Tadalafil-induced subretinal and choroidal hemorrhage in a patient with an unsuspected uveal (choroidal and ciliary body) melanoma.
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Carbolines↗
Biomedical subjects
Robert Folberg
Publications and source records attributed to Robert Folberg.
Accuracy Evaluation for Region Centroid-Based Registration of Fluorescent CLSM Imagery.
We present an accuracy evaluation of a semi-automatic registration technique for 3D volume reconstruction from fluorescent confocal laser scanning microscope (CLSM) imagery. The presented semi-automatic method is designed based on our observations that (a) an accurate point selection is much harder than an accurate region (segment) selection for a human, (b) a centroid selection of any region is less accurate by a human than by a computer, and (c) registration based on structural shape of a region rather than based on intensity-defined point is more robust to noise and to morphological deformation of features across stacks. We applied the method to image mosaicking and image alignment registration steps and evaluated its performance with 20 human subjects on CLSM images with stained blood vessels. Our experimental evaluation showed significant benefits of automation for 3D volume reconstruction in terms of achieved accuracy, consistency of results and performance time. In addition, the results indicate that the differences between registration accuracy obtained by experts and by novices disappear with the proposed semi-automatic registration technique while the absolute registration accuracy increases.
Journal Article↗
Osteopontin expression and serum levels in metastatic uveal melanoma: a pilot study.
PURPOSE: 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. METHODS: 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. RESULTS: 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%. CONCLUSIONS: 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.
Aged↗
Tumor cell plasticity in uveal melanoma: microenvironment directed dampening of the invasive and metastatic genotype and phenotype accompanies the generation of vasculogenic mimicry patterns.
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.
Biomarkers, Tumor↗
Association between microarray gene expression signature and extravascular matrix patterns in primary uveal melanomas.
PURPOSE: To determine whether there is an association between gene expression profile and looping extravascular matrix patterns in primary uveal melanomas. DESIGN: Laboratory investigation. METHODS: 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. RESULTS: A strong association was observed between looping patterns and the unfavorable class 2 molecular prognostic signature (P < .001). CONCLUSIONS: 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.
Gene Expression↗
Reconstruction and exploration of three-dimensional confocal microscopy data in an immersive virtual environment.
An immersive virtual environment for interactive three-dimensional reconstruction and exploration of confocal microscopy data is presented. For some structures automatic alignment of serial sections can lead to geometric distortions. The superior visual feedback of a Virtual Reality system is used to aid in registering and aligning serial sections interactively. An ImmersaDesk Virtual Reality display system is used for display and interaction with the volumetric confocal data. Detailed methods for handling both single-section and multi-section confocal data are described.
Humans↗
Chromatin organization measured by AluI restriction enzyme changes with malignancy and is regulated by the extracellular matrix and the cytoskeleton.
Given that expression of many genes changes when cells become malignant or are placed in different microenvironments, we asked whether these changes were accompanied by global reorganization of chromatin. We reasoned that sequestration or exposure of chromatin-sensitive sites to restriction enzymes could be used to detect this reorganization. We found that AluI-sensitive sites of nonmalignant cells were relatively more exposed compared to their malignant counterparts in cultured cells and human tumor samples. Changes in exposure and sequestration of AluI-sensitive sites in normal fibroblasts versus fibrosarcoma or those transfected with oncogenes, nonmalignant breast cells versus carcinomas and poorly metastatic versus highly invasive melanoma were shown to be independent of the cell cycle and may be influenced by proteins rich in disulfide bonds. Remarkably, regardless of degree of malignancy, AluI-sensitive sites became profoundly sequestered when cells were incubated with laminin, Matrigel, or a circular RGD peptide (RGD-C), but became exposed when cells were placed on collagen I or in serum-containing medium. Disruption of the actin cytoskeleton led to exposure, whereas disruption of microtubules or intermediate filaments exerted a sequestering effect. Thus, AluI-sensitive sites are more sequestered with increasing malignant behavior, but the sequestration and exposure of these sites is exquisitely sensitive to information conferred to the cell by molecules and biomechanical forces that regulate cellular and tissue architecture.
