Pilot trial of the safety, tolerability, and retinoid levels of N-(4-hydroxyphenyl) retinamide in combination with tamoxifen in patients at high risk for developing invasive breast cancer.

PURPOSE: N-(4-hydroxyphenyl) retinamide (¿4-HPR, Fenretinide; R.W. Johnson Pharmaceutical Research Institute, Springhouse, PA) and tamoxifen (TAM) have synergistic antitumor and chemopreventive activity against mammary cancer in preclinical studies. We performed a pilot study of this combination in women at high risk for developing breast cancer. PATIENTS AND METHODS: Thirty-two women were treated with four cycles of 4-HPR, 200 mg orally (PO) for 25 days of each 28-day cycle, and TAM, 20 mg PO once daily for 23 months beginning after 1 month of 4-HPR alone. Tolerability, dark adaptometry, tissue biopsies, and retinoid plasma concentrations (Cp) were evaluated. RESULTS: Symptomatic reversible nyctalopia developed in two patients (6%) on 4-HPR, but 16 (73%) of 22 patients had reversible changes in dark adaptation, which correlated with relative decrease in Cp retinol (P

Retinopathy in juvenile-onset type I diabetes of short duration.

We evaluated the prevalence and severity of diabetic retinopathy in 173 juvenile-onset, type I diabetic subjects and 78 nondiabetic controls of similar age, race, and sex distribution by stereoscopic fundus photography and fluorescein angiography, performed by a standardized protocol and evaluated by five expert, masked observers. The overall prevalence of retinopathy was 18% in the diabetic group and 0% in the controls. Retinopathy prevalence increased with duration of diabetes in the diabetic group, with a prevalence of 1% from 0--4 yr after diagnosis, 25% after 5--9 yr, and 67% 10--16 yr after onset of the systemic disease. There was an independent association with age, with little retinopathy before age 15 and a 48% prevalence in older persons. Retinopathy was also found to be independently associated with the following: diabetic "control," evaluated semiquantitatively but on a masked basis; lens opacities; and frequency of daily insulin injections. Among the 166 diabetic subjects who had both angiography and photography, a retinopathy prevalence of 17% was detected by angiography and 11% by photography. This difference was statistically significant (P = 0.01). This study provides baseline data for use in estimating sample size in controlled trials of therapeutic measures to prevent retinopathy in juvenile diabetic populations. The study also supports the hypothesis that long-term hyperglycemia as well as changes (possibly hormonal in nature) associated with puberty are causally related to diabetic retinopathy.

Plasma fibrinopeptide A, beta-thromboglobulin, and platelet factor 4 in diabetic retinopathy.

We examined plasma levels of fibrinopeptide A, beta-thromboglobulin, and platelet factor 4 in diabetic patients. Among diabetic patients (n = 33) plasma levels of fibrinopeptide A, beta-thromboglobulin and platelet factor 4 were significantly higher than in controls (n = 41). In the subgroups of diabetic patients with (1) minimal (n = 13), and (2) moderate-severe (n = 14) retinopathy only plasma fibrinopeptide A levels were significantly higher than in controls. Among the total group of diabetic patients plasma levels of fibrinopeptide A increased significantly with increasing severity of retinopathy. These results suggest that diabetic retinopathy is associated with in vivo activation of blood coagulation factors and that this activation increases with advancing retinopathy.

Low ocular rigidity in patients with osteogenesis imperfecta.

Sixteen patients with osteogenesis imperfecta (OI) have undergone a thorough eye examination. These patients had statistically significantly lower ocular rigidity measurements than a group of normal volunteers matched on age, sex, and refractive error. In addition, the corneal diameter and length of the eyeball was smaller in OI patients than that in controls. Possible correlations of low ocular rigidity with biochemical changes in scleral collagen await further investigation.

Measurement error in assessing the size of posterior subcapsular cataracts from retroillumination photographs.

