Reproductive factors and histologic subtype in relation to mortality after a breast cancer diagnosis.

Evidence suggests that certain reproductive factors are more strongly associated with the incidence of lobular than of ductal breast cancer. The mechanisms influencing breast cancer incidence histology may also affect survival. Women with invasive breast cancer (N = 22,302) diagnosed during 1986-2005 were enrolled in a series of population-based studies in three US states. Participants completed telephone interviews regarding reproductive exposures and other breast cancer risk factors. Histologic subtype was obtained from state cancer registries. Vital status and cause of death were determined through December 2006 using the National Death Index. Women were followed for 9.8 years on average with 3,050 breast cancer deaths documented. Adjusted hazard rate ratios (HR) and 95% confidence intervals (95% CI) were calculated using Cox proportional hazards regression models for breast cancer-specific and all-cause mortality. Parity was inversely associated with breast cancer-specific mortality (P (Trend) = 0.002). Associations were similar though attenuated for all-cause mortality. In women diagnosed with ductal breast cancer, a 15% reduction in breast cancer-specific mortality was observed in women with five or more children when compared to those with no children (HR = 0.85, 95% CI: 0.73-1.00). A similar inverse though non-significant association was observed in women with lobular subtype (HR = 0.70, 95% CI: 0.43-1.14). The trend did not extend to mixed ductal-lobular breast cancer. Age at first birth had no consistent relationship with breast cancer-specific or all-cause mortality. We found increasing parity reduced mortality in ductal and lobular breast cancer. The number of full-term births, rather than age at first birth, has an effect on both breast cancer-specific and overall mortality.

Inverse association of NSAID use and ovarian cancer in relation to oral contraceptive use and parity.

We examined the association between non-steroidal anti-inflammatory drug (NSAID) use and ovarian cancer by potential effect modifiers, parity and oral contraceptive use, in a population-based case-control study conducted in Wisconsin and Massachusetts. Women reported prior use of NSAIDs and information on risk factors in a telephone interview. A total of 487 invasive ovarian cancer cases and 2653 control women aged 20-74 years were included in the analysis. After adjustment for age, state of residence and other covariates, ever use of NSAIDs was inversely associated with ovarian cancer in never users of oral contraceptives (odds ratio (OR)=0.58, 95% confidence interval (CI) 0.42-0.80) but not for ever users (OR=0.98, 95% CI 0.71-1.35) (P-interaction=0.03). A reduced risk with NSAID use was also noted in nulliparous women (OR=0.47, 95% CI 0.27-0.82) but not among parous women (OR=0.81, 95% CI 0.64-1.04) (P-interaction=0.05). These results suggest that use of NSAIDs were beneficial to women at greatest risk for ovarian cancer.

Prospective study of regular aspirin use and the risk of breast cancer.

BACKGROUND: Evidence suggests that aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) can inhibit tumor development in the large bowel. An inverse association between the use of NSAIDs and the incidence of breast cancer has been observed, but this association has not been statistically significant in all studies. PURPOSE: We analyzed data from the prospective Nurses' Health Study to evaluate the influence of aspirin use on breast cancer risk. METHODS: We studied a population of 89,528 female registered nurses who reported no history of breast or other cancers (excluding nonmelanoma skin cancer) and who returned a mailed questionnaire in 1980 that elicited information concerning breast cancer risk factors and current and past aspirin use. Follow-up questionnaires were mailed to the participants every 2 years; the women were followed through 1992. Information concerning current aspirin use was obtained from each biennial questionnaire, except in 1986. Cases of breast cancer were identified through questionnaire responses, and permission was sought for a review of medical records to confirm the diagnoses. Our analysis was based on 2414 cases of invasive breast cancer, which included 2303 cases confirmed with medical records and 111 cases for which no records were obtained. Relative risks (RRs) with 95% confidence intervals (CIs), adjusted for age or age plus other known or potential breast cancer risk factors (i.e., multivariate), were calculated. RESULTS: Regular aspirin use (two or more tablets per week) in 1980 was unrelated to breast cancer incidence during the succeeding 12-year period (with no regular aspirin use as the referent, multivariate RR = 1.03; 95% CI = 0.95-1.12). The corresponding risk estimate for consistent regular aspirin use during the period from 1980 through 1988 was 1.01 (95% CI = 0.80-1.27). The risks were similar for heavy aspirin use (for more than two tablets per day [i.e., > 14 per week] in 1980 and in 1980 through 1988, the multivariate RRs [95% CIs] were 1.05 [0.89-1.23] and 1.09 [0.75-1.60], respectively) and for extended durations of regular use (e.g., for 20 years or more of regular use, multivariate RR = 1.00; 95% CI = 0.71-1.41). CONCLUSION: Our results indicate that regular aspirin use does not reduce the risk of breast cancer.