Cell Culture Techniques↗
Age of retinal hemorrhages by iron detection: an animal model.
Intraretinal hemorrhages have been found in some abusively injured infants and children. Intraretinal hemosiderin has been proposed as an indication of previous injury. The limits of the accuracy of the proposal have not been established. Experimental central retinal vein occlusion (CRVO) was produced in 20 eyes of adult rhesus monkeys as part of ongoing research by one of the authors (SSH). The animal experiments were conducted in accordance with a research protocol approved by the Animal Care Committee, University of Iowa. CRVO produced diffuse intraretinal hemorrhages. Clinical ocular examinations assessed the onset and time course of retinal hemorrhages. Enucleation specimens were used to assess hemosiderin in the retinas. Hemosiderin was detected within 2 days of induction of retinal hemorrhages. It was detected in only 4 of 11 eyes (36%) studied more than 1 week following induction of hemorrhages. In 2 eyes, hemosiderin was found 9 and 16.8 months after development of hemorrhages. Hemosiderin can represent organization of current hemorrhage rather than evidence of prior hemorrhage. This study does not allow specifying the duration of hemorrhages with greater precision than "more than 2 days prior to death," and that, only if there is no survival interval. Failure to detect hemosiderin does not exclude prior retinal hemorrhages.
Animals↗
Distinguishing fibrovascular septa from vasculogenic mimicry patterns.
CONTEXT: 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. OBJECTIVE: To delineate differences between vasculogenic mimicry patterns and fibrovascular septa in primary uveal melanomas. DESIGN: 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. RESULTS: 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. CONCLUSIONS: 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.
Azo Compounds↗
Panophthalmitis due to clostridium septicum.
PURPOSE: To describe patient survival in a rare case of endogenous Clostridium septicum sepsis with panophthalmitis. DESIGN: Observational case report. METHODS: Both eyes of a female patient were examined in a hospital setting. RESULTS: A 68-year-old woman had right orbital pain, proptosis, panophthalmitis, mental confusion and fever for 2 days. Blood cultures were significant for Clostridium septicum. The patient did not improve after treatment with intravenous broad-spectrum antibiotics and the right eye was enucleated. The patient survived the acute infection and extensive systemic evaluation revealed an undiagnosed colon carcinoma that may have been responsible for colonization and vascular dissemination of Clostridium septicum. CONCLUSIONS: Clostridium septicum panophthalmitis and sepsis can be the presenting sign in patients with unsuspected malignancies, particularly colon cancer. Patients can survive the infection with aggressive therapy with systemic antibiotics combined with removal of the infected tissue.
Acute Disease↗
Noninvasive in vivo detection of prognostic indicators for high-risk uveal melanoma: ultrasound parameter imaging.
