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Biomedical subjects

J Pe'er

Publications and source records attributed to J Pe'er.

At least 19 recordsLinked to original sources
PubMed1999

Microsatellite instability and p53 mutations in pediatric secondary malignant neoplasms.

BACKGROUND: The past decade has witnessed a growing frequency of therapy-related secondary tumors. The authors studied nine children with secondary malignancies. The primary tumors were bilateral retinoblastoma, neuroblastoma, brain tumor, Wilms' tumor, colon adenocarcinoma, and Hodgkin's disease. The secondary tumors were osteosarcoma at the site of previous radiotherapy, myelodysplastic syndrome, acute myelocytic leukemia, glioblastoma, thyroid carcinoma, and B-cell lymphoma. METHODS: DNA was extracted from the primary and secondary tumors and analyzed for genetic alterations in the p53 gene and in 7 separate microsatellites. RESULTS: The authors found p53 mutations in 7 patients, loss of heterozygosity in 1 patient, and both mutation and loss of heterozygosity in 1 patient. Mutations were demonstrated in the primary tumors only in two patients and in the secondary tumors only in three patients. Two patients had a mutation in both the primary and the secondary tumor; in both patients the two mutations were in different exons. Microsatellite instability (MIN) was identified in five to seven loci in the secondary tumors of all patients. CONCLUSIONS: The observed MIN is compatible with the presence of a mutator phenotype that predisposes these children to the development of secondary malignancies.

Child↗
PubMed1999

Multifocal choroidal malignant melanoma: at least 3 melanomas in one eye.

OBJECTIVES: To describe a case of an enucleated eye harboring multiple choroidal malignant melanomas. METHODS: Clinical, ultrasonographic, and histopathological evaluations. RESULTS: Meticulous sectioning of the globe did not disclose any structural continuity between the 3 choroidal melanomas. Fourth and fifth masses were connected to one of the tumors by fibrous tissue and therefore were not considered as additional distinct lesions. CONCLUSION: Although very rare, a single eye can harbor multiple distinct choroidal melanomas.

Aged↗
PubMed1999

Immunostaining of the estrogen receptor in conjunctival primary acquired melanosis.

Conjunctival primary acquired melanosis (PAM) is a frequent precursor of conjunctival melanoma. Since there is indirect evidence that the conjunctiva is an estrogen-responsive tissue, and since it was suspected that estrogen has a role in the etiology of melanoma, we decided to evaluate whether PAM may be responsive to estrogen. Formalin-fixed, paraffin-embedded sections from 13 cases of PAM and 2 cases of conjunctival melanoma were immunostained with an estrogen-receptor (ER)-specific antibody. All lesions and the normal conjunctival tissue adjacent to the lesions were found to be ER negative. It is concluded that PAM and normal conjunctiva are not sensitive directly to estrogen. When considering previously reported data, it is conceivable that the normal conjunctiva, but not PAM, is indirectly affected by estrogen.

Adolescent↗
PubMed1999

Morphologic changes in chronic high-pressure experimental glaucoma in rhesus monkeys.