Exposure to breast milk in infancy and adult breast cancer risk.

BACKGROUND: There is considerable interest in the possibility of an infectious etiology for human breast cancer. Although studies have shown that certain strains of mice transmit mammary tumor virus via breast milk, few epidemiologic studies have addressed this topic in humans. METHODS: We evaluated the relationship between having been breast-fed as an infant and breast cancer risk among 8299 women who participated in a population-based, case-control study of breast cancer in women aged 50 years or more. Case women were identified through cancer registries in three states (Massachusetts, New Hampshire, and Wisconsin); control women were identified through statewide driver's license lists (age <65 years) or Medicare lists (ages 65-79 years). Information on epidemiologic risk factors was obtained through telephone interview. We used multiple logistic regression to assess having been breast-fed and maternal history of breast cancer in relation to breast cancer occurrence both in premenopausal women (205 case women; 220 control women) and in postmenopausal women (3803 case women; 4071 control women). RESULTS: We found no evidence that having been breast-fed increased breast cancer risk in either premenopausal women (odds ratio [OR] = 0.65; 95% confidence interval [CI] = 0.41-1.04) or postmenopausal women (OR = 0.95; 95% CI = 0.85-1.07). In addition, breast cancer risk was not increased by having been breast-fed by a mother who later developed breast cancer. CONCLUSION: Our results do not support the hypothesis that a transmissible agent in breast milk increases breast cancer risk. Because premenopausal women were not well represented in our study population, our findings with regard to this group may not be generalizable and should be viewed with caution.

Patterns of tumor initiation in choroidal melanoma.

This study attempts to document the occurrence of tumors with respect to clock hour location and distance from the macula and to evaluate tumor location in relation to retinal topography and light dose distribution on the retinal sphere. Analysis of patterns of tumor initiation may provide new evidence to clarify the controversy regarding the possible light-related etiology of choroidal melanoma. Incident cases of choroidal and ciliary body melanoma in Massachusetts residents diagnosed between 1984 and 1993 were the basis for analysis. Conventional fundus drawings and photos were used to assess the initiation site of each tumor. The initiation site was defined as the intersect between the largest tumor diameter and the largest perpendicular diameter of the tumor. Initiation sites were recorded using spherical coordinates. The retinal sphere was divided into 61 mutually exclusive sectors defined according to clock hour and anteroposterior distance from the macula. Rates of initiation were computed for each sector, overall, and according to gender and other clinical factors. Results were similar in left and right eyes; therefore, these were combined in analysis. Tumor initiation had a predilection for the macula (P < 0.0001). Overall, no significant clock hour preference was observed (P = 0.63). However, the parafoveal zone showed a strong circular trend (P < 0.01), with highest rates occurring in the temporal region, and the lowest rates occurring in the nasal region. Rates of occurrence in six progressively more anterior concentric zones (designated as the foveal, parafoveal, posterior, peripheral, anterior, and ciliary body zones) were 21.4, 14.2, 12.1, 8.9, 4.5, and 4.3 counts per spherical unit per 1000 eyes, respectively. Concentric zone location did not vary by gender (P = 0.93) or laterality (P = 0.78). However, posterior location was associated with light iris color (P = 0.01). Tumor diameters were largest in the peripheral region of the fundus and smallest in the macular and ciliary body zone (P < 0.001). Clock hour location was not influenced by gender (P = 0.74), laterality (P = 0.53), iris color (P = 0.84), or tumor diameter (P = 0.73). Results suggest that tumor initiation is not uniformly distributed, with rates of occurrence concentrated in the macular area and decreasing monotonically with distance from the macula to the ciliary body. This pattern is consistent with the retinal topography and correlates positively with the dose distribution of solar light on the retinal sphere.

A computerized image analysis method for measuring elastic tissue.