PURPOSE: Primary malignant melanoma of the choroid and ciliary body has traditionally been treated without histologic staging, using purely clinical indicators. The presence of extravascular matrix patterns (EMP) in histologic sections of uveal melanoma has been shown to be an independent indicator of metastatic risk. These patterns are of a dimension and physical composition that are likely to be detected with ultrasound backscatter analysis. Our aim was to determine whether ultrasound parameter imaging could detect the presence of EMP at a diagnostically significant level for treatment staging and for planning investigational studies of therapeutic modalities. DESIGN: Prospective, masked ultrasound-pathologic correlative study. PARTICIPANTS: One hundred seventeen patients diagnosed with previously untreated choroidal melanoma were scanned within 2 weeks before enucleation. METHODS: Tumors were evaluated histologically and divided into high-risk and low-risk groups on the basis of the presence of 2% or more histologic cross-sectional area composed of EMP patterns. Digital ultrasound data were processed to generate parameter images representing the size and concentration of ultrasound scatterers. Histologic and ultrasound images and data were correlated, and linear and nonlinear statistical methods were used to create multivariate models for noninvasive differentiation of high-risk and low-risk tumors. MAIN OUTCOME MEASURES: Presence or absence of high-risk EMP and associated ultrasound parameter classification models. RESULTS: Of the 117 tumors, 69 were classified as low risk, and 48 were classified as high-risk with histologic analysis. A classification that used ultrasound parameter image features with linear discriminant analysis could correctly identify 79.5% of cases retrospectively and 75.2% of cases by use of cross-validation, an estimate of prospective classification ability. By use of a more powerful classification technique (support vector machine), 93.1% of cases were correctly classified retrospectively. With a cross-validation procedure, 80.10% of cases were correctly classified. CONCLUSIONS: Ultrasound can be used noninvasively to classify tumors into high-risk and low-risk groups by detecting the presence of EMP patterns. By the use of previous studies that compared the histologic presence of EMP patterns with patient survival, estimates of hazard rates associated with ultrasound risk groups can be made. The noninvasive ultrasound classification is potentially useful as a prognostic variable and as a tool for stratification of patient populations for tumor treatment evaluation.
Eye Enucleation↗
Vascular perfusion of choroidal melanoma by 3.0 tesla magnetic resonance imaging.
PURPOSE: Because signal-to-noise performance improves with increased magnetic field strength, the quality of magnetic resonance images is greater at 3.0 tesla (T) than at 1.5 T. Because of the longer T1 values at higher field strength, intravenously administered magnetic resonance contrast agents provide improved T1 enhancement at 3.0 T. We have used these factors to obtain high-quality contrast-enhanced imaging of small intraocular lesions using a standard head radiofrequency volume coil. Specifically, we have examined lesion size and magnitude of maximum contrast enhancement in a series of intraocular melanomas before and during therapy. METHODS: Eighteen patients with intraocular masses were examined by 3.0 T magnetic resonance imaging (MRI) including intravenous contrast enhancement. Precontrast images were acquired through the orbits followed by sequential postcontrast images at 1-minute intervals for 5 minutes. The magnitude of contrast enhancement of the lesion, extraocular muscles, and brain parenchyma was measured as a percentage increase in magnetic resonance signal over the preenhancement signal intensity. RESULTS: Lesions demonstrated different levels of enhancement ranging up to 130%. Three patterns of enhancement--0% to 20%, 20% to 50%, and >50%-were identified. Brain parenchyma, benign lesions, and responsive tumors following brachytherapy with 125I demonstrated enhancement of less than 20%. Four choroidal melanomas showed intermediate (20% to 50%) levels of enhancement. Four malignant lesions (three melanomas, one metastatic tumor), as well as the extraocular muscles, showed strong, rapid enhancement (>50%). Four patients who had MRI studies before and following plaque brachytherapy ultimately demonstrated a decline in the contrast enhancement following treatment. CONCLUSIONS: Contrast enhancement of intraocular lesions measured by 3.0 T MRI demonstrates different patterns of enhancement that may be useful for indicating the degree of malignancy and in monitoring response to therapy.
Adult↗
Optic nerve tissue shrinkage during pathologic processing after enucleation for retinoblastoma.
OBJECTIVES: To quantify and analyze the differences between the length of the optic nerve as measured by the ophthalmologist in the operating room after enucleation and the length as measured by the pathologist after fixation. METHODS: The authors performed a retrospective review of patients who underwent either primary or secondary enucleation for retinoblastoma at the Ophthalmic Oncology Center of the New York-Presbyterian Hospital-Cornell campus between November 1979 and August 2001. Intraoperative notes and pathologic reports were reviewed to determine the length of the resected optic nerve as recorded by both the surgeon and pathologist. RESULTS: Sufficient data for inclusion in the study were available from 100 enucleation specimens belonging to 96 patients. A significant degree of shrinkage of the optic nerve occurred after fixation, with a mean shrinkage of 30.3% from the time of enucleation to the time of measurement by the pathologist. Age at enucleation affected the degree of optic nerve shrinkage; nerves from younger children underwent more shrinkage than nerves from older patients. Sex of the patient and the laterality of disease did not significantly affect optic nerve shrinkage. CONCLUSIONS: A significant degree of shrinkage of the optic nerve occurs in retinoblastoma enucleation specimens after fixation prior to pathologic analysis. This finding must be taken into account when comparing different series and making recommendations for chemoprophylaxis based solely on histopathologic examination.