PURPOSE: To investigate morphologic changes in the posterior segment of the eye and optic nerve head (ONH) in rhesus monkeys with experimental glaucoma, and to evaluate the effect of age and vascular disease on the glaucomatous damage. METHODS: This study was conducted in 36 eyes of rhesus monkeys 11 to 24 years of age. Experimental glaucoma was produced by laser photocoagulation of the anterior chamber angle in 28 eyes, and the remaining 8 eyes served as the nonglaucomatous group. Of the 28 glaucomatous eyes, 19 belonged to animals with experimental atherosclerosis and chronic arterial hypertension (A-H group); the remaining 9 had no A-H (non-AH group). Among the 8 eyes without glaucoma, 5 belonged to A-H animals and the remaining 3 to animals without A-H. All eyes underwent IOP measurements and fundus photography before laser photocoagulation and serially thereafter for 4 to 60 months (median 22.5 months). After enucleation, eyes were fixed in formalin for light microscopic studies. Morphologic abnormalities were evaluated and graded. Correlation analyses between morphologic parameters and clinical data were performed. RESULTS: The highest IOP ranged from 44 to 80 mmHg, but during the follow-up period median IOP was mostly 28 mmHg (mean 27+/-4.8 mmHg). On histopathologic examination, the eyes showed moderate to severe atrophy of the temporal peripapillary choroid (67%), choriocapillaris (70%), and RPE (12%); axonal atrophy in the retinal nerve fiber layer (85%), prelaminar region (69%), lamina cribrosa (66%), and retrolaminar region (82%); fibrous septal thickening in the lamina cribrosa (77%) and retrolaminar region (86%); bowing backward of the lamina cribrosa (77%); overall tissue atrophy in the prelaminar region (81%); and retinal ganglion cell atrophy (74%). The data showed a positive correlation between the ONH damage and atrophic changes in the temporal peripapillary choroid, and suggested greater damage in animals with A-H than in those without A-H. CONCLUSION: Vascular disease may influence glaucomatous damage in the ONH, as damage in the ONH was greater in animals with A-H than in those without A-H. A similar relationship also may exist between age and glaucomatous damage, but this needs to be investigated further in a larger study. It is postulated that the bowing back of the lamina cribrosa seen in optic disc cupping is produced by retrolaminar septal fibrosis and axonal loss. Although elevated IOP no doubt played an important role, the data suggest that the glaucomatous changes that were observed in this study are not simply mechanical in nature (due to the raised IOP), but may represent a multifactorial phenomenon.

Aging↗
PubMed1998

Imaging the microvasculature of choroidal melanomas with confocal indocyanine green scanning laser ophthalmoscopy.

OBJECTIVE: To image the microvasculature of choroidal melanoma with a new confocal scanning laser ophthalmoscope. METHODS: Eighteen consecutive patients, each with a unilateral choroidal melanoma, were examined prospectively. Indocyanine green angiography was performed with a new confocal scanning laser ophthalmoscope that enabled serial optical sectioning through the tumor. Two additional patients were studied with indocyanine green angiography and confocal scanning laser ophthalmoscopy just before enucleation for posterior choroidal melanomas. The histologic identification of microvasculature patterns was compared with the angiograms for these patients. RESULTS: In the series of 18 patients, 16 (89%) indocyanine green angiograms with optical sectioning revealed tubular structures within the melanoma that were identified as tumor vessels based on their angiographic appearance. The microvasculature patterns identified by indocyanine green angiography correlated well with the histologic appearance of these microvasculature patterns in both patients for whom histologic verification was available. CONCLUSIONS: This preliminary study suggests that indocyanine green angiography with confocal scanning laser ophthalmoscopy images the microvasculature of choroidal melanomas and may be capable of detecting microvasculature patterns that have been shown to be prognostically significant from histopathological studies.

Adult↗
PubMed1998

Microcirculation architecture of metastases from primary ciliary body and choroidal melanomas.

PURPOSE: To describe the microcirculation architecture of metastatic choroidal and ciliary body melanoma. METHOD: Histologic sections of 35 metastases from 19 primary melanomas were stained to demonstrate microcirculation. RESULT: The appearance of microcirculatory networks in metastases is independent of the target organ but associated with the size of the metastatic deposit (estimated coefficient = 0.5959; SE = 0.3024; P = .0488). CONCLUSION: The microcirculatory patterns of primary uveal melanomas that are associated with metastatic behavior appear in foci of metastasis, regardless of the site of dissemination.

Choroid Neoplasms↗
PubMed1998

Nerve growth factor is preformed in and activates human peripheral blood eosinophils.