A computerized image analysis technique for quantifying area fractions of elastic tissue in light microscopic sections is presented that considers the nonuniform distribution of the elastic tissue. The method uses Verhoeff-van Gieson stained sections. The analysis is stratified vertically in three uniform layers starting at the dermo-epidermal junction and horizontally by two schemes. A standard method consists of five equally spaced measurements. The densest method uses the three areas that contain the most elastic tissue. The area fractions are determined by counting the positive and total pixels (thresholding). A validity test utilizing independent physical measurements demonstrated differences of no more than 1.7%. Reliability tests for reading the same section on different days and adjacent sections showed no significant differences (p less than 0.05) between the readings. Reliability tests of sections using different stain lots and adjacent biopsy sites also did not have significant differences. This method may be particularly useful for studies in which the distribution of the material to be measured may be very uneven, such as in solar elastosis.

Expression of interferon-gamma from hybrid yeast GPD promoters containing upstream regulatory sequences from the GAL1-GAL10 intergenic region.

The expression of human immune interferon (IFN-gamma) is toxic to yeast, resulting in low plasmid stability and copy number. The Saccharomyces cerevisiae glyceraldehyde-3-phosphate dehydrogenase gene (GPD) promoter [Bitter and Egan, Gene 32 (1984) 263-274] has been modified by introduction of upstream regulatory sequences from the yeast GAL1-GAL10 intergenic region [UASG; Guarente et al., Proc. Natl. Acad. Sci. USA 79 (1982) 7410-7414] and utilized to express IFN-gamma. In contrast to the native GPD promoter, the GPD(G) hybrid promoters are regulated by the carbon source. With glucose as the carbon source, a level of expression is observed which is much lower than that obtained with the native GPD promoter. Expression of the hybrid promoters is induced approx. 150- to 200-fold in shaker flask cultures by growth in galactose and similar levels of expression are observed after growth in lactate plus galactose. However, full galactose induction is not observed in the presence of glucose.? Utilization of these regulated promoters has allowed maintenance of plasmids at high copy number with glucose as the carbon source and, after induction with galactose, production of IFN-gamma mRNA at levels more than ten times higher than the native yeast PGK gene transcript. In contrast, the native GPD promoter directs comparable levels of expression when grown in either glucose or galactose resulting in low plasmid copy number and a correspondingly lower IFN-gamma transcript abundance. It is demonstrated that nucleotide sequences more than 240 bp upstream from the TATA box are required for optimal activity of the native GPD promoter.(ABSTRACT TRUNCATED AT 250 WORDS)

Expression of heterologous genes in Saccharomyces cerevisiae from vectors utilizing the glyceraldehyde-3-phosphate dehydrogenase gene promoter.

The promoter region from the cloned glyceraldehyde-3-phosphate dehydrogenase (GPD) gene of Saccharomyces cerevisiae (Musti et al., 1983) has been characterized. A 653-bp TaqI restriction fragment with a 3' border 24 bp upstream from the ATG initiation codon was isolated and demonstrated to contain all sequences necessary for promoter function in vivo. This DNA segment was converted to a portable promoter by cloning it into M13mp9, and the entire nucleotide sequence of the portable promoter was determined. Two generalized yeast expression vectors have been constructed utilizing the GPD portable promoter. The expression vectors include the yeast 2 mu origin of replication and amplification functions, such that the plasmids are maintained at high copy number in ciro yeast hosts. These vectors direct synthesis of a consensus alpha-interferon (IFN-alpha Con1) as 1% of total cell protein. Hepatitis B surface antigen (HBsAg) was also expressed from these vectors. The 5' end of the HBsAg gene was replaced with a synthetic DNA segment which restored the deleted GPD untranslated leader and utilized optimal yeast codons for the first 30 amino acids. The partially synthetic gene resulted in a 10- to 15-fold increased expression level from GPD vectors yielding HBsAg polypeptide as 2-4% of total cell protein.

Characterization of purified hepatitis B surface antigen containing pre-S(2) epitopes expressed in Saccharomyces cerevisiae.

