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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
PubMed2006

Long term ultrasonic follow up of choroidal naevi and their transformation to melanomas.

AIMS: To compare ultrasonographic (US) predicting factors for conversion of choroidal naevi into melanomas. METHODS: 659 consecutive eyes with choroidal naevi were examined between 1984 and 2004. 165 clinically suspicious naevi were followed clinically and ultrasonographically (thickness, base diameters, internal reflectivity and location in the eye) for 5.08 (SE 0.24) years. RESULTS: 17 naevi (2.6% of all naevi, 10.3% of suspicious naevi) converted to small choroidal melanomas. The thickness of benign and premalignant naevi differed significant only after 1.5 years of follow up. The mean initial thickness of benign and premalignant naevi was significantly different (p = 0.001), as was mean initial internal reflectivity (p = 0.002) and mean initial largest base diameter (LBD, p = 0.05). Posterior pole and nasally located naevi were more likely to become malignant. A thickness of > or = 2 mm and a LBD > or = 7 mm were most predictive of conversion to melanoma, as was a combined K(I) index of > or = 14.5 (KI = LBD + 4 x thickness + 1 (for nasal location) + 1 (for posterior pole location)). An artificial neural network did not have a better forecasting accuracy than the KI index. Logistic regression found the only significant parameters to influence the risk of conversion to melanoma to be the KI value and the initial tumour thickness. CONCLUSIONS: A follow up of at least 1.5 years is necessary to detect conversion of naevi to choroidal melanomas. The thickness and LBD of the lesion can be used for predicting the risk.

Cell Transformation, Neoplastic↗
PubMed2005

The pro-fibrogenic effect of nerve growth factor on conjunctival fibroblasts is mediated by transforming growth factor-beta.

BACKGROUND: Nerve growth factor (NGF) and nerve growth factor receptor (NGFR) expressions have been found to be increased in sub-conjunctival scarring. OBJECTIVE: The aim of this study was to investigate the in vitro effects of NGF on some pro-fibrogenic properties of human conjunctival fibroblasts. METHODS: Expression of NGF, trkA(NGFR) and p75NTR on human fibroblasts grown from conjunctival biopsies and incubated for 2 or 6 days with NGF were evaluated by immunofluorescence, RT-PCR, flow cytometry and ELISA. The fibrogenic effect of NGF on conjunctival fibroblasts was investigated by evaluating their migration (wound model), proliferation ([3H]-thymidine incorporation), collagen production (3H]-proline incorporation), expression of alpha-smooth muscle actin (alpha-SMA) (cell surface ELISA) and contraction of 3D collagen gels. RESULTS: NGF induced the expression of p75NTR in the fibroblasts that constitutively expressed only trkA(NGF) and increased the migration of wounded fibroblasts, but not their proliferation and collagen production. NGF induced the conversion of fibroblasts into myofibroblasts expressing alpha-SMA, and enhanced their contraction of a collagen matrix. Interestingly, chronic NGF treatment induced transforming growth factor-beta1 (TGF-beta1) production by fibroblasts, and following specific TGF-beta neutralization, all the NGF-induced effects were completely abrogated. CONCLUSION: Our findings indicate that NGF, via TGF-beta induction, is likely to be involved in the healing or fibrotic processes occurring in conjunctiva during some pathological conditions.

Actins↗
PubMed2005

Suppression of inflammatory and fibrotic responses in allergic inflammation by the amniotic membrane stromal matrix.