Twenty-six eyes with posterior subcapsular opacities of various sizes were photographed with the Neitz-Kawara Retroillumination camera. The outline of the opacity in a single photograph of each opacity was traced onto a transparent plastic overlay twice by two independent outliners. Two methods were used to estimate the area within the outlines of the opacities. In the first, a transparent overlay with a standard grid was used to count the number of boxes within the outlines. The second method used computer planimetry to estimate the area within the tracings. We estimated the measurement error associated with a single outlining of an opacity and the contribution of the measurement error to overall sample size requirements in studies comparing the mean areas of posterior subcapsular opacities. Variability in the measurement techniques contributed fewer than 20 additional subjects to overall sample size estimates, a small contribution to total sample size requirements in most studies. An outliner's inherent variability in outlining an opacity was a much larger contributor to the measurement error than was variability in assessing the area of the outline of the opacity. While within outliner variability was similar for the two persons outlining the opacities, there were systematic differences in the way the two traced the outlines. Variability from the use of separate photographs of the same opacity taken by different photographers was minimal.

Glutathione S-transferase M1 genotype and age-related cataracts. Lack of association in an Italian population.

PURPOSE: To investigate possible associations between the gene number and allelic forms of glutathione S-transferase M1 (GSTM1) and the occurrence of nucleic and cortical age-related cataracts. METHODS: Patients with cortical cataract, nuclear cataract, mixed and cortical cataract, and no cataract were sytematically selected from subjects evaluated in the Italian-American Study of the Natural History of Age-Related Cataract. The patients were typed for the A, B, and null alleles of GSTM1 using a variation of the amplification refractory mutation system. RESULTS: Forty-nine percent of patients (50/102) with cortical cataracts, 45% (13/29) with nuclear cataracts, 51% (36/71) with mixed nuclear and cortical cataracts, and 50% of controls (49/98) were homozygous for the null GSTM1 allele. Twenty-five percent of patients (26/102) with cortical cataracts, 24% (7/29) with nuclear cataracts, 31% with mixed nuclear and cortical cataracts, and 27% of controls (26/98) displayed only the A allele for GSTM1. Twenty-four percent of patients (24/102) with cortical cataract, 24% (7/29) with nuclear cataracts, 14% (10/71) with mixed nuclear and cortical cataract, and 18% of controls showed only the B allele for GSTM1. Two percent of patients (2/102) with cortical cataracts, 7% (2/29) with nuclear cataracts, 4% (3/71) with mixed nuclear and cortical cataracts, and 5% of controls (5/98) showed both A and B alleles for GSTM1. CONCLUSIONS: No associations between the GSTM1 alleles, including the null allele, and cataracts were detected in this study.

The incidence of retinoblastoma in the United States: 1974 through 1985.

We have estimated the incidence of retinoblastoma in the United States from data available form the Surveillance, Epidemiology, and End Results program of the National Cancer Institute, Bethesda, Md (1974 through 1985). The larger number of cases available (220) compared with those of previous US population-based studies enabled us to evaluate change in incidence over time and to more precisely estimate incidence according to various demographic characteristics. The incidence of retinoblastoma has been almost uniform form 1974 to 1985. The average annual incidence of retinoblastoma was 5.8 per million for children younger than 10 years and 10.9 per million for children younger than 5 years. There was no difference in the incidence of retinoblastoma by either sex or race. The overall 5-year cumulative survival rate was 91% (95% confidence interval, 87% to 95%). The data indicate a worsening survival with increasing age at diagnosis, through age 2 years, but a less clear relationship of survival with diagnosis beyond age 2 years.

Associations between siblings for esotropia and exotropia.

OBJECTIVE: To quantify familial aggregation of esotropia and exotropia in children examined in a large multicenter study. METHODS: Pregnant women and their children were examined in the Collaborative Perinatal Project of the National Institute of Neurological Disorders and Stroke, Bethesda, Md. Strabismus was evaluated in the children during follow-up examinations up to the age of 7 years. The second-order generalized estimating equations approach to logistic regression was used to estimate familial aggregation of esotropia and exotropia. RESULTS: For any pair of siblings, the odds for one sibling having esotropia more than doubled when the other sibling had esotropia. For exotropia, there were differences in sibling associations based on birth relationships. In particular, there was no statistically significant association between siblings from separate single births. On the other hand, for the pairs of siblings from multiple births (ie, twins, triplets, and quadruplets), the odds for exotropia in one sibling were increased by at least a factor of 17 when the other sibling from that birth also had exotropia. For both esotropia and exotropia, adjustment for previously identified risk factors only somewhat reduced the magnitudes of the observed associations. Limited data on zygosity showed a stronger association between monozygotic twins than between dizygotic twins. CONCLUSIONS: There is a significant familial component in the cause of strabismus. Furthermore, there are important contributions to this familial aggregation beyond those associated with known risk factors for strabismus.