The cloning and expression of the hepatitis B middle-protein surface antigen gene in the yeast Saccharomyces cerevisiae is described. A generalized expression vector carrying the yeast glyceraldehyde-3-phosphate dehydrogenase gene promoter was used. Expressed material, in the form of supramolecular particles, was purified and characterized. Severe proteolysis within the pre-S(2) region was observed for material expressed in a wild-type yeast host. This proteolysis was substantially reduced by utilization of a protease-deficient host. Immunoblotting of sodium dodecyl sulfate-polyacrylamide gels with several antibodies of differing specificity was performed to characterize the various protein species present. All species were analyzed by N-terminal sequencing after electroelution from gels. Carbohydrate staining of gels and glycosidase treatments of the purified antigen material indicated that full-length antigen was present in both glycosylated and unglycosylated forms. Glycosylation appeared to be of both asparagine-linked and threonine/serine-linked types. Site-directed mutagenesis was used to convert two arginine residues in the pre-S(2) region of the antigen to glutamine residues. The changes abolished reactivity with one polyclonal and two monoclonal antibodies specific for epitopes within the pre-S(2) region.

Risk factors for breast cancer in women with a breast cancer family history.

Family history (FH) is an important indicator of a woman's future risk of developing breast cancer. Using data collected in a large population-based case-control study (6705 cases and 9341 controls), we examined the associations of breast cancer with known risk factors in women reporting a first-degree FH (mother or sister), with an emphasis on lifestyle determinants that may be altered to reduce risk. First-degree FH was reported by 18.4% (n = 1234) of cases and 11.3% (n = 1058) of controls; the overall relative risk (RR) for breast cancer associated with a positive history was 1.70 [95% confidence interval (CI), 1.55-1.87] and 2.34 (95% CI, 1.80-3.02) for breast cancer at age 45 years or younger. Among women with a FH, statistically significant inverse associations were observed for increasing parity (RR per birth = 0.90; P < 0.0001), intake of carotene-rich foods (RR for >2000 IU/day = 0.73; P = 0.02), and strenuous activity as a young adult (RR per episode/week = 0.93; P = 0.02). Recent alcohol consumption increased risk (RR per 13 g/week = 1.21; P = 0.02), as did weight gain during adult life in postmenopausal women (RR per 5 kg = 1.08; P = 0.001). Breast-feeding for any duration was associated with a lower RR in parous, premenopausal women (RR = 0.59; P = 0.04). Associations for most risk factors with breast cancer were similar among women with and without a FH of breast cancer; however, a stronger inverse association was observed for parity in women with a positive history (P for interaction = 0.04). Based on these data, women with a FH may reduce their excess risk of breast cancer through adjustments in lifestyle and reproductive choices. The risk associated with FH of breast cancer seems to be largely independent of other known risk factors.

Collection of genomic DNA from adults in epidemiological studies by buccal cytobrush and mouthwash.

Blood samples are an excellent source of large amounts of genomic DNA. However, alternative sources are often needed in epidemiological studies because of difficulties in obtaining blood samples. This report evaluates the buccal cytobrush and alcohol-containing mouthwash protocols for collecting DNA by mail. Several DNA extraction techniques are also evaluated. The study was conducted in two phases. In phase 1, we compared cytobrush and mouthwash samples collected by mail in two different epidemiological studies: (a) cytobrush samples (n = 120) from a United States case-control study of breast cancer; and (b) mouthwash samples (n = 40) from a prospective cohort of male United States farmers. Findings from phase 1 were confirmed in phase 2, where we randomized cytobrush (n = 28) and mouthwash (n = 25) samples among participants in the breast cancer study to directly compare both collection methods. The median human DNA yield determined by hybridization with a human DNA probe from phenol-chloroform extracts was 1.0 and 1.6 microg/2 brushes for phases 1 and 2, respectively, and 27.5 and 16.6 microg/mouthwash sample for phases 1 and 2, respectively. Most (94-100%) mouthwash extracts contained high molecular weight DNA (>23 kb), in contrast to 55-61% of the brush extracts. PCR success rates for amplification of beta-globin gene fragments (268, 536, and 989 bp) were similar for cytobrush and mouthwash phenol-chloroform extracts (range, 94.4-100%). Also, we obtained high success rates in determining the number of CAG repeats in the androgen receptor gene, characterizing tetranucleotide microsatellites in six gene loci, and screening for mutations in the BRCA1/2 genes in a subset of phenol-chloroform DNA extracts. Relative to DNA extracted by phenol-chloroform from cytobrush samples, DNA extracted by NaOH had lower molecular weight, decreased PCR success rates for most assays performed, and unreliably high spectrophotometer readings for DNA yields. In conclusion, although DNA isolated from either mouthwash or cytobrush samples collected by mail from adults is adequate for a wide range of PCR-based assays, a single mouthwash sample provides substantially larger amounts and higher molecular weight DNA than two cytobrush samples.