BACKGROUND: Recent studies have shown that nerve growth factor (NGF) is produced by and can act on several immune-inflammatory cells. OBJECTIVES: The objective of this study was to study the effects of NGF on human peripheral blood eosinophils and assess whether these cells produce and store NGF. METHODS: Eosinophils were purified by negative immunoselection (magnetic cell sorting systems, purity 98% to 100%) from 13 subjects (9 to 26 years old) with mild blood eosinophilia, mainly of allergic origin. Eosinophils were incubated with NGF (50 to 1000 ng/mL), and supernatants were collected for measurement of eosinophil peroxidase (EPO, 20 minutes, colorimetric enzymatic assay) and IL-6 (12 hours, ELISA). Eosinophil viability was evaluated by Trypan blue test (days 2, 3, and 4). NGF content in freshly isolated eosinophils, after ultrasound disruption, was determined with a 2-site immunoenzymatic assay. The presence of mRNA for NGF was evaluated by reverse transcription PCR. RESULTS: NGF caused EPO release (highly significant at 1000 ng/mL NGF). IL-6 release from eosinophils was not higher than IL-6 spontaneously released into culture medium alone. NGF did not significantly affect the number of viable eosinophils. NGF was found in the eosinophil sonicates (1.5 to 17.8 pg/mL per 106 cells). Similarly, mRNA for NGF was detected by reverse transcription PCR in the freshly isolated eosinophils. CONCLUSIONS: NGF activates human peripheral blood eosinophils from subjects with mild eosinophilia to selectively release inflammatory mediators. Eosinophils store and produce NGF. Therefore the capability of NGF to induce a secretory response and its production and storage by circulating human eosinophils suggest a possible role for NGF in conditions associated with eosinophilia, including allergic disease.

Adolescent↗
PubMed1998

Vascular endothelial growth factor upregulation in human central retinal vein occlusion.

BACKGROUND AND OBJECTIVE: Vascular endothelial growth factor (VEGF), a key mediator of intraocular neovascularization, is triggered by hypoxia and has been shown in the eyes of animal models of central retinal vein occlusion (CRVO). However, there is little information on CRVO in humans, in particular, the identity of VEGF-producing cells. STUDY DESIGN: The study design was molecular localization of the site of VEGF production in the eyes of patients with CRVO. PARTICIPANTS: Ten formaldehyde solution-fixed and paraffin-embedded eyes removed surgically from patients with CRVO and neovascular glaucoma were studied. Five eyes with uveal melanoma and no neovascularization served as control specimens. METHODS: Thin whole-eye sections were hybridized in situ with a VEGF-specific probe to identify cells producing VEGF messenger RNA (mRNA). RESULTS: All ten eyes with CRVO showed evidence of intraretinal expression of VEGF mRNA. In all eyes, the inner nuclear layer showed VEGF-upregulated expression. Upregulation of VEGF mRNA was identified in four eyes in the ganglion cell layer and in two eyes with retinal detachment in the outer nuclear layer as well. CONCLUSIONS: The population of VEGF-producing retinal cells in each eye is likely to represent cells residing in ischemic regions of the retina. Hypoxia-induced VEGF is, most likely, the linking factor between retinal ischemia and iris and retinal neovascularization in CRVO.

Aged↗
PubMed1998

MIB-1 and PC-10 immunostaining for the assessment of proliferative activity in primary acquired melanosis without and with atypia.

AIMS: To compare the proliferative activity of intraepithelial melanocytes in primary acquired melanosis (PAM) without atypia and PAM with atypia by immunohistochemical staining for the Ki-67 antigen and the proliferating cell nuclear antigen (PCNA). METHODS: Formalin fixed, paraffin embedded sections from 35 archival specimens of PAM without atypia (n = 19) and with atypia (n = 16) were studied by immunostaining with MIB-1 and PC-10 monoclonal antibodies that react with the Ki-67 antigen and PCNA respectively. The results were calculated as the mean number of positive cells per eyepiece grid. All specimens were evaluated by two masked observers, and the interobserver reproducibility was assessed. RESULTS: The means of the positive cell count in PAM with atypia were significantly higher compared with PAM without atypia for both observers, in both the PC-10 and the MIB-1 stained sections. In a linear least square model that estimated the interobserver and between group variation, the difference of MIB-1 and PC-10 positive cell count between PAM without and with atypia remained highly significant. The difference between the observers was not significant. CONCLUSIONS: Immunostaining with MIB-1 and PC-10 demonstrated that PAM with atypia has higher proliferative activity than PAM without atypia. This method was found to be reproducible between different observers.