Color vision defects in early diabetic retinopathy.

Four color vision tests were used to assess color vision in 51 insulin-dependent diabetic patients and 41 normal controls. Right and left eyes of diabetic patients, selected because they had minimal retinopathy, had significantly more color vision defects than controls on Lanthony desaturated D-15, Farnsworth-Munsell 100-Hue, and chromagraph tests. The 100-Hue scores were significantly higher in both right and left eyes of diabetic patients than in controls. There were no significant associations between presence or absence of a color vision defect and age, sex, age at onset, duration of diabetes, or its metabolic control.

Posterior vitreous fluorophotometry in normal subjects.

We performed vitreous fluorophotometry using the Fluorotron Master and intravenous fluorescein injection of 14 mg/kg of body weight in 22 normal subjects. Various methods of analysis were used to evaluate vitreous fluorescein concentration at 3 mm from the retina as well as averaged over the posterior 6 mm. The various methods of calculation yielded mean (+/- SD) postinjection values ranging from 1.7 +/- 1.4 to 4.3 +/- 2.3 ng/mL at 30 minutes and from 7.1 +/- 2.4 to 10.8 +/- 2.7 ng/mL at 60 minutes. The permeability index determined 60 minutes after injection ranged from 0.92 +/- 0.40 X 10(-7) to 1.19 +/- 0.30 X 10(-7) cm/s, according to the protocol used. Replicate pairs of measurements in six subjects demonstrated that the procedure was reproducible to within 17% to 49%, depending on the analysis. The results suggest that if the current methods of data analysis are used, fluorescein leakage might be considered abnormally high if at 60 minutes the 3-mm posterior vitreous fluorescein concentration corrected for background fluorescence exceeds 14.3 ng/mL and/or the permeability index exceeds 2 X 10(-7) cm/s.

Risk factors for esotropia and exotropia.

OBJECTIVE: To identify risk factors associated with the two major types of strabismus--esotropia and exotropia--in a cohort of children followed up from gestation to age 7 years. DESIGN: Pregnant women were enrolled in the Collaborative Project of the National Institute of Neurological Disorders and Stroke, Bethesda, Md, from 1959 to 1965 at 12 university centers. This large multidisciplinary study was designed to evaluate the developmental consequences of complications during pregnancy and the perinatal period. Data on maternal, socioeconomic, perinatal, and neonatal characteristics were collected from 39,227 children and their mothers by medical examination and interview. Examinations of the children were performed at birth, 4 months, 8 months, 1 year, and 7 years. OUTCOME MEASURES: The evaluation of the presence of strabismus was performed during follow-up examinations and confirmed at the 7-year follow-up visit. Potential risk factors for strabismus were evaluated from the maternal, socioeconomic, perinatal, and neonatal characteristics. RESULTS: Esotropia developed in 1187 children (3.0%), and exotropia developed in 490 children (1.2%). Esotropia was more common in whites (3.9% in whites vs 2.2% in blacks, P < .0001). The occurrence of exotropia was similar in the two races (1.2% in whites and 1.3% in blacks). Results of multivariable logistic regression models showed that the risk of strabismus increased with low birth weight (P < .0001). For infants weighing 1500 g at birth compared with those weighing 4000 g at birth, the odd ratios were 3.26 (95% confidence interval, 2.50 to 4.25) for esotropia and 4.01 (95% confidence interval, 2.77 to 5.80) for exotropia. Maternal cigarette smoking during pregnancy also increased the risk of each type of strabismus (P < .0001). For offspring of mothers who smoked more than two packs of cigarettes per day compared with those whose mothers did not smoke, the odds ratios were 1.83 (95% confidence interval, 1.51 to 2.22) for esotropia and 2.32 (95% confidence interval, 1.72 to 3.13) for exotropia. Maternal age was also a significant risk factor for esotropia (P = .0005). The risk of esotropia increased with increasing age until age 34 years. In particular, the odds ratio for mothers aged 30 to 34 years relative to that for mothers aged 20 to 24 years was 1.43 (95% confidence interval, 1.19 to 1.70). CONCLUSIONS: Esotropia was more common in whites than in blacks. The occurrence of exotropia was similar in the two races. Maternal cigarette smoking during pregnancy and low birth weight were independent and important risk factors for both esotropia and exotropia. There was an increased risk of esotropia with increasing maternal age.