An NMR blood test for uveal melanoma?

In a recent article a simple nuclear magnetic resonance (NMR) blood test was suggested for the detection of the presence of cancer. The test's sensitivity to uveal melanoma of both pre- and posttreatment status has been investigated. Cases in this study were 95 patients with uveal melanoma, and controls were 70 participants in an ongoing case control study of retinal eye disease being conducted at the Massachusetts Eye and Ear Infirmary. Proton NMR evaluations at 4.7 T (200 MHz) were performed on plasma obtained from EDTA and citrated blood samples. The average line-width values were calculated from each spectrum. Statistical analysis revealed that mean proton NMR line widths were essentially equal for patients with treated (18.7 Hz) and untreated tumors (18.4 Hz) and for controls (18.5 Hz). Results based on this data set suggest that proton NMR spectroscopy has little predictive power in the detection of uveal melanoma or in the monitoring of therapy.

Evaluation of skin microtopography as a measure of ultraviolet exposure.

A pilot study was conducted to investigate the use of skin microtopography as a semiquantitative noninvasive method for estimating cumulative sun exposure in epidemiologic studies of eye disease. The subjects received a kit through the mail containing materials needed to make a replica of the skin texture of a sun-exposed area of the hand. Each subject previously had undergone a skin biopsy around the same site to evaluate elastotic degeneration, and all were interviewed about past sun exposures. A gradable skin impression was obtained from 96 of 115 (83%) participants after two mailings. The impressions were graded according to the degree of skin texture alteration using standard photographs; interobserver reliability was 0.73 using a weighted kappa statistic. The impression score was correlated most strongly with age (r = 0.53). Independent predictors of higher impression scores (more skin texture changes) were older age, cigar or pipe smoking, less education, lighter iris color, lighter skin color, male gender, and tendency to sunburn. After adjustment for age and the other predictor variables, the biopsy score was not correlated with the impression grade (r = 0.18, P = 0.13). Behaviors indexing sun exposure were not correlated with microtopography. These results suggest that skin microtopography as done in this study reflects aging from intrinsic parameters more than from actinic damage.

Metastatic melanoma death rates by anatomic site after proton beam irradiation for uveal melanoma.

BACKGROUND: Ciliary body location is an established prognostic factor for metastasis-related death from uveal melanoma. We evaluated alternative approaches for classifying this covariate when constructing predictive models of patient survival. METHODS AND DESIGN: The analyses were based on a consecutive series of 1848 primary choroidal and/or ciliary body melanoma patients treated with proton beam irradiation (70 cobalt gray equivalent in 5 fractions) at the Harvard Cyclotron Laboratory, Boston, Mass, between July 1975 and December 1995. For each patient, the anatomic site of the tumor was classified according to an estimate of the proportion of the tumor base lying anterior to the ora serrata. Using proportional hazards regression, we estimated relative risk ratios and death rates from melanoma metastasis according to the extent of ciliary body involvement. All estimates were adjusted for other established prognostic factors. RESULTS: Patients were followed up through April 30, 1998; none were lost to follow-up. Of 1848 patients analyzed, 378 died of melanoma metastasis. The median follow-up period among survivors was 9.5 years. Ciliary body origin (>50% of tumor base anterior to the ora serrata) was positively associated with tumor pigmentation (P<.001), tumor height (P<.001), and extrascleral extension of the tumor (P<.001). Compared with tumors involving only the choroid, melanoma-associated death rates increased with the proportion of the tumor base lying within the ciliary body (P =. 006); the multivariate-adjusted relative risk ratio for greater than 75% involvement was 2.30 (95% confidence interval [CI], 1.26-4.23). The covariate-adjusted 5-year death rates for ciliary body origin and choroidal origin were 15.9% (95% CI, 11.3%-21.2%) and 9.8% (95% CI, 8.3%-11.7%), respectively. CONCLUSION: Patients with melanomas of presumed ciliary body origin seem to be subject to a higher risk of death resulting from melanoma metastasis. Arch Ophthalmol. 2000;118:1066-1070

Iris color as a prognostic factor in ocular melanoma.