Child↗
Spectral parameter imaging for detection of prognostically significant histologic features in uveal melanoma.
Specific extracellular matrix patterns in uveal melanoma are associated with metastatic risk. The laminin-rich composition and dimensions (on the order of a wavelength or less) of these structures suggest that acoustic backscatter might be affected by their presence. In this study, 10-MHz radiofrequency (RF) ultrasound (US) data were acquired before surgical removal of 117 eyes with uveal malignant melanoma. Histologic sections were evaluated for the presence of matrix patterns and acoustic backscatter was characterized using calibrated spectrum analysis. Statistical correlations between acoustic and histologic patterns were determined and linear discriminant analysis (LDA) and radial basis networks (RBN) were used to develop classification models for histologically based risk groups. Statistically significant correlations were found between acoustic parameters and the presence of histologic matrix-rich patterns. Retrospective classification accuracies of 74.4% and 78.6% were obtained with LDA and RBN, respectively. Leave-one-out analyses indicated estimated predictive accuracies of 71.8% and 75.0% for LDA and RBN, respectively.
Extracellular Matrix↗
Recommendations for the reporting of tissues removed as part of the surgical treatment of common malignancies of the eye and its adnexa. The Association of Directors of Anatomic and Surgical Pathology.
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Carcinoma, Squamous Cell↗
Recommendations for the reporting of tissues removed as part of the surgical treatment of common malignancies of the eye and its adnexa.
The Association of Directors of Anatomic and Surgical Pathology developed recommendations for the surgical pathology report for common malignant tumors. The recommendations for tumors of the eye and its adnexa are reported.
Eye Neoplasms↗
Recommendations for the reporting of tissues removed as part of the surgical treatment of common malignancies of the eye and its adnexa.
The Association of Directors of Anatomic and Surgical Pathology developed recommendations for the surgical pathology report for common malignant tumors. The recommendations for tumors of the eye and its adnexa are reported.
Eye Neoplasms↗
Three-dimensional reconstruction of extravascular matrix patterns and blood vessels in human uveal melanoma tissue: techniques and preliminary findings.
PURPOSE: Looping patterns rich in laminin are present in tissue samples of primary aggressive human uveal melanomas and their metastases. Because these extravascular patterns connect to blood vessels and transmit fluid in vitro and in vivo, the three-dimensional configuration of these patterns has been the subject of considerable speculation. In the current study, methods were devised to describe the three-dimensional configuration of looping extravascular matrix patterns in archival human uveal melanoma tissue. METHODS: Twenty-five serial 4-microm-thick sections from primary uveal melanoma tissue were labeled with fluorescence-tagged laminin and examined by confocal microscopy to generate a Z-series within each 4-microm-thick section. The z-series from each section was stacked using an immersive three-dimensional environment (ImmersaDesk; Fakespace, Kitchener, Ontario, Canada) to allow for precise alignment and compensation for distortion artifact. RESULTS: Extravascular matrix patterns that appeared to form loops in two dimensions were shown to represent thin wrappings around branching and twisting cylindrical groupings of melanoma cells. Blood vessels joined with some of these laminin-positive cylindrical wrappings. CONCLUSIONS: In this preliminary study, periodic acid-Schiff (PAS)-positive laminin-rich looping patterns in two-dimensional tissue sections appear to outline cylindrical branching packets of melanoma cells rather than spheroidal nests. The conduction of fluid through this extravascular system may provide a novel delivery system for contrast and diagnostic agents.
Antigens, CD34↗