Effects of fenretinide (4-HPR) on dark adaptation.

OBJECTIVES: To assess the alterations in dark adaptation induced by low (200 mg/d) doses of fenretinide (4-HPR), to assess whether these effects were cumulative and whether they were reversible, and to attempt to elucidate the mechanism underlying the changes in night vision. DESIGN: Case series. SETTING: Outpatient eye clinic. PATIENTS: Twenty-two women enrolled in a breast cancer chemoprevention trial, and 18 normal control subjects. INTERVENTION: Measurements of absolute luminance thresholds during dark adaptation. MAIN OUTCOME MEASURES: Parameters of an exponential model of the dark-adaptation function before, during, and after administration of fenretinide. RESULTS: The most conspicuous effect of fenretinide on dark adaptation was a significant delay in the timing of the rod-cone break (P<.001). A minimal elevation of the final cone threshold was also observed. These effects were reversible after fenretinide therapy was discontinued and did not seem to be cumulative. An inverse relationship between delay of the rod-cone break and plasma retinol concentration was found. CONCLUSION: The dose of fenretinide used in this study produced clearly measurable, but not severe, changes in night vision, which were rarely symptomatic.

Association of interleukin 10 in the vitreous and cerebrospinal fluid and primary central nervous system lymphoma.

BACKGROUND: Diagnosis of primary central nervous system lymphoma (PCNSL) is usually made by identifying malignant lymphocytes in the brain, cerebrospinal fluid (CSF), or vitreous. However, these cells are few and friable, and misdiagnosis can occur, even in properly prepared specimens. Recent data suggest that levels of interleukin 10 (IL-10) are elevated in the serum and vitreous of patients with non-Hodgkin lymphoma; levels of interleukin 6 (IL-6) are elevated in the vitreous of patients with intraocular inflammation unrelated to a malignant neoplasm. We investigated whether PCNSL involving the vitreous or CSF is associated with elevated ratios of IL-10 to IL-6. PATIENTS: Vitreous specimens were obtained from 5 patients with PCNSL involving the eye and from 13 control patients with intraocular inflammation not related to a malignant neoplasm; CSF specimens were obtained from 11 patients with PCNSL. RESULTS: Levels of IL-10 exceeded those of IL-6 in all 5 patients with intraocular lymphoma but in none of the 13 patients with uveitis (P < .001). In patients with PCNSL, levels of IL-10 exceeded those of IL-6 in 6 of 11 CSF samples with malignant cells compared with 7 of 53 samples without malignant cells (P = .01). The calculated odds ratio (OR) suggests that the risk for malignant involvement of the CSF is about 8 times higher when IL-10 levels exceed IL-6 levels. METHODS: Levels of IL-10 and IL-6 were determined by enzyme-linked immunosorbent assay in both vitreous and CSF specimens. CONCLUSIONS: The occurrence of PCNSL in the eye was strongly associated with elevated vitreous levels of IL-10 relative to levels of IL-6. Moreover, among patients with diagnosed PCNSL, malignant cells were significantly more likely to be present in CSF when levels of IL-10 exceeded those of IL-6.

Association of visual field, cup-disc ratio, and magnetic resonance imaging of optic chiasm.