Antigens, Nuclear↗
PubMed1998

Biologic determinants of uveal melanoma metastatic phenotype: role of intermediate filaments as predictive markers.

The long-range goal of our research is to develop intervention strategies based on newly discovered biologic mechanisms responsible for the invasive dissemination of metastatic uveal melanoma. To accomplish this goal, we have focused on the biologic relevance of novel marker proteins contributing to the uveal melanoma metastatic phenotype. The expression of vimentin intermediate filaments (IFs), a mesenchymal marker, is typical of melanomas, whereas carcinomas typically express keratin IFs, which are markers for epithelia. Thus, cells that coexpress both IFs are regarded as "interconverted" in that they display both mesenchymal and epithelial phenotypes. Although the biologic functions of IFs have remained enigmatic, there is substantial support to suggest that the significance of vimentin/keratin coexpression is linked with poor patient outcome in cutaneous melanoma. Our data demonstrate that human uveal melanoma cell lines (isolated from primary choroidal or ciliary body melanomas and from foci of metastatic uveal melanoma to the liver), which contain predominant populations of cells that coexpress vimentin/keratins 8 and 18 (keratins 8,18) IFs, were 6-fold more invasive through collagenous extracellular matrices in vitro, compared with uveal melanoma cells expressing vimentin only, and were 8- to 13-fold more invasive than normal uveal melanocytes. Colocalization of vimentin/keratins 8,18 in cell cultures was corroborated by immunohistochemistry in histologic sections of tumors from which the cell lines were derived. Minor populations of these cells also coexpressed keratins 13 and 17. Experimental down-regulation of the predominant keratins 8,18 in the interconverted cells, using 16-mer antisense oligonucleotides, resulted in a significant decrease in the migratory ability of the cells-similar to levels achieved by cells positive only for vimentin. These findings provide justification for additional studies of the association between coexpression of IFs vimentin/keratins 8,18 and uveal melanoma metastasis.

Antisense Elements (Genetics)↗
PubMed1998

Regulation of uveal melanoma interconverted phenotype by hepatocyte growth factor/scatter factor (HGF/SF).

Human uveal melanoma disseminates initially and preferentially to the liver. This study describes the relationship between the expression of the c-met proto-oncogene (receptor for hepatocyte growth factor/scatter factor (HGF/SF)) in interconverted uveal melanoma cells (co-expressing vimentin and keratin intermediate filaments) and the regulation of their motogenic response to HGF/SF, a key step in local invasion and targeted dissemination to the liver. Expression of c-met in uveal melanoma cell lines correlates with both the appearance of an interconverted phenotype and invasive ability (measured in vitro). Using chemotactic checkerboard analysis, the greatest motogenic response to HGF/SF was achieved by invasive, interconverted, c-met-positive uveal melanoma cells. C-met was observed histologically in a uveal melanoma containing interconverted cells but was absent in a tumor composed of non-interconverted cells (vimentin positive/keratin negative). The c-met ligand, HGF/SF, although not expressed by uveal melanoma cell lines, was localized in tissue sections of primary uveal melanomas and metastatic melanoma to the liver. In the primary tumor, staining for HGF/SF was most intense at the level of the choriocapillaris, a finding that is significant because 1) highly remodeled neovascular loops and networks, which appear in tumors likely to disseminate, can be traced to the choriocapillaris and the draining vortex veins and 2) HGF/SF plays a role in tumor angiogenesis. Foci of metastatic melanoma to the liver stain diffusely for HGF/SF. Regulation of the uveal melanoma interconverted phenotype by HGF/SF may play an important role in the dissemination of this tumor.

