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IGHT FROM THE STARS IN STEPHAN’S QUINTET IN THE Pegasus constellation takes 270 million years to reach Earth. By the time this light arrives and allows observers to see these galaxies, the stars are no longer there. Observing the long-term outcomes for patients with minimally treated prostate cancer evokes a similar although much less extreme dilemma. In this issue of JAMA, Albertsen and colleagues 1 report updated results from a cohort of Connecticut men who received neither surgical nor radiation therapy for prostate cancer diagnosed between 1971 and 1984. This cohort is noteworthy because it is the largest of its kind yet assembled. In addition, it is populationbased and has a mean follow-up time of more than 20 years— which is virtually Hubble telescope range given the pace of

THE WOMEN’S HEALTH INITIATIVE (WHI) TRIAL OF EStrogen plus progestin hormone therapy represents a major landmark in medical research. The study demonstrates that alteration of a woman’s basic hormonal physiology over decades in the interest of long-term disease prevention is fraught with hazard. The WHI investigators terminated the trial after an assessment of the overall risk-benefit ratio of this combined hormone therapy regimen failed to demonstrate a benefit. A statistically significant 26% increase in breast cancer incidence contributed to the overall negative effect of estrogen plus progestin. In the past, women and their physicians had been reassured that although combined hormone therapy increases breast cancer risk, this increase is observed in cancers of a favorable type, is associated with long duration of use, and does not result in increased mortality. In this issue of THE JOURNAL, the study by Chlebowski and colleagues provides more detailed information on breast cancer outcomes with estrogen plus progestin. With a mean (SD) follow-up of 5.6 years (1.3) (compared with 5.2 years [1.3] in the initial article), 349 invasive and 84 in situ breast cancers were available for this analysis. A 24% increase in breast cancer risk was observed in the estrogen plus progestin group, but this increased risk was not evident until the third year of the study. This risk estimate is remarkably close to estimates derived from well-conducted observational research, such as the study by Li and colleagues, which is also reported in this issue. What is new here, apart from the strong confirmation that the association between combined hormone therapy and breast cancer is causal, and probably not due to unappreciated differences between combined hormone therapy users and nonusers? The expanded report from the WHI trial is significant because it strongly suggests that the breast cancers related to estrogen plus progestin use are not “good” ones, that they occur earlier than expected based on some previous studies, that there are no easily identified subgroups at higher risk, and that, to top it off, women using estrogen plus progestin experience a much higher rate of mammographic abnormalities leading to anxiety and further costly workups. The use of combined menopausal hormone therapy has been documented to decrease both the sensitivity and the specificity of mammography, because of an increase in radiographic breast density. Changes in breast density in response to combined therapy appear to occur during a relatively short interval. In the Postmenopausal Estrogen/ Progestin Interventions trial, the 16% to 26% of women taking estrogen plus progestin who experienced an increase in breast density did so within 12 months of initiating treatment. The finding by Chlebowski et al that significantly more women had an abnormal mammogram after 1 year is consistent with the results of case-control studies and is biologically plausible, given the well-documented effects of estrogen and progestin on the proliferation of normal breast epithelium. It is tempting to speculate that the findings of a delayed time to diagnosis as well as an increase in abnormal mammograms are because of an increase in breast density, but density was not measured in the WHI trial. The ability of combined hormone therapy to decrease mammographic sensitivity creates an almost unique situation in which an agent increases the risk of developing a disease while simultaneously delaying its detection. Thus, the incidence curves presented in the report by Chlebowski et al show a striking crossover. The incidence of breast cancer diagnosis is actually lower in the estrogen plus progestin group for the first 2 years, after which the slope of the incidence curve for estrogen plus progestin begins to increase, leading to a crossover in cumulative breast cancer occurrence at year 4 and continuing divergence in risk at the end of follow-up. Given these nonproportional hazards over time, the summary risk ratio of 1.24 from the proportional hazards model is probably conservative. The authors, having anticipated this problem, also provide a weighted analysis that down-weights the importance of the early years of follow-up. A simplified but conservative analysis based on an a priori analysis plan is justifiable, particularly in an initial study.