OBJECTIVE: To assess the association of visual field, vertical cup-disc (VC/D) ratio, and vertical height of optic chiasm. DESIGN: Case series. SETTING: Outpatient eye clinic. PATIENTS: Eighteen patients with low, normal, or elevated intraocular pressure, with or without visual field defects. INTERVENTION: Measurement of visual field, VC/D ratio, and vertical height of optic chiasm. MAIN OUTCOME MEASURES: Association between VC/D ratio and visual field defects compared with association between vertical height of optic chiasm and visual field defects. RESULTS: Visual field defects were graded as 0, 1 to 10, and 11 to 20 (from least to most severe). Group mean VC/D ratios were 0.47 (0), 0.55 (1-10), and 0.69 (11-20) for right eyes and 0.48 (0), 0.57 (1-10), and 0.75 (11-20) for left eyes. The significance level for trend was P = .02 for right eyes and P = .006 for left eyes. Group mean chiasm heights were 3.5 (0), 2.9 (1-10), and 2.2 (11-20) mm for right eyes and 3.5 (0), 2.8 (1-10), and 2.2 (11-20) mm for left eyes. The significance level for trend was P < .001 for right eyes and P = .002 for left eyes. To assess the simultaneous effects of VC/D ratio and chiasm height on the visual field defects groups, we used ordinal logistic regression models. Models with both variables implied that chiasm height was a stronger predictor of visual field defects group than VC/D ratio (for right eyes, P = .04 [VC/D ratio], P = .001 [chiasm height]; for left eyes, P = .11 [VC/D ratio], P = .005 [chiasm height]). CONCLUSIONS: When chiasm and VC/D ratio were analyzed in the same model, chiasm height was a stronger predictor of visual field defects. In advanced visual field defects, the optic chiasm is atrophic.

Cigarette smoking and the risk of development of lens opacities. The Framingham studies.

OBJECTIVE: To examine the association between cigarette smoking and the incidence of nuclear and non-nuclear lens opacities in members of the Framingham Eye Study Cohort. PARTICIPANTS AND METHODS: Eye examinations were conducted on surviving members of the Framingham Heart Study Cohort from 1973 to 1975 (Framingham Eye Study I) and again from 1986 to 1989 (Framingham Eye Study II). Smoking data, collected biennially since 1948 in the Heart Study, were used to examine the relationship between cigarette smoking and the incidence of lens opacities. Two thousand six hundred seventy-five persons were examined in the Framingham Eye Study I. Our analysis included 660 persons, aged 52 to 80 years, who were free of lens opacities at the first eye examination. RESULTS: During the approximately 12.5 years between eye examinations, lens opacities developed in a total of 381 persons, with nuclear opacities constituting the most frequent type. In logistic regression analyses that controlled for age, sex, education, and diabetes, a significant positive association with increasing duration of smoking and number of cigarettes smoked daily was found for nuclear lens opacities, alone or in combination (test for trend, P < or = .002), but not for nonnuclear opacities (test for trend, P = .62). Among the heavier smokers (persons who smoked > or = 20 cigarettes per day according to 6 or more biennial Framingham Heart Study examinations), 77% were still smoking at the time of the first eye examination. Persons who smoked 20 or more cigarettes per day at the time of the first eye examination were at substantially increased risk for the development of nuclear opacities than nonsmokers (odds ratio, 2.84; 95% confidence interval, 1.46-5.51). There was no apparent excess risk for persons with nonnuclear lens opacities (odds ratio, 1.42; 95% confidence interval, 0.65-3.07). CONCLUSION: This study provides further evidence that cigarette smokers have an increased risk of developing nuclear lens opacities. The risk was greatest for heavier smokers, who tended to be current smokers and who smoked more cigarettes and for a longer duration.

High intraocular pressure and survival: the Framingham Studies.

PURPOSE: To examine whether high intraocular pressure (greater than or equal to 25 mm Hg) or a history of treatment for glaucoma is associated with decreased survival and, if so, how such ocular markers might be explained. METHODS: Eye examinations, including applanation tonometry, were conducted on members of the Framingham Eye Study cohort from February 1, 1973, to February 1, 1975. Participants who reported a history of treatment for glaucoma were identified. Survival data, including information on the date of death, were available from the time of the Eye Study through March 31, 1990. RESULTS: Of the 1,764 persons under the age of 70 years at the baseline eye examination, 1,421 persons had low intraocular pressure (< or =20 mm Hg), 264 persons had medium intraocular pressure levels (20 to 24 mm Hg), and 79 persons had high intraocular pressure (> or =25 mm Hg) or history of glaucoma treatment. During the follow-up period, 29%, 30%, and 47% died in the groups with low, medium, and high intraocular pressure (or history of glaucoma treatment), respectively. In an age-and-sex adjusted Cox proportional hazards analysis, the death rate ratio for the group with medium intraocular pressure relative to the group with low intraocular pressure was 1.04. The corresponding death rate ratio for the group with high intraocular pressure was 1.56 with a 95% confidence interval of 1.11 to 2.19 (P < .001). After adjustment for age, sex, hypertension, diabetes, cigarette smoking, and body mass index, a positive relationship remained, but at a borderline level of significance (P = .075). CONCLUSIONS: High intraocular pressure or the presence of glaucoma is a marker for decreased life expectancy in the Framingham Eye Study cohort. The relationship is present even after adjustment for risk factors known to be associated with higher mortality such as age, sex, hypertension, diabetes, cigarette smoking, and body mass index. Special attention to the general health status of patients with high intraocular pressure or glaucoma seems warranted.