Blotting, Northern↗
PubMed1997

An experimental model for infiltration of malignant lymphoma to the eye and brain.

Currently there is no adequate experimental model available whereby the lethal infiltration of malignant lymphoma to the eye and CNS can be studied. Variant S49 mouse lymphoma cells that exhibit cell-cell adhesion properties (named Rev-2-T-6) were inoculated intraperitoneally into Balb/C mice at the ages of 6-60 days postnatal. Mice inoculated between days 6-11 postnatal developed signs of eye and CNS involvement with an apparent peak (58% of mice) at day 7. None of the mice inoculated beyond day 11 exhibited such signs. Histological analysis of these sites revealed tumorous infiltrates into a variety of structures in the orbit, intraocular tissues, along the optic nerve and in the brain. Additional analysis of the histopathological data, based on the structures demonstrating the highest frequency of lymphoma infiltration, suggests preferred routes of lymphoma entry to the brain and eye. Thus, entry to the brain can occur mainly through the choroid plexus and cranial nerves or cranial nerve ganglia. Entry to the eye may occur from the brain (along the optic nerve), and through hematogenous infiltration of orbital structures. No data were found that would support retrograde infiltration of the lymphoma from the eye to the brain. These findings present an experimental model for addressing the molecular mechanisms that govern homing of malignant lymphoma to the eye and brain, as well as the development of experimental therapeutic modalities for malignant lymphoma in these organs.

Animals↗
PubMed1997

Multiple conjunctival metastases as the initial sign of metastatic uveal melanoma.

PURPOSE: To describe a 31-year-old patient who was initially examined with a uveal malignant melanoma metastatic to the ipsilateral conjunctiva. METHOD: Thirteen months after ruthenium 106 plaque therapy for a ciliochoroidal malignant melanoma, numerous pigmented conjunctival lesions first appeared. RESULTS: These lesions were excised and found to be metastases of melanoma to the superficial subepithelial conjunctival tissue, composed of epithelioid cells. CONCLUSION: The appearance of darkly pigmented conjunctival lesions in a patient known to harbor a uveal malignant melanoma, even though lacking any evidence of extrascleral extension or metastatic involvement, may indicate metastatic disease.

Adult↗
PubMed1997

Mitomycin C treatment for conjunctival-corneal intraepithelial neoplasia: a multicenter experience.

OBJECTIVE: The purpose of the study is to evaluate the efficacy and risks of topical mitomycin C (MMC) for conjunctival-corneal intraepithelial neoplasia (CCIN). DESIGN: The study design was a clinical case series of CCIN. PARTICIPANTS: Seventeen patients, 16 with biopsy-confirmed CCIN and 1 with invasive squamous cell carcinoma (SCC), were included in the study. INTERVENTION: Patients received topical drops of MMC 0.02% to 0.04% four times daily from 7 to 28 days. Retreatment was done in cases of lesion recurrence. MAIN OUTCOME MEASURES: The size of the CCIN before and after the treatment and ocular complications post-MMC application were evaluated. RESULTS: Ten patients remained disease-free after one course of MMC application. In one case, residual CCIN remained very small without regrowth. In the one patient with invasive SCC and in five patients with CCIN, regrowth occurred within 6 months of the first treatment. After retreatment, invasive SCC and CCIN in an additional two patients were eradicated. In two cases, although the size of the lesions decreased after two and three applications of MMC, regrowth occurred, and the CCIN returned to its original size. In the final case, limited recurrence has occurred and no retreatment has been done. The complications of MMC use included mild-to-moderate conjunctival hyperemia and mild allergy, which resolved after discontinuation of the treatment. Severe pain manifested when treatment was longer than 14 days. CONCLUSIONS: Application of topical MMC is an efficient treatment for most but not all cases of CCIN.