BACKGROUND: The amniotic membrane (AM), which is the innermost layer of the placenta, was shown to possess anti-inflammatory and anti-fibrotic properties in various in vitro and clinical studies. PURPOSE: To evaluate the anti-fibrotic and anti-inflammatory effects of the AM matrix (AMM) on human conjunctival and lung fibroblasts in an in vitro system that tests fibrotic and inflammatory responses at the effector stages of allergic inflammation. METHODS: Human conjunctival or lung fibroblasts were seeded on plastic or on the stromal aspect of the AM, which was mounted on plastic inserts. Sonicates of human peripheral blood eosinophils activated with lipopolysaccharide (LPS), or human mast cell (HMC-1) leukaemia cell sonicates, were added to sub-confluent fibroblast monolayers. Proliferation of the sub-confluent fibroblasts was assessed using the [3H]-thymidine incorporation assay. The production of transforming growth factor (TGF)-beta1, granulocyte-macrophage colony-stimulating factor (GM-CSF) and IL-8 in conjunctival or lung fibroblasts was measured in conditioned media from these cultures by ELISA. RESULTS: After 4 days in culture, the [3H]-thymidine incorporation assay indicated a reduced proliferation of activated conjunctival and lung fibroblasts when cultured directly on the AMM. The production of both TGF-beta1 and IL-8 was significantly suppressed in activated conjunctival fibroblasts cultured on the AMM compared with those cultured on plastic, while the production of both TGF-beta1 and GM-CSF was decreased in human lung fibroblast cultured on the AMM. CONCLUSIONS: The AMM is capable of suppressing fibrotic responses in an in vitro system of effector stages of ocular allergic inflammation. These data may provide a basis for exploring matrix components in the AM for the treatment of allergic eye disease.

Amnion↗
PubMed2004

Post-brachytherapy initial tumour regression rate correlates with metastatic spread in posterior uveal melanoma.

AIM: To confirm the prognostic value of post-brachytherapy initial tumour regression rate in posterior uveal melanoma. METHODS: A prospective, comparative, observational cohort study was carried out on 147 eyes (147 patients) with choroidal melanoma (mean age 61 years) treated with Ru-106 brachytherapy. OBSERVATION PROCEDURE: Patients were followed clinically and ultrasonically every 6.7 (SD 0.3) months (1001 examinations). On average each patient was examined 5.8 times (mean follow up 9.6 (3.7) years). The echographic parameters included tumour base size, height, internal reflectivity, regularity, vascularity, and extrascleral extension. The clinical follow up included ocular examination and periodic metastatic screening (liver function tests and liver imaging). Main outcome measures were risk of liver metastasis in correlation with the post-brachytherapy initial tumour regression rate. RESULTS: At brachytherapy the mean tumour height was 5.2 mm (range 2.2-11.8 mm). After brachytherapy 142 tumours (96.6%) responded by a decrease in height. The initial height regression rate was 6.1% (0.8%) per month in patients who later developed metastasis v 4.3% (0.4%) per month in those who did not. Tumours higher than 6 mm, tumours with an internal reflectivity smaller than 50%, and tumours with an initial rate of height regression larger than 0.7 mm/month (10% per month) had higher 5 year melanoma related mortality. Kaplan-Meier survival analysis and the multivariate Cox proportional hazards model showed a significant role for tumour height and initial tumour regression rate on patients' survival. CONCLUSION: This study confirms that post-brachytherapy initial tumour regression rate has a prognostic value.

Adult↗
PubMed2001

Entry routes of malignant lymphoma into the brain and eyes in a mouse model.

We have recently developed a novel mouse model for studying the infiltration of malignant lymphoma to the eye and brain. After i.p. inoculation of variant S49 mouse lymphoma cells into young mice (optimum: day 7 postnatal), specific homing of these cells (named Rev-2-T-6) to the brain and eyes took place. This model offers an opportunity to study the routes of infiltration to these sites and spread thereof, as well as the molecular mechanisms that govern this metastasis. By applying a time course histopathological analysis, we demonstrate that infiltration of the brain and eyes can be visualized as early as days 9 and 14 after inoculation, respectively. The lymphoma cells enter the brain preferentially through the choroid plexus and cranial nerves. Infiltration of the rostral part occurs before the caudal part of the brain. Once within the brain, the cells spread within it as well as migrate along the optic nerve sheath into the eyes, where they continue to migrate along the choroid, ciliary body, iris, and into the anterior chamber of the eye. The orbit is also infiltrated by the lymphoma cells. However, this occurs independent of the brain-optic nerve-intraocular route.

Animals↗
PubMed2001

Orbital growth retardation in retinoblastoma survivors: work in progress.

