poorly invasive non-pattern-forming cells.
Fibrovascular septa are rare and prognostically insignificant in uveal melanomas, whereas vasculogenic mimicry patterns are associated with increased mortality. Type I collagen, seen focally in some vasculogenic mimicry patterns, may be synthesized by tumor cells, independent of a host stromal response.
Archives of pathology & laboratory medicine 08/2005; 129(7):884-92. · 2.58 Impact Factor
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Archives of Ophthalmology 10/2004; 122(9):1402-3. · 3.71 Impact Factor