BACKGROUND: Ocular melanoma may be more prevalent among patients with light irises than those with dark irises. OBJECTIVE: To examine a large clinical series of patients with intraocular melanoma to determine if light irises are associated with increased risk of death from these tumors. METHODS: A total of 1162 patients treated with proton irradiation between 1984 and 1996 were observed through 1997. RESULTS: Iris color in the patients was blue or gray in 48%, green or hazel in 30%, and brown in 23%. Tumors in patients with blue or gray irises were less heavily pigmented (P<.001) and closer to the optic disc and macula (P<.001). Five- and 10-year metastasis-related death rates were 0.14 and 0.21, respectively, for those with blue or gray irises and 0.10 and 0.15, respectively, for those with darker irises (P = .02). In a Cox proportional hazards regression controlling for tumor characteristics, patients with blue or gray irises died of metastatic disease at a rate 1.90 times (95% confidence interval, 1.26-2.85) that of patients with brown irises. The rate of metastatic death was not significantly elevated for those with green or hazel irises (relative risk, 1.43; 95% confidence interval, 0.91-2.23). CONCLUSION: Patients with blue or gray irises appear to be at increased risk of metastatic death from choroidal melanoma, independent of other risk factors.

Survival implications of enucleation after definitive radiotherapy for choroidal melanoma: an example of regression on time-dependent covariates.

OBJECTIVE: To evaluate whether the removal of the eye after radiotherapy alters the rates of metastatic death in patients with melanoma of the choroid. PATIENTS AND METHODS: Using an extension of the Cox model, we based our analysis on a cohort of 1541 consecutive patients with unilateral choroidal or ciliary body melanoma treated with protons (70 cobalt-gray equivalent in 5 to 7 fractions) at the Harvard University (Boston, Mass) cyclotron between July 1, 1975, through December 31, 1993, and who were observed prospectively up to September 30, 1995. Patient survival and the status of the treated eye were updated annually. RESULTS: By September 1995 (median follow-up among survivors, 8 years), 137 patients underwent enucleation after radiotherapy for complications (n=103) or tumor regrowth (n=34). The overall 10-year rate of eye retention was 89% (95% confidence interval, 87%-91%). Of the 1541 patients, 300 died of tumor metastasis, 38 following enucleation of the affected eye (mean interval from enucleation to death, 25 months). The multivariate rate ratio for metastatic death associated with enucleation (modeled as a time-dependent covariate) was 0.9 (95% confidence interval, 0.6-1.4) for enucleation due to complications and 3.8 (95% confidence interval, 2.3-6.3) for enucleation associated with tumor regrowth. CONCLUSIONS: In the absence of tumor viability, enucleation after primary irradiation for choroidal melanoma has no deleterious effect on patients' survival. Enucleation concurrent with tumor regrowth is associated with high death rates; growth of the tumor in the eye may presage systemic recurrence and death from metastasis.

Childbearing history associated with improved survival in choroidal melanoma.

BACKGROUND: Research in cutaneous melanoma suggests that women may experience better tumor-dependent survival than men, and some studies have shown that the advantage is specific to childbearing. OBJECTIVE: To examine whether childbearing may be a favorable prognostic factor in melanoma of the uveal tract. DESIGN: Prospective follow-up study. SETTING: Hospital. MAIN OUTCOME MEASURE: Death from metastatic choroidal melanoma. METHODS: We evaluated a consecutive series of 1818 patients with choroidal melanoma, 748 parous and 165 nulliparous women and 905 men, after treatment with proton irradiation. Three hundred fifty-two deaths from metastasis were documented in follow-up. RESULTS: Overall multivariate-adjusted death rates from metastasis were approximately 25% higher in nulliparous women (relative risk [RR], 1.23; 95% confidence interval [CI], 0.83-1.82) and men (RR, 1.25; 95% CI, 1.00-1.56) than in women who had given birth. The protective influence of parity was strongest in the early period following diagnosis and treatment (RR, 1.58; 95% CI, 0.88-2.86, and RR, 1.51; 95% CI, 1.04-2.19, in nulliparous women and men, respectively, during the first 36 months of follow-up). The level of protection increased with the number of live births (P for trend, .04). CONCLUSION: These data provide support for the hypothesis that a history of childbearing confers protection from death in choroidal melanoma.

A randomized controlled trial of varying radiation doses in the treatment of choroidal melanoma.