Administration, Topical↗
PubMed1997

Rubeosis iridis in retinoblastoma. Histologic findings and the possible role of vascular endothelial growth factor in its induction.

PURPOSE: Iris neovascularization (rubeosis iridis) is a common finding in eyes harboring retinoblastoma. The purpose of the current study is to evaluate the histologic factors that may affect the development of rubeosis iridis in eyes with retinoblastoma and to examine whether vascular endothelial growth factor (VEGF), a hypoxia-induced angiogenic factor, is produced by hypoxic retinoblastoma and retinal cells in these eyes. MATERIALS AND METHODS: One hundred eighty-one enucleated eyes containing retinoblastoma were the source for the current study. Histologic slides were evaluated for the presence and degree of rubeosis iridis as well as for other histologic factors. Univariate and multivariate statistical analyses were performed to find a correlation between rubeosis iridis and the other histologic factors. Eight of the eyes underwent in situ hybridization with a specific VEGF mRNA probe to locate tumor and retinal cells that may produce this hypoxia-induced angiogenic factor. RESULTS: The amount of tumor necrosis as well as choroidal and optic nerve invasion was found to be one of the most important factors that correlated with the presence and degree of rubeosis iridis in the examined eyes. All eight eyes that underwent in situ hybridization analysis showed strong signals of VEGF mRNA in retinoblastoma cells around necrotic regions and in the outer nuclear layers in areas of detached retina. CONCLUSIONS: There exists an association between rubeosis iridis and histologic factors found in advanced stages of retinoblastoma, especially the amount of tumor necrosis. Vascular endothelial growth factor may well be an angiogenic factor that is secreted by the hypoxic retinoblastoma and retinal cells and, reaching the iris, causes (presumably in collaboration with other factors) rubeosis iridis.

Child↗
PubMed1997

The microcirculation of choroidal and ciliary body melanomas.

The microcirculation of ciliary body and choroidal melanomas is remodelled into patterns. The presence of microvascular networks, composed of back-to-back loops that encircle microdomains of tumour, and parallel vessels with cross-linking, are associated with death from metastatic melanoma. The formation of these complex vascular patterns may result from reciprocal interactions between the tumour cell and the extracellular matrix, and pattern formation may reflect an invasive tumour cell phenotype. Ciliary body and choroidal melanomas are among the few forms of cancer treated before a pathologist assigns a grade to indicate whether tumour is likely to follow a benign or aggressive course. There is evidence to suggest that prognostically significant microcirculatory patterns may be detectable by non-invasive imaging techniques that may provide a substitute for biopsy to guide the clinical management of patients with these sight- and life-threatening tumours.

Choroid Neoplasms↗
PubMed1997

Thirty years of penetrating keratoplasty in Israel.

We studied the indications for keratoplasty and their changes during 30 years in Israel by retrospective evaluation of pathologic records of 1,018 corneal buttons (from 1961 to 1990). The population included 634 (62.3%) male patients and 384 (37.7%) female patients. Keratoconus (n = 222, 21.8%) was the most common indication, followed by corneal graft failure (n = 113, 11.1%), herpetic infections (n = 95, 9.3%), ocular trauma (n = 87, 8.5%), scarring (n = 74, 7.3%), pseudophakic bullous keratopathy (n = 72, 7.1%), nonherpetic infections (n = 71, 7.0%), and other indications. Whereas ocular infections were the most common indications for keratoplasty before 1970, keratoconus has been the most common indication since 1970. Pseudophakic bullous keratopathy became the second most common indication (13.8%) between the years 1981 and 1990. The number of keratoplasties increased in Israel during the past three decades, and the low percentage of pseudophakic bullous keratopathy is related to the types of intraocular lenses that we implanted in the late 1970s and the early 1980s.

Corneal Diseases↗