BACKGROUND: Orbital growth retardation, after enucleation and/or external beam radiation for retinoblastoma (RB), is a serious late effect. We measured orbital volumes of RB survivors treated at Hadassah University Hospital, Jerusalem, between 1980-1998. PROCEDURE: Forty-five orbits of 28 children with RB (17 bilateral, 11 unilateral) were examined. Thirty-six orbits were irradiated, 19 enucleated, and 10 both enucleated and irradiated. The orbital volumes were calculated from a three-dimensional orbital CT reconstruction. The orbits of RB survivors were compared to age-matched controls. RESULTS: The mean age at diagnosis was 13 months, mean follow-up time was 56 months. The mean volume of RB orbits (14.4 cc) was statistically significantly smaller than control orbits (17.8 cc). There was no difference between the mean volume of orbits treated with enucleation, irradiation or both. The orbital volume of children treated before the age of 12 months was statistically significantly smaller than those treated later. There was no difference between mean volume of fellow orbits in unilateral RB and controls. The mean orbital asymmetry index in control children (2.6%) was statistically significantly smaller than in RB survivors (14%). CONCLUSIONS: There was a significant orbital growth retardation after enucleation and/or irradiation for RB. There was no difference between mean orbital volumes after enucleation, radiation or both. Orbital growth retardation was most prominent in children treated in the first year of life. Although small in number, our study suggests that deferring enucleation and/or irradiation until after the age of 12 months may reduce long-term complications.

Age Factors↗
PubMed2001

Comparison of microcirculation patterns and MIB-1 immunoreactivity in iris and posterior uveal melanoma.

PURPOSE: To compare melanomas confined to the iris and those involving either the ciliary body or choroid for the histologic features of microcirculation patterns and tumor cell proliferation indices. DESIGN: Retrospective comparative human tissue study. PARTICIPANTS: Ninety-eight uveal melanomas were studied, including 18 tumors confined to the iris, 30 tumors involving the ciliary body, and 50 tumors confined to the choroid. METHODS: Formalin-fixed, paraffin-embedded sections from each tumor were stained with hematoxylin-eosin and with periodic acid-Schiff. Adjacent histologic sections were stained with the MIB-1 antibody that reacts with the Ki-67 antigen. MAIN OUTCOME MEASURES: Microcirculation patterns were assessed in the periodic acid-Schiff-stained sections. Proliferative activity was assessed in the MIB-1-stained sections. The mean MIB-1 positive cell count per high-power field (HPF) was calculated in 10 HPF (x 40) in the area of maximal immunoreactivity. Two observers evaluated each MIB-1-stained section, and the interobserver reproducibility was assessed. RESULTS: Histologic microcirculation patterns associated with death from metastatic disease in ciliary body and choroidal melanomas (parallel vessels with cross-linking and networks of back-to-back loops) were not found in any of the iris melanomas. By contrast, 34% and 63% of the choroidal and ciliary body melanomas, respectively, showed at least one of these patterns. The mean positive cell count per HPF +/- standard error was 19.9 +/- 3.5, 27 +/- 5.3, and 1.9 +/- 0.4 in choroidal, ciliary body, and iris melanoma, respectively (P: = 0.003, Kruskal-Wallis test). CONCLUSIONS: Melanoma confined to the iris is characterized by a low rate of proliferation and the histologic absence of microcirculation patterns associated with metastatic posterior uveal melanoma. Both features are consistent with the relatively benign nature of iris lesions compared with melanomas involving the ciliary body or choroid.

Adult↗
PubMed2001

Proliferative activity and p53 expression in primary and recurrent pterygia.

PURPOSE: To assess p53 expression and proliferative activity in primary and recurrent pterygia from the same eyes. DESIGN: Retrospective comparative human tissue study. PARTICIPANTS: Tissue from excised primary pterygia that did not recur (group A, n = 10) was compared with tissue from primary pterygia that recurred (group B, n = 10) and to the recurrent pterygia tissue that was excised from subjects in group B (group C, n = 10). Ten normal conjunctivas served as controls (group D). METHODS: Sections from each pterygium were immunostained with the MIB-1 and bp53. 12 monoclonal antibodies that react with Ki-67 and p53 antigens, respectively. MAIN OUTCOME MEASURES: Proliferative activity was calculated as the mean of the MIB-1 positive cell count per eyepiece grid in high magnification (x40) (positive cell count/grid). Percentage of positive cells of all cells in the grid area was evaluated in the p53-stained sections. RESULTS: Proliferative activity was found in the epithelium overlying the pterygia and normal conjunctiva. The mean MIB-1 positive cell count/grid +/- standard error was 2.84 +/- 1.07, 1.74 +/- 0.82, 3.83 +/- 1.35, and 0.86 +/- 0.33 in groups A, B, C, and D, respectively (P = 0.17, Kruskal-Wallis). P53 staining was found in 50% of pterygia in groups A, B, and C; none of the normal conjunctival tissues showed p53 immunoreactivity. Four of five p53-positive tissues in group B were p53-negative in group C. In the p53-positive pterygia, less than 10% of cells were p53 positive. However, p53-positive pterygia had higher mean MIB-1 positive cell count/grid +/- standard error as compared with the p53-negative lesions, 4.56 +/- 0.94 vs 1.39 +/- 0.59 (P = 0.021, Mann-Whitney). CONCLUSIONS: p53 immunoreactivity and high proliferative activity in the epithelium overlying the pterygium are not associated with recurrence of pterygium.