OBJECTIVE: To determine if a reduction in proton radiation dose from the standard dose of 70 cobalt gray equivalents (CGE) to 50 CGE would decrease radiation-induced complications, thereby improving visual prognosis, without compromising local tumor control for patients with uveal melanoma at high risk of these complications. DESIGN: Randomized, double-masked clinical trial. PARTICIPANTS: A total of 188 patients with small or medium-sized choroidal melanomas (<15 mm in diameter and <5 mm in height) near the optic disc or macula (within 4 disc diameters of either structure). METHODS: Patients were treated with proton beam therapy at doses of either 50 CGE or 70 CGE between October 1989 and July 1994, and followed up biannually through April 1998. Outcomes included visual acuity, radiation complications, melanoma recurrence, and metastasis. RESULTS: Proportions of patients retaining visual acuity of at least 20/200 were similar in the 2 dose groups at 5 years after radiation (approximately 55%). Similar numbers of patients in each group experienced tumor regrowth (2 patients at 50 CGE vs 3 patients at 70 CGE; P>.99) and metastasis (7 patients at 50 CGE vs 8 patients at 70 CGE;P=.79). Five-year rates of radiation maculopathy also were similar (for both groups, approximately 75% for tumors within 1 disc diameter and 40% for tumors >1 disc diameter from the macula). Rates of radiation papillopathy were nonsignificantly decreased in the 50-CGE treatment group when tumors were located 1 disc diameter or less from the optic disc (P=.20). Patients treated with the lower dose also experienced significantly less visual field loss. CONCLUSIONS: This level of dose reduction did not result in a lesser degree of visual acuity loss. The lower-dose group did experience significantly less visual field loss. Local tumor recurrence and metastatic death rates were similar in both dose groups. Arch Ophthalmol. 2000;118:773-778

Cataract extraction after proton beam irradiation for malignant melanoma of the eye.

We evaluated visual outcome and risk of metastases in patients who underwent cataract extraction after protonbeam irradiation of a uveal melanoma. A total of 84 patients underwent cataract extraction between 2 months and 11 years after irradiation. One year after cataract extraction, approximately half of the patients had visual acuity of 20/100 or better, and approximately one third had an acuity of 20/40 or better. Larger tumor size was highly correlated with poor visual outcome 1 year after extraction. Six patients underwent enucleation after cataract removal, five due to blind, painful eyes and one due to continued growth of a previously undiagnosed ring melanoma. The rate of metastases was not higher among patients who underwent cataract extraction (adjusted rate ratio, 0.83). Results suggest that cataract extraction offers improvement of vision in selected eyes previously irradiated for a uveal melanoma, without adding to the risk of metastases among patients undergoing the procedure.

Host factors, UV radiation, and risk of uveal melanoma. A case-control study.

Uveal melanoma threatens life, as well as sight. To evaluate the effect of constitutional factors and UV radiation on the risk of uveal melanoma, 197 cases in New England were compared with 385 matched population controls, identified by random-digit dialing, and 337 cases residing within the United States were compared with 800 sibling controls. In the population-based comparison, estimated relative risks (RRs) of uveal melanoma, after adjustment for other factors, were elevated for the following: ancestry from more northern latitudes with a substantially elevated risk for Northern European ancestry (RR, 6.5; 95% confidence interval [CI], 1.9 to 22.4) and more than a twofold risk for British ancestry (RR, 2.4; 95% CI, 1.1 to 5.1), as compared with Southern European or other Mediterranean heritage; light skin color as compared with dark (RR, 3.8; 95% CI, 1.1 to 12.6); and 10 or more cutaneous nevi as compared with none (RR, 2.7; 95% CI, 1.5 to 4.9). There was a statistically significant trend for increasing risk with more northern heritage and more moles. Southern residence (below latitude 40 degrees N) for more than 5 years also increased risk (RR, 2.8; 95% CI, 1.1 to 6.9), as compared with none. In both comparisons, use of sunlamps was a risk determinant (RR, 3.4; 95% CI, 1.1 to 10.3 with random-digit dialed controls and RR, 2.3; 95% CI, 1.2 to 4.3 with sibling controls, comparing occasional or frequent use to never use), as was intense sun exposure (RR, 1.7; 95% CI, 0.9 to 3.0 and RR, 2.1; 95% CI, 1.4 to 3.2, respectively). However, birthplace below latitude 40 degrees N and outdoor work were associated with a lower risk.(ABSTRACT TRUNCATED AT 250 WORDS)