PANCREATIC CANCER IS ONE OF THE MOST FORMIdable types of cancer a patient and his/her physician must face. These cancers are difficult to treat due to their inaccessible location, proximity to other vital organs, and inherently aggressive pattern of growth. Although advances in surgical techniques, radiation, and chemotherapy have provided incremental improvements in the length and quality of life, less than 5% of patients with pancreatic cancer will live beyond 5 years. Therefore, it is both surprising and gratifying that pancreatic cancer should be emerging as a form of cancer that might be preventable, at least in part through modification of lifestyle habits such as diet, exercise, and smoking. Cigarette smoking has long been recognized as an important determinant of pancreatic cancer risk; however, there are no other established, modifiable risk factors. The article by Michaud and colleagues in this issue of THE JOURNAL provides new information regarding the associations of height, obesity, and physical activity with risk of pancreatic cancer. The investigators used data from 2 welldesigned, large cohort studies, the Nurses’ Health Study and the Health Professionals Follow-up Study. Among 46648 men aged 40 to 75 years and 117041 women aged 30 to 55 years at baseline, 350 incident pancreatic cancer cases were identified during 20 years of follow-up. Analyses showed that tall height and greater body mass index (BMI) were independently and positively associated with pancreatic cancer risk, whereas physical activity of moderate intensity was inversely associated with risk. It is particularly interesting that among individuals with a BMI of less than 25 kg/m, total physical activity (both moderate and vigorous) was not related to risk of pancreatic cancer, whereas among overweight and obese individuals (BMI $25 kg/m), low total physical activity was associated with a higher risk. A higher risk of pancreatic cancer among persons with higher BMI and lower physical activity supports the hypothesis that hyperinsulinemia could play an important role in pancreatic carcinogenesis. Indeed, an association between abnormal glucose metabolism and pancreatic cancer has long been suspected. While in some cases, impaired glucose tolerance, clinical diabetes, or both appear to be a result of the tumor, a considerable amount of data now exist suggesting that in some cases these could be predisposing factors in pancreatic carcinogenesis. For example, a meta-analysis of epidemiologic studies estimated a 2-fold greater risk of pancreatic cancer associated with diabetes diagnosed at least 5 years prior to either diagnosis of pancreatic cancer or pancreatic cancer death. More recently, we reported a 2.2-fold higher risk of pancreatic cancer mortality for men and women whose postload plasma glucose level was 200 mg/dL ($11.1 mmol/L) or more at baseline compared with those patients whose level was 119 mg/dL (#6.6 mmol/L) or less. Two aspects of the findings of Michaud et al lend further indirect support for the insulin hypothesis. First, the form of activity most clearly associated with reduced risk was sustained exercise at a moderate intensity level, such as walking or hiking, rather than vigorous activity for shorter durations. This is consistent with the literature on the effects of various forms of exercise on the prevention or treatment of impaired glucose tolerance. Second, the group that appeared to benefit most from physical activity included those participants who were obese, followed by the group who were overweight, precisely those participants whose glucose tolerance and insulin levels could be improved, even in the absence of weight loss, by moderate exercise. Moreover, in a large case-control study of risk factors for pancreatic cancer, individuals who ate only 1 major meal a day (and presumably ate smaller amounts of food or little food throughout the day otherwise) had a 50% lower risk than those who ate 3 or more major meals per day. It is possible that avoidance of large meals might be one way to reduce overall insulin secretion. The pathogenic relationship of pancreatic cancer to insulin could, in part, be explained by anatomy: the exocrine cells of the pancreas, which give rise to fatal pancreatic cancers, are exposed to extremely high concentrations of insulin because their blood supply passes through the islet cell region. A growing body of intriguing evidence indicates that many pancreatic cancers could be prevented through lifestyle modifications. Silverman et al estimated that the proportion of

Objective. —To evaluate the validity of prostate-specific antigen (PSA) in identifying men who subsequently were or were not clinically diagnosed with prostate cancer, assess optimal test cutoff, measure lead time, and estimate relative risks (RRs) associated with discrete PSA levels. Design. —Nested case-control study of men providing plasma samples before a 10-year follow-up. Setting. —The Physicians' Health Study, an ongoing randomized trial that enrolled 22071 men aged 40 to 84 years in 1982. Participants. —A total of 366 men (cases) diagnosed with prostate cancer and 1098 men (three controls per case), matched by age, randomly selected from all cohort members at risk at the time of case diagnosis. Main Outcome Measures. —Sensitivity and specificity for each year of followup and for aggressive and nonaggressive cancers separately. Results. —At a cutoff of 4.0 ng/mL, sensitivity for the entire 10-year follow-up was 46% for total cases. Sensitivities for detection of total, aggressive, and nonaggressive cancers occurring in the first 4 years were 73%, 87%, and 53%. Overall, specificity was 91% and changed little by year of follow-up. Optimal validity was achieved at a cutoff of 3.3 ng/mL. Estimated mean lead time for all cancers was 5.5 years. Only 40% of cancers detected more than 5 years from baseline were nonaggressive. Compared with men with PSA levels less than 1.0 ng/mL, those with PSA levels between 2.0 and 3.0 ng/mL had an RR of 5.5 (95% confidence interval, 3.7 to 9.2). Conclusions. —A single PSA measurement had a relatively high sensitivity and specificity for detection of prostate cancers that arose within 4 years. Prostatespecific antigen values less than the usual cutoff were associated with substantial increases in risk compared with the lowest levels. Final evaluation of PSA screening must also consider cost and the ability of current treatments to improve the prognosis of screen-detected cases. ( JAMA . 1995;273:289-294)

To the Editor.— The appearance of two reports in The Journal on hydrogen sulfide (H2S) poisoning (1981; 246:1588) and mercury poisoning from home gold ore processing (1981; 246:1929) prompts us to report an unusual fatal case of poisoning that combines aspects of both reports. As the authors of the second report point out, the recent increase in the price of gold has stimulated many individuals to attempt to recover pure metal as a home "industry." The starting materials often include metals contained in waste industrial products. Silver, although not nearly as profitable to cover, is also processed, and makes up in part for its lower price by being much more readily available, particularly in outdated photographic film.Report of a Case.— A case was brought to our attention involving a 20-year-old man who engaged in full-time gold and silver processing in a friend's home. Two weeks before his