Antibodies, Monoclonal↗
PubMed2001

Microcirculation patterns other than loops and networks in choroidal and ciliary body melanomas.

PURPOSE: To provide ophthalmologists and pathologists with expanded criteria for separating patients at high risk of metastatic melanoma from those at low risk on the basis of microcirculation patterns in choroidal and ciliary body melanomas. DESIGN: Tissue culture studies and observational case series. PARTICIPANTS: The pattern-forming ability of four uveal melanoma cell lines of varying degrees of aggressive behavior was studied in vitro. Histologic sections of 234 eyes removed for choroidal or ciliary body melanoma were studied for the presence of microcirculation patterns. METHODS: The study was divided into two phases: the study of histologic sections of eyes removed for choroidal and ciliary body melanomas and observations on the in vitro behavior of cultured melanoma cells of varying degrees of invasive behavior. The presence or absence of each of nine microcirculation patterns was recorded from tissue sections, and interrelationships between different patterns were explored statistically. In vitro reconstitution of patterns and a study of the interrelationships of patterns in histologic sections was carried out. In the in vitro studies, uveal melanoma cell lines of varying degrees of aggressive potential were cultured to observe the development of architectural patterns other than loops and networks. MAIN OUTCOME MEASURES: In histologic studies, the outcome measure was the conditional probability of detecting loops or networks given the presence or absence of other patterns positive for periodic acid-SCHIFF: For tissue culture studies, the outcome measure was either the development or lack of development of patterns of different shapes in vitro. RESULTS: Histologic studies disclosed that given the presence of arcs without or with branching in a tissue section, it is likely that loops or networks will be detected in the same section plane, suggesting that the production of these patterns by aggressive tumor cells reflects a spectrum of architectural potential. In vitro studies confirmed this hypothesis by revealing that highly aggressive and metastatic uveal melanoma cell lines, but not poorly aggressive tumor cell lines, generated parallel channels with and without crosslinking and arcs with and without branching as well as loops and networks. CONCLUSIONS: The criteria for separating patients into low- and high-risk categories for metastasis from uveal melanoma should be expanded to include patterns other than loops or networks. In both the pathology laboratory as well as in a clinical setting, the detection of arcs or arcs with branching and parallel channels should prompt a careful search for loops and networks and for crosslinking parallel channels, respectively.

Choroid Neoplasms↗
PubMed2001

Advances in ocular allergy: basic mechanisms, clinical patterns and new therapies.

Ocular allergy presents unsolved mysteries in molecular and cellular mechanisms, and at the same time continues to challenge ophthalmologists daily in a wide array of disease forms. The recent understanding of the key role of the T helper type 2 cytokines, adhesion molecules and chemokines may provide future avenues for pharmacological targeting of releasable inflammatory mediators. More potent topical mast cell stabilizers and H1 receptor antagonists have become commercially available for the management of the prevalent and benign forms of allergic conjunctivitis. Immunostimulatory DNA sequences present an innovative and promising route for the treatment of ocular allergy, but clinical studies are needed to demonstrate their efficacy in humans. Surgical methods are suggested to reconstruct the ocular surface in the sight-threatening diseases vernal keratoconjunctivitis and atopic keratoconjunctivitis. This review presents an update of the major advances in both the basic mechanisms and clinical and therapeutic aspects of ocular allergic diseases that were reported during the past year.