Association of thyroid disease with retinitis pigmentosa and gyrate atrophy.

PURPOSE: To compare the prevalence of thyroid disease in patients with retinitis pigmentosa, in patients with gyrate atrophy of the choroid and retina, and in patients with no history of ocular disease. METHOD: Forty-four patients with retinitis pigmentosa, 34 patients with gyrate atrophy, and 30 normal control patients with no ocular disease were evaluated in a case-control study for the presence of thyroid disease. RESULTS: Thyroid disease was diagnosed in six of 44 patients with retinitis pigmentosa and seven of 34 patients with gyrate atrophy but in only one of 30 control patients. Compared with control patients, the odds ratio for the occurrence of thyroid disease was 6.2 for patients with retinitis pigmentosa and 12.7 for patients with gyrate atrophy. CONCLUSION: These data suggest an increased occurrence of thyroid disease in patients with retinitis pigmentosa and gyrate atrophy.

Glare sensitivity in early cataracts.

In a previous study significant glare sensitivity (using Vistech MCT8000) was found only in patients with posterior subcapsular cataracts (PSC) beyond the very early (LOCS II grade 1) stage. The aim of the present study was to evaluate glare sensitivity in patients with early cataracts. The brightness acuity tester (BAT) was used with the Pelli-Robson chart on 50 patients with early cataracts (LOCS II grade 1 or 2) and on 14 normal volunteers. Only age and PSC were found to be associated with change in contrast sensitivity at high glare. Eyes with grade 1 PSC were not significantly different from eyes with grade 0 PSC after adjusting for age. Eyes with grade 2 PSC had significant glare effect compared with eyes having grade 0 PSC. Thus, glare sensitivity is associated only with early (grade 2) PSC. Other tests still need to be developed to assess visual function changes in patients with early cortical and nuclear cataracts.

Conjunctival sign in sickle cell anaemia: an in-vivo correlate of the extent of red cell heterogeneity.

A consecutive series of 22 stable adult inpatients with sickle cell anaemia were examined for the presence and severity of spontaneous 'comma' signs of the conjunctiva. Fifteen patients had severe conjunctival signs (more than 10 commas in the worse eye). The presence of severe conjunctival signs was associated with a broader distribution of intraerythrocytic haemoglobin concentrations (p = 0.0005). The patient group with severe conjunctival signs was not found to be significantly different from the group without such signs for age, sex, haemoglobin value, reticulocyte count, alpha-globin gene number, percentage fetal haemoglobin, or the proportion of very dense cells (CHC greater than 37 g/dl). Thus the singular heterogeneity of the erythrocytes in sickle cell disease may be indicative of the factor(s) responsible for the diagnostic comma sign.

Is "relative" hypertension a risk factor for vaso-occlusive complications in sickle cell disease?

Supine arterial blood pressure measurements of 89 patients with homozygous sickle cell disease and normal renal function were compared with those of an age-, race-, and sex-matched normal population and with those of individuals who had similar levels of anemia due to beta thalassemia. Consistent with previous reports, sickle cell patients had significantly lower blood pressure than the normal population. However, within most age groups, sickle cell patients tended to have higher than expected blood pressure than individuals with similar or less severe degrees of anemia. Furthermore, the authors have found an association between cerebrovascular accident and elevated blood pressure in men, even in a range of systolic and diastolic pressures that would be considered normal by conventional standards. These results reiterate the intricate relationship that exists between factors governing red cell rheology and microvascular tone. They also raise the possibility that "relative" hypertension may be associated with other vaso-occlusive manifestations of the sickle cell syndromes.