Anti-Allergic Agents↗
PubMed2001

Cell proliferation activity in posterior uveal melanoma after Ru-106 brachytherapy: an EORTC ocular oncology group study.

AIM: To evaluate the cell proliferation activity in posterior uveal melanomas after Ru-106 brachytherapy. METHODS: Eyes containing choroidal or ciliary body melanoma from seven ocular oncology centres, which were enucleated after first being treated by Ru-106 brachytherapy and which had enough melanoma tissue to enable histological assessment, were included. The 57 eligible specimens were divided into a group of 44 eyes that were enucleated because of tumour regrowth, and a non-recurrent group of 13 eyes that were enucleated because of complications such as neovascular glaucoma. 46 non-irradiated eyes harbouring uveal melanoma served as a control group. All specimens underwent routine processing. They were cut into 5 microm sections, and were stained with two main cell proliferation markers: PC-10 for PCNA and MIB-1 for Ki-67. The stained sections were assessed, and the cells that were positive in the immunostaining were counted in each section. The results were evaluated by various statistical methods. RESULTS: The PC-10 score showed a statistically significant difference across the three groups (p = 0.002). The control group showed the highest PC-10 score (median 31.0 PCC/HPF) followed by the tumour regrowth group (median 4.9 PCC/HPF). The lowest PC-10 scores were found in the non-recurrent tumours (median 0.05 PCC/HPF). The MIB-1 score in the control group (median 5.77 PCC/HPF) was similar to the regrowth group (median 5.4 PCC/HPF). In contrast, the MIB-1 score in the non-recurrent tumours was statistically significantly lower (median 0.42 PCC/HPF). The PC-10 and MIB-1 scores were similar in tumours composed of either spindle cells or epithelioid cells in all groups. CONCLUSIONS: The non-recurrent melanomas demonstrate significantly lower cellular proliferation activity than melanomas that showed regrowth or that were not irradiated at all. In our hands, PCNA gave more meaningful information than Ki-67. Our findings strongly support the need for treating regrowing posterior uveal melanoma either by enucleation or re-treatment by brachytherapy. On the other hand, also in the non-recurrent uveal melanomas there are viable cells with potential for proliferation, although fewer in number, with unknown capacity for metastatic spread. Therefore, the irradiated tumours should be followed for many years, probably for life.

Analysis of Variance↗
PubMed2001

Gene transfer by viral vectors into blood vessels in a rat model of retinopathy of prematurity.

AIMS: To test the feasibility of gene transfer into hyaloid blood vessels and into preretinal neovascularisation in a rat model of retinopathy of prematurity (ROP), using different viral vectors. METHODS: Newborn rats were exposed to alternating hypoxic and hyperoxic conditions in order to induce ocular neovascularisation (ROP rats). Adenovirus, herpes simplex, vaccinia, and retroviral (MuLV based) vectors, all carrying the beta galactosidase (beta-gal) gene, were injected intravitreally on postnatal day 18 (P18). Two sets of controls were also examined: P18 ROP rats injected with saline and P18 rats that were raised in room air before the viral vectors or saline were injected. Two days after injection, the rats were killed, eyes enucleated, and beta-gal expression was examined by X-gal staining in whole mounts and in histological sections. RESULTS: Intravitreal injection of the adenovirus and vaccinia vectors yielded marked beta-gal expression in hyaloid blood vessels in the rat ROP model. Retinal expression of beta-gal with these vectors was limited almost exclusively to the vicinity of the injection site. Injection of herpes simplex yielded a punctuate pattern of beta-gal expression in the retina but not in blood vessels. No significant beta-gal expression occurred in rat eyes injected with the retroviral vector. CONCLUSIONS: Adenovirus is an efficient vector for gene transfer into blood vessels in an animal model of ROP. This may be a first step towards utilising gene transfer as a tool for modulating ocular neovascularisation for experimental and therapeutic purposes.

Animals↗
PubMed2000

Gallium-desferrioxamine protects the cat retina against injury after ischemia and reperfusion.

This study sought to determine whether gallium-desferrioxamine (Ga/DFO) can curb free radical formation and mitigate biochemical and electrophysiological parameters of injury in the cat retina subjected to ischemia followed by reperfusion. For the biochemical studies, cat eyes were subjected to 90 min of retinal ischemia followed by 5 min of reperfusion, and enucleation of one eye of each cat was used to measure retinal reperfusion injury. Before enucleation of fellow eyes, 2.5 mg/kg Ga/DFO was injected intravenously 5 min before reperfusion. The flux of hydroxyl radicals, as measured directly by conversion of salicylate to 2,3- and 2,5-dihydroxybenzoic acid (2,3- and 2,5-DHBA), was significantly lower in Ga/DFO-treated eyes. The mean normalized level of 2,3-DHBA (considered a specific marker of hydroxyl radicals) was 3.5 times higher in untreated eyes. Ga/DFO caused a significant reduction, by 2.56-fold, in lipid peroxidation, as reflected by levels of malondialdehyde. Ascorbic acid, a natural antioxidant present in the retina, is severely depleted in untreated eyes. In contrast, in Ga/DFO-treated eyes, levels were 10 times higher than the control. Energy charge was 2.38 times higher in treated eyes. Levels of purine catabolites (hypoxanthine, xanthine, and uric acid) that reflect excessive metabolism of purine nucleotides were approximately twice higher in untreated retinas. Electroretionographic studies, performed on a different subset of animals, substantiated the biochemical results. In Ga/DFO-treated eyes the amplitude of the mixed cone-rod response b-wave (as compared with fellow nonischemic eyes) fully recovered within 24 h after ischemia (b-wave ratio 1.04 +/- 0.09, [mean +/- SEM]) whereas ischemic/reperfused and nontreated eyes recovered to only 0.33 +/- 0. 05. The results show that severe biochemical and functional retinal injury occurs in cat eyes subjected to ischemia and reperfusion. These severe changes were significantly reduced by a single administration of Ga/DFO just before reperfusion. We hypothesize that the protection afforded by Ga/DFO is due to a combined effect of "Push-Pull" mechanisms interfering with transition metal-dependent and free radical-mediated injurious processes.

Adenine Nucleotides↗
PubMed2000

Conjunctival fibroblasts enhance the survival and functional activity of peripheral blood eosinophils in vitro.

PURPOSE: To examine the effect of human conjunctival fibroblasts on the survival and functional activity of human peripheral blood eosinophils. METHODS: Eosinophils were purified by negative immunoselection [magnetic activated cell sorter (MACS), purity > 97%] from volunteers with mild atopia. Fibroblasts were cultured from conjunctival specimens of healthy donors. Eosinophils were cultured on confluent monolayers of conjunctival fibroblasts or in culture medium alone. Eosinophil survival was evaluated by the trypan blue exclusion test. Eosinophil adherence was assessed by counting the attached cells after washing the cultures. Eosinophil viability and adherence in coculture were also assessed in the presence of anti-granulocyte-macrophage colony-stimulating factor (GM-CSF), anti-interleukin (IL)-3, and anti-IL-5 neutralizing antibodies. Cocultured eosinophils were activated by lipopolysaccharide (LPS) after 4 days in culture, and eosinophil peroxidase (EPO) release was determined as a marker of their activation. RESULTS: Eosinophils cocultured with conjunctival fibroblasts had a significantly increased viability of 35.9% (P = 0.004) and 12.8% (P = 0.003) on days 4 and 8, respectively. Fibroblast-conditioned medium did not enhance the survival of eosinophils. The increase in eosinophil survival in coculture was partially inhibited by anti-GM-CSF (P = 0.019), anti-IL-3 (P = 0.033), or anti-IL-5 (P = 0.011), whereas eosinophil adherence was reduced by anti-GM-CSF alone (P = 0.034). LPS activation of eosinophils cultured for 4 days with conjunctival fibroblasts induced higher EPO release than in freshly isolated eosinophils (P = 0.01). CONCLUSIONS: Human conjunctival fibroblasts induced prolonged survival and increased secretory function of human peripheral blood eosinophils. Increased survival is partially mediated by IL-3, IL-5, and GM-CSF. The coculture of conjunctival fibroblasts with eosinophils can serve as an in vitro system for the study of eosinophil behavior in the ocular surface and of cellular interactions in allergic eye diseases.

Adolescent↗
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↗